Rearrangements

655
Wagner-Meerwein
Rearrangement
(Wagner-Meerwein Migration,
Wagner-Meerwein Shift)
A. GENERAL DESCRIPTION OF THE REACTION
This reaction was first reported by Wagner in 1899,1 and subsequently extended by
Meerwein in 1914.2 It is a class of 1,2-rearrangement of carbocation intermediates, from
which the migratory group (phenyl, vinyl, alkyl, H, etc.) rearranges from an adjacent
carbon atom to the carbocation center to form a more stable carbocation or to alleviate
the ring strain. Therefore, this type of rearrangement is generally known as the Wagner-
Meerwein rearrangement.3,4 Occasionally, it is also referred to as the Wagner-Meerwein
migration,5 Wagner-Meerwein shift,6 Wagner-Meerwein type transposition,7 or Wagner-
Meerwein skeletal rearrangement.8 Likewise, the corresponding rearrangement initiated by
photo illumination is called the photo-Wagner-Meerwein rearrangement,9 or photochemi-
cal Wagner-Meerwein rearrangement,10 and the analogous 1,2-migration of trimethylsilyl
group (Me3 Si) is referred to as the 1,2-sila-Wagner-Meerwein rearrangement.3t,11
The Wagner-Meerwein rearrangement is generally observed in fused cyclic compounds,
such as bicyclic terpene systems.8 In addition, it also occurs for monocyclic compounds
(e.g., transformation of α-campholic acid to isolauric acid8 ) as well as noncyclic molecules,
as shown in the rearrangement of 2,2-dimethyl-3-hydroxy-3-phenyl propionic acid or ester
to α-carboxyl (or ester)-β,β-dimethylstyrene in superacid solution.4l The migratory groups
include phenyl,12 vinyl,13 methylene,12 hydrogen,14 the electron-donating groups such as
Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.
2930
GENERAL DESCRIPTION OF THE REACTION 2931
alkyl,14a methyl,4f,4i,15 and isopropyl,16 and the electron-withdrawing groups, such as car-
boxyl and ester.4l,4m In addition, fluorine has also been observed to migrate in a gaseous
cation of organofluoro compounds, even such migratory aptitude is less favored over methyl
groups by a factor of 2.9.4i
Some of the representative Wagner-Meerwein rearrangements include the conversions
of: (a) 9-(α-hydroxyalkyl)xanthenes to 10-substituted dibenz[b,f]oxepins,4a (b) 3,4-
dichloro-6,7:8,9-dibenzobicyclo[3.2.2]-nona-2,6,8-triene to endo- and exo-4,6-di-chloro-
2,3:8,9-dibenzobicyclo[3.2.2]nona-2,6,8-triene and, to a minor extent, 1,9-dichloro-3,4:6,
7-dibenzotricyclo[3.3.1.02,3 ]nona-3,6-diene;17 (c) 3β-acetoxy-l7a,17a-dimethyl-d-homo-
androstan-l7β-ol to 17,17a-dimethpl-d-homoandrost-17(l7a)-en-3β-ol acetate;18 (d)
farnesyl diphosphate to sativene, cyclosativene, longifolene, and longicyclene;4f and (e) 2,
2 -bis-azocamphane to isocamphane.19 In addition, many other fused cyclic compounds
have also been found to undergo the Wagner-Meerwein rearrangement, including dibenzo-
bicyclononatriene compounds such as bisnorallocholan-20-ol, 20-chlorobisnorallocholane,
and bisnorallochol-20-ene;17 7,8-benzo- and 7,8-thieno-annelated spiro[4,5]decan-6-ols;4c
tricyclo[3.1.0.02,6 ]hexane, tricyclo[4.1.0.02,7 ]heptane, and tricyclo[5.1.0.02,8 ]octane;4j
diphenylmethylenefenchane;10 2-azobornane;3z benzobicyclo-[2.2.2]octen-2-yl and -octa-
5,7-dien-2-yl brosylates;4q 3-aza-11-oxatricyclo-[6.2.1.01,6 ]undec-9-enes;8 2,2-dichloro-
norbornane,20 and 2-exo-propynyl-fenchol.4h
In general, the Wagner-Meerwein rearrangement can be initiated under different con-
ditions, which promote the generation of carbocation intermediates. These conditions
include solvolysis,9e,21 acetolysis,9b,22 photolysis,4j,4p thermolysis,19 and the use of a
protic acid (e.g., p-toluenesulfonic acid,4c methanesulfonic acid23 ) or Lewis acids (e.g.,
AlCl3 ,20,23 BF8,13b
3 ), a radical initiator (e.g., Cp2 TiCl for epoxide,24 or triphenylpyrylium
tetrafluoroborate under photo irradiation4k ), triflic anhydride,25 cobalt and molybdenum
cluster complex,4h and even an electrophile.25 It has been reported that Lewis acid cata-
lysts such as AlCl3 and BF3 are more effective than protic acids such as p-TsOH for the
promotion of the Wagner-Meerwein rearrangement.23
On the other hand, the Wagner-Meerwein rearrangement is strongly influenced by stere-
oelectronic effects,26 where the ground-state rearrangement proceeds with the migratory
group anti to the nucleofuge,9b and the excited-state rearrangement under photo-irradiation
occurs with the migratory group syn to the leaving group,9b,9c because the suprafacial
overlap between the vacant orbital of carbocation and the σ-bond is preferred over the
antarafacial manner.9c Therefore, during the rearrangement, the group attaining a con-
formation closer to the ideal alignment migrates preferentially. It has been reported that
the maximum allowable deviation from the antiperiplanarity is ∼ 30◦ .26b In addition, the
configuration of the migratory group is inversed after the rearrangement, so that a lot of chi-
ral cyclic compounds can be prepared by the Wagner-Meerwein rearrangement.8,9e When
the migratory group is phenyl, it has been reported that the ortho substituents on the aryl
ring actually disfavor the Wagner-Meerwein rearrangement due to the decreased resonance
stabilization of the carbocation and steric hindrance, unless the ortho group is a strong
electron-donating group such as NH2 and OH.5b
However, due to the carbocationic nature of the rearrangement, the Wagner-Meerwein
rearrangement sometimes leads to a complicated mixture of products,6b as evidenced by
the possible 5,4-hydride shift in 4-homoadamantyl cation22 and the competing Nametkin
Rearrangement8,25 in 3,3-dimethylnorborn-2-yl carbocation and consecutive 6,2-hydride
shift.25
2932 WAGNER-MEERWEIN REARRANGEMENT
B. GENERAL REACTION SCHEME
H+ Cl
Cl
H
C. PROPOSED MECHANISMS
In general, this reaction involves the formation of a cationic center, followed by the
migration of a neighboring group to this carbocation center. The migrating group varies,
depending on the migratory aptitude and the stereoelectronic effects. An example is given
below for the rearrangement of camphene hydrochloride to isobornyl chloride.
Cl– Cl
+ + Cl
Cl
Cl– H
D. MODIFICATION
Because the Wagner-Meerwein rearrangement represents a class of transformation

involving carbocation intermediates, the new methods for generating carbocation or radical
cation intermediates are considered the modifications for this rearrangement. Thus the mod-
ifications include the photolysis,4j,4p thermolysis of azo-compounds,19 and radical initiation
of epoxide by Cp2 TiCl24 and azo-compound by triphenyl pyrylium tetrafluoroborate.4k
E. APPLICATIONS
This reaction has a very broad application in organic synthesis.
F. RELATED REACTIONS
This reaction is related to the Bertram-Walbaum Rearrangement, Demjanov-Tiffeneau

Rearrangement, Nametkin Rearrangement, and Pinacol Rearrangement.
G. CITED EXPERIMENTAL EXAMPLES
1) Cp2TiCl2/Zn/THF
H O 2) NaH2PO4
(R) H OH
(R) O
O
72%
Reference 24.
REFERENCES 2933
A solution of 225 mg Cp2 TiCl2 (0.9 mmol) in 5 mL THF (dried over Na) was stirred
with 195 mg activated zinc dust (2.99 mmol) for 1 h under argon atmosphere (activated
zinc dust was prepared by washing 20 g commercially available zinc dust with 60 mL 4 N
HCl, thorough washing with water until the washings became neutral, and finally washing
with dry acetone, and then drying in vacuo). The resulting green solution was then added
dropwise to a stirred solution of 100 mg epoxide (0.43 mmol) in 12 mL dry THF at room
temperature under argon. The mixture was stirred for an additional 1 h and decomposed
with 10 mL saturated NaH2 PO4 solution. The solution was extracted with EtOAc and
concentrated. The residue was purified by column chromatography over silica gel using
EtOAc/light petroleum (1:19) to afford 72 mg (1R)-1-(2,2-dimethyl-3-methylenebicyclo-
[2.2.1]hept-1-yl)-2-(prop-2-ynyloxy)ethanol as a colorless liquid, in a yield of 72%.
AcO
NaOAc/HOAc
OH
Reference 27.
To a solution of 50 mg spiral-cyclopropyl camphor derivative (0.3 mmol) in 1 mL glacial

acetic acid was added 246 mg NaOAc (3.0 mmol), and the mixture was refluxed for 2 h. After
cooling to room temperature, the reaction mixture was neutralized with powdered NaHCO3 ;
diluted with ether; washed with saturated aqueous NaHCO3 , water, and brine; and dried
over MgSO4 . Upon removal of solvent, the residue was purified by chromatography on
silica gel to afford the norborenyl acetate as a colorless oil. (yield was not provided)
Other references related to the Wagner-Meerwein rearrangement are cited in the

literature.28
H. REFERENCES
1. Wagner, G., J. Russ. Phys. Chem. Soc., 1899, 31, 690.

2. (a) Meerwein, H., Ann., 1914, 405, 129. (b) Meerwein, H., Ann., 1918, 417, 255. (c) Meerwein,
H. and van Emster, K., Ber., 1920, 53, 1815. (d) Meerwein, H.; van Emster, K. and Joussen, J.,
Ber., 1922, 55, 2500. (e) Meerwein, H, J. Prakt. Chem., 1922, 104, 289. (f) Meerwein, H. and
Gerard, L., Ann., 1923, 435, 174. (g) Meerwein, H.; Hammel, O.; Serini, A. and vorster, J., Ann.,
1927, 453, 16.
3. (a) Reyes-Trejo, B.; Morales-Rios, M. S. and Joseph-Nathan, P., Magnet. Reson. Chem., 2007,
45, 346. (b) Iglesias-Arteaga, M. A.; Mendez-Stivalet, J. M. and Perez, N., Nat. Prod. Commun.,
2007, 2, 47. (c) Bose, G.; Ullah, E. and Langer, P., Chem. Eur. J., 2004, 10, 6015. (d) Justribo, V.;
Colombo, M. I. and Ruveda, E. A., J. Undergrad. Chem. Res., 2003, 2, 117. (e) Román, L. U.;
Cerda-Garcı́a-Rojas, C. M.; Guzmán, R.; Armenta, C.; Hernández, J. D. and Joseph-Nathan, P.,
J. Nat. Prod., 2002, 65, 1540. (f) Colombo, M. I.; Bohn, M. L. and Ruveda, E. A., J. Chem. Edu.,
2002, 79, 484. (g) Cerda-Garcia-Rojas, C. M.; Flores-Sandoval, C. A.; Roman, L. U.; Hernandez,
J. D. and Joseph-Nathan, P., Tetrahedron, 2002, 58, 1061. (h) Kobayashi, T. and Uchiyama, Y.,
J. Chem. Soc., Perkin Trans. I, 2000, 2731. (i) Knolker, H.-J.; Baum, E.; Graf, R.; Jones, P. G.
and Spiess, O., Angew. Chem. Int. Ed., 1999, 38, 2583. (j) Speranza, M. and Filippi, A., Chem.
Eur. J., 1999, 5, 845. (k) Speranza, M. and Filippi, A., Chem. Eur. J., 1999, 5, 834. (l) Evans,
P. A.; Nelson, J. D. and Rheingold, L., Tetrahedron Lett., 1997, 38, 2235. (m) Ranganathan, S.,
Resonance, 1996, 1, 28. (n) Nagamura, S.; Kanada, Y.; Asai, A.; Kobayashi, E.; Gomi, K. and
Saito, H., Chem. Pharm. Bull., 1996, 44, 933. (o) Cho, B. P. and Zhou, L., Tetrahedron Lett.,
1996, 37, 1535. (p) Okazaki, T.; Terakawa, E.; Kitagawa, T. and Takeuchi, K.-I., Tetrahedron
Lett., 1996, 37, 1035. (q) Hasegawa, T.; Kuwatani, Y.; Higuchi, H. and Ueda, I., Bull. Chem. Soc.
Jpn., 1993, 66, 3009. (r) Paquette, L. A.; Elmore, S. W.; Combrink, K. D.; Hickey, E. R. and
Rogers, R. D., Helv. Chim. Acta, 1992, 75, 1755. (s) Cherkaev, G. V. and Kron, A. A., Zh. Org.
Khim., 1992, 28, 208. (t) Knoelker, H. J.; Jones, P. G. and Pannek, J. B., Synlett, 1990, 429.
(u) Orito, K.; Ohto, M. and Suginome, H., J. Chem. Soc., Chem. Commun., 1990, 1076.
(v) Himbert, G. and Ruppmich, M., Angew. Chem., 1990, 102, 69. (w) Cristol, S. J.; Ali, M.
B. and Sankar, I. V., J. Am. Chem. Soc., 1989, 111, 8207. (x) Carrupt, P. A. and Vogel, P., J. Phys.
Org. Chem., 1988, 1, 287. (y) Mak, T. C. W.; Yip, Y. C. and Luh, T. Y., Tetrahedron, 1986, 42,
1981. (z) Berson, J. A.; Olsen, C. J. and Walia, J. S., J. Am. Chem. Soc., 1962, 84, 3337.
4. (a) Wang, A.-X.; Tu, Y.-Q.; Song, Z.-L.; Yuan, D.-Y.; Hu, X.-D.; Wang, S.-H. and Gao, S.-H.,
Eur. J. Org. Chem., 2006, 2691. (b) Storz, T.; Vangrevelinghe, E. and Dittmar, P., Synthesis, 2005,
2562. (c) Fröhlich, J.; Hametner, C. and Sauter, F., ARKIVOC, 2005, (v), 140. (d) Majchrzak, A.;
Mloston, G.; Linden, A. and Heimgartner, H., Helv. Chim. Acta, 2004, 87, 790. (e) Schröder, D.;
Trage, C.; Schwarz, H.; Danovich, D. and Shaik, S., Int. J. Mass Spectr., 2000, 200, 163. (f) Steele,
C. L.; Crock, J.; Bohlmann, J. and Croteau, R., J. Biol. Chem., 1998, 273, 2078. (g) Starling, S.
M. and Vonwiller, S. C., Tetrahedron Lett., 1997, 38, 2159. (h) Kondratenko, M.; Hafa, H. E.;
Gruselle, M.; Vaissermann, J.; Jaouen, G. and McGlinchey, M. J., J. Am. Chem. Soc., 1995, 117,
6907. (i) Shaler, T. A. and Morton, T. H., J. Am. Chem. Soc., 1994, 116, 9222. (j) Adam, W.;
Alt, C.; Braun, M.; Denninger, U. and Zang, G., J. Am. Chem. Soc., 1991, 113, 4563. (k) Adam,
W. and Dörr, M., J. Am. Chem. Soc., 1987, 109, 1570. (l) Berner, D.; Cox, D. P. and Dahn, H.,
J. Am. Chem. Soc., 1982, 104, 2631. (m) Berner, D.; Cox, D. P. and Dahn, H., Helv. Chim. Acta,
1982, 65, 2061. (n) Ermolaeva, V. N.; Sadovaya, N. K. and Zefirov, N. S., Zh. Org. Khim., 1981,
17, 1554. (o) Wenkert, E., Pure & Appl. Chem., 1981, 53, 1271. (p) Morrison, H. and Miller, A.,
J. Am. Chem. Soc., 1980, 102, 372. (q) Tanida, H.; Tori, K. and Kitahonoki, K., J. Am. Chem.
Soc., 1967, 89, 3212.
5. (a) Pachuau, Z. and Lyngdoh, R. H. D., J. Chem. Sci. (Bangalore), 2004, 116, 83. (b) Starling,
S. M.; Vonwiller, S. C. and Reek, J. N. H., J. Org. Chem., 1998, 63, 2262. (c) Hewlins, S. A.;
Murphy, J. A.; Lin, J.; Hibbs, D. E. and Hursthouse, M. B., J. Chem. Soc., Perkin Trans. I, 1997,
1559. (d) Paquette, L. A.; Waykole, L.; Jendralla, H. and Cottrell, C. E., J. Am. Chem. Soc., 1986,
108, 3739.
6. (a) Trost, B. M. and Xie, J., J. Am. Chem. Soc., 2006, 128, 6044. (b) Chiu, P. and Li, S. L.,
Org. Lett., 2004, 6, 613. (c) Trost, B. M. and Yasukata, T., J. Am. Chem. Soc., 2001, 123, 7162.
(d) Bushmelev, V. A. and Genaev, A. M., Zh. Org. Khim., 1992, 28, 1883. (e) Motoyoshiya, J.;
Yazaki, T. and Hayashi, S., J. Org. Chem., 1991, 56, 735. (f) Hayano, K.; Ohfune, Y.; Shirahama,
H. and Matsumoto, T., Helv. Chim. Acta, 1981, 64, 1347. (g) Gree, R.; Park, H. and Paquette, L.
A., J. Am. Chem. Soc., 1980, 102, 4397. (h) Johnson, W. S.; Gravestock, M. B.; Parry, R. J. and
Okorie, D. A., J. Am. Chem. Soc., 1972, 94, 8604. (i) Werstiuk, N. H., Can. J. Chem., 1970, 48,
2310. (j) Witkop, B. and Patrick, J. B., J. Am. Chem. Soc., 1951, 73, 713.
7. Greci, L.; Carloni, P. and Stipa, P., Top. Heterocycl. Systems: Synthesis, Reactions & Properties,
1996, 1, 53.
8. Zubkov, F. I.; Nikitina, E. V.; Turchin, K. F.; Aleksandrov, G. G.; Safronova, A. A.; Borisov, R.
S. and Varlamov, A. V., J. Org. Chem., 2004, 69, 432.
9. (a) Cristol, S. J.; Braun, D.; Schloemer, G. C. and Vanden Plas, B. J., Can. J. Chem., 1986, 64,
1081. (b) Cristol, S. J. and Aeling, E. O., J. Org. Chem., 1985, 50, 2698. (c) Cristol, S. J. and
Opitz, R. J., J. Org. Chem., 1985, 50, 4558. (d) Sonawane, H. R.; Sethi, S. C. and Merchant, S.
N., Indian J. Chem., Sect. B, 1984, 23B, 934. (e) Cristol, S. J.; Seapy, D. G. and Aeling, E. O.,
REFERENCES 2935
J. Am. Chem. Soc., 1983, 105, 7337. (f) Cristol, S. J. and Daussin, R. D., J. Am. Chem. Soc., 1980,
102, 2866.
10. Hixson, S. S.; Day, R. O.; Franke, L. A. and Rao, V. R., J. Am. Chem. Soc., 1980, 102, 412.
11. Parks, D. J. and Piers, W. E., Tetrahedorn, 1998, 54, 15469.
12. Cram, D. J. and Tadanier, J., J. Am. Chem. Soc., 1959, 81, 2737.
13. (a) Koizumi, T.; Mochizuki, E.; Kokubo, K. and Oshima, T., J. Org. Chem., 2004, 69, 4577.
(b) Koizumi, T.; Harada, K.; Mochizuki, E.; Kokubo, K. and Oshima, T., Org. Lett., 2004, 6,
4081.
14. (a) Protti, S.; Fagnoni, M.; Mella, M. and Albini, A., J. Org. Chem., 2004, 69, 3465. (b) Berson,
J. A.; Hammons, J. H.; McRowe, A. W.; Bergman, R. G.; Remanick A. and Houston, D., J. Am.
Chem. Soc., 1967, 89, 2590. (c) Collins, C. J.; Cheema, Z. K.; Werth, R. G. and Benjamin, B. M.,
J. Am. Chem. Soc., 1964, 86, 4913.
15. Shapiro, E. L.; Steinberg, M.; Gould, D.; Gentles, M. J.; Herzog, H. L.; Gilmore, M.; Charney,
W.; Hershberg, E. B. and Mandell, L., J. Am. Chem. Soc., 1959, 81, 6483.
16. Vrcek, V.; Saunders, M. and Kronja, O., J. Org. Chem., 2003, 68, 1859.
17. Cristol, S. J.; Stull, D. P. and Daussin, R. D., J. Am. Chem. Soc., 1978, 100, 6674.
18. Uskokovic, M.; Gut, M. and Dorfman, R. I., J. Am. Chem. Soc., 1960, 82, 3668.
19. Berson, J. A.; Olsen, C. J. and Walia, J. S., J. Am. Chem. Soc., 1960, 82, 5000.
20. Smith, K.; Conley, N.; Hondrogiannis, G.; Glover, L.; Green, J. F.; Mamantov, A. and Pagni, R.
M., J. Org. Chem., 2004, 69, 4843.
21. Davis, C. E.; Duffy, B. C. and Coates, R. M., J. Org. Chem., 2003, 68, 6935.
22. Kitagawa, T.; Okazaki, T.; Komatsu, K. and Takeuchi, K., J. Org. Chem., 1993, 58, 7891.
23. Kinugawa, M.; Nagamura, S.; Sakaguchi, A.; Masuda, Y.; Saito, H.; Ogasa, T. and Kasai, M.,
Org. Proc. Res. Dev., 1998, 2, 344.
24. Jana, S.; Guin, C. and Roy, S. C., J. Org. Chem., 2005, 70, 8252.
25. Cerero, S. de la M.; Martı́nez, A. G.; Vilar, E. T.; Fraile, A. G. and Maroto, B. L., J. Org. Chem.,
2003, 68, 1451.
26. (a) Eguchi, T.; Dekishima, Y.; Hamano, Y.; Dairi, T.; Seto, H. and Kakinuma, K., J. Org. Chem.,
2003, 68, 5433. (b) Kocovsky, P.; Turecek, F.; Langer, V.; Podlahová, J. and Podlaha, J., J. Org.
Chem., 1986, 51, 4888.
27. Li, W.-D. Z. and Yang, Y.-R., Org. Lett., 2005, 7, 3107.
28. (a) Bentley, T. W.; Engels, B.; Hupp, T.; Bogdan, E. and Christl, M., J. Org. Chem., 2006,
71, 1018. (b) Martı́nez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S. de la M.; Morillo, C. D.
and Morillo, R. P., J. Org. Chem., 2004, 69, 7348. (c) Guizzardi, B.; Mella, M.; Fagnoni, M.
and Albini, A., J. Org. Chem., 2003, 68, 1067. (d) Dastan, A., Turk. J. Chem., 2003, 27, 183.
(e) Nishide, K.; Ohsugi, S.-i.; Shiraki, H.; Tamakita, H. and Node, M., Org. Lett., 2001, 3, 3121.
(f) Smith, W. B., J. Org. Chem., 1999, 64, 60. (g) Kocovsky, P.; Dunn, V.; Gogoll, A. and Langer,
V., J. Org. Chem., 1999, 64, 101. (h) Fingerling, G. M. and Parlar, H., J. Agric. Food Chem.,
1997, 45, 4116. (i) Román, L. U., Hernández, J. D.; del Rio, R. E.; Bucio, M. A.; Cerda-Garcia-
Rojas, C. M. and Joseph-Nathan, P., J. Org. Chem., 1991, 56, 1938. (j) Roger, C.; Bodner, G. S.;
Hatton, W. G. and Gladysz, J. A., Organometallics, 1991, 10, 3266. (k) Badanyan, S.; Melikyan,
G. G. and Mkrtchyan, D. A., Russ. Chem. Rev., 1989, 58, 286. (l) Le Drian, C. and Vogel, P.,
Helv. Chim. Acta, 1987, 70, 1703. (m) Asaoka, M. and Takei, H., Tetrahedron Lett., 1987, 28,
6343. (n) Cristol, S. J.; Aeling, E. O.; Strickler, S. J. and Ito, R. D., J. Am. Chem. Soc., 1987,
109, 7101. (o) Michael, J. P.; Blom, N. F. and Boeyens, J. C. A., J. Chem. Soc., Perkin Trans. I,
1984, 1739. (p) Roush, W. R. and D’Ambra, T. E., J. Org. Chem., 1981, 46, 5045. (q) Ciganek, E.,
J. Org. Chem., 1980, 45, 1505. (r) Hogeveen, H. and van Kruchten, E. M. G. A., Top. Curr. Chem.,
1979, 80, 89. (s) Nakazaki, M.; Naemura, K. and Kadowaki, H., J. Org. Chem., 1978, 43, 4947.
(t) McCapra, F. and Beheshti, I., J. Chem. Soc., Chem. Commun., 1977, 517. (u) Brown, H. C.,
“The Non-classical Ion Problem”, Plenum, New York, 1977. (v) Olah, G. A., Acc. Chem. Res.,
1976, 9, 41. (w) Phan, T. H. and Dahn, H., Helv. Chim. Acta, 1976, 59, 335. (x) Cargill, R. L.;
Jackson, T. E.; Peet, N. P. and Pond, D. M., Acc. Chem. Res., 1974, 7, 106. (y) Morizur, J. P.; Furth,
B. and Kossanyi, J., J. Org. Chem., 1973, 38, 2698. (z) Akhrem, A. A.; Vesela, I. V.; Kamernitskii,
A. V. and Prokof”ev, E. P., Russ. Chem. Bull., 1972, 21, 1071. (aa) Cann, P. F. and Warren, S.,
J. Chem. Soc., Chem. Commun., 1970, 1026. (bb) Benjamin, B. M. and Collins, C. J., J. Am.
Chem. Soc., 1970, 92, 3183. (cc) Herzog, H. L.; Gnoj, O.; Mandell, L.; Nathansohn, G. G. and
Vigevani, A., J. Org. Chem., 1967, 32, 2906. (dd) Bystrov, V. F.; Azovskaya, V. A.; Petukhova,
N. P.; Stepanyants, A. U. and Prilezhaeva, E. N., Russ. Chem. Bull., 1966, 15, 358. (ee) Cram,
D. J., J. Am. Chem. Soc., 1964, 86, 3767. (ff) Anet, F. P. L. and Bavin, P. M. G., Can. J. Chem.,
1960, 38, 240. (gg) Herzog, H. L.; Gentles, M. J.; Mitchell, A.; Hershberg, E. B. and Mandell, L.,
J. Am. Chem. Soc., 1959, 81, 6478. (hh) Popp, F. D. and McEwen, W. E., Chem. Rev., 1958, 58,
321. (ii) Herzog, H. L.; Joyner, C. C.; Gentles, M. J.; Hughes, M. T.; Oliveto, E. P.; Hershberg,
E. B. and Barton, D. H. R., J. Org. Chem., 1957, 22, 1413. (jj) Cram, D. J.; Nyquist, H. L. and
Elhafez, F. A. A., J. Am. Chem. Soc., 1957, 79, 2876. (kk) Collins, C. J. and Bonner, W. A.,
J. Am. Chem. Soc., 1955, 77, 92. (ll) Vaughan, W. R. and Little, R. Q., J. Am. Chem. Soc., 1954,
76, 4130. (mm) Witkop, B. and Patrick, J. B., J. Am. Chem. Soc., 1951, 73, 1558. (nn) Witkop,
B. and Ek, A., J. Am. Chem. Soc., 1951, 73, 5664. (oo) Dostrovsky, I.; Hughes, E. D. and Ingold,
C. K., J. Chem . Soc., 1946, 192. (pp) Bartlett, P. D. and Pockel, I., J. Am. Chem. Soc., 1937, 59,
820.
186
Demjanov Rearrangement
This reaction was initially reported by Demjanov (sometimes spelled Demjanow or

Dem’yanov) in 1903.1 It is the conversion of primary amines into alcohols by means of the
diazotization of those amines with nitrous acid, accompanying the migration of the carbon
atom when the primary amino groups are on the ring or at the α-position of the side chain.
Therefore, this reaction is generally known as the Demjanov rearrangement2 or Demjanov
reaction.3 In the case of cyclic aliphatic amines, alcohols with enlarged or contracted rings
are formed, depending on the position of the amino group. If an amino group is directly
attached to the ring, then ring contraction occurs;4 in the case of primary amines, when
the amino group is connected to the cyclic ring via a methylene group, the ring expands
after diazotization.2g,5 The Demjanov rearrangement under this condition is also referred
to as the Demjanov ring expansion.5a,6 If an aromatic group is attached to the same position
where an aminomethylene sits, phenyl migration happens without ring enlargement.2f
HNO2
NH2 OH + OH
n n n
(n = 1, 2, ...)
NH2 OH OH
HNO2
+
n n
n

868
CITED EXPERIMENTAL EXAMPLES 869
D. MODIFICATION
N/A
E. APPLICATIONS
This reaction has general application in the preparation of cyclic compounds with
different sizes.
This reaction is related to the Tiffeneau-Demjanov Rearrangement and Wagner-

Meerwein Rearrangement, both involve carbocation intermediates.
Reference 4.
To a solution of 42.7 mg deacetylthiocolchicine (0.11 mmol) in 4 mL water was added

10.9 mg sodium nitrite in 1 mL water containing two drops of acetic acid. The reaction
mixture was stirred at room temperature for 24 h and extracted with CHCl3 (30 mL × 3).
The extract was washed with 5% NaHCO3 solution, water, and brine until pH = 7.
It was dried over anhydrous Na2 SO4 and concentrated. Purification of the residue by
preparative TLC plates with CHC13 /MeOH (95:5) as the eluant furnished 18.1 mg
870 DEMJANOV REARRANGEMENT
pure 5,6-dihydro-6(S)-(hydroxymethyl)-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta
[a]naphthalene-8-one. Crystallization from CH2 Cl2 -Et2 O afforded yellow crystals, in a
yield of 42%, m.p. 201–203◦ C.
Reference 2e.
Cyclohexanemethylamine (45.2 g, 0.4 mol) was treated with NaNO2 in dilute aqueous
orthophosphoric acid at room temperature for 1 h and then at 95◦ C for 1 h. Fractional
distillation of the crude product gave 9.4 g cycloalkene mixtures (b.p. 90–115◦ C) and
26.6 g alcohol mixtures (b.p. 50–95◦ C at 20 mmHg).
Other references related to the Demjanov rearrangement are cited in the literature.7
H. REFERENCES
1. Demjanov, N. J. and Lushnikov, M., J. Russ. Phys. Chem. Soc., 1903, 35, 26.
2. (a) Nikishova, N. G. and Bundel, Yu. G., Vestnik Moskovskogo Universiteta, Ser. 2: Khim., 1985,
26, 486. (b) Novikov, G. P. and Bundel, Yu. G., Dokl. Akad. Nauk SSSR, 1985, 280, 1366. (c)
Hass, E. C. and Plath, P. J., Bremer Briefe Chem., 1977, 1, 6. (d) Bundel, Y. G.; Funtova, S. M.
and Reutov, O. A., Dokl. Akad. Nauk SSSR, 1971, 200, 107. (e) Kotani, R., J. Chem. Eng. Data,
1966, 11, 248. (f) Diamond, J.; Bruce, W. F. and Tyson, F. T., J. Org. Chem., 1965, 30, 1840. (g)
Kotani, R., J. Org. Chem., 1965, 30, 350.
3. (a) Dmitriev, L. B.; Grandberg, I. I. and Moskalenko, V. A., Khim. Geterotsiklicheskikh Soedinenii,
1970, 1654. (b) Reutov, O. A. and Shatkina, T. N., Dokl. Akad. Nauk SSSR, 1962, 142, 835.
4. Sun, L.; McPhail, A. T.; Hamel, E.; Lin, C. M.; Hastie, S. B.; Chang, J.-J. and Lee, K.-H., J. Med.
Chem., 1993, 36, 544.
5. (a) Nakazaki, M.; Naemura, K. and Hashimoto, M., J. Org. Chem., 1983, 48, 2289. (b) Hall, H.
K., J. Am. Chem. Soc., 1960, 82, 1209. (c) Hall, H. K., J. Org. Chem., 1960, 25, 42.
6. Bundel, Y. G.; Prokhorenko, I. R. and Reutov, O. A., Izv. Akad. Nauk SSSR, Ser. Khim., 1972,
707.
7. (a) Fattori, D.; Henry, S. and Vogel, P., Tetrahedron, 1993, 49, 1649. (b) Nakazaki, M.; Nae-
mura, K.; Chikamutsu, H.; Iwasaki, M. and Hashimoto, M., J. Org. Chem., 1981, 46, 2300.
(c) Nakazaki, M.; Naemura, K.; Chikamatsu, H.; Iwasaki, M.; Hashimoto, M., Chem. Lett., 1980,
1571. (d) Dave, V.; Stothers, J. B. and Warnhoff, E. W., Can. J. Chem., 1979, 57, 1557. (e) Murray,
R. K. and Ford, T. M., J. Org. Chem., 1979, 44, 3504. (f) Bundel, Yu. G.; Funtova, S. M. and
Reutov, O. A., Izv. Akad. Nauk SSSR, Ser. Khim., 1972, 935. (g) Dmitriev, L. B.; Grandberg, I. I.
and Moskalenko, V. A., Chem. Heterocycl. Compds., 1970, 6, 1544. (h) Stetter, H. and Goebel,
P., Ber., 1963, 96, 550. (i) Smith, P. A. S. and Baer, D. R., Org. React., 1960, 11, 157. (j) Alder,
K. and Reubke, R., Ber., 1958, 91, 1525. (k) Ruzicka, L. and Brugger, W., Helv. Chim. Acta,
1926, 9, 339. (l) Wallach, O., Ann., 1907, 353, 318. (m) Demjanov, N. J. and Dojarenko, M.,
Ber., 1909, 41, 43. (n) Demjanov, N. J., Ber., 1907, 40, 4393, 4961. (o) Demjanov, N. J., J. Russ.
Phys. Chem. Soc., 1904, 36, 186.
224
Favorskii Rearrangement
This reaction was initially reported by Favorskii in 1894.1 It is a base-induced rear-

rangement of α-halo ketones to the corresponding carboxylic acid derivatives (e.g., acids,
esters, and amides) with the same number of carbon atoms in the skeletons; and the bases
can be hydroxide, alkoxide, or amines.2 Therefore, it is generally known as the Favorskii
rearrangement.3 Occasionally, it is also referred to as the Favorskii reaction.4
There have been at least six different mechanisms proposed for this rearrangement:
(a) the addition of alkoxide to the carbonyl group with the concomitant extrusion of a
halide ion to form a final product via the intermediate of epoxide;5 (b) the reaction of a
nucleophile with a ketene generated by the base-induced elimination of hydrogen halide;6
(c) the addition of alkoxide to the carbonyl group followed by the 1,2-migration of an
alkyl group (similar to the Benzilic Acid Rearrangement; therefore, it is also called the
semibenzilic acid mechanism7 or abnormal or quasi-Favorskii rearrangement8 ); (d) the
unimolecular dissociation of an α-halo ketone to a carbonium ion, which tautomerizes to
isomeric carbonium then rearranges to product;9 (e) the generation of a carbanion by depro-
tonation of α -hydrogen followed by a nucleophilic substitution to form cyclopropanone,
which undergoes rearrangement to a final product during alkoxide attacks10 (this mech-
anism is also called the Loftfield mechanism11 or cyclopropanone mechanism12 ); and
(f ) the formation of an oxyallylic anion that undergoes [4+3] cycloaddition.13 Among
these mechanisms, the semibenzilic acid mechanism and cyclopropanone mechanisms are
most plausible.7b,12a When α -hydrogens are available, the cyclopropanone mechanism is
preferred,10−12 whereas semibenzilic acid mechanism comes into play in the absence of

1026
PROPOSED MECHANISMS 1027
α -hydrogens (e.g., in nonenolizable ketones7b,14a ) or when the formation of cyclo-

propanone is prevented.14 However, it has been reported that in the gas phase the
semibenzilic acid mechanism is more favorable,7b,12a and the oxyallylic mechanism can be
limited using a non-nucleophilic solvent such as trifluoroethanol.13a Similarly, many exper-
imental results have shown that the actual reaction mechanisms depend on the reaction
conditions.15 Even the cyclopropanone mechanism can be concerted or unconcerted.16 In
this reaction, the deprotonation is the rate-limiting step, followed by a quick halo extrusion.17
In the case of cyclic α-halo ketones, ring contraction occurs.13b,18 A similar reaction occurs
on β-halo ketones via the elimination of a hydrogen halide to cyclobutanone followed
by the scission of cyclobutanone, known as the homo-Favorskii rearrangement.11,19 This
reaction has been proved to be a useful tool for synthesizing the highly strained esters,
bicyclic esters,13b and some steroids,20 norsteriods,21 etc. In addition, this reaction has
been successfully applied to the synthesis of saturated pyrollidine derivatives.18a Similarly,
the base-induced rearrangement of ketimines will afford imidates or amides.12b More details
about this reaction are described in reviews.22
X
Base O
or R X
R
O R OH
O
O COOH
X Base X = Cl, Br, etc.
Base = KOH, NaOH, NaOMe, etc.
Although several mechanisms have been proposed for this reaction, only cyclopropanone
mechanism (Scheme 1) and benzilic acid mechanism (Scheme 2) are displayed here.
SCHEME 1. Favorskii rearrangement via cyclopropanone mechanism.

1028 FAVORSKII REARRANGEMENT
SCHEME 2. Favorskii rearrangement occurring a benzilic acid mechanism.
D. MODIFICATION
N/A
E. APPLICATIONS
This reaction has been successfully used to prepare bicyclic esters, steroids, norsteroids,
pyrollidine, etc.
This reaction is related to Benzilic Acid Rearrangement.
Reference 13a.
To a solution of 50 mg 1,1-dichloro-7-furan-3 -yl-heptan-2-one (0.20 mmol) in 0.25 mL

1,1,1-trifluoroethanol (0.8 M) was added 60 µL triethylamine (0.44 mmol) at room temper-
ature. The reaction mixture was heated at 50◦ C (oil bath) for 24 h before quenching with
water and extracting with CH2 Cl2 . The organic layer was dried over MgSO4 and concen-
trated to give a residue that was purified by column chromatography (5:1, hexane/EtOAc)
to give 31.3 mg an inseparable mixture of trifluoroethyl acrylic esters in a 4:1 ratio, in a
yield of 57%, Rf = 0.68 (hexane/EtOAc, 5:1).
REFERENCES 1029
OH
+ MeO Li
THF
Br (91%)
O
OMe
MeO
Reference 8a.
To a cooled solution of 100 mg bromoketone (0.44 mmol) in 4.4 mL THF at −78◦ C was
added 2.2 eq. of 4-methoxyphenyl lithium solution dropwise. After being stirred at −78◦ C
for 1 h, the reaction mixture was warmed to room temperature over 2 h and then stirred for
an additional 4 h. It was quenched with distilled water, extracted by ether (3 × 10 mL),
washed with brine (5 mL), dried over MgSO4 , filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography with 5% EtOAc in hexane to
yield 91% of bis(4-methoxyphenyl)tricyclo[4.2.1.02,5 ]non-7-en-2-ylmethanol as an oil.
Other references related to the Favorskii rearrangement are cited in the literature.23
H. REFERENCES
1. Favorskii, A. E., J. Russ. Phys. Chem. Soc., 1894, 26, 559.

