DOI: 10.1002/chem.201500560
Communication
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Nickel N-Heterocyclic Carbene Catalyzed C¢C Bond Formation: A New Route to Aryl Ketones Li-Jun Gu,*[a, c] Cheng Jin,[b] and Hong-Tao Zhang[a] Abstract: A novel nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes with boronic esters for the synthesis of aryl ketones was developed. This reaction provides a mild, practical method toward aryl ketones, which are versatile intermediates and building blocks in organic synthesis.
Aryl ketones are common structural motifs in natural products and versatile building blocks for the synthesis of more complex natural products, pharmaceuticals, agricultural chemicals, dyes, and other commercially important materials.[1] Consequently, the development of synthetic methods for the preparation of aryl ketones has received considerable attention. One general approach is the Friedel–Crafts acylation of substituted aromatic rings. Under the acidic conditions of Friedel–Crafts reactions,[2] the formation of ortho and para isomers with untunable regioselectivity results in separation problems and makes aryl ketones with meta substituents difficult to access. Other significant approaches include the addition of an organometallic reagent to a partner with a higher oxidation state partner and the addition of an organometallic reagent to an aldehyde and reoxidation of the intermediate alcohol.[3] Both of these approaches suffer from a poor financial, time, step, and redox economy, as well as the requirement for moisture-sensitive organometallic reagents. An alternative approach is the reaction of diazo compounds with aldehydes, but the use of structurally diverse diazo compounds is hampered by their preparation and safety issues.[4] In recent years, significant progress has been achieved in carbonylative Suzuki–Miyaura cross-coupling reactions; various substituted aryl ketones have been successfully synthesized.[5] However, due to the high toxicity and odorless and flammable character of CO gas, transformations by [a] Prof. Dr. L.-J. Gu, H.-T. Zhang Key Laboratory of Chemistry in Ethnic Medicinal Resources State Ethnic Affairs Commission & Ministry of Education Yunnan Minzu University, Kunming, Yunnan, 650500 (P. R. China) [b] C. Jin New United Group Company Limited Changzhou, Jiangsu, 213166 (P. R. China) [c] Prof. Dr. L.-J. Gu Key Laboratory of Comprehensive Utilization of Mineral Resources in Ethnic Regions, Yunnan Minzu University Yunnan Minzu University, Kunming, Yunnan, 650500 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500560. Chem. Eur. J. 2015, 21, 8741 – 8744
using CO gas must be operated with special care. The carbon¢ carbon bond is the most widespread and fundamental bond that exists in organic compounds. Very recently, the preparation of aryl ketones by activation of C¢C bonds has received much attention.[1b, 6] Despite these advances,[7] versatile and efficient methods for the direct construction of aryl ketones that are compatible with various functional groups and use readily available starting materials remain highly desirable. Transition-metal-catalyzed cross-coupling reactions are highly versatile methods for the construction of complex molecules from simple building blocks.[8] Efficient catalytic systems for a wide range of substrates are utilized in both research laboratories and industry. The most efficient and commonly employed cross-coupling catalysts feature second- and third-row transition metals, most notably palladium, to achieve high turnover numbers.[9] Despite the maturity of this synthetic method, cross-coupling catalysis continues to attract significant interest, especially with respect to the development of more sustainable catalysts based on abundant first-row transition metals.[10] Various cross-coupling catalysts with first-row metals have been reported and those based on nickel are particularly promising.[11] So far, nickel-catalyzed cross-coupling reactions of aryl aldehydes with boronic esters have not been reported. Herein, we describe a new strategy to construct aryl ketones that relies on a nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes with boronic esters (Scheme 1). This protocol provides a practical, neutral, and mild synthetic approach to aryl ketones.
Scheme 1. New strategy to construct aryl ketones.
