Carboxylic acid alkyl esters, alkylation

Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion the reaction of carboxylic acids with diazo compounds, especially diazomethane and alkylation of carboxylate anions by halides or sulfonates. The esterification of carboxylic acids with diazomethane is a very fast and clean reaction.41 The alkylating agent is the extremely reactive methyldiazonium ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid. 

Scheme 24 Cathodic alkylation of carboxylic acids to esters R alkyl, aryl, R alkyl, yields 24-96%.

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Halogenations with dihalotriphenylphosphoranes have been reviewed briefly by Fieser and Fieser.4 Dibromotriphenylphos-phorane appears to have been studied somewhat more than the dichloro compound, but both reagents effectively convert alcohols to alkyl halides, carboxylic acids and esters to acid halides, etc. The reaction of 1,2-epoxycyclohexane with dibromotriphenylphos-phorane under conditions similar to those described here gives a mixture of cis- and trans-1,2-dibromocyclohexanes. A reagent prepared from triphenylphosphine and carbon tetrachloride has been used for similar transformations.5... 

Although the alkyl and acyl products shown in Eqs- 15.140 and 15 141 have been isolated and characterized, they are frequently allowed to simply form as intermediates. which are then treated directly to produce aldehydes, carboxylic acids, ketones, esters, or amides. 

So far, only a limited use of thiazolidine-2-carboxylic acid (12) in peptide synthesis has been reported. This amino acid has been acylated as the alkyl ester with suitably N-protected amino acids via the HOBt/DCC method. 165 Subsequent saponification of peptidyl-thiazolidine-2-carboxylic acid ethyl ester proceeds smoothly with 1M NaOH in dioxane/water mixtures. 165 ... 

Skubla [9] has designed a group contribution scheme which applies for various homologous series. His method relies on eq. 6.2.1 where both coefficients a0 and a have to be derived from group contributions and with respect to Nc. The model applies for n-alkanes, 1-alkenes, n-alkylcyclopentanes and n-alkylcyclohexanes, alkylbenzenes, 1-bromoalkanes, 1-alkanols, di-n-alkyl ethers, carboxylic acids and esters, 1-alkanethiols, 1-aminoalkanes, dialkylamines, alkaneamides, and some... 

An unexpected aromatization that takes place during the A-alkylation reaction performed on several 3-(2-nitrobenzoyl)-4,5-dihydro-l //-pyrazolc-5-carboxylic acid methyl esters, giving rise to a mixture of l-alkyl-3-(2-nitrobenzoyl)-4,5-dihydro-1 II-pyrazole-5-carboxylic acid methyl esters and 1 -al kyl-3-(2-ni trobcnzoyl)-1 //-pyrazole-5-carboxylic acid methyl esters is reported. It is suggested that reaction involves both inter- and intra-molecular oxidation by the nitro group.107... 

Solutions of triethylamine (Et3N) 14 (1.0M), premixed carboxylic acid/alkyl chloroformate (1.0 M respectively), and 4-dimethylaminopyri-dine 15 (0.5 M) in MeCN were introduced into the reactor from separate inlets and the reaction products collected at the outlet in MeCN, prior to analysis by gas chromatography-mass spectrometry (GC-MS). Under optimized reaction conditions, the authors were able to synthesize the methyl 16, ethyl 17, and benzyl 18 esters in quantitative conversion, with no anhydride or deprotection by-products detected (as observed in conventional batch reactions). In addition to the Boc-glycine derivatives illustrated in Scheme 4, the authors also esterified a series of aromatic carboxylic acids with yields ranging from 91 to 100%, depending on the additional functional groups present. 

With certain compounds, such as pyrazoline carboxylic acids and esters, potassium ferricyanide or silver nitrate has been used,509 and for those compounds unsubstituted on nitrogen, mercuric oxide or acetate.76 Lead dioxide has been successful for the oxidation of 1-alkyl-and 1-arylpyrazolines,9i 76,83 and in certain instances even chromic acid, but not hydrogen peroxide or silver oxide.76 See also L. Smith521 and Birkinshaw et al.b22... 

Functional Group Transformation Alcohols can be prepared by nucleophilic substitution of alkyl halides, hydrolysis of esters, reduction of carboxylic acids or esters, reduction of aldehydes or ketones, electrophilic addition of alkenes, hydroboration of alkenes, or substitution of ethers. 

All other carboxylic acid derivatives in Table 6.1, in which the leaving group is bound to the carboxyl carbon through an O atom, are increasingly better acylating agents than carboxylic acid alkyl esters (entry 3) in the order carboxylic acid phenyl ester (entry 4) < acyl isourea (entry 7) < mixed carboxylic acid/carbonic acid anhydride (entry 8) < carboxylic acid anhydride (entry 9) < mixed carboxylic acid anhydride (entry 10). 

Hydrides from carboxylic acids Carboxylic acids from hydrides Carboxylic acids from hydrides Esters from hydrides Hydrides from aldehydes Hydrides from aldehydes Alkyls from aldehydes Ketones from methylenes Ketones from ketones Alkyls from olefins Acetylenes from halides also acetylenes from acetylenes Esters from alcohols also esters from carboxylic acids Alkyls from olefins Alkyls from olefins... 

Alkynes from halides also alkynes from alkynes Esters from alcohols also esters from carboxylic acids Alkyls from alkenes (Conjugate Reduction)... 

Table 8 Examples of 3-Alkyl- and 3-Aryl-[l,2,4]triazolo[4,3-a]pyridines Prepared from 2-Hydrazinopyridines and Carboxylic Acids, Anhydrides, Esters or Ortho Esters <66JOC25i, 78JHC439.7OJHC703,70JHC1019)...

In aliphatic compounds the normal compound has usually the highest b.p.7 Menschutkin considered that, with alcohols, it is not the primary, secondary, or tertiary character that determines the b.p. (primary > secondary >tertiary), but the position of the side-chain relative to hydroxyl. With alcohols, alkyl halides, amines, carboxylic acids, and esters, the b.p. is lower the nearer the side chain is to the substituent. This holds especially for higher homologues, e.g. amyl, hexyl, and heptyl alcohols and derivatives. 

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