Thiophene reaction with carbenes

Furan and thiophene undergo addition reactions with carbenes. Thus cyclopropane derivatives are obtained from these heterocycles on copper(I) bromide-catalyzed reaction with diazomethane and light-promoted reaction with diazoacetic acid ester (Scheme 41). The copper-catalyzed reaction of pyrrole with diazoacetic acid ester, however, gives a 2-substituted product (Scheme 42). 

Saito et al. [33] described a new method for the synthesis of heterocycle-fused[c]thiophenes via reaction of aryl heteroaryl thioketones with carbene precursors. Heteroaromatic thioketones A react with carbenoids generated from bis(arylsulfon yl)diazomethanes or phenyliodonium bis(phenylsulfonyl)methylides to give hete-rocycle-fused[c]thiophenes B (Scheme 20). The reaction involves the ring closure of the intermediary thiocarbonyl ylides, followed by restorative aromatization via the elimination of a sulfenic acid. The present method provides simple and facile access to a variety of furo- 118, benzofuro- 119, thieno- 120, benzothieno- 121, pyrrolo-122, and indolo-123 fused [c]thiophenes (Scheme 20). 

Rh-catalysed intramolecular insertion into thiophene. 59, 204 cycloaddition to uracils, 55, 1% Carbene, 5,6-cycloadduct with 2H-thiopyran, 59, 225 Carbenes, a-keto-perfluoroalkyl-, generation, trapping. 60, 40 Carbenes, Fischer, reaction with N-(hexafluoroisopropylidene) amides,... 

The reactions of thiophene with carbenes and nitrenes were discussed in detail in CHEC-II(1996). The preparation of S,N-ylides by an improved method is discussed in Section 3.10.3.3. 

It seems probable that all of the product types observed in the reaction of carbenes with thiophene and its derivatives may be explained on the basis of... 

Even thiophene itself will react with carbenes, at sulfur, to produce isolable thiophenium ylides, and in these, the sulfur is definitely tetrahedral. The rearrangement of thiophenium bis(ethoxycarbonyl) methylide to the 2-substituted thiophene provides a rationalisation for the reaction of thiophene with ethyl diazoacetate, which produces what appears to be the product of carbene addition to the 2,3-double bond perhaps this proceeds via initial attack at sulfur followed by S C-2 rearrangement, then collapse to the cyclopropane. Acid catalyses conversion of the cyclopropanated compound into a thiophene-3-acetic ester. ° 2,5-Dichlorothiophenium bis(methoxycarbonyl)methylide has been used as an efficient source of the carbene simply heating it in an alkene results in the transfer of (Me02C)2C to the alkene. ... 

Although the behavior of thiophenes toward carbenes has been fairly well documented, the reaction of thiophene 1,1-dioxides with carbenes or carbenoids has scarcely been reported. The dibromide 3 reacted under the conditions given below to produce 3-dihalomethylenedihydrothiophene dioxide 15 in reasonable yields (Scheme 11) [101]. The reaction may involve the dihalocarbene adducts 16 of the parent thiophene 1,1-dioxide, but the reaction more probably proceeds... 

In the first edition (CHEC-I) <84CHEC-I(4)74i> it was mentioned that three types of products were identified in the reaction of thiophenes with carbenes generated from diazo compounds, cyclopropanes, 5,C-ylides, and 2-substituted thiophenes, corresponding to carbene attack at the 2,3-double bond, ring sulfur or at C-2, respectively. However, it now appears very likely that the... 

A new thiophen synthesis is based on deprotonation and cyclization of the resultant carbanion (65) of a keten dimethylthioacetal. Other applications of cr-(phenylthio)- or cr-(alkylthio)-alkyl-lithiums include preparations of disparlure (the sex pheromone of the gypsy moth) and other chiral epoxides,of an anti-peptic-ulcer diterpene from Croton sublyratus, of carbene-thiometal chelates through reaction with fCr(CO)gl or fW(CO)jl, of olefins via )ff-hydroxy-sulphides, and of Michael adducts of enones. In other work, the chiral solvent l,4-dimethylamino-2,3-dimethoxybutane is employed in enantioselective addition reactions of cr-thio-carbanions with ketones and Michael acceptors. a,P -Elimination of cr-thio-carbanions such as (66) provides a useful synthesis of olefins, and a 2-(lithiomethylthio)-A -oxazoline (67) has been used to prepare a C-labelled thiiran for a microwave study of the valence tautomerism of allene episulphide. ... 

Thiophenes undergo cycloadditions across the C-2/C-3 bond, for example, (2 + 1)-cycloaddition with carbenes ( 9) and (2 -I- 2)-cycloadditions with activated alkynes, as shown for the reaction of tetramethylthiophene with dicyanoacetylene under... 

Rhodium(II) acetate was found to be much more superior to copper catalysts in catalyzing reactions between thiophenes and diazoesters or diazoketones 246 K The outcome of the reaction depends on the particular diazo compound 246> With /-butyl diazoacetate, high-yield cydopropanation takes place, yielding 6-eco-substituted thiabicyclohexene 262. Dimethyl or diethyl diazomalonate, upon Rh2(OAc)4-catalysis at room temperature, furnish stable thiophenium bis(alkoxycarbonyl)methanides 263, but exclusively the corresponding carbene dimer upon heating. In contrast, only 2-thienylmalonate (36 %) and carbene dimer were obtained upon heating the reactants for 8 days in the presence of Cul P(OEt)3. The Rh(II)-promoted ylide formation... 

