VOL.27
NOTES
4108
The Reduction of 2 2 , 2 6 - 0 ~ i d o - A ~ ~ ( ~ ~ ) - An analogous sequence of reactions was carried out in the A6-series starting from kryptogenin.7 cholestene-3~,22-diol-l6-onewith The results were entirely analogous. Lithium Aluminum Hydride &lALCOLM
J. THOYPSOS, JAMESA. MOO RE,^ ERICH MOSETTIG
AKD
Experimental8
22,26-0xido-A17~z0~-cholestene-3p,22-diol-16-one (Ia).The isomerization of 5,6-dihydrokryptogen diacetate (10.0 .\-atzonal Institute of Arthritis and Metabolzc Diseases, 9.) with refluxing acetic anhydride containing a small amount Sational lnstitutes of Health, Bethesda, Maryland, and the of p-toluenesulfonic acid proceeded as described.? Three Department of Chemistry, University of Delaware, Newark, recrystallizations from methanol gave 6.0 g of A16,W(22)Delaware allofurostadiene-3~,26-diol3P126-diacetate, m.p. 94-96', [ C Y ] ~ D+lo', Amax 226 mp(E 10,5W)[lit.,2 m.p. 96-98', [ C Y ] ~ O D +lo", A ,, 226 mp (log e 4.05)]. The free diol, Keceiaed J u n e 29, 1962 m.p. 187-189', [ c Y ] ~ ~ D 30', Amrx 228 mp(s 10,1OO)[lit.,z m.p. 189-191", [ c Y ] ~ O D +31', Am,,227mp(loge4.03)]. In 1952, Kussbaum, et aLJ2converted 5,6-diWe observed that the pseudokryptogenins and their hydrokryptogenin diacetate through a series of derivatives exhibit two bands of moderate intensity in reactions to 22,26-0xido-A~~(~~)-cholestene-3p,22chloroform solution a t 1623 and 1572 em.-'. The presence diol-16-one (Ia). Reduction of I a with lithium of these bands may be used for the detection of a A1el'M(22)aluminum hydride was reported2 to yield IVa. furostadiene system. The A16~20(22)-allofurostadiene-3P,26-diol 3p,26-diacetate Compound IVa appeared to us to be an appropriate (5.0 9.) was oxidized with an excess of chromic acid in acetic starting material for the partial synthesis of 5,6- acid a t room temperature and the mixture worked up as dihydropennogenin of structure V, proposed by reported.2 The crude oily product, Amax 246 mp ( e 11,000), Marker and associates. An alternate formulation was immediately saponified by refluxing for 1 hr. with 2y0 1'1 has been sugested by Heusler and W e t t ~ t e i n . ~rnethanolic potassium hydroxide solution and extracting with a large volume of ether. The product crystallized We attempted to prepare IVa from 5,6-dihydro- from the dried ether extracted in a yield of 3.0 g.; spears kryptogenin by carrying out the sequence of reac- m.p. 204-206'. Recrystallization from ethyl acetate tions as previously reported.2 The intermediates gave 2.8 g. of I a as rods, m.p. 205-206", [ a I 2 O D -106', 3390, 1712, and 1672 em.-] leading to IVa were in regard to physical properties A,, 237 mp ( E 13,300) and yields in complete agreement with the published [lit.,? m.p. 20>206", [ c x ] ~ O D -105', Amax 237 mp (log E 4.19)]. data.2 While the physical properties of the final Anal. Calcd. for C27H4204: C, 75.30; H , 9.83. Found: product, supposed to be the IVa, were also in full C, 75.18; H, 9.79. agreement with those reported, the analytical data 22,26-0xido-A5~17~20~-cholestadiene-3B,22-diol-l6-one (Ib). of IIa and its derivatives, particularly of the acyl -This product was obtained from kryptogenin diacetate derivatives showed clearly that in the reduction of by repeating the sequence of reactions used in the preparation of 1a.7 I a a dialcohol of the structure of 22,26-0xido-A~'(~~)The intermediate ~j,16,20(22)-f~r~~tatriene-3P,26-diol 3p,26cholestene-3p,16E-diol (IIa)5 had been formed. diacetate was obtained in a yield of SO%, m.p. 94-95', Esterification gave readily diesters (acetate, di- [ c Y ] ~ ~ -44", D Amax 226 mp ( E 12,OW)[lit.,7 m.p. 94-95', nitrobensoate). Oxidation of IIa with chromic acid [ a ] 2 0 ~ -44O, A,, 226 (log E 4.16)]. Oxidation of 5.0 g. of led to the diketone 111. Its ultraviolet spectrum the A+,~(22)-furostatriene-3P,26-diol 3p,26-diacetate and immediate saponification of the oxidized product with 2% showed a band a t 237 mb practically identical with methanolic potassium hydroxide solution gave after isolathat of Ia. The strong bands a t 1706 and 1666 tion and purification 3.1 g. of Ib, m.p. 220-223", [ a I m D em. also indicated alp-unsaturated carbonyl. - - B o , A, 237 mp ( E 13,100), ~2:;' 3367, 1706, and 1669 The 3- and 16-ketone absorption bands overlap em.