Thiophene cycloadducts

Interestingly, in syntheses of thiophene cycloadducts 81 use of microwave irradiation led to lower yields [73] than conventional heating (23% compared with 43%), although reaction times were significantly reduced [74]. 

The 4-hydroxy-THISs react with electron-deficient alkynes to give cycloadducts (3) that spontaneously eliminate sulfur, producing 2-pyridones (3). Bulky 5-substituents lead to a decrease in the addition rate, and elimination of isocyanate with formation of thiophenes becomes favored (3, 12, 13). Benzyne yields an isolable adduct that exclusively extrudes isocyanate on thermolysis, but sulfur on irradiation (Scheme 7)... 

Electron-deficient alkenes add stereospecifically to 4-hydroxy-THISs with formation of endo-cycloadducts. Only with methylvinyl-ketone considerable amounts of the exo isomer are produced (Scheme 8) (16). The adducts (6) may extrude hydrogen sulfide on heating with methoxide producing 2-pyridones. The base is unnecessary with fumaronitrile adducts. The alternative elimination of isocyanate Or sulfur may be controlled using 7 as the dipolarenOphile. The cycloaddition produces two products, 8a (R = H, R = COOMe) and 8b (R = COOMe, R =H) (Scheme 9) (17). Pyrolysis of 8b leads to extrusion of furan and isocyanate to give a thiophene. The alternative S-elimi-nation can be effected by oxidation of the adduct and subsequent pyrolysis. 

Aminothiophenes and 3-aminobenzo[Z)]thiophene undergo thermal [2 + 2] cycloaddi-tion reactions with activated alkynes. The reactions are solvent dependent thus in non-polar solvents at -30 °C, 3-pyrrolidinothiophene adds to DMAD to give a [2 + 2] cycloadduct which is ultimately converted into a phthalic ester. In methanol, however, a tricyclic product is formed (Scheme 54) (81JOC424. ... 

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

Alkoxy)alkynylcarbene complexes have been shown to react with nitrones to give dihydroisoxazole derivatives [47]. Masked 1,3-dipoles such as 1,3-thia-zolium-4-olates also react with alkynylcarbene complexes to yield thiophene derivatives. The initial cycloadducts formed in this reaction are not isolated and they evolve by elimination of isocyanate to give the final products [48]. The analogous reaction with munchnones or sydnones as synthetic equivalents of... 

Thiophenes are less reactive than furans and therefore react with very reactive dienophiles. They behave somewhat differently from furans and in many cases the intermediate addition products are unstable and undergo cheleotropic extrusion of sulfur [30]. Thiophenes 30 undergo cycloaddition reactions with DMAD (Equation 2.11) to afford bicyclic cycloadducts which lead to phthal-ates by sulfur extrusion, thus offering a one-pot synthesis of dimethylphthalates [31]. 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

Only [4 + 2] cycloadducts 155 a, b were formed and isolated in 48 and 43% yield, respectively, in the reaction of bicyclopropylidene (1) with thiophene S-oxide derivatives 154 a, b under high pressure (Scheme 33) [128]. 

The cycloaddition of 1 with 1,2,4-triazines (324), bearing one or more electron-accepting substituents, directly affords the 3,8-methanoaza[10]annulene 325 after loss of N2 from the cycloadduct. Similarly, the tetrazine-dicarboxylate 326 reacts with 1 via cycloaddition/cycloelimination to 327, which has norcaradiene struc-ture. a-Pyrones (328) and 1 undergo cycloaddition/C02 extrusion to 1,6-methano[10]annulenes (329). The sequence cycloaddition/C02 extrusion has also been reported for the reaction of cyclopropa[/]phenanthrene (142) with a-pyrone (328, R = H). ° Substituted 1,6-methano[ 10]annulenes 331 are obtained by analogy via cycloaddition/S02 extmsion of 1 with thiophene-1,1-dioxides (330). ... 

The meso-ionic l,3-dithiol-4-ones (134) participate - in 1,3-dipolar cycloaddition reactions giving adducts of the general type 136. They show a remarkable degree of reactivity toward simple alkenes including tetramethylethylene, cyclopentene, norbomene, and norbor-nadiene as well as toward the more reactive 1,3-dipolarophilic olefins dimethyl maleate, dimethyl fumarate, methyl cinnamate, diben-zoylethylene, A -phenylmaleimide, and acenaphthylene. Alkynes such as dimethyl acetylenedicarboxylate also add to meso-ionic 1,3-dithiol-4-ones (134), but the intermediate cycloadducts are not isolable they eliminate carbonyl sulfide and yield thiophenes (137) directly. - ... 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

Cycloadditions with other symmetrical acetylenes were carried out by using thiocarbonyl (5)-methylide (69) (159). Interestingly, no reaction was observed when acetylene dicarboxamide was used. The reaction of 69 with cyclooctyne resulted in the formation of cycloadduct 103 (Scheme 5.38). Interestingly, the spirocyclic 2,5-dihydrothiophenes of type 103 or 104 undergo acid-catalyzed ring opening upon treatment with silica gel or trifluoroacetic acid to give thiophenes 105 and 106, respectively. 

