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Palladium-catalyzed oxidative C–H/C–H cross-coupling of benzothiazoles with thiophenes and thiazoles†
Received 16th January 2014, Accepted 26th February 2014
Xuxing Chen, Xiaojing Huang, Qian He, Yuyuan Xie and Chunhao Yang*
DOI: 10.1039/c4cc00362d www.rsc.org/chemcomm
A concise palladium-catalyzed method for oxidative C–H/C–H cross-coupling between benzothiazoles and thiophenes/thiazoles has been developed. This CDC reaction is insensitive to air and moisture with high functional group tolerance.
Biheteroarenes containing the benzothiazole motif usually possess a range of biological activities and unique optical properties; thus the important scaffold benzothiazole is frequently found in numerous pharmaceuticals and biochemicals (Scheme 1A).1 Recently, transition metal-catalyzed methods for their synthesis have been developed. Typically, either introduction of metal-containing functionalities and/or halides into at least one heteroarene as a coupling partner cannot be avoided.2 Based on the atom- and step-economic principles, the double C–H activation and cross-coupling of two simple heteroarenes would represent a very attractive, concise and sustainable approach towards the syntheses of these compounds. Since Fagnou3 and DeBoef4 independently reported the first Pd(OAc)2-catalyzed intermolecular oxidative heteroaryl–aryl
Scheme 1 (A) Important molecules containing 2-heteroarylated benzothiazoles. (B) Ring-opening reaction of benzothiazoles. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. E-mail: [email protected] † Electronic supplementary information (ESI) available: The experimental procedures, characterization data of compounds. See DOI: 10.1039/c4cc00362d
3996 | Chem. Commun., 2014, 50, 3996--3999
cross-coupling, various unsymmetrical biheteroaryls have been obtained successfully with high selectivity.5 However, due to the issues of reactivity, regioselectivity and decomposition of heteroarenes, intermolecular heteroarylations of heteroarenes via oxidative cross-coupling usually have limited scope. Though C–H bond cleavage is facile in benzothiazoles, this class of heteroarenes tends to form homocoupling products under oxidative conditions.6 And coupling products have a tendency to trap the metal catalyst to block the catalysis process. Furthermore, the C–S bond in benzothiazoles is known to be unstable in the presence of bases and transition-metal ions (Scheme 1B).7 Therefore, reaction conditions for their dehydrogenative heteroarylation have to be chosen carefully. In a previous work, Dr Ofial’s group described a palladiumcatalyzed cross-dehydrogenative coupling (CDC) of benzothiazoles with azoles to afford the unsymmetrical 2,20 -linkage between azoles.5d Since then, modifications and improvements of this type of transformation have been achieved by several groups.5e,l–n Recently, Li and co-workers also achieved the C-2 heteroarylations of benzothiazoles with the activated azine N-oxides.5g There are also sporadic cases about cross-dehydrogenative coupling of benzothiazole with indoles and pyrroles (only two substrates were explored and required a long reaction time)5c or directinggroup-bearing arenes (in 20% yield)5k have been reported. To the best of our knowledge, the CDC reaction of benzimidazoles/ benzoxazoles with thiophenes has been developed by Hu, You and co-workers;5a however, the direct C-2 heteroarylation of benzothiazoles with thiophenes has not been studied. Herein, we report a simple method for the direct C-2 heteroarylation of benzothiazoles with thiophenes and thiazoles through palladiumcatalyzed dehydrogenative C–C cross-coupling at the 2-position C–H in thiophenes or/and 5-position C–H in thiazoles under base-free conditions, which gave the corresponding products in moderate to excellent yields. Considering the similarity between benzothiazoles and benzimidazoles/benzoxazoles, initially, we conducted the reaction of benzothiazole 1a and 2-methylthiophene 2a according to the previous literature.5a Unfortunately, only a trace of the desired crosscoupling product 3aa was detected. Next, we screened different
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Table 1
Screening of reaction conditionsa
Entry
Oxidant
Ligand
Solvent
Time (h)
Yieldb (%)
1 2 3 4c 5 6 7 8 9 10 11 12 13d 14 15 16 17f 18g
AgOAc Ag2CO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3
None None None None AcOH PivOH Me-Gly-OH (Me)2-Gly-OH Pro-OH Boc-Me-Ala-OH 2,2 0 -Dipyridyl Phen Phen + PivOH Phen Phen Phen Phen Phen
DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMF NMP DMSO DMSO DMSO
20 20 12 12 12 10 5 5 12 2 10 10 4 10 10 10 10 10
18 21 28 27 29 36 18 17 14 22 45 50 40 31 27 69(63) 6 0
Table 2
Palladium-catalyzed CDC reaction of 1 with 2a
a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv.), 2a (4.0 mmol, 4.0 equiv.), solvent (3.0 mL), all reagents were mixed and stirred under air at r.t. for 5 minutes, then the sealed tubes were screw capped and heated at 110 1C until 1a disappeared. b Determined by 1H NMR analysis of the crude product using dimethyl terephthalate as an internal standard. c The reaction was carried out under N2 atmosphere. d Phen (15 mol%) and PivOH (15 mol%) were added. e The isolated yield is given in parentheses. f TEMPO (30 mol%) was added. g Pd(OAc)2 was not used.
