3204
COMMUNICATIONS TO THE EDITOR
Vol. 84
Raney nickel to give C11H3NH2. Possible one carbon species with this behavior are methylenimine, cyclodiazomethane and diaminomethane. One carbon species may be the precursor of both methane and methylamine. The mechanism of the primary process is not dealt with here but will be considered in the full paper dealing with these experiments, unreported data and work in progress on this system. Acknowledgments.-The authors wish to acknowledge the invaluable assistance of Dr. C. Baker, head of the BNL 60" cyclotron group. We also wish to acknowledge the help of Drs. G. Stocklin and D. Christman in carrying out some of the carbon-1 1determinations.
acetate (I) in dioxane solution gave 5,-bromopregnane-3P,GP-diol-2U-one %acetate (11) (m.p. 165-167", [a]D +6.5°.9 Found for C23H36BrO(: C, 60.36; H, 7.81; Br, 17.79; 0, 14.17). Treatment of I1 with 1.2 moles of dry lead tetraacetate in anhydrous benzene4,? afforded 6P,19-oxido-Sabrornopregnane-3~-01-20-oneacetate (111) (m.p. 152-154', [a]D 4-58', ~2:: 9071° cm.-l. Found for C23H33Br04: C, 61.18; H, 7.31; Br, 17.91; 0, 13.97). Mild alkaline hydrolysis of I11 gave the corresponding 30-alcohol IV (m.p. 179-180°, [a]D +61". Found for C21H31Br03: C , 61.52; H, 7.70; Br, 20.19) which was oxidized with chromium trioxide in aqueous acetic acid and then directly converted with zinc dust in isopropyl alcoholll (reflux 24 hours) into 19-hydroxy-A5 (14) Institute of Pharmaceutical Chemistry, University of Rome. pregnene-3,20-dione (V). Treatment of V with Visiting Associate Chemist, Brookhaven National Laboratory, 19611962. oxalic acid in ethanol afforded 19-hydroxyprogesterone (VI) (m.p. 169-171", [ a ] D +182", Xmax. CHEMISTRY DEPARTMENT FULVIO CACACE'* BROOKHAVEN h k T I O N A L L.4BORATORY 243 mp, log E 4.22. Found for C21H3003: C, 76.07; UPTON, L. I., N E W YORK -4LRRED P. WOLF H, 9.11; 0, 14.69). Oxidation of VI with 8 N RECEIVED MAY2, 1962 chromic acid in acetone solution furnished the corresponding 19-carboxylic acid VI1 (m.p. 147-149", [a]D +94", Xma, 243 mk, log E 4.19. Found for STEROIDS. CCII.' A NEW ROUTE TO 19-NOR C Z I H ~ ~ C, O ~73.43; : H, 8.22; 0, 18.33) smoothly STEROIDS converted by acidic methanol12 to 19-norprogesSir : terone13 (VIII) (m.p. 142-144", [ a ]4-141'). ~ The increasing importance of 19-nor steroids, 2a In a similar manner dehydroisoandrosterone particularly in the field of oral contraception,2bhas acetate (IX) gave 19-norandro~tene-3,17-dione'~ made i t attractive to investigate new routes to this (xv) (m.p. 166-168O, [a]D+127", Xmag 239 mp, class of compounds which do not proceed via Birch log E 4.23) via 5a-bromoandrostane-3P,B~-diol-17reduction3 of ring A aromatic precursors, since the one 3-acetate (X),4b,15 6P,19-oxido-5a-bromoandrolatter reaction in particular is inconvenient for stane-3B-ol-17-one acetate (XI) (m.p. 187-188', large scale operations. [ a ] 4-39'. ~ Found for C21H29Br04: C, 39.24; Recently we4 and others5-' described chemical H, 7.04; Br, 18.99), its corresponding 30-01 XI1 methods for the direct oxygenation of the C-19 (m.p. 209-211°, [ a ] +38". ~ Found for C19methyl group, a primary prerequisite for the sub- H27Br03: C, 59.74; H , 7.15; Br, 20.71), 19-hysequent conversion to 19-nor steroids. However, dro~y-A~-androstene-3,17-dione~~ (XIII) (m.p. 168none of these approaches offered a facile