DOI: 10.1002/chem.201302737
Copper-Catalyzed Aerobic Oxidative C H Functionalization of Substituted Pyridines: Synthesis of Imidazopyridine Derivatives Jipan Yu,[a] Yunhe Jin,[a] Hao Zhang,[a] Xiaobo Yang,[a] and Hua Fu*[a, b] Abstract: A novel, efficient, and practical method for the synthesis of imidazopyridine derivatives has been developed through the copper-catalyzed aerobic oxidative C H functionalization of substituted pyridines with N-(alkylidene)-4H-1,2,4-triazol-4-amines. The procedure occurs by cleavage of
the N N bond in the N-(alkylidene)4H-1,2,4-triazol-4-amines and activation of an aryl C H bond in the substiKeywords: C H activation · copper · homogeneous catalysis · nitrogen heterocycles · oxidation
Introduction The pyridine unit occurs widely in various natural products, and is a constituent of many pharmaceuticals and optical materials. Its functionalization has attracted considerable attention, however, because of the low reactivity of the p-electron-deficient pyridine skeleton, this remains a great challenge and halogenation and metalation are usually necessary before the pyridine ring can be substituted.[1] Clearly, direct C H functionalization of pyridines would be more economic and practical. Recently, transition-metal-catalyzed C H functionalization reactions have become the subject of intensive studies,[2] and the transition-metal-catalyzed C H functionalization of substituted pyridines has made significant progress,[3] but unfortunately examples remain very limited. In 2010, Barluenga, Toms and co-workers reported an efficient copper-catalyzed annulation of pyridines with highly active alkenyldiazoacetates leading to indolizines.[4] ImidazoACHTUNGRE[1,2-a]pyridine derivatives have shown diverse biological and pharmaceutical activities,[5] for example, they exhibit anticancer, antiviral, antiparasitic, and anti-HIV properties,[6] and some compounds have been used as NO synthase and GABAA inhibitors, and l-DOPA and dopamine pro-drugs.[7] In particular, the imidazoACHTUNGRE[1,2-a]pyridine unit is
[a] J. Yu, Y. Jin, H. Zhang, X. Yang, Prof. Dr. H. Fu Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry Tsinghua University, Beijing 100084 (P.R. China) Fax: (+ 86) 10-62781695 E-mail: [email protected] [b] Prof. Dr. H. Fu Key Laboratory of Chemical Biology (Guangdong Province) Graduate School of Shenzhen, Tsinghua University Shenzhen 518057 (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302737.
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tuted pyridines. This is the first example of the preparation of imidazopyridine derivatives by using pyridines as the substrates by transition-metal-catalyzed C H functionalization. This method should provide a novel and efficient strategy for the synthesis of other nitrogen heterocycles.
the core structure of many drugs currently on the market. Zolpidem (A) is the most widely applied drug in the world for treating insomnia,[8] Alpidem (B) as a peripheral benzodiazepine receptor ligand is an anxiolytic,[9] Zolimidin (C) acts as an anti-ulcer agent,[10] and Olprinone (D) as a phosphodiesterase 3 inhibitor is used for treating acute heart failure (Figure 1).[11] Accordingly, various efficient and useful
Figure 1. Representative examples of imidazoACHTUNGRE[1,2-a]pyridines in marketed drugs (see ref. [5a]).
approaches to imidazopyridine derivatives have been developed in which substituted 2-aminopyridines are usually employed as the starting materials.[5, 12] Compared with 2-aminopyridines, pyridines are more readily available and inexpensive. To the best of our knowledge, the annulation of pyridines to form imidazoACHTUNGRE[1,2-a]pyridine derivatives by transition-metal-catalyzed C H functionalization has not been reported. In view of the low cost, low toxicity, and high efficiency of copper catalysts,[13] herein we report an efficient copper-catalyzed aerobic oxidative approach to the synthesis of imidazopyridine derivatives by using readily available pyridines and N-(alkylidene)-4H1,2,4-triazol-4-amines (obtained from the reaction of 4amino-1,2,4-triazole with ketones[14]) in a cascade reaction
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FULL PAPER that involves the cleavage of the N N bond and activation of the pyridyl C H bond (Scheme 1).
