Dienol rearrangements catalyzed by nickel chloride - The Journal of

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1084

J. Org. Chem. 1984,49, 1084-1090

Dienol Rearrangements Catalyzed by Nickel Chloride Keith S. Kyler, A. Bashir-Hashemi, and David S. Watt* Department of Chemistry, University of Wyoming, Laramie, Wyoming 82071

Received September 14, 1983 The rearrangement of dienols R.&(OH)CH=CHC(X)=CR, which possess a nonterminal, aryltliio or alkylthio substituent was effected by using nickel chloride in aqueous tert-butyl alcohol at 60 "C to furnish the vicinally substituted dienol R,C==CHCH=C(X)CR,(OH).Application of this rearrangementto 24-(methy1thio)cholesta-5,22,24-trien-20-01 provided 24-(methylthio)cholesta-5,20(22),23-trien-25-01 and formed the basis for a new, five-step synthesis of (20R)-25-hydroxycholesterolfrom pregnenolone tetrahydropyranyl ether. The rearrangement process appeared to be driven by the relief of unfavorable steric interactions between the quaternary C-13 and C-20 centers in steroids and influenced by the nature of the nickel(I1)catalyst. The sulfur-containingsubstituent was not a prerequisite for the rearrangement since the desulfurized dienols underwent an analogous rearrangement. Preparation of these desulfurized dienols involved the use of a Raney nickel catalyst deactivated by heating in decalin. This catalyst selectively desulfurized vinyl thioethers to olefins. Inhoffen' and Julia2 have demonstrated the merit of dienol rearrangment~~ as synthetic transformations. In these cases, the rearrangement of acyclic dienob 1 bearing either a terminal alkoxy or halogen substituent furnishes unsaturated carbonyl compounds 2 as shown in Scheme I. We have explored the rearrangement of dienols 3 bearing nonterminal, heteroatom substituents leading to the vicinally substituted dienols 4 and applied this rearrangement to the partial synthesis of (20R)-25-hydroxycholesterol4 (5). We speculated that chelation of the heteroatom substituent and the hydroxyl group in dienol 4 favored the desired rearrangment. We now wish to report the details of these dienol rearrangements, a method for desulfurizing thio-substituted dienes without carboncarbon double bond reduction, and a reevaluation of our original mechanistic s ~ g g e s t i o n . ~ The sequential a,y-dialkylation of 1-(arylthio)- or 1(alkylthio)-1-(trimethylsily1)-2-propenes5 (6) furnished a convenient route to various arylthio- or alkylthio-substituted dienols 8 as shown in Scheme 11. In the first step in this process, condensation of the anion of 6 with various carbonyl compounds proceeded with high y-regioselectivity to give the adducts 7 shown in Table I. Subsequent condensation of the dianion derived from the adducts 7 with a second carbonyl compound proceeded with high a-regioselectivity to give the dieno18 in a Peterson-type olefination.6 The stereochemistry of the central double bond in dienols 8 was exclusively E according to the IH NMR spectra. We attributed the a-regimelectivity in the reactions of the dianions of 7 to unfavorable steric interactions or electrostatic repulsions involving condensation a t the alternate y-site. Successful condensations of these dianion species and a ketone invariably required an excess of the second carbonyl compound, and for obvious reasons, this restricted this approach to those cases where the dienol (1) (a) Inhoffen, H. H. Naturwissenschaften 1951, 38, 478. (b) Inhoffen, H. H.; Siemer, H.; MBhle, K.-D., Liebigs Ann. Chem. 1954,585, 126. (2) (a) Julia, M. Bull. SOC.Chim. Fr. 1951, C13. (b) Julia, M.; Bullot, J. Zbid. 1960, 28. (c) Zakharkin, L. I.; Sorokina, L. P. Zzuest. Akad. Nauk SSSR, Otdel. Khim. Nauk 1959,936; Chem: Abstr. l960,54,1402e. (d) Zakharkin, L. I.; Sorokina, L. P. Zzuest. Akad. Nauk SSSR, Otdel. Khim. Nauk 1960, 1583; Chem. Abstr. 1969,55, 9276g. (3) (a) de la Mare, P. B. D. "MolecularRearrangements";de Mayo, P., Ed.; Interscience: New York, 1963; Vol 1, Chapter 2. (b) von Brachel, H.; Bahr,V. 'Methoden der Organischen Chemie (Houben-Weyl)";Georg Thieme Verlag: Stuttgqt, 1970; Band V/lc, p 421f. (4) Kyler, K. S.; Watt, D. S. J . Am. Chem. SOC.1983, 105, 619. (5) Kyler, K. S.; Watt, D. S. J . Org. Chem. 1981, 46, 5182. (6) (a) Peterson, D. J. J. Org. Chem. 1968,33, 780. (b) Hudrlik, P. F.; Peterson, D. J. Am. Chem. SOC.1975, 97, 1464.

1

2 X

X

I

i

4

3

Scheme 11" SR

no TMS

I

R'

6a, R = C H ,

7

b, R = n-C,H, c, R = C,H, SR

SR

R'

R"

8

R'

R"

9

a a, sec-C,H,Li, R ' , C = O ; b, s e c - C , H , L i , R ' 2 C = O ;c , NiCl,, 40% aqueous t - C , H , O H .

8 was readily separated from excess carbonyl compound. Despite this limitation, this a,y-dialkylation strategy provided an approach to the cholestane side chain based on the sequential construction of the C-20,22 and C-24,25 bonds from readily available carbonyl compounds: pregnan-20-ones and acetone. We speculated that a transition metal ion capable of chelating a C-24 thioether and a C-25 hydroxy group would favor the rearrangement' of dieno18 to dieno19 as shown in Scheme 11. We were gratified, therefore, that the exposure of dienols 8 to nickel chloride in 40% aqueous tert-butyl alcohol led to dienols 9 shown in Table 11. The substitution of other solvents such as methanol or ethanol for aqueous tert-butyl alcohol led to the corresponding rearranged methyl ethers and ethyl ethers, respectively. (7) For dylic rearrangements promoted by transition metals, see: (a) Oae, S.; VanderWerf, C. A. J. Am. Chem. SOC.1953, 75,2724. (b) Hatch, L. F.; Morgan, L. 0.; Tweedie, V. L. Zbid. 1952, 74, 1826 and references therein.

0022-3263/84/1949-1084$01.50/00 1984 American Chemical Society

J. Org. Chem., Vol. 49, No. 6, 1984 1085

Dienol Rearrangements

(6) with Table I. Sequential a,y-Dialkylation of 1-(Arylthio) or l-(Alkylthio)-l-(trimethylsilyl)-2-propenes Carbonyl Compounds isolated isolated yield yield R in 6 R',C=O of 7, % R" ,C=O of 8, %

a b

C6HS

C

CH, n-C,H,

C6H5

d e

C6H5

1

CH, C6HS C6H5 C,HS

j

C6HS

f

g h

C6HS C,HS

k 1

substrate 8 8b

3-pentanone 50 cyclopentyl methyl ketone 45 cyclododecanone 62 50 cyclododecanone cyclododecanone 59 3p-[(tetrahydro-2H-pyran-2-yl)oxy]-5-pregnen-2O-one 54 3p-[(tetrahydro-2H-pyran-2-yl)oxy]-5-pregnen20-one 57 3p-[( tetrahydro-2H-pyran-2-yl)oxy]-5-pregnen-20-one 57 3p- [( tetrahydro-2H-pyran-2-yl)oxy]-5-pregnen-20-one 57 3p-[(tetrahydro-2H-pyran-2-yl)oxy]-5-pregnen-20-one 57 6p-methoxy-3a,5a-cyclopregnan-20-one 53 3p-methoxy-5-pregnen-20-one 59

acetone acetone acetone acetone acetone acetone acetone 3-pentanone 4-anisaldehyde cyclohexanone acetone acetone

