J.Org. Chem., Vol. 40,No. 10,1975
3~u,5-Cyclo-6~-niethoxy-5a-23,24-bisnorcholan-22-01 Tosylate (CH3)2A10C3H7-nr 54549-33-6; LiA1(CH3)3C4H9-nl 54549-40-5; LiAl(CeH5)3CdH9-n, 54549-45-0; 4-tert-butylcyclohexanone,9853-3; 2-methylcyclopentanone, 1120-72-5; n-butyllithium, 109-728; 4-tert- butylcyclohexanone-A1(CH~)~, 54549-41-6; 4-tert-butylcyclohexanone-All(C~H~)~, 54549-44-9; 2-methylcyclopentanoneAl(CsH5)3, 54549-43-8; 4-tert-butylcyclohexanone-AlC~~, 5454939-2; 2-methylcyclopentanone-A1(CH~)~, 54549-42-7.
References and Notes We are indebted to the National Science Foundation (Grant GP-31550~) for partial support of this work. (2) To whom correspondence should be addressed.
(1)
1475
(a) E. C. Ashby and S. H. Yu, J. Chem. SOC. D, 351 (1971): (b) E. C. Ashby, S. H. Yu, and P. V . Roling, J. Org. Chem., 37, 1918 (1973): (c) J. Laemmle, E. C. Ashby, and P. V. Roling, ibid., 38, 2526 (1973). (4) For a recent review concerning stereoalkylation of ketones, see E. C. Ashby and J. T. Laemmle, Chem. Rev., in press. (5) E. C. Ashby and R. D. Schwartz, J. Chem. Educ., 51,65 (1974). (6) (a) T. Mole and J. R. Surtees, Aust. J. Chem., 17, 310 (1964): (b) ibid., (3)
17, 961 (1964). (7) E. C. Ashby, J. Laemmle, and H. M. Neumann, J. Am. Chem. SOC.,80, 5179 (1968). (8) E. C. Ashby and S. H. Yu. J. Org. Chem., 35, 1034 (1970). (9) (a) E. A. Jefferyand T. Mole, Aust. J. Chem., 23, 715 (1970): (b) E. C. Ashby, J. Laemmle, and G. E. Parris, J. Organomet. Chem., 19, 24 (1969).
Abnormal Products Obtained during an Attempted Substitution of 3a,5-Cyclo-6~-methoxy-5a-23,24-bisnorcholan-22-01 Tosylate with a Grignard Reagent Involving y,y-Dimethylallyl Bromide Sunil K. Dasgupta and Marcel Gut* Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545 Received November 19,1974 Attempted coupling of 6~-methoxy-3~,5-cyclo-5ol-23,24-bisnorcholan-22-yl tosylate (2a) with y,y-dimethylallyl bromide (I) in the presence of magnesium leads to the formation of 22,22'-bis-6~-methoxy-3a,5-cyclo-5a-bisnorcholanyl (6), a novel disteroid, and 3a,5-cyclo-5a-23,24-bisnorcholan-6~-yl methyl ether (5) rather than to the expected desmosterol derivatives. The formation of these products has been attributed to a common 22-bisnorcholanylmagnesium bromide intermediate which undergoes Wurtz-type coupling or is hydrolyzed to an alkane during work-up.
