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Yue-Jin Liu,a Zhuo-Zhuo Zhang,a Sheng-Yi Yan,a Yan-Hua Liu,a Bing-Feng Shi*a,b Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5
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The first nickel-catalyzed alkenylation of unactivated C(sp3)-H bonds with vinyl iodides is described. The catalytic system comprises an inexpensive and air-stable Ni(acac)2 as catalyst and BINOL as ligand, which is highly efficient for the alkenylation of β-methyl C(sp3)-H bonds of a broad range of aliphatic carboxamides. The resulting olefins can serve as versatile handles for further elaboration. Additionally, we also demonstrated the synthesis of functionalized carboxamides bearing α-quaternary carbon centers from simple pivalamide via nickel-catalyzed sequential C(sp3)-H bond functionalization. Over the past decades, transition-metal-catalyzed C-H alkenylation has emerged as a versatile and powerful alternative to the Mizoroki-Heck reaction.1,2 This transformation provides an atom and step economical strategy for the synthesis of functionalized olefins. The alkenylation of (hetero)aryl C(sp2)-H bonds catalyzed by a variety of metal catalysts, such as Pd, Rh, Ru, Cu, Co and Ni, has been well investigated.2 These transformations have also been applied to the total synthesis and late-stage functionalization of natural products and drug molecules.3,4 In contrast, the direct alkenylation of unactivated C(sp3)-H bonds remains a great challenge, largely due to the inherent low reactivity of aliphatic C(sp3)-H bonds5 and the competitive coordination of the olefins to interfere with the C-H functionalization reaction.6 So far, only a few examples of such transformations have been reported (Scheme 1A). In 2010, Yu and coworkers reported a Pd-catalyzed olefination of β-methyl C(sp3)-H bonds with acrylates directed by a weakly coordinating N-arylamide (CONHAr) directing group.7a,b More recently, they have extended this dehydragenative olefination protocol to γC(sp3)-H bonds promoted by a quinoline-based ligand.7c The Sanford group reported a Pd/polyoxometalate-catalyzed pyridyldirected C(sp3)-H olefination with acrylates.7d However, the expected alkenylated products could not be isolated due to the intramolecular Michael addition to give the corresponding cyclization products. Recently, the direct alkenylation of unactivated C(sp3)-H bonds with vinyl iodides8 has been reported by Baran9a,b and Chen9c,d. The desired olefins could be synthesized through these protocols. In particular, the Baran group has demonstrated the total synthesis of Pipercyclobutanamide A by the use of this alkenylation reaction as a key step.9b While considerable progress has been achieved, these methods are limited to the use of noble metal palladium as catalyst and very specific substrates. Therefore, the development of a general and efficient protocol for the alkenylation of unactivated C(sp3)–H bonds using low-cost metal catalysts would be very challenging and extremely attractive. Recently, nickel has been identified as a powerful and promising catalyst for the functionalization of C-H bonds from This journal is © The Royal Society of Chemistry [year]
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the viewpoints of economics and versatility.10-15 Whereas seminal studies by Chatani,12 Ge13 and You14 have shown the success of nickel-catalyzed arylation and alkylation of unactivated C(sp3)-H bonds employing 8-aminoquinoline (AQ) as N,N-bidentate directing group,16 no example of nickel-catalyzed C(sp3)-H alkenylation has been reported.17,18 The chief barriers to C(sp3)-H alkenylation compared to the analogous arylation and alkylation are at least twofold: 1) the competitive coordination of the alkenylation reagents may inhibit the activation of C(sp3)-H bonds; 2) the resulting alkene and the intrinsic bidentate auxiliary may coordinate with nickel catalyst to form a thermodynamically stable tridentate complex and shut down the reaction.
Scheme 1. Transition-metal-catalyzed alkenylation of C(sp3)–H bonds.
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As part of our continuous program on functionalization of unactivated C(sp3)-H bonds,19 we became interested in developing methods for the alkenylation of aliphatic C(sp3)-H bonds in consideration of the great challenges associated. Here we describe a novel catalyst system that allows for efficient alkenylation of β-methyl C(sp3)-H bonds of a broad range of aliphatic carboxamides (Scheme 1B). The synthetic utility of this protocol is further demonstrated by the synthesis of [journal], [year], [vol], 00–00 | 1
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Ni(II)/BINOL-Catalyzed Alkenylation of Unactivated C(sp3)–H Bonds
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conditions, the corresponding alkenylated product 3l was obtained in 57% yield, with the aryl bromide remaining intact. The orthogonal reactivity of the C-H alkenylation and bromo groups provides a useful opportunity for further elaboration of the olefin products by traditional cross-coupling.
