Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles
A facile synthetic route towards either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.
INTRODUCTION<!>Synthesis of starting ynones.<!>Synthesis of 5-fluoroalkyl isoxazoles.<!>Synthesis of 3-fluoroalkyl-substituted isoxazoles.<!>Synthesis of 3-fluoroalkyl-substituted pyrazoles.<!>Synthesis of drug analogues.<!>CONCLUSIONS<!>General Methods.<!>General procedure for the preparation of the compounds 13.<!>5-((tert-Butyldimethylsilyl)oxy)-1,1-difluoropent-3-yn-2-one (13a).<!>5-((tert-Butyldimethylsilyl)oxy)-1,1,1-trifluoropent-3-yn-2-one (13b).56<!>6-((tert-Butyldimethylsilyl)oxy)-2,2-difluorohex-4-yn-3-one (13c).<!>6-((tert-Butyldimethylsilyl)oxy)-1,1,1,2,2-pentafluorohex-4-yn-3-one (13d).<!>1-Bromo-5-((tert-butyldimethylsilyl)oxy)-1-fluoropent-3-yn-2-one (13e).<!>1-Bromo-5-((tert-butyldimethylsilyl)oxy)-1,1-difluoropent-3-yn-2-one (13f).<!>6-((tert-Butyldimethylsilyl)oxy)-1,1-difluorohex-3-yn-2-one (13g).<!>5-((tert-Butyldimethylsilyl)oxy)-1,1-difluorohex-3-yn-2-one (13h).<!>General procedure for the preparation of the compounds 16.<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(difluoromethyl)-4,5-dihydroisoxazol-5-ol (16a).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ol (16b).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(1,1-difluoroethyl)-4,5-dihydroisoxazol-5-ol (16c).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-5-ol (16d).<!>5-(Bromofluoromethyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroisoxazol-5-ol (16e).<!>5-(Bromodifluoromethyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroisoxazol-5-ol (16f).<!>3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5-(difluoromethyl)-4,5-dihydroisoxazol-5-ol (16g).<!>6-((tert-Butyldimethylsilyl)oxy)-1,1-difluorohex-3-yn-2-one oxime (18g).<!>3-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-5-(difluoromethyl)-4,5-dihydroisoxazol-5-ol (16h).<!>General procedure for the preparation of the compounds 17.<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(difluoromethyl)isoxazole (17a).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(trifluoromethyl)isoxazole (17b).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(perfluoroethyl)isoxazole (17d).<!>5-(Bromofluoromethyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)isoxazole (17e).<!>5-(Bromodifluoromethyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)isoxazole (17f).<!>3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5-(difluoromethyl)isoxazole (17g).<!>3-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-5-(difluoromethyl)isoxazole (17h).<!>General procedure for the preparation of the compounds 21.<!>(5-(Difluoromethyl)isoxazol-3-yl)methanol (21a).<!>(5-(Trifluoromethyl)isoxazol-3-yl)methanol (21b).57<!>(5-(1,1-Difluoroethyl)isoxazol-3-yl)methanol (21c).<!>(5-(Perfluoroethyl)isoxazol-3-yl)methanol (21d).<!>(5-(Bromofluoromethyl)isoxazol-3-yl)methanol (21e).<!>2-(5-(Difluoromethyl)isoxazol-3-yl)ethanol (21g).<!>1-(5-(Difluoromethyl)isoxazol-3-yl)ethanol (21h).<!>General procedure for the preparation of the compounds 20.<!>(3-(Difluoromethyl)isoxazol-5-yl)methanol (20a).<!>(3-(Trifluoromethyl)isoxazol-5-yl)methanol (20b).20<!>(3-(1,1-Difluoroethyl)isoxazol-5-yl)methanol (20c).<!>(3-(Bromodifluoromethyl)isoxazol-5-yl)methanol (20f).<!>2-(3-(Difluoromethyl)isoxazol-5-yl)ethanol (20g).18<!>1-(3-(Difluoromethyl)isoxazol-5-yl)ethanol (20h).<!>General procedure for the preparation of the compounds 22a,h and 28c.<!>5-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)-1H-pyrazole (22a).<!>5-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)-1H-pyrazole (22h).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(1,1-difluoroethyl)-4,5-dihydro-1H-pyrazol-5-ol (28c).<!>5-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(1,1-difluoroethyl)-1H-pyrazole (22c).<!>General procedure for the preparation of the compounds 23 and 26b.<!>5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (23b).<!>3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole (26b).<!>5-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(1,1-difluoroethyl)-1-methyl-1H-pyrazole (23c).<!>5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-3-(perfluoroethyl)-1H-pyrazole (23d).<!>3-(Bromodifluoromethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole (23e).<!>5-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole (23h).<!>General procedure for the preparation of the compounds 24 and 25.<!>(3-(Difluoromethyl)-1H-pyrazol-5-yl)methanol (24a).<!>(3-(1,1-Difluoroethyl)-1H-pyrazol-5-yl)methanol (24c).<!>2-(3-(Difluoromethyl)-1H-pyrazol-5-yl)ethanol (24g).<!>1-(3-(Difluoromethyl)-1H-pyrazol-5-yl)ethanol (24h).58<!>(1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (25b).<!>2-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)ethanol (25g).<!>1-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)ethanol (25h).<!>(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)methanol (25a).59<!>(5-(Difluoromethyl)-1-methyl-1H-pyrazol-3-yl)methanol (27a).<!>5-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole (23a).<!>5-(Difluoromethyl)isoxazole-3-carboxylic acid (29a).<!>2-(3-(Difluoromethyl)isoxazol-5-yl)acetic acid (35g).<!>Ethyl 5-(difluoromethyl)isoxazole-3-carboxylate (30).<!>tert-Butyl 1-benzyl-2-(5-(difluoromethyl)isoxazole-3-carbonyl)hydrazinecarboxylate (33).<!>1-(4-(3-Chlorophenyl)piperazin-1-yl)-2-(3-(difluoromethyl)isoxazol-5-yl)ethanone (37).<!>5-(2-(4-(3-Chlorophenyl)piperazin-1-yl)ethyl)-3-(difluoromethyl)isoxazole (34).
<p>Importance of isoxazoles and pyrazoles for discovery of new therapeutics and agricultural ingredients was highlighted in a number of reviews.1–6 Because of advantageous capability of fluorinated substituents to modulate drug-related properties,7–13 their incorporation to azoles provide promising opportunity for drug discovery. For example, substitution of tert-butyl group at isoxazole ring of BRAFV600E inhibitor 1 to its fluorinated analogue in 3 prevented the metabolic oxidation of 1 to significantly less active derivative 2 (Figure 1, A)14 and led to the discovery of clinical candidate Agerafenib. In addition to that, the fluoroalkylated pyrazole moiety is present in structures of marketed anti-inflammatory drug Celecoxib,15 veterinary drugs Deracoxib16 and Mavacoxib17 (also from coxib series, Figure 1, B), as well as in structures of marketed agrochemicals Bixafen, Sedaxane, Isopyrazam, and Fluxapyroxad.5</p><p>Among the previously reported approaches to 3- and 5-fluoroalkyl-substituted isoxazoles, the most important are cycloaddition of nitrile oxides with either 1-substituted vinyl bromides or monosubstituted alkynes,18–22 and reaction of fluoroalkyl-substituted diketones and their synthetic equivalents with NH2OH.23–26 However, both these methods were studied for a limited scope of substrates and in several cases were accompanied with regioselectivity issues. In contrast to isoxazoles, the synthetic methods towards fluoroalkyl-substituted pyrazoles are more comprehensively studied.27 Recently, synthesis of 5-CF3- and 3-CF3-pyrazoles 4a and 5a by cyclocondensation of (hetero)aryl- and alkyl-substituted 1,1,1-trifluorobut-3-yn-2-ones 6 with mono- and unsubstituted hydrazines (Scheme 1) was reported in a series of works by Nenajdenkòs and Hseih`s research groups.28–32 Surprisingly, similar reaction of 6 with NH2OH leading to the formation of fluoroalkyl-substituted isoxazoles 4b and 5b was mentioned just in two patents33,34 and was studied only in a single article by Linderman and Kirillos in 1989.35 In their work, the synthesis of only 3- and 5-octyl-substituted isoxazoles bearing either CF3 or CHF2 group was achieved. Yet, the suggested cyclization conditions (either NaOMe in MeOH for preparation of 7b or AcOH with cat. HCl for 8b) would be hardly adaptable for the preparation of functionalized derivatives. Additionally, increased stability of fluoroalkyl-substituted hemiketal moiety in hydroxypyrazolines 7a and hydroxyisoxazolines 7b was previously reported to complicate the dehydration step;36–38 therefore, revision of the dehydration conditions was necessary.