Table 11. Dienol Rearrangements of 8 to 9 Promted by Nickel Chloride conditions produc'ta 9 NiCI, ( 2 equiv), CH,OH

p

54 44 79 63 37 80

54 60 45 38 73 39

isolated yield, % 50

CH)

9b

a

8e

NiCI, ( 2 equiv), 40% aqueous t-C,H,OH

8f 8g

NiCI, (2 equiv), 40% aqueous t-C,H,OH NiCI, ( 2 equiv), 40% aqueous f-C,H,OH

9f, R = CH, 9g, R = C6Hs

70 73

81 81 81

NiCI, ( 2 equiv), 40% aqueous f-C,H,OH NiC1, ( 2 equiv), CH,OH NiCl, ( 2 equiv), C,HsOH

91, R = H 91, R = CH, 91, R = C,Hs

46 84 68

44

Stereochemistry in rearranged products assigned by analogy t o compound 9f.

However, other Lewis acids such as nickel acetate, nickel bis(acetylacetonate), palladium chloride, and cupric chloride proved less effective than nickel chloride in promoting the desired rearrangement. These catalysts gave varying proportions of rearrangement and dehydration products. These same triene products were the exclusive product of treating dienols 8 with Brransted acids. This curious specificity of nickel chloride for the desired rearrangement seemed inconsistent with the simple chelation notion for which a broad spectrum of Lewis acids might well suffice.

Nickel borideEand deactivated Raney nickelg were reported to cleave vinylic carbon-sulfur bonds without concomitant carbon-carbon double bond reduction. However, application of a Raney nickel catalyst which was (8) Boar, R. B.; Hawkins, D. W.; McGhie, J. F.; Barton, D. H. R. J. Chem. SOC.,Perkin Trans. 1 1973, 654. (9) (a) Rosenkranz, G.;Kaufmann, St.; Romo, J. J.Am. Chem. SOC. 1949, 71, 3689. (b) Romo, J.; Romero, M.; Djerassi, C.; Rosenkranz, G. Ibid. 1951, 73, 1528.

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Kyler, Bashir-Hashemi, and Watt

1984

Table 111. Desulfurizations Effected by Using Raney Nickel Deactivated b y Heating in Decalin substrate 1 2 a

conditions

productapb 1 3

72

8 h, 7 6 ' C

X6H5

isolated yield, %

c6+5

C6h5

e

1 2 h . 76 "C

f

36 h , 25 "C

a7

CBH17

65

CgHgS

In the case of 1 3 c , spectral a All products 13a, 1 3 b , and 13d-f were identical with commercially available samples. data was in accord with literature values: Kawamoto, K . ; Imanaka, T . ; Teranishi, S . Bull. Chem. SOC.Jpn. 1 9 7 0 , 43, 2512.

deactivated by heating in acetone to the desulfurization of dienols 8f and 9f led to significant amounts of overreduced products. A partial solution to this problem was achieved by using Raney nickel deactivated by heating in decalin for 5 h a t 120 "C. This material effected the desulfurization of dienols 8f and 9f to dienols 10 and l l , respectively, as shown in Scheme I11 and, in addition, converted various phenylthio enol ethers 12 to the desulfurized products 13 shown in Table 111. Desulfurization of either the E- or 2-isomer of 12b led, as expected, to the same mixture of olefins 13b; desulfurization of 12c furnished 13c in which the double bond had isomerized; and desulfurization of the sensitive dienol8f proceeded in poor yield. Despite these limitations, this deactivated Raney nickel catalyst was preferable to other literature procedures for the desired desulfurizations. Exposure of the desulfurized dienol 10 to nickel chloride in aqueous tert-butyl alcohol provided the rearranged, desulfurized dienol 11 in excellent yield which discounted the chelation-driven explanation for the observed dienol rearrangements. With regard to the rearrangements in steroid systems, it appeared that the rearrangement process relieved unfavorable steric interactions between the quaternary C-13 and C-20 centers in dienol 8f or dienol 10. Consistent with this view, dienols Sa and 8b, which lack this steric crowding, failed to undergo the desired rearrangement using nickel chloride in aqueous tert-butyl alcohol. However, exposure of dienol8b to nickel chloride in methanol furnished the rearranged methyl ether 9b. This suggested, of course, that steric crowding in the starting material was not the whole explanation for the observed rearrangements. The nature of the nickel species undoubtedly varied with solventloand accounted for the anomalous rearrangement (10) (a) Pearson, R. G.; Ellgen, P. Znorg. Chem. 1967, 6, 1379. (b) Bennetto, H. P.; Bulmer, R.; Caldin, E. F. "Hydrogen Bonded Solvent Systems";Corringbn, A. K.; Jones, P., Eds.; Taylor and Francis: London, 1968, p 335. (c) Bennetto, H. P.; Caldin, E.F. J. Chem. SOC.,Chem. Commun. 1969, 599. (d) Wilkins, R. G. Acc. Chem. Res. 1970, 3, 408.

of dienol 8b in methanol but not in aqueous tert-butyl alcohol. If, for example, the rearrangements follow an SN1' mechanism in which dissociation of a dienol to a carbonium ion is the rate-determining step, then the rearrangement rates should respond to solvent changes according to Winstein's Y values.11J2 However, in a brief kinetic study, we demonstrated that dienol8f rearranges approximately lo3faster in ethanol (Y = -2.03; ET = 51.9 kcal/moP) than in 20% aqueous ethanol (Y = 0; ET= 53.7 kcal/mo113). Consequently, either a simple SNl' process is not operative here or the structure of the dienol-nickel(I1) complex varies with solvent in such a way that nickel alcoholates are more reactive catalysts than nickel hydrates. One application for this rearrangement process involved a partial synthesis of 25-hydroxycholesterol (5) from pregnenolone (14). As shown in Scheme 111,the sequential condensation of l-(methylthio)-l-(trimethylsilyl)-2-propene (6a) with the tetrahydropyranyl ether14of 14 and subsequently with acetone furnished the dienol 8f. Rearrangement of dienol8f using nickel chloride (2 equiv) in 40% aqueous tert-butyl alcohol at 60 "C led to the rearranged dienol9f in 70% yield. The 20(22)E,23Z-stereochemistry in 9f was tentatively assigned on the basis of the following 'H NMR observations: (1)the absence of long-range coupling15between the C-21 methyl and C-22 vinyl proton in 9f and (2) the small, downfield chemical (11) (a) Grunwald, E.; Winstein, S. J. Am. Chem. SOC.1948, 70, 846. (b) Winstein, S.; Grunwald, E.; Jones, H. W. Ibid. 1951, 73, 2700. (c) Fainberg, A. H.; Winstein, S. Zbid. 1956, 78, 2770. (12) A revised Y scale has recently been reported which is based on the solvolysis of 1-adamantyl chloride: Bently, T. W.; Carter, G. E. J. Am. Chem. SOC.1982,104, 5741. (13) (a) Reichardt, C. Pure Appl. Chem. 1982,54,1867. (b) Reichardt, C. Angew. Chem., Znt. Ed. Engl. 1979,18, 98. (14) (a) Lettre, H.; Greiner, J.; Rutz, K.; Hoffmann, L.; Egle, A.; Bieger, W. Leibigs Ann. Chem. 1972, 758,89. (b)Bottin, J.; Fetizon, M. BulZ. Chim. SOC. Fr. 1972, 2344. (15) (a) Whipple, E. B.; Goldstein, J. H.; McClure, G. R. J. Am. Chem. SOC.1960,82, 3811. (b) Bates, R. B.; Carnigham, R. H.; Rakutis, R. 0; Schauble, J. H. Chem. 2nd. (London) 1962, 1020.

