Carboxylic acid derivatives condensation reactions

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The same type of reaction has been applied to the preparation of 1,2-dihydroquinoline-3- and 277-l-benzothiopyran-3-carboxylic acid derivatives (equation 38) via a magnesium amide-induced sequential conjugate addition-aldol condensation reaction between 2-(alkylamino)phenylketones or 2-mercaptobenzophenones . 

The ring closure of L-cysteine by reaction with aldehydes or ketals 190 194 involving Schiff s base intermediates 195 leads to (4R)-thiazolidine-4-carboxylic acids. Except for formaldehyde and symmetrical ketones, the condensation of L-cysteine with aldehydes or unsymmetrical ketones generates a mixture of epimers, i.e. (25,4R)- and (2R,4R)-thiazolidine-4-carboxylic acid derivatives that can be separated by RP-HPLC or fractional crystallization. 139 ... 

The reaction of cysteine with aliphatic aldehydes, 196 e.g. acetaldehyde, or with aromatic aldehydes, 196 197 e.g. benzaldehyde, leads to the corresponding 5-monosubstituted thiazoli-dine-4-carboxylic acid derivatives, whereas condensation of cysteine with ketones, such as... 

Among the enolates of carboxylic acid derivatives, esters are the most widely used. Ester enolates cannot be used in crossed aldols with aldehydes because the aldehyde is both more enolizable and more electrophilic than the ester. It will just condense with itself and ignore the ester. The same is true for ketones. A specific enol equivalent for the ester will therefore be needed for a successful ester aldol reaction. 

An asymmetric total synthesis of (—)-secodaphniphylline was carried out using a mixed Claisen condensation between (—)-methyl homosecodaphniphyllate (11) and a carboxylic acid derivative 154 with the characteristic 2,8-dioxabicyclo[3.2.1]octane structure commonly found in the daphniphyllum alkaloids (Scheme 18.23) [68,69]. The necessary chirality was secured by an asymmetric Michael addition reaction of... 

The reaction of benzaldehyde with phenylacetic acid to produce a mixture of the a-carboxylic acid derivatives of Z- and -stilbene a form of aldol condensation known as the Perkin reaction, is effected by heating a mixture of the components with acetic anhydride and triethylamine. In the course of the reaction the phenylacetic acid is probably present both as anion and as the mixed anhydride resulting from equilibration with acetic anhydride. A reflux period of 5 h specified in an early procedure has been shortened by a factor of 10 by restriction of the amount of the volatile acetic anhydride, use of an excess of the less expensive, high-boiling aldehyde component, and use of a condenser that permits some evaporation and consequent elevation of the reflux temperature. 

L22,13 and L24.12,14 Many carboxylic acid derivatives such as esters, amides, and chlorides or anhydrides may also be used. The same reaction conditions can be applied to the condensation reaction of aromatic nitriles with o-phenylenediamine for the synthesis of H2L8,15 H2L13, and L13a.16,17... 

Generally the esters are warmed together and the alkane thiol driven off. The acids, on the other hand, are condensed in an alkali hydroxide solution and then refluxed with hydrochloric acid to make the ring closure go to completion. This same procedure is followed with the nitriles to hydrolyse the imino group which is formed as an intermediate. These reactions show much similarity to those of a-amino carboxylic acid derivatives with carbon disulfide (compare Section V). Table 32 shows the products which may be prepared by this technique. 

S,S-dioxides, those authors applied spHt/pool methodology. TWo different series of compounds were prepared such as compounds 376 containing an amino acid group acylated at the nitrogen atom. According to strategy 1 shown in Scheme 90, a series of structurally diverse carboxylic acid derivatives were prepared from supported aldehyde 373 condensed with different protected amino acids in the presence of NaBH(OAc)3 to afford intermediate 374, which was then acylated affording 375. After hydrolysis of ester and reaction with bromo derivative 368 (R = H) in PTC conditions, compounds 376 were obtained. 

Carboxylic acid derivatives, like aldehydes and ketones, can also undergo a-substitution and carbonyl-carbonyl condensation reactions. 

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

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