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. 2012 Jan 1;3(1):192-197.
doi: 10.1039/C1SC00397F.

The effect of the N-mesityl group in NHC-catalyzed reactions

Jessada Mahatthananchai, Jeffrey W Bode

The effect of the N-mesityl group in NHC-catalyzed reactions

Jessada Mahatthananchai et al. Chem Sci. .

Abstract

The majority of N-heterocyclic carbene catalyzed reactions of α-functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with N-mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the N-mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate. These studies rationalize the experimentally observed catalyst preference for all classes of NHC-catalyzed reactions of aldehydes and provide a roadmap for catalyst selection and design.

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Figures

Figure 1
Figure 1
Extent of deprotonation of azolium salts 1 and 2. A) 1H NMR spectra of DBU in CD2Cl2 as reference; B) and D) 1H NMR spectra of triazolium salts 1 and 2; C) and E) 1H NMR spectra of triazolium salts following addition of 1.0 equiv DBU.
Figure 2
Figure 2
A proposed theory and mechanistic probes
Figure 3
Figure 3
Roadmap for triazolium selection for the reaction modes available from NHC catalyzed reactions of aldehydes
Scheme 1
Scheme 1
Redox esterification of enal in the absence of base
Scheme 2
Scheme 2
Irreversible formation of the Breslow intermediate
Scheme 3
Scheme 3
Redox esterifications of α-functionalized aldehydes
Scheme 4
Scheme 4
NHC catalyzed esterifications
Scheme 5
Scheme 5
Titration of azoliums with DBU and cinnamaldehyde
Scheme 6
Scheme 6
Hydride transfer oxidative esterification comparison (reaction via initial adduct)
Scheme 7
Scheme 7
Comparison of reactions catalyzed by 1, 1,’ 2, and 2’
See this image and copyright information in PMC

References

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    1. For recent reviews on NHC catalysis, see Chiang P-C, Bode JW. N-Heterocyclic Carbenes. The Royal Society of Chemistry; 2011. pp. 399–435. Moore JL, Rovis T. Top. Curr. Chem. 2009;291:77–144. Nair V, Vellalath S, Babu BP. Chem. Soc. Rev. 2008;37:2691–2698. Enders D, Niemeier O, Henseler A. Chem. Rev. 2007;107:5606–5655.

    1. For the first report of a N-mesityl substituted triazolium precatalyst, see Sohn SS, Bode JW. Org. Lett. 2005;7:3873–3876. For the first chiral variant, see He M, Struble JR, Bode JW. J. Am. Chem. Soc. 2006;128:8418–8420. For the synthesis of N-mesityl triazolium salts, see: Struble JR, Bode JW. Org. Synth. 2010;87:362–376.