Benzofurans 3 + 2 cycloaddition reactions

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. 

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). 

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 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. 

The first total synthesis of the marine furanosesquiterpenoid tubipofuran was accomplished in the laboratory of K. Kanematsu. The c/s-fused furanodecalin system was constructed by the regioselective Diels-Alder cycloaddition reaction of benzofuran quinone and Danishefsky s diene in refluxing toluene. The reaction gave an 11 1 mixture of the desired ortho-endo adduct versus the undesired para-endo product in 98% isolated yield. The major isomer then was subjected to sequential radical deoxygenation reactions before it was finally converted to the natural product. 

The regioselectivity of the formal [3 + 2] cycloaddition reactions in Scheme 13 corresponds to the polarization of the olefinic bond and to partial charges in the ketocarbenoid. The only exception occurred with benzofuran, in agreement with the behavior of the carbenoid derived from ethyl 2-diazo-3-oxobutyrate As several examples in Scheme 13 show, the cycloaddition is sterospecific, i.e. the configuration about the enol ether double bond is retained in the dihydrofuran. The observation that in the case of 1-methoxy-1,3-butadiene highly selective cycloaddition of the unsubstituted double bond occurs, whereas for 2-methoxy-1,3-butadiene cycloaddition takes place at the more electron-rich double bond, finds a close analogy in the cyclopropanation of these same dienes with ethyl diazoacetate (see Table 9). 

Table 25. The AMI and The B3LYP/6-31G(d) computed activation barriers for selected Diels-Alder cycloaddition reactions with benzofuran, benzop3Trole, and...

Stork s strategy towards racemic morphine comprises a Diels-Alder cycloaddition reaction of a benzofuran to establish the B- and C-ring of morphine as the key step [53]. The reaction sequence started with the ketahzation of iodoisovaniUin 97 (Scheme 15). Subsequently, the phenol was reacted with methyl propiolate to afford 98 as precursor for the installation of the benzofuran moiety via a palladium-catalyzed Heck cyclization (99). Next, the key intermediate was prepared for the Diels-Alder reaction. Hydrolysis of the acetal under acidic conditions and Wittig homologation afforded aldehyde 100, which was converted to diene 101 via hydrozirconation of acetylene 105 employing the Schwartz reagent and subsequent reaction with aldehyde 100 followed by sUylation of the secondary alcohol. 

Fused Five-Membered Heterocyc/es 331 9.2.1.4 Synthesis of Benzofurans via 3 + 2 Cycloaddition Reactions... 

A catalyst-free 4 + 3-cycloaddition of in tM-generated azoalkenes (134) with C,(V-cyclicazomethine imines (135) yielded highly functionalized 1,2,4,5-tetrazepine derivatives (136) in high yields (76-92%) under mild conditions (Scheme 40). " The Lewis-acid-promoted 4 + 3-cycloaddition reaction between the allylic cation of a heterocyclic alcohol with a furan or thiophene produced seven-membered ring-fused 5,7,6-tricyclic adducts with high regio- and stereo-selectivity. For the first time, the 2jt components are benzofuran-3-yl alcohols, benzothiophene-3-yl alcohols, and indole-3-yl alcohols. ... 

When la was heated with the less reactive isoprene 5 in a sealed ampoule at 150-200°C for 72 h using benzene as solvent, it showed its dienophilic character taking part in the DA cycloaddition reactions. The reactions proceeded to produce the mixture of isomeric benzofurans 10a and 10b as the principal products and dihydrobenzofurans 9a and 9b (global yield 62%) (Della Rosa, et al, 2005). (Figure 2) In the same manner, in the case of 1-tosyl-2-nitropyrrole 2a, it reacted with isoprene furnishing dihydroindole isomers lla,b and... 

A series of 5-aminobenzofurans 170 and 2,3-dihydrobenzofurans 172 were successfully prepared from the reactive precursor, quinone monoamines 168, readily obtained through the DIB or PIFA-mediated oxidation of p-ami-nophenols 167 (Scheme 42). Reaction of quinone monoamine with ketene acetals 169 afforded the corresponding benzofurans [59]. Using this strategy, Barret et al. independently reported the synthesis of 2,3-dihydrobenzofurans 172 via [3+2] cycloaddition reaction of quinone monoamines with various azadienes 171. The utility of the developed protocol was demonstrated for the construction of 2,3-dihydrobenzofurans containing an adrenergic agent, Efaroxan 173 [60]. 

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. 

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). 

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... 

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