Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

Bohdan A Chalyk; Kateryna V Hrebeniuk; Yulia V Fil; Dr Konstantin S Gavrilenko; Dr Alexander B Rozhenko; Bohdan V Vashchenko; Dr Oleksandr V Borysov; Dr Angelina V Biitseva; Dr Pavlo S Lebed; Iulia Bakanovych; Dr Yurii S Moroz; Dr Oleksandr O Grygorenko

doi:10.1021/acs.joc.9b02264

. Author manuscript; available in PMC: 2020 Dec 20.

Published in final edited form as: J Org Chem. 2019 Oct 30;84(24):15877–15899. doi: 10.1021/acs.joc.9b02264

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

Bohdan A Chalyk ^†,^‡, Kateryna V Hrebeniuk ^†, Yulia V Fil ^†, Konstantin S Gavrilenko ^†,^§, Alexander B Rozhenko ^‡, Bohdan V Vashchenko ^†,^§, Oleksandr V Borysov ^†,^‡, Angelina V Biitseva ^†,^§, Pavlo S Lebed ^†,^§, Iulia Bakanovych ^†,^§, Yurii S Moroz ^†,^#, Oleksandr O Grygorenko ^†,^§

PMCID: PMC7341682 NIHMSID: NIHMS1597710 PMID: 31626546

Abstract

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3+2] cycloaddition of CF₃-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert – Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di- and trifluoromethylisoxazoles, e.g. fluorinated analogues of ABT-418 and ЕSI-09.

Graphical Abstract

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Introduction

Isoxazole ring has been recognized as an essential heterocyclic scaffold for organic synthesis and medicinal chemistry.^1–3 In particular, nearly two dozens of pharmaceuticals containing 3- or 5-methylisoxazole motif were approved by FDA to date, and many more have reached various phases of clinical studies (e.g. β-lactam antibiotics,^4,5 sulfonamide antibacterials,⁶ antidepressants,⁷ antirheumatic drugs,⁸, anti-inflammatory,⁹ antiviral,¹⁰ or hypoglycemic¹¹ agents, fungicides¹² and other classes)^13,14 (Figure 1). Introducing fluorine atoms into alkyl substituents is one of the most powerful design tools in drug discovery. Such modification often improves physicochemical characteristics and pharmacokinetic properties of the compounds.^15,16

Figure 1. — Some biologically active compounds bearing a 3- or 5-methylisoxazole moiety.

It is not surprising therefore that synthesis of fluoroalkyl-substituted isoxazoles have attracted significant interest. A classical approach to the synthesis of these compounds relies on the heterocyclization reaction of fluorinated 1,3-bis-electrophiles and hydroxylamine (Scheme 1, A).^17–23 Similar method involves condensation of enolizable oximes with trifluoroacetates (Scheme 1, B).²⁴ In addition to that, deoxofluorination of the oxygen-containing isoxazoles, e.g. alcohols or aldehydes, was described (Scheme 1, C).^25,26 An alternative approach includes [3+2] cycloaddition^27–32 of fluoroalkyl-substituted alkenes,^33–35 alkynes^35–37 or enolizable ketones^38–40 and generated in situ nitrile oxides (Scheme 1, D). To the best of our knowledge, many examples of aforementioned [3+2] cycloadditions were not regioselective under reported conditions.^41–45 In other cases, when 5-(fluoroalkyl)isoxazoles were the desired product, the observed regioselectivity led to target compounds only as minor product.^35,37,46 Moreover, limited substrate scope was typically demonstrated, often including only aryl-substituted nitrile oxides.

Scheme 1. — Known approaches to fluoroalkyl-substituted isoxazoles

In line with our continuous efforts to synthesize fluorinated oxazoles,^47–50 in this work we report a comprehensive study on the regioselective synthesis of various 5-(fluoroalkyl)isoxazoles via the [3+2] cycloaddition approach involving halogenoximes as the nitrile oxide source, focusing mainly on the preparation of functionalized substrates (e.g. bearing a protected amino group). In addition to that, we have aimed at expanding of chemical space covered by fluorinated isoxazoles with a series of small-molecule building blocks accessible on multigram scale.

