Benzofurans oxidative cyclization

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. 

Aerobic oxidative cyclization of 2,2-dihydroxystilbenes via oxygen cation radical leading to the formation of c -4b,9b-dihydrobenzofuro[3,2-h]benzofurans was carried out in an enantioselective manner by using (nitrosyl)Ru(salen) as a catalyst under irradiation conditions <02CL36>. 

A convenient method for the synthesis of benzofurans proceeds via Pd(ll)-catalyzed oxidative cyclization of o-allylphenols (Equation 112) <1998JOM(560)163>. Dimethylformamide (DMF) accelerates the reaction to completion within minutes and the addition of LiCl allows the reaction be run at room temperature. 

A Pd-catalyzed tandem reaction was developed to synthesize a group of interesting benzo[fc] furans as depicted below <05CC271>. The Pd-catdyzed cyclization of propargylic carbonates was also applied to make 2,3-dihydrofurans and benzofurans <05T4381>. Furthermore, an oxidative cyclization procedure catalyzed by Pd(II) and pyridine in the presence of molecular oxygen was carried out on a variety of 2-allylphenols to form 2-substituted as well as 2,2-disubstituted benzo[fc]furans <05JA17778>. 

If the allyl group of the aryl allyl ether featured a tri- or tetra-substituted alkene, then the thermodynamic isomerization to the aromatic benzofuran could not occur, and dihydroben-zofurans were consequently produced in good to excellent yields (Figure 9.8). As in the benzofuran systems, a host of aryl and alkyl substitution patterns were tolerated in this oxidative cyclization. A number of polycyclic and highly functionalized dihydrobenzofurans were obtained via this palladium(II)-catalysed oxidation. 

By using similar approach, Lu et al. developed a practical and high yielding method to prepare a series of 2-nitro-benzofurans 166 from 2-(2-nitroethyl)phenols 165 (Scheme 41). DIB-mediated tandem oxidative cyclization of different 2-(2-nitroethyl)phenols 165 could be useful to prepare various 2-nitrobenzofurans [58]. 

Besides six-membered heterocycles, the construction of five-membered analogs by C-H olefination of phenol derivatives has also been reported. In 2011, Wang and coworkers reported a palladium-catalyzed oxidative cyclization of 3-phenoxy acrylates to construct benzofurans via an intramolecular aromatic C-H olefination (Scheme 3.13) [31]. In the presence of 5 mol% Pd(OAc)2/PPh3 and 2.0 equiv. of CF3C02Ag, benzofurans were obtained in good yields in... 

Regioselective synthesis of polysubstituted benzofurans from phenols and alkynes using a Cu(OTf)2 catalyst and ZnClj as Lewis acid in O2 atmosphere in a one-pot procedure has been reported by Jiang et al. (Scheme 8.79). The transformation consists of a sequential nucleophihc addition of phenols to alkynes and oxidative cyclization. A wide variety of phenols and alkynes can be used in this reaction. The reaction might proceed via a Cu-catalyzed intermolecular nucleophilic addition and intramolecular Cu-catalyzed aryl C(sp )-H functionahzation [149]. 

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. 

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). 

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... 

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]. 

From a mechanistic point of view two possible hypotheses were discussed (Scheme 2). Since radical cations are intrinsically very acidic [29-32] one would expect enol radical cation 27 to deprotonate efficiently and rapidly thus providing an a-carbonyl radical (mechanism 1). In a further one-electron oxidation step the a-carbonyl cation is formed, that cyclizes to an intermediate cyclohexadienyl cation 28. After a 1,2-methyl shift and deprotonation the benzofuran 29 is obtained. The mechanistic proposal is in line with benzofuran formation from a-carbonyl cations as demonstrated by Okamoto [120]. Interestingly, the above mechanism was first proposed by Bailey to explain the formation of 3% of benzofuran 24 in the ozonization of enol 8 [121], Years later, however, the mechanistic hypothesis was proven to be untenable [122] under ozonization conditions. A priori, it cannot be excluded that intramolecular cyclization of the enol radical cation 27 " is faster than deprotonation (mechanism 2). The distonic radical cation formed is expected to lose a proton readily and after a second one-electron oxidation the same cyclohexadienyl cation intermediate as in mechanism 1 is formed. 

Pandey has tentatively proposed the involvement of enolates in the photo-induced electron transfer oxidation of arylacetones by the system 1,4-dicyano-naphthalene (8 mol%)/acetonitrile/aqueous NaOH [1 ]. The corresponding benzofurans were obtained in 50-60% yield, but the mechanism is speculative since no oxidant in stoichiometric amounts was present. It was assumed that cyclization takes place on the stage of the a-carbonyl radical. 

Benzohydrofuranes. 2-Allylphenols are cyclized oxidatively by Pd(OAc)2 (1 equiv.) to isomeric benzofuranes. In the presence of oxygen, the Pd(II) salt can be used in catalytic amounts. An example is formulated in equation (I). ... 

Several benzologs of furan and thiophene are conveniently formed by procedures of ring closure over dehydrogenation catalysts. o-Ethylphenol is cyclized at 620° over a palladium catalyst to benzofuran (11%). Chromium oxide on alumina at 450° converts o-ethylthiophenol to benzo-thiophene (42%). Alkyl groups in the alpha and beta positions are obtained by suitable variation of structure in the alkyl side chain. For the... 

The copper acetate-catalyzed aerial oxidation of 4-substituted-amino-6-hydroxy-2-phenylquinazolines in methanolic solution containing piperidine or dimethylamine gave the 5,6-quinones (17) in 64-79% yields. Some of these were also formed when 6-acetoxy-4-chloro-2-phenylquinazoline was oxidized under similar conditions. The 5,6-quinones (17) can be hydrolyzed by base to the 6-hydroxy-5,8-quinones (18) in high yields. They dimerize to the intermediate 6,6 -biquinazolinyl-5,8-quinones on prolonged heating at 80°-90°C, and these cyclize to form benzofuran derivatives. ... 

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