Carboxylic acids intermolecular addition

The effect of a carboxy group is illustrated by the reactivity of 2-bromopyridine-3- and 6-carboxylic acids (resonance and inductive activation, respectively) (cf. 166) to aqueous acid under conditions which do not give hydroxy-debromination of 2-bromopyridine and also by the hydroxy-dechlorination of 3-chloropyridine-4-car-boxylic acid. The intervention of intermolecular bifunctional autocatalysis by the carboxy group (cf. 237) is quite possible. In the amino-dechlorination (80°, 4 hr, petroleum ether) of 5-carbethoxy-4-chloropyrimidine there is opportunity for built-in solvation (167) in addition to electronic activation. This effect of the carboxylate ion, ester, and acid and its variation with charge on the nucleophile are discussed in Sections I,D,2,a, I,D,2,b, and II,B, 1. A 5-amidino group activates 2-methylsulfonylpyridine toward methanolic am-... 

Choi and Sakakura et al. reported that iron(III) triflate, in situ formed from FeCls and triflic acid, efficiently catalyzes the intermolecular addition of carboxylic acids to various alkenes to yield carboxylic esters. The reaction is applicable to the synthesis of unstable esters, such as acrylates (Scheme 40) [50]. 

Scheme 40 Iron(III)-catalyzed intermolecular addition of carboxylic acids to alkenes...

The intermolecular addition of carboxylic acids to dienes is not very efficient. Conjugated dienes generally form polymeric products 456 whereas nonconjugated dienes tend to give polycyclic products (equation 277J.464 The addition to allenes, on the other hand, is marred by regio- or stereo-isomerism (equation 27S).465... 

Intermolecular Markovnikov-type addition of phenols (ArOH), carboxylic acids (RCO2H), and protected amines (TsNH2) to alkenes, such as 4-MeOC6H4CH2CH= CH2, can be catalysed by triflic acid in low concentrations (1-5%). Functional groups, such as the methoxyl on aromatics, can be tolerated if the concentration of triflic acid and the reaction temperature are controlled appropriately. This reaction provides one of the simplest alkene addition methods and can serve as an alternative to metal-catalysed reactions.33... 

PhsPAuOTf has been shown to catalyse the intermolecular addition of phenols and carboxylic acids to terminal alkenes, RCH2CH=CH2, at 85 °C in toluene with Markovnikov selectivity to produce RCH2CH(OR)Me.131 AUCI3 triggers the electrophilic 6(0)ir n-endo-dig cyclization of 2-(alk-l-ynyl)alk-2-en-l-ones to produce highly substituted furans in analogy with other electrophiles (see above Scheme 3).40... 

Apart from these two examples, in the rest of the olefin activations, gold coordinates to the olefin, turning it susceptible to nucleophilic attack. The early examples of alkene functionalization by gold catalysis (equation 144) focused on the intermolecular addition of 1,3-diketones to styrenes. " An intramolecular version with ketoamides to yield pyrrolidinones was later developed and followed by the intermolecular addition of phenols (equation 145) and carboxylic acids to double bonds,a work that included an example of intramolecular addition of an aliphatic alcohol to an olefin. 

Sb(OEt)3 is highly effective for the metal-templated cyclization of tetramino esters to give macrocyclic spermine alkaloids such as buchnerine, verbacine, verbaskine, and verbascenine (Eq. 3) [9]. The accelerated rates and high regioselectivities suggest a mechanism in which the acyclic tetramino esters are covalently or coordinately attached to the antimony before the final cyclization step. In addition, Sb(OEt)3 is useful as an intermolecular amidation catalyst for reactions between esters or carboxylic acids and amines (Eq. 4) [9]. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

Fluorine can share three sets of lone-pair electrons with electron-deficient atoms intramo-lecularly or intermolecularly, in particular with a relatively acidic hydrogen bound to a heteroatom. In addition, as described in section 1.4, strongly electron-withdrawing per-fluoroalkyl groups increase the acidity of proximate functional groups such as alcohol, amine, amide, and carboxylic acid. 

In addition to intramolecular effects, intermolecular interactions have been shown to modify the observed partition coefficient. These include association of polar molecules in apolar systems, or dissociation of acids (e.g., carboxylic acids or pro-tonated forms of amines, which are the conjugated acids of the amines). The analysis of these effects has been presented in an explicit form (136, 149, 150). A distinction has to be made however, between the types of intermolecular interactions. Association of neutral polar molecules in apolar solvents may influence the observed partition coefficient, but there is little doubt that the monomer is the compound that influences the biological activity through its interaction with the biological system. 

The intermolecular direct arylation of simple benzenes was also evaluated [12]. Under conditions established for the fluorinated substrates, none of the desired cross-coupled product was formed. With the goal of increasing the amount of soluble base in the reaction mixture, varying amounts of different carboxylic acids were added. Both the amount and the type of acid was found to influence significantly the reaction outcome, with larger acids used in substoichiometric amounts providing superior outcomes. For example, as the steric bulk is increased from acetic acid to pivalic acid, an increase in conversion is noted. Under optimal conditions, addition of 30 mol% pivalic acid results in 100% conversion of the aryl bromide and an 82% isolated yield of benzene direct arylation is obtained. To rationalize the reactivity, it was proposed that the potassium pivalate may behave as... 

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