General Method for the Suzuki–Miyaura Cross ... - ACS Publications

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General Method for the Suzuki−Miyaura Cross-Coupling of Amides Using Commercially Available, Air- and Moisture-Stable Palladium/ NHC (NHC = N‑Heterocyclic Carbene) Complexes Peng Lei,‡,† Guangrong Meng,‡ and Michal Szostak* Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States S Supporting Information *

ABSTRACT: The direct Suzuki−Miyaura cross-coupling of amides catalyzed by Pd-NHC complexes is reported. Using a single protocol, commercially available, air- and moisturestable (NHC)Pd(R-allyl)Cl complexes can effect Suzuki− Miyaura cross-coupling of a wide range of amides with arylboronic acids in very good yields. The studies described herein represent the use of versatile Pd-NHC complexes as catalysts for transition-metal-catalyzed cross-coupling of amides by N−C bond activation. The Pd-NHC catalysts provide a significant improvement over all current Pd-PR3 systems employed for the amide N−C bond activation. Mechanistic studies provide strong support for the development of a unified reactivity scale of the amide bond for the generation of acyl-metal intermediates. KEYWORDS: palladium, N-heterocyclic carbenes (NHCs), N−C activation, Suzuki−Miyaura cross-coupling, amides

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remendous progress has been made in the past years in the area of transition-metal-catalyzed cross-coupling

Figure 2. Structures of carbene ligands and Pd-NHC catalysts. (Dipp = 2,6-diisopropylphenyl; Mes = mesityl; Cy = cyclohexyl.)

Cross-coupling of aryl electrophiles, including activation of C−O7 and C−N bonds,8 has been extensively studied.1−3 There has been an increasing effort to activate alternative carboxylic acid cross-coupling partners under oxidant-free conditions.9 In particular, amide bond cross-coupling benefits from the high bench stability of the amide precursors, biomedical relevance of the amide bond, and the ability to fine-tune the electrophilic reactivity by the tricoordinate N center unavailable in other precursors.7,10 Following the seminal report by Garg and co-workers on the C−O bond formation from amides,11 we and others have sought to address the challenges posed by amidic resonance (nN → πCO * barrier to rotation of ca. 15−20 mol/kcal in planar amides).12−19

Figure 1. Amides as electrophiles in TM catalyzed C−C crosscoupling: attractive alternative to stoichiometric Weinreb synthesis.

reactions.1 Within palladium catalysis, typically, electron-rich tertiary phosphines have been employed as ancillary ligands to enable cleavage of unreactive carbon−carbon or carbon− heteroatom bonds.2 Nucleophilic N-heterocyclic carbenes (NHCs) have been developed as another dominant direction in the cross-coupling arena.3 Specifically, the strong σ-donation and variable steric bulk around the metal center facilitate oxidative addition and reductive elimination steps enabling a range of challenging cross-couplings.4,5 However, so far, harnessing the reactivity of Pd-NHC complexes to enable selective cross-coupling by activation of inert C−N bonds in amides has not been used as a strategy for organic synthesis.6 © XXXX American Chemical Society

Received: December 21, 2016 Revised: January 30, 2017

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DOI: 10.1021/acscatal.6b03616 ACS Catal. 2017, 7, 1960−1965

Letter

ACS Catalysis Table 1. Optimization of the Reaction Conditionsa

entry

amide

1 2 3 4 5 6 7 8 9 10 11 12 13 14c 15d 16 17 18 19 20 21e 22f 23g 24h 25i 26 27 28 29 30 31 32 33 34

1b 1b 1b 1c 1c 1c 1a 1a 1a 1b 1c 1a 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1c 1a 1b 1c 1a 1b 1c 1a

catalyst

ligand

Pd(OAc)2 IMesHCl Pd(OAc)2 IPrHCl Pd(OAc)2 ICyHBF4 Pd(OAc)2 IMesHCl Pd(OAc)2 IPrHCl Pd(OAc)2 ICyHBF4 Pd(OAc)2 IMesHCl Pd(OAc)2 IPrHCl Pd(OAc)2 ICyHBF4 (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(allyl)Cl (IPr)Pd(allyl)Cl (IPr)Pd(allyl)Cl (SIPr)Pd(cinnamyl)Cl (SIPr)Pd(cinnamyl)Cl (SIPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl (IPr)Pd(cinnamyl)Cl

base

temperature, T (°C)

yield (%)b

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 K3PO4 KF KOH NaOt-Bu K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

110 110 110 110 110 110 110 110 110 60 60 60 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 60 60 40 40 40