Oxidative γ-Addition of Enals to Trifluoromethyl Ketones: Enantioselectivity Control via Lewis Acid/N-Heterocyclic Carbene Cooperative Catalysis

Abstract

An oxidative γ-functionalization of enals under N-heterocyclic carbene (NHC) catalysis to give unsaturated δ-lactones is disclosed. Enantioselectivity control involving the relatively remote enal γ-carbon was achieved via Lewis acid [Sc(OTf)(3) or combined Sc(OTf)(3)/Mg(OTf)(2)] and NHC cooperative catalysis.

Benzene construction via organocatalytic formal [3+3] cycloaddition reaction

“…We started by using enal 1a and enone 2a as the model substrates, in the presence of 2 equiv. quinone 4 as an oxidant [29][30][31][32][33] and Cs 2 CO 3 as a base. No formation of the proposed benzene 3a was observed in the absence of an NHC precatalyst (Table 1, entry 1).…”

“…Briefly, addition of the carbene catalyst to the aldehyde moiety of enal followed by deprotonation forms Breslow intermediate I [26][27][28] . This process is followed by oxidative transformation [29][30][31][32][33] , and former enal g-CH deprotonation 33 moiety. Subsequent g-CH deprotonation of IV lead to dienolate intermediate V that undergoes an intramolecular aldol to form a cyclic intermediate VI.…”

Metal and carbene organocatalytic relay activation of alkynes for stereoselective reactions

“…2a, while strong bases (such as NaH, KO t Bu, DBU) promote the formation of NHC-Cu complex B from the corresponding triazolium NHC pre-catalyst A and CuI, weak bases (such as TEA, DIEA, K 2 CO 3 ) led to little NHC-Cu complex after several hours. In our prior studies 27,[33][34][35] , it is known that weak bases such as DIEA or K 2 CO 3 are sufficient for the deprotonation of triazoliums to form the carbene catalyst. We therefore concluded that under 'weak' base conditions, there is a controllable kinetic/thermodynamic window that allows the carbene organocatalyst and Cu metal catalyst to co-exist with a meaningful level of concentrations.…”

“…Several efforts have been directed towards addressing such metal/organic catalysts' quenching issues. These efforts include the use of step-by-step protocols of sequential addition of catalysts 23 , the introduction of additional coordinating ligands to compete with the organocatalysts 24,25 and the use of early transition metals that do not show strong-coordinating properties 26,27 .…”

“…To the best of our knowledge, a simple combination of transition metal such as copper and strong-coordinating NHC (as organocatalyst) remains challenging and elusive [23][24][25][26][27] . Here we report the first success in using Cu and NHC cooperative catalysis for a direct activation of alkyne for stereoselective reactions (Fig.…”