Dual Behavior of Isatin-Based Cyclic Ketimines with Dicarbomethoxy Carbene: Expedient Synthesis of Highly Functionalized Spirooxindolyl Oxazolidines and Pyrrolines

Abstract

A highly stereo-, regio-, and chemoselective method has been devised for the synthesis of a wide range of spirooxindolyl oxazolidines via an intermolecular 1,3-dipolar cycloaddition of carbonyl ylides generated from dimethyl diazomalonate and aromatic aldehydes, with cyclic ketimines using 5 mol % of Rh2(OAc)4 under mild conditions. Similarly, highly functionalized spirooxindolyl pyrrolines have also been prepared through 1,3-dipolar cycloaddition of azomethine ylides generated from dimethyl diazomalonate and cyclic ketimines, with dimethyl acetylenedicarboxylate.

Copper-catalyzed condensation of imines and α-diazo-β-dicarbonyl compounds: modular and regiocontrolled synthesis of multisubstituted pyrroles

“…The decomposition of the diazo compound 2 with the copper catalyst generates an electrophilic copper carbenoid. Nucleophilic attack of the imine 1 to the carbenoid gives azomethine ylide I 2 – 6 and regenerates the copper catalyst. The tautomerization of I to α-enaminoketone II via proton transfer is followed by cyclocondensation to afford the pyrrole product 3 .…”

“…In contrast to the extensive studies on the carbenoid reactions with aldimines, reports on transition metal-catalyzed reactions of ketimines with diazocarbonyl compounds are very rare. While isatin-derived ketimines were reported to react with a rhodium carbenoid derived from diazomalonate to generate azomethine ylides for [3 + 2] cycloaddition, 6 in other examples, ketimines do not directly react with a metal carbenoid but undergo [2 + 2] cycloaddition with a ketene generated through a Wolff rearrangement of the carbenoid. 7 To our knowledge, reactions of other types of ketimines, including those bearing α-protons, with metal carbenoids have not been documented in the literature.…”

Metal-mediated synthesis of pyrrolines

“…Employing 3-alkylidene-2-oxoindoline (175) as the a,b unsaturated carbonyl and TiCl 4 (10 mol%), the 1-pyrroline-containing spiro structures 177 were obtained in excellent yields (72-95%). When a 2-alkylidenemalonate (178) was used, a series of 1-pyrrolines with various aryl, alkenyl and alkyl motifs (179) were obtained in satisfactory yields (58-75%). The proposed mechanism involves titaniumcatalyzed conjugate addition of vinyl azides to the a,b unsaturated carbonyl and subsequent denitrogenative ring-expansion of the transient azidocyclobutane intermediates formed to obtain the 1-pyrroline ring.…”

“…Synthesis of 3-pyrrolines by rhodium catalysis. A Rhcatalyzed multicomponent procedure was developed by Reddy et al 179 to obtain highly functionalized spirooxindolyl pyrrolines 401, which can be thought as hybrid drugs, as they present two active moeities (Scheme 128). The optimized multicomponent reaction required cyclic ketimines (398), dimethyl diazomalonate (399), and dimethyl acetylenedicarboxylate (400) in the presence of Rh 2 (OAc) 2 (5 mol%) in benzene (80 C, 15 min).…”

Synthesis of spiro-fused heterocyclic scaffolds through multicomponent reactions involving isatin

“…90 Similarly, highly functionalized spirooxindolyl pyrrolines 124 have been prepared through 1,3-dipolar cycloaddition of azomethine ylides generated from dimethyl diazomalonate 121 and cyclic ketimines 120, with dimethyl acetylenedicarboxylate 32 (Scheme 44).…”