The nitro-Mannich reaction (or aza-Henry reaction) is the nucleophilic addition of a nitroalkane (or the corresponding nitronate anion) to an imine, resulting in the formation of a beta-nitroamine. With the reaction involving the addition of an acidic carbon nucleophile to a carbon-heteroatom double bond, the nitro-Mannich reaction is related to some of the most fundamental carbon-carbon bond forming reactions in organic chemistry, including the aldol reaction, Henry reaction (nitro-aldol reaction) and Mannich reaction.

Although extensive research has been conducted into the aforementioned reactions, the nitro-Mannich reaction has been studied to a far lesser extent even though it has been known for well over 100 years. Significant attention only started to develop after the report of Anderson and co-workers at the turn of the century, and has since resulted in a wide range of novel methodologies. The interest into the nitro-Mannich reaction stems from the synthetic utility of the beta-nitroamine products. They can be further manipulated by various methods, including reductive removal of the nitro group allowing access to monoamines, reduction of the nitro group affords 1,2-diamines and conversion of the nitro group into a carbonyl functionality furnishes beta-aminocarbonyl compounds.

The first nitro-Mannich reaction was reported by Louis Henry [fr] in 1896. In this report, Henry described the addition of nitroalkanes to an imine derived from hemiaminal. Elimination of water forms in-situ an imine, which then reacts with the nitro group (as a nitronate ion) to form a beta-nitroamine that can subsequently react further forming one of the two adducts. Although this is the first report of the nitro-Mannich reaction, no yields of the products were given.

After Henry’s seminal report, Mousset and Duden made contributions to the field by studying the addition of branched nitroalkanes to hemiaminals using the same procedures reported by Henry. An example of nitro group reduction to an amine using SnCl₂ and HCl was also disclosed by Duden and co-workers, thus representing the first use of the nitro-Mannich reaction to prepare polyamines. The next report did not appear until 1931, when Cerf de Mauny conducted a thorough study of Henry’s original work using hemiaminals. The scope of the reaction was extended to higher order nitroalkanes affording a beta-nitroamine in excellent yields.

The next contributions appeared in 1946, when Senkus and Johnson independently reported their studies into the nitro-Mannich reaction. Senkus and co-workers illustrated that nitroalkanes may react with methanal (formaldehyde) and substituted primary amines in the presence of sodium sulfate (Na₂SO₄) to afford a variety of substituted beta-nitroamines in moderate to good yields. When using primary nitroalkane substrates, double addition of the nitroalkane to the imine was observed, but this could be avoided by employing secondary nitroalkanes. The study reported by Johnson and co-workers also employed formaldehyde, but this was used in conjunction with a selection of secondary amines, furnishing the corresponding beta-nitroamines in moderate to good yields. Both authors also reduced the nitro group to an amine functionality using Raney Nickel.

Up until this point, all of the nitro-Mannich methodologies reported had used imines that were formed in situ from an aldehyde and an amine. In 1950, Hurd and Strong reported the first nitro-Mannich reaction using a preformed imine. Exposing an imine to a nitroalkane afforded a substituted beta-nitroamines in moderate yields. The moderate yields obtained when using the preformed imine could possibly be attributed to a competing decomposition pathway of the imine or the product.

These early nitro-Mannich methodologies have been used by a number of groups for the synthesis of a variety of heterocyclic products, conjugated nitroalkenes (via elimination of the amino group) and dinitroamines.

Although the nitro-Mannich reaction enables access to synthetically useful beta-nitroamine motifs, the lack of selectivity in their synthesis remained a significant problem. Interest in the field started to increase considerably after Anderson and co-workers reported the first diastereoselective acyclic nitro-Mannich reaction. A nitroalkane and n-butyllithium (nBuLi) were combined at -78 °C to give the corresponding nitronate ions. A selection of N-PMB imines were then added to the reaction mixture and after quenching with acetic acid, the beta-nitroamine products were afforded in good yields with moderate to good diastereoselectivities.