Carboxylic acid derivatives bromination

Bromine-containing synthetic thyroid agonists, (II) and (III), prepared by Li (2) and Hangeland (3), respectively, and phenolic carboxylic acid derivatives, (IV), prepared by the author (3) were effective for diseases dependent on the expression of T3-regulated gene and used in treating hypothyroidism. 

A number of methods involve the rearrangement of carboxylic acid derivatives via nitrenes. The best known of these is the Hofmann degradation of amides. This involves treating an amide with bromine and alkali. The A-bromo compound undergoes an a-elimination in the presence... 

Kwart, H., Scaizi, F. V. Observations regarding the mechanism and steric course of the a-bromination of carboxylic acid derivatives. An electrophilic substitution reaction in nonpolar media. J. Am. Chem. Soc. 1964, 86, 5496-5503. 

The Hofmann rearrangement can also be used to convert a carboxylic acid derivative to an isocyanate. A carboxamide is treated with Br2 and aqueous base to give an isocyanate, which is usually hydrolyzed under the reaction conditions to give an amine with one fewer C atom than the starting material. The reaction proceeds by deprotonation of the amide and /V-bromination, then a second deprotonation and rearrangement. The amide N is more reactive than the amide O in the bromination step because N is deprotonated under the reaction conditions. 

Hydrodebromination. a-Brominated carboxylic acid derivatives undergo... 

Alkyl- and aryl-substituted carboxylic acid derivatives such as ethyl 4-methoxybenzoate, diethyl phthalate,104 aryl- and alkylcarboxylic add halides or anhydrides10,2 5 8 give benzoxazinones (193). When IA was brominated in glacial acetic acid, 193 (R2 = CHBr2) was obtained.259 Anthranilic acid (4) with A-methyl IA (24) leads to 194, which cyclizes in sulfuric acid to the benzoxazinone 195134 (Scheme 33). Reaction of /V-formylanthranilic acid (196) (available from 1A and formic acid) with IA again yields the quina-zolinone 19710 260 (Eq. 19). 

Base-catalyzed cyclization of the quinoxalinylaminopropionic esters 29 has recently been shown to give the pyrido[2,3-6]quinoxalines 30. These may be dehydrogenated by sequential treatment with bromine and triethylamine to give the compounds 30a. The carboxylic acids derived... 

Alkyl- and aryl-substituted carboxylic acid derivatives such as ethyl 4-methoxybenzoate, diethyl phthalate, " aryl- and alkylcarboxylic acid ha-lidesoranhydrides ° givebenzoxazinones (193). When lA was brominated in glacial acetic acid, 193 (R = CHBr2) was obtained. Anthranilic acid... 

An aldose is oxidized to a carboxylic acid derivative via treatment with aqueous copper sulfate, silver nitrate in ammonia, bromine, aqueous potassium permanganate, or nitric acid. 

The enolates of aldehydes and ketones undergo deuterium exchange, bromination, and alkylation reactions (Sections 22.4—22.6). Carboxylic acid derivatives react similarly. However, the added possibility of a competing nucleophilic acyl substitution reaction limits some of the substitution reactions at the a-carbon atom of acid derivatives. For example, acyl halides react with most bases in substitution reactions at the carbonyl carbon atom rather than by abstraction of the a-hydrogen atom. On the other hand, the pA of the a-hydrogen atoms of amides is very large, and these derivatives would require a very strong base for formation of enolates for synthetic reactions. Esters are the most convenient acyl derivatives for enolate formation and subsequent substitution at the a-carbon atom. The substituted ester can subsequently be converted into other acyl derivatives. 

Acid-catalyzed alpha halogenation does not work for esters, amides, or carboxylic acids, but it does work for acid halides. This fact can be exploited to generate a-brominated carboxylic acid derivatives as shown in Synthetic Transformation 25.5. 

Me3SiCH2CH=CH2i TsOH, CH3CN, 70-80°, 1-2 h, 90-95% yield. This silylating reagent is stable to moisture. Allylsilanes can be used to protect alcohols, phenols, and carboxylic acids there is no reaction with thiophenol except when CF3S03H is used as a catalyst. The method is also applicable to the formation of r-butyldimethylsilyl derivatives the silyl ether of cyclohexanol was prepared in 95% yield from allyl-/-butyldi-methylsilane. Iodine, bromine, trimethylsilyl bromide, and trimethylsilyl iodide have also been used as catalysts. Nafion-H has been shown to be an effective catalyst. 

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