J. Org. Chem., Vol. 49, No. 6, 1984 1087

Dienol Rearrangements

progenitor of vitamin D3 metabolites, 25-hydroxycholeT h e high calcifer01,'~ and la,25-dihydroxycholecal~iferol.~ degree of (2-20 stereoselectivity observed in t h e reduction of the C-20(22) bond (20R:20S = 41) was consistent with t h e 20(22)E-stereochemistryZ1in 9f.

Scheme HIa

L o

Experimental Section 14, R = H 15, R = THP

TMS

I C

THPO

8 f , R = SCH, 10,R = H

d. e

-

THPO

9 f , R = SCH, 11, R = H 16,R = SO,CH,

HO

/bv

5 a a, CH,=CHCH( SCH,)Si( CH,), (6a), sec-C,H,Li; b, sec-C,H,Li followed by acetone; c, NiCl,, 40% aqueous t-C,H,OH, 60 "C; d, Ra(Ni), C,H,OH, 50 "C; e, p-TsOH, CH,OH. shift of t h e C-23 vinyl proton in t h e methylsulfonyl derivativeI6 derived from the oxidation of 9f. Stereoselective reduction" of the dienol9f using h e y nickel in ethanol at 50 "Cand methanolysis of the tetrahydropyranyl ether provided (20R)-25-hydroxycholesterol's (5), a synthetic (16)Matter, U. E.;Pascual, C.; Pretsch, E.; Pross, A.; Simon, W.; Sternhell, S. Tetrahedron 1969,25,691. (17)(a)Schmit, J. P.; Piraux, M.; Pilette, J. F. J. Og. Chem. 1975,40, 1586. (b) McMorris, T.C.; Schow, S. R. J. Org. Chem. 1976,41,3759.

Infrared spectra were determined on a Beckman Microlab 600 spectrometer. The abbreviation TF denotes thin film. NMR spectra were determined on a JEOL 270 MHz SC spectrometer. Mass spectra were determined on either a Varian MAT CH5, a DuPont CEC 21-10B,or a Kratos MS-50 mass spectrometer. Melting points were determined by using a Thomas-Hoover melting point apparatus and are uncorrected. Elemental analyses were performed by Atlantic Microlabs, Atlanta GA. 1-(Met hy1thio)-1-(trimethylsilyl)-2-propene(sa). To 13.2 g (150"01) of l-(methylthio)-2-propenein 100 mL of anhydrous THF at -78 "C, under a nitrogen atmosphere, was added 158 mL of 1.14 M sec-butyllithium in cyclohexane followed by 20 mL of anhydrous hexamethylphosphoramide. After stirring at -78 "C for 1.5 h, 45 mL (354mmol) of chlorotrimethylsilane was added rapidly and the mixture was stirred for an additional 30 min at -78 OC. The reaction was quenched with 200 mL of water, diluted with 100 mL of ether, washed successivelywith 100 mL of water and 100 mL of brine, and dried over anhydrous magnesium sulfate. Solvent were removed by distillation at atmospheric pressure and the residue was distilled to afford 11.4 g (47%) of 6a: bp 89-90 OC (69 mm); IR (TF) 1622,1247 cm-'; 'H NMR (CDCl,) 6 0.08 (s, 9,Si(CH3)3),2.01 (8, 3,SCH3),2.56 (d, J = 9.9Hz, 1, allylic H), 4.98 and 5.58 (m, 3, vinylic H); mass spectrum (70 eV), m / e (relative intensity) 160 (M', 12) 145 (18),77 (loo),73 (62),59 (14); exact mass spectrum calcd for C7H16SSi,160.0742;found, 160.0738. Deletion of hexamethylphosphoramide from the above procedure gave only 5.5 g (23%) of 6a and 7.8 g (33%) of 1-(methylthio)-3-(trimethylsilyl)-l-propene:bp 47-48 OC (3mm); IR (TF) 1624,1248 cm-'; 'H NMR (CDCl,) 6 0.01 (s,9,Si(CHJ3), 1.55 (d, J = 8.6 Hz, 2, allylic H), 2.22 (s, 3, SCH3),5.59 and 5.76 (m, 2, vinylic H); mass spectrum (70eV), m / e (relative intensity) 160 (M', 35), 145 (38),77 (26),73 (100);exact mass spectrum calcd for C7HlBSSi,160.0742;found, 160.0745. General Procedure for the Condensation of Anions of 6 with Ketones. (6~,205,232)-2O-Hydroxy-6-methoxy-24(phenylthio)-24-(trimethylsilyl)-3a,5a-cyclochol-23-ene (7k). The procedure of Kyler and Watt5 was repeated by using 3.3 g (10mmol) of 6j3-methoxy-3a,5a-cyclopregnan-20-one22 and 2.87 g (13mmol) of l-(phenylthio)-l-(trimethylsilyl)-2-propene (6c) to afford, after MPLC chromatographyz3in 1:3:5 ether-hexane(18)(a) Dauben, W. G.; Bradlow, H. L. J. Am. Chem. SOC.1950,72, 4248. (b) Ryer, A. I.; Gebert, W. H.; Murrill, N. M. Ibid. 1950,72,4247. (c) B e r g " , W.; Dusza, J. P. J.Org. Chem. 1958,23,459. (d) Beckwith, A.L. J. R o c . Chem. SOC.1958,194.(e) Beckwith, A.L. J. J. Chem. SOC. 1961,3162. (f) Campbell, 3.A.; Squires, D. M.; Babcock, J. C. Steroids 1969,13,567. (9) Varma, K. R.; Wickramasinghe, J. A. F.; Caspi, E. J. Biol. Chem. 1969,244,3951. (h) van Lier, J. E.; Smith, L. L. J. Org. Chem. 1970,35,2627.(i) Morisaki, M.; Rubio-Lightbourn, J.; Ikekawa, N. Chem. Pharm. Bull. 1973,21, 457. 6)Partridge, J. J.; Faber, S.; Uskokovic, M.R. Helu. Chim. Acta 1974,57, 764. (k) Narwid, T.A.; Cooney, K. E.; Uskokovic, M. R. Ibid. 1974,57,771. (1) Rotman, A.; Mazur, Y. J . Chem. SOC.,Chem. Commun.1974,15. (m) Wicha, J.; Bal, K. Ibid. 1975,968. (n) Salmond, W. G.; Maisto,K. D. Tetrahedron Lett. 1977,987. (0)Salmond, W. G.; Sobala, M. C.; Maisto, K. D. Ibid. 1977, 1237. (p) Salmond, W. G.; Sobala, M. C. Ibid. 1977,1695. (9)Salmond, W. G.; Barta, M. A.; Havens, J. L. J.Org. Chem. 1978,43,790.(r) Segal, G.M.; Torgov, I. V. Bioorg. Khim. 1979,51668. ( 8 ) Ochi, K.; Matsunaga, I.; Shindo, M.; Kaneko, C. Chem. Pharm. Bull. 1979,27,252.(t) Cohen, Z.;Mazur, Y. J. Org. Chem. 1979,44,2318. (19)(a) Blunt, J. W.; DeLuca, H. F. Biochemistry 1969,8, 671. (b) Hakes, S.J.; Van Vliet, N. P. Red. Trau. Chim. Pays-Bas 1969,88,1080. (20)Barton, D.H.R.; Hesse, R. H.; Pechet, M.M.; Rizzardo, E. J. Chem. SOC.,Chem. Commun. 1974,203. (21)The high degree of selectivity for the 20R epimer during Raney nickel reduction of 9f contrasts with that observed in similar reductions: DuBois, G. E. J . Org. Chem. 1982,47, 5035. (22)Butenandt, A.; Grosse, W. Chem. Ber. 1937,70B,1446. (23)Purification was facilitated by treating the crude product with sodium borohydride which reduced the unreacted ketone to an alcohol having lower Rr than the desired product 7k.

