326
J . Org. Chem. 1983, 48, 326-332
also grateful for support as an Alfred P. Sloan Research Fellow and as a Camille and Henry Dreyfus TeacherScholar. Registry No. trans-la, 50930-15-9; trans-lb, 84064-83-5; trans-lc, 84064-84-6; trans-ld, 84064-85-7; trans-le, 84064-86-8;
trans-2, 84064-87-9; trans-3, 61608-79-5; trans-4, 33044-88-1; trans-5,84064-93-7;6a, 76510-29-7; 6b, 84064-88-0; 612, 1724-45-4; 7a, 84064-89-1; 7b, 84064-90-4; 7c,84064-91-5;trans-8,84064-92-6; n-BuLi, 109-72-8; l-buty-l-vinyl-transs-2,3-diphenylcyclopropane, 84064-94-8; l-bromo-l-methyl-truns-2,3-diphenylcyclopropane, 84064-95-9; l-methyl-truns-2,3-diphenylcyclopropane, 84064-96-0.
Wittig Reagents Bound to Cross-Linked Polystyrenes Margaret Bernard and Warren T. Ford* Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078 Received M a y 7, 1982
Insoluble benzyltriarylphosphonium and methyltriarylphosphonium salts have been prepared on 2 % and 8% divinylbenzene cross-linked polystyrene and on 20% divinylbenzene cross-linked macroporous polystyrene. Phosphoranes were generated with sodium methoxide or sodium ethoxide in T H F and with the dimethylsulfinyl carbanion in MezSO from the benzyl- and methylphosphonium salts, respectively. Reactions of the phosphoranes with a variety of aldehydes and ketones provided alkenes in 73-96% yields (by GLC analysis) with the 2% cross-linked polymer, 52-77% yields with the 8% cross-linked polymer, and 72-87% yields with the 20% cross-linked macroporous polymer. The rates of phosphorane generation and alkene formation depend on the polymer, decreasing in the order 2% > 20% macroporous > 8% cross-linked. The fraction of E double bond product from the benzylphosphonium salt and either benzaldehyde or cinnamaldehyde is greater with the 20% cross-linked macroporous polymer than with the 2 % cross-linked polymer. The byproduct polymer-bound phosphine oxides were reduced to phosphines with trichlorosilene, and the phosphines were reused for Wittig syntheses. A quantitative 31PNMR analysis of phosphine and phosphine oxide residues in polystyrene gels is reported.
Polymer-supported reagents in organic synthesis allow separation of the insoluble polymeric byproduct from the reaction mixture by simple filtration.' In some cases the polymeric reagent can be regenerated. The byproduct triphenylphosphine oxide from Wittig reactions in solution is often hard to separate from the product olefin. After use of a polymer-supported Wittig reagent the triarylphosphine oxide can be separated by filtration and can be recycled after reduction to the phosphine. The Wittig reaction is one of the most valuable in synthetic chemistry, for it gives regiospecific introduction of a carbon-carbon double bond.2 Earlier papers on polymer-supported Wittig reagent^^-^ reported syntheses of olefins in widely variable yields, depending on the particular reaction conditions and the (1)For reviews see: (a) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981,81,557-587.(b) FrBchet, J. M. J. Tetrahedron 1981,37,663-683. (c) Akelah, A. Synthesis 1981,413-438. (d) Hodge, P. In "PolymerSupported Reactions in Organic Synthesis"; Hodge, P., Sherrington, D. C., Eds.;Wiley: New York, 1980;pp 83-155. (e) Mathur, N. K.; Narang, C. K.; Williams, R. E. "Polymers as Aids in Organic Chemistry"; Academic Press: New York, 1980. (0 Kraus, M. A.; Patchornik, A. Macromol. Reu. 1980,15,55-106.(9) Manecke, G.; Reuter, P. Pure Appl. Chem. 1979,51,2313-2330.(h) Warshawsky, A. Zsr. J. Chem. 1979,18,318-324. (i) Daly, W. H. Makromol. Chem., Suppl. 1979,2,3-25.(j) Leznoff, C. C. Acc. Chem. Res. 1978,11, 327-333. (k) Heitz, W. Ado. Polym. Sci. 1977,23,1-23. (2) For reviews see: (a) Gosney, I.; Rowley, A. G. In *Organophosphorus Reagents in Organic Synthesis"; Cadogan, J. I. G. Ed.; Academic Press: New York, 1979;Chapter 2. (b)Bestmann, H. J. f i r e Appl. Chem. 1980,52, 771. (c) Maercker, A. Org. React. 1965,14, 27C-490. (3)(a) Camps, F.; Castells,J.; Font, J.; Vela, F. Tetrahedron Lett. 1971,1715-1716.(b) Castells, J.; Font, J.; Virgili, A. J. Chem. SOC.,Perkin Trans. 1 1979,1-6. (4)McKinley, S. V.; Rakshys, J. W. J. Chem. Soc., Chem. Commun. 1972,134-135. (5)Heitz, W.; Michels, R. Angew. Chem., Znt. Ed. Engl. 1972,11, 298-299. (6)Heitz, W.; Michels, R. Justus Liebigs Ann. Chem. 1973,227-230. (7)Akelah, A. Eur. Polym. J . 1982,18,559-561. (8)(a) Clarke, S. D.; Harrison, C. R.; Hodge, P. Tetrahedron Lett. 1980,21,1375-1378. (b) Hodge, P.;Waterhouse, J. Polymer 1981,22, 1153-1154. (c) Hodge, P.; Hunt, B. J.; Khoshdel, E.; Waterhouse, J. Polym. Prepr., Am. Chem. SOC.,Diu. Polym. Chem. 1982,23(l),147-148.