Our investigation began with the reaction of benzaldehyde (1 a) with phenylboronic acid pinacol ester (2 a) to optimize the reaction conditions (Table S1 in the Supporting Information). To our delight, when 1 a and 2 a were treated with a catalytic system consisting of a,a,a-trifluoroacetophenone (hydrogen acceptor, 1.5 equiv), Ni(cod)2 (5 mol %), and 1,3-bis(2,6bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene (IPr, ligand, 6 mol %) in THF at 40 8C, the desired benzophenone 3 aa was formed in 43 % yield (Table S1, entry 1). The benzyl 8741
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Communication benzoate by-product (4 a) was obtained in 31 % yield (Table S1, entry 1). After considerable effort, we found that hexafluoroacetone showed a remarkable enhancement in rate and selectivity for the formation of 3 aa (Table S1, entries 1–5). Different Ni catalysts were screened and Ni(cod)2 (cod = 1,5-cyclooctadiene) turned out to be the most effective catalyst (Table S1, entries 4 and 6–9). Other ligands, including phosphorus tricyclohexyl (PCy3), 1,3-di-tert-butylimidazol-2-ylidene (ItBu), and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (SIPr), were tested and found to be less effective than IPr (Table S1, entries 10–12). Of the solvents tested, THF proved particularly suitable (Table S1, entries 13–15). However, the reaction did not take place in the absence of a Ni catalyst (Table S1, entry 16). Next, we used the optimal reaction conditions to extend the substrate scope by using a series of alternative aryl aldehydes 1. As summarized in Table 1, the standard reaction conditions
fected the yield (Table 1, entry 3), further extending the scope of this methodology. Aromatic aldehyde 1 j with a naphthyl group also participated in this Ni-catalyzed cross-coupling reaction, affording the product in 75 % yield (Table 1, entry 4). Unfortunately, an aliphatic aldehyde did not deliver the corresponding ketone under the same reaction conditions (Table 1, entry 5). The cross-coupling method was also successfully applied to a variety of boronic esters 2. As shown in Table 2, a broad range of boronic esters 2 reacted smoothly with 1 a to give the corresponding aryl ketones in good yields. For example, ar-
Table 2. Scope of boronic esters.[a]
Table 1. Scope of aromatic aldehydes.[a]
Entry
Aromatic aldehyde 1
Ketone 3
Yield [%][b]
1
1 b: R = p-Me 1 c: R = p-OMe 1 d: R = p-F 1 e: R = p-Cl 1 f: R = p-CO2Me 1 g: R = o-Me 1 h: R = m-Me
3 ab: R = p-Me 3 ac: R = p-OMe 3 ad: R = p-F 3 ae: R = p-Cl 3 af: R = p-CO2Me 3 ag: R = o-Me 3 ah: R = m-Me
76 71 74 63 55 60 66 70
2
3
54
4
75
5
0
were found to be compatible with a wide range of aryl aldehydes 1. These results showed that the cross-coupling reaction can be realized in good yields irrespective of the nature and the position of the aryl substituents of substrate 1. Interestingly, the polysubstituted aromatic aldehyde 1 i gave the desired product 3 ai in a good yield (Table 1, entry 2). Notably, the replacement of the benzyl moiety by a 2-furanyl group hardly afwww.chemeurj.org
Boronic ester 2
Ketone 3
Yield [%][b]
1
2 b: R2 = p-Me 2 c: R2 = p-OMe 2 d: R1 = p-F 2 e: R2 = p-Ph 2 f: R2 = p-Me 2 g: R2 = m-Me
3 ba: R2 = p-Me 3 ca: R2 = p-OMe 3 da: R2 = p-F 3 ea: R2 = p-Ph 3 fa: R2 = p-Me 3 ga: R2 = m-Me
62 69 57 65 70 78
2
66
3
73
4
79
[a] Reaction conditions: 1 a (0.3 mmol), 2 (0.3 mmol), hexafluoroacetone (1.5 equiv), Ni(cod)2 (5 mol %), IPr (6 mol %), THF (2 mL), 40 8C, in Ar atmosphere for 10 h. [b] Isolated yield.
[a] Reaction conditions: 1 (0.3 mmol), 2 a (0.3 mmol), hexafluoroacetone (1.5 equiv), Ni(cod)2 (5 mol %), IPr (6 mol %), THF (2 mL), 40 8C, in Ar atmosphere for 10 h. [b] Isolated yield.