Our previous experience with [3+2] cycloadditions showed that regioselectivity of the reaction can be controlled by using alkenes bearing a leaving group (e.g. bromo or dialkylamino substituents) as the starting materials.⁵¹ To date, only a few examples of similar reactions with trifluoromethyl-substituted substrates were described in the literature, being limited to simple alkyl- or benzonitrile oxides and α,β-unsaturated esters (Scheme 2).^33,34,52

Scheme 2. — Known syntheses of 5-(fluoroalkyl)isoxazoles by [3+2] cycloaddition of nitrile oxides and α,β-unsaturated esters

Results and discussion

Synthesis of 5-(trifluoromethyl)isoxazoles.

In addition to that, reaction of chloroxime 1a and 2-bromo-3,3,3-trifluoroprop-1-ene (2) in the presence of Et₃N in Et₂O was disclosed in a patent.⁵³ In our hands, the latter transformation was not successful under the conditions reported (the corresponding furoxan was obtained as the major product); nevertheless, reaction of 1a and 2 occurred in the presence of NaHCO₃ in EtOAc as the solvent (Table 1, Entry 1). Using three-fold excess of 2 was necessary to achieve the complete conversion; with smaller amounts of 2, significant nitrile oxide dimerization was observed. On the contrary, using higher excess of 2 did not improve the yield of the product. The target compound 3a was isolated in 69% yield on up to 100 g scale after distillation in vacuo.

Table 1.

Synthesis of 5-(trifluoromethyl)isoxazoles 3a–o


Entry	Chloroxime	R	Product	Yield, %^a
1	1a	CO₂Et	3a	69
2	1b	Ph	3b	44
3	1c	4-MeOC₆H₄	3c	74
4	1d	4-FC₆H₄	3d	73
5	1e	2-thienyl	3e	40
6	1f		3f	89 (73^b)
7	1g		3g	72
8	1h		3h	76
9	1i		3i	85
10	1j		3j	42 (81^c)
11	1k		3k	94
12	1l		3l	95
13	1m		3m	57
14	1n		3n	40
15	1o		3o	42

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Yields of isolated products

At 160-g scale of 1f, 2.5-fold excess of 2 was used, which resulted in slightly diminished yield of the product

The reaction was performed in EtOAc – THF (1:1, v/v) due to limited solubility of 1j in EtOAc

It should be noted that alkene 2 can be considered as the synthetic equivalent of 3,3,3-trifluoroprop-1-yne, which is hardly accesssible and inconvenient to handle due to its low boiling point (−48…−47 °C).

Taking into account the literature examples of [3+2] cycloadditions of benzonitrile oxide shown in Scheme 2,^33,34,52 we have checked the developed procedure with aryl chloroximes 1b–e (Table 1, Entries 2–5). The title products 3b–e were obtained as single regioisomers in 40–74% yield after distillation in vacuo (3b) or chromatographic purification (3c–e). The method was also extended to amino acid-derived chloroximes 1f–o, prepared using a protocol reported by our group previously.⁵⁴ Reaction of 1f–o and 2 under the conditions described above led to the formation of 5-(trifluoromethyl)isoxazoles 3f–o bearing a protected amino function in 40–95% yield (Table 1, Entries 6–15). It is important to outline that the target products 3 could be obtained on up to 150 g scale (checked for 3f, 73% yield).

Interestingly, reaction of alkene 2 with dibromo derivative 4 in the presence of NaHCO₃ in less polar CH₂Cl₂ resulted in the formation of isoxazoline 5 (63% yield) (Scheme 3). Transformation of 5 into the product 6 required using NaHCO₃ in EtOAc (or K₂CO₃, CH₂Cl₂, rt, 1 week, 50% yield). Although formation of the intermediates of the type 5 bearing cyclic substituents or ester moiety was postulated for the [3+2] cycloadditions with nitrile oxides previously, but only a few examples of their isolation were reported to date.^55,56 Also, this transformation could be performed one-pot using 3-fold excess of NaHCO₃ in EtOAc (61% yield).