Scheme I
f-0 1
2
3
Ph2PtCH2PhBr-
4a
P
Ph,P+CH,I-
4b
polymer used. Heitz and Michels5found higher yields with a 0.5% cross-linked polystyrene support than with the standard 2% cross-linked polystyrene, which implies t h a t more highly cross-linked polystyrenes would give poor yields of Wittig products. A phase-transfer-catalyzed method of phosphorane generation from the polymerbound phosphonium salts offers the highest reported yields of olefins from activated benzyl and allyl phosphonium salts.8 Use of soluble Wittig reagents with polymer-bound aldehydes also has been r e p ~ r t e d . ~ (Polystyrylmethy1)triphenylphosphonium ions have been used to prepare alkenes bound to the polystyrene.sb,cJO (9)(a) Leznoff, C. C.; Greenberg, S. Can. J. Chem. 1976,54,3824-3829. (b) Leznoff, C. C.; Sywanyk, W. J . Org. Chem. 1977,42, 3203-3205.
0022-3263/83/1948-0326$01.50/0 0 1983 American Chemical Society
Wittig Reagents Bound to Cross-Linked Polystyrenes Table I. Phosphination of Bromopolystyrene
copolymer, % cross-linking
phosphine bromipolymer nated copolymer, mequiv mequiv mequiv of of of Brig a Br/g P/g
A. Lithium Diphenylphosphide Method 0.00 2.09 3.05 2.40 3.10 0.00 2.1 2 3.05 0.05 1.60 8 2.94 0.63 0.02 2.01 8' 3.00 20 3.08 1.63 0.97 2 2 2
% conversion
91 100 92 65 83 35
B. n-Butyllithium/Chlorodiphenylphosphine Method 0.00 1.86 80 2 3.10 0.03 1.13 38 20 3.08 A THF solution of 2.5 molar By elemental analysis. equiv of LiPPh, was added to the bromopolystyrene in THF at -10 OC,and the mixture was stirred for 48 h at room temperature. The reaction mixture was heated at reflux an additional 6 h. A hexane solution of 3.0 molar equiv of n-BuLi was added to the bromopolystyrene in toluene at -10 "C. After 10 h at 70 "Cthe excess n-BuLi was washed away, and 2.5 molar equiv of ClPPh, was added.
Our research on polymer-supported reagents is aimed at demonstration of methods that could be scaled up to the manufacture of fine chemicals and pharmaceuticals. The 0.5% and 2% cross-linked polystyrenes used in most previous polymer-supported reagents are too gelatinous in solvent-swollen form for large-scale filtration, so our attention has been directed to more highly cross-linked, more rigid polystyrene supports. These materials, however, might give poor yields because of poor transport of reagents into and out of the more highly cross-linked polymer matrices, particularly if the reactant and product molecules are as large as many organic natural products. This paper reports the use of Wittig reagents supported on polystyrenes with up to 20% cross-linking and with reactants as large as a 3-keto steroid and a C19 aliphatic ketone.
Results Conversions of 270, 8%, and macroporous 20% divinylbenzene cross-linked polystyrenes (see Experimental Section) to polymer-bound triarylphosphonium salts were carried out by the methods in Scheme I. All three polymers gave bromopolystyrene (2)" in 100% yield. Conversions of the bromopolystyrene to diphenylphosphinopolystyrene (3) proceeded with increasing difficulty in the order 2% < 8% < 20% macroporous cross-linked polymer by treatment with either lithium diphenylph~sphide'~or n-butyllithium and chlorodiphenylphosphine (see Table I). Conversions exceeded 90% with the 2% cross-linked polystyrene in 48 h at 20 "C, but an added 6 h at 65 "C was needed to reach an 83% conversion with lithium diphenylphosphide and the 8% cross-linked polystyrene. Even the extra 6 h at 65 "C provided only 35% phosphination of the 20% cross-linked macroporous polystyrene. A 38% conversion of the 20% cross-linked bromopolystyrene to phosphine was obtained by using n-butyllithium and chlorodiphenylphosphine. By the lithium diphenylphosphide method residual bromine (10) FrBchet, J. M. J.; Schuerch, C. J . Am. Chem. SOC.1971, 93, 492-496. (11) Farrall, M.J.;FrBchet, J. M. J. J.Org. Chem. 1976,41,3877-3882. (12) Relles, H.M.; Schluenz, R. W. J. Am. Chem. SOC.1974, 96, 6469-6475. (13) Regen, S.L.; Lee, D. P. J. Org. Chem. 1975, 40,1669-1670.
