DOI: 10.1002/chem.201402516
Communication
& Nickel Catalysis
Nickel-Catalyzed Decarboxylative Acylation of Heteroarenes by sp2 C H Functionalization Ke Yang,[a] Cheng Zhang,[a] Peng Wang,[a] Yan Zhang,*[a] and Haibo Ge*[a, b] (hetero)arenes with a-oxocarboxylic acids was developed in our laboratory, providing an efficient approach to access a variety of synthetically and medically important (hetero)aryl ketones.[5] However, under many circumstances, a directing group is required in this process, limiting the synthetic application of this method.[6] Azole ketones belong to an important structural family and are present in many medicinal compounds with a broad range of biological activities, including anti-cancer, anti-diabetic, antifibrotic, anti-infective, anti-inflammatory, anti-obesity, and antiulcer activities.[7] The current direct synthesis of these compounds relies primarily on a sequential process of deprotonation/metalation, followed by copper-mediated coupling with an acyl chloride, which suffers severely from poor functional group tolerance.[7, 8] Recently, Beller and co-workers reported an efficient alternative approach for the direct synthesis of azoles by a Pd-catalyzed sp2 C H functionalization process.[9] However, this process requires the use of excess azoles and relatively toxic CO under high pressure. Very recently, a Pd-catalyzed decarboxylative process was developed with limited examples.[6k] In our continuing efforts to develop novel transition-metal-catalyzed cross-coupling reactions, herein we disclose the Ni-catalyzed direct acylation of azoles with a-oxocarboxylic acids. It is noteworthy that this process represents the first example of decarboxylative cross-coupling reactions by a sp2 C H functionalization process involving Ni catalysis. Our investigation began with the decarboxylative cross-coupling of benzoxazole (1 a) and 2-oxo-2-phenylacetic acid (2 a) with catalytic [NiCl2(PCy3)2], in the presence of Ag2CO3 as an external oxidant at 170 8C (Table 1). After an extensive solvent screening, benzene was found to be optimal and desired product 3 a was obtained in 58 % yield (entry 2). Interestingly, it was then found that a ligand is not required for this reaction, and actually an improved yield was observed with a catalytic amount of NiCl2 in the absence of a ligand (entry 5). Next, we carried out a screening of the Ni catalysts. It turned out that this reaction could be effectively catalyzed by a variety of Ni species, among which Ni(ClO4)2 was optimal, providing the desired product in 86 % yield (entry 10). Additionally, this reaction is not sensitive to water, and a comparable yield was observed with Ni(ClO4)2·6 H2O (entry 11). It is also noteworthy that replacement of Ag2CO3 with several other oxidants resulted in either extremely low yield of product or no reaction (entries 12–15). Further optimization showed that the amount of Ni catalyst could be reduced to 7.5 % without an apparent effect on the reaction (entry 16). However, the reaction yield
Abstract: Nickel-catalyzed ligand-free decarboxylative cross-coupling of azole derivatives with a-oxoglyoxylic acids has been developed. This work represents the first example of decarboxylative cross-coupling reactions, in a C H bond functionalization manner, through nickel catalysis, and tolerates various functional groups. Additionally, this approach provides an efficient access to azole ketones, an important structural motif in many medicinal compounds with a broad range of biological activities.