Scheme 3. — Synthesis of 3-bromo-5-(trifluoromethyl)isoxazole (6)

It is important to outline that in all cases studied, only 3,5-disubstituted isomers 3a–o and 6 were obtained. The structure of the products was confirmed proven by single crystal X-ray diffraction analysis of the compound 3h (Figure 2).

Figure 2. — Molecular structure of 3h (thermal ellipsoids are shown at 50% probability level)

The regioselectivity of the process might be governed by steric and/or electronic factors. In particular, the transition state TS1 leading to the formation of 3,4-disubstituted isoxazolines 7 and corresponding isoxazoles 8 is unfavorable as compared to TS2 (leading to 3 via isoxazolines 9) due to steric repulsion between the R substituent, the trifluoromethyl group and the bromine atom (Scheme 4).

Scheme 4. — A plausible mechanism of the reaction between 1 and 2

In order to elucidate the observed regioselectivity, the reaction was studied using quantum chemical calculations (RI-BP86), modeling the preferable formation of derivatives 9b and 9f compared to the isomeric 7b and 7f. Since these structures contain sterically crowded t-Bu group (9f) or aromatic moiety (9b) disposed to interactions with large contributions of electron dispersion effects. This can significantly influence the ΔE and ΔG values computed using conventional DFT methods. Taking this fact into account, the structures corresponding to local minima were additionally optimized using Grimme’s RI-B97-D approximation having a dispersion correction. The calculations predicted negative energies of formation (either ΔE or ΔG) for cyclic products of the both types. Nevertheless, formation 9b and 9f appeared to be more favorable as compared to isomeric 7b and 7f (see Supporting information, Tables S1, S2 for more details). Therefore, the calculations confirmed formation of the products of type 9b and 9f in the thermodynamically controlled cyclization reaction. Considering dispersion interactions using the RI-B97-D functional slightly reduces the ΔE and ΔG negative values (Tables 2 and S3).

Table 2.

Optimized (RI-BP86) structures of TS1-b, TS2-b, TS1-f, and TS2-f. The ΔG values are given in kcal/mol relative to the starting reactants.

Transition state	RI-B97-D optimized structure	ΔG^‡ (kcal/mol)
TS1-b		29.5
TS2-b		25.6
TS1-f		26.7
TS2-f		23.0

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Geometries of the transition states TS2-b and TS2-f are shown in Table 2. The corresponding activation energy values are by 3.9–4.3 kcal/mol lower than for the isomeric TS1-b and TS1-f. Hence almost exclusive formation of the cyclization products 9b and 9f is favorable, which is observed in the experiments. Moderate activation energy magnitudes estimated at the DFT level of approximation (ΔG = 25.6 and 23.0 kcal/mol for 9b and 9f, respectively) agree well with rather soft reaction conditions used. Thus, for the given set of the substituents, both thermodynamic and kinetic factors direct the process towards the same type of products in the studied reactions.

Relative stability of the products is driven by similar electronic and steric factors determining higher stability for 9b and 9f relative to their regioisomers 7b and 7f. The steric factor in the transition states is probably of high importance. This is best seen by comparing the conformations of TS1-b and TS2-b (Table 2).

In TS2-b, the phenyl moiety is efficiently conjugated with the C–N–O fragment, whereas in TS1-b, the aromatic ring is orthogonal to it. Noteworthy, the located TS2 structures evidence rather synchronous [3+2] cycloaddition: the C–C and C–O distances corresponding to the newly formed bonds are comparable (2.196 and 2.489 Å for TS2-b, and 2.176 and 2.525 Å for TS2-f).

Frontier molecular orbitals (FMO), i.e. the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) for the starting material 2 and corresponding intermediates INT with corresponding orbital energies are shown in Figure 3. Two types of [3+2] HOMO – LUMO interactions are possible: HOMO(INT) – LUMO(2) vs HOMO(2) – LUMO(INT). The smaller ΔE values were found for the combinations of molecular orbitals HOMO(INT-b)–LUMO(2) and HOMO(INT-f)–LUMO(2) (13.53 and 12.10 eV, respectively), which corresponds to the FMO interaction between the highest occupied molecular orbital of the 1,3-dipole and the lowest unoccupied molecular orbital of the dipolarophile (the normal-electron demand). An alternative possibility for the 1,3-dipolar cycloaddition reactions, the interaction between the LUMO of the 1,3-dipole and the HOMO of the dipolarophile (the inverse-electron demand), is characterized here by higher ΔE values: 14.71 and 12.62 eV, respectively. Thus, the first type of interaction is expected in the considered cases.

