Solvent-free conditions aldol reactions

T pe of reaction C-C bond formation Reaction condition solvent-free Keywords aldol reaction, proline... 

Reproduced from Herndndez JG, Garcfa-Ldpez V, Juaristi Solvent-free asymmetric aldol reaction organocatalyzed by (S)-prollne-contalnlng thiodipeptides under ball-milling conditions. Tetrahedron 2012 68 92-7. Copyright (2012), with permission from Elsevier. 

Reproduced with permission from Machuca E, Rojas Y, Juarlsti E Synthesis and evaluation of (S)-prolhe-contalnlng a. p-dipeptides as organocatalysts In solvent-free asymmetric aldol reactions under ball-milling conditions. Asian J Org Chem 2015 4 46-53. Copyright (2015), Wiley. 

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. 

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. 

Loh et al. reported that InClj worked as an effective catalyst of aldol reactions of SEE in water [77]. Later, Kobayashi et al. reported different results [78] - hydrolysis of SEE is faster than the desired reaction in the InCls-catalyzed aqueous system the InCls-catalyzed reaction proceeds to some extent under solvent-free conditions InCls is an effective catalyst in micellar systems. 

Loh et al have demonstrated the stereoselective synthesis of 1,3-amino alcohols based on the InCla-catalyzed Mukaiyama aldol reaction of a keto ester under solvent-free conditions. The high selectivity has been explained by the influence of a remote group present in the keto ester (Scheme 5.45). 

Aldol reactions. Aldol products are obtained in good yields from reaction of ketones with glyoxylic acid monohydrate with assistance of ultrasound irradiation. Substrate-control (by 1,3- + 1,5-asynmietric induction) of the aldol reaction involving y-amino-a-ketoesters under solvent-free conditions is very effective.- With lithium dicyclohexylamide and InCl, the reaction of esters with aldehydes furnishes P-hydroxy esters, and that of a-bromo esters affords a,p-epoxy esters." These are typical Reformatsky and Darzens reaction products, respectively. 

Aldol reactions. Reaction between two aldehydes proceeds under solvent-free conditions. It is perhaps useful for the preparation of a-substituted cinnamaldehydes. 

Tanaka K, Asakura A, Muraoka T, Kalicki P, Urbanczyk-Lipkowska Z. Asymmetric direct aldol reactions catalyzed by chiral amine macrocycle-metal(II) complexes under solvent-free conditions. N J Chem 2013 37 2851-5. 

Hemindez J, Juaristi E. Asymmetric aldol reaction organocatalyzed by (5)-Proline-Containing Dipeptides Improved stereoinduction under solvent-free conditions. 1 Org Chem 2011 76 1464-7. 

Since the introduction of the first peptide organocatalyst in the 1980s, a considerable number of new peptide frameworks have been developed that are able to effectively catalyse several important transformations including alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxidation are discussed. A few successful examples of solid-supported peptides and reactions in ball milling under solvent-free conditions have been demonstrated. These methods combine the advantages of being economically and environmentally friendly processes. 

The cross-aldol reaction between propionaldehyde (5, R =Me) and several aromatic aldehydes (2, R =Ar) under dry or wet solvent-free conditions has been accomplished using BINAM-prolinamides 62 (5 mol%) or 63 (10 mol%) in the presence of benzoic acid as catalyst (10 and 5 mol%, respectively). After reduction... 

A more complex sulfur-proUne catalyst is sulfoimidamide of type 84 (Fig. 4.9). This catalyst, together with its diastereoisomer, have been tested in the aldol reaction between cyclohexanone (3b, 5 equiv.) and aromatic aldehydes to afford the corresponding aldol products, with best yields and selectivities being obtained using compound 84 (10 mol%) under ball-mill solvent-free conditions (22-84% yield, 84-92% de, 89-98% ee) [152]. 

Chiral pyrrolidine-triazole 91 (10 mol%), obtained by click chemistry , was used as catalyst in combination with TFA (1.5 mol%) in the aldol reaction between cyclohexanone (10 equiv.) and several aldehydes under solvent-free conditions at 0°C, affording the aldol products in good yields and diastereoselectivities (86-93% yield, 84-92% de) albeit with low enantioselectivities (23-28% ee) [161]. 

List demonstrated that the L-proline-catalyzed aldol reaction of hydroxyacetone (39) with aldehydes furnished a t/-aldols in a regio- and stereoselective manner but with modest yields [65]. Diastereoselectivity was high for aliphatic, branched aldehydes and low for aromatic ones [14]. The use of TBDMS-protected hydroxyacetone as a donor led to an increase in yield and diastereoselectivity and a decrease in enantioselectivity [66]. Under solvent-free conditions, (5)-BINAM 13a generates aldols with high regio- and diastereocontrol but with hardly any enantiomeric excess [34c]. The enantioselectivity increased to a satisfactory level after... 

A methodologically similar approach was successfully utilized independently for the synthesis of the oviposition attractant pheromone of the female Culex mosquito (—)-(5/ ,6S )-6-acetoxyhexadecanolide (28), by Kotsuki et al. 45) and Li et al. 46). While the Li group carried out a direct aldol reaction between undecanal (23) and cyclopentanone (24) to obtain the desired isomer 25 in excellent enantio- and diastereoselectivity, the Kotsuki group introduced the stereogenic centers by a reaction between 24 and the dithiane 26 under solvent-free conditions (Scheme 7). 

Chalcones (123) are commonly prepared by Claisen-Schmidt or aldol condensation. An important way to synthesize chalcones (123) is the Friedel-Crafts acylation involving treatment of acid chlorides (121) with arenes (122). Such a protocol for the synthesis of chalcones (123) was developed by More et al. (2012) using nano-ZnO heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 9.38). Arenes (122) of all sorts, activated as well as unactivated, reacted smoothly to afford the chalcones (123) in excellent yield. High regioselectivity was observed during the course of reaction, which occurred selectively at the para-position of OMe, Br, Me, and Cl. 

In the same context, Trombini et al. developed other organocatalysts of this type bearing an imidazolium. Under solvent-free conditions, these catalysts were shown to be highly efficient at a remarkably low catalyst loading of 0.1 mol % to induce excellent stereoselectivities in the aldol reaction of cyclohexanone with aldehydes in the presence of water (Scheme 2.8). Moreover, exceptionally high values of TON (up to 930) were achieved in the case of the most reactive aromatic aldehydes. 

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