J. CHEM. SOC. PERKIN TRANS. I 1985 647 Neighbouring Group Participation in the Allylic Oxidation of a A5-Steroid James R. Hanson * and Paul B. Reese School of Molecular Sciences, University of Sussex, Brighton, Sussex BN 7 9QJ When 3p-acetoxy-A5-steroids are treated with bromine and silver acetate, the product 3p- hydroxy-4b- acetate is formed by intramolecular acetoxy group migration via a 3~,4f3-acetoxyliniumion. The allylic acetoxylation of A5-steroids e.g. (l) by reaction with bromine in chloroform followed by treatment with silver acetate in pyridine at -60 "Cprovides a simple route to some 4P-acetoxy-A5-steroids e.g.(2)I.lThe reaction (see Scheme 1) is @0bsol;+C -0 0 /1 Me IMe HO@0 ii1 0 /0 =c 'Me Scheme 2. RO 0 0 (2) R =Ac (3) R =EtCO Scheme 1.Reagents: i, Br,; ii, AgOAc, pyridine limited to a certain extent by the nature of the 3P-s~bstituent.~ In the course of our studies on the scope and limitations of this reaction we observed that 3P-acetoxyandrost-5-en-17-one(5) gave the 4~-acetoxy-3P-hydroxy-A5-steroid(2) rather than the 3PPP-diacetate (4). The 'H n.m.r. spectrum of this compound showed the 3a-H resonance as a multiplet (63.65; w+ 20Hz) and the 4a-H resonance as a lower field doublet (6 5.4; J 4Hz). This contrasts with the isomeric 3P-acetoxy-4P-hydroxyandrost-5-en-17-one in which the 3a-H resonance was a multiplet (6 4.65; wi 14 Hz) whilst the 4a-H resonance appeared at 6 4.2as a doublet (J4 Hz). In the 3PPP-diacetate these signals appear at 6 4.73 and 5.53 re~pectively.~ An interpretation of this result (see Scheme 2) is that the 3P-acetate is participating in the syn allylic displacement of the 6P-bromide intermediate in the reaction with the formation of a 3P,4P-acetoxylinium ion which then undergoes hydrolysis.In this paper we present some evidence to support this reaction ~cheme.~ The reaction (see Scheme 1) proceeds by the addition of bromine followed by the stepwise elimination and allylic substitution of the 5a-and 6P-bromine atoms. Treatment of both 3~-acetoxy-5~,6~-dibromoandrostan-l7-one(9) and 3p- acetoxy-6P-bromoandrost-4-en-17-one (11) (obtained by dehydration in situ of the corresponding 5a-hydroxy-6P-bromo steroid with thionyl chloride) with silver acetate in pyridine gave the known 4~-acetoxy-3~-hydroxyandrost-5-en-17-one(2).' The rearrangement of the 3P-ester was independent of the anion since treatment of the 3P-propionate (6)with bromine followed by silver acetate gave the 3P-hydroxy-4P-propionate (3) rather Ac 0 (5) R = AC (41 (6) R= EtCO (7) R = Me14C0 (8) R = EtOCO than the 4P-acetate (2).The authentic 4P-propionate (3) was obtained from the reaction of the Sa,6P-dibromide (10)of the 3p- alcohol, dehydroisoandrosterone, with silver propionate. Indeed, when silver oxide was used in place of the silver acetate, the 3P-acetate (5) still gave the 4P-acetoxy-3p-hydroxy steroid (2) although in lower yield. The confirmation that an intramolecular acyl migration to C-4 had occurred was obtained when l'-'4C-3-acetoxyandrost-5-en-17-one (7) (specific activity, 11.4 kBq mmol-') was used as the substrate.The resultant 4P-acetoxy-3P-hydroxyandrost-5-en-17-one (2)had a specific activity of 10.3 kBq mmol-' having retained 89 of the radioactivity of the initial acetate (7). The intermediate acyloxonium ion was trapped by using 3P-ethoxy- carbonylandrost-5-en- 17-one (8) as a substrate. The product from this reaction was the cyclic 30,4P-carbonate (12)which was identified by its i.r. (vmax.1 780 cm-') and 3C n.m.r. (6, 155.0, O,C=O) spectra. The overall stereochemistry of the reaction followed from the fate of a 4P-deuterium label. 