Figure 3. — Chemissian⁵⁷ plots of FMOs for the 1,3-dipole molecules (**INT-b** and **INT-f**) and for the dipolarophile 2 calculated at the RHF/6–31G*//RI-B97-D/TZVP level of theory.

As can be seen from the FMO graphical representation, contributions from the corresponding atoms into HOMO(INT-b,f) and LUMO(2) participating in the reaction are very similar and hence, the orbital overlapping extent cannot explain the observed regioselectivity of the process. Additional information can be derived analyzing the natural bond orbital (NBO) atomic charges^58,59 in the reacting species (Figure 4). The shown transition states demonstrate favored C–C interaction (attraction of positive and negative charges) and less pronounced C–O repulsion than in the alternative structures. Thus, the charge distribution favors the product structures identical to those found experimentally.

Figure 4. — NBO atomic charges in the reagents (BP86/TZVP//RI-B97-D/TZVP level of theory).

Further studies of 5-trifluoromethyl derivatives obtained above included preparation of bulding blocks relevant to drug discovery, i.e. carboxylic acid 10, alcohol 11, chloride 12, and amines 13. Synthesis of the corresponding carboxylic acid 10 from ester 3a was found to be challenging (Scheme 5). Reactions of 3a with TMSBr or TMSI in HOAc, as well as KHMDS or TMSOK were unfruitful due to low yields of 10 and/or long reaction times (up to 72 h).

Scheme 5. — Synthesis of building blocks **10–12**

Thus, compound 10 was obtained in 68% yield via slow dropwise addition of 3a solution in MeOH to the homogenous solution of NaOH in MeOH at 0 °C. It should be noted that the aforementioned reaction was highly exothermic.

Reduction of 3a with LiAlH₄ was unfruitful in all attempts; thus, the corresponding alcohol 11 was smoothly synthesized from 3a in 81% yield via reaction with DIBAL in CH₂Cl₂ at –5 to 0 °C for 1 h, followed by aq HCl work-up.

In turn, preparation of alkylating agent 12 relied on the reaction of hydroxymethyl derivative 11 with SOCl₂. The yield of the product 12 was moderate (64%; 30% overall yield from 1a); the use of other reagents such as (COCl)₂ or NCS – PPh₃ did not improve the reaction outcome. More efficient approach to 12 relied on direct [3+2] cycloaddition reaction of chloroxime 1p and 3-fold excess of 2 (600 g), which led to the target derivative 12 in 46% yield on 100 g scale.

In turn, deprotection of the Boc derivatives 3f–m upon action of generated in situ methanolic HCl led to aliphatic amines 13f–m (92–98% yield, isolated as hydrochlorides except 13i, which was obtained and purified as a free base in 51% yield) (Table 3). It is important to stress out that the building blocks 13f·HCl, 13i, 13k–l·HCl could be obtained at multigram scale (up to 30 g).

Table 3.

Synthesis of amines 13f–m


Entry	Boc derivative	R	Product	Yield, %^a
1	3f		13f·HCl	95
2	3g		13g·HCl	93
3	3h		13h·HCl	92
4	3i		13i	51^b
5	3j		13j·HCl	95
6	3k		13k·HCl	97
7	3l		13l·HCl	98
8	3m		13m·HCl	92

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Yields of isolated products

Purified and isolated as a free base

Synthesis of other 5-(fluoroalkyl)isoxazoles.