</p><p>In this report, we have elaborated an efficient approach towards the synthesis of azoles 9–12 (Scheme 1) and applied it on a multigram scale. The reaction sequence was designed to meet three main objectives. First, we aimed at the method that could extend the diversity of fluoroalkyl substituents and use commercially available materials as fluorine-containing precursors. Second, the reaction sequence should result in azoles containing various functional groups, which may allow the incorporation of the final building blocks to the structures of more complex biologically active molecules by commonly used chemical transformations. The third goal was the preparation of all target products from common starting reagents as single regioisomers. In addition to that, the utility of the obtained compounds for isosteric replacement of 5-methylisoxazole and 5-methyl-1H-pyrazole moieties was demonstrated by synthesis of fluorinated Isocarboxazid39 and Mepiprazole40 analogues.</p><!><p>Our work commenced with synthesis of a series of ynones 13 (Scheme 2). In order to provide diversity of the fluoroalkyl substituents, the reaction of commercially available fluorinated acetic acid esters 14 with deprotonated terminal alkynes 15 was carried out. A selection of alkynes 15 containing TBS-protected alcohol moiety was envisaged to ensure the stability of the side chain group towards heterocyclization reaction conditions and its further mild removal. Thus, the resulting azole with a free OH group can be further transformed to other functionalized derivatives by commonly used reactions.</p><p>To prepare ynones 13, reaction of esters 14 and lithium acetylenides (obtained in situ from 15 and n-BuLi) was envisaged. It was found that at these conditions, complex mixtures were formed. Nonetheless, these side reactions could be suppressed when BF3·OEt2 was introduced into the reaction mixture32,41 immediately after the addition of esters 14, and the target compounds 13a–h were obtained in 58–87% yield. Importantly, when BF3·OEt2 was introduced to the reaction mixture more than one hour after the addition of 14, a significant yield decrease was observed for the products 13.</p><!><p>Next, the 1,4-addition of NH2OH to ynone 13a was studied in a series of solvents on 0.5 g scale (Table 1). When ynone 13a was mixed with 1.2 eq of NH2OH·HCl, no conversion of the starting material was observed in any solvent system mentioned in Table 1. Therefore, addition of 1.2 eq of NaHCO3 was essential for the reaction to proceed. Although alcohol and alcohol – H2O solvent systems are commonly used for the synthesis of non-fluorinated hydroxyisoxazolines,42 in the case of the ynone 13a, formation of a mixture containing 16a–20a was indicated by 1H NMR and 19F NMR at both rt and 0 °C. Although switching to polar aprotic solvents such as DMF and CH3CN increased the yield of 16a up to 74%, formation of the aforementioned byproducts was not eliminated completely. Instead, using nonpolar CH2Cl2 gave 16a as a single product with 91% yield. In order to facilitate the heterogeneous reaction of NaHCO3 with NH2OH·HCl in CH2Cl2, the two-phase CH2Cl2–H2O (10:1) system was used under vigorous stirring; this increased the product yield to 97%. Finally, the best result was achieved when a solution of ynone 16a in THF was treated with a solution of pre-synthesized NH2OH (from NH2OH·HCl and NaHCO3) in a minimal amount of H2O (99% on 0.5 g scale and 84% on 200 g scale). Formation of hydroxyisoxazolines 16 instead of isoxazoles 17 in the reaction of ynones 13 with NH2OH can be explained by modest aromaticity of isoxazoles43 along with electron-withdrawing effect of the fluoroalkyl substituents which stabilize hemiketals.38</p><p>Further dehydration of hydroxyisoxazolines 16 to isoxazoles 17 required careful optimization of the reaction conditions, which were performed with 0.5 g of 16a as a model substrate (Table 2). The evaluated methods included acylation and sulfonylation of alcohols followed by β-elimination (entries 1–4), as well as dehydration under acidic (entries 5–7) and basic (entry 8) conditions. In more detail, the unsuccessful experiments with both catalytic amounts of H2SO4 (entry 5) and 3 equiv of KOH (entry 8) resulted in the formation of mixtures of unidentified byproducts, whereas refluxing with strong cationite KU-2–8 (entry 6) had no effect on the starting reagent 16a. Reaction of 16a with TsCl (entry 3) gave only tosylated product and was not followed by further elimination.</p><p>Although some of the studied methods allowed the synthesis of compounds 17a and 21a either as single products or as a mixture, still all of them were inefficient for the multigram preparation of the target product 17a. Thus, we have elaborated a new method for dehydration of hydroxyisoxazolines 16 with carbonyldiimidazole (CDI), which provided mild conditions for this transformation (entries 9–11). The best yield (97%) was achieved using 1.1 eq of CDI in CH2Cl2 at rt (entry 11). Moreover, the scale-up of this procedure to 185 g of 16a resulted in 94% yield of the target product 17a. A proposed mechanism of this reaction is given in Scheme 3.</p><p>The optimized protocols for both steps were applied to ynones 13b–h. As a result, hydroxyisoxazolines 16a–h were obtained in 59–85% yield on a multigram scale and converted to isoxazoles 17a–h in 75–94% yield (Table 3). Further removal of the silyl group using KHF2 led to alcohols 21a–e,g,h in 70–92% yield. The product 21f could not be isolated in pure form due to its limited stability. In the case of alkyne 13g, the reaction with NH2OH led to a mixture of cyclization product 16g and corresponding oxime in ca. 2:1 ratio, presumably due to less electron-withdrawing effect of the TBS-protected hydroxyethyl group as compared to CH2OTBS. Thus, compound 16g was obtained in 59% yield after separation by column chromatography.</p><!><p>The synthetic route to regioisomeric 3-fluoroalkyl-substituted isoxazoles relied on metal-catalyzed 1,2-addition of NH2OH to ynones 13, followed by cyclization of the intermediate oxime. Previous reports discussing analogous cyclization of non-fluorinated ynones through methyl- or benzyl-O-substituted and O-non-substituted oxime intermediates used Au(III),44–48 Au(I),48 Ag(I),46,48 Cu(II),48 Cu(I),49,50 Pd(II),51 and Fe(III)52 catalysts. Therefore, salts of these transition metals (except for Au) were screened first for the reaction of 13a with NH2OH in THF (Table 4, entries 1–9). Generally, for these (entries 1–9) and other (entries 10–19) catalysts the reaction resulted in formation of oxime 18a, TBS-deprotected derivative 20a and other byproducts along with the target isoxazole 19a. In the case of Pd(OAc)2, ynone 13a was fully converted to a mixture of unidentified products. Conversely, the use of Ag(I) salts (entries 2–5) resulted in up to 67% yield of the target product 19a. However, the high 33% proportion of the starting material along with byproducts was unsatisfactory. The better results were obtained in Cu(I) and Cu(II) catalyst series (entries 6–9). In particular, the cumulative yield of 19a and 20a obtained under CuI catalysis was 82%.</p><p>Although other transition metal catalysts also appeared to be moderately effective for oxime 18a cyclization (up to 80% yield, entries 10–16), they did not surpass the results observed for Cu-based catalysts. Hence, the selection of the solvent and catalyst ratio was additionally studied using CuI. When the reaction was carried out in dioxane or dimethoxyethane, the yields of the products 19a and 20a were slightly lower as compared to the experiment carried out in THF, whereas the ratio of byproducts was increased. Optimization of the amount of CuI showed that usage of more than 0.10 equiv did not influence the reaction yield, while the usage of less than 0.10 equiv slowed the reaction and facilitated formation of undesirable byproducts. Further survey of other Cu-based catalysts allowed achieving even higher yields using Cu2O, Cu(OAc)2·H2O, and CuCN. These catalysts led to the product 19a in 87–90% yield (entries 17–19) in a mixture with ca. 10% of oxime 18a.</p><p>After ynones 13 were subjected to the reaction with NH2OH under Cu(I)-catalysis, the crude products 19 were further deprotected with KHF2 to give alcohols 20 (63–93% yield for 2 steps, Scheme 4), which were purified by distillation in vacuo. In all cases, CuCN was used as the catalyst at the first step, since it allowed retention of the highest isolated yields for the products 20 upon a scale-up. It should be noted that product 20f appeared to be unstable, and gradually decomposed after storing at 0 °C for more than one week.