Furan annelation

The furan annelation reaction represents a new method for the preparation of this important class of compounds. Furans are widely found in nature, and highly functionalised furans are desirable targets in total synthesis work, either as products themselves, or as intermediates. Commercially available or readily accessible furans are usually limited to substitution at the more reactive 2- and 5-positions of the ring. The need for the preparation of furans with substitution at other positions on the ring, or with sensitive functional groups present, led to the development in 1987 of a palladium-catalysed method for their preparation.  

The original work used p-keto esters and propargyl carbonates as substrates. Under palladium(O) catalysis, these react to give cxo-methylenefurans 

which isomerise readily under acidic conditions to give the corresponding furans 47. 

Tsuji found that the p-keto esters could be replaced with acetylacetone derivatives, to give acetyl furans, and with 1,3-cyclohexanedione, to give a ring-fused furan system. A range of alkylated propargyl carbonates could also be used. In all cases the yields of the reaction were excellent. 

The key intermediate in the mechanism of the reaction is the formation of a cT-allenylpalladium complex 48 together with methoxide which serves as an in situ base to deprotonate the nucleophile. 

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This rearrangement of allylic acetals can also be used for furan annelations, in which the formation of the new tetrahydrofuran ring is coupled with ring enlargement of the starting ring.3 The same dr-fused bicyclic tetrahydrofuran is formed from either one of the cis- or mwr-allylic diols used as starting materials. 

The 2-vinyloxiranes undergo Pd-catalysed furan annelation with soft nucleophiles [36,37], The allenylpalladium 170 is generated from ethynyloxirane 169, and the attack of acetoacetate anion 153 at the central carbon of 170 forms 171. The oxygen... 

This reagent is obtained by addition of Br Furan annelation.1 The reagent real (2) to form furan 3 in good yield. A simik NaOCH3 in CH3OH is accompanied by dc... 

The group of Takayama has carried out a considerable Eimount of work in this area and this has been reviewed [2]. They prepared the previously unknown furan annelated 3-sulfolene (22) in a facile three-step procedure, from 3,4-dimethyl-3-sulfolene (21) (Scheme 6.7) [103]. Intermediates used in this sequence had been described previously [15,91]. 

Ethynyloxiranes undergo Pd-catalyzed furan annelation with soft nucleophiles (Scheme The allenylpalladium is generated from 2-methyl-2-ethynyloxirane,... 

Senboku, H., Kajizuka, Y., Kobayashi, K., Tokuda, M., and Suginome, H., Photoinduced molecular transformations. 160. Furan annelation of 2-hydroxynaphthoquinone involving photochemical addition and radical fragmentation xeclusion of the intermediacy of [2-1-2] cycloadduct in a one-pot formation of furanoquinones by the regioselective 3-1-2 photoaddition of hydroxyquinones with alkenes. Heterocycles, 44, 341,1997. 

One of the more useful predicative applications of the relatively crude Hiickel method has been to illustrate quantitatively the effect of benzenoid annelation on the resonance energies of furan and thiophene. The results are summarized in Figure 1. As expected, thiophenes are more stable than the corresponding furans and 3,4-fusion results in less stable compounds than 2,3-fusion (77CR(C)(285)42l). 

The reaction can also be used for synthesis of furans by a [2 + 3]annelation. Example ... 

The lability of thieno[3,4-6]thiophene (3) and other iso-annelated systems, such as benzo[c]thiophene and benzole] furan, may be due to the strain effect (Mills-Nixon effect see also Zwanenburg et alP and references therein) in the condensed five-membered ring. The stability of the iso-annelated dithienothiophenes 7—9 is noteworthy. Simple LCAO MO method calculations on benzo[c]thiophene indicate that its instability is due to low specific delocalization energy and high free valence index at position 1. 

Annelation of a furan ring onto a thiophene is also possible by flash vacuum pyrolysis at 650 °C of the acrylate 368 and malonate 369, which gave 2-(methylthio)thieno[3,2-/ ]furan 370 and methyl-5-(methylthio)thieno[3,2- ]furan-2-carboxylate 371, respectively, in yields of 21% and 22% <1997J(P1)2483>. 

Vll. Benz-Annelated and Hetero-Substituted Benzo[<]furans and Larger... 

Linear benz-annelation enhances the reactivity and decreases the stability of benzo[c]furan, as with other o-quinonoid heterocycles.1,3-Diphenyl-naphtho[2,3-e]furan (299) has been obtained from 297 via lactol 298 as deep red glistening plates with mp 148-154°C in 89% yield.Although dried crystals of 299 could be stored for several months in the absence of light and air, solutions in organic solvents decolorized slowly on standing... 

Angular benz-annelated benzo[c ]furans (naphtho[l,2-c]furans) are also known. Compounds 307 have been synthesized in the usual manner (Scheme 20). ... 

Two furo-annelated benzo[c]furans, a benzo[2,l-Z) 3,4-c ]difuran (341) and a benzo[1.2-/ 3,4-c ]difuran (344) have been described. Acid-catalyzed ring closure of bisfuran 340, which is available from trans-trans-1,4-dibenzo-ylbutadiene (339) and /ranx-dibenzoylethylene. yields 341 in 83% yield. An independent synthesis which starts from 4-benzoyl-2-phenylfuran (343) is outlined in Scheme 21 the isomeric compound has been obtained similarly (Scheme 22). 

Preparation the linear tropone-annelated benzo [c] furans 371 (X = O) by direct condensation of dialdehyde 370 (X = O) with acetone, 1-phenyl-acetone, and 1,3-diphenylacetone, in alkaline medium was—in contrast to the corresponding benzo [c]thiophene (X = S)—unsuccessful. Interestingly, this condensation has been brought about with the Diels-Alder adduct 372 subsequent heat yields 371 (X = O), a rare case where V-phenylmaleimide is used as a protective group. Compounds 371 react with V-phenylmaleimide even at room temperature to give adducts 373. 

This method has since been used for synthesis of annelated furanes.2 An example is formulated in equation (II). The masked furane ring is introduced by reaction of an activated methylene group with dimethylformamide dimethyl acetal. 

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