1980 943 Synchronous Skeletal Rearrangement of D-Nor-Sa-androstane-l6a- and -16p-carbonyl m-Chlorobenzoyl Peroxides By Hiroshi Suginome and Tsutomu Uchida, Department of Chemistry, Faculty of Science, Hokkaido Univer- sity, Sapporo 060, Japan The reaction of D-nor-5a-androstan-l6~-carbonylchloride, a steroidal cyclobutanecarbonyl chloride, with m-chloroperbenzoic acid leads via rearrangement to a C-homo-D-bisnor-steroid. In contrast, the 16ct-isomer with m-chloroperbenzoic acid afforded the corresponding stable acyl aroyl peroxide which underwent competitively a carboxy-inversion reaction and the migration of the 13P-methyl group upon reflux in benzene. MIXED peroxides (3) derived from a reaction of acid chloride (1) with m-chloroperbenzoic acid (2), rearrange to the mixed carbonates (4) which further decompose to alkyl m-chlorobenzoates (5)lv2 (Scheme 1).The reaction 0 It RCOC 1 + C-OOH (1) R = alkyl 0 0 of the product (10) which exhibited two signals due to sp2 carbons at 8 111.2 and 151.3 p.p.m. confirmed this. These signals were assignable to a carbon bearing two protons and a tertiary carbon in the terminal methylene -II __II) R-0-C-0-C (4) Il-4 -co2 +CICI (5) SCHEME1 was examined for a number of acids and the generality of the transformation of an acid into an alcohol with the loss of one carbon atom was rep0rted.l The carboxy- inversion reaction of acyl peroxides is catalysed by proton 3 and Lewis acids and proceeds faster in polar solvent^.^ The rearrangement was shown to be stereo- ~pecific.~l80 Labelling experiments were also carried out in order to clarify the inversion step.In the course of an investigation of the photoreaction of a steroidal cyclobutanol derivative,' we treated D-nor-5a-androstane-16p-carbonylchloride (7), m.p. 232- 233", prepared by the reaction of the corresponding acid (6)with thionyl chloride, with m-chloroperbenzoic acid (MCPBA) in hydrocarbon solvents with the purpose of preparing u-nor-5a-androstan- 16p-01 (9). The product (lo),obtained virtually as a sole product, was found not to be the expected 16p-01 m-chloroper- benzoate (8). The product, purified by preparative t.l.c., resisted all attempts at crystallization. The molecular formula C,,H,, was determined by high- resolution mass spectrometry.The i.r. spectrum showed no hydroxy-band and exhibited bands at 1 640 and 895 cm-1 due to a terminal methylene group. The n.m.r. spectrum exhibited three cyclopropyl protons as a multiplet at T 9.20-9.52 and one cyclopropyl proton as a double doublet at 7 9.77 (J 9 and 5 Hz). It also showed a three-proton singlet at T 9.32 and two-proton broad singlet at T 5.22 ascribable to 19-H3 and the terminal methylene protons. The 13C n.m.r. spectrum group by the aid of an off-resonance decoupled spectrum. The c-homo-D-bisnor-steroid (lo), which is analogous to the product from the thermal decomposition of D-nor- steroid-1 6a-N-nitrosoace tamide,8 is fully consistent with these spectral properties.In contrast with the 16p-isomer (7), the reaction of CH, (6)R = OH (7)R = CL (8) R = rn-chloroperbenzoyl (9)R = H SCHEME2 the acid chloride (12), derived from the D-nOr-amp;-androst ane- 16a-carboxylic acid, with m-chloroperbenzoic acid led to a stable acyl aroyl peroxide (13),m.p. 101-103". No accompanying rearranged products, i.e. the corresponding mixed carbonate, m-chlorobenzoate, or c-homo-D-bisnor-steroid (lo),were found in this reaction as indicated by t.1.c. The acyl peroxide (13) was hydrolysed to the lS~-carboxylic acid (11) with methanolic sodium hydroxide and was transformed into a mixture of products when the