2. Castillo, R.; Andrés, J. and Moliner, V., J. Phys. Chem. B, 2001, 105, 2453.
3. (a) Miura, M.; Toriyama, M. and Motohashi, S., Synth. Commun., 2006, 36, 259. (b) Foehlisch,
B.; Franz, T. and Kreiselmeier, G., Eur. J. Org. Chem., 2005, 4687. (c) Guijarro, D. and Yus,
M., Curr. Org. Chem., 2005, 9, 1713. (d) Iglesias-Arteaga, M. A. and Velazquez-Huerta, G. A.,
Tetrahedron Lett., 2005, 46, 6897. (e) Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.;
Dorofeev, A. S.; Vereshchagin, A. N. and Nikishin, G. I., Russ. Chem. Bull., 2003, 52, 998.
(f) Elinson, M. N.; Feducovich, S. K.; Dorofeev, A. S.; Vereshchagin, A. N. and Nikishin, G. I.,
Russ. Chem. Bull., 2003, 52, 228. (g) Muldgaard, L.; Thomsen, I. B.; Hazell, R. G. and Bols, M.,
J. Chem. Soc., Perkin Trans. I, 2002, 1297. (h) Makarova, N. V.; Moiseev, I. K. and Zemtsova,
M. N., Russ. J. Gen. Chem., 2002, 72, 95. (i) Castillo, R.; Moliner, V.; Safont, V. S.; Oliva, M.
and Andres, J., THEOCHEM, 1998, 426, 299. (j) Inesi, A.; Rossi, L.; Feroci, M. and Rizzuto,
M., New J. Chem., 1998, 22, 57. (k) Quan, B. and Dong, H. S., Huaxue Yanjiu Yu Yingyong,
1997, 9, 555. (l) Lee, E.; Yoon, C. H.; Lee, Y. J. and Kim, H. J., Bull. Korean Chem. Soc., 1997,
18, 1247. (m) Krinitskaya, L. A., Russ. Chem. Bull., 1997, 46, 1140. (n) El-Wareth, A.; Sarhan,
A. O. and Hoffmann, H. M. R., J. Prakt. Chem./Chem.-Zeit., 1997, 339, 390. (o) Mathew, F.
and Myrboh, B., Synth. Commun., 1996, 26, 1097. (p) De Angelis, F.; Feroci, M. and Inesi, A.,
Bull. Soc. Chim. Fr., 1993, 130, 712. (q) Satoh, T.; Motohashi, S.; Kimura, S.; Tokutake, N.
and Yamakawa, K., Tetrahedron Lett., 1993, 34, 4823. (r) Satoh, T.; Oguro, K.; Shishikura, J.;
Kanetaka, N.; Okada, R. and Yamakawa, K., Bull. Chem. Soc. Jpn., 1993, 66, 2339. (s) Satoh, T.;
Oguro, K.; Shishikura, J.; Kanetaka, N.; Okada, R. and Yamakawa, K., Tetrahedron Lett., 1992,
33, 1455. (t) De Kimpe, N.; D’Hondt, L. and Moens, L., Tetrahedron, 1992, 48, 3183. (u) Carelli,
I.; Curulli, A.; Inesi, A. and Zeuli, E., J. Chem. Res. (S), 1991, 10. (v) Elinson, M. N.; Makhova,
I. V. and Nikishin, G. I., Izv. Akad. Nauk SSSR, Ser. Khim., 1989, 1208. (w) Donskaya, N. A.;
Bessmertnykh, A. G. and Shabarov, Yu. S., Zh. Org. Khim., 1989, 25, 332. (x) Johnson, D. W.
and Poulos, A., Biomed. Environ. Mass Spect., 1988, 18, 603. (y) De Kimpe, N.; Stanoeva, E.
and Schamp, N., Tetrahedron Lett., 1988, 29, 589. (z) Sakai, T.; Amano, E.; Miyata, K.; Utaka,
1030 FAVORSKII REARRANGEMENT
M. and Takeda, A., Bull. Chem. Soc. Jpn., 1987, 60, 1945. (aa) Sakai, T.; Ishikawa, M.; Amano,
E.; Utaka, M. and Takeda, A., Bull. Chem. Soc. Jpn., 1987, 60, 2295. (bb) Sakai, T.; Yamawaki,
A.; Katayama, T.; Okada, H.; Utaka, M. and Takeda, A., Bull. Chem. Soc. Jpn., 1987, 60, 1067.
(cc) Tsuboi, S.; Nagae, H.; Yamato, H. and Takeda, A., Bull. Chem. Soc. Jpn., 1987, 60, 836.
(dd) Kulinkovich, O. G.; Tishchenko, I. G. and Sviridov, S. V., Zh. Org. Khim., 1986, 22, 1416.
(ee) Engler, T. A. and Falter, W., Tetrahedron Lett., 1986, 27, 4115. (ff) Engler, T. A. and Falter,
W., Tetrahedron Lett., 1986, 27, 4119. (gg) Abad, A.; Arno, M.; Pedro, J. R. and Seoane, E., J.
Chem. Soc., Perkin Trans. I, 1983, 2471. (hh) Cambie, R. C.; Robertson, J. D.; Rutledge, P. S.
and Woodgate, P. D., Aust. J. Chem., 1982, 35, 183. (ii) Greuter, H.; Dingwall, J.; Martin, P. and
Bellus, D., Helv. Chim. Acta, 1981, 64, 2812.
4. (a) Isaev, S. D.; Novikova, M. I.; Chizhov, O. S.; Shchrbakov, M. V.; Shishkin, O. V. and Yurchenko,
A. G., Ukrainskii Khim. Zh., 1999, 65, 137. (b) Kurzer, F. and Patel, J. N., Monatsh. Chem., 1987,
118, 1363. (c) Itooka, T.; Matoba, K.; Yamazaki, T.; Muraoka, O. and Momose, T., Chem. Pharm.
Bull., 1986, 34, 2391. (d) Daum, S. J., Tetrahedron Lett., 1984, 25, 4725. (e) Martin, P., Helv.
Chim. Acta, 1983, 66, 1189.
5. (a) Aston, E. A., J. Am. Chem. Soc., 1940, 62, 2590. (b) Favorskii, A. E., J. Prakt. Chem., 1913,
88, 641.
6. Richard, G., Compt. Rend., 1933, 197, 1943.
7. (a) Harmata, M. and Rashatasakhon, P., Org. Lett., 2001, 3, 2533. (b) Lu, T.-J.; Liu, S.-W. and
Wang, S.-H., J. Org. Chem., 1993, 58, 7945. (c) Tchoubar, B. and Sackur, O., Compt. Rend.,
1939, 208, 1020.
8. (a) Harmata, M. and Wacharasindhu, S., J. Org. Chem., 2005, 70, 725. (b) Harmata, M. and
Bohnert, G. J., Org. Lett., 2003, 5, 59. (c) Gambacorta, A.; Turchetta, S, S.; Bovicelli, P. and
Botta, M., Tetrahedron, 1991, 47, 9097. (d) Kraus, G. A. and Shi, J., J. Org. Chem., 1991, 56,
4147. (e) Kraus, G. A. and Shi, J., J. Org. Chem., 1990, 56, 5424. (f) Stevens, C. L.; Pillai, P. M.
and Taylor, K. G., J. Org. Chem., 1974, 39, 3158. (g) Smissman, E. E. and Diebold, J. L., J. Org.
Chem., 1965, 30, 4005. (h) Smissman, E. E. and Hite, G., J. Am. Chem. Soc., 1960, 82, 3375.
9. (a) McPhee, W. and Klingsberg, E., J. Am. Chem. Soc., 1944, 66, 1132. (b) Richard, G., Compt.
Rend., 1935, 200, 1944.
10. (a) Loftfield, R. B., J. Am. Chem. Soc., 1951, 73, 4707. (b) Loftfield, R. B., J. Am. Chem. Soc.,
1950, 72, 632.
11. Zhang, L. M. and Koreeda, M., Org. Lett., 2002, 4, 3755.
12. (a) Moliner, V.; Castillo, R.; Safont, V. S.; Oliva, M.; Bohn, S.; Tunon, I. and Andres, J., J. Am.
Chem. Soc., 1997, 119, 1941. (b) Kimpe, N. D.; Sulmon, P.; Moens, L.; Schamp, N.; Declercq,
J.-P. and Meerssche, M. V., J. Org. Chem., 1986, 51, 3839. (c) Rappe, C.; Knufsson, L.; Turro,
N. J. and Gagosiad, R. B., J. Am. Chem. Soc., 1970, 92, 2032.
13. (a) Grainger, R. S.; Owoare, R. B.; Tisselli, P. and Steed, J. W., J. Org. Chem., 2003, 68, 7899.
(b) Bai, D. L.; Xu, R.; Chu, G. H. and Zhu, X. Z., J. Org. Chem., 1996, 61, 4600. (c) Bordwell, F.
G. and Scamehorn, R. G., J. Am. Chem. Soc., 1971, 93, 3410. (d) Bordwell, F. G. and Carlson, M.
W., J. Am. Chem. Soc., 1970, 92, 3377. (e) Turro, N. J., Acc. Chem. Res., 1969, 2, 25. (f) Aston,
J. G. and Newkirk, J. D., J. Am. Chem. Soc., 1951, 73, 3900.
14. (a) Harmata, M.; Bohnert, G.; Kurti, L. and Barnes, C. L., Tetrahedron Lett., 2002, 43, 2347.
(b) Selman, S. and Eastham, J. F., Quart. Rev. (London), 1960, 14, 221.
15. (a) Erian, A. W.; Sherif, S. M. and Gaber, H. M., Molecules, 2003, 8, 793. (b) Turro, N. J. and
Hammond, W. B., J. Am. Chem. Soc., 1965, 87, 3258. (c) House, H. O. and Frank, G. A., J. Org.
Chem., 1965, 30, 2948.
16. Engel, C. R.; Mérand, Y. and Côté, J., J. Org. Chem., 1982, 47, 4485.
17. (a) Myers, A. G. and Barbay, J. K., Org. Lett., 2001, 3, 425. (b) Bordwell, F. G.; Frame, R. R.;
Scamehorn, R. G.; Strong, J. G. and Meyerson, S., J. Am. Chem. Soc., 1967, 89, 6704.
REFERENCES 1031
18. (a) Sosnovsky, G. and Cai, Z.-W., J. Org. Chem., 1995, 60, 3414. (b) Lee, E. and Yoon, C. H., J.
Chem. Soc., Chem. Commun., 1994, 4, 479. (c) Brik, M. E., Synth. Commun., 1990, 20, 1487.
(d) Llera, J. M. and Fraser-Reid, B., J. Org. Chem., 1989, 54, 5544. (e) Paquette, L. A.; Farkas,
E. and Galemmo, R., J. Org. Chem., 1981, 46, 5434. (f) Buchi, G. and Ecceiz, B., J. Org. Chem.,
1971, 36, 2021. (g) Wolinsky, J. and Chan, D., J. Org. Chem., 1965, 30, 41.
19. (a) Ceccherelli, P.; Curini, M.; Pellicciari, R. and Wenkert, E., J. Org. Chem., 1982, 47, 3172.
(b) Bisceglia, R. H. and Cheer, C. J., J. Chem. Soc., Chem. Comm., 1973, 165. (c) Wolff, S. and
Agosta, W. C., J. Chem. Soc., Chem. Comm., 1973, 771. (d) Tsuda, Y.; Tanno, T.; Ukai, A. and
Isobe, K., Tetrahedron Lett., 1971, 2009. (e) Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht,
C. L. and Schenk, H. P., J. Am. Chem. Soc., 1971, 93, 3208.
20. Romo, J. and de Vivar, A. R., J. Am. Chem. Soc., 1957, 79, 1118.
21. (a) Nace, H. R. and Olsen, B. A., J. Org. Chem., 1967, 32, 3438. (b) Smith, B. B. and Nace, H.
R., J. Am. Chem. Soc., 1954, 76, 6119.
22. (a) Baretta, A. and Waegill, B., “A Survey of Favorskii Rearrangement Mechanisms,” in Reactive
Intermediates, ed. Abramovitch, R. A., Plenum Press, New York, 1982, pp. 527–585. (b) Chenier,
P. J., J. Chem. Edu., 1978, 55, 286. (c) Akhrem, A. A.; Ustynyuk, T. K. and Titov, Y. A., Russ.
Chem. Rev., 1970, 39, 732. (d) Kende, A. S., Org. React., 1960, 11, 261. (e) Jacquier, R., Bull.
Soc. Chim. Fr., 1950, 17, 35.
23. (a) Harmata, M. and Wacharasindhu, S., Org. Lett., 2005, 7, 2563. (b) Harmata, M.; Bohnert, G.;
Kurti, L. and Barnes, C. L., Tetrahedron Lett., 2002, 43, 2347. (c) Xiang, L. K.; Kalaitzis, J. A.;
Nilsen, G.; Chen, L. and Moore, B. S., Org. Lett., 2002, 4, 957. (d) Feroci, M.; Inesi, A.; Rossi,
L. and Sotgiu, G., Eur. J. Org. Chem., 2001, 2765. (e) Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.
and Sonawane, H. R., Tetrahedron, 1997, 53, 16789. (f) Rodios, N. A.; Bojilova, A.; Terzis, A.
and Raptopoulou, C. P., J. Heterocycl. Chem., 1994, 31, 1129. (g) Barbee, T. R.; Guy, H.; Heeg,
M. J. and Albizati, K. F., J. Org. Chem., 1991, 56, 6773. (h) Abad, A.; Agulló, C.; Arnó, M. and
Seoane, F., Tetrahedron, 1986, 42, 2429. (i) Sakai, T.; Tabata, H. and Takeda, A., J. Org. Chem.,
1983, 48, 4618. (j) Schaad, L. J.; Hem, B. A. and Zahradnlk, R., J. Org. Chem., 1981, 46, 1909.
(k) Sakai, T.; Katayama, T. and Takeda, A., J. Org. Chem., 1981, 46, 2924. (l) Sakai, T.; Amano,
E.; Kawabata, A. and Takeda, A., J. Org. Chem., 1980, 45, 43. (m) Galons, H.; Girardeau, J.
F. and Combet-Farnoux, C., Bull. Soc. Chim. Fr., 1977, 936. (n) Chenier, P. J. and Kao, J. C.,
J. Org. Chem., 1976, 41, 3730. (o) Vickers, S. and Smissman, E. E., J. Org. Chem., 1975, 40, 749.
(p) Koutek, B.; Pavlickova, L. and Soucek, M., Collect. Czech. Chem. Commun., 1973, 38, 3872.
(q) Müller, H., Angew. Chem. Int. Ed. Eng., 1971, 10, 652. (r) Bordwell, F. G. and Carlson, M.
W., J. Am. Chem. Soc., 1970, 92, 3370. (s) Bordwell, F. G.; Scamehorn, R. G. and Springer, W.
R., J. Am. Chem. Soc., 1969, 81, 2087. (t) Bordwell, F. G.; Carlson, M. W. and Knipe, A. C., J.
Am. Chem. Soc., 1969, 91, 3949. (u) Bordwell, F. G. and Almy, J., J. Org. Chem., 1973, 38, 571.
(v) Bordwell, F. G. and Strong, J., J. Org. Chem., 1973, 38, 579. (w) Bordwell, F. G. and Almy, J.,
J. Org. Chem., 1973, 38, 575. (x) Wolinsky, J. and Hutchins, R. O., J. Org. Chem., 1972, 37, 3294.
(y) Wolinsky, J.; Hutchins, R. O. and Gibson, T. W., J. Org. Chem., 1968, 33, 407. (z) House,
H. O. and Richey, F. A., J. Org. Chem., 1967, 32, 2151. (aa) Smissman, E. E.; Lemke, T. L. and
Kristiansen, O., J. Am. Chem. Soc., 1966, 88, 334. (bb) Goheen, D. W. and Vaughan, W. R., Org.
Syn. Coll. 1963, 4, 594. (cc) Fort, A. W., J. Am. Chem. Soc., 1962, 84, 4979. (dd) Fort, A. W.,
J. Am. Chem. Soc., 1962, 84, 2620. (ee) Fort, A. W., J. Am. Chem. Soc., 1962, 84, 2625. (ff) House,
H. O. and Gilmore, W. F., J. Am. Chem. Soc., 1961, 83, 3980. (gg) Stork, G. and Borowitz, I. J.,
J. Am. Chem. Soc., 1960, 82, 4307. (hh) Pappas, N. and Nace, H. R., J. Am. Chem. Soc., 1959,
81, 4556. (ii) Hesse, G. and Urbanek, F., Ber., 1958, 91, 2733. (jj) Tchoubar, B., Bull. Soc. Chim.
Fr., 1955, 22, 1363. (kk) Favorskii, A. E. and Bozhovskii, V. N., J. Russ. Phys. Chem. Soc., 1914,
46, 1097. (ll) Favorskii, A. E., J. Prakt. Chem., 1913, 88, 658.
252
Fritsch-Buttenberg-Wiechell
Rearrangement
This reaction was initially reported by Fritsch1 and Buttenberg,2 coincidently with
Wiechell,3 in 1894. It is a strong base (e.g., NaOEt) promoted rearrangement of 2,2-
diaryl-1-halo-alkenes into diarylacetylenes.4 Therefore, it is generally known as the
Fritsch-Buttenberg-Wiechell rearrangement.5 This reaction has been found to occur via
a carbenoid intermediate4,5n,5q,5r rather than the α-elimination of metal halide;5j in addi-
tion, the electron-donating groups normally facilitate or accelerate the migration of aryl
moiety.5j It is the aryl moiety trans to the halide that undergoes the 1,2-migration,6 thus
this reaction is also called 1,2-Fritsch-Buttenberg-Weichell rearrangement.5c Currently, this
reaction has been extended to the rearrangement of aryl or alkyl olefinic halides,5l and the
most recent development for this reaction is the mild transformation of alkyl olefinic dibro-
mides or alkyl alkoxy olefinic halides into alkyne derivatives proceeding via zinc carbenoids
with broad tolerance of functionalities.5e For the reaction of alkyl alkoxy olefinic halides,
the alkoxyalkyl moiety migrates exclusively;5g,5l in addition, this rearrangement occurs
only when a hydrogen, alkoxy, or aryl moiety is involved in the migration step.5g This
reaction has been widely used in the synthesis of polyalkynes containing 2–10 acetylene
units.5a
R X
NaOEt
R R′ X = Cl, Br, I, etc.
R′ H

1151
1152 FRITSCH-BUTTENBERG-WIECHELL REARRANGEMENT
It is believed that a carbenoid intermediate is involved in this reaction, as displayed

below.
D. MODIFICATION
This reaction has been modified via the formation of zinc carbenoids, which undergo
a mild rearrangement,5e with the retention of the configuration of the migrating group.5m
In addition, this reaction has been extended to occur under electrochemical5n and pho-
tochemical conditions. The rearrangement occurs under photo irradiation is known as
photo-Fritsch-Buttenberg-Wiechell rearrangement.7
E. APPLICATIONS
This reaction has been used in the synthesis of polyalkynes that contain different acety-
lene units.
N/A
Reference 5a.
A 0.010–0.016 M solution of the dibromoolefin in hexanes under nitrogen was cooled to

−78◦ C, and 1.1–1.2 eq. n-BuLi per dibromoolefin moiety was slowly added over a period
of ∼2 min. Reactions were allowed to warm to −10 to −5◦ C over a period of 30–60 min.
The reaction was quenched with 10 mL aqueous NH4 Cl at about −5◦ C. Diethyl ether was
added (20 mL), the organic layer was separated, and washed with aqueous NH4 Cl solution
(2 × 20 mL), and dried over MgSO4 . The solvent was removed in vacuo to give 70% 1,12-
bis(triisopropylsilyl)-1,3,5,7,9,11-dodecahexayne, m.p. 78–80◦ C, Rf = 0.87 (hexanes).
REFERENCES 1153
Br
Br n-BuLi
CH3
Hexanes
48%
CH3
Reference 5d.
To 10 mL cooled dry hexanes (−78◦ C) containing 0.131 g dibromoolefin (0.404 mmol)

was added dropwise 0.15 mL 2.5 M n-BuLi in hexane (0.38 mmol) over 10 min. The
mixture was warmed to −40◦ C for 30 min, recooled to −78◦ C, and quenched with a
saturated aqueous solution of NH4 Cl. Et2 O was added (50 mL), and the organic layer was
separated, washed with brine, and dried over magnesium sulfate. Solvent removal in vacuo
and by passing the residue through a short plug of silica gel gave 31.9 mg 2-non-1-en-
3,5,7-1-phenylhepta-1,3,5-triyne as a white solid, in a yield of 48%, m.p. 58◦ C, Rf = 0.40
(hexanes).
Other references related to the Fritsch-Buttenberg-Wiechell rearrangement are cited in

the literature.8
H. REFERENCES
1. Fritsch, P., Ann., 1894, 279, 319.

2. Buttenberg, W. P., Ann., 1894, 279, 324.
3. Wiechell, H., Ann., 1894, 279, 337.
4. Knorr, R., Chem. Rev., 2004, 104, 3795.
5. (a) Eisler, S.; Slepkov, A. D.; Elliott, E.; Luu, T.; McDonald, R.; Hegmann, F. A. and Tykwinski,
R. R., J. Am. Chem. Soc., 2005, 127, 2666. (b) Luu, T.; Elliott, E.; Slepkov, A. D.; Eisler, S.;
McDonald, R.; Hegmann, F. A. and Tykwinski, R. R., Org. Lett., 2005, 7, 51. (c) Liddle, S. T.
and Izod, K., Organometallics, 2004, 23, 5550. (d) Shun, A. L. K. S. and Tykwinski, R. R.,
J. Org. Chem., 2003, 68, 6810. (e) Shun, A. L. K. S.; Chernick, E. T.; Eisler, S. and Tykwinski, R.
R., J. Org. Chem., 2003, 68, 1339. (f) Simpkins, S. M. E.; Kariuki, B. M.; Aricó, C. S. and Cox, L.
R., Org. Lett., 2003, 5, 3971. (g) Normant, J. F., Acc. Chem. Res., 2001, 34, 640. (h) Deiters, A.
and Hoppe, D., J. Org. Chem., 2001, 66, 2842. (i) Heuft, M. A.; Collins, S. K.; Yap, G. P. A. and
Fallis, A. G., Org. Lett., 2001, 3, 2883. (j) Boche, G. and Lohrenz, J. C. W., Chem. Rev., 2001,
101, 697. (k) Chernick, E. T.; Eisler, S. and Tykwinski, R. R., Tetrahedron Lett., 2001, 42, 8575.
(l) Rezaei, H.; Yamanoi, S.; Chemla, F. and Normant, J. F., Org. Lett., 2000, 2, 419. (m) Creton,
I.; Rezaei, H.; Marek, I. and Normant, J. F., Tetrahedron Lett., 1999, 40, 1899. (n) Merz, A. and
Thumm, G., Justus Liebigs Ann. Chem., 1978, 1526. (o) Rebois, R.; Chauveau, J.; Deyris, M. and
Coudanne, H., Compt. Rend., 1976, 282, 947. (p) Fienemann, H. and Koebrich, G., Chem. Ber.,
1974, 107, 2797. (q) Koebrich, G.; Reitz, G. and Schumacher, U., Chem. Ber., 1972, 105, 1674.
(r) Kataoka, M.; Ando, T. and Nakagawa, M., Bull. Chem. Soc. Jpn., 1971, 44, 177. (s) Ando,
T. and Nakagawa, M., Bull. Chem. Soc. Jpn., 1971, 44, 172. (t) Koebrich, G. and Merkel, D.,
Angew. Chem. Int. Ed. Engl., 1970, 9, 243. (u) Koebrich, G. and Froehlich, H., Chem. Ber., 1965,
98, 3637. (v) Franzen, V., Chemiker-Zeit., 1958, 82, 220.
6. (a) Curtin, D. Y. and Flynn, E. W., J. Am. Chem. Soc., 1959, 81, 4714. (b) Curtin, D. Y.;
Flynn, E. W. and Nystrom, R. F., J. Am. Chem. Soc., 1958, 80, 4599. (c) Bothner-By, A. A.,
J. Am. Chem. Soc., 1955, 77, 3293.
1154 FRITSCH-BUTTENBERG-WIECHELL REARRANGEMENT
7. (a) Sket, B. and Zupan, M., J. Chem. Soc., Perkin Trans. I, 1979, 752. (b) Sket, B.; Zupan, M.
and Pollak, A., Tetrahedron Lett., 1976, 783.
8. (a) Eisler, S.; Chahal, N.; McDonald, R. and Tykwinski, R. R., Chem. Eur. J., 2003, 9, 2542.
(b) Yoshifuji, M., Phosphorus & Sulfur & Silicon Related Element, 2002, 177, 1827. (c) Tobe,
Y.; Iwasa, N.; Umeda, R. and Sonoda, M., Tetrahedron Lett., 2001, 42, 5485. (d) Eisler, S. and
Tykwinski, R. R., J. Am. Chem. Soc., 2000, 122, 10736. (e) Mouriès, V.; Waschbüsch, R.; Carran,
J. and Savignac, P., Synthesis, 1998, 271. (f) Kirmse, W., Angew. Chem. Int. Ed. Engl., 1997,
36, 1164. (g) Sato, H.; Isono, N.; Miyoshi, I. and Mori, M., Tetrahedron, 1996, 52, 8143. (h)
Kawase, T.; Darabi, H. R.; Uchimiya, R. and Oda, M., Chem. Lett., 1995, 499. (i) Satoh, T.;
Hayashi, Y. and Yamakawa, K., Bull. Chem. Soc. Jpn., 1993, 66, 1866. (j) Stang, P. J. and Fox,
D. P., J. Org. Chem. 1978, 43, 364. (k) Stang, P. J., Chem. Rev., 1978, 78, 383. (l) Köbrich,
G., Angew. Chem. Int. Ed. Engl., 1972, 11, 473. (m) Köbrich, G. and Buck, P., “Synthests of
Acetylenes and Poly-acetylenes by Elimination Reactions” in Chemistry of Acetylenes, ed. Viehe,
H. G., Marcel Dekker, New York, 1969, p.117. (n) Köbrich, G., Angew. Chem. Int. Ed. Engl.,
1965, 4, 49. (o) Simonetta, M. and Carra, S., Tetrahedron, 1963, 19, 467.
453
Neber Rearrangement
(Neber Reaction)
This reaction was first reported by Neber et al. in 1926.1 It is the transformation of
a ketoxime O-arylsulfonate into an α-amino ketone involving the deprotonation of an
α-methylene hydrogen by a base and the subsequent acidic hydrolysis of the resulting azirine
intermediate. Therefore, this reaction is generally known as the Neber rearrangement2 or
Neber reaction.2u,3 Different from the Beckmann Rearrangement,4 in which the configura-
tion of oxime controls the reaction direction, the Neber rearrangement does not hold such
stereospecificity.2u,2x In addition, the amino group is generally introduced to the α-position
with a higher acidic hydrogen in ketoxime O-arylsulfonate.2u,2x This rearrangement is gen-
erally carried out in ethanol by treatment of the ketoxime tosylate with sodium ethoxide,
followed by the acidic hydrolysis.2c For cyclic ketones, the amino group is generally intro-
duced at the equatorial positions at the α-carbon.5 For 2,4-dinitrophenylacetone, even a
weak base, like pyridine, is enough to trigger the rearrangement, as demonstrated in the
isolation of the resulting azirine-pyridine hydrochloride complex.6 It is interesting that the
aldoxime tosylate usually results in the formation of corresponding nitrile or isonitrile under
similar conditions.2x,7 It should be pointed out that the starting material is usually prepared
by the treatment of oxime with p-toluenesulfonyl chloride in pyridine.2u

2017
2018 NEBER REARRANGEMENT
O
O 1. NaOEt R1 = alkyl, aryl
R2
S N R1 R2 = H, alkyl, aryl
O O 2. H3O+
R2 NH2
R1
Although it has been proposed that this reaction is initiated by an alkoxide addition to
C=N double bond followed by the loss of tosyloxy group to form a nitrene intermediate,
which inserts to the α-carbon to form an alkoxy ethylenimine,2u more experimental evi-
dence indicates that the Neber rearrangement involves an initial base-induced elimination
of the more acidic α-proton accompanied by the loss of the tosyloxy group to give azirine
ring.2c,2x
D. MODIFICATION
This reaction has been modified by using a liquid-liquid phase transfer catalyst.2c
E. APPLICATIONS
This reaction has general application in the preparation of α-amino ketones.
This reaction is related to the Beckmann Rearrangement.

Reference 2b.
To a stirred solution of 23.3 mg tosyl oxime (0.0236 mmol) in 3.5 mL EtOH at 0◦ C was
added 450 µL 50% aqueous KOH dropwise over 1 min. The reaction mixture was stirred
at 0◦ C for 3 h; then 5 mL 6 N aqueous HCl was added. The reaction mixture was heated
to 60◦ C for 10 h, cooled to 23◦ C, and purified by loading to a reversed-phase Sep-Pak
column with water containing 0.1% TFA (w/v) and by washing with 15% acetonitrile in
water containing 0.1% TFA (w/v) to remove salts and then in 70% acetonitrile in water
containing 0.1% TFA (w/v) to collect the crude product. The solvents were removed under
reduced pressure to afford the hemiaminal intermediate, which was immediately mixed with
60 mg K2 CO3 (0.434 mmol) in 2 mL THF; 200 µL H2 O was added at 23◦ C. The reaction
mixture was stirred for 10 min and purified by a similar procedure for the hemiaminal
intermediate to afford the crude product. After the solvents were removed under reduced
pressure, the crude material was further purified by reversed-phased HPLC. Concentration
under reduced pressure provided 15.0 mg amino ketone as an orange/red oil, in a yield of
96%.
2020 NEBER REARRANGEMENT
Ph
Ph TsCl, chiral ammonium salt, MeOH
N KOH, toluene
OH
NHBz
PhCOCl/pyridine Ph 80% yield
Ph 51% e.e.
CH2Cl2
O
C6H4-4-CF3
Br
Chiral ammonium salt = N
C6H4-4-CF3
Reference 2c.
cis-Benzyl phenyl ketoxime (63 mg, 0.3 mmol), 69 mg p-toluenesulfonyl chloride

(0.36 mmol), 14 mg chiral quaternary ammonium salt (0.015 mmol, 5 mol %), and 123 µL
MeOH (3 mmol, 10 eq.) were dissolved in 3 mL toluene. Then 1 mL 50% aqueous KOH
was added to the mixture dropwise at 0◦ C. This mixture was stirred vigorously at 0◦ C for
48 hours. The resulting mixture was diluted with cooled water, and the organic layer was
separated. The aqueous layer was extracted with ether. The combined organic layers were
dried over MgSO4 . Upon removal of solvent, the residue was dissolved in 3 mL CH2 Cl2 .
Pyridine (485 µL, 6 mmol) and 174 µL benzoyl chloride (1.5 mmol) were added sequen-
tially, and the mixture was stirred at room temperature. After several hours, ∼6 mL 6 N
HCl was added, and the biphasic mixture was stirred vigorously for 3 h. The mixture was
extracted with ether and dried over Na2 SO4 . After removal of the solvent, the residue was
purified by silica gel column chromatography (ether/CH2 Cl2 /hexane, 1:30:20) to afford
76 mg α-benzamidylbenzyl phenyl ketone, in a yield of 80% and 51% e.e.
Other references related to the Neber rearrangement are cited in the literature.8
H. REFERENCES
1. Neber, P. W. and Friedolsheim, A., Ann., 1926, 449, 109.

2. (a) Garg, N. K.; Caspi, D. D. and Stoltz, B. M., J. Am. Chem. Soc., 2005, 127, 5970. (b) Garg,
N. K.; Caspi, D. D. and Stoltz, B. M., J. Am. Chem. Soc., 2004, 126, 9552. (c) Ooi, T.; Takahashi,
M.; Doda, K. and Maruoka, K., J. Am. Chem. Soc., 2002, 124, 7640. (d) Forns, P.; Rubiralta,
M. and Dı́ez, A., Contributions to Science, 2001, 2, 63. (e) Mphahlele, M. J.; Gheevarghese,
O. and Makhubela, N. F. H., Phosphorus, Sulfur & Silicon & Related Elements, 2000, 166,
303. (f) Oldfield, M. F. and Botting, N. P., J. Labelled Compd. & Radiopharm., 1998, 41, 29.
(g) Mphahlele, M. J. and Modro, T. A., Phosphorus, Sulfur & Silicon & Related Elements, 1997,
127, 131. (h) Moldvai, I.; Szantay, C. and Szantay, C., Heterocycles, 1996, 43, 2377. (i) Hyatt, J.
A., J. Org. Chem., 1981, 46, 3953. (j) Parcell, R. F. and Sanchez, J. P., J. Org. Chem., 1981, 46,
5229. (k) LaMattina, J. L. and Suleske, R. T., Synthesis, 1980, 329. (l) Friis, P.; Larsen, P. O. and
Olsen, C. E., J. Chem. Soc., Perkin Trans. I, 1977, 661. (m) Lap, B. V. and Williams, L. R., Aust.
J. Chem., 1977, 30, 2205. (n) Grouiller, A.; Pacheco, H. and Carret, G., J. Heterocycl. Chem.,
REFERENCES 2021
1976, 13, 853. (o) Tamura, Y.; Fujiwara, H.; Sumoto, K.; Ikeda, M. and Kita, Y., Synthesis, 1973,
215. (p) Parvu, D., Revista Fizica Chim., Ser. A, 1969, 6, 287. (q) Renfrow, W. B.; Witte, J. F.;
Wolf, R. A. and Bohl, W. R., J. Org. Chem., 1968, 33, 150. (r) Henery-Logan, K. R. and Fridinger,
T. L., J. Am. Chem. Soc., 1967, 89, 5724. (s) Dudykina, N. V. and Zagorevskii, V. A., Zh. Org.
Khim., 1966, 2, 2222. (t) Morrow, D. F. and Butler, M. E., J. Heterocycl. Chem., 1964, 1, 53.
(u) O’Brien, C., Chem. Rev., 1964, 64, 81. (v) Parcell, R. F., Chem. Ind. (London), 1963, 1396.
(w) House, H. O. and Berkowitz, W. F., J. Org. Chem., 1963, 28, 307. (x) Hatch, M. J. and Cram,
D. J., J. Am. Chem. Soc., 1953, 75, 38.
3. (a) Verstappen, M. M. H.; Ariaans, G. J. A. and Zwanenburg, B., J. Am. Chem. Soc., 1996, 118,
8491. (b) Corkins, H. G.; Storace, L. and Osgood, E., J. Org. Chem., 1980, 45, 3156. (c) Kakehi,
A.; Ito, S.; Manabe, T.; Maeda, T. and Imai, K., J. Org. Chem., 1977, 42, 2514. (d) Garst, M. E.;
Cox, D. D.; Harper, R. W. and Kemp, D. S., J. Org. Chem., 1975, 40, 1169.
4. See Beckmann Rearrangement and Beckmann Fragmentation herein (P. 288).
5. Drefahl, G. and Martin, D., Ber., 1960, 93, 2497.
6. Neber, P. W. and Burgard, A., Ann., 1932, 493, 281.
7. Mueller, E. and Narr, B., Z. Naturforsch., 1961, 16B, 845.
8. (a) Chung, J. Y. L.; Ho, G.-J.; Chartrain, M.; Roberge, C.; Zhao, D.; Leazer, J.; Farr, R.; Robbins,
M.; Emerson, K.; Mathre, D. J.; McNamara, J. M.; Hughes, D. L.; Grabowski, E. J. J. and
Reider, P. J., Tetrahedron Lett., 1999, 40, 6739. (b) Diez, A.; Voldoire, A.; Lopez, I.; Rubiralta,
M.; Segarra, V.; Pages, L. I. and Palacios, J. M., Tetrahedron, 1995, 51, 5143. (c) Padwa, A.
and Woolhouse, A. D., Aziridines and Fused Ring Derivatives in Comprehensive Heterocyclic
Chemistry, ed., Lowowski, W., Pergamon Press, New York, 1984, 7, chapter 5.04. (d) Nair, V.,
Small Ring Heterocycles in The Chemistry of Heterocyclic Compounds, ed., Hassner, A., John
Wiley & Sons, New York, 1983, 42.1, chapter 2. (e) Morrow, D. F.; Butler, M. E. and Huang, E.
C. Y., J. Org. Chem., 1965, 30, 579. (f) House, H. O. and Berkowitz, W. F., J. Org. Chem., 1963,
28, 2271. (g) Heldt, W. Z., J. Am. Chem. Soc., 1958, 80, 5880. (h) Cram, D. J. and Hatch, M. J.,
J. Am. Chem. Soc., 1953, 75, 33. (i) Neber, P. W.; Burgard, A. and Their, W., Ann., 1936, 526,
277. (j) Neber, P. W. and Huh, G., Ann., 1935, 515, 283.
323
Hofmann Degradation
(Hofmann rearrangement)
This reaction was first reported by Hofmann in 1881.1 It is the conversion of carboxylic
amides into primary amines with one less carbon atom via the isocyanate intermediate by
means of basic hypohalite treatment. Hence it is known as the Hofmann rearrangement,2
Hofmann degradation,2,3 or Hofmann reaction.2,3y,3z In this reaction, heat is needed; and
in some cases, cyanate is also formed.4 On the other hand, the Hofmann rearrangement of
carboxylic amides with α-halogen yields a certain amount of ketones as well.5 This reaction
is often used as a method for cuting a single carbon atom out of a chain. In addition, the
configuration of the hydrocarbon chain is retained during the migration.6 However, the
corresponding amide of pyrazine-2,5-dicarboxylic acid was found to be stable toward both
hypochlorous and hypobromous acids.3z
O
NaOH
+ Br2 R NH2
R NH2 H2O
It is known that this reaction proceeds in the following steps: base abstraction of an acidic
N-H proton to yield an anion, which reacts with bromine to form N-bromoamide; further
base abstraction of the remaining N-H proton to give a bromoamide anion, which rearranges
to isocyanate through the migration of an R group attaching to the carbonyl carbon and

1447
1448 HOFMANN DEGRADATION
cleavage of a bromide ion; nucleophilic addition of water to isocyanate affording a carbamic

acid, which loses carbon dioxide spontaneously to yield the primary amine.
D. MODIFICATION
This reaction has been modified by the substitution of a hypohalite with (diacet-
oxyiodo)benzene.7
E. APPLICATIONS
This reaction has general application for the conversion of carboxylic amides into amines.
This reaction is related to Curtius Rearrangement, Lossen Rearrangement, Schmidt

Reaction, Weerman Degradation, and Wolff Rearrangement.
OAc
H O
CONH2 I KOH N
+ OAc
MeOH
O O O O OMe
82%
Reference 7.
To 100 mL methanol solution containing 7.75 g (±)-trans-2-tetrahydro-2H-2-

pyranyloxy-1-cyclopropane carboxamide (41.84 mmol) and 6.03 g KOH (107.47 mmol)
was added 13.42 g (diacetoxyiodo)benzene (41.66 mmol) at 5◦ C under stirring, and the
stirring was continued at room temperature for an additional 2 h. The solvents were
removed under reduced pressure, the residue was mixed with 70 mL water and 30 mL
REFERENCES 1449
dichloromethane, and the aqueous layer was extracted with dichloromethane (4 × 30 mL).
The combined organic layers were washed with water and brine (50 mL each), dried, and
evaporated. After column chromatography (hexane → EtOAc/hexane, 1:2), 7.37 g (±)-
methyl N-[trans-2-tetrahydro-2H-2-pyranyloxycyclopropyl]carbamate was obtained as a
colorless oil, in a yield of 82%, Rf = 0.5 (EtOAc/hexane, 1:1).
Bz Bz
N
N
KOH H
+ NaOCl MeO N
O MeOH
OH O O
NH2
53%
Reference 2.
The crystalline mixture of 2.30 g hydroxyamide and its epimer (8.05 mmol) in 65 mL
methanol was treated with 0.85 g potassium hydroxide (15.2 mmol) in 15.7 mL 5.25%
aqueous NaOCl solution (11.0 mmol). The resulting solution turned yellow and warmed
spontaneously to ∼ 50◦ C. After 1 h it was poured into 300 mL brine, and the resulting
mixture was extracted five times with chloroform. The dried extracts were evaporated to
an oil, which crystallized from ether in colorless needles, 1.51 g tricyclic urethane was
obtained, in a yield of 53%, m.p., 147.5–149◦ C.
Other references related to the Hofmann degradation are cited in the literature.8
H. REFERENCES
1. Hofmann, A. W., Ber., 1881, 14, 2725.

2. (a) Moriarty, R. M., J. Org. Chem., 2005, 70, 2893. (b) Büchi, G.; Coffen, D. L.; Kocsis, K.;
Sonnet, P. E. and Ziegler, F. E., J. Am. Chem. Soc., 1966, 88, 3099.
3. (a) Shan, Y. H.; Wei, K. N.; Li, W. M.; Wu, G. Y. and Mao, Y. X., Huaxue Gongye Yu Gongcheng
Jishu, 2005, 26, 25. (b) Begam, T.; Tomar, R. S.; Nagpal, A. K. and Singhal, R., J. Appl. Poly. Sci.,
2004, 94, 40. (c) Hu, Z.-Y.; Zhang, S.-F.; Yang, J.-Z.; Tang, B.-T. and Tang, Y.-F., Dalian Ligong
Daxue Xuebao, 2002, 42, 659. (d) Moulay, S., Chem. Edu.: Res. Pract. Eur., 2002, 3, 33. (e) Lou,
H. X.; Hou, B. L.; Li, X.; Zhu, T. R.; Wang, L. and Hong, B. K., Zhongguo Yaoxue Zazhi (Beijing),
1995, 30, 291. (f) Bicak, N.; Sarac, A. S.; Koza, G.; Atay, T. and Senkal, F., Reactive Polymers,
1993, 21, 135. (g) Wrobel, J. T.; Scholl-Aleksandrowicz, A.; Cybulski, J. and Wojtasiewicz, K.,
Coll. Czech. Chem. Commun., 1989, 54, 2229. (h) Sonnenschein, H. and Schmitz, E., Synthesis,
1989, 443. (i) Leis, H. J., Rapid Commun. Mass Spectr., 1989, 3, 342. (j) Leis, H. J. and Gleispach,
H., J. Chromatography, 1989, 494, 324. (k) Turchin, K. F.; Levkovskaya, L. G.; Solov’eva, N. P.;
Safonova, T. S. and Sheinker, Yu. N., Dokl. Akad. Nauk SSSR, 1987, 293, 379. (l) Guo, J.; Lu, D.
and Ye, X. L., Gaodeng Xuexiao Huaxue Xuebao, 1985, 6, 1000. (m) Cybulski, J.; Wojtasiewicz,
K. and Wrobel, J. T., Heterocycles, 1984, 22, 2541. (n) Kajigaeshi, S.; Nakagawa, T.; Fujisaki,
S.; Nishida, A. and Noguchi, M., Chem. Lett., 1984, 713. (o) Cybulski, J. and Wojtasiewicz, K.,
J. Mol. Struct., 1984, 116, 1. (p) Cybulski, J.; Wojtasiewicz, K. and Wrobel, J. T., Heterocycles,
1983, 20, 1773. (q) Wert, K. L.; Chackalamannil, S.; Miller, E.; Dalton, D. R.; Zacharias, D. E. and
Glusker, J. P., J. Org. Chem., 1982, 47, 5141. (r) Kanmera, T.; Waki, M.; Kato, T. and Izumiya,
N., Peptide Chem., 1980, 18, 199. (s) Kanmera, T.; Aoyagi, H.; Waki, M.; Kato, T.; Izumiya, N.;
Noda, K. and Ueno, T., Tetrahedron Lett., 1981, 22, 3625. (t) Nomoto, S.; Sano, A. and Shiba, T.,
1450 HOFMANN DEGRADATION
Tetrahedron Lett., 1979, 521. (u) Nomoto, S.; Sano, A. and Shiba, T., Peptide Chem., 1978, 16,
35. (v) Tanaka, H., J. Poly. Sci., Poly. Lett. Ed., 1978, 16, 87. (w) Takano, S.; Kuzukawa, M. and
Yamanaka, M., J. Am. Oil Chem. Soc., 1977, 54, 484. (x) Baliah, V. and Jeyaraman, R., Indian
J. Chem., Sect. B, 1977, 15B, 796. (y) Stevens, C. L.; Mukherjee, T. K. and Traynelis, V. J., J.
Am. Chem. Soc., 1956, 78, 2264. (z) Spoerri, P. E. and Erickson, A., J. Am. Chem. Soc., 1938,
60, 400.
4. (a) Arcus, C. L. and Prydal, B. S., J. Chem. Soc., 1954, 4018. (b) Arcus, C. L. and Greenwood,
D. B., J. Chem. Soc., 1953, 1937.
5. Stevens, C. L. and Coffield, T. H., J. Am. Chem. Soc., 1951, 73, 103.
6. Wallis, E. S. and Moyer, W. W., J. Am. Chem. Soc., 1933, 55, 2598.
7. Csuk, R. and Kern, A., Z. Naturforsch., 2002, 57B, 1169.
8. (a) Matsumura, Y.; Satoh, Y.; Shirai, K.; Onomura, O. and Maki, T., J. Chem. Soc., Perkin Trans.
I, 1999, 2057. (b) Rane, D. S. and Sharma, M. M., J. Chem. Tech. Biotechnol., 1994, 59, 271.
(c) Jew, S. S.; Park, H. G.; Kang, M. H.; Lee, T. H. and Cho, Y. S., Arch. Pharm. Res., 1992, 15,
333. (d) Kajigaeshi, S.; Asano, K.; Fujisaki, S.; Kakinami, T. and Okamoto, T., Chem. Lett., 1989,
463. (e) Hori, I.; Igarashi, M. and Midorikawa, H., J. Org. Chem., 1961, 26, 4511. (f) Applequist,
D. E. and Roberts, J. D., Chem. Rev., 1954, 54, 1083. (g) Wallis, E. S. and Lane, J. F., Org. React.,
1949, 3, 267. (h) Franklin, E. C., Chem. Rev., 1934, 14, 219. (i) Hofmann, A. W., Ber., 1885,
18, 2734. (j) Hofmann, A. W., Ber., 1884, 17, 1406. (k) Hofmann, A. W., Ber., 1882, 15, 407.
(l) Hofmann, A. W., Ber., 1882, 15, 752. (m) Hofmann, A. W., Ber., 1882, 15, 762.
172
Curtius Rearrangement
This reaction was first reported by Curtius in 1890.1 It is the formation of isocyanate by
thermal decomposition of acyl azides prepared from acyl halide and sodium azide and is
generally known as the Curtius rearrangement.2 Although this reaction is thought to proceed
via a concerted mechanism3 and form carbonyl nitrene intermediate,3a,3b,3g,4 from which
the R group migrates to the nitrogen atom to give isocyanate, some evidence supporting
the stepwise mechanism has also been reported.3a Nevertheless, the Curtius rearrangement
occurs with complete retention of configuration at the migrating carbon,5 and the migration
from the carbon to the nitrogen atom is an irreversible intramolecular reaction in first-
order kinetics.6 Because it is an intramolecular rearrangement, a solvent or salt effect is not
evident.6 The intermediate isocyanate can be isolated or subjected to subsequent reaction
directly—for example, isocyanate reacts with water to form an unstable carbamic acid,
which undergoes spontaneous decarboxylation to produce amine with one fewer carbon
unit. This special reaction is referred to as the Curtius reaction.7 In addition, the Curtius
rearrangement is also known as the Curtius-type reaction,7b Curtius degradation,8 Hofmann-
Beckmann-Curtius-Lossen rearrangement,9 and Curtius-type rearrangement.10 On the one
hand, the Curtius rearrangement has been used with great success for the preparation of non-
commercially available isocyantes from a diverse assortment of carboxylic acids, including
aliphatic,11 aromatic,12 heterocyclic,13 unsaturated,14 and chiral acids.15 In addition, this
rearrangement is good for the preparation of tetrazoles,16 cyanamides,16 oxazolidones,17
amino alcohol,18 furano carbamate,7a etc. On the other hand, the pyrolysis of acyl azides
can also be carried out photolytically,3b,3g,4,19 via a concerted mechanism.3b When acyl

780
RELATED REACTIONS 781
azide contains a halogen or hydroxyl group at the α-position, an aldehyde or ketone forms.7c
It should be pointed out that benzenesulfonyl azide also undergoes a similar rearrangement
and gives a sulfurylaniline intermediate.10d Recently, the Curtius rearrangement was car-
ried out under microwave irradiation20 and was modified using phase-transfer catalysis;21
however, the most important modification of the Curtius rearrangement is to use the Shiori
reagent18 —that is, diphenylphosphoryl azide (DPPA).22
A simple mechanism involving a nitrene intermediate is displayed here.
D. MODIFICATION
This rearrangement has been modified to use the Shiori reagent as the azide source;22 in
addition, this reaction has been extended to proceed under photo 3b,3g,4,19 or microwave20
irradiation.
E. APPLICATIONS
The major applications of this rearrangement are the preparation of a variety of iso-
cyanates and amines. In addition, this reaction is also valuable for the preparation of
tetrazoles,16 cyanamides,16 oxazolidones,17 amino alcohol,18 and furano carbamate.7a
This reaction is related to the Hofmann Degradation, Lossen Rearrangement, and

Schmidt Reaction.
782 CURTIUS REARRANGEMENT
CN CN
O
1) DPPA, Et3N, DMF
OH
N 2) MeOH, ∆ N N OMe
H
Bn O Bn
Reference 22b.
To a solution of 7.04 g 1-benzyl-3-cyanopyrrole-2-carboxylic acid (31.12 mmol) in

75 mL N,N-dimethylformamide at 0◦ C was added 7.65 mL diphenylphosphoryl azide
(DPPA, 9.72 g, 35.30 mmol, 1.1 eq.) and 4.75 mL triethylamine (3.42 g, 33.80 mmol,
1.1 eq.). The solution was allowed to stir at room temperature for 6 h. Methanol (7 mL)
was added, and the reaction mixture was heated at 65◦ C for 8 h. The solvents were
evaporated in vacuo, and the resulting residue was dissolved in 140 mL EtOAc. The
solution was then extracted with 1 N aqueous HCl solution (3 × 80 mL), washed with
saturated aqueous NaHCO3 solution (3 × 80 mL), dried over anhydrous MgSO4 , and
concentrated to dryness. The residue was recrystallized from ethanol to give 4.695 g
1-benzyl-2-methoxycarbonylamino-3-cyanopyrrole, in a yield of 59%, m.p. 140–142◦ C.
Reference 23.
1,2,3,4,5-Pentaphenylferrocene-1 -carboxylic acid (2.00 g, 3.3 mmol) was suspended in

20 mL CH2 Cl2 . Oxalyl chloride (0.84 g, 0.58mL, 6.6 mmol) was added followed by a drop
of DMF. The mixture was stirred at room temperature for 3 h, after which the solvent and
residual oxalyl chloride were removed in vacuo. The red solid thus obtained was taken up in
20 mL CH2 Cl2 . Tetrabutylammonium bromide (0.004 g, 0.01 mmol) was added, followed
by a solution of 0.32 g NaN3 (4.9 mmol) in 4 mL H2 O, and the mixture was stirred rapidly
at room temperature for 18 h. An additional 50 mL water was added to the mixture, and the
organic layer was separated. The aqueous layer was extracted with CH2 Cl2 (2 × 20 mL),
the combined organic layers were dried over MgSO4 and filtered, and the solvent was
removed in vacuo. Column chromatography (1:1 CH2 Cl2 /petroleum ether) gave 1.69 g
1,2,3,4,5-pentaphenyl-1 -acylazidoferrocene as a red solid, in a yield of 81%, m.p. 250◦ C
(dec).
1,2,3,4,5-Pentaphenyl-1 -acylazideferrocene (1.48 g, 2.3 mmol) was dissolved in 15 mL
toluene; the solution was heated to 105◦ C, and 0.67 mL of 2-(trimethylsilyl)ethanol
(4.7 mmol) was added in a single portion. The red solution obtained was stirred at this
temperature for 3 h, by which time the color had changed to dark orange. The mixture was
cooled to room temperature, 50 mL 1 M NaOH was added, and the solution was stirred for
REFERENCES 783
5 min. The organic layer was separated, and the aqueous layer was extracted with CH2 Cl2
(2 × 20 mL). The combined organic layers were dried over MgSO4 and filtered, and the sol-
vent was removed in vacuo to give an orange solid. Chromatography (1:1 CH2 Cl2 /petroleum
ether) gave 1.61 g 1,2,3,4,5-pentaphenylferrocene-1 -(2-trimethylsilyl)-ethyl carbamate as
an orange solid, in a yield of 95%, m.p.132–134◦ C.
Other references related to the Curtius rearrangement are cited in the literature.24
H. REFERENCES
1. Curtius, T., Ber., 1890, 23, 3023.

