ALUMINUM AMALGAM

23

Aluminum Amalgam1

Ultrasound-promoted reduction of the C=O group of Nsubstituted phthalimides leads to hydroxylactams. The ultrasonic irradiation provides rapid fragmentation of the amalgam, giving a reactive dispersion and accelerates the reaction owing to the increase of mass transport between the solution and the A W g surface where reduction occurs. The reaction is highly sensitive to substrate structure and N-benzylglutarimide and Nbenzylsuccinimide are not reduced.'O

$ 7
(MW 26.98)

OMe

A1-Hg DME-H*O (7S:l)

0 "C, 6 h,

[lI 144-30-81

A1

I'o*o

61%

(reducing agent for many functional groups,' effects reductive dimerization of unsaturated compounds, can cleave carbon-element and element-element bonds.)
Physical Data: shiny solid. Preparative Methods: Aluminum turnings (oil-free) are etched with dilute Sodium Hydroxide to a point of strong hydrogen evolution and the solution is decanted. The metal is washed once with water so that it retains some alkali, then treated with 0.5%Mercury(ZZ) Chloride solution for 1-2 min, and the entire procedure is repeated. The shiny amalgamated metal is washed rapidly in sequence with water, ethanol, and ether and used at once.2 Aluminum amalgam (1) reacts vigorously with water with liberation of hydrogen in the amount equivalent to the amount of aluminum present and can be used to dry organic solvents (ether, ethanol).2a Aluminum amalgam can be also prepared from aluminum foil, which is cut into strips -10 cm x 1 cm and immersed, all at once, into a 2% aqueous solution of HgCl2 for 15 s. The strips are rinsed with absolute alcohol and then with ether and cut immediately with scissors into pieces -1 cm square, directly into the reaction vessel.2b Before immersion, each strip may be rolled into a cylinder -1 cm in diameter. Each cylinder is amalgamated, rinsed successively with ethanol and ether and then placed in the reaction Handling, Storage, and Precautions: moisture-sensitive. Precautions should be taken as it readily reacts with water with hydrogen evolution. Can be stored under dry ether. Toxic.

- H2N\jlC02H
HCI reflux, 6 h 74%

~0.g

(l)

17%ee
10 equiv AI-Hg THF-H20 (9:1)

Reductive dimerization of carbonyl compounds to pinacols does not always effectively compete with reduction to alcohols, but in certain cases it becomes the main process (eq 3).'.'' Factors which determine reduction-dimerization ratios include steric inhibition, torsion strain, and angle strain.'

Q-x, - 0 S H O
A1-Hg

(3)

CHZC12. reflux, 1-4 h, 21-38% C&-EtOH (1:1), reflux, 4 h, 95% THF-HzO (9: l), -10 "C -+ rt, 94%

A special case of reduction involves removal of the carbonyl oxygens from anthraquinones12a3b and related compound^'^ with rearomatization (eq 4).'2b
A1-Hg, EtOH-H20 (4:9) sat aq NHhOH

HO

60-65 OC, 2 h

C=C Bond Reduction. Alkenic substrates are transformed into saturated compounds upon reaction with Al-Hg. Substrates with carbon-carbon double bonds activated by electronwithdrawing substituents are most easily r e d ~ c e d The . ~ reaction may proceed with asymmetric induction and high chemoselectivity, leaving other functionalities unchanged (eq l).4 Reduction of 1,3-dienes5' and a-nitroalkenesSb results in 1,4-addition of hydrogen to the v-system. Aluminum amalgam can also promote reductive dimerization of a,P-unsaturated acid esters.6a*b C=O Bond Reduction. Cycloalkanones and aldehydes are reduced to the corresponding alcohols (eq 2). Acyclic ketones remain almost inert.' In spite of the ability of carboxylic acid esters to be reduced to alcohols,8 in oxosuccinic acid esters only the ketone carbonyl group is reduced?

78%

HO=OH

(4)

C=N Bond Reduction. Aluminum amalgam reduces Schiff bases to the corresponding arnine~.'~ Among these reactions of great importance is the reduction of A*-thiazolines to thia~olidines,'~-'' widely used in the synthesis of aldehydes (eq 5),15 P-hydroxy aldehydes, and homoallylic alcohols.16 Aluminum amalgam also induces reductive dimerization of Schiff base^'^^,^* to produce 1,2-diamines. This process has been used in macrocyclic ring closure.18aIn respect to reductive dimerization of A'-pyrrolines, aluminum amalgam is much more effective than Zinc in aqueous NH4C1.'8b Similar to Schiff bases,
Avoid Skin Contact with All Recigents

24

ALUMINUM AMALGAM

oximes are also readily reduced to corresponding amines," while reduction of hydrazides provides hydrazines?O

("-,??
N

1. BuLi, THF, -78 "C

10-12 equiv A1-Hg EtZO-HzO

b

2.RI, THF, -78 "C

74%

reflux, 1 h or n, 4 h 90%

and oxiranes?l undergo reductive cleavage with formation of alcohols. Among thereactions listed, the reductive cleavage of epoxides (eq 9pZais presumably of the most importance. It has been widely used in the synthesis of prostaglandin^,^'^,^^^^ steroids:l''d erythronolide B,33 and vitamin precursors.%
A1-Hg EtOH-HzO-THF-sat aq NaHC03

R = Ph(CH2)zCHz

' N '
H

d M ,
n, 2 h
71%

R
'

(87:48:303), 0 "C, 3 h 99%

H& 3

NO2 and N3 Group Reduction. Aluminum amalgam reduction is an excellent method for deoxygenation of aliphatic and aromatic nitro groups to produce aminesZ1(eq Q 2 1 d Nitro alkenes can be chemoselectively reduced, retaining the C=C bond.21a In moist ether the reduction can be stopped at the stage of hydroxylamine formation."