Since unlike 2-bromo-3,3,3-trifluoroprop-1-ene (2), the corresponding mono- and difluorinated alkenes are not readily available, we have switched to the deoxofluorination strategy for the preparation of the 5-(fluoromethyl)- and 5-(difluoromethyl)isoxazoles. Only a few examples of similar transformations were reported in the literature, including synthesis of the compounds 14 and 15 (Scheme 6).^25,26

Scheme 6. — Synthesis of 5-((di)fluoromethyl)isoxazoles 18 and 19 *via* deoxofluorination

We anticipated that alcohols 16 and the corresponding aldehydes 17 (obtained by oxidation of 16) might be proper key intermediates for the preparation of the target products 18 and 19, respectively. In turn, synthesis of hydroxymethyl derivatives 16 might rely on [3+2] cycloaddition of functionalized halogenoximes 1 and propargylic alcohol. To the best of our knowledge, only a single example of analogous transformation which involved metal catalysis was mentioned in the literature to date.⁶⁰

In this work, a transition metal-free version of this reaction was used. In particular, it was found that chloroximes 1f–m smoothly reacted with propargyl alcohol under the standard conditions (NaHCO₃, EtOAc, rt) to give the target products 16f–m in 84–96% yield (Table 4). Deoxofluorination of 16f–l with morph-DAST in CH₂Cl₂ at −10 °C gave the title isoxazoles 18f–l in low to moderate yields (6–31% after chromatographic purification).

Table 4.

Synthesis of 5-((di)fluoromethyl)isoxazoles 18–21


	R	Alcohol 16 (yield, %^a)	Product 18 (yield, %)	Product 20·HCl (yield, %^a)	Aldehyde 17 (yield, %)	Product 19 (yield, %^a)	Product 21·HCl (yield, %^a)
1		16f (94)	18f (6^b, 93^c)	N/A^d	N/A^d	N/A^d	N/A^d
2		16g (96)	18g (10^b, 97^c)	N/A^d	17g (66^e, 78^f)	19g (23)	21g·HCl (96)
3		16h (95)	18h (12^b, 98^c)	N/A^d	17h (67^e, 76^f)	19h (25)	21h·HCl (95)
4		16i (91)	18i (30^b, 93^c)	20i·HCl (92)	17i (80^e, 83^f)	19i (28)	21i·HCl (93)
5		16j (84)	18j (16^b, 96^c)	N/A^d	17j (43^e, 14^f)	19j (35)	21j·HCl (91)
6		16k (90)	18k (31^b)	20k·HCl (94)	17k (78^e, 81^f)	19k (53)	21k·HCl (96)
7		16l (92)	18l (25^b)	20l·HCl (95)	17l (75^e, 80^f)	19l (61)	21l·HCl (98)
8		16m (85)	18m (N/A^d)	N/A^d	17m (55^e, 69^f)	N/A^d	N/A^d

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Yield of isolated products

Yield of isolated products given for the deoxofluorination reaction (Morph-DAST, CH₂Cl₂, −35 °C to −10 °C, 1.5 h)

Yield of isolated products given for the Finkelstein reaction (KHF₂, MeCN, 18-crown-6, reflux, overnight)

The compound was not prepared due to the low yield of the starting material on the previous step of the reaction sequence

Yield of isolated products of oxidation performed with PCC, SiO₂, CH₂Cl₂

Yield of isolated products of oxidation via using of DMSO, Py·SO₃, Et₃N.

To obtain the difluoromethyl-substituted products 19, alcohols 16f–m were first oxidized the corresponding aldehydes 17g–m with PCC (43–80% yield). Oxidation with the Parikh – Doering reagent gave better reaction outcome (69–83% yield, except 17j obtained in 14% yield); meanwhile, using the Dess – Martin reagent was unfruitful due to low yields of the products. Aldehyde 17f appeared to be too unstable to be isolated, whereas other compounds of this series could be isolated and stored at +4 °C. Deoxofluorination of 17g–l under the aforementioned conditions led to the formation of 19g–l in moderate yields (23–61%). Deprotection of 18 and 19 with methanolic HCl proceeded smoothly and gave building blocks 20 and 21, respectively, in 91–98% yield.