2. (a) Zabalov, M. V. and Tiger, R. P., Russ. Chem. Bull., 2007, 56, 7. (b) Davis, M. C., Synth.
Commun., 2007, 37, 1457. (c) Sawada, D.; Sasayama, S.; Takahashi, H. and Ikegami, S., Eur. J.
Org. Chem., 2007, 1064. (d) Tada, T.; Ishida, Y. and Saigo, K., Synlett, 2007, 235. (e) Yamat-
sugu, K.; Kamijo, S.; Suto, Y.; Kanai, M. and Shibasaki, M., Tetrahedron Lett., 2007, 48, 1403.
(f) Lebel, H. and Leogane, O., Org. Lett., 2006, 8, 5717. (g) Sawada, D.; Sasayama, S.; Takahashi,
H. and Ikegami, S., Tetrahedron Lett., 2006, 47, 7219. (h) Jung, D. Y.; Kang, S.; Chang, S. and
Kim, Y. H., Synlett, 2006, 86. (i) Zabalov, M. V. and Tiger, R. P., Russ. Chem. Bull., 2005, 54,
2270. (j) Lebel, H. and Leogane, O., Org. Lett., 2005, 7, 4107. (k) Babu, V. V. S.; Kantharaju;
T. and Subramanyam, J., Int. J. Peptide Res. Therap., 2005, 11, 131. (l) Gomez-Sanchez, E. and
Marco-Contelles, J., Tetrahedron, 2005, 61, 1207. (m) Dussault, P. H. and Xu, C. P., Tetrahedron
Lett., 2004, 45, 7455. (n) Moore, J. D.; Sprott, K. T. and Hanson, P. R., J. Org. Chem., 2002,
67, 8123. (o) Braibante, M. E. F.; Braibante, H. S. and Costenaro, E. R., Synthesis, 1999, 943.
(p) Sunami, S.; Sagara, T.; Ohkubo, M. and Morishima, H., Tetrahedron Lett., 1999, 40, 1721.
(q) Am Ende, D. J.; DeVries, K. M.; Clifford, P. J. and Brenek, S. J., Org. Proc. Res. Dev.,
1998, 2, 382. (r) Khoukhi, M.; Vaultier, M.; Benalil, A. and Carboni, B., Synthesis, 1996, 483.
(s) Batori, S.; Messmer, A. and Timpe, H. J., Heterocycles, 1991, 32, 649. (t) Okada, Y.; Tsuda,
Y. and Yagyu, M., Chem. Pharm. Bull., 1980, 28, 2254. (u) Saikachi, H. and Kitagawa, T., Chem.
Pharm. Bull., 1978, 26, 1054. (v) Brandstrom, A.; Lamm, B. and Palmertz, I., Acta Chem. Scand.,
Ser. B, 1974, 28, 699. (w) Washburne, S. S. and Peterson, W. R., J. Am. Oil Chem. Soc., 1972,
49, 694. (x) Wilds, A. L.; Woolsey, N. F.; Berghe, J. V. D. and Winestock, C. H., Tetrahedron
Lett., 1965, 4841. (y) Stolle, R. and Merkle, N., J. Prakt. Chem., 1928, 119, 275.
3. (a) Liu, J.; Mandel, S.; Hadad, C. M. and Platz, M. S., J. Org. Chem., 2004, 69, 8583. (b) Lwowski,
W.; de Mauriac, R. A.;Thompson, M.; Wilde, R. E. and Chen, S.-Y., J. Org. Chem., 1975, 40, 2608.
(c) Eibler, E. and Sauer, J., Tetrahedron Lett., 1974, 2569. (d) Hayashi, Y. and Swern, D., J. Am.
Chem. Soc., 1973, 95, 5205. (e) Lwowski, W., “Carbonylnitrenes” in “Nitrenes”, ed. Lwowski, W.,
Wiley-Interscience, New York, 1970, pp. 185–224. (f) Boyer, J. H., “Rearrangements Involving
Nitrene Intermediates” in “Mechanisms of Molecular Migration”, ed. Thyagarajan, B. S., Wiley-
Interscience, New York, 1969, 2, pp. 267–318. (g) Linke, S.; Tisue, G. T. and Lwowski, W.,
J. Am. Chem. Soc., 1967, 89, 6308.
4. Denmark, S. E. and Dorow, R. L., J. Org. Chem., 1989, 54, 5.
5. (a) Hibbs, D. E.; Hursthouse, M. B.; Jones, I. G.; Jones, W.; Malik, K. M. A. and North, M.,
J. Org. Chem., 1998, 63, 1496. (b) Ghosh, A. K. and Fidanze, S., J. Org. Chem., 1998, 63, 6146.
(c) Ghosh, A. K. and Liu, W. M., J. Org. Chem., 1996, 61, 6175. (d) Grunewald, G. L. and Ye, Q.,
J. Org. Chem., 1988, 53, 4021. (e) Glass, R. S.; McConnell, W. W. and Andruski, S. P., J. Org.
Chem., 1986, 51, 5123. (f) Smith, P. A. S., Derivatives of Hydrazine and other Hydronitrogens
Having N-N Bonds, Benjamin, Reading, 1983, pp. 272–273. (g) Shioiri, T.; Ninomiya, K. and
Yamada, S., J. Am. Chem. Soc., 1972, 94, 6203. (h) Banthorpe, D. V., “Rearrangements Involving
784 CURTIUS REARRANGEMENT
Azido Groups” in The Chemistry of Azide Group, ed. Patai, S., Interscience, New York, 1971, pp.
397–440. (i) Forster, M. O., J. Chem. Soc., 1909, 95, 433.
6. Newman, M. S.; Lee, S. H. and Garrett, A. B., J. Am. Chem. Soc., 1947, 69, 113.
7. (a) Kedrowski, B. L., J. Org. Chem., 2003, 68, 5403. (b) de Kimpe, N.; Boeykens, M. and Tehrani,
K. A., J. Org. Chem., 1994, 59, 8215. (c) Zook, H. D.; Ream, M. and Delchamps, E. W., J. Am.
Chem. Soc., 1953, 75, 5590.
8. Mason, C. D. and Nord, F. F., J. Org. Chem., 1951, 16, 1869.
9. Franklin, E. C., Chem. Rev., 1934, 12, 219.
10. (a) Kumar, N. S.; Kumar, K. P.; Kumar, K. V. P. P.; Kommana, P.; Vittal, J. J. and Swamy, K. C.
K., J. Org. Chem., 2004, 69, 1880. (b) Baceiredo, A.; Bertrand, G.; Majoral, J.-P.; Anba, F. E.
and Manuel, G., J. Am. Chem. Soc., 1985, 107, 3945. (c) Baceiredo, A.; Bertrand, G.; Majoral,
J.-P.; Wermuth, U. and Schmutzler, R., J. Am. Chem. Soc., 1984, 106, 7065. (d) Abramovitch, R.
A. and Holcomb, W. D., J. Chem. Soc. D, 1969, 1298. e) Lwowski, A. and Scheiffele, E., J. Am.
Chem. Soc., 1965, 87, 4359.
11. Guan, H.-P.; Ksebati, M. B.; Cheng, Y.-C.; Drach, J. C.; Kern, E. R. and Zemlicka, J., J. Org.
Chem., 2000, 65, 1280.
12. Hitotsuyanagi, Y.; Kobayashi, M.; Morita, H.; Itokawa, H. and Takeya, K., Tetrahedron Lett.,
1999, 40, 9107.
13. Arranz, M. E.; Diaz, J. A.; Ingate, S. T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq,
E. and Vega, S., Bioorg. Med. Chem., 1999, 7, 2811.
14. Pais, G. C. G. and Maier, M. E., J. Org. Chem., 1999, 64, 4551.
15. Wiberg, K. B. and Oesterle, C., J. Org. Chem., 1999, 64, 7763.
16. Imhof, R.; Ladner, D. W. and Muchowski, J. M., J. Org. Chem., 1977, 42, 3709.
17. Vaughan, W. R. and Spencer, J. L., J. Org. Chem., 1960, 25, 1077.
18. Sasmal, S.; Geyer, A. and Maier, M. E., J. Org. Chem., 2002, 67, 6260.
19. Chehade, K. A. H. and Spielmann, H. P., J. Org. Chem., 2000, 65, 4949.
20. Patil, B. S.; Vasanthakumar, G.-R. and Babu, V. V. S., J. Org. Chem., 2003, 68, 7274.
21. Groszek, G., Org. Proc. Res. Dev., 2002, 6, 759.
22. (a) Spino, C.; Tremblay, M.-C. and Gobdout, C., Org. Lett., 2004, 6, 2801. (b) Chien, T.-C.; Meade,
E. A.; Hinkley, J. M. and Townsend, L. B., Org. Lett., 2004, 6, 2857. (c) Spino, C. and Gobdout,
C., J. Am. Chem. Soc., 2003, 125, 12106. (d) Ecija, M.; Diez, A.; Rubiralta, M.; Casamitjana,
N.; Kogan, M. J. and Giralt, E., J. Org. Chem., 2003, 68, 9541. (e) Armstrong, A. and Scutt, J.
N., Org. Lett., 2003, 5, 2331. (f) Ghosh, A. K.; Bischoff, A. and Cappiello, J., Org. Lett., 2001,
3, 2677. (g) Back, T. G. and Nakajima, K., J. Org. Chem., 1998, 63, 6566. (h) Jacobi, P. A.;
Murphree, S.; Rupprecht, F. and Zheng, W. J., J. Org. Chem., 1996, 61, 2413.
23. Butler, D. C. D. and Richards, C. J., Organometallics, 2002, 21, 5433.
24. (a) Miller, J. A. and Nguyen, S. T., Mini-Rev. Org. Chem., 2005, 2, 39. (b) Englund, E. A.; Gopi,
H. N. and Appella, D. H., Org. Lett., 2004, 6, 213. (c) Marinescu, L.; Thinggaard, J.; Thomsen,
I. B. and Bols, M., J. Org. Chem., 2003, 68, 9453. (d) Nettekoven, M. and Jenny, C., Org. Proc.
Res. Dev., 2003, 7, 38. (e) Smith, A. B.; Safonov, I. G. and Corbett, R. M., J. Am. Chem. Soc.,
2002, 124, 11102. (f) Okaniwa, M.; Takeuchi, K.; Asai, M. and Ueda, M., Macromolecules, 2002,
35, 6224. (g) Okaniwa, M.; Takeuchi, K.; Asai, M. and Ueda, M., Macromolecules, 2002, 35,
6232. (h) Govindan, C. K., Org. Proc. Res. Dev., 2002, 6, 74. (i) Sibi, M. P. and Deshpande, P. K.,
J. Chem. Soc., Perkin Trans. 1, 2000, 1461. (j) Migawa, M. T. and Swayze, E. E., Org. Lett., 2000,
2, 3309. (k) Padwa, A. and Wu, T. H., ARKIVOC, 2000, (i), 193. (l) Zhang, C. Y. and Tour, J. M.,
J. Am. Chem. Soc., 1999, 121, 8783. (m) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K. and Wu,
T. H., J. Org. Chem., 1999, 64, 3595. (n) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J.
S.; Ripin, D. H. B. and Tedrow, J. S., J. Org. Chem., 1999, 64, 6411. (o) Yao, Y. X.; Lamba, J. J.
REFERENCES 785
S. and Tour, J. M., J. Am. Chem. Soc., 1998, 120, 2805. (p) Broggini, G.; Garanti, L.; Molteni,
G. and Zecchi, G., J. Chem. Res (S)., 1998, 688. (q) Zhang, C.; Lomenzo, S. A.; Ballay, C. J.;
Trudell, M. L., J. Org. Chem., 1997, 62, 7888. (r) Sibi, M. P.; Lu, J. L. and Edwards, J., J. Org.
Chem., 1997, 62, 5864. (s) Olsen, R. K.; Hennen, W. J. and Wardle, R. B., J. Org. Chem., 1982,
47, 4605. (t) Brower, K. R., J. Am. Chem. Soc., 1961, 83, 4370. (u) Yukawa, Y. and Tsuno, Y., J.
Am. Chem. Soc., 1959, 81, 2007. (v) Yukawa, Y. and Tsuno, Y., J. Am. Chem. Soc., 1958, 80,
6346. (w) Yukawa, Y. and Tsuno, Y., J. Am. Chem. Soc., 1957, 79, 5530. (x) Bothnerby, A. A.
and Friendman, L., J. Am. Chem. Soc., 1951, 73, 5391. (y) Hauser, C. R. and Kantor, S. W.,
J. Am. Chem. Soc., 1950, 72, 4284. (z) Saunders, J. H. and Slocombe, R. J., Chem. Rev.,
1948, 43, 205. (aa) Newman, M. S. and Gildenhorn, H. L., J. Am. Chem. Soc., 1948, 70, 317.
(bb) Smith, P. A. S., Org. React., 1946, 3, 337.
64
Beckmann Rearrangement
and Beckmann
Fragmentation
This reaction was first reported by Beckmann in 1886.1 It is the rearrangement of an

oxime to its corresponding amide in the presence of an acid and is generally known as
the Beckmann rearrangement.2 Oximes of cyclic ketones give lactams as the final products,
resulting in the ring enlargements. An important example is the conversion of cyclohexanone
oxime into ε-caprolactam, which is a basic component for the fabrication of nylon 6.3 The
oxime is formed by the reaction of a ketone with hydroxyamine. The Beckmann rearrange-
ment of oxime derivatives proceeds stereospecifically, and the stereo-configuration of the
migrating group is retained. The migrating substituent is the electrofuge that can better sta-
bilize a partially positive charge.4 This rearrangement has been applied to the construction
of a variety of nitrogen-containing compounds, including amines (via imines),5 amidines,6
thioimidates,7 imidoyl halides,8 iminophosphonates,9 and enaminones.10 However, certain
oximes, particularly those having a quarternary carbon anti to the hydroxyl, are likely to
undergo the rearrangement to form nitriles instead of amides. This type of transformation
is called the Beckmann fragmentation,11,12 which was first reported by Werner and Piguet
in 1904.13 Because this kind of transformation is so different from the regular Beckmann
rearrangement, it is sometimes called abnormal Beckmann rearrangement,2y,4,11a,11f,14
secondary Beckmann rearrangement,15 Beckmann fission,16 etc. Besides those oximes
having a quarternary carbon anti to the hydroxyl group, other oximes such as the bridged
bicyclic ketoximes17 and oximes with an electron-donating substituent at the α-carbon also
undergo fragmentation rather than rearrangement under Beckmann rearrangement condi-
tions. A variety of substituents, notably alkyl, aryl, hydroxy, alkoxy, amino, and thioalkoxy

288
MODIFICATION 289
(thioether) can stabilize the intermediate carbonium ion and facilitate fragmentation.2y,18
The Beckmann fragmentation has been applied to the modification of steroids and other
organic syntheses.19 Owing to their importance, both the Beckmann rearrangement and
the Beckmann fragmentation have been extensively reviewed.20 Currently, the Beckmann
rearrangement has been carried out under mild conditions21 and in supercritical water;22 it
has also been modified to be catalytic.23
Beckmann rearrangement Beckmann fragmentation
It is commonly assumed that the reaction involves an initial protonation at the oxygen
atom of the oxime moiety, giving an oxonium cation, and is followed by the migration of
an alkyl group plus the departure of a water molecule to give the nitrilium cation. The latter
ion is, in turn, hydrolyzed in a basic solution to finally yield an amide.24 The mechanism is
illustrated below.
D. MODIFICATION
This reaction has been modified to be catalytic23 and to occur under mild conditions,21
in supercritical water,22 and under photo-irradiation.25
290 BECKMANN REARRANGEMENT AND BECKMANN FRAGMENTATION
E. APPLICATIONS
This reaction has been used to synthesize different types of nitrogen-containing

compounds.
This reaction is related to the Schmidt Reaction and Tiemann Rearrangement.
Reference 26.
A solution of 25 mg (1R,4S,12S,13S,16R)-9-methoxy-13-(methoxymethoxy)-11-
oxapentacyclo[8.6.1.01,12 .04,16 .06,17 ]-heptadeca-6(17),7,9-trienone oxime (0.072 mmol),
28 mg p-bromobenzenesulfonyl chloride (0.11 mmol), 16 µL Et3 N (0.12 mmol), and
a catalytic amount of DMAP in 5 mL CH2 Cl2 was stirred for 1 h at ambient tem-
perature. The solvent was removed under reduced pressure, and the residue was taken
up by 2 mL acetic acid. The resulting solution was stirred for 1 h and was neutral-
ized with saturated aqueous NaHCO3 . The mixture was extracted with CH2 Cl2 , washed
with saturated aqueous NaCl, dried over anhydrous Na2 SO4 , and concentrated under
reduced pressure. Chromatography of the residue on silica gel column (6 g, EtOAc/MeOH,
12:1) gave 17 mg (1R,5S,13S,14S,17S)-10-methoxy-14-(methoxymethoxy)-12-oxa-4-
azapentacyclo[9.6.1.01,13 .05,17 .07,18 ]-octadeca-7(18),8,10-trien-3-one as a colorless oil, in
a yield of 69%. [R]23
D = +114.2 (c 1.47, CHCl3 ).
Reference 21.
To 2 mL DMF was added 1.83 g 2,4,6-trichloro-[1,3,5]triazine (TCT, 10.0 mmol) at

25◦ C. After the formation of a white solid, the reaction was monitored by TLC until the
complete disappearance of TCT, then 1.41 g ethylcyclohexanone oxime (10.0 mmol) in
15 mL DMF was added. After the addition, the mixture was stirred at room temperature
and monitored by TLC until completion (∼8 h). Then 20 mL water was added, and the
product was extracted with organic solvent. The organic phase was washed with 15 mL of a
REFERENCES 291
saturated solution of Na2 CO3 , followed by 1 N HCl and brine. The organic layer was dried
over Na2 SO4 , and evaporation of the solvent gave 1.41 g 7-ethylazepan-2-one without other
purifications, in a yield of 100%, m.p. 91◦ C.
Other references related to the Beckmann rearrangement and the Beckmann fragmenta-
tion are cited in the literature.27
H. REFERENCES
1. (a) Beckmann, E., Ber., 1886, 19, 988. (b) Beckmann, E., Ber., 1887, 20, 1507.
2. (a) Fernandez, A. B.; Lezcano-Gonzalez, I.; Boronat, M.; Blasco, T. and Corma, A., J. Catal.,
2007, 249, 116. (b) Zhang, Y. J.; Wang, Y. Q.; Bu, Y. F.; Wang, L.; Mi, Z. T.; Wu, W.; Min, E. Z.;
Fu, S. B.; Zhu, Z. H.; He, F. and Han, S., Reaction Kinetics & Catal. Lett., 2007, 90, 365. (c) Forni,
L.; Fornasari, G.; Trifiro, F.; Aloise, A.; Katovic, A.; Giordano, G. and Nagy, J. B., Microporous &
Mesoporous Mater., 2007, 101, 161. (d) Bonelli, B.; Forni, L.; Aloise, A.; Nagy, J. B.; Fornasari,
G.; Garrone, E.; Gedeon, A.; Giordano, G. and Trifiro, F., Microporous & Mesoporous Mater.,
2007, 101, 153. (e) Sardarian, A. R.; Shahsavari-Fard, Z.; Shahsavari, H. R. and Ebrahimi, Z.,
Tetrahedron Lett., 2007, 48, 2639. (f) Thomas, B. and Sugunan, S., Microporous & Mesoporous
Mater., 2006, 96, 55. (g) Marthala, V. R. R.; Jiang, Y. J.; Huang, J.; Wang, W.; Glaeser, R. and
Hunger, M., J. Am. Chem. Soc., 2006, 128, 14812. (h) Fernandez, A.-B.; Marinas, A.; Blasco, T.;
Fornes, V. and Corma, A., J. Catal., 2006, 243, 270. (i) Xiao, L. F.; Peng, J. J. and Xia, C. G.,
Chinese Chem. Lett., 2006, 17, 617. (j) Yoo, K. H.; Choi, E. B.; Lee, H. K.; Yeon, G. H.; Yang,
H. C. and Pak, C. S., Synthesis, 2006, 1599. (k) Curtis, M.; Bunnelle, W.; Pagano, T.; Gopalakrish-
nan, M. and Faghih, R., Synth. Commun., 2006, 36, 321. (l) Blaszczyk, K.; Koenig, H.; Mel, K. and
Paryzek, Z., Tetrahedron, 2006, 62, 1069. (m) Ngamcharussrivichai, C.; Wu, P. and Tatsumi, T.,
J. Catal., 2005, 235, 139. (n) Mao, D. S.; Lu, G. Z. and Chen, Q. L., J. Mol. Catal. A: Chem., 2005,
240, 164. (o) Li, W.-C.; Lu, A.-H.; Palkovits, R.; Schmidt, W.; Spliethoff, B. and Schueth, F.,
J. Am. Chem. Soc., 2005, 127, 12595. (p) Sirijaraensre, J.; Truong, T. N. and Limtrakul, J., J. Phy.
Chem. B, 2005, 109, 12099. (q) Fernandez, A. B.; Boronat, M.; Blasco, T. and Corma, A., Angew.
Chem. Int. Ed., 2005, 44, 2370. (r) Bucko, T.; Hafner, J. and Benco, L., J. Phys. Chem. A, 2004,
108, 11388. (s) Wu, M. S.; Chen, R. Y. and Huang, Y., Synthesis, 2004, 2441. (t) Chang, J.-C.
and Ko, A.-N., Reaction Kinetics & Catal. Lett., 2004, 83, 283. (u) Chang, J.-C. and Ko, A.-N.,
Catal. Today, 2004, 97, 241. (v) Forni, L.; Fornasari, G.; Giordano, G.; Lucarelli, C.; Katovic, A.;
Trifiro, F.; Perri, C. and Nagy, J. B., Phys. Chem. Chem. Phys., 2004, 6, 1842. (w) Takuwa, T.;
Minowa, T.; Onishi, J. Y. and Mukaiyama, T., Chem. Lett., 2004, 33, 322. (x) Gui, J. Z.; Deng, Y.
Q.; Hu, Z. D. and Sun, Z. L., Tetrahedron Lett., 2004, 45, 2681. (y) Wang, C. D.; Jiang, X.; Shi,
H. J.; Lu, J.; Hu, Y. F. and Hu, H. W., J. Org. Chem., 2003, 68, 4579. (z) Chandrasekhar, S. and
Gopalaiah, K., Tetrahedron Lett., 2001, 42, 8123.
3. Hendrickson, J. B; Cram, D. J. and Hammond, G. S., Organic Chemistry, 3rd ed., McGraw-Hill,
Tokyo, 1970, p. 708.
4. Rosenberg, M. G.; Haslinger, U. and Brinker, U. H., J. Org. Chem., 2002, 67, 450.
5. (a) Hattori, K.; Maruoka, K. and Yamamoto, H., Tetrahedron Lett., 1982, 23, 3395. (b) Hattori,
K.; Matsumura, Y.; Miyazaki, T.; Maruoka, K. and Yamamoto, H., J. Am. Chem. Soc., 1981, 103,
7368.
6. Oxley, P. and Short, W. F., J. Chem. Soc., 1948, 1514.
7. Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K. and Yamamoto,
H., J. Am. Chem. Soc., 1983, 105, 2831.
8. Ishida, Y.; Sasatani, S.; Maruoka, K. and Yamamoto, H., Tetrahedron Lett., 1983, 24, 3255.
9. Yokomatsu, T.; Minowa, T.; Yoshida, Y. and Shibuya, S., Heterocycles 1997, 44, 111.
10. Matsumura, Y.; Fujiwara, J.; Maruoka, K. and Yamamoto, H., J. Am. Chem. Soc., 1983, 105,
6312.
11. (a) Rakitin, O. A.; Rees, C. W.; Williams, D. J. and Torroba, T., J. Org. Chem., 1996, 61, 9178.
(b) Hill, R. K. and Cullison, D. A., J. Am. Chem. Soc., 1973, 95, 2933. (c) Sasaki, T.; Eguchi, S.
and Toru, T., Tetrahedron Lett., 1971, 1109. (d) Stevens, T. E., J. Org. Chem., 1969, 34, 2451.
(e) Huitric, A. C. and Nelson, S. D., J. Org. Chem., 1969, 34, 1230. (f) Conley, R. T. and Nowak,
B. E., J. Org. Chem., 1962, 27, 1965. (g) Bencee, W. L. and Allen, M. J., J. Org. Chem., 1957, 22,
352. (h) Burrows, W. D. and Eastman, R. H., J. Am. Chem. Soc., 1957, 79, 3756. (i) Regan, B. M.
and Hayes, F. N., J. Am. Chem. Soc., 1956, 78, 639. (j) Bartlett, P. D. and Stiles, M., J. Am. Chem.
Soc., 1955, 77, 2806. (k) Lyle, K. E.; Fielding, H. L.; Crtnquil, G. and Rouaand, J., J. Org. Chem.,
1955, 20, 623. (l) Hatch, M. J. and Cram, D. J., J. Am. Chem. Soc., 1953, 75, 38. (m) Kaufmann,
S., J. Am. Chem. Soc., 1951, 73, 1779. (n) Price, C. C. and Mueller, G. P., J. Am. Chem. Soc.,
1944, 66, 634. (o) Perkin, W. H. and Titley, A. F., J. Chem. Soc., 1921, 119, 1089. (p) Schroeter,
G., Ber., 1911, 44, 1201. (q) Glover, W. H., J. Chem. Soc., 1908, 93, 1285. (r) Wallach, O., Ann.,
1890, 259, 309. (s) Leuckart, R. and Bach, E., Ber., 1887, 20, 104.
12. (a) Cao, L. Y.; Sun, J. W.; Wang, X. Y.; Zhu, R.; Shi, H. J. and Hu, Y. F., Tetrahedron, 2007,
63, 5036. (b) Wang, C. D.; Rath, N. P. and Covey, D. F., Tetrahedron Lett., 2006, 47, 7837.
(c) Passacantilli, P.; Centore, C.; Ciliberti, E.; Piancatelli, G. and Leonelli, F., Eur. J. Org. Chem.,
2004, 5083. (d) Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S. and
Lora Maroto, B., Tetrahedron, 2004, 60, 9447. (e) Garcia Martinez, A.; Teso ilar, E.; Garcia Fraile,
A.; De la Moya Cerero, S. and Lora Maroto, B., Eur. J. Org. Chem., 2002, 781. (f) Laxmisha,
M. S. and Rao, G. S. R. S., Tetrahedron Lett., 2000, 41, 3759. (g) Kirihara, M.; Niimi, K.; Okumura,
M. and Momose, T., Chem. Pharm. Bull., 2000, 48, 220. (h) Coskun, N.; Tat, F. T. and Guven, O.
O., Synth. Commun., 1999, 29, 3889. (i) Petukhov, P. A. and Tkachev, A. V., Tetrahedron, 1997,
53, 2535. (j) Pejanovic, V. M.; Petrovic, J. A.; Csanadi, J. J.; Stankovic, S. M. and Miljkovic,
D. A., Tetrahedron, 1995, 51, 13379. (k) Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de
la Moya Cerero, S.; Diaz Oliva, C.; Subramanian, L. R. and Maichle, C., Tetrahedron: Asymmetry,
1994, 5, 949. (l) Fujioka, H.; Miyazaki, M.; Kitagawa, H.; Yamanaka, T.; Yamamoto, H.; Takuma,
K. and Kita, Y., J. Chem. Soc., Chem. Commun., 1993, 1634. (m) Petukhov, P. A. and Tkachev,
A. V., Synlett, 1993, 580. (n) Fujioka, H.; Kitagawa, H.; Yamanaka, T. and Kita, Y., Chem. Pharm.
Bull., 1992, 40, 3118. (o) Fujioka, H.; Yamamoto, H.; Miyazaki, M.; Yamanaka, T.; Takuma,
K. and Kita, Y., Tetrahedron Lett., 1991, 32, 5367. (p) Fujioka, H.; Yamanaka, T.; Takuma, K.;
Miyazaki, M. and Kita, Y., J. Chem. Soc., Chem. Commun., 1991, 533. (q) Fujioka, H.; Miyazaki,
M.; Yamanaka, T.; Yamamoto, H. and Kita, Y., Tetrahedron Lett., 1990, 31, 5951. (r) Bakale,
R. P.; Scialdone, M. A. and Johnson, C. R., J. Am. Chem. Soc., 1990, 112, 6729. (s) VerHaeghe,
D. G.; Weber, G. S. and Pappalardo, P. A., Tetrahedron Lett., 1989, 30, 4041. (t) Hill, R. K.;
McKinnie, B. G.; Conley, R. T.; Darby, P. S.; Van Halbeek, H. and Holt, E., Tetrahedron, 1988,
44, 3405. (u) Nishiyama, H.; Sakuta, K.; Osaka, N.; Arai, H.; Matsumoto, M. and Itoh, K.,
Tetrahedron, 1988, 44, 2413. (v) Nishiyama, H.; Sakuta, K. and Itoh, K., Tetrahedron Lett.,
1984, 25, 223. (w) Nishiyama, H.; Sakuta, K.; Osaka, N. and Itoh, K., Tetrahedron Lett., 1983,
24, 4021. (x) Bosch, J.; Moral, M. and Rubiralta, M., Heterocycles, 1983, 20, 509. (y) Oxenrider,
B. C. and Rogic, M. M., J. Org. Chem., 1982, 47, 2629. (z) Redeker, U.; Engel, N. and Steglich,
W., Tetrahedron Lett., 1981, 22, 4263. (aa) Miljkovic, D. and Petrovic, J., J. Org. Chem., 1977,
42, 2101. (bb) Bondavalli, F.; Schenone, P. and Longobardi, M., Gazz. Chim. Ital., 1975, 105,
1317. (cc) Maeda, K.; Moritani, I.; Hosokawa, T. and Murahashi, S., J. Chem. Soc., Chem.
Commun., 1975, 689. (dd) Grob, C. A. and Ide, J., Helv. Chim. Acta, 1974, 57, 2562. (ee) Grob,
C. A. and Ide, J., Helv. Chim. Acta, 1974, 57, 2571. (ff) Miljkovic, D.; Petrovic, J.; Stajic, M.
and Miljkovic, M., J. Org. Chem., 1973, 38, 3585. (gg) Hill, R. K. and Cullison, D. A., J. Am.
Chem. Soc., 1973, 95, 2923. (hh) Autrey, R. L. and Scullard, P. W., J. Am. Chem. Soc., 1968, 90,
4924. (ii) Eisele, W.; Grob, C. A.; Renk, E. and Von Tschammer, H., Helv. Chim. Acta, 1968,
51, 816. (jj) Stevens, T. E., Tetrahedron Lett., 1967, 3017.
13. (a) Werner, A. and Piguet, A., Ber., 1904, 37, 4295. (b) Werner, A. and Detscheff, T., Ber., 1905,
38, 69.
REFERENCES 293
14. (a) Confalone, P. N. and Huie, E. M., J. Org. Chem., 1987, 52, 79. (b) Palmere, R. M.; Conley,
R. T. and Rabikowitz, J. L., J. Org. Chem., 1972, 37, 4095. (c) Hill, R. K.; Conley, R. T. and
Chortyk, O. T., J. Am. Chem. Soc., 1965, 87, 5646. (d) Conley, R. T. and Nowak, B. E., J. Org.
Chem., 1961, 86, 692. (e) Graham, S. H. and Williams, A. J. S., J. Chem. Soc., 1959, 4066.
(f) Lyle, R. E. and Lyle, G. G., J. Org. Chem., 1953, 18, 1058.
15. (a) Cavä, M. P. and Ahmed, Q. A., J. Org. Chem., 1968, 33, 2440. (b) Autrey, R. L. and Scullard,
P. W., J. Am. Chem. Soc., 1965, 87, 3284. (c) Freemam, J. P., J. Org. Chem., 1961, 26, 3507.
16. (a) Ikeda, M.; Uno, T.; Homma, K.; Ohno, K.; Tamura, Y., Synth. Commun., 1980, 10, 437.
(b) Huitric, A. C. and Nelson, S. D., J. Org. Chem., 1969, 34, 1230.
17. (a) Gates, M. and Malchick, S. P., J. Am. Chem. Soc., 1957, 79, 5546. (b) Hall, H. K., J. Am.
Chem. Soc., 1960, 82, 1209.
18. (a) Conley, R. T. and Ghosh, S., Mech. Mol. Migr., 1971, 4, 197. (b) Ohno, M. and Terasawa, I.,
J. Am. Chem. Soc., 1966, 88, 5683. (c) Hill, R. K., J. Org. Chem., 1962, 27, 29. (d) Hill, R. K.
and Conley, R. T., J. Amer. Chem. Soc., 1960, 82, 645.
19. (a) Catsoulacos, P. and Catsoulacos, D., J. Heterocycl. Chem., 1993, 30, 1. (b) Oka, K. and Hara,
S., J. Org. Chem., 1978, 43, 3790. (c) Paisley, J. K. and Weiler, L., Tetrahedron Lett., 1972, 261.
(d) Olson, E. S. and Richards, J. H., J. Org. Chem., 1968, 33, 434. (e) Singh, H. and Parashar,
V. V., Tetrahedron Lett., 1966, 983. (f) Cava, M. P.; Glamkowski, E. J.; and Weintraub, P. M.,
J. Org. Chem., 1966, 31, 2755. (g) Ohta, G.; Takegoshi, T.; Ueno, K. and Shimizu, M., Chem.
Pharm. Bull. (Tokyo), 1965, 13, 1445. (h) Doorenbos, N. J. and Havranek. R. E., J. Org. Chem.,
1965, 30, 2474. (i) Shoppee, C. W.; Lack, R. E.; Mirrington, R. N. and Smith, C. R., J. Chem.
Soc., 1965, 5868. (j) Shoppee, C. W.; Lack, R. K. and Newman, B. C., J. Chem. Soc., 1964, 3388.
(k) Shoppee, C. W.; Akhtar, M. I. and Lack, R. E., J. Chem. Soc., 1964, 3392. (l) Mazur, R.,
J. Org. Chem., 1963, 28, 248. (m) Shoppee, C. W.; Kruger, G. and Mirrington. R. N., J. Chem.
Soc., 1962, 1050. (n) Shoppee, C. W.; Killick, R. W. and Kruger, G., J. Chem. Soc., 1962, 2275.
(o) Zderic, J. A. and Iriarte, J., J. Org. Chem., 1962, 27, 1756. (p) Hassner, A. and Pomerants, I.
H., J. Org. Chem., 1962, 27, 1760. (q) Shoppee, C. W. and Kruger, G., J. Chem. Soc., 1961, 3641.
(r) Knof, L., Ann., 1961, 642, 194. (s) Blickenstaff, R. T. and Foster, E. L., J. Org. Chem., 1961,
26, 5029. (t) Bladon, P. and McMeekin, W., J. Chem. Soc., 1961, 3504. (u) Jacobs, T. A. and
Brownfield, B. B., J. Am. Chem. Soc., 1960, 82, 4033. literature covered up to 1960. (v) Litvan,
F. and Robinson, R., J. Chem. Soc., 1938, 1997.
20. (a) Hauske, J. R., Comp. Org. Syn., 1991, 1, 98. (b) Maruoka, K. and Yamamoto, H., Comp.
Org. Syn., 1991, 6, 763. (c) Carig, D., Comp. Org. Syn., 1991, 6, 689. (d) Hesse, M., Ring
Enlargement in Organic Chemistry, VCH, Weinheim, 1991. (e) Jochims, J. C.; Hehl, S. and
Herzberger, S., Synthesis, 1990, 1128. (f) Gawley, R. E., Org. React., 1988, 35, 1. (g) Conley, R.
T. and Ghosh, S., Abnormal Beckmann rearrangements, in Mechanisms of Molecular Migrations
ed. Thyagarajan, B. S., Wiley-Interscience, New York, 1971, pp. 197–308. (h) McCarty, C. G.,
Syn-anti Isomerizations and Rearrangements, in The Chemistry of the Carbon-Nitrogen Double
Bond, ed. Patai, S., Interscience, New York, 1970, pp. 408–438. (i) Beckwith, A. L. J., Synthesis
of Amides, in The Chemistry of Amides, ed. Zabicky, J., Interscience, New York, 1970; p.
131. (j) Hornke, G.; Krauch, H. and Kunz, W., Chem. Ztg., 1965, 89, 525. (k) Smith, P. A. S.,
Rearrangements Involving Migration to an Electron-Deficient Nitrogen or Oxygen, in Molecular
Rearrangements, ed. de Mayo, P., Interscience: New York, 1963, p 45. (l) Donaruma, L. G.
and Heldt, W. Z., Org. React., 1960, 11, 1. (m) Popp, F. D. and McEwen, W. E., Chem. Rev.,
1958, 58, 370. (n) Moller, F., Amine nach Speziellen Methoden, In Methoden der Organischen
Chemie, ed. Muller, E., Thieme Verlag, Stuttgart, 1957, XI, Part 1, p. 892. (o) Jones, B., Chem.
Rev., 1944, 35, 335. (p) Blatt, A. H., Chem. Rev., 1933, 12, 215.
21. Luca, L. D., Giacomelli, G. and Porcheddu, A., J. Org. Chem., 2002, 67, 6272.
22. (a) Boero, M.; Ikeshoji, T.; Liew, C. C.; Terakura, K. and Parrinello, M., J. Am. Chem. Soc., 2004,
126, 6280. (b) Ikushima, Y.; Hatakeda, K.; Sato, O.; Yokoyama, T. and Arai, M., J. Am. Chem.
Soc., 2000, 122, 1908. (c) Sato, O.; Ikushima,Y. and Yokoyama, T., J. Org.Chem., 1998, 63, 9100.
23. (a) Arisawa, M. and Yamaguchi, M., Org. Lett., 2001, 3, 311. (b) Kusama, H.; Yamashita, Y. and
Narasaka, K., Bull. Chem. Soc. Jpn., 1995, 68, 373. (c) Narasaka, K.; Kusama, H.; Yamashita, Y.
and Sato, H., Chem. Lett., 1993, 489. (d) Mukaiyama, T. and Harada, T., Chem. Lett., 1991, 1653.
(e) Harada, T.; Ohno, T.; Kobayashi, S. and Mukaiyama, T., Synthesis, 1991, 1216. (f) Izumi, Y.,
Chem. Lett., 1990, 2171.
24. Nguyen, M. T.; Raspoet, G. and Vanquickenborne, L. G., J. Am. Chem. Soc., 1997, 119, 2552.
25. (a) Smith, B. T.; Wendt, J. A. and Aubé, J., Org. Lett., 2002, 4, 2577. (b) Ogata, Y.; Takagi,
K. and Mizuno, K., J. Org. Chem., 1982, 47, 3684. (c) Suginome, H. and Takahashi, H., Bull.
Chem. Soc. Jpn., 1975, 576. (d) Sasaki, T.; Eguchi, S. and Tom, T., J. Chem. Soc., D, 1970, 1239.
(e) Oine, T. and Mukai, T., Tetrahedron Lett., 1969, 157. (f) Taylor, R. T.; Douek, M. and Just, G.,
Tetrahedron Lett., 1966, 4143. (g) Amin, J. H. and de Mayo, P., Tetrahedron Lett., 1963, 1585.
26. White, J. D., Hrnciar, P. and Stappenbeck, F., J. Org. Chem. 1999, 64, 7871.
27. (a) Lee, G. S.; Nakagawa, Y.; Hwang, S. G.; Davis, M. E.; Wagner, P.; Beck, L. and Zones, S.
I., J. Am. Chem. Soc., 2002, 124, 7024. (b) Boruah, M. and Konwar, D., J. Org. Chem, 2002, 67,
7138. (c) Jiang, X.; Wang, C.; Hu, Y.; Hu, H. and Covey, D. F., J. Org. Chem., 2000, 65, 3555.
(d) Katritzky, A. R.; Monteux, D. A. and Tymoshenko, D. O., Org. Lett., 1999, 1, 577. (e) Krow,
G. R., Szczepanski, S. W., Kim, J. Y., Liu, N., Sheikh, A., Xiao, Y. and Yuan, J., J. Org.
Chem.,. 1999, 64, 1254. (f) Kuhl, A.; Karele, H. and Kreiser, W., Helv. Chim. Acta, 1999,
82, 30. (g) Holderich, W. F.; Roseler, J.; Heitmann, G. and Liebens, A. T., Catal. Today,
1997, 37, 353. (h) Han, M. and Covey, D. F., J. Org. Chem., 1996, 61, 7614. (i) Krow, G.
R.; Cheung, O. H.; Hu, Z. and Lee, Y. B., J. Org. Chem., 1996, 61, 5574. (j) Yokomatsu,
T.; Yoshida, Y.; Nakabayashi, N. and Shibuya, S., J. Org. Chem., 1994, 59, 7562. (k) Niko-
laropoulos, S.; and Catsoulacos, P., J. Heterocycl. Chem., 1990, 27, 1997. (l) Dolle, R.
E.; Allaudeen, H. S. and Kruse, L. I., J. Med. Chem., 1990, 33, 877. (m) Burguet, M. C.;
Aucejo, A. and Corma, A., Can. J. Chem. Eng., 1987, 65, 944. (n) Fráter, G.; Müller, U.
and Günther, G., Tetrahedron Lett., 1984, 25, 1133. (o) Sakane, S.; Matsumura, Y.; Yama-
mura, Y.; Ishida, Y.; Maruoka, K. and Yamamoto, H., J. Am. Chem. Soc., 1983, 105, 672.
(p) Krow, G. and Szczepanski, S., J. Org. Chem. 1982, 47, 1153. (q) Carter, K. N. and Hulse, J. E.,
J. Org. Chem., 1982, 47, 2208. (r) Novoselov, E. F.; Isaev, S. D.; Yurchenko, A. G.; Vodichka, L.
and Trshiska, Y., J. Org. Chem. USSR, 1981, 17, 2284. (s) Hattori, K.; Matsumura, Y.; Miyazaki, T.;
Maruoka, K. and Yamamoto, H., J. Am. Chem. Soc., 1981, 103, 1368. (t) Krow, G. R., Tetrahedron,
1981, 37, 1283. (u) Pfenninger, J. and Graf, W., Helv. Chim. Acta, 1980, 63, 2338. (v) Schlatter,
H.-R. and Graf, W., Helv. Chim. Acta, 1980, 63, 1554. (w) Olah, G. A. and Fung, A. P., Synthesis,
1979, 537. (x) Sasaki, T.; Eguchi, S. and Hiroaki, O., J. Org. Chem., 1976, 41, 1803. (y) Mammato,
D. C. and Eadon, G. A., J. Org. Chem., 1975, 40, 1784. (z) Chapman, J. C. and Pinhey, J. T.,
Aust. J. Chem., 1974, 27, 2421. (aa) Cohen, K. F.; Kazlauskas, R. and Pinhey, J. T., J. Chem. Soc.,
Perkin Trans. 1, 1973, 2076. (bb) Moriconi, E. J. and Stemniski, M. A., J. Org. Chem., 1972, 37,
2035. (cc) Ogura, H.; Takayanaqi, H. and Miyahara, C., J. Org. Chem., 1972, 37, 519. (dd) Kelly,
K. K. and Matthews, J. S., J. Org. Chem., 1971, 36, 2159. (ee) Sasaki, T.; Eguchi, S. and Toru, T.,
J. Org. Chem., 1971, 36, 2454. (ff) Fenselau, A. H.; Hamamura, E. H. and Moffatt, J. G., J. Org.
Chem., 1970, 35, 3546. (gg) Sasaki, T.; Eguchi, S. and Toru, T., J. Org. Chem., 1970, 35, 4109.
(hh) Korsloot, J. G.; Keizer, V. G. and Schlatmann, J. L. M. A., Recl. Trav. Chim. Pays-Bas, 1969,
88, 447. (ii) Narayanan, V. L. and Setescak, L., J. Heterocycl. Chem., 1969, 6, 445. (jj) Korsloot,
J. G. and Keizer, V. G., Tetrahedron Lett., 1969, 3517. (kk) Potti, N. D. and Nobles, W. L.,
J. Pharm. Sci., 1968, 57, 1785. (ll) Lansbury, P. T. and Mancuso, N. R., J. Am. Chem. Soc., 1966,
88, 1205. (mm) Morita, K.-I, and Suzuki, Z., J. Org. Chem., 1966, 31, 233. (nn) Hassner, A. and
Wentworth, W. A., Chem. Commun., 1965, 44. (oo) Grob, C. A.; Fischer, H. P.; Raudenbusch,
W. and Zergenyi, J., Helv. Chim. Acta, 1964, 47, 1003. (pp) Conley, R. T., J. Org. Chem., 1963,
28, 278. (qq) Conley, R. T. and Lange, R. J., J. Org. Chem., 1963, 28, 210. (rr) Conley, R. T.
and Annis, M. C., J. Org. Chem., 1962, 27, 1961. (ss) Hill, R. K. and Chortyk, O. T., J. Am.
Chem. Soc., 1962, 84, 1064. (tt) Conley, R. T. and Frainier, L. J., J. Org. Chem., 1962, 27, 3844.
REFERENCES 295
(uu) Lansbury, P. T. and Colson, J. G., J. Am. Chem. Soc., 1962, 84, 4167. (vv) Elderfield, R. C.
and Losin, E. T., J. Org. Chem., 1961, 26, 1703. (ww) Ferris, A. F., J. Org. Chem., 1960, 25, 12.
(xx) Hill, R. K. and Conley, R. T., Chem. Ind. (London), 1956, 1314. (yy) Snyder, H. R. and
Elston, C. T., J. Am. Chem. Soc., 1954, 76, 3039. (zz) Shechter, H. and Kirk, J. C., J. Am. Chem.
Soc., 1951, 73, 3087. (aaa) Sanford, J. K.; Blair, F. T.; Arroya, J. and Sherk, K. W., J. Am. Chem.
Soc., 1945, 67, 1941. (bbb) Blatt, A. H. and Barnes, R. P., J. Am.. Chem. Soc., 1934, 56, 1148.
566
Schmidt Reaction
(Schmidt Rearrangement)
This reaction was first reported by Schmidt in 1923.1 It is a reaction between a hydroazoic
acid (i.e., azoimide) and a carboxylic acid or a carbonyl compound via an 1,2-migration
to form a nitrogen-containing molecule such as primary amine or amide. Therefore, this
reaction is generally known as the Schmidt reaction.2 In particular, the reaction between a
hydroazoic acid and a carboxylic acid to yield a primary amine with one less carbon atom
by decarboxylation is referred to as the Schmidt rearrangement,3 Schmidt degradation,4 or
Schmidt decarboxylation.5 In comparison, the reaction between a hydroazoic acid and a
carbonyl compound, generally yielding two possible amides from a ketone or formamide
from an aldehyde, is known as the Schmidt rearrangement6 or Schmidt transformation.7
Today, the scope of the Schmidt reaction has been extended to include reactions between
hydroazoic acid or alkyl azide and other molecules that can form carbocation intermedi-
ates under acidic conditions, such as olefins,4o,8 tertiary alcohols,9 and some secondary
alcohols (e.g., benzhydrols).3k As a result, the Schmidt reaction is very versatile and has
the advantages of simplicity, readily available reactants, mild reaction conditions, and
a certain level of functional group tolerance.2h For example, this reaction is often car-
ried out in sulfuric acid,10 and hydroazoic acid can be generated in situ from sodium
azide.2h,4n,10a,10d
For the degradation of carboxylic acid, factors that may affect the reaction outcome
are the ratio of sulfuric acid/carboxylic acid, the reaction temperature and the dilution
extent of sulfuric acid.4o Even though some of the Schmidt degradations of carboxylic

2503
2504 SCHMIDT REACTION
acids are known to be quantitative,4n the decarboxylation of carboxylic acids with chain
branching at the α-position often gives amines in yields less than the theoretical values,
along with the formation of some by-products, such as carbon monoxide, ketones, alco-
hols, and ammonia.4o However, it is intriguing that the reaction between sodium azide and
2-phenyl-2-methylhexanoic acid in sulfuric acid gives 55% aniline.10a
The Schmidt reaction between hydroazoic acid and aldehyde often gives formamide.10d
However, the reaction with benzaldehyde produces both benzonitrile and formanilide, with
the yields varying from 70% and 13% to 5% and 50%, respectively, when the ratio of
sulfuric acid/benzaldehyde changes from 0.72 to 5.4.11
It should be pointed out that the reaction between hydroazoic acid and ketone is much
more complicated, yielding two possible amides by the migration of different alkyl or aryl
groups, and the ratio of two amides depends on the strength of acid and the migratory
aptitude of the two groups. Generally speaking, the aryl group is preferred over the alkyl
group for the migration from aminodiazonium ion,12 and the migrating tendency corre-
lates well with the Hammett substituent constant, in which an electron-donating group on
aryl facilitates the migration while an electron-withdrawing group decreases the migrating
ability.13 For example, the migratory aptitude in diarylethylene is found in the order of
p-anisyl > p-tolyl > p-biphenyl > phenyl > p-chlorophenyl > methyl.8c However, such
a trend does not always apply to the Schmidt reaction of ketones, where the electronic
effect might not be as apparent as that in diarylethylenes.14 For example, both p-chloro-
p -methoxybenzophenone and p-nitro-p -methoxybenzophenone give two amides in 1:1
ratio.8b In addition, the strength of acid also affects the constitution of products. For
example, the Schmidt reaction of adamantan-2-one in methanesulfonic acid yields 88%
4(e)-methanesulfonoxyadamantan-2-one and 11% 4-azatricyclo[4.3.1.11,8 ]undecan-5-one
whereas the same reaction in methanesulfonic acid-acetic acid, water, trichloroacetic acid
or trifluoroacetic acid gives 40–61% of bicyclo[3.3.1]non-6-one-3-carbonitrile and 27–60%
of 4-azatricyclo[4.3.1.11,8 ]undecan-5-one, and also produces 4-acetoxy-adamantan-2-one,
4-hydroxyadamantan-2-one, and 4-azatricyclo[4.3.1.11,8 ]-undecan-5-one in sulfuric acid–
acetic acid.15 Moreover, the particular reaction of benzyl azide may give a normal Schmidt
reaction product and the unexpected Mannich Reaction product, and the ratio of these
two products varies, depending on the acid applied.16 For example, when TiCl4 is used,
the Schmidt product is favored, whereas in the presence of TfOH, the Mannich product
predominates.16b Furthermore, solvent also affects the reaction outcome, even though most
reactions are carried out in chloroform. For example, the reactions in ether or benzene in
the presence of a 76% sulfuric acid take place in two different pathways, in which the
reaction in benzene/76% sulfuric acid is fast and all the substrates remain in the sulfuric
acid phase, whereas the reaction in ether is much slower and the reactants stay in the ether
phase.6e
The Schmidt reaction of a simple cyclic ketone yields lactams with the ring
expanded,2g,2h while the intramolecular Schmidt reaction of cyclic ketone with an azido
group at the side chain leads to the formation of bicyclic lactams with nitrogen at the posi-
tion of fusion.2h,17 It is interesting that the reaction between a cyclic ketone and 2-azido
ethanol can form either a lactam or a lactone by means of the treatment with a different
base, in which the lactam is formed when the reaction system is treated with KOH, whereas
lactone is generated when NaHCO3 is used as the base.18 Especially, the reaction between
4-tert-butylcyclohexanone and 3-azido-2-methyl-2-phenylpropanol gives lactam in 19:1
stereoselectivity.19
O HN3
R NH2
R OH H2SO4
O O H
HN3
R CN and/or
R H H2SO4 NH R = alkyl, aryl
R
O O R′ = alkyl, aryl
O HN3
R′ and/or R
R R′ H2SO4 R N R′ N
H H
R R R
HN3
R OH N
H2SO4
R R
For the degradation of carboxylic acid, it is known that the reaction involves an acyl azide
intermediate, in a manner similar to the Curtius Rearrangement,2g as shown in Scheme 1.
Similar to the acid-catalyzed esterification of alcohol, it is assumed that the carbonyl oxygen
is protonated rather than the hydroxyl oxygen. However, for the Schmidt reaction of ketones,
it is well accepted that the reaction undergoes in two different routes, both involve the
α-hydroxyhydrazidium ion arising from the nucleophilic addition of hydroazoic acid to the
protonated carbonyl group.2m,20 The resulting α-hydroxyhydrazidium ion may rearrange to
amides along with the evolution of nitrogen, and the ratio of amides produced depends on
the inherent migratory aptitudes of both groups and the abilities of the group acting as the
stationary group to stabilize the positive charge. Alternatively, the α-hydroxyhydrazidium
ion undergoes dehydration to form iminodiazonium ion,6d and the stereospecific migration
of the group antiperiplanar to the azido group produces an acylium ion, which upon hydra-
tion forms the corresponding amide,2m as shown in Scheme 2. In this mechanism, the ratio
of amides depends on the population of syn- and anti-iminodiazonium ions arising from
different steric repulsions in the transition state of dehydration, which cannot isomerize
but may interchange into each other only through the hydration and dehydration process.
If the hydration and dehydration process is fast enough, then two iminodiazonium ions
can quickly reach an equilibrium, this situation is controlled by the migratory tendency of
substituents in the hydroxyhydrazinium ion.2m,14,20,21
SCHEME 1. Schmidt degradation of a carboxylic acid.