parameters to determine the optimal conditions (Table 1 and ESI†). After investigation of several oxidants (entries 1–3, Table 1; Table S1, ESI†), we found that AgNO3 was the best choice (entry 3). Under these conditions, 3aa was obtained in a 28% NMR yield after 20 h. Similar yields were achieved when the reaction was conducted either under ambient air without exclusion of moisture or under a nitrogen atmosphere (entries 3 and 4). Considering that acetic acid and pivalic acid could promote the concerted metalation/ deprotonation process (CMD), we added acetic acid and pivalic acid as additives in the catalytic system. As a result, 1a disappeared in 12 h and 10 h, and 3aa was obtained in 29% and 36%, respectively (entries 5 and 6). When amino acid ligands were used, the consumption rate of 1a increased dramatically, but yields of 3aa decreased (entries 7–10). Presumably, these ligands might promote the decomposition of 1a. And we also found that carboxyl group containing ligands could increase homocoupling of 2a. Gratifyingly, bisdentate pyridyl ligands were found to increase the yields of the cross-coupling product (entries 11 and 12). A 50% yield of 3aa was obtained when 30 mol% 1,10-phenanthroline monohydrate (Phen) was employed as the ligand (entry 12). The combination of 15 mol% 1,10-phenanthroline and 15 mol% pivalic acid diminished the yield of 3aa to 40% (entry 13). Solvent effect in this reaction was also investigated (entries 12, 14–16). The use of DMSO instead of DMA gave 3aa in 63% isolated yield (entry 16). However, addition of bases was found to be ineffective in improving the yield (Table S4, ESI†), and Pd(OAc)2 was necessary for this transformation (entries 16 and 18). Thus, the standard conditions for the dehydrogenative
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a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv.), 2 (4.0 mmol, 4.0 equiv.), DMSO (3.0 mL), all reagents were mixed and stirred under air at r.t. for 5 minutes, then the sealed tubes were screw capped and heated at 110 1C for 10 h, and isolated yields based on 1a were given. b 2 (10.0 mmol, 10.0 equiv.) was used. c Heated for 40 h. d 32% homocoupling product of 1m was isolated.
