Benzofurans, cycloaddition

Substituted 1-benzoxepins can be obtained by the cycloaddition of activated acetylenes to the benzofuran system. When 2-(Af-mcthylanilino)benzofurans is treated with dimethyl acetylene-dicarboxylate, substituted 1-benzoxepins 1 are obtained in reasonable yield.180,181 This reaction presumably involves a 2a,7b-dihydrocyclobuta[6]bcnzofuran as an intermediate (see Section 4.2).182... 

The Diels-Alder reaction of 2-vinylfurans 73 with suitable dienophiles has been used to prepare tetrahydrobenzofurans [73, 74] by an extra-annular addition these are useful precursors of substituted benzofurans (Scheme 2.29). In practice, the cycloadditions with acetylenic dienophiles give fully aromatic benzofurans directly, because the intermediate cycloadducts autoxidize during the reaction or in the isolation procedure. In the case of a reaction with nitro-substituted vinylbenzofuran, the formation of the aromatic products involves the loss of HNO2. 

Furoquinones, such as naphtho[2,3-b]fiiran-4,9-dione, naphtho[l,2-b]fiiran-4,5-dione, benzofuran-4,7-dione and benzofiiran-4,5-dione derivatives are available by the ceric ammonium nitrate mediated [3+2] cycloaddition of 2-hydroxy-1,4-naphthoquinones and 2-hydroxy-1,4-benzoquinones with alkenes or phenylacetylene <96CL451>. 

From the copper-catalyzed reaction of methyl 2-diazo-3-oxobutyrate 57 a with Z-3-methoxystyrene, dihydrofuran 59 (formed with retention of olefin configuration) and butadienol 60 result130). Such an acyclic by-product also occurs when benzofuran is the cycloaddition partner. In that case, however, regioisomers 61 and 62, arising from the connection of the former diazo carbon with either the 2- or 3-position of the heterocycle, are obtained similarly, two isomeric dihydrofurans 63 and 64 are formed under Cu(hfacac)2 catalysis130). 

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

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>. 

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

To obtain further insight into the [3 + 2] cycloaddition of alkylideneallyl cation 5, the reaction with 2,3-benzofuran was carried out as shown in Scheme 15. The reaction of 4a gave a simple [3 + 2] cycloadduct 30 as a single regioisomer in 76 % isolated yield. The regioisomeric structure of 30 confirmed by NOE measurements is well compatible with the cyclic structure of 29. These... 

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],... 

The nature of the substituents on the allene can have an impact on the outcome of a [2 + 2] cycloaddition reaction, as was illustrated by the Lewis acid catalyzed cycloadditions of l-thioaryl-3,3-dimethylallene (24) and 1 -methyl- 1-trimethylsilylallene to various 2-alkoxy-p-benzoquinones 25 (e.g. equation 8)17. The reactions were considered to proceed via carbocation intermediates formed by nucleophilic attack of the thioallene on the Lewis acid activated quinone. At lower temperatures, these carbocations closed to cyclobutanes 26, whereas at higher temperatures, the thermodynamically more stable benzofurans 27 were formed. 

Cycloaddition Reactions with Other Nucleophiles The anodic two-electron oxidation of catechol affords o-quinone that may react with the enolates of 4-hydroxycoumarine or 5,5-dimethyl-1,3-cyclohexanedione (dimedone). The resulting adducts undergo a second anodic oxidation leading to benzofuran derivatives in good yields (90-95%) (Scheme 53) [75, 76]. 

When these cycloaddition reactions are carried out with alkynes, furan derivatives are formed. lodonium ylide 5, for instance, on photochemical reaction with alkynes 43, gives benzofurans 44 (86JOC3453) (Eq. 19). In a similar way, the iodonium ylide derived from 2-hydroxy-1,4-naphthoquinone undergoes a cycloaddition reaction with phenylacety-lene to yield benzofuran 45 (Scheme 16) (89LA167). 

It was shown <1998CCC681> that [l]benzothieno[3,2-3]furan 60, due to its low furan aromaticity, possesses dienophilic behavior and reacts with electron-rich dienes with the formation of a new heterocyclic system [l]ben-zothieno[3,2-3][l]benzofuran 93. Furthermore, it was reported <1999CCC389> that introduction of a vinyl moiety at C-2 of 57 created a reactive diene 94, which reacted with various dienophiles. Thus, both cycloaddition reactions led to new derivatives of heterocycle 93 substituted in the benzofuran part of the heterocyclic system (Scheme 10). 

The direct electrochemical oxidation of phenols generates phenoxonium cations which are able to undergo [3-1-2] cycloaddition in the presence of unactivated alkenes to produce benzofurans <1999JOC7654>. Thus, electrolysis of methyl 2,5-dihydroxybenzoate in a solution of lithium perchlorate in nitromethane in the presence of acetic acid and 2-methyl-2-butene produces the dihydrobenzofuran in excellent yield (Equation 88). 

Cycloaddition of oxazoles with arynes provides a route to substituted polycyclic ethers and hydrocarbons (80TL3627). Oxazole (354), for example, reacted with anthranilic acid and isoamyl nitrite to provide the cyclic ether (357) by way of the benzofuran (356). The ether was then treated with zinc in glacial acetic acid to furnish hydrocarbon (358) in 70% yield based on the starting oxazole (Scheme 77). 

Intramolecular [2 + 2]cycloadditions benzofurans. On dehydrochlorination with triethylamine in refluxing C6H6, these acid chlorides are converted into (o-acylphenoxy)ketenes, which undergo a [2 + 2]cycloaddition reaction to form p-lactones, which are converted to benzofurans by spontaneous decarboxylation in 53-82% yield.1... 