SCHEME 2. Schmidt reaction with a general ketone.
D. MODIFICATION
This reaction has been extensively modified. First, the Schmidt reaction is often car-
ried out in a halogenated solvent, such as chloroform, so there exists a potential to form
explosive multi-azides. For this matter, DME is suggested as the solvent,22 or polyphospho-
ric acid is applied as both acid and reaction medium.6e,7,23 Second, alkyl azide, retaining
the important dipolar character of the azido group, has been widely used for the Schmidt
reaction,6c,16b,17,24 even though it is much less nucleophilic than hydroazoic acid.2g In
addition, it has been suggested that a higher yield could be obtained for the degradation
of succinic acid if it were converted into succinic anhydride before the degradation.25
Other modifications include the photoinduced Schmidt reaction,26 the P2 O5 /SiO2 cat-
alyzed one-pot reaction,2e the ionic exchange resin2j or silica sulfuric acid2f catalyzed
Schmidt reaction, the trimethylsilyl azide3h or azidotrimethylsilane2b,3g mediated Schimdt
reaction, and the transition metal activated Schmidt reaction. For example, the reaction
between alkyl azide and gold (I) activated alkynes has been used in the preparation of
multisubstituted pyrroles;24a likewise, mercury salt has been used to promote the Schmidt
reaction,8a which has the following advantages: the wide applicability, e.g., to even 1,2-
disubstituted olefins rather than to only tertiary, allylic, benzylic, or propargylic alcohol
to form a stable carbocation intermediate under strong acid conditions as required by the
normal Schmidt reaction; tolerance to acid-labile functionalities; and no carbocation rear-
rangement before the cyclization/rearrangement, which usually occurs in the acid-promoted
Schmidt reactions.2l,8a
E. APPLICATIONS
The degradation of carboxylic acid has been used for the preparation of amines,2l,4o,10a,27
amino acids,28 and structural elucidation, especially via 14 C labeling.4n The reaction with
carbonyl compounds has an even wider application in organic synthesis.
REFERENCES 2507
This reaction is related to the Curtius Rearrangement, Hofmann Rearrangement, Lossen

Rearrangement, and Stieglitz Rearrangement.
O NaN3/H2SO4 HCl
CH3NH2 · HCl
OH ∆
87%
Reference 4o.
A mixture of 20.0 g 99.5% pure acetic acid (0.33 mol), 232 g concentrated sulfuric
acid in chemical purity (2.37 mol), and 27.9 g NaN3 (0.43 mol) was stirred at 60◦ C. The
methylamine was collected in concentrated HCl, which was evaporated to afford 21.5 g
crude methylamine hydrochloride, m.p. 186–220◦ C. The crude product was recrystallized
from absolute ethanol to give 19.5 g beautiful plates without improvement for melting point,
in a yield of 87%, in good agreement with the 89% yield of carbon dioxide obtained. In
addition, sodium azide was found to decompose ∼ 26%.
O
O
TiCl4
+ N3 N
CH2Cl2
100%
Reference 16b.
To a mixture of 119 mg 2-adamantanone (0.79 mmol), 200 mg 1-azidohexane

(1.58 mmol), and 2.5 mL methylene chloride in an ice bath was added 380 mg TiCl4
(2.0 mmol) dropwise. The reaction was allowed to warm to room temperature, with imme-
diate gas evolution noted. A precipitate formed after 15 min, but the suspension was stirred
for a total of 16 h, at which time it was diluted with 20 mL EtOAc and partitioned between
200 mL EtOAc and 30 mL saturated NaHCO3 solution. The organic layer was washed with
30 mL brine and dried over anhydrous Na2 SO4 . Upon evaporation of the EtOAc, the residue
was purified by flash column chromatography with EtOAc/hexane (1:4) as the eluent to give
197 mg 4-hexyl-4-azahomoadamantane, as a clear oil, in a yield of 100%.
Other references related to the Schmidt reaction are cited in the literature.29
H. REFERENCES
1. Schmidt, K. F., Angew. Chem., 1923, 36, 511.

2. (a) Yao, L. and Aube, J., J. Am. Chem. Soc., 2007, 129, 2766. (b) Pozgan, F.; Krejan, M.; Polanc,
S. and Kocevar, M., Heterocycles, 2006, 69, 123. (c) Gu, P. M.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y.
F. and Zhang, F. M., Org. Lett., 2006, 8, 5271. (d) Nyfeler, E. and Renaud, P., Chimia, 2006,
60, 276. (e) Hassankhani, A., Synth. Commun., 2006, 36, 2211. (f) Eshghi, H.; Hassankhani, A.
and Mosaddegh, E., J. Chem. Res., 2006, 218. (g) Lang, S. and Murphy, J. A., Chem. Soc. Rev.,
2006, 35, 146. (h) Casey, M.; Donnelly, J. A.; Ryan, J. C. and Ushioda, S., ARKIVOC, 2003, (vii),
310. (i) Chandrasekhar, S. and Gopalaiah, K., Tetrahedron Lett., 2003, 44, 7437. (j) Ammar, H.;
Fakhfakh, M.; Le Bigot, Y. and El Gharbi, R., Synth. Commun., 2003, 33, 1821. (k) Pozgan, F.;
Polanc, S. and Kocevar, M., Heterocycles, 2002, 56, 379. (l) Pearson, W. H. and Fang, W.-k.,
J. Org. Chem., 1995, 60, 4960. (m) Bach, R. D. and Wolber, G. J., J. Org. Chem., 1982, 47, 239.
3. (a) Tapia, R. A. and Centella, C., Synth. Commun., 2004, 34, 2757. (b) Mphahlele, M. J., J. Chem.
Soc., Perkin Trans. I, 1999, 3477. (c) Krow, G. R.; Szczepanski, S. W.; Kim, J. Y.; Liu, N.; Sheikh,
A.; Xiao, Y. S. and Yuan, J., J. Org. Chem., 1999, 64, 1254. (d) Mphahlele, M. J. and Kaye, P. T.,
Magnet. Reson. Chem., 1998, 36, 69. (e) Daich, A. and Decroix, B., J. Heterocycl. Chem., 1996,
33, 873. (f) Norris, P.; Horton, D. and Levine, B. R., Tetrahedron Lett., 1995, 36, 7811. (g) Kaye,
P. T.; Mphahlele, M. J. and Brown, M. E., J. Chem. Soc., Perkin Trans. II, 1995, 835. (h) Kaye, P.
T. and Mphahlele, M. J., Synth. Commun., 1995, 25, 1495. (i) Mérour, J. Y.; Cossais, F.; Piroelle,
S. and Mazeas, D., J. Heterocycl. Chem., 1994, 31, 87. (j) Merour, J. Y.; Piroelle, S. and Faure,
R., J. Heterocycl. Chem., 1994, 31, 141. (k) Tietz, R. F. and McEwen, W. E., J. Am. Chem. Soc.,
1955, 77, 4007.
4. (a) Kolattukudy, P. E. and Buckner, J. S., Biochem. Biophys. Res. Commun., 1972, 46, 801.
(b) Tokoroyama, T. and Kubota, T., J. Chem. Soc. C, 1971, 2703. (c) Dahn, H. and Murchu, C. O.,
Helv. Chim. Acta, 1970, 53, 1379. (d) Fleshood, H. L. and Pitot, H. C., J. Biol. Chem., 1970, 245,
4414. (e) Reinhold, K. and Renz, P., Ann., 1969, 729, 231. (f) Berger, H.; Paul, H. and Hilgetag,
G., Chem. Ber., 1968, 101, 1525. (g) Kaplan, B. H. and Stadtman, E. R., J. Biol. Chem., 1968, 243,
1794. (h) Alexander, N. M.; Scheig, R. and Klatskin, G., J. Lipid Res., 1966, 7, 197. (i) Whereat,
A. F., J. Lipid Res., 1966, 7, 671. (j) Gatenbeck, S. and Bentley, R., Biochem. J., 1965, 94, 478.
(k) Brenner-Holzach, O. and Leuthard, F., Helv. Chim. Acta, 1965, 48, 1804. (l) Smith, G. N. and
Bu’Lock, J. D., Biochem. Biophys. Res. Commun., 1964, 17, 433. (m) Birch, A. J.; Hussain, S.
F. and Rickards, R. W., J. Chem. Soc., 1964, 3494. (n) Rabinowitz, J. L. and Pritzker, B., Anal.
Chem., 1964, 36, 403. (o) Schuerch, C. and Huntress, E. H., J. Am. Chem. Soc., 1949, 71, 2233.
5. (a) Monson, K. D. and Hayes, J. M., Geochim. Cosmochim. Acta, 1982, 46, 139. (b) Akhila, A.;
Banthorpe, D. V. and Rowan, M. G., Phytochemistry, 1980, 19, 1433. (c) Vogler, E. A. and Hayes,
J. M., J. Org. Chem., 1979, 44, 3682. (d) Law, S. W. T. and Burton, D. N., Can. J. Chem., 1973,
51, 241. (e) Hawke, J. C. and Stumpf, P. K., J. Biol. Chem., 1965, 240, 4746.
6. (a) Krow, G. R.; Cheung, O. H.; Hu, Z. L. and Lee, Y. B., J. Org. Chem., 1996, 61, 5574.
(b) Makhova, N. N.; Blinnikov, A. N.; Khmel’nitskii, L. I., Mendeleev Commun., 1995, 56.
(c) Sprecher, M. and Kost, D., J. Am. Chem. Soc., 1994, 116, 1016. (d) Richard, J. P.; Amyes,
T. L.; Lee, Y.-G. and Jagannadham, V., J. Am. Chem. Soc., 1994, 116, 10833. (e) Prager, R. H.;
Tippett, J. M. and Ward, A. D., Aust. J. Chem., 1978, 31, 1989. (f) Doorenbos, N. J. and Wu, M.
T., J. Org. Chem., 1961, 26, 2548.
7. Conley, R. T., J. Org. Chem., 1958, 23, 1330.
8. (a) Pearson, W. H.; Hutta, D. A. and Fang, W.-K., J. Org. Chem., 2000, 65, 8326. (b) Westland,
R. D. and McEwen, W. E., J. Am. Chem. Soc., 1952, 74, 6141. (c) McEwen, W. E.; Gilliland, M.
and Sparr, B. I., J. Am. Chem. Soc., 1950, 72, 3212.
9. Mehta, G. and Kotha, S., Tetrahedron, 2001, 57, 625.
10. (a) Palmere, R. M. and Conley, R. T., J. Org. Chem., 1970, 35, 2703. (b) Khuthier, A.-B. and
Robertson, J. C., J. Org. Chem., 1970, 35, 3760. (c) Carter, K. N., J. Org. Chem., 1966, 31, 4257.
(d) McEwen, W. E.; Conrad, W. E. and VanderWerf, C. A., J. Am. Chem. Soc., 1952, 74, 1168.
(e) Smith, P. A. S. and Ashby, B., J. Am. Chem. Soc., 1950, 72, 2503. (f) Dice, J. R. and Smith,
P. A. S., J. Org. Chem., 1949, 14, 179.
11. Schmidt, K. F., Ger. Pat., Apr. 20, 1926, 427,828.
12. Pearson, W. H. and Fang, W.-K., J. Org. Chem., 2000, 65, 7158.
13. McEwen, W. E. and Mehta, N. B., J. Am. Chem. Soc., 1952, 74, 526.
REFERENCES 2509
14. Smith, P. A. S., J. Am. Chem. Soc., 1954, 76, 431.

15. Sasaki, T.; Eguchi, S. and Toru, T., J. Org. Chem., 1970, 35, 4109.
16. (a) Wrobleski, A. and Aubé, J., J. Org. Chem., 2001, 66, 886. (b) Desai, P.; Schildknegt, K.;
Agrios, K. A.; Mossman, C.; Milligan, G. L. and Aubé, J., J. Am. Chem. Soc., 2000, 122, 7226.
17. Aubé, J. and Milligan, G. L., J. Am. Chem. Soc., 1991, 113, 8965.
18. Aubé, J. and Forsee, J. E., J. Org. Chem., 1999, 64, 4381.
19. Katz, C. E. and Aubé, J., J. Am. Chem. Soc., 2003, 125, 13948.
20. Fikes, L. E. and Shechter, H., J. Org. Chem., 1979, 44, 741.
21. Amyes, T. L. and Richard, J. P., J. Am. Chem. Soc., 1991, 113, 1867.
22. Gálvez, N.; Moreno-Mañas, M.; Sebastián, R. M. and Vallribera, A., Tetrahedron, 1996, 52, 1609.
23. (a) Conley, R. T. and Nowak, B. E., J. Org. Chem., 1961, 26, 692. (b) Conley, R. T., Chem. &
Ind., 1958, 438. (c) Conley, R. T., and Nowak, B. E., Chem. & Ind., 1956, 1161. (d) Snyder, H.
R., and Elstron, C. T., J. Am. Chem. Soc., 1954, 76, 3039. (e) Snyder, H. R., Elston, C. T., and
Kellom, D. B., J. Am. Chem. Soc., 1953, 75, 2014.
24. (a) Gorin, D. J.; Davis, N. R. and Toste, F. D., J. Am. Chem. Soc., 2005, 127, 11260. (b) Milligan,
G. L.; Mossman, C. J. and Aubé, J., J. Am. Chem. Soc., 1995, 117, 10449.
25. Phares, E. F. and Long, M. V., J. Am. Chem. Soc., 1955, 77, 2556.
26. Evans, P. A. and Modi, D. P., J. Org. Chem., 1995, 60, 6662.
27. Datta, S. K.; Grundmann, C. and Bhattacharyya, N. K., J. Chem. Soc, C, 1970, 2058.
28. Rothchild, S. and Fields, M., J. Org. Chem., 1951, 16, 1080.
29. (a) Iyengar, R.; Schildknegt, K.; Morton, M. and Aubé, J., J. Org. Chem., 2005, 70, 10645. (b)
Clive, D. L. J.; Yu, M. L. and Li, Z. Y., Chem. Commun., 2005, 906. (c) Zeng, Y. B.; Reddy, D. S.;
Hirt, E. and Aubé, J., Org. Lett., 2004, 6, 4993. (d) Wrobleski, A.; Sahasrabudhe, K. and Aubé,
J., J. Am. Chem. Soc., 2004, 126, 5475. (e) Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B.
T.; Katz, C. E.; Reddy, D. S. and Aubé, J., J. Am. Chem. Soc., 2003, 125, 7914. (f) Fürmeier, S.
and Metzger, J. O., Eur. J. Org. Chem., 2003, 885. (g) Pellicciari, R.; Camaioni, E.; Costantino,
G.; Marinozzi, M.; Macchiarulo, A.; Moroni, F. and Natalini, B., Farmaco, 2003, 58, 851. (h)
Moroni, F.; Meli, E.; Peruginelli, F.; Chiarugi, A.; Cozzi, A.; Picca, R.; Romagnoli, P.; Pellicciari,
R. and Pellegrini-Giampietro, D. E., Cell Death & Diff., 2001, 8, 921. (i) Iyengar, R.; Schildknegt,
K. and Aubé, J., Org. Lett., 2000, 2, 1625. (j) Woodroofe, C. C.; Zhong, B. Y.; Lu, X. L. and
Silverman, R. B., J. Chem. Soc., Perkin Trans. II, 2000, 55. (k) Gracias, V.; Milligan, G. L. and
Aubé, J., J. Am. Chem. Soc., 1995, 117, 8047. (l) Pearson, W. H.; Walavalkar, R.; Schkeryantz,
J. M.; Fang, W.-k. and Blickensdorf, J. D., J. Am. Chem. Soc., 1993, 115, 10183. (m) Lévai, A.;
Timar, T.; Frank, L. and Hosztafi, S., Heterocycles, 1992, 34, 1523. (n) Yeh, M.-Y.; Tien, H.-J.
and Nonaka, T., J. Org. Chem., 1983, 48, 1382. (o) Narayanan, R. and Balaram, P., FEBS Letters,
1978, 93, 38. (p) Koldobskii, G. I.; Ostrovskii, V. A. and Gidaspov, B. Z., Chem. Heterocycl.
Compd., 1975, 11, 626. (q) Palmere, R. M.; Conley, R. T. and Rabinowitz, J. L., J. Org. Chem.,
1972, 37, 4095. (r) Moriconi, E. J. and Stemniski, M. A., J. Org. Chem., 1972, 37, 2035. (s) Sasaki,
T.; Eguchi, S. and Toru, T., J. Org. Chem., 1971, 36, 2454. (t) Koldobskii, G. I.; Tereshchenko,
G. F.; Gerasimova, E. S. and Bagal, L. I., Russ. Chem. Rev., 1971, 40, 835. (u) Fishel, D. L.;
Kletecka, G. and Muralidhara, R., Ohio J. Sci., 1970, 70, 371. (v) Hassner, A.; Ferdinandi, E. S.
and Isbister, R. J., J. Am. Chem. Soc., 1970, 92, 1672. (w) Zbarskii, V. L.; Shutov, G. M.; Zhilin,
V. F. and Orlova, E. Yu., Chem. Heterocycl. Compd., 1967, 3, 124. (x) Moore, H. W. and Shelden,
H. R., J. Org. Chem., 1967, 32, 3603. (y) Andrews, P.; Hough, L. and Picken, J. M., Biochem. J.,
1965, 97, 27. (z) Stockel, R. F. and Hall, D. M., Nature, 1963, 197, 787. (aa) Lansbury, P. T. and
Colson, J. G., J. Am. Chem. Soc., 1962, 84, 4167. (bb) Boyer, J. H. and Sanders, M., J. Org. Chem.,
1961, 26, 1644. (cc) Arcus, C. L. and Barrett, G. C., J. Chem. Soc., 1961, 1408. (dd) Zook, H. D.
and Paviak, S. C., J. Am. Chem. Soc., 1955, 77, 2501. (ee) Kohlbrenner, P. J. and Schuerch, C.,
J. Am. Chem. Soc., 1955, 77, 6066. (ff) Dickerman, S. C. and Moriconi, E. J., J. Org. Chem., 1955,
20, 206. (gg) Dickerman, S. C. and Besozzi, A. J., J. Org. Chem., 1954, 19, 1855. (hh) Ropp, G.
A.; Bonner, W. A.; Clark, M. T. and Raaen, V. F., J. Am. Chem. Soc., 1954, 76, 1710. (ii) Bunce,
S. C. and Cloke, J. B., J. Am. Chem. Soc., 1954, 76, 2244. (jj) Nielsen, D. R. and McEwen, W.
E., J. Am. Chem. Soc., 1954, 76, 4042. (kk) Lieber, E.; Henry, R. A. and Finnegan, W. G., J. Am.
Chem. Soc., 1953, 75, 2023. (ll) Smith, P. A. S. and Horwitz, J. P., J. Am. Chem. Soc., 1950, 72,
3718. (mm) Szmant, H. H. and McIntosh, J. J., J. Am. Chem. Soc., 1950, 72, 4835. (nn) Kuhn,
L. P. and DiDomenico, J., J. Am. Chem. Soc., 1950, 72, 5777. (oo) Benson, F. R.; Hartzel, L. W.
and Savell, W. L., J. Am. Chem. Soc., 1949, 71, 1111. (pp) Schuerch, C. and Huntress, E. H.,
J. Am. Chem. Soc., 1949, 71, 2238. (qq) Newman, M. S. and Gildenhorn, H. L., J. Am. Chem.
Soc., 1948, 70, 317. (rr) Smith, P. A. S., J. Am. Chem. Soc., 1948, 70, 320. (ss) Wolff, H., Org.
React., 1946, 3, 307. (tt) Schmidt, K. F., Ber., 1924, 57, 704.
398
Lossen Rearrangement
This reaction was first reported by Lossen in 1872.1 It is a thermal or alkaline conversion
of hydroxamic acid into an isocyanate via the intermediacy of its O-acyl, sulfonyl, or
phosphoryl derivative. In the presence of water, amine, or alcohol, the isocyanate is converted
into amine, urea or urethane, respectively. Therefore, this reaction is generally known as
the Lossen rearrangement.2,3 Occasionally, it is also referred to as the Lossen reaction,4
Lossen degradation,5 or Lossen transformation.6
Initially, this reaction was thought to occur via a similar mechanism of Curtius Rear-
rangement or Hofmann Rearrangement7 by means of the formation of an univalent nitrogen
intermediate (known as nitrene), from which the alkyl group migrates from the carbon to
the nitrogen atom to form isocyanate.7 However, such idea of the reaction mechanism is
challenged on the basis of the modern valence theory, thus a few mechanisms are pro-
posed to rationalize the Lossen rearrangement,2k,2n,3bb,4c,4f including the one proposed by
Jones and Hurd.8 In addition, the recently accepted mechanism2k,2n,3bb,4c,4f involves the
deprotonation of N-H from a base, followed by the concurrent migration of an alkyl group
and release of a carboxylate (or sulfonate or phosphonate) if the hydroxamic acid is acti-
vated by an acyl group (or correspondingly by a sulfonyl or phosphoryl group2n ). It has
been found that the rearrangement rate is directly proportional to the acidity of the leaving
group or the conjugate acid of the leaving group if the leaving group is an anion;2h in addi-
tion, in the case of O-benzoyl phenylhydroxamic acid, the electron-donating group on the
phenyl and electron-withdrawing group on the benzoyl moiety will facilitate the rearrange-
ment, especially when these substituents are in the meta- or para-positions.4c It has been

1772
MODIFICATION 1773
found that the stereochemistry of the migrating group is retained after the migration.2l,3bb
Unfortunately, because of the intrinsic self-condensation reaction between the hydroxamic
acid and the isocyanate, and the general unavailability of hydroxamic acid,2b this reaction
had not been widely used in organic synthesis until recent modifications.2f In fact, the
desired hydroxamic acid can easily be prepared from the reaction between hydroxamine
and acyl halide, ester, or anhydride.3bb The Lossen rearrangement has been modified by
the addition of a water-soluble carbodiimide,2j application of lithium aluminum hydride
as base and reducing reagent,2m or protection of hydroxamic acid with a t-butylcarboxyl
group2b as well as carrying out the reaction in the presence of formamide2f and using an
enzyme to catalyze the reaction.2e,3x
H
R N R′ Base or ∆ R
N
C R = alkyl, aryl
O O R′ = acyl, sulfonyl, phosphoryl
O
A simple mechanism is depicted here for this rearrangement, including the formation of
isocyanate derivatives.
D. MODIFICATION
This reaction has been modified to occur under different conditions, such as the addition
of carbodiimide, and formamide, as described in Section A.
1774 LOSSEN REARRANGEMENT
E. APPLICATIONS
This reaction has general application in the preparation of amine, urea, and urethane
derivatives.
This reaction is related to the Curtius Rearrangement and Hofmann Rearrangement.
O 10 mol % Zn(OTf)2
O 2,6-DTBP, BnOH NH
N CH3CN, ∆ O-t-Bu
MsO O-t-Bu O
81%
Reference 2b.
To a solution of 610 mg N-(t-butyloxycarbonyl)-N-(methanesulfonyloxy)cyclopent-

3-enylcarboxamide (2.0 mmol) in 10 mL CH3 CN were added 238 mg benzyl alcohol
(2.2 mmol), 382 mg 2,6-di-t-butylpyridine (2.0 mmol), and 72 mg zinc triflate (0.2 mmol).
The mixture was heated with stirring at 85◦ C for 16 h and then cooled to room tem-
perature. It was then diluted with 50 mL EtOAc, washed with water, 1 M H3 PO4, and
brine (50 mL each). The combined aqueous layers were back extracted with ethyl acetate
(2 × 50 mL); the combined organic layers were dried over MgSO4 , filtered, and concen-
trated in vacuo. The residue was flash chromatographed (4:1, hexanes/EtOAc) to afford
352 mg N-(benzyloxycarbonyl)cyclopent-3-enylamine as a colorless solid, in a yield of
81%, m.p. 50–52◦ C.
1) EtOH/H2O/NaOH
N O NO2 2) H2SO4
O2N
81%
O
NO2
O
NH
+
O2N O2N NH
O
9:1
Reference 9.
REFERENCES 1775
To a 22-L, of clean, three-necked flask were added 4.650 L deionized water and 10.75 L
absolute ethanol. To this solution was added 236 g NaOH (5.9 mol, 4.04 eq.). The resul-
tant solution was cooled to 10◦ C, and 620 g N-(2,4-dinitrophenoxy)-4-nitronaphthalimide
(1.46 mol, 1.0 eq.) was added. The mixture was stirred for 44 h at ambient temperature until
the completion was detected by TLC (CHCl3 /MeOH, 95:5). The pH was adjusted to 3 with
175 mL conc. H2 SO4, and the mixture was cooled to < 10◦ C and filtered. The wet filter
cake was reslurried in 3 L deionized water, and the pH was adjusted to 7–8 by the addition
of saturated aqueous NaHCO3 solution. The mixture was filtered, washed with water and
95% ethanol, and dried under vacuum to yield 254 g 5-nitrobenz[cd]indol-2(1H)-one, in a
yield of 81%. 1 HNMR analysis of the product showed that the product was contaminated
with ∼10% of the regioisomer 6-nitrobenz[cd]indol-2(1H)-one.
Other references related to the Lossen rearrangement are cited in the literature.10
H. REFERENCES
1. Lossen, W., Ann., 1872, 161, 347.

2. (a) Zalipsky, S., Chem. Commun., 1998, 69. (b) Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.;
Suh, E. M. and Feldman, P. L., J. Org. Chem., 1998, 63, 10040. (c) Hirrlinger, B. and Stolz, A.,
Appl. Environ. Microbio., 1997, 63, 3390. (d) Salomon, C. J. and Breuer, E., J. Org. Chem., 1997,
62, 3858. (e) Groutas, W. C.; Stanga, M. A. and Brubaker, M. J., J. Am. Chem. Soc., 1989, 111,
1931. (f) Eckstein, Z.; Jadach, T. and Lipczynska-Kochany, E., J. Chem. Eng. Data, 1983, 28,
279. (g) Tserng, K.-Y. and Bauer, L., J. Org. Chem., 1973, 38, 3498. (h) Swenson, J. S.; Davis, A.
M.; Deyo, R. A.; Graham, B. W.; Jahn, E. P. and Mattice, J. D., J. Org. Chem., 1973, 38, 3956. (i)
Zvilichovsky, G., J. Org. Chem., 1969, 34, 486. (j) Hoare, D. G.; Olson, A. and Koshland, D. E.,
J. Am. Chem. Soc., 1968, 90, 1638. (k) Berndt, D. C. and Adams, W. J., J. Org. Chem., 1966, 31,
976. (l) Bauer, L. and Miarka, S. V., J. Org. Chem., 1959, 24, 1293. (m) Bauer, L., J. Am. Chem.
Soc., 1956, 78, 1945. (n) Stolberg, M. A.; Tweit, R. C.; Steinberg, G. M. and Wagner-Jauregg, T.,
J. Am. Chem. Soc., 1955, 77, 765. (o) Hurd, C. D.; Bauer, L. and Klotz, I. M., J. Am. Chem. Soc.,
1953, 75, 624. (p) Franklin, E. C., Chem. Rev., 1934, 219.
3. (a) Yagupolskii, L. M.; Shelyazhenko, S. V.; Maletina, I. I.; Sokolenko, L. V.; Chernega, A. N.;
Rusanov, E. B. and Tsymbal, I. F., J. Fluor. Chem., 2007, 128, 515. (b) Needs, P. W.; Rigby,
N. M.; Ring, S. G. and MacDougall, A. J., Carbohydr. Res., 2001, 333, 47. (c) Abbady, M. S.;
Kandeel, M. M. and Youssef, M. S. K., Phosphorus, Sulfur & Silicon & Related Elements, 2000,
163, 55. (d) Podlaha, J.; Cisarova, I.; Soukupova, L.; Schraml, J. and Exner, O., J. Chem. Res.
(S), 1998, 520. (e) Casteel, D. A.; Gephart, R. S. and Morgan, T., Heterocycles, 1993, 36, 485. (f)
Fawcett, J.; Harger, M. J. P. and Sreedharan-Menon, R., J. Chem. Soc., Chem. Commun., 1992,
227. (g) Adams, G. W.; Bowie, J. H. and Hayes, R. N., J. Chem. Soc., Perkin Trans. II, 1991,
689. (h) Harger, M. J. P. and Smith, A., J. Chem. Soc., Perkin Trans. I, 1990, 1447. (i) Pihuleac,
J. and Bauer, L., Synthesis, 1989, 61. (j) Groutas, W. C.; Giri, P. K.; Crowley, J. P.; Castrisos, J.
C. and Brubaker, M. J., Biochem. Biophys. Res. Commun., 1986, 141, 741. (k) Harger, M. J. P., J.
Chem. Soc., Perkin Trans. I, 1983, 2699. (l) Harris, R. B. and Wilson, I. B., J. Biol. Chem., 1983,
258, 1357. (m) Van Verst, M. E.; Bell, C. L. and Bauer, L., J. Heterocycl. Chem., 1979, 16, 1329.
(n) Harger, M. J. P., J. Chem. Soc., Chem. Commun., 1979, 930. (o) Fahmy, A. F. M.; Aly, N. F.;
Nada, A. and Aly, N. Y., Bull. Chem. Soc. Jpn., 1977, 50, 2678. (p) Bergman, J.; Lindstroem, J.
O.; Abrahamsson, J. and Hadler, E., Tetrahedron Lett., 1976, 3615. (q) Bittner, S.; Grinberg, S.
and Kartoon, I., Tetrahedron Lett., 1974, 1965. (r) Dell, D.; Boreham, D. R. and Martin, B. K.,
J. Pharm. Sci., 1971, 60, 1368. (s) Beck, W. and Lindenberg, B., Angew. Chem. Int. Ed. Engl.,
1970, 9, 735. (t) BeMiller, J. N. and Wisely, G. T., Trans. Illinois State Acad. Sci., 1967, 60, 117.
1776 LOSSEN REARRANGEMENT
(u) Bauer, L. and Mahajanshetti, C. S., J. Heterocycl. Chem., 1967, 4, 325. (v) Gallop, P. M.;
Seifter, S.; Lukin, M. and Meilman, E., J. Biol. Chem., 1960, 235, 2619. (w) Behringer, H. and
Meier, H., Ann., 1957, 607, 67. (x) Ettlinger, M. G. and Lundeen, A. J., J. Am. Chem. Soc., 1957,
79, 1764. (y) Andersen, W., Acta Chem. Scand., 1954, 8, 1721. (z) Hurd, C. D. and Bauer, L., J.
Am. Chem. Soc., 1951, 73, 4387. (aa) Bright, R. D. and Hauser, C. R., J. Am. Chem. Soc., 1939,
61, 618. (bb) Wallis, E. S. and Dripps, R. D., J. Am. Chem. Soc., 1933, 55, 1701.
4. (a) Chandrasekhar, S. and Sridhar, M., Tetrahedron: Asymmetry, 2000, 11, 3467. (b) Knobler, Y.;
Frydman, N. and Eliasoff, H., Isr. J. Chem., 1971, 9, 165. (c) Berndt, D. C. and Shechter, H., J.
Org. Chem., 1964, 29, 916. (d) Snyder, H. R. and Elston, C. T., J. Am. Chem. Soc., 1954, 76,
3039. (e) Wieland, T. and Fritz, H., Chem. Ber., 1953, 86, 1186. (f) Renfrow, W. B. and Hauser,
C. R., J. Am. Chem. Soc., 1937, 59, 2308.
5. (a) Joensson, N. A. and Moses, P., Acta Chem. Scand., Ser. B, 1974, 28, 441. (b) Feinstein, G.;
Bodlaender, P. and Shaw, E., Biochemistry, 1969, 8, 4949. (c) Holm, A., Acta Chem. Scand., 1968,
22, 2019. (d) Bauer, L. and Mahajanshetti, C. S., J. Heterocycl. Chem., 1968, 5, 331. (e) Lund,
H., Acta Chem. Scand., 1960, 14, 359.
6. Anilkumar, R.; Chandrasekhar, S. and Sridhar, M., Tetrahedron Lett., 2000, 41, 5291.
7. (a) Stieglitz, J. and Leech, P. N., J. Am. Chem. Soc., 1914, 36, 272. (b) Stieglitz, J., Am. Chem. J.,
1903, 29, 49. (c) Stieglitz, J., Am. Chem. J., 1896, 18, 751.
8. Jones, L.W. and Hurd, C.D. J. Am. Chem. Soc., 1921, 43, 2422. Jones, L.W. and Hurd, C.D.
9. Marzoni, G. and Varney, M. D., Org. Proc. Res. Dev., 1997, 1, 81.
10. (a) Simanenko, Y. S.; Prokopeva, T. M.; Popov, A. F.; Bunton, C. A.; Karpichev, E. A.; Savelova,
V. A. and Ghosh, K. K., Russ. J. Org. Chem., 2004, 40, 1337. (b) Burungule, A. S.; Bondge, S.
P.; Munde, S. B.; Bhingolikar, V. E. and Mane, R. A., Synth. Commun., 2003, 33, 1923. (c) Dadd,
M. R.; Claridge, T. D. W.; Pettman, A. J. and Knowles, C. J., Biotechnology Lett., 2001, 23, 221.
(d) Hecht, S. S., Drug Metabol. Rev., 2000, 32, 395. (e) Shikita, M.; Fahey, J. W.; Golden, T.
R.; Holtzclaw, W. D. and Talalay, P., Biochem. J., 1999, 341, 725. (f) Horspool, K. R.; Stevens,
M. F. G.; Newton, C. G.; Lunt, E.; Walsh, R. J. A.; Pedgrift, B. L.; Baig, G. U.; Lavelle, F. and
Fizames, C., J. Med. Chem., 1990, 33, 1393. (g) Lwowski, W.; de Mauriac, R. A.; Thompson, M.;
Wilde, R. E. and Chen, S.-Y., J. Org. Chem., 1975, 40, 2608. (h) Bauer, L. and Exner, O., Angew.
Chem. Int. Ed. Engl., 1974, 13, 376. (i) Linke, S.; Tisue, G. T. and Lwowski, W., J. Am. Chem.
Soc., 1967, 89, 6308. (j) Lwowski, W. and Scheiffele, E., J. Am. Chem. Soc., 1965, 87, 4359.
(k) Cohen, L. A. and Witkop, B., Angew. Chem., 1961, 73, 260. (l) Walling, C. and Naglieri, A.
N., J. Am. Chem. Soc., 1960, 82, 1820. (m) Popp, F. D. and McEwen, W. E., Chem. Rev., 1958,
58, 374. (n) Hurd, C. D.; Buess, C. M. and Bauer, L., J. Org. Chem., 1952, 17, 865. (o) Hauser,
C. R. and Kantor, S. W., J. Am. Chem. Soc., 1950, 72, 4284. (p) Yale, H. L., Chem. Rev., 1943,
33, 209. (q) Bright, R. D. and Hauser, C. R., J. Am. Chem. Soc., 1939, 61, 618.
681
Wolff Rearrangement
This reaction was first reported by Wolff in 1902.1 It is a thermal, photochemical or

catalytic transformation of α-diazoketones into ketenes, and is generally known as the
Wolff rearrangement2,3 or Wolff-rearrangement.2q,4 Occasionally, it is also referred to as
the Wolff transposition.2f,5 It should be pointed out that the Wolff rearrangement initi-
ated or induced by photo illumination is termed the photochemical Wolff rearrangement,6
photo-Wolff reaction,7 photo-Wolff rearrangement,8 photolytic Wolff rearrangement,9 or
photoinduced Wolff rearrangement.10 In addition, a special case of the Wolff rearrange-
ment for the conversion of β,γ-unsaturated α-diazoketones into γ,δ-unsaturated esters,
which are usually prepared from the Johnson-Claisen Rearrangement,11 is called the viny-
logous Wolff rearrangement.4c,12 The resulting ketenes from the Wolff rearrangement can
be simply converted into carboxylic acids or esters in the presence of water or alcohols,
respectively.2m,2q It should be pointed out that the one-carbon homologation of carboxylic
acids by the formation of α-diazoketones is known as the Arndt-Eistert Synthesis.13
The Wolff rearrangement readily takes place under various conditions, such as
those under photo illumination,2h−2j,2p,4,6−10 electron-beam induction,13 microwave14 or
ultrasound15 irradiation, heating,2d,2p,7a,16 and flash vacuum pyrolysis,2h,2l,2o and the appli-
cation of transition metal catalyst.2b,2e,17 The readiness of Wolff rearrangement is probably
due to the evolution of a nitrogen molecule, forming a carbenic intermediate.18 Some transi-
tion metal catalysts used include the copper (I) salt12g,12h (e.g., CuI17b ), silver (I) salt2b,12g,19
(e.g., silver trifluoroacetate,2a and silver benzoate18c,21 ), rhodium (II) salt2e,3k,3p,3t,12b,12c,21

3073
3074 WOLFF REARRANGEMENT
(e.g., Rh2 (OAc)4 ·2H2 O21 ) and even neutral silver nano particles.19a,22 It has been
reported that the copper salt can facilitate the generation of a carbene intermediate and
lower the energy barrier for the Wolff rearrangement,2b however, a silver salt is even
better than the copper salt for such purpose.2b,17a Notably, the Wolff rearrangement under
microwave irradiation in benzylamine has equivalent behavior of the photochemical Wolff
rearrangement.14b
In addition, other factors can also affect the outcome of the Wolff rearrangement, such
as the actual structures of the α-diazo ketones, conformation of the molecules, solvents, and
the presence of carbon monoxide or oxygen. It has been reported that cyclic α-diazoketones
undergo the Wolff rearrangement to give the ring-contracted cyclic carboxylic acids, which
has become a general method for the preparation of small ring compounds of high ring-
strain23 that might not be easily attained from other methods,2d,6r as exemplified by the
formation of benzocyclobutanoic acid from α-diazoindanone.2d Moreover, the Wolff re-
arrangement for the cyclic α-diazoketones is accelerated,10 except for the reaction with an
increased strain at the transition state because of the ring contraction.6h In the case of β-
oxy-α-diazoketones, such as β-hydroxy-α-diazoketones, the regular alkyl migration in the
normal Wolff rearrangement is depressed by the competitive 1,2-H shift from hydroxyl to
carbene, leading to 100% of vinyl ketones.2f In terms of the structures of α-diazoketones,
α-diazo malonates often form vinyl alkyl ethers due to the loss of carbon monoxide;24
for comparison, α,β-unsaturated homologues do not afford the expected rearrangement
products, due to the potential cyclopropanation between the carbene and C−C double
bond.2q However, non-α,β-unsaturated α-diazoketones under basic conditions may give
regular Wolff rearrangement products, such as the unsaturated or dienic acids.2q A type
of Wolff rearrangement involving non-α,β-unsaturated α-diazoketones is the vinylogous
Wolff rearrangement.6l,12 Furthermore, both carbon monoxide and oxygen are reported to
suppress the Wolff rearrangement, and carbon monoxide is especially effective. For exam-
ple, the Wolff rearrangement might be completely suppressed in the presence of 5% CO,
and such suppression is notable even in the presence of 1% CO.2i Regarding the solvent
effect, due to the electrostatic interaction, the 1,2-H shift of ketocarbene intermediate is
favored in polar solvents, whereas the Wolff rearrangement is favored in nonpolar sol-
vents because of the dispersion interactions.2f It is interesting that even conformation can
affect the Wolff rearrangement.2o,6o,14b,25 For example, 2-diazodibenzyl malonate under-
goes the Wolff rearrangement more easily than 2-diazodimethyl malonate in the presence
of a transition metal catalyst because the conformational energy minimum of the complex
from 2-diazodibenzyl malonate is closer to the preferred conformational orientation for the
Wolff rearrangement to occur.2b
It should be pointed out that the Wolff rearrangement of α-diazoketones with a chirality
at the α -carbon next to the carbonyl group proceeds with retention of configuration during
the migration of the α -carbon to the carbenic atom,2g,20b,26 as evidenced in the preparation
of the optically pure β-amino acids through an Arndt-Eistert Synthesis,2g,22 as well as the
synthesis of indolizidines.2g
The reversal of the Wolff rearrangement, known as the retro-Wolff rearrange-
ment,2l,16a,27 has also been reported, although this transformation is very rare.21 One
example is the decomposition of hydridosilylketenes.2l
Even though the Wolff rearrangement has been known for more than 100 years, the reac-
tion mechanism is still controversial. The controversies are twofold: is the rearrangement
a concerted process or a nonconcerted process? If the reaction is a nonconcerted process,
then which carbene intermediate is involved, a triplet or a singlet? The concerted process is
favored by the stereochemical and CIDNP evidence;6h,28 whereas carbon atom labeling,2m
chemical trapping,2m and the diversion of the Wolff rearrangement in carbon monoxide
or dopped CO-matrix2i all are consistent with a nonconcerted Wolff rearrangement. On
the other hand, it has been reported that the triplet α-ketocarbenes generated from photo-
sensitized decomposition of α-diazoketones do not undergo the Wolff rearrangement,28,29
however, some other experimental evidence supports the involvement of a ground-state
triplet ketocarbene,6h such as the ring contraction under photolysis.2o For the stepwise
Wolff rearrangement, oxirene is suggested as the intermediate2k,2m,2n,6h,6o,6q,10,24 which
undergoes either a ring opening or an alkyl group migration.2n This mechanistic controversy
might be caused by the conformation of α-diazoketones. It has been reported that s-Z dia-
zoketones undergo a concerted Wolff rearrangement at singlet excited state with elimination
of nitrogen, whereas s-E conformers proceed in a stepwise manner to dissociate nitrogen
and form singlet ketocarbenes,18,30 which then undergo insertion, 1,2-H shift or ketene
formation.18 It should be pointed out that upon the elimination of nitrogen, the carbenic
atom becomes less negative, which can be stabilized by the inductive effect of the attached
alkyl groups, thus an alkyl group will facilitate the loss of nitrogen.31 For the vinylogous
Wolff rearrangement, a mechanism involving a bicyclo[2.1.0]pentane intermediate and/or
a zwitterionic species arising from the insertion of ketocarbene to β,γ-unsaturated C=C
bond has been suggested.12g Moreover, the treatment of α-diazoketones in an alcohol with a
solution of silver benzoate in Et3 N has been proposed to involve both ionic and free radical
intermediates.17c A simple illustration of the reaction mechanism is given here.30a
D. MODIFICATION
The Wolff rearrangement has been extensively modified. The most important and use-
ful modification might be the vinylogous Wolff rearrangement,6l,12 which transforms
β,γ-unsaturated α -diazoketones into γ,δ-unsaturated esters, usually available from the
Johnson-Claisen Rearrangement.11 For such rearrangement, the overall reactivity follows
the order of tetra- > tri- > di- > monosubstituted olefin, and monocyclic and acyclic sys-
tems have similar reactivities. In addition, the highest yield of rearranged products could
be obtained from the substrates with disubstitution at the α-carbon, and this reaction is
optimally promoted by the combination of CuOTf and benzyl alcohol.12f
In addition, although the application of rhodium catalyst for diazoketone decomposition
suppresses the Wolff rearrangement,2e,17a rhodium(II) octanoate,2e and Rh2 (OAc)4 ·2H2 O21
mediated Wolff rearrangements have been developed. Other modifications include the Wolff
rearrangement in a homogenous medium by the treatment of α-diazoketone in an alcohol
with a solution of silver benzoate in Et3 N,17c the application of silver nanoclusters as electron
mediators by addition of Ag(I) oxide to the solution of α-diazoketones,19a,22 and an aza
Wolff rearrangement to convert 4-oxo-4H-quinolizine-3-diazonium tetrafluoroborates into
alkyl indolizine-3-carboxylates.32
E. APPLICATIONS
This reaction has very broad application in organic synthesis as described earlier. In
addition, this reaction also is important for industrial imaging.33
This reaction is closely related to the Arndt-Eistert Synthesis and Nierenstein Reaction.
Reference 6e.
To a Pyrex bottle were added 0.77 g methyl 4-(diazoacetyl)-8-(phenylmethoxy)-

2-naphthalenecarboxylate (2.13 mmol), 0.87 mL N-methyl-(2-phenyl)-ethylamine
(5.98 mmol), and 120 mL toluene. The resulting mixture was irradiated with a Hanovia
REFERENCES 3077
mercury lamp for 5 h and then concentrated under vacuum. The residue was purified by
flash column chromatography using EtOAc/hexanes (1:9–6:4) to afford 0.87 g methyl 4-
[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-8-(phenylmethoxy)-2-naphthalenecarbox-
ylate as an oil, in a yield of 87%.
Reference 15a.
To an oven-dried flask equipped with a nitrogen inlet connecting with a tube with
an external reflux condenser (outside the microwave oven), were added 989 mg Cbz-
Ala-CHN2 (4.0 mmol), 1.61 g N-benzyl-furan-2-carbaldimine (8.0 mmol), and 50 mL
1,2-dichlorobenzene. The mixture was irradiated at 160◦ C for 30 min with a 500-W
microwave. After that, the mixture was loaded directly onto a silica gel column (120 g,
35 cm), and washed by light petroleum/EtOAc (5:1→3:1→1:2) to remove the solvent.
The collected diastereoisomers in amount of 1.43 g (88%) was analyzed by 1 H NMR and
HPLC as a 65:35 ratio and was then separated by medium pressure liquid chromatography
(light petroleum/isopropanol, 97:3) to afford 803 mg (3R,4S,1 S)-1-benzyl-3-[1-
(benzyloxycarbonylamino)ethyl]-4-(2-furyl)-azetidin-2-one (50%, m.p. 110–113◦ C) and
415 mg (3S,4R,1 S)-1-benzyl-3-[1-(benzyloxycarbonylamino)ethyl]-4-(2-furyl)-azetidin-
2-one (26%, m.p. 111–112◦ C, light petroleum/i-PrOH).
Other references related to the Wolff rearrangement are cited in the literature.34
H. REFERENCES
1. Wolff, L., Ann., 1902, 325, 129.