heteroarylation of benzothiazoles were determined to be Pd(OAc)2 (10 mol%), AgNO3 (2.0 equiv.) and Phen (30 mol%) in DMSO (3.0 mL), heated at 110 1C for 10 h. With the optimal reaction conditions in hand, the reaction scope of both coupling partners for the CDC reaction was then examined (Table 2). A wide range of functional groups on the thiophenes were tolerated including electron-donating and -withdrawing groups, which would enable the cross-coupling products to be used in further transformations (3ab–3ak). It may be due to AgNO3 serving as a halogen scavenger, 10.0 equivalents of halo-substituted thiophenes were needed. 2-Chlorothiophene reacted under these conditions to give the desired product in 86% yield (3ac), and 2-bromothiophene reacted very slowly, giving 34% yield in 40 h (3ad). By increasing the amount of thiophenes, 2-phenylthiophene 2e, benzothiophene 2j and 2,3-disubstituted thiophene 2k also proceeded smoothly in 53%, 64% and 86% yields, respectively (3ae, 3aj and 3ak). It is noteworthy that 3ak represents a class of unexplored drug-like molecules. We were pleased that benzothiazole 1a was also successfully cross-coupled with electron-deficient compounds 2l–2n at the 5-position C–H on the thiazole ring (3al–3an). However, this cross-coupling reaction is not compatible with more electron-rich furan derivatives because of oxidative degradation (3ao and 3ap). Subsequently, a variety of benzothiazoles were tested with thiophenes and thiazoles. This system was highly tolerant to a variety of functional groups on the benzothiazole phenyl ring such as methoxyl, methyl, halide, phenyl, ester, trifluoromethyl (3bb–3jb, 3bm, 3dm, 3em). Both electron-rich
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and -deficient substrates could proceed smoothly to afford the corresponding biheteroaryls in moderate to good yields. In general, benzothiazoles with electron-donating groups gave the corresponding products in better yields than those with electron-withdrawing groups. When 10.0 equivalents of 4,6-dichlorobenzothiazole 1g were used, 3gb was also accessible in 67% yield by the CDC reaction. Replacing benzothiazoles by benzimidazole or benzoxazole, only low yields of the desired products were isolated (3kb, 3lb). The simple 4,5-dimethyl thiazole 1m was also investigated, and the crosscoupling product 3mb was obtained in 24% yield accompanied with 32% yield of the homocoupling product of thiazole. To understand the mechanism of this CDC reaction, the following experiments were carried out. Addition of TEMPO (30 mol%) as a radical scavenger to the reaction system under the optimized conditions inhibited the reaction considerably, which indicates that radical species may be involved in the cross-coupling process (entry 17 vs. 16, Table 1). The H/D exchange experiment for benzothiazole 1a was performed in the presence of Pd(OAc)2 (10 mol%), DMSO and D2O at 110 1C for 10 h (eqn (1), Scheme 2A). Significant deuterium incorporation at the C-2 position was observed, which was in accordance with the CMD process of 1a. Next, inter-kinetic isotope effect (KIE) experiments for both coupling partners were investigated (eqn (2) and (3), Scheme 2A). A KIE of 1.1 between benzothiazole 1a and its deuterated derivate 1a-[D1] was observed, indicating that the cleavage of the C-2 C–H bond in benzothiazole is not involved in the rate-limiting step. A significant KIE (KH/KD = 3.0) between benzothiophene 2j and its deuterated derivate 2j-[D1] was observed. These observations indicated that the C-2 C–H breaking of 2j might be related to the rate-limiting step. Based on the above facts, the mechanistic proposal for the CDC reaction is presented in Scheme 2B. An initial carboxylate-ligandassisted CMD pathway of acidic C-2 C–H in 1a generates benzothiazolylpalladium(II), which may go through a Pd(II)/Pd(0) catalytic cycle. Alternatively, heteroaryl–Pd(II)–Ln species may be captured by Ag(I) through Pd–Ag donor–acceptor bond.8 Silver(I) salts facilitate a one-electron oxidative cleavage of the Pd–C bond to give a heteroaryl radical.9 We proposed that the radical may transfer
Scheme 2 pathways.
(A) Preliminary study on mechanism. (B) Plausible reaction
3998 | Chem. Commun., 2014, 50, 3996--3999
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to Pd(II) to give a Pd(III) complex or Ag(I) directly oxidizes Pd(II) to Pd(III) via a single-electron-transfer (SET) process.10 Because there is not enough evidence, neither Pd(II)/Pd(0) nor Pd(III)/Pd(I) catalytic cycle can be ruled out at this time. The phenanthroline ligand in this system should play a similar role postulated by Yu, which is that the phenanthroline ligand coordinates strongly with palladium centers and weakens coordination of the N- and S-atoms of benzothiazole and thiophene substrates.11 The enhanced dissociation of substrates increases the local concentration of substrates in the vicinity of palladium for productive p binding which triggers the corresponding C–H activation. In conclusion, we have developed a concise palladium-catalyzed method for the direct C-2 heteroarylation of benzothiazoles with the S-atom containing five-membered aromatic heterocycles. This oxidative cross-coupling reaction, which is insensitive to air and moisture, is compatible with a wide range of functional groups. Additionally, the palladium-catalyzed system allows the oxidative cross-coupling not only between electron-deficient and electron-rich heteroarenes but also between two electron-deficient heteroarenes. Further investigations of the mechanism and other applications are underway in our laboratory. The authors are grateful to SKLDR/SIMM (SIMM1203ZZ-0103).
