CANADIAN JOURNAL O F CIIEMISTRY. VOL.

33
ATISINE: THE FUNCTIONAL GROUPS1

The suggestion is implicit in the structure recently suggested for dihydro-

atisine (9) that atisine and isoatisine are oxazolidines rather than vinylamines.
This possibility was ignored in our earlier consideration of the environment of
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the nitrogen in these alkaloids (2) because both bases gave methane equivalent
to two active hydrogens when heated with methyl Grignard reagent a t 100°
in anisole. Since the value of this evidence has been questioned by Dr. Wiesner
(private communication) it was decided to accumulate further evidence
bearing on the question.
Infrared spectra of atisine, isoatisine, and dihydroatisine were compared a t
identical concentrations in chloroform. The intensity of the C=C stretching
band in all three was identical, while an extra OH stretching band appeared
in the latter. This indicates oxazolidine rather than vinylamine structures for
the bases.
Pelletier and Jacobs (7) have very recently reached the saine conclusion
after examining the properties of several oxidation products of atisiile and
Can. J. Chem. 1955.33:448-451.

isoatisine.
On the basis of the oxazolidine structures, the bases should give inonoacetate
with no free hydroxyl, or diacetates with one free hydroxyl. Jacobs and Craig
(5) obtained a diacetate hydrochloride from atisine hydrochloride. However,
we have obtained instead a triacetate hydrochloride by the action of acetic
anhydride or acetic anhydride - pyridine mixture on atisine or isoatisine
hydrochlorides. The amorphous sensitive base liberated from this hydro-
chloride showed no hydroxyl absorption in the infrared. On hydrolysis with
potassium hydroxide in aqueous methanol it gave isoatisine nearly quantita-
tively. However, on hydrolysis with sodium carbonate solution a t room tem-
perature atisine was obtained. Thus the triacetate is a derivative of atisine,
probably containing the following partial structures:

The formation of the triacetate from isoatisine involves the first example of
the isomerization of isoatisine to atisine. So far, attempts to obtain crystalline
mono- or di-acetates from atisine or isoatisine have failed.
Wiesner's structures do not readily account for the extra active hydrogen
found in isoatisine and distilled atisine (2). These results seen1 to demand the
presence of hydrogen on the carbons a to the masked aldehyde or ketone
carbons.
lIssued as N.R.C. No. 5491.
2National Research Council Postdoctorate Fellow. Present address: Governnzent College, Lzcdhiana,
East Pzcnjab, India.
 EDWARDS AND SINGH: ATISINE 449

Jacobs and Craig (5) showed that atisine gave 0.71 mole fraction of acetic
acid in the Icuhn-Roth determination. There is some possibility that the
exocyclic methylene might isomerize t o give a C-methyl prior t o oxidation by
the chromic acid, although the experience of other workers with gelsemine
(3) and baltanltosine ( I ) makes this seem unlikely. Thus it proved desirable
to investigate further the source of the acetic acid.
I t has now been found that isoatisine, the C20H290N base (2), and the lac-
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tam tricarboxylic acid from isoatisine (4) give 0.52, 1.13, and 0.57 mole fraction
of acetic acid in the I<uhn-Roth determination indicating one, two, and one
C-methyl respectively.
The infrared spectrum of a film ol atisine has a band a t 1375 cm.-I, which
is also present in the spectra of chloroform solutions of isoatisine and the
C20H?90Kbase. These bands can be ascribed with certainty to a methyl
group (6). A conlparison of the appai-eilt integrated absorption intensities (8)
of this band in the last two bases indicated that two methyl groups are present
in the C20 base if isoatisine has one, in agreement with the suggested mode of
forn~ationol this base (2) and with the results of the Icuhn-Roth determina-
tion. The inll-ared spectrum of a perfluorohydrocarbon mull of the lnctam
Can. J. Chem. 1955.33:448-451.

tsicarboxylic acid froin isoatisine contained a methyl band a t 1380 cm-I.

Thus all the evidence is consistent with the conclusion that atisine has one
methyl group.
I t is inost probable that it is this C-methyl group which becomes the
1-methyl substituent on the phenanthrene derivatives obtained by selenium
tlehyclrogenation of atisine derivatives. In this respect the structure suggested
by \Viesner is satisfactory.