Deoxygenation of certain terpene oxides with A1 foil activated by HgC12 has been reported instead of reduction to the desired alcohols.35 N - O and N-N Bond Cleavage. On exposure to excess A1-Hg in aqueous THF at 0 "C for several hours, N-O bonds in bicyclic Diels-Alder adducts are readily cleaved.36 Mild conditions provide a highly chemoselective process and carbon-carbon double bonds and acid labile functional groups survive, in contrast to the alternative methods employed such as catalytic hydrogenolysis or reduction withzinc-Acetic The reaction occurs with high stereoselectivity and the product is formed with a cis disposition of N- and 0-containing substituents (eq lo).%
0

02KoH
100%

ether-MeOH A1-Hg *

Ph

Ph

Organic azides are also readily reduced to the corresponding amines. The procedure has been used in a general synthesis of a$-unsaturated a-amino acids.23

M e S ,
1. A1-Hg (excess)

THF-H20 (1O:l). 0 "C

Reactions of Carbon-Halogen Bonds. Organic halides exhibit diverse behavior in reactions with Al-Hg. Thus a trichloromethyl group has been reduced to a dichloromethyl group.24At the same time, A1 inserts into the C-Br bond of silylated propargyl bromide affording the allenylaluminum reagent, whereas only direct metalation without rearrangement has been observed in metalation with Zinc Amalgam (eq 7).25
1. A1-Hg, dry THF reflux, 3 h

2. A c ~ O py-DMAP , 41%

bAc

Aluminum analgam is also highly effective in reductive cleavage of N-N bonds to produce a m i n e ~ . ~ ~

Me3Si

. I
2.cyclohexanone, 0 "C, 1 h 70%

LJ

Me3Si

\ Br
1.Zn-HgC12, dry THF 0-25 OC,5-8 h
2. cyclohexanone, 0 "C, 1 h

(7)

Reductive Desulfurization. The ability of A1-Hg to reduce C-S bonds is widely used in organic synthesis in conjunction with methodology involving reactions of highly reactive a-sulfinyl- and a-sulfonylalkyl car bani on^^^,^^ as well as (a-sulfoximidoy1)alkyl car bani on^.^^ Removal of the activating sulfur substituent is frequently accomplished using Al-Hg. The methodology offers facile synthetic approaches to ketone^?^^^*^^^ enones!' di- and trike tone^,^^^^^ hydroxy ketones (eq 11),"3 unsaturated acids,44 and y-0x0-a-amino acids.45
1.2 BuLi, dry THF, -90 'C

75%

PhS02CgH17
2.

Mild reductive deacetoxybromination of glycosyl bromides offers an approach to glucals bearing acid-sensitive substituents (eq 8).26

0
,O0C

3. aq NH&O

"C

618

Aco7
A1-Hg rt.6h 85%

Aco7
OAc
I

PhS02+0H

A1-Hg THF-H2O (9:l) reflux, 3-6 h 99%

C7H1S

C-0 Bond Cleavage. Ether linkages of various substrates, for example g l y c o s i d e ~1,3-dioxolanes$ ,~~ tetra hydro fur an^,^^^^
Lists ofAbbreviations and Journal Codes on Endpapers

Readily removed on treatment with A1-Hg asymmetric sulfinyl and sulfonimidoyl groups may serve as chiral auxiliaries in enantiocontrolled synthesis of 3-substituted c y c l ~ a l k a n o n e and s ~ ~ 3hydroxy4' and 3-arylcarboxylic acid esters.@

ALUMINUM AMALGAM

25

Aluminum amalgam mediated cleavage of C-S bonds plays an important role in sulfoximine-based alkenation of carbonyl compounds via p-hydroxysulfoximines49(eq 12).49b
rS-Ph

9
Phd

NMe

LDA
t

THF,-85 C under N l
91%

Aluminum amalgam can also be employed in reductive eliminastereotion of phenylthio groups from 2-phenylthioalkanone~,~~ specific reduction of sulfoximines,51 selective cleavage of the sulfinyl sulfur-methylene carbon bond in the presence of a disulfide moiety? and reductive scission of S-S and S-N bond^.^^,^^ For some reactions mediated by aluminum activated with mercury(11) chloride, also see Aluminum.

Related Reagents. See Classes R-1, R-2, R-3, R-5, R-6, R9, R-10, R-15, R-16, R-21, R-22, R-23, R-24, R-25, R-27, R-30, R-31, and R-32, pages 1-10,