-' [lit.,7 m.p. 225-226', [ a ] 2 0 ~ -173", Amax 236 m p because of the shift of the 16-ketone band to lower (log €4.17)]. (IIa).-A solufrequency (conjugation with the C-17(20)-do~ble 22,26-0xido-A17(20~-cholestene-3p,16~-diol tion of 2.0 g. of 22,26-oxido-A17~~~-cholestene-3~,22-diol-16hond). Compound I11 gave a crystalline mono- one ( I a ) , 1.5 g. of lithium aluminum hydride, and 150 ml. oxime which exhibited strong bands a t 1706 and of tetrahydrofuran was refluxed for 1 hr. Decomposition of 1666 cm.-' indicating that only the 3-ketone was the excess reagent with ethyl acetate, followed by addition involved in oxime f ormation.6 Lithium aluminum of water and dilute sulfuric acid, filtration of the precipitate, and recrystallization from methanol gave 1.2 g . of elongated hydride reduction of I11 gave I I a in a yield of 60y0. needles, m.p. 228-230", [ C Y ] ~ D-11', noselectiveabsorption
+
(1) L)eimrtmriit of Chemistry, LIniversity < i f Dehwar?, Newark, Ilelaware. (2) A. L. Nussbaurn. A. Sandoval. C:. Rosenkrana, and C. Djerassi, J . O r g . C h s n . , 17, 426 (1952). ( 3 ) E. Marker, R. B. Wagner, D. P. J . Goldsmith, P. R . Ulshafer. and C. H. Ruof, J. Am. Chem. SOC.,66, 1248 (1943). (4) K. Ileusler and A. Wettstein, Chem. Bsr., 87, 1301 (1954). ( 5 ) The configuration at (2-22 as shown in the structural formulas l a , I l a , and I11 ie arbitrary. (6) .1 compound of similar structure t o I11 was observed to exhibit wnsirlerable hindrance at (2-16, I. Scheer, M. J. Thompson, and E. XIusrttig. J. Am. Chem. SOC, 79,3218 (1957).
(7) .4. Sandoval, J. Romo. G. Rosenkranz, St. Kaufmann. and (7. Djerassi. ibid.. 73, 3820 (1951). (8) All melting points were determined on Kotler block. Rotstions were determined in approximately 1% solutions in chloroform and ultraviolet spectra in absolute ethanol with a Cary Model 11 recording spectrophotometer. Infrared speotra were obtained with a PerkinElmer Model 21 double beam spectrophotometer with sodium chloride priam and cells. Microanalyses are by the Analytical Service Laboratory of this Institute under the direction of Dr. William C. Alford. Infrared spectra were determined by MI. H. K. Miller and ultraviolet sliectra by RIrs. A . "right of this laboratory.
NOVEMBER, 1962
KOTES
4109
in the ultraviolet, free hydroxyl in the infrared but no Furazan Oxides. 11. Evidence for -12"). ~ carbonyl (lit.,289sm.p. 226-228" [ a l Z 0 Equilibria of Benzofurazan Oxides Anal. Calcd. for C27&08: C, 77.83; H, 10.65. Found: C, 77.64; H , 10.38. with o-Dinitrosobenzenes' The diacetate (acetic anhydride-pyridine, steam bath, 2 hr.) was obtained as plates from methanol, m.p. 218-220", FRAXK B. MALLORY AND CLELIAS. WOOD [ a I z 0-go, ~ acetate but no free hydroxyl bands in the infrared (lit.,2t0bm.p. 223-225", [ a I m D -8". Marion Edwards Park Laboratory of Bryn Mawr College, Anal. Calcd. for C31H1805:C, 74.36; H , 9.66; acetyl, Bryn Mawr, Pennsylvania 17.1. Found: C, 74.29; H , 9.56; acetyl, 16.3 The bis-3,5-dinitrobenzoate (3,5-dinitrobenzoyl chlorideReceived July 2, 1962 pyridine, 3 hr., steam bath) was obtained as plates from acetone-methanol, m.p. 186-187', [ a I 2 O D 4-35". The fact that the pyrolysis of either of the sub=InaZ. Calcd. for C41H48013x4: C, 61.18; H, 6.01; S , stituted nitroazides of the type shown below yields 6.96. Found: C, 61.29; H , 6.14; K,6.85. a single compound X-C6H3N2O2 rather than two 22,26-0xido-A~~1~(2~~-cholestadiene-3P,16g-d~01 (IIb).The lithium aluminum hydride reduction of 22,26-oxido- separate isomeric benzofurazan oxides such as