Recently, a new approach to 3,4-disubstituted thiophenes via the 3,4-disilylated thiophene 108 was reported (160). The synthesis includes the cycloaddition of la to bis(trimethylsilyl)acetylene and subsequent dehydration of cycloadduct 107 with DDQ to give 108 (Scheme 5.39). The trimethylsilyl groups can be substituted in a stepwise manner to give unsymmetrical 3,4-disubstituted thiophenes (109). 

The unstable l,3-bis(methoxycarbonyl)selenolo- 190 and l,3-bis(methoxycarbonyl)tellurolo[3,4-f]thiophene 191 underwent Diels-Alder reaction with DMAD to produce cycloadducts, which lost selenium or tellurium and collapsed to tertracarbomethoxybenzo[f]thiophene 192 in low yields <20020L1193>. 

Cyclobut[f]thiophene is a poor dipolarophile and requires prolonged reaction times to produce the 1,3-dipolar cycloaddition product 84 on reaction with diazomethane (Equation 44) <1999J(P1)605>. Reactions with nitrile imines or azomethine imines fail to provide cycloadducts. 

Cyclobut[c]thiophene also undergoes 1,3-dipolar cycloaddition reactions with nitrones and nitrile oxides to produce cycloadducts, such as 80, albeit in moderate yields (Scheme 9) <1999J(P1)605>. 

Allylcyclopent-2-enones photoisomerize regioselectively to tricyclo[3.2.1.03 6]octan-2-ones 40 42 Similarly, 2-acetyl- or 2-methyl-2-(prop-2-enyl)-furan-3(2/y)-ones or -thiophen-2-ones afford the corresponding 7-heteratricyclooctan-2-ones 15.43,44 Photolysis of 5-(pent-4-enyl)-3-phenylcyclopent-2-enone yielded only 9-phenyltricydo[5.2.1.03-9]dccan-10-one (the straight cycloadduct).45... 

While the Diels-Alder reactions of thiophenes with various dienophiles are relatively rare, it is interesting to note that 2,5-dimethoxythiophene (297) prepared from 2,5-diiodothiophene does react with maleic anhydride to form the bis-adduct (299) (75JCS(P1)2483>. Sulfur extrusion from the primary cycloadduct delivers a new diene system (298) which then undergoes the second Diels-Alder reaction (Scheme 63). 

Irradiation of l,3-diphenylbenzo[c]thiophene in the presence of oxygen converts it to 1,2-dibenzoylbenzene, probably via a cycloadduct (Scheme 29) (B-67MI31402). Similar oxidative ring opening has been observed when l,3-diarylbenzo[c]thiophenes are reacted with peracetic acid or aqueous KMnC>4 (72AHC(14)33l). 

Similar results have also been obtained with 3-pyrrolidinobenzo[6]thiophene. In nonpolar solvents at -20 °C the formation of the cycloadduct (283) can be observed (77AHC(21)253), whereas in methanol the product isolated is (284) (81JOC424). 

Such [2 + 2] cycloadditions have also been observed when the alkyne is electron-rich and the benzo[6 ]thiophene electron-poor. Thus 3-nitrobenzo[6]thiophene reacts with ynamines to form the cycloadduct (285) the addition is regioselective and the product shows no tendency to isomerize to the corresponding benzothiepin (74TL2503). 

Benzo[c]thiophene 2,2-dioxides, generated in situ, react easily with Af-phenylmaleimide the [4+2] cycloadducts lose S02, and the product so obtained can either add on another molecule of /V-phenylmaleimide, or aromatize (Scheme 198) (75JOC72). 

The perfluoroalkyl Dewar thiophene, unlike Dewar benzene, reacts with aryl, alkyl, as well as the unusual hydrogen azide at room temperature to give 80-94% yields of cycloadducts the t-butyl compound (Scheme 20)159-161 is... 

There have been several studies utilizing the ability of 4,6-dinitrobenzofuroxan (DNBF) to act as a super-electrophile. It has been shown that the initial product of its reaction with phenoxide ions is the O-bonded adduct (29), although this rearranges to give die C-bonded adduct.117 The reaction of DNBF with ethyl vinyl ether yields a dihydrooxazine A -oxidc cycloadduct as a mixture of two diastereoisomers, and in the presence of excess ether a di-adduct (30) is formed.118 Rate constants have been reported for the reaction of DNBF with 3-methoxythiophene in DMSO-water mixtures. The reaction results in a er-adduct which is the product of Se-At substitution in the thiophene, and the results were used to probe the carbon basicity of the thiophene derivative.119... 

---