Table 1. Optimization of the reaction conditionsa
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Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c
Ligand BDMAE BDMAE BDMAE BDMAE PPh3 dppb BINAP TMEDA 1,10-Phen L1 L2 L3 L4 L5 L6 L3
Base Na2CO3 Li2CO3 K2CO3 KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA + Li2CO3
Yield (%)b 23 11 8 25 9 13 10 17 trace 34 38 73 63 58 48 78d
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Reaction conditions: 1a (0.1 mmol), [Ni] (10 mol%), Ligand (20 mol%), base (2.0 equiv) in DMSO (1 mL) at 140 oC for 8 h under N2. b1H NMR yields using CH2Br2 as the internal standard. c40 mol% L3 was used. dIsolated yield. AQ = 8-quinolinyl, BDMAE = bis(2-dimethylaminoethyl)ether, DME = dimethoxyethane, TFA = trifluoroacetoxyl.
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Scheme 2. The scope of styrenyl iodides. Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3 (0.2 mmol), KTFA (0.2 mmol) in 1.0 mL DMSO, 140 oC, under N2, 8 h, isolated yield.
The scope of carboxamides was explored next. We found that a wide variety of carboxamides bearing both linear and cyclic chains were compatible with this protocol (Scheme 3). However, consistent with previous reports, a quaternary α-carbon is necessary for the success of this reaction.12-14 Notably, vinyl functional group was tolerated and gave the corresponding divinyl products 4i in moderate yield. In addition, the selective activation of β-methyl C(sp3)-H bonds over γ-aromatic C(sp2)-H bonds was observed when 2-phenyl-substituted carboxamides (1i1o) were used.
The scope of this alkenylation protocol was first examined by varying the vinyl iodides. As shown in Scheme 2, both electrondeficient and electron-rich E-β-iodostyrenes reacted smoothly with carboxamide 1a to exclusively give the E-isomers 3 in moderate to good yields.20 Substituents at the ortho-, meta-, or para-positions of the styrene were tolerated. Various functional groups were tolerated under the optimized reaction conditions, including fluoro (3d), methoxy (3e), cyano (3f), chloro (2g and 3i) and trifluoromethyl (3k). Moreover, when styrenyl iodide bearing a m-bromo substituent was subjected to the standard reaction 2 | Journal Name, [year], [vol], 00–00
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functionalized carboxamides bearing α-quaternary carbon centers from simple pivalamide via nickel-catalyzed sequential C(sp3)-H bond functionalization. We initially examined the alkenylation of carboxamide 1a with styrenyl iodide 2a. At the outset, we were pleased to find that the desired alkenylated product 3a was obtained in 23% yield by using 10 mol% Ni(acac)2 and BDMAE with Na2CO3 as base in DMSO under atmosphere of N2 (Table 1, entry 1). Further screening revealed that the combination of Ni(acac)2 and KTFA was the optimal (entry 4). Extensive investigation of a number of privileged ligands that often used in nickel catalysts, such as phosphines and amines, provided little improvement in yield (entries 4-10, for detailed screening, see SI). Instead, a series of diol-type ligands showed superior reactivity (entries 11-15). Use of BINOL (L3) provided the best results and gave the desired products 3a in 73% yield (entry 12). The yield was further improved to 78% when a combination of KTFA and Li2CO3 with 40 mol% BINOL was used (entry 16).
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functionalization. Reagents and conditions: a) ArI, Ni(OTf)2 ( 10 mol%), MesCO2H (20 mol%), Na2CO3, DMF, 140 oC; b) i) vinyl iodide, Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3, KTFA DMSO, 140 oC, 62% yield; ii) Pd/C, HCO2NH4, MeOH, 80 oC, 92% yield; c) vinyl iodide, Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3, KTFA DMSO, 140 oC, 72% yield.
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Finally, further functionalization of the resulting olefincontaining products was demonstrated. As shown in Scheme 5, 4k was readily dihydroxylated to give the corresponding diol 8 in 85% yield (dr = 1:1). The hydrogenation of 4k also proceeded smoothly to give 9 in 78% yield.
