Organocatalytic nitroalkanes

In summary, several reports have shown that asymmetric modified aldol reactions using y-dienolates, nitroalkanes, or nitrones as donors can (in principal) be performed by use of organocatalysts. Often, however, enantioselectivity is moderate only, and must still be improved. Because these organocatalytic reactions give important intermediates, e.g. for synthesis of pharmaceuticals, it can be expected that this field of modified aldol reactions with organocatalysts will gain further synthetic importance in the future. 

Halland N, Hazell RG, Jprgensen KA (2002) Organocatalytic asymmetric conjugate addition of nitroalkanes to alpha,beta-unsaturated enones using novel imidazoline catalysts. J Qrg Chem 67 8331-8338... 

Nitroalkenes as Acceptors. The organocatalytic asymmetric Michael addition of activated methylenes to nitroalkenes is an important carbon-carbon bond-forming reaction, which provides access to synthetically useful enantioen-riched nitroalkanes. In 2003, Takemoto and co-workers [77] disclosed the first highly... 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

In 2009, Zhu and Lu reported organocatalytic asymmetric Michael additions of nitroalkanes to another Michael acceptor such as vinyl sulfone mediated by another cinchona alkaloid-derived thiourea catalyst, which afforded the desired Michael products with good enantioselectivities of up to 84% ee (Scheme 1.20). This method in combination with a ready desulfonation represented a new approach to access a-alkylated chiral amines. 

On the other hand, Palomo et al. have developed efficient organocatalytic asymmetric aza-Henry reactions under phase-transfer conditions. This method was based on the reaction of a nitroalkane with an azomethine generated from an a-amido sulfone promoted by CSOH.H2O as a base in toluene and in the presence of cinchonine-derived ammonium catalysts. The corresponding. syw-products were obtained in good yields, moderate to good diastereoselectivities (10-86% de) and moderate to excellent enantioselectivities... 

Organocatalytic Henry reactions with synthetically useful levels of yields and enantioselectivities came a decade later with the independent work of Nagasawa and Hiemstra. Nagasawa used guanidinium salt/thiourea brfimctional catalyst 2 for the reaction of nitromethane or nitroethane with aliphatic aldehydes (no reaction was observed when aromatic aldehydes were used) [7]. The reaction works under PTC with the assistance of KOH, and to overcome the retro-nitroaldol reaction K1 as an additive was required (Scheme 29.2). Two years later, the same group extended this reaction to nitroalkanes other than nitromethane, a process that yields the corresponding xyn-nitroalcohols preferentially. 

Another important reaction by which to form C-C bonds is the nitroalkane Michael addition. The first attempt to obtain a nitroalkane enantioselective addition to enones was reported by Yamaguchi in 1994, using as a catalyst rubinate salts of proline. The first truly enantioselective organocatalytic addition of nitroalkanes to enones was developed by Hanessian using proline as catalyst in the presence of an amine additive. The reaction affords good yields and enantioselectivities when cyclic enones were used (up to 93% ee) however, the addition to chalcones renders the products in lower enantioselectivities (up to 68% ee) [90]. 

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