Nitro-Mannich Aza-Henry Reactions

Herrera, Bernardi, and coworkers demonstrated that the addition of nitromethane to a wide range of aromatic and aliphatic N-Boc imines generated in situ from the 

Molecular modeling studies designed to rationalize the observed sense of stereoselectivity revealed that the nucleophile (i.e., the conjugate base of the nitroalkane) is linked by hydrogen-bond to both the thiourea moiety and the protonated quinucli-dine catalyst and that one face of the nucleophile is blocked by the quinoline ring. According to the calculation, the Re-face attack of the nucleophile on the imine to 

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On the other hand, there is a report regarding a cascade Michael reaction followed by intramolecular nitro-Mannich (aza-Henry) reaction occurring between imides derived from diethyl aminomalonate and nitrostyrenes using thiourea 68a as catalyst (Scheme 7.63). This reaction results in a formal [3 + 2] cycloaddition between these two reagents, with this aminomalonate-derived... 

The lanthanide-alkali metal heterobimetallic complexes have also been shown to promote other reactions, such as nitro-Mannich (aza-Henry) reaction [154],... 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

It was also reported that diastereo- and enantioselective Mannich reactions of activated carbonyl compounds with a-imino esters were catalyzed by a chiral Lewis acid derived from Cu(OTf)2 and a bisoxazoline (BOX) ligand [31] [(Eq. (6)]. Catalytic enantioselective addition of nitro compounds to imines [32], and aza-Henry reactions of nitronates with imines [33] also proceeded under similar reaction conditions. 

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Another important type of transformation, which is has inspired the above developments, is the nitro-Mannich (or aza-Henry) reaction catalyzed by Jacobsen thiourea catalysts (Scheme 4.16) [77]. The reaction is highly 5yn-selective, and the corresponding products were isolated in high yields and ees. 

It is also noteworthy that Ricci and co-workers have disclosed phase nitro-Mannich (or aza-Henry) reaction using Al-Carbamoyl imines generated in situ from a-amido Sulfones using phase-transfer catalysts [78]. Ricci s direct use of a-amido sulfones as acceptors has also inspired developments in aminocatalysis as described vide infra. Here the 7/-benzyl quininium chloride catalyst has a dual function by generating the corresponding Al-carbamoyl imines in situ and next activate the nucleophile for the highly stereoselective addition (Scheme 4.17). 

In 1998, Anderson reported a diastereoselective synthesis of vicinal diamines involving acid-catalyzed aza-Henry (or nitro-Mannich) reactions of nitro-alkanes 296 with imines 297 (Scheme 11.38) (188). Subsequent reduction of the nitro group could be carried out with Sml2 to give the corresponding 1,2-anti diamines 299. The development of catalytic enantioselective aza-Henry reactions would provide access to such structurally important 1,2-diamino building blocks in optically active form and has been the subject of considerable attention [23, 189]. 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

Ph (SbFe)2 Ph Ph TIO OTf Ph 84 Scheme 14 Catalytic asymmetric aza-Henry (nitro-Mannich-type) reactions... 

Takemoto et al. discovered N-phosphinoyl-protected aldimines as suitable electrophilic substrates for the enantioselective aza-Henry [224] (nitro-Mannich) reaction [72] with nitromethane, when utilizing thiourea 12 (10mol%) as the catalyst in dichloromethane at room temperature [225]. The (S)-favored 1,2-addition of nitromethane to the electron-deficient C=N double bond allowed access to various P-aryl substituted N-phosphinoyl-protected adducts 1-5 in consistently moderate to good yields (72-87%) and moderate enantioselectivities (63-76%) as depicted in Scheme 6.73. Employing nitroethane under unchanged reaction conditions gave adduct 6 as a mixture of diastereomers (dr 73 27) at an ee value of 67% (83% yield) of the major isomer (Scheme 6.73). 

Scheme 6.73 Typical products of the enantioselective aza-Henry (nitro-Mannich) reaction between nitroalkanes and N-phosphinoylimines proceeding in the presence of catalyst 12.

The N-sulfinyl (thio)ureas are modular and easily accessible in one step by condensing tert-butanesulfinamide with the appropriate isocyanate or isothiocyanate. Figure 6.64 shows a representative selection of the prepared N-sulfinyl (thio)ureas evaluated for their catalytic activity in the aza-Henry (nitro-Mannich) reaction of N-Boc-protected benzaldimine and nitroethane producing adduct 1. 

As described above, N-protected aromatic imines can be successfully employed as substrates for Mannich reactions. However, although N-protected alkyl imines constitute another important class of imine substrates, their instability hampers their use. N-protected alkyl imines are spontaneously tautomerized into the corresponding enamines even at low temperature. In aza-Henry (nitro-Mannich) reactions, this problem was overcome independently by Palomo [33a] and the group of Herrera, Bernardi, and Ricci [33b] by using the stable a-amidosulfones 73 from... 

The aza-Henry (nitro-Mannich) reaction of A-diphenylphosphinoylimines with nitroalk-anes under solvent-free conditions was efficiently catalysed with TMG (1) to give a series of p-nitroamines in excellent yields and high diastereoselectivity [31] (Table 4.1). 

TMG (1), TBD (3a) and MTBD (3b) act as effective catalysts for the aza-Henry (nitro-Mannich) reaction of A -diphenylphosphinoyl ketimines and nitromethane. The addition product is given in good to high yields [32]. A phophazene ( Bu -P1) can be also workable as a superior base. 

Addition of Nitroalkanes to C=NR (The Aza-Henry or Nitro-Mannich Reaction) 851... 

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