I n our recentlv reDorted svnthesis of desmostero1.l we tested t h e utility of allylic organometallics as synthons for construction of the steroid side chain. Recent communicat i o n ~along ~ ~ Bimilar ~ lines prompted us t o report the results of our experiments. T h e chemistry of allyl Grignard and allyllithium reagents has been well d ~ c u m e n t e d .Notable ~,~ problems associated with the use of these reagents are self-coupling a n d allylic rearrangements of the Grignard reagents, which leads t o mixtures of isomeric products. Unsymmetrical allylic Grignard reagents react with unhindered electrophilic substrates, such as carbonyl compounds6 and epoxides,'~* t o afford branched products. Less branched carbinols are preferentially formed, however, in reactions with relatively hindered ketones. This phenomenon, as suggested by Felkin and coworkersyJO is due t o the differences in the steric strain in the two possible allylic transition states. A NMR study of y,y-dimethylallylmagnesiumbromidell has indicated t h a t t h e reagent exists as a rapidly equilibrating pair of classical structures (la and lb) with t h e I
la
_
lb
equilibrium well on the side of form la. Reaction of 1 with carbon dioxide12 and with cyclohexanone5 has been reported t o give a tertiary acid and a tertiary carbinol, respectively, suggesting the predominance of form lb. y,yDimethylallyllithium, however, when treated with an equimolar amount of t h e allylic bromide in a cross-coupling reaction, gives rise t o mixtures5 of direct and transposed products with allylic transposition limited t o t h e allylic portion derived from either la or lb. It was therefore of interest t o determine whether 3a,5cyclo-22-tosyloxy-5a-23,24-bisnorcholan-6~-016-methyl
ether (2a) could be successfully substituted with the allyl Grignard reagent 1. Coupling of aryl Grignard reagents with alkyl sulfates and sulfonates is well known and has been reviewed by Kharasch.13 Earlier, it was observed t h a t t h e tosylate 2 could be easily displaced with sodium iodide1v3 or with sodium salts of activated methylene comp o u n d ~ Recently .~~ it has been also shown3 t h a t t h e tosylate 2 undergoes a smooth nucleophilic displacement with t h e lithium salt of 3-methyl-1-butyn-3-01 tetrahydropyranyl ether. Our specific interest in t h e attempted allyl Grignard reaction, however, was t o examine the reaction products for t h e presence of compound 3 and the product of allylic transposition 4. The latter was envisaged as a key intermediate for the preparation of 23,23-dimethylcholester01, a substance desirable t o us for biological oxidation studies. T h e coupling experiment was carried out under the conditions described by Seyferth15J6 for magnesium-induced condensation of triphenyltin chloride with allyl bromide. T h e reaction mixture was separated by column chromatography, b u t none of the products could be identified as the expected structures 3 or 4. Instead, two crystalline steroidal products differing in their respective mobility on thin layer chromatography were isolated. T h e less polar product showed infrared spectral bands a t 1090, 1010, a n d 970 cm-l, indicating t h e presence of a 6methoxy i-steroid moiety. This was supported by the appearance of signals a t 3.32 (3 H), 2.77 (1 H),and broad multiplets a t 0.33-0.67 ppm in the NMR spectrum, confirming t h e presence of a methyl ether residue, 6 a - H , and cyclopropyl hydrogens, respectively. T h e other characteristic methyl proton signals, besides the two singlets a t 0.72 (3 H) and 1.01 (3 H) ppm due to 18- and 19-methyls, were three sharp peaks at 0.78,0.89, and 0.99 ppm (J = 6 Hz,6 H). T h e latter three signals would seem t o represent a pair of overlapping doublets for two methyls which could be due t o 21 and 22 secondary methyls. This speculation was con-
1476 J. Org. Chem., Vol. 40, No. 10, 1975
Dasgupta and Gut
firmed by the NMR spectrum of 7, which also exhibited three sharp signals a t 0.78, 0.89, and 0.99 ppm (J = 6 Hz, 6 H) in addition to the singlets for 18- and 19-methyls see Experimental Section). The mass spectrum of the less polar product (mle 330, M+) and the other spectral data are in reasonable agreement with the proposed structure 5. This structure was confirmed by comparison of its ir and NMR spectra and mixture melting point with those of an authentic sample of 5. Its preparation will be described later.
ABX pattern17 of the olefinic -CH=CH2 protons were absent as well, thus proving t h a t the dimethylallyl residue had not been coupled in either of its two forms, l a or lb. The mass spectrum exhibits a molecular ion at mle 658, suggesting t h a t the product results from the coupling of the two C22 steroid units, derived from the 22-tosylate 2a. On the basis of the spectral evidence, and from mechanistic considerations (see later), structure 6 has been assigned to the more polar product. It is likely that a common intermediate is involved in the generation of 5 and 6 during the Grignard reaction. Since the compositionls of the Grignard solution may involve the Schlenklg equilibrium, Le., 2RMgX R2Mg MgX2 + R2Mg MX2, both R2Mg and MgX2 could compete for reaction with electrophilic substrates. The 22-tosylate 2a is readily converted to the 22.~ bromide (2b) under conditions of a Grignard r e a ~ t i o n The bromide 2b could then form an organomagnesium derivative which, on decomposition with water, would result in t h e formation of the hydrocarbon 5. Moreau et ale2 observed the formation of a hydrocarbon derivative from an analogous 22-bromide during a coupling with y,y-dimethylallyl bromide in the presence of magnesium, but attributed the process to a reductive elimination involving a cyclic seven-membered transition state. In our opinion, the facile decomposition of Grignard reagents with water t o yield hydrocarbons is too well known20*21t o warrant any other explanation. The disteroid 6, however, was formed by a Wurtz-type coupling of the organomagnesium derivative. An authentic sample of 5 was prepared by lithium aluminum hydride reduction of the tosylate 2a, as well as by catalytic reduction of the 20-methylene derivative 8. The latter was prepared by the solvolysis of the tosyl derivative 9c of the previously described 3-hydroxy compound 9a in the presence of pyridine and methanol. Compound 7 was prepared by controlled catalytic reduction of 9b in the presence of 5%P d on calcium carbonate.