Scheme 1. Our Strategy for Synthesis of ImidazoACHTUNGRE[1,2-a]pyridines.
Results and Discussion As shown in Table 1, the copper-catalyzed aerobic oxidative reaction of pyridine (1 a) with N-(1-phenylethylidene)-4H1,2,4-triazol-4-amine (2 a) leading to 2-phenylimidazoACHTUNGRE[1,2-
Table 1. Optimization of the copper-catalyzed aerobic oxidative reactions of pyridine (1 a) with N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2 a) leading to 2-phenylimidazoACHTUNGRE[1,2-a]pyridine (3 a).[a]
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Cat.
Solvent
T [oC]
Yield [%][b]
CuCl CuBr CuI Cu2O CuCl2 CuBr2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OTf)2 CuACHTUNGRE(TFA)2[c] – CuI CuI CuI CuI CuI CuI CuI
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMSO dioxane toluene DMF DMF DMF DMF
110 110 110 110 110 110 110 110 110 110 110 110 110 80 130 110 110
47 55 63 21 41 36 8 17 13 0 27 11 trace 21 53 32[d] 0[e]
[a] Reaction conditions: pyridine (1 a, 5 mmol), N-(1-phenylethylidene)4H-1,2,4-triazol-4-amine (2 a, 0.5 mmol), catalyst (0.05 mmol), solvent (2 mL), oxygen atmosphere (1 atm), 80–130 8C, 36 h. [b] Isolated yields. [c] TFA = CF3COO . [d] In air. [e] Under nitrogen atmosphere.
a]pyridine (3 a) was chosen as the model to optimize the reaction conditions, including the catalyst, solvent, and temperature. Nine copper catalysts (10 mol % relative to the amount of 2 a) were first screened (entries 1–9) with DMF as the solvent and oxygen as the oxidant at 110 8C, CuI showing the highest activity (entry 3). No product was observed in the absence of a copper catalyst (entry 10). The
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effect of solvent was next investigated (compare entries 3 and 11–13), and DMF provided the best result (entry 3). When the reaction temperature was changed to 80 (entry 14) or 130 8C (entry 15), the yields decreased (compare entries 3, 14, and 15). The catalytic efficiency was lower when the reaction was performed in air (compare entries 3 and 16) and no target product was observed in the absence of oxygen (entry 17). Therefore the optimum conditions for the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines are as follows: 10 mol % CuI as the catalyst in DMF as solvent at 110 8C under an atmosphere of oxygen (1 atm). Having obtained the optimum reaction conditions, we investigated the scope of the copper-catalyzed aerobic oxidative C H functionalization of substituted pyridines 1 with N-(alkylidene)-4H-1,2,4-triazol-4-amines 2 leading to imidazoACHTUNGRE[1,2-a]pyridine derivatives 3. As shown in Table 2, the tested substrates provided moderate-to-good yields of the product 3, the reaction efficiency being dependent on electronic effects and steric hindrance. Pyridines with electron-donating substituents showed higher reactivity than those with electron-withdrawing groups. For 3-methylpyridine, the copper-catalyzed aromatic C H functionalization occurred at the 2- and 6-positions to give two isomers, the isomer obtained by functionalization of the 2-position predominating (entry 19). The aromatic C H functionalization of isoquinoline selectively occurred at the a position because of high electronic density at the a-carbon atom (entry 22). 