384
various heteroatom-based substituents, e.g., O-, N-, S-, Se-, halogen-, B-, Si-, and
recently Ge-based groups.
Keywords Hetero-functionalization · C–H bond cleavage · Carboxylic acid esters
· Bidentate · Monodentate
1 Introduction
Aliphatic carboxylic acid equivalents/derivatives, particularly embracing
heteroatom- based substituents positioned at diverse carbon centers (e.g., α-, β-, γ-,
δ-, etc.) in the alkyl residue, possess tremendous applications in fine chemicals and
pharmaceutical industries [1–13]. Traditional methods to access those elegant molecules demand multistep synthetic protocols employing practically inconvenient
and frequently hazardous operational conditions that produce large quantity of nondisposable chemical wastes. The concept of transition metal-catalyzed direct functionalizations by cleaving of a specific C–H bond has recently emerged as an
attractive tool for installing heteroatom-based groups onto an aliphatic carboxylic
acid substrate under mild and environmentally benign conditions [14–21]. However,
the latter class of transformation holds several fundamental challenges owing to the
robust nature and intrinsic inertness of aliphatic C–H bonds (BDE = ~90−100 kcal/
mol, pKa = ~45−60, etc.). The decisive cleavage with succeeding functionalization
of a specific C−H bond of alkanes in the presence of numerous chemically identical
C–H bonds also seems extremely intricate [15]. Two independent approaches are
generally conceived to realize the transition metal-catalyzed C–H bond functionalization of carboxylic acid derivatives directly [22–25]: (1) a directed approach in
which the carboxylate counterpart pre-associates with the metal catalyst to hold it in
the proximity of the cleavable C(sp
3
)–H bond, thereby promoting the heterofunctionalization process at the distal-selective β-, γ-, and/or even δ-positions, and
(2) a non-directed C(sp
3
)–H hetero-functionalization approach, which commonly
proceeds through the formation of a stabilized enol or carbon-centered radical intermediate typically resulting in α-functionalized carboxylic acid synthons. The present chapter sketches the advances in the field of transition metal-catalyzed C(sp
3
)–H
bond hetero-functionalization of aliphatic carboxylic acid equivalents. Due to considerable progress in recent years, only frequently employed transition metals,
including palladium, iridium, nickel, copper, iron, and cobalt, which promoted reactions have been described.
2 Directed C(sp
3
)–H Hetero-functionalization Approaches
In directed hetero-functionalization approaches, the carboxylate equivalent of the
substrate serves as a polar chelating metal template that assists to form a five- or
six-membered metallacycle intermediate via the selective activation of the β- or
A. Gupta et al.
various heteroatom-based substituents, e.g., O-, N-, S-, Se-, halogen-, B-, Si-, and
recently Ge-based groups.
Keywords Hetero-functionalization · C–H bond cleavage · Carboxylic acid esters
· Bidentate · Monodentate
1 Introduction
Aliphatic carboxylic acid equivalents/derivatives, particularly embracing
heteroatom- based substituents positioned at diverse carbon centers (e.g., α-, β-, γ-,
δ-, etc.) in the alkyl residue, possess tremendous applications in fine chemicals and
pharmaceutical industries [1–13]. Traditional methods to access those elegant molecules demand multistep synthetic protocols employing practically inconvenient
and frequently hazardous operational conditions that produce large quantity of nondisposable chemical wastes. The concept of transition metal-catalyzed direct functionalizations by cleaving of a specific C–H bond has recently emerged as an
attractive tool for installing heteroatom-based groups onto an aliphatic carboxylic
acid substrate under mild and environmentally benign conditions [14–21]. However,
the latter class of transformation holds several fundamental challenges owing to the
robust nature and intrinsic inertness of aliphatic C–H bonds (BDE = ~90−100 kcal/
mol, pKa = ~45−60, etc.). The decisive cleavage with succeeding functionalization
of a specific C−H bond of alkanes in the presence of numerous chemically identical
C–H bonds also seems extremely intricate [15]. Two independent approaches are
generally conceived to realize the transition metal-catalyzed C–H bond functionalization of carboxylic acid derivatives directly [22–25]: (1) a directed approach in
which the carboxylate counterpart pre-associates with the metal catalyst to hold it in
the proximity of the cleavable C(sp
3
)–H bond, thereby promoting the heterofunctionalization process at the distal-selective β-, γ-, and/or even δ-positions, and
(2) a non-directed C(sp
3
)–H hetero-functionalization approach, which commonly
proceeds through the formation of a stabilized enol or carbon-centered radical intermediate typically resulting in α-functionalized carboxylic acid synthons. The present chapter sketches the advances in the field of transition metal-catalyzed C(sp
3
)–H
bond hetero-functionalization of aliphatic carboxylic acid equivalents. Due to considerable progress in recent years, only frequently employed transition metals,
including palladium, iridium, nickel, copper, iron, and cobalt, which promoted reactions have been described.
2 Directed C(sp
3
)–H Hetero-functionalization Approaches
In directed hetero-functionalization approaches, the carboxylate equivalent of the
substrate serves as a polar chelating metal template that assists to form a five- or
six-membered metallacycle intermediate via the selective activation of the β- or
A. Gupta et al.