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PHOSPHINE-CATALYZED ADDITIONS OF NUCLEOPHILES AND ELECTROPHILES TO α,β–UNSATURATED CARBONYL COMPOUNDS Reported by Michael Scott Bultman November 4, 2004 INTRODUCTION Organophosphorous compounds are becoming increasingly important in organic synthesis. Phosphines serve as precursors to phosphonium ylides in the Wittig reaction,1 and as nucleophilic triggers in the Mitsunobu2 and Staudinger3 reactions. In these processes, the phosphine is stoichiometrically consumed and converted into a phosphine oxide. Phosphines are also commonly used as ligands for transition metal-catalyzed reactions, to modulate reactivity and stereocontrol.4 On the other hand, the use of phosphines as nucleophilic catalysts for organic reactions has only gained attention in the last ten years. First reported by Rauhut and Currier in 1963,5 phosphine catalysis has since been reinvestigated after the phosphine ligands in some transition-metal-catalyzed reactions were found to be better catalysts than the metal/phosphine complexes alone!6 Phosphines are well suited for catalyzing the addition of both nucleophiles and electrophiles to electron deficient alkenes, alkynes, and allenes. Activation of these α,β-unsaturated carbonyl systems with the phosphine enables the formation of new bonds at the α-, β-, and γ-positions. This report will highlight these different modes of addition to α,β-unsaturated carbonyl systems under phosphine catalysis that allow for the formation of a wide array of products from a single class of substrates. GENERAL REACTIVITY OF PHOSPHINES Key characteristics required for successful nucleophilic catalysis lie in the balance of leaving group ability, nucleophilicity, and ease of ylid formation. Increasing leaving group ability can often be correlated with decreasing basicity. Whereas phosphines are less basic than amines (pKa values: HPEt3+ (8.7), HNEt3+ (10.7) in H2O), and therefore better leaving groups, they have strikingly different nucleophilic profiles. Tertiary phosphines are much stronger nucleophiles than corresponding amines. For example, the rate of the SN2 substitution of C2H5I with Et2PhP is more than 500 times faster than that of Et2PhN.7 Greater nucleophilicity is observed with electron-donating alkyl substituents than with aryl groups, resulting in an increased nucleophilic reactivity of trialkyl phosphines. Lastly, the ability to stabilize an adjacent carbanion to form an ylide is an important characteristic of phosphines. This unique combination of properties allows phosphines to act as strong nucleophiles for conjugate addition, stabilize high energy intermediates, and still possess the ability to serve as an efficient leaving group. Copyright © 2004 by Michael S. Bultman 49 RAUHUT-CURRIER AND MORITA-BAYLIS-HILMAN REACTIONS Formation of new bonds at the α-position Scheme 1 O of α,β-unsaturated carbonyl compounds using O 2.5 mol% PPh CH 3 O 3 phosphine catalysis was first observed by Rauhut H C 3 t-BuOH, 118 oC H3C and Currier5 during the course of their studies on 60% 1 2 8 the dimerization of activated olefins (Scheme 1). Later work by Morita, Baylis, and Hillman expanded the scope of the reaction to include aldehydes as the electrophilic component. Unfortunately, long reaction times and limited substrate dependence precluded broad application of this method in synthesis. Scheme 2 O O As is the case with all reactions catalyzed by O R' phosphines, the proposed catalytic cycle for the R' 4 R' Rauhut-Currier PR3 3 8 H begins with the conjugate addition of phosphine 3 to enone 4 to provide β-phosphonium enolate 5 (Scheme 2). O O reaction O R' Subsequent conjugate addition of 5 to another R' R' 7 molecule of enone 4 affords δ-phosphonium 5 PR3 PR3 enolate 6. Finally, a proton transfer provides β- O O R' H phosphonium enolate 7, which undergoes βO R' 6 elimination to regenerate catalyst 3 and form the R' PR3 4 dimerized enone product 8. Krische9 and Roush10 have developed intramolecular variants of the Rauhut-Currier reaction, which eliminate the problem of homo-dimerization found in the coupling of different alkenes (Scheme 3). In cases where enones of similar