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. 2018 Oct 3;140(39):12415-12423.
doi: 10.1021/jacs.8b05143. Epub 2018 Sep 19.

Cation-π Interactions in the Benzylic Arylation of Toluenes With Bimetallic Catalysts

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Free PMC article

Cation-π Interactions in the Benzylic Arylation of Toluenes With Bimetallic Catalysts

Sheng-Chun Sha et al. J Am Chem Soc. .
Free PMC article

Abstract

A method to directly arylate toluene derivatives with aryl bromides to generate diarylmethanes, which are important building blocks in drug discovery, is described. In this method, KN(SiMe3)2 in combination with a (NIXANTPHOS)Pd catalyst accomplished the deprotonative activation of toluene derivatives to permit cross-coupling with aryl bromides. Good to excellent yields are obtained with a range of electron-rich to neutral aryl bromides. Both electron-rich and electron-poor toluene derivatives are well tolerated, and even 2-chlorotoluene performs well, providing a platform for introduction of additional functionalization. This discovery hinges on the use of a main group metal to activate toluene for deprotonation by means of a cation-π interaction, which is secured by a bimetallic K(NIXANTPHOS)Pd assembly. Mechanistic and computational studies support acidification of toluene derivatives by the K+-cation- π interaction, which may prove pertinent in the development of other, new reaction systems.

Figures

Figure 1.
Figure 1.
A) Structures of neutral and deprotonated NIXANTPHOS and Xantphos, B–C) Arylation of 2-benzylfuran, cation and crown ether dependent selectivity and D) Calculated cation-π interaction.
Figure 2.
Figure 2.
Relative Gibbs free energies and enthalpies (in brackets) for deprotonation of toluene relative to corresponding oligomeric intermediates, kcal/mol. Values calculated with SMD-toluene-M06/6–311+G(d,p)//B3LYP/6–31G(d).
Figure 3.
Figure 3.
Relative Gibbs free energies and enthalpies (in parenthesis) of ligand-assisted deprotonation of toluene, kcal/mol. Values calculated with SMD-toluene-M06/6–311+G(d,p)/Pd:LANL2DZ //B3LYP/6–31G(d)/Pd:LANL2DZ relative to the isolated dimeric base units, toluene and deprotonated ligand.
Figure 4.
Figure 4.
Relative Gibbs free energies and enthalpies (in brackets) of ligand-assisted deprotonation of toluene, kcal/mol. Values calculated with SMD-toluene-M06/6–311+G(d,p)/Pd,Br: LANL2DZ //B3LYP/6–31G(d)/Pd,Br: LANL2DZ relative to corresponding oligomeric intermediates
Figure 5.
Figure 5.
Relative Gibbs free energies and enthalpies (in parenthesis) of deprotonation of toluene in Br and Cl systems, kcal/mol. Values calculated with SMD-toluene-M06/6–311+G(d,p),Pd:LANLl2DZ//B3LYP/6–31G(d),Pd:LANL2DZ
Figure 6.
Figure 6.
PM6-optimized transition states of deprotonation of toluene derivatives. The relative values of rate constants are provided.
Scheme 1.
Scheme 1.
Copper catalyzed activation of toluenes.
Scheme 2.
Scheme 2.
Ideal Dual Catalytic Cycle for Toluene Activation
Scheme 3.
Scheme 3.. Arylation of Toluene with Aryl Bromidesa
a Reactions conducted on a 0.1 mmol scale b 5 mol % Catalyst was used.
Scheme 4.
Scheme 4.. Arylation of Toluene Derivativesa
a Reactions conducted on a 0.1 mmol scale b Reactions conducted with 1:1 mixture of Buchwald Pd G3 dimer and NIXANTPHOS.
Scheme 5.
Scheme 5.
Deprotonation Study - Benzylation
Scheme 6.
Scheme 6.
Reactivity of the 4-tert-butyltoluene

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