3.4- disubstituted thiophenes

Mechanistically, the reaction of diketosulfides and glyoxal likely proceeds via an initial aldol reaction to provide 22. A second intramolecular aldol reaction and the elimination of two equivalents of water produce the thiophene 23. The timing of the elimination reactions and the ring-closing, carbonyl condensation reaction is not completely understood. However, 2,5-disubstituted thiophenes 23 are available in good yields via this process. 

The Bogert synthesis of 2,4-diarylthiophenes consisting of the reaction of sulfur with the anils of arylalkyl ketones, has been shown to lead to a mixture of 2,4- and 2,5-disubstituted thiophenes. ... 

In the reactions of 2,5-disubstituted thiophenes elimination of an a-substituent occurs to a much greater extent than in the benzene series. The Friedel-Crafts acetylation of 5-bromo-2-ethylthiophene in the presence of SnCE gives 2-ethyl-5-acetyIthiophene. Elimination of an a-bromine occurs also in the chloromethylation of 2,5-di-bromothiophene, leading to a mixture of 2-bromo-5-chloromethyIthio-phene and 2,5-dibromo-3-chloromethyIthiophene. Bromine atoms at both the and -position are exchanged for chlorine in the... 

The investigation of deprotonated hexa-2,4-diyne [KCH2C C=CCH3 H2C=C=C(K)C=CCH3] has shown (90DIS) that both carbanions are formed. In some cases CS2 reacts with the diyne carbanion to afford 2,5-disubstituted thiophenes 71 (90DIS). 

On the other hand, the thiaozonides 13 were unknown but could be prepared analogously via singlet oxygenation of 2,5-disubstituted thiophenes and subsequent diimide reduction at low temperature (Eq. 10)25). 

Disubstituted thiophenes 96 and 1,2,5-tri- and 2,5-disubstituted pyrrole derivatives 97 are available readily from m-3,6-disubstituted-3,6-dihydro-l,2-dioxins in a one-pot synthesis. The reaction proceeds by an initial Kornblum-de la Mare rearrangement of the 3,6-dihydro-l,2-dioxin to its isomeric 1,4-diketone followed by the condensation with Lawesson s reagent, ammonium carbonate, or a primary amine (Scheme 21) <2002TL3199>. 

In another variation, a 2-alkanone can be reacted with a Grignard reagent, followed by acid-catalyzed dehydration to a mixture of alkenes, and catalytic reduction (Figure 8.2E) (Hwang et al., 1976 Suzuki, 1981 Lacey et al., 2008). Other methods have also been used. For example, in some of the pioneering work on insect cuticular hydrocarbons and their analyses, Pomonis and co-workers prepared a large number of monomethyl and dimethylalkanes from 2,5-disubstituted thiophenes (e.g., Pomonis et al., 1978). However, this route cannot be recommended because it requires as many as 12 steps per hydrocarbon. 

An interesting photochemical synthesis of 2,5-disubstituted-thiophenes 38 stems from the first report of the photoinduced sulfur extrusion from variously 3,6-disub-stituted 1,2-dithiins 35a by exposure to daylight in ethyl acetate or in DCM, or by irradiation at 365 nm in methanol (Scheme 12.11) [29]. Other examples involve naturally occurring thiarubrines 35b [30], as well as variously substituted synthetic derivatives [ 31]. This photochemical reactivity has been generalized with an application in the synthesis of selenophene 40 obtained in almost quantitative yield from 39 [32]. 

A one-pot synthesis of 2,5-disubstituted thiophenes 595 from 3,5-dihydro-l,2-dioxines 593 has been reported. The reaction proceeds by a Kornblum-de la Mare rearrangement to 1,4-diketones 594 followed by sulfuration with LR (Scheme 90) <2002TL3199>. 

Disubstituted and 2,5-disubstituted thiophenes are lithiated ortho to the more powerful group . 

Much use has been made of conjugated diynes, which are also at the oxidation level of 1,4-dicarbonyl-compounds, which react smoothly with hydrosulhde or sulhde, under mild conditions, to give 3,4-unsubstituted thiophenes. Unsymmetrical 2,5-disubstituted thiophenes can be produced in this way too. ° Since nearly all naturally occurring thiophenes are found in plant genera, and co-occur with polyynes, this laboratory ring synthesis may be mechanistically related to their biosynthesis. 

The simplest method is sulfurization followed by cyclizing dehydration of 1,4-dicarbonyl compounds 14 analogous to the Paal-Knorr synthesis of furans. This cyclocondensation is carried out with P4S10 or HiS, and furnishes 2,5-disubstituted thiophenes 15 (Paul synthesis) ... 

The thiophoie-1,1-dioxide moiety is also used as a diene in Diels-Alder reactions. These molecules react with dienophiles such as 7V-phenylmaleimide to produce disubstituted phthalimides or in some cases the bismaleimide adduct 87 <94TL442S>. When a bisthiophene crown ether is treated with MCPBA and N-phenylmaleimide, a bicyclic sulfoxide is isolated. When this material is treated with potassium permanganate, the SO moiety is oxidatively removed to form phthalimide crown ether 88 <94JCS(P1)2323>. The 2,5-disubstituted thiophene-... 

Oxidation of a thiophene leads to a dioxide, which in the case of thiophene itself dimerises in low yield, but with substituted thiophenes can be isolated peracids or 2,2-dimethyloxirane, which improves yields from 2,5-disubstituted thiophenes, can be used. The 5,5-dioxides are no longer aromatic thiophenes and react as dienes in Diels-Alder reactions generally sulfur dioxide is extruded from the initial adduct, leading to further reaction" - eventual aromatisation in the example shown. ... 

Brandsma and De Jong have reported a one-pot synthesis of substituted as well as underivatized T23bT (Scheme 11.2) using derivatives of 1,3-pentadiynes in yields of roughly 50% [ 11 ]. This procedure relies on the reaction of the intermediate potassiated diyne through the allenic form. One of the major impurities found is the 2,5-disubstituted thiophene thiolate that is easily separated owing to its water solubility. 

Syntheses of Thiophens by Ring-closure Reactions.—The base-catalysed reaction between 3-amino-substituted dithioacrylate esters or amides (1), which are easily available from trithione, and a-halogenocarbonyl compounds yields 2,5-disubstituted thiophens (2). The same is true for... 

Scheme 93 Addition-rearrangement reactions of 2,5-disubstituted thiophene 1,1-dioxides with 2,5-disubstituted furans [116]...

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