The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds

Abstract

The nitro-Mannich (aza-Henry) reaction, in which a nitroalkane and an imine react to form a β-nitroamine, is a versatile tool for target-oriented synthesis. Although the first stereoselective reaction was developed only 20 years ago, and enantioselective and diastereoselective versions for the synthesis of non-racemic compounds soon after, there are nowadays a variety of reliable methods which can be used for the synthesis of APIs and other biologically active substances. Hence many anticancer drugs, antivirals, antimicrobials, enzyme inhibitors and many more substances, containing C-N bonds, have been synthesized using this reaction. Several transition metal complexes and organocatalysts were shown to be compatible with the presence of a wide range of functional groups in these molecules, and very high levels of asymmetric induction have been achieved in some cases. The reaction has also been applied in cascade processes. The structural diversity of the products, ranging from simple heterocycles or azabicycles to complex alkaloids, iminosugars, amino acids or diamino acids and phosphonates, shows the versatility of the nitro-Mannich reaction and its potential for future developments.

Recent advancement in drug development of nitro(NO2)‐heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis

“…Nitro(NO 2 )‐based compounds occupy a considerable space in the medicinal chemistry field (Paula et al, 2009). In the last decade (2011–2021), this pharmacophore class has shown significant pharmacological activities or properties (Faisca Phillips et al, 2020; McCormick et al, 1976; Olender et al, 2018; Palmieri, 2017; Rice et al, 2021). Most of the data presented in this review were from in vitro assays against the H 37 Rv strain.…”

The Last Fortress of Tin's Tyranny – Protodenitration of Nitroalkanes

“…Due to the higher acidity of the α‐position next to the nitro group, nitroalkanes could be deprotonated, giving rise to nitronates, which further react in C ‐alkylation [3] and C ‐arylation, [1b] the Henry reaction, [1a,b] the Michael addition [1a,b] and the nitro‐Mannich reaction [4a] . With the rise of stereoselective synthesis, nitroalkanes became irreplaceable even in the stereoselective synthesis of many enantiomerically pure building blocks, especially ß‐nitroamines [4b] . The reactivity richness has been so overwhelming that in 1985 Seebach described the nitro group as having “chameleon qualities” (from German “ Chamäleon‐Qualitäten ”) [5a] .…”

Asymmetric Cascade Aza-Henry/Lactamization Reaction in the Highly Enantioselective Organocatalytic Synthesis of 3-(Nitromethyl)isoindolin-1-ones from α-Amido Sulfones

“…Our attention was focused on the asymmetric aza-Henry reaction, also known as nitro-Mannich reaction, since it is an important tool in the synthesis of active pharmaceutical ingredients (API) and other biologically active compounds. 9 However, isoindolinones monosubstituted at the 3-position with a nitromethyl side chain have never been reported ( Scheme 1 ). 10 , 11 Cascade reactions of 2-cyanobenzaldehyde with active methylene compounds or heteronucleophiles are important tools in the synthesis of 3-monosubstituted isoindolinones ( Scheme 1 b).…”

“…Our attention was focused on the asymmetric aza-Henry reaction, also known as nitro-Mannich reaction, since it is an important tool in the synthesis of active pharmaceutical ingredients (API) and other biologically active compounds . However, isoindolinones monosubstituted at the 3-position with a nitromethyl side chain have never been reported (Scheme ).…”