J . Org. Chem., Vol. 48, No. 3, 1983 327
in the 20% cross-linked polymer accounted for the low conversion. (See the Experimental Section for a sample calculation of the percent conversion.) By the n-butyllithium method there was almost no residual bromine. Treatments of all of the polymer-bound phosphines with benzyl bromide and with methyl iodide gave benzyldiphenylpolystyrylphosphonium bromide (4a) and methyldiphenylpolystyrylphosphonium iodide (4b) in 86-96 % yields, as determined by ion-exchange analyses (see Experimental Section) of the bromide and iodide contents of the polymer beads. The benzylidenephosphoranes were generated by addition of an equimolar amount of sodium methoxide in methanol or sodium ethoxide in ethanol to the THFswollen polymer-bound benzylphosphonium salt. The 2 % and macroporous 20% cross-linked samples attained the characteristic orange-red phosphorane color in 3-4 h of stirring at room temperature. The 8% cross-linked sample required 12-16 h to attain full color. Wittig reactions of the benzylidenephosphoranes with aldehydes were complete after 16 h at room temperature and 2-4 h at 60 "C with the 2% and macroporous 20% cross-linked polymers, and after 24 h at room temperature and 4 h at 60 "C with the 8% cross-linked polymer. Results are given in Table 11. In some experiments with 2 % cross-linked polystyrene 91-95% of the calculated quantity of bromide ion was released in the Wittig reaction, as determined by washing the NaBr from the polymer and titrating the solution for bromide ion. The yields of olefins and amounts of recovered aldehyde in Table I1 indicate that the rates of phosphorane formation and/or olefination decrease in the order 2% cross-linked > macroporous 20% cross-linked > 8% cross-linked polymer. The Z / E product ratios decrease in the order 2% > 8% > macroporous 20% cross-linked polymer. ' The methylidenephosphoranes were generated by addition of 3 molar equiv of the sodium salt of dimethyl sulfoxide to the polymer-bound methylphosphonium salt swolen in a 1:l (v/v) mixture of THF and Me,SO and stirring for 6 h. The phosphorane polymer beads were green-black. The excess base was drained, and the polymer was washed with THF before addition of the carbonyl compound. A 5-25% excess of phosphonium salt was used with cyclohexanone, cinnamaldehyde, and benzophenone. A 4040% excess of phosphonium salt was used, and the mixture was held 24 h at 60 "C with the larger ketones, 10-nonadecanone and cholest-4-en-3-one. Most of the recovered phosphine oxide polymers were analyzed for residual iodide ion. Results are given in Table 111. Only the 8% cross-linked polymers contained I-, indicating incomplete generation of the phosphorane. Yields of olefins in all cases depended on the polymer: 2% > macroporous 20% > 8% cross-linked. Samples of the 2 % cross-linked polystyryldiphenylphosphine oxide byproduct were reduced with trichlorosilane to the phosphine6J3in 290% yield, as determined by quantitative 31PNMR analysis. The recycled polymers gave benzylphosphonium salts and (E)-and (a-stilbenes by Wittig reactions with benzaldehyde with no reduction in yield over three cycles. The 20% cross-linked macroporous polymer also was recycled and gave a 75% yield of stilbenes (see Table IV). Discussion Successful polymer-supported syntheses require penetration of the reagents from solution into all of the functional sites in the polymer gel. The method by which the potentially reactive sites are introduced, the swelling of the polymer matrix, the size of the penetrating reagent,
328 J. Org. Chem., Vol. 48, No. 3, 1983
Bernard and Ford
Table 11. Olefins from Polymer-Supported Benzylphosphonium Salts a mequiv copolymer, % cross-linking
mequiv of P+
2 8 20 f 2 8 20 f 2 2
2.42 2.60 2.38 2.45 2.00 2.06 2.53 3.20
of
aldehyde
aldehyde
PhCHO PhCH=CHCHO PhCH=C( CH,)CHO n-C,,H,,CHO
% Brisomer recovered released, ratio aldehyde mequiv
%
product
yield
PhCH=CHPh
2.5 2.23 1.86 3.27 1.85 2.09 2.53 3.07
PhCH=CHCH=CHPh PhCII=C(CH,)CH=CHPh n-C,,H,,CH=CHPh
93 73 80 89 779 72 89
e
57/43 48/52 28/72 40160 35/65 17/83 30170 43/57
0.00 e