Due to the low yields of the deoxofluorination of alcohols 16f–h, 16j and 16m, the Finkelstein reaction was successfully applied for preparation of CH₂F-derivatives 18 (Scheme 7). The bromide substitution of 22f–h, 22j and 22m proceeded in 93–98% yield by refluxing of the substrate, KHF₂ and 18-crown-6 as catalyst in MeCN. Applying dibenzo-18-crown-6 as a phase-transfer catalyst did not improve the yields of 18.

Scheme 7. — Synthesis of 18 *via* the Finkelstein reaction of 22

In turn, bromides 22 were obtained in 61–72% yield by cycloaddition reaction of chloroxime 1f–h, 1j and 1m and freshly distilled propargyl bromide in the presence of 1.1-fold excess of NaHCO₃ in EtOAc. This approach was also extended to chloroxime 1a to obtain isoxazole 22a (68% yield), which was used for the preparation of fluoromethyl derivative 18a bearing an ester moiety (65% yield).

Analogous synthetic strategy was also implemented for the preparation of difluoromethyl-substituted building blocks bearing ester of bromine at C-3 position (Scheme 8).

Scheme 8. — Preparation of building blocks 28 and 29

The reaction sequence commenced with the reaction of halogenoxymes 1a or 4 with propargyl alcohol resulted in the hydroxymethyl isoxazoles 23 or 24 in 57% and 68% yield, respectively. Oxidation of 23 and 24 to the corresponding aldehydes 25 and 26 was more efficient with PCC, while the Parikh – Doering reagent led to extremely low yields (13% yield for 25). It is interesting to outline that deoxofluorination of aldehydes 25 and 26 proceeded smoothly, and the products 27 and 28 were obtained in 73% yield and 72% yield (for two steps), respectively. Mild alkaline hydrolysis of ester 27 using the method applied for the synthesis of 10 provided the carboxylic acid 29 in 73% yield. Building blocks 28 and 29 were obtained at up to 40 g scale. It should be noted that very similar approach was described in the literature for the preparation of 30.²⁶

The aforementioned method was further applied for the preparation of a homologue of 29, i.e. 1,1-difluoroethyl derivative. The reaction sequence included the cycloaddition of 1a and methyl ethynyl ketone (resulted in 5-acetylisoxazole-3-carboxylate 31), deoxofluorination to the derivative 32 (1 week, 83% yield) and its mild alkaline hydrolysis, which gave 33 in 91% (Scheme 9). Modified Curtius rearrangement of 33 using DPPA, t-BuOH, Et₃N gave the corresponding amine 34 in 39% yield after Boc-protection group cleavage.

Scheme 9. — Preparation of 1,1-difluoroethyl carboxylic acid 33 and amine 34

Next, similar strategy was used for the preparation of the F₂HC-containing analogue of the alkylating agent 12. Thus, the corresponding oxime 35 was transformed to isoxazole 36 by treatment with NCS, HCl in DMF at 0 °C to rt, followed by addition of propargyl alcohol and NaHCO₃ (Scheme 10). The reaction proceeded for 48 h and led to isoxazole 36 in 41% yield on up to 150 g scale. Subsequent oxidation of the chloromethyl derivative 36 to the corresponding aldehyde 37 was performed with PCC in the presence of SiO₂ in CH₂Cl₂ at 0 °C to rt. The intermediate 37 was isolated in 68% yield after distillation and then subjected to the deoxofluorination step providing the target building block 38 in 37% yield.

Scheme 10. — Synthesis of difluoromethyl-containing alkylating agent 38

Alternatively, aldehydes of the type 17 were transformed into 5-(fluoroalkyl)isoxazoles 39 via reaction with the Ruppert – Prakash reagent (TMSCF₃) (Scheme 11). In this case, N-Boc-protected amino alcohols 39g, 39h and 39k–m were obtained in 44–95% yield. Subsequent oxidation of 39k and 39l with the Parikh – Doering reagent led to corresponding ketones isolated as a hydrates 40k and 40l (45–48% yield), while the Swern reagent led to 40 only in 13% in the most successful case.