+
I
I
OCHB 3
OCHB 2a, R = OTs b, R = Br
I
I OCHB
OCH3 5
4
-
Experimental Section OCH3
OCH3 6
8
7
R
O \M 9a,R=H b,R=Ac c,R=Ts d,R=Me
The more polar steroidal product also exhibited the usual ir and NMR signals associated with a 3,5-cyclo-6methoxy moiety described above. The NMR spectra further revealed the presence of 18- and 19-methyls as denoted by two singlets at 0.70 and 1.01 ppm, respectively. However, the characteristic signals at 0.78, 0.88, and 0.98 ppm assigned t o the 21 and 22 secondary methyls of structure 5 were conspicuously absent. A vinylic methyl group and the
Melting points are uncorrected. NMR spectra, reported in parts per million, were obtained in deuteriochloroform solution on a 60MHz Varian Associates DA-60 spectrometer using tetramethylsilane as an internal reference. The microanalyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y. Attempted Coupling of 3a,5-Cyclo-22-tosyloxy-5a-23,24-bisnorcholan-6P-yl Methyl Ether (2a) with 7,y-Dimethylallyl Bromide in the Presence of Magnesium. In a flask were placed 150 mg of magnesium shavings, 3 ml of anhydrous ether, and a trace of iodine. A drop of y,y-dimethylallyl bromide was added and the mixture was stirred under nitrogen a t 20°. After a few minutes the brown color of the iodine began to fade to a cloudy yellow. A solution of 0.45 g of y,y-dimethylallyl bromide, previously distilled under reduced pressure, and 1 g of 3a,5-cyclo-GP-methoxy-5a-23,24-bisnorcholan-22-ol tosylate (2a) in 4 ml of anhydrous tetrahydrofuran was added with stirring to the gently refluxing magnesium suspension during 5 hr. After the addition was complete, 5 ml of dry benzene was added and the reaction mixture was heated to reflux for an additional 5 hr. The complex was decomposed by cautious addition of ice-cold saturated ammonium chloride solution. The mixture was transferred to a separatory funnel and extracted with ether. The ether extract was washed repeatedly with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, leaving behind a gum which was dissolved in hexane and chromatographed on 45 g of alumina. The hexane eluates furnished 250 mg of an oil which was further purified by preparative layer chromatography on 1 mm thick silica gel plates developed with benzene-hexane (1: 1). There was obtained 150 mg of 3a,5-cyclo-5a-23,24-bisnorcholan-6P-yl methyl ether (5): mp 61-63O (acetone); ir 1090,1010, and 970 cm-l (6-OMe-i); NMR 0.72 (18-CH3), one pair of overlapping doublets 0.78,0.89,0.99 ( J = 6 Hz, 21-, 22-methyls), 1.01 (19-CH3), 3.32 (6/3-OCH3),broad multiplets at 0.33-0.67 (cyclopropyl hydrogens) and 2.77 ppm (6a-H);mass spectrum mle 330 (M+), 315 (M - CH3), 298 (M- CHsOH), 283 [M - (CH3OH + CHs)], 272 [M -
3a,5-Cyclo-6~-imethoxy-5a-23,24-bisnorcholan-22-01 Tosylate
+
+
J.Org. Chem., Vol. 40,No. 10,1975 1417
Anal. Calcd for C23H360: C, 84.08; H, 11.05. Found: C, 84.36; H, (CH3 (CH3)2CH)], 268 [M - (MeOH 2CH3)], 255 [M 10.82. (MeOH + (CH&CH)]. 23,24-Bisnorchola-5,20-dien-3p-y1 Methyl Ether (Sd). The Anal. Calcd for CzaH38O: C, 83.57; H, 11.59. Found C, 83.80; H, eluates with 10%benzene in hexane of the above-mentioned chro11.64. matography furnished 150 mg of crystalline 9d: mp 88-89’ Eluates combining 5-10% benzene in hexane furnished 200 mg (MeOH); NMR 0.58 (18-CH3), 1.00 (19-CH3),3.33 (Bp-OCHs),1.75 of a glass, which on purification by preparative layer chromatogra(21 olefinic methyl), multiplets at 4.69-4.86 (22 terminal methyphy on 1 mm thick silica gel plates, developed with 10% hexanebenzene, gave 125 mg of 