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J. Org. Chem., Vol. 49, No. 6, 1984

dichloromethane, 2.94 g (53%) of 7k which could not be induced to crystallize: IR (TF) 3500,1585 cm-'; 'H NMR (CDCI,) 6 0.12 (s, 9, Si(CH,),), 0.96 (s, 3, (2-18 angular CH,), 1.10 (s, 3, C-19 angular CH,), 1.38 (s, 3, C-21 CH,), 2.84 (s, 1, OH), 3.40 (s, 3, OCH,), 6.77 (t, J = 6.8 Hz, 1, C-23 vinylic H), and 7.0-7.3 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 534 (M+ - HzO, 8), 502 (4), 281 (ll),222 (loo), and 73 (54). Anal. Calcd for C,,H5,OzSSi: C, 73.85; H, 9.48. Found: C, 74.01; H, 9.49. Summary of Spectral Data for Adducts 7 in Table I. 7a: IR (TF) 3440, 1581, 1245 cm-'; 'H NMR (CDCl,) 6 0.04 (s, 9, Si(CH,),), 0.86 (t, J = 7.9 Hz, 6, CH,CH,), 1.48 (q, J = 7.9 Hz, 4, CHzCH3),2.58 (d, J = 6.6 Hz, 2, allylic H), 6.71 (t,J = 6.6 Hz, 1,vinylic H), 7.19 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 308 (M', 0.6), 222 (55), 167 (65), 87 (43), 73 (100);exact mass spectrum calcd for C17HBOSSi,308.1619 found, 308.1635. 7b: IR (TF) 3460,1582,1246 cm-'; 'H NMR (CDC1,) 6 0.12 (s, 9, Si(CH3),), 1.23 (9, 3, C(OH)CH,), 2.69 (d, J = 6.6 Hz, 2, allylic H), 6.85 (t,J = 6.6 Hz, 1,vinylic H), 7.28 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 334 (M', lo), 316 (6), 222 (53), 167 (43), 73 (100); exact mass spectrum calcd for ClsH,,OSSi, 334.1765; found, 334.1786. 7c: IR (TF) 3315,1582,1243 cm-l; 'H NMR (CDCl,) 6 0.18 (s, 9, Si(CH,),), 2.18 (s, 3, SCH,), 2.50 (d, J = 6.6 Hz, 2, allylic H), 6.37 (t,J = 6.6 Hz, 1,vinylic H); mass spectrum (70 eV), m / e (relative intensity) 342 (M', 0.3), 325 (3), 255 (4), 160 (100);exact mass spectrum calcd for ClSH380SSi,342.2412; found, 342.2401. 7d: IR (TF) 3404, 1590 cm-'; 'H NMR (CDCl,) 6 0.18 (s, 9, Si(CH3),), 0.90 (t,J = 7.3 Hz, 3, S(CHZ),CH3),2.53 (d, J = 6.5 Hz, 2, allylic CHz),2.60 (t,J = 6.5 Hz, SCH2(CH2)&H3),6.45 (t, J = 6.5 Hz, 1,vinylic H); mass spectrum (70 eV), m / e (relative intensity) 384 (M', 4), 369 (3), 327 (9), 202 (100). Anal. Calcd for CZ2HM0SSi:C, 68.68; H, 11.53. Found: C, 68.92; H, 11.66. 7e: see ref 5. 7 f IR (KBr) 3460,1575,1243, cm-'; 'H NMR (CDCl,) 6 0.19 (s, 9, Si(CH,)J, 0.87 (s, 3, (2-18 angular CH,), 1.01 (s, 3, C-19 angular CH3), 1.29 (6, 3, C-21 CH,), 2.19 (s, 3, SCH,), 2.54 (m, 2, (2-22 allylic H), 4.72 (m, 1,H-2' in THP), 5.35 (m, 1,C-6 vinylic H), 6.27 (t, J = 6.6 Hz, 1,C-23 vinylic H); mass spectrum (70 eV), m / e (relative intensity) 560 (M', 0.5), 297 (18), 160 (loo),85 (63). Anal. Calcd for C33H5603SSi:C, 70.65; H, 10.06. Found: C, 70.75; H, 10.08. 7g: see ref 5. 71: see ref 5. General Procedure for the Reaction of Dianions from Adducts 7 with Carbonyl Compounds. (3j3,20SI22E)-24(Methy1thio)-3-[ (tetrahydro-2H-pyran-2-yl)oxy]cholesta5,22,24-trien-20-01(8f). To 1.68 g (3 mmol) of 7f in 20 mL of anhydrous THF at -78 "C under a nitrogen atmosphere was added 7.9 mL (9 mmol,1.5 eq) of 1.14 M sec-butyllithium in cyclohexane followed by 0.5 mL of anhydrous hexamethylphosphoramide. After stirring for 2 h at -78 "C, this solution was added, via a syringe jacketed with dry ice, to 8 mL of anhydrous acetone at 0 "C and the mixture was stirred an additional 1h at 0 "C. The reaction was quenched with 25 mL of water, diluted with 100 mL of ether, washed successively with 50 mL of water and 50 mL of brine, and dried over anhydrous magnesium sulfate. Removal of solvent gave a white solid which was recrystallized from ethanol to afford 1.27 g (80%)of 8f: mp 119-120 OC; IR (KBr) 3460,1670, 1640, cm-'; 'H NMR (pyridine-d,) 6 1.06 (s,3, C-18 angular CH,), 1.18 (s,3, C-19 angular CH,), 1.72 (s,3, C-21 CH,), 1.88 and 2.23 (two s, 6, (2-26, C-27 vinylic CH,), 2.17 (s, 3, SCH,), 4.95 (m, 1, H-2' in THP), 5.45 (m, 1, C-6 vinylic H), 6.68 and 6.95 (two d, J = 15 Hz, C-22, C-23 vinylic H); mass spectrum (70 eV), m / e (relative intensity) 528 (M', 37), 510 (16), 255 (4), 87 (100). Anal. Calcd for C&5203& C, 74.95; H, 9.91. Found C, 74.89 H, 9.93. Summary of Spectral Data for Dienols 8 in Table I. 8a: IR (TF) 3450,1620, 1575 cm-'; 'H NMR (CDCl,) 6 0.67 (t, J = 7 Hz, 6, CHzCH3),1.43 (q, J = 7 Hz, 4, CHzCH,), 2.07, 2.14 (two s, 6, two vinylic CH,), 6.00, 6.64 (two d, J = 15 Hz, 2, vinylic H), 7.12 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 276 (M', 25), 247 (54), 167 (60), 137 (49),57 (100);exact mass spectrum calcd for Cl7HZ40S,276.1541; found, 276.1551.

