xug. 5 , 1959
4015
RE.4RRXNGEMENT I N T H E P Y R I D I N E S E R I E S
column. The combined ether solutions were evaporated to give 16.7 g. ( i l y o ) of white solid, m.p. 99-111'. This material had bands in the infrared a t 3.30, 4.46, 5.84 and 6.08 p . Four recrystallizations of a 5.0-g. sample of the product, m.p. 99-11l0, from 1 : 6 methylene chloride-ether The infrared mixture gave 2.2 g. of V I I , m.p. 120-121'. spectrum of VI1 showed absorption in the infrared at 4.46 and 5.84 p but none a t 3.30 and 6.08 p . The ultraviolet spectrum of VI1 in acetonitrile showed no maxima above 215 mp. Anal. Calcd. for C14H1~S4:C, 71.16; H , 5.12; X , 23.72; mol. wt., 236. Found: C, 71.33; H , 5.13; N, 23.57; mol. wt., 227. The crude product, m.p. 99-11l0, was estimated to contain 807, of V I 1 by intensitv measurements of the 5.84 p band in the infrared using 1,2-dichloroethane solvent and
solutions of known concentration of pure 1.11 as references. Ozonolysis of VI1.-Ozone was passed into a solution of 1.0 g. of VI1 in 50 ml. of absolute methanol a t -80' until a blue color persisted (0.5 hour). 1Vhile a slow stream of nitrogen was passed through the mixture, it was allowed to warm t o room temperature over the course of 0.5 hour. T o the methanolic suspension of ozonide mas added 150 nil. of methanol and 0.25 g. of 10% palladium-on-charcoal. This mixture was shaken under 2.5 atm. of hydrogen for 0.25 hour and then filtered to remove the catalyst. When 200 ml. of this solution was distilled into a solution of 1.6 g. of 2,4-dinitrophenylhydrazinein 8 ml. of sulfuric acid, 12 nil. of water and 40 ml. of methanol, 0.75 g. (75%) of acetone 2,4-dinitrophenylhydrazone was obtained, m.p. 123.5124.5', alone or mixed with an authentic sample. ~VILMISGTON 98, DELA.
I Amphenone Analogs. 111. Pinacol-Pinacolone Type Rearrangement in the Pyridine Series1 [ C U ~ T R I B U T FROM IOV
THE
KESEARCH DEPARTMEST, CIBAPHARMACEUTICAL PRODCCTS, Ivc
BY W. L. BENCZEAND M. J. ALLEN KECEIVED JANUARY 12, 1959 The three isomeric acctylppridines were reduced to the corresponding pinacols which in turn were rearranged.
During the last eight years Amphenone B, a pinacolone-type ketone, was widely investigated in numerous biological and clinical studies due to the striking endocrine effects exerted by this compound in animals as well as in man.2 ilmphenone B was prepared by subjecting the butanediol (I) (R = p-dimethylaminophenyl) to the pinacol-pinacolone rearrangement. The paminophenyl group was observed to migrate exclusively, hence structure 111 recently has been assigned to Amphenone B . 4 The isomeric pinacolone I1 also has been prepared and was found to possess a narrower spectrum of endocrine activity.'
r c n
x
1
or hv
+
CHsCHOHCHZ
/
Q - C O - C O ~
i.:
OH
-
IV, (2 -pyridyl) IV, (3 -pyridyl) IV, (4-pyridyl)
s
2 CHSMgI
The photochemical reduction6 could be rendered more efficient by irradiating the samples with ultraRCOCR +-- RC-JR -+ CHaCOCCH3 violet lamps rather than sunlight. The 2-pyridylbutanediol also was obtained by reaction of a1 ' I I CHI CHs CH, K pyridyl with methylmagnesium iodide. UnforI1 1 111 tunately the difficulty in obtaining the P- and 7pyridil precluded investigation of this reaction in The present report deals with the pinacol-piiia- the 3- and 4-pyridyl-series. The "pyridylbutanecolone rearrangement of the butanediols I (R = diol thus obtained was not identical with the prod2 - , 3-, and 4-pyridyl) which gave the pyridyl uct obtained from the photochemical reduction of analogs of Amphenone R . The three diols used '-acetylpyridine. S o attempt has thus far been were first prepared by bimolecular electrolytic re- made to investigate the resolvability of these pinaduction of the respective pyridyl ketones5 Subse- cols in order to assign to them the meso or racemic quently it was found that these diols could also be structure, respectively. prepared photochemically. Concentrated sulfuric acid was used as the rtarranging agent for all three isomeric butanediols (1) Amphenone Analogs 11. W. I< Hencze. I , . 1. R a r c k y , X I . J . 1V. The rearrangement of I V (3-pyridyl) resulted Allen and E . Schlittler, Helo. C'htin. Acta, 41, 882 (1458) (2) (a) M. J. Allen, R . Hertz and W. W Tullner, Proc. .Soc r r p . Bioi. in a binary mixture of pinacolones V and V I . J l e d . , 14, 632 (1960); (b) R. Hertz, W. W. Tullner, J . A . Schticker, Their separation was accomplished by chromatogF. G. Dhyse and L. F. Hallman, "Recent Progr. in Hormone Reraphy on aluminum oxide, or by converting them search," G. Pincus, ed.. Academic Press, Inc., New York, N . Y . , 1955, to their oximes with subsequent fractional recrystalVol. XI, P. 119; (c) 0. Picinelli, Favmaco ( P a v i a ) Ed. Sci., 12, 428 (1957); (d) H . Kless, Arsneimitrel-Fovsch.,8 , 83 (1968). lization and hydrolysis to the parent ketones. A (3) M. J. Allen and A. H. Corwin, THIS J O U R N A L , 72, 117 (1Q;jO). partial separation also was achieved by distillation, (4) (a) W. L. Bencze and M . J. Allen. J . O r g . Chem., 2 2 , 362 (1967); whereby ketone V appeared in the first fractions (b) J. Korman and E. C. Olson, ibid., 22, 870 (1967). followed by a distillate composed of the two com( 5 ) (a) M. J. Allen, ibid., 16, 435 (1950); (b) M . J. Allen, C a ~ zJ. . CHa
I
OH
OH
R
I
Chem., 97, 257 (1969); (c) M. J. Allen and H . Cohen, J . A m e r . Electvochem. S O L . 106, , 451 (1953).