22,22’-bis-6~-methoxy-3a,5-cyclo-5a-lene) and 5.34 ppm (6 H). Anal. Calcd for C23H360: C, 84.08; H, 11.05. Found: C, 83.90; H, 23,24-bisnorcholanyl (6): mp 95O (acetone); ir 1090, 1010, and 965 10.96. cm-l (6-OMe-i); NMR 0.70 (l8-CH3), 1.01 (19-CH3), 3.32 (6p3~,5-Cyclo-5a-23,24-bisnorcholan-6~-yl Methyl Ether ( 5 ) OCH3),broad multiplets at 0.33-0.67 (cyclopropyl hydrogens) and from 8. A solution of 100 mg of 8 was dissolved in 5 ml of ethyl ac2.77 ppm (6a-H); mass spectrum m/e 658 (M+), 643 (M - 151,626 etate and stirred under an atmosphere of hydrogen in the presence (M CHaOH), 611 [M - (MeOH CH3)]. of 50 mg of 5% palladium on calcium carbonate. Uptake of hydroAnal. Calcd for Cd~H7402:C, 83.82; H, 11.32. Found C, 83.85; H, gen was complete in 30 min. The ethyl acetate solution was filtered 11.38. through Celite and concentrated to dryness. The residue, on crys23,24-Bisnorcho1-5-en-3j3-01 Acetate (7). A solution of 200 mg tallization from acetone, furnished 90 mg of 5, mp 61-63O, not deof 20-methylenepregn-5-en-3P-01 acetate (9b)23in 10 ml of ethyl pressed by admixture with the other samples described previously. acetate was magnetically stirred under an atmosphere of hydrogen in the presence of 80 mg of 5% palladium on calcium carbonate. Acknowledgment. We are thankful to Dr. T. A. WittsUptake of the calculated amount of hydrogen was over in 30 min. The ethyl acetate suspension was filtered through Celite. Evaporatruck and Mrs. D. N. Davis for the NMR spectra. The aution of the filtrate furnished a solid which was recrystallized from a thors are grateful for the support by U. S. Public Health methylene chloride-methanol solution to give 185 mg of the 20Service Grant AM-03419 from the Institute of Arthritis methyl derivative 7: ir 1720 cm-l (CH&OO-); NMR 0.67 (18and Metabolic Diseases, by a contract from the Atomic EnCH3), one pair of overlapping doublets 0.78, 0.89, 0.99 ( J = 6 Hz, ergy Commission, AT(l1-1)-3026, and by a grant from the 21-, 22-methyls), 1.01 (19-CH3),2.02 (acetate methyl), 4.64 (3or-H), National Science Foundation, GB-38612. and 5.36 ppm (6 H). Anal. Calcd for C~H3802:C, 80.39; H, 10.68. Found C, 80.51; H, Registry No.-2a, 51231-24-4; 5, 54446-73-0; 6, 54446-74-1; 7, 10.83. 3ru,5-Cyclo-5a-23,24-bisnorcholan-6~-yl Methyl Ether (5) by 33168-84-2; 8, 54446-75-2; 9a, 17879-91-3; 9b, 38388-16-8; 9c, 54446-76-3; Sd, 54446-77-4; y,y-dimethylallyl bromide, 870-63-3; the Lithium Aluminum Hydride Reduction of 6B-Methoxy3a,5-cycl0-5a-23,24-bisnorcholan-22-01 Tosylate (2a). A solup-toluenesulfonyl chloride, 98-59-9. tion of 500 mg of the tosylate 2al in 10 ml of anhydrous tetrahydrofuran was added slowly to a stirred slurry of 200 mg of lithium References and Notes aluminum hydride in 10 ml of tetrahydrofuran. After the addition (1) S. K. Dasgupta, D. R. Crump, and M. Gut, J. Org. Chem., 39, 1658 was complete, the mixture was refluxed for 6 hr. It was decom(1974). posed by the cautious addition of 2 N sodium hydroxide solution. (2) J. P. Moreau, D. J. Aberhart, and E. Caspl, J. Org. Chem., 39, 2018 The tetrahydrofuran solution was filtered through Celite. Concen(1974). tration of the filtrate gave a residue which was dissolved in hexane (3) J. J. Partridge, S. Faber, and M. UskokoviC, Helv. Chim. Acta, 57, 764 (1974). and filtered through a short column of alumina. The hexane el(4) R. A. Benkeser, Synthesis, 347 (1971). uates furnished 250 mg of 5,which was recrystallized from acetone, (5) J. A. Katzenellenbogen and R. S.Lenox, J. Org. Chem., 38,326 (1973). mp 