2-Methylpyridine gave a lower yield due to steric hindrance of the o-methyl group (entry 18). For the N-(1-arylethylidene)-4H-1,2,4-triazol-4-amines 2, substrates with electron-withdrawing groups on the aromatic ring afforded higher yields than those with neutral or electron-donating groups. The copper-catalyzed aerobic oxidative reactions tolerated various functional groups, including C Cl (Table 2, entries 4, 5, and 21), C Br (entry 6), and C F bonds (entries 7–9), cyano (entry 10), trifluoromethyl (entry 11), and nitro groups (entries 12, 13, 17, and 21), and oxygen, sulfur, and nitrogen heterocycles (entries 14–16) in the substrates. Interestingly, the reactions underwent pyridine activation to form two C N bonds and therefore the present method should provide a novel and useful strategy for the synthesis of nitrogen heterocycles. We attempted the synthesis of Zolimidin (C), an antiulcer agent, on a gram scale by using our method (Scheme 2). The reaction of pyridine (1 a) with N-{1-[4(methylsulfonyl)phenyl]ethylidene}-4H-1,2,4-triazol-4-amine (2 r) under the standard conditions provided the target product in a high yield (84 %). Therefore the present method is very effective for the synthesis of imidazoACHTUNGRE[1,2-a]pyridines with biological and pharmaceutical activities. In an attempt to synthesize 3-substituted imidazoACHTUNGRE[1,2a]pyridines, 1-phenyl-N-(4H-1,2,4-triazol-4-yl)propan-1imine (2 s) was treated with pyridine (1 a) under the standard conditions (Scheme 3), but unfortunately the reaction failed for steric hindrance of 2 s, so the present method is
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Table 2. Copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2a]pyridines (3).[a]
Table 2. (Continued) Entry
2
3 (Yield [%][b])
12
13 Entry
2
3 (Yield [%][b])
14
1
15 2
16 3
17 4
5
6
18
2a
19[c]
2a
20
2a
21
2l
22
2a
7
8
9 [a] Reaction conditions: substituted pyridine 1 (2.5 mmol for entries 12, 13, and 17; 5 mmol for the others), N-(alkylidene)-4H-1,2,4-triazol-4amine 2 (0.5 mmol), CuI (0.05 mmol), DMF (2 mL), oxygen atmosphere (1 atm), 110 8C, 36 h. [b] Isolated yield. [c] Using 3-methylpyridine (1 c) as the substrate.
10
not suitable for the synthesis of 3-substituted imidazoACHTUNGRE[1,2a]pyridines. To explore the reaction mechanism of the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines, the radical scavenger 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO) was added to the reaction system of pyridine
11
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Synthesis of Imidazopyridine Derivatives
FULL PAPER the alkenyl moiety in III affords V with the elimination of 4H-1,2,4-triazole (IV), and intramolecular cycloaddition of V yields VI with the regeneration of the catalyst CuI. The isomerization of VI leads to VII, and final oxidation of VII by oxygen gives the target product 3.
Scheme 2. Copper-catalyzed aerobic oxidative synthesis of Zolimidin (C) on a gram scale under the standard conditions.
Conclusion
Scheme 3. Treatment of 1-phenyl-N-(4H-1,2,4-triazol-4-yl)propan-1-imine (2 s) with pyridine (1 a) under the standard conditions.
(1 a) and N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2 a); the reaction was not affected by TEMPO (Scheme 4), which shows that the cleavage of the N N bond in 2 does not produce a radical intermediate during the synthesis of
Scheme 4. Copper-catalyzed aerobic oxidative reaction of pyridine (1 a) with N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2 a) in the presence of TEMPO under the standard conditions.
