Chloroacetic acid, decarboxylation

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

Trichloroacetic acid K = 0.2159) is as strong an acid as hydrochloric acid. Esters and amides are readily formed. Trichloroacetic acid undergoes decarboxylation when heated with caustic or amines to yield chloroform. The decomposition of trichloroacetic acid in acetone with a variety of aUphatic and aromatic amines has been studied (37). As with dichloroacetic acid, trichloroacetic acid can be converted to chloroacetic acid by the action of hydrogen and palladium on carbon (17). 

Dissolve 1 g of chloroacetic acid in 3 ml of water, and add slowly, cooling in tap water, 0.6 g of solid sodium carbonate. Add 4 ml of a 20 per cent solution of sodium nitrite and a small boiling stone. Heat the tube slowly until a vigorous evolution of carbon dioxide begins, and then remove from the flame and allow the decarboxylation to proceed. The solution becomes yellowish brown and develops a strong odor of nitromethane. If desired, the nitromethane can be distilled from the reaction mixture. The yield is about 0.5 g. 

If glacial acetic acid or chloroacetic acid is chlorinated at a temperature rising slowly from 80° to 110° until the density (at 20°) reaches 1.6, a product is obtained of which about two-thirds is dichloro- and about one-third trichloro-acetic acid, together with about 3% of monochloroacetic acid.541 The trichloroacetic acid is removed by decarboxylation, achieved by heating the mixture (1500 g) with water (11) until no more chloroform distils. The water is distilled off and the residue fractionated in a vacuum, dichloroacetlc acid distilling at 102°/ 20 mm (900 g). 

Such decarboxylations are occasionally of industrial importance for example, primary amines may be monomethylated by converting them by chloroacetic acid into JV-substituted glycines which can then be decarboxyl-ated 15 / -(methylamino)phenol (Metol) is prepared industrially in this way. 

Aminopyrine (amidopyrine) may be prepared commercially first by treating antipyrine with nitrous acid to yield nitrosoantipyrine. The resulting product can now be routed through two different course of reactions, namely (a) treatment with two moles of chloroacetic acid followed by decarboxylation... 

Bromothieno[3,2-h]thiophene (19) was made by monolithiation of 3,4-dibromothiophene (14), followed by consecutive addition of elemental sulfur and chloroacetic acid to form the acid 15 (Scheme 3). After esterification, a carbaldehyde unit was introduced regioselectively by Vilesmeier reaction to yield 17. Treatment of 17 with sodium ethoxide induced ring closure and hence formation of 18, decarboxylation with the assistance of copper powder and quinoline giving 3-bromothieno[3,2-b]thiophene (19) [23]. 

Illustrative of its usefulness in organic chemistry is the O-alkylation of salicylaldehyde with chloroacetic acid, followed by decarboxylation of the resulting ether, produces benzofuran. 

Bugge68 also synthesized 3-methylthieno[2,3-hlthiophene (72) conveniently by metalation of 3-acetylthiophene ethylene ketal (69) followed by treatment with sulfur and methyl chloroacetate, cyclization of 70, and decarboxylation of 3-methylthieno[2,3- ]thiophene-2-carboxylic acid (71) [Eq. (26)]. 

The limited knowledge of thermal behaviour of halogenated acids has been extended significantly by a pyrolysis (infrared laser-powered) and semiempirical study which has established that mono-, di- and tri-chloroacetic, trifluoroacetic, and bromoacetic acid eliminate HX and that both bromo- and iodo-acetic acid undergo C—X bond homolysis acetic acid undergoes decarboxylation and dehydration under the same conditions.46 The semiempirical calculations of corresponding activation energies are consistent with these conclusions. 

The analysis depicted for (64) reveals that the synthesis of benzofuran involves the conversion of salicylaldehyde into the corresponding aryloxyacetic acid by reaction with sodium chloroacetate in the presence of alkali, followed by heating with a mixture of acetic anhydride, acetic acid and sodium acetate (Expt 8.24). The ensuing cyclisation may be regarded as an internal Perkin reaction (Section 6.12.3, p. 1036) accompanied by a decarboxylative dehydration step. 

Since glycidic esters can usually be prepared from carbonyl compounds and chloroacetic esters, hydrolysis of the ester group and decarboxylation of the resulting glycidic acid gives as end-product the aldehyde containing one carbon atom more than those in the aldehyde or ketone ... 

A further synthesis of quinuclidine was devised by Clemo and Metcalfe (197), who decarboxylated 2,4-lutidinic acid (CLVIII), obtuned by oxidation of 2,4-lutidine, and reduced the resulting pyridine-4-carT boxylic acid (CLIX) with sodium and alcohol. Esterification of the product afforded ethyl piperidine-4-carboxylate (CLX), which was condensed with ethyl chloroacetate to give ethyl piperidine-l-acetate-4-carboxylate (CLXII). Dieekmann cyclization followed by decarboxylation yielded 3-ketoquinuclidine, which on reduction by the Wolff-Kishner or Clemmensen methods gave quinuclidine. 

The alkylation of 38 with menthyl chloroacetate produced a diastereomeric mixture of phosphine oxides 39 and 39. These mixtures could be separated into individual diastereomers in 10 1% yields by fractional recrystallisation in hexane. Each epimer was subjected to hydrolysis to the corresponding acid and subsequent decarboxylation to afford the optically pure methylphosphine oxides 40. Both transformations occurred in very high, often quantitative, yield. This method was an advance because, as seen before, the introduction of encumbered groups by the original Mislow method is cumbersome. Moreover, methylphosphine oxides 40 are key intermediates to prepare diphosphines of the DiPAMP family (see Scheme 2.11). The chemistry of Scheme 2.14 has been used much more recently by Hii and co-workers to prepare series of ami-nohydroxy phosphine oxide ligands by coupling the acid derived from 39 (R = t-Bu) with (-)-norephedrine and (S)-valinol. 

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