61-63O, melts unchanged on admixture with the less polar (6) J. D. Roberts and W. G. Young, J. Am. Chem. SOC.,67, 148 (1945). product obtained from the previously described coupling experi(7) M. Andrac, F. Gaudeman, M. Gaudemar, B. Cross, L. Miginiae, P. Migment; ir and NMR were found to be identical. iniac, and C. Prevost, Bull. SOC.Chim. fr., 1385(1963). (8) L. S. Wu, R. A. Finnegan, and K. W. Greenlee, Abstracts, 142nd Natlon23,24-Bisnorehola-5.20-dien-3~-01 Tosylate (9c). A solution a1 Meeting of the American Chemical Society, Atlantic City, N.J., Sept of 2 g of 23,24-bisnorchola-5,20-dien-3P-o1 (Sa)22and 2.6 g of p-to1962, p 70. luenesulfonyl chloride in 32 ml of dry pyridine was left standing (9) H. Felkin and C. Frajeman, Tetrahedron Lett., 1045 (1970). for 18 hr at 5O. Cold water was added dropwise while stirring and (10) M. Cherest, H. Felkin, and C. Frajerman, Tetrahedron Lett., 379 (1971). the resulting precipitate was filtered off and washed with a large (11) J. E. Nordlander, W. G. Young, and J. D. Roberts, J. Am. Chem. Soc., 83, 494 (1961). excess of water. Crystallization from hexane furnished 1.8 g of 9c: (12) H. Kwart and R. K. Miiier, J. Am. Chem. Soc., 76, 5403 (1954). mp 95-99’; ir 1180 and 1145 (tosylate), 890 cm-I (=CH2). (13) M. S.Kharasch and Otto Relnmuth, “Grlgnard Reactions of Non-metallic Anal. Calcd for C2eH4003S: C, 74.36; H, 8.55. Found: C, 74.38; H, Substances”, Prentice-Hall, Englewood Cliffs, N.J., 1954, pp 10138.59. 1045. 3a,5-Cyclo-5ar-23,24-bisnorchol-20-en-6~-yl Methyl Ether (14) Unpublished results from this laboratory. (15) D . Seyferth and M. Welner, “Organic Syntheses”, Collect. Vol. V, (8). A solution of‘ 1.8 g of the tosylate 9c in 13 ml of anhydrous pyrWiley, New York, N.Y., 1973, p 452. idine and 190 ml of dry methanol was heated on a steam bath for 2 (16) Following the same procedure we have successfully synthesized dlhr, after which time the methanol was removed by distillation in methylallyitriphenyltin: unpublished results from this laboratory. vacuo. After the addition of water the mixture was extracted with (17) N. S. Bhacca and D. H. Williams, “Applications of NMR Spectroscopy In ethyl acetate. The organic extract was washed with 2 N acetic acid. Organic Chemistry”, Holden-Day, San Francisco, Calif., 1964, pp 8586. Then the extract was washed with water, saturated bicarbonate so(18) E. C. Ashby, 0.Rev. Chem. Soc.,21, 259 (1967). lution, and again with water. It was dried over anhydrous sodium (19) W. Schlenk and W. Schlenk,Jr., Ber., 62, 920 (1929). sulfate and evaporated to dryness. The residue was dissolved in (20) V. Grignard, C. R. Acad. Sci., 130, 1322 (1900). hexane and chromatographed over 60 g of alumina. Careful elution (21) T. Zerevitinov, Ber., 40, 2023 (1907). with hexane furnished 400 mg of an oil which showed a single spot (22) F. Sondheimer and R. Mechoulam, J. Am. Chem. Soc., 79, 5031 (1957). on TLC. An analytical sample was crystallized from methanol: mp (23) This compound was prepared by the acetylation of 9a2*with pyridine 41-42’; ir 1090,1010, and 965 (6-OMe-i),891 cm-l (=CH2); NMR and acetic anhydride and gave mp 128-131O; Ir 1720, 1230 0.63 (18-CH31, 1.02 (19-CH3), 1.75 (21 olefinic methyl), 3.33 (66(CH&OO-), 1615, 887 cm-’; NMR 0.58 (18-CH3), 1.03 (19-CH3), 1.78 OCH3), broad multiplets at 0.33-0.67 (cyclopropyl hydrogens), (olefinic21-methyl), 2.03 (acetate methyl), 4.73-4.87 (terminal methy2.77 (6a-H), multiplets at 4.69-4.86 ppm (terminal methylene). lene),and 5.41 ppm (6 vinylic proton).
-
+
