Letter pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Oxidative Cross-Coupling of Unreactive C(sp3)−H Bonds with C(sp2)−H Bonds Guangying Tan and Jingsong You* Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P.R. China S Supporting Information *
ABSTRACT: The development of the oxidative cross-coupling of unreactive C(sp3)−H bonds with (hetero)arene C(sp2)−H bonds is considerably appealing, yet conceptually and practically challenging. Here, we disclose the rhodiumcatalyzed oxidative heteroarylation of unactivated C(sp3)−H bonds with heteroarene C(sp2)−H bonds. This method provides a step-economic route to β-heteroarylated 2-ethylpyridine derivatives, which exhibits relatively broad substrate scope, high tolerance level of sensitive functional groups, and high selectivity. The protocol can also be extended to the coupling reaction between 8-methylquinoline derivatives and heteroarenes.
O
2a).7−9 However, the analogous heteroarylation of unreactive C(sp3)−H bonds remains rare so far. The obstacle is probably
ver the past decade, transition-metal-catalyzed direct (hetero)arylation of C(sp3)−H bonds has been an area of intense research in the synthetic organic community.1 Since the incipient C(sp3)−H arylation of 8-methylquinoline was reported,2 various catalytic systems have been developed for the arylation of remote aliphatic C−H bonds based on different transition-metal catalysts (e.g., Pd, Ni, Fe, Rh, and Ir).3 These high-efficiency methods have been applied to synthesize natural products, pharmaceuticals, and biologically active molecules.4 Despite significant progress, those direct (hetero)arylation reactions of unreactive aliphatic C−H bonds required preactivated (hetero)arylating reagents such as (hetero)aryl halides/pseudohalides or organometallic reagents (Scheme 1).
Scheme 2. Transition-Metal-Catalyzed C−H Heteroarylationa
Scheme 1. Transition Metal-Catalyzed (Hetero)arylation of Remote Unreactive C(sp3)−H Bondsa a
a
attributed to high bond strengths of inert C(sp3)−H bonds, low reactivity of rhodium−C(alkyl) species, and competitive βhydride elimination.3i,10 β-Heteroarylated 2-ethylpyridines, including β-thienyl/furyl 2-ethylpyridines, are the cores of numerous pharmaceuticals and biologically active molecules (Scheme 3).11 Given that 2ethylpyridine derivatives are easily available and have emerged to display excellent chelating ability in transition-metalcatalyzed C−H activation/functionalization,3i,10 we envisioned that β-heteroarylated 2-ethylpyridine derivatives would be synthesized rapidly via the selective heteroarylation of an inert methyl C(sp3)−H bond of 2-ethylpyridine derivatives with a heteroarene C(sp2)−H bond with the assistance of the inherent pyridyl unit as the directing group (Scheme 2b).
DG = directing group.
Undoubtedly, expanding this chemistry to nonpreactivated (hetero)arenes is considerably appealing, yet conceptually and practically challenging.5 Recently, Ge reported a landmark work on the copper-promoted oxidative cross-coupling of unactivated C(sp3)−H bonds of amides with C(sp2)−H bonds of acidic polyfluoroarenes with the aid of an 8-aminoquinoline auxiliary as a bidentate directing group.5a Thiophene and furan are two important classes of heterocycles found frequently in pharmaceuticals, natural products, biologically active molecules, and functional materials.6 These electron-rich heteroarenes have been demonstrated with transition-metal-catalyzed oxidative coupling reactions with C(sp2)−H bonds with the aid of directing groups (Scheme © 2017 American Chemical Society
DG = directing group.