Scheme 5. Functionalization of C–H alkenylated product 4k.
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Scheme 3. The scope of aliphatic carboxamides. Reaction conditions: 1 (0.1 mmol), 2e (0.2 mmol), Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3 (0.2 mmol), KTFA (0.2 mmol) in 1.0 mL DMSO, 140 oC, under N2, 8 h, isolated yield. To demonstrate the utility of this alkenylation protocol, the synthesis of functionalized carboxamides 7 bearing α-quaternary carbon centers from pivalamide 1d via Ni-catalyzed sequential C(sp3)-H bonds functionalization was developed. As shown in Scheme 4, nickel-catalyzed arylation of pivalamide 1d proceeded smoothly to give arylated product 5.12a Subsequently, 5 was subjected to our alkenylation protocol followed by hydrogenation to furnish compound 6, which was reacted with styrenyl iodide under the standard alkenylation conditions to afford carboxamides 7.
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In conclusion, we have developed a novel nickel-catalyzed direct alkenylation of unactivated C(sp3)-H bonds with styrenyl iodides employing AQ as a bidentate directing group. The reaction is accomplished by an inexpensive and air-stable catalytic system consisting of Ni(acac)2 and unusual BINOL as ligand. A wide variety of functional groups were tolerated under the optimized reaction conditions. The synthesis of functionalized carboxamides bearing α-quaternary carbon centers from simple pivalamide via Ni-catalyzed sequential C(sp3)-H bonds functionalization was also demonstrated. Efforts to expand the scope of this transformation to other types of substrates and elucidate mechanistic details are underway.21
Acknowledgements Financial support from the National Basic Research Program of China (2015CB856600), the NSFC (21422206, 21272206) and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.
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Scheme 4. Synthesis of highly functionalized carboxamide 7 from pivalamide 1d via Ni-catalyzed sequential C-H This journal is © The Royal Society of Chemistry [year]
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Department of Chemistry, Zhejiang University, Hangzhou 310027, China. E-mail: [email protected] b State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China † Electronic Supplementary Information (ESI) available: Detailed experimental procedures, and analytical data for all new compounds, see DOI: 10.1039/b000000x/ ‡ Footnotes should appear here. These might include comments relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. 1. The Mizoroki–Heck Reaction (Ed.: M. Oestreich), Wiley, Chichester, 2009.
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For recent reviews on C-H alkenylation, see: a) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; b) T. W. Lyons, M. S, Sanford, Chem. Rev. 2010, 110, 1147; c) R. Rossi, F. Bellina, M. Lessi, Synthesis 2010, 4131; d) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212; e) J. Le Bras, J. Muzart, Chem. Rev. 2011, 111, 1170; f) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; g) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780; h) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879; i) G. Song, F. Wang, and X. Li, Chem. Soc. Rev. 2012, 41, 3651; j) F. Patureau, W. J. Wencel-Delord, and F. Glorius, Aldrichimica Acta 2012, 45, 31; k) S. I. Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4, 886; For selected examples, see: a) D.-H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2011, 33, 5767; b) D.-H. Wang, K. M. Engle, B.-F. Shi, J.-Q. Yu, Science 2010, 327, 315; c) E. M. Beck, R. Hatley, M. J. Gaunt, Angew. Chem. Int. Ed. 2008, 47, 3004; d) N. K. Garg, D. D. Caspi, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 1586; e) P. S. Baran, E. J. Corey, J. Am. Chem. Soc. 2002, 124, 7904. For selected reviews on the application of C-H functionalization in total synthesis, see: a) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885; b) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2012, 51, 8960; c) W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976; d) K. Collins, F. Glorius, Nat. Chem. 2013, 5, 597; e) K. M. Engle, J.-Q. Yu, J. Org. Chem. 2013, 78, 8927. For selected reviews on C(sp3)–H activation, see: a) G. Rouquet, N. Chatani, Angew. Chem. Int. Ed., 2013, 52, 11726; b) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464; c) O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902; d) J. F. Hartwig, Chem. Soc. Rev. 2011, 40, 1992; e) H. Li, B.-J. Li, Z.-J. Shi, Catal. Sci. Technol. 2011, 1, 191; f) M. Wasa, K. M. Engle, J.