electrophilicities are used, no selectivity is observed and mixtures are obtained. Instead, the use of enones with sufficiently different electrophilicity ensures the generation of a single constitutional isomer. As shown from the product ratio the catalyst favors addition to the (more electrophilic) α,β-unsaturated thioester. The (less electrophilic) α,β-unsaturated ester then serves as the conjugate acceptor for the ring-closing step, strongly favoring the production of 10.9 Scheme 3 O O EtS 9 ( )n O OEt 20 mol% PMe3 t-BuOH 30 oC O O O EtS 10 ( )n OEt EtS n = 1, 89% yield (98:1 10:11) 11 ( )n n = 2, 82% yield (99:1 10:11) OEt 50 CONJUGATE ADDITION TO ACTIVATED ALKENES AND ALKYNES Phosphines are very effective catalysts for the addition of nucleophiles to α,β-unsaturated Phosphines mediate the conjugate addition of nucleophiles such as alcohols,11 carbonyl compounds. oximes,12 and carbon acids7,13 to activated alkenes (Scheme Scheme 4 O O 4). NuH, PR3 R' Whereas these reactions are generally R' 4 catalyzed by a strong alkoxide base, 12 O the use of phosphines allows the H3C addition to occur under much milder O C6H4p-NO2 EtO 13 H3C conditions. Nu O OMe 14 85% O EtO N NO2 15 CH3 CH 3 82% 85% The mechanism for conjugate addition differs significantly from the Rauhut-Currier reaction in that Nu-H Scheme 5 O O 16 4 catalyze the addition of the nucleophile to 5 PR3 3 β- phosphine-generated phosphonium enolate 5 acts as a base to R' R' the enone 4 (Scheme 5). PR3 Addition of the phosphine 3 to enone 4, generates βO O R' R' 17 PR3 19 O O H Nu 18 R' 17 PR3 Nu O R' 20 Nu of enone 4 to generate enolate 19. phosphonium enolate 5, which serves as the active catalyst by deprotonating pronucleophile 16 to generate β- phosphonium ketone 17. The resulting activated nucleophile 18 then undergoes R' 4 conjugate addition into another molecule Subsequent deprotonation of phosphonium ketone 17 then regenerates 5 and produces the β-substituted product 20. The analogous conjugate addition of alcohols activated to terminal alkynes has also been achieved. Inanaga described the addition of benzyl alcohol to ynones to form vinylogous benzyl esters in excellent yields and olefin selectivities (Scheme 6).14 Carbon acids, saturated secondary and tertiary alcohols failed to add under similar conditions. O These results indicate that nucleophiles with minimal steric hinderance are essential for successful addition. Scheme 6 21 10 mol% PBu3 BnOH THF, 10 min 98% O 22 OBn Not surprisingly, tributylphosphine is more effective than triphenylphosphine because of its increased nucleophilicity and reduced steric hindrance. 51 Under certain conditions with specific nucleophiles attack will take place at the α-position of an activated alkyne (Scheme 7).15 The addition at both the a- and b-carbons of activated alkynes can be understood by the unified mechanism shown in Scheme 8. The conjugate addition of phosphine 3 to alkyne 26 protonation followed with by pronucleophile (Nu-H) affords phosphonium salt 28. This intermediate two possesses Scheme 7 the 10 mol% PPh3 O 50 mol% HOAc O 50 mol% NaOAc N toluene EtO O 105 oC Ph 25 82% O O HN EtO Ph O 23 24 electrophilic centers; one at the β-position (from conjugation with the carbonyl group) and another at the α-position (from electrostatic activation by the phosphonium ion). Under buffered acidic conditions with weak nucleophiles, nucleophilic attack occurs at the α-position. Alternatively, attack occurs at the β-position under neutral conditions with strong alkoxide nucleophiles. Subsequent proton transfers and phosphine elimination afford the addition product 29 and 30 and regenerate the catalyst. O Scheme 8 α−addition O PR3 3 O Nu O R' Nu-H R' R'' 26 Nu R' R'' 27 PR3 29 R'' R' R'' 28 O PR3 R' β−addition R'' 30 Nu γ-ADDITION AND ISOMERIZATION OF ACTIVATED ALKYNES AND ALLENES A novel mode of reactivity is available when activated alkynes bear acidic protons at the γposition. This variant was first demonstrated by Trost16 in the addition of carbon nucleophiles (Scheme 9). A contemporaneous report by Lu17 employed activated allenes as the starting materials under milder conditions to create the same product 33. This