4634 Chem. Commun., 2013, 49, 4634--4636 This journal is c The Royal Society of Chemistry 2013 Cite this: Chem. Commun., 2013, 49, 4634 Pd-catalyzed C3-selective arylation of pyridines with phenyl tosylates† Fenglin Dai, Qingwen Gui, Jidan Liu, Zhiyong Yang, Xiang Chen, Ruqing Guo and Ze Tan* We have discovered that phenyl tosylates can be used to arylate pyridines at the C3-position using a Pd(OAc) 2 –1,10-phenanthroline catalyst system. We also discovered that the reaction of 4-methyl- pyridine with naphthyl tosylates occurred on the methyl group instead of at the C3-position. Recently transition metal-catalyzed arylation of arenes based on the C–H activation mode has been developed as a valuable tool for the construction of biaryls. 1 Compared with the traditional cross coupling methods, 2 these reactions do not need the usually expensive organo- metals or metal equivalents; instead a C–H activation process is involved in the reaction. As a result, the requirements for the starting materials are less demanding and the overall synthetic efficiency is considerably higher. In order to achieve selective activation of desired arene C–H bonds, chemists have used directing groups such as oximes, 3 imines, 4 pyridines, 5 amides 6 as well as carboxylates 7 to direct the reactive site and excellent selectivities have been demonstrated. While numerous methods have been developed for the arylation of benzenes and other heterocycles, 1,8 transition metal-catalyzed aryla- tion of pyridines is much underdeveloped. 9 This is to be expected due to the electron-poor nature of the pyridine ring and its tendency to form a non-productive complex with the transition metal catalyst center. To overcome these problems, chemists have used masked pyridines to circumvent these difficulties. For example, pyridine N-oxides and N-iminopyridium ylides have been used as pyridine surrogates to allow selective C2-arylations. 10 As for the arylation of unmasked pyridines, 11–16 most of the successes have been achieved with substituted pyridines. For example, C2-selective arylations have been developed with 2-methyl pyridines 11 and C3- and C4-selective arylations 12 have been achieved with perfluoropyridines, 13 pyridines with directing groups and pyridines with a strong electron- withdrawing group at the C4 position. 14,15 On the other hand, the non-directed C3-arylation of pyridines is rare. In fact, it was until very recently that the C3-arylation 16a of pyridines was reported by Yu’s group using a catalyst system consisting of Pd(OAc) 2 and 1,10-phenanthroline (eqn (1)). They also demonstrated that the same catalyst system could enable the C3-alkenylation of unsubstituted pyridines as well. 16b Inspired by these results, we wonder if phenol esters such as triflates or tosylates could be used in place of aryl iodides or bromides since, in this way, phenol derivatives could be used as aryl sources for the synthesis of C3-arylpyridine. Herein we report that this Pd-catalyzed C3-selective arylation of pyridines could be indeed extended to phenyl tosylates (eqn (2)). (1) (2) Initial experiments started with the reaction of pyridines with phenyl triflate. When 3 mL of pyridine ( 1a) was treated with 0.5 mmol of phenyl triflate and 1.5 mmol of Cs 2 CO 3 in the presence of Pd(OAc) 2 (5 mol%) and 1,10-phenanthroline (15 mol%) at 140 1 C for 48 h, only a trace amount of the desired product, 3-phenylpyr- idine ( 3a), was isolated. The major side-product was phenol derived from the hydrolysis of the starting triflate. Since tosylates 17 are much more stable than the corresponding triflates, we next tested the coupling between pyridines and phenyl tosylate (2a) under Yu’s conditions. Much to our delight, the desired 3-phenylpyridine ( 3a) could be isolated in 21% yield (ESI,† Table S1, entry 1). Increasing the amount of Pd-catalyst to 10 mol% increased the yield to 32% (ESI,† Table S1, entry 2). The yield can be increased to 38% if the ligand 1,10-phenanthroline was also increased to 30 mol% (ESI,† Table S1, entry 3). After a series of tests, we found that running the reaction at 150 1C led to production of the