Chem. Eur. J. 2015, 21, 8741 – 8744
Entry
ylboronic esters bearing electron-rich (methoxy, methyl) and electron-deficient (halogen, phenyl) substituents on the aryl ring underwent this reaction to give the corresponding products in generally moderate to good yields (57–79 %). Substituents at the ortho-, meta-, or para-positions had no distinct influence on the reaction. For example, substrates 2 b, 2 f, and 2 g with a Me group were transformed into products 3 ba, 3 fa, and 3 ga, respectively, with similar yields. Notably, the introduction of heterocycles into this system made this methodology more useful for the preparation of pharmaceuticals and materials (Table 2, entry 2). Efforts were made to apply this methodology to the synthesis of aryl alkyl ketones; it was found that reactions with 2 i–2 j proceeded smoothly to give the aryl alkyl ketones 3 ia–3 ja in good yields (Table 2, entries 3 and 4). To gain an insight into the course of the reaction, we conducted a series of control experiments. In the absence of a boronic ester, we observed decarbonylation of benzaldehyde 1 a
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Communication and materials applications. This method offers marked improvements in terms of operational simplicity, reaction conditions, general applicability, and good isolated yields of products.
Experimental Section General procedure
Scheme 2. Experiments for mechanistic studies.
to produce benzene and reduction of hexafluoroacetone (Scheme 2 a).[12] This result supports the intermediacy of an acyl nickel hydride species, which can undergo decarbonylation in the absence of a boronic ester. When a 1:1 mixture of 1 a and [D6]-1 a was subjected to the Ni-catalyzed cross-coupling reaction conditions, we obtained the cross-coupling products 3 aa and [D5]-3 aa in a ratio of 5.7:1.[13] The result suggests that C¢H bond activation is rate-determining (Scheme 2 b). Computational studies by Fu and co-workers support the concept of electron-deficient p-ligands on nickel promoting oxidative addition into aldehyde C¢H bonds.[14] On the basis of these preliminary results, and those of previous studies, we propose the mechanism shown in Scheme 3. Hexafluoroacetone binds to nickel to form complex A, which
An oven-dried Schlenk tube (10 mL) was charged with aryl aldehyde 1 (0.3 mmol), boronic ester 2 (0.3 mmol), hexafluoroacetone (0.45 mmol), Ni(cod)2 (5 mol %), IPr (6 mol %), and THF (2 mL). Then, the tube was charged with argon and stirred at 40 8C for about 10 h. After the reaction was complete, the reaction mixture was diluted with EtOAc (5 mL). The solution was filtered through a celite pad and washed with EtOAc (15–20 mL). The organic portion was washed with a saturated solution of brine (3 Õ 8 mL), dried (Na2SO4), and concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to provide the desired product 3.
Acknowledgements We are grateful for financial support from the Program for Innovative Research Team (in Science and Technology) in University of Yunnan Province (IRTSTYN 2014-11) and the State Ethnic Affairs Commission (12YNZ05). Keywords: aryl ketones · C¢C bond formation · N-heterocyclic carbenes · nickel
Scheme 3. Possible mechanism.
can coordinate to benzaldehyde (1 a) to give intermediate B. Oxidative addition to the C¢H bond of the aldehyde generates C,[12] which reduces the hydrogen acceptor hexafluoroacetone to yield acyl nickel alkoxide D. Ligand exchange with phenylboronic acid pinacol ester (2 a) affords E and reductive elimination provides the final product 3 aa. Coordination of hexafluoroacetone may occur prior to or immediately after the reductive elimination.[15] The coordination inhibits the formation of the by-product 4 a by disrupting the formation of a cycloisomerization intermediate between two aryl aldehydes. In summary, we have described a nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes and boronic esters to construct functionalized aryl ketones, a ubiquitous component of many natural products, biomolecules, Chem. Eur. J. 2015, 21, 8741 – 8744
