Carboxylic acid chlorides oxalyl chloride-dimethylformamide

Preparation of acid chlorides. The thionyl chloride method of preparing acid chlorides fails with some carboxylic acids (e.g., p-NOjCsHaCOzH) and with all sulfonic acids. Bosshard and co-workers" found that dimethylformamide catalyzes both reactions, either when used as solvent or when employed in catalytic amount in an inert solvent. The reactive, hygroscopic intermediate dimethylformirainium chloride was isolated from one equivalent each of dimethylformamide and thionyl chloride, and also obtained by reaction of dimethylformamide with phosgene, oxalyl chloride, or phosphorus pentachloride. It reacts with an acid with regeneration of dimethylformamide, the catalyst. In one example, 0.3 mole of p-nitrobenzoic acid was heated briefly at 90-95° with 0.315 mole of thionyl chloride and 0.03 mole... 

Briefly, carboxylic acid 14 which must be an essentially pure enantiomer (ratio 98 2) is converted to acid chloride 15 which is an oil that needs to be directly reacted with Meldrum s acid 16 in the presence of 2 moles of pyridine to yield 17 as a stable solid however, a slurry of 17 is treated with glacial acetic acid to provide 18 directly and 17 is not isolated. The process is telescoped in practice, and all the reactions are carried out in dichloromethane, which is recovered and recycled. Thus, 14 is converted into 15 using only a 10% molar excess of oxalyl chloride using 10 mole% of dimethylformamide as catalyst. The reaction is complete after 3 h reaction at room temperature (20 to 25°C) concentration and removal of the dichloromethane yields 15 as a crude oil that is suitable for direct reaction with Meldrum s acid and pyridine at 0 to 5°C in the relative molar ratio 1 2 in fresh dichloromethane. Workup with dilute hydrochloric acid and layer separation followed by water washes results in a solution of 17 in dichloromethane. The solution is concentrated to a slurry, which is treated with acetic acid at about 70 to 80°C to form 18. The reaction mixture is worked up by adding dichloromethane and washing with aqueous sodium carbonate followed by water washes. Concentration of the washed dichloromethane layer yields enantiomer 18 that is equal in optical purity to that of the starting carboxylic acid 14. The concentrate is vacuum distilled to provide a chemically stable and chemically pure ketone 18. This material has been shown to have a shelf life of 5 years at room temperature (Scheme 11.4). 

It is formed on treatment of dimethylformamide with SOCl2, PC15, PC13, oxalyl chloride, or phosgene and affords the acid chlorides from carboxylic or suflonic acids [reaction (g)]. 

Pettit and Nelson (1986) have designed an apparatus for diazo ketone preparation in which the carboxylic acid is first treated with oxalyl chloride dissolved in ether in one compartment. The acid chloride is formed after addition of triethylamine and a catalytic amount of dimethylformamide. Then the solution is filtered and added to ethereal diazomethane at -78°C in the second compartment. 

The main applications of oxalyl chloride, as described in Chapter 4, are the formation of aryl isocyanates and chloroformates (by reactions with amines and hydroxylic substrates, respectively), and the formation of acyl chlorides from carboxylic acids under very mild conditions. Oxalyl chloride reacts with amides to give acyl isocyanates, and it is used with dimethyl sulfoxide as a mild reagent for the oxidation of alcohols (Swern-type oxidation). It is also used with N,N-dimethylformamide as a mild reagent for chlorination and formylation. Oxalyl chloride is widely used in commercial formulations of speciality polymers, antioxidants, photographic chemicals, X-ray contrasting agents, and chemiluminescent materials. Other physical properties are presented in Chapter 3. 

Esterification.—iVAWW -Tetramethylchloroformamidinium chloride, which is readily prepared from iVAWW -tetramethylurea and oxalyl chloride, is an efficient reagent for the esterification of carboxylic acids with alcohols yields of between 66 and 97% are obtained, and the method has also been applied to macrolide synthesis. A modified one-pot procedure for the esterification of carboxylic acids, using phenyl dichlorophosphate-dimethylformamide complex, has appeared. A simple method of activation of carboxylic acids, using methanesulphonyl chloride and triethylamine followed by addition of the alcohol and 4-dimethylaminopyridine, leads to esters in 57— 96% yield for thirteen examples. 0-Methylcaprolactim reacts with carboxylic acids to give methyl esters in 73—91 % yield for seven examples and 2-iodoethyl esters are prepared from acyl chlorides, ethylene oxide, and sodium iodide. Transesterification, catalysed by titanium(iv) alkoxides, provides an effective method for synthesis of esters. Diethyl trichloromethylphosphonate reacts with carboxylic acids to give ethyl esters via transesterification, in 52 to 98 % yield. ... 

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