2. (a) Hughes, A. B. and Sleebs, B. E., Aust. J. Chem., 2005, 58, 778. (b) Julian, R. R.; May, J.
A.; Stoltz, B. M. and Beauchamp, J. L., J. Am. Chem. Soc., 2003, 125, 4478. (c) Kirmse, W.,
Eur. J. Org. Chem., 2002, 2193. (d) Mehta, G. and Kotha, S., Tetrahedron, 2001, 57, 625.
(e) Marsden, S. P. and Pang, W.-K., Chem. Commun., 1999, 1199. (f) Calvo-Losada, S.;
Suárez, D.; Sordo, T. L. and Quirante, J. J., J. Phys. Chem. B, 1999, 103, 7145. (g) Wang,
J. B. and Hou, Y. H., J. Chem. Soc., Perkin Trans. I, 1998, 1919. (h) Lippert, T.; Stout-
land, P. O., Appl. Surface Sci., 1997, 109/110, 43. (i) McCluskey, A. and Dunkin, I. R.,
Aust. J. Chem., 1995, 48, 1107. (j) de Lucas, N. C.; Andraos, J.; Netto-Ferreira, J. C. and
Scaiano, J. C., Tetrahedron Lett., 1995, 36, 677. (k) Scott, A. P.; Nobes, R. H.; Schaefer,
H. F. and Radom, L., J. Am. Chem. Soc., 1994, 116, 10159. (l) Nguyen, M. T.; Hajnal, M.
R.; Ha, T.-K.; Vanquickenborne, L. G. and Wentrup, C., J. Am. Chem. Soc., 1992, 114, 4387.
(m) Lovejoy, E. R.; Kim, S. K.; Alvarez, R. A. and Moore, C. B., J. Chem. Phys., 1991, 95, 4081.
(n) Tanigaki, K. and Ebbesen, T. W., J. Am. Chem. Soc., 1987, 109, 5883. (o) McMahon, R.
J.; Chapman, O. L.; Hayes, R. A.; Hess, T. C. and Krimmer, H.-P., J. Am. Chem. Soc., 1985,
107, 7597. (p) Hacker, N. P. and Turro, N. J., Tetrahedron Lett., 1982, 23, 1771. (q) Hudlicky,
T. and Sheth, J. P., Tetrahedron Lett., 1979, 2667. (r) Roth, H. D. and Manion, M. L.,
J. Am. Chem. Soc., 1976, 98, 3392.
3. (a) Gomez, M.; Paneque, M.; Poveda, M. L. and Alvarez, E., J. Am. Chem. Soc., 2007, 129,
6092. (b) Koepke, T.; Pink, M. and Zaleski, J. M., Org. Biomol. Chem., 2006, 4, 4059.
(c) Liao, M. Y.; Dong, S. W.; Deng, G. S. and Wang, J. B., Tetrahedron Lett., 2006, 47, 4537.
(d) Sudrik, S. G.; Chaki, N. K.; Chavan, V. B.; Chavan, S. P.; Chavan, S. P.; Sonawane, H.
R. and Vijayamohana, K., Chem. Eur. J., 2006, 12, 859. (e) Kornilov, V. I.; Glebova, Z. I. and
Sudareva, T. P., Russ. J. Gen. Chem., 2005, 75, 1883. (f) Popik, V. V., Can. J. Chem., 2005, 83,
1382. (g) Kantharaju, B. S. Patil; B. and Vommina V. S., Indian J. Chem., Sect. B, 2005, 44B,
2611. (h) Davies, J. R.; Kane, P. D.; Moody, C. J. and Slawin, A. M. Z., J. Org. Chem., 2005,
70, 5840. (i) Akai, N.; Kudoh, S. and Nakata, M., J. Photochem. Photobio., A: Chem., 2005,
169, 47. (j) Kresge, A. J., Chemtracts, 2004, 17, 456. (k) Yanez, E. C. and Almanza, R. C.,
Revista Soc. Quim. Mexico, 2004, 48, 46. (l) Hu, J.; Liu, Y. B.; Khemtong, C.; El Khoury, J.
M.; McAfoos, T. J. and Taschner, I. S., Langmuir, 2004, 20, 4933. (m) Sato, T.; Niino, H.
and Yabe, A., J. Am. Chem. Soc., 2003, 125, 11936. (n) Zimmerman, H. E. and Wang, P. F.,
Can. J. Chem., 2003, 81, 517. (o) Bucher, G.; Strehl, A. and Sander, W., Eur. J. Org. Chem., 2003,
2153. (p) Dayoub, W.; Diab, Y. and Doutheau, A., Tetrahedron Lett., 2001, 42, 8455. (q) Calvo-
Losada, S.; Sordo, T. L.; Lopez-Herrera, F. J. and Quirante, J. J., Theo. Chem. Acct., 2000, 103,
423. (r) Tilekar, J. N.; Patil, N. T. and Dhavale, D. D., Synthesis, 2000, 395. (s) Borisov, Yu.
A.; Garrett, B. C. and Feller, D., Russ. Chem. Bull., 1999, 48, 1642. (t) Lee, Y. R.; Suk, J. Y.
and Kim, B. S., Tetrahedron Lett., 1999, 40, 8219. (u) Leost, F.; Chantegrel, B. and Deshayes,
C., Tetrahedron, 1998, 54, 6457. (v) Calvo-Losada, S. and Quirante, J. J., THEOCHEM, 1997,
398–399, 435–443. (w) Leost, F.; Chantegrel, B. and Deshayes, C., Tetrahedron, 1997, 53, 7557.
(x) Huang, G. Y.; Guo, J. Y. and Liang, X. T., Chinese Chem. Lett., 1996, 7, 1077. (y) Chantegrel,
B.; Deshayes, C. and Faure, R., Tetrahedron Lett., 1995, 36, 7859. (z) Uyehara, T.; Takehara, N.;
Ueno, M. and Sato, T., Bull. Chem. Soc. Jpn., 1995, 68, 2687.
4. Vleggaar, J. J. M.; Huizer, A. H.; Kraakman, P. A.; Nijssen, W. P. M.; Visser, R. J. and Varma, C.
A. G. O., J. Am. Chem. Soc., 1994, 116, 11754.
5. Garbarino, J. A., Annali dell’Instituto Superiore di Sanita, 1968, 4, 590.
6. (a) Kresge, A. J., Chemtracts, 2004, 17, 269. (b) Zeller, K.-P.; Blocher, A. and Haiss, P.,
Mini-Rev. Org. Chem., 2004, 1, 291. (c) Haiss, P. and Zeller, K.-P., Org. Biomol. Chem., 2003,
1, 2556. (d) Haiss, P. and Zeller, K.-P., Zeitsch. Naturforsch., B: Chem. Sci., 2003, 58, 595.
(e) Pendrak, I. and Chambers, P. A., J. Org. Chem., 1996, 60, 3249. (f) Ulbricht, M.; Thurner,
J. U.; Siegmund, M. and Tomaschewski, G., Zeitsch. Chem., 1988, 28, 102. (g) Kloetzer,
W.; Doerler, G.; Stanovnik, B. and Tisler, M., Heterocycles, 1984, 22, 1763. (h) Hayes, R.
A.; Hess, T. C.; McMahon, R. J. and Chapman, O. L., J. Am. Chem. Soc., 1983, 105, 7786.
(i) Blaustein, M. A. and Berson, J. A., Tetrahedron Lett., 1981, 22, 1081. (j) Georgian, V.;
Boyer, S. K. and Edwards, B., J. Org. Chem., 1980, 45, 1686. (k) Bramwell, F. B.; Zad-
jura, R. E.; Paley, C. and Fahrenholtz, S. R., J. Chem. Edu., 1978, 55, 403. (l) Branca, S.
J.; Lock, R. L. and Smith, A. B., J. Org. Chem., 1977, 42, 3165. (m) Spangler, R. J.; Kim,
J. H. and Cava, M. P., J. Org. Chem., 1977, 42, 1697. (n) Boelsing, F. and Spanuth, E.,
Zeitsch. Naturforsch., Teil B, 1976, 31B, 1391. (o) Fenwick, J.; Frater, G.; Ogi, K. and Strausz,
O. P., J. Am. Chem. Soc., 1973, 95, 124. (p) Wheeler, T. N. and Meinwald, J., Org. Synth., 1972,
52, 53. (q) Frater, G. and Strausz, O. P., J. Am. Chem. Soc., 1970, 92, 6654. (r) Cava, M. P. and
Spangler, R. J., J. Am. Chem. Soc., 1967, 89, 4550.
REFERENCES 3079
7. (a) Bogdanova, A. and Popik, V. V., J. Am. Chem. Soc., 2003, 125, 1456. (b) Chiang, Y.; Kresge,
A. J. and Popik, V. V., J. Am. Chem. Soc., 1999, 121, 5930.
8. Chiang, Y.; Kresge, A. J. and Popik, V. V., J. Chem. Soc., Perkin Trans. II, 1999, 1107.
9. Chiang, Y.; Kresge, A. J.; Nikolaev, V. A.; Onyido, I. and Zeng, X., Can. J. Chem., 2005, 83, 68.
10. Lippert, T.; Koskelo, A. and Stoutland, P. O., J. Am. Chem. Soc., 1996, 118, 1551.
11. See Claisen Rearrangement herein (P. 649).
12. (a) Ceccherelli, P.; Curini, M.; Epifano, F.; Marcotullio, M. C. and Rosati, O.,
Synth. Commun., 1995, 25, 301. (b) Ceccherelli, P.; Curini, M.; Marcotullio, M. C. and Rosati,
O., Gazz. Chim. Ital., 1994, 124, 177. (c) Motallebi, S. and Mueller, P., Chimia, 1992, 46, 119.
(d) Saha, B.; Bhattacharjee, G. and Ghatak, U. R., J. Chem. Soc., Perkin Trans. I, 1988, 939.
(e) Saha, B.; Bhattacharjee, G. and Ghatak, U. R., Tetrahedron Lett., 1986, 27, 3913. (f) Smith,
A. B.; Toder, B. H. and Branca, S. J., J. Am. Chem. Soc., 1984, 106, 3995. (g) Smith, A. B.;
Toder, B. H.; Richmond, R. E. and Branca, S. J., J. Am. Chem. Soc., 1984, 106, 4001. (h) Smith,
A. B.; Toder, B. H. and Branca, S. J., J. Am. Chem. Soc., 1976, 98, 7456. (i) Smith, A. B.,
J. Chem. Soc., Chem. Commun., 1974, 695.
13. Pacansky, J. and Coufal, H., J. Am. Chem. Soc., 1980, 102, 400.
14. (a) Lindler, M. R. and Podlech, J., Org. Lett., 2002, 3, 1849. (b) Sudrik, S. G.; Chavan, S. P.; Chan-
drakumar, K. R. S.; Pal, S.; Date, S. K.; Chavan, S. P. and Sonawane, H. R., J. Org. Chem., 2002,
67, 1574.
15. Mueller, A.; Vogt, C. and Sewald, N., Synthesis, 1998, 837.
16. (a) Barton, T. J. and Groh, B. L., J. Am. Chem. Soc., 1985, 107, 7221. (b) Wilds, A. L.; von
Trebra, R. L. and Woolsey, N. F., J. Org. Chem., 1969, 34, 2401. (c) Smith, L. I. and Hoehn, H.
H., Org. Synth. Coll. 1955, 3, 356.
17. (a) Bien, S. and Segal, Y., J. Org. Chem., 1977, 42, 1685. (b) Yates, P. and Crawford, R. J.,
J. Am. Chem. Soc., 1966, 88, 1562. (c) Newman, M. S. and Beal, P. F., J. Am. Chem. Soc., 1950,
72, 5163.
18. Tomioka, H.; Okuno, H. and Izawa, Y., J. Org. Chem., 1980, 45, 5278.
19. (a) Sudrik, S. G.; Maddanimath, T.; Chaki, N. K.; Chavan, S. P.; Chavan, S. P.; Sonawane,
H. R. and Vijayamohanan, K., Org. Lett., 2003, 5, 2355. (b) Yuhawa, Y.; Tsuno, Y. and
Ibata, T., Bull. Chem. Soc. Jpn., 1967, 40, 2613. (c) Yuhawa, Y.; Tsuno, Y. and Ibata, T.,
Bull. Chem. Soc. Jpn., 1967, 40, 2618. (d) Bachmann, W. E. and Struve, W. S., Org. React., 1946,
1, 38. (e) Lane, J. F.; Willenz, J.; Weissberger, A. and Wallis, E. S., J. Org. Chem., 1940, 5, 276.
20. (a) Lee, V. and Newman, M. S., Org. Synth. Coll. 1988, 6, 613. (b) Wiberg, K. B. and Hutton, T. W.,
J. Am. Chem. Soc., 1956, 78, 1640. (c) Newman, M. S. and Beal, P. F., J. Am. Chem. Soc., 1950,
72, 3.
21. Lee, D. J.; Kim, K. and Park, Y. J., Org. Lett., 2002, 4, 873.
22. Sudrik, S. G.; Sharma, J.; Chavan, V. B.; Chaki, N. K.; Sonawane, H. and Vijayamohanan, K. P.,
Org. Lett., 2006, 8, 1089.
23. (a) Redmore, D. and Gutsche, C. D., Adv. Alicyclic Chem., 1971, 3, 125. (b) Kirmse, W.,
Carbene Chemistry, 2nd ed., Academic Press, New York, 1971, p. 485.
24. Richardson, D. C.; Hendrick, M. E. and Jones, M., J. Am. Chem. Soc., 1971, 93, 3790.
25. Pomerantz, M. and Levanon, M., Tetrahedron Lett., 1991, 32, 995.
26. (a) Sax, K. J. and Bergmann, W., J. Am. Chem. Soc., 1955, 77, 1910. (b) Lane, J. F. and Wallis,
E. S., J. Am. Chem. Soc., 1941, 63, 1674.
27. Giao, G. G. H.; Meutermans, W.; Wong, M. W.; Träubel, M. and Wentrup, C., J. Am. Chem. Soc.,
1996, 118, 3852.
28. Meier, H. and Zeller, K.-P., Angew. Chem. Int. Ed. Engl., 1975, 14, 32.
29. (a) Tomioka, H.; Okuno, H.; Kondo, S. and Izawa, Y., J. Am. Chem. Soc., 1980, 102, 7123.
(b) Trozzolo, A. M., Acc. Chem. Res., 1968, 1, 329.
30. (a) Visser, P.; Zuhse, R.; Wong, M. W. and Wentrup, C., J. Am. Chem. Soc., 1996, 118, 12598.
(b) Kaplan, F. and Mitchell, M. L., Tetrahedron Lett., 1979, 759. (c) Kaplan, F. and Meloy, G. K.,
J. Am. Chem. Soc., 1966, 88, 950.
31. Borch, R. F. and Fields, D. L., J. Org. Chem., 1969, 34, 1480.
32. Recnik, S.; Svete, J. and Stanovnik, B., Eur. J. Org. Chem., 2001, 3705.
33. Rabek, J. F., Mechanism of Photophysical Processes and Photochemical Reactions in Polymers,
John Wiley & Sons, Inc. New York, 1987, p. 446.
34. (a) Khemtong, C. and Hu, J., J. Sulfur Chem., 2005, 26, 105. (b) Koch, K. and Podlech, J.,
Synth. Commun., 2005, 35, 2789. (c) Urdabayev, N. K. and Popik, V. V., J. Am. Chem. Soc., 2004,
126, 4058. (d) Haiss, P. and Zeller, K.-P., Z. Naturforsch., 2003, 58b, 595. (e) Sarpong, R.; Su, J.
T. and Stoltz, B. M., J. Am. Chem. Soc., 2003, 125, 13624. (f) Patil, B. S.; Vasanthakumar, G.-R.
and Babu, V. V. S., Lett. Peptide Sci., 2002, 9, 231. (g) Ma, Z. H.; Liu, C.; Zhao, Y. H.; Li, W.
and Wang, J. B., Chin. Chem. Lett., 2002, 13, 721. (h) Scott, A. P.; Platz, M. S. and Radom, L.,
J. Am. Chem. Soc., 2001, 123, 6069. (i) Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W. and
Roberts, E., Org. Lett., 2000, 2, 2177. (j) Kim, C. K. and Lee, I., Bull. Korean Chem. Soc., 1997,
18, 395. (k) Doyle, M. P. and McKervey, M. A., J. Chem. Soc., Chem. Commun., 1997, 983.
(l) Podlech, J. and Linder, M. R., J. Org. Chem., 1997, 62, 5873. (m) Fujiwara, H.; Nakajima, Y.;
Fukumura, H. and Masuhara, H., J. Phys. Chem., 1995, 99, 11481. (n) Murata, S.; Yamamoto,
T. and Tomioka, H., J. Am. Chem. Soc., 1993, 115, 4013. (o) Winnik, M. A.; Wang, F.;
Nivaggioli, T.; Hruska, Z.; Fukumura, H. and Masuhara, H., J. Am. Chem. Soc., 1991, 113,
9702. (p) Wheeler, T. N. and Meinwald, J., Org. Synth. Coll., 1988, 6, 840. (q) Torres, M.,
Pure & Appl. Chem., 1980, 52, 1623. (r) Stevens, R. V.; Bisacchi, G. S.; Goldsmith, L. and
Strouse, C. E., J. Org. Chem., 1980, 45, 2708. (s) Henkin, J., J. Biol. Chem., 1977, 252, 4293.
(t) Kammula, S. L.; Tracer, H. L.; Shelvin, P. B. and Jones, M., J. Org. Chem., 1977, 42, 2931.
(u) Smith, L. R. and Meinwald, J., J. Org. Chem., 1977, 42, 415. (v) Strausz, O. P.; Gosavi,
R. K.; Denes, A. S. and Csizmadia, I. G., J. Am. Chem. Soc., 1976, 98, 4784. (w) Csizmadia,
I. G.; Gunning, H. E.; Gosavi, R. K. and Strausz, O. P., J. Am. Chem. Soc., 1973, 95, 133.
(x) Skell, P. S. and Valenty, S. J., J. Am. Chem. Soc., 1973, 95, 5042. (y) Thornton, D. E.; Gosavi,
R. K. and Strausz, O. P., J. Am. Chem. Soc., 1970, 92, 1768. (z) Csizmadia, I. G.; Font, J. and
Strausz, O. P., J. Am. Chem. Soc., 1968, 90, 7360. (aa) Wenkert, E.; Mylari, B. L. and Davis, L.
L., J. Am. Chem. Soc., 1968, 90, 3870. (bb) Lane, J. F. and Wallis, E. S., J. Org. Chem., 1941 6,
443. (cc) Schroeter, G., Ber., 1916, 49, 2697. (dd) Schroeter, G., Ber., 1916, 49, 2704. (ee) Wolff,
L., Ann., 1912, 394, 25. (ff) Wolff, L., Ann., 1912, 394, 23. (gg) Schroeter, G., Ber., 1909, 42,
2336.
36
Baeyer-Villiger Oxidation
(Baeyer-Villiger Reaction,
Baeyer-Villiger Rearrangement)
This reaction was first reported by Baeyer and Villiger in 1899.1 It is the oxidation of
ketones or cyclic ketones into esters or lactones by peracids or hydrogen peroxide. This
reaction is thus known as the Baeyer-Villiger oxidation,2 Baeyer-Villiger reaction,3 and
Baeyer-Villiger rearrangement.4 Typical peracids in this oxidation include peroxybenzoic
acid, m-chloroperoxybenzoic acid (mCPBA), peroxyacetic acid, and trifluoroperoxyacetic
acid. In this reaction, the more substituted group often migrates preferentially, and the
migratory aptitudes of these groups are tertiary > secondary > cyclohexyl > benzyl >
phenyl > primary > methyl. More importantly, both the stereochemistry and chirality of
the migrating group are retained during the migration. This reaction has been extensively
reviewed.5
O O
R1 R2 RCO3H R1 O
R2
Dashed line, cyclic ketone.

150
RELATED REACTIONS 151
A general mechanism is displayed here.
D. MODIFICATION
Because alkenes react readily with peroxyacids to form epoxides, the Baeyer-
Villiger oxidation has been modified using bis[trimethylsilyl]peroxide6a or basic hydrogen
peroxide.6b Recently, a modification of Baeyer-Villiger oxidation on cyclohexanone using
tin-infused zeolite as catalyst and hydrogen peroxide as oxidation reagent has been
developed.6c,6d This method can be extended to other ketones with high selectivity. It
is said that this route is more environmentally friendly than the traditional manufac-
turing methods for caprolactone and other lactones. Moreover, as an environmentally
friendly reagent, hydrogen peroxide has been widely applied for the Baeyer-Villiger oxida-
tion under various conditions: (a) using [(triphosPO)Pt]2+ ,7a montmorillonite-supported
SnCl2 ,7b Sn-palygorskite,7c organoselenium,7d selenoxides,7e aminomethyl polystyrene
resin-supported tin complex,7f and water-tolerant Lewis acid in molecular sieves7g as cat-
alysts; (b) using H2 O2 /nitrile as oxidant, such as H2 O2 /nitrile over Mg(OH)2 or MgO,7h
Mg/Al hydrotalcite,7i and H2 O2 /benzonitrile over hydrotalcite;7j,7k and (c) with tailor-
ing Pt(II) chiral catalyst7l and Pt(II) catalyst7m or CH3 ReO3 /H2 O2 in ionic liquids.7n In
addition, other kinds of reagents have been applied as oxidant for the Baeyer-Villiger
oxidation, including potassium peroxomonosulfate,8a,8b bis-cationic platinum (II) com-
plex ([Pt(mu-OH)(Pom-Pom)]2 [BF4 ]2 [Pom-Pom = (OMe)2 PCH2 CH2 P(OMe)2 ]),8c and
molecular oxygen/benzaldehyde.8d Furthermore, microbial9a and enzymatic9b,9c Baeyer-
Villiger oxidation (e.g., monooxygenases,9d−9h cunninghamella echinulata NRRL 3655,9i
and arabidopsis CYP85A29j ).
E. APPLICATIONS
This reaction has broad applications in organic synthesis for the preparation of esters
and lactones.
N/A
152 BAEYER-VILLIGER OXIDATION
BnO2C BnO2C
N CH3CO3H N
HAc/NaAc O O
O
Reference 10.
To a solution of 400 mg N-carbobenzyloxy-2-azabicyclo[2.2.2]octan-5-one (1.53 mmol)

in 1 mL acetic acid containing 0.1 g sodium acetate was added 1 mL 28% peracetic
acid. After the mixture was stirred in the dark for 24 h, 10 mL methylene chloride
was added, and the solution was washed with saturated sodium sulfite (4 × 5 mL) fol-
lowed by saturated sodium bicarbonate (2 × 5 mL). After removal of the solvent, the
residue was purified by flash chromatography, and 338.0 mg 6-(benzyloxycarbonyl)-2-
oxa-3-oxo-6-azabicyclo[3.2.2]-nonane was obtained, in a yield of 80%, b.p. 145–150◦ C
(0.025 mmHg).
O O
O
mCPBA O O
O CH2Cl2/Li2CO3 O
CO2Et
CO2Et EtO2C CO2Et
Reference 11.
To a solution of 0.045 mmol 4,4-dicarbethoxy-3,7β-dioxa-8,2-dioxobicyclo[4.3.0]-

nonane-2-spiro-1 -cyclopentane in 1.0 mL dichloromethane were added a catalytic amount
of Li2 CO3 and 0.068 mmol mCPBA. The mixture was stirred for 5 h at room tem-
perature and quenched by 0.5 mL 10% Na2 S2 O4 solution. The product was extracted
with chloroform (3 × 5 mL), and the combined organic layers were washed with 10%
K2 CO3 and brine and then dried over Na2 SO4 . Upon removal of solvent, the residue was
purified by flash chromatography to afford 70–75% of 5,5 -dicarbethoxy-3,7β,2β-trioxa-
8,3-dioxobicyclo[4.3.0]nonane-2-nonane-1-cyclohexane.
Other references related to the Baeyer-Villiger oxidation are cited in the literature.12
H. REFERENCES
1. (a) von Baeyer, A. and Villger, V., Ber., 1899, 32, 3625. (b) von Baeyer, A. and Villiger, V., Ber.,
1900, 33, 858.
2. (a) Cernuchova, P. and Mihovilovic, M. D., Org. Biomol. Chem., 2007, 5, 1715. (b) Huang, J.; Li,
J. X.; Dai, W. L.; Cao, Y. and Fan, K. N., Shiyou Huagong, 2007, 36, 200. (c) Li, C. L.; Wang, J. Q.;
Yang, Z. W.; Hu, Z. G. and Lei, Z. Q., Catal. Commun., 2007, 8, 1202. (d) Li, C.-L.; Yang, Z.-W.;
Wu, S. and Lei, Z.-Q., React. Funct. Polymers, 2007, 67, 53. (e) Llamas, R.; Jimenez-Sanchidrian,
C. and Ruiz, J. R., React. Kinet. Catal. Lett., 2007, 90, 309. (f) Sgarbossa, P.; Scarso, A.; Michelin,
REFERENCES 153
R. A. and Strukul, G., Organometallics, 2007, 26, 2714. (g) Sgarbossa, P.; Scarso, A.; Pizzo, E.;
Sbovata, S. M.; Tassan, A.; Michelin, R. A. and Strukul, G., J. Mol. Catal. A: Chem., 2007, 261,
202. (h) Zhang, Q. H.; Wang, S. F. and Lei, Z. Q., Chinese Chem. Lett., 2007, 18, 4. (i) Baldwin,
C. V. F. and Woodley, J. M., Biotechnol. Bioeng., 2006, 95, 362. (j) Fantin, G.; Giovannini, P. P.;
Guerrini, A.; Maietti, S.; Medici, A. and Pedrini, P., Biotechnol. Lett., 2006, 28, 805. (k) Grein, F.;
Chen, A. C.; Edwards, D. and Crudden, C. M., J. Org. Chem., 2006, 71, 861. (l) Hilker, I.; Baldwin,
C.; Alphand, V.; Furstoss, R.; Woodley, J. and Wohlgemuth, R., Biotechnol. Bioeng., 2006, 93,
1138. (m) Iwaki, H.; Wang, S. Z.; Grosse, S.; Bergeron, H.; Nagahashi, A.; Lertvorachon, J.;
Yang, J. Z.; Konishi, Y.; Hasegawa, Y. and Lau, P. C. K., Appl. Environ. Microbio., 2006, 72,
2707. (n) Koopmans, C.; Iannelli, M.; Kerep, P.; Klink, M.; Schmitz, S.; Sinnwell, S. and Ritter,
H., Tetrahedron, 2006, 62, 4709. (o) Mihovilovic, M. D., Curr. Org. Chem., 2006, 10, 1265.
(p) Mihovilovic, M. D.; Mueller, B.; Spina, M.; Durrani, A. I.; Stanetty, P.; Dazinger, G. and
Kirchner, K., Monatsh. Chem., 2006, 137, 785. (q) Mihovilovic, M. D.; Snajdrova, R. and Groetzl,
B., J. Mol. Catal. B: Enzymatic, 2006, 39, 135. (r) Mikami, K.; Yamanaka, M.; Islam, Md. N.;
Tonoi, T.; Itoh, Y.; Shinoda, M. and Kudo, K., J. Fluor. Chem., 2006, 127, 592. (s) Scafato, P.;
Larocca, A. and Rosini, C., Tetrahedron: Asymmetry, 2006, 17, 2511. (t) Wang, B.; Shen, Y.-M. and
Shi, Y., J. Org. Chem., 2006, 71, 9519. (u) Zhang, M.; Wei, J.-F. and Shi, Z., Xibei Daxue Xuebao,
Ziran Kexueban, 2006, 36, 403. (v) Corma, A. and Renz, M., Coll. Czech. Chem. Commun., 2005,
70, 1727. (w) Hilker, I.; Wohlgemuth, R.; Alphand, V. and Furstoss, R., Biotechnol. Bioeng., 2005,
92, 702. (x) Mihovilovic, M. D.; Snajdrova, R.; Winninger, A. and Rudroff, F., Synlett, 2005,
2751.
3. (a) Yamabe, S. and Yamazaki, S., J. Org. Chem., 2007, 72, 3031. (b) Bolm, C., Asymmetric
Synthesis, 2007, 57. (c) Frison, J.-C.; Palazzi, C. and Bolm, C., Tetrahedron, 2006, 62, 6700. (d)
Zhang, P.; Yang, M.; Lue, X. P. and Han, P. F., Huaxue Tongbao, 2005, 68, 897. (e) Song, Z.-G.;
Li, J.; Liu, Q.-W.; Li, Y.-Z. and Huang, H.-M., Gaodeng Xuexiao Huaxue Xuebao, 2005, 26,
2264. (f) Iglesias-Arteaga, M. A.; Velazquez-Huerta, G. A.; Mendez-Stivalet, J. M.; Galano, A.
and Alvarez-Idaboy, J. R., ARKIVOC, 2005, (vi) 109. (g) Bolm, C.; Palazzi, C. and Beckmann,
O., Trans. Metal Org. Synth., 2004, 2, 267. (h) Snowden, M.; Bermudez, A.; Kelly, D. R. and
Radkiewicz-Poutsma, J. L., J. Org. Chem., 2004, 69, 7148. (i) Bolm, C.; Frison, J.-C.; Zhang, Y.
and Wulff, W. D., Synlett, 2004, 1619. (j) Bernini, R.; Coratti, A.; Fabrizi, G. and Goggiamani,
A., Tetrahedron Lett., 2003, 44, 8991. (k) Sever, R. R. and Root, T. W., J. Phys. Chem. B, 2003,
107, 10848. (l) Sever, R. R. and Root, T. W., J. Phys. Chem. B, 2003, 107, 10521. (m) Ito, Y.,
Organomet. News, 2002, 140. (n) Murahashi, S.-I.; Ono, S. and Imada, Y., Angew. Chem. Int. Ed.,
2002, 41, 2366. (o) Peng, Y.; Feng, X.; Yu, K.; Li, Z.; Jiang, Y. and Yeung, C.-H., J. Organomet.
Chem., 2001, 619, 204.
4. (a) Alvarez-Idaboy, J. R.; Reyes, L. and Cruz, J., Org. Lett., 2006, 8, 1763. (b) Reyes, L.; Castro,
M.; Cruz, J. and Rubio, M., J. Phys. Chem. A, 2005, 109, 3383. (c) Bernini, R.; Mincione, E.;
Cortese, M.; Aliotta, G.; Oliva, A. and Saladino, R., Tetrahedron Lett., 2001, 42, 5401. (d) Cadenas,
R.; Reyes, L.; Lagunez-Otero, J. and Cetina, R., THEOCHEM, 2000, 497, 211. (e) Barrero, A. F.;
Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda, R.; Chahboun, R.; Meneses, R. and Aparicio B.,
M., Synlett, 1999, 713. (f) Zhu, Y. J., Daxue Huaxue, 1998, 13, 48. (g) Bhaumik, A.; Kumar, P. and
Kumar, R., Catal. Lett., 1996, 40, 47. (h) Alcaide, B.; Aly, M. F. and Sierra, M. A., Tetrahedron
Lett., 1995, 36, 3401. (i) Paryzek, Z. and Blaszczyk, K., Liebigs Ann., 1995, 341. (j) Gordon, N.
J. and Evans, S. A., J. Org. Chem., 1993, 58, 4516. (k) Mak, A. Y. and Swinney, D. C., J. Am.
Chem. Soc., 1992, 11, 8309. (l) Kuo, Y. H.; Shih, K. S. and Lee, S. M., J. Photochem. Photobio. A:
Chem., 1988, 45, 97. (m) Levin, D. and Warren, S., Tetrahedron Lett., 1986, 27, 2265. (n) Boger,
D. L. and Coleman, R. S., J. Org. Chem., 1986, 51, 5436. (o) Trost, B. M.; Buhlmayer, P. and Mao,
M., Tetrahedron Lett., 1982, 23, 1443. (p) Stoute, V. A.; Winnik, M. A. and Csizmadia, I. G., J.
Am. Chem. Soc., 1974, 96, 6388. (q) Rodewald, W. and Achmatowicz, B., Roczniki Chem., 1972,
46, 2193. (r) Isaka, I.; Kojima, T. and Murakami, M., Yakugaku Zasshi, 1968, 88, 71. (s) Granger,
R.; Orzalesi, H. and Joyeux, P., Compt. Rend., 1965, 260, 923. (t) Mislow, K. and Brenner, J., J.
Am. Chem. Soc., 1953, 75, 2318.
154 BAEYER-VILLIGER OXIDATION
5. (a) Brink, G.-J. T.; Arends, I. W. C. E. and Sheldon, R. A., Chem. Rev., 2004, 104, 4105.
(b) Krow, G. R., Org. React., 1993, 43, 251. (c) Krow, G. R., Comp. Org. Syn., 1991, 7, 671.
(d) Lee, J. B. and Uff, B. C., Quart. Rev. Chem. Soc., 1967, 21, 429. (e) Smith, P. A. S., in Molec-
ular Rearrangements, ed., de Mayo, P., Wiley-Interscience, New York, 1963, part 1. (f) Hassal,
C. H., Org. React., 1957, 9, 73.
6. (a) Suzuki, M.; Takada, H. and Noyori, R., J. Org. Chem., 1982, 47, 902. (b) Trost, B. M., Acc.
Chem. Res., 1974, 7, 85. (c) Corma, A.; Nemeth, L. T.; Renz, M. and Valencia, S., Nature, 2001,
412, 423.
7. (a) Brunetta, A.; Sgarbossa, P. and Strukul, G., Catal. Today, 2005, 99, 227. (b) Lei, Z. Q.; Ma, G.
F. and Jia, C. G., Catal. Commun., 2007, 8, 305. (c) Lei, Z. Q.; Zhang, Q. H.; Wang, R. M.; Ma, G.
F. and Jia, C. G., J. Organomet. Chem., 2006, 691, 5767. (d) Ichikawa, H.; Usami, Y. and Arimoto,
M., Tetrahedron Lett., 2005, 46, 8665. (e) Goodman, M. A. and Detty, M. R., Synlett, 2006, 1100.
(f) Zhang, Q. H.; Wen, S. X. and Lei, Z. Q., React. Funct. Polymers, 2006, 66, 1278. (g) Corma,
A.; Fornes, V.; Iborra, S.; Mifsud, M. and Renz, M., J. Catal., 2004, 221, 67. (h) Llamas, R.;
Jimenez-Sanchidrian, C. and Ruiz, J. R., Appl. Catal. B: Environ., 2007, 72, 18. (i) Llamas, R.;
Jimenez-Sanchidrian, C. and Ruiz, J. R., Tetrahedron, 2007, 63, 1435. (j) Jimenez-Sanchidrian,
C.; Hidalgo, J. M.; Llamas, R. and Ruiz, J. R., Appl. Catal. A: General, 2006, 312, 86. (k) Ruiz,
J. R.; Jimenez-Sanchidrian, C. and Llamas, R., Tetrahedron, 2006, 62, 11697. (l) Colladon, M.;
Scarso, A. and Strukul, G., Synlett, 2006, 3515. (m) Conte, V.; Floris, B.; Galloni, P.; Mirruzzo,
V.; Scarso, A.; Sordi, D. and Strukul, G., Green Chem., 2005, 7, 262. (n) Bernini, R.; Coratti, A.;
Fabrizi, G. and Goggiamani, A., Tetrahedron Lett., 2005, 46, 6169.
8. (a) Gonzalez-Nunez, M. E.; Mello, R.; Olmos, A. and Asensio, G., J. Org. Chem., 2006, 71,
6432. (b) Gonzalez-Nunez, M. E.; Mello, R.; Olmos, A. and Asensio, G., J. Org. Chem., 2005,
70, 10879. (c) Sgarbossa, P.; Scarso, A.; Pizzo, E.; Sbovata, S. M.; Tassan, A.; Michelin, R. A.
and Strukul, G., J. Mol. Catal. A: Chem., 2007, 261, 202. (d) Kawabata, T.; Fujisaki, N.; Shishido,
T.; Nomura, K.; Sano, T. and Takehira, K., J. Mol. Catal. A: Chem., 2006, 253, 279.
9. (a) Luna, A.; Gutierrez, M.-C.; Furstoss, R. and Alphand, V., Tetrahedron: Asymmetry, 2005, 16,
2521. (b) Ottolina, G.; de Gonzalo, G.; Carrea, G. and Danieli, B., Adv. Synth. Catal., 2005, 347,
1035. (c) Moonen, M. J. H.; Westphal, A. H.; Rietjens, I. M. C. M. and van Berkel, W. J. H., Adv.
Synth. Catal., 2005, 347, 1027. (d) Mihovilovic, M. D.; Mueller, B.; Spina, M.; Durrani, A. I.;
Stanetty, P.; Dazinger, G. and Kirchner, K., Monatsh. Chem., 2006, 137, 785. (e) Mihovilovic,
M. D.; Rudroff, F.; Winninger, A.; Schneider, T.; Schulz, F. and Reetz, M. T., Org. Lett., 2006, 8,
1221. (f) Mihovilovic, M. D.; Rudroff, F.; Groetzl, B. and Stanetty, P., Euro. J. Org. Chem., 2005,
809. (g) Lee, W.-H.; Park, Y.-C.; Lee, D.-H.; Park, K. and Seo, J.-H., Appl. Biochem. Biotechnol.,
2005, 121. (h) Reetz, M. T.; Brunner, B.; Schneider, T.; Schulz, F.; Clouthier, C. M. and Kayser, M.
M., Angew. Chem. Int. Ed., 2004, 43, 4075. (i) Fairlamb, I. J. S.; Grant, S.; Grogan, G.; Maddrell,
D. A. and Nichols, J. C., Org. Biomol. Chem., 2004, 2, 1831. (j) Kim, T.-W.; Hwang, J.-Y.; Kim,
Y.-S.; Joo, S.-H.; Chang, S. C.; Lee, J. S.; Takatsuto, S. and Kim, S.-K., Plant Cell, 2005, 17,
2397.
10. Krow, G. R.; Johnson, C. A.; Guare, J. P.; Kubrak, D.; Henz, K. J.; Shaw, D. A.; Szczepanski, W.
and Carey, J. T., J. Org. Chem., 1982, 47, 5239.
11. Haddad, N.; Rukhman, I. and Abramovich, Z., J. Org. Chem., 1997, 62, 7629.
12. (a) Cotarca, L.; Delogu, P.; Nardelli, A.; Maggioni, P.; Bianchini, R.; Sguassero, S.; Alini, S.;
Dario, R.; Clauti, G.; Pitta, G.; Duse, G. and Goffredi, F., Org. Proc. Res. Dev., 2001, 5, 69.
(b) Laird, T. and Hermitage, S. A., Org. Proc. Res. Dev., 2001, 5, 544. (c) Rychnovsky, S. D. and
Dahanukar, V. H., J. Org. Chem., 1996, 61, 7648. (d) Carling, R. W.; Clark, S. J.; Holmes, A. B.,
J. Chem. Soc., Perkin Trans. I, 1992, 83. (e) Wilson, S. R. and Di Grandi, M. J., J. Org. Chem.,
1991, 56, 4766. (f) Garland, R. B.; Miyano, M. M.; Pireh, D.; Clare, M.; Finnegan, P. M. and
Swenton, L., J. Org. Chem., 1990, 55, 5854. (g) Hammond, M. L.; Kopka, I. E.; Zambiaz, R. A.;
Caldwell, C. G.; Boger, J.; Baker, F.; Bach, T.; Luell, S. and MacIntyre, D. E., J. Med. Chem.,
1989, 32, 1006. (h) Shishido, K.; Takahashi, K. and Fukumoto, J., J. Org. Chem., 1987, 52, 5704.
REFERENCES 155
(i) Zibuck, R.; Liverton, N. J. and Smith. A. B., J. Am. Chem. Soc., 1986, 108, 2451. (j) Klunder,
A. J. H.; Ariaans, G. J. A.; Loop, E. A. R. M. and Zwanenburg, B., Tetrahedron, 1986, 42, 1903.
(k) Sosnowski, J. J.; Danaher, E. B. and Murray, R. K., J. Org. Chem., 1985, 50, 2759. (l) Hart,
D. J. and Tsia, Y.-M., J. Am. Chem. Soc., 1984, 106, 8209. (m) Mergelsberg, I.; Langhals, H. and
Ruchardt, C.,Ber., 1983, 116, 360. (n) Krafft, G. A. and Katzenellenbogen, J. A., J. Am. Chem.
Soc., 1981, 103, 5459. (o) Hudrlik, P. F.; Hudrlik, A. M.; Nagendrappa, G.; Yimenu, T.; Zellers,
E. T. and Chin, E., J. Am. Chem. Soc., 1980, 102, 6894. (p) Hannan, R. L.; Barber, R. B. and
Rapoport, H., J. Org. Chem., 1979, 44, 2153. (q) Baldwin, S. W. and Wilkinson, J. M., Tetrahedron
Lett., 1979, 20, 2657. (r) Salomon, R. G.; Coughlin, D. J. and Easler, E. M., J. Am. Chem. Soc.,
1979, 101, 3961. (s) Marron, N. A. and Cano, J. E., J. Am. Chem. Soc., 1976, 98, 4653. (t) Dauben,
W. G. and Aoyagi, E. I., J. Org. Chem., 1976, 37, 251. (u) Trost, B. M. and Bodganowicz, M. J.,
J. Am. Chem. Soc., 1973, 95, 5321. (v) Trost, B. M. and Bogdanowicz, M. J., J. Am. Chem. Soc.,
1973, 95, 5321. (w) Bogdanowicz, M. J.; Ambelang, T. and Trost, B. M., Tetrahedron Lett., 1973,
923. (x) Weinshenker, N. M. and Stephenson, R., J. Org. Chem., 1972, 37, 3741. (y) Grieco, P. A.,
J. Org. Chem., 1972, 37, 2373. (z) Klunder, A. J. H. and Zwanenburg, B., Tetrahedron Lett., 1972,
28, 4131. (aa) Eadon, G., Popov, S. and Djerassi, C., J. Am. Chem. Soc., 1972, 94, 1282. (bb)
Zwanenburg, B. and Klunder, A. J. H., Tetrahedron Lett., 1971, 1717. (cc) Tsuda, Y.; Tanno, T.;
Ukai, A. and Isobe, K., Tetrahedron Lett., 1971, 2009. (dd) Corey, E. J. and Ravindranathan, T.,
Tetrahedron Lett., 1971, 4753. (ee) Meinwald, J.; Labana, L. L. and Wheeler, T. N., J. Am. Chem.
Soc., 1970, 92, 1006. (ff) Horton, J. A.; Laura, M. A.; Kalbag, S. M. and Petterson, R. C., J. Org.
Chem., 1969, 34, 3366. (gg) Robertson, J. C. and Swelim, A., Tetrahedron Lett., 1967, 30, 2871.
(hh) Pinhey, J. T. and Schaffner, K., Tetrahedron Lett., 1965, 601. (ii) Mateos, J. L. and Menchaca,
H., J. Org. Chem., 1964, 29, 2026. (jj) Cope, A. C. and Woo, G. L., J. Am. Chem. Soc., 1963, 85,
3601. (kk) Mcclure, J. D. and Williams, P. H., J. Org. Chem., 1962, 27, 24. (ll) Hawthorne, M. F.;
Emmons, W. D. and McCallum, K. S., J. Am. Chem. Soc., 1958, 80, 6393. (mm) Hawthorne, M.
F. and Emmons, W. D., J. Am. Chem. Soc., 1958, 80, 6398. (nn) Sager, W. and Duckworth, A.,
J. Am. Chem. Soc., 1955, 77, 188. (oo) Emmons, W. D. and Lucas, G. B., J. Am. Chem. Soc., 1955,
77, 2287. (pp) Buu-Hoi, N. P. and Lavit, D., J. Org. Chem., 1955, 20, 1191. (qq) Mislow, K. and
Brenner, J., J. Am. Chem. Soc., 1953, 75, 2318. (rr) Friess, S. L. and Pinson, R., J. Am. Chem. Soc.
1952, 74, 1302. (ss) Turner, R. B., J. Am. Chem. Soc., 1950, 72, 878. (tt) Rivera, D. G.; Pando,
O.; Suardiaz, R. and Coll, F., Steroids, 2007, 72, 466. (uu) Yoshida, A.; Yoshimura, M.; Uehara,
K.; Hikichi, S. and Mizuno, N., Angew. Chem. Int. Ed., 2006, 45, 1956. (vv) Boronat, M.; Corma,
A.; Renz, M.; Sastre, G. and Viruela, P. M., Chem. Eur. J., 2005, 11, 6905. (ww) Jastrzebska, I.
and Morzycki, J. W., Pol. J. Chem., 2005, 79, 1245. (xx) Imada, Y.; Iida, H.; Murahashi, S.-I.
and Naota, T., Angew. Chem. Int. Ed., 2005, 44, 1704. (yy) Cristau, H.-J.; Marat, X.; Vors, J.-P.;
Virieux, D. and Pirat, J.-L., Curr. Org. Synth., 2005, 2, 113. (zz) Yadav, J. S.; Reddy, B. V. S.;
Basak, A. K. and Narsaiah, A. V., Chem. Lett., 2004, 33, 248. (aaa) Watanabe, A.; Uchida, T.;
Irie, R. and Katsuki, T., Proc. Nat. Acad. Sci. USA, 2004, 101, 5737. (bbb) Moulines, J.; Bats,
J.-P.; Lamidey, A.-M. and Da Silva, N., Helv. Chim. Acta, 2004, 87, 2695. (ccc) Mihovilovic, M.
D.; Rudroff, F. and Groetzl, B., Curr. Org. Chem., 2004, 8, 1057. (ddd) Hilker, I.; Gutierrez, M.
C.; Alphand, V.; Wohlgemuth, R. and Furstoss, R., Org. Lett., 2004, 6, 1955. (eee) Kosaka, N.;
Hiyama, T. and Nozaki, K., Macromolecules, 2004, 37, 4484. (fff) Laurent, M.; Ceresiat, M. and
Marchand-Brynaert, J., J. Org. Chem., 2004, 69, 3194. (ggg) Fukuda, O.; Sakaguchi, S. and Ishii,
Y., Tetrahedron Lett., 2001, 42, 3479. (hhh) Crudden, C. M.; Chen, A. C. and Calhoun, L. A.,
Angew. Chem. Int. Ed. Engl., 2000, 39, 2851. (iii) Hickman, Z. L.; Sturino, C. F. and Lachance,
N., Tetrahedron Lett., 2000, 41, 8217. (jjj) Renz, M. and Meunier, B., Eur. J. Org. Chem.,
1999, 4, 737. (kkk) Bolm, C. and Beckmann, O., Compr. Asymmetric Catal. I-III, 1999, 2, 803.
(lll) Becker, D. and Birnbaum, D., J. Org. Chem., 1980, 45, 570.
601
Stevens Rearrangement
This reaction was initially reported by Stevens et al. in 1928.1 It is an intramolecular

thermal [1,2]-electrophilic migration of an alkyl group from the heteroatom of an ylide to the
adjacent carbanion center upon the treatment with a strong base, resulting in the formation of
a neutral molecule such as sulfide2 or a tertiary amine.1 Therefore, this reaction is generally
known as the Stevens rearrangement.3 Occasionally, this reaction is also referred to as the
Stevens reaction,4 Stevens [1,2]-shift,5 Stevens [1,2]-rearrangement,5c,6 or [1,2]-Stevens
rearrangement.7
An earlier example of this rearrangement is the conversion of phenylacylbenzyldimethy-
lammonium bromide into 2-(dimethylamino)-3-phenylpropiophenone.1 Likewise, the
comparable rearrangement initiated by photo irradiation is known as the photo-Stevens
rearrangement.3y,8 Although the Stevens rearrangements are most commonly observed
on the ammonium and sulfonium salts, the heteroatom of the ylides can be nitrogen,1
sulfur,2,9 oxygen (e.g., oxonium ylide),3u phosphorus,10 arsenic11 or antimony.11 It
has been found that only under harsh conditions, does a phosphorus ylide undergoe
the Stevens rearrangement,3w and this particular rearrangement is also known as the
phospha-Stevens rearrangement,3w as shown by the rearrangement of 1-phenyl-(2,2-
diphenylvinyl)diphenylmethylene phosphorane.10a In general, the Stevens rearrangement
occurs for the listed ylides bearing a rather acidic α-proton but missing the β-hydrogens,3cc
otherwise, the competitive Hofmann Elimination may take place. Even though the Stevens
rearrangement is normally carried out at an elevated temperature, it is often competed with
an auto-oxidation/cleavage occurring at the low temperatures.3z In addition, the thermolysis
of certain 1-benzyl substituted acylaminimides has been found to give a mixture arising from
both the Stevens and Curtius Rearrangements.3bb In the Stevens rearrangement, it has been

