Synthesis and Physicochemical Properties of 3‐Fluorocyclobutylamines

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 pKa 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.

Synthesis and Physical‐Chemical Properties of cis‐ and trans‐1‐Amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic Acids

“…Previously, we observed a similar behavior of other 3‐aryl‐3‐fluorocyclobutane amines and derivatives …”

“…Recently, we synthesized fluorine‐containing cyclobutylamines of general structure 10 and described their physical‐chemical properties . Continuing our investigations in this field and taking into account a profound interest in cyclobutane‐containing fluorinated amino acids, we considered compounds 11 as potential analogues of Fluciclovine ( 1 ) bearing fluorine on a quaternary carbon atom (Figure ).…”

Synthesis of Electron-Deficient Heteroaromatic 1,3-Substituted Cyclobutyls via Zinc Insertion/Negishi Coupling Sequence under Batch and Automated Flow Conditions

“…Inspired by these two methodologies and considering the potential for the emergence of flow chemistry to generate organometallic reagents, we identified an opportunity to develop a general method to synthesize 1,3-disubstituted heteroaryl cyclobutanes (Figure , eq 3). Indeed, rapid access to this attractive motif is scarce and limited to α-arylation of cyclobutyl carbonyl derivatives and direct addition of organolithium or organomagnesium reagents to cyclobutanone derivatives . Isolated examples of cross-coupling reactions between cyclobutyl iodides and arylboronic acids have also been achieved .…”

Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

“…According to a rule of thumb, introducing an F‐atom at the β‐position to an amino group leads to a drop in p K a by around 1.7 units. In γ‐fluoroalkylamines, the additional methylene group between the F‐atom and amino moiety lowers as an insulator the through‐bond impact, so that the p K a value is lowered by approximately 0.7 units . The deviation of one unit in the p K a value by shifting the F‐atom from the β‐ into the γ‐position could experimentally be verified by comparison the p K a values of compounds 16b (p K a : 7.30) and 16c (p K a : 8.34).…”