Kyler, Bashir-Hashemi, and Watt

8b: IR (TF) 3450, 1625, 1580 cm-'; 'H NMR (CDClJ 6 1.02 (s, 3, C(OH)CH,), 1.90,1.98 (two, s, 6, two vinylic CH,), 5.97, 6.50 (two d, J = 15 Hz, 2, vinylic H), 7.00 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 302 (M', ll),284 (32), 233 (loo), 151 (60), 110 (40), 91 (43); exact mass spectrum calcd for C19H.&S, 302.1699; found, 302.1707. 8c: IR (TF) 3320, 1700, 1620 cm-'; 'H NMR (CDCl,) b 1.92, 2.08 (two, s, 6, two vinylic CHJ, 2.11 (s, 3, SCH,), 6.26, 6.51 (two d, J = 15 Hz, 2, vinylic H); mass spectrum (70 eV), m / e (relative intensity) 310 (M+,9), 292 (18), 277 (25), 237 (35), 183 (37),95 (54), 55 (96), 54 (100);exact mass spectrum calcd for CISH3,0S, 310.2331; found, 310.2328. 8d: IR (TF) 3420, 1695, 1633 cm-'; 'H NMR (CDClJ 6 0.88 (t, J 7.3 Hz, 3, S(CHZ),CH3),1.92, 2.10 (two s, 6, vinylic CHJ, 6.26, 6.53 (two d, J = 15.4 Hz, 2, vinylic H); mass spectrum (70 eV), m / e (relative intensity) 334 (M+- HzO,4), 277 (ll),178 (24), 98 (44), 55 (100);exact mass spectrum (no parent but M+ - HzO) calcd for C22H38S,334.2694; found, 334.2670. &: IR (TF)3386,1582cm-'; 'H NMR (CDC13)6 2.05,2.12 (two s, 6, vinylic CH,), 6.18, 6.66 (two d, J = 15.4 Hz, 2, vinylic H), 7.0-7.2 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 372 (M+,25) 357 (3), 354 (5), and 263 (100);exact mass spectrum (no parent but M+ - HzO calcd for CZ4H3,S,354.2390; found, 354.2382. 8g: mp 123.5-124 "C; IR (KBr) 3460, 1590 cm-'; 'H NMR (CDCl,) 6 0.65, 0.96 (two s, 6, C-18, (2-19 angular CHJ, 1.20 (s, 3, C-21 CH,), 1.99, 2.04 (two s, 6, C-26, C-27 CH,), 4.65 (m, 1, H-2' in THP), 5.24 (m, 1, C-6 vinylic H), 6.12, 6.45 (two d, J = 15 Hz, 2, C-22 and C-23 vinylic H), 6.90-7.28 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 590 (M', 2), 572 (ll),488 (7), 483 (9), 233 (30), and 85 (100). Anal. Calcd for C3H,0,S: C, 77.24; H, 9.21. Found: C, 77.00; H, 9.21. 8h: mp 121-122 "C (from methanol); IR (KBr) 3472,1580cm-'; 'H NMR (CDC1,) 6 0.73,0.99 (two s, 6, C-18, C-19 angular CH3), 1.24 (s, 3, C-21 CH,), 4.70 (m, 1, H-2' in THP), 5.58, 5.67 (two d, J = 16 Hz, 2, C-22, C-23 vinylic H), 7.18-7.39 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 600 (M+ 18, l),532 (16), 448 (32), 256 (62), 135 (100). Anal. Calcd for C4OHsO3S: C, 77.62; H, 9.44. Found C, 77.38; H, 9.14. 8i: mp 190-191 "C (from methanol); IR (KBr) 3460,1600,1585 cm-'; 'H NMR (CDCl,) 6 0.63,0.98 (two s, 6, C-18, '2-19 angular CH,), 1.23 (s, 3, C-21 CH,), 3.77 (s, 3, OCH,), 4.70 (m, 1, H-2' in THP), 5.33 (m, 1, C-6 vinylic H), 6.12, 6.41 (two d, J = 16 Hz, 2, C-22, C-23 vinylic H), 6.87-7.72 (m, 9, aromatic H) ; mass spectrum (70 eV), m / e (relative intensity) 668 (12), 650 (78), 321 (75), 229 (go), 121 (100). Anal. Calcd for CaHE04S: C, 77.21; H, 8.44. Found: C, 77.12; H, 8.44. 8j: IR (TF) 3472, 1582 cm-'; 'H NMR (CDC13)6 0.63, 1.00 (two s, 6, C-18, C-19 angular CH,), 1.23 (s, 3, C-21 CH,), 4.70 (m, 1, H-2' in THP), 5.33 (m, 1, C-6 vinylic H), 6.16, 6.62 (two d, 2, J = 16 Hz, C-22, C-23 vinylic H), 7.13-7.27 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 401 (0.5), 383 (l),298 (60), 149 (71), 85 (100); exact mass spectrum (no parent but M+ - HzO) calcd for C41H5602S, 612.3999; Found, 612.4000. 8k: IR (KBr) 3480, 1585 cm-'; 'H NMR (CDCl,) 6 0.73 (s, 3, C-18 angular CH,), 0.99 (s, 3, C-19 angular CH,), 1.24 (s, 3, C-21 CH,), 2.06, 2.12 (two s, 6, vinylic CH,), 3.31 (s, 3, OCH3),6.18, 6.62 (two d, J = 15.1 Hz, 2, vinylic H), 7.0-7.2 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 520 (M', 18), 502 (64), 411 (20), 233 (52), 91 (100). This material deteriorated significantly within several hours at 25 "C, and a satisfactory analysis was not obtained. 81: mp 119-119.5 O C ; IR (KBr) 3430, 1580 cm-'; 'H NMR (CDCl,) 6 0.66 (s, 3, C-18 angular CH,), 0.97 (s, 3, C-19 angular CH,), 1.24 (s, 3, C-21 CH,), 2.06, 2.12 (two s, 6, vinylic CH,), 3.34 (s, 3, OCH,), 6.20, 6.62 (two d, J = 15.4 Hz, 2, vinylic H), 7.0-7.2 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 520 (M', 7), 502 (55), 411 (23), 242 (351, 233 (100). Anal. Calcd for C2H,02S: C, 78.42; H, 9.29. Found: C, 78.43; H, 9.32. General Procedure for the Rearrangement of Dienols 8 in 40% Aqueous tert -Butyl Alcohol. (3(3,20(22)3,232)-24(Methy1thio)-3-[(tetrahydro-2H-pyran-2-yl)oxy]cholesta-