-Q. Yu, Isr. J. Chem. 2010, 50, 605; g) K. Godula, D. Sames, Science, 2006, 312, 67. R. Giri, N. Maugel, B. M. Foxman, J.-Q. Yu, Organometallics, 2008, 27, 1667. a) M. Wasa, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 3680; b) J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs, J.-Q. Yu, Science 2014, 343, 1216; c) S. Li, G. Chen, C. G. Feng, W. Gong, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 5276; d) K. J. Stowers, K. C. Fortner, M. S. Sanford, J. Am. Chem. Soc. 2011, 133, 6541. For the pioneering use of haloolefins as coupling partners in C(sp2)-H alkenylation, see: a) V. G. Zaitsev, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 4156; b) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128. a) W. R. Gutekunst, P. S. Baran, J. Org. Chem. 2014, 79, 2430; b) W. Gutekunst, R. Gianatassio, P. S. Baran, Angew. Chem. Int. Ed. 2012, 51, 7507; c) G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192; d) B. Wang, C. Lu, S.-Y. Zhang, G. He, W. A. Nack, G. Chen, Org. Lett. 2014, 16, 6260. For selected reviews, see: a) S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509, 299; b) X. Hu, Chem. Sci. 2011, 2, 1867; c) Kulkarni, A. A.; Daugulis, O. Synthesis. 2009, 4087. For selected reviews and examples on nickel-catalyzed functionalization of acidic C-H bonds, see: a) J. Yamaguchi, K. Muto, K. Itami, Eur. J. Org. Chem. 2013, 19; b) Y. Nakao, Chem. Rec. 2011, 11, 242; c) K. S. Kanyiva, Y. Nakao, T. Hiyama, Angew. Chem. Int. Ed. 2007, 46, 8872; d) Y. Nakao, K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2008, 130, 2448; e) J. Canivet, J. Yamaguchi, I. Ban, K. Itami, Org. Lett. 2009, 11, 1733; f) T.
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Truong, J. Alvarado, L. D. Tran, O. Daugulis, Org. Lett. 2010, 12, 1200; g) H. Hachiya, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2010, 49, 2202; h) M. E. Doster, J. A. Hatnean, T. Jeftic, S. Modi, S. A. Johnson, J. Am. Chem. Soc. 2010, 132, 1923; i) N. Matsuyama, M. Kitahara, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 2358; j) O. Vechorkin, V. Proust, X. Hu, Angew. Chem. Int. Ed. 2010, 49, 3061; k) K. Muto, J. Yamaguchi, K. Itami, J. Am. Chem. Soc. 2012, 134, 169; l) R. Tamura, Y. Yamada, Y. Nakao, T. Hiyama, Angew. Chem., Int. Ed. 2012, 51, 5679; m) K. Muto, J. Yamaguchi, A.-W. Lei, K. Itami, J. Am. Chem. Soc. 2013, 135, 16348. And references therein. a) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2014, 136, 898; b) M. Iyanaga, Y. Aihara, N. Chatani, J. Org. Chem. 2014, 79, 11933; a) X. Wu, Y. Zhao, H. Ge, J. Am. Chem. Soc. 2014, 136, 17891792; b) X. Wu, Y. Zhao, H. Ge, Chem. Eur. J. 2014, 20, 95309533. M. Li, J. Dong, X. Huang, K. Li, Q. Wu, F. Song, J. You, Chem. Commun. 2014, 50, 3944. a) H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011, 133, 14952; b) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2013, 135, 5308; c) W. Song, L. Ackermann, Chem. Commun. 2013, 49, 6638; d) W. Song, S. Lackner, L. Ackermann, Angew. Chem. Int. Ed. 2014, 53, 2477; e) A. Yokota, Y. Aihara, N. Chatani, J. Org. Chem. 2014, 79, 11922; f) Y. Aihara, M. Tobisu, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2014, 136, 15509. For pioneering work of the use of bidentate auxiliary, see: a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154–13155; b) D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965–3972. For a representative review, see: ref 5a. For recent examples of nickel-catalyzed alkyl-Heck-type reactions, see: a) Q. Qian, Z. Zang, Y. Chen, W. Tong, H. Gong, Mini Rev. Med. Chem. 2013, 13, 802; b) E. A. Standley, T. F. Jamison, J. Am. Chem. Soc. 2013, 135, 1585; c) C. Liu, S. Tang, D. Liu, J. Yuan, L. Zheng, L. Meng, A. Lei, Angew. Chem. Int. Ed. 2012, 51, 3638; d) R. Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am. Chem. Soc. 2011, 133, 19020. For an example of nickel-catalyzed alkenylation of azoles with enols and esters, see: L. Meng, Y. Kamada, K. Muto, J. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2013, 52, 10048. a) Q.Zhang, K. Chen, W.-H. Rao, Y.-J. Zhang, F.-J. Chen, B.-F. Shi, Angew. Chem. Int. Ed. 2013, 52, 13588; b) K. Chen, F. Hu, S.Q. Zhang, B.-F. Shi, Chem. Sci. 2013, 4, 3906; c) Q. Zhang, X.-S. Yin, S. Zhao, S.-L. Fang, B.-F. Shi, Chem. Commun. 2014, 50, 8353; d) K. Chen, B.-F. Shi, Angew. Chem. Int. Ed. 2014, 53, 11950; e) K. Chen, S.-Q. Zhang, J.-W. Xu, F. Hu, B.-F. Shi, Chem. Commun. 2014, 50, 13924; f) K, Chen, S.-Q. Zhang, H.-Z. Jiang, J.-W. Xu, B.-F. Shi, Chem. Eur. J. DOI: 10.1002/chem.201405942. Z-β-Iodostyrenes and aliphatic vinyl iodides didn’t react under the optimized reaction conditions. Although a Ni(II)/Ni(IV) catalytic cycle via the oxidative addition of styrenyl iodide to the resulting Ni(II) intermediate as described by Chatani in Ni-catalyzed C-H arylation (ref 12 and 15b) is reasonable, a migratory insertion followed by β-I elimination pathway could also be operative. For elegant studies of βheteroatom elimination, see: a) G. Zhu, X. Lu, Organometallic 1995, 14, 4899; b) Z. Wang, Z. Zhang, X. Lu, Organometallic 2000, 19, 775.