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[1] a) B. Skillinghaug, C. Skçld, J. Rydfjord, F. Svensson, M. Behrends, J. Svmarker, P. J. R. Sjçberg, M. Larhed, J. Org. Chem. 2014, 79, 12018. [2] a) N. Wan, Y. Hui, Z. Xie, J. Wang, Chin. J. Chem. 2012, 30, 311; b) J. H. Wynne, C. T. Lloyd, S. D. Jensen, S. Boson, W. M. Stalick, Synthesis 2004, 14, 2277. [3] Y. Uto, T. Ogata, K. Yohei, Y. Ueno, Y. Miyazawa, H. Kurata, T. Deguchi, N. Watanabe, M. Konishi, R. Okuyama, N. Kurikawa, T. Takagi, S. Wakimoto, J. Ohsumi, Bioorg. Med. Chem. Lett. 2010, 20, 341. [4] a) C. A. Loeschorn, M. Nakajima, P. J. McCloskey, P. J. Anselme, J. Org. Chem. 1983, 48, 4407; b) A. J. Wommack, D. C. Moebius, A. L. Travis, J. S. Kingsbury, Org. Lett. 2009, 11, 3202. [5] X. Wu, H. Neumann, M. Beller, ChemSusChem 2013, 6, 229. [6] a) L. Gu, J. Liu, H. Zhang, Chin. J. Chem. 2014, 32, 1267; b) L. Gu, H. Zhang, RSC Adv. 2015, 5, 690; c) L. Gu, C. Jin, H. Zhang, L. Zhang, J. Org. Chem. 2014, 79, 8453; d) G. Wang, X. Li, J. Dai, H. Xu, J. Org. Chem. 2014, 79, 7220. [7] For selected examples of other methods for the synthesis of aryl ketones, see: a) B. K. Dey, J. Dutta, M. G. B. Drew, S. Bhattacharya, J. Organomet. Chem. 2014, 750, 176; b) K. V. Tran, D. Bickar, J. Org. Chem. 2006, 71, 6640; c) Y. Huang, K. K. Majumdar, C. Cheng, J. Org. Chem. 2002, 67, 1682. [8] a) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417; b) S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509, 299; c) J. Wu, L. Gong, Y. Xia, R. Song, Y. Xie, J. Li, Angew. Chem. Int. Ed. 2012, 51, 9909; Angew. Chem. 2012, 124, 10047; d) B. D. Sherry, A. Furstner, Acc. Chem. Res. 2008, 41, 1500; e) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780; f) A. Suzuki, J. Organomet. Chem. 1999, 576, 147. [9] C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51, 5062; Angew. Chem. 2012, 124, 5150. [10] a) O. Vechorkin, X. Hu, Angew. Chem. Int. Ed. 2009, 48, 2937; Angew. Chem. 2009, 121, 2981; b) A. K. Steib, O. M. Kuzmina, S. Fernandez, D. Flubacher, P. Knochel, J. Am. Chem. Soc. 2013, 135, 15346; c) D. Liu, C.
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Communication Liu, A. Lei, Angew. Chem. Int. Ed. 2013, 52, 4453; Angew. Chem. 2013, 125, 4549; d) C. Liu, S. Tang, D. Liu, J. Yuan, L. Zheng, L. Meng, A. Lei, Angew. Chem. Int. Ed. 2012, 51, 3638; Angew. Chem. 2012, 124, 3698; e) J. Wang, C. Liu, J. Yuan, A. Lei, Angew. Chem. Int. Ed. 2013, 52, 2256; Angew. Chem. 2013, 125, 2312. [11] a) Z. Csok, O. Vechorkin, S. B. Harkins, R. Scopelliti, X. Hu, J. Am. Chem. Soc. 2008, 130, 8156; b) G. D. Jones, J. L. Martin, C. McFarland, O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon, T. Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J. Am. Chem. Soc. 2006, 128, 13175; c) X. Hu, Chem. Sci. 2011, 2, 1867; d) R. Takise, K. Muto, J. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2014, 53, 6791; e) D. Liu, C. Liu, A. Lei, Pure Appl. Chem. 2014, 86, 321; f) C. Liu, D. Liu, W. Zhang, L. Zhou, A. Lei, Org. Lett. 2013, 15, 6166; g) J. Yuan, J. Wang, G. Zhang, C. Liu, X. Qi, Y. Lan, J. T. Miller, A. J. Kropf, E. E. Bunel, A. Lei, Chem. Commun. 2015, 51, 576; h) J. Wang,
Chem. Eur. J. 2015, 21, 8741 – 8744
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C. Liu, J. Yuan, A. Lei, Chem. Commun. 2014, 50, 4736; i) S. Tang, C. Liu, A. Lei, Chem. Commun. 2013, 49, 2442; j) D. Liu, S. Tang, H. Yi, C. Liu, X. Qi, Y. Lan, A. Lei, Chem. Eur. J. 2014, 20, 15605. A. M. Whittaker, V. M. Dong, Angew. Chem. Int. Ed. 2015, 54, 1312. J. Nan, Z. Zuo, L. Luo, L. Bai, H. Zheng, Y. Yuan, J. Liu, X. Luan, Y. Wang, J. Am. Chem. Soc. 2013, 135, 17306. H. Yu, Y. Fu, Chem. Eur. J. 2012, 18, 16765. a) R. Giovannini, P. Knochel, J. Am. Chem. Soc. 1998, 120, 11186; b) J. B. Johnson, E. A. Bercot, J. M. Rowley, G. W. Coates, T. Rovis, J. Am. Chem. Soc. 2007, 129, 2718.