Received: July 16, 2017 Published: August 30, 2017 4782
DOI: 10.1021/acs.orglett.7b02167 Org. Lett. 2017, 19, 4782−4785
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Organic Letters
effective for the process (Table S1, entries 13−16). When PivOH was replaced with AcOH, 3a could be delivered in 57% yield (Table S1, entry 17). Through further optimization of the reaction parameters, such as the amounts of AcOH and solvent, and reaction temperature, 3a was obtained in 72% yield under the optimal catalytic system comprising [Cp*RhCl2]2 (5 mol %) (Cp* = pentamethyl cyclopentadienyl), AgSbF6 (20 mol %), Ag2O (3.0 equiv), and AcOH (30 mol %) in THF/t-BuOH (4:1, v/v) at 140 °C for 20 h (Table S1, entry 23). With the optimal conditions in hand, the scope of 2ethylpyridine derivatives was examined. As shown in Scheme 5,
Scheme 3. Pharmaceutical and Biologically Active Molecules Containing β-Heteroarylated 2-Ethylpyridine Derivatives
Scheme 5. Scope of 2-Alkylpyridine Derivativesa,b Rhodium-catalyzed C(sp2)−H bond activation has been proven to be a versatile synthetic tool for the construction of various carbon−carbon and carbon−heteroatom bonds.12 Recently, rhodium-catalyzed oxidative C(sp2)−H/C(sp2)−H cross-coupling reactions between two (hetero)arenes have been developed with the help of various directing groups such as the amide, N-heteroarene, and carboxylic acid by Glorius, You, and other groups.7 In sharp contrast, the rhodium-catalyzed unactivated C(sp3)−H functionalization is still in its infancy. Very recently, Glorius reported the rhodium-catalyzed C(sp3)− H activation/arylation of 2-alkylpyridine derivatives with triphenylboroxine as the aryl source.3i Our and Li’s groups successively demonstrated the rhodium-catalyzed C(sp3)−H activation/amination.13,14 In our previous work, a fivemembered cyclometalated Rh(III) species A was successfully isolated (Scheme 4a).13 With this Rh(III) species A in hand, we Scheme 4. Preliminary Stoichiometric Reactions
a
Reactions were performed with 1 (0.2 mmol) and 2 (0.6 mmol) in 0.3 mL of THF/t-BuOH (4:1, v/v) at 140 °C for 20 h under N2. b Yields of isolated products. c64% yield was obtained from a 1.0 mmol scale reaction. d150 °C for 48 h.
first performed a stoichiometric reaction of A with benzothiophene 2a at 140 °C in the presence of AgSbF6 and Ag2O, affording the desired product 3a in 34% yield (Scheme 4b). The exciting result of the stoichiometric heteroarylation mentioned above drove us to optimize the reaction conditions to allow the occurrence of reaction in a catalytic version. Our investigation commenced with the reaction between 2-tertbutylpyridine 1a and benzothiophene 2a (for detailed optimization, see Table S1). According to the preliminary stoichiometric heteroarylation, various solvents were first examined. THF proved to be superior to MeOH, t-AmylOH, t-BuOH, hexafluoroisopropanol (HFIP), DCE, dioxane, toluene, and DMF (Table S1, entries 1 and 5−12) and gave rise to 3a in 46% yield (Table S1, entry 12). Other oxidants such as AgOAc, Ag2CO3, Cu(OAc)2, and PhI(OAc)2 were less
various 2-alkylpyridine derivatives could smoothly react with 2a, delivering the corresponding products (Scheme 5, 3a−e). The electron-donating substituents such as methyl and methoxyl on the pyridine ring were tolerated well (Scheme 5, 3f,g). Substrates with functional groups such as benzyl, phenyl, trifluoromethyl, and even ester on alkane skeletons could react with methyl 3-methylthiophene-2-carboxylate (2f) in satisfactory yields (Scheme 5, 3h−k). Moreover, the heteroarylated products 3a and 4h could further react with 2f, giving the desired products in good yields (Scheme 5, 3l,m). Subsequently, we attempted 2-alkylpyridine derivatives with a more challenging tertiary α-carbon. For example, the substrates 1l, 1m, and 1n, which have only one methyl or isopropyl at the 4783
DOI: 10.1021/acs.orglett.7b02167 Org. Lett. 2017, 19, 4782−4785
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Organic Letters benzylic position of the pyridine ring, afforded the corresponding products in synthetically useful yields (Scheme 5, 3n−p). Next, the scope of heteroarenes was investigated. To our delight, a wide range of thiophene derivatives bearing various functional groups such as amide, acyl, ester, formyl, bromo, and vinyl were tolerated well, delivering the desired products in good yields (Scheme 6, 4a−j). Benzothiophenes with the
Scheme 7. Reaction of 8-Methylquinoline Derivatives with Heteroarenesa,b
Scheme 6. Scope of Heteroarenesa,b
a
Reactions were performed with 5 (0.2 mmol) and 2 (0.6 mmol) in 0.3 mL of THF at 120 °C for 20 h under N2. bYields of isolated products.