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The first nickel-catalyzed alkenylation of unactivated C(sp3)-H bonds with vinyl iodides is described.
ChemComm Accepted Manuscript
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This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Yue-Jin Liu,a Zhuo-Zhuo Zhang,a Sheng-Yi Yan,a Yan-Hua Liu,a Bing-Feng Shi*a,b Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5
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The first nickel-catalyzed alkenylation of unactivated C(sp3)-H bonds with vinyl iodides is described. The catalytic system comprises an inexpensive and air-stable Ni(acac)2 as catalyst and BINOL as ligand, which is highly efficient for the alkenylation of β-methyl C(sp3)-H bonds of a broad range of aliphatic carboxamides. The resulting olefins can serve as versatile handles for further elaboration. Additionally, we also demonstrated the synthesis of functionalized carboxamides bearing α-quaternary carbon centers from simple pivalamide via nickel-catalyzed sequential C(sp3)-H bond functionalization. Over the past decades, transition-metal-catalyzed C-H alkenylation has emerged as a versatile and powerful alternative to the Mizoroki-Heck reaction.1,2 This transformation provides an atom and step economical strategy for the synthesis of functionalized olefins. The alkenylation of (hetero)aryl C(sp2)-H bonds catalyzed by a variety of metal catalysts, such as Pd, Rh, Ru, Cu, Co and Ni, has been well investigated.2 These transformations have also been applied to the total synthesis and late-stage functionalization of natural products and drug molecules.3,4 In contrast, the direct alkenylation of unactivated C(sp3)-H bonds remains a great challenge, largely due to the inherent low reactivity of aliphatic C(sp3)-H bonds5 and the competitive coordination of the olefins to interfere with the C-H functionalization reaction.6 So far, only a few examples of such transformations have been reported (Scheme 1A). In 2010, Yu and coworkers reported a Pd-catalyzed olefination of β-methyl C(sp3)-H bonds with acrylates directed by a weakly coordinating N-arylamide (CONHAr) directing group.7a,b More recently, they have extended this dehydragenative olefination protocol to γC(sp3)-H bonds promoted by a quinoline-based ligand.7c The Sanford group reported a Pd/polyoxometalate-catalyzed pyridyldirected C(sp3)-H olefination with acrylates.7d However, the expected alkenylated products could not be isolated due to the intramolecular Michael addition to give the corresponding cyclization products. Recently, the direct alkenylation of unactivated C(sp3)-H bonds with vinyl iodides8 has been reported by Baran9a,b and Chen9c,d. The desired olefins could be synthesized through these protocols. In particular, the Baran group has demonstrated the total synthesis of Pipercyclobutanamide A by the use of this alkenylation reaction as a key step.9b While considerable progress has been achieved, these methods are limited to the use of noble metal palladium as catalyst and very specific substrates. Therefore, the development of a general and efficient protocol for the alkenylation of unactivated C(sp3)–H bonds using low-cost metal catalysts would be very challenging and extremely attractive. Recently, nickel has been identified as a powerful and promising catalyst for the functionalization of C-H bonds from This journal is © The Royal Society of Chemistry [year]
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the viewpoints of economics and versatility.10-15 Whereas seminal studies by Chatani,12 Ge13 and You14 have shown the success of nickel-catalyzed arylation and alkylation of unactivated C(sp3)-H bonds employing 8-aminoquinoline (AQ) as N,N-bidentate directing group,16 no example of nickel-catalyzed C(sp3)-H alkenylation has been reported.17,18 The chief barriers to C(sp3)-H alkenylation compared to the analogous arylation and alkylation are at least twofold: 1) the competitive coordination of the alkenylation reagents may inhibit the activation of C(sp3)-H bonds; 2) the resulting alkene and the intrinsic bidentate auxiliary may coordinate with nickel catalyst to form a thermodynamically stable tridentate complex and shut down the reaction.