avenue is made possible by isomerization of electron deficient alkynes to allenes under the buffered acidic reaction conditions. In general, better yields are obtained with activated alkynes than with the corresponding allenes. Heteroatom nucleophiles (e.g. alcohols and imides), and intramolecular additions have also been employed.18 52 Scheme 9 O O MeO CH3 31 MeO 10 mol% PPh3 50 mol% HOAc 50 mol% NaOAc toluene 105 oC 63% O OMe 32 O O MeO MeO 34 O 32 O O MeO OMe 33 5 mol% PPh3 benzene, rt 65% OMe OMe O If hydrogens are present on the δ-position of the substrate, yet another mode of reactivity can be accessed. For example, in the absence of a nucleophile activated alkynoate 35 will isomerize to 2,4dienoate 36 (Scheme 10). Trost,6 Lu,19a and Rychnovsky19b have all used this method synthetically for the production of polyenes. As shown in Scheme 10, only electron deficient alkynes undergo isomerization under these conditions. Differentiation of activated alkynes of different electrophilicities and the use of activated allenes have also been explored under isomerization conditions.6 Scheme 10 10-40 mol% PPh3 50 mol% AcOH O H3C O CH3 35 xylene, 60 oC, 5 h 79% O H3C O CH3 36 A mechanism proposed for these competitive processes is shown in Scheme 11. After conjugate addition of phosphine 3 to the electron poor alkyne 37, a proton transfer forms extended β-phosphonium enolate 39. Protonation by the pronucleophile (Nu-H) results in phosphonium salt 40, which is uniquely electrophilic at the γ-position. If the nucleophile is sufficiently strong and conditions allow, attack occurs at the γ-position; otherwise deprotonation at the δ-position predominates. Subsequent proton transfers and elimination of the phosphine affords the respective products 41 and 42 with regeneration of the catalyst. Scheme 11 37 PR3 3 CH3 NuH R' R' R' CH3 R3P 38 R3P R' O O O O R' O γ-addition CH3 39 α Nu β δ R3P 40 γ 41 O H CH3 Nu R' isomerization 42 In specific cases, the product distribution can be controlled to favor isomerization or the γaddition product. For example, use of a polar coordinating solvents such as DMSO with triphenylphosphine as a catalyst strongly favors formation of the isomerized dienoate 45 (Scheme 12).18b 53 On the other hand, switching from a monodentate phosphine to the bidentate 1,3-bis(diphenylphosphino)propane (dppp, 46) strongly favors formation of the γ-addition product 44. The bidentate phosphine is thought to act as a nucleophile and a general base catalyst in order to mediate formation of γ-addition product. Scheme 12 O O O conditions MeO MeO MeO OH O 43 PPh3, HOAc, DMSO, 110 oC dppp, HOAc, PhCH3, 110 oC OH 44 45 9% 97% 91% 3% PPh2 PPh2 dppp 46 ANNULATIONS - Bifunctional Nucleophiles The potential for addition to adjacent positions in α,β-unsaturated carbonyl compounds using phosphine catalysis allows for annulation reactions. Tethered bifunctional nucleophiles allow for nonconcerted annulations. Lu has constructed seven member rings, as well as dihydrofuran systems, with this method (Scheme 13).20 The reaction proceeds through a phosphine-catalyzed nucleophilic addition to the α-position of the activated alkyne, followed by a separate phosphine-catalyzed conjugate addition with the second tethered nucleophile. Scheme 13 [3 + 2] Cycloadditions Electron alkenes are OEt deficient used as TsHN NHTs 47 48 O NTs 10 mol% PPh3 toluene 80 oC, 72 h TsN OEt 49 88% O dipolarophiles in phosphinecatalyzed [3+2] cycloadditions to form substituted cyclopentenes from allenes.21 Poor regioselectivity in the cycloaddition limits the utility of this process. However, alkynes are found to give better yields and selectivities (Scheme 14). The proposed mechanism begins with conjugate addition of the phosphine to generate phosphonium enolate 52 followed by [3+2] cycloaddition with the activated alkene. Subsequent proton transfers allow for the elimination of the phosphine and formation of isomers 53 and 54. The observation that diethyl fumarate and maleate react stereospefically to afford exclusively trans and cis cycloadducts, respectively, provides support for a concerted reaction.21 54 Scheme 14 O O CN EtO 50 Me 51 10% PBu3 O EtO benzene