Notes and references 1 (a) A. E. Johnson, F. Jeppsson, J. Sandell, D. Wensbo, J. A. M. Neelissen, A. Jureus, P. Stroem, H. Norman, L. Farde and S. P. S. Svensson, J. Neurochem., 2009, 108, 1177; (b) L. Racane, V. Tralic-Kulenovic, P. S. Kraljevic, I. Ratkaj, P. Peixoto, R. Nhili, S. Depauw, M.-P. Hildebrand, M.-H. David-Cordonnier, K. Pavelic and G. Karminski-Zamola, J. Med. Chem., 2010, 53, 2418; (c) C. Andrade, C. O. Yanez, H.-Y. Ahn, T. Urakami, M. V. Bondar, M. Komatsu and K. D. Belfield, Bioconjugate Chem., 2011, 22, 2060; (d) G. Rai, V. N. Vyjayanti, D. Dorjsuren, A. Simeonov, A. Jadhav, D. M. Wilson and D. J. Maloney, J. Med. Chem., 2012, 55, 3101; (e) J. R. Rodrigues, J. Charris, J. Camacho, A. Barazarte, N. Gamboa, B. Nitzsche, M. Hoepfner, M. Lein, K. Jung and C. Abramjuk, J. Pharm. Pharmacol., 2013, 65, 411. 2 For selected examples, see: (a) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2007, 129, 12404; (b) G. L. Turner, J. A. Morris and M. F. Greaney, Angew. Chem., Int. Ed., 2007, 46, 7996; (c) D. Zhao, W. Wang, S. Lian, F. Yang, J. Lan and J. You, Chem.–Eur. J., 2009, 15, 1337; (d) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D. Larsen and M. M. Faul, J. Am. Chem. Soc., 2010, 132, 3674; (e) S. Ranjit and X. Liu, Chem.–Eur. J., 2011, 17, 1105. 3 D. R. Stuart and K. Fagnou, Science, 2007, 316, 1172. 4 T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn and B. DeBoef, Org. Lett., 2007, 9, 3137. 5 For examples of catalytic CDC for synthesis of biheteroaryls, see: With Pd catalysts: (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) X. Gong, G. Song, H. Zhang and X. Li, Org. Lett., 2011, 13, 1766; (c) Z. Wang, K. Li, D. Zhao, J. Lan and J. You, Angew. Chem., Int. Ed., 2011, 50, 5365; (d) W. Han, P. Mayer and A. R. Ofial, Angew. Chem., Int. Ed., 2011, 50, 2178; (e) J. Dong, Y. Huang, X. Qin, Y. Cheng, J. Hao, D. Wan, W. Li, X. Liu and J. You, Chem.–Eur. J., 2012, 18, 6158; ( f ) J. Rentner and R. Breinbauer, Chem. Commun., 2012, 48, 10343; ( g) X.-P. Fu, Q.-Q. Xuan, L. Liu, D. Wang, Y.-J. Chen and C.-J. Li, Tetrahedron, 2013, 69, 4436; (h) B. Liu, Y. Huang, J. Lan, F. Song and J. You, Chem. Sci., 2013, 4, 2163; (i) C.-Y. He, Z. Wang, C.-Z. Wu, F.-L. Qing and X. Zhang, Chem. Sci., 2013, 4, 3508. With Cu catalysts: ( j) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2011, 133, 13577; (k) M. Nishino, K. Hirano, T. Satoh and M. Miura, Angew. Chem., Int. Ed., 2012, 51, 6993; (l ) X. Qin, B. Feng, J. Dong, X. Li, Y. Xue, J. Lan and J. You, J. Org. Chem., 2012, 77, 7677; (m) Z. Mao, Z. Wang, Z. Xu, F. Huang, Z. Yu and R. Wang, Org. Lett., 2012, 14, 3854; (n) S. Fan, Z. Chen and X. Zhang, Org. Lett., 2012, 14, 4950. With Rh catalysts: (o) N. Kuhl, M. N. Hopkinson and F. Glorius, Angew. Chem., Int. Ed.,
