Aza-Henry reaction of nitroalkane

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... 

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... 

Scheme 16.27 Asymmetric aza-Henry reactions of nitroalkane with azomethines generated from a-amidosulfones under PTC conditions.

During the same year, Takemoto and coworkers reported the asymmetric aza-Henry reaction of nitroalkanes with N-Boc imines utilising thiourea 15. 5yn-p-Nitroamines were isolated in good diastereoselectivities and high enantioselectivities, while the thiourea group was revealed to play a dual role, both activating the substrates and inducing chirality. Various types... 

Connon introduced binaphthyl-derived bis-thiourea 31 and demonstrated that it could catalyze the addihon of N-methyhndole to various nitroalkenes, including those incorporating P-aliphahc substituents, although the enantioselectivity was generally moderate (Scheme 7.56) [84]. The utility of 31 was also proven by Wulff through use with a sub-catalytic amount of triethylamine for stereoselectively facilitating the aza-Henry reaction of nitroalkanes with N-Boc imines [85]. 

Johnston and coworkers reported in 2004 an enantioselective aza-Henry reaction of nitroalkanes with Boc-protected imines catalyzed by the mono-protonated chiral bis-amidine salt 61 (Scheme 10.58) [154]. This catalyst class was also found to be... 

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... 

The applieation of another bifunctional thiourea-secondary amine derived from trflHi-cyclohexane diamine to the asymmetric aza-Henry reaction of A-Boc imines with nitroalkanes was reported by Wang et al., providing the corresponding aza-Henry adducts with excellent enantioselectivities (96-99% ee) and high awti-selectivities (86-98% de) for a broad scope of substrates (Scheme 3.23). ... 

A multi-component aza-Henry reaction of an aldehyde (R CHO), aniline and a nitroalkane (R R CHN02) yields -nitroamines (27) in high de, ee, and yield in brine, with an optimal rate at pH 5.5, using a hydrogen-bond donor (a chiral thiourea or squaramide), and a tertiary amine as Lewis base. ... 

The aza Henry reaction of N-phosphinyl aldimines with nitroalkanes was promoted by (9) to give P-nitroamines with good enantioselectivity (Scheme 2.37) [88]. The thiourea activated the nitro group, thereby facilitating the formation of the nucleophilic nitronate anion. They subsequently found that the use of N-Boc imine improved the enantioselectivity with reversal of the facial selectivity (Scheme 2.38) [89]. 

A dihydroquinidine-derived chiral thiourea (DHQD-30), which demonstrated significantly better stereocontrol than other cinchona alkaloids, was utilized in the aza-Henry reaction with nitroalkanes and aldimines by Schaus and coworkers (Scheme 13.8) [26]. The utility of the nitroethane pronucleophile conveniently offers a tertiary stereogenic center in the P-nitroamine product 32. The methodology is also conveniently applicable to novel a,P-unsaturated aliphatic imines 29, which are difficult substrates in asymmetric conjugate addition reactions. Similar reaction conditions can be appHed towards to the use of dimethyl malonates as pronucleophiles that generate adducts in high enantioselectivity, which then convert smoothly into P-amino esters under the Nef conditions. 

Scheme 29.14 Scope of nitroalkanes in the enantioselective aza-Henry reaction of N-Boc imines catalyzed by 25, and compound CP-99,994 synthesized employing the methodology.

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]. 

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.

Nucleophilic addition to the C=N bond of imine derivatives is quite important in organic chemistry for the synthesis of functionalised amines and related nitrogen-containing compounds. This section introduces an enan-tioselective Mannich reaction, including an aza-Henry reaction that uses nitroalkanes as a nucleophile, via PTC catalysis in the presence of Cinchona-derived quaternary ammonium salts. 

On the other hand, Palomo et al. have developed efficient organocatalytic asymmetric aza-Henry reactions under phase-transfer conditions. This method was based on the reaction of a nitroalkane with an azomethine generated from an a-amido sulfone promoted by CSOH.H2O as a base in toluene and in the presence of cinchonine-derived ammonium catalysts. The corresponding. syw-products were obtained in good yields, moderate to good diastereoselectivities (10-86% de) and moderate to excellent enantioselectivities... 

Discussion of the Henry reaction to this point has focused on the addition of nitroalkanes to aldehydes and ketones however, Jorgensen and coworkers have reported significant advances toward highly enantioselective copper-catalyzed aza-Henry reactions. Initial communication in this area presented the addition... 

A purely ionic hydrogen bond activation mechanism might be involved in the aza-Henry reaction between a-iminoesters, a very reactive subclass of imines, and various nitroalkanes catalyzed by the BINOL phosphoric acid 44 [54]. The corresponding P-nitro-a-amino acid esters were produced in good yields, diastereo- and enantioselectivities (Scheme 29.23). The authors postulated a dual role of catalyst 44 through activation of the a-iminoester by protonation and control over the nitroaUcane/nitronate equilibrium (Scheme 29.24). 

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