1 . Smith, M. Reduction Techniques and Applications in Organic Synthesis; Augustine, R. L., Ed.; Dekker: New York, 1968; pp 95-170. 2. (a) Wislecenus, H.; Kaufmann, L. CB 1895, 28, 1323. (b) Corey, E. J.; Chaykovsky, M. JACS 1965,87, 1345. (c) Calder, A,; Forrester, A. R.; Hepburn, S. P. OS 1972,52,77. 3. (a) Ghatak, U.; Saha, N. N.; Dutta, P. C. JACS 1957, 79, 4487. (b) Tankard, M. H.; Whitehurst, J. S. JCS(P1) 1973, 615. (c) Stahly, G. P.; Jackson, A. JOC 1991,56,5472. 4. Tamura, M.; Harada, K. BCJ 1980,53,561. 5. (a) Miller, R. E.; Nord F. F. JOC 1951, 16, 1380. (b) Mladenov, I.; Boeva, R.; Aleksiev, D.; Lyubcheva, M. God. Vissh. Khim.-Tekhnol. Inst., Burgas, Bulg. 1977/1978,2,25; C A 1979.90, 137 409t. 6. (a) Crombie, L.; Hancock, J. E. H.; Linstead, R. P. JCS 1953, 3496. (b) Leraux, Y. CR(C) 1971,273, 178. 7. Hulce, M.; LaVaute, T. TL 1988,29, 525. 8. Ray, J. N.; Mukherji, A.; Gupta, N. D. JIC 1961,38, 705. 9. Nguyen, D. A,; Cerutti, E. BSF(2) 1976,596 10. Luzzio, F. A.; OHara, L. C. SC 1990,20,3223. 1 1 . (a) Schreibmann, A. A. P. TL 1970, 4271. (b) Stocker, J. H.; Walsh, D. J. JOC 1979,44,3589. 12. (a) Bilger, C.; Demerseman, P.; Royer, R. JHC 1985,22, 735. (b) Petti, M. A.; Shepadd, T. J.; Barrans, Jr., R. E.; Dougherty, D. A. JACS 1988, 110,6825. 13. Atwell, G. J.; Rewcastle, G. W., Baguley, B. C.; Denny, W. A. JMC 1987, 30, 664. 14. (a) Thies, H.; Schonenberger, H.; Bauer, K. H. AP 1960, 293, 67. (b) Takeshima, T.; Muraoka, M.; Asaba, H.; Yokoyama, M. BCJ 1968,41, 506. 15. Meyers, A. I.; Durandetta, J. L. JOC 1975,40, 2021. 16. Meyers, A. I.; Durandetta, J. L.; Munavu, R. JOC 1975,40,2025.

\I

Cqe[,R.D, G.; Jose, F. L.JACS 1972,94,1021.

D. St. C. AJC 1968,21,2497.

19. (a) Berlin, K. D.; Claunch, R. T.; Gaudy, E. T. JOC 1968,33, 3090. (b) Hosmane, R. S . ; Lim, B. B. TL 1985,26,1915. (c) Muratake, H.; Okabe, K.; Natsume, M. T 1991,40, 8545. 20. Gilchrist, T. L.; Hughes, D.; Wasson, R. TL 1987, 28, 1537. 21. (a)Boyer,J.H.;Alul,H. JACS1959,81,2136.(b)Corey,E. J.;Andersen. N. H.; Carlson R. M.; Paust, J.; Vedejs, E.; Vlattas, I.; Winter, R. E. K. JACS 1968, 90, 3247. (c) Kraus, G. A,; Fraizer, K. TL 1978, 3195. (d) Trost, B. M.; King, S . A.; Schmidt, T. JACS 1989,111,5902. 22. Healey, K.; Calder, I. C. AJC 1979, 32, 1307. 23. (a) Shin, C.; Yonezawa, Y.; Yoshimura, J. CL 1976, 1095. (b) SmodiS, J.; Zupet, R.; Petnc, A.; Stanovnik, B.; TiSler, M. H 1990, 30, 393. 24. Inoi, T.; Gericke, P.; Horton, W. J. JOC 1962, 27,4597. 25. Daniels, R. G.; Paquette, L. TL 1981,22, 1579. 26. Jain, S.; Suryawanshi, S. N.; Bhakuni, D. S. IJC(B) 1987,26,866. 27. Kennedy, R. M.; Abiko, A.; Masamune, S. TL 1988,29,447. 28. Johnson, C. R.; Penning, T. D. JACS 1986,108,5655. 29. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. T1986, 42,4035. 30. Arai, Y.; Kawanami, S.; Koizumi, T. CL 1990, 1585. 31. (a) Schneider, W. P.; Bundy, G. L., Lincoln, F. H. CC1973,254. (b) Corey, E. J.; Ensley, H. E. JOC 1973, 38, 3187. (c) Narwid, T. A,; Blount, J. F.; Iacobelli, J. A.; Uskokovic, M. R. HCA 1974, 57, 781. (d) Hossain, A. M. M., Kirk, D. N.; Mitra, G. Steroids 1976, 27, 603. (e) Brough, P. A.; Gallagher, T.; Thomas, P.; Wonnacott, S.; Baker, R.; Abdul Malik, K. M.; Hursthouse, M. B. CC 1992, 1087. 32. (a) Greene, A. E.; Teixeira, M. A.; Barreiro, E.; Cruz, A,; Crabbe. P. JOC 1982,47,2553. (b) Schneider, W. P.; Bundy, G. L., Lincoln, F. H.; Daniels, E. G.; Pike, J. E. JACS 1977,99, 1222. (c) Danieli, R.; Martelli, G.; Spunta, G.; Rossini, S . ; Cainelli, G.; Panunzio, M. JOC 1983, 48, 123. 33. Corey, E. J.; Trybulski, E. J.; Melvin, L. S . ; Nicolaou, K. C.; Secrist. J. A.; Lett, R.; Sheldrake, P. W.; Falck, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S.; Yoo, S. JACS 1978,100,4618. 34. Solladie, G.; Hutt, J. JOC 1987, 52, 3560. 35. Mitchell, P. W. D. OPP 1990, 22, 534. 36. (a) Keck, G. E.; Fleming, S . ; Nickell, D.; Weider, P. SC 1979,9,281, (b) King, S. B.; Ganem, B. JACS 1991,113,5089. 37. (a) Mellor, J. M.; Smith, N. M. JCS(P1) 1984,2927. (b) Athnson, R. S.; Edwards, P. J.; Thomson, G. A. CC 1992, 1256. 38. Corey, E. J.; Chaykovsky, M. JACS 1964,86, 1639. 39. Johnson, C. R. ACR 1973,6, 341. 40. (a) Stetter, H.; Hesse, R. M 1967,98,755. (b) Fulmer, T. D.; Bryson, T. A. JOC 1989,54,3496. (c) He, X. S . ; Eliel, E. L.; T 1987,43,4979. 41. Ohtsuka, Y.; Sasahara, T.; Oishi, T. CPB 1982,30, 1106. 42. Cannon, J. R.; Chow, P. W.; Fuller, M. W.; Hamilton, B. H.; Metcalf, B. W.; Power, A. J. AJC 1973,26,2257. 43. Cavicchioli, S.; Savoia, D.; Trombini, C.; Umani-Ronchi, A. JOC 1984, 49, 1246. 44. Ohnuma, T.; Hata, N.; Fujiwara, H.; Ban, Y. JOC 1982,47, 4713. 45. Baldwin, J. E.; Adlington, R. M.; Codfrey, C. R. A,; Gollins, D. W.; Smith, M. L.; Russel, A. T. SL 1993,51. 46. (a) Posner, G. H.; Mallamo, J. P.; Hulce, M.; Frye, L. L. JACS 1982,104, 4180. (b) Posner, G. H.; Hulce, M. TL 1984,25,379. (c) Posner, G . H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.; Cun-heng, H.; Clardy, J. T 1986,42,2919. 47. (a) Mioskowski, C.; Solladie, G. T 1980, 36, 227. (b) Fujisawn, T.; Fujimura, A,; Sato, T. BCJ 1988,61, 1273. 48. Pyne, S. G. JOC 1986,51,81. 49. (a) Johnson, C. R.; Shanklin, J. R.; Kirchhoff, R. A. JACS 1973,95,6462. (b) Boys, M. L.; Collington, E. W.; Finch, H.; Swanson, S.; Whitehead, J. F. TL 1988,29, 3365.

