STETTER 1,4 Dicarbonyl synthesis

Two other examples of microwave-assisted Paal-Knorr reactions were reported in 2004, describing the synthesis of a larger set of pyrroles with different substituents around the ring. The methods differ mainly in the syntheses employed to produce the 1,4 dicarbonyl compounds required for the cyclization. A variation of the Stetter reaction between an acyl silane and dif-... 

In a related process, Johnson and co-workers have developed an asymmetric metallophosphite-catalyzed intermolecular Stetter-hke reaction employing acyl silanes [81, 82], Acyl silanes are effective aldehyde surrogates which are capable of forming an acyl anion equivalent after a [l,2]-Brook rearrangement. The authors have taken advantage of this concept to induce the catalytic enantioselective synthesis of 1,4-dicarbonyls 118 in 89-97% ee and good chemical yields for a,p-unsaturated amides (Table 11). Enantioselectivities may be enhanced by recrystallization. 

The 1,4-dicarbonyl compounds resulting from Stetter reactions have been used by Muller and colleagues [52] and by Bharadwaj and Scheidt [53] in efficient one-pot Stetter-Paal-Knorr protocols for the synthesis of highly substituted pyrroles. In an analogous fashion, Frantz et al. converted their a-ketoamides into the corresponding imidazoles by treatment with a primary amine [54]. 

Despite the unrivaled easy access to 1,4-dicarbonyl compounds, only a few examples of the application of Stetter reactions in the synthesis of natural products have been reported to date [55]. Tius et al. have employed a diastereoselective in-termolecular Stetter reaction and a ring-closing metathesis reaction as the key steps in their elegant synthesis of roseophilin (58 Scheme 9.16) [56]. The 1,4-... 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

The Stetter reaction is an extremely useful Umpolung procedure for the synthesis of 1,4-dicarbonyl compounds [41,42,43]. Since its discovery in 1973, it has found widespread application in the preparation of key organic intermediates and in natural product synthesis. However, despite the importance and useful-... 

The efficiency of the Sila-Stetter reaction for the synthesis of 1,4-dicarbonyl compounds prompted us to extend this methodology to a single-flask protocol for the Paal-Knorr synthesis of furans and pyrroles [82, 83]. Finally, we also took advantage of acylsilanes to develop the 1,2-addition of carbanion equivalents to activated imines for the synthesis of a-amino ketones [84]. 

Scheme 14. Synthesis of 1,4-dicarbonyl compounds by the Stetter reaction...

In a series of publications beginning in 1973, Hermann Stetter and coworkers reported that activated olefins could intercept the putative acylanion intermediate of the benzoin reaction. Typical catalysts for the benzoin reaction, sodium cyanide and thiazolylidine carbenes, were found to perform well in this new reaction. Stetter also established that the success of the reaction is due to the reversible nature of the benzoin condensation relative to the irreversible formation of 1,4-dicarbonyl products. As a consequence, benzoins or aldehydes can be used interchangeably as reactants. The reaction has proven to be a highly efficient method for the synthesis of 1,4-dicarbonyl compounds and 4-oxonitriles. A resurgence of interest in acyl anion chemistry has resulted in many new discoveries, including alternative acyl donors, as well as catalysts capable of highly enantioselective intra- and intermolecular Stetter reactions. ... 

Simple and efficient, the Stetter hydroacylation reaction quickly became a popular route for the production of 1,4-dicarbonyl compounds as precursors for the synthesis of pyrrole, furan, and pyridazine heterocycles. The Parke-Davis route to atorvastatin (Lipitor ) illustrates the use of a Stetter/Paal-Knorr sequence to access a high value pharmaceutical intermediate (16) from 4-fluorobenzaldehyde 12 and benzylidine amide 13. ... 

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