Benzofuran ring opening

Tri- and tetrasubstituted furans are obtained from benzofuranyl carbinols and 1,3-dicarbonyls via a Bronsted acid-catalyzed benzofuran ring opening and furan ring closure sequence (13JOC10427). 

Benzothiophenes offer a much wider variety of organometallic representatives than benzofurans. Alongside the classical -q mode there occur -q, bridging, and ring-opened patterns. 

This article aims to review papers that were published in 2006 on reactions and syntheses of furans, benzofurans and their derivatives. Two reviews have summarized the syntheses of furans <06OBC1627> and tetrahydrofurans <06EJO1627>. Another review <06001613> records the progress of transition metal-catalyzed asymmetric ring opening of oxabenzonorbornadienes. 

Photochemical [2+2]cycloaddition between benzo[b]furan and 3-cyano-2-alkoxy-pyridines in benzene has been reported to follow a very interesting mechanism supported also by Frontier-MO calculations using the PM3 Hamiltonian. It is believed that the singlet excited state of the pyridine and the ground state benzofuran react to form a [2+2] adduct and is followed by ring opening to the cyclooctatriene, which cyclizes to the secondary endo- and exo-isomers shown below <00CC1201>. 

The robust nature of the rhodium-iodide catalyst is also revealed in reactions with ortho-halo phenols that proved to be problematic with the first-generation catalyst system (Section 9.3.1). By employing the [Rh(PPF-P Bu2)I] catalyst, complete conversion is obtained with 2-bromophenol to give 6 in 94% yield, and with 95% enantiomeric excess after only 1.5 h of reaction time at 1 mol% catalyst loading (Scheme 9.3) [11]. The ready availability of these ring-opened compounds has been utilized to prepare enan-tiomerically enriched benzofurans 7. 

Additional heterocyclic ring systems, such as benzofurans [125], dihydropyrroles and dihydroazepines [41], piperidines and dihydropyrimidines 36 [126], and fused oxazole derivatives [127], have been described (Eq. 7). The formation of epoxides and aziri-dines, formally emanating from ylides, was recently reported by Doyle et al. [77]. Rho-dium(II)-catalyzed isomiinchnone cycioaddition followed by Lewis acid-mediated ring opening has been used as an entry into the protoberberine azapolycyclic ring structure [128]. 

A similar synthesis of mechanistic interest rather than preparative value involves the thermal reaction of dimethyl 2,5-bisdiazo-3,4-diketoadipate (89, Scheme 23) with benzofuran (91)." The presumed intermediate is the pyrone cation 90 produced from the adipate 89 by the Wolff rearrangement, cyclization, and loss of nitrogen. Electrophilic substitution then affords the benzofuran 92, which can be isolated. Ring opening and cyclization of the resultant ketene 93 then affords the dibenzofuran 94 in poor (0.4%) yield. 

Numerous instances exist of the preparation of benzofurans (poly-substituted by more or less complex groups) of ring-opening or ring-contraction reactions of natural products. 

The photoconversion of spiro[benzofuran-2,r-cyclohexa-3, 5 -diene]-2, 3(2//)-diones to dibenzofurans is recorded (81JCS(Pi)870). It was proposed that excitation of the dienone chromophore of the grisedienone (401) causes either concerted or radical ring opening to pairs of stereoisomeric dienylketenes. One member of each pair can undergo a thermal intramolecular va + tts cyclization to yield a /3-lactone subsequent loss of C02 would yield the products. 

Examples of 47i electrocyclization and related ring openings in oxygen-and sulfur-containing heterocycles have been widely reported. The effect of substituents on the ease of photocyclization of 1-benzoxepins (1) to cyclo-buta[b]-l-benzofurans (2) has been studied.3 1,3-Dioxepin (3) is readily converted to 2,4-dioxabicyclo[3.2.0]hept-6-ene (4) on irradiation in diethyl... 

Selective ring opening of benzofuran with lithium, in the presence of a catalytic amount of 4,4 -di( z/-butyl)diphenyl (TDBB), forms the (Z)-dilithiated species 72, which upon addition of a ketone or aldehyde forms 2//-chromenes (Scheme 24) <2001EJ02809>. 

One synthesis of benzofurans is based on cyclofragmentation. An appropriately substituted sulfone is used as a nucleophile in intramolecular ring opening of an epoxide. The resulting molecule loses a sulfinate and formaldehyde. By immobilization of the sulfinate on a resin this sequence can be used for the cleavage of benzofurans from solid supports [112] (Scheme 6.1.31). 

As an extension of this work, photoinduced [2+2]-cycloadditions of 1-acetylisatin (13) with cyclic enolethers (furan, benzofuran, 2-phenylfuran, 8-methoxypsoralen), and acyclic enolethers (//-butyl vinyl ether and vinyl acetate) were investigated which afforded the spiro-oxetanes in high yields (82-96%) and with high regio- and diastereoselectivity (Sch. 4) [19]. Treatment of the furan-derived oxetane 15 with acid resulted in oxetane ring opening and yielded the 3-(furan-3-yl)indole derivative 16. 

Reductions in aqueous THF-TBABF4 of benzo[b]thiophene [55], benzofurans, and 1-methylindole [56] have been shown to yield the 2,3-dihydro compounds this is probably a direct electrochemical reduction, whereas the further reduction involving ring opening of the hetero ring seems to be mediated by TBA(Hg). 

In the case of 2,3-benzofuran (55), a stereoselective ring opening lithiation takes place under the same reaction conditions as for 2,3-dihydrobenzofuran (47) shown in Scheme 13, yielding the (Z)-organolithium intermediate (56) which, by reaction with different electrophiles and final acidic hydrolysis, gives the expected (Z)-products (57). The cyclization of the products obtained by reaction of intermediate (56) with carbonyl compounds under acidic conditions, affords the expected substituted 2H-chromenes (58) (Scheme 15) (01EJ02809). 

The rhodium- or copper-catalyzed cyclopropanation of furan and its derivatives with diazo-acetic esters,300-302 or ethyl 2-diazopropanoate300 usually leads to a mixture of the 2-oxa-bicyclo[3.1.0]hex-3-ene-e co-6-carboxylate, ring-opened (4Z)-6-oxohexa-2,4-dienoates, and ring-substituted furans. Only with electron-deficient furans methyl furan-2-carboxylates, 2-[( )-2-methoxycarbonylvinyl]furan300 and with benzofuran,301,303 was the cyclopropane product obtained exclusively. Examples 37-40 are representative.300... 

The synthetic strategy involving an intramolecular hydroxyl epoxide opening was applied to build up the cyclopenta[i)]benzofuran ring for the total synthesis of the naturally occurring rocaglaol <04OL4595>. 

Under conditions of irreversible deprotonation (BuLi in THF or Et20), the 2-position of the hetero ring is metallated [1, 2, 9]. The pK values of benzofuran and benzothiophene [124] are slightly lower than those of the non-condensed heterocycles, so that complete metallation in the 2-position presumably can be effected with LDA in THF. However, the difference in acidity between the 2- and 3-protons is probably less than that in furan and thiophene. Ring opening therefore seems relatively easy under suitable basic reaction conditions (compare [141]), e.g.) ... 

Some research has addressed the question of oxacarbene-oxirene equilibria (see later for further examples). One example of this, accompanied by a ring-opening process, has been observed for the ketocarbene developed from 497 in toluene. This reaction affords the ring-opened ynone 498 and the benzofuran 499 03... 

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