(b)Bapat,J.B.;B\ack, 18. (a) Bastian, J.-M.; Jaunin,R. HCA 1963,46,1248.

50. Monteiro,H. J. JOC 1977,42,2324.

51
Johnson, C. R.; Jonsson, E. U.; Wambsgans, A. JOC 1919,44,2061.
Avoid Skin Contact with All Reagents

26

ALUMINUM HYDRIDE
~ ~~

52. Block, E.; O'Connor, J. JACS 1974,96, 3929. 53. Komblum, N.; Widmer, J. JACS 1978,100, 7086. 54. Arzeno, H.B.; Kemp, D. S . S 1988,32.

Emmanuil I. Troyansky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia

Aluminum Hydridel
[7784-2I -61

lactones, from which the corresponding alcohol is the isolated product. Amides, nitriles, oximes, and isocyanates are reduced to amines. Nitro compounds are inert to AlHs. Sulfides and sulfones are unreactive, but disulfides and sulfoxides can be reduced. Tosylates are also not reduced by AlH3. The reduction of ketones with AlH3 has selectivity different from other hydride reagents (eqs 5 and 6).'O The hydroxymethylation of ketones via a two-step procedure has also been accomplished (eq 7)." The conversion of a,P-unsaturated ketones to allylic alcohols can be carried out with very good selectivity using A1H3 (eq 8);" however, DIBAL is the reagent of choice for this transformation (see Diisobutylaluminum Hydride).lZc

(MW 29.99)
LiAlh AIH3

(reducing agent for many functional groups; used in hydroalumination of alkynes; allylic rearrangements) Alternate Name: alane. Physical Data: colorless, nonvolatile solid in a highly polymerized state; mp 110C (dec). X-ray data have also been obtainede2 Solubility: sol THF and ether; precipitates from ether after standing for approximately 30 min depending upon method of preparation. Analysis o f Reagent Purity: hydride concentration can be determined by hydrolyzing aliquots and measuring the hydrogen ev~lved.~ Preparative Methods: can be prepared by treating an ether solution of Lithium Aluminum Hydride with Aluminum Chloride (eq l).4 This affords an ether solution of AlH3 after precipitation of LiC1. Solutions have to be used immediately otherwise AlH3 precipitates as a white solid which consists of a polymeric material with ether. The solvent can be removed and the solid redissolved in THE5 Alternatively, THF solutions can be prepared directly according to one of the reactions shown in eqs 2-4.596
3 LiAlH4

trans:& = 1.9:1 7.3:l

LiA1H(O-t-Bu)3 AIH~

0:lOO

91:9

1. NaH, EtOzCH

2. NaH, A1H3

t-Bu

t-Bu

+ AIC13

2 LiAlH4 2 LiAIK

+ BeClz

+ + ZnC12

2 LiAlH4

+ 3 LiCl 2 AIH3 + LiBeH2C12 2 AIH3 + Li2SO4 + 2 Hz 2 A1H3 + 2 LiCl + ZnHz

4 A1H3

(1)

(2)
(3)
(4)

Handling, Storage, and Precautions: solutions of AlH3 are not spontaneously i~~flammable.~ However, since A1H3 has reactivity comparable to LiAlH4, one should follow similar handling and precautions as those exercised for LiAIH4. Solutions of AIH3 are prepared in situ but are known to degrade after 3 days, and long term storage of solutions is not possible. Use in a fume hood. Functional Group Reductions. Reductions by alane take place primarily by a two-electron However, evidence for a SET pathway exists.' AIH3 will reduce a wide variety of functional group^.^ These include aldehydes, ketones, quinones, carboxylic acids, anhydrides, acid chlorides, esters, and
Lists of Abbreviations and Journal Codes on Endpapers