EXPERIMENTAL
Infrared spectra were determined on a Perkin-Elmer model 21 double
b e a n spectrophotometer with a sodium chloride prism. In order to obtain a
more reliable value for the integrated absorption intensity, a trace was made
with two cells containing chloroform. The chloroform in one cell mas then
replaced by a chloroform solution of the compound and the spectrum recorded.
The background trace was taken as the 0% absorption line for the calculations.
Method 1 of Ramsay (8) was used and the value 1.57 was taken for K. Per-
centage absorption values are cited in brackets after the position of peaks in
wave numbers.
Atisine
Obtained a s a resin from ether solution. Infrared spectrum (65.8 mgm. per
nil., 0.1 mm. cell) : 3590 (20), 1655 (13).
Isoatisine
M.p. 152". Found: C-methyl, 2.27. Calc. for C22H3302N: one C-methyl,
4.38. Infrared spectrum (30.6 mgm. per ml. in chlorofor~n,0.1 mm. cell):
a t 1375 cm.-I log,,(Io/I) = 0.049, Av: = 10.5 cm-I. A = 1800. At a concentra-
tion of 63.2 mgm. per ml., 0.1 mm. cell: 3600 (19), 1652 (11).
 450 CANADIAN JOURNAL O F CHEMISTRY. VOL. 33

Dihydroatisine
Infrared spectrum (64.8 mgm. per ml., 0.1 mnl. cell): 3600 (21), 3470 (19),
1655 (12).
The CzoHZ90N Base
M.p. 82-84". Found: C-methyl 5.65. Calc. for C20H2sON:two C-methyls,
10.04. Infrared spectrum (30.0 per ml. in chloroform, 0.1 mm. cell): a t 1376
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cm.-I loglo(I~/I)= 0.054, Av; = 17 cm-'. A = 3300. At 1710 cm.-I (62) and
1649 cm.-I (24).
Lactam Tricarboxylic Acid from Isoatisine
This was prepared by the method of Huebner and Jacobs (4). After two
recrystallizations from aqueous methanol the tiny plates melted a t 253-255"
(dec.) when immersed a t 230". Found: C-methyl, 2.10. Calc. for C21H2907N:
one C-methyl, 3.69. Infrared spectrum (perfluorohydrocarbon mull) : a
broad band centered about 1700 cm.-I (COOH); 1610 (lactam); 1515, 1465,
1450, 1405 (CHZ's); 1380 (CHX).
Triacetylatisine Ilydrochloride
Can. J. Chem. 1955.33:448-451.

(a) A suspension of atisine hydrochloride (0.15 gm.) in 3 cc. of acetic anhy-

dride was boiled for 10 min. The crystals dissolved to give a light orange
solution. The reagent was removed under reduced pressure, and the residue
crystallized from methanol-ether. The 104 mgm. of crystals melted a t 230"
dec. After two recyrstallizations the melting point was 235". The infrared
spectrum was identical with that of the products from (b) and (c).
Atisine was left overnight in solution in acetic anhydride. The reagent was
removed under reduced pressure, methanol added, and the solution agai11
taken to dryness. The residue was converted to its hydrochloride. The crys-
talline product melted a t 233". After one recrystallization it melted a t 242"
dec., and did not depress the melting point of the triacetate hydrochloride.
(b) From 145 mgm. of isoatisine, treated as in (a), was obtained 96 mgm.
of acetate hydrochloride. After one recrystallization from very concentrated
methanol solution on addition of ethyl acetate, it melted a t 241" dec. I t
showed no mixed melting point depression with product from (c) and had the
same infrared spectrum.
(c) A suspension of 918 mgm. of finely divided atisine hydrochloride in
20 cc. of 50% pyridine - acetic anhydride was refluxed for five minutes. The
solution was cooled to 0°, giving 984 mgm. of fine needles, m.p. 230" dec.
After two recrystallizations from methanol -ethyl acetate the melting point
was 241°when immersed a t 210". [a]:- 18 =t 1" (c = 2.0 in ethanol). Found: C,
63.67, 63.76, 64.16; H, 8.49, 8.50, 8.11; C1, 7.11, 7.17. Calc. for C2&4206 NCl:
C, 64.16; H , 8.08; C1, 6.77. I.R. spectrum: 3580 (40), 3440 (39), 3350
(40), 1740 (go), 1679 (40), 1650 (51), 1333 (29), 1320 (25), 1309 (29), 1250 (92),
1210 (461, 1128 (29), 1111 (23), 1094 (25), 1071 (45), 1060 (51), 1039 (53), 1020
(57), 985 (34), 973 (35), 955 (25), 948 (55), 902 (38), 843 (16), 831 (16). Isoatisine
hydrochloride treated in the same way gave a good yield of the same triacetate
hydrochloride.
 EDWARDS A N D SINGH: ATISINE 451

