NCPS-AsPh3 is a soluble polymer-supported triphenylarsine that performed equally well compared to free triphenylarsine as ligands in the Stille cross-coupling reaction of organic electrophiles and organostannanes, with the advantage that it can be conveniently and efficiently separated from the reaction by precipitation, and recycled for further use. The performance of this non-cross-linked polystyrene-supported arsine was found to be generally superior in Stille coupling reactions over the analogous polymer-supported phosphine, paralleling observations on the free ligands. Palladium-catalyzed modification of the polymer-supported arsine was possible through Pd-Ar/As-Ph exchange. Exploiting the ease of isolation of the polymer-supported reagent, the modified arsine is recycled for reuse in the Stille reaction and has led to a reduction in the yield of undesired scrambling products. © 2007 Elsevier Ltd. All rights reserved.postprin

Chiu, P

Lau, KCY

Tetrahedron Letters

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Title Family Comes First: A Family-based Resource Model for theWife’s Pre-migration Adjustment When Couples Live ApartAuthor(s) Lau, KCY; Chiu, PCitation Tetrahedron Letters, 2007, v. 48 n. 10, p. 1813–1816Issued Date 2007URL http://hdl.handle.net/10722/54248Rights Creative Commons: Attribution 3.0 Hong Kong License10203040TETL 31472 No. of Pages 413 January 2007 Disk usedARTICLE IN PRESSTetrahedron Letters xxx (2007) xxx–xxxFThe application of non-cross-linked polystyrene-supportedtriphenylarsine in Stille coupling reactionsKelvin Chi Yin Lau and Pauline Chiu*Department of Chemistry and Open Laboratory of Chemical Biology, Institute of Molecular Technology for DrugDiscovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, PR ChinaReceived 5 December 2006; revised 2 January 2007; accepted 4 January 2007PROOAbstract—NCPS–AsPh3 is a soluble polymer-supported triphenylarsine that performed equally well compared to free triphenylar-sine as ligands in the Stille cross-coupling reaction of organic electrophiles and organostannanes, with the advantage that it can beconveniently and eﬃciently separated from the reaction by precipitation, and recycled for further use. The performance of this non-cross-linked polystyrene-supported arsine was found to be generally superior in Stille coupling reactions over the analogous poly-mer-supported phosphine, paralleling observations on the free ligands. Palladium-catalyzed modiﬁcation of the polymer-supportedarsine was possible through Pd–Ar/As–Ph exchange. Exploiting the ease of isolation of the polymer-supported reagent, the modiﬁedarsine is recycled for reuse in the Stille reaction and has led to a reduction in the yield of undesired scrambling products. 2007 Published by Elsevier Ltd.C5060NCORRETriphenylarsine has synthetic applications in the gener-ation of arsonium salts and highly nucleophilic ylides,1as an eﬀective ligand in various palladium-catalyzedcarbon–carbon bond forming reactions,2 and as anepoxidation agent3 and a mediator for converting iso-cyanates to carbodiimides in its oxide form.4 Due tothe rather inhibitive toxicity of arsenic reagents, wethought it desirable to examine the immobilization oftriphenylarsine on polymer support that would providean alternative reagent for arsine-mediated reactions,but would also be conveniently separated to simplifyreaction workup and puriﬁcation, exploiting the advan-tages of supported reagents in organic synthesis.5 Thepotentially convenient recovery of immobilized triph-enylarsine would facilitate re-use and would allowarsine-mediated reactions to be conducted in a more‘green’ manner. Thus, we have recently synthesizedcross-linked and non-cross-linked polystyrene-supp-orted triphenylarsine reagents.6 Their utility in Suzukicross-coupling reactions, aryl halide homocouplingand alkene epoxidations have been demonstrated.6,7Herein we evaluate non-cross-linked triphenylarsine (1)in the Stille reaction, which accomplishes the cross-cou-U0040-4039/$ - see front matter  2007 Published by Elsevier Ltd.doi:10.1016/j.tetlet.2007.01.005* Corresponding author. Tel.: +852 2859 8949; fax: +852 2857 1586;e-mail: pchiu@hku.hkPlease cite this article in press