Steroids and related studies. Part XXXV. Further studies on the schmidt reaction with cholest-4-ene-3,6-dione

摘要

1210 J.C.S. Perkin ISteroids and Related Studies. Part XXXV? Further Studies on theSchmidt Reaction with Cholest-4-ene-3,6-dioneBy Harkishan Singh,rsquo; Kamlesh K. Bhutani, and Layak R . Gupta, Department of PharmaceuticalSciences, Panjab University, Chandigarh 16001 4, IndiaTreatment of cholest-4-ene-3,6-dione (1 ) with an excess of hydrazoic acid-boron trifluoride in chloroform yields3-aza-~-homocholest-4a-eno3,4-dtetrazol-6-one (2). 3,6-diaza-~~-bishomocholest-4a-eno 3,4-d 6,7-d bis-tetrazole (7). and 3-aza-~-homocholest-4a-ene-4,6-dione (1 1 ). The bistetrazole (7) was obtainable from themonotetrazole (2).TREATMENT of chole~t-4-ene-3~6-dione (1) with anequimolar quantity of sodium azide in polyphosphoricReaction with an excess of hydrazoic acid in thepresence of boron trifluoride in chloroform gave acomplex mixture, separated by column chromatographyon alumina into products (A), C,,H,,N,O (33.4y0), (B),For the product (A) evidently a monotetrazole,A,, 260 nm, v,, 1695 (GO) and 1626 cm-l (C=C),structures (2)-(5) were considered.The methylenefunctions in the tetrazole (6) 3 are reported to exhibit then.m.r. multiplets as indicated. The spectrum ofproduct (A) exhibited a broad two-proton multiplet at6 4.65, which in the light of our previous studies 4,5 favoursstructures (2) and (5). During our earlier work,5 it wasnoted that in steroidal 3-aza-~-homo-Pa-eno3,4-d-tetrazoles the vinylic 4a-proton signal at 6 6.50 wascharacteristically ca. 0.75 p.p.m. downfield of the signalof a vinylic 4-proton (6 5.75) in 4-en-3-ones.Theproduct (A) showed a vinylic proton signal at 6 7.20,C2,H4amp; (5) , and (C), C27H43N02 (5.6) -(6)acid has been reported to yield the lactams 4-aza-~-homocholest4a-ene-3,6-dione and S-aza-~-homo-~holest4a-ene4~6-dione ; 4,6-diaza-~~-bishomocholest-4a-ene-3,7-dione was obtained by use of 2 mol. equiv.of sodium azide.2 This paper describes the productsisolated when the Schmidt reaction of the enedione (1)was carried out with an excess of hydrazoic acid.1 Part XXXIV, H. Singh, R. K. Malhotra, A. S. Chawla, andN. K. Luhadiya, Indian J . Chem., in the press.H. Singh, S. Padmanabhan, A. K. Bose, and I. Kugajevsky,J.C.S. Perkin I, 1972, 993.downfield by 1.03 p.p.m. from the signal at 6 6.17 inthe spectrum of compound (1).This supports theG. DiMaio and V. Permutti, Tetrahedron, 1966, 22, 2059.H. Singh, R. B. Mathur, and P. P. Sharma, J.C.S. Pevkizin I,H. Singh, R. K. Malhotra, and N. K. Luhadiya, J.C.S.1972, 990.Perkin I, 1974, 14801976 1211assignment of structure (2). Structure (5) may also beexcluded in view of the greater reactivity of the 3-carbonyl g r ~ u p . ~ , ~For the product (B), apparently a bistetrazole, A,,246 nm, v,= 1 681 cm-l (C=C), structures (7)-(10) wereconsidered. Two-proton n.m.r. multiplets at 6 4.85and 3.43 could be assigned to the methylene groups in(7) or (lo), excluding structures (8) and (9). Treatmentof the monotetrazole (2) with hydrazoic acid-borontrifluoride in chloroform gave a mixture from which thebistetrazole (7) was obtained in 10 yield.However,when this reaction was carried out in benzene solution?the bistetrazole (7) was isolated in 73 yield. Theproduct (B) therefore has structure (7).onthe basis of spectral comparison. However, the m.p.was higher than that reported.2The monolactam (C) was assigned structure (11)EXPERIMENTALOptical rotations were measured for solutions in chloro-form. 1.r. spectra were obtained for potassium bromidediscs. N.m.r. spectra (60 MHz) were recorded for solutionsin deuteriochloroform containing tetramethylsilane asinternal reference. T.1.c. was carried out on silica gel G(Merck); plates were developed by exposure to iodinevapour. Anhydrous sodium sulphate was employed asdrying agent.Schmidt Reaction with Cholest-4-ene-3,6-dione (1) .