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Communication 2012, 51, 8230; (p) X. Qin, H. Liu, D. Qin, Q. Wu, J. You, D. Zhao, Q. Guo, X. Huang and J. Lan, Chem. Sci., 2013, 4, 1964; (q) Y. Shang, X. Jie, H. Zhao, P. Hu and W. Su, Org. Lett., 2014, 16, 416. 6 M. Zhu, K.-i. Fujita and R. Yamaguchi, Chem. Commun., 2011, 47, 12876. 7 For selected examples, see: (a) S. Liu, R. Chen, X. Guo, H. Yang, G. Deng and C.-J. Li, Green Chem., 2012, 14, 1577; (b) Z. Yang, X. Chen, S. Wang, J. Liu, K. Xie, A. Wang and Z. Tan, J. Org. Chem., 2012, 77, 7086; (c) Q. Gao, X. Wu, F. Jia, M. Liu, Y. Zhu, Q. Cai and A. Wu, J. Org. Chem., 2013, 78, 2792. ´s, C. Fortun ˜o, 8 For selected examples, see: (a) E. Alonso, J. Fornie A. Martı´n and A. G. Orpen, Organometallics, 2003, 22, 5011; ´s, C. Fortun ˜ o, S. Iba ´n ˜ ez, A. Martı´n, P. Mastrorilli and (b) J. Fornie V. Gallo, Inorg. Chem., 2011, 50, 10798.
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ChemComm 9 A. L. Seligson and W. C. Trogler, J. Am. Chem. Soc., 1992, 114, 7085. 10 For recent literatures of Pd(III) catalysts, see: (a) D. C. Powers and T. Ritter, Higher Oxidation State Organopalladium and Platinum Chemistry, Springer, 2011, pp. 129; (b) D. Kalyani, K. B. McMurtrey, S. R. Neufeldt and M. S. Sanford, J. Am. Chem. Soc., 2011, 133, 18566; (c) G. Maestri, M. Malacria and E. Derat, Chem. Commun., 2013, 49, 10424; (d) P. S. Thuy-Boun, G. Villa, D. Dang, P. Richardson, S. Su and J.-Q. Yu, J. Am. Chem. Soc., 2013, 135, 17508. 11 (a) M. Ye, G.-L. Gao and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 6964; (b) M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 19090.
Chem. Commun., 2014, 50, 3996--3999 | 3999
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Palladium-catalyzed oxidative C–H/C–H cross-coupling of benzothiazoles with thiophenes and thiazoles†
Received 16th January 2014, Accepted 26th February 2014
Xuxing Chen, Xiaojing Huang, Qian He, Yuyuan Xie and Chunhao Yang*
DOI: 10.1039/c4cc00362d www.rsc.org/chemcomm
A concise palladium-catalyzed method for oxidative C–H/C–H cross-coupling between benzothiazoles and thiophenes/thiazoles has been developed. This CDC reaction is insensitive to air and moisture with high functional group tolerance.
