Carbomethoxypropionyl Chloride

Methyl hydrogen succinate. A mixture of 400 g. (4 moles) of succinic anhydride (Note 1) and 194 ml. (4.8 moles) of methanol (Note 2) in a 1-1. round-bottomed flask is refluxed on a steam bath. After about 35 minutes the mixture is swirled frequently until it becomes homogeneous (this requires 15-30 minutes) the flask is then half immersed in the steam bath for an additional 30-25 minutes (Note 3). 

The excess methanol is removed by distillation in vacuo (water pump) from a steam bath, and the residual liquid is poured into an 18- to 25-cm. evaporating dish which is cooled in a shallow pan of cold water. As the half ester crystallizes, it is stirred and scraped off the dish in order to prevent formation of a solid cate. After being dried to constant weight in a vacuum desiccator (5-8 days), the product weighs 502-507 g. (95-96%) and melts at 57-58° (Notes 4 and 5). 

0-Carbomethoxypropionyl chloride. In a 1-1. flask (Note 6) bearing a reflux condenser are placed 264 g. (2 moles) of methyl hydrogen succinate and 290 ml. (4 moles) of thionyl chloride (Note 7), and the solution is warmed in a bath at 30-40° for 3 hours (Note 8). The condenser is replaced by a modified Claisen still head, the excess thionyl chloride is removed on a steam bath in vacuo, and the /3-carbomethoxypropionyl chloride is distilled (Notes 9 and 10). The yield of colorless product is 270-278 g. (90-93%), b.p. 92-93°/18 mm. (Notes 11 and 12). 

Synthetic methanol was used. Since this anhydrous alcohol is hygroscopic, partially filled bottles that have been opened intermittently in the laboratory should be rejected. 

Thirty minutes is allowed if solution resulted after 15 minutes of swirling 25 minutes if 30 minutes was needed for homogeneity. 

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Carbomethoxypropionyl chloride, ml95 Carbon bromotrichloride, b432 /V-Carbonylsulfamyl chloride, c249 Carbonyl sulfide, cl2 Carboxybenzaldehyde, f37... 

Carbomethoxypropionyl chloride has been prepared from methyl hydrogen succinate by the use of thionyl chloride 6 or phosphorus pentachloride.3... 

Alkoxybenzo[6]thiophenes undergo electrophilic substitution in the 2-position. Thus, 6-ethoxybenzo[6]thiophene affords its 2-bromo, 2-formyl, and 2-acetyl derivatives on bromination, Vilsmeier-Haack formylation, and Friedel-Crafts acetylation, respectively,424 and 6-methoxybenzo[6]thiophene undergoes Friedel-Crafts reaction with /3-carbomethoxypropionyl chloride in the 2-position.618... 

A new synthesis of 1,2-disubstituted perhydropyridazine-3,6-diones has been developed. Succinic anhydride or 3-carbomethoxypropionyl chloride. 

The procedure described failed completely when a secondary bromide, 2-bromopentane, was used however, when the cadmium derivative was prepared at —5° to —7° and allowed to react in ether at this temperature with /3-carbomethoxypropionyl chloride, methyl 4-keto-5-methyloctanoate was obtained in a yield of 19.3%, b.p. 130.5-130.7721 mm. 

In some instances, at least, the cyclization can be carried out under very mild conditions.42 Treatment of a-aminoacetophenone hydrochloride, for example, with /3-carbomethoxypropionyl chloride in the presence of pyridine gives methyl /3-(5-phenyloxazole-2-yl) propionate (2). 

A soln. of 3-carbomethoxypropionyl chloride in abs. benzene added slowly with stirring to an ice-cooled soln. of y -(l-cyclohexenyl)elhylamine in dry pyridine-benzene, allowed to stand 3 hrs. at room temp., heated 0.5 hr. on a water bath, then stored overnight 3-carbomethoxypropionyl- -(1-cyclohexenyl)ethyl-amine. Y 82%. F. e. s. W. Schneider and R. Menzel, Arch. Pharm. 295, 911 (1962). 

Beta-carbomethoxypropionyl chloride (Org. Synth. 25,19 (1945)). Dissolve 400 g succinic anhydride in 190 ml methanol in 1 L round bottom flask and reflux (steam bath) one-half hour. Stir until homogeneous (about twenty minutes) and reflux one-half hour. Evaporate in vacuum and cool the residual liquid to precipitate about 500 g methyl-hydrogen succinate (1). Dissolve 264 g (1) in 200 ml SOCl2 in a 1 L round bottom flask with a reflux condenser and warm at 30-40° in water bath for three hours. Evaporate in vacuum the SOCl2 (can heat flask in steam bath) to get 270 g of the title compound (can distill 92/18). 

J-Carbomethoxypropionyl chloride treated during 1 hr. with trimethylsilyl azide in refluxing CCI4, and the product isolated after 1.5 hrs. heating methyl / -iso-cyanatopropionate. Y 84%. F. e., also from carboxylic acid anhydrides, and sterically hindered compds., s. S. S. Washburne and W. R. Peterson, Jr., Synth. Commun. 2, 227 (1972) J. Am. Oil Chemists Soc. 49, 694 (1972) s. a. reactions with silyl azides, H. R. Kridieldorf, Synthesis 1972, 551, 695. 

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