Reactions of Thiophen Aldehydes and Ketones

Reactions of Thiophen Aldehydes and Ketones.— The Stobbe condensation of some thienylcarbonyl compounds with dimethyl methylsuccinate in the presence of potassium t-butoxide or sodium hydride gave predominantly the ( -half esters of (156), while condensation with dimethyl homophthalate gave predominantly the (Z)-half ester of (157). Thiophen-2-aldehydes were shown to add smoothly to a -unsaturated ketones and nitriles, under the catalytic influence of cyanides, to form (158) and (159), respectively. Thiophen-2-aldehydes have been condensed with aliphatic amines and phenylenediamine to give Schiff bases  

Valenta, and P. Holy, Coll. Czech. Chem. Comm., 1974, 39, 959. 

Some new chalcones derived from thiophen-2-aldehyde have been obtained and their Michael additions investigated. With arylthiolate anions (169) was 

Reactions of Thiophen Aldehydes and Ketones.—The synthesis of bis-(4-methylpent-3-enyl)thiophens was achieved by applying the Wittig reaction to (106). A convenient method for the synthesis of (2-thienyl)ethylene oxide from thiophen-2-aldehyde and a sulphur ylide has been worked out. From 2-thenil and diethyl ketone, (107) was prepared, and its Diels-Alder reactions have been studied. The reaction of (108) with different Grignard reagents has been 

Hawkins, O. Meth-Cohn, and H. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1979, 3207. 

Studied. The reaction of pinacoline with 2-acetylthiophen gave 2,2-dimethyl-5-(2-thienyl)-5-hydroxyhexan-3-one.  

Further work on the use of the gcm-dimorpholine derivative of 2-thienylgly-oxal for the synthesis of gem-di(acylamino)- and other derivatives has appeared. In connection with work on surfactant complexes of ruthenium, thiophen-2-aldehydes were condensed with 4,4 -dimethyl-2,2 -bipyridyls. From the easily available 2,3,4-trichlorothiophen, the 5-formyl- and 5-acetyl-derivatives have been prepared, and from them a large number of derivatives.  

Reactions of Thiophen Aldehydes and Ketones.— Thiophen aldehydes have been extensively used as components in the Wittig reaction. - - It was found that o-halogeno-substituted thiophen aldehydes with o-halogeno-substituted thenyltriphenylphosphonium salts gave especially high proportions of substituted cis-1,2-dithienylethenes, and also in the phospho-nate modification unusually much cis-isomer was found. Some oligomeric aa-unsymmetrically disubstituted dithienylenevinylenes (171) were pre- 

3 Thienothlophens, their Benzo-derivatives, and Analogous Compounds 

Synthesis.—The reactions of thiophen-2- and 3-acrylic acid with thionyl chloride in the presence of pyridine yield a mixture of chlorinated derivatives of thieno[3,2-b]thiophen-2-carboxylic acid and thieno[2,3-b]-thiophen-2-acrylic acid. From thiophen-2,5-diacrylic acid, (241) was obtained. Aromatization of (66) gives thieno[2,3-b]thiophens. Reaction of (242) with methyl thioglycolate yielded (243). Ethylthiophen was 

Theoretical Studies and Physical Properties.—Quantum chemical calculations on the reactivity of thienothiophens have been carried out. The e.s.r. spectra of the radical anions of carbonyl, nitro, and cyano derivatives of the two [b]-fused thiophens have been studied. The proton chemical shifts of 2-substituted thieno[2,3-b]thiophens have been correlated with the two-parameter equation of Swain and Lupton.  

The interaction of the sulphonyl group with an adjacent unsaturated centre has been studied in the sulphone (246) and in its differently fused isomers.  

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Application of the Reformatsky Reaction to Thiophene Aldehydes and Ketones. J. org. Chemistry 15, 89 (1950). 

Reaction of Thiophen Aldehydes, Ketones, and Carboxylic Acids.-The dielectric absorptions were determined for heterocyclic aldehydes, among them 2-thiophenaldehyde, in a polystyrene matrix. The... 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

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. 

The condensation of thiophene with ketones in presence of 70% H2S04 gives di-2-thienylmethane derivatives (63AHC(l)l). Thus acetone leads to (85). Intramolecular versions of such acid-catalyzed condensations with aldehydes and ketones are known (Scheme 14) (73JOC1056, 70AHC(11)177). The Bradsher reaction has been used for the synthesis of thienobenzothiophenes in low to moderate yields (Scheme 15) (70CC1094). 

Cyclopropane derivatives of type III/64 (Scheme III/ll) have been shown to be useful starting materials for a smooth transformation to furanones [63] and thiophenes [64]. The aldol reaction of III/64 and a ketone or aldehyde yielded III/65, which forms, on desilylation, an ester diol (by a retro aldol reaction). 

The normal reactions of aldehydes and ketones attached to thiophenes or benzo[ ]thiophenes have been discussed exhaustively in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Only novel reactions, or those leading to products with special applications, are discussed here. 

The reaction is most useful for the preparation of olefinic, halo, and nitro alcohols from the corresponding substituted aldehydes and ketones. These substituents ate very often affected by other reduction procedures. Excellent directions are found in the preparations of crotyl alcohol (60%), l-bromo-5-hexanol (64%), l-chloco-4-pentanol (76%), /S,/S,/S-trichloroethyl alcohol (84%), methyl-p-chlorophenylcarbinol (81%), and o-nitrobenzyl alcohol (90%). The reaction has also been used in the preparation of certain tetralols and decalols as well as 9-fluo-renylcarbinol (50%). The thiophene and furan nuclei are not reduced. 

Acid-catalysed reaction of thiophene with aldehydes and ketones is not a viable route to hydroxyalkyl-thiophenes, for these are unstable under the reaction conditions. Chloromethylation can, however, be achieved, and with the use of zinc chloride, even thiophenes carrying electron-withdrawing groups react (CAUTION. Bis(chloromethyl) ether, a carcinogen, is formed as a by-product). Care is needed... 

The common reactions of aldehydes and ketones attached to thiophene rings have already been dealt with exhaustively in earlier reviews <84CHEC-I(4)74i, 86HC(44/3)324>. Only new and interesting applications will therefore be discussed in this section. 

Thienyl-lithium derivatives prepared through halogen-metal exchange and containing acetal-protected carbonyl groups have been used in the synthesis of di- and tri-formyl derivatives of thiophen, t-butoxy-sub-stituted thiophen aldehydes, and formylacetylthiophens. Symmetrical thienyl-substituted ketones have been obtained from thienyl-lithium derivatives and carbamates. " Mixed heterocyclic carbinols have been obtained through the reaction of thienyl-lithium derivatives with heterocyclic aldehydes. Thienyl-lithium derivatives react with cyclohexanone, and various phenylthiophens have been made by aromatization of the intermediate cyclohexenyl derivative. The reaction of thienyl-lithium derivatives with NN-dimethylacetamide, which has been used for the synthesis of... 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

Microwave irradiation has been used to accelerate the Gewald reaction for the one-pot synthesis of N-acyl aminothiophenes on solid support [67]. A suspension of cyanoacetic acid Wang resin 35, elemental sulfur, DBU and an aldehyde or ketone 36 in toluene was irradiated for 20 min at 120 °C in a single-mode microwave synthesizer (Scheme 13). Acyl chloride 37 was added, followed by DIPEA, and the mixture was irradiated for 10 min at 100 °C. After cooling to room temperature, the washed resin was treated with a TEA solution to give M-acylated thiophenes 38 in 81-99% yield and purities ranging from 46-99%. 

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