Received: February 10, 2015 Published online on April 29, 2015
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Communication
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Nickel N-Heterocyclic Carbene Catalyzed C¢C Bond Formation: A New Route to Aryl Ketones Li-Jun Gu,*[a, c] Cheng Jin,[b] and Hong-Tao Zhang[a] Abstract: A novel nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes with boronic esters for the synthesis of aryl ketones was developed. This reaction provides a mild, practical method toward aryl ketones, which are versatile intermediates and building blocks in organic synthesis.
Aryl ketones are common structural motifs in natural products and versatile building blocks for the synthesis of more complex natural products, pharmaceuticals, agricultural chemicals, dyes, and other commercially important materials.[1] Consequently, the development of synthetic methods for the preparation of aryl ketones has received considerable attention. One general approach is the Friedel–Crafts acylation of substituted aromatic rings. Under the acidic conditions of Friedel–Crafts reactions,[2] the formation of ortho and para isomers with untunable regioselectivity results in separation problems and makes aryl ketones with meta substituents difficult to access. Other significant approaches include the addition of an organometallic reagent to a partner with a higher oxidation state partner and the addition of an organometallic reagent to an aldehyde and reoxidation of the intermediate alcohol.[3] Both of these approaches suffer from a poor financial, time, step, and redox economy, as well as the requirement for moisture-sensitive organometallic reagents. An alternative approach is the reaction of diazo compounds with aldehydes, but the use of structurally diverse diazo compounds is hampered by their preparation and safety issues.[4] In recent years, significant progress has been achieved in carbonylative Suzuki–Miyaura cross-coupling reactions; various substituted aryl ketones have been successfully synthesized.[5] However, due to the high toxicity and odorless and flammable character of CO gas, transformations by [a] Prof. Dr. L.-J. Gu, H.-T. Zhang Key Laboratory of Chemistry in Ethnic Medicinal Resources State Ethnic Affairs Commission & Ministry of Education Yunnan Minzu University, Kunming, Yunnan, 650500 (P. R. China) [b] C. Jin New United Group Company Limited Changzhou, Jiangsu, 213166 (P. R. China) [c] Prof. Dr. L.-J. Gu Key Laboratory of Comprehensive Utilization of Mineral Resources in Ethnic Regions, Yunnan Minzu University Yunnan Minzu University, Kunming, Yunnan, 650500 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500560. Chem. Eur. J. 2015, 21, 8741 – 8744
using CO gas must be operated with special care. The carbon¢ carbon bond is the most widespread and fundamental bond that exists in organic compounds. Very recently, the preparation of aryl ketones by activation of C¢C bonds has received much attention.[1b, 6] Despite these advances,[7] versatile and efficient methods for the direct construction of aryl ketones that are compatible with various functional groups and use readily available starting materials remain highly desirable. Transition-metal-catalyzed cross-coupling reactions are highly versatile methods for the construction of complex molecules from simple building blocks.[8] Efficient catalytic systems for a wide range of substrates are utilized in both research laboratories and industry. The most efficient and commonly employed cross-coupling catalysts feature second- and third-row transition metals, most notably palladium, to achieve high turnover numbers.[9] Despite the maturity of this synthetic method, cross-coupling catalysis continues to attract significant interest, especially with respect to the development of more sustainable catalysts based on abundant first-row transition metals.[10] Various cross-coupling catalysts with first-row metals have been reported and those based on nickel are particularly promising.[11] So far, nickel-catalyzed cross-coupling reactions of aryl aldehydes with boronic esters have not been reported. Herein, we describe a new strategy to construct aryl ketones that relies on a nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes with boronic esters (Scheme 1). This protocol provides a practical, neutral, and mild synthetic approach to aryl ketones.