2668
MODIFICATION 2669
found that the configuration of the migratory group is moderately or highly retained after
the migration to the adjacent carbon atom,4a as shown in the case of the cyclic ammonium
ylides,12 and the preference of the migration depends on the functional groups present that
can assist the bond cleavage between carbon and heteroatom.5c
Even though the Stevens rearrangement is a reaction of relatively long history,

it has been observed with different mechanistic characters. For example, the rear-
rangement of benzyldimethylphenacyl-ammonium ylide is proposed to occur through
a two-step process: allowed [1,4]- and forbidden [1,3]-sigmatropic shifts rather
than a one-step [1,2]-forbidden process,3aa while the interchange between [R,3R]-
(+)- and [S,3R]-(-)-4,5-dihydro-4,4-dimethyl-3H-dinaphth[2,1-c:1 ,2 -e]azepinium salt is
suggested to involve competition between suprafacial (concerted) and antarafacial
(nonconcerted) processes.3x In addition, the treatment of 3-dimethylamino-3-methyl-
1-butyne methiodide with sodium amide in liquid ammonia is proposed to occur
via a homolytic cleavage-recombination mechanism, as supported by the observed
products, such as N,N,N ,N -tetramethylethylenediamine, 3,3-dimethyl-4-(N,N-dimethyl-
amino)-1-butyne, and 3,3,4,4-tetramethyl-1,5-hexadiyne.13 Moreover, the highly retained
configuration during the rearrangement favors either a rapid radical recombination5a,6b or
a non-ionic but nucleophilic displacement mechanism, via either a frontal/rearward (SN 2)
or a lateral (SN i) attack.5hh Displayed here is a simplified illustration for the mechanism
of the Stevens rearrangement for the ammonium salt, in combination of both radical and
nucleophilic displacement processes.
D. MODIFICATION
The initial protocol of the Stevens rearrangement has been extended to the ylides with
a heteroatom other than nitrogen and sulfur, such as those with oxygen,3u phosphorus,10
2670 STEVENS REARRANGEMENT
arsenic,11 and antimony.11 In addition, the thermal Stevens rearrangement has been modified
to occur under the condition of photo irradiation.3w
E. APPLICATIONS
This reaction has very broad application in organic synthesis.
This reaction is related to the Hofmann Elimination, Meisenheimer Rearrangement,

Sommelet-Hauser Rearrangement, and [1,2]-Wittig Rearrangement.
Reference 14.
To a solution of 0.95 g (13R)-13-methyl-7,12-dihydro-5H-6,12-methanodibenzo-

[c,f ]azocine (4.0 mmol, 1.0 eq.) in 5 mL dry acetone was added 0.75 mL iodomethane
(12.0 mmol, 3.0 eq.) at room temperature. The mixture was refluxed with stirring for 1 h.
Evaporation of solvent and an excess of iodomethane gave the desired quaternary salt, which
was dissolved in 10 mL dry 1,4-dioxane, and 700 mg potassium tert-butoxide (6.0 mmol,
1.5 eq.) was added. The mixture was stirred at 80◦ C for 3 h and diluted with water. The aque-
ous solution was extracted with CH2 Cl2 , and the combined organic layers were washed with
brine, dried over Na2 SO4 , and concentrated in vacuo. The crude product was purified by
flash chromatography using 5–10% MeOH/EtOAc as the eluent to give 0.84 g (5S,6R,12R)-
N-methyl-6-methylisopavine as a white solid, in a yield of 85%, m.p. 82–83◦ C, Rf = 0.5
(5% MeOH in EtOAc).
CO2Me CO2Me NMe2

+ I– CsF NMe2 CO2Me
N +
DMF
SiMe3 7:3
81%
Reference 15.
To a 20-mL flask equipped with a magnetic stirrer, a septum, and a test tube that was
connected to the flask with a short bent glass tubing, were added 0.81 g N,N-dimethyl-
N-[(trimethylsilyl)methyl]-α-(methoxycarbonyl) benzylammonium iodide (2.0 mmol). In
addition, 0.96 g CsF (6.0 mmol) was placed in the test tube. After the apparatus was dried
under reduced pressure and flushed with nitrogen, 10 mL DMF was added to the flask
REFERENCES 2671
via a syringe, and CsF was transferred to the flask through the bent glass tubing. The
resulting mixture was stirred at room temperature for 12 h, then poured into 100 mL water
and extracted with Et2 O (4 × 50 mL). The combined organic layers were washed with
water (3 × 100 mL) and 50 mL brine, dried over MgSO4 , and concentrated under reduced
pressure to afford 335 mg methyl 3-(dimethylamino)-2-phenylpropionate and methyl 3-
(dimethylamino)-3-phenylpropionate mixture as a colorless oil, in ratio of 7:3 as determined
by 1 H NMR. The yield was 81%, b.p. 100◦ C (1 mmHg).
Other references related to the Stevens rearrangement are cited in the literature.16
H. REFERENCES
1. Stevens, T. S., Creighton, E. M.; Gordon, A. B. and McNicol, M., J. Chem. Soc., 1928, 3193.
2. Dunn, J. L. and Stevens, T. S., J. Chem. Soc., 1932, 1926.
3. (a) Manukyan, M. O.; Babakhanyan, A. V.; Panosyan, G. A.; Gyul’nazaryan, A. Kh. and
Kocharyan, S. T., Russ. J. Gen. Chem., 2007, 77, 1370. (b) Manukyan, M. O.; Babakhanyan, A.
V. and Panosyan, G. A., Hayastani Kimiakan Handes, 2007, 60, 865. (c) Chukhadzhyan, E. O.;
Gevorkyan, A. R. and Nalbandyan, M. K., Russ. J. Org. Chem., 2006, 42, 1771. (d) Osyan,
A. M., Hayastani Kimiakan Handes, 2006, 59, 87. (e) Manukyan, M. O.; Babakhanyan, A. V.;
Panosyan, G. A. and Kocharyan, S. T., Russ. J. Gen. Chem., 2006, 76, 574. (f) Ellis-Holder,
K. K.; Peppers, B. P.; Kovalevsky, A. Yu. and Diver, S. T., Org. Lett., 2006, 8, 2511. (g) Okazaki,
Y.; Asai, T.; Ando, F. and Koketsu, J., Chem. Lett., 2006, 35, 98. (h) Vanecko, J. A.; Wan, H. and
West, F. G., Tetrahedron, 2006, 62, 1043. (i) Manukyan, M. O., Hayastani Kimiakan Handes,
2005, 58, 53. (j) Babakhanyan, A. V.; Manukyan, M. O.; Baltayan, A. O. and Kocharyan, S. T.,
Russ. J. Gen. Chem., 2005, 75, 1648. (k) Sargsyan, G. T.; Babayan, L. A.; Karapetyan, B. E.;
Grigoryan, J. V.; Panossyan, H. A. and Kocharyan, S. T., Hayastani Kimiakan Handes, 2004,
57, 41. (l) Valpuesta, M.; Diaz, A.; Suau, R. and Torres, G., Eur. J. Org. Chem., 2004, 4313.
(m) Babakhanyan, A. B.; Ovakimyan, S. A.; Grigoryan, V. V. and Kocharyan, S. T., Russ. J. Gen.
Chem., 2004, 74, 1221. (n) Babakhanyan, A. V.; Ovsepyan, V. S.; Panosyan, G. A. and Kocharyan,
S. T., Russ. J. Org. Chem., 2004, 40, 936. (o) Ovsepyan, V. S., Hayastani Kimiakan Handes,
2004, 57, 78. (p) Shakhbazyan, L. G.; Babakhanyan, A. V.; Grigoryan, D. V. and Kocharyan, S. T.,
Russ. J. Gen. Chem., 2003, 73, 1608. (q) Babakhanyan, A. V.; Shakhbazyan, L. G.; Grigoryan, D.
V. and Kocharyan, S. T., Russ. J. Org. Chem., 2003, 39, 1227. (r) Babakhanyan, A. V.; Ovsepyan,
V. S.; Kocharyan, S. T. and Panosyan, G. A., Russ. J. Org. Chem., 2003, 39, 820. (s) Pedrosa, R.;
Andres, C. and Delgado, M., Synlett, 2000, 893. (t) Feldman, K. S. and Wrobleski, M. L., J. Org.
Chem., 2000, 65, 8659. (u) Feldman, K. S. and Wrobleski, M. L., Org. Lett., 2000, 2, 2603.
(v) Ng, L-K.; Hupé, M.; Harnois, J. and Lawrence, A. H., Anal. Chem., 1998, 70, 4389.
(w) Makita, K.; Koketsu, J.; Ando, F.; Ninomiya, Y. and Koga, N., J. Am. Chem. Soc., 1998, 120,
5764. (x) Stará, I. G.; Stary, I.; Tichy, M.; Závada, J. and Hanus, V., J. Am. Chem. Soc., 1994,
116, 5084. (y) Zhang, J.-J. and Schuster, G. B., J. Org. Chem., 1988, 53, 716. (z) Pine, S. H.
and Fujita, E., J. Org. Chem., 1977, 42, 1460. (aa) Pine, S. H. and Cheney, J., J. Org. Chem.,
1975, 40, 870. (bb) Smith, R. F.; Blondell, R. D.; Abgott, R. A.; Lipkowitz, K. B.; Richmond,
J. A. and Fountain, K. A., J. Org. Chem., 1974, 39, 2036. (cc) Adams, B. L. and Kovacic, P., J.
Org. Chem., 1974, 39, 3090. (dd) Pine, S. H.; Catto, B. A. and Yamagishi, F. G., J. Org. Chem.,
1970, 35, 3663. (ee) Takeda, M.; Jacobson, A. E. and May, E. L., J. Org. Chem., 1969, 34, 4158.
(ff) Jacobson, A. E. and Parfitt, R. T., J. Org. Chem., 1967, 32, 1894. (gg) Hill, R. K. and Chan,
T.-H., J. Am. Chem. Soc., 1966, 88, 866. (hh) Brewster, J. H. and Kline, M. W., J. Am. Chem.
Soc., 1952, 74, 5179.
4. (a) Kametani, T.; Huang, S.-P.; Koseki, C.; Ihara, M. and Fukumoto, K., J. Org. Chem., 1977,
42, 3040. (b) Saito, S. and May, E. L., J. Org. Chem., 1962, 27, 948.
2672 STEVENS REARRANGEMENT
5. (a) Marmsäter, F. P.; Murphy, G. K. and West, F. G., J. Am. Chem. Soc., 2003, 125, 14724.
(b) Vanecko, J. A. and West, F. G., Org. Lett., 2002, 4, 2813. (c) Padwa, A.; Beall, L. S.; Eidell,
C. K. and Worsencroft, K. J., J. Org. Chem., 2001, 66, 2414. (d) Chelucci, G.; Saba, A.; Valenti,
R. and Bacchi, A., Tetrahedron: Asymmetry, 2000, 11, 3449. (e) Heard, G. L. and Yates, B. F.,
J. Org. Chem., 1996, 61, 7276. (f) West, F. G. and Naidu, B. N., J. Am. Chem. Soc., 1993, 115,
1177. (g) Eberlein, T. H.; West, F. G. and Tester, R. W., J. Org. Chem., 1992, 57, 3479. (h) Hauser,
C. R.; Beard, W. Q. and van Eenam, D. N., J. Org. Chem., 1961, 26, 2062.
6. (a) Beall, L. S. and Padwa, A., Tetrahedron Lett., 1998, 39, 4159. (b) Ollis, W. D.; Rey, M. and
Sutherland, I. O., J. Chem. Soc., Perkin Trans. I, 1983, 1009.
7. (a) Tayama, E.; Nanbara, S. and Nakai, T., Chem. Lett., 2006, 35, 478. (b) Vial, L.; Goncalves,
M.-H.; Morgantini, P.-Y.; Weber, J.; Bernardinelli, G. and Lacour, J., Synlett, 2004, 1565.
8. Morita, H.; Kamiyama, H.; Kyotani, M.; Fujii, T.; Yoshimura, T.; Ono, S. and Shimasaki, C.,
Chem. Commun., 1997, 1347.
9. (a) Baldwin, J. E.; Erickson, W. F.; Hackler, R. E. and Scott, R. M., J. Chem. Soc., Chem.
Commun., 1970, 576. (b) Baldwin, J. E. and Hackler, R. E., J. Am. Chem. Soc., 1969, 91,
3646. (c) Blackburn, G. M.; Ollis, W. D.; Plackett, J. D.; Smith, C. and Sutherland, I. O.,
J. Chem. Soc., Chem. Commun., 1968, 186. (d) Baldwin, J. E.; Hackler, R. E. and Kelly, D.
P., J. Chem. Soc., Chem. Commun., 1968, 537. (e) Baldwin, J. E.; Hackler, R. E. and Kelly, D. P.,
J. Chem. Soc., Chem. Commun., 1968, 538. (f) Baldwin, J. E.; Hackler, R. E. and Kelly, D. P., J.
Chem. Soc., Chem. Commun., 1968, 1083.
10. (a) Maercker, A.; Bsata, A. and Jung, R., Main Group Met. Chem., 1987, 10, 11. (b) Gilheany,
D. G.; Kennedy, D. A.; Malone, J. F. and Walker, B. J., J. Chem. Soc., Chem. Commun., 1984,
1217.
11. Wittig, G. and Laib, H., Ann., 1953, 580, 57.
12. Glaeske, K. W.; Arif, A. M. and West, F. G., Org. Lett., 1999, 1, 31.
13. Hennion, G. F. and Shoemaker, M. J., J. Am. Chem. Soc., 1970, 92, 1769.
14. Hanessian, S.; Parthasarathy, S. and Mauduit, M., J. Med. Chem., 2003, 46, 34.
15. Zhang, C.; Ito, H.; Maeda, Y.; Shirai, N.; Ikeda, S.-I. and Sato, Y., J. Org. Chem., 1999, 64, 581.
16. (a) Kurti, L. and Czako, B., Strategic Applications of Named Reactions in Organic Synthesis,
Academic Press, Burlington, Mass. 2005. (b) Reinecke, M. G.; Mazza, D. D. and Obeng, M.,
J. Org. Chem., 2003, 68, 70. (c) Allin, S. M.; Button, M. A. C. and Shuttleworth, S. J., Synlett,
1997, 725. (d) Oku, A.; Murai, N. and Baird, J., J. Org. Chem., 1997, 62, 2123. (e) Kitano,
T.; Shirai, N.; Motoi, M. and Sato, Y., J. Chem. Soc., Perkin Trans. I, 1992, 2851. (f) Tanaka,
T.; Shirai, N.; Sugimori, J. and Sato, Y., J. Org. Chem., 1992, 57, 5034. (g) Stamegna, A. and
McEwen, W. E., J. Org. Chem., 1981, 46, 1653. (h) Pine, S. M., Org. React., 1970, 18, 403.
(i) Brewster, J. H. and Jones, R. S., J. Org. Chem., 1969, 34, 354. (j) Anderson, A. G. and
Wills, M. T., J. Org. Chem., 1968, 33, 536. (k) Jacobson, A. E., J. Org. Chem., 1966, 31, 1569.
(l) Fullerton, S. E.; Ager, J. H. and May, E. L., J. Org. Chem., 1962, 27, 2554. (m) Fry, E. M. and
May, E. L., J. Org. Chem., 1961, 26, 2592. (n) Thomson, T. and Stevens, T. S., J. Chem. Soc.,
1932, 55.
675
[1,2]-Wittig Rearrangement
This reaction was first reported by Schörigen in 1924,1 subsequently by Schlenk and
Bergmann in 1928,2 and extended in 1942 by Wittig et al.3 It is a transformation of an
ether into a secondary alkoxide via a [1,2]-carbon shift by treatment of the ether with
a strong base such as alkyl lithium. Therefore, this reaction is generally known as the
[1,2]-Wittig rearrangement,4 1,2-Wittig rearrangement,4k,5 or [1,2] Wittig rearrangement.6
Occasionally, it is also referred to as the [1,2]-Wittig reaction4n or [1,2]-Wittig process.4g
Similarly, the analogous transformation of thioether into thiol is called the thio-Wittig
rearrangement,4l and the corresponding conversion of imine is known as imino 1,2-Wittig
rearrangement.7 This reaction generally works for allyl and benzyl ethers, of which the
vinyl or phenyl group activates the corresponding allylic or benzylic proton and stabilizes
the negative charge generated upon the deprotonation at the α-position of the oxygen.8 The
driving force for this reaction is the instability of the α-oxygenated carbanion.4f The reaction
rate increases with more base.4e Because three atomic centers, i.e., oxygen, α-carbanion
carbon and the migrating carbon, are involved in this reaction, all having a complete octet
of electrons, the yield of the [1,2]-Wittig rearrangement is usually low, and the reaction
might be complicated by other reactions.9 For example, a ketone is generated from the
ether bearing a good leaving group while that is also an electron-withdrawing group (e.g.,
CN) in the presence of a base.10 Although alkyl, allyl, benzyl, phenyl and vinyl groups all
can migrate in the [1,2]-Wittig rearrangement,11 alkyl and benzyl migrations are common in
the known rearrangements.4f Among the alkyl groups that migrate, the migratory aptitude
is in the order of an alkyl group’s ability to stabilize a radical, i.e., methyl < primary alkyl
< secondary alkyl < tertiary alkyl.4m,5g,9

3043
3044 [1,2]-WITTIG REARRANGEMENT
It has been found that the [1,2]-Wittig rearrangement is solvent dependent, as demon-
strated by the reaction of allyl alkyl ether that proceeds readily in THF to afford both
[1,2]- and [1,4]-products when treated by n-BuLi; in contrast, the same reaction in
hexane gives an enol ether, an alcohol, and 1-heptene rather than [1,2]- or [1,4]-Wittig
product.4l For ethers with two activating components (e.g., allyl benzyl ethers), mixtures of
rearrangement products are expected; however, for furylmethyl allyl ethers, even though the
deprotonation may selectively occur at the allylic position, either the [1,2]- or [2,3]-Wittig
Rearrangement proceeds preferentially, depending on the base used.12 For example,
[1,2]-Wittig rearrangement is favored by sec-BuLi, while [2,3]-Wittig Rearrangement
dominates when tert-BuLi is used.12
In spite of the fact that the [1,2]-Wittig rearrangement proceeds via homolytic disso-
ciation and the radical recombination mechanism,4f,4l,4m,5g,9,13 “the stereogenicities of
the two proradical centers are retained to appreciable extents”,4m where the configura-
tion of migratory carbon is kept but the configuration of lithium bearing carbanion is
inverted.4k,4m,14 For example, β-alkoxyalkyl allyl ethers afford syn-1,3-diols with useful
levels of diastereoselectivity;6c β-alkoxy α -tributylstannyl ethers also afford syn-1,3-diols
with 94% retention of configuration at the migrating center as the main products, regardless
of configuration at the α-position and the variation of a solvent system.4k Such a stereo-
chemistry trend is probably due to the chelation effect of lithium; as a result, the inversion
of configuration of the carbanion bearing the lithium cation could be suppressed or even
overturned by variation of the chelation effect.4k
Many mechanistic aspects of the [1,2]-Wittig rearrangement have been reported; how-
ever, the mainstream idea of such forbidden reaction4l is that the rearrangement is a stepwise
reaction,4l,5g consisting of deprotonation to form a carbanion, the homolytic cleavage of
an alkoxy carbanion to radical-radical anion pair and recombination of radical pairs, with
the second step as the rate-limiting step.5g This mechanism is supported by the detection
of CIDNP13 and the correlation of migratory aptitude with the radical stabilizing ability of
an alkyl group.5g,9 Both radical and radical anions may reorient to form more stable rad-
icals before the combination of radical pairs or escape from the solvent cage (Scheme 1).
Alternatively, a ionic mechanism involving a heterolytic cleavage of α-alkoxyl carbanion
to afford ketone and anion and subsequent nucleophilic addition of anion to the car-
bonyl group has been proposed.9 In addition, the ab initio calculation on MeOCH2 - to
APPLICATIONS 3045
form ethoxide anion also favors an anionic mechanism without a discrete intermediate
(Scheme 2).15 Moreover, the [1,2]-Wittig rearrangement of aryl allyl ether may also proceed
via a Meisenheimer intermediate rather than a radical pair mechanism (Scheme 3).16
SCHEME 1. Mechanism of the [1,2]-Wittig rearrangement involving a radical-pair.
SCHEME 2. Anionic mechanism for the [1,2]-Wittig rearrangement.
SCHEME 3. Mechanism of the [1,2]-Wittig rearrangement involving a Meisenheimer intermediate.
D. MODIFICATION
This reaction has been modified extensively, including the imino [1,2]-Wittig rear-
rangement of allyl furohydroximate,7a the thio-[1,2]-Wittig rearrangement of allyl alkyl
thioether,4l and the transformation of silyl and germyl ethers (or sulfides).17 In addition, this
reaction has been used for the preparation of stereo-defined C-glycosides from O-glycosides
with efficient stereocontrol over the anomeric center and the new chiral center.4m Moreover,
a mild reaction condition without the use of a strong base has recently been developed with
good yield and excellent diastereoselectivity (> 20:1) for O-benzyl glycolate methyl esters
when treated with Bu2 BOTf/Et3 N, where the corresponding O-cyclohexyl and O-ethyl
glycolate methyl esters do not undergo such rearrangement.4a
E. APPLICATIONS
This reaction should have wide applications in organic synthesis, but has not been
exploited extensively yet.
This reaction is related to the Stevens Rearrangement and Meisenheimer Complexes.
TIPS TIPS
H
OH
O H n-BuLi/TMEDA
THF
78%
O
O H
H
Reference 5d.
To a solution of 154.5 mg (2R*,4S*)-2-isobutyl-4-[3-(triisopropylsilanyl)prop-2-

ynoxy]-3,4-dihydro-2H-pyran (0.441 mmol) in 4.0 mL THF at −78◦ C under N2 was
added 150 µL TMEDA (0.994 mmol, 2.3 eq.) followed by 0.85 mL 1.2 M n-BuLi
in hexanes (0.960 mmol, 2.2 eq.). The resulting black reaction mixture was stirred for
20 min., quenched with 3.0 mL saturated aqueous NH4 Cl, and warmed to room tempera-
ture. The orange-colored mixture was diluted with water and extracted with ethyl ether. The
combined organic layers were washed with brine, dried over Na2 SO4 , filtered, and concen-
trated to give an orange oil. Purification by silica gel chromatography using hexanes/ethyl
ether/Et3 N (95:5:1) as the eluent afforded 120.1 mg (2R*,4S*)-2-isobutyl-3,4-dihydro-4-
[(1S*)-3-(triisopropylsilanyl)-1-hydroxyprop-2-yn-1-yl]-2H-pyran as a pale yellow oil, in
a yield of 78%.
1) BuLi/THF MeS
+ H SMe
S S MeS H
2) MeI SMe
74%
88:12
Reference 18.
To a suspension of 5.0 g 7H,9H,16H,18H-dinaphtho[1,8-cd:1 ,8 -ij][1,7]-

dithiacyclododecin (13.4 mmol) in 400 mL absolute THF was added within 10 min.
33.7 mL 15% n-BuLi in hexane (53.6 mmol) at 0◦ C under argon with stirring. The
resulting dark brown solution was stirred for 2 h at room temperature. After the mixture
was cooled to 0◦ C, 15.22 g methyl iodide (107.2 mmol) was added quickly. After the
addition of 500 mL water, the organic phase was separated and washed twice with
water. Addition of Et2 O to the organic phase yielded a precipitate. After filtration,
the residue was washed with Et2 O. It remained a white crystalline product, consisting
of 12% 8,9,17,18-tetrahydro-9,18-bis[(methylthio)methylene][1,1](2,8)naphthalenophane
REFERENCES 3047
and 88% anti-7,8,15,16-tetrahydro-7,15-bis(methylthio)cyclodeca-[1,2,3-de:6,7,8-d e ]-

dinaphthalene with a total yield of 74%. The latter could be obtained by recrystallization
from toluene, m.p. 260–261.5◦ C. A separation of both isomers could be achieved by
MPLC with silica gel.
Other references related to the [1,2]-Wittig rearrangement are cited in the literature.19
H. REFERENCES
1. (a) Schörigen, P., Ber., 1924, 57, 1634. (b) Schörigen, P., Ber., 1925, 58, 2028. (c) Schörigen, P.,
Ber., 1926, 59, 2510.
2. Schlenk, W. and Bergmann, E., Ann., 1928, 464, 35.
3. (a) Wittig, G. and Löhmann, L., Ann., 1942, 550, 260. (b) Wittig, G., Angew. Chem., 1954, 66,
10. (c) Wittig, G., Experientia, 1958, 14, 389.
4. (a) Bertrand, M. B. and Wolfe, J. P., Org. Lett., 2006, 8, 4661. (b) Gomez, C.; Macia, B.; Lillo, V. J.
and Yus, M., Tetrahedron, 2006, 62, 9832. (c) Soloshonok, V. A.; Ohkura, H. and Yasumoto, M.,
J. Fluor. Chem., 2006, 127, 708. (d) Lemiegre, L.; Regnier, T.; Combret, J.-C. and Maddaluno,
J., Tetrahedron Lett., 2003, 44, 373. (e) Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T.
D.; Candelario, A.; Huffman, M. A.; Zhao, M. M.; Li, J.; Craig, B.; Song, Z. G. J.; Tschaen, D.
M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P. G.; Reamer, R. A.; Welch, C. J.;
Mathre, D. J.; Tsou, N. N.; McNamara, J. M. and Reider, P. J., J. Am. Chem. Soc., 2003, 125, 2129.
(f) Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C. and Trabada, M., Org. Lett., 2002, 4, 1587.
(g) Garbi, A.; Allain, L.; Chorki, F.; Ourévitch, M.; Crousse, B.; Bonnet-Delpon, D.; Nakai, T.
and Bégué, J. P., Org. Lett., 2001, 3, 2529. (h) Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.;
Keong, P.-H. and Nakai, T., Angew. Chem. Int. Ed., 2000, 39, 4502. (i) Gartner, P.; Letschnig, M.
and Knollmuller, M., Monatsh. Chem., 2000, 131, 867. (j) Tomooka, K.; Kikuchi, M.; Igawa, K.;
Keong, P.-H. and Nakai, T., Tetrahedron Lett., 1999, 40, 1917. (k) Maleczka, R. E. and Geng, F.,
J. Am. Chem. Soc., 1998,120, 8551. (l) Ahmad, M. R.; Dahlke, G. D. and Kass, S. R., J. Am. Chem.
Soc., 1996,118, 1398. (m) Tomooka, K.; Yamamoto, H. and Nakai, T., J. Am. Chem. Soc., 1996,
118, 3317. (n) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A. and Keay, B. A., J. Am. Chem.
Soc., 1996, 118, 10766. (o) Kiyooka, S.-I.; Tsutsui, T. and Kira, T., Tetrahedron Lett., 1996, 37,
8903. (p) Superchi, S.; Sotomayor, N.; Miao, G. B.; Joseph, B.; Campbell, M. G. and Snieckus,
V., Tetrahedron Lett., 1996, 37, 6061. (q) Tomooka, K.; Igarashi, T. and Nakai, T., Tetrahedron,
1994, 50, 5927. (r) Hoffmann, R.; Rueckert, T. and Brueckner, R., Tetrahedron Lett., 1993, 34,
297. (s) Hoffmann, R. and Brueckner, R., Chem. Ber., 1992, 125, 1957.
5. (a) Miyata, O.; Asai, H. and Naito, T., Chem. Pharm. Bull., 2005, 53, 355. (b) Miyata, O.;
Hashimoto, J.; Iba, R. and Naito, T., Tetrahedron Lett., 2005, 46, 4015. (c) Miyata, O.; Koizumi,
T.; Asai, H.; Iba, R. and Naito, T., Tetrahedron, 2004, 60, 3893. (d) Wipf, P. and Graham, T. H.,
J. Org. Chem., 2003, 68, 8798. (e) Kitagawa, O.; Momose, S.-i.; Yamada, Y.; Shiro, M. and
Taguchi, T., Tetrahedron Lett., 2001, 42, 4865. (f) Sheldon, J. C.; Taylor, M. S.; Bowie, J. H.;
Dua, S.; Chia, C. S. B. and Eichinger, P. C. H., J. Chem. Soc., Perkin Trans. II, 1999, 333.
(g) Chia, C. S. B.; Taylor, M. S.; Dua, S.; Blanksby, S. J. and Bowie, J. H., J. Chem. Soc., Perkin
Trans. II, 1998, 1435.
6. (a) Soloshonok, V. A.; Ohkura, H. and Yasumoto, M., Mendeleev Commun., 2006, 165.
(b) Tomooka, K.; Yamamoto, K. and Nakai, T., Angew. Chem. Int. Ed., 1999, 38, 3741.
(c) Schreiber, S. L. and Goulet, M. T., Tetrahedron Lett., 1987, 28, 1043.
7. (a) Miyata, O.; Iba, R.; Hashimoto, J. and Naito, T., Org. Biomol. Chem., 2003, 1, 772. (b) Miyata,
O.; Asai, H. and Naito, T., Synlett, 1999, 1915.
8. Schöllkopf, U., Angew. Chem. Int. Ed. Engl., 1970, 9, 763.
9. Garst, J. F. and Smith, C. D., J. Am. Chem. Soc., 1976, 98, 1526.
10. Katritzky, A. R.; Zhang, Y. M. and Singh, S. K., ARKIVOC, 2002, (vii) 146.
11. Rautenstrauch, V.; Büchi, G. and Wüest, H., J. Am. Chem. Soc., 1974, 96, 2576.
12. Tsubuki, M.; Kamata, T.; Okita, H.; Arai, M.; Shigihara, A. and Honda, T., Chem. Commun.,
1999, 2263.
13. Garst, J. F. and Smith, C. D., J. Am. Chem. Soc., 1973, 95, 6870.
14. (a) Verner, E. J. and Cohen, T., J. Am. Chem. Soc., 1992, 114, 375. (b) Verner, E. J. and Cohen,
T., J. Org. Chem., 1992, 57, 1072.
15. Antoniotto, P. and Tonachini, G., J. Org. Chem., 1993, 58, 3622.
16. Strunk, S. and Schlosser, M., Eur. J. Org. Chem., 2006, 4393.
17. Antoniotti, P. and Tonachini, G., Organometallics, 1999, 18, 4538.
18. Gleiter, R.; Schaaff, H. P.; Huber-Patz, U.; Rodewald, H.; Götzmann, W. and Irngartinger, H.,
J. Org. Chem., 1987, 52, 3979.
19. (a) Bunte, J. O.; Cuzzupe, A. N.; Daly, A. M. and Rizzacasa, M. A., Angew. Chem. Int. Ed., 2006,
45, 6376. (b) Smitha, G. and Reddy, C. S., Synth. Commun., 2006, 36, 1795. (c) Cermola, M.;
DellaGreca, M.; Iesce, M. R.; Previtera, L. Rubino, M.; Temussi, F. and Brigante, M., Environ.
Chem. Lett., 2005, 3, 43. (d) Tokic-Vujosevic, Z.; Petrovic, G.; Rakic, B.; Matovic, R. and Saicic,
R. N., Synth. Commun., 2005, 35, 435. (e) Vilotijevic, I.; Yang, J.; Hilmey, D. and Paquette, L. A.,
Synthesis, 2003, 1872. (f) Wu, D. G.; Ashkenasy, G.; Shvarts, D.; Ussyshkin, R. V.; Naaman, R.;
Shanzer, A. and Cahen, D., Angew. Chem. Int. Ed., 2000, 39, 4496. (g) Paquette, L. A. and Zeng,
Q., Tetrahedron Lett., 1999, 40, 3823. (h) Azzena, U.; Denurra, T.; Melloni, G. and Piroddi, A.
M., J. Org. Chem., 1990, 55, 5532. (i) Schlosser, M. and Strunk, S., Tetrahedron, 1989, 45, 2649.
(j) Adam, S., Tetrahedron, 1989, 45, 1409. (k) Hoffmann, R. W., Nachr. Chem. Tech. Lab., 1982, 30,
483. (l) Hoffmann, R. W., Angew. Chem., 1979, 91, 625. (m) Tennant, G., Ann. Rep. Prog. Chem.
Sec. B, 1972, 68, 241. (n) Schöllkopf, U.,Ind. Chim. Belg., 1971, 36, 1057. (o) Schöllkopf, U.,
Angew. Chem., 1970, 82, 795. (p) Brandsma, L. and Arens, J. F., “Differences and Analogies with
Ethers,” in Chemistry of the Ether Linkage, Patai, S., ed., Interscience, New York, 1967, pp. 570–
580. (q) Zimmerman, H. E., “Base-catalyzed rearrangements,” in Molecular Rearrangements,
ed. de Mayo, P., Wiley-Interscience, New York, 1963, Pt. I, pp. 345–406. (r) Schöllkopf, U.
and Fabian, W., Ann., 1961, 642, 1. (s) Curtin, D. Y. and Proops, W. R., J. Am. Chem. Soc., 1954,
76, 494.
676
[2,3]-Wittig Rearrangement
The initial rearrangement of ether upon the treatment of a strong base was first
reported by Schörigen in 1924,1 subsequently by Schlenk and Bergmann in 1928,2
and extended by Wittig et al. in 1942.3 It is a highly regioselective [2,3]-sigmatropic
rearrangement of the conjugate bases of allylic ethers (or benzylic ethers) to alcohols
with concomitant C-C bond formation. Therefore, this type of anionic [2,3]-sigmatropic
rearrangement is generally known as the [2,3]-Wittig rearrangement4,5 or [2,3]-Wittig sig-
matropic rearrangement.5v,6 Occasionally, this reaction is also referred to as the [2,3]-Wittig
reaction,4w,7 [2,3]-Wittig process,5n,5v,5w or [2,3] sigmatropic Wittig rearrangement.5d,8 In
1978, this rearrangement was extended to α-alkoxystannes by Still and Mitra for which
the carbanion can be generated regioselectively via a tin-lithium exchange,9 this version
of [2,3]-sigmatropic rearrangement involving an α-alkoxystanne is thus referred to as the
Still-Wittig [2,3]-sigmatropic rearrangement,10 [2,3]-Wittig-Still rearrangement,5i,11 [2,3]
Wittig-Still sigmatropic rearrangement,12 or simply the Wittig-Still rearrangement.4w,5i,13
Analogously, the rearrangement of silyl anion from a silyl allylic ether is termed as the
siloxy-[2,3] Wittig rearrangement14 or [2,3]-sila-Wittig rearrangement;5e,15 and the rear-
rangement of an allylic amine in the presence of a strong base is called the aza-2,3-Wittig
rearrangement,16 aza-[2,3]-Wittig rearrangement5c,5o,16c,17 or aza-[2,3]-Wittig sigmatropic
rearrangement.5c,17,18
The driving force for this rearrangement is probably the conversion of a moderately
stabilized carbanion to a more stable alkoxide;5l as a result, an early transition state
is expected for this exothermic reaction.5r,5v Different from the [1,2]-Wittig Rearrange-
ment, the [2,3]-Wittig rearrangement obeys the Woodward-Hoffmann’s orbital symmetry

3049
conservation theory, and proceeds via a concerted route in both the gas5n and the liq-
uid phase,5d involving a five-membered envelope-like transition state.5s,6j It has been
proposed that the breaking C-O bond and the forming C-C bond in the transition state
are almost eclipsed, and the steric effect and electronic interaction at this point result
in a high stereoselectivity.5s For example, the [2,3]-Wittig rearrangement of 2-lithio-6-
vinyltetrahydropyran requires a trans-disposition of the two substituents, affording product
of configuration reversed at the lithium-bearing carbon atom.5p The general high level of
regioselectivity and stereoselectivity of the [2,3]-Wittig rearrangement5w has been demon-
strated in the following facts: (a) the rearrangement of methyl allyl ethers,5m trialkylstannyl
substituted methyl allyl ethers,5s and α-alkoxy-substituted allyl ethers19 often give pre-
dominantly or exclusively Z-alcohols, whereas the alkyl allyl ethers with substituents
of alkenyl, alkynyl or aryl on the alkyl moiety at the α position of oxygen afford E-
homoallyl alcohols;5m,5s (b) the rearranged products from Z-allylic ethers have erythro
configuration at the new chiral centers, while threo chirality exists in the products from
E-allylic ethers,5s,5w,20 except for the allyl ethers with a carbonyl group at the α position
of oxygen;5s and (c) the stereochemical outcome is dramatically affected by a stereocenter
outside the electrocyclic arena6l,21 (i.e., by a chiral auxiliary5q ). In addition, the zirconium
enolate of alkenyloxyacetic acid ester also favors the Z-selectivity.22 Such a high level of
stereoselectivity would be attributed to a highly ordered transition state.6n
For the symmetric bis-allylic ethers, the deprotonation occurring at either allylic moiety
gives the same products; however, the deprotonation of an asymmetric bis-allylic ether
should afford the product of a mixture. Fortunately, due to the accessibility and higher
acidity of the allyl protons at the allylic moiety with less substituent at the α-position, a
single regioisomer is usually produced from the exclusive lithiation on the less substituted
allylic moiety.23 Like other allyl ethers, the bis-(Z)-allyl ethers will give alcohols of erythro
configurations, and bis-(E)-allyl ethers afford products of threo selectivity.20 In contrast,
the tertiary bis-allyl ethers do not undergo the [2,3]-Wittig rearrangement when treated
with butyl lithium, but proceeds readily when treated with the combination of t-BuOK and
t-BuLi.5q For the tertiary bis-allyl ether derived from (+)-camphor, the rearrangement occurs
via an endo-transition state to afford products of R-configuration.5q
On the other hand, the substituent at either α- or γ-position of the allylic moiety will
depress the lithiation, and the depressing effect at γ-position is especially apparent.24
However, the rearrangement can also be accelerated by the trimethylsilyl group,17 or an
electron-withdrawing group such as CF3 .5k It is reported that the diastereoselectivity is
enhanced by the trimethylsilyl group as well.17 In addition, SmI2 is recently applied to
induce the rearrangement under a nonbasic condition, via regioselective metalation.24
For the thio-[2,3]-Wittig rearrangement of allyl thioether with group G at the α-position
of alkyl group, and group R at the γ-position of the allylic moiety, the rearrangement reactiv-
ity is observed in the order of G = Ph > CO2 Li > CN > CO2 Et > COCH, and R = Ph > H >
CH3 for G = CO2 Et or CN.5v Although the ortho-[2,3]-Wittig rearrangement is assumed
not likely to occur in kinetics for benzylic ethers, due to the de-aromatization and the great
migratory aptitude of the benzyl group in [1,2]-Wittig Rearrangement,6b such rearrange-
ment in fact is quite common, as shown in the rearrangement of α-benzylthio-alkyllithium,25
the Sommelet-Hauser Rearrangement of an N- and S-ylide, and enolate ortho-[2,3]-Wittig
rearrangement.6b In the case of 3-furylmethyl ethers, the [2,3]-Wittig rearrangement is
indeed competed with [1,2]-Wittig Rearrangement, and the actual outcome depends on the
bases applied.26 As a result, it is suggested that the [2,3]-Wittig rearrangement should be
carried out at low temperature to reduce the competing [1,2]-Wittig Rearrangement.5v
Overall, the [2,3]-Wittig rearrangement is very common and widely used in organic syn-
thesis. Its general popularity is probably due to its intrinsic features, such as the regiospecific
C-C bond formation and allylic transposition of oxygen atoms, formation of homoallyl
alcohols with expected olefin geometry, transfer of chirality and stereoselective creation of
vicinal chiral centers.5v
This reaction consists of two steps: deprotonation and rearrangement. The step of
rearrangement is a thermally allowed sigmatropic process according to the Woodward-
Hoffmann rule and Fukui’s frontier orbital theory,5v thus the rearrangement will proceed
via a concerted mechanism involving a five-membered envelope-like transition state, where
the breaking C-O bond and forming C-C bond are almost eclipsed, as illustrated here by
the rearrangement of allyl E-2-butenol ether shown here.5s,6j
D. MODIFICATION
This reaction has been extensively modified. Among these modifications, the most impor-
tant ones are the rearrangement of α-alkoxystannes and α-alkoxysilanes, both lead to the
regioselective generation of carbanions, via tin-lithium exchange in α-alkoxystannes9,27 and
desilylation with CsF in the latter.5h In addition, the recently reported SmI2 -induced [2,3]-
Wittig rearrangement is also an important modification, which proceeds via a 1,5-hydrogen
transfer under nonbasic conditions.4s,24 Moreover, some non-traditional [2,3]-Wittig rear-
rangements have been developed, such as a chiral base4y (e.g., Sparteine4t ) mediated
[2,3]-Wittig rearrangement; the silicon-assisted [2,3]-Wittig rearrangement,17 and Lewis
base,4c,4g ammonium carboxylate,4e and product-catalyzed [2,3]-Wittig rearrangement.4d
E. APPLICATIONS
This reaction has very broad application in organic synthesis.
This reaction is related to the [1,2]-Wittig Rearrangement, Meisenheimer Rearrange-

