576 J. Chem. SOC. (C), 1966 Acid-catalysed Reactions of 5-Hydroxy-steroids. Part IV.” A Mew Route to Sa,!ja-Acetoniurn Ion Perchlorates By M. J. Coppen, M. P. Hartshorn, and D. N. Kirk A new route to 3cc.5a-acetonium ions via the 38-acetyl sulphate derivatives of 3p-hydroxy-5 a-acetoxy-compounds has been described. RE-ICTIOS of 3 p,5a-diacetoxy-6 p-fluorocholestane (Ia) with perchloric acid in acetic anhydride gives a 3cc,5a- acetonium ion (IIa) as the perchlorate salt.1 Attempted preparation of the corresponding 6 p-acetoxy-ion (IIc) was complicated by extensive oxidation of the steroidal material. In addition no bridged ion could be obtained by this procedure from 3p,5a-diacetoxy-6P-chloro- cholestane (Ib) . Other procedures for the formation of such bridged ions from 3~-hydroxy-5a-acetoxy-compounds involve the solvolysis of the 3p-tosyloxy- or 3p-methylsul- phony!ox3--derivatives under conditions such that the bridged structures have only transient existence.Recently 3 we have shown that 6a-hydroxy-compounds in acetic anhydride-acetic acid containing sulphuric acid are converted rapidly into the corresponding 53-acetyl sulphates which compounds readily undergo hetesolysis. Accordingly it was considered that the formation in situ of the 3P-acetylsulphate of a 3P-hydr- osy-5“-acetoxy-steroid followed by displacement of the gmd leaving group, the acetylsulphate ion, by intra- molecular attack of the 5a-acetate group should re- present a convenier,t synthetic route to the 3rx,5a-ace- tonium ion. 2\ . . . . AcO @ Acb x ( I ! o,+,o CIy C x ( [ I 1 CH, c104- (a;; X = p-F, H (a); X = P-F, H ‘ 9 ) ; X = P-Cl, H (c); X P-OAC, H (c); X P-OAC, H (b); X = P-Cl, H (a); x = 0 (d); X = 0 The required 3~-hydrosy-5a-acetoxy-compounds {IIIa, b, c) were prepared by acid catalysed hydrolysis of the corresponding 3p,5a-diacetates (Ib, c, d).In each case the structure of the 3p-hydroxy-compound was confirmed by (1) re-acetylation and (2) oxidation by chromic acid in acetone to the corresponding 3-ketone. React ion of each 5 a-acet oxy-3 p-h ydroxy-compound (IIIa, b, c) with sulphuric acid in either acetic anhydride- acetic acid or acetic anhydride, followed by addition of pcrchioric acid and dilution with ether, gave the ace- toniuni ions (ITb, c, d) as the perchloric salts. The residues, after removal of the insoluble salts, when * Part 111, J .TT. Blunt, A. Fischer, ILL P. Hartshorn, I?. W. Jmiey, D. X. Kirk, and S. TV. Yoong, Tetrahedron, 1965, 1567. 1 J . TI-. Blunt, 31. P. Hartshorn, and D. N. Kirk, J . Chem. Plattner and W. Lang, Heh. Ckim. Acta, 1044, 27, 13’72; 1’1. A. Plattner, A. Furst, F. Koller, and IV. Lang, ibid., 1948, 31, 1455. S ~ I C , 1963, 1073. PI. quenched in aqueous sodium hydrogen carbonate con- sisted largely in each case of the 3p,5a-diacetates Hydrolysis of each perchlorate salt using sodium hydrogen carbonate in aqueous acetone at 20” gave the corresponding 3a-liydroxy-5a-acetoxy-compounds (IVa, c, e) the structures of which were assigned (cf. ref. 1) on the basis of identity of the 3-ketones obtained from them on mild oxidation and those derived by oxidation of the epimeric 3 p-hydroxy-materials.