Scheme 8. Deuterium Labeling and Kinetic Isotope Effect Experiments
a Reactions were performed with 1a (0.2 mmol) and 2 (0.6 mmol) in 0.3 mL of THF/t-BuOH (4:1, v/v) at 140 °C for 20 h under N2. b Yields of isolated products.
chloro or bromo group could be engaged in this reaction (Scheme 6, 4k,l). Moreover, furans could also undergo this type of heteroarylation (Scheme 6, 4m,n). Other heteroarenes such as indole and pyrimidine could not be tolerated with this protocol. Considering that α-heteroarylated 8-methylquinolines are pharmaceutical and biologically active molecules, 15 the analogous heteroarylation of C(sp3)−H bonds of 8-methylquinoline derivatives was performed. As shown in Scheme 7, 8methylquinolines with either the electron-donating (methyl) or electron-withdrawing (Br and CF3) group could react with methyl 3-methylthiophene-2-carboxylate (2f), producing the desired products (Scheme 7, 6a−f). Benzothiothene (2a) and thiophene-2-carbaldehyde (2h) could also undergo this reaction (Scheme 7, 6g,h). To gain insight into the reaction mechanism, hydrogen/ deuterium exchange experiments were performed for both coupling partners. Under the standard conditions, the reaction of 1e with 20 equiv of CD3OD in either the presence or absence of benzothiophene (2a) for 6 h did not lead to any deuterated [Dn]-1e (Scheme 8a,c) and 3e was obtained in 23% yield in the presence of 2a (Scheme 8c), suggesting that the primary C(sp3)−H bond cleavage was an irreversible process. While 2a reacted with CD3OD in the absence and presence of 1e, the H/D exchange ratios of 2a were approximately 35% and 30%, respectively, implying that the cleavage of the C−H bond
of 2a was a reversible process (Scheme 8b,c). Then, kinetic isotope effects (KIE) for both coupling partners were investigated. Two parallel competition reactions between 1e or [D6]-1e with 2a give a significant kinetic isotope effect (KIE) value (kH/kD = 4.3) (Scheme 8d). On the other hand, a primary KIE value of 1.3 was observed for 2a and [D]-2a with 1e (Scheme 8e). The above results revealed that the unreactive C(sp3)−H bond cleavage might be related with the ratedetermining step. On the basis of the above results and previous Rh(III)catalyzed C(sp2)−H heteroarylation,7 a plausible mechanistic pathway is proposed in Scheme 9. First, the coordination of 2tert-butylpyridine 1a with a Rh(III) species generated from a ligand exchange and subsequent chelation-assisted activation of primary C(sp3)−H bond form the intermediate IM1. Next, IM1 reacts with heteroarene 2 to produce the intermediate 4784
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Lett. 2005, 7, 3657. (c) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (3) For selected examples of transition-metal-catalyzed unreactive C(sp3)−H bond activation/(hetero)arylation, see: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (b) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (c) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192. (d) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030. (e) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem., Int. Ed. 2013, 52, 13588. (f) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 898. (g) Gu, Q.; Mamari, H. H. A.; Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem., Int. Ed. 2014, 53, 3868. (h) Gao, P.; Guo, W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z. J. Am. Chem. Soc. 2015, 137, 12231. (i) Wang, X.; Yu, D.-G.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 10280. (4) For selected examples, see: (a) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076. (b) He, G.; Zhang, S.