</p><!><p>In addition to the synthesis of isoxazoles, the potential of 1-fluoroalkyl substituted ynones 13 was further demonstrated by the preparation of pyrazoles containing functionalized side chain. In particular, cyclization of ynones 13 with either N2H4 or MeNHNH2 led to the compounds 22 and 23, respectively, in 72–95% yield (Table 5). Further deprotection of these derivatives with KHF2 gave alcohols 24 and 25 in up to 97% yield. It was also found that reaction of MeNHNH2 with ynones 13 at 0 °C gave compounds 23g and 23h from 13g and 13h, respectively, as single products, whereas substrates 13a,b led to the target pyrazoles 23a,b and 26a,b as ca. 9:1 regioisomeric mixtures. In the case of the compounds 25a and 27a (89% and 6% yield, respectively), the individual isomers were separated by distillation of the products obtained after deprotection of the crude mixture of 23a and 26a. Conversely, for 23b and 26b, the separation was achieved by column chromatography immediately after the cyclization step, and led to individual products 23b and 26b in 86% and 10% yields, respectively.</p><p>For all ynones 13 (except 13c), direct preparation of aromatic products 22 was achieved without isolation of intermediate 5-hydroxypyrazolines 28. Although derivatives 28 were usually present in the reaction mixture along with main products 22 prior to work-up, the concentration of the reaction mixture in vacuo and filtration through silica plug led to the rapid dehydration of 28 to give 22. Yet, the reaction of 13c with N2H4 resulted in 5-hydroxypyrazoline 28c as a single product (97% yield). Thus, intermediate 28c was further dehydrated using CDI in CH2Cl2 to give 22c in 95% yield.</p><!><p>One of the primary goals of this work was to develop an efficient synthetic route towards fluoroalkyl-substituted isoxazoles and pyrazoles, which can be easily used for isosteric replacement of heterocyclic moieties in biologically active compounds. In previous reviews, promising building blocks for drug discovery were referred to as the compounds containing a structural moiety which can be considered as attractive for medicinal chemistry, and one or several functional groups with predictable and controllable chemical reactivity.53,54 From this point of view, a number of functionalized derivatives bearing carboxylic acid, amine, aldehyde, ketone, halide, azide functional groups were synthesized from alcohols 20, 21, 24 and 25 (see Supporting Information for more details). Application of the obtained building blocks was demonstrated by the preparation of antidepressant Isocarboxazid39 and anxyolitic Mepiprazole40 analogues (Scheme 5). In order to access the CHF2-substituted Isocarboxazid analogue, carboxylic acid 29a was obtained from 21a and converted to its ethyl ester 30 (92% yield). The treatment of 30 with aq N2H4 led to the formation of unstable hydrazide 31, which was immediately converted to 32 by reductive amination of benzaldehyde. However, purification of the intermediate 32 appeared to be problematic; therefore, crude 32 was subjected to the reaction with Boc2O to give Boc-protected Isocarboxazid analogue 33, which was obtained as a pure product after column chromatography (42% yield for three steps).</p><p>Preparation of Mepiprazole analogue 34 was achieved from 20g by a three-step reaction sequence. After Jones oxidation of alcohol 20g, carboxylic acid 35g was subjected to amide coupling with amine 36 (92% yield). Further reduction of amide moiety in 37 with LiAlH4 gave the target 3-(difluoromethyl)isoxazole-containing analogue of Mepiprazole 34 (71% yield).</p><!><p>Reaction of fluoroalkyl-substituted ynones with NH2OH, N2H4 and MeNHNH2 was used for efficient preparation of 3- or 5-fluoroalkyl isoxazoles and pyrazoles on up to 200 g scale. The studied methods allowed to obtain the target products as single regioisomers by either 1,2- or 1,4-addition route. Thorough and careful optimization of the reaction conditions was performed for each of the key steps of the synthetic sequences. This allowed preparation of 5-fluoroalkyl isoxazoles with up to 79% overall yield for cyclization and dehydration steps, 3-fluoroalkyl isoxazoles – with up to 93% overall yield for cyclization and side chain desilylation steps, and 3-fluoroalkyl pyrazoles – with up to 95% at the cyclization step. Importantly, using a series of previously unknown fluorinated ynones allowed to increase the scope of fluoroalkyl substituents for incorporation to heterocyclic motifs, as well as provided possibility for extensive functionalization of the side chain. The utility of obtained building blocks for isosteric replacement of alkyl substituted isoxazole and pyrazole moieties was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues. Therefore, the discussed protocols and fluorinated derivatives might provide new opportunities for lead optimization programs.</p><!><p>The solvents were purified according to the standard procedures.55 All starting materials were purchased from commercial sources. Melting points were measured on automated melting point system. Column chromatography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. 1H, 19F and 13C NMR spectra were recorded at 500 MHz or 400 MHz, 470 or 376 MHz, and 126 MHz or 101 MHz, respectively. Chemical shifts are reported in ppm downfield from TMS as an internal standard. Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Taras Shevchenko National University of Kyiv. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (APCI), electrospray ionization (ESI)) and Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization (EI)). The X-ray diffraction data sets were collected with a CCD diffractometer for compound 29a, 35g, 24h. CCDC- 1945644 (29a), - 1945645 (35g), - 1945642 (24h) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.</p><!><p>To a pre-cooled (–78 °C) solution of alkyne 15 (1.00 mol) in THF (1 L) under argon, 2.5 M solution of n-BuLi (1.00 mol, 400 mL) in hexanes was added dropwise. The resulting mixture was warmed to –15 °C, stirred for additional 15 min at the same temperature and then cooled to –40 °C. The corresponding ethyl ester 14 (1.00 mol) was added dropwise, followed by BF3·Et2O (1.05 mol, 129.6 mL) in one portion. The resulting mixture was allowed to warm to rt and stirred overnight. After the reaction was complete, the mixture was quenched by addition of cold saturated solution of NH4Cl (500 mL) at 0 °C under argon flow. The organic layer was separated and concentrated under reduced pressure, whereas the aqueous layer was extracted with EtOAc (4×350 mL). The residue obtained after evaporation of THF and EtOAc solution was combined, washed with brine (2×150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the final product was achieved by distillation in vacuo.</p><!><p>Yield 309 g (80%), from 265 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 193 g of CHF2CO2Et. Colorless liquid, bp = 80–81 °C/7.7 mbar. 1H NMR (400 MHz, CDCl3): δ 5.77 (t, J = 54.0 Hz, 1H), 4.55 (s, 2H), 0.92 (s, 9H), 0.16 – 0.12 (m, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 175.1 (t, J = 30.0 Hz), 108.8 (t, J = 253.0 Hz), 99.1, 79.9, 51.7, 25.8, 18.3, –5.2 ppm. 19F NMR (376 MHz, CDCl3): δ –126.5 (d, J = 54.0 Hz) ppm. GC−MS (m/z): 248 (M+), 197 (M+ – CHF2). Anal. Calcd. for C11H18F2O2Si: C, 53.20; H, 7.31. Found: C, 52.81; H, 7.12.</p><!><p>Yield 180 g (81%), from 142 g of of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 119 g of CF3CO2Et. Colorless liquid, bp = 61–62 °C/7.7 mbar. 1H NMR (400 MHz, CDCl3): δ 4.57 (s, 2H), 0.92 (s, 9H), 0.14 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 167.0 (q, J = 42.4 Hz), 114.8 (q, J = 288.1 Hz), 100.5, 78.9, 51.7, 25.7, 18.3, –5.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –78.8 ppm. GC−MS (m/z): 209 (M+ – C(CH3)3), 197 (M+ – CF3). Anal. Calcd. for C11H17F3O2Si: C, 49.61; H, 6.43. Found: C, 49.41; H, 6.47.</p><!><p>Yield 61.4 g (83%), from 48.0 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 40.0 g of CF2(CH3)CO2Et. Colorless liquid, bp = 53–54 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 4.54 (s, 2H), 1.76 (t, J = 18.6 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 176.7 (t, J = 36.0 Hz), 116.5 (t, J = 249.0 Hz), 98.0, 80.0, 51.7, 25.7, 19.7 (t, J = 25.2 Hz), 18.3, –5.2 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –100.1 ppm. GC−MS (m/z): 205 (M+ – C(CH3)3), 197 (M+ – CF2CH3). Anal. Calcd. for C12H20F2O2Si: C, 54.93; H, 7.68. Found: C, 55.02; H, 7.49.