of other fluoroalkyl-substituted cyclobutanes commenced from known cyclobutanone 19 (Scheme 5, A). The CHF2 group was introduced via a two-step protocol, involving base-promoted addition of PhSO2CHF2 to the carbonyl moiety and subsequent desulfonylation with Mg in MeOH. After column chromatography, diastereomers cis-20 and trans-20 were isolated separately in 39% and 15% yield, respectively. Perfluorinated groups (i.e. CF3 and C2F5) were introduced by F --catalyzed reaction of cyclobutanone 19 with TMSCF3 or TMSC2F5. Obtained intermediate O-TMS protected products 22 were immediately treated with equivalent amounts of anhydrous TBAF, giving desired products 21d and 21e in 78% and 80% overall yield after stereoisomer separation by column chromatography. Notably, the reaction of ketone 19 with the Ruppert-Prakash reagent (TMSCF3) was accompanied by formation of byproduct 23 (up to 15%) upon scale-up (Scheme 5, B). We believe that this compound might be obtained by elimination of BnOH from 19 and further reaction of the α,β-unsaturated intermediate with another molecule of 19 and TMSCF3. To obtain the target building blocks 1 and 2, compounds cis-and trans-21c-e were separately converted to corresponding mesylates cis-and trans-24c-e in high yields (Scheme 6, A). Subsequent hydrogenolysis of the benzyl protection group and Ru-catalyzed oxidation of resulting alcohols cis-and trans-25c-e gave carboxylic acids cis-and trans-26c-e in 88-99% yield. Elimination of the mesylate moiety promoted with tBuOK as a base allowed preparation corresponding cyclobutenecarboxylic acid derivatives 27c-e in 62-78% yields on up to 26 g scale. Worth noting a significant impact of the relative stereochemistry of mesylates cis-and trans-26c-e on the outcome of the elimination process. Typically, trans-substituted mesylates 26 cleanly produced target products 27, whereas cis-isomers underwent partial cleavage of the methanesulfonic fragment (likely through the neighbouring COOH group participation), giving up to 20 mol. % of corresponding hydroxycarboxylic acids cis-28 (detected by LCMS of the crude mixture; Scheme 6, B). Unfortunately, all attempts to separate alkenes 27 from byproducts 28 failed; therefore, these mixtures were used in the next step without purification. Catalytic syn-hydrogenation of the double bond, a typical and well-renowned method for the preparation of cis-disubstituted saturated cyclic fragments, faced an unexpected issue in our case (Table ). While the reduction of the CHF2-substutited cyclobutene 27c resulted in acceptable 2 mol. % admixture of undesired isomer trans-2c, the same conditions applied to CF3and C2F5-substituted substrates 27d and 27e resulted in 12% and 20 mol. % of trans-isomers, respectively. An optimisation of the reaction conditions improved the ratio of cis-and trans-substituted products 2; however, we have found that these compounds could be enriched to 98% de by column chromatography (for the CF3substituted cyclobutane) or by recrystallization from apolar solvent (for the C2F5-substituted derivative), giving products cis-2d and cis-2e in up to 72% overall yield on up to 17 g scale. To complete the series of cis-and trans-1,2-disubstituted cyclobutane building blocks containing the fluoroalkyl group (already including the trans isomers described previously and the cis isomers prepared in this work), a diastereomerically impure fraction of carboxylic acid cis-2e was isomerised to trans-2e by treatment with tBuOK in THF in 83% yield. Finally, carboxylic acids cis-2c-e and trans-2e were converted to corresponding amine hydrochlorides 1 by Curtius rearrangement via mixed anhydride strategy (64-84% yield after recrystallization, Scheme 7). Physicochemical evaluation: acidity. After achieving our synthetic goals, we turned our attention to the physicochemical properties of the prepared compounds. At first, we established the effects of the fluoroalkyl groups on the acidity of the corresponding functional groups in cis-1,2-disubstituted cyclobutanes and compared them with the reported data for transisomers, as well as parent compounds 1f/2f (Figure ). For both amine hydrochlorides 1a-e and carboxylic acids 2a-e, substitution at β-position led to an increase in acidity (from ΔpKa = -0.1 for trans-2b/2f up to ΔpKa = -2.1 for cis-1d/1f). Expectedly, the observed effect was significantly higher for hydrochlorides 1 (average ΔpKa = -1.1) as compared to carboxylic acids 2 (average ΔpKa = -0.4), confirming the prevalence of the inductive effect (fading with increasing the through-bond distance) on the acid-base properties. Notably, introduction of the methyl group (commonly classified as a -electron donor substituent) led to decreased pKa values similar to the case of electron-withdrawing CH2F group (compare the 1a/1b and 2a/2b pairs). This observation correlates with results of recent studies on the electronic properties of alkyl groups. In the series of hydrochlorides 1a-d, the acidity correlated with the number of fluorine atoms for both cis and trans isomers. Counterintuitively, for C2F5-substituted derivatives 1e, the pKa effects were close or even less pronounced than for CF3substituted counterparts 1d. For the carboxylic acids 2a-e, the pKa trends were similar to those described above for hydrochlorides 1a-e albeit less pronounced. Worth noting higher acidity of cis derivatives as compared to the corresponding trans isomers; moreover, the cis vs trans difference increased in the series CH2F<CHF2≤CF3. This trend could be explained by the through-space field effects of fluorine-containing groups, also observed in the previous works. Lipophilicity. LogP values were measured for anilides 29a-e and benzamides 30a-e (prepared by the reaction of carboxylic acids 2 with aniline and N-benzoylation of hydrochlorides 1, respectively, under the standard reaction conditions, see the Supporting Information) using the classical shake-flask method combined with HPLC quantitative analysis as reported previously (Figure ). In general, the lipophilicity trend in the series of compounds 29 and 30 with various fluorination patterns correlated with the literature data; thus, the LogP values typically increased in the following series: CH2F≤CHF2<CH3≤CF3<C2F5. At the same time, the relative configuration appeared to be crucial in certain cases. Indeed, while the lipophilicities of the compounds with CH3, CH2F and CHF2 substituents were very close for the cis and trans isomer pairs (ΔLogP = -0.07…0.15, 0.04 on average), the derivatives with CF3 and C2F5 groups demonstrated significant differences (ΔLogP = 0.29…0.61, 0.47 on average). This effect was especially prominent for anilides cis-/trans-29d and cis-/trans-29e. With anticipated increase in lipophilicity of ca. 0.4-0.6 LogP units upon transition from the CHF2-to CF3-substituted derivatives, cis-29d was significantly less lipophilic than expected (LogP = 2.31 vs 2.29 for 29c). In turn, this effect resulted in the large LogP difference between cis-29d and trans-29d (ΔLogP = 0.69). Similar effect was also observed for C2F5substituted cyclobutanes cis-26e and trans-29e (ΔLogP = 0.61).