Ligand-Accelerated ortho-C–H Alkylation of Arylcarboxylic Acids using Alkyl Boron Reagents

Abstract

A protocol for the Pd(II)-catalyzed ortho-C–H alkylation of phenylacetic and benzoic acids using alkylboron reagents is disclosed. Mono-protected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was also investigated.

A Simple and Versatile Amide Directing Group for C−H Functionalizations

“…Our early development of the catalytic cycle for Pd(II)-catalyzed coupling of C–H bonds with organometallic reagents including organotin [9] and organoboron reagents [10,11a] prompted us to extend this catalytic reaction to simple substrates such as carboxylic acids. While the ortho -C(sp 2 )–H coupling of benzoic acids and phenyl acetic acids afford high yields, [11] the coupling of the β-C(sp 3 )–H bonds in aliphatic acids with organoboron compounds is inefficient due to the homo-coupling of the organoboron reagents prior to C–H activation.…”

“…While the ortho -C(sp 2 )–H coupling of benzoic acids and phenyl acetic acids afford high yields, [11] the coupling of the β-C(sp 3 )–H bonds in aliphatic acids with organoboron compounds is inefficient due to the homo-coupling of the organoboron reagents prior to C–H activation. [11a] Considering the utility and availability of aryl and alkyl boronic acid reagents, we set out to overcome this limitation. We reasoned, while the weakly coordinating potassium carboxylate is capable of directing C–H activation, the side reaction of the aryl or alkyl boronic acids with Pd(II) is more facile.…”

“…Based on structural information regarding the coordination of alkali carboxylates with Pd(II), [11,12] we proposed that the alkali carboxylate coordinates with Pd(II) as a neutral σ-donor in the transition state (Scheme 3). We therefore envisioned that a more Lewis basic carboxylate mimetic could bind to Pd(II) more efficiently, minimizing homo-coupling background reactions of boronic acid derivatives in Pd(II)/Pd(0) catalytic manifolds.…”

“…Although Pd-catalyzed coupling of C–H bonds with organometallic reagents have been extensively studied since 2005, [9,10,11] analogous transformation using Rh(III) catalysts have not been fully established. In 2012, the Cheng group reported a rare example of such a catalytic transformation through which phenanthridinones could be prepared from the Rh(III)-catalyzed C(sp 2 )–H coupling with aryl boronic acids using the N-methoxy amide directing group.…”

Improving Transformations Through Organotrifluoroborates

“…In the presence of Pd, C-H activation on an arene ortho to an activating group (e.g., carboxylic acid or amide) allows subsequent alkylation using alkyltrifluoroborate substrates [65,66]. The addition of n-BuBF 3 K to a variety of phenylacetic acid derivatives was demonstrated, and it was noted that the presence of an aryl chloride did not inhibit the reaction.…”