The study of this cycloaddition and its mechanism is complicated by the formation in small yield of additional photoproducts. Irradiation of phenanthraquinone (308) in, for example, 2-methylpropene affords the oxetane (309), arising by 1,2-cycloaddition of the alkene to the carbonyl, in addition to the expected 1,4-dioxene (310).334 Oxetanes are the principal products of photoaddition of phenanthraquinone to benzofuran, furano[3,2-y]coumarin, and isocoumarin.329 A further product has the structure (311), and is undoubtedly the... 

As 2-vinylfuran rapidly polymerizes even in a nitrogen atmosphere in the presence of a stabilizer, yields obtained for these Diels-Alder reactions were very low. In fact, when the more stable 5-(4-nitrophenyl)-2-vinylfuran lb reacted with DMAD, the yield of the aromatized cycloadduct, dimethyl 2-(4-nitrophenyl)benzofuran-4,5-dicarboxylate 4b, was 50%. The 4-nitrophenyl group not only deactivated the vinylfuran for oxidation and polymerization, but also deactivated the diene system toward cycloadditions, and the reaction was successful only when conducted in boiling xylene. The decrease in reactivity of the reactive diene may account for the relatively low yield of methyl 2-(4-nitrophenyl)benzo-furan-4-carboxylate 6b obtained in a similar reaction with MP (73-AJC1059). 

A formal iron-catalyzed [3 + 2]-cycloaddition of styrene derivatives with benzoqui-none was reported by Itoh s group [96]. The process is believed to proceed via electron-transfer reactions mediated by a proposed Fe3+/Fe2+ couple, which generates a styrene radical cation and a semiquinone. These intermediates undergo stepwise addition to yield the benzofuran product 51 (Scheme 9.38). The reaction seems to be limited to electron-rich alkoxy-functionalized styrenes, as the Fe3+/Fe2+ redox couple is otherwise unable to transfer the electrons from the styrene to the quinone. 

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... 

Isatine derivatives gave the corresponding cycloadducts with high stereoselectivity when irradiated in the presence of furan and benzofuran [72]. The reaction of furan with acyl cyanides yields the corresponding oxetanes, but both diastereoisomeric endo- and exo-oxetanes are formed (Scheme 3.36). When chiral acyl cyanides are used, low asymmetric induction is observed [73]. Furan also reacts with chiral ketones. In this case, an ot-cleavage reaction before the 2+2 cycloaddition modifies the expected products (Scheme 3.37). When (—)-menthone was used as a substrate, a chiral product was obtained as a 2 1 diastereoisomeric mixture the most abundant product has the (1/ , 3R) configuration [74]. When the reaction was performed on carbohydrate 36, a complex reaction mixture was obtained (Scheme 3.38) [74, 75]. 

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. 

Although obtained only in low yields upon troublesome chromatography of product mixtures that contained much polymeric material, the tricyclic benzofuran and benzothiophene lactones (61) were shown to be isolable products from attempted Diels-Alder reactions on the allene ester precursors shown in Equation (32) <85JCS(Pl)747>. Although it was noted in the case of the two thiophenes that the tricyclics appeared to be forming from a precursor (presumably a dihydro form) on the chromatographic column, it was not possible to convert the crude suspected cycloaddition adducts directly into the aromatics by dehydrogenation with DDQ. Complex mixtures were obtained instead. It is possible that the actual dienophiles in these Diels-Alder reactions are alkynes. In a related study, the bis-lactone (62) was also obtained (Equation (33)) <86H(24)88l>. 

The 4,5-double bond of 2(3//)-oxazolones participates in thermal [4 + 2] cycloaddition reactions. With dialkyl azodicarboxylates the addition occurs at 80 C to give the cycloadducts 430 (Scheme 97). With a chiral substituent attached to N(3), diastereoselectivities as high as 72% can be obtained. Cycloadditions with cyclopentadiene or benzofuran require higher temperatures and longer reaction times, but can yield highly efficient chiral oxazolidin-2-one auxiliaries. 

Two derivatives of the fully conjugated 1,2-diazocine system 8 were reported in the past decade but in poor yields (14-20%) from the reaction of 2-methyl-7-tosylfuro[2,3-r/]pyridazine 101 with ynamines by a [2+2] cycloadditionring-expansion sequence (Equation 4). From the reaction mixture, the penta-substituted pyridine derivatives (14%) by an N-N bond cleavage of the pyridazine ring and benzofuranes, as the major products (31-34%) by a [4+2] cycloaddition-denitrogen reaction, were also isolated <1996H(43)199>. 

Annulation to carbonyl functions has also been achieved with Trost s bifunctional reagents. Whereas the parent silyl acetate (97) yields only simple alkylation products with aldehydes under normal conditions, addition of only a few mole % of trimethyltin acetate to the reaction mixture results in facile formation of methylenetetrahydrofurans Furthermore, excellent diastereoselectivity is observed in the cycloaddition to a galactose-derived aldehyde (125) (equation 136). The tin acetate co-catalyst also promotes addition to relatively unreactive ketone carbonyls, such as in the case of benzofuran (126) and the acetylenic ketone (127) (equations 137, 138). It is remarkable that even the sterically hindered enone (128) reacts preferentially at the ketone function (equation 139). A tributyltin analog (129) of (97) has been used in the stepwise formation of a methylenetetrahydrofuran from aldehydes. Similarly, pyrrolidines can be prepared from the corresponding imines in two steps via a Lewis acid-catalyzed 1,2-addition of the tin reagent, which is then followed by a Pd-catalyzed cyclization (equation 140). Direct formation of pyrrolidine from the imine is possible if one uses a mesylate analog of (97) and a nickel(O) catalyst (equation 141). ... 

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