Benzofuran-3-acetic acids

The effect of other substituents on the products of alkaline hydrolysis is well illustrated in the conversion of 4-chloromethylcoumarin (293) to the benzofuran-3-acetic acid (294) in high yield (79CHE815), of 4-hydroxy-6-phenacylpyran-2-one (259) into the benzophenone (295) (70T5255) and of 5-amino-3-methylisocoumarin (297) (formed from the nitro compound 296) into the indole (298) <76JCS(P1)1073, 81CPB249). 

Chloromethylcoumarins can be converted into benzofuran-3-acetic acids by exposure to alkali - hydrolysis of the lactone and then reclosure with displacement of chloride by the phenolate leads to the benzofuran. ... 

Coumarin and some of its methoxy-derivatives undergo acetoxymethylation, usually at C-3, in yields of up to 87% when heated with manganese(iii) acetate in a solvent such as acetic acid-acetic anhydride. Varying amounts of the 3-(diacetoxymethyl)-derivatives were also isolated in some experiments, and in the reaction with 7,8-dimethoxycoumarin the benzene ring was sufficiently reactive to allow the formation of 3,6-di(acetoxymethyl)-7,8-dimethoxy-coumarin. Ring-contraction of 4-(chloromethyl)coumarin in aqueous alkali proceeded in 92% yield to give benzofuran-3-acetic acid. " ... 

The Pechmann condensation also played a key role in the Biichi group s efforts toward the total synthesis of aflatoxin Bi (44). In this work, the central coumarinic ring system of aflatoxin was prepared by condensing the racemic tricyclic phenol 40 with ethyl methyl-3-oxoadipate (41) in methanolic HCl at 5 °C to provide tricycle 42 in 57% yield. The use of methanol as a solvent was crucial to the success of this reaction, as attempts to perform this reaction in sulfuric acid led to the rapid isomerization of 40 to the corresponding benzofuran-3-acetic acid, which could be converted to the analogous coumarin product only in very poor yield. Subsequent cyclization of the pendant ester moieties of 42 afforded pentacyclic lactone 43. Treatment of 43 with disiamylborane resulted in selective reduction of the dihydrofuranone to the corresponding hemiaminal, which was then acetylated and pyrolyzed (240 °C) to provide ( )-aflatoxin Bi (44). 

A plausible pathway is that the aromatisation of the cyclohexadienone 92 by a proton shift is accelerated in the presence of Ac20 under formation of acetate 93. The simultaneously generated acetic acid then cleaves the acetate to form the free phenol 94 (Scheme 44). This effect was observed for the first time during studies towards the total synthesis of the lipid-alternating and anti-atherosclerotic furochromone khellin 99 [64].The furanyl carbene chromium complex 96 was supposed to react with alkoxyalkyne 95 in a benzannulation reaction to give the densely substituted benzofuran derivative 97 (Scheme 45). Upon warming the reaction mixture in tetrahydrofuran to 65 °C the reaction was completed in 4 h, but only a dimerisation product could be isolated. This... 

Benzofuran in boiling dioxane and acetic acid, in the presence of equimolar proportions of styrene and palladium(II) aeetate, yields 2,3-diphenyl-dibenzofuran (26%) as well as 2-styryl- (16%) and 3-styrylbenzofuran (3%). The reaction presumably involves electrophilic substitution at the 2-position of benzofuran by palladium(II) acetate, followed by addition to the alkene and loss of palladium hydride. Further reaction at the 3-position of the resultant 2-styrylbenzofuran would yield an intermediate that could undergo... 

Methoxy-6-propyl-l,4-benzoquinone (170, Scheme 43) with hydrogen chloride undergoes dimerization and yields the biquinone 171 and the di-benzofuran 172. 2-Hydroxy-3,6-dimethyl-1,4-benzoquinone (173, Scheme 44), however, on treatment with boron trifluoride etherate in ether, or with concentrated sulfuric acid in acetic acid at room temperature, yields the extended quinone 174, which on reductive acetylation affords the dibenzo-furan 175. 

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. ... 

For the preparation of [l]benzothieno[3,2- ][l]benzofuran-10,10-dioxide 64, hydrogen peroxide in acetic acid, 3-chloroperoxybenzoic acid, and also the urea-hydrogen peroxide adduct with phthalic anhydride were employed. All three methods provided 64 in excellent yields (88-94%). Monitoring the course of the reaction showed the... 

Thieno[3,2- ][l]benzofuran 61 was synthesized on a preparative scale starting with benzo[/ ]furan-2-carbaldehyde 344. Condensation of aldehyde 344 with 2-thioxothiazolidin-4-one in the presence of sodium acetate in acetic acid afforded 345, which by base-catalyzed hydrolysis gave 346 in good yield. Upon treatment with bromine, acid 346 was cyclized to give acid 347, which on standard decarboxylation by treatment with copper in quinoline afforded 61 in high yield (Scheme 35) <1997CCC1468>. 

The direct electrochemical oxidation of phenols generates phenoxonium cations which are able to undergo [3-1-2] cycloaddition in the presence of unactivated alkenes to produce benzofurans <1999JOC7654>. Thus, electrolysis of methyl 2,5-dihydroxybenzoate in a solution of lithium perchlorate in nitromethane in the presence of acetic acid and 2-methyl-2-butene produces the dihydrobenzofuran in excellent yield (Equation 88). 

