DOI: 10.1002/chem.201403356
Communication
& C H Activation
Nickel-Catalyzed Site-Selective Amidation of Unactivated C(sp3) H Bonds Xuesong Wu,[a] Yan Zhao,[a, b] and Haibo Ge*[a, b] ligand-assisted direct functionalization of unactivated C H bonds from the Daugulis’ group,[10] NiII-catalyzed site-selective direct arylation and alkylation reactions of aliphatic amide derivatives were demonstrated very recently in Chatani’s and our laboratories, respectively (Scheme 1).[11] It is believed that a catalytic NiII/NiIII cycle is involved in the case of alkylation from oxidation of the cyclic NiII species by an alkyl radical.[11b] On the basis of the above results, it is envisaged that with an external
Abstract: Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp3 carbon atoms by a nickel-catalyzed C H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C H bonds of b-methyl groups over the g-methyl or b-methylene groups. Additionally, a predominant preference for the b-methyl C H bonds over the aromatic sp2 C H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp3 C H bonds.
Transition-metal-catalyzed direct C H bond functionalization of unactivated sp2 and sp3 carbon atoms is of current research interest.[1] Compared with the traditional cross-coupling reactions, this process avoids the prefunctionalization of the unactivated C H bonds, and thus is more efficient and favorable from the economic point of view. Among this reaction class, Ni0 or NiII-catalyzed cross-couplings on aromatic sp2 carbon atoms has received considerable attention, and significant progress has been made over the last few years.[2] For example, Ni0-catalyzed direct functionalization on acidic C H bonds of pyridine,[3] perfluorobenzene,[4] and azole derivatives[5] has been well documented. Recently, the reaction scope was successfully extended to benzene derivatives.[6] Meanwhile, NiIIcatalyzed direct C H bond functionalization of azole derivatives was also established.[7] Very recently, the bidentate ligand-assisted direct alkylation of benzamide derivatives by a NiII-catalyzed C H bond functionalization process was also demonstrated.[8] In comparison, Ni-catalyzed direct C H bond functionalization of unactivated sp3 carbon atoms is underdeveloped. In 2011, dehydrogenative [4+2] cyclization of formamides with alkynes was reported in Hiyama’s laboratory by a Ni0-catalyzed in situ sp3 C H bond activation process.[9] Inspired by the development of the PdII-catalyzed bidentate
Scheme 1. NiII-catalyzed sp3 C H functionalization. acac = acetylacetone; dppbz = 1,2-bis(diphenylphosphino)benzene.
single-electron oxidant, selective reductive elimination of the resulting NiIII complex could potentially be achieved. Herein, we report the first example of Ni-catalyzed intramolecular cyclization on unactivated sp3 carbon atoms.[12] It is also noteworthy that the products, the monocyclic or spiro-b-lactam derivatives, are important subunits in biologically active natural products and pharmaceutical compounds.[13] Our investigation began with nickel-catalyzed dehydrogenative cyclization of 2-ethyl-2-methyl-N-(quinolin-8-yl)pentanamide (1 a) with TEMPO as the external single-electron oxidant (Table 1). After an initial solvent screening, butyronitrile proved to be optimal, albeit with low yield (Table 1, entry 7). As expected, high site-selectivity was observed for this reaction, favoring the b-methyl group over the b-methylene and g-methyl groups. Next, an extensive screening of nickel source was carried out. Interestingly, while the majority of catalysts failed to yield the desired product, the reaction was significantly improved by NiI2 (entry 11). Additionally, the reaction yield was further increased with [Ni(dme)2I2] as the catalyst (entry 12). Further optimization showed that this reaction was improved by the addition of a catalytic amount of TBAI (entry 17). It was then noticed that a high reaction yield could be obtained by using the solvent mixture of butyronitrile and benzonitrile in a 3:2 ratio (entry 18).