Triacetyl Atisine
Cold potassium hydroxide solution was added to a cold solution of the tri-
acetyl hydrochloride in water. T h e precipitate was extracted quickly into
petroleum ether (30-60°), the solution dried, and the solvent removed under
reduced pressure. The clear gum would not crystallize from ether or petroleum
ether. Infrared spectrum (film): 3080 (18), 2945 (85), 2890 (75), 1740 (92),
1652 (35),1582 (45),1450 (57),1415 (44), 1375 (76), 1329 (31), 1310 ( 3 1 ) ,1240
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(97), 1182 (32), 1155 (27), 1113 (311, 1070 (45), 1028 (78), 985 (57), 947 ( 3 3 ) ,
901 (49), 827 (25).
Saponijication of the Triacetate
( a ) A sample of the amorphous triacetate prepared a s described above was
hydrolyzed for four hours a t room temperature followed by 0.5 hr. reflux in
aqueous methanol containing potassium hydroxide. The solvent was largely
removed under reduced pressure, the residue taken up in water and extracted
with ether. The base crystallized readily and completely from concentrated
ether solution. iv1.p. 149'; mixed m.p. with isoatisine 151'.
(b) A solution of 69 mgm. of triacetate hydrochloride and 100 mgm. of
sodium carbonate in 2 cc. of water soon became milky. I t was clarified by
Can. J. Chem. 1955.33:448-451.

addition of methanol and left for 24 hr. a t room temperature. The mixture was
worked up as in (a) giving 39 mgm. of base. This would not crystallize. I t s
infrared spectrum (film) had every peak coincident with that of atisine except
for a very small extra peak a t 1727 cm-I. I t gave a hydrochloride, m.p. 300°
dec., which when mixed with atisine hydrochloride melted a t 302O dec.
ACKNOWLEDGMENT
The authors wish to thank Dr. R. N. Jones and Mr. R. Lauzoil for taliing
the infrared spectra.

I. BALENOVIC, I<., DANIKER,N. U., GOUTAREL, R., JANOT,M.-M., and PRELOG,V. Helv.
Chim. Acta, 35: 2519. 1952.
2. EDWARDS, 0. E. and SINGH,T. Can. J. Chem. 32: 465. 1954.
3. GOUTAREL. R.. TANOT. M.-M., PRELOG.
. V... SNEEDON.R. P. A.. and TAYLOR. W. I. Helv.
Chim. ~ c t a 34:
; 1139. 1951.
4. NUEBNER, C. F. and JACOBS,W. A. J . Biol. Chem. 174: 1001. 1948.
5. JACOBS,W. A. and CRAIG,L. C. J. Biol. Chem. 143: 589. 1942.
6. JONES,R. N. and COLE,A. R. N. J. Am. Chem. Soc. 74: 5648. 1952.
7. PELLETIER, S. W. and JACOBS, W. A. J. Am. Chem. Soc. 76: 4496. 1954.
8. RAMSAY, D. A. J . Am. Chem. Soc. 74: 72. 1952.
9. WIESNER,K., ARMSTRONG, R., BARTLETT,M. F., and EDWARDS,J. A. Chemistry &
Industry, 132. 1954.
 This article has been cited by:

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3. S. W. Pelletier. 1964. The chemistry of certain imines related to the diterpene alkaloids. Experientia 20:1, 1-10. [Crossref]
4. S.W Pelletier. 1961. Recent developments in the chemistry of the atisine-type diterpene alkaloids. Tetrahedron 14:1-2, 76-112.
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Can. J. Chem. 1955.33:448-451.