The dissertation work is devoted to the study of synthetic approaches to novel functionalized cyclobutanes containing fluorine atoms or fluoroalkyl groups in various positions.
The proposed sequence of transformations commenced with the chemoselective monohydrolysis of trans-cyclobutane-1,2-dicarboxylate (obtained in eight steps from adipic acid), subsequent deoxofluorination under the action of SF4 of an alkoxycarbonyl-substituted carboxylic acid, and subsequent alkaline hydrolysis of the group ester led to the formation of (1R*,2R*)-2-(trifluoromethyl)cyclobutanecarboxylic acid in 67% yield. The Curtius rearrangement of the carboxylic acid took place under the action of diphenylphosphoryl azide and Et3N in t-BuOH, and treatment with a solution of HCl in 1,4-dioxane ensured provided (1R*,2R*)-2-(trifluoromethyl)cyclobutan¬aminium chloride in 75% yield over two steps.
In turn, (1R*,2R*)-2-(Methoxycarbonyl)cyclobutanecarboxylic acid was converted to an orthogonally protected diester containing tert-butyl and methyl groups using DMAP–Boc2O. The subsequent alkaline hydrolysis led to 2-(hydroxymethyl)cyclo¬butane¬¬carboxylate, whose oxidation, according to Swern, made it possible to synthesize an aldehyde - a necessary precursor of deoxofluorination for the introduction of the CHF2 group by the action of morph-DAST. Further removal of tert-butyl protection of the carboxyl group made it possible to obtain (1R*,2R*)-2-(difluoromethyl)cyclobutane-carboxylic acid, which was converted to a primary amine by the Curtius reaction.
It is shown that (1R*,2R*)-tert-butyl 2-(hydroxymethyl)cyclobutanecarboxylate serves as a good starting compound for the synthesis of monofluoromethyl-containing building blocks based on cyclobutane. The synthetic sequence included a mesylation reaction, TMAF-mediated nucleophilic substitution, and the transformation of tert-butylcarboxylate to the corresponding carboxylic acid (56% yield over three steps). Finally, the synthesis of (1R*,2R*)-2-(fluoromethyl)cyclobutanamine consisted in a Curtius rearrangement of the latter compound in 69% over two steps.
None of the above stages of the conducted synthetic schemes (with the shortest of 11 stages) was not accompanied by epimerization, which made possible the preparation of pure trans isomers of the building blocks proposed on up to 65 grams in a single run. An alternative approach was proposed, which is based on the cyanotrifluoromethylation of cyclobutene under the action of the Togni II reagent, TMS–CN and Cu(OTf)2. This method resulted in the formation of trans-CF3-containing cyclobutanecarbonitrile, and alkaline hydrolysis allowed to obtain (1R*,2R*)-2- (trifluoromethyl)cyclobutane¬carboxylic acid in 38% over three steps.
In addition, the direct azidotrifluoromethylation of cyclobutene by the Togni II reagent, TMS–N3, and Cu(MeCN)4PF6 provided the formation of a CF3-containing azidocyclobutane, which was converted to a primary N-Boc-protected amine by the Staudinger reaction followed by Boc2O treatment. Instead, the direct method of functionalization turned out to be less efficient (overall yield 8%) compared to the general method of synthesis of amines by the Curtius reaction.
According to the results of physical and chemical studies, it was established that the measured pKa values of the target compounds, as well as unsubstituted cyclobutylamine and cyclobutanecarboxylic acid, correspond to the theoretically predicted trend and correlate with literature data for acyclic analogues. This indicates that the acidity or basicity of these series mainly depends on the degree of bond polarization caused by fluorine atoms. The lipophilicity of compounds also changed according to the analogous tendency: H > CH2F ≤ CHF2 << CF3. This series correlates with the literature data for the corresponding acyclic compounds. It is important to note that the introduction of CH2F- or CHF2-substituents into the cyclobutane framework instead of a hydrogen atom did not change or even increased the hydrophilicity of the compounds, despite the increase in the number of carbon atoms.