ment, Mislow-Evans Rearrangement, and the Sommelet-Hauser Rearrangement.
Reference 10.
To a solution of 9.60 g stannane (13.1 mmol) in 150 mL anhydrous THF cooled at −78◦ C,
was added slowly via a cannula 15 mL 2.5 M n-BuLi (39 mmol) also cooled to −78◦ C. The
resulting mixture was stirred for 1.5 h at the same temperature, then quenched with MeOH
and concentrated. The residue was diluted with 700 mL EtOAc, and the solution was washed
with NH4 Cl (2 × 150 mL) and 150 mL brine, dried over Na2 SO4 , and concentrated. The
residue was purified by silica gel chromatography using 15% EtOAc in hexanes to afford
3.0 g cis-product (53 %) and 1.57 g trans-product (28%) as clear oils.
BnO CO2-i-Pr
HO CO2-i-Pr
LDA
O BnO
THF, –78 °C
OBn
BnO
(±)-syn-α-hydroxy ester
57% (syn/anti = 95:5)
Reference 5a.
REFERENCES 3053
To a stirred solution of LDA prepared in situ from 1.7 mL diisopropylamine (12.0 mmol,
1.2 eq.) and 4.6 mL 2.3 M n-BuLi in hexane (10.5 mmol, 1.05 eq.) in THF at –78◦ C, was
added a cooled solution (–78◦ C) of 4.11 g allyl vinyl ether (10.0 mmol, 1.0 eq.) in THF.
The reaction mixture was allowed to warm to –10◦ C overnight, quenched with saturated
aqueous NH4 Cl, and extracted with CH2 Cl2 (3 × 30 mL). The combined organic phases
were dried over MgSO4 and concentrated. The residue was purified by silica gel column
chromatography using heptane/EtOAc (20:1–10:1) as the eluent to afford 2.36 g (±)α-
hydroxyester with syn/anti ratio of 95:5, in a yield of 57%, Rf = 0.59 (heptane EtOAc, 1:1).
Other references related to the [2,3]-Wittig rearrangement are cited in the literature.28
H. REFERENCES
1. (a) Schörigen, P., Ber., 1924, 57, 1634. (b) Schörigen, P., Ber., 1925, 58, 2028. (c) Schörigen, P.,
Ber., 1926, 59, 2510.
2. Schlenk, W. and Bergmann, E., Ann., 1928, 464, 35.
3. (a) Wittig, G. and Löhmann, L., Ann., 1942, 550, 260. (b) Wittig, G., Angew. Chem., 1954, 66,
10. (c) Wittig, G., Experientia, 1958, 14, 389.
4. (a) Mihara, Y.; Ojima, H.; Imahori, T.; Yoshimura, Y.; Ouchi, H. and Takahata, H., Heterocycles,
2007, 72, 633. (b) McNally, A.; Evans, B. and Gaunt, M. J., Angew. Chem. Int. Ed., 2006, 45,
2116. (c) Sato, Y.; Fujisawa, H. and Mukaiyama, T., Bull. Chem. Soc. Jpn., 2006, 79, 1275.
(d) Sato, Y.; Fujisawa, H. and Mukaiyama, T., Chem. Lett., 2006, 35, 124. (e) Sato, Y.; Fujisawa,
H. and Mukaiyama, T., Chem. Lett., 2005, 34, 1188. (f) Macia, B.; Gomez, C. and Yus, M.,
Tetrahedron Lett., 2005, 46, 6101. (g) Sato, Y.; Fujisawa, H. and Mukaiyama, T., Chem. Lett.,
2005, 34, 588. (h) Barrett, I. M. and Breeden, S. W., Tetrahedron: Asymmetry, 2004, 15, 3015.
(i) Li, Y.-J.; Lee, P.-T.; Yang, C.-M.; Chang, Y.-K.; Weng, Y.-C. and Liu, Y.-H., Tetrahedron Lett.,
2004, 45, 1865. (j) Toyota, M.; Hirota, M.; Asoh, T. and Ihara, M., Heterocycles, 2003, 61, 133.
(k) Hiersemann, M.; Abraham, L. and Pollex, A., Synlett, 2003, 1088. (l) McGowan, G., Aust. J.
Chem., 2002, 55, 799. (m) Pevet, I.; Meyer, C. and Cossy, J., Tetrahedron Lett., 2001, 42, 5215.
(n) Itoh, T. and Kudo, K., Tetrahedron Lett., 2001, 42, 1317. (o) Nakata, D.; Kusaka, C.; Tani,
S. and Kunishima, M., Tetrahedron Lett., 2001, 42, 415. (p) Tomooka, K.; Harada, M.; Hanji, T.
and Nakai, T., Chem. Lett., 2000, 1394. (q) Hiersemann, M.; Lauterbach, C. and Pollex, A., Eur.
J. Org. Chem., 1999, 2713. (r) Tomooka, K.; Igarashi, T.; Kishi, N. and Nakai, T., Tetrahedron
Lett., 1999, 40, 6257. (s) Kunishima, M.; Hioki, K.; Nakata, D.; Nogawa, S. and Tani, S., Chem.
Lett., 1999, 683. (t) Kawasaki, T. and Kimachi, T., Tetrahedron, 1999, 55, 6847. (u) Enders, D.;
Bartsch, M. and Runsink, J., Synthesis, 1999, 243. (v) Hiersemann, M., Tetrahedron, 1999, 55,
2625. (w) Maleczka, R. E. and Geng, F., Org. Lett., 1999, 1, 1115. (x) Tomooka, K.; Komine, N.
and Nakai, T., Tetrahedron Lett., 1998, 39, 5513. (y) Gibson, S. E.; Ham, P. and Jefferson, G. R.,
Chem. Commun., 1998, 123. (z) Gulea-Purcarescu, M.; About-Jaudet, E.; Collignon, N.; Saquet,
M. and Masson, S., Tetrahedron, 1996, 52, 2075.
5. (a) Pollex, A.; Millet, A.; Müller, J.; Hiersemann, M. and Abraham, L., J. Org. Chem., 2005, 70,
5579. (b) Sasaki, M.; Higashi, M.; Masu, H.; Yamaguchi, K. and Takeda, K., Org. Lett., 2005, 7,
5913. (c) Anderson, J. C. and Whiting, M., J. Org. Chem., 2003, 68, 6160. (d) Haeffner, F.; Houk,
K. N.; Schulze, S. M. and Lee, J. K., J. Org. Chem., 2003, 68, 2310. (e) Kawachi, A.; Maeda,
H.; Nakamura, H.; Doi, N. and Tamao, K., J. Am. Chem. Soc., 2001, 123, 3143. (f) Fokin, A. A.;
Kushko, A. O.; Kirij, A. V.; Yurchenko, A. G. and Schleyer, P. V. R., J. Org. Chem., 2000, 65,
2984. (g) Liang, J.; Hoard, D. W.; Khau, V. V.; Martinelli, M. J.; Moher, E. D.; Moore, R. E. and
Tius, M. A., J. Org. Chem., 1999, 64, 1459. (h) Maleczka, R. E. and Geng, F., Org. Lett., 1999, 1,
1111. (i) Ghosh, A. K. and Wang, Y., J. Org. Chem., 1998, 63, 6735. (j) Nakai, T. and Tomooka,
K., Pure & Appl. Chem., 1997, 69, 595. (k) Konno, T.; Umetani, H. and Kitazume, T., J. Org.
Chem., 1997, 62, 137. (l) Patel, S. T.; Percy, J. M. and Wilkes, R. D., J. Org. Chem., 1996, 61,
166. (m) Katritzky, A. R.; Wu, H. and Xie, L. H., J. Org. Chem., 1996, 61, 4035. (n) Ahmad, M.
R.; Dahlke, G. D. and Kass, S. R., J. Am. Chem. Soc., 1996, 118, 1398. (o) Ahman, J. and Somfai,
P., J. Am. Chem. Soc., 1994, 116, 9781. (p) Verner, E. J. and Cohen, T., J. Am. Chem. Soc., 1992,
114, 375. (q) Keegan, D. S.; Midland, M. M.; Werley, R. T. and McLoughlin, J. I., J. Org. Chem.,
1991, 56, 1185. (r) Wu, Y.-D. and Houk, K. N., J. Org. Chem., 1991, 56, 5657. (s) Wu, Y.-D.;
Houk, K. N. and Marshall, J. A., J. Org. Chem., 1990, 55, 1421. (t) Luengot, J. I. and Koreeda,
M., J. Org. Chem., 1989, 54, 5415. (u) Takahashi, T.; Nemoto, H.; Kanda, Y.; Tsuji, J. and Fujise,
Y., J. Org. Chem., 1986, 51, 4315. (v) Nakai, T. and Mikami, K., Chem. Rev., 1986, 86, 885.
(w) Nakai, T.; Mikami, K.; Taya, S. and Fujita, Y., J. Am. Chem. Soc., 1981, 103, 6492.
6. (a) Pevet, I.; Meyer, C. and Cossy, J., Synlett, 2003, 663. (b) Garbi, A.; Allain, L.; Chorki, F.;
Ourévitch, M.; Crousse, B.; Bonnet-Delpon, D.; Nakai, T. and Bégué, Org. Lett., 2001, 3, 2529.
(c) Tomooka, K.; Komine, N. and Nakai, T., Chirality, 2000, 12, 505. (d) Makomo, H.; Saquet, M.;
Simeon, F.; Masson, S.; About-Jaudet, E.; Collignon, N. and Gulea-Purcarescu, M., Phosphorus,
Sulfur & Silicon & Related Elements, 1996, 109–110, 445. (e) Yokomatsu, T.; Yamagishi, T. and
Shibuya, S., Synlett, 1995, 1035. (f) Shi, X. W.; Webster, F. X. and Meinwald, J., Tetrahedron,
1995, 51, 10433. (g) Mitchell, T. N.; Giesselmann, F. and Kwetkat, K., J. Organomet. Chem.,
1995, 492, 191. (h) Mikami, K.; Takahashi, O.; Fujimoto, K. and Nakai, T., Synlett, 1991, 629.
(i) Granja, J. R., Synth. Commun., 1991, 21, 2033. (j) Mikami, K. and Nakai, T., Synthesis, 1991,
594. (k) Mikami, K.; Kawamoto, K. and Nakai, T., Tetrahedron Lett., 1985, 26, 5799. (l) Mikami,
K.; Fujimoto, K.; Kasuga, T. and Nakai, T., Tetrahedron Lett., 1984, 25, 6011. (m) Mikami, K.;
Azuma, K. and Nakai, T., Tetrahedron, 1984, 40, 2303. (n) Mikami, K.; Kimura, Y.; Kishi, N.
and Nakai, T., J. Org. Chem., 1983, 48, 279.
7. Nakai, T. and Mikami, K., Org. React., 1995, 46, 105.
8. (a) Enders, D.; Backhaus, D. and Runsink, J., Tetrahedron, 1996, 52, 1503. (b) Metz, P. and
Schoop, A., Tetrahedron, 1995, 51, 9023. (c) Enders, D.; Backhaus, D. and Runsink, J., Angew.
Chem. Int. Ed. Engl., 1994, 33, 2098. (d) Tsai, D. J.-S. and Midland, M. M., J. Am. Chem. Soc.,
1985, 107, 3915. (e) Tsai, D. J.-S. and Midland, M. M., J. Org. Chem., 1984, 49, 1842.
9. Still, W. C. and Mitra, A., J. Am. Chem. Soc., 1978, 100, 1927.
10. Wang, X. D. J.; Hart, S. A.; Xu, B. L.; Mason, M. D.; Goodell, J. R. and Etzkorn, F. A., J. Org.
Chem., 2003, 68, 2343.
11. (a) Schaudt, M. and Blechert, S., J. Org. Chem., 2003, 68, 2913. (b) Sugimura, H.; Hasegawa, Y.
and Osumi, K. Heterocycles, 2000, 52, 99. (c) Ghosh, A. K. and Wang, Y., Tetrahedron, 1999,
55, 13369.
12. (a) Mulzer, J. and Riether, D., Org. Lett., 2000, 2, 3139. (b) Ovaa, H.; Codee, J. D. C.; Lastdrager,
B.; Overkleeft, H. S.; Van der Marel, G. A. and Van Boom, J. H., Tetrahedron Lett., 1999, 40,
5063.
13. (a) Bol, K. M. and Liskamp, R. M. J., Tetrahedron, 1992, 48, 6425. (b) Bol, K. M. and Liskamp,
R. M. J., Tetrahedron Lett., 1991, 32, 5401. (c) Kruse, B. and Brueckner, R., Tetrahedron Lett.,
1990, 31, 4425. (d) Priepke, H.; Brueckner, R. and Harms, K., Chem. Ber., 1990, 123, 555.
(e) Priepke, H. and Brueckner, R., Chem. Ber., 1990, 123, 153.
14. Nakai, E. and Nakai, T., Tetrahedron Lett., 1988, 29, 5409.
15. (a) Kawachi, A.; Maeda, H. and Tamao, K., Chem. Lett., 2000, 1216. (b) Kawachi, A. and Tamao,
K., Bull. Chem. Soc. Jpn., 1997, 70, 945.
16. (a) Somfai, P.; Jarevang, T.; Lindstrom, U. M. and Svensson, A., Acta Chem. Scand., 1997, 51,
1024. (b) Ulibarri, G.; Audrain, H.; Nadler, W.; Lhermitte, H. and Grierson, D. S., Pure & Appl.
Chem., 1996, 68, 601. (c) Åhman, J.; Jareváng, T. and Somfai, P., J. Org. Chem., 1996, 61, 8148.
(d) Åhman, J. and Somfai, P., Tetrahedron Lett., 1996, 37, 2495. (e) Åhman, J. and Somfai, P.,
Tetrahedron, 1995, 51, 9747. (f) Åhman, J. and Somfai, P., Tetrahedron Lett., 1995, 36, 303.
REFERENCES 3055
17. Anderson, J. C.; Siddons, D. C.; Smith, S. C. and Swarbrick, M. E., J. Org. Chem., 1996, 61,
4820.
18. (a) Anderson, J. C.; Ford, J. G. and Whiting, M., Org. Biomol. Chem., 2005, 3, 3734. (b) Anderson,
J. C. and Skerratt, S., J. Chem. Soc., Perkin Trans. I, 2002, 2871. (c) Anderson, J. C. and Flaherty,
A., J. Chem. Soc., Perkin Trans. I, 2001, 267. (d) Anderson, J. C.; Flaherty, A. and Swarbrick,
M. E., J. Org. Chem., 2000, 65, 9152. (e) Anderson, J. C.; Dupau, P.; Siddons, D. C.; Smith, S.
C. and Swarbrick, M. E., Tetrahedron Lett., 1998, 39, 2649. (f) Anderson, J. C. and Roberts, C.
A., Tetrahedron Lett., 1998, 39, 159. (g) Anderson, J. C.; Smith, S. C. and Swarbrick, M. E., J.
Chem. Soc., Perkin Trans. I, 1997, 1517. (h) Anderson, J. C.; Siddons, D. C.; Smith, S. C. and
Swarbrick, M. E., J. Chem. Soc., Chem. Commun., 1995, 1835.
19. Marshall, J. A. and Jenson, T. M., J. Org. Chem., 1988, 53, 4631.
20. Marshall, J. A. and Jenson, T. M., J. Org. Chem., 1984, 49, 1707.
21. (a) Denmark, S. E. and Marlin, J. E., J. Org. Chem., 1987, 52, 5743. (b) Kallmerten, J. and Gould,
T. J., J. Org. Chem., 1986, 51, 1152. (c) Kurth, M. J. and Decker, O. H. W., J. Org. Chem., 1986,
51, 1377. (d) Kurth, M. J.; Decker, O. H. W.; Hope, H. and Yanuck, M. D., J. Am. Chem. Soc.,
1985, 107, 433.
22. Uchikawa, M.; Katsuki, T. and Yamaguchi, M., Tetrahedron Lett., 1986, 27, 4581.
23. Marsden, A. and Thomas, E. J., ARKIVOC, 2002, (ix), 78.
24. Kunishima, M.; Hioki, K.; Kono, K.; Kato, A. and Tani, S., J. Org. Chem., 1997, 62, 7542.
25. Brickmann, K. and Brückner, R., Chem. Ber., 1993, 126, 1227.
26. Tsubuki, M.; Kamata, T.; Okita, H.; Arai, M.; Shigihara, A. and Honda, T., Chem. Commun.,
1999, 2263.
27. Bruckner, R. and Priepke, H., Angew. Chem. Int. Ed. Engl., 1988, 27, 278.
28. (a) Tsubuki, M.; Takahashi, K. and Honda, T., J. Org. Chem., 2003, 68, 10183. (b) Pilli, R. A.;
Böckelmann, M. A. and Corso, A. D., J. Chem. Ecology, 1999, 25, 355. (c) Manabe, S., Chem.
Commun., 1997, 737. (d) Okajima, T. and Fukazawa, Y., Chem. Lett., 1997, 81. (e) Smith, A.
B.; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M. and Salvatore, B. A., J. Am. Chem. Soc., 1995,
117, 12013. (f) Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D. and Houk, K. N., Tetrahedron,
1994, 50, 5917. (g) Marshall, J. A. and Wang, X., J. Org. Chem., 1992, 57, 2747. (h) Marshall,
J. A. and Wang, X.-J., J. Org. Chem., 1992, 57, 2141. (i) Marshall, J. A. and Wang, X.-J., J. Org.
Chem., 1991, 56, 4913. (j) Wei, S.-Y.; Tomooka, K. and Nakai, T., J. Org. Chem., 1991, 56, 5973.
(k) Williams, R. M.; Sabol, M. R.; Kim, H.-D. and Kwast, A., J. Am. Chem. Soc., 1991, 113, 6621.
(l) Marshall, J. A. and Wang, X.-J., J. Org. Chem., 1990, 55, 2995. (m) Marshall, J. A.; Robinson,
E. D. and Zapata, A., J. Org. Chem., 1989, 54, 5854. (n) Rossano, L. T.; Plata, D. J. and Kallmerten,
J., J. Org. Chem., 1988, 53, 5189. (o) Sugimura, T. and Paquette, L. A., J. Am. Chem. Soc., 1987,
109, 3018. (p) Mikami, K.; Taya, S.; Nakai, T. and Fujita, Y., J. Org. Chem., 1981, 46, 5447.
(q) Still, W. C.; McDonald, J. H.; Collum, D. B. and Mitra, A., Tetrahedron Lett., 1979, 593.
(r) Baldwin, J. E.; DeBernard, J. and Patrick, J. E., Tetrahedron Lett., 1970, 353. (s) Schöllkopf,
U. and Fellenberger, K., Ann., 1966, 698, 80. (t) Makisumi, Y. and Notzumoto, S., Tetrahedron
Lett., 1966, 6393. (u) Cast, J.; Stevens, T. S. and Holmes, J., J. Chem. Soc., 1960, 3521.
138
Chapman Rearrangement
This reaction was first reported by Mumm and co-workers in 19151 and was extensively
investigated by Chapman in 1920s and 1930s.2 It is the thermal rearrangement of aryl
imidates to N, N-diaryl amides, and is generally known as the Chapman rearrangement.3
Occasionally, this reaction is also referred to as the Beckmann-Chapman rearrangement.4
It was found that this rearrangement follows approximately a first-order kinetics5 and pro-
ceeds readily with high yields in either polar or nonpolar solvents,2e but it is accelerated by
polar solvents. In addition, this reaction can even take place in a solid state at one-fifteenth
to one-fifth the rate of that estimated in solution.4c In fact, it is an intramolecular nucle-
ophilic aromatic substitution that proceeds stereospecifically with migration of that aryl
ring attached to oxygen, and the ortho substituents on the aryl ring connecting to oxygen
atom have been shown to enhance the migration rate. This effect is known as steric accel-
eration due to the hindered rotation (SAHR) effect,3l,3m as the free rotation will restrict the
formation of a four-membered ring in the transition state.3l Moreover, it is also found that
a para electron-donating group also increases the migration rate, whereas a para electron-
withdrawing group (Cl, NO2 , etc.) decreases the reaction rate.4c This rearrangement has
been used for the preparation of substituted N-phenylanthranilic acids.3r It should be pointed
out that if the migrating aryl moiety has an α-acidic hydrogen at the ortho position, then an
“abnormal” Chapman Rearrangement also occurs.3q

627
628 CHAPMAN REARRANGEMENT
O N ∆ O N
Ar′ Ar′
Ar Ar
The Chapman rearrangement involves the ipso attack of a nitrogen atom and the subse-
quent cleavage of the C O bond, as displayed here.
O N O N O N
Ar′ Ar′ Ar′
Ar Ar Ar
D. MODIFICATION
N/A
E. APPLICATIONS
This reaction has general application in the preparation of N-acyl anilines.
This reaction is related to the Newman-Kwart Rearrangement.
Reference 3m.
The Preparation of 2,6-di-t-Butylphenyl N-Phenylbenzimidate

Exactly 10.0 g 2,6-di-t-butylphenol (0.0486 mol) and 0.1 g triphenylmethane were dis-
solved in 150 mL tetrahydrofuran. While the solution was stirred under nitrogen, ∼31 mL
1.6 M butyllithium in hexane was added, whereupon the red color of the triphenylmethyl car-
banion just appeared. Then 10.47 g N-phenylbenzimidoyl chloride (0.0486 mol) in 75 mL
tetrahydrofuran was added, and the system was stirred overnight at room temperature under
nitrogen. After the reaction mixture was combined with 400 mL ethyl ether, it was extracted
with water, dried with anhydrous magnesium sulfate, and freed of solvent on a rotary evapo-
rator to give 19.35 g of a viscous red oil. Chromatography on 400 g alumina, using hexane as
the elution solvent, afforded some 2,6-di-t-butylphenol and impure 2,6-disubstituted phenyl
N-phenylbenzimidates. Two recrystallizations from methanol afforded 4.28 g imidate as
colorless plates, in a yield of 23%, m.p. 127.5–128.5◦ C.
The Chapman Rearrangement

A 1.0 g 2,6-disubstituted phenyl N-phenylbenzimidate was sealed in a glass tube in
air and heated at 305◦ C for 6 h. The resulting cooled mass was chromatographed to give
N-(2,6-di-t-butylphenyl)benzanilide with a broad melting point of 129–133.5◦ C.
Reference 3r.
To a solution of NaOEt prepared from 0.11 g sodium (4.7 mmol) and 10 mL absolute
ethanol, cooled in an ice bath, was added in rapid succession 0.88 g methyl 2-chloro-
6-hydroxybenzoate (4.7 mmol) and a solution of 1.14 g N-4-methoxyphenylbenzimidyl
chloride (4.7 mmol) in 30 mL dry ether. The reaction mixture was shaken vigorously,
whereupon a precipitate of sodium chloride began to form. The mixture was allowed to
stand at room temperature for 48 h, the solvent was evaporated, and the residue was diluted
with water. The resulting oily solid was removed by extraction with ether, the ethereal
solution was dried, and the ether was distilled. The crude imido ester was heated in a
nitrogen atmosphere at 210–215◦ C for 70 min, then dissolved in 10.8 mL ethanol; the
alcoholic solution was diluted with 5.4 mL water and 5.4 mL of a 1 M ethanolic sodium
ethoxide. The solution was refluxed for 1.5 h, the alcohol was evaporated on a steam
bath, and the aqueous solution was acidified with dilute HCl. The dark oil that formed
was separated by decantation, and the crude benzoate of the substituted anthranilic acid was
dissolved in 22 mL ethanol. A solution of 7.2 g sodium hydroxide in 7.2 mL water was
added, and the mixture was refluxed for 1 h. The alcohol was evaporated, and the solution
was then acidified. The brown solid was extracted exhaustively with boiling water to remove
the benzoic acid, and the remaining brown solid was recrystallized from aqueous ethanol.
The yellow needle-like crystals of N-(4 -methoxyphenyl)-6-chloroanthranilic acid, in a total
amount of 0.36 g, was obtained, in a yield of 27.7%, m.p., 139.5–140.5◦ C (dec).
Other references related to the Chapman rearrangement are cited in the literature.6
630 CHAPMAN REARRANGEMENT
H. REFERENCES
1. Mumm, O.; Hesse, H. and Volquartz, H., Ber., 1915, 48, 379.
2. (a) Chapman, A. W., J. Chem. Soc., 1925, 1992. (b) Chapman, A. W., J. Chem. Soc.,1927, 1743.
(c) Chapman, A. W., J. Chem. Soc., 1929, 569. (d) Chapman, A. W., J. Chem. Soc., 1930, 2462.
(e) Chapman, A. W. and Howis, C. C., J. Chem. Soc., 1933, 806. (f) Chapman, A. W., J. Chem.
Soc., 1934, 1550. (g) Chapman, A. W. and Fidler, F. A., J. Chem. Soc., 1936, 451.
3. (a) Noroozi-Pesyan, N., Heterocycl. Commun., 2006, 12, 329. (b) Burdukovskii, V. F.; Mognonov,
D. M.; Allayarov, S. R.; Botoeva, S. O. and Mazurevskaya, Z. P., Russ. Chem. Bull., 2004, 53,
1773. (c) Wang, X. S.; Cai, Y. L. and Xu, Z. X., Zhongguo Yaoxue Zazhi (Beijing), 1997, 32, 774.
(d) Kimura, M.; Okabayashi, I. and Isogai, K., J. Heterocycl. Chem., 1988, 25, 315. (e) Kimura,
M., J. Chem. Soc., Perkin Trans. II, 1987, 205. (f) Peterson, L. H.; Douglas, A. W. and Tolman,
R. L., J. Heterocycl. Chem., 1981, 18, 659. (g) Shawali, A. S.; Hassaneen, H. M. and Almousawi,
S., Bull. Chem. Soc. Jpn., 1978, 51, 512. (h) Ramirez, F.; Telefus, C. D. and Prasad, V. A. V.,
Tetrahedron, 1975, 31, 2007. (i) Goldberg, V. D. and Harris, M. M., J. Chem. Soc., Perkin Trans. II,
1973, 1303. (j) Hegarty, A. F.; Kearney, J. A. and Scott, F. L., J. Chem. Soc., Perkin Trans. II, 1973,
1422. (k) Wheeler, O. H.; Roman, F.; Santiago, M. V. and Quiles, F., Can. J. Chem., 1969, 47, 503.
(l) Relles, H. M. and Pizzolato, G., J. Org. Chem., 1968, 33, 2249. (m) Relles, H. M., J. Org.
Chem., 1968, 33, 2245. (n) Bock, G., Chem. Ber., 1967, 100, 2870. (o) Barclay, R., Can. J. Chem.,
1965, 43, 2125. (p) Schulenberg, J. W. and Archer, S., Org. React., 1965, 14, 1. (q) Schulenberg,
J. W. and Archer, S., J. Am. Chem. Soc., 1960, 82, 2035. (r) Dauben, W. G. and Hodgson, R. L.,
J. Am. Chem. Soc., 1950, 72, 3479.
4. (a) Snegirev, V. F.; Antipin, M. Y.; Khrustalev, V. N. and Struchkov, Y. T., Izv. Akad. Nauk, Ser.
Khim., 1994, 1073. (b) Rozantsev, E. G.; Chudinov, A. V. and Sholle, V. D., Izv. Akad. Nauk SSSR,
Ser. Khim., 1980, 2114. (c) McCullough, J. D.; Curtin, D. Y. and Paul, I. C., J. Am. Chem. Soc.,
1972, 94, 874. (d) Fischer, H. P. and Funk-Kretschmar, F., Helv. Chim. Acta, 1969, 52, 913.
5. Wiberg, K. B. and Rowland, B. I., J. Am. Chem. Soc., 1955, 77, 2205.
6. (a) Dubau-Assibat, N.; Baceiredo, A.; Dahan, F. and Bertrand, G., Bull. Soc. Chim. Fr., 1995, 132,
1139. (b) Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T. and Sautet, P., J. Chem. Soc., Chem.
Commun., 1992, 132. (c) Suttle, N. A. and Williams, A., J. Chem. Soc., Perkin Trans. II, 1983,
1369. (d) Peterson, L. H.; Douglas, A. W. and Tolman, R. L., J. Heterocyclic Chem., 1981, 18,
659. (e) Shawali, A. S. and Hassaneen, H. M., Tetrahedron, 1972, 28, 5903. (f) Schulenberg, J. W.
and Archer, S., Org. React., 1965, 14, 1. (g) Smith, P. A. S., “Chapter 8, Rearrangements Involv-
ing Migration to an Electron–Deficient Nitrogen or Oxygen” in Molecular Rearrangements, ed.
de Mayo, P., Interscience, New York, 1963.
657
Wallach Rearrangement
(Wallach Transformation)
This reaction was first reported by Wallach and Belli in 1880.1 It is a strong acid-
promoted conversion of azoxybenzene and its derivatives into 4-hydroxyazobenzene
and the corresponding substituted hydroxyazobenzenes, and is generally known as
the Wallach rearrangement.2 Occasionally, it is also referred to as the Wallach
transformation.2x,2ff,2mm,2nn,3 However, the corresponding rearrangement can also be initi-
ated by photo irradiation, and such conversion under photo illumination is referred to as the
photo-Wallach rearrangement.4 It has been reported that the Wallach rearrangement gives
p-hydroxyazobenzene with an even distribution of 15 N label from azoxybenzene specifically
labeled on one nitrogen atom.5 For the azoxybenzene series, the hydroxy group is always
introduced into the para-position;2y whereas in the naphthyl azoxy series, the hydroxy
group is primarily attached to the ortho-position.2y For comparison, under photo-Wallach
rearrangement conditions, both the azoxybenzene series (λ = 320 nm4b ) and naphthyl azoxy
series give exclusively the rearranged products with an hydroxy group ortho to the azo group,
as indicated by the reaction of 1,1 - and 2,2 -azoxynaphthalenes under sunlight or ultraviolet
light.6 It has been found that the relative reactivity follows the order of phenyl < 2-naphthyl
< 1-naphthyl, in an inverse pKa-reactivity relationship for the substrates.2y

2942
APPLICATIONS 2943
The mechanism of the Wallach rearrangement has been extensively

studied.2h,2k,2w,2x,2ff,2oo,2pp,2ss Although the Wallach rearrangement is similar to
the Benzidine Rearrangement, the former generally requires a high concentration of
strong acid (e.g., 60–100% H2 SO4 ), whereas the Benzidine Rearrangement takes place
readily in a dilute acid solution, such as 0.05–1.0 M HClO4 .2y Under such strong
acidic conditions, both nitrogen atoms could be protonated,2ii and a kinetic study has
shown that the rate of rearrangement continually increases beyond the stage of complete
monoprotonation of the azoxybenzenes, indicating that a dicationic intermediate is
involved, arising from double proton transfer.2y It has been found from kinetic studies
that this rearrangement may take two paths,2x depending on the acidic concentration:
< 75% H2 SO4 , the mechanism involving a quinoid intermediate is followed; while > 80%
H2 SO4 , the dicationic intermediate route prevails.2b,2g Within the concentration range
(75%–80% H2 SO4 ), both paths are possible.2y An illustrative mechanism is given here.
D. MODIFICATION
N/A
E. APPLICATIONS
This reaction has general application in the preparation of hydroxyazobenzenes and

hydroxyazonaphthalenes.
2944 WALLACH REARRANGEMENT
This reaction is related to the Benzidine Rearrangement.
OH
O–
+ H2SO4
N N
N N
Br Br
Reference 7.
The desired azobenzenes were treated with a strong acid (H2 SO4 ). After the completion
of the rearrangement, the products were isolated in two different methods. In the first method,
the strong acidic solution was neutralized very slowly with concentrated NaOH solution
(∼ 35–36 N) while cooled in an acetone–dry ice bath until the pH of the solution reached
9. The precipitate that formed was removed by filtration, and the filtrate was extracted with
ether. By this method, 4-hydroxyazobenzenc and 4-hydroxy-4 -bromoazobenzene were iso-
lated from the corresponding rearranged azoxy compounds. In the second method, the
reaction mixture in acidic solution was refluxed and then was poured into an ice water
bath. A precipitate appeared, which was removed by filtration and washed several times
with ice water. The crude product was recrystallized from 95% EtOH. By this method
2-hydroxy-4 -methylazobenzene was isolated. (No yields were provided.)
Other references related to the Wallach rearrangement are cited in the literature.8
H. REFERENCES
1. Wallach, O. and Belli, L., Ber., 1880, 13, 525.

2. (a) Ejsmont, K.; Doman’ski, A. A.; Kyziol, J. B. and Zaleski, J., J. Mol. Struct., 2005, 753, 92.
(b) Cox, R. A.; Fung, D. Y. K.; Csizmadia, I. G. and Buncel, E., Can. J. Chem., 2003, 81, 535.
(c) Zaleski, J.; Ejsmont, K.; Doman’ski, A. A. and Kyzio, J. B., Acta Cryst., 2002, A58 (suppl.),
C152. (d) Lalitha, A.; Pitchumani, K. and Srinivasan, C., J. Mol. Catal., A: Chem., 2000, 160,
429. (e) Özen, A. S.; Erdem, S. S. and Aviyente, V., Struct. Chem., 1998, 9, 15. (f) Keum, S.
R. and Lee, H. I., J. Korean Chem. Soc., 1993, 37, 148. (g) Kolck, H., Zeitsch. Chem., 1989,
29, 18. (h) Furin, G. G., Uspekhi Khim., 1987, 56, 911. (i) Furin, G. G.; Andreevskaya, O. I.;
Rezvukhin, A. I. and Yakobson, G. G., J. Fluor. Chem., 1985, 28, 1. (j) Buncel, E. and Keum, S. R.,
J. Chem. Soc., Chem. Commun., 1983, 578. (k) Oae, S. and Shimao, I., Kagaku no Ryoiki, 1983,
37, 111. (l) Shimao, I. and Oae, S., Bull. Chem. Soc. Jpn., 1983, 56, 643. (m) Yamamoto, J.; Aimi,
H.; Masuda, Y.; Sumida, T.; Umezu, M. and Matuura, T., J. Chem. Soc., Perkin Trans. II, 1982,
1565. (n) Yamamoto, J.; Nishigaki, Y.; Umezu, M. and Matsuura, T., Tetrahedron, 1980, 36, 3177.
(o) Yamamoto, J.; Maki, J. and Umezu, M., Nippon Kagaku Kaishi, 1980, 153. (p) Shimao, I. and
Matsumura, S., Bull. Chem. Soc. Jpn., 1978, 51, 926. (q) Yamamoto, J.; Sato, N.; Koshikawa, M.
and Umezu, M., Yuki Gosei Kagaku Kyokaishi, 1977, 35, 581. (r) Yamamoto, J.; Sakamoto, T.;
Kusunoki, K.; Umezu, M. and Matsuura, T., Nippon Kagaku Kaishi, 1977, 66. (s) Shimao, I. and
REFERENCES 2945
Matsumura, S., Bull. Chem. Soc. Jpn., 1976, 49, 2294. (t) Yamamoto, J.; Nishigaki, Y.; Imagawa,
M.; Umezu, M. and Matsuura, T., Chem. Lett., 1976, 261. (u) Andreevskaya, O. I.; Furin, G. G.
and Yakobson, G. G., Zh. Org. Khim., 1977, 13, 1684. (v) Khan, K. A., Pakistan J. Sci. Ind. Res.,
1975, 18, 205. (w) Cox, R. A.; Delenko, A. J. and Buncel, E., J. Chem. Soc., Perkin Trans. II, 1975,
471. (x) Buncel, E.; Cox, R. A. and Dolenko, A., Tetrahedron Lett., 1975, 215. (y) Buncel, E.,
Acc. Chem. Res., 1975, 8, 132. (z) Cox, R. A. and Buncel, E., J. Am. Chem. Soc., 1975, 97, 1871.
(aa) Dolenko, A. and Buncel, E., Can. J. Chem., 1974, 52, 623. (bb) Cox, R. A. and Buncel, E.,
Can. J. Chem., 1973, 51, 3143. (cc) Buncel, E. and Cox, R. A., J. Chem. Soc., Chem. Commun.,
1972, 1259. (dd) Olah, G. A.; Dunne, K.; Kelly, D. P. and Mo, Y. K., J. Am. Chem. Soc., 1972,
94, 7438. (ee) Buncel, E. and Dolenko, A., Tetrahedron Lett., 1971, 113. (ff) Hendley, E. C. and
Duffey, D., J. Org. Chem., 1970, 35, 3579. (gg) Buncel, E. and Strachan, W. M. J., Can. J. Chem.,
1970, 48, 377. (hh) Strachan, W. M. J. and Buncel, E., Can. J. Chem., 1969, 47, 4011. (ii) Strachan,
W. M. J.; Dolenko, A. and Buncel, E., Can. J. Chem., 1969, 47, 3631. (jj) Buncel, E.; Strachan, W.
M. J.; Gillespie, R. J. and Kapoor, R., J. Chem. Soc. D, 1969, 765. (kk) Buncel, E. and Strachan,
W. M. J., Can. J. Chem., 1969, 47, 911. (ll) Buncel, E.; Dolenko, A.; Csizmadia, I. G.; Pincock, J.
and Yates, K., Tetrahedron, 1968, 24, 6671. (mm) Duffey, D. and Hendley, E. C., J. Org. Chem.,
1968, 33, 1918. (nn) Behr, L. C. and Hendley, E. C., J. Org. Chem., 1966, 31, 2715. (oo) Buncel, E.
and Lawton, T. B., Can. J. Chem., 1965, 43, 862. (pp) Oae, S.; Fukumoto, T. and Yamagami, M.,
Bull. Chem. Soc. Jpn., 1963, 36, 601. (qq) Buncel, E. and Lawton, B. T., Chem. & Ind. (London),
1963, 1835. (rr) Singh, J.; Singh, P.; Boivin, J. L. and Gagnon, P. E., Can. J. Chem., 1963,
41, 499. (ss) Oae, S.; Fukumoto, T. and Yamagami, M., Bull. Chem. Soc. Jpn., 1961, 34, 1873.
(tt) Shemyakin, M. M.; Maimind, V. I. and Vaichunaite, B. K., Chem. & Ind. (London), 1958,
755. (uu) Shemyakin, M. M.; Maimind, V. I. and Vaichunaite, B. K., Zh. Obsh. Khim., 1958, 28,
1708.
3. Gore, P. H. and Hughes, G. K., Aust. J. Sci. Res., 1951, 4A, 185.
4. (a) Shine, H. J.; Subotkowski, W. and Gruszecka, E., Can. J. Chem., 1986, 64, 1108. (b) Squire,
R. H. and Jaffé, H. H., J. Am. Chem. Soc., 1973, 95, 8188.
5. Shemyakin, M. M.; Maimind, V. I. and Vaichunaite, B. K., Chem. Ind. (London), 1958, 755.
6. (a) Cumming, W. M. and Steel, J. K., J. Chem. Soc., 1925, 127, 2374. (b) Cumming, W. M. and
Steel, J. K., J. Chem. Soc., 1923, 123, 2464. (c) Bandish, O. and Fürst, R., Ber., 1912, 45, 3427.
7. Hahn, C.-S. and Jaffé, H. H., J. Am. Chem. Soc., 1962, 84, 946.
8. (a) Basch, H. and Hoz, T., Mol. Phys., 1997, 91, 789. (b) Yamamoto, J.; Aimi, H.; Masuda,
Y.; Sumida, T.; Umezu, M. and Matuura, T., J. Chem. Soc., Perkin Trans. II, 1982, 1565.
(c) Cox, R. A. and Buncel, E. “Rearrangements of Hydrazo, Azoxy, and Azo Compounds,”
in The Chemistry of Hydrazo, Azo and Azoxy Groups, ed., Patai, S., John Wiley & Sons,
New York, 1975, 2 pp. 775–859. (d) Goon, D. J. W.; Murray, N. G.; Schoch, J.-P. and
Bunce, N. J., Can. J. Chem., 1973, 51, 3827. (e) Spence, G. G.; Taylor, E. C. and Buchardt,
O., Chem. Rev., 1970, 70, 231. (f) Buncel, E. and Strachan, W. M. J., Can. J. Chem., 1970,
48, 377. (g) Buncel, E., “Azoxy Rerrangements,” in Mechanisms of Molecular Migrations,
ed. Thyagarajan, B. S. John Wiley & Sons, New York, 1968, 1, pp. 61–119. (h) Bun-
cel, E. and Lawton, B. T., Can. J. Chem., 1965, 43, 862. (i) Buncel, E. and Lawton, B.
T., Chem. Ind. (London), 1963, 1835. (j) Shemyakin, M. M.; Maimind, V. I. and Vaichu-
naite, B. K., Russ. Chem. Bull., 1960, 9, 808. (k) Stevens, T. E., J. Org. Chem., 1967, 33,
2664. (l) Hahn, C. S.; Lee, K. W. and Jaffé, H. H., J. Am. Chem. Soc., 1967, 89, 4975.
(m) Oae, S.; Fukumoto, T. and Yamagami, M., Bull. Chem. Soc. Jpn., 1963, 36, 601.
(n) Shemyakin, M. M. and Maimind, V. I., “Mechanism of the Isomerization of Azoxy Com-
pounds” in Recent Progress in the Chemistry of Natural and Synthetic Coloring Matters and
Related Fields, ed. Gore, T. S. Academic Press, New York, 1962, p. 441–149 (o) Hahn, C. S. and
Jaffé, H. H., J. Am. Chem. Soc., 1962, 84, 949. (p) Oae, S.; Fukumoto, T. and Yamagami, M.,
Bull. Chem. Soc. Jpn., 1961, 34, 1873. (q) Badger, G. M. and Buttery, R. G., J. Chem. Soc., 1954,
2243.
471
Orton Rearrangement
This reaction was first reported by Bender in 1886,1 subsequently by Armstrong in

1890,2 and was extensively explored by Orton et al. beginning in 1899.3 It is the rear-
rangement of an N-chloro acyl anilide into an N-acyl p-chloroanilide in the presence of
an acid such as HCl. Therefore, it is generally known as the Orton rearrangement.4 This
reaction is assumed to proceed via a multistep processes, including the liberation of chlo-
rine and subsequent electrophilic substitution,4i,5 as suggested by Orton.3a The former step
is reversible, whereas the electrophilic substitution is irreversible.4i,5 Although hypochlor-
ous acid has been proposed as the intermediate during the chlorination at the aromatic
ring3e because the Orton rearrangement occurs readily in a chlorinating solution in which
HClO is the major species,4b this mechanism was abandoned by Orton.3p It is known that
the Orton rearrangement is promoted simultaneously by proton (i.e., H+ ) and chloride.5b
The rearrangement of acetyl N-chloroanilide in acetic acid containing NaCl and sodium
acetate buffer is a first-order reaction, and the reaction rate is accelerated by the addition of
acetanilide or N-acetonaphthalide, with a maximal rate limit.5c It has been found that both
solvent composition5a and substrate influence this rearrangement.4i For example, in acetic
acid, no hydrogen chloride is detected,5a and no chlorination products are formed by the
treatment of tertiary acyl anilides such as N-methyl benzanilide and N-phenyl benzanilide.6
In addition, the Orton rearrangement can be triggered by a Lewis acid, such as AgBF4 ,7
as well as by light,8 such as irradiation from a mercury-vapor lamp even in solid state.9
Furthermore, the chlorination of acyl anilide from chlorine can proceed by two paths: the
normal Orton rearrangement via N-chlorination or the direct chlorination of the aromatic
ring, which may take place independently and simultaneously.4i

2092
Similar to the migration of chlorine, the nitro group has also been found to rearrange
in a similar fashion when N-nitro-anilides are treated with a strong acid.10 During these
rearrangements, when the para position of the aniline moiety is occupied by an electron-
donating group (such as Me, F, Cl, Br, Ph, and PhO), the ortho-nitroanilides are formed.
In one case, the para-bromo group is found to be replaced by a nitro group. However,
when the para-position is occupied by an electron-withdrawing group, such as a nitro,
cyano, or sulfonyl group, then the rearrangement is relatively suppressed.10c It has been
found that both the rearrangement yield and the ortho/para ratio of isomers increase when
the solvent viscosity is increased.10a It is interesting that in the presence of HNO3 , H2 SO4 ,
HCl, or HClO4 , N-nitro-2,4-dichloroaniline is converted into 2-nitro-4,6-dichloroaniline,11
whereas 2,4-dichlorobenzenediazonium bromide is obtained quantitatively in the presence
of HBr.12
Although a mechanism involving the formation of chlorine and subsequent electrophilic

substitution has been proposed, it is possible that the N-Cl bond in the protonated N-
chloro acyl anilide cleaves homolytically to form a chloro radical and an anilide radical,
and the chloro radical adds to the para-position of the aniline moiety to form a conjugated
iminium cation, followed by the elimination of the para-proton to give the rearranged
product (Scheme 1). Alternatively, it is possible that after the protonation of N-chloro
acyl anilide, chloride undergoes a halophilic substitution to form chlorine, then chlorine
undergoes the electrophilic substitution (Scheme 2).
SCHEME 1. Orton rearrangement involving a radical mechanism.

2094 ORTON REARRANGEMENT
SCHEME 2. Orton rearrangement involving the chlorination by chlorine.
D. MODIFICATION
N/A
E. APPLICATIONS
This reaction is useful for the preparation of para-halo anilides.
N/A
Cl
Cl
CuCl2 N N
+ +
N
Dry CH3CN, ∆ N
51% Cl 20% Cl
7%
Reference 4e.
Anhydrous copper chloride (0.121 g, 0.9 mmol) was dissolved in 10 mL boiling MeCN
(distilled on CaH2 ), and a yellow solution was obtained. Then 0.3 mmol N-(azulen-1-
ylmethylene)aniline was added, and the color of the solution turned to red. The solution
was vigorously refluxed for 5 h, then MeCN was evaporated to ∼5 mL. After cool-
ing to room temperature, 50 mL benzene and 50 mL saturated NaHCO3 solution were
REFERENCES 2095
added, and the color of the organic layer turned to green. The organic layer was washed
with water and dried over Na2 SO4 . The solvent was evaporated in vacuo to give 51%
N-(3-chloroazulen-1-ylmethylene)aniline, 7% N-(azulen-1-ylmethylene)-4-chloroaniline,
and 20% N-(3-chloroazulen-1-ylmethylene)-4-chloroaniline.
NO2 NO2
H
N HCl N
MeOH, ∆
85%
MeO MeO
Reference 10c.
A mixture of 1.0 g p-methoxy-N-nitro-N-methylaniline, 50 mL methanol, and 50 mL

conc. HCl was refluxed for 2 h and then allowed to stand for 20 h at 25◦ C. The solution
was cooled to 0◦ C, and the solid product was collected by suction filtration. The solid was
purified by neutral alumina column chromatography using benzene as the eluent to afford
85% 2-nitro-4-methoxyl-N-methylaniline, m.p. 98–99◦ C.
Other references related to the Orton rearrangement are cited in the literature.13
H. REFERENCES
1. Bender, G., Ber., 1886, 19, 2272.

