P-Nitroamines

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. 

Ricci et al. [85] reported the use of a quinidine-derived chiral catalyst in the asymmetric addition of nitromethane to iV-Boc imine 40. At around the same time, S chans and co-workers used a dihydroquinidine-derive chiral thiourea DHQD-134 applicable to nitromethane and nitroethane 149 [86]. The application of nitroethane conveniently generates a tertiary stereogenic center in the P-nitroamine product 151. The methodology presented by Schaus is also applicable to novel... 

Scheme 6.74 Typical N-Boc-protected syn-P-nitroamines obtained from the enantio- and diastereoselective aza-Henry (nitro-Mannich) reaction between N-Boc-protected (hetero) aromatic aldimines and nitroalkanes in the presence of biflinctional thiourea catalyst 12.

These quinone derivatives, by further reduction, can produce only arnidophenols. If the quinone formation is prevented from taking place, for instance by esterifying the hydroxyl-group, the normal reaction to azoxy-bodies occurs, o- and p-Nitroanisol pass smoothly into azoxy- or azo-derivatives. The acylizing of the amido-group in the case of o- and p-nitroamines hinders likewise the quinone, and. therewith the amine, formation. The azoxy-body is smoothly formed, thus ... 

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). 

Synthesis of P-nitroamines via Mannich and aza-Henry reactions including the synthesis ofnitro N- and S-heterocycles 13COC1200. Synthesis of heteroaromatic compounds by newly extended Pummerer reactions 13YGK341. 

He and coworkers utilised catalyst 48e prepared from quinine and ben-zotriazole, which catalysed the aza-Henry reaction efficiently for a wide range of a-amidosulfones to give the desired products in good yields and with excellent enantioselectivities (up to 99% enantiomeric excess) and diaster-eoselectivities (up to 99 l). Compared with the N-benzyl catalyst 48d, the benzotriazole derivative of quinine 48e yielded the opposite enantiomer of p-nitroamines [(5 )-86, (S, J )-87a]. The practicability of this methodology was demonstrated by the conversion of the optically enriched aza-Henry products into chiral vicinal diamines or a-amino acids (Scheme 16.28). ... 

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... 

Anderson, J. C., Stepney, G. J., Mills, M. R., Horsfall, L. R., Blake, A. J., Lewis, W. (2011). Enantioselective conjugate addition nitro-Mannich reactions Solvent controlled synthesis of acyclic anti- and yn-p-nitroamines with three contiguous stereocenters. Jonrnal of Organic Chemistry, 76,1961-1971. 

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]. 

Schaus et al. employed (15a) as a catalyst for the enantioselective addition of stabilized nucleophiles such as nitroethane and malonates to N-acyl aldimines [109]. P-Nitroamines were obtained in good yields with 90-97% enantioselectivities and up to 97% diastereoselectivities (Scheme 2.53). 

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. 

Apart from linear unfunctionahzed nitroalkanes, various other prochiral nitro-aUcanes bearing aryl, alcohol, ether, and ester groups also participate effectively in reactions promoted by 25, producing sy -P-nitroamines in good yields and high enantiomeric excesses [32]. The utihty of this methodology was demonstrated by the synthesis of the neurokinin-1 receptor antagonist CP-99,994 (Scheme 29.14). 

As mentioned above, the intrinsic non-directional nature of electrostatic interactions between substrates and monofunctional BB catalysts makes the development of highly selective processes in a predictable manner difficult. As an illustration, the few chiral guanidine organocatalysts that have been described that are capable of promohng the aza-Henry reaction between N-Boc aryl imines and nitromethane lead to the corresponding P-nitroamines in generally low enanhomeric excesses (20-70% ee) [43]. 

The success of the sp C-H/sp C-H and sp C-H/sp C-H couplings led us to explore the possibility of the even more challenging CDC reaction between sp C-H and sp C-H bonds. We started with the reaction of an a-sp C-H bond of nitrogen in amines with nitroalkanes, which would provide aza-Henry-type reaction products. Using CuBr as the catalyst and TBHP as the terminal oxidant, various p-nitroamine derivatives were generated by this new methodology (Scheme 1.22). ... 

Scheme 29.27 Representative P-nitroamines synthesized and formal catalytic enantioselective 2-ethoxycarbonylvinylation of N-acyl imines.

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