Transition-metal-catalyzed cross-coupling reactions of arenes and heteroarenes by means of sp2 C H functionalization remains to be one of the most powerful methods for selective carbon–carbon (C C) bond construction, and has found broad applications in synthetic organic and medicinal chemistry research.[1] Compared with the traditional approaches, these methods are more economically favorable due to the avoidance of the prefunctionalization of (hetero)arenes. Moreover, this methodology can avoid the use of stoichiometric amounts of expensive and/or moisture-sensitive organometallic coupling partners and, thus, prevents the generation of stoichiometric amounts of toxic metal waste. Among these methods, transition-metal-catalyzed decarboxylative processes have been of great interest in recent years due to the low cost, ready availability, and environmentally benign properties of carboxylic acids.[2] In 2008, Crabtree and co-workers reported the first example of direct decarboxylative cross-coupling reactions of (hetero)arenes with benzoic acid derivatives through a Pd-catalyzed sp2 C H functionalization process.[3] Since then, extensive efforts have been devoted to extend the substrate scope, and it was found that heteroaromatic acids are also effective substrates.[4] Very recently, the direct acylation of [a] K. Yang, C. Zhang, P. Wang, Prof. Dr. Y. Zhang, Prof. Dr. H. Ge Institute of Chemistry & BioMedical Sciences School of Chemistry and Chemical Engineering State Key Laboratory of Analytical Chemistry for Life Science Nanjing University, Nanjing 210093 (P. R. China) E-mail: [email protected] [b] Prof. Dr. H. Ge Department of Chemistry and Chemical Biology Indiana University Purdue University Indianapolis Indianapolis, Indiana 46202 (USA) Fax: (+ 1) 317-2744701 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402516. Chem. Eur. J. 2014, 20, 1 – 5
These are not the final page numbers! ÞÞ
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication Table 1. Optimization of reaction conditions.[a]
Entry
Ni source [(mol %)]
Oxidant [(equiv)]
Solvent
Yield [%][b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18[d] 19[d]
[NiCl2(PCy3)2] (10) [NiCl2(PCy3)2] (10) [NiCl2(PCy3)2] (10) [NiCl2(PCy3)2] (10) NiCl2 (10) NiBr2 (10) Ni(OAc)2 (10) Ni(OTf)2 (10) [Ni(cod)2] (10) Ni(ClO4)2 (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (7.5) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (7.5) Ni(ClO4)2·6 H2O (10)
Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) AgOAc (3) Ag2O (3) AgClO4 (3) K2S2O8 (3) Ag2CO3 (3) Ag2CO3 (2) Ag2CO3 (3) Ag2CO3 (3)
toluene benzene o-xylene p-xylene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene
39 58 5 6 69 55 59 62 11 86 88 6 13 0
Communication
& Nickel Catalysis
Nickel-Catalyzed Decarboxylative Acylation of Heteroarenes by sp2 C H Functionalization Ke Yang,[a] Cheng Zhang,[a] Peng Wang,[a] Yan Zhang,*[a] and Haibo Ge*[a, b] (hetero)arenes with a-oxocarboxylic acids was developed in our laboratory, providing an efficient approach to access a variety of synthetically and medically important (hetero)aryl ketones.[5] However, under many circumstances, a directing group is required in this process, limiting the synthetic application of this method.[6] Azole ketones belong to an important structural family and are present in many medicinal compounds with a broad range of biological activities, including anti-cancer, anti-diabetic, antifibrotic, anti-infective, anti-inflammatory, anti-obesity, and antiulcer activities.[7] The current direct synthesis of these compounds relies primarily on a sequential process of deprotonation/metalation, followed by copper-mediated coupling with an acyl chloride, which suffers severely from poor functional group tolerance.[7, 8] Recently, Beller and co-workers reported an efficient alternative approach for the direct synthesis of azoles by a Pd-catalyzed sp2 C H functionalization process.[9] However, this process requires the use of excess azoles and relatively toxic CO under high pressure. Very recently, a Pd-catalyzed decarboxylative process was developed with limited examples.[6k] In our continuing efforts to develop novel transition-metal-catalyzed cross-coupling reactions, herein we disclose the Ni-catalyzed direct acylation of azoles with a-oxocarboxylic acids. It is noteworthy that this process represents the first example of decarboxylative cross-coupling reactions by a sp2 C H functionalization process involving Ni catalysis. Our investigation began with the decarboxylative cross-coupling of benzoxazole (1 a) and 2-oxo-2-phenylacetic acid (2 a) with catalytic [NiCl2(PCy3)2], in the presence of Ag2CO3 as an external oxidant at 170 8C (Table 1). After an extensive solvent screening, benzene was found to be optimal and desired product 3 a was obtained in 58 % yield (entry 2). Interestingly, it was then found that a ligand is not required for this reaction, and actually an improved yield was observed with a catalytic amount of NiCl2 in the absence of a ligand (entry 5). Next, we carried out a screening of the Ni catalysts. It turned out that this reaction could be effectively catalyzed by a variety of Ni species, among which Ni(ClO4)2 was optimal, providing the desired product in 86 % yield (entry 10). Additionally, this reaction is not sensitive to water, and a comparable yield was observed with Ni(ClO4)2·6 H2O (entry 11). It is also noteworthy that replacement of Ag2CO3 with several other oxidants resulted in either extremely low yield of product or no reaction (entries 12–15). Further optimization showed that the amount of Ni catalyst could be reduced to 7.5 % without an apparent effect on the reaction (entry 16). However, the reaction yield
Abstract: Nickel-catalyzed ligand-free decarboxylative cross-coupling of azole derivatives with a-oxoglyoxylic acids has been developed. This work represents the first example of decarboxylative cross-coupling reactions, in a C H bond functionalization manner, through nickel catalysis, and tolerates various functional groups. Additionally, this approach provides an efficient access to azole ketones, an important structural motif in many medicinal compounds with a broad range of biological activities.