benzene solution was J.C.S. Perkin I collapse of the doublet into a singlet. All these spectral results can be accommodated in structure (14), i.e.16p-methyl-18-nor-~-nor-5~-androst-12-ene. D-Nor-h-androstan-l6a-01 (15),resulting from a normal carboxy- inversion reaction, was also obtained in 44 yield as the least mobile compound in this thermal decomposition. SCHEME3 refluxed for 13.5 h. Separation by t.1.c. afforded a clear oil (14) (26) as the most mobile compound, the mole- cular formula of which was determined as C,,H,, by high- resolution mass spectrometry. The electron-impact mass spectrum of (14) exhibited an intense molecular- ion peak at m/c 244 (52.1o/b),an intense Mf -CH, peak at m/e 229 (44.2), and the base peak at m/e 134. The i.r. spectrum exhibited a medium absorption at 1716 It is apparent that the rearranged products (10) and (14) are formed before inversion to the mixed carbonates type (a) since stable 3p-methoxy-~-nor-5a-androstan-16p-01 toluene-P-sulphonate can be prepared.* Thus, it is believed that the observed rearrangements from (7) to (10) and (11) to (14) occur directly from acyl aroyl peroxides e.p.(13). Since ~-nor-5a-androstane-l6@-carboxylic acid and its 16a-isomer respectively give SCHEME4 cm-l, assignable to an exocyclic double bond attachcd to a strained ring9 and a strong absorption at 806 and 828 cm-l, assignable to a trisubstituted double bond. The n.1n.r. spectrum showed the presence of a singlet attributable to 19-H, at T 9.26, a three proton doublet at T 8.95 (J 6.6 Hz), and a one proton broad singlet at T 4.83 (W4 18 Iamp;) due to an olefinic proton.In double- resonance experiments, irradiation at T 7.06 causecl a. different rearranged products (10) and (14), the inter- vention of a common C-16 carbonium ion in both re- actions is excluded, and the two rearrangements, the pathways of which are depicted in Scheme 4,are one- step processes. It is believed that the geometry of the conformationally rigid cyclobut ane ring of the transition states in these rearrangements would permit the C(13)-C(14) or C(13)-C(18) bond to migrate immediately to fill the developing $-orbital at the C(l6) as was observed by Meinwald and his colleaguesS for the re- arrangements of 3p-methoxy-~-norandrostan-l6p-arid -16a-ylamine, their derivatives, and the l6p-toluene-p- sulyhonate.* It is of interest to note that in the case of the 16~- isomer, migration of the 13p-methyl group can compete with the carboxy-inversion reaction which leads directly to alcohol (15).This indicates that the geometry of the C(13)-C( 18) bond for methyl migration in peroxide (13)is not as suitable as that for skeletal rearrangement of the 16p-isomer. It is also noteworthy that the carboxy-inversion reaction of the peroxide (13)resulted in a product with retention of the original configuration at the C(16) as found in the reaction of other peroxide^.??^ The present results may bear significance for fuller understanding of the nature of the carboxy-inversion reaction. EXPERIMENTAL Instruments and general procedures are described in ref.10. The mass spectra of compounds (7), (lo), and (12) were taken with a Hitachi RMU-6E spectrometer (source temperature 200deg;, ionizing voltage 80 eV) in the Faculty of Pharmaceutical Sciences of this University and the mass spectrum of compound (14) was taken with a Hitachi JMS-I) 300 spectrometer (ionizing voltage 70 eV) in the Faculty of Agriculture of this University. The high-resolution mass spectra of the olefins (10) and (14) were measured with a Hitachi IiMU 7MF double-focusing mass spectrometer (direct inlet system; ionizing voltage 70 eV) in the Coal Research Institute, Faculty of Engineering, Hokkaido University. 