Scheme 1. New strategy to construct aryl ketones.
Our investigation began with the reaction of benzaldehyde (1 a) with phenylboronic acid pinacol ester (2 a) to optimize the reaction conditions (Table S1 in the Supporting Information). To our delight, when 1 a and 2 a were treated with a catalytic system consisting of a,a,a-trifluoroacetophenone (hydrogen acceptor, 1.5 equiv), Ni(cod)2 (5 mol %), and 1,3-bis(2,6bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene (IPr, ligand, 6 mol %) in THF at 40 8C, the desired benzophenone 3 aa was formed in 43 % yield (Table S1, entry 1). The benzyl 8741
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Communication benzoate by-product (4 a) was obtained in 31 % yield (Table S1, entry 1). After considerable effort, we found that hexafluoroacetone showed a remarkable enhancement in rate and selectivity for the formation of 3 aa (Table S1, entries 1–5). Different Ni catalysts were screened and Ni(cod)2 (cod = 1,5-cyclooctadiene) turned out to be the most effective catalyst (Table S1, entries 4 and 6–9). Other ligands, including phosphorus tricyclohexyl (PCy3), 1,3-di-tert-butylimidazol-2-ylidene (ItBu), and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (SIPr), were tested and found to be less effective than IPr (Table S1, entries 10–12). Of the solvents tested, THF proved particularly suitable (Table S1, entries 13–15). However, the reaction did not take place in the absence of a Ni catalyst (Table S1, entry 16). Next, we used the optimal reaction conditions to extend the substrate scope by using a series of alternative aryl aldehydes 1. As summarized in Table 1, the standard reaction conditions
fected the yield (Table 1, entry 3), further extending the scope of this methodology. Aromatic aldehyde 1 j with a naphthyl group also participated in this Ni-catalyzed cross-coupling reaction, affording the product in 75 % yield (Table 1, entry 4). Unfortunately, an aliphatic aldehyde did not deliver the corresponding ketone under the same reaction conditions (Table 1, entry 5). The cross-coupling method was also successfully applied to a variety of boronic esters 2. As shown in Table 2, a broad range of boronic esters 2 reacted smoothly with 1 a to give the corresponding aryl ketones in good yields. For example, ar-
Table 2. Scope of boronic esters.[a]
Table 1. Scope of aromatic aldehydes.[a]
Entry
Aromatic aldehyde 1
Ketone 3
Yield [%][b]
1
1 b: R = p-Me 1 c: R = p-OMe 1 d: R = p-F 1 e: R = p-Cl 1 f: R = p-CO2Me 1 g: R = o-Me 1 h: R = m-Me
3 ab: R = p-Me 3 ac: R = p-OMe 3 ad: R = p-F 3 ae: R = p-Cl 3 af: R = p-CO2Me 3 ag: R = o-Me 3 ah: R = m-Me
76 71 74 63 55 60 66 70
2
3
54
4
75
5
0
were found to be compatible with a wide range of aryl aldehydes 1. These results showed that the cross-coupling reaction can be realized in good yields irrespective of the nature and the position of the aryl substituents of substrate 1. Interestingly, the polysubstituted aromatic aldehyde 1 i gave the desired product 3 ai in a good yield (Table 1, entry 2). Notably, the replacement of the benzyl moiety by a 2-furanyl group hardly afwww.chemeurj.org
Boronic ester 2
Ketone 3
Yield [%][b]
1
2 b: R2 = p-Me 2 c: R2 = p-OMe 2 d: R1 = p-F 2 e: R2 = p-Ph 2 f: R2 = p-Me 2 g: R2 = m-Me
3 ba: R2 = p-Me 3 ca: R2 = p-OMe 3 da: R2 = p-F 3 ea: R2 = p-Ph 3 fa: R2 = p-Me 3 ga: R2 = m-Me
62 69 57 65 70 78
2
66
3
73
4
79
[a] Reaction conditions: 1 a (0.3 mmol), 2 (0.3 mmol), hexafluoroacetone (1.5 equiv), Ni(cod)2 (5 mol %), IPr (6 mol %), THF (2 mL), 40 8C, in Ar atmosphere for 10 h. [b] Isolated yield.