rt CN O EtO Bu3P CN EtO 80% yield 54 (93:7 53:54) 53 52 CN The scope of dipolarophiles has been expanded to include imines for the synthesis of pyrrole derivatives,22a exocyclic alkenes to form spirocycles.22b 22c have been explored as starting materials. In addition, traditional phosphonium ylides Intramolecular and enantioselective variants of the [3+2] cycloaddition have also been devised.23 [4 + 2] Cycloadditions Stepwise [4+2] cycloadditions of α-substituted allenoates with a wide variety of imines have been developed by Kwon.24 This cyclization allows access to highly substituted tetrahydropyridines in excellent yields and diastereoselectivities (Scheme 15). Scheme 15 O O EtO Ph NTs 20 mol% PBu3 Ph CH2Cl2, rt 56 57 Ph EtO O NTs Bu3P Ph 58 O Ph EtO NTs Bu3P Ph EtO NTs Ph 59 Ph 60 98% Substitution at the α-position of 2,3-butadienoate 56 with an alkyl group blocks the α-attack and instead leads to γ-addition of the zwitterionic intermediate 58 into the dipolarophile 57. Two proton transfers allow the new zwitterionic intermediate 59 to undergo 6-endo cyclization; expulsion of the catalyst generates tetrahydropyridine 60. CONCLUSION Trialkyl and triaryl phosphines catalyze the formation of adducts from a variety of nucleophiles and electrophiles with α,β-unsaturated carbonyl compounds. Although some of the reactions are limited by substrate specificity and long reaction times, this class of reactions has become a useful tool in organic synthesis. This is illustrated by applications in the production of polymers25 and the synthesis of natural products.26 The versatility of this methodology relies in the ability to form a wide array of products from a single substrate class. Limitations result from the scope of reaction partners, and further work is needed to expand this field. Future work is also required to elucidate the factors that dictate product distribution and develop more effective enantioselective methods. 55 REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) Rein, T.; Pedersen, T. M. Synthesis 2002, 5, 579. Dembinkski, R. Eur. J. Org. Chem. 2004, 13, 3130. Gololobov, Y. G.; Kashukin, L. F. Tetrahedron. 1992, 48, 1353. Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201. Rauhut, M.; Currier, H. (American Cyanamide Co.). U.S. Patent 3,074,999, 1963; Chem. Abstr. 1963, 58, 11224a. Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933. White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 37, 3597. (a) Morita, K.; Suzuki, Z.; Hirose. H. Bull. Chem. Soc. Jpn. 1968, 2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2,155,113, 1972; Chem. Abstr. 1972, 77, 34174q. Wang, L. C.; Luis, A. L.; Agapiou, K.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402. (a) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404. (b) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett. 2002, 4, 3157. Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696. Bhuniya, D.; Mohan, S.; Narayanan, S. Synthesis 2003, 1018. Gomez-Bengoa, E.; Cuerva, J. M.; Mateo, C.; Echavarren, M. J. Am. Chem. Soc. 1996, 118, 8553. Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241. Trost, B. M.; Drake, G. R. J. Am. Chem. Soc. 1997, 119, 7595. Trost, B.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 3167. Zhang, C.; Lu, X. Synlett 1995, 645. (a) Trost, B. M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670. (b) Trost. B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 10819. (a) Gou, C.; Lu, X. J. Chem. Soc. Perkin Trans. 1 1993, 1921. (b) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659. Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67, 8901. (c) Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42, 1035. (a) Wang, J. C.; Krische, M. J. Angew. Chem., Int. Ed . 2003, 42, 5855. (b) Guoxin, Z.; Chen, Z.; Qiongzhong, J.; Dengming, X.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. Zhu, X. F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. Kuroda, H.; Tomita, I.; Endo, T. Macromolecules 1995, 28, 433. (a) Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737. (b) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (c) Methot, J. L.; Roush, W. R. Adv. Synth. Cat. 2004, 346, 1035. 56