Synthesis of Thiophenes

Thiophene is manufactured by the gas-phase interaction of C4 hydrocarbons and elemental sulfur at 600 °C. Using n-butane, the sulfur first effects dehydrogenation and then interacts with the unsaturated hydrocarbon by addition, further dehydrogenation generating the aromatic system. 

The reaction of a 1,4-dicarbonyl compound (cf. 16.16.1.1 and 18.13.1.1) with a source of sulfide, traditionally phosphorus sulfides, latterly Lawesson s reagent (LR), or bis(trimethylsilyl)sulfide, gives thiophenes, presumably, but not necessarily, via the bis(thioketone). 

When the process is applied to 1,4-dicarboxylic acids, a reduction must occur at some stage, for thiophenes, and not 2- or 5-oxygenated thiophenes result.  

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. 

Finally in this category, the efficient synthesis of 3,4-dimethoxythiophene from 2,3-dimethoxy-l,3-butadiene on reaction with sulfur dichloride is notable it was easily transformed into EDOT (31.6.6.1). Here the sulfur source is electrophilic in character. 

4-Dicarbonyl compounds can be reacted with a source of sulfur to give thiophenes. 

Much use has been made of conjugated diynes, also at the oxidation level of 1,4-dicarbonyl compounds, which react smoothly with hydrosulfide or sulfide, under mild conditions, to give 3,4-unsubstituted thiophenes. Unsymmetrical 2,5-disubsti- 

---

Process Description. Reactors used in the vapor-phase synthesis of thiophene and aLkylthiophenes are all multitubular, fixed-bed catalytic reactors operating at atmospheric pressure, or up to 10 kPa and with hot-air circulation on the shell, or salt bath heating, maintaining reaction temperatures in the range of 400—500°C. The feedstocks, in the appropriate molar ratio, are vaporized and passed through the catalyst bed. Condensation gives the cmde product mixture noncondensable vapors are vented to the incinerator. 

The Hinsberg synthesis of thiophene derivatives describes the original condensation of diethyl thiodiglycolate and a-diketones under basic conditions which provides 3,4-disubstituted-thiophene-2,5-dicarboxylic acids upon hydrolysis of the crude ester product with aqueous acid. ... 

Another reagent system that has been recently employed in the Paal synthesis of thiophenes is the combination of bis(trialkyltin)- or bis(triaryltin) sulfides with boron trichloride. Known as the Steliou reagent,it has been utilized in the transformation of 1,4-diketone 11 to thiophene 12. Higher yields are obtained in shorter reaction times in contrast to the use of Lawesson s reagent. Additionally, others have noted the relative ease of the work-up procedure using the Steliou conditions, and the fact that the tributyltinchloride byproduct of the reaction is reusable. Similarly, the combination of the bis(trimethylsilyl)sulfide has been used in conjunction with trimethylsilyltriflate for the preparation of thiophenes in an analogous manner. ... 

The Paal synthesis of thiophenes from 1,4-diketones, 4-ketoaldehydes and 1,4-dialdehydes has found great use in the synthesis of medicinally active compounds, polymers, liquid crystals and other important materials. Furthermore, the discovery of the catalyzed nucleophilic 1,4-conjugate addition of aldehydes, known as the Stetter reaction (Eq. 5.4.1), has enabled widespread use of the Paal thiophene synthesis, by providing 1,4-diketones from readily available starting materials. ... 

In the development of thiophene chemistry three periods can be clearly distinguished the Victor Meyer era, the Steinkopf period, and the modem development starting with the discovery of the synthesis of thiophene from butane and sulfur, making thiophene potentially available in unlimited amounts. Hartough in his well-known monograph, has reviewed the intense and hectic thiophene research toward the end of the 1940 s carried out mainly at the Socony-Vacuum laboratories, but also at many academic institutions. An article by Nord et al. appeared in 1955 in which the research work in thiophene chemistry at Fordham University, as well as progress in general up to 1954, was reviewed. 

A review of earlier work on the synthesis of thiophenes through ring closure has appeared in Organic Reactions ... 

The synthesis of thiophene from diacetylene was first performed by Schulte (62CB1943), who used sodium sulfide in aqueous alcohol (pH 8-10), the yield being no more than 20%. 

Benzothiepins 2 can be synthesized by a double Knoevenagel condensation starting from phthalaldehydes I and diesters of thiodiglycolic acid, or diphenacyl sulfide.33-63 " 66 In principle, this is an extension of Hinsberg s synthesis of thiophenes (see Houben-Weyl, Vol. E6a, p 282) which employs 1,4-dialdehydes rather than 1,2-dicarbonyl compounds. 