4P,17a-2H2-3P,17P-Diacetoxy-androst-5-ene (13) was prepared by an adaption of a known 0 0 Br (9) R= AC (10) R = H 0 (12 1 procedure 5,6 involving the reduction of 3P-acetoxy-6P-chloro- androst-4-en- 17-one (14) with lithium aluminium deuteride and subsequent acetylation of the product. The 'H n.m.r.spectrum of the diacetate showed signals at S(2H) 2.29 (4P-2H) and 4.59 (1 7a-'H). The deuterium-labelled steroid was treated with bromine and subsequently silver acetate in pyridine. The 'H n.m.r. spectrum of the resultant 4P,17P-diacetoxy-3P-hydroxy-androst-Sene (15) showed only one signal at 6 4.58 which was attributed to the 17a-'H. There was no signal at 6 5.37 which could be assigned to the 4a-'H. This 4a-H signal remained in the 'H n.m.r. spectrum of the product. Hence the 4P-acetate has replaced a 4P-deuterium label and the reaction has proceeded with an overall retention of configuration.The reaction sequence can therefore be formulated as the addition of bromine to the A5-double bond, the trans elimination of the 4P-proton and the 5a-bromine atom, followed by a syn intramolecular silver ion assisted substitution of the 6P-bromine atom by the 3P-acetoxy group to form a 3P,4P-acetoxylinium ion. This then collapses to afford the 4P- acetoxy-3P-hydroxy steroid. The intervention of a 3P,4P-acetoxylinium ion has been invoked in a number of previous studies including the allylic displacement of a A4-6-chloride,5 the opening of a 3P-acetoxy-4~,5a-epoxide,' and the addition of hypobromous acid to a 3P,17P-diacetoxyoe~tr-4-ene.~An interesting feature of each of these rearrangements is that the intermediate 3P,4P-acetoxylinium ion opens to give the less stable 4P-axial acetate, a feature which has recently been rationalized in terms of stereoelectronic effects.' Experimental Acetoxylation of 3~-Acetoxyandrost-5-en-17-one(5).-3p-Acetoxyandrost-5-en- 17-one (4 g) in chloroform (30 ml) was cooled to -60 "C.Bromine (0.7 ml) was added with swirling followed by silver acetate (6 g) in pyridine (9 ml). The reaction mixture was stirred and allowed to attain room temperature in the dark during 24 h. The mixture was poured into dilute hydrochloric acid and the steroids were extracted into chloroform. The extract was washed with water and aqueous sodium hydrogen carbonate and dried.The solvent was evaporated and the residual gum was chromatographed on silica. Elution with 25 ethyl acetate-light petroleum gave 4~-acetoxy-3~-hydroxyandrost-5-en-l7-one(2) (2.5 g) which crystallized from acetone as needles, m.p. 198.5-200 "C, .ID-62"(c 0.3 in CHCl,)(lit.,' m.p. 192-193 "C, .ID -60.7"). J. CHEM. SOC. PERKIN TRANS. I 1985 0 H R'0 CI (13) R' = Ac, R2= 2H (14) (15) R'= H, R2 = OAC The product was identified by its i.r. and n.m.r. spectra. Under similar conditions 3~-acetoxy-5a,6~-dibromoandrostan-1~-one (500 mg) gave 4P-acetoxy-3P-hydroxyandrost-5-en-17-one (200 mg). Preparation yf 3P-A ce foxy-6P-bromo-5a-hydroxyandrostan-17-one.