Copper-Catalyzed Intermolecular Amidation and Imidation of Unactivated Alkanes

Abstract

We report a set of rare copper-catalyzed reactions of alkanes with simple amides, sulfonamides, and imides (i.e., benzamides, tosylamides, carbamates, and phthalimide) to form the corresponding N-alkyl products. The reactions lead to functionalization at secondary C–H bonds over tertiary C–H bonds and even occur at primary C–H bonds. [(phen)Cu(phth)] (1-phth) and [(phen)Cu(phth)2] (1-phth2), which are potential intermediates in the reaction, have been isolated and fully characterized. The stoichiometric reactions of 1-phth and 1-phth2 with alkanes, alkyl radicals, and radical probes were investigated to elucidate the mechanism of the amidation. The catalytic and stoichiometric reactions require both copper and tBuOOtBu for the generation of N-alkyl product. Neither 1-phth nor 1-phth2 reacted with excess cyclohexane at 100 °C without tBuOOtBu. However, the reactions of 1-phth and 1-phth2 with tBuOOtBu afforded N-cyclohexylphthalimide (Cy-phth), N-methylphthalimide, and tert-butoxycyclohexane (Cy-OtBu) in approximate ratios of 70:20:30, respectively. Reactions with radical traps support the intermediacy of a tert-butoxy radical, which forms an alkyl radical intermediate. The intermediacy of an alkyl radical was evidenced by the catalytic reaction of cyclohexane with benzamide in the presence of CBr4, which formed exclusively bromocyclohexane. Furthermore, stoichiometric reactions of [(phen)Cu(phth)2] with tBuOOtBu and (Ph(Me)2CO)2 at 100 °C without cyclohexane afforded N-methylphthalimide (Me-phth) from β-Me scission of the alkoxy radicals to form a methyl radical. Separate reactions of cyclohexane and d12-cyclohexane with benzamide showed that the turnover-limiting step in the catalytic reaction is the C–H cleavage of cyclohexane by a tert-butoxy radical. These mechanistic data imply that the tert-butoxy radical reacts with the C–H bonds of alkanes, and the subsequent alkyl radical combines with 1-phth2 to form the corresponding N-alkyl imide product.

Efficient synthesis of 2-arylquinazolines via copper-catalyzed dual oxidative benzylic CH aminations of methylarenes

“…On the basis of the above results and the previous reports [39][40][41][42][43][44][45][46][47][48][49][50], a plausible catalytic cycle of this transformation is proposed (Scheme 2). Initially, the coordination of 1a to one Cu II species and subsequent ligand exchange generates the copper complex A, which forms the benzyl/Cu II species B by benzylic C-H activation.…”

“…Recently, transition-metal-catalyzed oxidative aminations of sp 3 C-H bond have emerged as important methods for C-N bond formations because of short steps and atom-economical advantages [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. In particular, copper as an inexpensive and lowly toxic metal catalyst, has been employed to catalyze the formation of C-N bond via a sp 3 C-H amination [39][40][41][42][43][44][45][46][47][48][49]. For instance, copper-catalyzed cascade coupling of 2-halobenzaldehyde with acetamidine hydrochloride (or benzaldehyde) to construct C-N bond was reported [53][54].…”

Metal-Catalyzed and Metal-Free Intermolecular Amination of Light Alkanes and Benzenes

“…Two closely related studies by Hartwig 58 and Kanai 59 examine copper-catalyzed reactions of light alkanes (among other substrates) with various primary and secondary amides, carbamates, phthalimides, and isocyanates, using di- tert -butyl peroxide as oxidant. In contrast to the cases noted above, in which a putative metal-nitrene species is considered responsible for H-atom abstraction, the Hartwig and Kanai systems engage t ert-butoxy radicals as the primary H-atom abstraction entities.…”

“…Hartwig’s study 58 explores the benzamidation of two light alkanes, 3-ethylpentane and 2,4-dimethylpentane, used in excess (1.0 mL), in the presence of t BuOO t Bu (4.0 equiv.) (Scheme 13(a)).…”

Chiral Counterion Strategy in Cu-Catalyzed Asymmetric Allylic Oxidation of Linear Alkenes

“…Cyclohexene afforded the corresponding allylic benzoate 4, while in the case of terminal alkene 2, selective formation of a branched isomer 5 was observed (5/6 ratio 99:1). The mechanistic aspects of this reaction were later investigated by experimental and theoretical methods [5][6][7][8][9][10][11][12]. As compounds 4 and 5 feature a stereogenic centre, attempts at the asymmetric variant of this transformation soon followed, though these early efforts met with limited success [13,14].…”