Chloroacetamides

Di- and tri-chloroacetamide, oxamide, guanidine, and cyanoguanidine (dicyanodiamide) do not give satisfactory results. 

Much of the chloroacetyl chloride produced is used captively as a reactive intermediate. It is useful in many acylation reactions and in the production of adrenalin [51-43-4] diazepam [439-15-5] chloroacetophenone [532-27-4] chloroacetate esters, and chloroacetic anhydride [541-88-8]. A major use is in the production of chloroacetamide herbicides (3) such as alachlor [15972-60-8]. 

Chloroacetate esters are usually made by removing water from a mixture of chloroacetic acid and the corresponding alcohol. Reaction of alcohol with chloroacetyl chloride is an anhydrous process which Hberates HCl. Chloroacetic acid will react with olefins in the presence of a catalyst to yield chloroacetate esters. Dichloroacetic and trichloroacetic acid esters are also known. These esters are usehil in synthesis. They are more reactive than the parent acids. Ethyl chloroacetate can be converted to sodium fluoroacetate by reaction with potassium fluoride (see Fluorine compounds, organic). Both methyl and ethyl chloroacetate are used as agricultural and pharmaceutical intermediates, specialty solvents, flavors, and fragrances. Methyl chloroacetate and P ionone undergo a Dar2ens reaction to form an intermediate in the synthesis of Vitamin A. Reaction of methyl chloroacetate with ammonia produces chloroacetamide [79-07-2] C2H ClNO (53). 

The carboxamidomethyl ester was prepared for use in peptide synthesis. It is formed from the cesium salt of an A-protected amino acid and a-chloroacetamide (60-85% yield). It is cleaved with 0.5 M NaOH or NaHCOa in DMF/H2O. It is stable to the conditions required to remove BOC, Cbz, Fmoc, and r-butyl esters. It cannot be selectively cleaved in the presence of a benzyl ester of aspartic acid. ... 

The chloroacetamide can also be cleaved by first converting it to the pyridinium-acetamide (Pyr, 90°, 1 h, 70-90% yield) followed by mild basic hydrolysis (0.1 7/NaOH, 25°). ... 

Functionalization may be accomplished before cyclization by preparing the appropriate diethanolamine derivative first . An alternative and more straightforward approach is simply to prepare 9 by any of the typical methods and then substitute the secondary nitrogens afterward. Reaction between 9 and chloroacetamide and acrylonitrile yielded compounds 10 and 11 in 61% and 100% yields respectively. 

Development of paddy field rice herbicide Thenylchlor, A-(2,6-dimethyl-phenyl)-A-(3-methoxy-2-thenyl)chloroacetamide 98YGK221. 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Conden-... 

Condensation, of 2-aminobiphenyl with boron trichloride, 46, 65 of a-chloroacetamide with oxalyl chloride, 46,16... 

To a solution of 130 g. (0.6 mole) of arsanilic acid (Org. Syn. 3, 13) in 600 cc. (0.6 mole) of normal sodium hydroxide is added 52 g. (0.62 mole) of sodium bicarbonate and 70 g. (0.75 mole) of chloroacetamide (Org. Syn. 7, 16). The mixture is heated 011 a water bath to 90-1000 and a steady evolution of carbon dioxide occurs. At the end of two hours, when gas evolution has practically ceased, the mixture is cooled to 40° C., stirred vigorously and 150 cc. of 1 1 hydrochloric acid poured in rapidly. /i-Arsonophenylglycinamide crystallizes at once and, after cooling to room temperature, is filtered by suction and washed once with 2 per cent hydrochloric acid (Note 1), then with cold water. The crude product thus obtained is contaminated with some arsanilic acid and possibly other products. These are removed during purification. The crude product is suspended in about 400 cc. of water and with vigorous stirring, treated carefully with 25 per cent aqueous sodium hydroxide until solution is just complete. At this point the mixture is still acid to litmus and an excess of sodium hydroxide is to be avoided to prevent decomposition of the product. About 15 g. of boneblack... 

Condensation of 165 with chloroacetamide derivatives afforded (89JIC246) carbamoylhydrazino derivatives 168. Some are active against S. aureus and Escherichia coli. Condensation of 165 with ethyl cyanoace-tate, malononitrile, ethyl acetoacetate, or acetylacetone gave (87AP1191, 87PHA664 89JHC769) 169 and 170, whose bactericidal activity has been reported. 

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