Preparation of Thiophenes

Although the present rapid development of thiophene chemistry is owang to the commercial availability of thiophene, many thiophene derivatives can still advantageously be prepared by means of ring-closure reactions instead of by a complex series of substitution reactions starting with thiophene. 

The reaction of 1,2-dibenzoylethane with hydrogen sulfide and hydrogen chloride in chloroform, with zinc chloride as a catalyst, gives 2,5-diphenylthiophene in high yield and is claimed to be better than the classic P2S5 method.  

Substituted thiophenes, such as 2-iodo-, 2-bromo-, 2 chloromethyl-, and 2-acetyl-thiophene have been obtained by reacting crude, coal-tar benzene with the appropriate reagents.  

The reaction of olefins,alcohols,and epoxides with or at high temperatures over catalysts such as 

Al Os or CrzOg-AlgOg has been used for the preparation of simple thiophenes in moderate yields. 

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Carbon-sulfur bonds can be formed by the reaction of elemental sulfur with a lithio derivative, as illustrated by the preparation of thiophene-2-thiol (201) (700S(50)104). If dialkyl or diaryl disulfides are used as reagents to introduce sulfur, then alkyl or aryl sulfides are formed sulfinic acids are available by reaction of lithium derivatives with sulfur dioxide. 

The reaction of diketosulfides with 1,2-dicarbonyl compounds other than glyoxal is often not efficient for the direct preparation of thiophenes. For example, the reaction of diketothiophene 24 and benzil or biacetyl reportedly gave only glycols as products. The elimination of water from the P-hydroxy ketones was not as efficient as in the case of the glyoxal series. Fortunately, the mixture of diastereomers of compounds 25 and 26 could be converted to their corresponding thiophenes by an additional dehydration step with thionyl chloride and pyridine. 

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. ... 

Structure-activity studies of 5,6,7,8-tetrahdyro-5,5,8,8-tetramethyl-2-quinoxaline derivatives necessitated the preparation of thiophene-containing compound 17. Stetter conditions using thiazolium salt 20 as catalyst resulted in the preparation of 1,4-diketone 21 from 18 and 19. Condensation of 21 with phosphorus pentasulfide followed by saponification resulted in 17. In this fashion, the authors replaced the amide linker of parent compound 22 with the rigid thiophene moiety. 

The thenyl cyanides are of great importance for the preparation of thiophene derivatives. Because of the acidifying effects of both the thienyl and of the cyano groups, carbanions are easily obtained through the reaction with sodamide or sodium ethoxide, which can be alkylated with halides, carbethoxylated with ethyl carbonate, or acylated by Claisen condensation with ethyl... 

B. Compounds of Pharmacological Interest During recent years a certain slackening in interest in the preparation of thiophenes for pharmacological studies can be noticed. As an excellent review on the biological activity of thiophenes has recently been published, the latest developments in this field will only briefly be sketched. 

Preparation of Thiophenes by Microwave-Promoted Gewald Synthesis. .. 101... 

A brown explosive form is produced if excess sodium is used in preparation of thiophene homologues—possibly because of sulfur compounds [1], As normally produced, it is a dry stable solid, but material prepared from acetylene and sodium-oil dispersions ignites in air [2],... 

Examples of reactions involving replacement and cyclization are the long-known preparation of thiophenes (89) from 1,4-diketones, and the formation of l,2-dithiole-3-thione (90) from the salicylate ester analog (91).120 In the latter instance, oxidative cyclization with formation of an S—S bond has occurred this is a common feature of these reactions, particularly if such a link is needed to complete a five-membered ring. Another example of this aspect is afforded by the reaction of the propane-1,3-dione derivatives (92) which yield 3,5-diaryl-1,2-dithiolylium salts (93) when heated with phosphorus pentasulfide in carbon disulfide, followed by perchloric acid.121... 

One of the most common strategies for the preparation of thiophenes involves the intramolecular condensation of a-thioglycolates (and related a-substituted thiols) onto adjacent carbonyls. One prominent example involved the synthesis of naturally occurring... 

King, W. J., and F. F. Nord Preparation of Thiophene-2-Aldehyde and Some... 

Sommelet process org chem The preparation of thiophene aldehydes by treatment of thiophene with hexamethylenetetramine.. so-mal ya, pra-s3s ) Sonnenschein s reagent analychem A solution of phosphomolybdicadd that forms a yellow precipitate with alkaloid sulfates. z6n-3n,shTnz r5,a-j3nt) sonocatalysis chem 1. Initiation of a catalytic reaction by irradiation with sound or ultrasound. 2. Use of sound to impart catalytic activity to a chemical compound. san-3-k3 tal-3-s3s)... 

This chapter will review synthetic methods for the preparation of thiophenes, benzothiophenes and polycyclic thiophenes. In addition, a survey of the applications of thiophenes and derivatives will supplement the specific discussion included in Chapters 1.04 through 1.16 of this work. 

The synthesis of the thiophene ring system by formation of a bond between the two /3-carbons of a diethyl sulfide derivative, or between the (3 -carbon and an ortho position of a phenylthio ethyl derivative, has been one of the most widely exploited methods for the preparation of thiophene derivatives. 

Hydrosilylation was also applied to the preparation of thiophene-terminated dimethyl-siloxane macromonomer, which is used for the synthesis of thiophene-dimethylsiloxane graft copolymers by oxidative polymerization281. Polycarbosilanes have been prepared by hydrosilylation-polymerization of l,4-bis(ethenylmethylphenylsilyl)benzene with 1,4-bis(methylphenylsilyl)benzene in various ratios282. 

As outlined earlier, three methods of polymerization have been established for the preparation of thiophenes, viz. electrochemical polymerization [189, 190], oxidative chemical polymerization using Lewis acid catalysts such as FeCl3 [191,192], and step-growth condensation polymerization using transition metal-catalyzed coupling reactions [lj]. 

When considering the synthesis of phospholes, one has to forget most of the classical and powerful methods employed for the preparation of thiophenes and pyrroles. For example, Paal-Knorr condensation, direct ortho-lithiation, halogenation with NBS or I2/Hg2+ and Vilsmeier-Haack formylation are not operative in phosphole chemistry. Likewise, no chemical or electrochemical oxidative polymerization... 

Preparation of thiophene-2-carboxylic acid (2- 3-[3-(4-chloro-phenoxy)-pyrrolidin-l-yl]-2-hydroxy-propoxy -phenyl)-amide... 

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