Cross-benzoin reactions intermolecular

Compared with the aldehyde-ketone cross-benzoin reaction, intermolecular aldehyde-aldehyde coupling reactions are much more challenging, as the addition of the second aldehyde means the number of possible products is quadrupled. 

Attempted intermolecular cross-benzoin reactions typically generate a thermodynamically controlled mixture of products [50], although several groups including Enders [51], Suzuki [52] and You [53] have utilised catalysts 116-118 for the intramolecular crossed benzoin of keto-aldehydes (Scheme 12.22). 

In contrast to the previously described intermolecular condensation reaction, intramolecular crossed benzoin reactions have been developed much less for a long time (Cookson and Lane 1976). 

In the same year, through the development of a new electron-deficient, valine-derived triazolium catalyst precursor. Gravel and co-workers realized a highly enantioselective intermolecular cross-benzoin reaction of aldehydes with a-keto esters. Excellent enantioselectivity was observed between aliphatic aldehydes (1.5 equiv.) and various aryl ct-keto esters (up to 98% yield, 94% ee) (Scheme 7.8). 

Intermolecular Cross-Benzoin Reaction. Compared to the well-... 

In 2011, Connon, Zeitler, and coworkers reported detailed studies on intermolecular cross-benzoin reactions using triazoUum and thiazoUum salts [26]. These systematic studies clearly showed the intricate interplay of various factors influencing the outcome of cross-benzoin reactions. In line with the results of Miller and coworkers, the use of o-substituted benzaldehydes resulted in selective formation of benzylic alcohol products using either triazolium or thiazolium salts. When using o-unsubstituted benzaldehydes, the same chemoselectivity could be achieved with an a-branched aliphatic aldehyde and an N-QFs triazolium catalyst. Crossover experiments showed the reaction to be under kinetic control in many cases. When using chiral catalyst 31, good chemo- and enantioselectivity was achieved in the reaction between o-trifluoromethylbenzaldehyde (30) and propanal (29) (Scheme 18.3). 

Connon, Zeitler, and coworkers showed a-ketoesters to be competent reaction partners when using N-C Fs triazolium salt 17 [31]. Even aliphatic a-ketoesters could serve as substrates while avoiding possible competing aldol pathways. The enantioselective version of the reaction proved challenging, and cross-benzoin product 44 could be obtained in only moderate yield and enantioselectivity (Scheme 18.6). Intermolecular formal cross-benzoin reactions using pyruvate as an aldehyde equivalent were also shown to be possible, using a thiamine-dependent enzyme, with broad substrate scope [32]. 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

Enders D, Henseler A (2009) A direct intermolecular cross-benzoin type reaction N-heterocyclic carbene-catalyzed coupling of aromatic aldehydes with trifluoiomethyl ketones. Adv Synth Catal 351 1749-1752... 

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