</p><!><p>Yield 108 g (58%), from 100 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 113 g of C2F5CO2Et. Colorless liquid, bp = 57–59 °C/7.7 mbar. 1H NMR (400 MHz, CDCl3): δ 4.58 (s, 2H), 0.92 (s, 9H), 0.14 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 169.2 (t, J = 31.2 Hz), 117.8 (qt, J = 286.9, 34.4 Hz), 106.5 (tq, J = 266.0, 38.8 Hz), 101.3, 79.5, 51.7, 25.7, 18.3, –5.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –82.2 (s, 3F), –122.5 (s, 2F) ppm. GC−MS (m/z): 316 (M+), 259 (M+ – C(CH3)3), 197 (M+ – C2F5). Anal. Calcd. for C12H17F5O2Si: C, 45.56; H, 5.42. Found: C, 45.20; H, 5.33.</p><!><p>Yield 138 g (76%), from 100 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 109 g of CHFBrCO2Et. Light yellow liquid, bp = 46–48 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 6.61 (d, J = 51.2 Hz, 1H), 4.55 (s, 2H), 0.92 (s, 9H), 0.15 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 174.6 (d, J = 27.4 Hz), 98.2 (d, J = 1.8 Hz), 86.9 (d, J = 268.3 Hz), 78.9, 51.6, 26.0 – 25.6 (m), 18.3, –5.2 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –151.6 ppm. GC−MS (m/z): 251/253 (M+ – C(CH3)3), 197 (M+ – CHFBr). Anal. Calcd. for C11H18BrFO2Si: C, 42.72; H, 5.87; Br, 25.84. Found: C, 42.53; H, 5.73; Br, 26.14.</p><!><p>Yield 97.0 g (69%), from 73.0 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 87.2 g of CF2BrCO2Et. Light yellow liquid, bp = 49–50 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 4.58 (s, 2H), 0.92 (s, 9H), 0.15 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 168.0 (t, J = 32.6 Hz), 112.6 (t, J = 316.7 Hz), 100.4, 77.7, 51.8, 25.7, 18.3, –5.2 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –64.3 ppm. GC−MS (m/z): 269/271 (M+ – C(CH3)3), 197 (M+ – CF2Br). Anal. Calcd. for C11H17BrF2O2Si: C, 40.37; H, 5.24; Br, 24.42. Found: C, 40.21; H, 4.88; Br, 24.23.</p><!><p>Yield 105 g (87%), from 85 g of (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (15b) and 57.3 g of CHF2CO2Et. Colorless liquid, bp = 49–51 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 5.74 (t, J = 54.2 Hz, 1H), 3.83 (t, J = 6.6 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 0.90 (s, 9H), 0.08 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 175.4 (t, J = 29.6 Hz), 108.8 (t, J = 252.7 Hz), 100.8, 77.6, 60.4, 25.9, 23.9, 18.3, –5.4 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –126.4 ppm. GC−MS (m/z): 247 (M+ – CH3), 211 (M+ – CHF2), 205 (M+ – C(CH3)3). Anal. Calcd. for C12H20F2O2Si: C, 54.93; H, 7.68. Found: C, 55.27; H, 7.32.</p><!><p>Yield 214 g (81%), from 185 g of (but-3-yn-2-yloxy)(tert-butyl)dimethylsilane (15c) and 125 g of CHF2CO2Et. Colorless liquid, bp = 73–74 °C/23 mbar. 1H NMR (400 MHz, CDCl3): δ 5.76 (t, J = 54.1 Hz, 1H), 4.72 (q, J = 6.7 Hz, 1H), 1.51 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 175.3 (t, J = 29.8 Hz), 108.8 (t, J = 252.8 Hz), 102.4, 78.3, 59.0, 25.7, 24.3, 18.2, –4.7, –5.0 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –126.5 ppm. GC−MS (m/z): 247 (M+ – CH3), 211 (M+ – CHF2). Anal. Calcd. for C12H20F2O2Si: C, 54.93; H, 7.68. Found: C, 55.31; H, 7.74.</p><!><p>Aqueous solution of NH2OH was prepared by stirring NH2OH·HCl (83.4 g, 1.20 mol) and NaHCO3 (101 g, 1.20 mol) in H2O (300 mL) for 30 min. This solution was added dropwise to a pre-cooled to 0 °C solution of the corresponding ynone 13 (1.00 mol) in THF (2.5 L), and the mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), the resulting solution was concentrated in vacuo and the residue was dissolved in EtOAc (1.5 L). The organic phase was washed with brine (2×500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure.</p><!><p>Yield 0.56 g (99 %) from 0.50 g of 13a, or 191 g (84 %) from 200 g of 13a. White solid, mp = 67–69 °C, bp = 104 °C/1 mbar. 1H NMR (500 MHz, CDCl3): δ 5.84 (t, J = 55.1 Hz, 1H), 4.46 (s, 2H), 3.48 (br s, 1H), 3.33 (d, J = 18.4 Hz, 1H), 3.08 (d, J = 18.4 Hz, 1H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 159.7, 112.2 (t, J = 247.9 Hz), 104.2 (t, J = 25.8 Hz), 58.3, 42.0, 25.8, 18.4, –5.32, –5.34 ppm. 19F NMR (376 MHz, CDCl3): δ –130.3 (dd, J = 289.2, 55.1 Hz, 1F), –132.6 (dd, J = 289.2, 55.1 Hz, 1F) ppm. Anal. Calcd. for C11H21F2NO3Si: C, 46.96; H, 7.52; N, 4.98. Found: C, 47.21; H, 7.12; N, 5.03.</p><!><p>Yield 234 g (83 %) from 251 g of 13b. White solid, mp = 62–64 °C, bp = 87–90 °C/1 mbar. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 1H), 4.42 (s, 2H), 3.42 (d, J = 18.6 Hz, 1H), 3.12 (d, J = 18.6 Hz, 1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 158.9, 122.4 (q, J = 284.4 Hz), 102.9 (q, J = 32.8 Hz), 57.7, 42.4, 25.6, 17.8, –5.52, –5.53 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –82.7 ppm. Anal. Calcd. for C11H20F3NO3Si: C, 44.13; H, 6.73; N, 4.68. Found: C, 43.74; H, 6.33; N, 4.55.</p><!><p>Yield 10.4 g (77 %) from 12.0 g of 13c. White solid, mp = 84–85 °C. 1H NMR (400 MHz, CDCl3): δ 4.45 (s, 2H), 3.54 (br s, 1H), 3.39 (d, J = 18.5 Hz, 1H), 3.05 (d, J = 18.5 Hz, 1H), 1.75 (t, J = 18.7 Hz, 3H), 0.90 (s, 9H), 0.11 – 0.09 (m, 6H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 158.5, 121.3 (t, J = 244.4 Hz), 105.6 (t, J = 30.9 Hz), 58.1, 41.3, 25.6, 18.1 (t, J = 25.2 Hz), 17.9, –5.48, –5.50 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –102.7 (d, J = 245.8 Hz, 1F), –104.5 (d, J = 245.8 Hz, 1F) ppm. Anal. Calcd. for C12H23F2NO3Si: C, 48.79; H, 7.85; N, 4.74. Found: C, 48.61; H, 7.51; N, 4.97.</p><!><p>Yield 148 g (75 %) from 179 g of 13d. White solid, mp = 77–79 °C, bp = 81–84 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 4.43 (s, 2H), 3.47 (d, J = 18.7 Hz, 1H), 3.12 (d, J = 18.7 Hz, 1H), 0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 159.8, 118.7 (qt, J = 286.9, 35.0 Hz), 111.3 (tq, J = 262.1, 36.7 Hz), 103.9 (dd, J = 27.5, 25.2 Hz), 58.1, 44.1, 25.8, 18.3, –5.37, –5.39 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –79.9 (s, 3F), –123.2 (d, J = 273.3 Hz, 1F), –127.6 (d, J = 273.3 Hz, 1F) ppm. Anal. Calcd. for C12H20F5NO3Si: C, 41.25; H, 5.77; N, 4.01. Found: C, 41.47; H, 5.41; N, 3.71.</p><!><p>Yield 42.4 g (85 %) from 45.0 g of 13e. Brown solid, mp = 65–66 °C. The compound was obtained as ca. 1:1 diastereomeric mixture. 1H NMR (400 MHz, DMSO-d6): δ 7.76 (br s, 1H), 7.71 (br s, 1H), 6.83 (d, J = 47.8 Hz, 1H), 6.75 (d, J = 48.4 Hz, 1H), 4.38 (s, 2×2H), 3.33 (d, J = 18.5 Hz, 1H), 3.29 (d, J = 18.2 Hz, 1H), 2.95 (dd, J = 18.4, 3.0 Hz, 1H), 2.93 (dd, J = 18.4, 2.2 Hz, 1H), 0.87 (s, 2×9H), 0.08 – 0.06 (m, 2×6H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 158.6 and 158.4, 107.2 (d, J = 23.1 Hz) and 106.0 (d, J = 21.8 Hz), 94.6 (d, J = 256.9 Hz) and 93.6 (d, J = 256.5 Hz), 58.1, 42.9 and 41.7, 25.6 (d, J = 3.6 Hz), 17.9, –5.5 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –146.1 and –147.8 ppm. Anal. Calcd. for C11H21BrFNO3Si: C, 38.60; H, 6.18; N, 4.09; Br, 23.34. Found: C, 38.46; H, 6.45; N, 4.17; Br, 23.32.</p><!><p>Yield 2.41 g (73 %) from 3.00 g of 13f. Brown solid, mp = 75–77 °C. 1H NMR (400 MHz, CDCl3): δ 4.45 (s, 2H), 3.58 (br s, 1H), 3.47 (d, J = 18.5 Hz, 1H), 3.22 (d, J = 18.5 Hz, 1H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 159.8, 120.8 (t, J = 312.4 Hz), 106.4 (t, J = 27.4 Hz), 58.3, 43.0, 25.8, 18.3, –5.32, –5.33 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –62.2 (d, J = 166.1 Hz, 1F), –63.4 (d, J = 166.1 Hz, 1F) ppm. Anal. Calcd. for C11H20BrF2NO3Si: C, 36.67; H, 5.60; N, 3.89; Br, 22.18. Found: C, 36.61; H, 5.79; N, 4.14; Br, 22.30.</p><!><p>The product was obtained after column chromatography (gradient hexanes–t-BuOMe as eluent) of the mixture of 16g and 18g. Yield 53.2 g (59 %) from 80.0 g of 13g. White solid, mp = 71–73 °C (dec). 1H NMR (500 MHz, CDCl3): δ 5.81 (t, J = 55.3 Hz, 1H), 5.23 – 5.11 (m, 1H), 3.90 – 3.77 (m, 2H), 3.34 (d, J = 18.5 Hz, 1H), 2.99 (d, J = 18.5 Hz, 1H), 2.67 – 2.54 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 159.1, 112.2 (t, J = 247.4 Hz), 104.0 (t, J = 26.1 Hz), 60.4, 44.1, 30.9, 25.9, 18.2, –5.4 ppm. 19F NMR (470 MHz, CDCl3): δ –129.8 (dd, J = 287.9, 55.3 Hz, 1F), –131.8 (dd, J = 287.9, 54.9 Hz, 1F) ppm. Anal. Calcd. for C12H23F2NO3Si: C, 48.79; H, 7.85; N, 4.74. Found: C, 48.65; H, 7.61; N, 4.70.</p><!><p>An analytical sample was obtained after column chromatography (gradient hexanes–t-BuOMe as eluent) of the mixture of 16g and 18g. Colorless liquid. 