Synthesis and Physicochemical Properties of 3‐Fluorocyclobutylamines

Abstract

Abstract Hitherto unknown cis ‐ and trans ‐3‐alkyl‐ and 3‐aryl‐3‐fluorocycobutylamines have been synthesised selectively from 3‐oxocyclobutane carboxylic acid in six or seven steps. Comparison of their p K a and log D values with those of the fluorine‐free parent compounds showed acidification by about 0.8 units, irrespective of the stereochemistry. This indicates that there are no through‐space interactions between fluorine and the amino function – a conclusion that was supported by the results of X‐ray analysis. Fluorinated trans ‐compounds were found to be more lipophilic (Δ log P ≈ 1) compared with the non‐fluorinated analogues, whereas the difference was marginal for cis isomers.