2. Armstrong, H. E., J. Chem. Soc., Trans., 1900, 77, 1047.
3. (a) Chattaway, F. D. and Orton, K. J. P., J. Chem. Soc., 1899, 75, 1046. (b) Chattaway, F. D.;
Orton, K. J. P. and Hurtley, W. H., J. Chem. Soc., Trans., 1900, 77, 800. (c) Chattaway, F. D. and
Orton, K. J. P., J. Chem. Soc., Trans., 1900, 77, 797. (d) Chattaway, F. D. and Orton, K. J. P.,
J. Chem. Soc., Trans., 1900, 77, 787. (e) Chattaway, F. D. and Orton, K. J. P., J. Chem. Soc.,
Trans., 1900, 77, 134. (f) Chattaway, F. D. and Orton, K. J. P., J. Chem. Soc., Trans., 1901, 79, 816.
(g) Orton, K. J. P., Proc. Chem. Soc., (London), 1902, 18, 200. (h) Orton, K. J. P. and Smith, A.
E., J. Chem. Soc., 1905, 87, 389. (i) Orton, K. J. P. and Smith, A. E., Proc. Chem. Soc., 1905,
21, 91. (j) Kipping, F. S.; Orton, K. J. P.; Ruhemann, S.; Lapworth, A. and Hewitt, J. T., Brit.
Assoc. Rep., 1905, 103. (k) Reed, W. W. and Orton, K. J. P., J. Chem. Soc., Trans., 1907, 91, 1543.
(l) Smith, A. E. and Orton, K. J. P., Proc. Chem. Soc., 1907, 23, 14. (m) Orton, K. J. P. and Pearson,
C., J. Chem. Soc., Trans., 1908, 93, 725. (n) Smith, A. E. and Orton, K. J. P., Proc. Chem. Soc.,
1908, 24, 27. (o) Kipping, F. S.; Orton, K. J. P.; Rhemann, S.; Lapworth, A. and Hewitt, J. T.,
Chem. News & J. Ind. Sci., 1908, 96, 85. (p) Orton, K. J. P. and Jones, W. J., J. Chem. Soc., Trans.,
1909, 95, 1456. (q) Orton, K. J. P. and Jones, W. J., Proc. Chem. Soc., 1909, 25, 196. (r) Jones,
W. J. and Orton, K. J. P., J. Chem. Soc., Trans., 1909, 95, 1056.
4. (a) Madhavi, N.; Sundar, B. S. and Radhakrishnamurti, P. S., Oxidation Commun., 2006, 29, 908.
(b) Soice, N. P.; Maladono, A. C.; Takigawa, D. Y.; Norman, A. D.; Krantz, W. B. and Greenberg,
A. R., J. Appl. Poly. Sci., 2003, 90, 1173. (c) Medina, I. C. R. and Hanson, J. R., J. Chem. Res.,
2003, 428. (d) Ghosh, S. and Baul, S., Synth. Commun., 2001, 31, 2783. (e) Razus, A. C.; Nitu,
C.; Carvaci, S.; Birzan, L.; Razus, S. A.; Pop, M. and Tarko, L., J. Chem. Soc., Perkin Trans. 1,
2001, 1227. (f) Kannan, P.; Venkatachalaphathy, C. and Pitchumani, K., Indian J. Chem., Sect.
B, 1999, 38B, 384. (g) Yamamoto, J.; Tada, M. and Isoda, Y., Nihon Yukagakkaishi, 1999, 48,
607. (h) Yamamoto, J.; Tada, M.; Kojima, H. and Isoda, Y., Nihon Yukagakkaishi, 1999, 48, 463.
(i) Glater, J.; Hong, S.-k and Elimelech, M., Desalination, 1994, 95, 325. (j) Yamamoto, J. and
Matsumoto, H., Chem. Express, 1988, 3, 419. (k) Jayaram, B. and Mayanna, S. M., React. Kinetics
2096 ORTON REARRANGEMENT
Catal. Lett., 1983, 24, 379. (l) Golding, P. D.; Reddy, S.; Scott, J. M. W.; White, V. A. and Winter,
J. G., Can. J. Chem., 1981, 59, 839. (m) Mahadevappa, D. S.; Rangappa, K. S. and Gowda, N. M.
M., React. Kinetics Catal. Lett.,1980, 15, 13. (n) Scott, J. M. W. and Martin, J. G., Can. J. Chem.,
1966, 44, 2901. (o) Verma, S. M. and Srivastava, R. C., Indian J. Chem., 1965, 3, 266. (p) Scott,
J. M. W. and Martin, J. G., Can. J. Chem., 1965, 43, 732. (q) Scott, J. M. W., Can. J. Chem., 1960,
38, 2441. (r) Dewar, M. J. S. and Scott, J. M. W., J. Chem. Soc., 1957, 2676. (s) Dewar, M. J. S.
and Scott, J. M. W., J. Chem. Soc., 1957, 1445. (t) Dewar, M. J. S. and Scott, J. M. W., J. Chem.
Soc., 1955, 1845.
5. (a) Olson, A. R. and Hornel, J. C., J. Org. Chem., 1939, 4, 76. (b) Percival, J. O. and La Mer, V.
K., J. Am. Chem. Soc., 1936, 58, 2413. (c) Barnes, C. D. and Porter, C. W., J. Am. Chem. Soc.,
1930, 52, 2973.
6. Kawaguchi, T. and Tamura, H., J. Appl. Poly. Sci., 1984, 29, 3359.
7. Loeppky, R. N. and Rotman, M., J. Org. Chem., 1967, 32, 4010.
8. Naumov, P.; Sakurai, K.; Tanaka, M. and Hara, H., J. Phys. Chem. B, 2007, 111, 10373.
9. Porter, C. W. and Wilbur, P., J. Am. Chem. Soc., 1927, 49, 2145.
10. (a) White, W. N.; White, H. S. and Fentiman, A., J. Org. Chem., 1976, 41, 3166. (b) White, W.
N.; Hathaway, C. and Huston, D., J. Org. Chem., 1970, 35, 737. (c) White, W. N. and Klink, J. R.,
J. Org. Chem., 1970, 35, 965. (d) White, W. N. and White, H. S., J. Org. Chem., 1970, 35, 1803.
11. Orton, K. J. P., Chem. News, 1912, 106, 236.
12. Orton, K. J. P., Brit. Assoc. Advan. Sci. Rep., 1908, 115.
13. (a) Rhee, E. S. and Shine, H. J., J. Am. Chem. Soc., 1986, 108, 1000. (b) White, W. N. and
Golden, J. T., J. Org. Chem., 1970, 35, 2759. (c) Bieron, J. F. and Dinan, F. J., “Rearrangement
and Elimination of the Amido Group,” in The Chemistry of Amides, ed., Zabicky, J., Wiley
Interscience, New York, 1970, pp. 263–266. (d) Orton, K. J. P.; Soper, F. G. and Williams, G.,
J. Chem. Soc., 1928, 998. (e) Kipping, F. S.; Orton, K. J. P.; Ruhemann, S.; Hewitt, J. T. and Grey,
W. H., Chem. News, 1913, 108, 155. (f) Orton, K. J. P. and Jones, W. J., J. Chem. Soc., 1909, 95,
1456.
45
Bamberger Rearrangement
This reaction was first reported by Bamberger in 1894.1 It is an intermolecular rearrange-

ment of N-phenylhydroxylamines in acidic aqueous solution to afford the corresponding
4-aminophenols, e.g., in aqueous sulfuric acid. Thus this reaction is generally known as the
Bamberger rearrangement.2 Occasionally, it is also termed the Bamberger reaction.3 It is
believed that in this rearrangement the hydroxyl group is introduced into the aromatic ring
via a nucleophilic attack of a hydrosulfate ion on the anilenium ion, which is generated
by the heterolytic N-O bond cleavage of O-protonated N-phenylhydroxylamine.4 It has
been found that alkoxy, halogen, phenoxy are incorporated into the aromatic ring when the
rearrangement of N-phenylhydroxylamine is carried out in nucleophilic solvents, such as
alcohols, hydrogen halides, and phenols.5 There is much mechanistic evidence to favor the
heterolytic N-O bond cleavage.6 This rearrangement has been reviewed.7
H
N NH2
OH H2SO4
H2O HO
Under acidic conditions, phenylhydroxylamine is first protonated and subsequently trans-

formed into anilenium by releasing a water molecule, during which the aromatic ring carries

191
192 BAMBERGER REARRANGEMENT
a partial positive charge so that the nucleophilic attacking occurs at the para position (the
amino group is an ortho and para-determining group). The mechanism of this rearrangement
has been extensively studied in detail.2g,4,6g,8
D. MODIFICATION
This type of rearrangement has been extended to pyridines and isoquinolones.9a It is

reported that the nitro group (NO2 ) will migrate to the ortho position when it is connected
to nitrogen atom of aniline.9b−d However, in the case of O-phenylhydroxylamine, the amino
group will migrate to both the ortho and the para positions.4 It has been found that when
hydrogen is replaced by a sulfur atom in phenylhydroxylamine [i.e, PhN(OH)SR], the
rearrangement rate will be 106 as fast as normal Bamberger rearrangement.10
E. APPLICATIONS
N/A
N/A
CH3 CH3
NO2 NO2
H2SO4
O2N O2N NO2
HN NH2
NO2
Reference 9b.
To a flask were added 10 mL conc. H2 SO4 and 0.5 g 4-amino-N,2,5-trinitrotoluene

(2.06 mmol). The mixture was cooled at 0◦ C, stirred for 69 h, and then poured into 100 mL
ice water. The resulting precipitate was filtered off and washed with water to give 0.44 g
REFERENCES 193
4-amino-2,3,5-trinitrotoluene, in a yield of 88%, m.p., 145–151◦ C. Further recrystallization

from hot ethanol gave pure 4-amino-2,3,5-trinitrotoluene, in 40% of recovery, m.p., 150–
153◦ C.
1) Ac2O
N + NH
2) NaOH, H2O
O–
O
Reference 9a.
In a typical experiment, 18.12 g isoquinoline-N-oxide was added to 150 mL acetic

anhydride and refluxed gently for 5 h. The liquid soon turned dark red. The acetic anhydride
was removed under an aspirator vacuum, and the residue was distilled. The volatile portion
was collected in one fraction, which boiled at ∼ 142◦ C (0.9 mmHg); however, an appreciable
non-volatile portion remained. The solid distillate was heated on the steam bath with 4 g
NaOH and 75 mL water for 40 min and then allowed to stand at room temperature overnight.
A pale yellow solid was filtered off and washed with water to give 9.02 g isocarbostyril, in
a yield of 53%, m.p., 208.0–209.5◦ C.
Other references related to the Bamberger rearrangement are cited in literature.11
H. REFERENCES
1. (a) Bamberger, E., Ber., 1894, 27, 1347. (b) Bamberger, E., Ber., 1894, 27, 1548.
2. (a) Schenzle, A.; Lenke, H.; Spain, J. C. and Knackmuss, H.-J., J. Bacteriology, 1999, 181, 1444.
(b) Naicker, K. P.; Pitchumani, K. and Varma, R. S., Catal. Lett., 1998, 54, 165. (c) Hughes, J.
B.; Wang, C.; Yesland, K.; Richardson, A.; Bhadra, R.; Bennett, G. and Rudolph, F., Environ.
Sci. Technol., 1998, 32, 494. (d) Fishbein, J. C. and McClelland, R. A., Can. J. Chem., 1996, 74,
1321. (e) Shcherbinin, M. B.; Erusalimskii, G. B.; Bal’tser, A. E.; Bazanov, A. G. and Ostrovskii,
V. A., Zh. Org. Khim., 1995, 31, 1829. (f) Zoran, A.; Khodzhaev, O. and Sasson, Y., J. Chem.
Soc., Chem. Commun., 1994, 2239. (g) Fishbein, J. C. and McClelland, R. A., J. Am. Chem. Soc.,
1987, 109, 2824. (h) Moehrle, H. and Mieger, T., Pharmazie, 1986, 41, 26. (i) Corbett, M. D.;
Corbett, B. R. and Doerge, D. R., J. Chem. Soc., Perkin Trans. I, 1982, 345. (j) Matschiner, H.;
Tanneberg, H. and Maschmeier, C. P., J. Prakt. Chem., 1981, 323, 924. (k) Sone, T.; Hamamoto,
K.; Seiji, Y.; Shinkai, S. and Manabe, O., J. Chem. Soc., Perkin Trans. II, 1981, 1596. (l) Krylov,
A. I. and Stolyarov, B. V., Zh. Org. Khim., 1981, 17, 811. (m) Sone, T.; Tokuda, Y.; Sakai, T.;
Shinkai, S. and Manabe, O., J. Chem. Soc., Perkin Trans. II, 1981, 298. (n) Sone, T.; Karikura,
M.; Shinkai, S. and Manabe, O., Nippon Kagaku Kaishi, 1980, 245. (o) Sone, T.; Karikura, M.;
Shinkai, S. and Manabe, O., Nippon Kagaku Kaishi, 1979, 1532.
3. Tordeux, M. and Wakselman, C., J. Fluor. Chem., 1995, 74, 251.
4. Haga, N.; Endo, Y.; Kataoka, K.-I.; Yamaguchi, K. and Shudo, K., J. Am. Chem. Soc., 1992, 114,
9795.
5. (a) Bamberger, E., Ann., 1921, 424, 233. (b) Bamberger, E., Ann., 1912, 390, 131. (c) Bamberger,
E. and Lugutt, J., Ber., 1898, 31, 1500. (d) Bamberger, E., Ber., 1895, 28, 245.
6. (a) Novak, M. and Lagerman, R. K., J. Org. Chem., 1988, 53, 4762. (b) Novak, M.; Pelecanou, M.
and Pollack, L., J. Am. Chem. Soc., 1986, 108, 112. (c) Kohnstam, G.; Petch, W. A. and Williams,
D. L. H., J. Chem. Soc., Perkin Trans. II, 1984, 423. (d) Gassman, P. G. and Granrud, J. E.,
J. Am. Chem. Soc., 1984, 106, 1498. (e) Novak, M.; Pelecanou, M.; Roy, A. K.; Andronico, A. F.;
Plourde, F. M.; Olefirowicz, T. M. and Curtin, T. J., J. Am. Chem. Soc., 1984, 106, 5623. (f) Sone,
194 BAMBERGER REARRANGEMENT
T.; Tokudo, Y.; Sakai, T.; Shinkai, S. and Manabe, O., J. Chem. Soc., Perkin Trans. II, 1981, 298.
(g) Sone, T.; Hamamoto, K.; Seiji, Y.; Shinkai, S. and Manabe, O., J. Chem. Soc., Perkin Trans.
II, 1981, 1596. (h) Gassman, P. G.; Campbell, G. and Frederick, R., J. Am. Chem. Soc., 1972,
94, 3884. (i) Gassman, P. G. and Campbell, G., J. Am. Chem. Soc., 1972, 94, 3891. (j) Gassman,
P. G. and Campbell, G., J. Am. Chem. Soc., 1971, 93, 2567. (k) Heller, H. E.; Hugh, E. D. and
Ingold, K. C., Nature, 1951, 168, 909.
7. (a) Shine, H. J., Aromatic Rearrangements, Elsevier, Amsterdam, 1967, pp. 182–190. (b) Dewar,
M. J. S., Aromatic Rearrangements, in Molecular Rearrangements, ed., de Mayo, P., Interscience,
New York, 1963, pp. 295–344. (c) Ingold, K. C., Structure and Mechanism in Organic Chemistry,
Cornell University Press, Ithaca, N.Y., 1953, pp. 621–624
8. Bolton, J. L. and McClelland, R. A., J. Am. Chem. Soc., 1989, 111, 8172.
9. (a) Robison, M. M. and Robison, B. L., J. Org. Chem., 1957, 21, 1337. (b) Nielsen, A. T.; Christian,
S. L.; Chafin, A. P. and Wilson, W. S., J. Org. Chem., 1994, 59, 1714. (c) Atkins, R. L. and Wilson,
W. S., J. Org. Chem., 1986, 51, 2572. (d) White, W. N. and Klink, J. R., J. Org. Chem., 1970, 35,
965.
10. Kazanis, S. and McClelland, R. A., J. Am. Chem. Soc., 1992, 114, 3052.
11. (a) Hughes, J. B.; Wang, C.; Yesland, K.; Richardson, A.; Bhadra, R.; Bennett, G. and Rudolph, F.,
Environ. Sci. Technol., 1998, 32, 494. (b) Preuss, A.; Rieger, P.-G., Anaerobic Transformation of
2,4,6-Trinitrotoluene and Other Nitroaromatic Compounds, in Biodegradation of Nitroaromatic
Compounds, Spain, J. C., Plenum Press: New York, 1995; 49, pp 69–86. (c) Corbett, M. D.;
Corbett, B. R., Biodegradation of Nitroaromatic Compounds, ed., Spain, J. C., Plenum Press:
New York, 1995; 49, pp 151–182. (d) M. Tordeux, C. Wakselman, J. Fluor. Chem., 1995, 74,
251. (e) Olszewski, J. D.; Marshalla, M.; Sabat, M. and Sundberg, R. J., J. Org. Chem., 1994, 59,
4285. (f) Nishino, S. F.; Spain, J. C., Appl. Environ. Microbiol., 1993, 59, 2520. (g) Sakamoto,
Y.; Yoshioka, T. and Uematsu, T., J. Org. Chem., 1989, 54, 4449. (h) Johnston, D. and Elder, D.,
J. Labelled Compd. Radiopharm., 1988, 25, 1315. (i) Novak, M.; Bonham, G. A.; Mohler, L. K.
and Peet, K. M., J. Org. Chem., 1988, 53, 3903. (j) McClelland, R. A.; Panicucci, R. and Rauth, A.
M., J. Am. Chem. Soc., 1985, 107, 1762. (k) Sternson, L. A. and Chandrasakar, R., J. Org. Chem.,
1984, 49, 4295. (l) Sone, T.; Tokudo, Y.; Sakai, T.; Shinkai, S.; Manabe, O., J. Chem. Soc., Perkin
Trans. II, 1981, 298. (m) Shudo, K.; Ohta, T. and Okamoto, T., J. Am. Chem. Soc., 1981, 103,
645. (n) Buncel, E., Acc. Chem. Res., 1975, 8, 132. (o) Mudge, P. R.; Salter, D. A. and Scilly, N. R.
J. Chem. Soc., Chem. Commun., 1975, 509. (p) Patrick, J. A.; Schield, J. A. and Kirchner, D. J.,
J. Org. Chem., 1974, 39, 1758. (q) Hughes, E. D. and Ingold, C. K. Q., Chem. Soc. Rev., 1952,6,
34. (r) Dewar, M. J. S., Nature (London), 1946, 156, 784. (s) Reese, J. S., Chem. Rev., 1933, 33, 55.
(t) Bamberger, E., Ann., 1925, 441, 297. (u) Bamberger, E., Ann., 1921, 424, 230. (v) Bamberger,
E., Ann., 1921, 424, 233. (w) Bamberger, E., Ber., 1918, 51, 636. (x) Bamberger, E., Ann., 1912,
390, 131. (y) Johnson, T. B. and Guest, H. H., J. Am. Chem. Soc., 1910, 32, 1279. (z) Bamberger,
E., Ber., 1907, 40, 1906. (aa) Bamberger, E. and Rising, A., Ber., 1901, 34, 229. (bb) Bamberger,
E., Ber., 1900, 33, 3600. (cc) Bamberger, E., Ber., 1895, 28, 251. (dd) Bamberger, E., Ber., 1894,
27, 1522. (ee) Bamberger, E. and Landsteiner, K., Ber., 1893, 26, 485.
516
Pummerer Rearrangement
(Pummerer Reaction)
This reaction was first reported by Pummerer in 1909.1 It is an acid (e.g., HCl) or
an anhydride (e.g., Ac2 O or TFAA) promoted transformation of sulfoxide bearing an
α-proton to α-substituted sulfide through a sulfenium (or thionium) intermediate;2 more
generally, it is the reduction of sulfonium sulfur with concomitant oxidation or sub-
stitution at the α-carbon of sulfonium.3 Therefore, this reaction is generally known as
the Pummerer rearrangement4,5 or Pummerer reaction.2a,3,4a,4k,4o,4s,4t,6 Occasionally, the
Pummerer cyclization is used to stand for the formation of heterocycles via the addition of an
intramolecular nucleophile to the sulfenium intermediate.4h,6o,6p,7 Besides HCl and acyclic
anhydrides, some other Brønsted acids or Lewis acids are also used to activate this reac-
tion, such as p-toluenesulfonic acid,4y ZnI2 ,4h TMSOTf,4m,6o DAST(diethylaminosulfur
trifluoride),8 and Me3 SiX.9 In addition, the Pummerer rearrangement can also occur under
thermal conditions without promoters,4u,4y although it may be suppressed by the appli-
cation of zeolite.10 In this reaction, the formed sulfenium (or sulfonium) intermediate is
very electrophilic, which can even react with some weak nucleophiles such as xylene and
anisole.4y

2284
MODIFICATION 2285
Many mechanisms have been proposed for this reaction, that include: (a) the rearrange-
ment via a carbonium intermediate involving either a concerted cyclic elimination of acetic
acid, elimination of HOAc with an external base or elimination to form a sulfonium ylide,
(b) internal transfer of the acetoxy group through either cyclic rearrangement, 1,2-shift of
ylide, homolytic dissociation and recombination, or nucleophilic displacement of ylide.3
Nevertheless, all these mechanisms involve the intermediate of a sulfur-stabilized carbonium
ion, and if there isn’t a conjugate electron-withdrawing group (e.g., carbonyl group) at the
β-position of sulfoxide group,11 the acetoxyl group always migrates to the least substituted
α-carbon of sulfoxide.3 Overall, the general accepted mechanism involves the activation
of the sulfoxide through the conversion of the sulfoxide oxygen into a good leaving group
either by acylation or protonation, followed by the formation of a sulfenium (thionium)
ion,2b,4h a rate- and product-determining step,3 and subsequent nucleophilic addition from
different nuclophiles. It should be pointed out that after the activation of the sulfoxide oxy-
gen atom, the migration of hydrogen to form a sulfenium ion affords the normal Pummerer
rearrangement product, whereas the cleavage of α-alkyl group to generate a new sulfe-
nium ion leads to the formation of new sulfide, and this process is known as the Pummerer
fragmentation.5b An illustrative mechanism is provided here.
D. MODIFICATION
Because of its versatility, this reaction has been extended to different variants. For
example, the thermal conversion of linear α-silyl sulfoxides into siloxymethyl sulfide
for the preparation of carbonyl compounds,12 vinyl sulfides,4j etc. is now known as sila-
Pummerer rearrangement;4e,5a,7e,12,13 in addition, the base treatment of α-chlorosulfoxide
in the presence of trimethylsilyl chloride to form thioester is known as the silicon
Pummerer rearrangement.4x Likewise, the reaction of vinylic sulfoxides4e,9 or
o-alkylphenyl sulfoxides5c via an electrophilic thionium ion from γ-proton loss is known
as the vinylogous Pummerer reaction. Moreover, if a nucleophile adds to the vinylic bond,
then this variant is also known as additive Pummerer reaction;4j,6i,14 whereas the treatment
of sulfoxide with DAST8 or n-Bu4 NH2 F35s to produce α-fluorosulfide is referred to as
the fluoro-Pummerer rearrangement, and the rearrangement involving the cleavage of
an α-stannyl or an allylic stannyl group is called the tin-Pummerer rearrangement5m or
2286 PUMMERER REARRANGEMENT
vinylogous tin-Pummerer rearrangement,4e respectively. The comparable rearrangement of

selenium compounds is known as seleno Pummerer reaction or additive seleno Pummerer
rearrangement.4j
On the other hand, sulfoxides bearing an α-proton may undergo a similar reaction to
form thioether when they are treated with a Grignard reagent,15 and α-thiomethyl ester
might eliminate α-proton to form thionium for nucleophilic addition when it is treated with
phenyliodine(III) bis-trifluoroacetate.16
E. APPLICATIONS
This reaction has very broad application in organic synthesis, such as the formation of an
aldehyde by hydrolysis of α-acyloxysulfide,17 the generation of vinyl sulfide by elimination
of α-acyloxy group,18 and the synthesis of glyoxal from β-ketosulfoxide.4z In addition, the
formed vinyl sulfide has been used as an intermediate for many other reactions, such as
Diels-Alder Cycloaddition4s and Michael Addition.4j
N/A
Reference 11.
(3S)-3-(N-Benzyloxycarbonyl)amino-1-methylsulfinyl-2-oxo-4-phenylbutane (166.2 mg,

0.462 mmol) was added to a mixture of 4.6 mL CH2 Cl2 , 0.5 mL pyridine, and 0.5 mL
acetic anhydride, followed by 3 mg 4-dimethylamino pyridine. The resulting mixture
was stirred at ambient temperature for 17.5 h, then 10 mL 1 M HCl and 15 mL EtOAc
were added. The organic layer was separated and washed with 10 mL saturated
NaHCO3 aqueous solution and 10 mL brine, dried over Na2 SO4 and concentrated under
reduced pressure. The resulting residue was purified through preparative silica gel
thin-layer chromatography to afford 124.5 mg (3S)-1-acetoxy-3-(N-benzyloxy-
carbonyl)amino-1-methylthio-2-oxo-4-phenylbutane as a colorless solid, in a yield of
67.1%.
Alternatively, 708.6 mg (3S)-3-(N-benzyloxycarbonyl)amino-1-methylsulfinyl-2-oxo-
4-phenylbutane (1.97 mmol) was dissolved in a mixture of 15 mL DMSO and 6 mL THF.
Then 7.5 mL 2 M HCl was added. After the mixture was stirred for 18 h at ambient
temperature, it was cooled in an ice bath and neutralized with 15 mL saturated NaHCO3
REFERENCES 2287
aqueous solution (15 mL). Water (50 mL) and 50 mL EtOAc were added to the mix-
ture. After the organic layer was separated, the resulting aqueous layer was extracted with
EtOAc (2 × 25 mL). The combined organic layers were washed with 50 mL water and
30 milliliter brine, dried over anhydrous Na2 SO4 , and concentrated under reduced pressure.
The resulting residue was crystallized in n-hexane/EtOAc to give 659.7 mg crude (3S)-3-(N-
benzyloxycarbonyl)amino-1-hydroxy-1-methylthio-2-oxo-4-phenylbutane as a colorless
crystal, in yield of 93.2%. This intermediate was then acetylated in CH2 Cl2 with pyridine
and acetyl chloride to afford 91.5% (3S)-1-acetoxy-3-(N-benzyloxycarbonyl)amino-1-
methylthio-2-oxo-4-phenylbutane.
O S
Tol
S 1. LDA, –78°C
Tol 2. TMSCl OH
3. NH4Cl
69%
> 98 e.e.
Reference 9.
To 3.0 mL THF solution containing 0.89 mmol i-Pr2 NH was added 0.6 mmol 2.3 M
n-BuLi in hexane at 0◦ C. After being stirred for 30 min, the mixture was cooled to −78◦ C.
Then a solution of 0.5 mmol (S)-1-ethyl-2-(p-tolylsulfinyl)benzene in 2 mL THF was added.
After the mixture was stirred for 1 h, 1.5 mmol freshly distilled TMSCl was added at −78◦ C.
When the reaction was completed (< 1 min), the mixture was hydrolyzed with a mixture of
1 mL saturated NH4 Cl and 1 mL CH3 CN at −78◦ C, then the solution was warmed to room
temperature for overnight. The mixture was extracted with Et2 O (3 × 10 mL), washed twice
with 10 mL saturated NH4 Cl, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash silica gel column chromatography using hexane/EtOAc
(2:1) as the eluent to afford 69% (1R)-1-2-(p-tolylsulfanyl)phenylethan-1-ol as a colorless
oil, with 98% e.e.
Other references related to the Pummerer rearrangement are cited in the literature.19
H. REFERENCES
1. Pummerer, R., Ber., 1909, 42, 2282.

2. (a) Padwa, A., Pure & Appl. Chem., 2003, 75, 47. (b) Bates, D. K.; Winters, R. T. and Picard, J.
A., J. Org. Chem., 1992, 57, 3094.
3. Johnson, C. R. and Phillips, W. G., J. Am. Chem. Soc., 1969, 91, 682.
4. (a) Veerapen, N.; Taylor, S. A.; Walsby, C. J. and Pinto, B. M., J. Am. Chem. Soc., 2006, 128,
227. (b) Keum, G. C.; Hwang, C. H.; Kang, S. B.; Kim, Y. S. and Lee, E., J. Am. Chem. Soc.,
2005, 127, 10396. (c) Tai, C.-H.; Wu, H.-C. and Li, W.-R., Org. Lett., 2004, 6, 2905. (d) Keum,
G. C.; Kang, S. B.; Kim, Y. S. and Lee, E., Org. Lett., 2004, 6, 1895. (e) Ruano, J. L. G.; Aleman,
J. and Padwa, A., Org. Lett., 2004, 6, 1757. (f) Paquette, L. A.; Fabris, F.; Gallou, F. and Dong,
S. Z., J. Org. Chem., 2003, 68, 8625. (g) Zhang, X. G. and Qing, F.-L., J. Org. Chem., 2002, 67,
1016. (h) Padwa, A.; Danca, D. M.; Ginn, J. D. and Lynch, S. M., J. Braz. Chem. Soc., 2001,
12, 571. (i) Fustero, S.; Navarro, A.; Pina, B.; Soler, J. G.; Bartolomé, A.; Asensio, A.; Simón,
A.; Bravo, P.; Fronza, G.; Volonterio, A. and Zanda, M., Org. Lett., 2001, 3, 2621. (j) Hagiwara,
H.; Kafuku, K.; Sakai, H.; Kirita, M.; Hoshi, T.; Suzuki, T. and Ando, M., J. Chem. Soc., Perkin
2288 PUMMERER REARRANGEMENT
Trans. I, 2000, 2577. (k) Iwama, T.; Kataoka, T.; Muraoka, O. and Tanabe, G., J. Org. Chem.,
1998, 63, 8355. (l) Ueng, S.-N.; Blumenstein, M. and Grohmann, K. G., J. Org. Chem., 1997, 62,
2432. (m) Yoshimura, Y.; Watanabe, M.; Satoh, H.; Ashida, N.; Ijichi, K.; Sakata, S.; Machida,
H. and Matsuda, A., J. Med. Chem., 1997, 40, 2177. (n) Yoshimura, Y.; Kitano, K.; Yamada, K.;
Satoh, H.; Watanabe, M.; Miura, S.; Sakata, S.; Sasaki, T. and Matsuda, A., J. Org. Chem., 1997,
62, 3140. (o) Volonterio, A.; Zanda, M.; Bravo, P.; Fronza, G.; Cavicchio, G. and Crucianelli, M.,
J. Org. Chem., 1997,62, 8031. (p) Callis, D. J.; Thomas, N. F.; Pearson, D. P. J. and Potter, B.
V. L., J. Org. Chem., 1996, 61, 4634. (q) McElhinney, R. S.; McCormick, J. E.; Bibby, M. C.;
Double, J. A.; Radacic, M. and Djumont, P., J. Med. Chem., 1996, 39, 1403. (r) Arnone, A.; Bravo,
P.; Capelli, S.; Fronza, G.; Meille, S. V.; Zanda, M.; Cavicchio, G. and Crucianelli, M., J. Org.
Chem., 1996, 61, 3375. (s) Padwa, A.; Cochran, J. E. and Kappe, C. O., J. Org. Chem., 1996, 61,
3706. (t) Bonjoch, J.; Catena, J. and Valls, N., J. Org. Chem., 1996, 61, 7106. (u) Wladislaw, B.;
Marzorati, L. and Biaggio, F. C., J. Org. Chem., 1993, 58, 6132. (v) Kim, C. U.; Misco, P. F. and
McGregor, D. N., J. Org. Chem., 1982, 47, 170. (w) Mikolajczyk, M.; Zatorski, A.; Grzejszczak,
S.; Costisella, B. and Midura, W., J. Org. Chem., 1978, 43, 2518. (x) More, K. M. and Wemple,
J., J. Org. Chem., 1978, 43, 2713. (y) Bates, D. K., J. Org. Chem., 1977, 42, 3452. (z) Becker,
H.-D.; Mikol, G. J. and Russell, G. A., J. Am. Chem. Soc., 1963, 85, 3410.
5. (a) Suslova, E. N.; Ushakov, I. A. and Shainyan, B. A., Russ. J. Gen. Chem., 2007, 77, 253.
(b) Laleu, B.; Machado, M. S. and Lacour, J., Chem. Commun., 2006, 2786. (c) Garcia Ruano,
J.; Aleman, J.; Aranda, M.; Arevalo, M. and Padwa, A., Phosphorus, Sulfur & Silicon & Related
Elements, 2005, 180, 1497. (d) Fujita, J.; Matsuda, H.; Yamamoto, K.; Morii, Y.; Hashimoto,
M.; Okuno, T. and Hashimoto, K., Tetrahedron, 2004, 60, 6829. (e) Tai, C.-H.; Wu, H.-C. and Li,
W.-R., Org. Lett., 2004, 6, 2905. (f) Matsuda, H.; Fujita, J.; Morii, Y.; Hashimoto, M.; Okuno,
T. and Hashimoto, K., Tetrahedron Lett., 2003, 44, 4089. (g) Crescenza, A.; Botta, M.; Corelli, F.
and Tafi, A., Heterocycles, 1999, 51, 1639. (h) Hu, Y. H.; Ou, L. G. and Bai, D. L., Tetrahedron
Lett., 1999, 40, 545. (i) Kirpichenko, S. V.; Suslova, E. N.; Albanov, A. I. and Shainyan, B. A.,
Tetrahedron Lett., 1999, 40, 185. (j) Kobayashi, K.; Takahashi, O.; Namatame, K.; Kikuchi, O.
and Furukawa, N., Chem. Lett., 1998, 515. (k) Yoshimura, Y.; Kitano, K.; Yamada, K.; Sakata,
S.; Miura, S.; Ashida, N.; Machida, H. and Matsuda, A., Nucleic Acids Symp. Ser., 1997, 37, 43.
(l) Naka, H.; Sato, S.; Horn, E. and Furukawa, N., Heterocycles, 1997, 46, 177. (m) Hatlelid, J.;
Bennech, T. and Undheim, K., Acta Chem. Scand., 1997, 51, 1092. (n) Cassel, S.; Chaimbault,
P.; Lafosse, M.; Lorin, C. and Rollin, P., Sulfur Lett., 1996, 20, 63. (o) Harwood, L. M. and
Lilley, I. A., Synlett, 1996, 1010. (p) Kita, Y.; Takeda, Y.; Iio, K.; Yokogawa, K.; Takahashi, K.
and Akai, S., Tetrahedron Lett., 1996, 37, 7545. (q) Dwyer, O., Synlett, 1995, 1163. (r) Arnone,
A.; Bravo, P.; Bruche, L.; Crucianelli, M.; Vichi, L. and Zanda, M., Tetrahedron Lett., 1995, 36,
7301. (s) Furuta, S.; Kuroboshi, M. and Hiyama, T., Tetrahedron Lett., 1995, 36, 8243. (t) Stamos,
I. K. and Kotzamani, H. K., J. Heterocycl. Chem., 1995, 32, 947.
6. (a) Akai, S. and Kita, Y., Top. Curr. Chem., 2007, 274, 35. (b) Miller, M.; Tsang, W.; Merritt, A.
and Procter, D. J., Chem. Commun., 2007, 498. (c) Feldman, K. S. and Karatjas, A. G., Org. Lett.,
2006, 8, 4137. (d) Nagao, Y.; Miyamoto, S.; Miyamoto, M.; Takeshige, H.; Hayashi, K.; Sano,
S.; Shiro, M.; Yamaguchi, K. and Sei, Y., J. Am. Chem. Soc., 2006, 128, 9722. (e) Hou, R.-S.;
Wang, H.-M.; Chang, Y.-W. and Chen, L.-C., J. Chinese Chem. Soc., 2006, 53, 431. (f) Akai, S.;
Kawashita, N.; Wada, Y.; Satoh, H.; Alinejad, A. H.; Kakiguchi, K.; Kuriwaki, I. and Kita, Y.,
Tetrahedron Lett., 2006, 47, 1881. (g) Feldman, K. S.; Vidulova, D. B. and Karatjas, A. G., J. Org.
Chem., 2005, 70, 6429. (h) Feldman, K. S. and Skoumbourdis, A. P., Org. Lett., 2005, 7, 929.
(i) Padwa, A.; Nara, S. and Wang, Q., J. Org. Chem., 2005, 70, 8538. (j) Jaoued, N. G.; Oueslati,
R. and Hedhli, A.,Synth. Commun., 2005, 35, 543. (k) Hahn, H.-G.; Nam, K. D. and Mah, H.,
J. Korean Chem. Soc., 2004, 48, 443. (l) Feldman, K. S. and Vidulova, D. B., Org. Lett., 2004,
6, 1869. (m) Bur, S. K. and Padwa, A., Chem. Rev., 2004, 104, 2401. (n) Nakayama, J.; Lida,
S.; Sugihara, Y. and Ishii, A., J. Sulfur Chem., 2004, 25, 13. (o) Montaño, R. G. and Zhu, J. P.,
Chem. Commun., 2002, 2448. (p) Amat, M.; Hadida, S.; Pshenichnyi, G. and Bosch, J., J. Org.
REFERENCES 2289
Chem., 1997, 62, 3158. (q) Nishizono, N.; Koike, N.; Yamagata, Y.; Fujii, S. and Matsuda, A.,
Tetrahedron Lett., 1996, 42, 7569. (r) Trofimov, B. A.; Chernysheva, N. A.; Khilko, M. Y. and
Gusarova, N. K., Russ. Chem. Bull., 1991, 40, 1919. (s) Fedorov, N. V.; Anisimov, A. V. and
Viktorova, E. A., Chem. Heterocycl. Compd., 1989, 25, 1083. (t) King, R. R., J. Org. Chem.,
1978, 43, 3784.
7. (a) Horiguchi, Y.; Ogawa, K.; Saitoh, T. and Sano, T., Chem. Pharm. Bull., 2004, 52, 214.
(b) Saitoh, T.; Shikiya, K.; Horiguchi, Y. and Sano, T., Chem. Pharm. Bull., 2003, 51, 667.
(c) Padwa, A.; Heidelbaugh, T. M. and Kuethe, J. T., J. Org. Chem., 2000, 65, 2368. (d) Padwa,
A.; Heidelbaugh, T. M. and Kuethe, J. T., J. Org. Chem., 1999, 64, 2038. (e) Still, I. W. J. and
Toste, F. D., Heteroatom Chem., 1994, 5, 251. (f) Amat, M. and Bosch, J., J. Org. Chem., 1992,
57, 5792. (g) Vishwakarma, L. C. and Martin, A. R., J. Heterocycl. Chem., 1982, 19, 103.
8. Zhou, H. and van der Donk, W. A., Org. Lett., 2001, 3, 593.
9. Ruano, J. L. G.; Alemán, J.; Aranda, M. T.; Arévalo, M. J. and Padwa, A., Org. Lett., 2005, 7, 19.
10. Clennan, E. L.; Zhou, W. H. and Chan, J., J. Org. Chem., 2002, 67, 9368.
11. Suzuki, T.; Honda, Y.; Izawa, K. and Williams, R. M., J. Org. Chem., 2005, 70, 7317.
12. Shainyan, B. A.; Kirpichenko, S. V. and Freeman, F., J. Am. Chem. Soc., 2004, 126, 11456.
13. (a) Perales, J. B.; Makino, N. F. and Van Vranken, D. L., J. Org. Chem., 2002, 67, 6711. (b) Reich,
H. J. and Shah, S. K., J. Org. Chem., 1977, 42, 1773.
14. Craig, D. and Daniels, K., Tetrahedron, 1993, 49, 11263.
15. Cheng, W.-L. and Luh, T.-Y., J. Org. Chem., 1992, 57, 3516.
16. Pohnert, G., J. Prakt. Chem., 2000, 342, 731.
17. Sugihara, H.; Tanikaga, R. and Kaji, A., Synthesis, 1978, 881.
18. Hagiwara, H.; Nakayama, K. and Uda, H., Bull. Chem. Soc. Jpn., 1975, 48, 3769.
19. (a) Choo, H.; Chen, X.; Yadav, V.; Wang, J. N.; Schinazi, R. F. and Chu, C. K., J. Med. Chem.,
2006, 49, 1635. (b) Boudou, M. and Enders, D., J. Org. Chem., 2005, 70, 9486. (c) Padwa, A.,
Pure & Appl. Chem., 2004, 76, 1933. (d) Notz, W.; Hartel, C.; Waldscheck, B. and Schmidt,
R. R., J. Org. Chem., 2001, 66, 4250. (e) Bell, R. P. L.; Sobolev, A.; Wijnberg, J. B. P. A. and
de Groot, A., J. Org. Chem., 1998, 63, 122. (f) Kita, Y.; Shibata, N.; Kawano, N.; Fujui, S. and
Fujimori, C., Tetrahedron Lett., 1994, 35, 3575. (g) Majumdar, G. and Mal, D., Indian J. Chem.,
1994, 33B, 700. (h) Jug, M. E.; Kim, C. and von dem Busschez, L., J. Org. Chem., 1994, 59,
3248. (i) Su, H.; Hiwatari, Y.; Soenosawa, M.; Sasuga, K.; Shirai, K. and Kumamoto, T., Bull.
Chem. Soc. Jpn., 1993, 66, 2603. (j) De Lucchi, O.; Miotti, U. and Modena, G., Org. React.,
1991, 40, 157. (k) Kita, Y.; Tamura, O.; Miki, T. and Tamura, Y., Tetrahedron Lett., 1987, 28,
6479. (l) Kita, Y.; Yasuda, H.; Tamura, O.; Itoh, F. and Tamura, Y., Tetrahedron Lett., 1984, 25,
4681. (m) Pummerer, R., Ber., 1910, 43, 1401.
651
von Richter Reaction
This reaction was first reported by von Richter in 1871.1 It is the preparation of an aro-
matic carboxylic acid by treatment of a para- or meta-substituted aromatic nitro compound
with potassium cyanide in aqueous alcoholic solution at high temperature, by which the
carboxyl group occupies the position ortho to the eliminated nitro group. Therefore, this
reaction is generally known as the von Richter reaction.2 The von Richter reaction has
been found to take place exclusively at the ortho-position of the eliminated nitro group.2g
For example, reaction of p-bromonitrobenzene with KCN gives only m-bromobenzoic
acid, and the reaction between m-bromonitrobenzene and KCN yields a mixture of o- and
p-bromobenzoic acid, whereas the reaction of o-bromonitrobenzene with KCN produces
only a small amount of m-bromobenzoic acid.2g,3 In addition, it has been reported that
this reaction is best performed in an aqueous alcoholic solution,2f,2g,3 especially in 48%
EtOH aqueous solution.2g Under these conditions, the reaction is dramatically accelerated
by refluxing the mixture of aromatic compound and KCN.2g However, it has also found that
the yields of the corresponding aromatic carboxylic acids have never exceeded 50%,2f,2g
and usually are < 20%,2f even when all of the nitro compounds have been consumed. In
addition, the yields are found to be roughly independent of reaction temperature between
155◦ and 195◦ C, and extension of reaction time will not apparently improve the yields.3
The low yields of this reaction may be caused by other side reactions such as the hydrol-
ysis or alcoholysis of cyanide and reduction of nitro compounds under alkaline alcoholic
solution.2g Moreover, the von Richter reaction can be inhibited in the presence of potassium
ferricyanide (K3 Fe(CN)6 ) and sodium sulfite.2g It sounds plausible that the von Richter
reaction may involve an intermediate of aromatic nitrile. It has been reported that nei-
ther benzonitrile nor benzamide is the reaction intermediate,2e so that the actual aromatic

2911
2912 VON RICHTER REACTION
nitrile has never been isolated.2g For those aromatic nitro compounds with extra activa-
tion groups, they may undergo an alternative reaction route when treated with alcoholic
cyanide. For example, the treatment of m-dinitrobenzene with KCN in boiling MeOH gives
2-methoxy-6-nitrobenzonitrile,4 whereas the reactions of 2,4-dinitrochlorobenzene5 and
6-nitroquinoline6 under a similar condition yield 2-nitro-3-chloro-6-methoxybenzonitrile
and 5-cyano-6-methoxy-quinoline, respectively.
It has been proposed that this reaction involves an initial attack by cyanide ion at the ortho-
position of the nitro group in a fashion of a Michael Addition, followed by aromatization with
expulsion of the ortho-proton. At the same time, the nitro group is simultaneously reduced
to a nitroso group, and the entering cyano group is converted into an amido group.2e,2g The
last step is the expulsion of nitrite to form the corresponding aromatic carboxylic acid, as
illustrated here by the reaction between p-bromonitrobenzene and potassium cyanide.
D. MODIFICATION
N/A
E. APPLICATIONS
This reaction has limited application in organic synthesis.
N/A
Reference 2g.
A mixture of 20.0 g KCN, 4.0 g 2,4-dibromonitrobenzene, and 100 mL 48% EtOH

was refluxed for 48 h. The reaction mixture was diluted to 300 mL with water and filtered
to remove the unreacted starting material and neutral amorphous by-products. Unreacted
starting material was recovered by crystallization of the filter cake from ethanol, in which the
neutral amorphous by-products are insoluble. The filtrate was heated to boiling, acidified,
digested 15 min on a steam bath, reheated to boiling, and filtered. Tarry acidic by-products
were often separated by this process; the 3,5-dibromobenzoic acid was soluble in the volume
of hot water used. The filtrate was made alkaline with sodium carbonate, evaporated to
50 mL, acidified almost to the point of precipitation, and treated repeatedly with decolorizing
charcoal until the color had changed from dark red to yellow. The solution was then acidified,
cooled, and filtered. The filter cake was dissolved in dilute ammonium carbonate solution,
and the solution was treated with decolorizing charcoal, acidified, cooled, and filtered. The
last cycle was repeated several times until a white acid was obtained.
Other references related to the von Richter reaction are cited in the literature.7
2914 VON RICHTER REACTION
H. REFERENCES
1. (a) Von Richter, V., Ber., 1871, 4, 21. (b) Von Richter, V., Ber., 1871, 4, 459. (c) Von Richter, V.,
Ber., 1871, 4, 553.
2. (a) Tomitori, E.; Okamoto, T. and Ido, T., Yakugaku Zasshi, 1983, 103, 601. (b) Ellis, A. C. and
Rae, I. D., J. Chem. Soc., Chem. Commun., 1977, 152. (c) Cullen, E. and L’Ecuyer, P., Can. J.
Chem., 1961, 39, 382. (d) Cullen, E. and L’Ecuyer, P., Can. J. Chem., 1961, 39, 144. (e) Bunnett,
J. F. and Rauhut, M. M., J. Org. Chem., 1956, 21, 944. (f) Rauhut, M. M. and Bunnett, J. F.,
J. Org. Chem., 1956, 21, 939. (g) Bunnett, J. F.; Rauhut, M. M.; Knutson, D. and Bussell, G. E.,
J. Am. Chem. Soc., 1954, 76, 5755.
3. Bunnett, J. F.; Cormack, J. F. and McKay, F. C., J. Org. Chem., 1950, 15, 481.
4. (a) Lobry de Bruyn, C. A. and van Geuns, J. W., Rec. Trav. Chim. Pays-Bas, 1904, 23, 26.
(b) Lobry de Bruyn, L., Rec. Trav. Chim. Bays-Bas, 1883, 2, 210.
5. (a) Blanksma, J. J., Rec. Trav. Chim. Bays-Bas, 1902, 21, 424. (b) van Heteren, W. J., Rec. Trav.
Chim. Bays-Bas, 1901, 20, 107.
6. Huisgen, R., Ann., 1948, 559, 101.
7. (a) Acheson, R. M. and Harvey, C. W. C., J. Chem. Soc., Perkin Trans. I, 1976, 465. (b) Rogers, G.
T. and Ulbricht, T. L. V., Tetrahedron Lett., 1968, 9, 1028. (c) Ibne-Rasa, K. M. and Koubak, E.,
J. Org. Chem., 1963, 28, 3240. (d) Ullman, E. F. and Bartkus, E. A., Chem. & Ind. (London), 1962,
93. (e) Cullen, E. and L’Ecuyer, P., Can. J. Chem., 1961, 39, 154. (f) Cullen, E. and L’Ecuyer,
P., Can. J. Chem., 1961, 39, 862. (g) Samuel, D., J. Chem. Soc., 1960, 1318. (h) Sauer, J. and
Huisgen, R., Angew. Chem., 1960, 72, 314. (i) Rosenblum, M., J. Am. Chem. Soc., 1960, 82, 3796.
(j) Bunnett, J. F., Quart. Rev., 1958, 12, 15.

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655

A. GENERAL DESCRIPTION OF THE REACTION

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

B. GENERAL REACTION SCHEME

Because the Wagner-Meerwein rearrangement represents a class of transformation

This reaction has a very broad application in organic synthesis.

This reaction is related to the Bertram-Walbaum Rearrangement, Demjanov-Tiffeneau

G. CITED EXPERIMENTAL EXAMPLES

To a solution of 50 mg spiral-cyclopropyl camphor derivative (0.3 mmol) in 1 mL glacial

Other references related to the Wagner-Meerwein rearrangement are cited in the

1. Wagner, G., J. Russ. Phys. Chem. Soc., 1899, 31, 690.

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was initially reported by Demjanov (sometimes spelled Demjanow or

B. GENERAL REACTION SCHEME

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

This reaction is related to the Tiffeneau-Demjanov Rearrangement and Wagner-

G. CITED EXPERIMENTAL EXAMPLES

To a solution of 42.7 mg deacetylthiocolchicine (0.11 mmol) in 4 mL water was added

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was initially reported by Favorskii in 1894.1 It is a base-induced rear-

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

α -hydrogens (e.g., in nonenolizable ketones7b,14a ) or when the formation of cyclo-

B. GENERAL REACTION SCHEME

SCHEME 1. Favorskii rearrangement via cyclopropanone mechanism.

SCHEME 2. Favorskii rearrangement occurring a benzilic acid mechanism.

This reaction is related to Benzilic Acid Rearrangement.

G. CITED EXPERIMENTAL EXAMPLES

To a solution of 50 mg 1,1-dichloro-7-furan-3 -yl-heptan-2-one (0.20 mmol) in 0.25 mL

1. Favorskii, A. E., J. Russ. Phys. Chem. Soc., 1894, 26, 559.

A. GENERAL DESCRIPTION OF THE REACTION

B. GENERAL REACTION SCHEME

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

It is believed that a carbenoid intermediate is involved in this reaction, as displayed

G. CITED EXPERIMENTAL EXAMPLES

A 0.010–0.016 M solution of the dibromoolefin in hexanes under nitrogen was cooled to

To 10 mL cooled dry hexanes (−78◦ C) containing 0.131 g dibromoolefin (0.404 mmol)

Other references related to the Fritsch-Buttenberg-Wiechell rearrangement are cited in

1. Fritsch, P., Ann., 1894, 279, 319.

A. GENERAL DESCRIPTION OF THE REACTION

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

B. GENERAL REACTION SCHEME

This reaction has general application in the preparation of α-amino ketones.

This reaction is related to the Beckmann Rearrangement.

G. CITED EXPERIMENTAL EXAMPLES

Chiral ammonium salt = N

cis-Benzyl phenyl ketoxime (63 mg, 0.3 mmol), 69 mg p-toluenesulfonyl chloride

1. Neber, P. W. and Friedolsheim, A., Ann., 1926, 449, 109.

A. GENERAL DESCRIPTION OF THE REACTION

B. GENERAL REACTION SCHEME

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

cleavage of a bromide ion; nucleophilic addition of water to isocyanate affording a carbamic

This reaction is related to Curtius Rearrangement, Lossen Rearrangement, Schmidt

G. CITED EXPERIMENTAL EXAMPLES

To 100 mL methanol solution containing 7.75 g (±)-trans-2-tetrahydro-2H-2-

1. Hofmann, A. W., Ber., 1881, 14, 2725.

A. GENERAL DESCRIPTION OF THE REACTION

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

B. GENERAL REACTION SCHEME

A simple mechanism involving a nitrene intermediate is displayed here.

This reaction is related to the Hofmann Degradation, Lossen Rearrangement, and

G. CITED EXPERIMENTAL EXAMPLES

To a solution of 7.04 g 1-benzyl-3-cyanopyrrole-2-carboxylic acid (31.12 mmol) in

1,2,3,4,5-Pentaphenylferrocene-1 -carboxylic acid (2.00 g, 3.3 mmol) was suspended in

1. Curtius, T., Ber., 1890, 23, 3023.

To a solution of 154.5 mg (2R,4S)-2-isobutyl-4-[3-(triisopropylsilanyl)prop-2-