Arylation of benzofuran

Table 9.4 Catalytic direct arylations of benzofurans, benzothiophenes, and indoles. 

In 2010, Kim [92] achieved the total synthesis of diptoindonesin G via C- H arylation of benzofurans. Treatment of benzofuran with 4-bromoanisole under Fagnou s conditions [30, 82] gave the corresponding coupHng product 73 demethylation of the methoxy group completed the total synthesis of diptoindonesin G. 

Employing a C-H arylation of benzofuran as a key step, Kim s group was able to complete the synthesis of diptoindonesin G (Scheme 16.20) under a catalytic system similar to Fagnou s work (see Section 16.2.3.2) that coupled benzofuran 77 and bromoarene 78 [40]. 

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[il)]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(ll)-catalyzed cycliza-tion[263]. 

The reactions of enamines with positively activated olefins have been extended to arylations with />-quinones (350,362-369) and quinone sulfoni-mides (365-368,370). Thus a new pathway for the facile formation of benzofurans and indoles became available. 

Ohta s group coupled aryl bromides such as 2-bromonitrobenzene with benzofuran [85]. The heteroaryl Heck reaction took place at the more electron-rich C(2) position of benzofuran. They later described the heteroaryl Heck reactions of chloropyrazines with both furan and benzofuran [86],... 

In order to determine whether or not these and similar reactions proceed through radical species, 2-(3,3-diphenylprop-2-enyloxy)phenyllead triacetate, a compound containing an internal radical trap, was prepared, and its behavior in base-catalyzed C-arylation reactions investigated. The absence of benzofuran derivatives among the products excluded the participation of radical species in these processes.35... 

One potential approach for the preparation of benzofuran derivatives involves the acid-catalyzed cyclization of O-aryl oximes 1193. 39 (equation 36). The transformation is analogous to well-known Fisher indole synthesis. The reaction proceeds through a [3,3]-sigmatropic rearrangement of enehydroxylamine 120 to compound 121 followed... 

Larock, R. C. Stinn, D. E. Synthesis of Benzofurans via Palladium-Promoted Cyclization of Ortho-Substituted Aryl Allyl Ethers, Tetrahedron Lett. 1988,29,4687-4690. 

Thiolate anions37 38 and oxime alkoxides38 react under phase transfer conditions to give aryl sulfides and O-aryl oximes, respectively the o-dichloro benzene complex can be converted selectively to the monosubstitution product (equation 9). The arylation of oximes leads to a simple process for benzofuran formation (equation 10). Simple primary and secondary amine nucleophiles react smoothly in the absence of added base, in a very general and efficient process for aniline derivatives.49... 

Coupling of aryl bromides with diethyl sodiomalonate. CuBr is the most effective Cu(I) catalyst for effecting coupling of aryl iodides or bromides with the sodium salts of active methylene compounds such as diethyl sodiomalonate. Coupling is facilitated by ori/io-substituents in the halide, particularly nitro, carbomethoxy, and methoxy groups.1 This reaction has been adapted to synthesis of benzofurane-2-ones.2... 

Double cyclopropanation of furans and pyrroles with aryl diazoacetates catalysed by Rh2(S-DOSP)4 have been reported to occur with opposite stereochemistry depending on the nature of the heterocycle.55 Better yields and ees are achieved for tricycles (69) derived from furan than for (68) derived from more bulky pyrroles. Monocyclo- propanation (with high yields and ees) is achieved on the furan ring of benzofuran, whereas double cyclopropanation of the indole is observed. 

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>. 

Alkynes. The cross-coupling of aryl halides with monosubstituted alkynes is a versatile synthetic method, and the simple substitution of THF for an amine as solvent can give significantly higher yields. With o-functionalized aryl halides the assembly of benzofurans, alkylidenephthalides, and alkylideneisoindolin-l-ones can be achieved in one or two steps. 1 - Alkynes undergo dimerization in high yields in a procedure that employs diisopropylamine. ... 

Bisseret recently reported the conversion of dibromoalkenols, a new class of benzofuran precursors, into 2-phosphonylated and 2-aryl benzo furans [174]. For example, reaction of dibromalkenol 213 with phenyl boronic anhydride provides 2-phenylbenzofuran in 80% yield. The proposed mechanism for this transformation starts with a Suzuki coupling of the more reactive E vinyl bromide and the boronic anhydride followed by a second Pd-catalyzed coupling between the Z vinyl bromide and the alcohol oxygen. 

Benzofurans are available via ( -arylation of enolates as reported by Willis [187]. In the simplest example, tricyclic benzofuran 237 was prepared from bromoketone 236 upon treatment with cesium carbonate and DPEphos. In total, eight other benzofurans were prepared in good to excellent yield using this methodology. 

Starting from 2-ethynylaniline, some 2-aryl- and 2-cycloalkenyl-indoles have been prepared in the solution phase by coupling and subsequent cyclization utilizing Pd-catalyzed reactions [157, 158]. Adaptation of the reaction sequence to the solid phase was first reported in ref [152]. Since the authors introduced only one point of diversity in their synthesis, a later publication -with three independently variable residues is discussed here [159]. Interestingly, Pd-catalyzed heteroannulation of terminal alkynes has been similarly used for the solid-phase synthesis of benzofurans utilizing ortho-hydroxy aryl iodides [160]. 

Benzofurans and Other Annelated Furans.-A new synthesis of benzofurans (73) is by the reaction of the phosphonium salt (72) with acid chlorides RCOCl in the presence of triethylamine. The benzofuran (74) results from the condensation of hexafluorobenzene with acetylacetone. Three instances of the formation of benzofurans from O-aryl-hydroxylamines, i.e. the oxygen analogue of the Fischer indole synthesis, have been reported O-phenylhydroxylamine hydrochloride and benzenesulphonylacetone give a 2 1 mixture of compounds (73 R = CH2S02Ph) and (75), the oxime ether (76) is converted into the aldehyde (77 ... 

This process is commonly known as the Sonogashira reaction and has proven extraordinarily useful for the synthesis of a wide variety of aryl alkynes or enynes. When neighboring functionality exists, Pd and Cu salts are well known to effect cyclization to the corresponding hetero- or carbocycle. Thus, the reaction of terminal alkynes and aryl or vinylic halides bearing neighboring functionality often leads directly to heterocycles or carbocycles, providing a particularly useful synthesis of benzofurans and indoles. 

Larock, R.C. and Stinn, D.E. (1988) Synthesis of benzofurans via palladium-promoted cyclization of )ri/i )-substituted aryl allyl ethers. Tetrahedron Lett., 29, 4687-90. 

The arene substrates are not limited to simple benzene derivatives. A variety of het-eroarenes can also participate in alkene arylations to generate the desired coupling products. Stoichiometric oxidative coupling of aromatic heterocycles such as furan, thiophene, selenophene, A-methylpyrrole, benzofiiran and benzothiophene with a variety of alkenes, including acrylonitrile, styrene and methyl acrylate, have been extensively studied by Fu-jiwara and coworkers [8]. Furan, thiophene, selenophene and A-methylpyrrole are easily alkenylated with alkenes to give 2-alkenylated and 2,5-dialkenylated heterocycles in relatively low yields (3 6%) [8a], while the reactions of benzofuran and benzothiophene with alkenes produced a mixture of 2- and 3-alkenylated products [8b]. 

Scheme 14.3 Synthesis of benzofurans by [3,3]-rearrangements of aryl oxime ethers.

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