desired 3-phenylpyridine ( 3a) in 63% yield (ESI,† Table S1, entry 4). Surprisingly the yield actually dropped slightly when the catalyst amount was further increased to 15 mol% (ESI,† Table S1, entry 5). The tests also showed that running the reaction at 160 1C did not benefit the reaction (ESI,† Table S1, entry 6). It is important to note that we did not observe any appreciable amount of 2-phenylpyridine or 4-phenylpyridine in our crude product mixture, indicating that the C3-selectivity is very high. 18 While the use of PdCl 2 instead of Pd(OAc) 2 resulted in a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China. E-mail: [email protected]; Tel: +86 731 88822400 † Electronic supplementary information (ESI) available: Detailed experimental procedures and characterization of all products. See DOI: 10.1039/c3cc41066h Received 7th February 2013, Accepted 26th March 2013 DOI: 10.1039/c3cc41066h www.rsc.org/chemcomm ChemComm COMMUNICATION Downloaded by University of California - San Diego on 26/04/2013 04:03:10. Published on 28 March 2013 on http://pubs.rsc.org | doi:10.1039/C3CC41066H View Article Online View Journal | View Issue
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4634 Chem. Commun., 2013, 49, 4634--4636 This journal is c The Royal Society of Chemistry 2013
Cite this: Chem. Commun.,2013,49, 4634
Pd-catalyzed C3-selective arylation of pyridines withphenyl tosylates†
We have discovered that phenyl tosylates can be used to arylate
pyridines at the C3-position using a Pd(OAc)2–1,10-phenanthroline
catalyst system. We also discovered that the reaction of 4-methyl-
pyridine with naphthyl tosylates occurred on the methyl group
instead of at the C3-position.
Recently transition metal-catalyzed arylation of arenes based on theC–H activation mode has been developed as a valuable tool for theconstruction of biaryls.1 Compared with the traditional cross couplingmethods,2 these reactions do not need the usually expensive organo-metals or metal equivalents; instead a C–H activation process isinvolved in the reaction. As a result, the requirements for the startingmaterials are less demanding and the overall synthetic efficiency isconsiderably higher. In order to achieve selective activation of desiredarene C–H bonds, chemists have used directing groups such asoximes,3 imines,4 pyridines,5 amides6 as well as carboxylates7 to directthe reactive site and excellent selectivities have been demonstrated.While numerous methods have been developed for the arylation ofbenzenes and other heterocycles,1,8 transition metal-catalyzed aryla-tion of pyridines is much underdeveloped.9 This is to be expected dueto the electron-poor nature of the pyridine ring and its tendency toform a non-productive complex with the transition metal catalystcenter. To overcome these problems, chemists have used maskedpyridines to circumvent these difficulties. For example, pyridineN-oxides and N-iminopyridium ylides have been used as pyridinesurrogates to allow selective C2-arylations.10 As for the arylation ofunmasked pyridines,11–16 most of the successes have been achievedwith substituted pyridines. For example, C2-selective arylations havebeen developed with 2-methyl pyridines11 and C3- and C4-selectivearylations12 have been achieved with perfluoropyridines,13 pyridineswith directing groups and pyridines with a strong electron-withdrawing group at the C4 position.14,15 On the other hand, thenon-directed C3-arylation of pyridines is rare. In fact, it was untilvery recently that the C3-arylation16a of pyridines was reported by
Yu’s group using a catalyst system consisting of Pd(OAc)2 and1,10-phenanthroline (eqn (1)). They also demonstrated that the samecatalyst system could enable the C3-alkenylation of unsubstitutedpyridines as well.16b Inspired by these results, we wonder if phenolesters such as triflates or tosylates could be used in place of aryliodides or bromides since, in this way, phenol derivatives could beused as aryl sources for the synthesis of C3-arylpyridine. Herein wereport that this Pd-catalyzed C3-selective arylation of pyridines couldbe indeed extended to phenyl tosylates (eqn (2)).
