Introducing the <i>Cis‐</i> 2,3‐Bis(trifluoromethyl)cyclopropyl Chemotype: Late‐Stage Installation and Stereoelectronic Properties

A protocol for the multigram scale synthesis of the bench stable salt S ‐( cis‐ 2,3‐bis(trifluoromethyl)cyclopropyl)dibenzothiophenium tetrafluoroborate 1 is reported. This compound is used as a versatile reagent for the mild transfer of the cis‐ 2,3‐bis(trifluoromethyl)cyclopropyl moiety ( cis ‐BTFC) to structurally complex heterocycles under photochemical conditions. The radical process tolerates a number of functional groups and proceeds with retention of the original cis ‐configuration. The newly introduced cis ‐BTFC chemotype is characterized by a van der Waals volume of 115 Å 3 , which sets its steric demand between those of the heptafluoroisopropyl (HFIP, 99 Å 3 ) and the perfluorotertbutyl units (PFTB, 128 Å 3 ). Notably, the experimentally determined lipophilicity value (Log P ) indicates that the cis ‐BTFC scaffold imparts significant higher polarity to the carrying structure than both HFIP and PFTB, making this motif potentially attractive for the optimization of pharmacokinetic profiles during drug optimization campaigns. Interestingly, under basic treatment, typical N‐, O‐, or S‐nucleophiles also react with 1 , but mixtures of the cis‐ and trans‐ BTFC containing products are obtained in varying ratios. Mechanistic studies confirm the in situ generation of 1,3‐bis(trifluoromethyl)cyclopropane, which subsequently reacts with nucleophiles in a Michael‐type fashion.