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. 2010 Oct 13;132(40):14137-51.
doi: 10.1021/ja105044s.

Ligand-accelerated C-H activation reactions: evidence for a switch of mechanism

Keary M Engle  1 , Dong-Hui Wang, Jin-Quan Yu
Affiliations

Ligand-accelerated C-H activation reactions: evidence for a switch of mechanism

Keary M Engle et al. J Am Chem Soc. .

Abstract

Initial rate studies have revealed dramatic acceleration in aerobic Pd(II)-catalyzed C-H olefination reactions of phenylacetic acids when mono-N-protected amino acids are used as ligands. In light of these findings, systematic ligand tuning was undertaken, which has resulted in drastic improvements in substrate scope, reaction rate, and catalyst turnover. We present evidence from intermolecular competition studies and kinetic isotope effect experiments that implies that the observed rate increases are a result of acceleration in the C-H cleavage step. Furthermore, these studies suggest that the origin of this phenomenon is a change in the mechanism of C-H cleavage from electrophilic palladation to proton abstraction.

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Figures

Scheme 1
Scheme 1
The versatile reactivity of [Pd(II)–R] intermediates.
Scheme 2
Scheme 2
Depiction of three scenarios for the pre-transition state coordination structures prior to Pd(II)-mediated C–H cleavage: (I) The substrate contains a strong directing group (DG) and is dominantly bound to Pd(II), precluding ligand (L) coordination. The reaction may take place, but the transition state energy for C–H cleavage will be unaffected by the ligand. (II) The substrate and ligand possess matched coordinative affinities for Pd(II), allowing one molecule of each to bind. The reaction may take place, and the transition state energy for C–H cleavage will be affected by ligand binding. (III) The ligand is a strong σ-donor and outcompetes substrate molecules for coordination to Pd(II). The reaction will not take place.
Scheme 3
Scheme 3
Preliminary results for ligand-promoted C–H olefination of 1.
Scheme 4
Scheme 4
Gram-scale synthesis of 1a using 0.2 mol% Pd(OAc)2 and 1 atm O2.
Scheme 5
Scheme 5
A representative example of our previously reported 2,6-diolefination reaction of phenylacetic acids using Ac-Val-OH.
Scheme 6
Scheme 6
Mechanistic hypothesis to explain the preferential formation of 1f, rather than the thermodynamically favored conjugated product.
Scheme 7
Scheme 7
Mechanistic models for the C–H cleavage transition state with Pd(II).
Scheme 8
Scheme 8
Conceptually relevant proton abstraction mechanistic proposals for Pd(0)/ArX catalytic systems.
Scheme 9
Scheme 9
Qualitative evidence for a change in the mechanism of C–H cleavage: C–H activation of highly electron-deficient arenes in the presence of Ac-Ile-OH.
Scheme 10
Scheme 10
Possible mechanisms for C–H cleavage without ligands: electrophilic palladation (H), oxidative addition (I), and proton abstraction (J).
Scheme 11
Scheme 11
Possible mechanisms for C–H cleavage: (K and L) electrophilic palladation, (M) oxidative addition, (N–P) and proton abstraction.
Scheme 12
Scheme 12
Proposed catalytic cycle.
Figure 1
Figure 1
Initial rate studies of C–H olefination of o-trifluoromethylphenylacetic acid (1). BQ (5 mol%) and Boc-Val-OH (10 mol%). Each data point represents the average of three trials, with the exception of the Boc-Val-OH trials from 60 min to 120 min, which represent single trials. See Supporting Information for experimental details.
Figure 2
Figure 2
Kinetic studies of C–H olefination of o-tolylacetic acid (2). BQ (5 mol%) and Boc-Val-OH (10 mol%). Each data point represents the average of three trials, with the exception of the Boc-Val-OH trials from 60 min to 120 min, which represent single trials. See Supporting Information for experimental details.
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