Carboxylic acids and esters are reduced more rapidly by A1H3 than by LiAlH4, whereas the converse is true for alkyl halides. As a result, acids and esters can be reduced in the presence of halides (eq 9). In addition, esters can be reduced in the presence of nitro groups (eq 10).This stands in contrast to LiAlH4 in which nitro groups are reduced. Acetals can also be reduced to the half protected diol as illustrated in eq 11.I3

ALUMINUM HYDRIDE

27

In reductions of amides to amines there is a competition between C-0 and C-N bond cleavage which depends upon the reaction conditions. This complication does not occur with AIH3. A quantitative yield of amine is obtained with short reaction times. Conjugated amides can be cleanly reduced to the allylic amine (eq 121.~
0

d NMq

LiAlH4

P h N M e Z

(12)

AlH3

0% 94%

Epoxide Ring Opening. With most epoxides, hydride attack occurs at the least sterically hindered site to give the corresponding alcohol (eq 19).19However, due to the electrophilic nature of AlH3 compared to L i A l a , it is possible for ring opening to occur at the more hindered site. With phenyl substituted epoxides, mechanistic studies have shown that attack at a benzylic carbenium ion or a 1,Zhydride shift followed by hydride attack gives products with the same regiochemistry but with different stereochemistry (eq 20).6320 The stereoselectivity of AlH3 mediated epoxide openings has been studied in depth.21

The less basic AIH3 appears to be better than LiAlH4 for reducing nitriles with relatively acidic a-hydrogens to amines, and enolizable keto esters to diols (eq 13).6

Ph

98%

Ph

Ph

AlD3

The reduction of p-lactams to azetidines can be accomplished 4 ) , 1 4while ring opening was observed with with A1H3 (eq 1 LiAlH4. AlH3 can also convert enamines to the corresponding alkenes (eq 1 5 ) . 1 5
R4 R 4 * 'R 3 '
R' R3

1
A ~ D ~

(20)

&Ao

63-81%

R4 R3

A ~ H ~ R4-44.R3'

R'

While alkyl halides are usually inert to AIH3, the reduction of cyclopropyl halides to cyclopropanes (eq 1 6 ) 1 6 and glycosyl fluorides to tetrahydropyrans (eq 17)" are known.

Hydroalumination. The addition of AIH3 across a triple bond has been shown to occur in propargylic systems.22When the reactions are quenched with Zodine, A1H3 gives the 2-iodo-(a-alkene while LiAIH4 gives the 3-iodo-(E)-alkene (eq 21). A1H3 can also be used in conjunction with Titanium(ZV)Chloride to carry out a reaction similar to a h y d r ~ b o r a t i o nThus . ~ ~ 1-hexene is converted to hexane upon aqueous work-up or to the corresponding alcohol upon exposure of the reaction intermediate to oxygen (eq 22). Similar results were obtained with nonconjugated dienes.

Ph
Ph Ph

f OH

1. AlH3 2. 12
I

O H -

1. LiAIH4

"'"T,IBn Bnoq,
5
90%

NaOMe 2.12

(17)

BnO'"'

BnO'"'

OBn

"'OBn OBn

60-75%

Desulfurization of sultones is rapid and proceeds in good yield with AlH3 while LiAlH4 affords poor yields with long reaction times (eq 18).18

90%

Avoid Skin Contact with All Reagents

28
~

ALUMINUM ISOPROPOXIDE
DePriest, R. N.; Goel, A. B.; Wenderoth, B.; Pharn, T. N. JOC 1984. 49,3545. (d) Ashby, E. C.; Pham, T. N. JOC 1986,51,3598. (e) Ashby. E. C.; Pharn, T. N. TL 1987,28,3197. (a) Ayres, D. C.; Sawdaye, R. JCS(P2) 1967,581. (b) Ayres, D. C.; Kirk, D. N.; Sawdaye, R. JCS(P2) 1970, 505. (c) Guyon, R.; Villa, P. BSF 1977, 145. (d) Guyon, R.; Villa, P. BSF 1977, 152. (e) Martinez, E.; Muchowski, J. M.; Velarde, E. JOC 1977,42, 1087. Corey, E. J.; Cane, D. JOC 1971,36,3070. (a) Jorgenson, M. J. TL 1962, 559. (b) Brown, H. C.; Hess, H. M. JOC 1969,34,2206. (c) Wilson, K. E.; Seidner, R. T.; Masamune, S. CC 1970, 213. (d) Dilling, W. L.; Plepys, R. A. JOC 1970,35,2971. (e) Ashby, E. C.; Lin, J. J. TL 1976, 3865. (a) Danishefsky, S.; Regan, J. TL 1981, 22, 3919. (b) Takano, S.; Akiyarna, M.; Sato, S.; Ogasawara, K. CL 1983, 1593. (c) Richter, W. J. JOC 1981,46,5119. Jackson, M. B.; Mander, L. N.; Spotswood, T. M. AJC 1983,36,779. Coulter, J. M.; Lewis, J. W.; Lynch, P. P.T 1968,24,4489. Muller, P. HCA 1974, 57, 704. Nicolaou, K. C.; Dolle, R. E.; Chucholowski, A.; Randal, J. L. CC 1984, 1153. (a) Wolinsky, J.; Marhenke, R. L.; Eustace, E. J. JOC 1973, 38, 1428. (b) Smith, M. B.; Wolinsky, J. JOC 1981,46, 101. Maruoka, K.; Saito, S.; Ooi, T.; Yarnarnoto, H. SL 1991, 255. Lansbury, P. T.; Scharf, D. J.; Pattison, V.A. JOC 1967, 32, 1748. Elsenbaumer, R. L.; Mosher, H. S.; Momson, J. D.; Tornaszewski, J. E. JOC 1981,46,4034. Corey, E. J.; Katzenellenbogen,J. A.; Posner, G. H. JACS 1967,89,4245. Sato, F.;Sato, S.; Kodama, H.; Sato, M. JOM 1977, 142, 71. Claesson, A.; Olsson, L.4. JACS 1979,101, 7302. Castelhano, A.; Krantz, A. JACS 1987,109,3491.