Cycloaddition of oxazoles with arynes provides a route to substituted polycyclic ethers and hydrocarbons (80TL3627). Oxazole (354), for example, reacted with anthranilic acid and isoamyl nitrite to provide the cyclic ether (357) by way of the benzofuran (356). The ether was then treated with zinc in glacial acetic acid to furnish hydrocarbon (358) in 70% yield based on the starting oxazole (Scheme 77). 

The methoxy derivatives may be treated directly o-methoxyphenyl-acetone, heated with hydrobroniic acid in acetic acid, gives 2-methyl-benzofuran.326 o-Methoxylated phenylacetones are readily prepared by glycidic synthesis from o-methoxylated aromatic aldehydes the intermediate glycidic ester (127) can be directly converted by pyridine hydrochloride into a 2-alkylbenzofuran in 40-80% yield.105... 

Treatment of some substituted o-benzyloxy-ketones with hydrochloric acid in acetic acid gives, e.g., the carboxylic ester (130, R = COOMe), then the corresponding benzofuran (130, R = H) through debenzylation, ring closure, hydrolysis, and decarboxylation.331... 

An important extension of this method has made it possible to synthesize polycyclic benzofurans under the influence of various demethylating and dehydrating media.335 For such ring closures, pyridine hydrochloride is especially suitable thus coumestan has been synthesized from 4-hydroxy-3-(2-methoxyphenyl)coumarin.8 4,7-Di hydroxy-3-(2,4-dimethoxyphenyl)coumarin gives coumestol with aniline hydrochloride 336 other polymethoxycoumestans have been obtained with pyridine hydrochloride or with HBr (or HI) and acetic acid.337-339... 

By elaboration of benzofurans, dibenzofurans can be obtained. The annelation of 4-isopropyl-7-methylbenzofuran-2-carbaldehyde (393) by Wittig reaction with 2-carboxy-l-methoxycarbonylethyltriphenylphosphorane gave the itaconic half ester (394), which on treatment with hot acetic acid cyclized to the dibenzofuran (395). Functional group modification furnished cannabifuran (396) (82JCS(P1)1605). 

If no acetic acid is used, benzofuran is formed in only 30-31% yield, and coumarilic acid, mp. 194-196°, is isolated in about 45% yield. 

To a solution of 5.2 g of 2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydro-benzofuran in 20 mL glacial acetic acid there was added 3 mL nitroethane followed by 1.6 g anhydrous ammonium acetate. This mixture was heated for 4 h on the steam bath, and then a small amount of H20 was added to the hot solution. This instigated the formation of a copious deposition of brick-red crystals which were, after cooling, removed by filtration, and recrystallized from 50 mL boiling MeOH. After air drying there was thus obtained 2.7 g of day-glo yum-yum orange crystals of 2,2-dimethyl-5-methoxy-6-(2-nitro- l-propenyl)-2,3-dihydrobenzofuran. An additional 0.6 g of product was obtained by working the mother liquors. 

The analysis depicted for (64) reveals that the synthesis of benzofuran involves the conversion of salicylaldehyde into the corresponding aryloxyacetic acid by reaction with sodium chloroacetate in the presence of alkali, followed by heating with a mixture of acetic anhydride, acetic acid and sodium acetate (Expt 8.24). The ensuing cyclisation may be regarded as an internal Perkin reaction (Section 6.12.3, p. 1036) accompanied by a decarboxylative dehydration step. 

Benzofuran. Heat under reflux for 8 hours a mixture of 20 g (0.11 mol) of o-formylphenoxyacetic acid, 40 g of anhydrous sodium acetate, 100 ml of acetic anhydride and 100 ml glacial acetic acid. Pour the light brown solution into 600 ml of iced water, and allow to stand for a few hours with occasional stirring to aid the hydrolysis of acetic anhydride. Extract the solution with three 150 ml portions of ether and wash the combined ether extracts with 5 per cent aqueous sodium hydroxide until the aqueous layer is basic the final basic washing phase acquires a yellow colour. Wash the ether layer with water until the washings are neutral, dry the ethereal solution over anhydrous calcium chloride and remove the ether on a rotary evaporator. Distil the residue and collect the benzofuran as a fraction of b.p. 170-172°C. The yield of colourless product is 9.5 g (91%). 

The industrial synthesis of vinyl acetate [14] via palladium-catalyzed oxidative coupling of acetic acid and ethene using direct 02 reoxidation has already been mentioned (Scheme 3, d). Some NaOAc is required in the reaction medium, and catalysis by Pd clusters, as alternative to Pd(II) salts, was proposed to proceed with altered reaction characteristics [14]. Similarly, the alkenyl ester 37 (Table 5) containing an isolated vinyl group yields the expected enol acetate 38 [55] whereas allylphenol 39 cyclizes to benzofuran 40 with double bond isomerization [56]. 

Meta-chloroperoxybenzoic acid or osmiumtetroxide/sodium periodate chromic acid anhydride in acetic acid or acetic anhydride give good results with the benzofurans, but was unsatisfactory in the naphthofuran (VIII/172, R-R, CH= CH-CH=CH-) series. Ozonolysis, however, was very effective with both types of compounds (yields 63-86%). 

The reaction of 1,1-enediamines with 1,4-benzoquinone takes a different course132. Acyclic 1,1-enediamines 149 react with 1,4-benzoquinone in refluxing acetic acid to give after workup two products 150 and 151, resulting from dehydration and deamination, respectively (equation 57). Only benzofurans 152 (21-27%) are isolated in the case of enediamines 8 derived from 4-bromoacetophenone. Cyclic 1,1-enediamine 8 (n = 2, R = H) examined in the reaction leads exclusively to a low yield (9%) of the tricyclic indole 153. 

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