as: Lau, K. C. Y.; Chiu, P., TetrahTEDpling between organic electrophiles and organostann-anes, and is one of the classic palladium-catalyzedcarbon–carbon bond forming reactions in the organicchemist’s repertoire.8 The studies by Farina and co-workers have shown that triphenylarsine was a superiorligand to triphenylphosphine in improving the yield,reactivity and turnover rates in Stille reactions.4 Triphen-ylarsine promotes the rate-determining transmetalla-tion step and can induce a rate increase in the Stillereaction by a factor of over 1000.2 In this Letter, wedemonstrate the applicability of the triphenylarsineimmobilized on non-cross-linked polystyrene (NCPS)in Stille coupling reactions, and the modiﬁcation ofthe immobilized triphenylarsine by palladium-catalyzedPd–Ar/As–Ph exchange to enhance the yields of thedesired cross-coupling products.Using 10% NCPS–AsPh3 (1) as the ligand,9 variousStille coupling reactions of aryl halides and triﬂates wereexamined and the results are shown in Table 1. TheStille reaction using free triphenylarsine as the ligandfor palladium compared to the reaction using 1 as theligand were found to occur at the same rates to givesimilarly excellent yields of product (Table 1, entries 1and 2). The non-cross-linked polystyrene support of 1is a soluble polymer and this provided solution-phase-like conditions for the reaction. Similar reaction ratesusing the free triphenylarsine and 1 had been observedalso in the Suzuki coupling reactions.6edron Lett. (2007), doi:10.1016/j.tetlet.2007.01.005CT708090100110120130140150Table 1. Stille coupling reactions with organostannanesXR'RR'5% Pd(PhCN)2Cl210% Ligand, RSnBu3dioxane, reflux, 18 hEntry R X R0 Liganda Yieldb (%)1 Ph Br H AsPh3 88 (83)c2 Ph Br H 1 95 (81)c3 Ph Br CHO 1 (82)4 Ph Br OMe 1 695 Ph Br Cl 1 726 Ph Br Ph 1 747 Ph I H 1 72 (61)8 Ph OTf H 1 91d9 Vinyl Br Cl 1 87e10 Vinyl I Cl 1 93e11 Vinyl Br Ph 1 (86)e12 Ph Br Cl 2 6113 Ph Br Ph 2 6714 Ph I H 2 3315 Ph OTf H 2 99da NCPS–AsPh3 (1); NCPS–PPh3 (2).b Yields determined by GC; yields in brackets are isolated yields.c Reaction time was 5 h.d 2.5% Pd2(dba)3, 100 C, NMP.e 2.5% Pd2(dba)3, 80 C, NMP.2 K. C. Y. Lau, P. Chiu / Tetrahedron Letters xxx (2007) xxx–xxxTETL 31472 No. of Pages 413 January 2007 Disk usedARTICLE IN PRESSUNCORREThe eﬀectiveness of 1 as a ligand was surveyed for vari-ous Stille reactions of electron-rich and electron-deﬁ-cient substrates, aryl halides and triﬂates (Table 1,entries 3–8). All reactions occurred under typical reac-tion conditions as expected. The Stille coupling of vinyl-tributylstannane proceeded with excellent yields (Table1, entries 9–11). In each case, removal of the arsinewas done by precipitation. The product mixture wasconcentrated and redissolved in a minimum amount ofhot THF, then added to 20% ether in hexane to precip-itate 1. Compound 1 can then be isolated by suction ﬁl-tration, with a recovery of about 90–95%. The rest of theproduct mixture was washed with saturated aqueous KFbefore GC analysis and/or puriﬁcation by columnchromatography.Comparison was also made with NCPS–PPh3 reagent(2) as a ligand for Stille reactions (Table 1, entries12–15). The observations by Farina and co-workers thatthe arsine ligand was generally superior was conﬁrmedfor the soluble polymer-supported reagents as well.2In Stille arylation reactions using phenyltributylstann-ane, biphenyl was consistently found as a side product.Biphenyl could result from two other reactions. Onewas the homocoupling of PhSnBu3 itself.2c,10 Anotherwas the Stille reaction after the exchange of aryl groupsbetween ligand 1 and the aryl halide. Segelstein et al.have reported that, especially in Stille coupling reactionsinvolving less reactive, electron-rich substrates, phenylgroups on Ph3P exchange with the electron-rich arylgroup of the organopalladium intermediate, and thenproceeded to couple with the organostannane to gener-ate biphenyl, and result in a lower yield of the desiredcross-coupling product.11 Such scrambled couplingPlease cite this article in press as: Lau, K. C. Y.; Chiu, P., TetrahPROOFproducts have been obtained in palladium-catalyzedreactions in yields varying from 4% to 58%.This Pd-aryl/P-aryl exchange process has