As described above for the synthesis of thiophenes, the microwave assisted Lawesson s reagent mediated cyclization of various 1,4-dicarbonyl compounds yielded the desired 2-alkoxythiazoles in 90% yields [1] (Scheme 9). 

Reaction of /3-carbonyl amides with the Lawesson s reagent under microwave irradiation gave thiazoles in acceptable yields [37]. The reaction was the same one previously reviewed for the synthesis of thiophenes and was also employed for the preparation of thiadiazoles (Scheme 10, X = NH, Y = CH). 

Thiophenes can also be obtained from aldehydes, as in the synthesis of thiophene itself from crotonaldehyde (2-butenal), or the production of 2,4-dimethylthiophene from propanal both reactions are carried out at high temperatures and in the presence of catalysts (Scheme 2).5... 

This reagent appears quite frequently in the older literature it was used by Victor Meyer in his classic synthesis of thiophene from disodium succinate. It appears that it is (or was) a mixture, with phosphorus heptasulfide (P4S7) being a major component. Louis and Mary Fieser126 quote, with obvious relish, an out-of-doors preparation from red phosphorus and sulfur which often gives an excellent display of fireworks. A standard preparation of 3-methylthiophene uses the heptasulfide.127... 

The same group of authors has recently reported a combination of various palladium- and copper-catalyzed Suzuki, cyanation, and Ullmann condensation reactions for the synthesis of thiophene-based selective angiotensin II AT2 receptor antagonists (Scheme 6.24) [55],... 

Flynn et al. described the synthesis of thiophene-containing analogs of CA-4, 7 [70]. The synthesis of compound 142 was performed using intermediate 96 (a description of the formation of this intermediate is given in Scheme 23). Aromatization of 96 with DDQ and acetate hydrolysis yielded the hydroxyl intermediate 143. Dilithiation of 143 and reaction with 3,4,5-... 

The Stille reaction is the key step in some synthesis of thiophene-containing condensed heteroaromatics. Enlisting a Stille-Kelly reaction, Iyoda et al. treated dibromide 125 with hexamethylditin in the presence of Pd(Ph3P)4 to afford dithienothiophene (126) [111]. 

One-pot synthesis of thiophene S,S-dioxide and reaction with trihalomethyl anions... 

A limited number of hypervalent iodine-mediated synthesis of thiophenes and benzothiophenes have been reported. An indirect approach for the synthesis of thiophenes involves formation of 1,4-butanediones [85JC-S(CC)420 87JCS(P1)559 88TL3703 89JOC2605], followed by treatment with phosphorus pentasulfide. This approach is especially useful for the synthesis of 3,2 5, 3"-terthiophene (134) starting from 1,4-diketone 65 (85SC789). 

When studying the carcinogenic activity of polycyclic hydrocarbons and their antdogs containing thiophene rings (cf. Tilak "), Tilak et al synthesized both thienothiophene 1 and its isomer 2 in low yield from 2-thienyl dimethoxyethyl sulfide (23) and 3-thienyl diethoxyethyl sulfide (24), respectively, by the method developed for synthesis of thiophenes and thiopyrans - [Eqs. (10) and (11)]. The compounds 23 and 24 were prepared from 2- and 3-mercaptothiophenes. ... 

Finally, a synthesis of thiophene-2-phosphate (150), an interesting organic-inorganic hybrid molecule, has been reported <99JMAT2559>. Treatment of 2-bromothiophene (148) with triethylphosphite and NiClj gave 149 which was converted into 150 by a two step procedure. 

Much work has been directed towards the synthesis of thiophene oligomers and polymers. This is due to the current interest in research on conducting polymers and molecular electronics (92CRV711). Two main approaches have been used for making such polymers (i) chemical (e.g. FeCl3) or electrochemical oxidation of monomeric thiophenes and (ii) transition metal-catalyzed cross-coupling reactions. 

Reactions of the Feist-Benary type have been applied to the synthesis of thiophenes (140 — 141) (75ZC100). The use of a-halocarbonyl halides provides an entree to 3-furanones (142 — 143) (73RTC73I). 

Synthesis of Thiophenes by Coupling Two Two-carbon Units with Sulfur 899... 

Synthesis of Thiophenes by Coupling a Three-carbon Unit and a One-carbon Unit with... 

SYNTHESIS OF THIOPHENES BY FORMING FIVE BONDS SIMULTANEOUSLY 901... 

Several good methods for the synthesis of thiophene derivatives start with a sulfur derivative attached to a four-carbon chain bearing some functional group at the other end. 

---