Synthesis of 5-Azaspiro[2.4]heptan and Penta-Substituted Pyrrole Derivatives via Pd-Catalyzed Intramolecular Cyclization Reaction of Alkynyl Carboxamides

Abstract

Penta-substituted pyrrole derivatives, including a three-membered ring (5-azaspiro[2.4]heptan), were readily prepared in moderate to excellent yields by the Pd-catalyzed intramolecular cyclization reaction of alkynyl carboxamide compounds. When an excess amount of ZnCl₂ acted as a Lewis acid and a source of halide, the one-pot bi-metallic system could afford more valuable penta-substituted chloroethyl pyrrole products under similar conditions. This indicates that the present method is a powerful tool for the preparation of a wide range of functionalized and polysubstituted pyrroles.

GRAPHICAL ABSTRACT

Keywords:

• Alkynyl carboxamide
• 5-azaspiro[2.4]heptan
• Pd-catalyzed
• penta-substituted
• pyrrole derivatives

ACKNOWLEDGMENTS

The authors thank the National Natural Science Foundation of China (30800720) and China Postdoctoral Science Foundation (20090450843) for the financial support of this work.

Notes

^a Reactions were carried out on a 0.3 mmol scale in 3.0 mL of solvent under argon atmosphere with 1.0 equivalent of 1a, 1.5 equivalents of base, and 0.05 equivalent of catalyst at reflux for 8 h.

^b Isolated yields.

^c 1.0 eq TBAF was used.

^a Reactions were carried out on a 0.3 mmol scale in 3.0 mL of THF under argon with 1.0 equivalent of 1a, 1.5 equivalents of Cs₂CO₃, and 0.05 equivalent of Pd(PPh₃)₄ at reflux for an appropriate time.

^b Isolated yields.

^a Reactions were carried out in 3.0 mL of refluxing toluene under argon with 0.3 equivalent of 1a, 0.45 equivalent of Cs₂CO₃, 0.6 equivalent of ZnCl₂, and 5 mol% of Pd(PPh₃)₄ for an appropriate time.

^b Isolated yields.