been produc-tively exploited by Chan and co-workers to synthesizefunctionalized arylphosphines12 and arylarsines.13 Theexchange reactions resulted in 25–68% yields of thefunctionalized phosphines or arsines, which were iso-lated from an excess of Ph3P or Ph3As typically by con-ventional column chromatography.In the Stille reactions using 1 as a ligand, the Pd-aryl/P-aryl exchange would result in a modiﬁcation in thestructure of the polymer-supported arsine. If this newreagent 1 0 could be successfully recycled and reemployedin Stille reactions involving the same aryl halide, thescrambling process should have a diminished eﬀect onthe yield of the desired coupling product, since thecross-coupling product and the scrambled productwould eﬀectively be the same. Alternatively, pretreating1 with an aryl halide in the presence of palladium shouldalso lead to a similar modiﬁcation of the arsine polymer(Eq. 1). This pretreatment could serve as a way to‘prime’ 1 to promote the formation of the desired het-ero-coupling product. Without resorting to conven-tional isolation techniques such as chromatography, bytaking advantage of the ease of recovery of the poly-mer-supported arsine, we demonstrate the exploitationof this scrambling process to modify 1 to 1 0.edron LEDAsPh2PhAsPhPh(2-n) Ar(n= 1,2)( )( )1 8( )(  )1 8Stille conditionsor cat. Pd, Ar-X ð1ÞTo examine the eﬃciency and eﬀect of recycling 1, theStille reaction using 4-bromoanisole as an electron-richaryl halide substrate was carried out using a higher-than-usual loading of 1 (20 mol %), for the purpose ofobserving a more pronounced eﬀect of scrambling.When fresh 1 was used as a ligand in the ﬁrst run, onlya 43% yield of p-methoxybiphenyl was obtained, to-gether with 37% of the biphenyl side product (Table 2,cycle 1). The subsequent reaction using recycled 1 re-sulted in an increase in the yield of 4-methoxybiphenylwith a concomitant decrease in the yield of biphenyl ofabout 20%, clearly demonstrating that the use of recy-cled 1 enhanced the yield of the cross-coupling product(Table 2, cycle 2). The yields of both products did notfurther increase or decrease in subsequent cycles 3–5.The 15–20% yield of biphenyl that was still producedin the reactions using recycled 1 is attributed to thehomocoupling of tributylphenyltin. This was quantiﬁedby experiment, where a 16% yield of biphenyl was ob-tained under the Stille conditions without the additionof any aryl bromide.A second set of recycling experiments examined theStille reaction of 4-bromochlorobenzene (Table 3). Ayield enhancement of about 10% was observed usingett. (2007), doi:10.1016/j.tetlet.2007.01.005CE16017180190200210220Table 2. Recycling of 1 in the Stille reaction of 4-bromoanisoleBrMeOPhMeOPh Ph5% Pd(PhCN)2Cl220 mol% 1PhSnBu3, dioxanereflux, 18 h+Cycle Yield (4-MeO-biphenyl)a (%) Yield (Ph–Ph)a (%)1 43 372 62 203 70 204 67 155 61 19aGC yield.Table 3. Recycling of 1 in the Stille reaction of 4-bromochlorobenzeneBrClPhClPh Ph5% Pd(PhCN)2Cl220 mol% 1PhSnBu3, dioxanereflux, 18 h+Cycle Yield (4-Cl-biphenyl)a (%) Yield (Ph–Ph)a (%)1 69 342 80 16aGC yield.Table 4. Stille reaction using 1 and 1 0BrMeOPhMeOPh Ph5% Pd2(dba)320 mol% ligandPhSnBu3dioxane, reflux+Ligand Yield (4-MeO-biphenyl)a Yield (Ph–Ph)a (%)1 64 341 0 81 15a Isolated yield.K. C. Y. Lau, P. Chiu / Tetrahedron Letters xxx (2007) xxx–xxx 3TETL 31472 No. of Pages 413 January 2007 Disk usedARTICLE IN PRESSUNCORREthe recycled 1 compared to fresh 1, with a concomitantreduction in the yield of biphenyl.Finally, 1 was treated with 4-bromoanisole in the pres-ence of Pd2(dba)3 to produce 10 which was isolated(Eq. 2). The 1H NMR spectrum of 1 0 clearly shows amodiﬁed polymer-supported arsine with the incorpora-tion of the methoxybenzene group, indicated by theappearance of a broad peak at d 3.62–3.92 ppm, whichis diﬀerent from the sharp methoxy singlet signal of 4-bromoanisole at 3.78 ppm. The broadness of this meth-oxy signal is indicative of incorporation into a polymericstructure.AsPh2PhOMeBrAsPhPh(2-n)OMe( )( )1 8( )( )1 85 equiv.25% Pd2(dba)31 1'dioxanereflux, 16 hn= 1,2ð2Þ0When 1 0 thus obtained was used as the ligand in theStille reaction, a 17% increase in the yield of methoxybi-phenyl and a