[a] Dr. X. Wu, Y. Zhao, 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] [b] Y. Zhao, Prof. Dr. H. Ge Institute of Chemistry and BioMedical Sciences and School of Chemistry and Chemical Engineering Nanjing University, Nanjing 210093 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403356. Chem. Eur. J. 2014, 20, 1 – 5
These are not the final page numbers! ÞÞ
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
Communication that a tertiary a-carbon atom is required for this process since amides 3–5 failed in this reaction.[14] Furthermore, C H bond functionalization on the g-sp3 carbon atom of 3,3-dimethyl-N(quinolin-8-yl)butanamide (6) Entry Ni source Base Additive Solvent (v/v) Yield was also not effective, which in[mol %] (2.0 equiv) (0.1 equiv) [%][b] dicated that the formation of 1 Ni(OAc)2 (10) K2HPO4 – toluene 0 the six-membered ring inter2 Ni(OAc)2 (10) K2HPO4 – DMSO
Communication
& C H Activation
Nickel-Catalyzed Site-Selective Amidation of Unactivated C(sp3) H Bonds Xuesong Wu,[a] Yan Zhao,[a, b] and Haibo Ge*[a, b] ligand-assisted direct functionalization of unactivated C H bonds from the Daugulis’ group,[10] NiII-catalyzed site-selective direct arylation and alkylation reactions of aliphatic amide derivatives were demonstrated very recently in Chatani’s and our laboratories, respectively (Scheme 1).[11] It is believed that a catalytic NiII/NiIII cycle is involved in the case of alkylation from oxidation of the cyclic NiII species by an alkyl radical.[11b] On the basis of the above results, it is envisaged that with an external
Abstract: Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp3 carbon atoms by a nickel-catalyzed C H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C H bonds of b-methyl groups over the g-methyl or b-methylene groups. Additionally, a predominant preference for the b-methyl C H bonds over the aromatic sp2 C H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp3 C H bonds.
Transition-metal-catalyzed direct C H bond functionalization of unactivated sp2 and sp3 carbon atoms is of current research interest.[1] Compared with the traditional cross-coupling reactions, this process avoids the prefunctionalization of the unactivated C H bonds, and thus is more efficient and favorable from the economic point of view. Among this reaction class, Ni0 or NiII-catalyzed cross-couplings on aromatic sp2 carbon atoms has received considerable attention, and significant progress has been made over the last few years.[2] For example, Ni0-catalyzed direct functionalization on acidic C H bonds of pyridine,[3] perfluorobenzene,[4] and azole derivatives[5] has been well documented. Recently, the reaction scope was successfully extended to benzene derivatives.[6] Meanwhile, NiIIcatalyzed direct C H bond functionalization of azole derivatives was also established.[7] Very recently, the bidentate ligand-assisted direct alkylation of benzamide derivatives by a NiII-catalyzed C H bond functionalization process was also demonstrated.[8] In comparison, Ni-catalyzed direct C H bond functionalization of unactivated sp3 carbon atoms is underdeveloped. In 2011, dehydrogenative [4+2] cyclization of formamides with alkynes was reported in Hiyama’s laboratory by a Ni0-catalyzed in situ sp3 C H bond activation process.[9] Inspired by the development of the PdII-catalyzed bidentate
Scheme 1. NiII-catalyzed sp3 C H functionalization. acac = acetylacetone; dppbz = 1,2-bis(diphenylphosphino)benzene.
single-electron oxidant, selective reductive elimination of the resulting NiIII complex could potentially be achieved. Herein, we report the first example of Ni-catalyzed intramolecular cyclization on unactivated sp3 carbon atoms.[12] It is also noteworthy that the products, the monocyclic or spiro-b-lactam derivatives, are important subunits in biologically active natural products and pharmaceutical compounds.[13] Our investigation began with nickel-catalyzed dehydrogenative cyclization of 2-ethyl-2-methyl-N-(quinolin-8-yl)pentanamide (1 a) with TEMPO as the external single-electron oxidant (Table 1). After an initial solvent screening, butyronitrile proved to be optimal, albeit with low yield (Table 1, entry 7). As expected, high site-selectivity was observed for this reaction, favoring the b-methyl group over the b-methylene and g-methyl groups. Next, an extensive screening of nickel source was carried out. Interestingly, while the majority of catalysts failed to yield the desired product, the reaction was significantly improved by NiI2 (entry 11). Additionally, the reaction yield was further increased with [Ni(dme)2I2] as the catalyst (entry 12). Further optimization showed that this reaction was improved by the addition of a catalytic amount of TBAI (entry 17). It was then noticed that a high reaction yield could be obtained by using the solvent mixture of butyronitrile and benzonitrile in a 3:2 ratio (entry 18).
[a] Dr. X. Wu, Y. Zhao, 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] [b] Y. Zhao, Prof. Dr. H. Ge Institute of Chemistry and BioMedical Sciences and School of Chemistry and Chemical Engineering Nanjing University, Nanjing 210093 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403356. 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 that a tertiary a-carbon atom is required for this process since amides 3–5 failed in this reaction.[14] Furthermore, C H bond functionalization on the g-sp3 carbon atom of 3,3-dimethyl-N(quinolin-8-yl)butanamide (6) Entry Ni source Base Additive Solvent (v/v) Yield was also not effective, which in[mol %] (2.0 equiv) (0.1 equiv) [%][b] dicated that the formation of 1 Ni(OAc)2 (10) K2HPO4 – toluene 0 the six-membered ring inter2 Ni(OAc)2 (10) K2HPO4 – DMSO