Dienol Rearrangements

5,20(22),23-trien-25-01(9f),To 528 mg (1"01) of 8f suspended in 20 mL of 40% (v/v) aqueous tert-butyl alcohol was added 474 mg (2 mmol) of nickel chloride hexahydrate. The mixture was heated at 60 "C for 26 h, diluted with 100 mL of ether, washed successively with 50 mL of water and 100 mL of brine, and dried over anhydrous magnesium sulfate. The product was chromatographed on silica gel in 1:4 ethyl acetate-hexane to afford 375 mg (71%) of 9f which was recrystallized from ethyl acetate mp 141.5-143 "C; IR (KBr) 3450,1625 cm-'; 'H NMR (CDC13)6 0.61 (8, 3, C-18 angular CH,), 1.01 (e, 3, C-19 angular CH3), 1.45 (8, 6, C-26, C-27 CH3), 1.85 (s,3, C-21 vinylic CHJ, 2.22 (8, 3, SCHJ, 4.72 (m, 1,H-2' in THP), 5.35 (m, 1C-6 vinylic H), 6.45,6.89 (two d, J = 10.5 Hz, 2, C-22, C-23 vinylic H); mass spectrum (70 eV), m / e (relative intensity) 528 (M', 39), 510 (13), 426 (4), 87 (100). Anal. Calcd for C33H5203S: C, 74.95; H, 9.91. Found C, 74.89; H, 9.93. Summary of Spectral Data for Rearranged Dienols 9 in Table 11. 9e: IR (TF)3405,1628,1580 cm-'; 'H NMR (CDC1,) 6 1.47 ( ~ , 6C(OH)(CHJZ), , 2.09, 2.27 (two t, J = 6.6 Hz, 4, allylic CH,), 6.36 (d, J = 11Hz,1, vinylic H), 7.09 (m, 1,vinylic H), 7.20 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity), 372 (M', 44), 354 (63), 245 (32), 119 (56), 81 (65), 55 (100); exact mass spectrum calcd for C24H360S,372,2482; found, 372.2489. 9g: IR (KBr) 3420,1622,1580 cm-'; 'H NMR (CDC13)6 0.37 (9, 3, C-18 angular CH3), 0.98 (9, 3, C-19 angular CH3), 1.47 (8, 6, C-26, C-27 CH,), 1.86 (s, 3, (3-21 vinylic CH3),4.70 (m, 1,H-2' in THP), 5.32 (m, 1, C-6 vinylic H); 6.30 (d, J = 10.5 Hz, 1,vinylic H), 7.08 (m, 1, vinylic H), 7.20 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 590 (M+, 4), 572 (25), 488 (411, 85 (100); exact mass spectrum calcd for C38Hb403S,590.3783; found, 590.3779. 91 (R = H in Table II): IR (TF)3420,1700,1625cm-';'H NMR (CDCl,) 6 0.37 (8, 3, (2-18angular CH,), 0.97 (8, 3, (2-19 angular CH3), 1.47 (s, 6, C-26, C-27 CH,), 1.86 (8, 3, C-21 vinylic CH3), 3.35 (s,3, OCH,), 5.35 (m, 1,C-6 vinylic H), 6.30 (d, J = 10.5 Hz, 1, C-23 vihylic H), 7.09 (m, 1, C-22 vinylic H), 7.20 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 520 (M', l), 502 (80),242 (22), 147 (loo), 133 (42); exact mass spectrum calcd for CHHa02S, 520.3196; found, 520.3175. General Procedure for the Rearrangement of Dienols 8 in Alcoholic Media. 3j3,25-Dimethoxy-24-(phenylthio)cholesta-5,20(22),23-triene (91,R = CH,in Table 11). A mixture of 41.4 mg (0.796 mmol) of 81 and 28.9 mg (0.123 "01) of nickel chloride hexahydrate in 3 mL of methanol was refluxed 2 h. The methanol was evaporated, and the residue was chromatographed on silica gel in 1:3:5 ether-hexane-dichloromethane to afford 35.6 mg (84%) of 91 (R = CH3 in Table 11)as a foam which could not be induced to crystallize: IR (TF) 1625, 1580 cm-'; 'H NMR (CDCl,) 6 0.39 (s, 3, C-18 angular CH,), 0.98 (8, 3, C-19 angular CH3), 1.43 (8, 6, C-26, C-27 CH3), 1.87 (8, 3, C-21 CH3), 3.16 (8, 3, C-25 OCH3),3.35 (s, 3, C-38 OCH3),5.33 (m, 1,C-6 vinylic H), 6.34 (d, J = 10.8 Hz, 1,C-22 vinylic H), 7.0-7.3 (m, 5, aromatic H); mass spectrum (70 eV), m/e (relative intensity) 534 (M+,63), 502 (73), 279 (14), 242 (27), 216 (42), 149 (74), 73 (100). Anal. Calcd for CSHw0& C, 78.61; H, 9.42. Found C, 78.52; H, 9.45. Summary of Spectral Data for Rearranged Dienyl Ethers 9 in Table 11. 9b: IR (TF) 1628,1580 cm-'; 'H NMR (CDCl,) 6 1.40 ( 8 , 6, C(OCH3)(CH3)a,1.83 (8, 3, vinylic CH,), 3.15 (8, 3, OCH,), 6.33 (d, J = 10.5 Hz, 1,vinylic H), 7.10 (m, 1, vinylic H), 7.20 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 316 (M', 4), 284 (31), 181 (loo), 91 (33), 73 (72);exact mass spectrum calcd for CzoHz80S,316.1861; found, 316.1884. 91 (R = CzH6in Table 11): IR (TF) 1625,1581 cm-'; 'H NMR (CDCl,) 6 0.39 (s, 3, C-18 angular CH3), 0.97 ( 8 , 3, C-19 angular CH3), 1.17 (t,J = 7 Hz, 3, OCH,CH3), 1.43 ( ~ , 6C-26, , (2-27 CH3), 1.86 (s,3, C-21 vinylic CH3),3.33 (9, J = 7 Hz, 2, OCH,CH,), 3.35 (s, 3, OCH,), 5.40 (m, 1, C-6 vinylic H), 6.37 (d, J = 10.5 Hz, 1, vinylic H), 7.09 (m, 1,vinylic H), 7.18 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 548 (M+, I),502 (loo), 231 (83), 51 (63). Anal. Calcd for C36H520#: C, 78.79; H, 9.55. Found C, 78.61; H, 9.59. (3&2OS,22E)-3-[ (Tetrahydro-2H-pyran-2-yl)oxy]cholesta-5,22,24-trien-20-01(10). The procedute described for the

