Thiophene-2,5-dicarbonyls

Condensation of diethyl thiodiglycolate and a-diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarbonyls upon hydrolysis of the crude ester product with aqueous acid. 

By applying thiophene-2,5-dicarbonyl dichloride (4a) and 2,5-diethy-nylthiophene (5f) in the sense of a pseudo five-component reaction under slightly adjusted reaction conditions, symmetrically substituted and regioisomeric terthiophenes 46 and quinquethiophenes 47 can be synthesized in a straightforward fashion (Scheme 28) (2013OBC(l 1)3541). 

Polymers from Thiophen Derivatives.—The bifunctionality of thiophen and its potential availability in large quantities at a low price has for many years attracted the interest of polymer chemists. However, progress has been slow. 2,5-Dichlorothiophen has been polymerized to a solid in 93% yield on treatment with aluminium chloride and cupric chloride in carbon disulphide. The product is believed to be poly-5-chloro-2,3-thienylene. Thiophen-2,5-dicarboxylic hydrazide was prepared by the reaction of thiophen-2,5-dicarbonyl chloride with the corresponding dihydrazide and then cyclodehydrated to poly-(thienylene-[2,5]-alt-l,3,4-oxadiazolylene-[2,5]-amer) (258) by polyphosphoric acid. This polymer could also be obtained directly from thiophen-2,5-dicarboxylic acid and hydrazine in oleum. The polymers produced were investigated in view of their thermal stability and as polymeric organic semiconductors. The same research... 

In a series of papers in late 1884 and early 1885, Paal and Knorr demonstrated that several 1,4-dicarbonyls could be transformed into furans, pyrroles, and thiophenes. Paal first discovered this transformation and used it to prepare di-, tri-, and tetrasubstituted furans. For example, dicarbonyl 3 yielded disubstituted furan 4 upon treatment with weak acid. 

Shortly thereafter, Knorr reported that combining ammonia or primary amines with 1,4-dicarbonyls furnished substituted pyrroles (see Section 2.2), and Paal produced thiophenes by addition of hydrogen sulfide with 1,4-dicarbonyls. ... 

A significant number of examples exist in which 1,3-dicarbonyl derivatives undergo reaction with thioglycolates to produce thiophenes. ° Such reactions are particularly effective when used in conjunction with P-ketoesters, as demonstrated by the preparation of 27. ... 

Tetrasubstituted thiophenes obtained by the Gewald reaction serve as templates for structural diversification and semi-automated library synthesis. Thiophene 31, prepared from 3-ketoester 29 and t-butylcyanoacetate 30, could be selectively derivatized at three of the four substituents to maximize library diversity. This procedure represents an improvement over previously published methods for utilizing 1,3-dicarbonyl compounds in the Gewald reaction. 

The Hinsberg thiophene synthesis has seen limited use owing to the potential for regioisomeric mixtures when unsymmetrical 1,2-dicarbonyls are condensed with unsymmetrical thiodiacetates. Thus, symmetrically substituted thiophenes are generally prepared in this manner. 

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. 

Finally, the Hinsberg synthesis has been extended to the use of a-aryl-a-carboethoxydimethyl sulfide in conjunction with a series of 1,2-dicarbonyl compounds. Specifically, the 4-nitroaryl substituent provides for sufficient activation of the a-proton to allow condensation and ring closure. These examples appear general and suggest future opportunities for the Hinsberg thiophene protocol. 

The Paal thiophene synthesis involves the addition of a sulfur atom, typically from phosphorus pentasulfide, to 1,4-dicarbonyl compounds and subsequent dehydration. 

This 1,3-migration of hydrogen was also observed when 40 reacted with Lawesson s reagent to produce the dithiolactone 41. However, when y-hydroxy-a,P-unsaturated aldehyde 42 was reacted under similar conditions, thiophene 43 was prepared efficiently. These results are not surprising considering that the oxidation state of 42 is equivalent to the traditional saturated 1,4-dicarbonyl substrates of the Paal thiophene reaction via tautomerization of the double bond, and aromaticity is reestablished in the fully conjugated 43. 

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). 

The use of microwaves for the preparation of aromatic five-membered heterocycles has been intensely investigated with excellent results in terms of yields and purities of the products prepared. The Paal-Knorr reaction, namely the cyclocondensation of a 1,4-dicarbonyl compound to give furans, pyrroles and thiophenes has been successfully carried out with the aid of microwaves. 

Thiophenes of type 31 (X-Y = CH) were generated via Lawesson s reagent-mediated cyclization of 1,4-dicarbonyl compounds 30 under microwave irradiation in the absence of solvent [37]. The reaction was carried by mixing the two solid reagents in a glass tube inserted inside a household microwave apparatus and irradiating until the evolution of H2S ceased. An interesting application of this method is the preparation of liquid crystals and other ferro- and antiferroelectric material such as compound 33 (Scheme 10). 

