Paal thiophene synthesis

Thiophene synthesis from addition of a sulfur atom to 1,4-dicarbonyl compounds and subsequent dehydration. 

The reaction now is frequently carried out using the Lawesson s reagent. For the mechanism of carbonyl to thiocarbonyl transformation, see Lawesson s reagent on page 348. 

Mullins, R. J. WUliams, D. R. Paal Thiophene Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds., Wiley Sons Hoboken, NJ, 2005, 207—217. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 187, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 200, Springer International Publishing Switzerland 2014 

In 1885, Paal reported the synthesis of 2-phenyl-5-methylthiophene 2 from 1.  

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). 

Until 1952, it was postulated that the Paal thiophene synthesis proceeded via an initially formed furan via dehydration of the 1,4-diketone, followed by conversion of the furan to 

Based on these observations, it is likely that the mechanism involves initial formation of thione 3 (X = O or S), which is followed by tautomerization to 4 and cyclization to 5. Aromaticity drives the facile elimination of either H2O or H2S resulting in the thiophene product. 

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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. ... 

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... 

An interesting variation on the Paal thiophene synthesis is observed when applied to an a,p-unsaturated 7-dialdehyde. Thus, treatment of o-phthaldehyde with Lawesson s reagent produced the dithiolactone 36. When 2,3-napthalenedicarboxaldehyde reacted under similar conditions, dithio-2,3-naphthalide 37 was produced in excellent yield. ... 

The mechanism for the redistribution in oxidation states begins similarly to that of the Paal thiophene synthesis. However, upon formation of dithione 38, nucleophilic addition of one thiocarbonyl into the other produces the intermediate zwitterion 39. A 1,3-tautomerization of hydrogen then gives... 

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