imidazoACHTUNGRE[1,2-a]pyridines 3. In addition, 4H-1,2,4-triazole was also isolated in the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines and the reactions needed the presence of oxygen. On the basis of the above observations, a possible mechanism for the synthesis of imidazoACHTUNGRE[1,2a]pyridines is proposed in Scheme 5. First, the isomerization of N-(alkylidene)-4H-1,2,4-triazol-4-amine (2) gives I, coordination of the copper catalyst (CuI) to I provides complex II with the liberation of HI, and treatment of II with HI leads to III. Nucleophilic attack of substituted pyridine 1 on
We have developed a novel and efficient copper-catalyzed aerobic oxidative C H functionalization of substituted pyridines with N-(alkylidene)-4H-1,2,4-triazol-4-amines leading to imidazoACHTUNGRE[1,2-a]pyridine derivatives. The protocol uses inexpensive CuI as the catalyst, economic and environmentally friendly oxygen as the oxidant, and readily available substituted pyridines and N-(alkylidene)-4H-1,2,4-triazol-4amines as the starting materials, and the corresponding imidazoACHTUNGRE[1,2-a]pyridine derivatives were obtained in moderate-to-good yields. The reaction proceeds by cleavage of the N N bond in the N-(alkylidene)-4H-1,2,4-triazol-4-amines and activation of an aryl C H bond in the substituted pyridines. In summary, this method is a novel, efficient, and practical approach to the synthesis of imidazopyridine derivatives, which are biologically and pharmaceutically active molecules. This is the first example of the preparation of this type of compound by the transition-metal-catalyzed C H functionalization of pyridines as substrates. We believe that this strategy could be applied to the synthesis of other nitrogen heterocycles.
Experimental Section General procedure for synthesis of compounds 3 a–v and Zolimidin (C): A 25 mL Schlenk tube was charged with a magnetic stirrer and DMF (2.0 mL). Substituted pyridine 1 (2.5–5 mmol), N-(alkylidene)-4H-1,2,4triazol-4-amine 2 (0.5 mmol), and CuI (0.05 mmol, 9.5 mg) were added to the tube. The tube was then sealed and the mixture stirred at 110 8C for 36 h under oxygen (1 atm). The resulting mixture was cooled to room temperature, the solvent was removed on a rotary evaporator, and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to give the desired target product. The characterization data of the products can be found in the Supporting Information.
Acknowledgements The authors wish to thank the National Natural Science Foundation of China (Grant nos. 21172128, 21372139 and 21221062), and the Ministry of Science and Technology of China (Grant no. 2012CB722605) for financial support.
Scheme 5. Possible mechanism for the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines.
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[1] D. M. Smith, In Rodds Chemistry of Carbon Compounds, Vol. 4, Part F (Ed.:S. Coffey), Elsevier, Amsterdam, 1976, pp. 27 – 229. [2] For recent reviews, see: a) A. S. Dudnik, V. Gevorgyan, Angew. Chem. 2010, 122, 2140; Angew. Chem. Int. Ed. 2010, 49, 2096; b) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; c) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212; d) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009, 121, 9976; Angew. Chem. Int. Ed. 2009, 48, 9792; e) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42, 1074; f) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed. 2009, 48, 5094; g) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949; h) L. C. Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2008, 41, 1013; i) Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222; j) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; k) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173; l) A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62, 2439; m) Z. Li, D. S. Bohle, C.