synthesis 170", Xmax 243 mp, log e 4.21) and the 19-carboxyof 19-nor-A4-3-ketones. lic acid X I v I 2 (m.p. 148-150", [a]D+242", Xmax The conversion of several A5-3P-alcohols into 244 mp, log c 4.18. Found for C19H2404: C, their corresponding 19-nor-A5-3-ketones by an 72.13; H, 7.69; 0,20.27). efficient process8is now described, which is exempli19-Nor-l7a-acetoxyprogesterone (XXIII) also fied by the conversion of pregnenolone acetate (I) was prepared from 17a-hydroxypregnenolone 3,17into 19-norprogesterone (VIII) in an over-all diacetatel' (XVI), by an alternate reaction seyield of 37y0. quence. Addition of hypobromous acid (N-bromoacetReaction of 5 a-bromopregnane-3,8,6P, 17a-triolamide and aqueous perchloric acid) to pregnenolone 20-one 3,17-diacetate (XVII) (m.p. 184-186", [ a ] -49". ~ Found for C25H37Br08: C, 55.41; (1) Steroids C C I , P. CrabbC and J. Romo, Cicncia, in press. 3 , 7 . 3 1 ; Br, 16.04; 0, 18.23) with lead tetraacetate (2) (a) D. A. McGinty and C. Djerassi, A n n . N . Y . Acad. Sci., 71, 500 (1955); (b) G. Pincus and A. P. Merrill, "Control of Ovulation," gave 6~,19-oxido-3a-bromopregnane-3,~,17a-diolEd. by C . A . Villee, Perpamon Press, New York. 20-one 3,17-diacetate (XVIII) (m.p. 202-208", (3) A. J. Birch and H. Smith, QuaYt. Rev. ( L o n d o n ) , 12, 17 (1958). (4) ( a ) A. Bowers, I, C. Ibiiiez. M. E. Cabezas and H. J. Ringold, Chem. and Ind. ( L o n d o n ) , 1299 (1960); (b) A. Bowers, E. Denot, L. C. IbLfiez, R I . E. Cabezas and H. J. Ringold, J. Org. Chem., 27,
1562 (1962). (6) D. H. R . Barton, J, 11. Beaton, I,. E. Geller and M. M.Pechet, J . A m . C h e m SOL., 82, 2640 (1960); hl. Akhtar and D. H. R , Barton, i h i d . , 83, 2213 (1961); D. H. R . Barton and J. hI. Beaton, ibid., 84, 190 (1962). ( 6 ) J. S. Mills and V. Petrow, Chein. and I n d . ( L o n d o n ) ,946 (1961). (7) Ch. Meystre, K. Heusler, J. Kalvoda, P. Wieland, G. Anner and A. Wettstein, Ezpsrieniia, 17, 475 (1961). ( 8 ) Recently G. Gardi and C. Pedrali, Gaee. Chim. Iiul., 91, 1420 (1L461), also M. Akhtar and D. H. R . Barton, J . A m . Chem. Soc., 84, 1496 (19621, described t h e synthesis of 19-nor steroids from A5-33hydroxyandrostenes by processes utilizlnf. a n ultraviolet light irradiation procedure a s the k e y step. Also cf. R . Kwok, T. Jen and M. Wolff, Abstracts 141st Meeting of the American Chemical Society, March 1962, p . 43-N.
(9) All rotations in chloroform solution and ultraviolet spectra in 95% ethanol. (10) All compounds with t h e 6,9,19-oxide bridge were characterized by a sharp meoium intensity band between 903-910 cm.-'. (11) I n contrast t o t h e ~a-bromo-6,19-oxides, t h e corresponding Sa-chloro-6.19-oxides [ e . p . , 5a-chloro-6j3,19-oxidoandrostane-3P-ol20-one acetate (m.p. 1SG-189°, [ a ]f 5~3 9 ] were recovered unchanged
after treatment with zinc in isopropyl alcohol under reflux. (12) H. Hagiwara, S . Soguchi and M. Nishikawa, Chem. Pharm. Bull. J a p a n , 8, 84 (1960). (13) L . Miramontes, G. Rosenkranz and C . Djerassi, J . .4m.Chem. Soc., 73, 3540 (1951). (14) A. L. Wilds and N . A. Nelson, J . A m . Chem. SOL.,76, -5366 (1953). (15) V. Grenville, D. K . Patel, V . Petrow, I . A . Stuart-Webb and D. M. Williamson, J . Chem. Soc., 4105 (1967). (16) A. S. Meyer, Experienlia, 11, 99 (1955), reports m . p . 108-170°. ( 1 7 ) R. B . Turner, J. Ani. Chetn. Soc., 76, 3180 (1963).
