Green and Facile Assembly of Diverse Fused N-Heterocycles Using Gold-Catalyzed Cascade Reactions in Water

Abstract

The present study describes an AuPPh3Cl/AgSbF6-catalyzed cascade reaction between amine nucleophiles and alkynoic acids in water. This process proceeds in high step economy with water as the sole coproduct, and leads to the generation of two rings, together with the formation of three new bonds in a single operation. This green cascade process exhibits valuable features such as low catalyst loading, good to excellent yields, high efficiency in bond formation, excellent selectivity, great tolerance of functional groups, and extraordinarily broad substrate scope. In addition, this is the first example of the generation of an indole/thiophene/pyrrole/pyridine/naphthalene/benzene-fused N-heterocycle library through gold catalysis in water from readily available materials. Notably, the discovery of antibacterial molecules from this library demonstrates its high quality and potential for the identification of active pharmaceutical ingredients.

Gold-Catalyzed Addition–N-Boc Cleavage–Cyclization of N,O-Acetal with Ynamides for Construction of 6-(tert-Butyldimethylsilyl)oxy-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-ones

“…On the basis of literature studies, ,, and our experimental results, a mechanism for Au­(I)-catalyzed addition and cyclization is tentatively proposed (Figure ). The gold species activate the triple bond of the ynamide, affording keteniminium ion intermediate B followed by a loss of SIPrAu–OH to form intermediate C and D .…”

Catalytic C3 aza-alkylation of indoles

“…Interestingly from an ecologic point of view, the process worked quite well also in water as solvent. 41 Another class of noble metal-based Lewis acids, employable in indoles C3 aza-alkylation, is constituted by palladium salts. These catalysts are widely diffused, due to their high tolerance toward several functional groups.…”

Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles

“…In this regard, the construction of cyclic or polycyclic structures by means of cascade processes involving alkynes is a rapidly emerging field on account of the increasing number of reports on this topic [1][2][3][4]. A particularly appealing cascade reaction between alkynoic acids and dinucleophiles was discovered due to the elegant works by Dixon [5][6][7], Patil [8,9], Liu-Zhao [10][11][12][13][14][15][16][17], Reddy [18,19] and Lei [20]. Au(I) (often Au(I)-Ag(I)), Cu(II), and recently, Ru(II) catalysts were the key for this transformation leading to a number of polyheterocycles, including structural analogues of quinazoline alkaloids Tryptanthrine, Batracyclin, Peganine, Vasicinone, or Mackinazoline, and the inhibitor of aldo-keto reductase AKR1C3 depicted in Figure 1 [21,22].…”

“…In most cases, a plausible reaction mechanism has been proposed, suggesting an initial cycloisomerization of the alkynoic acid followed by a nucleophilic attack at the corresponding enol lactone intermediate to form a ketonamide that under acidic (Brönsted or Lewis) conditions leads to the cyclized product via an acyliminium ion intermediate (Scheme 1). A minimum amount of 0.5 mol% of metal catalyst is required to affect the cascade process (catalyst loading ranging from 0.5 to 20 mol%) [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”