Base-Promoted Three-Component Cascade Reaction of α-Hydroxy Ketones, Malonodinitrile, and Alcohols: Direct Access to Tetrasubstituted NH-Pyrroles

Abstract

A base-promoted three-component cascade reaction of α-hydroxy ketones, malonodinitrile, and alcohols has been developed, providing a direct and efficient route to a range of structurally diverse and synthetically useful 2-alkyloxy-1H-pyrrole-3-carbonitrile derivatives. The reaction involved three different bond (C−C, C−O, and C− N) formations in a single step, and its regioselectivity was depended on the structure of the α-hydroxy ketones employed. The use of easily available starting materials, wide substrate scope, good functional group tolerance, operational simplicity, and high atom economy are attractive features of the new method.

Cascade Cyclization/Amination of para‐Quinone Methides with β‐Ketodinitriles: Synthesis of Polysubstituted Furans

“…Based on the control experiments and Hammett research, a possible mechanism for the phosphoric acid-catalyzed cascade cyclization/amination of p-QMs with β-ketodinitriles is illustrated in Scheme 4. [19,20] Initially, H 3 PO 4 activates the cyano substituent of βketodinitrile The potential anticancer effects of furan heterocyclic compounds, as reported in existing literature, [21] spurred our investigation into the preliminary activity of synthesized functionalized furan derivatives. The anticancer activity of these compounds was evaluated by using human hepatocellular carcinoma cell line…”

“…All reactions were performed under an atmosphere of air unless specified otherwise. 1 H (400 MHz), 13 C (100 MHz) and 19 F (376 MHz) NMR spectra were recorded on a 400 MHz spectrometer in CDCl 3 . 1 H NMR chemical shifts were reported using TMS as internal standard while 13 C NMR chemical shifts were reported relative to CDCl 3 .…”

I2-promoted formal [3 + 1 + 1 + 1] cyclization to construct 5-cyano-1H-pyrazolo[3,4-b]pyridine using malononitrile as a C1 synthon

“…Malononitrile has multiple reaction sites and typically participates in multi-component tandem cyclization reactions as a C2 or C3 synthon [Scheme 2A(b and c)]. 3,4 For example, spirooxindole-pyran derivatives and benzopyrano[2,3- c ]pyrazole derivatives were reported by Zhang's group and Jagdamba Singh's group, respectively, using malononitrile as a C2 synthon and C3 synthon under the promotion of visible light, respectively. 5 In recent years, it has also been reported that malononitrile participates in cyclization reactions as a C1 synthon under base- or transition metal-catalyzed reaction conditions for the construction of gem-dicyano compounds [Scheme 2A(a)].…”

Efficient synthesis of pentasubstituted pyrroles via intramolecular C-arylation

“…1) at the beginning of this millennium triggered a tremendous effort to develop strategies applicable for the synthesis of polysubstituted pyrroles. Consequently, a number of different approaches based on the cycloaddition of diverse intermediates, [15][16][17][18][19][20][21][22][23][24] oxidative reactions, 25,26 various couplings 27,28 and diverse catalysts [29][30][31][32][33][34][35][36][37][38] have appeared in the past decade. Notably, the application of polymer-supported chemistry has also been described, typically using the concept of multicomponent reactions.…”