(Ib, c, d). AcO X (111) R’O X (IV) (a); X = P-Cl, H (b); X=P-OAc, H (a); R = H , R’ = Ac, X = $ X I , H (b); R = Ac, R’ = H; X = P-Cl, H (d); R = Ac, R’ 1 H, X = P-OAC, H ( e ) ; R = H, R’ = Ac, X = 0 (c); X = 0 (c); R = H, R’ == Ac; X = P-OAC, H Recently Winstein et nL4 reported that 1 ,%cis- acetoniunicyclohexane tetrafluoroborate gave the cis- 1,Z-hydroxyacetate in reaction with aqueous acetic acid whilst reaction with dry buffered acetic acid gave a crude product consisting largely of the tvaFzs-l,Z-diace- tate and a dimeric material. However in the present work whilst reaction of the 6P-acetoxy-acetonium ion perchlorate with cold aqueous acetic acid gave the expected 3a-hydroxy-5a-acetoxy-compound (IVc) the corresponding reaction with warm anhydrous acetic acid buffered with sodium acetate gave mainly the 3a- acetoxy-5a-hydroxy compound (IVd) , a product clearly derived by isomerisation of the 3 ~-hydroxy-5a-acetoxy- compound under the reaction conditions. EXPERIMENTAL Rotations were measured for chloroform solutions at room temperature, Infrared spectra were recorded in carbon disulphide, except where stated.The alumina used for chromatography was P. Spence, grade “H,” which was treated with 5% of 10% acetic acid. Light petroleum had b. p. 50-70”. 5a-A cetoxy-6~-chlovoclzolestan-3~-02 (IIIa) .-A solution of 3~,5a-diacetoxy-6~-chlorocholestane (1.5 g.) in methanol (500 c.c.) containing aqueous sulphuric acid (45 c.c.; 10%) was heated under reflux for 2.5 hr.Isolation by means of pentane and crystallisation from methanol gave the 3fi-hydron.y-conzpound (1-1 g.) as needles, m. p. 156- 3 J. W. Blunt, M. P. Hartshorn, F. W. Jones, and D. N. Kirk, Tetvahedron Lettevs, 1964, 1399; J. W. Blunt, A. Fischer, M. P. Hartshorn, F. W. Jones, D. N, Kirk, and S. W. Yoong, Tetrahedron, 1965, 1567. 4 C. B. Anderson, E. C. Friedrich, and S. TVinstein, Tetra- hedron Letters, 1963, 2037.Org. 577 156.5", [a], -13" (c 1.05) (Found: C, 71.9; H, 10.5; C1, 8.0. C2gH,gC10, requires C, 72.3; H, 10.2; C1, 7.4%); vmax. 3550 cm.-l (OH), 1735 and 1235 cm.-l (OAc). 5a,6~-Diuceto=cychoZesta~z-3@-01 (IIIb) .--A solution of 3@,5a,6@-triacetoxycholestane (10 g.) in methanol (1 1.) containing aqueous sulphuric acid (180 c.c.; 10%) was heated under reflux for 1.5 hr.The crude product isolated by means of pentane was adsorbed on alumina (120 g.). Elution with light petroleum-benzene (1 : 1) and crystall- isation from methanol gave starting material (4.2 g.) as needles, m. p. and mixed m. p. 154-154.5". Elution with benzene-ether (1 : 1) gave a gum which on crystallisation from pentane gave the 3@-hydroxy-co~npound (3.6 g.) as plates, m. p. 146-148", [a], -28" (c 1.06) (Found: C, 73.3; H, 10.6. C31H5205 requires C, 73.7; H, 10.4%); vmsx. 3600 cm.-l (OH), 1753, 1246, and 1221 cm.