13CN.m.r. spectra were taken with a JEOL JNM-FX 100 spectrometer (25 MHz; CDCl,; Me,Si as internal reference) in the Faculty of Pharmaceutical Sciences of this University.Rotations were measured with a JASCO DIP-SL automatic polarimeter. n-Nor-5a-androstane- 16p-carbonyl Chloride (7).-The carb-oxylic acid (6) (185 mg) in thionyl chloride (2 ml) was set aside for 3 h at 0". After removal of thionyl chloride with added benzene, the residue (203 mg) was recrystallized froin hexane to afford the acid chloride (7) (57 mg), m.p. 232--233" (Found: C. 73.4; H, 9.55; C1, 10.4. C,,H,,C10 requires C, 73.9; H, 9.4; C1, 11.5); vnYdx.1798 (COCl), 1 007, 1 061, 1046, 1028, 770, and 715 cm-l; nz/e 308 (Jf', 3.5), 2R3 (8.2), 273 (Ci.5), 272 (8.8), 257 (10.0), 218 (80), 217 (IOO), 203 (36), 175 (47), 148 (48), 135 (25), 121 (26), lo!) (72), 108 (50),95 (45), 93 (30), 91 (el), 81 (45), 67 (41), 55 (48), and 36 (78); T 8.89 (3 H, s, 18-H:J, !1,17 (3 H, s, 19-H3), and 6.85 (1 H, dd, J 6.0and 7.2 Hz, 1Sa-H).Heactioia of the Acid Chloride (7) with m-Chloroperbenzoic Acid.-'l'o the acid chloride (7) (93 mg) and m-chloro- perbenzoic acid (103 nig) in hexane (1 ml) was added pyridine (0.1 ml) in cyclohexane (0.4 ml) at 0". The solution was set aside for 35 min. The solution was washed with 50,b Na,S,O,, 2~-hydrochloric acid, and water, and then dried over Na,SO,. After removal of the solvent, the residue was subjected to preparative t.1.c. bsol;vith hexane to remove a small amount of polar material. The more mobile major portion (50 mg) was the olefin (10) as a gum (Found: m/e, 244.2215.C,,H,, requires M, 244.2189); aID24 +34.4" (c 0.3 CHC1,); vmex. (neat) 1640 (C=CH,), 1 447, 1 371, 1028, and 895 cm-l (C=CH,); for n.m.r. spectrum see text; wz/e 244 (Mf, 36), 299 (loo), 216 (14), 215 (la), 201 (49), 187 (16), 175 (19), 161 (26), 133 (43), 119 (55), 109 (41), 107 (38), 105 (36), 95 (50), 93 (53), 91 (52), 81 (53),79 (52), 77 (28), 67 (52), 55 (47), 41 (47), and 28 (57). n-Nor-5a-androstane- 16a-carbonyl Chloride ( 12) .-The 16a-carboxylic acid (1 1) (200 mg) in thionyl chloride ( 1 ml) was set aside for 2 h at 0". After removal of thionyl chloride with added benzene, the residue (172 mg) was re- crystallized from hexane to aford the acid chloride (12) (36mg), m.p. 83-85"(Found: C, 73.95; H, 9.45; Cl, 10.2. C,,H,,ClO requires C, 73.9; H, 9.4; C1, 11.5); v,,,,.1 790 (COCl), 1 033, 1018, 998, 859, 833, 780, and 715 cm-l; m/e 308 (amp;It,4), 293 (8),272 (8), 219 (12), 218 (83), 217 (loo), 203 (8), 202 (45), 189 (81, 175 (39), 163 (O), 162 (17), 161 (18), 149 (21), 148 (39), 147 (13), 135 (18), 122 (16), 121 (191, 108 (43),95 (28), 93 (20), 81 (27), 79 (19), 67 (26), and 55 (27); T 8.73 (3 H, s, 18-H,), 9.20 (3 H, s, 19-H,), and 6.76 (1 H, dd, J 1.5 and 6.0 Hz, 16p-H). Reaction of the 16a-Carbonyl Chloride with m-Chloroper-benzoic Acid.-The 16a-acid chloride (82 ing) and wt-chloro- perbenzoic acid (100 mg) in hexane (1 ml) was stirred at 0". To this solution were added pyridine (0.1 ml) and cyclo- hexane (0.4 nil) and the solution was stirred for a further 0.5 h at 0".The solution was extracted with hexane and benzene and the organic layer was washed with water and dried (Na,SO,). After removal of the solvent, the residue (1 13 mg) was subjected to column chromatography (Wako gel C-200). The column was eluted with benzene to afford the crude acyl aroyl peroxide (13) (88 mg) and then the 16a-acid (1 1) (7 nig). The crude acyl aroyl peroxide (13) was subjected to preparative t.1.c. with 2 : 3 benzene-- hexane (Wako gel B-5F) to afford pure compound (13) (63 mg). This was recrystallized from di-isopropyl ether, m.p. 101-103" (Found: C, 70.6; H, 7.5; C1, 8.1. C,,H,,C10, requires C, 70.25; H, 7.45; C1, 7.9); v,,,. 