corresponding 19% reduction in the yieldof biphenyl was observed compared to the same reactionusing fresh 1 (Table 4).In summary, we have demonstrated the general applica-bility of triphenylarsine immobilized on non-cross-linked polystyrene (1) as a recyclable ligand in Stille cou-pling reactions. Triphenylarsine in this form could bePlease cite this article in press as: Lau, K. C. Y.; Chiu, P., TetrahOFconveniently separated and puriﬁed by concentrationand precipitation. The Pd-aryl/P-aryl exchange reactioncould be exploited to synthesize a modiﬁed polymer-supported arsine 1 0 that could be similarly isolated, puri-ﬁed and characterized or recycled in subsequent Stillereactions to signiﬁcantly improve the yield of the desiredcross-coupling product.DPROAcknowledgementsThis research was supported by the University of HongKong, the Research Grants Council of Hong KongSAR (HKU 7017/04 P), and the Areas of ExcellenceScheme established under the University Grants Com-mittee of the Hong Kong Special Administrative Re-gion, China (Project No. AoE/P-10/01). K.C.Y.L.thanks the CRCG for a conference grant. We also thankProfessor P. H. Toy, University of Hong Kong for hisgifts of 1 and 2.T Supplementary dataAll products are known compounds. The detailed exper-imental procedures, and 1H NMR spectrum of 1 0 areavailable free of charge via the Internet. Supplementarydata associated with this article can be found, in theonline version, at doi:10.1016/j.tetlet.2007.01.005.References and notes1. (a) Lloyd, D.; Gosney, I.; Ormiston, R. A. Chem. Soc.Rev. 1987, 16, 45–74; (b) He, H. S.; Chung, C. W. Y.; But,T. Y. S.; Toy, P. H. Tetrahedron 2005, 61, 1385–1405; (c)Goddard, J.; Lixon, P.; Le Gall, T.; Mioskowski, C. J.Am. Chem. Soc. 2003, 125, 9242–9243; (d) Dai, W. M.;Wu, J.; Huang, X. Tetrahedron: Asymmetry 1997, 8, 1979–1982.2. (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,9585–9595; (b) Faust, R.; Go¨belt, B. J. Prakt. Chem. 1998,340, 90–93; (c) Farina, V.; Krishnan, B.; Marshall, D. R.;Roth, G. P. J. Org. Chem. 1993, 58, 5434–5444.3. van Vliet, M. C. A.; Arends, I. W. C. E.; Sheldon, R. A.Tetrahedron Lett. 1999, 40, 5239–5242.4. (a) Monagle, J. J. J. Org. Chem. 1962, 27, 3851–3855; (b)Smith, C. P.; Temme, G. H. J. Org. Chem. 1983, 48, 4681–4685.5. (a) Kirschning, A.; Monenschein, H.; Wittenberg, R.Angew. Chem., Int. Ed. 2001, 40, 650–679; (b) Bhalay, G.;edron Lett. (2007), doi:10.1016/j.tetlet.2007.01.0052302404 K. C. Y. Lau, P. Chiu / Tetrahedron Letters xxx (2007) xxx–xxxTETL 31472 No. of Pages 413 January 2007 Disk usedARTICLE IN PRESSDunstan, A.; Glen, A. Synlett 2000, 1846–1859; (c) Toy, P.H.; Shi, M. Tetrahedron 2005, 61, 12025.6. Lau, K. C. Y.; He, H. S.; Chiu, P.; Toy, P. H. J. Comb.Chem. 2004, 6, 955–960.7. He, H. S.; Zhang, C.; Ng, C. K. W.; Toy, P. H.Tetrahedron 2005, 61, 12053–12057.8. (a) Farina, V.; Krishnamurthy, V. Org. React. 1997, 50, 1–676; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.Chem., Int. Ed. 2005, 44, 4442–4489; (c) Espinet, P.;Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704–4734.9. The NCPS–AsPh3 polymer (1) used was determined tohave a loading of 0.79 mmol AsPh3/g as determined byUNCORRECPlease cite this article in press as: Lau, K. C. Y.; Chiu, P., Tetrahoxidation,3 which is close to the theoretical value of0.83 mmol AsPh3/g.3,610. Kang, S. K.; Namkoong, E. Y.; Yamaguchi, T. Synth.Commun. 1997, 27, 641–646.11. Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J. Org.Chem. 1995, 60, 12–13.12. (a) Kwong, F. Y.; Lai, C. W.; Yu, M.; Tian, Y.; Chan, K.S. Tetrahedron 2003, 59, 10295–10305; (b) Kwong, F. Y.;Lai, C. W.; Yu, M.; Chan, K. S. Tetrahedron 2004, 60,5635–5645; (c) Wang, Y.; Lai, C. W.; Kwong, F. Y.; Jia,W.; Chan, K. S. Tetrahedron 2004, 60, 9433–9439.13. Kwong, F. Y.; Lai, C. W.; Chan, K. S. J. Am. Chem. Soc.2001, 123, 8864–8865.TEDPROOFedron Lett. (2007), doi:10.1016/j.tetlet.2007.01.005

The application of non-cross-linked polystyrene-supported triphenylarsine in Stille coupling reactions

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Family Comes First: A Family-based Resource Model for the Wife’s Pre-migration Adjustment When Couples Live Apart

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