摘要：

The nitro-Mannich reaction belongs to a formidable suite of carbon-carbon bond-forming reactions, the aldol, Mannich, and Henry reactions that are all well understood and used routinely in molecular construction. They are all linked by the common addition of a stabilized anion to a carbonyl derivative. It seems peculiar that one permutation of this set of reactions, addition of a nitronate anion to an imine (nitro-Mannich or aza-Henry reaction), has lagged behind its congeners. The likely explanation is due to the fact that the β-nitro amine products from the nitro-Mannich reaction are often prone to Scheme 156. Umpolung Amide Bond Formation Using Bromonitroamines retro-addition if they do not contain an electron-withdrawing group on the amine nitrogen. In early experiments with imines derived from ammonia or aliphatic/aromatic amines this complicated their isolation and purification and impeded further transformations. Experiments in the early 20th century consisted mainly of unselective, noncatalyzed, thermal methods with simple amines and nitroalkanes with formaldehyde. They relied upon natural formation of nitronic acid or deprotonation to nitronate species. Use of the nitro-Mannich reaction as a tool to prepare other functionality was recognized as far back as 1905 by Duden, who prepared polyamines by reduction of the product β-nitro amines (Scheme 5).29 However, this disconnection was rarely used throughout the whole of the 20th century. Notable exceptions include synthesis of polyamines by Johnson in 1946 (Scheme 10)36 and Rychnovsky's use of the disconnection in a synthesis of chiral nitroxides as late as 1998 (Scheme 9).38 Studies which characterized the diastereoselectivity of the reaction were rare and limited to cyclic products formed from lactamization using nitroesters. Building on a reaction characterized by Muhlstadt and Schulze (Scheme 28),75 Jain was the first to show that in formation of piperidinones a trans relationship between the two new chiral centers was formed in the key nitro-Mannich reaction (Scheme 29).76 The trans(anti) selectivity of this reaction has subsequently persisted throughout all but a very few examples (vide infra) of the nitro-Mannich reaction. Publication of the first diastereoselective nitro-Mannich reactions in 1998 formulated some mechanistic understanding that the reaction was proton centered, was inherently anti-selective, and that this appeared to be kinetic diastereoselectivity (Scheme 31).6 In this comprehensive review there are 55 publications before that paper that detail a nitro-Mannich reaction or nitro-Mannich product, whereas in the last 14 years there have been over 200 reports of the same reaction. The recognition that the reaction was proton centered invited the use of chiral Lewis acids to catalyze the nitro-Mannich reaction.6 At the time there was incredible activity in the field of asymmetric catalysis, and a surge of workers reported asymmetric catalytic nitro-Mannich reactions. The first of these was by Shibasaki in 1999 using mixed Lewis-acid/Bronsted-base catalysts (Scheme 54).105 Racemic Lewis-acid-catalyzed reactions in 2000 (Scheme 44)79 were followed by Jorgensen's studies using bis-oxazoline chiral copper triflate Lewis-acid complexes in 2001 (Schemes 46 and 56).97,107 The field dramatically widened from then on to include not only other asymmetric metal-centered systems (sections 4.2 and 5.2) but also a host of organocatalysts relying on chiral hydrogen-bond donors, chiral Bronsted acids, phasetransfer catalysts, and Bronsted-base catalysts (section 6). One of the most efficient asymmetric organocatalytic nitro-Mannich protocols is that by Wang, which gives high yields and enatioselctivities of anti diastereoisomers (Scheme77).132 In the extreme majority of reports the anti-diastereoisomer of the β- nitro amine products is formed. There are very few reports of syn-selective methods, and known methods are limited by particular reaction conditions, catalysts, or substrates. The most successful direct metal-catalyzed nitro-Mannich reaction to date and

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