A6~17(m)-cholestadiene-3~,22-diol-16-one (Ib) carried out Ta and I b was originally thought2 to indicate a exactly as in the preparation of I I a gave I I b in a yield of 6570 as needles after recrystallization from methanol, m.p. 236-237", [CY]'~D -80" (lit.,7?g0m.p. 236-237', [ a I m D 8 1.3"). X Anal. Calcd. for Cz7H4203: C, 78.21; H, 10.21. Found: C, 78.28; H, 10.10. The diacetate (acetic anhydride-pyridine, 2 hr., steam bath) was obtained as rectangular plates from chloroformmethanol, m.p. 258-260", [ a l Z o-71' ~ m.p. 260262" [ a ] " D -70.7'). Anal. Calcd. for C31H4606:C, 74.66; H, 9.29; acetyl, 17.3. Found: C, 74.53; H , 8.99; acetyl, 17.1. L The bis-3,5-dinitrobenzoate (3,5-dinitrobenzoyl chloride0 Ib pyridine 3 hr., steam bath) was obtained as thin plates from Ia acetone-methanol, m.p. 206-207", [ a ]2 0 ~ 1'. Anal. Calcd. for C41H4&N4: C, 61.34; H, 5.77; N, symmetrical configuration of the Y202 grouping. '6.97. Found: C,61.52; H,5,72; ?;,6.77. However, recent n . m ~ .and ~ . ~X-ray5 results have 22,26-O~ido-A~~(~~~-~holestene-3,16-dione (111).-To a demonstrated the validity of the unsymmetrical Ytirred solution of 300 mg of 22,26-oxido-A17(~)-cholestene-N-oxide formulation I for this class of compound. 36,lGg-diol ( I I a ) in 200 ml. of acetone a t 20°, was added These results require the existence of an equilibradropwise, an 8 N solution of chromic acid in dilute sulfuric tion Ia Ib such that only the more stable isomer acid (ca. 40%) until a persistent orange-brown coloration is isolated. This type of equilibration was origiindicated oxidation was complete. The mixture was diluted nally postulated by Hammick6 and has recently with water and the crystalline precipitate was collected, been demonstrated by n.m.r. s t ~ d i e s . ~ ?For ~ washed with water, and dried to yield 280 nig. of 111, m.p. 182-188". Recrystallization from ethanol raised the melt- example, the proton resonance pattern of the 236 ( E 10,400), parent benzofurazan oxide (I with X = H) is a ing point to 195-197", [ ~ ] ? O D -78", A,, CHCla Y 1706 c m . 3 strong (3-ketone and 16-ketone) and 1666 complicated ABCD type a t low temperatures but cm.+, strong (double bond in conjugation with a carbonyl). changes to a symmetrical A2B2pattern at higher Anal. Calcd. for C27H4003: C, 78.59; H, 9.77. Found: temperatures when the rate of the I a I b interC, 78.82; H , 9.54. conversion is sufficiently rapid that only the averThe nionooxime (hydroxylamine hydrochloride, methanol-. age proton environments are detected. Similarly, pyridine, water, steam bath, 2 hr.) was obtained a9 plates t'he two peaks of the 0'' n.m.r. spectrum of I (X from ethanol, n1.p. 234-237", with slight decomposition. = H) at, room temperat,ure roalesce to a single .lnal. Calcd. for C27Hd103N: C, 75.83; H , 9.67, N , peak above 45°.4 3 . 2 8 . Found: C, 73.70; H, 9.50; N, 3.33. (1) Presented before the Organic Divlsion at the National Meet,Reduction of IT1 with lithiiini aluminum hydride g a w tho ing of the, American Chemical Society. Atlantic City, N. .J.. Sept. 13, original diol 1T:i i n a. yield of 607;. 1962.
e
e
Acknowledgment. -\?.'e are indebted to Dr. G. Rosenkranz, Syntex, S.A., Mexico, for a generous supply of kryptogenin. (9) ( a ) Considered p r e v i o t d y to he I V a ; ( h ) awt,atr of [ \ ' a : ( c ) considcwd ilreviously to be I V b ; ((1) wrtate of I V b ,
(2) hl. 0. b'orster and h l . F. Barker, ,I. Chem,. S o r . , 103, 1918 (1913). (3) G. Englert, Z. anal. Chem., 181, 447 (1961); F. B. Mallory and C. S. Wood, Proc. Natl. Acad. Sci., 47, 697 (1961); G. Englert. 2. Naturlowch, 16b, 413 (1961); A. R. -Katritaky, S. Pksne, and R. K. Harris, Chem Ind. (London), 990 (1961). (4) P. Diehl, H. A. Christ, a n d F. B. Mallory, Helu. Chim. Acta, 46, 504 (1962). (5) D. Britton and W. E. Noland, Chem. Ind. (London), 583 (1962). (6) r). L. Hammick, W. A . If. Edwards, and E. R . Steiner, J. Chem. Sur., :3308 ( 1 9 3 1 ) .