Aug. 20, 1962
COIIMUNICATIONS TO THE
3205
EDITOR
[ a ] -lo. ~ Found for Cp5H35Br06: C, 58.77; 247 mp ( E 14,500), v::: 1665, 1610 cm.-l, n.m.r. H, 6.79; Br, 15.55; 0, 18.67) which was treated (all in CC14) a t 4.25 (1H singlet) ; 8.82 7 (6H singlet) with zinc dust in isopropyl alcohol to afford and the desired cyclopentenone (9) (40%) m.p. looo, 1695, 1635cm.-', three A5-pregnene-3P,17a,19-triol-20-one3,17-diacetate hE:H 246 mp ( E 13,000), (XIX) (m.p. 228-229", [ a ] -48". ~ Found for methyl resonance peaks in the n.m.r. spectrum a t C2SH3806:C, 69.10; H, 8.66; 0, 22.36). Hydrolysis 8.95, 9.05 and 9.15 7 . The latter ketone (9) was of X I X gave the 3P-alcohol X X (m.p. 245-247", nearly completely racemized, indicating reversible [ a ] -63'. ~ Found for C23H3406:C, 70.59; H , isomerization of 8 and the meso-acid (2) prior to cy8.53; 0, 20.62) which underwent Oppenauer clization. This was avoided as follows : Hydroboraoxidation (10 min.) to furnish 19-hydroxy-17a- tion of 3 followed by oxidation with hydrogen per~ acetoxyprogesterone (XXI) (m.p. 252-254O, [ a ] ~oxide gave the diol (6),m.p. 138-139', [ a ]-25' + 7 2 O , A,, 242 mp, log E 4.17. Found for CZ3- identical with the product available by reduction of 4 H3206:C, 71.38; H, 8.36; 0, 20.34). Oxidation with lithium aluminum hydride which was monoacetylated, dehydrated with phosphorus oxychloride of X X I to the 19-acid X X I I (m.p. 166-168', [ a ] +116', ~ A,, 244 mp, log E. 4.18. Found for in pyridine and the resulting acetate reduced with C23H3006: C, 68.72; H , 7.60; 0, 23.36) and treat- lithium aluminum hydrideto the unsaturated alcohol ment with acid gave 19-nor-17a-acetoxyproges- (7). Oxidation with chromium trioxide furnished the acid ( 8 ) , m.p. 81-82', n.m.r. signals a t -2.2 teroneI8 (XXIII) (m.p. 227-229', [ a ] +IS0, ~ ( l H ) , 4.9 (1H broad), 9.0 (3H), 9.087 (6H) (over-all A,, 239 mp, log E 4.23). yield 3 to 8,65%). (18) A. Zaffaroni. H. J. Ringold, G . Rosenkranz, F. Sondheimer, Treatment of its acid chloride with aluminum G . H. Thomas and C. Djerassi, J . 4 m . Chpm. Sa.,8 0 , 6110 (19.58). chloride in carbon disulfide afforded 9, m.p. 110', A . BOWERS RESEARCH LABORATORIES R. VILLOTTI [ a ] D -149' J. A. EDWARDS SYNTEX, S. A. .kPt\RTADO POSTAL 2679 E. DESOT MBxrco, D. F. 0. HALPERN RECEIVED JVNE 13, 1962
(41%).
b 4
SYNTHESIS OF PATCHOULI ALCOHOL'
Sir: After structurai studies on the tricyclic sesquiterpene patchouli alcohol (1)2 were complete we initiated work directed toward a synthesis of this natural product and the related patchoulione (19), a substance with highly desirable olfactory properties. A synthesis verifying both structure and absolute configuration of 1 is now presented.
\
5
/
OH
& -
R
7, R=CHZOH 8, R = COOH
1
Addition of allylmagnesium chloride to ( -) homocamphor3 (prepared from (+)-camphor) gave the carbinol (3) (go%), m.p. 36-36.5', [ a ] -20' ~ (all in CHCls) which on treatment with diborane4 followed by oxidation with Jones' reagent5J was converted to the spirolactone (4) (54%), m.p. 89-90', [ a ] D -45', :::Y 1770 cm.-'. Dehydration in the presence of lYO ZnCls in hot acetic anhydride-acetic acid solution (3 : 1) furnished the meso-ketone ( 5 ) . (lo%), m.p. 101-103°, A%:" (1) Terpenes X V t i . (2) G. Biichi, R. E. EricKson and N. Wakahayashi, J . A m Chem. SOC.,83, 927 (1961). (3) H. Favre and J.-C. Richer, Can. J . Chem., 37, 417 (1959); H. R u p e and C. Frey, IIelPi. Chim. Acta, 2 7 , 627 (1944). (4) H. C. Brown and G. Zweifel, J . A m . Chem. SOC.,81, 247 (1959.) (5) A. Bowers, T. G . Halsall, E. R. H . Jones and A. J. Lemin, J. Chem. Soc., 2548 (1953). (6) Cf. oxidation of secondary boranes to ketones, R . Pappo, J . A m . Chem. SOL.,81, 1010 (1S5Y); H. C. Brown and C. P. G a r s , i b i d , , 83, 2951 (1961).
O
9
Wittig condensation' with triphenylghosphinemethylene in peroxide free tetrahydrofuran furnished an unstable liquid diene (lo), 256 mp which on hydrogenation over Raney nickel W2 in ethyl acetate gave an olefin, over-all yield 9 to 11, 38%, [ a ] D -42'. Identity with P-patchoulene (11) was established by comparison of infrared and n.m.r. spectra, optical rotation and retention time in the gas chromatogram. The tricyclic skeleton of patchouli alcohol (1) had to be constructed from 11 using some version of the Wagner-Meenvein rearrangement. Direct isomerization was ruled out because the equilibrium between 11 and 20 is quantitatively in favor of 11. Epoxidation of 11 with peracetic acid produced the liquid epoxide (12) (99%), [a]D -8" which was isomerized with boron fluoride in ether solution (20', 5-10 min.) to the unsaturated alcohol (13) (57%), m.p. 30-31', [ a ] -14O, ~ (7) U. Schollkopf, Angew. Chcm.. 71, 280 (1959).