Scheme 1. Transition-metal-catalyzed alkenylation of C(sp3)–H bonds.
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As part of our continuous program on functionalization of unactivated C(sp3)-H bonds,19 we became interested in developing methods for the alkenylation of aliphatic C(sp3)-H bonds in consideration of the great challenges associated. Here we describe a novel catalyst system that allows for efficient alkenylation of β-methyl C(sp3)-H bonds of a broad range of aliphatic carboxamides (Scheme 1B). The synthetic utility of this protocol is further demonstrated by the synthesis of [journal], [year], [vol], 00–00 | 1
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Ni(II)/BINOL-Catalyzed Alkenylation of Unactivated C(sp3)–H Bonds
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conditions, the corresponding alkenylated product 3l was obtained in 57% yield, with the aryl bromide remaining intact. The orthogonal reactivity of the C-H alkenylation and bromo groups provides a useful opportunity for further elaboration of the olefin products by traditional cross-coupling.
Table 1. Optimization of the reaction conditionsa
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Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c
Ligand BDMAE BDMAE BDMAE BDMAE PPh3 dppb BINAP TMEDA 1,10-Phen L1 L2 L3 L4 L5 L6 L3
Base Na2CO3 Li2CO3 K2CO3 KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA KTFA + Li2CO3
Yield (%)b 23 11 8 25 9 13 10 17 trace 34 38 73 63 58 48 78d
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Reaction conditions: 1a (0.1 mmol), [Ni] (10 mol%), Ligand (20 mol%), base (2.0 equiv) in DMSO (1 mL) at 140 oC for 8 h under N2. b1H NMR yields using CH2Br2 as the internal standard. c40 mol% L3 was used. dIsolated yield. AQ = 8-quinolinyl, BDMAE = bis(2-dimethylaminoethyl)ether, DME = dimethoxyethane, TFA = trifluoroacetoxyl.
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Scheme 2. The scope of styrenyl iodides. Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3 (0.2 mmol), KTFA (0.2 mmol) in 1.0 mL DMSO, 140 oC, under N2, 8 h, isolated yield.
The scope of carboxamides was explored next. We found that a wide variety of carboxamides bearing both linear and cyclic chains were compatible with this protocol (Scheme 3). However, consistent with previous reports, a quaternary α-carbon is necessary for the success of this reaction.12-14 Notably, vinyl functional group was tolerated and gave the corresponding divinyl products 4i in moderate yield. In addition, the selective activation of β-methyl C(sp3)-H bonds over γ-aromatic C(sp2)-H bonds was observed when 2-phenyl-substituted carboxamides (1i1o) were used.