J. Org. Chem., Vol. 49, No. 6,1984 1089 preparation of 11 was repeated by using 42.2 mg (0.08 mmol) of 8f to afford 5 mg (11%) of 10 IR (KBr) 3390,1612 cm-'; 'H NMR (CDC13)6 0.81 (s,3, C-18 angular CH3), 1.00 (s, 3, C-19 angular CH,), 1.35 (e, 3, (2-21 CH,), 1.76 (s,6, (2-26 and C-27 vinylic CH3), 4.71 (m, 1, H-2' in THP), 5.34 (m, 1, C-6 vinylic H), 5.69 (d, J = 15 Hz, 1, C-22 vinylic H), 5.80 (d, J = 11.2 Hz, 1, (2-24 vinylic H),6.36 (dd, J = 15 Hz and 11.2 Hz, 1, C-23 vinylic H); mass spectrum (70 eV), m / e (relative intensity) 464 (M+ - HzO, 35), 362 (68), 125 (100);exact mass spectrum (no M+ but M+ - H,O) calcd for C32HeO2, 464.3616; found, 464.3654. (@,20(22)E,23E)-3-[ (Tetrtihydro-2H-pyran-2-yl)oxy]cholesta-5,20(22),23-trien-25-01(11). To 42.4 mg (0.08 mmol) of 9f ih 15 mL of absolute ethanol and ca. 7 mL of ethyl acetate was added ca. 200 mg of h e y nickel which was deactivated by prior heating in decalin for 2 at 120 "C. The suspension was heate4 to reflux for 21 h. The product was filtered and concentrated to give a white solid which was chromatographed on silica gel in 1:4 ethyl acetate-hexane to afford 30.6 mg (80%) of 11: R,0.24; IR (KBr) 3396, 1614 cm-'; 'H NMR (CDCl,) 6 0.57 (8, 3, C-18 angular CH3), 1.01 (9, 3, C-19 angular CH3), 1.36 (8, 6; C-26 and C-27 CH3), 1.80 (8, 3, C-21 vinylic CH,), 4.72 (m, 1, H-2' in THP), 5.35 (m, 1, C-6 vinylic H), 5.74 (d, J = 15.1 Hz, 1, C-24 vinylic H), 5.89 (d, J = 10.5 Hz, 1,C-22 vinylic H), 6.51 (dd, J = 15 Hz and 10.5 Hz, 1, (2-23 vinylic H); mass spectrum (70 eV), m / e (relative intensity) 464 (M+ - HzO, 12), 362 (58), 149 (100); exact mass spectrum (no M+ but M+ - HzO) calcd for C32HuO2, 464.3645; found 464.3645. 2-Phenyl-l-(phenylthio)cyclohexene(12a). A solution of 1.74 g (10 mmol) of 2-phenylcyclohexanone, 50 mg of p toluenesulfonic acid, 1mL (9 mmol) of thiophenol, and 20 mL of toluene was refluxed undei a Dean-Stark trap for 6 h under a nitrogen atmosphere. The product was diluted with ethyl acetate, washed successivelywith saturated sodium bicarbonate solution and brine, and dried over d y d r o u s sodium sulfate. The product was chromatographed on Merck silica gel 60 using 1:l dichloromethane-hexane to afford 2.1 g (88%)of 12a: mp 39-40 "C; IR (TF) 1592, 1579, 1473, 1437 cm-'; 'H NMR (CDCl,) 6 1.65-1.87 (m, 4, CH,), 2.22-2.32 (m, 2, allylic H), 2.42-2.52 (m, 2, allylic H), 7.0-7.4 (m, 10, aromatic H); '% NMR (CDClJ 6 22.9, 23.8,31.1,33.8,125.6,126.8,127.8,127.9,128.7,129.3,132.2,138.4, 141.0, 142.3; mass spectrum (76 eV), m / e (relative intensity) 266 (M', loo), 157 (30), 129 (45), 115 (30). Anal. Calcd for ClsH18S: C, 81.20; H, 6.76; S, 12.03. Found: C, 81.16; H, 6.82; S, 12.10. 1-(Pheny1thio)cyclododecene (12b). The procedure described for the preparation of 12a was repeated using 1.82 g (10 "01) of cyclododecanone, 100 mg of p-toluenesulfonic acid, and 1mL (9 "01) of thiophenol to afford, after chromatography on Mekck silica gel 60 using 1:l dichloromethane-hexane, 2.05 g (83%) of 12b as a mixture of E I Z - i s o m e r ~ .Further ~~ chromatography on Merck silica 60 using hexane gave 1.0 g (40%) of (E)-12b(IR (TF) 1580, 1473, 1457 cm-'; 'H NMR (CDC13) 6 1.09-1.57 (m, 16, CH2),2.15-2.27 (m, 2, allylic H), 2.3-2.45 (m, 2, allylic H), 6.1 (t,J = 8 Hz, 1, vinylic H), 7.1-7.3 (m, 5, aromatic H); '% NMR (CDCld 6 23.6, 24.1,24.3,24.5,25.8,26.0,26.6,27.18, 29.19, 125.7, 128.7, 129.5, 132.3, 135.3, 139.4) and 0.93 g (38%) of (Z)-12b (mp 33-34 "C; IR (Nujol) 1531,1462,1441cm-'; 'H NMR (CDC13) 6 1.12-1.86 (m, 16, CH2),2.15-2.35 (m, 4, allylic H), 5.90 (t,J = 9 Hz, 1,vinylic H), 7.15-7.38 (m, 5, aromatic H); 13C NMR (CDC13) 6 22.1, 22.7, 23.7, 24.3, 24.5, 25.0, 25.6, 26.6, 26.8,126.1, 128.7, 130.0, 134.4,138.4; mass spectrum (70 eV), m / e (relative intensity) 274 (M+, loo), 164 (60), 150 (80), 109 (70)). Anal. Calcd. for C18HES: C, 78.83; H, 9.48; S, 11.67. Found: C, 78.70; H, 9.49; S, 11.60. 4-Phenyl-4-(phenylthio)-l-butene (12c). To a solution of 2 g (10 mmol of benzyl phenyl sulfide and 2 mL of hexamethylphosphoramide in 40 mL of anhydrous THF at -78 "C under a nitrogen atmosphere was added 7.8 mL of 1.3 M (10 mmol) sec-butyllithium in hexane. The solution was allowed to stir for 2 h at -78 "C and 1mL (12 mmol) of allyl bromide was added dropwise. The solution was stirred for 2 h at -78 "C and quenched with ethyl acetate. The product was washed successively with saturated ammonium chloride solution and brine and dried (24) Trost, B. M.; Lavoie, A. C. J. Am. Chem. SOC.1983, 105,5075.

1090 J. Org. Chem., Vol. 49, No. 6, 1984 over anhydrous magnesium sulfate. The product was chromatographed on Merck silica gel 60 using 1:6 ethyl acetate-hexane to afford 2.10 g (88%) of 12c: IR (TF) 1580,1488,1476 cm-'; 'H NMR (CDCl,) 6 2.62-2.72 (m, 2, allylic H), 4.1 (t, J = 8 Hz, 1, benzylic H), 4.95-5.04 (m, 2, vinylic H), 5.62-5.79 (m, 1,vinylic H), 7.1-7.3 (m, 10, aromatic H); 13CNMR (CDC1,) 6 40.3, 53.1, 117.1, 127.0, 127.1, 127.8, 128.2, 128.5, 132.3, 134.7, 135.0, 141.3; mass spectrum (70 eV), m/e (relative intensity) 240 (351, 199 (80), 169 (12), 131 (loo), 109 (16). Anal. Calcd. for CI6Hl6S: C, 80.00; H, 6.66; S, 13.33. Found: C, 79.90; H, 6.71; S, 13.28. 3-(Phenylthio)-5a-cholest-2-ene (12d). The procedure described for the preparation of 12a was repeated using 818 mg (2.12 mmol) of 5a-cholestan-3-one, 5 mg of p-toluenesulfonic acid, and 0.22 mL (2.0 mmol) of thiophenol to afford, after chromatography on Merck silica gel 60 using 1:5 dichloromethane-hexane, 584 mg (61%) of 12d: mp 83-83.5 "C (from ethyl acetate-methanol); IR (KBr) 1580,1465,1440 em-'; 'H NMR (CDCI,) 6 0.65 (s,3, '2-18 angular CH,), 0.77 (s, 3, C-19 angular CH,), 6.0 (m, 1, C-2 vinylic H), 7.1-7.3 (m, 5, aromatic H); mass spectrum (70 eV), m/e (relative intensity) 478 (loo), 162 (45). Anal. Calcd for C3,HWS:C, 82.78; H, 10.53. Found: C, 82.67; H, 10.55. 3-(Phenylthio)cholesta-3,5-diene(12f). The procedure described for the preparation of 12a was repeated by using 1.0 g (2.6 "01) of cholest-4-en-3-one,70 mg of pyridine hydrochloride, 2 mL of absolute ethanol, and 0.25 mL (2.2 mmol) of thiophenol to afford, after chromatography using 1:l dichloromethanehexane, 420 mg (40%) of 12E mp 68-70 "C (from methanol); UV (CHZClz)A, 264 nm; 'H NMR (CDCl,) 6 0.70 (s,3, C-18 angular CH,), 5.21-5.30 (m, 1,vinylic H), 6.2 (s, 1,vinylic H), 7.15-7.34 (m, 5, aromatic H). Anal. Calcd for C3,HaS: C, 83.19; H, 10.08; S, 6.72. Found: C, 83.10; H, 10.18; S, 6.53. Deactivated Raney Nickel. A mixture of ca. 2 g of Raney nickelz5was heated in 20 mL of decalin (distilled from sodium) at 120 "C for 5 h (unless otherwise specified). Note: this deactivated Raney nickel was pyrophoric and exposure to air should be minimized. General Procedure for Desulfurization Using Raney Nickel Deactivated by Heating in Decalin. A mixture of 200 mg (1.2 mmol) of 12a,ca. 2 g of deactivated Raney nickel, 2 mL of ethyl acetate, and 8 mL of absolute ethanol was refluxed for 8 h. The mixture was diluted with dichloromethane, filtered through a Celite pad, cqncentrated, and chromatographed on a Merck silica gel F254 preparative layer plate to afford 86 mg (72%) of 1-phenylcyclohexene (13a)identical with an authentic sample.