1H NMR (500 MHz, CDCl3): δ 9.97 (s, 1H), 6.72 (t, J = 54.1 Hz, 1H), 3.82 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 0.90 (s, 9H), 0.10 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 140.9 (t, J = 26.3 Hz), 104.6 (t, J = 241.3 Hz), 95.3, 71.2, 61.4, 25.9, 23.8, 18.5, –5.3 ppm. 19F{1H} NMR (376 MHz, , CDCl3): δ –125.1 ppm. Anal. Calcd. for C12H21F2NO2Si: C, 51.96; H, 7.63; N, 5.05. Found: C, 51.99; H, 7.60; N, 4.89.</p><!><p>Yield 6.69 g (82 %) from 10.0 g of 13h. White solid, mp = 60–62 °C, bp = 84–86 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.33 (t, J = 52.7 Hz, 1H), 6.97 (s, 1H), 5.08 (q, J = 6.5 Hz, 1H), 1.43 (d, J = 6.5 Hz, 3H), 0.85 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 167.7, 162.7 (t, J = 28.5 Hz), 107.5 (t, J = 236.2 Hz), 103.0 (t, J = 3.6 Hz), 63.1, 25.5, 23.7, 17.7, –5.1, –5.3 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –118.5 ppm. Anal. Calcd. for C12H23F2NO3Si: C, 48.79; H, 7.85; N, 4.74. Found: C, 48.68; H, 7.77; N, 4.86.</p><!><p>The corresponding 5-hydroxyisoxazoline 16 (0.10 mol) was dissolved in CH2Cl2 (250 mL) and CDI (17.8 g, 0.11 mol) was added. The resulting mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), the organic layer was washed with sat. NaHSO4 (2×80 mL) and brine (2×80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure.</p><!><p>Yield 163 g (94 %) from 185 g of 16a. Colorless liquid, bp = 49–51 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.33 (t, J = 52.7 Hz, 1H), 6.93 (s, 1H), 4.78 (s, 2H), 0.87 (s, 9H), 0.09 (s, 6H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 163.8, 162.7 (t, J = 28.3 Hz), 107.5 (t, J = 236.1 Hz), 104.4 (t, J = 3.7 Hz), 56.5, 25.6, 17.9, –5.5 ppm. 19F NMR (376 MHz, DMSO-d6): δ –118.4 (d, J = 52.3 Hz) ppm. Anal. Calcd. for C11H19F2NO2Si: C, 50.17; H, 7.27; N, 5.32. Found: C, 50.54; H, 7.42; N, 5.65.</p><!><p>Yield 197 g (91 %) from 230 g of 16b. Colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.74 (s, 1H), 4.80 (s, 2H), 0.92 (s, 9H), 0.12 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 164.6, 158.8 (q, J = 42.6 Hz), 118.1 (q, J = 270.1 Hz), 104.7, 57.1, 25.8, 18.4, –5.4 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –64.8 ppm. Anal. Calcd. for C11H18F3NO2Si: C, 46.96; H, 6.45; N, 4.98. Found: C, 47.09; H, 6.30; N, 4.62.</p><!><p>Yield 122 g (89 %) from 145 g of 16d. Colorless liquid, bp = 43–44 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 6.79 (s, 1H), 4.82 (s, 2H), 0.92 (s, 9H), 0.11 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.5, 157.9 (t, J = 31.6 Hz), 118.0 (qt, J = 286.1, 36.2 Hz), 108.2 (tq, J = 254.4, 41.1 Hz), 106.2, 56.8, 25.5, 18.1, –5.8 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –85.0 (s, 3F), –115.8 (s, 2F) ppm. Anal. Calcd. for C12H18F5NO2Si: C, 43.50; H, 5.48; N, 4.23. Found: C, 43.24; H, 5.36; N, 4.42.</p><!><p>Yield 33.4 g (85 %) from 41.5 g of 16e. Yellowish liquid, bp = 92–94 °C/1 mbar. 1H NMR (500 MHz, CDCl3): δ 7.38 (d, J = 48.6 Hz, 1H), 6.59 (s, 1H), 4.77 (s, 2H), 0.92 (s, 9H), 0.11 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 166.2 (d, J = 27.9 Hz), 164.4 (d, J = 1.2 Hz), 102.6 (d, J = 1.5 Hz), 80.3 (d, J = 250.2 Hz), 57.2, 25.8, 18.3, –5.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –141.5 ppm. Anal. Calcd. for C11H19BrFNO2Si: C, 40.74; H, 5.91; N, 4.32; Br, 24.64. Found: C, 40.97; H, 5.64; N, 4.18; Br, 24.68.</p><!><p>Yield 1.18 g (83 %) from 1.50 g of 16f. Yellowish liquid, bp = 66–68 °C/1 mbar. 1H NMR (500 MHz, CDCl3): δ 6.65 (s, 1H), 4.79 (s, 2H), 0.92 (s, 9H), 0.11 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 164.5, 163.7 (t, J = 33.5 Hz), 109.3 (t, J = 299.8 Hz), 102.7, 57.2, 25.9, 18.3, –5.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –48.3 ppm. Anal. Calcd. for C11H18BrF2NO2Si: C, 38.60; H, 5.30; N, 4.09; Br, 23.35. Found: C, 38.94; H, 5.12; N, 3.77; Br, 23.61.</p><!><p>Yield 35.2 g (75 %) from 50.0 g of 16g. Colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.68 (t, J = 53.8 Hz, 1H), 6.50 (s, 1H), 3.86 (d, J = 5.8 Hz, 2H), 2.89 (d, J = 5.8 Hz, 2H), 0.84 (s, 9H), 0.00 (s, 6H) ppm. 13C{1H}NMR (101 MHz, CDCl3): δ 163.0 (t, J = 30.7 Hz), 162.2, 107.4 (t, J = 238.8 Hz), 104.6 (t, J = 2.2 Hz), 61.4, 29.6, 25.9, 18.3, –5.4 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –118.2 ppm. Anal. Calcd. for C12H21F2NO2Si: C, 51.96; H, 7.63; N, 5.05. Found: C, 51.74; H, 7.39; N, 4.81.</p><!><p>Yield 2.26 g (83 %) from 2.90 g of 16h. Colorless liquid, bp = 81–84 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.33 (t, J = 52.7 Hz, 1H), 6.97 (s, 1H), 5.08 (q, J = 6.5 Hz, 1H), 1.43 (d, J = 6.5 Hz, 3H), 0.85 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 167.7, 162.7 (t, J = 28.4 Hz), 107.5 (t, J = 236.2 Hz), 103.0 (t, J = 3.3 Hz), 63.1, 25.5, 23.7, 17.7, –5.1, –5.3 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –118.5 ppm. Anal. Calcd. for C12H21F2NO2Si: C, 51.96; H, 7.63; N, 5.05. Found: C, 51.83; H, 7.73; N, 5.02.</p><!><p>KHF2 (3.91 g, 0.05 mol) was added to a solution of isoxazole 17 (0.10 mol) in MeOH–H2O (9 : 1) mixture (250 mL), and the reaction mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), MeOH was evaporated under reduced pressure. The residue was dissolved in EtOAc (250 mL) and washed with brine (2×70 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained product was purified by distillation in vacuo.</p><!><p>Yield 77.3 g (91 %) from 150 g of 17a. Colorless liquid, bp = 41–43 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 6.70 (t, J = 53.6 Hz, 1H), 6.60 (s, 1H), 4.70 (s, 2H), 3.96 (br s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 163.9, 163.7 (t, J = 31.0 Hz), 107.2 (t, J = 239.2 Hz), 103.1, 56.2 ppm. 19F NMR (376 MHz, CDCl3): δ –118.6 (d, J = 53.6 Hz) ppm. GC–MS (m/z): 149 (M+), 130 (M+ – F). Anal. Calcd. for C5H5F2NO2: C, 40.28; H, 3.38; N, 9.39. Found: C, 40.64; H, 3.33; N, 9.14.</p><!><p>Yield 79.0 g (70 %) from 190 g of 17b. Colorless liquid, bp = 64–66 °C/10 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.36 (s, 1H), 5.69 (t, J = 5.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 165.6, 156.8 (q, J = 41.7 Hz), 118.1 (q, J = 269.6 Hz), 106.2, 54.7 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –64.2 ppm. GC–MS (m/z): 167 (M+), 148 (M+ – F). Anal. Calcd. for C5H4F3NO2: C, 35.94; H, 2.41; N, 8.38. Found: C, 36.24; H, 2.26; N, 8.56.</p><!><p>The product was synthesized from 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1,1-difluoroethyl)-4,5-dihydroisoxazol-5-ol (16c) (9.50 g, 32.2 mmol), which was first converted to 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1,1-difluoroethyl)isoxazole (17c) by the general procedure for the preparation of the compounds 17. The obtained crude product 17c was subjected to desilylation by general procedure for the preparation of the compounds 21 without additional purification. Yield 3.88 g (74 %) from 9.50 g of 16c. Colorless liquid, bp = 59–62 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 6.56 (s, 1H), 4.79 (s, 2H), 2.44 (s, 1H), 2.01 (t, J = 18.4 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 166.3 (t, J = 36.2 Hz), 163.9, 115.9 (t, J = 237.3 Hz), 101.7, 56.1, 23.0 (t, J = 26.5 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –89.4 ppm. GC–MS (m/z): 163 (M+), 144 (M+ – F). Anal. Calcd. for C6H7F2NO2: C, 44.18; H, 4.33; N, 8.59. Found: C, 43.79; H, 4.36; N, 8.73.</p><!><p>Yield 68.4 g (87 %) from 120 g of 17d. Colorless liquid, bp = 72–74 °C/32 mbar. 1H NMR (500 MHz, CDCl3): δ 6.85 (s, 1H), 4.84 (s, 2H), 2.32 (s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.3, 158.6 (t, J = 31.8 Hz), 118.1 (qt, J = 285.9, 35.8 Hz), 108.2 (tq, J = 254.8, 41.2 Hz), 106.3, 56.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –85.1 (s, 3F), –116.0 (s, 2F) ppm. GC−MS (m/z): 217 (M+), 198 (M+ –F), 148 (M+ –CF3). Anal. Calcd. for C6H4F5NO2: C, 33.20; H, 1.86; N, 6.45. Found: C, 33.46; H, 1.76; N, 6.47.</p><!><p>Yield 15.8 g (81 %) from 30.0 g of 17e. Colorless liquid, bp = 96–98 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 48.6 Hz, 1H), 6.62 (s, 1H), 4.77 (s, 2H), 2.63 (br s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 166.3 (d, J = 27.7 Hz), 164.0, 102.5, 80.0 (d, J = 250.1 Hz), 56.1 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –141.9 ppm. LC–MS (m/z): 210/212 (M + H+). Anal. Calcd. for C5H5BrFNO2: C, 28.60; H, 2.40; N, 6.67; Br, 38.05. Found: C, 28.98; H, 2.17; N, 6.74; Br, 37.83.