Allylic Rearrangements (SN~'). The S N ~ displacement ' of a good leaving group to give the rearranged allylic system can be carried out with A1H3.24This reaction appears not to be sterically demanding as a variety of displacements are possible (eq 23).
P h T " h 3
*IH3
~

10.

h E:Z = 2:3

a 11. 12.

51%

P h p ; P h l Ph
98%

php (23)
Ph

13.

Preparation of allenes from propargylic systems can also be accomplished." Most systems show a preference for syn elimination; however, mesylates prefer an anti mode of elimination (eq 24). This same procedure has been used to prepare fluoroallenes (eq 25).25
X ) e
P h

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

- >*=(+
A1H3

H H >*=(ph anti

(24)

Ph

X = OH, OMS,Br

syn

Dialkylaluminum hydrides also behave as hydroalumination reagents (see Diisobutykduminum Hydride) and are more commonly used than AlH3.

Paul Galatsis University of Guelph, Ontario, Canada

Related Reagents. See Classes R-1, R-4, R-5, R-12, R-13, R-20, R-23, R-27, R-30, and R-32, pages 1-10.

Aluminum Isopropoxide'
[555-31-71

1. (a) Gaylord, N. G. Reduction With Complex Metal Hydrides; Interscience: New York, 1956. (b) Semenenko, K. N.; Bulychev, B. M.; Shevlyagina, E. A, RCR 1966, 35, 649. (c) Rerick, M. N. Reduction TechniquesandApplications in Organic Synthesis, Augustine, R. L., Ed.; Dekker: New York, 1968. (d) Cucinella, S.;Mazzei, A.; Marconi, W. ICA Rev. 1970.51. (e) Walker, E. R. H. CSR 1976, 5, 23. (f) Brown, H. C.; Krishnarnurthy, S. T1979,35,567. (g) Hajos, A. Complex Hydndes and Related Reducing Agents in Organic Synthesis; Elsevier: Amsterdam, 1979. (h) Seyden-Penne, J. Reduction by the Alumino- and Borohydrides in Organic Synthesis; VCH: New York, 1991. 2. Turley, J. W.; Rim, H. W. ZC 1969, 8, 18. 3. Yoon, N. M.; Brown, H. C. JACS 1968,90,2927. 4. Finholt, A. E.; Bond, A. C.; Schlesinger, H. I. JACS 1947,69, 1199. 5. (a) Brown, H. C.; Yoon, N. M. JACS 1966,88, 1464. (b) Browner, E M.; Matzek, N. E.; Reigler, P. E; Rim, H. W.; Roberts, C. B.; Schmidt, D. L.; Snover, J. A.; Terada, K. JACS 1976,98,2450. 6. Ashby, E. C.; Sanders, J. R.; Claudy, P,; Schwarts, P. JACS 1973, 95, 6485. 7. Laszlo, P.; Teston, M. JACS 1990, 112, 8751. 8. (a) Park, S.-U.;Chung, S.-K.; Newcornb, M. JOC 1987, 52, 3275. (b) Yarnataka, H.; Hanafusa, T. JOC 1988,53,773.

C9H21 A103

(MW 204.25)

(mild reagent for Meenvein-Ponndorf-Verley reduction;' Oppenauer oxidation;13hydrolysis of oximes;16rearrangement of epoxides to allylic alcohol^;'^ regio- and chemoselective ring opening of epoxides;20preparation of ethers21) Alternate Name: triisopropoxyaluminum. Physical Data: mp 138-142 "C (99.99+%), 118 "C (98+%); bp 140.5 "C; d 1.035 g ~ m - ~ . Solubility: sol benzene; less sol alcohols. Form Supplied in: white solid (99.99+% or 98+% purity based on metals analysis). Preparative Methods: see example below. Handling, Storage, and Precautions: the dry solid is corrosive, moisture sensitive, flammable, and an irritant. Use in a fume hood.

9. (a) Ashby, E. C.; Goel, A. B. TL 1981, 22, 4783. (b) Ashby, E. C.;
" 1983, 24, 2825. (c) Ashby, E. C.; DePriest, R. N.; Pharn, T. N. 2
Lists of Abbreviations and Journal Codes on Endpapers

NMR Analysis of Aluminum Isopropoxide. Evidence from molecular weight determinations indicating that aluminum isopropoxide aged in benzene solution consists largely of the tetramer

ALUMINUM ISOPROPOXIDE

29

(l),whereas freshly distilled molten material is trimeric (2),2 is fully confirmed by NMR spectro~copy.~
L -I

R O '

Meerwein-Ponndorf-Verley Reduction. One use of the Al(O-l-Pr)3, 250 O C reagent is for the reduction of carbonyl compounds, particularly of unsaturated aldehydes and ketones, for the reagent attacks only 95% carbonyl compounds. An example is the reduction of crotonaldeanthraquinone * anthracene hyde to crotyl alcohol (eq l).' A mixture of 27 g of cleaned Alu- , 75% minum foil, 300 mL of isopropanol, and 0.5 g of Mercury(ZZ) anthracene anthrone 92% Chloride is heated to boiling, 2mL of carbon tetrachloride is added as catalyst, and heating is continued. The mixture turns gray, and vigorous evolution of hydrogen begins. Refluxing is continued until gas evolution has largely subsided (6-12 h). The solution, which is black from the presence of suspended solid, can be concentrated and the aluminum isopropoxide distilled in vacuum (colorless liquid) or used as such. Thus the undistilled solution prepared as described from 1.74 mol of aluminum and 500 mL of isopropanol is treated with 3 mol of crotonaldehyde and 1 L of isopropanol. On reflux at a bath temperature of 110 "C, acetone slowly distills at 60-70 'C. After 8-9 h, when the distillate no longer gives a test for acetone, most of the remaining isopropanol is distilled at reduced pressure and the residue is cooled This reducing agent is the reagent of choice for reduction and hydrolyzed with 6 N sulfuric acid to liberate crotyl alcohol of enones of type (14) to the qj3-unsaturated alcohols (15) from its aluminum derivative. (eq 6). Usual reducing agents favor 1,4-reduction to the saturated alcohol.'