-J. Li, Proc. Natl. Acad. Sci. USA 2006, 103, 8928; n) H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103, 2861; o) F. Kakiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345, 1077; p) J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507; q) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359; r) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633. [3] For selected examples of the C H functionalization of pyridines, see: a) C. J. Lewis, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2007, 129, 5332; b) T. Kawashima, T. Takao, H. Suzuki, J. Am. Chem. Soc. 2007, 129, 11006; c) A. M. Berman, J. C. Lewis, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2008, 130, 14926; d) Y. Nakao, K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2008, 130, 2448; e) D. A. Black, R. E. Beverigde, B. A. Arndtsen, J. Org. Chem. 2008, 73, 1906; f) D. F. Fischer, R. Sarpong, J. Am. Chem. Soc. 2010, 132, 5926; g) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L. Sobel, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 13194. [4] J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lpez, M. Toms, J. Am. Chem. Soc. 2010, 132, 13200. [5] a) C. Enguehard-Gueiffier, A. Gueiffier, Mini-Rev. Med. Chem. 2007, 7, 888, and references cited therein; b) D. K. Nair, S. M. Mobin, I. N. N. Namboothiri, Org. Lett. 2012, 14, 4580. [6] a) J. B. Vron, H. Allouchi, C. Enguehard Gueiffier, R. Snoeck, G. A. E. De Clercq, A. Gueiffier, Bioorg. Med. Chem. 2008, 16, 9536; b) A. Kamal, J. S. Reddy, M. J. Ramaiah, D. Dastagiri, E. V. Bharathi, M. V. P. Sagar, S. N. C. V. L. Pushpavalli, P. Ray, M. PalBhadra, Med. Chem. Commun. 2010, 1, 355; c) O. Kim, Y. Jeong, H. Lee, S.-S. Hong, S. Hong, J. Med. Chem. 2011, 54, 2455; d) A. Scribner, R. Dennis, J. Hong, S. Lee, D. McIntyre, D. Perrey, D. Feng, M. Fisher, M. Wyvratt, P. Leavitt, P. Liberator, A. Gurnett, C. Brown, J. Mathew, D. Thompson, D. Schmatz, T. Biftu, Eur. J. Med. Chem. 2007, 42, 1334; e) C. Enguehard, J.-L. Renou, H. Allouchi, J.-M. Leger, A. Gueiffier, Chem. Pharm. Bull. 2000, 48, 935; f) M. L.
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Received: July 14, 2013 Revised: August 28, 2013 Published online: October 21, 2013
Chem. Eur. J. 2013, 19, 16804 – 16808
Copper-Catalyzed Aerobic Oxidative C H Functionalization of Substituted Pyridines: Synthesis of Imidazopyridine Derivatives Jipan Yu,[a] Yunhe Jin,[a] Hao Zhang,[a] Xiaobo Yang,[a] and Hua Fu*[a, b] Abstract: A novel, efficient, and practical method for the synthesis of imidazopyridine derivatives has been developed through the copper-catalyzed aerobic oxidative C H functionalization of substituted pyridines with N-(alkylidene)-4H-1,2,4-triazol-4-amines. The procedure occurs by cleavage of
the N N bond in the N-(alkylidene)4H-1,2,4-triazol-4-amines and activation of an aryl C H bond in the substiKeywords: C H activation · copper · homogeneous catalysis · nitrogen heterocycles · oxidation
Introduction The pyridine unit occurs widely in various natural products, and is a constituent of many pharmaceuticals and optical materials. Its functionalization has attracted considerable attention, however, because of the low reactivity of the p-electron-deficient pyridine skeleton, this remains a great challenge and halogenation and metalation are usually necessary before the pyridine ring can be substituted.[1] Clearly, direct C H functionalization of pyridines would be more economic and practical. Recently, transition-metal-catalyzed C H functionalization reactions have become the subject of intensive studies,[2] and the transition-metal-catalyzed C H functionalization of substituted pyridines has made significant progress,[3] but unfortunately examples remain very limited. In 2010, Barluenga, Toms and co-workers reported an efficient copper-catalyzed annulation of pyridines with highly active alkenyldiazoacetates leading to indolizines.[4] ImidazoACHTUNGRE[1,2-a]pyridine derivatives have shown diverse biological and pharmaceutical activities,[5] for example, they exhibit anticancer, antiviral, antiparasitic, and anti-HIV properties,[6] and some compounds have been used as NO synthase and GABAA inhibitors, and l-DOPA and dopamine pro-drugs.[7] In particular, the imidazoACHTUNGRE[1,2-a]pyridine unit is
[a] J. Yu, Y. Jin, H. Zhang, X. Yang, Prof. Dr. H. Fu Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry Tsinghua University, Beijing 100084 (P.R. China) Fax: (+ 86) 10-62781695 E-mail: [email protected] [b] Prof. Dr. H. Fu Key Laboratory of Chemical Biology (Guangdong Province) Graduate School of Shenzhen, Tsinghua University Shenzhen 518057 (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302737.