Biheteroarenes containing the benzothiazole motif usually possess a range of biological activities and unique optical properties; thus the important scaffold benzothiazole is frequently found in numerous pharmaceuticals and biochemicals (Scheme 1A).1 Recently, transition metal-catalyzed methods for their synthesis have been developed. Typically, either introduction of metal-containing functionalities and/or halides into at least one heteroarene as a coupling partner cannot be avoided.2 Based on the atom- and step-economic principles, the double C–H activation and cross-coupling of two simple heteroarenes would represent a very attractive, concise and sustainable approach towards the syntheses of these compounds. Since Fagnou3 and DeBoef4 independently reported the first Pd(OAc)2-catalyzed intermolecular oxidative heteroaryl–aryl
Scheme 1 (A) Important molecules containing 2-heteroarylated benzothiazoles. (B) Ring-opening reaction of benzothiazoles. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. E-mail: [email protected] † Electronic supplementary information (ESI) available: The experimental procedures, characterization data of compounds. See DOI: 10.1039/c4cc00362d
3996 | Chem. Commun., 2014, 50, 3996--3999
cross-coupling, various unsymmetrical biheteroaryls have been obtained successfully with high selectivity.5 However, due to the issues of reactivity, regioselectivity and decomposition of heteroarenes, intermolecular heteroarylations of heteroarenes via oxidative cross-coupling usually have limited scope. Though C–H bond cleavage is facile in benzothiazoles, this class of heteroarenes tends to form homocoupling products under oxidative conditions.6 And coupling products have a tendency to trap the metal catalyst to block the catalysis process. Furthermore, the C–S bond in benzothiazoles is known to be unstable in the presence of bases and transition-metal ions (Scheme 1B).7 Therefore, reaction conditions for their dehydrogenative heteroarylation have to be chosen carefully. In a previous work, Dr Ofial’s group described a palladiumcatalyzed cross-dehydrogenative coupling (CDC) of benzothiazoles with azoles to afford the unsymmetrical 2,20 -linkage between azoles.5d Since then, modifications and improvements of this type of transformation have been achieved by several groups.5e,l–n Recently, Li and co-workers also achieved the C-2 heteroarylations of benzothiazoles with the activated azine N-oxides.5g There are also sporadic cases about cross-dehydrogenative coupling of benzothiazole with indoles and pyrroles (only two substrates were explored and required a long reaction time)5c or directinggroup-bearing arenes (in 20% yield)5k have been reported. To the best of our knowledge, the CDC reaction of benzimidazoles/ benzoxazoles with thiophenes has been developed by Hu, You and co-workers;5a however, the direct C-2 heteroarylation of benzothiazoles with thiophenes has not been studied. Herein, we report a simple method for the direct C-2 heteroarylation of benzothiazoles with thiophenes and thiazoles through palladiumcatalyzed dehydrogenative C–C cross-coupling at the 2-position C–H in thiophenes or/and 5-position C–H in thiazoles under base-free conditions, which gave the corresponding products in moderate to excellent yields. Considering the similarity between benzothiazoles and benzimidazoles/benzoxazoles, initially, we conducted the reaction of benzothiazole 1a and 2-methylthiophene 2a according to the previous literature.5a Unfortunately, only a trace of the desired crosscoupling product 3aa was detected. Next, we screened different
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Table 1
Screening of reaction conditionsa
Entry
Oxidant
Ligand
Solvent
Time (h)
Yieldb (%)
1 2 3 4c 5 6 7 8 9 10 11 12 13d 14 15 16 17f 18g
AgOAc Ag2CO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3
None None None None AcOH PivOH Me-Gly-OH (Me)2-Gly-OH Pro-OH Boc-Me-Ala-OH 2,2 0 -Dipyridyl Phen Phen + PivOH Phen Phen Phen Phen Phen
DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMF NMP DMSO DMSO DMSO
20 20 12 12 12 10 5 5 12 2 10 10 4 10 10 10 10 10
18 21 28 27 29 36 18 17 14 22 45 50 40 31 27 69(63) 6 0
Table 2
Palladium-catalyzed CDC reaction of 1 with 2a
a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv.), 2a (4.0 mmol, 4.0 equiv.), solvent (3.0 mL), all reagents were mixed and stirred under air at r.t. for 5 minutes, then the sealed tubes were screw capped and heated at 110 1C until 1a disappeared. b Determined by 1H NMR analysis of the crude product using dimethyl terephthalate as an internal standard. c The reaction was carried out under N2 atmosphere. d Phen (15 mol%) and PivOH (15 mol%) were added. e The isolated yield is given in parentheses. f TEMPO (30 mol%) was added. g Pd(OAc)2 was not used.