</p><!><p>Yield 17.9 g (91 %) from 33.5 g of 17g. Colorless liquid, bp = 84–86 °C/1 mbar. 1H NMR (500 MHz, CDCl3): δ 6.73 (t, J = 53.8 Hz, 1H), 6.53 (s, 1H), 4.02 – 3.95 (m, 2H), 3.01 – 2.94 (m, 2H), 2.06 (br s, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 163.5 (t, J = 30.8 Hz), 162.0, 107.4 (t, J = 239.1 Hz), 104.4 (t, J = 1.9 Hz), 60.5, 29.6 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –118.3 ppm. LCMS (m/z): 164 (M + H+). Anal. Calcd. for C6H7F2NO2: C, 44.18; H, 4.33; N, 8.59. Found: C, 44.37; H, 3.97; N, 8.96.</p><!><p>Yield 1.03 g (92 %) from 1.90 g of 17h. Colorless liquid, bp = 92–94 °C/10 mbar. 1H NMR (400 MHz, CDCl3): δ 6.73 (t, J = 53.6 Hz, 1H), 6.63 (s, 1H), 5.09 (q, J = 6.6 Hz, 1H), 2.27 (s, 1H), 1.58 (d, J = 6.6 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 167.8, 163.6 (t, J = 30.7 Hz), 107.2 (t, J = 239.0 Hz), 102.0, 62.7, 22.5 ppm. 19F NMR (376 MHz, CDCl3): δ –118.6 (d, J = 53.6 Hz) ppm. GC–MS (m/z): 163 (M+), 144 (M+ – F). Anal. Calcd. for C6H7F2NO2: C, 44.18; H, 4.33; N, 8.59. Found: C, 44.32; H, 4.37; N, 8.27.</p><!><p>To the corresponding ynone 13 (0.10 mol) and NH2OH·HCl (8.34 g, 0.12 mol) in THF (240 mL), CuCN (0.90 g, 0.01 mol) was added, and the reaction was stirred at rt overnight. When the conversion of the starting substrate 13 was complete (monitored by 1H NMR analysis), NaHCO3 (10.1 g, 0.12 mol) was added to the mixture, and the reaction was stirred overnight. The resulting solution was concentrated under reduced pressure; the residue was dissolved in t-BuOMe (250 mL) and filtered through a silica plug. The filtrate was concentrated in vacuo, and the obtained crude product was subjected to the next step without additional purification. KHF2 (3.91 g, 0.05 mol) was added to a solution of crude isoxazole (0.10 mol) in MeOH–H2O (9 : 1) mixture (250 mL), and the reaction mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), MeOH was evaporated under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with brine (2×70 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained product was purified by distillation in vacuo.</p><!><p>Yield 60.8 g (92 %) from 110 g of 13a. Colorless liquid, bp = 45–47 °C/1 mbar. For spectral and physical data, see ref.18</p><!><p>Yield 70.1 g (93 %) from 120 g of 13b. Colorless liquid, bp = 49–52 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.01 (s, 1H), 5.84 (br s, 1H), 4.67 (s, 2H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 177.0, 154.9 (q, J = 37.6 Hz), 120.1 (q, J = 270.5 Hz), 99.6, 55.0 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –62.7 ppm. GC−MS (m/z): 167 (M+), 148 (M+ –F). Anal. Calcd. for C5H4F3NO2: C, 35.94; H, 2.41; N, 8.38. Found: C, 36.28; H, 2.33; N, 8.77.</p><!><p>Yield 13.7 g (63 %) from 35.0 g of 13c. Colorless liquid, bp = 42–44 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 6.69 (s, 1H), 5.74 (d, J = 5.8 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 2.03 (t, J = 19.3 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 175.2, 160.8 (t, J = 33.0 Hz), 118.1 (t, J = 235.0 Hz), 99.2, 54.8, 23.1 (t, J = 25.8 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –87.2 ppm. LC−MS (m/z): 164 (M + H+). Anal. Calcd. for C6H7F2NO2: C, 44.18; H, 4.33; N, 8.59. Found: C, 43.78; H, 4.58; N, 8.24.</p><!><p>Yield 0.79 g (72 %) from 1.27 g of 13f. Colorless liquid, bp = 66–68 °C/1 mbar. 1H NMR (400 MHz, CDCl3): δ 6.70 (s, 1H), 4.81 (s, 2H), 2.11 (br s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.02, 164.01 (t, J = 31.8 Hz), 109.1 (t, J = 299.9 Hz), 102.6, 56.4 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –48.6 ppm. GC−MS (m/z): 227/229 (M+), 208/210 (M+ – F). Anal. Calcd. for C5H4BrF2NO2: C, 26.34; H, 1.77; N, 6.14; Br, 35.05. Found: C, 26.19; H, 1.86; N, 6.01; Br, 34.81.</p><!><p>Yield 8.59 g (92 %) from 15.0 g of 13g. Colorless liquid, bp = 68–70 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.22 (t, J = 53.3 Hz, 1H), 6.63 (s, 1H), 4.91 (t, J = 5.2 Hz, 1H), 3.75 – 3.69 (m, 2H), 2.96 (t, J = 6.3 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 174.1, 158.7 (t, J = 28.7 Hz), 109.8 (t, J = 235.0 Hz), 99.1, 58.5, 30.1 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –116.4 ppm. GC–MS (m/z): 163 (M+), 144 (M+ – F). Anal. Calcd. for C6H7F2NO2: C, 44.18; H, 4.33; N, 8.59. Found: C, 44.58; H, 4.41; N, 8.26.</p><!><p>Yield 0.72 g (92 %) from 1.25 g of 13h. Colorless liquid, bp = 51–53 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.07 (t, J = 53.4 Hz, 1H), 6.52 (s, 1H), 5.73 (d, J = 5.4 Hz, 1H), 4.87 (quint, J = 6.2 Hz, 1H), 1.45 (d, J = 6.2 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 179.0, 158.7 (t, J = 28.6 Hz), 110.0 (t, J = 235.1 Hz), 98.0, 61.7, 22.3 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –116.4 ppm. GC−MS (m/z): 163 (M+), 148 (M+ – CH3), 144 (M+ – F). Anal. Calcd. for C6H7F2NO2: C, 44.18; H, 4.33; N, 8.59. Found: C, 43.96; H, 4.69; N, 8.46.</p><!><p>To a solution of ynone 13 (0.10 mol) in THF (100 mL), a solution of N2H4 in H2O (25 mL, 20% wt) was added dropwise at 0°C, and the mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), the resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL), filtered through a silica plug, and concentrated in vacuo.</p><!><p>Yield 85.3 g (95 %) from 85.0 g of 13a. Colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 13.19 (s, 1H), 6.92 (t, J = 54.9 Hz, 1H), 6.39 (s, 1H), 4.70 (s, 2H), 0.87 (s, 9H), 0.06 (s, 6H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 146.2 (t, J = 28.8 Hz), 143.9, 112.0 (t, J = 231.1 Hz), 100.5, 56.1, 25.7, 18.0, –5.5 ppm. 19F NMR (376 MHz, DMSO-d6): δ –110.4 (d, J = 54.9 Hz) ppm. Anal. Calcd. for C11H20F2N2OSi: C, 50.36; H, 7.68; N, 10.68. Found: C, 50.04; H, 7.80; N, 10.72.</p><!><p>Yield 4.88 g (93 %) from 5.00 g of 13h. Colorless liquid. 1H NMR (500 MHz, CDCl3): δ 6.68 (t, J = 55.1 Hz, 1H), 6.26 (s, 1H), 5.04 (q, J = 6.4 Hz, 1H), 1.48 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 149.6, 147.4, 111.4 (t, J = 233.4 Hz), 98.8, 64.3, 25.8, 25.4, 18.2, –4.8, –5.0 ppm. 19F NMR (376 MHz, CDCl3): δ –111.9 (d, J = 55.1 Hz) ppm. Anal. Calcd. for C12H22F2N2OSi: C, 52.15; H, 8.02; N, 10.14. Found: C, 52.30; H, 8.20; N, 10.12.</p><!><p>Yield 5.44 g (97 %) from 5.00 g of 13c. Colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.88 (s, 1H), 4.40 (d, J = 13.1 Hz, 1H), 4.34 (d, J = 13.1 Hz, 1H), 3.79 (br s, 1H), 3.12 (d, J = 18.1 Hz, 1H), 2.79 (d, J = 18.1 Hz, 1H), 1.73 (t, J = 18.7 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 154.4, 122.1 (t, J = 243.7 Hz), 94.0 (t, J = 28.0 Hz), 60.7, 42.0, 25.9, 19.3 (t, J = 26.3 Hz), 18.4, –5.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –102.8 (d, J = 247.0 Hz), –104.3 (d, J = 247.0 Hz) ppm. Anal. Calcd. for C12H24F2N2O2Si: C, 48.95; H, 8.22; N, 9.52. Found: C, 48.83; H, 8.57; N, 9.28.</p><!><p>To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1,1-difluoroethyl)-4,5-dihydro-1H-pyrazol-5-ol (28c) (5.00 g, 17.0 mmol) in CH2Cl2 (50 mL), CDI (3.03 g, 19.0 mmol) was added. The resulting mixture was stirred overnight. The organic layer was washed with cold 10% aq K2CO3 (2×15 mL) and brine (2×15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Yield 4.46 g (95 %). Colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.28 (s, 1H), 4.79 (s, 2H), 2.01 (t, J = 18.4 Hz, 3H), 0.92 (s, 9H), 0.11 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 144.5 (2С), 119.2 (t, J = 232.5 Hz), 99.7, 57.5, 25.9, 23.9 (t, J = 27.5 Hz), 18.4, –5.3 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –84.9 ppm. LC–MS (m/z): 277 (M + H+). Anal. Calcd. for C12H22F2N2OSi: C, 52.15; H, 8.02; N, 10.14. Found: C, 52.23; H, 8.23; N, 10.18.</p><!><p>NH2NHMe (7.84 mL, 0.15 mol) was added to a solution of ynone 13 (0.10 mol) in THF (250 mL) at 0°C, and the mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), the resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (250 mL), filtered through a silica plug, and concentrated in vacuo.</p><!><p>The reaction led to the formation of ca. 9:1 regioisomeric mixture of 23b and 27b, which was subjected to chromatographic separation (gradient hexanes–t-BuOMe as eluent). Isomer 23b was isolated as a single product. Yield 114 g (86 %) from 120 g of 13b. Colorless liquid. 