Cyclopropyl boronic derivatives in parallel synthesis of sp3-enriched compound libraries

The Suzuki–Miyaura coupling of cyclopropyl boronic derivatives with (het)aryl halides was evaluated as a method for parallel synthesis of sp3-enriched compound libraries. The scope and limitation of the procedure were established. It was shown that the method was applicable to a wide range of cyclopropyl trifluoroborates and (het)aryl bromides. Limitations of the method included trifluoroborates bearing bulky substituents at the α position, as well as (het)aryl bromides with ester moieties. A 96-member library was prepared to illustrate the concept with 68% success rate and 30% average yield. Calculated physico-chemical properties of the products obtained (in particular, sp3-hybrid carbon atom fraction Fsp3 = 0.16-0.83 range, 0.52 on average), as well as neglectable “LogP drift” effect, observed experimentally (0.02 units) showed that the method is well-compatible with lead-oriented synthesis criteria.