&

& *&
Al(O-i-R)j

C5Hll (6)

The Meerwein-Ponndorf-Verley reduction of the ketone (3) involves formation of a cyclic coordination complex (4) which, by hydrogen transfer, affords the mixed alkoxide (5), hydrolyzed to the alcohol (6) (eq 2).4 Further reflection suggests that under forcing conditions it might be possible to effect repetition of the hydrogen transfer and produce the hydrocarbon (7). Trial indeed shows that reduction of diary1 ketones can be effected efficiently by heating with excess reagent at 250 "C (eq 3).' A study6 of this reduction of mono- and bicyclic ketones shows that, contrary to commonly held views, the reduction proceeds at a relatively high rate. The reduction of cyclohexanone and of 2-methylcyclohexanone is immeasurably rapid. Even menthone is reduced almost completely in 2 h. The stereochemistry of the reduction of 3-isothujone (8) and of 3-thujone (11) has been examined (eqs 4 and 5). The ketone (8) produces a preponderance of the cis-alcohol (9).The stereoselectivity is less pronounced in the case of 3-thujone (ll),although again the cis-alcohol (12) predominates. The preponderance of the cis-alcohols can be increased by decreasing the concentration of ketone and alkoxide.

%HI1

BPCO

BPCO

OH

(14) BPC = biphenylcarbonyl

(15) 20%, each isomel

The Meerwein-Ponndorf-Verley reduction of pyrimidin2( lH)-ones using Zirconium Tetraisopropoxide or aluminum isopropoxide leads to exclusive formation of the 3,4-dihydro isomer (eq 7).* The former reducing agent is found to be more effective.

I Bn R = H, halide

17

Zr(O-i-Pr)4 or Al(O-i-Pr)s

i-PrOH, 90 OC, 2 days 20-9 1%

Bn

Reductions with Chiral Aluminum Alkoxides. The reduction of cyclohexyl methyl ketone with catalytic amounts
Avoid Skin Contact with All Reugents

30

ALUMINUM ISOPROPOXIDE

of aluminum alkoxide and excess chiral alcohol gives (S)-1cyclohexylethanol in 22% ee (eq 8).9

elimination of the resulting p-alkoxy ketone, easily gives an optically pure alcohol in good yield. Several examples of the reaction are summarized in Table 1,
Table 1 Reductive Cleavages of Acetals Using Al(OC6F& Catalyst

22% ee

"'"'fl
Al(OC6F5)3 (5 mol %) CH2C12

Isobornyloxyaluminum dichloride is a good reagent for reducing ketones to alcohols. The reduction is irreversible and subject to marked steric approach control (eq 9).1

O R' x R2 0

* R'XR2

R'
C5Hii

R2

Yield (%)
83 61 90 71 78 89 67

Ratio (S:R)
82:18 73:27 94:6 >99:1 92:8 955 81:19

Me
Me Me Me Et

i-Bu
i-Pr

Ph Ph c-Hex

Me

CH2 CH2

Diastereoselective Reductions of Chiral Acetals. Recently, it has been reported that Pentufluorophenol is an effective accelerator for Meenvein-Ponndorf-Verley reduction." Reduction of 4-t-butylcyclohexanone with aluminum isopropoxide (3 equiv) in yield for dichloromethane, for example, is very slow at 0 "C (4% 5 h), but in the presence of pentafluorophenol(1 equiv), the reduction is cleanly completed within 4 h at 0 "C (eq 10).The question of why this reagent retains sufficient nucleophilicity is still open. It is possible that the o-halo substituents of the phenoxide ligand may coordinate with the aluminum atom, thus increasing the nucleophilicity of the reagent.
Al(O-i-Pr)3 (3 equiv) C6F50H (1 equiv) CH2C12,O 'C

U
I

(trans:cis)

GBU

Although the detailed mechanism is not yet clear, it is assumed that an energetically stable tight ion-paired intermediate is generated by stereoselective coordination of Al(OC&)3 to one of the oxygens of the acetal; the hydrogen atom of the alkoxide is then transferred as a hydride from the retentive direction to this departing oxygen, which leads to the (S)configuration at the resulting ether carbon, as described (eq 12).

