Letter pubs.acs.org/acscatalysis
Ruthenium(II)-Catalyzed Regioselective C−H Arylation of Cyclic and N,N‑Dialkyl Benzamides with Boronic Acids by Weak Coordination Pradeep Nareddy, Frank Jordan, Stacey E. Brenner-Moyer, and Michal Szostak* Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States S Supporting Information *
ABSTRACT: We disclose a general method for selective ortho-C−H arylation of cyclic and N,N-dialkyl benzamides with boronic acids enabled by versatile ruthenium(II) complexes. This method features a general C−H arylation of ubiquitous aromatic tertiary benzamides by weak O-coordination. The transformation is characterized by its operational simplicity, the use of inexpensive, air-stable Ru(II) catalysts, scalability, and wide substrate scope. The reaction proceeds with high monoarylation selectivity to furnish valuable tertiary amide biaryls. Most crucially, the method provides the long-sought alternative to the classic directed-ortho-metalation (DoM) strategy, obviating the need for cryogenic conditions and strong lithium bases. KEYWORDS: C−H activation, ruthenium, amides, boronic acids, directed-ortho-metalation
O
the difficulty of direct arylation of N,N-dimethylbenzamide, cf. N-methylbenzamide (Pd: 9% vs 54%), 10c and weakly coordinating ketones (Ru: 8% vs 95%, tert-butyl ketone).10d As part of our program in functionalization of amide bonds by transition-metal catalysis (by author M.S.),12 we report the first general ortho-arylation of cyclic and N,N-dialkyl benzamides with boronic acids,13 which provides direct access to tertiary amide biaryls that are unattainable using conventional DoM.1−5 Notable features of our new method include (i) the first general C−H arylation of tertiary amides;6−10 (ii) the use of versatile Ru(II) catalysts14 and commercial reagents;15 (iii) the use of a wide range of tertiary amide directing groups, including cyclic amides, that are amenable to synthetic manipulation;16 (iv) in contrast to DoM, significantly improved substrate scope (halides, aldehydes), obviating the need for strong bases and cryogenic conditions. Given the versatile role of ortho-arylated tertiary benzamides and the lack of methods for their preparation, we believe that the developed process will find many applications in organic synthesis. We required facile access to ortho-arylated tertiary amides bearing sensitive functional groups under economic catalytic regimen.12 After extensive screening of various Pd conditions,6−8 we were attracted to inexpensive, cationic Ru(II) catalysts.14 Recently, cationic Ru(II) catalysts have emerged as viable cost-effective alternatives for arene functionalization, exploiting weakly coordinating directing groups.17 Although only traces or no desired arylation product were detected using aryl halides as coupling partners,18 we were delighted to find, after very extensive experimentation, that a cocktail containing
rtho-arylated tertiary benzamides are key structural motifs that appear in a large number of pharmaceuticals, natural products, and functional materials.1 Moreover, orthoarylated tertiary benzamides serve as versatile intermediates for the synthesis of functionalized heterocycles, phenantrene natural products, organic semiconductors, and liquid crystals.2 Consequently, various methods for the synthesis of tertiary amide biaryls have been developed,3 the most important being the classic directed-ortho-metalation (DoM) pioneered by Snieckus.4 However, despite the undisputable utility of DoM, the method requires strong lithium bases, cryogenic conditions, and sterically hindered amides to prevent self-condensation.4 As a consequence, new methods that allow to overcome the limitations of DoM and extend the concept to the synthesis of tertiary amide biaryl motifs without the need of cryogenic conditions and strong bases are in high demand (see Figure 1).5 Transition-metal-catalyzed C−H activation reactions are among the most useful methods for the synthesis of biaryl motifs.6 In this context, the evolution of weakly coordinating carboxylate directing groups presents, arguably, the most reliable method for direct C−H functionalization of readily available synthetic building blocks.7 However, direct ortho-C− H functionalization of tertiary amides poses a unique synthetic challenge because of the requirement for N−amidate coordination mode (acidic N−H bond) to minimize the entropic cost for C−H activation, which precludes tertiary amides from participating in this reaction manifold.8 Despite the major advances in transition-metal-catalyzed C−H activation,9 generally applicable methods for direct arylation of tertiary amides remain elusive.10 Most notably, methods for direct arylation of medicinally relevant cyclic amides11 are absent in the C−H activation toolbox altogether. The challenge of direct C−H arylation of tertiary amides is underscored by © XXXX American Chemical Society
