Halogenated benzofurans

Iodobenzofuran was readily prepared by lithiation of benzofuran followed by iodine quench [8]. Bromination of benzofuran with bromine gave 2,3-dibromobenzofuran, which, when subjected to a regioselective halogen/metal exchange at the C(2) position with n-BuLi followed by quenching with methanol furnished 3-bromobenzofuran [9]. 

Halogenation of dibenzofuran produces the 2-halo compounds. Bromina-tion can be achieved in good yield with bromine in acetic acid " or with N-bromosuccinimide in boiling carbon tetrachloride. The 2,8-dibromo compound has been made, using dioxane dibromide. Chlorination of dibenzofuran in acetic acid in the presence of iron powder can be controlled to yield the 2-chloro or the 2,8-dichloro compounds. 2-Chlorodi-benzofuran is best prepared by reaction of dibenzofuran with phosphorus pentachloride. 2-Iododibenzofuran (45%) results from treatment of dibenzofuran with iodine in boiling chloroform in the presence of nitric acid. 2,8-Diododibenzofuran is best prepared by reaction of dibenzofuran with iodine and iodic acid in aqueous acetic acid. ... 

A recent halogen-free benzofuran that shares many structural features with its predecessor shows activity in controlling arrythmias. The synthesis starts with an unusual scheme for building the furan ring. Reaction of the benzyl bromide (2-1) with triphenylphosphine leads to phosphonium salt (2-2). Treatment of the salt with valeryl chloride in the presence of pyridine results in acylation on the now highly activated benzylic carbon (2-3). That product cyclizes to the benzofuran (2-4) on heating with expulsion of triphenylphosphine. Friedel-Crafts acylation of (2-4) with anisoyl chloride in the presence of stannic chloride proceeds on the... 

Reaction of the imidazole (7-4) with the benzofuran derivative (6-7) leads to the displacement of the benzylic halogen and the formation of the alkylation product (8-1). Treatment of that intermediate with trifluoroacetic acid breaks open the urethane to afford the corresponding free amine. This is allowed to react with ttiflic anhydride to afford the trifluoromethyl sulfonamide (8-2). The ester group on the imdidazole is then saponified, and the newly formed acid is reacted with carbonyl diimidazole. Reaction with ammonia converts the activated carboxyl group to the amide. There is thus obtained the angiotensin antagonist saprisartan (8-3) [6]. 

Numerous derivatives of (1) have been thus prepared, notably 2,3-dimethyl (or dialkyl)benzofurans Bz-substituted by alkyl radicals,36,213-218 methoxyl groups,101,219-221 halogen atoms,217,222-224 aryl groups,225 acetyl groups,215,218,226 formyl groups,222,226 and carboxyl groups.226,227 The method is especially valuable in the case of formyl derivatives, which are difficult to obtain otherwise. 

F, Furan T, thiophene BF, benzofuran BT, benzothiophene DCE, dichloroethane ATFA, acetyl trifluoroacetate. c Relative rate of halogenation of the 2-methoxycarbonyl derivatives. 

Other decarboxylations are noteworthy. Thermal decomposition of 2,4,6-trinitrobenzoic acid furnishes 1,3,5-trinitrobenzene in 46% yield. In an adaptation of a procedure for the decarboxylation of halogenated furoic acids with boiling quinoline and powdered copper, 2- and 3-nitro-benzofuran are prepared from nitro acids and 5-nitrothionaphthene is formed from the corresponding 2-carboxylic acid. ... 

Similar elimination reactions are employed in the synthesis of the benzologs of five-membered heterocyclic compounds. For example, /3-phenylethyl alcohols having hydroxyl, sulfhydryl, and amino groups in the ortbo position ate cyclized to the dihydro derivatives of benzofuran, benzothiophene, and benzopyrrole, respectively. Likewise, dehydro-halogenation of /3-(o-hydroxyphenyl)-ethyl bromide gives dihydtobenzo-furan in 72% yield. ... 

V. Condensation of o-hydroxylated aromatic ketones (256, R H) with a-halogenated ketones. Although some authors have maintained that o-hydroxylated aromatic ketones could not be used for the synthesis of benzofurans by condensation with chloroacetone, several instances are quoted in Table XIII. Compounds with vasodilatory properties, e.g., 267, have thus been prepared from the ketone 266. The... 

A common strategy for the synthesis of 3-halobenzofurans involves a 2-step procedure of halogenation, then ehmination. Benzofuran 5 reacts with bromine to yield tribromide 6 which furnishes dibromobenzofuran 7 upon treatment with potassium hydroxide [20]. Chlorination can be achieved via an analogous reaction sequence [21]. 2,3,5-Tribromobenzofuran can be prepared using a similar strategy in three steps and 52% overall yield from 5-bromobenzofuran (5) [18]. 

Side-chain halogen and 0-acylphenol functions interact under basic conditions to give a moderately good yield of benzofuran. An o-(2-chloroallyl)phenol is cyclized on wanning with mineral acid, but yields are only moderate for 6-chloro- and 6-methoxy-benzofuran. This type of cyclization may give higher yields in a strongly alkaline medium [3943]. This particular synthesis failed in cold sulphuric acid and in hot diethylaniline. 

High-yielding Suzuki substitutions of halogen in halo-boronates are also possible using Al-methylimino-diacetic acid (MIDA) to form the protected boronate, which resists coupling under anhydrous conditions. This approach has been applied to aryl and heteroaryl (only thiophene and benzofuran, shown below) systems, and also for polyene synthesis. ... 

In some of the earliest uses of n-butyllithium, 2-lithiobenzofuran was obtained by metal-halogen exchange between the 2-bromo-heterocycle and n-butyllithium, or by metallation of benzofuran. The generation of 3-metallated benzofurans generally results in fragmentation with the production of... 

Lithio-benzothiophenes can be generated, and reacted with electrophiles, if the temperature is kept low. ° Direct deprotonation of benzothiophenes follows the usual pattern for flve-membered heterocycles and takes place adjacent to the heteroatom,"" and in concord with this pattern, metal-halogen exchange processes favour a 2- over a 3-halogen the sequence below shows how this can be utilised to develop substituted benzothiophenes. 2-Lithiated reagents react with electrophiles for example with p-toluenesulfonyl cyanide, 2-cyano derivatives are produced and similarly, 2-trimethylstannylbenzofuran and -benzothiophene and benzofuran-2- and benzothiophene-2-boronic acids can be prepared. 

---