-l (OAc). Finally elution with ether-methanol (1 : 2) gave a gum (2-0 g.). 5a-A ceto~~~~-3-@-hydrox~choZe~tu~z-6-o.tze (IIIc) .-A solution of 3Q, 5ct-diacetoxycholestan-6-one (1.6 g.) in methanol (350 c.c.) containing aqueous sulphuric acid (40 c.c.; 10%) was heated under reflus for 3 hr.Isolation by means of pentane and crystallisation from aqueous ethanol gave the 311-Jzydvo~3~-co~~po~~~~d (1-2 g.) as needles, m. p. 183-183.5", [a], -6" (c 0-84) (Found: C, 75.9; H, 10.8. C2gH4804 requires C, 75-6; H, 10.4y0); v,,~ 3630 cm.-l (OH), 1738 cm.-l (GO), 1755, 1252, and 1227 cni.-l (0-4c). Pvepwation of 3r,5u-Acetoniunz Ion Perch1orates.-(a) 6p-ChZoro. 5a-Acetoxy-6/3-chlorocholestan-3~-ol (450 mg.) was dissolved in methylene dichloride (2 c.c.) and acetic anhydride (5 c.c.) and treated with sulphuric acid (0.1 c.c.; 36~3). After 2 niin. perchloric acid (0.19 c.c.; 60%) was added followed by dry ether (100 c.c.) and the mixture cooled to 0'. Filtration gave the GP-chloro-acetoniunz per- &ovate (170 mg.) as needles, m.p. 141-145' (decomp.) (Found: C, 61.8; H, 8.8; C1, 12.6. C2,H,8C120, requires C, 61.8; H, 8.5; C1, 13.0%); vmax. (Nujol) 1106, 1098, and 1081 cm.-l (C104-) .l The filtrate (above) when treated with excess of aqueous sodium hydrogen carbonate and isolation by means of pentane afforded a crude product which crystallised from methanol to give 6@-chloro-3~,5a-diacetoxycholestane (260 mg.) as needles, m. p. and mixed m. p. 168---168.5°. (b) 6/3-Acetoxy. 5~,6~-Diacetoxycholestan-3f3-01 (300 mg.) treated as for (a) above gave the 6@-acetoxy-uceto~ziu~ pevchlorate (258 mg.) as needles, m. p. 136" {decomp.) (Found: C, 63.3; H, 9-1; C1, 6.8. C3,H,,C10, requires C, 63.3; H, 8.7; C1, 6.1%); v,,, (Nujol) 1767 cni.-l (OAc), 1103 cm.-1 (C104-) .The filtrate, treated as for (a), gave the 3P,5~,6P-tri- acetate (20 mg.) as needles (from methanol), m. p. and mixed m. p. 153-154'. (c) 6-Ketone. 5a-Acetoxy-3@-hydroxycholestan-6-one (330 mg.) treated as for (a) above gave the 6-oxo-acetomCwtz percldovute (20 mg.) as needles, m. p. 162-164' (decomp.), v,,,. (Nujol) 1735 cni.-l ( G O ) , 1164, 1147, 1117, and 1101 cm.-l (ClO,-). Satisfactory analytical data could not be obtained owing to the rapid decomposition (ca. 12 hr.) of the perchlorate salt. The filtrate, treated as for (a), gave the 3P,5a-diacetoxy- cholestan-6-one (290 mg.) as needles (from methanol), m. p. and mixed m. p. 173-174". Hydvol?jsis of the 3c(, 5%-Acetoniunz I o n Perchlorates.- 6Q-CMovo. A saturated solution of sodium hydrogen carbonate (1 c.c.) was added to the perchlorate salt (59 mg.) and acetone (3 c.c.).The precipitated steroid was crystall- ised from methanol to give 5a-acetoxy-6~-chZovochoZesta~z- 3a-02 (IVa) (30 mg.) as needles, m. p. 167-170", [a], -t5" (c 1.05) (Found: C, 72.1; H, 10.3; C1, 7.5. C,,H4,C10, requires C, 72.3; H, 10.2; C1, 7.4%); vmax. 3625 cm.-l (OH), 1740 and 1241 crn.