Transition Henry reactions

In general, the Henry reaction proceeds in a non-selective way to give a mixture of anti (erythro) and syn (threo) isomers. Ab initio calculations on the Henry reaction suggest that free nitronate anions (not influenced by cations) react with aldehydes via transition states in which the nitro and carbonyl dipoles are antiperiplanar to each other. This kind of reaction yields anti-nitro alcohols. The Henry reaction between lithium nitronates and aldehydes is predicted to occur via cyclic transition states yielding syn-nitro alcohols as major products (Eq. 3.64).108... 

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). 

The nitroaldol (Henry) reaction, first described in 1859, is a carbon-carbon bondforming reaction between an aldehyde or ketone and a nitroalkane, leading to a nitroalcohol adduct [29]. The nitroalcohol compounds, synthetically versatile functionalized structural motifs, can be transformed to many important functional groups, such as 1,2-amino alcohols and a-hydroxy carboxylic acids, common in chemical and biological structures [18, 20, 30, 31]. Because of their important structural transformations, new synthetic routes using transition metal catalysis and enzyme-catalyzed reactions have been developed to prepare enantiomerically pure nitroaldol adducts [32-34]. 

This syn selectivity can be explained by considering the intermediate 98 with a Cu-containing six-membered ring. The relatively strong Lewis acidity of the CuOTf catalyst would favor the diastereoselective Henry reaction via this cyclic transition state. Finally, protonation of the Cu alkoxide 99 and aromatization furnishes the desired product 93 and regenerates the catalyst 95. The additive 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) enhances the release of the products 93 from the catalyst. These products 93 could be readily envisaged as key starting materials in the synthesis of hydroxytryptamines [33]. 

Historical perspective C. H. Heathcock, Comp. Org. Syn. 2, 133-179 (1991). General review T. Mukaiyama, Org. React. 28,203-331 (1982). Application of lithium and magnesium enolates C. H. Heathcock, Comp. Org. Syn. 2, 181-238 (1991) of boron enolates B. M. Kim etal, ibid. 239-275 of transition metal enolates I. Paterson, ibid. 301-319. Stereoselective reactions of ester and thioester enolates M. Braun, H. Sacha, J. Prakt. Chem. 335,653-668 (1993). Review of asymmetric methodology A. S. Franklin, I. Paterson, Contemp. Org. Syn. 1,317-338 (1994). Cf. Claisen-Schmidt Condensation Henry Reaction Ivanov Reaction Knoevenagel Condensation Reformatskv Reaction Robinson Annulation. 

Figure 3.12 Structures of the transition states leading to the formation of R (TS9) and S (TSIO) products of the Henry reaction. Strong conventional hydrogen bonds are shown in blue, and the weak disperse interactions in orange dotted lines. (Adapted with permission from Breugst, M. and Houk, K. N., /. Org. Chem., 79, 6302-6309. Copyright 2014 American Chemical Society.)...

The scope, limitations and mechanisms of asymmetric Henry reactions catalysed by transition metal complexes have been reviewed. ... 

The nitroaldol (Henry) reaction provides 1,2-nitro alkanols under atom-economical proton transfer conditions, which allows for easy access to highly versatile 1,2-amino alcohols (Scheme 6) [31]. A number of catalytic systems have been devised to render this useful C-C bond-forming reaction asymmetric however, diastereoselectivity remained a longstanding problem, in particular for a ri-selective reactions [14, 32, 33]. syw-Selective reaction can be achieved by a monometalhc catalytic system as shown in Fig. 9a, where both an aldehyde and a nitronate coordinate to the metal center to give syn product due to steric repulsion [34—36]. To make the reaction proceed in fluft-selective manner, different strategy in catalyst design is required [37, 38]. Simultaneous activation of both the aldehyde and the nitronate in an anti-paraUel fashion can afford the anti-1,2-nitro alkanols preferentially (Fig. 9b). To attain the a ri-paraUel transition state, a heterobimetalhc catalyst offers a suitable... 

Scheme 29.12 Enantioselective aza-Henry reaction of N-Boc imines catalyzed by 25, and the proposed transition state model.

FIGURE 27.2. Proposed transition state of the Henry reaction catalyzed by 108. 

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. ... 

The idea of the activated complex was developed by, among others, Henry Eyring at Princeton in the 1930s. It forms the basis of the transition-state model for reaction rate, which assumes that the activated complex—... 

The most widely accepted treatment of reaction rates is transition state theory (TST), devised by Henry Eyring.17 It has also been known as absolute rate theory and activated complex theory, but these terms are now less widely used. 

Building on the Lindemarm Theory described above, Henry Eyring, and independently also M.G. Evans and Michael Polanyi, developed around 1935 a theory for the rate of a reaction that is still used, namely the transition state theory. 

Enzyme Catalyzed. The enzyme aldolases are the most important catalysts for catalyzing carbon-carbon bond formations in nature.248 A multienzyme system has also been developed for forming C-C bonds.249 Recently, an antibody was developed by Schultz and co-workers that can catalyze the retro-aldol reaction and Henry-type reactions.250 These results demonstrate that antibodies can stabilize the aldol transition state but point to the need for improved strategies for enolate formation under aqueous conditions. 

Scheme 6.167 Proposed transition-state models for the enantioselective Henry (nitroaldol) reaction in the presence of (S,S)-configured catalyst 183 TS 1 anti, anti conformation TS 2 gauche-onfi conformation TS 3 gauche-onfi conformation.

Scheme 6.170 Suggested transitions states for the anti-diastereoselective Henry (nitroaldol) reaction promoted by (R,R)-catalyst 186 (TS 1) and its (S,S)-isomer 183 (TS 2) to demonstrate the match/mismatch relationship between guanidine-thiourea catalyst and (S)-a-aldehyde.

Scheme 5.64. Phosphinate transition-state analogue hapten. Henry type-retro-aldol reaction catalyzed by catalytic antibody.

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