1H NMR (500 MHz, DMSO-d6): δ 6.62 (s, 1H), 4.75 (s, 2H), 3.86 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 143.6, 139.0 (q, J = 37.4 Hz), 121.5 (q, J = 267.8 Hz), 103.4, 55.4, 37.1, 25.5, 17.7, –5.7 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –61.2 ppm. Anal. Calcd. for C12H21F3N2OSi: C, 48.96; H, 7.19; N, 9.52. Found: C, 49.13; H, 6.95; N, 9.83.</p><!><p>The compound was synthesized by the same procedure described for 23b. The product was obtained as a single isomer after chromatographic separation (gradient hexanes–t-BuOMe as eluent) of ca. 9:1 regioisomeric mixture of 23b and 26b. Yield 13.3 g (10 %) from 120 g of 13b. Colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.38 (s, 1H), 4.68 (s, 2H), 3.92 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 143.6, 138.9 (q, J = 37.4 Hz), 121.5 (q, J = 267.8 Hz), 103.5, 55.4, 37.2, 25.6, 17.8, –5.6 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –60.1 ppm. Anal. Calcd. for C12H21F3N2OSi: C, 48.96; H, 7.19; N, 9.52. Found: C, 48.61; H, 7.42; N, 9.29.</p><!><p>Yield 5.09 g (92 %) from 5.00 g of 13c. 1H NMR (400 MHz, CDCl3): δ 6.29 (s, 1H), 4.66 (s, 2H), 3.88 (s, 3H), 1.98 (t, J = 18.3 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 147.8 (t, J = 33.3 Hz), 142.5, 119.2 (t, J = 232.4 Hz), 102.6, 56.2, 37.0, 25.8, 23.9 (t, J = 27.8 Hz), 18.2, –5.4 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –84.7 ppm. LC–MS (m/z): 291 (M + H+). Anal. Calcd. for C13H24F2N2OSi: C, 53.76; H, 8.33; N, 9.65. Found: C, 53.91; H, 8.70; N, 9.99.</p><!><p>Yield 4.14 g (79 %) from 5.00 g of 13d. 1H NMR (400 MHz, CDCl3): δ 6.41 (s, 1H), 4.69 (s, 2H), 3.94 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 143.3, 139.4 (t, J = 28.6 Hz), 119.1 (qt, J = 285.1, 37.9 Hz), 111.0 (tq, J = 250.0, 39.0 Hz), 105.0, 56.1, 37.5, 25.7, 18.2, –5.5 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –85.3 (s, 3F), –113.4 (s, 2F) ppm. LC–MS (m/z): 345 (M + H+). Anal. Calcd. for C13H21F5N2OSi: C, 45.34; H, 6.15; N, 8.13. Found: C, 45.16; H, 5.91; N, 7.82.</p><!><p>Yield 3.91 g (72 %) from 5.00 g of 13e. 1H NMR (400 MHz, CDCl3): δ 6.36 (s, 1H), 4.66 (s, 2H), 3.92 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 147.1 (t, J = 29.0 Hz), 142.9, 114.5 (t, J = 298.4 Hz), 102.8 (t, J = 2.2 Hz), 56.0, 37.4, 25.7, 18.1, –5.5 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –42.1 ppm. LC–MS (m/z): 355/357 (M + H+). Anal. Calcd. for C12H21BrF2N2OSi: C, 40.57; H, 5.96; N, 7.88; Br, 22.49. Found: C, 40.92; H, 5.87; N, 7.61; Br, 22.30.</p><!><p>Yield 4.87 g (88 %) from 5.00 g of 13h. 1H NMR (500 MHz, CDCl3): δ 6.62 (t, J = 55.4 Hz, 1H), 6.30 (s, 1H), 4.97 (q, J = 6.5 Hz, 1H), 3.92 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), –0.01 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 147.5, 145.2 (t, J = 29.2 Hz), 111.5 (t, J = 233.4 Hz), 101.2 (t, J = 1.7 Hz), 63.7, 37.8, 25.8, 24.1, 18.2, –4.7 ppm. 19F NMR (376 MHz, CDCl3): δ –111.80 (d, J = 55.4 Hz), –111.83 (d, J = 55.4 Hz) ppm. Anal. Calcd. for C13H24F2N2OSi: C, 53.76; H, 8.33; N, 9.65. Found: C, 53.61; H, 8.53; N, 9.43.</p><!><p>KHF2 (3.91 g, 0.05 mol) was added to a solution of pyrazole 22 or 23 (0.10 mol) in MeOH–H2O (9 : 1) mixture (250 mL), and the reaction mixture was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), MeOH was evaporated under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with brine (2×70 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.</p><!><p>Yield 45.2 g (97 %) from 80.0 g of 22a. Yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 6.91 (t, J = 54.8 Hz, 1H), 6.37 (s, 1H), 5.37 (t, J = 5.6 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 146.1 (t, J = 28.3 Hz), 145.4, 112.1 (t, J = 230.9 Hz), 100.4, 54.5 ppm. 19F NMR (376 MHz, DMSO-d6): δ –110.3 (d, J = 54.8 Hz) ppm. GC–MS (m/z): 148 (M+), 131 (M+ – OH). Anal. Calcd. for C5H6F2N2O: C, 40.55; H, 4.08; N, 18.91. Found: C, 40.48; H, 4.36; N, 18.52.</p><!><p>Yield 2.39 g (95 %) from 4.28 g of 22c. Yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.28 (s, 1H), 4.69 (s, 2H), 1.93 (t, J = 18.4 Hz, 3H) ppm. OH and NH protons were exchanged with HDO. 13C{1H} NMR (101 MHz, CDCl3): δ 148.6 (t, J = 32.2 Hz), 145.3, 118.9 (t, J = 233.5 Hz), 101.0, 55.6, 24.1 (t, J = 27.8 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –85.2 ppm. LC–MS (m/z): 161 (M – H+). Anal. Calcd. for C6H8F2N2O: C, 44.45; H, 4.97; N, 17.28. Found: C, 44.24; H, 4.92; N, 17.57.</p><!><p>The product was synthesized from ynone 13g (5.00 g, 19.1 mmol), which was first converted to 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)-1H-pyrazole (22g) by the general procedure for the preparation of the compounds 22. The obtained crude intermediate 22g was subjected to the next desilylation by the general procedure for the preparation of the compounds 24 and 25 without additional purification. Yield 2.76 g (82 %) from 5.00 g of 13g. Colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 12.94 (s, 1H), 6.87 (t, J = 54.9 Hz, 1H), 6.29 (s, 1H), 4.79 (t, J = 5.1 Hz, 1H), 3.62 (td, J = 6.8, 5.1 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 146.1 (t, J = 28.4 Hz), 142.6, 112.2 (t, J = 230.7 Hz), 100.9, 60.1, 28.9 ppm. 19F NMR (376 MHz, DMSO-d6): δ –110.2 (d, J = 54.9 Hz) ppm. Anal. Calcd. for C6H8F2N2O: C, 44.45; H, 4.97; N, 17.28. Found: C, 44.57; H, 5.29; N, 17.03.</p><!><p>Yield 2.45 g (95 %) from 4.40 g of 22h. White solid, mp = 61–63 °C (lit. 62–63 °C)58. 1H NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 6.90 (t, J = 54.9 Hz, 1H), 6.33 (s, 1H), 5.44 (d, J = 5.0 Hz, 1H), 4.80 (quint, J = 6.1 Hz, 1H), 1.39 (d, J = 6.4 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 149.9, 146.0 (t, J = 28.4 Hz), 112.2 (t, J = 230.9 Hz), 98.9, 61.3, 23.8 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –110.3 ppm. Anal. Calcd. for C6H8F2N2O: C, 44.45; H, 4.97; N, 17.28. Found: C, 44.84; H, 4.79; N, 17.35.</p><!><p>Yield 62.7 g (94 %) from 109 g of 23b. White solid, mp 52–54 °C. 1H NMR (400 MHz, DMSO-d6): δ 6.59 (s, 1H), 5.45 (t, J = 5.4 Hz, 1H), 4.54 (d, J = 5.4 Hz, 2H), 3.87 (s, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 145.0, 138.9 (q, J = 37.1 Hz), 121.7 (q, J = 267.7 Hz), 103.6, 53.7, 37.1 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –60.9 ppm. LC–MS (m/z): 181 (M + H+). Anal. Calcd. for C6H7F3N2O: C, 40.01; H, 3.92; N, 15.55. Found: C, 39.65; H, 3.83; N, 15.57.</p><!><p>The compound was synthesized from ynone 13g (5.00 g, 19.1 mmol), which was first converted to 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole (23g) by the general procedure for the preparation of the compounds 23. The obtained crude intermediate 23g was subjected to the next desilylation by the general procedure for the preparation of the compounds 24 and 25 without additional purification. Yield 2.59 g (77 %) from 5.00 g of 13g. Colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.59 (t, J = 55.3 Hz, 1H), 6.30 (s, 1H), 3.86 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 2.85 (t, J = 6.4 Hz, 2H), 2.34 (s, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 144.9 (t, J = 28.7 Hz), 142.2, 111.1 (t, J = 233.5 Hz), 102.2 (t, J = 2.0 Hz), 60.2, 36.2, 28.6 ppm. 19F NMR (376 MHz, CDCl3): δ –112.0 (d, J = 55.3 Hz) ppm. Anal. Calcd. for C7H10F2N2O: C, 47.73; H, 5.72; N, 15.90. Found: C, 47.82; H, 5.50; N, 15.69.</p><!><p>Yield 2.46 g (97 %) from 4.18 g of 23h. Yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 6.89 (t, J = 54.8 Hz, 1H), 6.39 (s, 1H), 5.39 (d, J = 5.7 Hz, 1H), 4.87 – 4.79 (m, 1H), 3.85 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 148.4, 143.9 (t, J = 28.6 Hz), 111.8 (t, J = 231.2 Hz), 100.5, 60.1, 37.1, 22.5 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –110.7 ppm. Anal. Calcd. for C7H10F2N2O: C, 47.73; H, 5.72; N, 15.90. Found: C, 48.06; H, 5.59; N, 16.01.</p><!><p>The compound was synthesized from ynone 13a (100 g, 0.617 mol), which was first converted to 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole (23a) by the general procedure for the preparation of the compounds 23. The reaction led to ca. 9:1 regioisomeric mixture of 23a and 27a, which was subjected to the next step without separation of the two isomers. Desilylation by the general procedure for the preparation of the compounds 24 and 25 resulted in ca. 9:1 regioisomeric mixture of 25a and 26a, which was subjected to separation by vacuum distillation. The isomer 25a was isolated as a single product. Yield 89.0 g (89 %) from 100 g of 13a. Yellow liquid, bp = 131–132 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 6.90 (t, J = 54.9 Hz, 1H), 6.41 (s, 1H), 5.37 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 144.7, 144.5 (t, J = 28.7 Hz), 112.0 (t, J = 231.4 Hz), 102.9, 54.2, 36.8 ppm. 19F NMR (376 MHz, DMSO-d6): δ –110.8 (d, J = 54.9 Hz) ppm. Anal. Calcd. for C6H8F2N2O: C, 44.45; H, 4.97; N, 17.28. Found: C, 44.26; H, 4.60; N, 17.54.