Benzo furans, 2-substituted

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

Vll. Benz-Annelated and Hetero-Substituted Benzo[<]furans and Larger... 

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>. 

Since halogen-substituted benzo[. ]furans play an important role in the transition metal-catalyzed coupling of benzo[. ]furans with other substrates, synthetic methods to regioselectively synthesize substituted benzo[ ]furan halides have become very critical routes. Several syntheses of benzo[ ]furan based aryl halides are described here. 

A phenylacetylene-substituted benzo[ ]furan was prepared by reaction of 2-lithiated benzo[3]furan with l-(phe-nylethynyl)-l/7-l,2,3-benzotriazole (Equation 85) <2002JOC7526>. 

Several substituted benzo[ ]furans were synthesized efficiently in one-pot procedures by reaction of salicyaldehydes and ethyl diazoacetate in the presence of HBF/EtjO in high yields as shown below. A plausible mechanism was also given <0681711>. Two types of naphtha[2,3-fc]furan derivatives were made respectively by Lewis acid and HCl catalyzed ring cyclizations <06T8045>. AuBrj-catalyzed [4+2] benzannulation between enynal units and enol ethers was also applied to prepare benzo[Z)]furans <06JOC5249>. 

Table 4 Experimental bond lengths and angles in substituted benzo[ ]furans. 

Flash thermolysis converts the methylene lactone (46) to benzofuran (Scheme 41) <81TU597>. Probably ketoketenes (47) are interm iates in this reaction. If the Pd-catalyzed cyclization is conducted in the presence of CO/CHjOH the corresponding 3-methoxycarbonyl-substituted benzo-furans are obtained (Scheme 42) <89H(29)ioi3>. 

Other parameters of the palladium(n)-catalysed benzofuran synthesis were explored. Ultimately, it was found that the ideal system employed a 2 1 ligand/palladium ratio (10mol% Pd(OAc)2 and 20mol% ethyl nicotinate) and a substoichiometric amount (20mol%) of NaOAc at 100 °C. With this system in hand, a variety of substituted benzo-furans were accessed (Figure 9.7). The reaction was limited to electron-rich aryl systems the palladation event required a sufficiently nucleophilic arene in order to occur. The aryl subunit, however, tolerated an array of alkyl and alkoxy substitution patterns within the... 

Benzo[l)]furan-6-carbonitrile and 6-cyanobenzo[l>]furan-2-boronic acid pinacol ester were prepared in the presence of Cu. (13SC1974) 2-Substituted benzo[ ]furans were synthesized by employing easily accessible A/-tosylhy-drazones and o-hydroxy or o-amino phenylacetylenes as substrates. (13OBC1490) One-pot access to either 2-naphthols or benzo[l>]furans via the aerobic Wacker-type oxidation/intramolecular aldol cyclization was accomplished. (13T1532 ) 5,5-Disubstituted-2,2 -bisbenzofuran derivatives were produced by treatment of 4-substituted-2-(2-trimethylsilylethynyl) phenyl tert-butyldimethylsilyl ether analogues with CuCl as a catalyst (13TL2655). 

Wang and Chen et al. developed the three-component reaction of arylglyoxals, phenols and p-toluenesulfonamide for the synthesis of highly substituted benzo-furans, and InCls was found to be better than Hf(OTf)3, their previous catalyst of choice, for this reaction [223] (Figure 8.102). 

Synthesis of 2-alkyl- or 2-aryl-substituted benzo[b]furans has been reported, involving a CuITMEDA complex which catalyzes the transformation of readily available ketone derivatives into the corresponding benzofurans in good-to-excellent yields in water (Eq. 6.13).29... 

Some early examples involving microwave-assisted solvent-free Sonogashira couplings using palladium powder doped on alumina/potassium fluoride as catalyst were described by Kabalka and coworkers (Scheme 4.4) [150], In addition, this novel catalytic system has been used in microwave-assisted solvent-free Sonogashira coupling-cyclization of ortho-iodophenol with terminal alkynes, and similarly of ortho-ethynylphenols with aromatic iodides, to generate 2-substituted benzo[b]furans... 

Condensation of salicylaldehyde and its derivatives with a variety of esters of chlo-roacetic acids in the presence of TBAB led to the synthesis of benzo[fo]furans by means of a solid-liquid PTC reaction under the action of microwave irradiation [33], This was a modification of one of the most popular routes to substituted benzo[fo]fu-... 

Substituted benzo[b]furan can be oxidatively converted to the lactone 57 in 81% yield, which is allowed to react with chloroformate containing a chiral trans-( R,2R)-2-phenylcyclohexyl group (R ) to give the benzo[ft]furan-based enol carbonate. When the carbonate is treated with DMAP, nearly complete conversion to the new benzo-fused y-lactone 58 is observed in dichloromethane or in THF with a diastereomeric ratio of 3 1 <00OL1031>. 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

Figure 1.6 Hydrogenation of olefins without privileged substitution and of (benzo)furanes.

The substitution reactions of benzo[/ ]furans differ from those of indoles and both positions C-3 ami C-2 can be attacked by electrophiles. 

A new approach to 2,3-disubstituted benzo[b]furans from o-alkynylphenols via 5-endo-dig-iodocyclization reaction was reported. The iodinated compounds are starting materials for a variety of substituted benzo[f>]furans <99SL1432>. 

Substituted benzo[ ]thiophene derivatives have been prepared in excellent yields by a tandem Pummer rearrange-ment/Diels-Alder reaction of the intermediate furan with maleic anhydride or A -phenylmaleimide (Equation 87) <1996JOC6166>. 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[ ]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(II)-catalyzed cycliza-tion[263]. 

Benzo[c]furan (4) exhibits a long-wave absorption band of medium intensity in the region of 340 nm. Lack of solvent dependence together with mirror relationship to the fluorescence spectrum signifies a tt-ti band a rotational analysis of the vapor phase spectrum led to an assignment as 82 <- Ap 1,3-Diaryl-substituted benzo[c]furans show a strong absorption band in the region of 415 nm in sterically hindered compounds, this... 

Recently a number of heteroatom-substituted benzo[c]furans have been... 

In fact, benzo[ ]furan undergoes mainly a-substitution, benzo[ ]thiophene undergoes mainly 13-substitution and indole undergoes almost exclusive (3-substitution. This again illustrates the very strong directing effect of the oxygen atom to the a-position. 

Halogens react with benzo[ ]furan by an addition-elimination mechanism to give 2- and 3-substituted products (76JCS(P2)266). Treatment of benzo[ ]thiophene with chlorine or bromine in acetic acid gives predominantly 3-substituted products (71JCS(B)79). 2,2,3,3,4,5,6,7-Octachloro-2,3-dihydrobenzothiophene is obtained when benzo[ ]thiophene is treated with chlorine in the presence of 1 equivalent of iodine (80JOC2151). 

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