Construction of 1,3-Oxazolidines through a Three-Component [3+2] Cycloaddition of Tetrahydroisoquinolines, Aldehydes, and Ethyl Ketomalonate

Abstract

A chemoselective and diastereoselective synthesis of fused oxazolidines was achieved by a three-component cascade reaction of tetrahydroisoquinolines (THIQs), α,β-unsaturated aldehydes, and diethyl 2-oxomalonate. Probably due to the reactivity difference between the aldehyde and the ketone, the reaction proceeded through the condensation of THIQs with α,β-unsaturated aldehydes and 1,3-dipolar cycloaddition of the generated azomethine ylide intermediate with 2-oxomalonate. The key features are easily available starting materials, mild reaction conditions, broad substrate scope, and high chemo- and diastereoselectivity.

Stereoselective synthesis of fused-, spiro- and bridged heterocycles via cyclization of isoquinolinium salts: a recent update

“…In 2020, Wu and co-workers devised an efficient protocol for the synthesis of fused oxazolidines 34 via a three-component one-pot [3 + 2] cycloaddition of 1,2,3,4-tetrahydroisoquinolines (THIQs) 31, α,β-unsaturated aldehydes 32, and diethyl 2-oxomalonate 33 (Scheme 9). 25 The diethyl 2-oxomalo-nate participated in the 1,3-dipolar cycloaddition with antidipole (anti-35) rather than syn-dipole (syn-35) to generate the corresponding cycloadduct 34. The reaction is highly diastereoselective (up to 20 : 1 dr), which resulted in the formation of a wide range of oxazolidines in moderate to good Scheme 7 Catalyst-free [3 + 2] cycloaddition of isoquinoline-N-oxides with ynediones.…”

Condensation-Based Methods for the C–H Bond Functionalization of Amines

“…Recently, Wu, Li and coworkers reported related reactions involving Ecinnamaldehydes to access products 57 (Scheme 28). 45 Here, highly reactive ethyl ketomalonate acts as the dipolarophile. Reactions are performed under mild conditions.…”

“…hydes to access products 57 (Scheme 28). 45 Here, highly reactive ethyl oxomalonate acts as the dipolarophile. Reactions are performed under mild conditions.…”

Iron Trichloride-Mediated Cascade Reaction of Aminosugar Derivatives for the Synthesis of Fused Tetrahydroisoquinoline–Tetrahydrofuran Systems

“…While synthetic efforts have been devoted to the construction of 1-substituted, 1,3-disubstituted, 1,4-disubstituted, or 1,3,4-trisubstituted THIQs, the formation of more complex fused polycyclic systems containing THIQ has not been fully explored. A few examples are the construction of (spiro)­polyheterocycles by combining an Ugi reaction with Pd catalyst or 1,3-oxazolidines by cycloaddition of THIQs, aldehydes, and ethyl ketomalonate …”

“…A few examples are the construction of (spiro)polyheterocycles by combining an Ugi reaction with Pd catalyst 14 or 1,3-oxazolidines by cycloaddition of THIQs, aldehydes, and ethyl ketomalonate. 15 The requirements to achieve the THIQ core are the existence of amines and aldehydes in the presence of strong acids. In turn, it is also necessary to incorporate an aromatic group to the structure to reach the alkaloid skeleton.…”