Aza-Henry

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... 

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]. 

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. 

Meanwhile, chiral (thio)urea catalysts have been employed for a variety of imine addition reactions consisting of Mannich, aza-Henry, Pictet-Spengler, and hydrophosphonylation reactions. ... 

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). 

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.

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.

Scheme 6.76 Total synthesis ofNK-1 receptor antagonist (-)-CP-99,994 utilizing the 12-catalyzed enantio- and diastereoselective aza-Henry methodology.

Scheme 6.122 Products of the 122-catalyzed aza-Henry (nitro-Mannich) addition of nitromethane and nitroethane to acylated aldimines.

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.

In 2008, Tang and co-workers reported the utilization of tertiary amine-functionalized saccharide-thiourea 211 as a bifunctional hydrogen-bonding catalyst for the enantioselective aza-Henry [224] (nitro-Mannich) addition [72] of... 

Scheme 6.178 Typical products provided from the asymmetric aza-Henry addition of nitromethane to N-Boc-protected aldimines in the presence of saccharide thiourea 211 as bifunctional hydrogen-bonding catalyst.

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

The authors suggested that 222 operates in a bifunctional mode by hydrogenbonding activation of the nitroalkane and subsequent a-deprotonation through the basic oxazoline nitrogen providing a nucleophilic nitronate, which attacks the imine and give the observed aza-Henry adduct (Scheme 6.183) [345]. 

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. 

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