Carboxylic acid derivatives intermolecular

The halogenated derivatives of six membered heterocycles, like their carbacyclic analogues, usually participate readily in coupling reactions that involve the incorporation of an olefin or carbon monoxide. The insertion of carbon monoxide commonly leads to the formation of either a carboxylic acid derivative or a ketone, depending on the nature of the other reactants present. Intermolecular and intramolecular variants of the insertion route are equally popular, and are frequently utilized in the functionalization of heterocycles or the formation of annelated ring systems. 

Additions of alkyl radicals onto carbonyl groups are reversible and energetically unfavorable because of strong n bond strengths of carbonyl bonds. Fragmentation reactions of oxy radicals are faster than additions to carbonyl groups. Thus, it is anticipated that carbonyl derivatives cannot be used as elficient radical traps. Only several carbonyl derivatives are effective to some extent in radical cyclizations. The intermolecular addition of alkyl radicals to carboxylic acid derivatives represents a radical acylation reaction in which carboxylic acid derivatives are required to be... 

Amides. Despite many investigations in the 1970s and 1980s on Pd-catalyzed a-arylation of carboxylic acid derivatives, that of amides had not been studied until recently. In 1998, the reaction of potassium enolates of 7V,7V-dimethylacetamide (DMA) and other amides with aryl bromides in the presence of catalytic amounts of Pd(dba)2 and bidentate phosphines, such as BINAP and dppf, was shown to provide the desired a-arylated products in up to roughly 70% yields, as shown in Table Diarylation competed with monoaryladon to the extent of up to 18%. Under the conditions used, the intermolecular reactions of amides other than acetamides were rather disappointing, as indicated by the last two entries in Table 5. Clearly, additional development is desirable. Its intramolecular cyclic version, however, is considerably more favorable, as discussed in the following subsection. 

For a complete description of the synthetic utility of the Houben-Hoesch reaction as it applies to other aromatic systems, as well as some mechanistic discussions, the reader is directed to two reviews on the subject. Due to the diminished electrophilic reactivity of nitriles compared to other carboxylic acid derivatives as well as the broad number of Friedel-Crafts substrates, most Houben-Hoesch pyrrole acylation reactions are conducted intramolecularly. However, an impressive intermolecular example was delineated by Chang and co-workers in efforts directed toward the synthesis of novel 2-[5-aroylpyrrolo]alkanoic acids, for evaluation of their potential analgesic and anti-inflammatory activities. Treatment of substituted pyrrole 4 and 3-cyanopyridine (5) with acid in dry chloroform resulted in the preparation of 6 in good yield. 

A one-pot synthesis of 1-indanones and 1-tetralones in good to excellent yields have been developed by reacting a series of alkenyl carboxylic acid derivatives with arenes in TfOH medium. The reaction involves dicationic intermediates involving intermolecular alkylation followed by intramolecular acylation (eq 31). These reactions have been further investigated. ... 

In 2007, Milstein reported an approach for the transition metal catalysed intermolecular formation of amides from alcohols and amines in the absence of a hydrogen acceptor (Scheme 12.19). In contrast with conventional amide synthesis from activated carboxylic acid derivatives which produces chemical waste, this environmentally benign approach produces hydrogen gas as the only byproduct. The catalyst used for this reaction is a dearomatised Ru(PNN)pincer complex which serves as a bifunctional catalyst. The ligands, as well as the metal centre, play a role in bond making or bond breaking steps of the catalytic cycle. 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

Pyrazolidine derivatives 16 were obtained from the intermolecular [3+2] cydo dd- between hydrazones 14 and olefins 15 <03TL3351>. A convenient method for the symhel s of 7//-pyrazole-4-carboxylic acid esters 18 from 3-ketaminoesters 17 has been reported using... 

The X-ray analysis allowed comparison of the geometrical features and the intermolecular interaction of the optically pure 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid 8 with some racemic derivatives <2006TA3179>. 

Figure 3.28 Nucleophilic participation by carboxylate in the departure of various leaving groups from mixed acetals of phthalic hemialdehyde Rate enhancements of these spontaneous processes of 100 for 3,5-dichloro-phenolate departure, 22 for thiophenolate departure " and 20 for catechol monoanion departure were estimated from the rates of the p-phthalic derivatives intermolecular general acid catalysis of the catechol was also accelerated.

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