Aza Henry reaction

Recently, enantioselective organo-catalytic procedures for the aza-Henry reaction have been disclosed. The presence of either an acidic or a basic function appears to be a requisite of the catalyst. In fact, the condensation of ni-tromethane with M-phosphinoyl arylimines 72 is catalyzed by the chiral urea 85 derived from (R,R)-l,2-diaminocyclohexane and gives the product (R)-74 with good yield and moderate enantioselectivity (Scheme 15) [50]. The N-phosphinoyl substituent is determinant, as the addition of nitromethane to the N-phenyl benzaldimine failed and the reaction of the N-tosyl ben-zaldimine gave the expected adduct with quantitative yield but almost no... 

Scheme 15 Organo-catalytic enantioselective aza-Henry reactions...

An enantioselective aza-Henry reaction catalysed by the same bifimctional organocatalyst was recently reported by the same group (Scheme 47) [163]. 

The aza-Henry reaction is the nucleophilic addition of nitroalkanes to imines to give nitroamine derivatives. This reaction was also studied with metal-based catalysts [164]. 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

The Michael reaction of malonates to nitroolefins and the aza-Henry reaction of nitroalkanes to Al-phosphinoylimines are catalyzed by thiourea derivative 5a to provide the respective products in good and moderate enantioselectivities. Thiourea... 

The aza-Henry reaction of imines to nitroalkanes promoted by modified Cinchona alkaloids has been investigated by several groups. Optically active p-nitroamine products are versatile functional building blocks. In 2005 and 2006, several reports regarding use of chiral thioureas emerged, using nitroalkanes in the aza-Henry reaction to various imines. 

Takemoto and co-workers communicated that bifunctional organocatalyst 166 would promote aza-Henry reactions of phosphinoyl imines with nitroalkanes (Scheme 52) [104]. The catalytic additions provided high selectivities and yields... 

Fig. 7 Proposed role of cyclohexane-diamine thiourea 166 for the asymmetric aza-Henry reaction...

Recently, Takemoto and co-workers reported the use of bifunctional ihiourea catalyst 166 for the aza-Henry reaction of nitroalkanes to A -Boc imines [107, 108], Using a... 

Mechanistically, the aza-Henry reaction presumably proceeds via a six-membered transition state. Brpnsted acid 14r is expected to activate both the electrophile and the nncleophile (Fig. 8). 

Scheme 6.75 Proposed mechanism of the enantio- and diastereoselective aza-Henry reaction between N-Boc-protected aldimines and nitroalkanes in the presence of biflinctional catalyst 12 and catalyzed epimerization of the syn-adduct at increased temperature.

Ricci and co-workers published a protocol for the enantioselective aza-Henry reaction [224] of N-protected aldimines with nitromethane in the presence of C9-epi-quinine thiourea 121 [8]. The reaction was ophmized for 20mol% loading of... 

Scheme 6.128 Product range of 121-catalyzed asymmetric aza-Henry reactions between N-protected aldimines and nitromethane. The configurations of the products were not determined.

Figure 6.62 Oxazoline-thioureas screened in the aza-Henry reaction of N-Boc-protected benzaldimine with nitromethane.

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. 

A cheap and efficient enantioselective aza-Henry reaction of nitromethane with a variety of A-protected arylaldimines has been reported.73 Using zinc triflate and (-)-A-methylephedrine at -20 °C, yields and ees of up to 99% have been achieved with wide tolerance of aryl substituent in terms of both electronic nature and position. The auxiliary is also easily recycled. 

An enantioselective aza-Henry reaction has been performed in the presence of zinc triflate and A-methylephedrine 47 This method features tolerance to imines that bear aryl groups of diverse electronic nature and substitution patterns. 

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