(1)
(2)
Initial experiments started with the reaction of pyridines withphenyl triflate. When 3 mL of pyridine (1a) was treated with 0.5 mmolof phenyl triflate and 1.5 mmol of Cs2CO3 in the presence ofPd(OAc)2 (5 mol%) and 1,10-phenanthroline (15 mol%) at 140 1Cfor 48 h, only a trace amount of the desired product, 3-phenylpyr-idine (3a), was isolated. The major side-product was phenol derivedfrom the hydrolysis of the starting triflate. Since tosylates17 are muchmore stable than the corresponding triflates, we next tested thecoupling between pyridines and phenyl tosylate (2a) under Yu’sconditions. Much to our delight, the desired 3-phenylpyridine (3a)could be isolated in 21% yield (ESI,† Table S1, entry 1). Increasingthe amount of Pd-catalyst to 10 mol% increased the yield to 32%(ESI,† Table S1, entry 2). The yield can be increased to 38% if theligand 1,10-phenanthroline was also increased to 30 mol% (ESI,†Table S1, entry 3). After a series of tests, we found that running thereaction at 150 1C led to production of the desired 3-phenylpyridine(3a) in 63% yield (ESI,† Table S1, entry 4). Surprisingly the yieldactually dropped slightly when the catalyst amount was furtherincreased to 15 mol% (ESI,† Table S1, entry 5). The tests also showedthat running the reaction at 160 1C did not benefit the reaction (ESI,†Table S1, entry 6). It is important to note that we did not observe anyappreciable amount of 2-phenylpyridine or 4-phenylpyridine in ourcrude product mixture, indicating that the C3-selectivity is veryhigh.18 While the use of PdCl2 instead of Pd(OAc)2 resulted in a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
† Electronic supplementary information (ESI) available: Detailed experimentalprocedures and characterization of all products. See DOI: 10.1039/c3cc41066h
Received 7th February 2013,Accepted 26th March 2013
This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 4634--4636 4635
slight drop in terms of product yield, the use of Pd(TFA)2 as a catalystgave the desired product 3a only in 15% yield (ESI,† Table S1, entries 7and 8). Substituting the base Cs2CO3 with K2CO3 or K3PO4 alsoproduced inferior results (ESI,† Table S1, entries 9 and 10) whereasthe use of strong bases such as tBuONa or tBuOK led to disastrousfailures (not shown in ESI,† Table S1). Similar to Yu’s reaction, DMFcan also be used as a cosolvent in our procedure, but it can only beused as a minor component (ESI,† Table S1, entries 11 and 12).Controlexperimentsshowedthatthereactiondidnotproceedwithoutthe Pd-catalyst (ESI,† Table S1, entry 13). Finally we decided to setreaction of 0.5 mmol of tosylate with 3 mL of pyridine and 3 equiv.of Cs2CO3 in the presence of 10 mol% of Pd(OAc)2 and 30 mol% of1,10-phenanthroline at 150 1C for 48 h as our standard condition.