1796 (CO, attached to four-membered ring), 1 765 (CO, of m-chloroperbenzoyl), 1 590 (aromatic C=C), 1 229 (C-0), 1 048, 860, and 732 cm-l; m/e 400 (.W+-CO,, O.lyo),358 (0.4), 296 (l.l),294 (1.6), 218 (11), 148 (18), 139 (ClC,H,CO,+, loo), 109 (35), 95 (lo), 93 (ll),91 (ti), 81 (13), 67 (13), 55 (13), 44 (23),and 41 (11); z 8.82 (3 H, s, 18-H,), 9.21 (3 H, s, 19-H,), 7.29 (1 H, dd, J 1 and 5 Hz, 16P-H), and 6.32 (3 H, s, CO,CH,).Hydvolysis of Peroxide ( 13) .-Peroxide ( 13) ( 17 mg) was dissolved in inethanol (2 nil), diethyl ether (0.5 ml), and water (0.5 nil) containing sodium hydroxide (128 nig). The solution was stirred for 1.5 h at room temperature and was refluxed for 2 11. The solution was worked up in the usual manner. The residue was subjected to preparative t.1.c. with 3 : 2 benzene-diethyl ether (Walio gel B-5F) to afford the lba-carboxylic acid (1 1) (6 mg),identical with an authentic specimen.Tlaerinal Decomposition of Peroxide (13) in Benzene.- Acyl aroyl peroxide (13) (23 mg) in dry benzene (3 ml) was refluxed for 13.5 h. After removal of the solvent, the residue was subjected to preparative t.1.c. (Wako gel B-5F) with 3 : 2 hexane-benzene to afford three fractions. The most mobile fraction (6 mg) was the oily hydrocarbon (14). This fraction was again purified by preparative t.1.c. (Whatman KC-18) with 9 : 1 methanol-water to afford an oil (3 mg) (Found: m/e, 244.2186. C,,H,, requires M, 244.2189); w/e 244 (M+,52.1), 229 (M+-CH,, 44.2), 149 (43.8), 148 (34.2), 134 (loo), 119 (51.1), 109 (63.0), 105 (48.4), 95 (43.7), 93 (54.3), 91 (61.5), 81 (63.1), 79 (46.0), ti7 (50.7), 55 (50.4), and 41 (45.1); OL~~*+3.8* (c 0.4 CHCl,).The second mobile fraction (8 mg) was a mixture of three unidentified minor compounds. The least mobile fraction (11 mg) was again purified by preparative t.1.c. (Wako gel B-5F) with 1 : 1 benzene-diethyl ether to afford ~-nor-5a-androstan-16a-01 (15) (6 mg). We thank Miss H. Maki for the measurements of n.m.r. spectra and spin decoupling. We also thank Mr. T. Kato, Coal Research Institute, Faculty of Engineering, for the measurements of high-resolution mass spectra, the staff in the Faculty of Pharmaceutical Sciences for mass and 13C n.m.r. spectra, and elemental analyses, and the staff in the Faculty of Agriculture for mass spectra.9/664 Received, 30th April, 19791 J.C.S. Perkin I REFERENCES 1 D. B. Denney and N. Sherman, J. Org. Chem., 1965, 30, 3760 and papers cited therein. 2 For review see R. Hiatt, ' Organic Peroxides,' ed. D. Swern, Wiley, New York, 1971, vol. 2, p, 799. 3 J. E. Leffler, J. Amer. Chem. SOC.,1950, 72, 67; J. E. Leffler and C. C. Petropoulos, ibid., 1957, 79, 3068. 4 D. 2. Denney, T. M. Valega, and D. B. Denny, J. Amer. Chem. SOC.,1964, 86, 46. H. H..Lau and H. Hart, J. Amer. Chem. SOC.,1959, 81, 4897; F. D. Greene, H. P. Stein, C. C. Chu, and F. M. Vane, ibid., 1964, 86, 2080; C. Walling, H. N. Moulden, J. H. Waters, and R. C. Neuman, ibid., 1965, 87, 518. D. B. Denney and D. G. Denney, J. Amer. Chem. SOC.,1957, 79, 4806. 7 H. Suginome and T. Uchida, J.C.S. Chem. Comm., 1979, 702. 8 J. Meinwald and T. N. Wheeler, J.Amer. Chem. SOC.,1970, 92, 1009. N. B. Colthup, J. Chem. Educ., 1961, 38, 394. lo H. Suginome, N. Yonekura, and T. Masamune, Bull. Chem. Soc. Japan, 1980, 53, 210.
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