parameters to determine the optimal conditions (Table 1 and ESI†). After investigation of several oxidants (entries 1–3, Table 1; Table S1, ESI†), we found that AgNO3 was the best choice (entry 3). Under these conditions, 3aa was obtained in a 28% NMR yield after 20 h. Similar yields were achieved when the reaction was conducted either under ambient air without exclusion of moisture or under a nitrogen atmosphere (entries 3 and 4). Considering that acetic acid and pivalic acid could promote the concerted metalation/ deprotonation process (CMD), we added acetic acid and pivalic acid as additives in the catalytic system. As a result, 1a disappeared in 12 h and 10 h, and 3aa was obtained in 29% and 36%, respectively (entries 5 and 6). When amino acid ligands were used, the consumption rate of 1a increased dramatically, but yields of 3aa decreased (entries 7–10). Presumably, these ligands might promote the decomposition of 1a. And we also found that carboxyl group containing ligands could increase homocoupling of 2a. Gratifyingly, bisdentate pyridyl ligands were found to increase the yields of the cross-coupling product (entries 11 and 12). A 50% yield of 3aa was obtained when 30 mol% 1,10-phenanthroline monohydrate (Phen) was employed as the ligand (entry 12). The combination of 15 mol% 1,10-phenanthroline and 15 mol% pivalic acid diminished the yield of 3aa to 40% (entry 13). Solvent effect in this reaction was also investigated (entries 12, 14–16). The use of DMSO instead of DMA gave 3aa in 63% isolated yield (entry 16). However, addition of bases was found to be ineffective in improving the yield (Table S4, ESI†), and Pd(OAc)2 was necessary for this transformation (entries 16 and 18). Thus, the standard conditions for the dehydrogenative
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a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv.), 2 (4.0 mmol, 4.0 equiv.), DMSO (3.0 mL), all reagents were mixed and stirred under air at r.t. for 5 minutes, then the sealed tubes were screw capped and heated at 110 1C for 10 h, and isolated yields based on 1a were given. b 2 (10.0 mmol, 10.0 equiv.) was used. c Heated for 40 h. d 32% homocoupling product of 1m was isolated.
heteroarylation of benzothiazoles were determined to be Pd(OAc)2 (10 mol%), AgNO3 (2.0 equiv.) and Phen (30 mol%) in DMSO (3.0 mL), heated at 110 1C for 10 h. With the optimal reaction conditions in hand, the reaction scope of both coupling partners for the CDC reaction was then examined (Table 2). A wide range of functional groups on the thiophenes were tolerated including electron-donating and -withdrawing groups, which would enable the cross-coupling products to be used in further transformations (3ab–3ak). It may be due to AgNO3 serving as a halogen scavenger, 10.0 equivalents of halo-substituted thiophenes were needed. 2-Chlorothiophene reacted under these conditions to give the desired product in 86% yield (3ac), and 2-bromothiophene reacted very slowly, giving 34% yield in 40 h (3ad). By increasing the amount of thiophenes, 2-phenylthiophene 2e, benzothiophene 2j and 2,3-disubstituted thiophene 2k also proceeded smoothly in 53%, 64% and 86% yields, respectively (3ae, 3aj and 3ak). It is noteworthy that 3ak represents a class of unexplored drug-like molecules. We were pleased that benzothiazole 1a was also successfully cross-coupled with electron-deficient compounds 2l–2n at the 5-position C–H on the thiazole ring (3al–3an). However, this cross-coupling reaction is not compatible with more electron-rich furan derivatives because of oxidative degradation (3ao and 3ap). Subsequently, a variety of benzothiazoles were tested with thiophenes and thiazoles. This system was highly tolerant to a variety of functional groups on the benzothiazole phenyl ring such as methoxyl, methyl, halide, phenyl, ester, trifluoromethyl (3bb–3jb, 3bm, 3dm, 3em). Both electron-rich
Chem. Commun., 2014, 50, 3996--3999 | 3997