(6) W. E. Bachmann, "Organic Syntheses." Coll. VoI. 11. and Sons, Inc., iYew York, N . Y., 1443, p. 71
Jilhn
Wiley
ponents V and VI in an equimolar ratio indicative of a stoichiometric azeotropic relationship of the two pinacolones in the vapor phase. Further investigation revealed that the isolation of ketone V could be accomplished readily by oxidation of the binary mixture with nitric acid, whereby ketone V remained unaffected and methyl ketone VI was oxidized. The composition of the mixture was found to be 68-72% of ketone V and 32-28% of ketone VI. Accordingly the intrinsic migratory aptitude' of the 3-pyridyl residue, when compared with the migration of the methyl group, was found to be 0.43 0.04/1. Variation of the temperature in the range from 5 to 7.5' had no effect on the migratory aptitude.
*
IKOH
CHi
-.CII?COOH
Degradations of both isomeric pinacolones were undertaken to verify the assigned structures. hlethanolic potassium hydroxide caused fission of pinacolone V yielding nicotinic acid and 2-(3pyridy1)-propane. Under the same conditions pinacolone VI gave l,l-bis-(3-pyridyl)-ethane and acetic acid.
XI1
XI11
graphic separation of the reaction mixture yielded five components: the pinacolone X, and the butadiene XI, both showing ultraviolet absorption spectra comparable to the analogous 4-pyridyl isomers VI1 and IX. For the third compound isolated, structure X I I , 6-(2-pyridyl)-7-methy1-5H-lpyridine is proposed. Elemental analysis and identical boiling points of compounds X I and XI1 indicate that both of them possess the same empirical formula C14H1&2. Ultraviolet and infrared absorption spectra are in agreement with the proposed structures of X I and XII.8 A fourth compound was found to be identical with 2picolyl 2-pyridyl ketone (XIII),9awhich was synthesized according to the method of Goldberg, et d 9 b In this instance the diol lost both methyl groups under the influence of concentrated sulfuric acid. The fifth compound isolated appeared to have lost one methyl group as indicated by elemental analysis. No structural formula has been assigned to this last compound. 2-Methyl-1,2-bis-(3-pyridyl)-l-propanone (V) (Su-4885), was found to possess distinctive effects on the adrenal cortex, similar to those exhibited by -4mphenone B, lo Acknowledgment.-We wish to express our appreciation to Dr. E. Schlittler for his continued interest and encouragement throughout this project. We are grateful to Mr. L. Dorfman and his staff for the micro-analysis and the spectral data. Experimental General Method for the Bimolecular Pinacol Reduction.-
h mixture of 10 g. of an acetylpyridine, 50 ml. of isopropyl alcohol and 0.5 ml. of acetic acid was irradiated by an ultra-
Rearrangement of the 4-pyridyl isomer of glycol IV gave ketones VI1 and VI11 in approximately the same ratio as in the case of the 3-pyridyl isomers. In addition, the two ketones were accompanied by a third compound, which was identified as 2,3-bis- (4-pyridyl)-butadiene (IX). Catalytic hydrogenation of I X gave 2,3-bis-(4-pyridyl)butane. Consequently, rearrangement and dehydration of the 4-pyridyl isomer of diol IV occurred simultaneously. Rearrangement of the 2-pyridyl isomer of diol I V resulted in a complex mixture. An infrared absorption spectrum of the distilled reaction mixture indicated the absence of an unconjugated carbonyl absorption. Thus, the methyl ketone type pinacolone could not be isolated. Chromato17) C tillti
\V
,Sor~