-l (OAc). (a) Reaction of the perchlorate salt (200 mg.) a t 20" as above gave 5a,6~-diacetoxychoZeestan-3a-oZ (IVc) (120 mg.) as needles (from methanol), m. p. 146- 147', [XI, -21" (c 1-05?) (Found: C, 73.6; H, 10-5. C31H5205 requires C, 73.7; H, 10*4y0); vmsx. 3601 cm.-l (OM), 1755, 1270, 1252, 1230, and 1209 cm.-1 (0-4c). (b) The perchlorate salt (500 nig.), dioxan (30 c.c.), and a saturated solution of sodium hydrogen carbonate (1 c.c.) were heated under reflux for 7 hr.The crude product was isolated by means of ether and crystallisation from methanol gave 6fLacetoxycholestane-3a, 5a-diol (320 mg.) as needles, m. p. 182-182.5", [ a ] , -27" (G 0.92) (lit.,5 m. p. 177- Reaction of the perchlorate salt (55 mg.) at 20" as for (a) above gave 5x-acetoxy--3a-hydroxycholestan- 6-one (38 mg.) as needles (from hexane), m. p. and mixed 5u-Acetoxy-6@-cJzlorocJaolestm-3-olze.-(a) FYOWI tlze 3i.3- hyd~o,vy-com~oz,~nd (IIIa). The steroid (50 mg.) was oxid- ised with 8N-chromic acid in acetone. Isolation and crystallisation of the crude product from inethanol gave the ketone (38 mg.) as needles, m. p. 160--161", [a], -9" (c 0.92) (Found: C, 72.0; H, 10.2; C1, 8-0. C2,H4,ClO, requires C, 72.5; H, 10.0; C, 7.4%); v,,,.1721 cm.-l ( G O ) , 1736, 1227, and 1210 cm.-l (OAc). The steroid (30 mg.) treated as above gave thc ketone (22 mg.) as needles, m. p. and mixed m. p. 159-161". 5a,6~-DiacetoxychoZesta~z-3-one.-(a) From the 3p-hydroxy- cowzpound (IIIb). The steroid (50 mg.) treated as above gave the ketoize (40 mg.) as plates (from methanol), in. p. 169-169-5", [a], -28" (c 1.30) {Found: C, 74.2; H, 9.8. C,,H,,O, requires C, 73.8; H, 10.3%); v,,,. 1730 cm.-l (GO), 1760, 1241, 1225, 1213, and 1205 cm.-l (OAc). The steroid (70 mg.) treated as above gave the ketone (45 gm.) as plates, m. p. and mixed m. p. 168-169". Reactions of 3a,5a-Aceto~zizt~n-6~-acetoxycholestnns Pev- chZorate.-(a) With aqueous acetic acid. A solution of the perchlorate (200 mg.) in acetic acid (10 c.c.) and water (2 c.c.) was kept a t 20" for 10 min. Isolation and crystall- isation of the crude product from methanol gave 5a,6@-di- acetoxycholestan-3a-01 (120 mg.) as needles, ni. p. and mixed m. p, 167-168". A solution of the per- chlorate (274 mg.) and sodium acetate (700 mg. ; anhydrous) in acetic acid ( 5 c.c.) were heated at 100" for 40 min. Isolation and crystallisation of the crude product from methanol gave 3a,6~-diacetoxycholestan-5a-ol (140 mg.) as needles, m, p. and mixed ni. p. 89-91". The residual gum (30 mg.) from the above crystallisation was shown by thin-layer chromatography to contain seven components in morc or less equal quantities. We thank the Research Cornmittee of the New Zealand Universities Grants Committee for financial support. 6P-Acetoxy. 178", [a], -29"). 6-0x0. 111. p. 140-142". (b) From the 3r-Jz~droxy-cornpound (IVa). (b) Fvom tlze 3u-l~ydvoxy-coi.:t~z,~~d (IIIc) . (b) With buflered acetic acid. THE UNIVERSITY- OF CAKTERBURY, CHRISTCHURCII 1, NEW ZEALAXD. [5/633 Received, June 18th, 19651 5 P1. ,4. Plattner, ,4. Furst, F. Koller, and XI. H. Kuhn, Helv. Ckinz. A d a , 1954, 37, 258.