With the optimized conditions in hand, we next set out to explorethe scope and limitation of this reaction. Using various pyridines andtosylates as the coupling partners, a variety of C3-aryl substitutedpyridines were successfully synthesized in 32–67% yield and theresults are summarized in Table 1. Substituents such as methyl,fluoro, tBu, methoxy and trifluoromethyl as well as phenyl groups arewell tolerated on the aromatic rings of the tosylates, and the reactionsof these tosylates with pyridines afforded the desired products 3b–3j
in synthetically useful yields (Table 1, entries 1–9). Naphthyl tosylatesworked satisfactorily too (Table 1, entries 10–14 and 18–20). 3-Methyl,3-ethyl substituted pyridines did not give any problem at all thoughthe amount of Pd catalyst and the 1,10-phenanthroline ligandneeded to be increased in order to achieve good yields (Table 1,entries 13–21). On the other hand, attempts to couple 2-methylpyridine with phenyl tosylate did not furnish any of the C3-arylationproduct, instead it gave an unidentifiable side-product (not shown inTable 1). The reaction of 4-methyl substituted pyridine with tosylatesis a completely different story. The reaction of 4-methyl pyridine withmethyl and dimethyl substituted phenyl tosylates proceeded in anormal fashion to afford the desired C3-phenyl pyridines 3w and 3xin yields of 61% and 53%, respectively (Table 1, entries 22 and 23).However, when the phenyl tosylates were replaced by naphthyltosylates, their reactions with 4-methyl pyridine did not producethe C3-naphthyl substituted pyridines, instead the C–H activationoccurred on the methyl group to give the diaryl methane products(Table 2). For example, the reaction of 4-methyl pyridine with2-naphthyl tosylate gave product 3y in 51% yield while the reactionof 4-methyl pyridine with 1-naphthyl tosylate gave 3z in slightly loweryield. In addition, the coupling of a phenyl substituted 2-naphthyl
Table 1 Pd-catalyzed C3-arylation of pyridines with tosylatesa
Entry Tosylate ProductYieldb
(%) Entry Tosylate ProductYieldb
(%) Entry Tosylate ProductYieldb
(%)
1 55 9 57 17 56c
2 59 10 60 18 46c
3 67 11 52 19 47c
4 61 12 60 20 49c
5 41 13 52c 21 53c
6 46 14 51c 22 61c
7 32 15 54c 23 53c
8 48 16 50c
a Reaction conditions: pyridine (3.0 mL) and 2 (0.5 mmol) were stirred with 3 equiv. of Cs2CO3, Pd(OAc)2 (0.05 mmol) and 1,10-phenanthroline(0.15 mmol) at 150 1C in a sealed tube under N2 for 48 h. b Isolated yields. c Pd(OAc)2 (15 mol%) and ligand (45 mol%) were used.
4636 Chem. Commun., 2013, 49, 4634--4636 This journal is c The Royal Society of Chemistry 2013
tosylate with 4-methyl pyridine led to production of the product 3aain 59% yield. It should be mentioned that the same type of productwas also observed when we tried to couple 4-methyl pyridine with1-bromonaphthalene and 2-bromonaphthalene. It is possible thatthe large size of the naphthyl ring has made it difficult for the3-position of the pyridine ring to be activated. Consequently thereaction took place at the less sterically crowded benzylic position.
On the basis of literature reports,1 we reason that the reactionstarts with the oxidative insertion of the Pd(0) catalyst into theC–OTs bond to form phenyl–Pd(II) intermediate I. I next reacts withpyridine either through C–H activation or proton abstraction toform a diaryl–Pd(II) intermediate II. After reductive elimination, thedesired product is obtained and the Pd(0) catalyst is regenerated.Alternatively, the reaction may go through a Pd(II)/Pd(IV) catalyticcycle19 and intermediates such as III and IV may be involved. Atpresent, the exact mechanism remains to be clarified (Scheme 1).
In summary, we have demonstrated that C3-selective aryla-tion of pyridines can be accomplished with phenyl tosylatesusing Pd(OAc)2–1,10-phenanthroline as the catalyst and Cs2CO3
as the base. The coupling of naphthyl tosylates with 4-methylpyridine was found to occur on the methyl group instead of atthe C3 position. Detailed mechanistic investigations are stillongoing and the results will be reported in due course.
This work was supported by grants from the NationalScience Foundation of China (No. 21072051), NCET program(NCET-09-0334) and the Fundamental Research Funds for theCentral Universities, Hunan University.
Notes and references1 For recent reviews, see: (a) L. Ackermann, R. Vicente and A. R. Kapdi,
Angew. Chem., Int. Ed., 2009, 48, 9792; (b) F. Bellina and R. Rossi,Tetrahedron, 2009, 65, 10269; (c) G. P. McGlacken and L. M. Bateman,Chem. Soc. Rev., 2009, 38, 2447; (d) I. V. Seregin and V. Gevorgyan, Chem.Soc. Rev., 2007, 36, 1173; (e) D. Alberico, M. E. Scott and M. Lautens, Chem.Rev., 2007, 107, 174.
