Knorr thiophene synthesis

Bis-(4-methoxyphenyl)-[l,3,2,4]dithiadiphosphetane 2,4-disulfide, transforms the carbonyl groups of ketones, amides and esters into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis. 

The microwave-mediated condensation of hydroxylamine with enaminoketones to generate isoxazoles has been mentioned earlier (refer to Scheme 3.12)17. In a procedure analogous to the Paal-Knorr thiophene synthesis, 2-aminoacyl carbonyl compounds... 

The Paal-Knorr Thiophene Synthesis allows the generation of thiophenes by condensation of a 1,4-dicarbonyl compound in the presence of an excess of a source of sulfur such as phosphorous pentasulfide or Lawesson s reagent. 

Bis(4-methoxyphenyl)-l,3 thiadiphosphetane-2,4-disulfide transforms the carbortyl groups of aldehydes, ketones, amides, lactams, esters and lactones into the corresponding thiocaifaonyl conq)ounds. Cf. Knorr thiophene synthesis. 

Other interesting methods can generate furans. One method treats an allylic diol such as 125 with pyridinium chlorochromate (PCC see Chapter 17, Section 17.2.3), in an oxidative-cyclization process, to give 3-ethylfuran, 126. Thiophene derivatives can also be prepared from 1,4-dicarbonyl compounds. A Paal-Knorr thiophene synthesis reacts 2,4-hexanedione (115) with phosphorus pentasulfide (P4S10) to give 2,5-dimethylthiophene, 127. 

Separately, Paal and Knorr described the initial examples of condensation reactions between 1,4-diketones and primary amines, which became known as the Paal-Knorr pyrrole synthesis. Paal also developed a furan synthesis in related studies. The central theme of these reactions involves cyclizations of 1,4-diketones, either in the presence of a primary amine (Paal-Knorr pyrrole synthesis), in the presence of a sulfur(II) source (Paal thiophene synthesis), or by dehydration of the diketone itself (Paal furan synthesis). 

Furans can be hydrolyzed under mild conditions to y-dicarbonyl compounds. The reaction may be viewed as the reverse of the Paal-Knorr-type synthesis of furans. Pyrrole polymerizes under these reaction conditions, whereas thiophene is stable. 

The Paal-Knorr synthesis utilizes 1,4-diketones to generate furans, thiophenes and pyrroles, 1,5-diketones to generate pyridines, and 1,3-diketones to generate subunits containing two heteroatoms. 

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). 

Paal synthesis thiophenes, 4, 884-885 Paal-Knorr synthesis furan synthesis by, 4, 97 in heterophane synthesis, 7, 770 pyrroles, 4, 118... 

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... 

The Paal-Knorr synthesis can similarly be applied to thiophenes, e.g. compounds 2.17 - 2.20. 

The thioamides themselves are conveniently prepared from the corresponding amides by treatment with phosphorus (V) sulphide (see the Paal—Knorr synthesis of thiophenes, Chapter 2, for this type of conversion). A variation of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen and not a carbon substituent. For instance, thiourea itself is used in the preparation of 2-aminothiazoles such as 3.32. 

The Paal-Knorr synthesis of furans as well as thiophenes and pyrroles has been carried out on solid support and a library of heterocyclic compounds has been prepared <2003SL711>. It has been shown that the acid-catalyzed synthesis of 2,3>4-substituted furans from 1,4-diketones can be assisted by microwave irradiation <20040L389>. 

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) ... 

Hydrogen sulfide can replace ammonia in the Paal-Knorr process and provide a synthesis of the thiophene ring. As in the synthesis of pyrroles, many 1,4-dicarbonyl compounds can be used in this process, which is exemplified by the synthesis of 3,4-dimethylthiophene (Scheme 4.4). 

Paal-Knorr synthesis of furans, thiophenes, and pyrroles... 

The reaction of the y-diketone (42) with P4S10 did not lead to the expected thiophen derivative, but gave instead the furan (43). The Paal-Knorr synthesis has been used for the synthesis of the cyclopenta[6]thiophen derivative (43a) from (43b). ... 

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