-Y.; Nack, W. A.; Pearson, R.; Rabb-Lynch, J.; Chen, G. Org. Lett. 2014, 16, 6488. (5) (a) Wu, X.; Zhao, Y.; Ge, H. Chem. Sci. 2015, 6, 5978. (b) During the preparation of this paper, the Yin group reported the nickel-catalyzed oxidative cross-coupling of unactivated C(sp3)−H bonds with thiophene and furan with the aid of the 8-aminoquinoline auxiliary. See: Wang, X.; Xie, P.; Qiu, R.; Zhu, L.; Liu, T.; Li, Y.; Iwasaki, T.; Au, C.-T.; Xu, X.; Xia, Y.; Yin, S.-F.; Kambe, N. Chem. Commun. 2017, 53, 8316. (6) (a) Ashwood-Smith, M. J.; Poulton, G. A.; Barker, M.; Mildenberger, M. Nature 1980, 285, 407. (b) Mishra, A.; Ma, C.-Q.; Bäuerle, P. Chem. Rev. 2009, 109, 1141. (7) For selected examples of chelation-assisted rhodium-catalyzed heteroarylation of (hetero)arene C(sp2)−H bonds, see: (a) WencelDelord, J.; Nimphius, C.; Wang, H.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 13001. (b) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2013, 52, 580. (c) Huang, Y.; Wu, D.; Huang, J.; Guo, Q.; Li, J.; You, J. Angew. Chem., Int. Ed. 2014, 53, 12158. (d) Shang, Y.; Jie, X.; Zhao, H.; Hu, P.; Su, W. Org. Lett. 2014, 16, 416. (e) Qin, X.; Li, X.; Huang, Q.; Liu, H.; Wu, D.; Guo, Q.; Lan, J.; Wang, R.; You, J. Angew. Chem., Int. Ed. 2015, 54, 7167. (f) Deng, H.; Li, H.; Wang, L. Org. Lett. 2016, 18, 3110. (8) Gao, D.-W.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2016, 138, 2544. (9) Zhao, S.; Yuan, J.; Li, Y.-C.; Shi, B.-F. Chem. Commun. 2015, 51, 12823. (10) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. (11) (a) Frick, W.; Kirsch, R.; Glombik, H.; Heuer, H. WO00/ 20410A1. (b) Griffith, R. C.; Schmiesing, R. J.; Griffith, R. J. US005607935A. (c) Adams, R.; Duffey, M.; Gould, A. E.; Greenspan, P. D.; Kulkarni, B. A.; Vos, T. J. WO2008/079277A1. (12) For selected reviews on rhodium-catalyzed C−H activation/ functionalization, see: (a) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (13) Huang, X.; Wang, Y.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2015, 54, 9404. (14) Wang, H.; Tang, G.; Li, X. Angew. Chem., Int. Ed. 2015, 54, 13049. (15) Andries, K. J. L. M.; Koul, A.; Guillemont, J. E. G.; Pasquier, E. T. J.; Lancois, D. F. A. WO2007/014940A2.
Scheme 9. Plausible Mechanistic Pathway
IM2. Finally, IM2 undergoes a reductive elimination, delivering the desired product 3 or 4. The generated Cp*Rh(I) species is reoxidized to the Cp*Rh(III) species by Ag salt to furnish the catalytic cycle. In summary, we have demonstrated a rhodium(III)-catalyzed oxidative cross-coupling of inert C(sp3)−H bonds with C(sp2)−H bonds of heteroarenes, which exhibits relatively broad substrate scope and entire monoselectivity. A wide range of sensitive functional groups such as amide, acyl, ester, formyl, chloro, bromo, and vinyl are tolerated well, which can easily undergo further transformations. The protocol can be extended to the reaction between 8-methylquinoline derivatives and heteroarenes. We believe that this protocol could offer an easy way to β-heteroarylated 2-ethylpyridine derivatives in medical chemistry.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02167. Detailed experimental procedures, characterization data, and 1H and 13C NMR spectra of final products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jingsong You: 0000-0002-0493-2388 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the National NSF of China (No 21432005). REFERENCES
(1) For selected reviews on transition-metal-catalyzed C(sp3)−H bond activation/(hetero)arylation, see: (a) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902. (b) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726. (c) Qiu, G.; Wu, J. Org. Chem. Front. 2015, 2, 169. (2) For selected examples of C(sp3)−H arylation of 8-methylquinoline, see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (b) Shabashov, D.; Daugulis, O. Org. 4785
DOI: 10.1021/acs.orglett.7b02167 Org. Lett. 2017, 19, 4782−4785
