Chloral aldol reaction

Isocyanophosphonates, aldol reactions, 227 Isoquinoline synthesis, enamide reactions, 33 Isomerization allylic amines, 9, 95 olefins, 118, 171 see also specific compounds Isopulegol, 102 Isotactic polymers, 174 chloral, 182 photoirradiation, 347 methacrylates, 181 propylene, 174 Isotacticity, 177... 

In the case of the 9-catalyzed aldol reactions of ketones and aldehyde donors that have a high affinity for water (e.g., chloral, trifluoroacetaldehyde, aqueous formaldehyde or the corresponding hydrates of the aldehydes), the addition of 100-500 mol% water to the reaction mixture accelerated the reaction rate and afforded the products with higher enantiomeric excess (Scheme 2.13) [16]. The presence of a catalytic amount of water (20 or 50 mol%) or no addition of water... 

Scheme 2.13 Aldol reaction of a ketone and chloral catalyzed by 9 [16].

A similar trend may be seen in a study of the reaction of chloral with unsymmetrical ketones (equation S3 Table 3). Reactions were carried out in glacial acetic acid with or without added sodium acetate as catalyst. Several control experiments showed that the isomer ratios obtained were kinetic. The lack of reversibility in this reaction implies that AG is much more negative than for the simple aldol reactions discussed previously. This is presumably because of the inductive effect of the chlorines, which is known to favor hydration and other nucleophilic additions to chloral. 

Table 3 Regiochemistry of Aldol Reactions of Chloral with 2-Alkanones (equation 53)...

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

Mimicking the pyruvate aldol reaction has been a long-standing goal for chemists. In 2005, Dondoni and co-workers reported the dimerization of ethyl pyruvate in the presence of a diamine catalyst [53]. This donor also reacts with chloral monohydrate, giving the desired aldol with both moderate enantioselectivity (86% cc) and yield (55%), most likely due to insufficient reactivity [28c]. Pyruvic aldehyde dimethyl acetal is a decent aldol donor for aromatic as well as aliphatic aldehydes (Chart 3.3)... 

Proviso (iii) is more obvious and yet perhaps more often catches people out. It is not always clear in exactly what form the product is produced in the reaction mixture, though a good mechanistic understanding and careful thought should reveal this. The reaction between the simple aldehyde 14 and chloral (Cl3C.CHO) looks like a straightforward route to the aldol 17, and might reasonably be carried out via the enamine 16. 

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