-.4 solution of 3~-acetoxy-5a,6a-epoxyandrostan-17-one (1 g) in chloroform (10 ml) was treated with an ice-cold solution of lithium bromide (1 g) in water (1 ml) and 48 hydrobromic acid (1 ml) for 12 h.Chloroform was added and the organic layer was separated, and washed with water and aqueous sodium hydrogen carbonate. The solvent was evaporated to afford 3P-acetoxy-6P-bromo-5a-hydroxy-undrostan-17-one (1.1 g) which crystallized from acetone as small prisms, m.p. 180-183 "C, .ID -14.3" (Found: C, 60.5; H, 7.5. C,,H,,BrO, requires C, 59.0; H, 7.3); vmaX,3 540, 1 740, and 1 730 cm-'; S 0.90 (3H, s, 18-H), 1.36 (3 H, s, 19-H), 2.03 (3 H, s, OAc), 4.0 (1 H, m, w3 4 Hz, 6-H), and 5.08 (1 H, m, w+ 30 Hz, 3- H). Dehydration of 3~-Acetoxy-6~-bromo-5a-hydroxyandrostun-17-one and the Reaction with Pyridine and Silver Acetate.-The bromo steroid (1 g) in dry pyridine (15 ml) was treated with thionyl chloride (0.5 ml) at 0 "C.The mixture was allowed to attain room temperature and then poured onto ice-water. The steroids were extracted with diethyl ether. The extract was washed thoroughly with aqueous copper sulphate and saturated sodium chloride solution. The extract was dried (Na,SO,) and the solvent was evaporated to give a gum which was redissolved in methylene dichloride and cooled to -60 "C. Silver acetate (1 g) in pyridine (2 ml) was added and the mixture was stirred at -60 "C for 1 h and then allowed to attain room temperature in the dark during 40 h. The mixture was diluted with methylene dichloride and filtered.The solution was washed with dilute hydrochloric acid, water, and aqueous sodium hydrogen carbonate. The solvent was evaporated and the residue was chromatographed on silica. Elution with 50 ethyl acetate-light petroleum gave 4P-acetoxy-3P-hydroxy-androst-5-en-17-one (290 mg) which was identified by its i.r. and n.m.r. ~pectra.~ Reaction of 3~-Propionyloxyandrost-5-en-17-onewith Bromine and Silver Acetate.-3P-Propionyloxyandrost-5-en-17-one (2 g) lo in chloroform (10 ml) was treated with bromine (0.4ml) at -60 "C. Silver acetate (3 g) in pyridine (6 ml) was then added and the mixture was allowed to attain room temperature in the dark during 20 h, when poured into dilute hydrochloric acid and the steroid extracted with chloroform. The extract was washed with water and aqueous sodium hydrogen carbonate. The solvent was evaporated and the residue was chrom-atographed on silica. Elution with 25 ethyl acetate-light petroleum gave 3 ~-hydroxy-4~-propionyloxyandrost-5-en-17-one (700 mg), m.p.155-158 "C, identical (i.r. and n.m.r.) with the material prepared2 by the action of silver propionate and bromine on dehydroisoandrosterone. J. CHEM. SOC. PERKIN TRANS. I 1985 Reaction qf 3~-Aceto.xyandrost-5-en-17-one with Bromine and Silver Oxide.-Bromine (0.9 ml) was added to a solution of 3P- acetoxyandrost-5-en-17-one (500 mg) in chloroform (5 ml) at -60 "C. Moist silver oxide (1 g) in pyridine (1 ml) was added in two equal portions and the mixture was stirred at room temperature in the dark during 6 days.The mixture was poured into dilute hydrochloric acid and the steroids were recovered in ethyl acetate. The extract was washed with water and aqueous sodium hydrogen carbonate. The solvent was evaporated and the residue chromatographed on silica. Elution with 50 ethyl acetate-light petroleum gave 4P-acetoxy-3P-hydroxyandrost-5-en-17-one (43 mg) which was identified by its i.r. and n.m.r. ~pectra.