2 E.-I. Negishi, Handbook of Organopalladium Chemistry forOrganic Synthesis, Wiley, New York, 2002.
3 (a) D. Kalyani, K. B. McMurtrey, S. R. Neufeldt and M. S. Sanford,J. Am. Chem. Soc., 2011, 133, 18566; (b) A. S. Tsai, M. Brasse,R. G. Bergman and J. A. Ellman, Org. Lett., 2011, 13, 540;(c) C.-L. Sun, N. Liu, B.-J. Li, D.-J. Yu, Y. Wang and Z.-J. Shi, Org.Lett., 2010, 12, 184; (d) K. Parthasarathy and C.-H. Cheng, J. Org.Chem., 2009, 74, 9359; (e) V. S. Thirunavukkarasu, K. Parthasarathy
and C.-H. Cheng, Angew. Chem., Int. Ed., 2008, 47, 9462;( f ) L. V. Desai, H. A. Malik and M. S. Sanford, Org. Lett., 2006, 8, 1141.
4 (a) B. Li, K. Devaraj, C. Darcel and P. H. Dixneuf, Tetrahedron, 2012,68, 5179; (b) B. Li, C. B. Bheeter, C. Darcel and P. H. Dixneuf, ACS Catal.,2011, 1, 1221; (c) K. Ueura, T. Satoh and M. Miura, Org. Lett., 2005, 7, 2229.
5 (a) W.-Y. Yu, W. N. Sit, Z. Zhou and A. S. C. Chan, Org. Lett., 2009,11, 3174; (b) T. Vogler and A. Studer, Org. Lett., 2008, 10, 129;(c) J. Norinder, A. Matsumoto, N. Yoshikai and E. Nakamura, J. Am.Chem. Soc., 2008, 130, 5858; (d) K. L. Hull, E. L. Lanni and M. S. Sanford,J. Am. Chem. Soc., 2006, 128, 14047; (e) D. Kalyani, N. R. Deprez,L. V. Desai and M. S. Sanford, J. Am. Chem. Soc., 2005, 127, 7330.
6 (a) X.-G. Zhang, H.-X. Dai, M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2012,134, 11948; (b) Y. Hashimoto, K. Hirano, T. Satoh, F. Kakiuchi andM. Miura, Org. Lett., 2012, 14, 2058; (c) X. Wang, D. Leow and J.-Q. Yu,J. Am. Chem. Soc., 2011, 133, 13864; (d) G.-W. Wang, T.-T. Yuan andD.-D. Li, Angew. Chem., Int. Ed., 2011, 50, 1380; (e) B.-J. Li, S.-L. Tian,Z. Fang and Z.-J. Shi, Angew. Chem., Int. Ed., 2008, 47, 1115; ( f ) S. Yang,B. Li, X. Wan and Z. Shi, J. Am. Chem. Soc., 2007, 129, 6066; (g) O. Daugulisand V. G. Zaitsev, Angew. Chem., Int. Ed., 2005, 44, 4046; (h) V. G. Zaitsevand O. Daugulis, J. Am. Chem. Soc., 2005, 127, 4156.
7 (a) S. Mochida, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2011,76, 3024; (b) T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh andM.Miura, Org. Lett.,2011, 13, 706; (c) Y.-H. Zhang,B.-F. Shi andJ.-Q.Yu, J. Am.Chem. Soc., 2009, 131, 5072; (d) D.-H. Wang, T.-S. Mei and J.-Q. Yu, J. Am.Chem. Soc., 2008, 130, 17676; (e) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang,S.P.Breazzano,L.B.SaundersandJ.-Q.Yu, J. Am. Chem. Soc.,2007,129,3510.
8 For some reviews, see: (a) P. B. Arockiam, C. Bruneau andP. H. Dixneuf, Chem. Rev., 2012, 112, 5879; (b) D. A. Colby,R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624;(c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147.
