Reactivity of Some Unsaturated 17-Oxo Steroids under Conditions of Diimide Reduction{ Ljubinka Lorenc,a Lidija Bondarenko-Gheorghiub and Mihailo Lj. Mihailovic � *a aFaculty of Chemistry, University of Belgrade, Studentski trg12^16, P.O. Box158,YU-11001, Belgrade, Yugoslavia bCenter for Chemistry, ICTM, P.O. Box 815,YU-11001, Belgrade,Yugoslavia The olefinic double bond in 17-oxo steroids 1, 5 and 7 is either reduced with diimide very slowly (compound 1) or it cannot be reduced at all (compounds 5 and 7), thus enabling hydrazine (accumulated by disproportionation of the diimide) to react with their respective17-oxo groups to give hydrazones 3, 6 and 8.It is known that the diimide reduction of a carbon±carbon multiple bond can be selectively carried out in the presence of a variety of reactive functional groups,1 including allylic halides,2,3 ethers,2 amines,2 disul®des,4 unsaturated ketones,2,5 peroxides6,7 and some other functions.1 A limi- tation of the use of diimide as a reducing agent is the com- petition between hydrogenation of the carbon±carbon multiple bond and disproportionation,1,8 i.e., hydrogenation of the diimide nitrogen±nitrogen double bond by another diimide molecule to form nitrogen and hydrazine (Scheme 1). Which of these processes will prevail depends on the relative rate at which diimide reacts with the unsaturated substrate.If the rate of reduction is su�ciently slower than the rate of disproportionation of diimide, the latter reaction will dominate and no reduction will be accomplished.For these particular cases it was anticipated1 that if the substrate contains any other functional group capable of reacting with hydrazine, reaction at that function with hydrazine formed by diimide disproportionation would occur. In this paper we report on the diimide reactions of some unsaturated 17-oxo steroids, i.e., 17-oxo-5,8a-epidioxy-5a- androst-6-en-3b-yl acetate (1), 17-oxoandrost-5-en-3b-yl acetate (5) and 17-oxo-7-norandrost-5-en-3b-yl acetate (7) (Schemes 2 and 3), which illustrate the reactivity of such substrates.When the 17-oxo epidioxide 1 was treated with an excess of diimide, generated in situ from dipotassium azodicarboxy- late and acetic acid (for details see Experimental section), it gave, after column chromatography on SiO2 (Scheme 2), the expected saturated 17-oxo epidioxide 2 in only 16% yield, the major reaction product being a Z±E mixture of the cor- responding hydrazone 3 (isolated in 58% yield).The 17-oxo compound 2 was identi®ed by comparison with an authentic sample,7 while the structure 3 was deduced as follows. In product 3 the original ole®nic D6-double bond (1H NMR: AB quartet centred at d 6.42) and the ®ve-membered-ring 17-oxo group (IR: absorption at 1748 cm¡1) were missing, indicating that both these functions had participated in the diimide reaction. In accordance with the proposed structure, the IR spectrum of 3 contained new absorptions at 3450 and 1661 cm¡1 assignable to the hydrazone NH2 group and C1N bond, respectively, while its 1H NMR spectrum, con- taining parts of two singlets for the CH3-18 group (at d 0.92 and 0.98), indicated that this product consisted of the Z and E stereoisomers. In an attempt to purify the hydrazone 3 by recrystal- lization from an acetone±methanol mixture, it was spontaneously transformed to the corresponding isopropyli- denehydrazono derivative 4.This compound was obtained in only one, Z or E, stereoisomeric form, and its identi®- cation based on elemental microanalysis (C24H36N2O4) and spectral characteristics (see Experimental section) con®rmed the hydrazone structure 3. On the other hand, when the D5-unsaturated androstene and B-norandrostene derivatives 5 and 7, respectively, were subjected to the diimide reaction as above, they