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tuted pyridines. This is the first example of the preparation of imidazopyridine derivatives by using pyridines as the substrates by transition-metal-catalyzed C H functionalization. This method should provide a novel and efficient strategy for the synthesis of other nitrogen heterocycles.
the core structure of many drugs currently on the market. Zolpidem (A) is the most widely applied drug in the world for treating insomnia,[8] Alpidem (B) as a peripheral benzodiazepine receptor ligand is an anxiolytic,[9] Zolimidin (C) acts as an anti-ulcer agent,[10] and Olprinone (D) as a phosphodiesterase 3 inhibitor is used for treating acute heart failure (Figure 1).[11] Accordingly, various efficient and useful
Figure 1. Representative examples of imidazoACHTUNGRE[1,2-a]pyridines in marketed drugs (see ref. [5a]).
approaches to imidazopyridine derivatives have been developed in which substituted 2-aminopyridines are usually employed as the starting materials.[5, 12] Compared with 2-aminopyridines, pyridines are more readily available and inexpensive. To the best of our knowledge, the annulation of pyridines to form imidazoACHTUNGRE[1,2-a]pyridine derivatives by transition-metal-catalyzed C H functionalization has not been reported. In view of the low cost, low toxicity, and high efficiency of copper catalysts,[13] herein we report an efficient copper-catalyzed aerobic oxidative approach to the synthesis of imidazopyridine derivatives by using readily available pyridines and N-(alkylidene)-4H1,2,4-triazol-4-amines (obtained from the reaction of 4amino-1,2,4-triazole with ketones[14]) in a cascade reaction
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FULL PAPER that involves the cleavage of the N N bond and activation of the pyridyl C H bond (Scheme 1).
Scheme 1. Our Strategy for Synthesis of ImidazoACHTUNGRE[1,2-a]pyridines.
Results and Discussion As shown in Table 1, the copper-catalyzed aerobic oxidative reaction of pyridine (1 a) with N-(1-phenylethylidene)-4H1,2,4-triazol-4-amine (2 a) leading to 2-phenylimidazoACHTUNGRE[1,2-
Table 1. Optimization of the copper-catalyzed aerobic oxidative reactions of pyridine (1 a) with N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2 a) leading to 2-phenylimidazoACHTUNGRE[1,2-a]pyridine (3 a).[a]
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Cat.
Solvent
T [oC]
Yield [%][b]
CuCl CuBr CuI Cu2O CuCl2 CuBr2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OTf)2 CuACHTUNGRE(TFA)2[c] – CuI CuI CuI CuI CuI CuI CuI
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMSO dioxane toluene DMF DMF DMF DMF
110 110 110 110 110 110 110 110 110 110 110 110 110 80 130 110 110
47 55 63 21 41 36 8 17 13 0 27 11 trace 21 53 32[d] 0[e]
[a] Reaction conditions: pyridine (1 a, 5 mmol), N-(1-phenylethylidene)4H-1,2,4-triazol-4-amine (2 a, 0.5 mmol), catalyst (0.05 mmol), solvent (2 mL), oxygen atmosphere (1 atm), 80–130 8C, 36 h. [b] Isolated yields. [c] TFA = CF3COO . [d] In air. [e] Under nitrogen atmosphere.
