A Direct Intermolecular Cross‐Benzoin Type Reaction: N‐Heterocyclic Carbene‐Catalyzed Coupling of Aromatic Aldehydes with Trifluoromethyl Ketones

Abstract

A direct intermolecular cross-benzointype condensation catalyzed by an N-heterocyclic carbene has been developed. The cross-coupling of commercially available aromatic aldehydes and trifluoromethyl ketones results in a-hydroxy-a-trifluoromethyl ketones bearing a quaternary stereocenter with excellent chemoselectivity and good to excellent yields.Keywords: cross-benzoin reaction; N-heterocyclic carbenes; organocatalysis; trifluoromethyl substitution; umpolungIn their pioneering and historic paper on the benzoyl compounds of 1832 [1] Wçhler and Liebig not only started the chemistry of aromatic compounds, such as benzaldehyde, benzoic acid, benzoyl chloride and benzamide, but also reported the cyanide-catalyzed (bitter almond oil) formation of benzoin, which in a sense can be seen as the start of organocatalysis. Since these early days of organic chemistry, the cyanide-and later carbene-catalyzed coupling of two aldehyde molecules to form the corresponding a-hydroxy ketones (benzoin, acyloin) has been investigated extensively. [2] Although significant progress has been made with enantioselective and intramolecular versions in recent years, [3] there still are limitations in the intermolecular coupling of two different aldehydes and of aldehydes with ketones. In these cases the outcome is typically a mixture of all possible symmetrical and unsymmetrical acyloins, with the chemoselectivity strongly depending on the relative thermodynamic stability of the corresponding products.[4] In order to overcome this problem several research groups have made excellent contributions by developing enzymatic approaches [5] or utilizing acylsilanes [6] and acylphosphonates [7] as acyl anion equivalents in cyanide-catalyzed transformations. In addition, very recently Scheidt et al. reported intermolecular cross-acyloin reactions by fluoride-promoted addition of O-silylthiazolium salts.[8] However, to the best of our knowledge, there is no precedent for a direct organocatalytic intermolecular coupling of aldehydes with ketones, which we would like to report in this communication.Based on our mechanistic proposal for the Stetter reaction, which relies on a reversible formation of the benzoin product prior to the Stetter product formation, [9] we envisaged to use benzoins as masked aldehyde equivalents.[10] To our delight, benzoin (1) in combination with an excess of trifluoroacetophenone (2) as reactive electrophilic ketone component led chemoselectively to the crossed acyloin product 3 in high yield, employing 20 mol% of the bicyclic triazolium salt 4[11] as precatalyst in the presence of 20 mol% DBU in THF at room temperature (Scheme 1).Since the crossed acyloin product 3 containing a tertiary alcohol seemed to be energetically preferred relative to benzoin (1) a simpler and more practical version of this concept would be to employ the aldehyde component directly in this transformation (Scheme 2). Under the reaction conditions given (10 mol% carbene precursor 4 and 10 mol% DBU), it was indeed possible to obtain the cross-co...

Enantioselective Intermolecular Aldehyde–Ketone Cross‐Coupling through an Enzymatic Carboligation Reaction

“…[7,8] Most recently, Enders and Henseler described the direct intermolecular cross-coupling between aldehydes and trifluoromethyl ketones using a bicyclic triazolium salt as the catalyst. [9] The asymmetric intermolecular non-enzymatic coupling reaction with ketone acceptors should be more difficult, owing to the lower electrophilicity of the ketone carbonyl group, and the increased steric hindrance compared with aldehyde substrates, and has not yet been reported in the literature. Herein, we present an asymmetric intermolecular aldehyde-ketone carboligation reaction using a ThDP-dependent enzyme as the catalyst (Scheme 1).…”

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

“…An NHC-catalysed union of aryl aldehydes and aryl trifluoromethyl ketones was developed in the laboratory of Enders. This direct intermolecular cross-benzoin reaction proceeded with high yields and chemoselectivity [ 27 ]. The reaction furnished excellent yields of α-hydroxy-α-trifluoromethyl ketones 25 possessing a quaternary stereocentre.…”

A Method for the Analysis of Free Carbenes Present after NHC‐Organocatalyzed Transformations

“…The NHC-catalyzed cross-coupling of aromatic aldehydes with trifluoromethyl ketones to afford α-hydroxy α′-trifluoromethyl ketones was uncovered by Enders and Henseler. [21] By applying this procedure, the reaction of benzaldehyde 1b with 5 in the presence of the NHC generated from the triazolium salt 7 using DBU (1,8-diazabicyclo[5.4.0]undec-1-ene) followed by treatment of the reaction mixture with elemental sulfur resulted in the formation of 6 in 95 % yield and the thiourea derivative 8 in 69 % yield based on the amount of 7 used (Scheme 5). The formation of 8 in 69 % yield indicates the availability of free carbene at the end of the cross-benzoin reaction.…”