9 For a recent review on C–H functionalization of pyridines, see:Y. Nakao, Synthesis, 2011, 3209.
10 For C2 arylation of pyridine N-oxides and N-iminopyridiniums, see:(a) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. You, J. Am.Chem. Soc., 2010, 132, 1822; (b) H.-Q. Do, R. M. K. Khan and O. Daugulis,J. Am. Chem. Soc., 2008, 130, 15185; (c) S. H. Cho, S. J. Hwang andS. Chang, J. Am. Chem. Soc., 2008, 130, 9254; (d) A. Larivee, J. J. Mousseauand A. B. Charette, J. Am. Chem. Soc., 2008, 130, 52; (e) L.-C. Campeau,S. Rousseaux and K. Fagnou, J. Am. Chem. Soc., 2005, 127, 18020.
11 (a) A. M. Berman, J. C. Lewis, R. G. Bergman and J. A. Ellman, J. Am.Chem. Soc., 2008, 130, 14926; (b) T. Kawashima, T. Takao andH. Suzuki, J. Am. Chem. Soc., 2007, 129, 11006; (c) M. Tobisu,I. Hyodo and N. Chatani, J. Am. Chem. Soc., 2009, 131, 12070.
12 For intramolecular direct C3 and C4 arylation of pyridines usingtethered ArX, see: (a) J. Roger, A. L. Gottumukkala and H. Doucet,ChemCatChem, 2010, 2, 20; (b) L. Basolo, E. M. Beccalli, E. Borsiniand G. Broggini, Tetrahedron, 2009, 65, 3486.
13 For C4 arylation of perfluoropyridines, see: (a) Y. Wei and W. Su,J. Am. Chem. Soc., 2010, 132, 16377; (b) C.-Y. He, S. Fan and X. Zhang,J. Am. Chem. Soc., 2010, 132, 12850; (c) Y. Wei, J. Kan, M. Wang, W. Suand M. Hong, Org. Lett., 2009, 11, 3346; (d) H.-Q. Do and O. Daugulis,J. Am. Chem. Soc., 2008, 130, 1128; (e) M. Lafrance, C. N. Rowley,T. K. Woo and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 8754.
14 For Pd(0)-catalyzed C3 arylation of pyridines using directing groups,see: (a) N. Gurbuz, I. Ozdemir and B. Cetinkaya, Tetrahedron Lett.,2005, 46, 2273; (b) M. Wasa, B. T. Worrell and J.-Q. Yu, Angew. Chem.,Int. Ed., 2010, 49, 1275.
15 P. Guo, J. M. Joo, S. Rakshit and D. Sames, J. Am. Chem. Soc., 2011,133, 16338.
16 (a) M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morrisand J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 19090; (b) M. Ye, G.-L. Gaoand J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 6964.
17 For some examples of Pd-catalyzed cross-coupling of aryl tosylates, see:(a) A. H. Roy and J. F. Hartwig, Organometallics, 2004, 23, 194; (b) H. N.Nguyen, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 11818;(c) L. A. Zhang, T. H. Meng and J. Wu, J. Org. Chem., 2007, 72, 9346;(d) C. M. So, C. P. Lau, A. S. C. Chan and F. Y. Kwong, J. Org. Chem., 2008,73, 7731.
18 For some examples of C3-selective activation of pyridines, see: (a) I. A.I. Mkhalid, D. N. Coventry, D. Albesa-Jove, A. S. Batsanov, J. A. K. Howard,T. B. Marder and R. N. Perutz, Angew. Chem., Int. Ed., 2006, 45, 489;(b) J. M. Murphy, X. Liao and J. F. Hartwig, J. Am. Chem. Soc., 2007,129, 15434; (c) B.-J. Li and Z.-J. Shi, Chem. Sci., 2011, 2, 488.
19 For a review on Pd(IV) chemistry, see: L.-M. Xu, B.-J. Li, Z. Yang andZ.-J. Shi, Chem. Soc. Rev., 2010, 39, 712.
Table 2 Pd-catalyzed coupling of naphthyl tosylates with 4-methylpyridinea
a Reaction conditions: 1b (3.0 mL), tosylate (0.5 mmol), Pd(OAc)2
(15 mol%), ligand (45 mol%), and Cs2CO3 (1.5 mmol) at 150 1C for 48 h.b Isolated yields.