Kyler, Bashir-Hashemi, and Watt 5.34 (m, 1, C-6 vinylic H), 6.82, 7.14 (two d, J = 11 Hz, 2, C-22, C-23 vinylic H); mass spectrum (70 eV), m/e (relative intensity) 459 (M' - THP, 2) 440 (12), 85 (100); exact mass spectrum (no M+ but Mt- THP) d c d for CBH,03S, 459.2915; found, 459.2942. (20R)-25-Hydroxycholesterol(5).A mixture of 75 mg (0.14 mmol) of 9f and 700 mg of Raney nickelz5in 20 mL of absolute ethanol was heated at 50 "C for 4 h. The mixture was filtered, and the ethanol was evaporated. The residue was dissolved in 15 mL of methanol, and 10 mg of p-toluenesulfonic acid monohydrate was added. After stirring for 1h at 25 "C, the mixture was diluted with 50 mL of ethyl acetate. The product was washed successively with saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. The product was chromatographed on Merck silica gel 60 in 1:l ethyl acetate-benzene to afford 29.2 mg (52 %) of (20R)-25-hydroxycholesterol (5): 13CNMR 6 37.24 (C-l),31.64 (C-2),71.74 (C-3), 42.32 (C-4),140.76 (C-5), 121.4 (C-6),29.36 (C-7),29.19 (C-8),50.10 (C-g), 36.5 (C-lo), 21.07 (C-11), 39.77 (C-12), 42.32 (C-13), 56.75 (C-14),24.27 (C-15),28.24 (C-16),56.05 (C-17), 11.88 (C-18),19.41 (C-19),35.75 (C-20), 18.70 (C-21),36.45 (C-22),20.77 (C-23),44.42 (C-24), 71.11 (C-25), 31.89 (C-26,27). The product 5 also had infrared, 'H NMR, and mass spectra identical with those of an authentic sample.

Acknowledgment. We thank the National Institutes of Health (CA 30065) for their generous financial support, Dr. Richard A. Heppner of the University of Wyoming Research Corporation for determining mass spectra, and Drs. J. J. Partridge (Hoffmann-LaRoche), W. G. Salmond, (The Upjohn Company), and R. Chorvat (G. D. Searle and Co.) for various authentic samples. Registry No. 5,2140-46-7; 6a,84051-40-1; 6b,84029-11-8; 6c,

78905-13-2; 7a, 88904-65-8; 7b, 88904-66-9; 7c, 88904-67-0;7d, 88904-68-1; 7e, 79409-68-0; 7f, 88930-41-0; 7g, 88930-42-1; 7k, 88930-43-2; 71, 88930-44-3; 8a, 88904-69-2; 8b, 88904-70-5; 8c, 84051-48-9; 8d, 84051-49-0; 8e, 84051-50-3; 8f, 84056-76-8; 8g, 84051-51-4; 8h, 84056-77-9; 8i, 88904-71-6; Sj, 88904-72-7; 8k, 84051-52-5; 81, 84051-53-6; 9b, 88904-73-8; 9e, 88904-74-9; 9f, 84051-41-2;9g,84051-55-8; 91 (R = H), 84051-56-9; 91 (R = CH,), 84056-97-3; 91 (R = CZH,), 84051-57-0; 10, 88904-75-0; 11, 84051-44-5; 12a, 88904-76-1; (E)-12b, 85894-83-3; (Z)-12b, 85894-84-4;12c,21213-27-4; 12d,88904-77-2;12e,132-65-0;12f, 88904-78-3; 13a,771-98-2; (E)-13b,1486-75-5;(Z)-13b,1129-89-1; 13c, 824-90-8; 13d, 570-73-0; 13e, 92-52-4; 13f, 747-90-0; 15, 35961-41-2; 16, 84051-43-4; NiCl,, 7718-54-9; 1-(methy1thio)-2propene, 10152-76-8;chlorotrimethylsilane, 75-77-4; 1-(methyl(3~,20E,232)-24-(Methylsulfonyl)-3-[(tetrahydro-2H- thio)-3-(trimethylsilyl)-l-propene,88904-79-4; 2-phenylcyclopyran-2-yl)oxy]cholesta-5,20(22),23-trien-25-01(16). To 37 hexanone, 1444-65-1;thiophenol, 108-98-5;benzyl phenyl sulfide, mg (0.07 mmol) of 9f in 2.0 mL of dichloromethane at 25 "C was 831-91-4;allyl bromide, 106-95-6;5a-cholestan-3-one, 566-88-1; added 31 mg (0.18 mmol) of m-chloroperoxybenzoic acid. After cholest-4-en-3-one, 601-57-0; 3-pentanone, 96-22-0; cyclopentyl stirring for 30 min, the mixture was diluted with 50 mL of ether, methyl ketone, 6004-60-0;cyclododecanone, 830-13-7;6P-methwashed successively with saturated aqueous sodium bicarbonate oxy-3a,5a-cyclopregnan-20-one, 32249-55-1;3P-methoxy-5-pregsolution and brine, and dried over anhydrous magnesium sulfate. nen-20-one, 511-26-2;acetone, 67-64-1;4-anisaldehyde, 123-11-5; The product was chromatographed on silica gel in 1 : l O ethercyclohexanone, 108-94-1. dichloromethane to afford 11 mg (28%) of 16: Rf0.46; IR (KBr) 3490,1622 cm-'; 'H NMR (CDCl,) 6 0.61 (s, 3, C-18 angular CH,), 1.00 (s, 3, C-19 angular CH,), 1.60 (9, 6, C-26, C-27 CH,), 1.91 (s, (25) Billica, H. R.; Adkins, H. "Organic Syntheses";Wiley: New York, 1955; Collect. Vol. 3, p 176. 3, C-21 vinylic CH,), 3.04 (s,3, SOzCH3),4.71 (m, 1,H-2' in THP),