gave (Scheme 3) the D5-unsaturated hydrazones 6 and 8, respect- ively, in quantitative yield.Signals for the ole®nic HC(6) protons in the 1H NMR spectra of 6 and 8 (at d 5.39 for the former and at d 5.44 for the latter compound) clearly indicated that the D5-double bond in both substrates remained unattacked by the diimide molecule.9 Other spec- tral data were also in full agreement with the structures 6 and 8, respectively. These results have unequivocally con®rmed the validity of the above mentioned assumption. Since the ole®nic double bond in the investigated 17-oxo steroids is either reduced with diimide very slowly (compound 1) or it cannot be reduced at all (compounds 5 and 7), reaction of their J.Chem. Research (S), 1998, 102±103$ Scheme 1 O AcO O O 1 HN NH O AcO O O 2 (~16%) N AcO O O 4 one isomer acetone NNH2 AcO O O Z and E isomer 3 (~58%) N C Me Me •• •• + Scheme 2 $This is a Short Paper as de®ned in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J.Chem. Research (M). *To receive any correspondence. 102 J. CHEM. RESEARCH (S), 1998respective 17-oxo groups with hydrazine (accumulated by diimide disproportionation) is the main process. Experimental Mps are uncorrected. IR spectra were recorded on a Perkin- Elmer 337 spectrometer and NMR spectra on a Varian Gemini 2000 spectrometer (1H at 200 MHz, 13C at 50MHz) in CDCl3 solution at room temperature, using SiMe4 as internal standard (d in ppm, J in Hz).Mass spectra were measured on a Finnigan- MAT 8230 spectrometer at 70 eV. Column chromatography was carried out on silica gel 0.063¡¾0.200mm. TLC (control of reactions and separation of products) was performed on silica gel G (Stahl) (detection with 50% aqueous H2SO4). 17-Oxo-5,8 -epidioxy-5 -androst-6-en-3 -yl Acetate (1)11.�¢Mp 239¡¾240 8C (from acetone¡¾methanol); [ ]D=+ 66.0 (c, 0.50 in CHCl3); max/cm¢§1 (KBr) 1748, 1735, 1248; H 0.93 (3 H, s, H-18), 1.00 (3 H, s, H-19), 2.03 (3 H, s, OCOCH3), 5.00 (1 H, m, H-3), 6.32, 6.52 (2 H, AB, J 8.6 Hz, H-6, H-7) (Found: C, 69.75: H, 7.79.C21H28O5 requires C, 69.98; H, 7.83%). Diimide Reduction of 17-Oxo-5,8 -epidioxy-5 -androst-6-en-3 -yl Acetate (1).�¢To a stirred solution of 1 (1.08 g, 3 mmol) in CH2Cl2 (50 ml) and absolute MeOH (70 ml) dipotassium azodicarboxylate (5 g, 13.5 mmol) was added and the suspension cooled in an ice- bath. To this mixture was added dropwise a solution of AcOH (3 ml) in absolute MeOH (30 ml) within ca. 1 h. Stirring was continued at room temperature for an additional 20 h, when the yellow colour disappeared. The mixture was taken up in water (250 ml) and extracted twice with CH2Cl2, the combined organic extract was washed with saturated aq. NaHCO3 solution and water, dried (Na2SO4) and evaporated and the residue (01.2 g) was chromatographed on SiO2 (50 g). Elution with toluene¡¾EtOAc 9:1 and 8:2 a€orded 5,8 -epidioxy-17-oxo-5 -androstan-3 -yl acetate (2) (182 mg, 16.1%), mp (141 8C), IR and 1H NMR identical with those of an authentic sample.7 Toluene¡¾EtOAc 2:8 and EtOAc eluted a mixture of (Z)- and (E)- hydrazone 3 (655 mg, 58.1%): max/cm¢§1 (KBr) 3450, 1733, 1661, 1252; dH 0.92, 0.98 (3 H, parts of two s, H-18 of Z and E isomers), 1.03 (3 H, s, H-19), 2.00 (3 H, s, OCOCH3), 4.81 (1 H, m, H-3).Upon recrystallization from acetone¡¾methanol, hydrazone 3 a€orded 5,8a-epidioxy-17-isopropylidenehydrazono-5a-androstan-3b- yl acetate 4 (384 mg), mp 205 8C; max/cm¢§1 (KBr) 1742, 1670, 1254; dH 0.98 (3 H, s, H-18), 1.04 (3 H, s, H-19), 1.81, 1.99 [6 H, 2 s, N=C(CH3)2],, 2.00 (3 H, s, OCOCH3), 4.82 (1 H, m, H-3); dC 17.3 (q, C-18), 17.5 (q, C-19), 18.0 (q, CH3C=N), 19.3 (t, C-11), 20.9 (t, C-2), 21.0 (q, OCOCH3), 21.5 (t, C-15), 24.7 (q, CH3C=N), 25.7 (t, C-1), 26.4 (t, C-6), 27.9 (t, C-16), 33.5 (t, C-4) 35.4 (t, C-7), 35.5 (s, C-10), 36.0 (t, C-12), 44.8 (s, C-13), 51.7 (s, C-9), 51.9 (d, C-14), 69.4 (d, C-3), 78.5 (s, C-8), 80.4 (s, C-5), 159.3 [s, N=C(CH3)2], 169.7 (s, OCOCH3), 173.2 (s, C-17); m/z 416 (M+) (Found: C, 68.83; H, 8.50; N, 7.11. C24H36N2O4 requires C, 69.20; H, 8.71; N, 7.44%).Diimide Reaction of 17-Oxoandro3 -yl Acetate (5).