2,3-Unsubstituted benzofurans

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

Unsubstituted benzofuran and dibenzofuran show very intense peaks of the molecular ions,22b reflecting their high stability, caused by the lack of bonds which can be cleaved easily. The spectra of benzofurans substituted with a methyl group in the benzene ring (15) are characterized by abundant ions at M-l. They are assumed to have the oxonium ion structure [17] (see Budzikiewicz,11 p. 230) rather than that of a tropylium ion [16],22b as might be supposed considering the decomposition of analogous benzene compounds.22b... 

In contrast to many furan syntheses, this method uses 2-(2-hydroxyalkyl)phenoIs containing a leaving group at the benzylic carbon atom. Thus, 2-(I-isopropyl-thio-2-hydroxy)phenol cyclizes on heating with concentrated hydrochloric acid, but when 2-(2-hydroxyethyl)phenol was similarly treated, cyclization did not occur. When R = H, 2-unsubstituted benzofurans are obtained in good yield minor modifications were made in the synthesis of the 2-phenyl derivatives, and... 

In order to produce hetero-ring unsubstituted benzothiophenes an arylthioacetaldehyde acetal is generally employed, prepared in turn, from bromoacetaldehyde acetal and the thiophenol. An exactly parallel sequence produces 2,3-unsubstitutedbenzofurans. 2-Aryloxy-acetates (or 1-aryloxy-acetones) heated with DMFDMA, produce enamines which cycUse on treatment with zinc chloride, giving 3-unsubstituted benzofuran-2-carboxylates (3-unsubstituted 2-acetyl-benzofurans). ... 

Unsubstituted benzofuran-3-carboxylates are formed as the major products by the reaction of f-butyl (o-methoxyphenyl) (oxo)acetates with TMSC(MgBr)N2 (eq 26). Alkylidene carbenes are first formed from a-ketoesters, which cyclize to oxonium ylides. Elimination of methylene affords benzofurans. 

Several research groups have detailed syntheses of benzofurans via similar routes [110,111], including use of on-water chemistry [112] and the use of aldehyde substrates with copper catalysis to yield 2-unsubstituted benzofurans [113]. 

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

No studies were located regarding metabolism of 2,3-benzofuran in humans or animals. However, the metabolism of several other substituted furans has been shown to involve oxidation by P-450, with the unsubstituted double bond of the furan ring converted either to an epoxide (Boyd 1981) or to a dialdehyde (Ravindranath et al. 1984). Pretreatment with inducers and inhibitors of P-450 modified the toxicity of a single intraperitoneal injection of 2,3-benzofuran to male mice (McMurtry and Mitchell 1977). Oral exposure to 2,3-benzofuran altered the activity of P-450 and other enzymes in the livers of female mice (Heine et al. 1986). These experiments indicate that cytochrome P-450 may be involved in the toxicity of 2,3-benzofuran, but do not provide a clear picture of 2,3-benzofuran metabolism. 

With an unsubstituted 1,3-diphenol and two moles of benzoin, linear furo[3,2-/]benzofuran derivatives (165) are formed.410 A... 

Methylpyridazin-3 (2H)-one 1-oxides unsubstituted at position 6 afford photochemi-cally a mixture of the corresponding 6-hydroxypyridazin-3(2H)-one, lactone (46) and isomaleimide (47). 4-Methylcinnoline 1-oxide gives a mixture of the methyl substituted benzofuran (48), the indazole (49) and the indole (50), while 4-methylcinnoline 2-oxide gives a mixture of the deoxygenated starting compound, benzisoxazole (51) and o-aminoacetophenone (Scheme 16). 

As can be seen in the scheme below, a series of substituted 2-(2-aminothiazol-4-yl)-benzo[ ]furans with inhibitory activity for leukotriene B4 were made from benzofurans via acylation, followed by Hantzsch thiazole formation <070BC3083>. 2-Substituted benzo[ ]furans could also be generated via an aerobic oxidative coupling of 2-unsubstituted benzo[ ]furans with arenes through the palladium-catalyzed double C-H activation <07OL3137>. In addition, 2,3-diarylbenzo h I uran could be constructed by a palladium-catalyzed arylation of benzo[6]furan with an aryl chloride in the presence of a bulky, and electron-rich phosphine <07OL1449>. 

In contrast, diisopropyl ether-solvated 2-lithio-3-bromobenzofuran dimer 4 contains two crystallographically identical Li-C-O cycles, a difference ascribed to monodentate ether versus bidentate TMEDA in 3. Again the anionic carbon lies ca. 0.3 A closer to the other lithium LijA than to Lij. Bond distance t/(Li-0) = 1.954(6) A is much smaller than that for unsubstituted 3, while d(C-0) = 1.470(4) A is almost 0.1 A longer than typical for benzofuran C-O bonds. 

The regioselectivity of the formal [3 + 2] cycloaddition reactions in Scheme 13 corresponds to the polarization of the olefinic bond and to partial charges in the ketocarbenoid. The only exception occurred with benzofuran, in agreement with the behavior of the carbenoid derived from ethyl 2-diazo-3-oxobutyrate As several examples in Scheme 13 show, the cycloaddition is sterospecific, i.e. the configuration about the enol ether double bond is retained in the dihydrofuran. The observation that in the case of 1-methoxy-1,3-butadiene highly selective cycloaddition of the unsubstituted double bond occurs, whereas for 2-methoxy-1,3-butadiene cycloaddition takes place at the more electron-rich double bond, finds a close analogy in the cyclopropanation of these same dienes with ethyl diazoacetate (see Table 9). 

A 2,3-unsubstituted furo ring is formed when the acetal of a phenoxyacetalde-hyde is heated with PPA. Recent developments in the chemistry of benzofurans, have been reviewed [3894, 3983]. 

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