~ Reaction of' 1'-'4C-3P-Acetoxyandrost-5-en-17-onewith Bromine and Silver Acetute.- l'-14C-3P-Acetoxyandrost-5-en- 17-one was prepared from 1'-14Cacetic anhydride and pyridine. The labelled steroid (1 g, specific activity, 11.4 kBq mmol-') was treated with bromine (0.2 mi) in chloroform (10 ml) at -60 "C. Silver acetate (1 g) in pyridine (2 ml) was added and the mixture was stirred for 0.5 h.A further portion of silver acetate (0.5 g) in pyridine (1 ml) was then added and the solution was allowed to attain room temperature in the dark during 24 h. The products were recovered as above to afford 4P-1'-'4Cacetoxy-3P-hydroxyandrost-5-en-17-one (500 mg) which was crystallized to constant radioactivity. It had specific activity 10.3kBq mmol-'. 3P-Etho.xycarbon~~landrost-5-en-17-one.-3 P-Hydroxy-androst-5-en-17-one (2 g) in pyridine (15 ml) was treated with ethyl chloroformate (5 ml) overnight. The solution was poured onto ice-water and the steroid was recovered in diethyl ether. The extract was washed thoroughly with aqueous copper sulphate, saturated sodium chloride solution, and dried.The solvent was evaporated to afford 3P-ethoxycarbonylandro~t-5-en- 17-one (2.4 g) which crystallized from acetone as prisms, m.p. 179-;82 "C, xD + 1' (~0.2)(Found:C, 73.3; H, 8.9. C22H32O4 requires C, 73.3; H, 8.95); v,,,, 1 740, 1 665 cm-'; 6 0.89 (3 H, s, carbonate. The organic phase was dried and made up to 100 ml with diethyl ether. Lithium aluminium deuteride (500mg) was added and the mixture was heated under reflux for 2.5 h. Ethyl acetate and water were then added. The ether was removed under reduced pressure, the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid, water, and aqueous sodium hydrogen carbonate. The solvent was evaporated and the residue dissolved in pyridine (9 ml) and treated with acetic anhydride (4 ml) for 24 h.The solution was poured into dilute hydrochloric acid and the steroids were extracted with ethyl acetate. The extract was washed with water and aqueous sodium hydrogen carbonate and dried. The solvent was evaporated and the residue was chromatographed on silica. Elution with 10 ethyl acetate-light petroleum gave 4P, 17~~H~1-3p, 17P-diacetox yandrost-5-ene (7 10 mg) which crystallized from ethyl acetate-light petroleum as plates, m.p. 158-160 "c, ID-62-(c 0.4)(lit.," 165-166 "c,I, -69"); 6, (360 MHz) 0.79 (3 H, S, 18-H), 1.02 (3 H, S, 19-H), 2.02 (3 euro;4, S, OAc). 2.03 (3 H, s, OAc), 4.60 (1 H, m, wt 15 Hz, 3-H), and 5.36 (1 H, m, 6-H); 6 ('H) 2.29 (4P-H), 4.59 (1 7-H). Reaction of 4p, 17n-2H,-3P,17~-Diaceto.x,vandrost-5-ene(13) with Bromine and Silver Acetate.---Bromine (0.1 ml) was added to a solution of 4P,17a-2H23P,17P-diacetoxyandrost-5-ene (380 mg) in chloroform (10 ml) at -60 "C.Silver acetate (I g) in pyridine (2 ml) was added in two portions.The mixture was allowed to warm to room temperature and stirred for 24 h in the dark. The mixture was poured into dilute hydrochloric acid and the steroids were extracted with chloroform. The extract was washed with water and aqueous sodium hydrogen carbonate, dried and the solvent was evaporated. The residue was chromatographed on silica. Elution with 25 ethyl acetate- light petroleum gave 17~-~fl-4P,17P-diaceto~,-3P-hydro.