R i Y o O F R*

t-Bu

t-BU

Chiral acetals derived from (-)-(2R,4R)-2,4-Pentanediol and ketone are reductively cleaved with high diastereoselectivity by a 1 :2mixture of diethylaluminum fluoride and pentafluorophenol." Furthermore, aluminum pentafluorophenoxide is a very powerful Lewis acid catalyst for the present reaction.12 The reductive cleavage in the presence of 5mol % of Al(OC6F5)3 affords stereoselectively retentive reduced p-alkoxy ketones. The reaction is an intramolecular Meenvein-Ponndorf-Verley reductive and Oppenauer oxidative reaction on an acetal template (eq 11).
EtzAlF-2C6FsOH (1.2 equiv)

, ' L I

Oppenauer Oxidation13. Cholestenone is prepared by oxidation of cholesterol in toluene solution with aluminum isopropoxide as catalyst and cyclohexanone as hydrogen acceptor (eq 13).14
AI(O-i-Pr)s

R1 > R2

HO

cyclohexanone toluene 72-74%

The direct formation of a,P-alkoxy ketones is quite useful. Removal of the chiral auxiliary, followed by base-catalyzed pLists of Abbreviations and Journal Codes on Endpapers

A formate, unlike an acetate, is easily oxidized and gives the For oxidation of (16)to (17)the same product as the free alcoh01.l~

ALUMINUM ISOPROPOXIDE

31

combination of cyclohexanone and aluminum isopropoxide and a hydrocarbon solvent is used: xylene (bp 140 "C at 760 mmHg) or toluene (bp 1 1 1 "C at 760 mmHg) (eq 14).
Al(O-i-Pr)3 cyclohexanone xylene or toluene 86%

%,\OCOMe

a-Pinene oxide (22) rearranges to pinocarvenol(23) in the presence of 1 mol % of aluminum isopropoxide at 100-120C for 1h.'* The oxide (22) rearranges to pinanone (24) in the presence of 5 mol % of the alkoxide at 140-170 "C for 2 h. Aluminum iso(2OO0C, 3 h, propoxide has been used to rearrange (23) to (24) 80% yield) (eq 17).19

Al(O-i-h)s, 100 "C

OH

(16)

&
(17)

(14)

8(22)

(17)
0

Al(O-i-Pr)3, 150 "C

69%

Hydrolysis of Oximes.16 Oximes can be converted into parent carbonyl compounds by aluminum isopropoxide followed by acid hydrolysis (2N HCl) (eq 15). Yields are generally high in the case of ketones, but are lower for regeneration of aldehydes.

(24)

Regio- and Chemoselective Ring Opening of Epoxides. Functionalized epoxides are regioselectively opened using trimethylsilyl azidelaluminum isopropoxide, giving 2-trimethylsiloxy azides by attack on the less substituted carbon (eq 18)."
R g
Me3SiN3 (1.5 equiv) Al(O-i-Pr)3 (0.1 equiv) CHzC12 59-93%

Rearrangement of Epoxides to Allylic Alcohols. The key step in the synthesis of the sesquiterpene lactone saussurea lactone (21) involved fragmentation of the epoxymesylate (U),obtained from a-santonin by several steps (eq 16)." When treated with aluminum isopropoxide in boiling toluene (N2.72 h), (18) is converted mainly into (20). The minor product (19) is the only product when the fragmentation is quenched after 12 h. Other bases such as potassium t-butoxide, LDA, and lithium diethylamide cannot be used. Aluminum isopropoxide is effective probably because aluminum has a marked affinity for oxygen and effects cleavage of the epoxide ring. Meenvein-Ponndorf-Verley reduction is probably involved in one step.

H O H

. "9
(18)

TMSO

R2

Preparation of Ethers. Ethers ROR' are prepared from aluminum alkoxides, Al(OR)3, and alkyl halides, R'X. Thus EtCHMeOH is treated with Al, HgBr2, and Me1 in DMF to give EtCHMeOMe (eq 19).'l
AI(OR)3

+ R'X

DMF, reflux, 2 days

* RORI
20-806

(19)

R, R' = alkyl; X = halide

Related Reagents. See Classes R-1, R-10, and R-12, pages

1-10.

MsO
5 steps

1. 2. 3. 4.
5.

6.

(19) 9%

(20) 68%

7.

8. 9. 10. 11.

Wilds, A. L. OR 1944,2, 178. Shiner, V. J.; Whittaker, D.; Fernandez, V. P. JACS 1963,85,2318. Worrall, I. J. J. Chern. Educ. 1969,46, 510. Woodward, R. B.; Wendler, N. L.; Brutschy, F. J. JACS 1945, 67, 1425. Hoffsommer, R. D.; Taub, D.; Wendler, N. L. C2(L) 1964,482. Hach, V. JOC 1973,38,293. Picker, D. H.; Andersen, N. H.; Leovey, E. M. K. SC 1975, 5, 45 1. Hoseggen, T.; Rise, F.; Undheim, K. JCS(PI) 1986,849. Doering, W. von E.; Young, R. W. JACS 1950,72,631. Nasipuri, D.; Sarker, G. JZC 1967,44, 165. Ishihara, K.; Hanaki, N.; Yamarnoto, H. JACS 1991,123,7074.

12. Ishihara, K.; Hanaki, N.; Yarnamoto, H. SL 1993, 127;JACS, 1993,115, 10695. Avoid Skin Contact with All Reagents

32

ALUMINUM ISOPROPOXIDE
19. Schmidt, H. CB 1929,62, 104. 20. Emziane, M.; Lhoste, P.; Sinou, D. S 1988,541. 21. Lompa-Krzymien,L.; Leitch, L. C. Pol. J. Chem. 1983,57,629.

13. Djerassi, C. OR 1951, 6,207. 14. Eastham, J. F.;Teranishi, R. OSC 1963,4, 192. 15. Ringold, H. J.; Loken, B.; Rosenkranz, G.; Sondheimer, F. JACS 1956, 78, 816. 16. Sugden, J. K. CI(L) 1972,680. 17. Ando, M.; Tajima, K.; Takase, K. CL 1978, 617. 18. Scheidl, F. S 1982, 728.

Kazuaki Ishihara & Hisashi Yamamoto Nagoya University, Japan

Lists of Abbreviations and Journal Codes on Endpapers