Transition-metal-catalyzed cross-coupling reactions of arenes and heteroarenes by means of sp2 C H functionalization remains to be one of the most powerful methods for selective carbon–carbon (C C) bond construction, and has found broad applications in synthetic organic and medicinal chemistry research.[1] Compared with the traditional approaches, these methods are more economically favorable due to the avoidance of the prefunctionalization of (hetero)arenes. Moreover, this methodology can avoid the use of stoichiometric amounts of expensive and/or moisture-sensitive organometallic coupling partners and, thus, prevents the generation of stoichiometric amounts of toxic metal waste. Among these methods, transition-metal-catalyzed decarboxylative processes have been of great interest in recent years due to the low cost, ready availability, and environmentally benign properties of carboxylic acids.[2] In 2008, Crabtree and co-workers reported the first example of direct decarboxylative cross-coupling reactions of (hetero)arenes with benzoic acid derivatives through a Pd-catalyzed sp2 C H functionalization process.[3] Since then, extensive efforts have been devoted to extend the substrate scope, and it was found that heteroaromatic acids are also effective substrates.[4] Very recently, the direct acylation of [a] K. Yang, C. Zhang, P. Wang, Prof. Dr. Y. Zhang, Prof. Dr. H. Ge Institute of Chemistry & BioMedical Sciences School of Chemistry and Chemical Engineering State Key Laboratory of Analytical Chemistry for Life Science Nanjing University, Nanjing 210093 (P. R. China) E-mail: [email protected] [b] Prof. Dr. H. Ge Department of Chemistry and Chemical Biology Indiana University Purdue University Indianapolis Indianapolis, Indiana 46202 (USA) Fax: (+ 1) 317-2744701 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402516. Chem. Eur. J. 2014, 20, 1 – 5
These are not the final page numbers! ÞÞ
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Communication Table 1. Optimization of reaction conditions.[a]
Entry
Ni source [(mol %)]
Oxidant [(equiv)]
Solvent
Yield [%][b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18[d] 19[d]
[NiCl2(PCy3)2] (10) [NiCl2(PCy3)2] (10) [NiCl2(PCy3)2] (10) [NiCl2(PCy3)2] (10) NiCl2 (10) NiBr2 (10) Ni(OAc)2 (10) Ni(OTf)2 (10) [Ni(cod)2] (10) Ni(ClO4)2 (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (7.5) Ni(ClO4)2·6 H2O (10) Ni(ClO4)2·6 H2O (7.5) Ni(ClO4)2·6 H2O (10)
Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) Ag2CO3 (3) AgOAc (3) Ag2O (3) AgClO4 (3) K2S2O8 (3) Ag2CO3 (3) Ag2CO3 (2) Ag2CO3 (3) Ag2CO3 (3)
toluene benzene o-xylene p-xylene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene benzene
39 58 5 6 69 55 59 62 11 86 88 6 13 0
