Reaction at the Carboxyl Group

The chemical transformations of the carboxyl group include formation of halo[ C]acetyl halides, amides, imides, alcohols, aldehydes and amines. Methods for the preparation of halo[ C]acetyl halides from [ C]acetic acid have already been mentioned. In addition, chloro[ C]acetyl chloride has become available through treatment of chloro[ C]acetic acid with thionyl chloride or phthaloyl chloride, whereas for bromo[ C]acetyl chloride, thionyl chloride or phosphorus pentachloride is recommended. Numerous applications of halol Clacetyl halides have been published, out of which the following C-, N- and 0-acylations may illustrate their versatility. 

Friedel-Crafts acylation of fluorobenzene using bromo[l- C]acetyl chloride provided exclusively 2-bromo-4 -fluoro[carbonyl- C]acetophenone 1821. which was an early intermediate in the synthesis of [ C]fluvastatin (85), a HMG-CoA reductase inhibitor . Reaction of 82 with N-isopropylaniline followed by ZnCla-mediated cyclization of the resulting /3-aminoketone 83 gave 3-(4-fluorophenyl)-l-isopropyl-l//-[3- C]indole 1841. a key intermediate in the synthetic pathway selected. 

The alcoholysis of halo[ C]acetyl halides is one of the standard methods for the preparation of low molecular weight alkyl chloro- and bromo[ C]acetates . Other methods comprise the esterification of the free haloacids with diazomethane or -ethane (methyl/ethyl halo[ C]acetates) , with the respective primary alcohol in the presence of HCl gas or with 1,3-dicyclohexylcarbodiimide and 4-pyrrolidinopyridine (tert-butyl and benzyl halo[ C]acetates) .  

Reduction of bromo[l- C]acetic acid with BH3-Me2S in ether or THF or of methyl bromofl- Clacetate with AIH3 in ether furnishes 2-bromo[l- C]ethanol (94) in 

If the corresponding nucleophilic partners (or centers) are located in the same molecule, then 94 may be exploited for the construction of heterocyclic systems. This is illustrated in 

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The identities of the two VL complexes are not known with certainty, but the available evidence suggests the -557 ppm-type products arise from monodentate reaction at the carboxylate group, whereas the -544 ppm products derive from monodentate reaction at the nitrogen functionality. Additional products from amino acids with reactive sidechains, as found in serine or aspartic acid, have not been reported.51V chemical shifts for products formed with histidine are similar to those observed for other amino acids, except that an additional signal (-571 ppm) has been observed [66],... 

Figure 4. Exchange reactions at the carboxyl group (1) hydrolysis (Chapter xx), (2) esterification (Chapter xx), (3) acidolysis (Chapter xx), (4) alcoholysis (Chapter xx), and (5) glycerolysis (Chapterxx). The starting ester RCOOR will often be a triacylglycerol. MAG—monoacylglycer-ol DAG—diacylglycerol TAG—triacylglycerol.

Using the zwitterion form of alanine (53) as an example, treatment with acid generates 85. The amine unit already exists as its ammonium salt, and the carboxylate anion reacts with aqueous acid to give the COOH unit. There is no unshared electron pair on nitrogen in the ammonium salt, so there is no interference with reactions at the carboxyl group. Therefore, if 85 is treated with ethanol in this acidic solution, the product is the ammonium ester 86. 

Lipase PS has also demonstrated excellent biocatalytic potential for use in the O-acylation ofhydroxymethylated P-lactam compounds. Lipase PS, much like CAL-B, is capable of catalyzing N-acylation as well as reactions at the carboxylic group of the P-amino ester [27]. 

Preparation of Carbon-14-Labeled Compounds 309 6.2.1 Reaction at the Carboxyl Group... 

Reactions at the double bond and at the a-carbon Reactions of the carboxyl group ... 

An important example of this type of reaction is the formation of esters, which was discussed previously in connection with the reactions of alcohols in Section 15-4D. Similar addition-elimination mechanisms occur in many reactions at the carbonyl groups of acid derivatives. A less obvious example of addition to carboxyl groups involves hydride ion (H 0) and takes place in lithium aluminum hydride reduction of carboxylic acids (Sections 16-4E and 18-3C). 

