Transition-Metal-Catalyzed, Coordination-Assisted Functionalization of Nonactivated C(sp³)–H Bonds

Abstract

Transition-metal-catalyzed, coordination-assisted C(sp 3 )−H functionalization has revolutionized synthetic planning over the past few decades as the use of these directing groups has allowed for increased access to many strategic positions in organic molecules. Nonetheless, several challenges remain preeminent, such as the requirement for high temperatures, the difficulty in removing or converting directing groups, and, although many metals provide some reactivity, the difficulty in employing metals outside of palladium. This review aims to give a comprehensive overview of coordination-assisted, transitionmetal-catalyzed, direct functionalization of nonactivated C(sp 3 )−H bonds by covering the literature since 2004 in order to demonstrate the current state-of-the-art methods as well as the current limitations. For clarity, this review has been divided into nine sections by the transition metal catalyst with subdivisions by the type of bond formation. Synthetic applications and reaction mechanism are discussed where appropriate.

Experimental and Theoretical Study of NiII‐ and PdII‐Promoted Double Geminal C(sp3)−H Bond Activation Providing Facile Access to NHC Pincer Complexes: Isolated Intermediates and Mechanism

“…[58][59][60][61][62][63] The activation and functionalization of C sp 3À H bonds remain targets of considerable interest but are often challenging because of the low reactivity associated to the non-acidic character of these bonds. [64][65][66][67] Among the diverse CÀ H activation methods available, [64,68] those leading to carbenetransition metal complexes, [69] or promoted by NHC-transition metal complexes have been recently reviewed. [5,70] Palladium complexes are most competent for achieving the activation/ functionalization of non-activated C sp 3À H bonds and because of steric hindrance during the CÀ H metalation step, methylene C sp 3À H bonds are generally more difficult to functionalize than primary C sp 3À H bonds.…”

“…[5,70] Palladium complexes are most competent for achieving the activation/ functionalization of non-activated C sp 3À H bonds and because of steric hindrance during the CÀ H metalation step, methylene C sp 3À H bonds are generally more difficult to functionalize than primary C sp 3À H bonds. [67] The first report of the double C sp 3À H bond activation of a methylene group described the reaction of an alkyl diphosphine with IrCl 3 to give pincer carbene complexes. [71] Other PCP pincer complexes in which the central donor has carbene character have been successfully prepared, often in moderate yield, by double CÀ H bond activation with Fe 0 , [72] Ru II , [73][74][75] Os IV , [74] Rh I , [76,77] Ir I , [76,78] Ni II , [79] and Pd II precursor complexes.…”

“…The activation and functionalization of C −H bonds remain targets of considerable interest but are often challenging because of the low reactivity associated to the non‐acidic character of these bonds [64–67] . Among the diverse C−H activation methods available, [64,68] those leading to carbene‐transition metal complexes, [69] or promoted by NHC‐transition metal complexes have been recently reviewed [5,70] .…”

“…Among the diverse C−H activation methods available, [64,68] those leading to carbene‐transition metal complexes, [69] or promoted by NHC‐transition metal complexes have been recently reviewed [5,70] . Palladium complexes are most competent for achieving the activation/functionalization of non‐activated C −H bonds and because of steric hindrance during the C−H metalation step, methylene C −H bonds are generally more difficult to functionalize than primary C −H bonds [67] . The first report of the double C −H bond activation of a methylene group described the reaction of an alkyl diphosphine with IrCl 3 to give pincer carbene complexes [71] .…”

Transition‐Metal‐Catalyzed Remote C(sp3)−H Functionalization Of Carboxylic Acid And Its Derivatives

“…Recently, several groups successfully demonstrated γ-C-(sp 3 )À H bond functionalization of carboxylic acid and its derivatives using transition metal catalysis, [73] however δ-C(sp 3 )À H functionalization is still in its infancy. Although, few reviews are available on remote CÀ H functionalization, [74][75][76][77][78] a focused and detailed review on remote C(sp 3 )À H functionalization of carboxylic acid and its derivative was missing (Scheme 2).…”