a]pyridine (3 a) was chosen as the model to optimize the reaction conditions, including the catalyst, solvent, and temperature. Nine copper catalysts (10 mol % relative to the amount of 2 a) were first screened (entries 1–9) with DMF as the solvent and oxygen as the oxidant at 110 8C, CuI showing the highest activity (entry 3). No product was observed in the absence of a copper catalyst (entry 10). The
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effect of solvent was next investigated (compare entries 3 and 11–13), and DMF provided the best result (entry 3). When the reaction temperature was changed to 80 (entry 14) or 130 8C (entry 15), the yields decreased (compare entries 3, 14, and 15). The catalytic efficiency was lower when the reaction was performed in air (compare entries 3 and 16) and no target product was observed in the absence of oxygen (entry 17). Therefore the optimum conditions for the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines are as follows: 10 mol % CuI as the catalyst in DMF as solvent at 110 8C under an atmosphere of oxygen (1 atm). Having obtained the optimum reaction conditions, we investigated the scope of the copper-catalyzed aerobic oxidative C H functionalization of substituted pyridines 1 with N-(alkylidene)-4H-1,2,4-triazol-4-amines 2 leading to imidazoACHTUNGRE[1,2-a]pyridine derivatives 3. As shown in Table 2, the tested substrates provided moderate-to-good yields of the product 3, the reaction efficiency being dependent on electronic effects and steric hindrance. Pyridines with electron-donating substituents showed higher reactivity than those with electron-withdrawing groups. For 3-methylpyridine, the copper-catalyzed aromatic C H functionalization occurred at the 2- and 6-positions to give two isomers, the isomer obtained by functionalization of the 2-position predominating (entry 19). The aromatic C H functionalization of isoquinoline selectively occurred at the a position because of high electronic density at the a-carbon atom (entry 22). 2-Methylpyridine gave a lower yield due to steric hindrance of the o-methyl group (entry 18). For the N-(1-arylethylidene)-4H-1,2,4-triazol-4-amines 2, substrates with electron-withdrawing groups on the aromatic ring afforded higher yields than those with neutral or electron-donating groups. The copper-catalyzed aerobic oxidative reactions tolerated various functional groups, including C Cl (Table 2, entries 4, 5, and 21), C Br (entry 6), and C F bonds (entries 7–9), cyano (entry 10), trifluoromethyl (entry 11), and nitro groups (entries 12, 13, 17, and 21), and oxygen, sulfur, and nitrogen heterocycles (entries 14–16) in the substrates. Interestingly, the reactions underwent pyridine activation to form two C N bonds and therefore the present method should provide a novel and useful strategy for the synthesis of nitrogen heterocycles. We attempted the synthesis of Zolimidin (C), an antiulcer agent, on a gram scale by using our method (Scheme 2). The reaction of pyridine (1 a) with N-{1-[4(methylsulfonyl)phenyl]ethylidene}-4H-1,2,4-triazol-4-amine (2 r) under the standard conditions provided the target product in a high yield (84 %). Therefore the present method is very effective for the synthesis of imidazoACHTUNGRE[1,2-a]pyridines with biological and pharmaceutical activities. In an attempt to synthesize 3-substituted imidazoACHTUNGRE[1,2a]pyridines, 1-phenyl-N-(4H-1,2,4-triazol-4-yl)propan-1imine (2 s) was treated with pyridine (1 a) under the standard conditions (Scheme 3), but unfortunately the reaction failed for steric hindrance of 2 s, so the present method is
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Table 2. Copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2a]pyridines (3).[a]
Table 2. (Continued) Entry
2
3 (Yield [%][b])
12
13 Entry
2
3 (Yield [%][b])
14
1
15 2
16 3
17 4
5
6
18
2a
19[c]
2a
20
2a
21
2l
22
2a
7
8
9 [a] Reaction conditions: substituted pyridine 1 (2.5 mmol for entries 12, 13, and 17; 5 mmol for the others), N-(alkylidene)-4H-1,2,4-triazol-4amine 2 (0.5 mmol), CuI (0.05 mmol), DMF (2 mL), oxygen atmosphere (1 atm), 110 8C, 36 h. [b] Isolated yield. [c] Using 3-methylpyridine (1 c) as the substrate.
