Conjugate additions of nitroalkanes to electron-poor alkenes : recent results

Abstract

Conjugate addition of carbon nucleophiles to electron-poor alkenes is of paramount importance among the large body of synthetic processes devoted to carbon-carbon bond formation. The first nucleophilic systems used for this purpose, more than a century ago, were stabilized carbanions that can be prepared in polar solvents from malonates and β-dicarbonyl derivatives in relatively mild conditions using bases of moderate strength. This process is usually re ferred to as Michael addition, and ever since the number of carbanionic species that have been used for conjugate additions has considerably increased to include various enolate systems and strong nucleophilic species such as organometallic reagents. The utilization of these carbon nucleophiles has allowed the accomplishment of many synthetic processes with an outstanding degree of selectivity even though the related experimental procedures are often elaborated and not amenable to scale-up at the industrial level. Conjugate additions using highly stabilized carbanions are still of interest since a growing number of these procedures can be carried out in environmentally benign solvents such as water and using catalytic amounts of the basic promoter. In addition, the achievement of diastereoand enantioselective pro-cesses is no longer an exclusive domain of highly reactive carbanionic systems working in carefully controlled conditions but can be nowadays conducted even at room temperature using easily available substrates and suitable base/solvent combinations. Nitroalkanes are a valuable source of stabilized carbanions since the high electron-withdrawing power of the nitro group provides an outstanding enhancement of the hydrogen acidity at the R-position (cf. pka MeNO2 ) 10). Nitronate anions 2 that can be generated from nitroalkanes 1 using a wide range of bases act as carbon nucleophiles with common electrophiles including haloalkanes, aldehydes, and Michael acceptors, leading to carbon-carbon bond formation. The obtained adducts 3-5 still retain the nitro function, and therefore, a suitable transformation of the nitro group very often follows the main addition process. Reduction of the nitro group to a primary amine 7 can be easily carried out providing a modification of the oxidation state of the nitrogen atom. Alternatively, the nitro group can be removed from the molecule using two distinct synthetic strategies. Replacement of the nitro group with hydrogen gives the corresponding denitrated product 8 so that the whole process (nucleophilic addition-denitration) closely resembles the addition of an organometallic reagent to an electrophilic substrate. The presence at the β-position of an electron-withdrawing group allows a base-assisted elimination of nitrous acid with consequent introduction of a double bond in the molecular framework 9. A further option is represented by conversion of the nitro group into a carbonyl group 10, a transformation widely known as the Nef reaction, which ultimately leads to a reversal in the polarity of the neighboring carbon atom from nucleophilic to electrophilic. This review is focused on the utilization of nitroalkanes as nucleophiles in conjugate additions with electron-poor alkenes and covers the new procedures and related applications appearing in the literature after 1990. Emphasis will be given to asymmetric additions carried out using optically active alkenes or with the aid of chiral catalysts.