[a] Reaction conditions: 1 (0.3 mmol), 2 a (0.3 mmol), hexafluoroacetone (1.5 equiv), Ni(cod)2 (5 mol %), IPr (6 mol %), THF (2 mL), 40 8C, in Ar atmosphere for 10 h. [b] Isolated yield.
Chem. Eur. J. 2015, 21, 8741 – 8744
Entry
ylboronic esters bearing electron-rich (methoxy, methyl) and electron-deficient (halogen, phenyl) substituents on the aryl ring underwent this reaction to give the corresponding products in generally moderate to good yields (57–79 %). Substituents at the ortho-, meta-, or para-positions had no distinct influence on the reaction. For example, substrates 2 b, 2 f, and 2 g with a Me group were transformed into products 3 ba, 3 fa, and 3 ga, respectively, with similar yields. Notably, the introduction of heterocycles into this system made this methodology more useful for the preparation of pharmaceuticals and materials (Table 2, entry 2). Efforts were made to apply this methodology to the synthesis of aryl alkyl ketones; it was found that reactions with 2 i–2 j proceeded smoothly to give the aryl alkyl ketones 3 ia–3 ja in good yields (Table 2, entries 3 and 4). To gain an insight into the course of the reaction, we conducted a series of control experiments. In the absence of a boronic ester, we observed decarbonylation of benzaldehyde 1 a
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Communication and materials applications. This method offers marked improvements in terms of operational simplicity, reaction conditions, general applicability, and good isolated yields of products.
Experimental Section General procedure
Scheme 2. Experiments for mechanistic studies.
to produce benzene and reduction of hexafluoroacetone (Scheme 2 a).[12] This result supports the intermediacy of an acyl nickel hydride species, which can undergo decarbonylation in the absence of a boronic ester. When a 1:1 mixture of 1 a and [D6]-1 a was subjected to the Ni-catalyzed cross-coupling reaction conditions, we obtained the cross-coupling products 3 aa and [D5]-3 aa in a ratio of 5.7:1.[13] The result suggests that C¢H bond activation is rate-determining (Scheme 2 b). Computational studies by Fu and co-workers support the concept of electron-deficient p-ligands on nickel promoting oxidative addition into aldehyde C¢H bonds.[14] On the basis of these preliminary results, and those of previous studies, we propose the mechanism shown in Scheme 3. Hexafluoroacetone binds to nickel to form complex A, which
An oven-dried Schlenk tube (10 mL) was charged with aryl aldehyde 1 (0.3 mmol), boronic ester 2 (0.3 mmol), hexafluoroacetone (0.45 mmol), Ni(cod)2 (5 mol %), IPr (6 mol %), and THF (2 mL). Then, the tube was charged with argon and stirred at 40 8C for about 10 h. After the reaction was complete, the reaction mixture was diluted with EtOAc (5 mL). The solution was filtered through a celite pad and washed with EtOAc (15–20 mL). The organic portion was washed with a saturated solution of brine (3 Õ 8 mL), dried (Na2SO4), and concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to provide the desired product 3.
Acknowledgements We are grateful for financial support from the Program for Innovative Research Team (in Science and Technology) in University of Yunnan Province (IRTSTYN 2014-11) and the State Ethnic Affairs Commission (12YNZ05). Keywords: aryl ketones · C¢C bond formation · N-heterocyclic carbenes · nickel
Scheme 3. Possible mechanism.
can coordinate to benzaldehyde (1 a) to give intermediate B. Oxidative addition to the C¢H bond of the aldehyde generates C,[12] which reduces the hydrogen acceptor hexafluoroacetone to yield acyl nickel alkoxide D. Ligand exchange with phenylboronic acid pinacol ester (2 a) affords E and reductive elimination provides the final product 3 aa. Coordination of hexafluoroacetone may occur prior to or immediately after the reductive elimination.[15] The coordination inhibits the formation of the by-product 4 a by disrupting the formation of a cycloisomerization intermediate between two aryl aldehydes. In summary, we have described a nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes and boronic esters to construct functionalized aryl ketones, a ubiquitous component of many natural products, biomolecules, Chem. Eur. J. 2015, 21, 8741 – 8744
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Received: February 10, 2015 Published online on April 29, 2015
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