�¢To a stirred solution of 5 (200 mg, 0.6 mmol) in CH2Cl2 (10 ml) and absolute MeOH (15 ml) dipotassium azodicarboxylate (1.0 g, 2.7 mmol) was added and the suspension cooled in an ice-bath. To this mixture was added dropwise a solution of AcOH (0.6 ml) in MeOH (6 ml) within ca. 30 min and stirring was continued overnight at room temperature.Work-up as above a€orded a crystalline solid (220 mg) which was chromatographed on SiO2 (12 g). Elution with EtOAc gave a mixture of (Z)- and (E)- hydrazones 6 (167 mg, 80.1%), mp 275¡¾276 8C (decomp.); max/ cm¢§1 (KBr) 3344, 1733, 1669, 1250; H 0.87, 0.92 (3 H, parts of two s, H-18 of Z and E isomers), 1.05 (3 H, s, H-19), 2.04 (3 H, s, OCOCH3), 4.61 (1 H, m, H-3), 5.39 (1 H, d, J 5.0 Hz, H-6); C 16.4, 16.6 (q, C-18), 19.2 (q, C-19), 20.5 (t, C-11), 21.3 (q, OCOCH3), 23.2, 23.3 (t, C-15), 24.3 (t, C-2) 27.6 (t, C-7), 31.2 (d, C-8), 31.2 (t, C-12), 33.7, 33.9 (t, C-16), 36.6 (t, C-1), 36.8 (s, C-10), 38.0 (t, C-4), 43.7, 43.9 (s, C-13), 50.2 (d, C-9), 53.5, 53.8 (d, C-14), 73.7 (d, C-3), 122.0 (d, C-6), 139.8 (s, C-5), 170.5 (s, OCOCH3), 165.9 173.6 (s, C-17); m/z 344 (M+).Diimide Reaction of 17-Oxo-7-norandrost-5-en-3 -yl Acetate (7).�¢ A stirred ice-cooled suspension of 7 (200 mg, 0.63 mmol) and potassium azodicarboxylate (1.0 g, 2.7 mmol) in CH2Cl2 (10 ml) and MeOH (15 ml) was treated with a solution of AcOH (0.6 ml) and MeOH (15 ml) as above.The mixture was left overnight at room temperature and worked up as above. The residue (210 mg) was puri¢çed by column chromatography on SiO2 (12 g). Toluene¡¾ EtOAc (6:4 and 1:1) eluted the hydrazone 8 (201 mg, 96.2%), mp 224¡¾225 8C (decomp.); max/cm¢§1 3445, 1733, 1662, 1245; H 0.92 (3 H, s, H-18), 0.93 (3 H, s, H-19), 2.04 (3 H, s, OCOCH3), 4.64 (1 H, m, H-3), 5.44 (1 H, br, s, H-6); C 14.4 (q, C-18), 17.1 (q, C-19), 20.5 (t, C-11), 21.3 (q, OCOCH3), 23.5 (t, C-15), 27.8 (t, C-2), 29.6 (t, C-12), 32.7 (t, C-4), 34.1 (t, C-16), 36.7 (t, C-1), 44.7 (d, C-14), 45.6 (s, C-10), 45.7 (s, C-13), 51.3 (d, C-8), 62.5 (d, C-9), 73.5 (d, C-3), 125.1 (d, C-6), 148.5 (s, C-5), 170.4 (s, OCOCH3), 173.1 (s, C-17); m/z 330 (M+).We thank the Serbian Academy of Sciences and Arts and the Ministry of Sciences and Technology of Serbia for ¢çnan- cial support. Received, 9th September 1997; Accepted, 31st October 1997 Paper E/7/06570A References 1 D. J. Pasto, Reduction of C1C and C2C by Noncatalytic Chemical Methods in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 8, p. 471. 2 E. E. van Tamelen, M. Davis and M. F. Deem, Chem. Commun., 1965, 71. 3 S. Uemura, A. Onoe, H. Okazaki, M. Okano and K. Ichikawa, Bull. Chem. Soc. Jpn., 1976, 49, 1437. 4 E. E. van Tamelen, R. S. Dewey, M. F. Lease and W. H. Pirkle, J. Am. Chem. Soc., 1961, 83, 4302. 5 G. Dauben and C. H. Schallhorn, J. Am. Chem. Soc., 1971, 93, 2254. 6 W. Adam and H. J. Eggelte, J. Org. Chem., 1977, 42, 3987. 7 Lj. Lorenc, L. Bondarenko, V. PavlovicA , H. Fuhrer, G. Rihs, J. Kalvoda and M. Lj. MihailovicA , Helv. Chim. Acta, 1989, 72, 608. 8 R. Tang, M. L. McKee and D. M. Stanbury, J. Am. Chem. Soc., 1995, 117, 8967. 9 A successful diimide reduction of the ole¢çnic double bond in some 5-B-nor-steroids has been recently reported,10 using toluene-p-sulfonyl hydrazide in collidine at 150 8C. 10 A. Kasal, H. Chodounska and W. J. Szczepek, Tetrahedron Lett., 1996, 37, 6221. 11 L. Bondarenko-Gheorghiu, Ph.D. Thesis, University of Belgrade, 1986. Scheme 3 J. CHEM. RESEARCH (S), 1998