Benzaldehydes Henry reaction

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acetylacetone) to trans-(R)-mtrostyvQnQ, catalyzed by the bifunctional thiourea catalyst shown in Scheme 6 [46]. The analogous Michael-addition involving dimethyl malonate and nitroethylene as substrates, and a simplified catalyst was calculated at the same level of theory by Liu et al. [47]. Himo et al. performed a density functional study on the related cinchona-thiouTQa catalyzed Henry-reaction between nitromethane and benzaldehyde [48]. 

For the model Henry reaction between benzaldehyde and nitromethane a solvent dependency of the enantioselectivity was detected (e.g., CH2CI2 6% ee MeOH 49% ee THF 62% ee aU at rt). Under optimized reaction conditions concerning catalyst loading (10 mol% of 131), solvent (TH F), and reaction temperature... 

A few years later, Hass reported an alternative synthesis of racemic amphetamine, which exemplifies the use of a nitroalkane as the source of the nitrogen atom (Scheme 17.4) (Hass et al., 1950). In this route, calcium-hydroxide-promoted Henry reaction of nitroethane and benzaldehyde (12) afforded an 86% yield of the nitro alkene 13. Simultaneous hydrogenation... 

The amines 3 reported by Morao and Cossio also constitute neutral dendritic catalysts without metal sites they consist of a simple amine core functionalised with Frechet dendrons (Fig. 6.44) [74]. Such amines can catalyse the nitroaldol or Henry reaction [75] between aromatic aldehydes and nitroalkanes. Whereas neither the yield nor the stereoselectivity (syn/anti 1 1) of the reaction of p-nitro-benzaldehyde with nitroethane was found to change on use of different generations of dendritic catalysts, a distinctly negative dendritic effect was observed in the reaction of benzaldehyde with 3-nitro-l-propanol. Catalysts 3 a and 3 b gave... 

Figure 3.39 a The structure and proposed mode of action of the modified Cinchona alkaloid catalyst b an example ofthe catalytic Henry reaction between benzaldehyde and nitromethane. 

After the reaction reached completion, the solid product was filtered off and identified by NMR spectroscopy and X-ray crystallography. By analyzing the data, the unexpected formation of amide product 40 from benzaldehyde 37C and its corresponding intermediate 39C was revealed. This represented a new transformation pathway, for which only a few related systems have been reported [58-60]. Scheme 14 displays the proposed mechanistic formation of amide product 40, supported by density functional theory (DFT) calculations [61]. In the presence of triethylamine as catalyst, the key intermediate 39C was formed from nitroaldol (Henry) reaction of 2-cyanobenzaldehyde 37C and nitroethane 38. The nitroaldol adduct 39C then underwent internal cyclization (5-exo-dig) to give iminolactone 41,... 

A stereoselective Henry reaction has also been observed between bicyclic trimethylsilyl nitronates and benzaldehyde with fluoride ion as the catalyst. The reaction results in the formation in high yield of a cyclic hemiacetal (equation 20) and is highly diastereoselective (95% ds)P-... 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

TABLE 5.2. Achiral Henry Reaction Catalyzed by IMfferent Crystallites of MgO Between Benzaldehyde and Nitromethane at 25 °C... 

TABLE 53. Asymmetric Henry Reaction Between Nitromethane and Benzaldehyde Catalyzed by NAP-MgO with Different Ligands at —78 °C... 

A fascinating variant of the enzymatic cyanohydrin formation consists in the use of nitroalkanes (as nonnatural nucleophiles) instead of cyanide (Scheme 2.209) [1568,1569]. Overall, this constitutes a biocatalytic equivalent to the Henry-reaction producing vicinal nitro-alcohols, which are valuable precursors for amino alcohols. Using (5)-HNL, the asymmetric addition of nitromethane to benzaldehyde gave the nitroalcohol in 92% e.e., while for p-nitrobenzaldehyde the stereoselectivity dropped sharply. With nitroethane, two stereocenters are created Whereas the stereoselectivity for the alcoholic center was high (e.e. 95%), the recognition for the adjacent center bearing the nitro moiety was modest and other (dia)stereomers were formed in up to 8%. 

Recently, a Henry reaction between aldehydes (e.g., benzaldehyde 26) and nitroalkanes (e.g., nitromethane 27) catalyzed by cyclophane-based thiourea 28 was reported (Scheme 3.27). ... 

A series of mono- and dialkylated, chiral 1,2-amino-phosphinamide ligands (752) have been successfully applied in the chiral phosphinamide-Zn(ii) catalysed asymmetric Henry reaction between benzaldehyde and nitromethane (Scheme 210). The effects of the N-substituent sizes of chiral ligands (752) on the enantioselectivities in this reaction have been correlated using a predictive quantitative structure-activity relationship (QSAR) mathematical model. A quantitative correlation model has been also established based on subtractive Sterimol parameters. Ligand optimisation based on the QSAR model led to chiral 1,2-amino-phosphinamide ligand (752a), which produced (R)-p-nitroalcohol (753) in excellent yield (99%) and enantioselectivity (92% ee). ... 

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]. 

As shown in the Table 29.1, the screening of several chiral tetraaminophosphonium salts, in the test Henry reaction of nitromethane and benzaldehyde, showed that the aromatic substituent (Ar) on the diazaphosphacycle has a significant effect on catalyst efficiency. Thus, while catalyst 5 (Ar = Ph, 86% yield and 89% ee), and especially 6 (Ar = m-Xylyl, 36% yield and 45% ee), shown suboptimal performance, catalyst 7 (Ar = P-CF3-C6H4) provides the corresponding final nitroaldol with... 

MichaeU-Henry Reaction Liu et al. and Xie et al. independently found that tertiary amine-thioureas could stereoselectively promote the addition of diethyl a-aminomalonate-derived azomethine ylides to nitroolefms, affording Michael adducts other than dipolar cycloaddition adducts as the major products. Using monofunctional chiral thioureas 140d instead of tertiary amine-thiourea catalysts, Liu et al. successfully developed a three-component [3-1-2] dipolar cycloaddition of benzaldehydes 3, diethyl a-aminomalonates 45a, and nitrostyrenes 165, resulting directly in the enantioenriched pyrrolidines 208 as the only products (Scheme 2.56) [81a] while Xie et al. efficiently converted the Michael adducts 210 to pyrrolidines 208 in high yield and maintained ee by the use of 30 equiv of 2,2,2-trifluoroethanol as the additive (Scheme 2.56) [81b]. 

Enantioselective A. thaliana hydroxynitrile lyase (>1Henry reaction of benzaldehyde and MeNO, [23]. 

QM/MM calculations and experimental kinetic study have explored the effects of solvation on the transition states for reaction between nitromethane and formaldehyde and between nitropropane and benzaldehyde. Asymmetric reactions of nitromethane with various aldehydes have been promoted by Cu(II) coordinated with amino alcohols, 0 imidazolium/pyrrolidinium-tagged Indabox, and imidazolium-taggedbis(oxazoline)-based chiral ligands. The Henry reaction has also been promoted by Mn(OAc)2/Schiff bases bearing a triazole structure, with up to 99% yield, and by phosphonium ionic ligands MeP+(octyl)3 R0C02 without solvent. ... 

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