Benzofuran oxidation

Enols sterically protected at the -carbon have also been investigated. In general, the cyclic voltammetric response exhibits only the already mentioned ECE process, while the reversible benzofuran oxidation is not detected. The pertinent electrode potentials are compiled in Table 2. In the case of the enolato species, the ECE process probably proceeds through separated one-electron oxidations as those of Table 1. 

R (V) oxidation (V) 2" oxidation E" (V) (benzofuran oxidation) Solvent Reference... 

Scheme 51), so it has been suggested that the initial reaction involves the dinitrosobenzene. It does seem, however, that this may be an over-simplification, as there are documented cases where mono-iV-oxides rather than the di-iV-oxides are formed for instance, the reaction of benzofuran-3(2//)-ones with benzofuroxan yields 3-(o-hydroxyphenyI)quinoxa-line 1-oxide (Scheme 52). Other mechanistic possibilities may also be put forward but it seems probable that more than one pathway may be operating, particularly in view of the more recent findings on the reactions of benzofuroxans (81AHC(29)251). 

Basicities 565-567 Basis orbitals 2-5 Benzisothiazolinone dioxides 163 Benzofurans 638 Benzoic acids, pKa values of 586 Benzoxathiazine 2-oxides 71 Benzyne intermediates 306 Beta scales 559... 

The synthesis of a new sulfur analogue of angelicin, a thiopyrano[2,3-e]benzofuran, was reported <96JOC4842>. The reaction of 3(2//)-benzofuranone with SjClj yields bis-2-spirocoumaranoylidenetetrathiane instead of oxindigo (an oxidative coupling of a coumaranone) (Scheme 12, <96T1961>). 

The studies dealing with opportunity of photosensibilized formation of 02 from the surface of deposited oxides were studied in a vial similar to that described in [24]. The identification of C>2 was provided by similar techniques. The evaluation of concentration of C>2 molecules in gaseous phase involved the assessment of oxidation rate of 1,3-diphenil-benzofurane in hexadecane. It occurred that in this case the concentration of 02 molecules amounts to 10 cm. ... 

Rhodococcus sp. Strain WU-K2R A Rhodococcus strain capable of sulfur-specific desulfurization of benzothiophene, naphthothiophene (NT), and some of their alkyl derivatives was reported [35]. The metabolites of BT desulfurization were BT sulfone, benzo[c][l,2]oxanthiin S-oxide, benzo[c][l,2]oxanthiin S,S-dioxide, o-hydroxystyrene, 2,(2 -hydroxyphenyl)ethan-l-al, and benzofuran. The NT metabolites were NT sulfone, 2 -hydroxynaphthyl ethene, and naphtho[2,l-b]furan [35], The exact biochemical pathway was not determined, however, part of the pathway for BT desulfurization was speculated to be similar to Paenibacillus All-2. 

The desulfurization pathway was proposed to be BT -> BT sulfone -> benzo[e][l,2]oxanthiin S-oxide -> o-hydroxystyrene. Additionally, formation of the intermediate benzo(e)(l,2)oxathiin S,S dioxide was inferred to a side pathway resulting in formation of benzofuran as shown in Fig. 7. This pathway is similar to that reported for Sinorhizobium KT55, Paenibacillus sp. strain All-2 and R. erythropolis KT462. 

As depicted in the following scheme, in the presence of sodium iodate and pyridine, several 5,6-dihydroxylated benzofuran derivatives were synthesized via an oxidation-Michael addition of P-dicarbonyl compounds to catechols in a one-pot procedure <06TL2615 06JHC1673>. A novel additive Pummerer reaction of 2-benzo[fc]furan sulfilimines with carbon nucleophiles derived from P-dicarbonyl compounds was also employed to the synthesis of 2,3-disubstituted benzo[b]furans <06TL595>. 

Cyclodesulfurization of thiosemicarbazides, containing pyrazole <2002PS67> or benzofuran <2002PS863, 2004PS1577> units, by yellow mercuric oxide or by l,3-dibromo-5,5-dimethylhydantoin in the presence of potassium iodide <2006TL4889> afforded the respectively substituted oxadiazoles. 

Benzidine, N,N -diethyl-, 36, 21 Benzidine dihydrochloride, 36, 22 Bcnzil, 34, 42 Benzil dihydrazone, 34, 42 Benzilic acid, 33, 37 2-Benzimidazolethiol, 30, 56 l,2-Benzo-3,4-dihydrocarbazole, 30, 91 Benzofuran, 3-methyl, 33, 43 Benzofurazan oxide, 31,14, 15 37,1 Benzoguanamine, 33,13 Benzoic acid, 32, 94 37, 21 Benzoic acid, -acetyl-, methyl ester, 32, 81... 

