Conjugate Henry reaction

Chiu et al. developed the first example of a reductive intramolecular Henry reaction induced by Stryker s reagent (Scheme 30) [53]. The conjugate reduction of keto-nitroalkenes with [Ph3PCuH]6 (150 mol%) triggers spontaneous nitro-aldol reaction at - 40 °C to produce (f-hydroxy nitro compounds in moderate yield. 

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

In the synthesis we should not wish to make 21 as it would cyclise and, in any case, we d rather reduce nitrile, nitro and alkene all in the same step by catalytic hydrogenation. The very simple method used for the conjugate addition is possible only because of the slow aldol reaction of the hindered aldehyde 24. The aldol 25, also called a Henry reaction, needs a separate dehydration step but the three functional groups in 26 are reduced in one step in good yield.7... 

The derivatives 3 and 6 without any additional modification at the C9 position are infrequently used for organocatalysis. Recent examples include the synthesis of enantioenriched 1,3,4-trisubstituted thiochromanes by a tandem conjugate addition-Henry reaction between 2-thio-substituted benzaldehydes and nitrosty-renes (Scheme 6.10) [26] and the Henry reaction between isatin and simple nitro-alkanes to form 3-substituted 3-hydro-oxindoles (Scheme 6.11) [27]. 

With respect to cupreidine, C9 0-benzoyl esters of this cinchona derivative were demonstrated to be the best catalysts for the nitroaldol reaction of a-ketoesters [55], the conjugate addition of anthrone to nitroalkenes [56], the Henry reaction with fluoromethyl ketones (Scheme 6.25) [57], and an aza-Friedel-Crafts reaction of naphthols with N-sulfonyl imines [58]. 

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. 

Chiral ammonium betaines are a particular class of bifunctional BB-based catalysts that have been successfully applied in the aza-Henry reaction of N-Boc imines and a-substituted a-nitroesters [42]. The catalyst structure displays an intramolecular ion-pairing quaternary ammonium aryl-oxide and the mode of action may involve deprotonation of the pronucleophile by the basic anion to furnish and onium ion as its conjugate acid form. Catalyst loadings as low as lmol% produced the corresponding quaternary-tertiary aza-Henry adducts in excellent yields and enantioselectivities, albeit with low to moderate diastereoselectivities (Scheme 29.18). The lowest de s (up to 33%) were obtained with aliphatic N-Boc imines (R = CH2CH2Ph, -octyl). 

Conjugated nitroalkenes were also synthesized by the reaction between aromatic aldehydes and nitroalkenes in the presence of catalytic amount of ammonium acetate by microwave-assisted Henry reaction in solvent-free conditions (Varma et al, 1997b). The p-nitroalcohols were formed as intermediates. 

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