The scope of this alkenylation protocol was first examined by varying the vinyl iodides. As shown in Scheme 2, both electrondeficient and electron-rich E-β-iodostyrenes reacted smoothly with carboxamide 1a to exclusively give the E-isomers 3 in moderate to good yields.20 Substituents at the ortho-, meta-, or para-positions of the styrene were tolerated. Various functional groups were tolerated under the optimized reaction conditions, including fluoro (3d), methoxy (3e), cyano (3f), chloro (2g and 3i) and trifluoromethyl (3k). Moreover, when styrenyl iodide bearing a m-bromo substituent was subjected to the standard reaction 2 | Journal Name, [year], [vol], 00–00
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functionalized carboxamides bearing α-quaternary carbon centers from simple pivalamide via nickel-catalyzed sequential C(sp3)-H bond functionalization. We initially examined the alkenylation of carboxamide 1a with styrenyl iodide 2a. At the outset, we were pleased to find that the desired alkenylated product 3a was obtained in 23% yield by using 10 mol% Ni(acac)2 and BDMAE with Na2CO3 as base in DMSO under atmosphere of N2 (Table 1, entry 1). Further screening revealed that the combination of Ni(acac)2 and KTFA was the optimal (entry 4). Extensive investigation of a number of privileged ligands that often used in nickel catalysts, such as phosphines and amines, provided little improvement in yield (entries 4-10, for detailed screening, see SI). Instead, a series of diol-type ligands showed superior reactivity (entries 11-15). Use of BINOL (L3) provided the best results and gave the desired products 3a in 73% yield (entry 12). The yield was further improved to 78% when a combination of KTFA and Li2CO3 with 40 mol% BINOL was used (entry 16).
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functionalization. Reagents and conditions: a) ArI, Ni(OTf)2 ( 10 mol%), MesCO2H (20 mol%), Na2CO3, DMF, 140 oC; b) i) vinyl iodide, Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3, KTFA DMSO, 140 oC, 62% yield; ii) Pd/C, HCO2NH4, MeOH, 80 oC, 92% yield; c) vinyl iodide, Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3, KTFA DMSO, 140 oC, 72% yield.
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Finally, further functionalization of the resulting olefincontaining products was demonstrated. As shown in Scheme 5, 4k was readily dihydroxylated to give the corresponding diol 8 in 85% yield (dr = 1:1). The hydrogenation of 4k also proceeded smoothly to give 9 in 78% yield.
Scheme 5. Functionalization of C–H alkenylated product 4k.
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Scheme 3. The scope of aliphatic carboxamides. Reaction conditions: 1 (0.1 mmol), 2e (0.2 mmol), Ni(acac)2 (10 mol%), BINOL (40 mol%), Li2CO3 (0.2 mmol), KTFA (0.2 mmol) in 1.0 mL DMSO, 140 oC, under N2, 8 h, isolated yield. To demonstrate the utility of this alkenylation protocol, the synthesis of functionalized carboxamides 7 bearing α-quaternary carbon centers from pivalamide 1d via Ni-catalyzed sequential C(sp3)-H bonds functionalization was developed. As shown in Scheme 4, nickel-catalyzed arylation of pivalamide 1d proceeded smoothly to give arylated product 5.12a Subsequently, 5 was subjected to our alkenylation protocol followed by hydrogenation to furnish compound 6, which was reacted with styrenyl iodide under the standard alkenylation conditions to afford carboxamides 7.
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In conclusion, we have developed a novel nickel-catalyzed direct alkenylation of unactivated C(sp3)-H bonds with styrenyl iodides employing AQ as a bidentate directing group. The reaction is accomplished by an inexpensive and air-stable catalytic system consisting of Ni(acac)2 and unusual BINOL as ligand. A wide variety of functional groups were tolerated under the optimized reaction conditions. The synthesis of functionalized carboxamides bearing α-quaternary carbon centers from simple pivalamide via Ni-catalyzed sequential C(sp3)-H bonds functionalization was also demonstrated. Efforts to expand the scope of this transformation to other types of substrates and elucidate mechanistic details are underway.21
Acknowledgements Financial support from the National Basic Research Program of China (2015CB856600), the NSFC (21422206, 21272206) and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.
Notes and references 50
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Scheme 4. Synthesis of highly functionalized carboxamide 7 from pivalamide 1d via Ni-catalyzed sequential C-H This journal is © The Royal Society of Chemistry [year]
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, China. E-mail: [email protected] b State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China † Electronic Supplementary Information (ESI) available: Detailed experimental procedures, and analytical data for all new compounds, see DOI: 10.1039/b000000x/ ‡ Footnotes should appear here. These might include comments relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. 1. The Mizoroki–Heck Reaction (Ed.: M. Oestreich), Wiley, Chichester, 2009.
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The first nickel-catalyzed alkenylation of unactivated C(sp3)-H bonds with vinyl iodides is described.
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