Carboxylic acids synthesis from alkyl halides

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Polymeric phosphonium salt-bound carboxylate, benzenesulphinate and phenoxide anions have been used in nucleophilic substitution reactions for the synthesis of carboxylic acid esters, sulphones and C/O alkylation of phenols from alkyl halides. The polymeric reagent seems to increase the nucleophilicity of the anions376 and the yields are higher than those for corresponding polymer phase-transfer catalysis (reaction 273). 

Cristol, S J, Firth, W C, Convenient synthesis of alkyl halides from carboxylic acids, J. Org. Chem., 26, 280 1961. 

A combination of two of the reactions discussed in this chapter—alkylation of an a-carbon and decarboxylation of a j8-dicarboxylic acid—can be used to prepare carboxylic acids of any desired chain length. The procedure is called the malonic ester synthesis because the starting material for the synthesis is the diethyl ester of malonic acid. The first two carbons of the carboxylic acid come from malonic ester, and the rest of the carboxylic acid comes from the alkyl halide used in the second step of the reaction. 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Strategy The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane. 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

A procedure for enantioselective synthesis of carboxylic acids is based on sequential alkylation of the oxazoline 8 via its lithium salt. Chelation by the methoxy group leads preferentially to the transition state in which the lithium is located as shown. The lithium acts as a Lewis acid in directing the approach of the alkyl halide. This is reinforced by a steric effect from the phenyl substituent. As a result, alkylation occurs predominantly from the lower face of the anion. The sequence in which the groups R and R are introduced... 

Hydrolytic reactions can also be applied in the synthesis of aldehydes or ketones via the corresponding 1,3-oxazine derivatives. The anion formed from 3-methyl-2-(4-pyridyl)tetrahydro-l,3-oxazine 155 on treatment with BuLi proved to react with various electrophiles (alkyl halides, carboxylic esters, acid chlorides, or aldehydes) exclusively at position 2 of the 1,3-oxazine ring and not at the pyridine nitrogen atom. The readily formed 2,2-disubstituted-l,3-oxazine... 

Most commonly, the carboxylate anion is treated directly with an alkyl halide to give the corresponding ester212,371-373. A variety of metal counterions have been used to influence the yield, depending upon the substrates being used. Silver oxide has been used to assist this process in the synthesis of depsipeptide analogues from 2-bromocarboxamides and N-protected amino acids (equation 46)374. 

The malonic ester synthesis converts a primary or secondary alkyl halide into a carboxylic acid with two more carbons (a substituted acetic acid). Identify the component that originates from malonic ester (the acid component). The rest of the molecule comes from the alkyl halide, which should be primary or methyl. 

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