Efficient synthesis of substituted 3-azabicyclo[3.1.0]hexan-2-ones from 2-iodocyclopropanecarboxamides using a copper-free Sonogashira coupling

The copper-free Sonogashira coupling between N-substituted cis- 2-iodocyclopropanecarboxamides and terminal aryl-, heteroaryl-alkynes or enynes, followed by 5-exo-dig cyclization of the nitrogen amide onto the carbon-carbon triple bond, provides a remarkably efficient access to a variety of substituted 4-methylene-3-azabicyclo[3.1.0]hexan-2-ones in excellent yields. Protonation of these latter enamides generates bicyclic N-acyliminium ions that can be involved in Pictet-Spengler cyclizations leading to new 3-azabicyclo[3.1.0]hexan-2-ones, possessing a quaternary stereocenter at C4, with high diastereoselectivities. This strategy constitutes an attractive complementary alternative to the classical route that relies on the addition of organometallic reagents to cyclopropyl imides. A copper-free Sonogashira coupling between cis-2-iodocyclopropanecarboxamides and terminal aryl-, heteroaryl-alkynes or enynes followed by 5-exo-dig cyclization provides an efficient access to substituted 4-methylene-3-azabicyclo[3.1.0]hexan-2-ones (see scheme). Protonation of these enamides generates N-acyliminium ions, which can be involved in Pictet-Spengler cyclizations leading to new 3-azabicyclo[3.1.0] hexan-2-ones containing a quaternary stereocenter at C4 with high diastereoselectivities.