Thiophene derivatives cycloadditions

Cycloproparenes in which the benzene ring is fused to a five-membered heterocyclic moiety are accessible by the cycloaddition route from the appropriate dienes 188. Both the fiiran and thiophene derivatives 189 and 190 are isolable, but both are highly reactive. TTie difluoro derivative 191, prepared by an analogous route, has also been synthesized but decomposed rapidly in solution, while 192 was not isolable." ... 

Thiophene 1,1-dioxides, unlike most other thiophene derivatives, are dienes and combine with dieneophiles to form adducts that are prone to retro-cycloaddition, extruding sulfur dioxide in the process (Scheme 6.34b). 

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). 

The role of the zwitterion intermediate 164 and its rearrangement in the photocyclization of aromatic thioethers 163 to arene dihydro thiophene derivatives 165 is supported [81] by its independent trapping (via 1,3-dipolar cycloaddition) with biphenyl maleimide to obtain 166 in high yields (Scheme 8.47). 

CR(Q(262)1017>. The nucleophilic reactivity of the oxygen atom has been observed in the acetylation by acetic anhydride of 2-aryl- and 2-heteryl-A2-thiazolin-4-ones (Scheme 136). 2-Alkoxy and 2-methyl derivatives of A2-thiazolin-4-one (196) react with OPCl3 to yield thiazolylphosphoric esters (197) which have insecticidal uses (Scheme 137). An example of the electrophilic reactivity of the C-4 atom is the easy formation of oxime and phenylhydrazone derivatives. 5-Aryl-A2-thiazolin-4-one (198) gives the 1,3-dipolar cycloaddition product (199) with methyl fumarate and methyl maleate (Scheme 138). Under similar conditions, treatment of (198) with dimethyl acetylenedicarboxylate (DMAD) yields a thiophene derivative (202) when R = Ph and a pyridone derivative (203) when R = H (Scheme 139). The proposed mechanism involves the formation of a mesoionic intermediate (200) which reacts in a cycloaddition with a second molecule of DMAD, yielding (201), the decomposition of which depends on the R substituent. 

With unsymmetrically substituted mesoionic 1,3-dithiolones (2) and alkynes, the cycloaddition reactions normally yield the two possible isomeric thiophene derivatives. Thus methyl propiolate reacts with (2a) to produce an 81 19 ratio of the two possible isomeric thiophenes (88) and (89) in 90% yield, whereas the same reaction with the isomeric 1,3-dithiolone (2b) yields the thiophene derivatives in a 30 70 ratio (99%) (78CB2028). A further example is provided by the reaction of phenylacetylene with (2a) which proceeds with formation of the thiophene isomers (90) and (91) in an 89 11 ratio however, in the case of (2b) and the same substrate, the product isomer ratio is completely reversed (11 89) (78CB2028). 

An interesting example of an intramolecular cycloaddition reaction has been observed in the case of the mesoionic 1,3-dithiolone (97) which contains a non-activated alkyne in the same molecule. Thus, on heating (97) at 40-45 or 100 °C, the tricyclic thiophene derivative (99) is obtained via the non-isolable primary adduct (98) (81LA347). 

In an analogous reaction of (2) with norbomadiene, the tetracyclic adduct (116) is formed which on heating undergoes a retro Diels-Alder reaction with formation of the thiophene derivative (117). Further cycloaddition reactions of mesoionic 1,3-dithiolones have been carried out with cyclopentadiene, 1,3-cyclohexadiene and 1,5-cyclooctadiene (78CB3037). 

An interesting aspect of the type A heteropentalenes is the fact that each molecule is associated with two 1,3-dipolar fragments (45a<->45b) and, in principle, unsymmetrical systems can form two types of cycloadduct (46 or 47). In some cases the kinetically controlled product (46) is obtained at low temperature and the thermodynamically controlled product (47) is obtained at higher temperatures (see thieno[3,4-c]pyrroles, Chapter 3.18). For a given set of reaction conditions cycloaddition is usually site specific. For example, the non-classical thiophene derivatives of general structure (48) usually add across the thiocar-bonyl ylide fragment. This site selectivity is probably determined by the relative size of the HOMO coefficients at the alternative sites of addition. 

By analogy, 2-vinylthiophene reacts with tetrabromocyclopropene by [4 + 2] cycloaddition subsequent loss of HBr with concomitant opening of the cyclopropane ring leads to the benzo[A]thiophene derivative 350. 

Thiazoles have a low reactivity in cycloaddition reactions due to their high aromatic character. However, it has been possible to achieve intramolecular Diels-Alder reactions in some cases. The reaction of the acetylenic thiazole (66) in decalin at 350 °C affords, after loss of acetonitrile, the thiophene derivative (67) in 75% yield (Equation (16)). The reaction is also applicable to other thiazoles although with some limitations <88T3327>. 

The observed regioselectivities during these cycloadditions have been explained in terms of qualitative frontier molecular orbital perturbation theory <78CB2028>. An intramolecular cycloaddition has been observed for the 1,3-dithiolone (111) to afford the tricyclic thiophene derivative (112) (Equation (13)) <81LA347>. 

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