Needing 2,5-dimethylfuran as a masked 1,4-dicarbonyl equivalent, Scott and Naples found that the ion-exchange resin Amberlyst 15 is extremely effective in catalyzing the cyclization of hexane-2,5-dione to this compound.31 Some unusual Paal-Knorr reactions have been described. In one, phos-phorus(V) sulfide gave none of the expected thiophene when it acted upon the diketoester 3, the thioester 4 being obtained instead.32 Against all... 

Soon after thiophene and its derivatives had been prepared by treating 1,4-dicarbonyl compounds with P2S3, Biedermann and Jacobson extended this procedure to citric and tricarballylic acids. By heating a mixture of citric acid and PjSj, they obtained a compound CJH4S2, b.p. 224°-226°, in about 1% yield. The structure 1 was ascribed to this compound, which was called thiophthene [Eq. (1)]. 

Whereas it was reported in CHEC-II(1996) <1996CHEC-II(7)229> that examples of this system were rare, the increase in synthetic activity since then has been significant. Such compounds can be obtained using either a thiophene or a pyrazine precursor. Virtually all of the molecules prepared from thiophene precursors follow the pathway shown in Equation (185). The appropriate diaminothiophenes 491, usually obtained by reduction of the corresponding nitro groups, are condensed with the desired 1,2-dicarbonyl compound under generally mild conditions to yield 492. 

Dithiophene-4,8-diones are produced by the cyclic diacylation of methylthiophenes using thiophene-2,3-dicarbonyl chloride and aluminium trichloride to afford the corresponding diones in low yields (Equation 98) <1999BMG1025>. 

Problem 20.5 Pyrroles, furans, and thiophenes are made by heating 1,4-dicarbonyl compounds with (NH4)2C0, P4O, and PjS, respectively. Which dicarbonyl compound is used to prepare (o) 3,4-dimethyl-furan. (h) 2,5-dimethylthiophene. (c) 2,3-dimethylpyrrole <... 

Paal-Knorr synthesis It is a useful and straightforward method for the synthesis of five-membered heterocyclic compounds, e.g. pyrrole, furan and thiophene. However, necessary precursors, e.g. dicarbonyl compounds, are not readily available. Ammonia, primary amines, hydroxylamines or hydrazines are used as the nitrogen component for the synthesis of pyrrole. 

Paal-Knorr synthesis can also be used to synthesize furan and thiophene ring systems. A simple dehydration of a 1,4-dicarbonyl compound provides the furan system, whereas thiophene or substituted thiophenes can be prepared by treating 1,4-dicarbonyl compounds with hydrogen sulphide (H2S) and hydrochloric acid (HCl). 

Introduction of a sulfur atom has been effected in many cases with phosphorus pentasulfide for example, ring closure of 1,4-dicarbonyl compounds 81 (X = CH) under typical Paal-Knorr conditions gives fused thiophenes 82 (X = CH).75,76 Fused thiazoles [82 (X = N) and Eqs. (6), (7)] have been prepared in the same way.77-80... 

Hinsburg first reported that various a-dicarbonyl compounds (256) condensed with thiodiglycolic esters in the presence of alcoholic sodium ethoxide to give various substituted thiophene-2,5-dicarboxylic esters (257). R1 and R2 in (256) could be H, OH, alkyl, OR, aryl or carboxyl groups o-quinones will also condense. If the condensation is carried out in aqueous alcohol, as is the case when glyoxal (256 R1 = R2 = H) is used, the thiophene-2,5-dicarboxylic acid is isolated directly. Pyruvic acid gives the half-ester of (257 R1 = Me, R2 = OH). The earlier work has been reviewed (52HC(3)l). 

Sequential addition of hydrogen sulfide to an a,/3 -unsaturated ketone, followed by condensation with an a -dicarbonyl compound, leads directly to thiophenes. Thus addition of hydrogen sulfide to a benzene solution of cyclohexenone, followed by an a -dicarbonyl compound and reflux, gave the respective 6,7-dihydro-5//-benzo[6]thiophene-4-ones (274). Compounds were obtained by this method where R1 and R2 = H, R1 = Ph or Me and R2 = H, and where R1 = R2 = Me (71lJS(A)(i)62). This is closely related to a patented process previously described (cf. Section 3.15.3.4). 

Pyrroles, furans, thiophenes and pyrazolones from dicarbonyl compounds. 

These methods [which are known as the Paal-Knorr (pyrrole and furan) or Paal (thiophene) syntheses] are applicable to other 1,4-dicarbonyl compounds, the limitation being the accessibility of the dicarbonyl starting material. 

---