Direct α-Functionalization of Simple Aldehydes via Oxidative N-Heterocyclic Carbene Catalysis

Abstract

A direct α-functionalization of simple aldehydes under N-Heterocyclic Carbene (NHC) catalysis and direct generation of ester enolate equivalents from nonfunctionalized aldehydes are disclosed. The catalysis involves selective enolate generation from an oxidatively generated NHC-bounded ester intermediate as a key step. The ester enolate intermediates undergo stereoselective reactions with enones and trifluoromethyl ketones.

Direct β‐Activation of Saturated Aldehydes to Formal Michael Acceptors through Oxidative NHC Catalysis

“…Notably, CÀH activation involving the b-carbon atom of saturated esters and amides is pursued by several groups employing transitionmetal catalysis. This transformation (II!III) was reported in our earlier work on ester activation [6] and in the recent studies by Rovis and co-workers [3] and our group [4] on oxidative NHCcatalyzed a-functionalization of aldehydes. [13] Despite the impressive progress, catalytic direct b-activation of saturated carbonyl compounds has largely remained underdeveloped, and new strategies that contribute to this subject should be of broad interests.…”

“…[8a] Lupton and co-workers have recently pioneered the NHC-mediated activation of a,bunsaturated enol ester and acyl fluorides for eventual functionalizations of the b-sp 2 carbon atoms. This transformation (II!III) was reported in our earlier work on ester activation [6] and in the recent studies by Rovis and co-workers [3] and our group [4] on oxidative NHCcatalyzed a-functionalization of aldehydes. [11] Several catalytic approaches are available for the direct activation of a-carbon atoms of carbonyl compounds (and bsp 2 carbon atoms of unsaturated carbonyl compounds), but the direct activation of the typically inert b-C(sp 3 ) of saturated carbonyl compounds is challenging.…”

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Saturated carbonyl compounds, such as aldehydes and esters, are basic building blocks for the synthesis of organic molecules and materials. Very recently, Rovis and co-workers [3] and our laboratory [4] independently reported a-carbon functionalization of saturated aldehydes through oxidative catalysis mediated by N-heterocyclic carbenes (NHCs). In organocatalysis, several powerful approaches have been developed for the asymmetric functionalization of a-CH of aldehydes and esters.

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A reaction mode of carbene-catalysed aryl aldehyde activation and induced phenol OH functionalization

“…Notably, in the gram scale synthesis, the use of 1 mol% NHC precatalyst was sufficient to produce 3b (1.5 g) in 98% yield and with 96:4 e.r. Additionally, the organic oxidant ( DQ ) could be used in catalytic amount by using inexpensive MnO 2 as a terminal oxidant43 (Fig. 3b).…”

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

“…Surprisingly,t he direct catalytic enantioselective aldol reaction [3,4] engaging a-fluorinated ketones and a-oxygenated carbonyl compounds is little explored. [6][7][8][9] Whereas amides and carboxylic acids,w hich are regarded as more challenging aldol donor substrates in terms of reluctant enolization, have been incorporated in the direct aldol reaction manifold, [10] no enantioselective variants have been reported (Scheme 1b). [6][7][8][9] Whereas amides and carboxylic acids,w hich are regarded as more challenging aldol donor substrates in terms of reluctant enolization, have been incorporated in the direct aldol reaction manifold, [10] no enantioselective variants have been reported (Scheme 1b).…”