Solvent-free aldol reaction

Some aldol condensation reactions proceed more efficiently and stereoselectively in the ab.sence of solvent than in solution [18]. When the solvent-free aldol reaction is carried out in an inclusion complex with a chiral host complex, diastereo-and enantioselective reactions occur, although enantioselectivity is not high [18]. 

To better evaluate both methods the results of the direct aldol reaction of acetone with selected aromatic aldehydes catalyzed by prohne are presented in Figure 21.2. Although in general the Kotsuki approach offers much better yields, in the Hayashi method higher enantioselectivities (temperature effect) can be obtained. This methodology was also tested in a solvent-free aldol reaction with cyclopentanone but no improvement was noticed [23]. 

Bolm [59-61] applied ball-milling to an asymmetric solvent-free aldol reaction catalyzed by L-proline (Scheme 21.27). Especially, reactions of cyclohexanone (1.1 equiv) and various crystalline aromatic aldehydes were studied under the ballmilling conditions (250-400 rpm) at room temperature. To evaluate the effect of the mechanochemical technique, comparative studies using conventional stirring were carried out for each reaction. 

Scheme 21.28 Influence of milling parameters on the solvent-free aldol reaction.

Another proUne-based catalyst was also tested in solvent-free aldol reactions under baU-miUing conditions, for example, derivatives of l,T-binaphthyl-2,2 -diamine or proUne-based dipeptides. Nijera [62] and coworkers used a combination of (SJ-binam-bis-L-prolinamide and benzoic acid to catalyze a direct aldol reaction under solvent-free conditions using conventional magnetic stirring. In addition, comparative studies with ball milling (400 rpm) were carried out for the reaction of cyclohexanone and 4-nitrobenzaldehyde but no improvement was observed. After 1.5 h quantitative conversion and similar diastereoselectivity and enantioselectivity were obtained using these methods [62]. Moreover, a study... 

When aliphatic nitro compounds are used instead of aldehydes or ketones, no reduction occurs, and the reaction has been referred to as a Tollens reaction (see 16-43). However, the classical condensation of an aliphatic nitro compound with an aldehyde or ketone is usually called the Henry reaction or the Kamlet reaction, and is essentially a nitro aldol reaction. A variety of conditions have been reported, including the use of a silica catalyst, Mg—A1 hydrotalcite, a tetraalkylam-monium hydroxide,proazaphosphatranes, " or an ionic liquid.A solvent free Henry reaction was reported in which a nitroalkane and an aldehyde were reacted on KOH powder. Potassium phosphate has been used with nitromethane and aryl aldehydes. The Henry reaction has been done using ZnEt2 and 20%... 

Chemoselective, Solvent-free aldol Condensation Reactions... 

Raston. C.L. Scott. J.L. Chemoselective, solvent-free aldol condensation reaction. Green Chem. 2000. 2. 49-52. 

The isomerization of an O-silyl ketene acetal to a C-silyl ester is catalyzed by a cationic zirconocene—alkoxide complex [92], This catalysis was observed as a side reaction in the zirconocene-catalyzed Mukaiyama aldol reactions and has not yet found synthetic use. The solvent-free bis(triflate) [Cp2Zr(OTf)2] also catalyzes the reaction in nitromethane (no reaction in dichloromethane), but in this case there may be competitive catalysis by TMSOTf (cf. the above discussion of the catalysis of the Mukaiyama aldol reaction) [91] (Scheme 8.51). 

Arnett and coworkers later examined the reaction of lithium pinacolone enoiate with substituted benzaldehydes in THE at 25 °C. The determination of the heat of reaction indicated that the Hammett p value for the process is 331. Although the aldol reaction was instantaneous in THF at 25 °C, the reaction with o- or p-methylbenzaldehyde could be followed using a rapid injection NMR method in methylcyclohexane solvent at —80 °C. Application of Eberson s criterion based on the Marcus equation, which relates the free energy of ET determined electrochemically and the free energy of activation determined by kinetics, revealed that the barriers for the ET mechanism should be unacceptably high. They concluded that the reaction proceeds via the polar mechanism . Consistent with the polar mechanism, cyclizable probe experiments were negative . The mechanistic discrepancy between the reactions of benzaldehyde and benzophenone was later solved by carbon kinetic isotope effect study vide infraf. ... 

Catalysis in reaction systems with undissolved substrates and products is not restricted to biocatalysis. High yields in sobd-state synthesis, sohd-to-sohd reactions, and solvent-free systems have also been reported for aldol condensation, Baeyer-Villiger oxidation, oxidative coupling of naphthols, and condensation of amines and aldehydes [1, 2]. 

The Cannizzaro reaction, that is, the base-catalysed disproportionation of a carbonyl compound to an alcohol and a carboxylic acid, has gained some importance as an economically viable alternative to the reduction with borohydrides. However, the reaction is restricted to carbonyl compounds without any a-hydrogen, which do not undergo competing aldol reactions. Thus, mainly aromatic aldehydes are used for this kind of transformation. The protocols developed for microwave applications typically involve solvent-free conditions using alumina as the solid support. Under these conditions, a significant acceleration of the reaction was achieved. 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

A variety of Brpnsted acid sources - benzoic acid, silica gel, 3 A molecular sieves - catalyse vinylogous aldol reactions of O-silyl dienolates, under solvent-free conditions.140... 

The indium trichloride-catalyzed Mukaiyama aldol reaction of 3-aminoketoesters with various silylenolethers gave under solvent-free conditions 1,3-amino alcohols with high stereoselectivity [36], Several Robinson annelation reactions have been carried out enantio-selectively using (S)-proline as a chiral catalyst [37]. Remarkably, the enantioselectivity was distinctly higher in the absence of solvent than in DMSO. 

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