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

The phenolic oxygen on 2-allyl-4-bromophenol (7) readily underwent oxypalladation using a catalytic amount of PdCl2 and three equivalents of Cu(OAc)2, to give the corresponding benzofuran 8. This process, akin to the Wacker oxidation, was catalytic in terms of palladium, and Cu(OAc)2 served as oxidant [17]. Benzofuran 10, a key intermediate in Kishi s total synthesis of aklavinone [18], was synthesized via the oxidative cyclization of phenol 9 using stoichiometric amounts of a Pd(II) salt. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

Applying Buchwald s Pd-catalyzed animation methodology, Thomas and coworkers prepared a range of bicyclic piperazine [108]. While Pd-catalyzed animation of 5-bromobenzofuran led to 5-benzofurylpiperizine 136 in 65% yield after deprotection, the corresponding reaction of 7-bromobenzofuran only gave 7-benzofurylpiperizine 137 in 20% yield. They speculated that either steric hindrance of the oxidative addition intermediate or the interaction between the oxygen lone pair and the metal center was responsible for the low yield. The debrominated benzofuran was the major by-product. 

Cycloaddition Reactions with Other Nucleophiles The anodic two-electron oxidation of catechol affords o-quinone that may react with the enolates of 4-hydroxycoumarine or 5,5-dimethyl-1,3-cyclohexanedione (dimedone). The resulting adducts undergo a second anodic oxidation leading to benzofuran derivatives in good yields (90-95%) (Scheme 53) [75, 76]. 

Anodic oxidations of heteroaromatic cycles (furans, pyrroles, benzofurans) in the presence of methanol have been extensively studied [148-165]. The electromethoxyla-tion of differently substituted furans gives 2,5-dimethoxy-2,5-dihydrofurans in moderate to good yields (Scheme 96) [148-159, 166-170]. 

Sterically hindered, mesityl-substituted, stable enols 72 have been examined with regard to one-electron oxidation. Using two equivalents of a one-electron oxidant such as triarylaminium salts, iron(III)phenanthroline, thianthrenium perchlorate or ceric ammonium nitrate in acetonitrile-benzofurans 73 are obtained in good yields within a few seconds [111]. 

Two possible mechanisms are proposed. Primarily the enol radical cation is formed. It either undergoes deprotonation because of its intrinsic acidity, producing an a-carbonyl radical, which is oxidized in a further one-electron oxidation step to an a-carbonyl cation. Cyclization leads to an intermediate cyclo-hexadienyl cation. On the other hand, cyclization of the enol radical cation can be faster than deprotonation, producing a distonic radical cation, which, after proton loss and second one-electron oxidation, leads to the same cyclo-hexadienyl cation intermediate as in the first reaction pathway. After a 1,2-methyl shift and further deprotonation, the benzofuran is obtained. Since the oxidation potentials of the enols are about 0.3-0.5 V higher than those of the corresponding a-carbonyl radicals, the author prefers the first reaction pathway via a-carbonyl cations [112]. Under the same reaction conditions, the oxidation of 2-mesityl-2-phenylethenol 74 does not lead to benzofuran but to oxazole 75 in yields of up to 85 %. The oxazole 75 is generated by nucleophilic attack of acetonitrile on the a-carbonyl cation or the proceeding enol radical cation. 

Several synthetic routes are available for oxazoles and related compounds. The first one, outlined in Scheme 41, is based on previously discussed syntheses of benzofurans (Scheme 17) and imidazoles (Scheme 40). Thus, a-aroyloxyacetophenones (147), which are obtained by HTIB-induced oxidation of 51 followed by treatment with para-substituted benzoic acids, can be cyclized to oxazoles 148 (95JIC129) (Scheme 41). 

Anodic oxidation of catechols enables the unstable quinones to be prepared and reacted in situ. Reaction of the 1,2-quinone with a 1,3-dicarbonyi compound gives a high yield of a benzofuran [123, 124]. Both 1,2- and 1,4-quinones, prepared electrochemically in nitromethane, are efficiently topped in Diels-Alder reactions with butadienes [125]. 

A convenient preparation has been reported for benzofuran annulated 2-phenyl-l,5-benzothiazepine derivatives 318 by oxidative cyclocondensation of phenolic diketones 317 with o-aminothiophenol in DMSO (Equation (36) (2000M393)). 

Oxidative cleavage of P-hydroxyethers to keto-lactones was accomplished by RuClj/aq. Na(10 )/CCl -CH3CN thus hexahydro-benzofuran-3a-diol gave the corresponding nine-membered ketolactones (R =Me, Bu, R =H, Me Fig. 5.14) [87]. 

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. 

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