Acetic bromo -, methyl ester, preparation

The next three procedures provide useful synthetic intermediates. A stereospecific synthesis of ETHYL (Z)-3-BROMO-2-PROPENOATE affords an alternative vinyl bromide partner for the coupling chemistry in the preceding procedure. A very simple but elegant illustration of the flash vacuum pyrolysis technique is used to prepare BENZOCYCLOBUTENONE from o-toluoyl chloride. Another member of the functionalized indole family of synthetic intermediates is presented in a four-step procedure for 5-METHOXYINDOLE-2-ACETIC ACID METHYL ESTER. 

Alternatively, a-bromo-(2-chlorophenyl)acetic acid (15) was prepared by treatment of 2-chlorobenzaldehyde with tribromomethane in dioxane with an aqueous solution of potassium hydroxide, Fonnation of methyl ester 16 was followed by an Sn2 displacement by thieno[3,2-c]pyridine (8) to afford ) an 88% yield of ( )-clopidogrel (2 in two steps. 

Tocopheryl)propionic acid (50) is one of the rare examples that the o-QM 3 is involved in a direct synthesis rather than as a nonintentionally used intermediate or byproduct. ZnCl2-catalyzed, inverse hetero-Diels-Alder reaction between ortho-qui-none methide 3 and an excess of <2-methyl-C,<9-bis-(trimethylsilyl)ketene acetal provided the acid in fair yields (Fig. 6.37).67 The o-QM 3 was prepared in situ by thermal degradation of 5a-bromo-a-tocopherol (46). The primary cyclization product, an ortho-ester derivative, was not isolated, but immediately hydrolyzed to methyl 3-(5-tocopheryl)-2-trimethylsilyl-propionate, subsequently desilylated, and finally hydrolyzed into 50. 

Preparation of the quaternary anticholinergic agent benzilonium bromide (47) is begun by conjugate addition of ethylamine to methylacrylate, giving aminoester 42. Alkylation of 42 with methyl bromo-acetate leads to diester 43, which is transformed into pyrrolidone 44 by Dieckmann cyclization, followed by decarboxylation. Reduction of 44 by lithium aluminum hydride leads to the corresponding amino-alcohol (45). Transesterification of alcohol 45 with methyl benzilate leads to 46. Benzilonium bromide (47) is obtained by alkylation of ester 46 with ethyl bromide. 2... 

The ammonium formate in formic acid procedure has rendered possible the first preparation of isomeric 4,5-disubstituted oxazoles.03101 Bredereck, Gompper, and Reich101 have reported the anomalous behavior of certain long-chain a-bromo ketones a single a-bromo ketone on reaction with ammonium formate in formic acid gives a mixture of two isomeric oxazoles. Refluxing of a-bromo ketones or of a-chloro-/3-keto esters with ammonium acetate in acetic acid results in the formation of substituted 2-methyl-oxazoles.40 102 Ethyl a-chloroacetoacetate on heating with ammonium carbonate or formamide in formic acid yields 4-methyloxazole-5-carboxylic ester.40 103... 

Preparation by reaction of chromium trioxide with 6-bromo-5-methyl-2,3-diphenylbenzofuran in acetic acid, followed by saponification of the keto ester formed (2-benzoyloxy -bromo-5-methylbenzophe-none) with sodium hydroxide in ethanol [501], (73%) [502]. 

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