Interaction of an electrophilic carbene or carbenoid with R—S—R compounds often results in the formation of sulfonium ylides. If the carbene substituents are suited to effectively stabilize a negative charge, these ylides are likely to be isolable otherwiese, their intermediary occurence may become evident from products of further transformation. Ando 152 b) has given an informative review on sulfonium ylide chemistry, including their formation by photochemical or copper-catalyzed decomposition of diazocarbonyl compounds. More recent examples, including the generation and reactions of ylides obtained by metal-catalyzed decomposition of diazo compounds in the presence of thiophenes (Sect. 4.2), allyl sulfides and allyl dithioketals (Sect. 2.3.4) have already been presented. 

The coupling reaction of Fischer carbene complexes, 96, with 3-alkynyl-2-thiophene carboxaldehyde leads to the formation of thieno[2,3-c]pyranones (Scheme 25) <2001TL777, 2002JOC4177>. This reaction is applicable to the oxygenated derivatives. 

Sulfonium ylides generated through base-promoted deprotonation of sulfonium salt have been extensively studied. The reaction of sulfides with a diazo carbonyl compound in the presence of a transition metal catalyst is an alternative approach to obtain sulfonium ylides. Sulfonium ylides are more stable than the corresponding oxonium ylides. Stable sulfonium ylides generated by the reaction of an Rh(ii) carbene complex with thiophene have been reported (Figure 5). ... 

The comparison of thiophene with thioethers on the one hand and with enol thioethers on the other, in regard to its behaviour towards conventional electrophiles, has been made in Section 3.02.2.3. Attack on carbon is the predominant mode of reaction (Section 3.14.2.4) reaction at sulfur is relatively rare (Section 3.14.2.5). Carbenes are known to act as electrophiles attack at both carbon and sulfur of thiophene has been reported. The carbene generated from diazomalonic ester by rhodium(II) catalysis attacks the sulfur atom of thiophene, resulting in an ylide. It has also been shown that the carbenoid species derived by thermolysis of such an ylide functions as an electrophile, attacking the a-carbon of a second molecule of thiophene (Section 3.14.2.9). Singlet nitrene is electrophilic. However, in contrast to carbenes, it invariably attacks only the carbon atom (Section 3.14.2.9). 

Pericyclic reactions involving thiophenes have been utilized to prepare a variety of complex heterocycles. The intramolecular Diels-Alder reaction of 2-vinylbenzo[i]thiophene 92 produced a pair of tetracyclic adducts 93 and 94 <02TL3963>. Coupling of Fischer carbene 96 with 3-alkynylthiophene 95 led to the formation of thieno[2,3-c]pyran-3-one 97 in one step <02JOC4177>. An intramolecular cycloaddition of 97 then afforded tetracyclic adduct 98. A ruthenium-catalyzed cyclodimerization reaction involving bis-thienyl acetylene derivatives was... 

E5.3 Reaction of this penicillin-derived carbene, a, with thiophene, b, gives at least three adducts. The H NMR properties of two of the adducts, summarized below, are consistent with addition of the carbene to the thiophene double bond. Use die observed NOEs to elucidate the stereochemistry of these adducts. 

The same product 50 was also obtained in 66% yield when 2-fluoro-3-phenylbenzo[ ]thiophene was treated with excess BuLi. It has been suggested that this reaction involves a rearrangement of a carbene intermediate (Scheme 8). 

Reaction of ketene, J,y-acetals 631 with lithiotrimethylsilyldiazomethane generates alkylidenecarbene intermediates 633 through the diazo alkoxides 632. The carbene undergoes an intramolecular cyclization and subsequent elimination to afford 2-(alkylthio)thiophenes 634 (Scheme 94) <2002H(57)1313>. 

There can now be little doubt that the reaction of singlet carbenes and car-benoids with thiophene proceeds by attack of the carbene at the ring sulfur atom to generate the S,C-ylid. However, only in the special cases indicated above do these ylids enjoy any real stability. In the majority of cases, other products usually result from rearrangement of the intermediate ylids and the nature of the products formed is remarkably sensitive to both steric and electronic effects. Broadly speaking, six major reaction pathways have been observed (1) 2-substituted thiophene formation, (2) 2H-thiopyran formation, (3) formation of derivatives of 2-thiabicyclo[3.1.0]hex-3-ene, (4) 3-substituted thiophene formation, (5) oxathiocin formation, and (6) carbenic fragmentation. 

Frequently, two or more of the product types are observed under the same reaction conditions, suggesting an extremely complex potential energy surface with many local minima. This, of course, means that it is impractical to consider the formation of each product type independently since small changes in substitution of the thiophene ring, or the carbene precursor, can bring about changes in product distribution. In addition, the temperature at... 

Formally, the insertion of a carbene(oid) into the 2,3-doubIe bond of the thiophene ring should result in the formation of the 2-thiabicyclo [3.1.0] hex-3-ene ring system. Copper(II)-catalyzed reaction of thiophene with diazomethane results in the formation of 24 (R = H) in modest yield (63TL1047). Analogously, the reaction of thiophene with ethyl diazoacetate yields 24 (R = COjEt) (22LA154). Although these reactions appear to be simple carbene insertion reactions, it is probable that this simple mechanism is not in operation. Rather, the cyclopropane derivatives 24 probably result from the initial formation of the ylid (e.g., 18), which subsequently rearranges. 

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