Of benzofurans

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]. 

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). 

An analogous synthesis of benzofurans from O-aryloximes has been exemplified, but not investigated in any detail (Scheme 39e) (66TL5225,67TL2867,73KGS31). 

The base-promoted ring contraction of 3-bromo-2-pyrones to 2-furoic acids cf. Scheme llOd) is a well exemplified reaction 01CB1992,69JCS(C)1950,73JCS(P1)1130> which has also been applied to the obtention of benzofuran-2-carboxylic acids frorn 3-bromocoumarins 08CB830,70KGS(S2)166), Similar base treatment of 3-amino-2-pyrones provides pyrrole-2-carboxylic acids (Scheme IlOe) 75JHC129). 

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. 

An alternative preparation of benzofurans was carried out via a microwave-assisted Mannich condensation of paraformaldehyde and a secondary amine followed by cyclization with an alkynyl phenol 185 mediated by alumina doped with Cul (Scheme 67). The reaction can be carried out in a single-step... 

Scheme 66 Phase-transfer catalyzed synthesis of benzofuran carboxylates...

NHC-Pd(ll) complexes have also been used in tandem reactions involving a Sonogashira couphng and hydroalkoxylation of the resulting alkyne for the synthesis of benzofurans [131] as well as sequential Heck-Sonogashira couphngs [132] (Scheme 6.44). 

Acylation of benzofuran Zeolite Y Acctyibcnzofuran Fine chemicals... 

Most recently, the Abbott group disclosed a series of benzofurans with potent affinity for the human and rat receptors. ABT-239 (29) is one of the more extensively profiled members of this series. (29) has a K of 0.45 nM at the human receptor [95], good rat pharmacokinetics and demonstrated efficacy in models of cognition [96]. Recently, a scaleable synthesis of ABT-239 has been reported [97] and the researchers have published detailed accounts on the pre-clinical pharmacokinetics and efficacy of this compound [98, 99], indicating continued interest in this series of H3 antagonists. 

Howlett DR, Perry AE, Godfrey F, Swatton JE, Jennings KH, Spitzfaden C, Wadsworth H, Wood SJ, Markwell RE. Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans. Biochem J 1999 ... 

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. 

Tethered alkenes feature in the synthesis of benzofuran-fused chromans 48 <00JCS(P1)1387> through intramolecular cycloadditions. 

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... 

Iodobenzofuran was readily prepared by lithiation of benzofuran followed by iodine quench [8]. Bromination of benzofuran with bromine gave 2,3-dibromobenzofuran, which, when subjected to a regioselective halogen/metal exchange at the C(2) position with n-BuLi followed by quenching with methanol furnished 3-bromobenzofuran [9]. 

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... 

Intramolecular [4+2]-cycloaddition reactions, which involve base-induced isomerization of a propargyl ether to an allenyl ether, have been extensively studied. Treatment of 157 with a base caused an intramolecular Diels-Alder reaction of the intermediate allenyl ether to give tricyclic compounds 158 [131]. An asymmetric synthesis of benzofuran lactone 159 was achieved by an analogous procedure [132],... 

Sun Y-Y, Liao J-H, Fang J-M, Chou P-T, Shen C-H, Hsu C-W, Chen L-C (2006) Fluorescent organic nanoparticles of benzofuran-naphthyridine linked molecules formation and fluorescence enhancement in aqueous media. Org Lett 8 3713-3716... 

The cyclative-cleavage strategy is different to the cases in which the cycUzation occurs in solution after the cleavage (Scheme 3.6). This is true for most acidic cleavage conditions in these cases the uncyclized reactant is also found in the hquid-phase. Examples of this strategy are the synthesis of benzofurans [184], imidazo-quinoxalinones [185, 186] and diketopiperazines [187]. 

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). 

Lu K, Luo TP, Xiang Z, You ZJ, Eathi R, Chen JH, Yang Z (2005) A concise and diversity-oriented strategy for the synthesis of benzofurans and indoles via Ugi and Diels-Alder reactions. J Comb Chem 7 958-967... 

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