10
not suitable for the synthesis of 3-substituted imidazoACHTUNGRE[1,2a]pyridines. To explore the reaction mechanism of the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines, the radical scavenger 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO) was added to the reaction system of pyridine
11
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Synthesis of Imidazopyridine Derivatives
FULL PAPER the alkenyl moiety in III affords V with the elimination of 4H-1,2,4-triazole (IV), and intramolecular cycloaddition of V yields VI with the regeneration of the catalyst CuI. The isomerization of VI leads to VII, and final oxidation of VII by oxygen gives the target product 3.
Scheme 2. Copper-catalyzed aerobic oxidative synthesis of Zolimidin (C) on a gram scale under the standard conditions.
Conclusion
Scheme 3. Treatment of 1-phenyl-N-(4H-1,2,4-triazol-4-yl)propan-1-imine (2 s) with pyridine (1 a) under the standard conditions.
(1 a) and N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2 a); the reaction was not affected by TEMPO (Scheme 4), which shows that the cleavage of the N N bond in 2 does not produce a radical intermediate during the synthesis of
Scheme 4. Copper-catalyzed aerobic oxidative reaction of pyridine (1 a) with N-(1-phenylethylidene)-4H-1,2,4-triazol-4-amine (2 a) in the presence of TEMPO under the standard conditions.
imidazoACHTUNGRE[1,2-a]pyridines 3. In addition, 4H-1,2,4-triazole was also isolated in the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines and the reactions needed the presence of oxygen. On the basis of the above observations, a possible mechanism for the synthesis of imidazoACHTUNGRE[1,2a]pyridines is proposed in Scheme 5. First, the isomerization of N-(alkylidene)-4H-1,2,4-triazol-4-amine (2) gives I, coordination of the copper catalyst (CuI) to I provides complex II with the liberation of HI, and treatment of II with HI leads to III. Nucleophilic attack of substituted pyridine 1 on
We have developed a novel and efficient copper-catalyzed aerobic oxidative C H functionalization of substituted pyridines with N-(alkylidene)-4H-1,2,4-triazol-4-amines leading to imidazoACHTUNGRE[1,2-a]pyridine derivatives. The protocol uses inexpensive CuI as the catalyst, economic and environmentally friendly oxygen as the oxidant, and readily available substituted pyridines and N-(alkylidene)-4H-1,2,4-triazol-4amines as the starting materials, and the corresponding imidazoACHTUNGRE[1,2-a]pyridine derivatives were obtained in moderate-to-good yields. The reaction proceeds by cleavage of the N N bond in the N-(alkylidene)-4H-1,2,4-triazol-4-amines and activation of an aryl C H bond in the substituted pyridines. In summary, this method is a novel, efficient, and practical approach to the synthesis of imidazopyridine derivatives, which are biologically and pharmaceutically active molecules. This is the first example of the preparation of this type of compound by the transition-metal-catalyzed C H functionalization of pyridines as substrates. We believe that this strategy could be applied to the synthesis of other nitrogen heterocycles.
Experimental Section General procedure for synthesis of compounds 3 a–v and Zolimidin (C): A 25 mL Schlenk tube was charged with a magnetic stirrer and DMF (2.0 mL). Substituted pyridine 1 (2.5–5 mmol), N-(alkylidene)-4H-1,2,4triazol-4-amine 2 (0.5 mmol), and CuI (0.05 mmol, 9.5 mg) were added to the tube. The tube was then sealed and the mixture stirred at 110 8C for 36 h under oxygen (1 atm). The resulting mixture was cooled to room temperature, the solvent was removed on a rotary evaporator, and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to give the desired target product. The characterization data of the products can be found in the Supporting Information.
Acknowledgements The authors wish to thank the National Natural Science Foundation of China (Grant nos. 21172128, 21372139 and 21221062), and the Ministry of Science and Technology of China (Grant no. 2012CB722605) for financial support.
Scheme 5. Possible mechanism for the copper-catalyzed aerobic oxidative synthesis of imidazoACHTUNGRE[1,2-a]pyridines.
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Received: July 14, 2013 Revised: August 28, 2013 Published online: October 21, 2013
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