Paal synthesis

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

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. ... 

This strategy has been effectively used to prepare a number of 1,4-symmetrical diketones which have served as precursors to thiophenes such as 30, 31, and 32 via the Paal synthesis. 

Ring closure of 1,4-dicarbonyl compounds with phosphorus sulfides (Paal synthesis) 884... 

The treatment of 1,4-diketones with hydrogen sulfide and acid catalysts at low temperatures generally leads to the formation of the expected thiophenes in much better yields than has been observed for the Paal synthesis with the same diketones. For example, 1,2-dibenzoylethane (160 X = H) was converted to 2,5-diphenylthiophene (161) in only 25% yield under Paal conditions, but gave (161) in better than 45% yield when treated with hydrogen sulfide and dry HC1 in chloroform containing anhydrous zinc chloride at room temperature (52JOC1405). Yields were even better when the benzene rings of (160) were substituted. When X = Br in (160), a 69% yield of pure crystalline (161 X = Br) was obtained, and when X = OMe, the yield of (161) was 60%. 

Monoacetals of substituted succinaldehydes (162), readily prepared by hydroformylation of optically active a,(3-unsaturated aldehyde acetals, were used to synthesize 3-substituted thiophenes having an optically active substituent (163). In these cases, while the use of hydrogen sulfide and HC1 in methanol at room temperature was more convenient, comparison with formation of (163) by the Paal synthesis from an appropriately substituted succinic acid salt gave products having about the same amount of racemization (73JOC2361). 

There are few good synthetic methods for these compounds because they are unstable, and must be preserved at low temperatures (Section 3.14.3.6). 2-Hydroxythiophene was first prepared by oxidation of the Grignard reagent, and later from 2-thienyllithium. The compound was also obtained by acid-catalyzed dealkylation of 2-r-butoxythiophene (equation 60). 3-Hydroxythiophene was also obtained by oxidation of 3-thienyllithium (63AHC(1)1>. 5-Methyl-2-hydroxythiophene was obtained in low yield by the Paal synthesis from levulinic acid (equation 61 Section 3.15.3.1.3). 3,5-Dinitro-2-chlorothiophene was converted to 3,5-dinitro-2-hydroxythiophene by hydrolysis with sodium formate in anhydrous methanol (equation 62). 

Suifuration of 1,4-dlcarbonyl and related compounds (Paal synthesis)... 

Reaction of a four-carbon unit with sulfur sources such as hydrogen sulfide, carbon disulfide, and elemental sulfur is one of the traditional thiophene syntheses that belong to this category (Equation 18). A wide variety of hydrocarbons, for example, alkanes, alkenes, dienes, alkynes, and diynes, serve as four-carbon units. Another practical method is the sulfuration of 1,4-dicarbonyl compounds (Paal synthesis). The method has become very popular with development of sulfuration reagents such as Lawesson s reagent. The reaction of a,/3-unsaturated nitriles with elemental sulfur in basic media, Gewald synthesis, is also useful for the preparation of 2-aminothiophenes which are important compounds in dyestuff and pharmaceutical industries. 

Sulfuration of 1,4-dicarbonyl and related compounds (Paal synthesis) provides one of the most widely used methods for the preparation of thiophenes. P2SS (P4S10), combination of hydrogen sulfide and an acid catalyst, Lawesson s reagent, bis(trialkyltin) sulfides, and hexamethyldisilathiane are the sulfuration reagents used most commonly. 

The 1,3-oxazole ring is also of considerable importance in pharmaceutical chemistry. Of several methods for forming the ring, we will discuss here only the use of variations of the Paal synthesis, which has been used to prepare some notable biologically active compounds. The synthesis of the anti-inflammatory agent romazarit ° (9.40) is illustrative... 

Paal synthesis (thiophene) 96 Paal-Knorr synthesis... 

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