</p><!><p>The compound was synthesized by the same procedure described for 25a. The product was obtained as a single isomer after separation of ca. 9:1 regioisomeric mixture of 25a and 27a by vacuum distillation. Yield 6.00 g (6 %) from 100 g of 13a. Yellow liquid, bp = 92–94 °C/1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.26 (t, J = 53.7 Hz, 1H), 6.50 (s, 1H), 5.11 (t, J = 5.8 Hz, 1H), 4.38 (d, J = 5.8 Hz, 2H), 3.84 (s, 3H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 152.0, 135.7 (t, J = 27.1 Hz), 109.3 (t, J = 232.8 Hz), 105.1 (t, J = 3.2 Hz), 56.9, 37.2 ppm. 19F NMR (376 MHz, DMSO-d6): δ –113.7 (d, J = 53.7 Hz) ppm. Anal. Calcd. for C6H8F2N2O: C, 44.45; H, 4.97; N, 17.28. Found: C, 44.55; H, 4.99; N, 17.45.</p><!><p>An analytical sample of the compound was obtained by column chromatography (gradient hexanes–t-BuOMe as eluent) of the mixture of 23a and 27a (1.00 g), prepared by the protocol described for the compound 25a. Colorless liquid. 1H NMR (500 MHz, DMSO-d6): δ 6.89 (t, J = 54.8 Hz, 1H), 6.43 (s, 1H), 4.73 (s, 2H), 3.82 (s, 3H), 0.87 (s, 9H), 0.07 (s, 6H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 144.0 (t, J = 28.8 Hz), 143.0, 111.5 (t, J = 231.4 Hz), 102.4, 55.6, 36.7, 25.5, 17.8, –5.7 ppm. 19F NMR (376 MHz, DMSO-d6): δ –110.9 (d, J = 54.8 Hz) ppm. Anal. Calcd. for C12H22F2N2OSi: C, 52.15; H, 8.02; N, 10.14. Found: C, 52.46; H, 7.77; N, 10.02.</p><!><p>To a solution of 21a (67.0 g, 0.450 mol) in acetone (675 mL), a solution of CrO3 (64.8 g, 0.648 mol) and conc. H2SO4 (55.8 mL) in H2O (225 mL) was added slowly at 0 °C, and the reaction was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), the resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (675 mL), then washed with H2O (300 mL) and brine (2×300 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Yield 65.7 g (90 %) from 67.0 g of 21a. White solid, mp = 77–79 °C (dec). 1H NMR (400 MHz, D2O): δ 7.03 (s, 1H), 6.95 (t, J = 52.8 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, D2O): δ 164.9 (t, J = 30.2 Hz), 161.5, 157.0, 107.0 (t, J = 237.8 Hz), 105.0 ppm. 19F{1H} NMR (376 MHz, D2O): δ –119.7 ppm. LC–MS (m/z): 118 (M – H+ – CO2). Anal. Calcd. for C5H3F2NO3: C, 36.83; H, 1.85; N, 8.59. Found: C, 36.75; H, 1.59; N, 8.78.</p><!><p>The compound was synthesized by the same procedure described for 29a. Yield 2.01 g (43 %) from 4.30 g of 20g. White solid, mp = 90–92 °C (dec). 1H NMR (400 MHz, CDCl3): δ 10.25 (br s, 1H), 6.76 (t, J = 53.5 Hz, 1H), 6.56 (s, 1H), 3.96 (s, 2H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 173.0, 166.4, 159.2 (t, J = 30.1 Hz), 108.9 (t, J = 237.1 Hz), 101.0, 32.4 ppm. 19F NMR (470 MHz, CDCl3): δ –115.7 (d, J = 53.5 Hz) ppm. Anal. Calcd. for C6H5F2NO3: C, 40.69; H, 2.85; N, 7.91. Found: C, 40.89; H, 2.58; N, 7.53.</p><!><p>To a solution of 29a (1.50 g, 7.85 mmol) in anhydrous EtOH (15 mL), conc H2SO4 (0.042 mL, 0.79 mmol) was added, and the solution was refluxed overnight. After the reaction was complete (monitored by 1H NMR analysis), the mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (15 mL). The organic phase was washed with aq NaHCO3 (5 mL), and brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The compound was purified by distillation in vacuo. Yield 1.62 g (92%). Colorless oil, bp 46–49 °C / 1 mbar. 1H NMR (400 MHz, DMSO-d6): δ 7.41 (s, 1H), 7.40 (t, J = 53.8 Hz, 1H), 4.39 (q, J = 6.9, 2H), 1.33 (t, J = 6.9 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6): δ 165.0 (t, J = 29.1 Hz), 158.9, 156.8, 107.6 (t, J = 237 Hz), 106.0 (t, J = 3.6 Hz), 62.6, 14.0 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –119.2 ppm. Anal. Calcd. for C7H7F2NO3: C, 43.99; H, 3.69; N, 7.33. Found: C, 44.04; H, 3.33; N, 7.67.</p><!><p>Ethyl 5-(difluoromethyl)isoxazole-3-carboxylate (30) (1.55 g, 8.12 mmol) and N2H4 in H2O (3.90 mL, 20% wt, 24.4 mmol) were dissolved in EtOH (8 mL) and refluxed for 15 h. Then, the reaction mixture was concentrated in vacuo to dryness, and the residue was redissolved in THF (8 mL). PhCHO (0.90 g, 8.53 mol) was added to the solution of 31, followed by the addition of NaBH(OAc)3 (2.59 g, 12.2 mol) at 0 °C. To the resulting mixture, CH3COOH (0.974 g, 16.2 mmol) was added, and the reaction was stirred at rt overnight. The solvent was removed by evaporation under reduced pressure, and the residue was partitioned between EtOAc (5 mL) and H2O (5 mL). The organic layer was washed with aq NaHCO3 (5 mL), brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL), and di-tert-butyl dicarbonate (2.24 mL, 9.74 mmol) and 4-dimethylaminopyridine (0.23 g, 1.9 mmol). The mixture was stirred at rt overnight, than washed with H2O (4 mL), and brine (4 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by gradient reverse phase chromatography (gradient CH3CN–H2O as eluent). Yield 1.25 g (42%) from 30 (1.55 g). White solid, mp 88–90 °C. The compound was obtained as a mixture of rotamers. 1H NMR (500 MHz, CDCl3): δ 8.27 (s, 1H), 7.38 – 7.27 (m, 5H), 7.04 (s, 1H), 6.77 (t, J = 53.3 Hz, 1H), 4.76 (s, 2H), 1.49 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 165.0 (t, J = 31.5 Hz), 157.0, 156.9, 154.5, 136.3, 128.8, 128.5, 128.0, 106.8 (t, J = 240.4 Hz), 104.3, 82.5, 54.3 and 52.8, 28.2 ppm. 19F NMR (470 MHz, CDCl3): δ –117.95 (d, J = 53.3 Hz) and –117.97 (d, J = 53.3 Hz) and –118.01 (d, J = 53.3 Hz) ppm. LC–MS (m/z): 366 (M – H+). Anal. Calcd. for C17H19F2N3O4: C, 55.58; H, 5.21; N, 11.44. Found: C, 55.81; H, 5.58; N, 11.63.</p><!><p>Carbonyldiimidazole (708 mg, 4.38 mmol) was added to a solution of 2-(3-(difluoromethyl)isoxazol-5-yl)acetic acid (35g) (645 mg, 3.64 mmol) in THF (5 mL), and the solution was stirred for 2 h. Then 1-(3-chlorophenyl)piperazine (36) (788 mg, 4.00 mmol) was added, and the reaction mixture was stirred overnight. The obtained solution was concentrated in vacuo, the residue was dissolved in CH2Cl2 (10 mL), washed with 5% aq HCl (5 mL), NaHCO3 (5 mL), and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. Yield 1.19 g (92%). White solid, mp 89–92 °C. 1H NMR (500 MHz, CDCl3): δ 7.19 (t, J = 8.4 Hz, 1H), 6.92 – 6.85 (m, 2H), 6.79 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 53.8 Hz, 1H), 6.53 (s, 1H), 3.96 (s, 2H), 3.80 (s, 2H), 3.69 (s, 2H), 3.20 (s, 4H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 168.2, 164.5, 159.0 (t, J = 29.8 Hz), 151.7, 135.0, 130.2, 120.2, 116.3, 114.5, 109.0 (t, J = 237.1 Hz), 100.5, 48.9, 48.6, 45.8, 41.8, 31.9 ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –115.9 ppm. LC–MS (m/z): 356/358 (M + H+). Anal. Calcd. for C16H16ClF2N3O2: C, 54.02; H, 4.53; N, 11.81; Cl, 9.96. Found: C, 54.22; H, 4.72; N, 11.64; Cl, 9.81.</p><!><p>To a suspension of LiAlH4 (146 mg, 3.84 mmol) in THF (10 mL), TMSCl (0.51 mL, 4.00 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred for 30 min. Then, a solution of 1-(4-(3-chlorophenyl)piperazin-1-yl)-2-(3-(difluoromethyl)isoxazol-5-yl)ethanone (37) (1.19 g, 3.34 mmol) in THF (12 mL) was added dropwise at –5 °C, and the reaction was stirred overnight. After the reaction was complete (monitored by 1H NMR analysis), H2O (0.15 mL) was added dropwise at 0 °C. After that, a solution of NaOH (58.0 mg, 1.45 mmol) in H2O (0.15 mL) was added dropwise at 10 °C, followed by the addition of another portion of H2O (0.42 mL). Formed precipitate was filtered off, and the solution was concentrated under reduced pressure. The crude product was purified by gradient reverse phase chromatography (gradient CH3CN–H2O as eluent). Yield 810 mg (71 %). White solid, mp 78–81 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.16 (t, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.85 – 6.57 (m, 3H), 6.32 (s, 1H), 3.23 – 3.17 (m, 4H), 3.03 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.68 – 2.62 (m, 4H) ppm. 13C{1H} NMR (101 MHz, DMSO-d6): δ 174.2, 158.5 (t, J = 28.6 Hz), 152.2, 133.8, 130.3, 118.0, 114.5, 113.6, 109.6 (t, J = 235.0 Hz), 98.9, 54.8, 52.1, 47.6, 23.9 ppm. 19F{1H} NMR (376 MHz, DMSO-d6): δ –116.3 ppm. LC–MS (m/z): 342/344 (M + H+). Anal. Calcd. for C16H18ClF2N3O: C, 56.23; H, 5.31; N, 12.29; Cl, 10.37. Found: C, 55.85; H, 5.65; N, 12.14; Cl, 10.32.</p>