-Asolution of compound (1) (5.0 g) in dry chloroform (200 ml)was added to a mixture of boron trifluoride-ether com-plex (5 ml) and hydrazoic acid solution in chloroform(300 nil) 4 during 4 h at 0 "C.The mixture waskept at 23-25 OC for 20 h, then washed successivelywith aqueous sodium hydrogen carbonate (10)and water. The chloroform layer was dried andevaporated, and the brown residue (4.32 g), which gavefive spots on t.1.c. (chloroform-methanol, 32 : 1) waschromatographed on a column of alumina (250 g) in drybenzene. Elution with benzene-chloroform (9 : 1; 23 x100 ml) yielded a solid residue (2.04 g), which afforded3-aza-~-honzocholest-4a-eno3,4-dtetrazol-6-one (2) (1.5 g,33.4), m.p.220-222" (from methanol), -42.5"(c 0.30), amp;.(MeOH) 260 nm (log E 4.16), vmx. 2 941,1 695, 1 626, 1 527, 1460, 1418, and 1 389 cm-l, 6 0.75(3 H, s ) , 1.15 (3 H, s), 4.65 (2 H, m), and 7.20 (1 H, s)(Found: C, 73.85; H, 9.55; N, 12.4. C27H42N40 requiresC, 73.9; H, 9.65; N, 12.75).Further elution with the same solvent (13 x 100 ml)yielded a solid residue (0.3 g), which afforded 3,6-diaza-~~-bishounocholest-4a-eno3,4-d 6,7-dbistetrazole (6) (0.25 g,5), m.p. 206-210" (from ethanol), aD25 -11.9" (c 0.37),LJEtOH) 246 nm (log E 4.29), V- 2 933, 1681, 1538,1471, 1435, and 1 377 cm-1, 6 0.74 (3 H, s), 0.92 (3 H, s ) ,3.43 (2 H, m), 4.85 (2 H, m), and 7.10 (1 H, s) (Found: C,68.05; H, 8.95; N, 23.2. C,,H,,N, requires C, 67.75; H,8.85; N, 23.4).Elution with solvents of increasing polarity was carriedout; fractions (8 x 100 ml) obtained with benzene-chloroform (1 : 1) yielded a solid (0.31 g), which afforded3-aza-~-homocholest-4a-ene-4,6-dione (1 1) (0.27 g, 5.6),m.p.213-215" (from methanol) (lit.,2 200-204"), aJD25-124" (c 0.15), amp;,.(MeOH) 234 nm (log E 4.20), vmax.3 125, 2 933, 1695, 1667, 1639, and 1608 cm-l, 8 0.71(3 H, s), 1.04 (3 H, s), 3.25 (2 H, m), 5.98 (1 H, d, J 1.5 Hz,collapsing to s on deuterium exchange), and 7.34 (1 H, m,disappearing on deuterium exchange) (Found : C, 77.9;H, 10.7; N, 3.45. Calc. for C,,H,,NO,: C, 78.4; H, 10.5;3,6-Diaza-~~-bishomocholest-4a-eno3,4-d 6,7-d bistetvu-zole (6) from the Monotetrazole (2).-(u) A solution ofcompound (2) (1.0 g) in dry chloroform (20 ml) was addedt o a mixture of boron trifluoride-ether complex (1 ml) andhydrazoic acid solution in chloroform (30 nil) during 4 hat 0 "C.The mixture was kept a t 25-28 "C for 24 h,then washed successively with aqueous sodium hydrogencarbonate (10) and water. The chloroform layer wasdried and evaporated; the residue (0.65 g), which showedsix spots on t.1.c. (chloroform-methanol, 3 : l ) , was partiallyseparated on a column of alumina (22 g) in benzene to givea two-component mixture (0.3 g) . Further chroniato-graphy of this on an alumina column (25 g) in benzeneelution with benzene (8 x 100 ml) gave a solid which oncrystallisation from methanol afforded the product (6)(0.1 g, lo), m.p. 209-210".(b) Compound (2) (0.1 g) in benzene (5 ml) was added toa mixture of boron trifluoride-ether complex (1 ml) andhydrazoic acid solution in benzene (15 ml).* The mixturewas heated at 40 f 5 "C for 15 h. Crushed ice was addedand the mixture was washed successively with aqueoussodium hydroxide (5) and water. The benzene layer wasdried and evaporated; the residue (0.1 g) was crystallisedfrom methanol to afford the product (6) (0.08 g, 73), m.p.N, 3.4).208-208".We thank Professor W. B. Whalley, University ofLondon, for many of the spectra and elemental analyses.Research fellowships from the Panjab University (toK. K. B.) and the University Grants Commission (toL. R. G.) are gratefully acknowledged.5/2186 Received, 10th November, 197516 J. DCcombe, R. Jacquemain, and J. Rabinovitch, Bull. SOC. L. F. Fieser, J . Amer. Chem. Soc., 1954, 76, 1945.chirn. France, 1948, 447. 8 R. Mechoulam, Israel J . Chem., 1968, 6, 909