CoA labeled with 14C (radioactive carbon) at the carboxyl group, CH3—14C—SCoA, into the citric acid cycle, the 2-oxopentanedioate acid (2-ketoglutarate) formed in the fourth step of the cycle would have all of the 14C in the carboxylate group farthest away from the ketone carbonyl group. For some years, this result was used to argue that citric acid itself could not be an intermediate in the formation of 2-oxopentanedioate. Review Section 19-8 and explain how, in stereospecific enzyme-induced reactions, citric acid could be an intermediate in the formation of 2-oxopentanedioate even if the 14C would not appear equally in both carboxylic carbons of the product. 

An interesting method for the introduction of substituents into the 2-position of the quinuclidine ring starting from 3-substituted A2-dehydroquinuclidines (126) has been described.47 By the reaction of methyl J2-dehydroquinuclidine-3-carboxylate (130) with iso-propylmagnesium bromide, 1,4-addition with formation of 2-iso-propyl-3-methoxycarbonylquinuclidine (131) took place instead of a sterically hindered Grignard reaction at the alkoxycarbonyl group. 

Intermediate 23b can be obtained by a direct nucleophilic attack of the uncharged amino group (present at low equilibrium concentration at pH 7) but the mechanism of this step may be more complex as shown by the observation of a catalytic effect of CO2 in amidations using CDI [191]. Moreover, the reaction of the carboxylate group followed by an intramolecular acyl transfer is also a possibility. CDI-promoted peptide formation was shown to display... 

In other words the higher the electronegativity of the leaving group X in the acylating agent R—C(=0)—X, the better stabilized is the tetrahedral intermediate of an SN reaction at the carboxyl carbon. Whether this tetrahedral intermediate happens to be an alkoxide and is... 

As the last example of an SN reaction at the carboxyl carbon of a carbonic acid derivative, consider the synthesis of dicyclohexylurea in Figure 6.39. In this synthesis, two equivalents of cyclohexylamine replace the two methoxy groups of dimethyl carbonate. Dicyclohexylurea can be converted into the carbodiimide dicyclohexylcarbodiimide (DCC) by treatment with tosyl chloride and triethylamine. The urea is dehydrated. The mechanism of this reaction is identical to the mechanism that is presented in Figure 8.9 for the similar preparation of a different carbodiimide. 

In a similar manner the reaction of sodium 2-bromobenzoate with the carbanion derived from pentane-2,4-dione initially yields the dioxo acid (490). In ethanol, a retro-Claisen deacylation leads to 2-acetonylbenzoic acid (491), but at higher temperatures 3-methyI-isocoumarin is formed (Scheme 177) (75JCS(P1)1267). Copper(I) bromide may be used as a catalyst, although this is only necessary for the initial step. The cyclization process is considered to involve reaction between the carboxylate group and an enolate ion arising from loss of one of the acyl groups. A similar reaction occurs with l-bromo-2-naphthoic and 3-bromo-2-naphthoic acids giving the naphtho[2,l-c]pyran-4-one (492) and naphtho[2,3-c]pyran-l-one (493), respectively. 

Photoreactions involving benzoic add are not common, but it is now reported that the arene moiety is susceptible to substitution in the presence of sodium hypochlorite in aqueous alkali at pH > 12. At ratios of the order of 0.1 for [Q0 ] [PhC02 l, hydroxylation and chlorination of the aromatic ring occur simultaneously with ipso substitution at the carboxylate group (which yields phenol). At high relative concentrations of hypochlorite, the photo-products react further in the dark to yield polychlorinated derivatives. The reaction is discussed in terms of the initial steps being the generation of the active species 0( P), 0( D), O, and Cl from irradiation of C10 . 

Reaction of iV,A -unsubstituted selenoureas with a 1,2-diaza-l,3-butadiene affords 2-amino-4,5-dihydro-l,3-selenazol-4-ones 81 mainly in the hydrazono form. The reaction proceeds via nucleophilic addition of the selenium atom to the terminal carbon atom of the heterodiene. The subsequent intramolecular nucleophilic attack by the imidic NH at the carboxylate group with the loss of methanol leads to the selenazole ring closure (Scheme 14) <2002EJO2323, 2001SL144>. 

Any reaction that takes place at the carboxyl group C-C = C-C = C/-COOH... 

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