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and -deficient substrates could proceed smoothly to afford the corresponding biheteroaryls in moderate to good yields. In general, benzothiazoles with electron-donating groups gave the corresponding products in better yields than those with electron-withdrawing groups. When 10.0 equivalents of 4,6-dichlorobenzothiazole 1g were used, 3gb was also accessible in 67% yield by the CDC reaction. Replacing benzothiazoles by benzimidazole or benzoxazole, only low yields of the desired products were isolated (3kb, 3lb). The simple 4,5-dimethyl thiazole 1m was also investigated, and the crosscoupling product 3mb was obtained in 24% yield accompanied with 32% yield of the homocoupling product of thiazole. To understand the mechanism of this CDC reaction, the following experiments were carried out. Addition of TEMPO (30 mol%) as a radical scavenger to the reaction system under the optimized conditions inhibited the reaction considerably, which indicates that radical species may be involved in the cross-coupling process (entry 17 vs. 16, Table 1). The H/D exchange experiment for benzothiazole 1a was performed in the presence of Pd(OAc)2 (10 mol%), DMSO and D2O at 110 1C for 10 h (eqn (1), Scheme 2A). Significant deuterium incorporation at the C-2 position was observed, which was in accordance with the CMD process of 1a. Next, inter-kinetic isotope effect (KIE) experiments for both coupling partners were investigated (eqn (2) and (3), Scheme 2A). A KIE of 1.1 between benzothiazole 1a and its deuterated derivate 1a-[D1] was observed, indicating that the cleavage of the C-2 C–H bond in benzothiazole is not involved in the rate-limiting step. A significant KIE (KH/KD = 3.0) between benzothiophene 2j and its deuterated derivate 2j-[D1] was observed. These observations indicated that the C-2 C–H breaking of 2j might be related to the rate-limiting step. Based on the above facts, the mechanistic proposal for the CDC reaction is presented in Scheme 2B. An initial carboxylate-ligandassisted CMD pathway of acidic C-2 C–H in 1a generates benzothiazolylpalladium(II), which may go through a Pd(II)/Pd(0) catalytic cycle. Alternatively, heteroaryl–Pd(II)–Ln species may be captured by Ag(I) through Pd–Ag donor–acceptor bond.8 Silver(I) salts facilitate a one-electron oxidative cleavage of the Pd–C bond to give a heteroaryl radical.9 We proposed that the radical may transfer
Scheme 2 pathways.
(A) Preliminary study on mechanism. (B) Plausible reaction
3998 | Chem. Commun., 2014, 50, 3996--3999
Communication
to Pd(II) to give a Pd(III) complex or Ag(I) directly oxidizes Pd(II) to Pd(III) via a single-electron-transfer (SET) process.10 Because there is not enough evidence, neither Pd(II)/Pd(0) nor Pd(III)/Pd(I) catalytic cycle can be ruled out at this time. The phenanthroline ligand in this system should play a similar role postulated by Yu, which is that the phenanthroline ligand coordinates strongly with palladium centers and weakens coordination of the N- and S-atoms of benzothiazole and thiophene substrates.11 The enhanced dissociation of substrates increases the local concentration of substrates in the vicinity of palladium for productive p binding which triggers the corresponding C–H activation. In conclusion, we have developed a concise palladium-catalyzed method for the direct C-2 heteroarylation of benzothiazoles with the S-atom containing five-membered aromatic heterocycles. This oxidative cross-coupling reaction, which is insensitive to air and moisture, is compatible with a wide range of functional groups. Additionally, the palladium-catalyzed system allows the oxidative cross-coupling not only between electron-deficient and electron-rich heteroarenes but also between two electron-deficient heteroarenes. Further investigations of the mechanism and other applications are underway in our laboratory. The authors are grateful to SKLDR/SIMM (SIMM1203ZZ-0103).
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ChemComm 9 A. L. Seligson and W. C. Trogler, J. Am. Chem. Soc., 1992, 114, 7085. 10 For recent literatures of Pd(III) catalysts, see: (a) D. C. Powers and T. Ritter, Higher Oxidation State Organopalladium and Platinum Chemistry, Springer, 2011, pp. 129; (b) D. Kalyani, K. B. McMurtrey, S. R. Neufeldt and M. S. Sanford, J. Am. Chem. Soc., 2011, 133, 18566; (c) G. Maestri, M. Malacria and E. Derat, Chem. Commun., 2013, 49, 10424; (d) P. S. Thuy-Boun, G. Villa, D. Dang, P. Richardson, S. Su and J.-Q. Yu, J. Am. Chem. Soc., 2013, 135, 17508. 11 (a) M. Ye, G.-L. Gao and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 6964; (b) M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 19090.
Chem. Commun., 2014, 50, 3996--3999 | 3999
