Conjugate Additions of Nitroalkanes to Electron-Poor Alkenes: Recent Results Roberto Ballini,* Giovanna Bosica, Dennis Fiorini, Alessandro Palmieri, and Marino Petrini* Dipartimento di Scienze Chimiche, Universita ` di Camerino, via S. Agostino, 1, I-62032 Camerino, Italy Received September 30, 2004 Contents 1. Introduction 933 2. General Aspects of the Conjugate Addition of Nitroalkanes 934 2.1. Multiple Additions 934 2.2. Basic Catalysts 935 3. New Basic Catalysts for the Conjugate Addition 936 4. Diastereoselective Conjugate Additions 936 4.1. Intermolecular Additions 936 4.2. Intramolecular Additions 948 5. Asymmetric Conjugate Additions Promoted by Chiral Catalysis 949 6. Conjugate Addition-Elimination Reactions 953 7. Synthetic Applications 957 7.1. Pyrrolidines and Derivatives 957 7.2. Lactones and Oxygenated Heterocycles 960 7.3. Carbocycles 963 7.4. Amino Acids and Derivatives 965 7.5. Other Applications 965 8. Conclusion 968 9. Abbreviations 968 10. Acknowledgments 968 11. References 969 1. Introduction Conjugate addition of carbon nucleophiles to elec- tron-poor alkenes is of paramount importance among the large body of synthetic processes devoted to car- bon-carbon bond formation. 1 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 -dicarbonyl derivatives in relatively mild conditions using bases of moderate strength. 2 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 nucleo- philic 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 carban- ions are still of interest since a growing number of these procedures can be carried out in environmen- tally benign solvents such as water and using cata- lytic amounts of the basic promoter. In addition, the achievement of diastereo- and enantioselective pro- cesses is no longer an exclusive domain of highly reactive carbanionic systems working in carefully controlled conditions 3 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 enhance- ment of the hydrogen acidity at the R-position (cf. pk a MeNO 2 ) 10). 4-8 Nitronate anions 2 that can be generated from nitroalkanes 1 using a wide range of bases act as carbon nucleophiles with common elec- trophiles including haloalkanes, 9 aldehydes, 10,11 and Michael acceptors, 1 leading to carbon-carbon bond formation (Scheme 1). 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 modi- fication of the oxidation state of the nitrogen atom (Scheme 2). 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. 5,12 The presence at the -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 repre- sented by conversion of the nitro group into a carbo- nyl 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. 13,14 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. * To whom correspondence should be addressed. Phone: +39 0737 402270. Fax: +39 0737 402297. E-mail: roberto.ballini@unicam.it; marino.petrini@unicam.it. 933 Chem. Rev. 2005, 105, 933-971 10.1021/cr040602r CCC: $53.50 © 2005 American Chemical Society Published on Web 02/03/2005