Received: May 15, 2016 Revised: June 11, 2016
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DOI: 10.1021/acscatal.6b01360 ACS Catal. 2016, 6, 4755−4759
Letter
ACS Catalysis
Table 1. Optimization of Ru(II)-Catalyzed C−H Arylation of Tertiary Amidesa
entry
oxidant
1 2c 3 4d 5 6 7 8 9 10 11 12 13e 14 15 16 17f 18g
Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Cu(OAc)2 Cu(OAc)2 Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O
additive
additive
Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
K2CO3 Cs2CO3 K3PO4
Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 HBF4 Cu(OAc)2 Cu(OTf)2 Cu(OTf)2
H2O H2O H2O H2O H2O H2O
solvent
yield (%)b
THF THF THF THF i-PrOH dioxane DMF THF THF THF THF THF THF THF THF THF THF THF
15 38 59 21 20 30 45 30 32 20 N,Ni-Pr2, which is consistent with steric effect expected for weak Ocoordination in cationic Ru(II) catalysis.14 (4) Deuterium incorporation studies revealed reversibility of the C−H activation step (Scheme 4D).14 The observed amide selectivity (Scheme 4C) is particularly valuable, from the synthetic perspective, because it (i) complements the classic DoM mechanism,4,5 and (ii) allows access to ortho-arylated cyclic amides,11 which are prevalent motifs in pharmaceuticals and agrochemicals. Further studies to elucidate the mechanism are ongoing. Importantly, the C−H activation was carried out on a gram scale in high yield and with exquisite arylation selectivity (see Scheme 5), showing the robustness of our protocol and demonstrating potential for practical applications.14d
a
Conditions: amide (R′R″ = pyrrolidine, 0.2 mmol), [RuCl2(pcymene)]2 (5 mol %), AgSbF6 (20 mol %), PhB(OH)2 (2.5 equiv), Ag2O (2 equiv), Cu(OTf)2 (20 mol %), water (3 equiv), air, THF, 120 °C (0.20 M), 24 h. bIsolated yields. See Supporting Information for full details.
Scheme 2. C−H Arylation of Tertiary Amides: Scope of Nucleophilesa,b
a
See Scheme 1. bSee Supporting Information for full details.
See Scheme 1. bSee the Supporting Information for full details.
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DOI: 10.1021/acscatal.6b01360 ACS Catal. 2016, 6, 4755−4759
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Scheme 4. Mechanistic Studies
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was provided by Rutgers University. The Bruker 500 MHz spectrometer used in this study was supported by the NSF-MRI grant (No. CHE-1229030). We thank SEED Grant (Rutgers University) to the Center for Sustainable Synthesis for partial support of this project.
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Scheme 5. Large-Scale Arylation
In conclusion, we have demonstrated the first general method for highly selective ortho-C−H arylation of cyclic and N,N-dialkyl amides with boronic acids enabled by versatile ruthenium(II) complexes. Most notably, this new protocol features the first general C−H arylation of ubiquitous aromatic tertiary amides by weak O-coordination. The method provides the long-sought alternative to the classic DoM strategy, obviating the need for cryogenic conditions and the use of strong bases. The development of this coupling further highlights the beneficial use of inexpensive Ru(II) catalysts for C−H activation, while exploiting weakly coordinating directing groups. We anticipate that this strategy will find widespread use as a practical alternative to the classic DoM chemistry in organic synthesis. Further mechanistic studies and extension to a variety of coupling partners are currently underway in our laboratories.
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S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b01360. Procedures and analytical data (PDF) 4758
DOI: 10.1021/acscatal.6b01360 ACS Catal. 2016, 6, 4755−4759
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ACS Catalysis 1885−1898. (h) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087− 4109. (i) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17−117. (j) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726−11743. (k) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174−238. (10) Ir(III)/(V), diaryliodonium salts (one example): (a) Gao, P.; Guo, W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z. J. Am. Chem. Soc. 2015, 137, 12231−12240. Ir(III)/(V), diazonium salts (one example): (b) Shin, K.; Park, S. W.; Chang, S. J. Am. Chem. Soc. 2015, 137, 8584−8592. Pd(II)/(IV) (two examples, 8%−11%): (c) Neufeldt, S. R.; Sanford, M. S. Adv. Synth. Catal. 2012, 354, 3517− 3522. Ru(0)/(II) (
