Nitro-Mannich reaction

[5] Significant attention only started to develop after the report of Anderson and co-workers at the turn of the century,[6] and has since resulted in a wide range of novel methodologies.

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 study reported by Johnson and co-workers[11] 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.

Interest in the field started to increase considerably after Anderson and co-workers reported the first diastereoselective acyclic nitro-Mannich reaction.

Firstly, the nitro group was reduced to amines using samarium iodide, followed by PMB removal in the presence of ceric ammonium nitrate (CAN).

[16][17] In 2000, Anderson and co-workers reported the racemic nitro-Mannich reaction of TMS-protected nitronate with N-PMB or N-PMP imines catalysed by Sc(OTf)3.

As a result, the TMS-protected nitronate was used in conjunction with Scandium(III) trifluoromethanesulfonate [Sc(OTf)3] (4 mol%) to afford the beta-nitroamine products in moderate to excellent yields for a range of alkyl and aryl N-PMB and N-PMP protected imines.

Following Anderson’s report, Qian and co-workers described the Ytterbium(III) trifluoromethanesulfonate [Yb(OiPr)3] catalysed nitro-Mannich reaction of N-sulfonyl imines and nitromethane.

The authors propose that the reaction proceeds via the chair-like transition structure, where both the N-PMP-α-iminoester and the nitronate anion bind to the Cu(II)-BOX complex.

In 2007, Feng and co-workers reported that CuOTf used in conjunction with the shown chiral N-oxide ligand and DIPEA is an efficient catalytic system for the enantioselective nitro-Mannich reaction of nitromethane with N-sulfonyl imines.

[22] Combining all of the reagents in THF at –40 °C resulted in the formation of β-nitroamines in excellent yields (up to 99%) and good enantioselectivities for a variety of substituted aryls groups.

The postulated intermediate complex is similar to the transition structure proposed by Jørgensen and co-workers, where the ligated copper species binds to the N-sulfonyl imine.

This area of organic chemistry received limited attention until the seminal work of Jacobsen and Sigman[26] in which they reported a highly enantioselective Strecker reaction using a H-bond donor organocatalyst: Building on the work of Jacobsen, it was recognised that H-bond donor motifs can be linked via a chiral scaffold to Brønsted basic moieties, creating a new class of bifunctional organocatalysts (see concept figure below).