~?.-androst-5-ene (160 mg) which crystallized from acetone-ligh t petroleum as needles, m.p.125-128 "C, .ID -119" (c. 0.3) (Found: C, 70.8; H, 8.8. C23H340, requires C, 70.7; H, 8.8); v,,,, 3 530, 3 490, 3 380, 1 740, and 1 700 cm-'; 6, (360 MHz) 0.79 (3 H, S, 18-H), 1.09 (3 H, S, 19-H), 2.03 (3 H, S, OAC), 2.07 (3 H,s,OAc),3.64(1 H,m, W+ 15 Hz,3-H)5.37(1 H,d, J4Hz,4-H), 18-H), 1.04(3H,s, 19-H), 1.31(3H,t,J7H~,OCH,CH3),4.19(2 H, q, J 7 Hz, OCH,CH,), 4.28 (1 H, m, 3-H), and 5.43 (1 H, m, 6- H). Reaction of 3P-Efhoxycarbonylandrost-5-en-17-one with Bromine and Silver Acetate.-Bromine (0.4 ml) was added to a solution of 3~-ethoxycarbonylandrost-5-en-17-one (2 g) in methylene dichloride (1 5 ml) at -60 "C. Silver acetate (3 g) in pyridine (6 ml) was then added during 10 min and the mixture was allowed to attain room temperature during 3 days. The solution was filtered, diluted with methylene dichloride, washed with saturated copper sulphate solution, and water, dried and evaporated to give a residue which was chromatographed on silica.Elution with 2004 ethyl acetate-light petroleum gave the starting material (1.2 g). Further elution with 35 ethyl acetate- light petroleum gave the 3p,4P-cyclic carbonate of 3P,4P-dihydroxyandrost-Sen- 17-one (550 mg) which crystallized from ethyl acetate-light petroleum as plates, m.p. 229-232 "C, and which was identified by its i.r. and n.m.r. spectra.' ' Preparation of 4P, 17cc-'H2-3P, 17P-Diacetoxyandrost-5- em.-3 P-Acetoxy-4P-hydroxyandrost-5-en-17-one (2 g) (pre-pared by the partial acetylation of the 3,4-diol)' in dry diethyl ether (80 ml) and pyridine (0.4 ml) was treated with thionyl chloride (0.5 ml) in diethyl ether (8 ml).The suspension was stirred for 24 h. The mixture was washed with ice-cold dilute hydrochloric acid, water, and aqueous sodium hydrogen and 5.82 (1 H, m, 6-H); 6(2H) 4.58 (1 7-'H). References 1 V. A. Petrow,f. Chrm. Soc., 1937,1077;V. A. Tetrow, 0.Rosenheim, and W. W. Starling, f. Chem. Soc., 1943, 135. 2 J. R. Hanson, P.B. Reese, and H. Wadsworth, J. Chem. Soc., Perkin Trans. 1, 1984, 294 1. 3 D. Baldwin, J. R. Hanson, and A. M. Holtom, J. Chem. Soc., Perkin Trans. 1, 1973, 1704 4 For a preliminary communication see J. R. Hanson, P. B. Reese, and I. H. Sadler. Tetrahedron Lerr., 1982, 1851. 5 R. E. Ireland, T. I. Wrigley, and W. G. Young, f. Am. Chem. Soc.. 1959,81,2818. 6 W. J. S. Lockley, H. H. Rees, and T. W. Goodwin, J. Labelled Compounds, 1978,15,413. 7 S. Julia and B. Furer, Bull. Soc. Chim. (Fr), 1966, 1106. 8 D. F. Covey and V. D. Parikh, Steroid.7, 1980,36,451. 9 P. Deslongchamps, 'Stereoelectronic Effects in Organic Chemistry,' Pergamon Press, Oxford, 1983, pp. 82-85. 10 T. Nakano, N. Yamada, and T. Wada, Jap. Patent 11 100/1966 (Chem. Absrr., 1966,65, 12264). 11 J. R. Hanson and P. B. Reese, J. Chem. Soc., Perkin Trans. 1, 1985, Issue 1. 12 L. Ruzicka and A. Wettstein, Helu. Chim. Acta, 1935,18, 1264. Received 30th July 1984; Paper 41 133 1
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