P-Enaminoesters

Prior to this work, Renaud and coworkers described an alternative phosphoric acid-catalyzed approach to DHPs 113 commencing with p-enaminoesters such as 114 and cinnamaldehydes 111. Besides developing a catalytic nonasymmetric protocol, the authors attempted a BINOL phosphate (5)-3k-catalyzed (R = 1-naphthyl) asymmetric version attaining moderate enantioselectivity (50% ee) (Scheme 45) [70]. 

Oxazololactams 206 can be obtained easily by reaction of p-enaminoesters with acryloyl derivatives <02TL2521>. 

Recently Gordeev et al. reported (140, 141) the synthesis and iterative deconvolution of a 300-member focused library of 1,4-dihydropyridines L5 as potential calcium channel blockers inspired by the strucmre of nifedipine and other known bioactive compounds. The library was built on SP as 30 pools of 10 individuals, following the synthetic scheme shown in Fig. 7.18. Rink amine resin was deprotected, split into 10 portions (steps a and b), and treated with P-ketoesters (step c. Mi, 10 representatives A-J, Fig. 7.19) to give 10 discrete N-supported P-enaminoesters 7.30. The resin aliquots were then mixed (step d) and split again into 30 identical, 10-member pools (step e). Each resin portion was treated with a different combination of 1,3-dicarbonyls (M2, three representatives K-M, Fig. 7.19) and aldehydes (M3, 10 representatives N-W, Fig. 7.19) to give 30 pools of 10 open-chain precursors 7.31 (step f), which were cyclatively cleaved to give the final hbrary L3 (step g. Fig. 7.18). Library QC was performed by off-bead MS, identifying all the expected molecular ions in several pools. 

Heterocyclic p-enaminoesters, versatile synthons in heterocyclic synthesis , Wamhoff, H., A /v. Heterocycl. Chem., 1985, 38, 299. 

Other synthons for 1,3-dicarbonyl compounds which have been successfully applied include p-chloro-a,P-unsaturated ketones and aldehydes, " P-amino-a,P Unsaturated ketones, vinylamidinium salts, and propiolic acid, reaction of which with urea gives uracil directly in about 50% yield. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ortho-aminonitnl s and in general, from P-enaminoesters. ... 

This MCR domino process involves initial CFsCOOH-promoted propargylation of the 1,3-dicarbonyl system and subsequent condensation between the resulting y-ketoalkyne 89 and the primary amine to afford the propargylated P-enaminoester 90, which undergoes an Ru-catalyzed 5-exo-dig aimulation to form the cyclic enamine 91, finally tautomerizing to the pyrrole 88. 

This sequence is thought to proceed through (1) Ag(I)-catalyzed propargyl-CiAisEN rearrangement to produce allenic ketoesters 95, (2) condensation of 95 with the primary amine to give allenic P-enaminoesters 96, and (3) Au(I)-catalyzed 5-endo-dig cyclization of 96 to the 2-methylpyrrole-4-carboxylate 94. 

Sukach VA, Tkachttk VM, Rusanov EB, Roeschenthtiler G-V, Vovk MV (2012) Heterocyclization of N-(l-chloro-2,2,2-trifluoroethylidene)carbamates with P-enaminoesters - a novel synthetic strategy to functionalized trifluoromethylated pyrimidines. Tetrahedron 68 8408-8415... 

Plaquevent and coworkers re-examined and sharply improved this method for a rapid access to enantioenriched P-trifluoromethyl-P-amino acid [47]. Nine cinchona-based catalysts were screened, and the best result was obtained using (DHQ)2PHAL 80. The reaction was performed starting with the p-nitrobenzyl enaminoester 81 at 80 °C and afforded the expected imine ester 82 in 90% isolated yield and 71% ee (Scheme 7.36). The authors put a special emphasis on the mechanistic aspect of the reaction using a deuterated substrate. According to the results, the deprotonation is both rate and asymmetric determining step. 

In 2012 we also use this class of catalysts to reduce a series of iV-benzyl and N-a methyl benzyl (3-enaminoesters (Scheme 15.12) [39]. Best results were obtained with Cat. 8 and, once again, an improvement of the enantioselectivity was observed by using chiral auxiliary. Then, hydrogenolysis of the enantiomerically enriched N-benzyl (3-aminoesters, followed by LDA-promoted ring closure, afforded enantiomerically pure 4-aryl or 4-aIkyl substituted p-lactams. 

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