Coupling reaction, acyl anion addition

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

Pathway C seemed to be especially attractive, because it should enable addition of acyl anion equivalents to a large number of readily accessible activated carboxylic acids (Figure 3.6.10). Thus diversity in all relevant positions should be readily attainable. High-loaded triphenyl phosphine resin 12 (1.6 mmol g-1) was alkylated with bromoacetonitrile under the action of microwave irradiation yielding phos-phonium salt 13 quantitatively. 13 was converted into stable ylide 14 by treatment with tertiary amine. Carboxylic acids were activated in the presence of N-(3-dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDC) and reacted with 14 yielding acyl cyanophosphoranes 15. The reaction was monitored by ATR-IR coupling yields could be determined by spectrophotometric Fmoc-determination and were 90% for Fmoc-phenylalanine as reference amino acid. 

Lithiation of compound 560 with s-BuLi-TMEDA in THF at —78 °C following an inverse addition protocol provided the anion 561. It reacts with primary alkyl iodides and triflates, silyl chlorides, diphenyl disulfide, epoxides, aldehydes, ketones, imines, acyl chlorides, isocyanates and sulfonyl fluorides to yield the expected compounds 562 (Scheme 152). The transmetallation of compound 561 with ZnBr2 allowed the palladium-catalyzed cross-coupling reaction with aryl and vinyl bromides837. When the reaction was quenched with 1,2-dibromotetrafluoroethane, the corresponding bromide 562 (X = Br) is obtained838. 

Finally, the coupling reaction of vinyl and alkylidene (see Alkylidene) ligands in complexes of the type (166) results in the formation of (jj -allyl)FeCp(CO) complexes (equation 38). The vinyl substituent in these reactions is most often an enolate, whereas the alkyhdene unit is formally of the Fischer carbene type. The ultimate product depends upon the starting material and additional reagents. In the case of (ferra-/3-diketonato)difluoroboron complexes (167), the resulting anion is isolated as tetramethylammonium salt (168). In the case of Fp(acyl) complexes as starting materials, benzoylation of the resultant anions gives complexes (163 ... 

Likewise, intermolecular reactions are possible and lead to coupling products which correspond retrosynthetically to the addition of an acyl anion synthon to a ketone. The presence of a proton-donor cosolvent is crucial, otherwise j8-hydroxy nitriles are formed preferentially. The nitrile addition reaction proceeds with good stereoselectivity, e.g. preferentially one diastereoisomer is formed from the electro-reductive addition of acetonitrile (which can advantageously be used as solvent) to dihydrocarvone. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of a,P-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2... 

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