Synfacts 2011(1): 0022-0022  
DOI: 10.1055/s-0030-1259199
Synthesis of Heterocycles
© Georg Thieme Verlag Stuttgart ˙ New York

Horner-Wadsworth-Emmons Reagent as 1,3-Dipolar Cycloaddition Precursor

Contributor(s): Victor Snieckus, Cédric Schneider
M. S. T. Morin, D. J. St-Cyr, B. A. Arndtsen*
McGill University, Montréal, Canada
Further Information

Publication History

Publication Date:
21 December 2010 (online)


Reported is the synthesis of polysubstituted pyrroles 5 from amido-substituted Horner-Wadsworth-Emmons reagents 4 (azomethineylide analogues) and unsymmetrical alkynes via a [3+2] cycloaddition process (see Review). Based on previous results (D. J. St. Cyr, B. A. Arndtsen J. Am. Chem. Soc. 2007, 129, 12366; K. N. Houk and co-workers J. Org. Chem. 2010, 75, 4261), the air-stable phosphonate precursors 4 are generated via the TMSOTf-catalyzed ­Arbusov reaction of phosphites 3, imines 1, and acid chlorides 2. Reaction of 4 in a 1,3-dipolar ­cycloaddition with alkynes leads to pyrroles 5 in a one-pot process. Optimized conditions involved P(o-catechyl)-OTMS as phosphonate precursor and TMSCl as a Lewis acid. A range of functionalized aryl- and heteroaryl-substituted imines as well as various aryl-substituted acid chlorides may be used. The irreversibility of phosphonate formation also allows the use of less stable imine/acid chloride reagents. Electron-poor dipolarophiles are the most reactive; however, alkynes may be replaced with electron-deficient alkenes. The ­cycloaddition with unsymmetrical alkynes results in the formation of a single isomeric product, in which the EWG is directed away from the phosphorus-bound carbon.