Scheme 11. — Preparation of fluorinated isoxazoles 39 and 40

Moreover, we have tested an approach to the isomers of 40k and 40l from previously described carboxylic acids 41 (Scheme 12).⁵⁴ In turn, carboxylic acids 41 were transformed to Weinreb amides 42 (90–93% yield), which were used in the aforementioned reaction with TMSCF₃ and CsF in THF, resulted in 43 in 72–74% yield.

It should be noted that in the case of isomeric trifluoromethyl ketones 43a and 43b, no hydrate formation was observed.

Reaction of chloroximes with aliphatic di- and trifluoromethyl ketones.

As it was mentioned above, fluoroalkyl-substituted isoxazoles can be obtained by reaction of chloroximes and fluorinated ketones.^39,40,61 The scope of the method studied so far was limited by aryl- or CO₂Et-substituted chloroximes (Scheme 13).

Scheme 13. — Known reactions of chloroximes and fluorinated ketones

Therefore, we have studied base-mediated reaction of fluorinated β-ketoesters 44 and 45 or α-bromoketones 46 and 47 with chloroximes 1f and 1h–j (Scheme 14). Surprisingly, neither target isoxazoles 48 nor isoxazolines 49 were detected in the reaction mixture; instead, 1,4,2-dioxazole derivatives 50 and 51 were obtained from 44 and 45, respectively, in 39–57% yield. Replacing the starting ketones 44 and 45 with the corresponding enamines 54 and 55 gave the same products 50 and 51, but with lower yields (36–44%).

Scheme 14. — Formation of 1,4,2-dioxazoles **50–53** (yields from 54 and 55 are given in brackets)

Analogously, 1,4,2-dioxazoles 52j and 53j were synthesized via reaction of α-bromoketones 46 and 47 with chloroxime 1j in 37% and 40% yields, respectively. Although similar transformations leading to the formation of 1,4,2-dioxazoles were described in the literature recently: they were obtained as minor products in reactions of chloroximes and α-keto esters.⁶²

Nevertheless, the product of the type 48, i.e. difluoromethyl isoxazole 48f, could be obtained in low yield (13%) by reaction of 45 and 1f in the presence of NiCl₂·6H₂O (10% mol.) (Scheme 15).⁶² Other catalysts like CuSO₄, Cu(OAc)₂·H₂O, Cu(OAc)₂·H₂O – TMEDA, or NiCl₂·6H₂O – TMEDA did not improve the reaction outcome.

Scheme 15. — Preparation of trisubstituted isoxazole **48f**

Synthesis of ABT-418 and ESI-09 analogues.

In the above sections, a number of fluorinated heterocyclic building blocks were obtained at multigram scale. To demonstrate their utility for medicinal chemistry, several fluorinated isosteric analogues of known biologically active compounds were prepared. In particular, trifluoromethyl-substituted analogues of ABT-418 – (R)- and (S)-enantiomers of the compound 56 – were obtained from amines 13k and 13l in 88% and 90% yield, respectively (Scheme 16).

Scheme 16. — Fluorinated analogues of ABT-418

In turn, F₃C-containing analogue 57 of exchange factor directly activated by cAMP (EPAC) inhibitor ESI-09 was synthesized from ester 3a (Scheme 17). The compound 3a reacted with generated in situ (cyanomethyl)lithium to give β-ketonitrile 58, which was used in subsequent step without additional purification. F₃C-ESI 09 57 was obtained from 58 by azo coupling with M–chlorophenyldiazonium⁶³ in 46% overall yield.

Conclusions

Synthetic potential of functionalized halogenoximes for the preparation of fluorinated isoxazole derivatives has been studied thoroughly. As a result, several different approaches were identified (Scheme 18). In particular, one-pot metal-free [3+2] cycloaddition of 2-bromo-3,3,3-trifluoropropene and in situ generated nitrile oxides bearing ester, bromine, chloromethyl, aryl and protected amino groups is general and regioselective approach to 3-functionalized 5-(trifluoromethyl)isoxazoles (40–95% yield) (method A).

Scheme 18. — Summary of methods for the preparation of 5-(fluoroalkyl)isoxazoles developed in this work

Base-promoted reaction of halogenoximes and propargilic alcohol was used for the preparation of 3-substituted 5-((di)fluoromethyl)isoxazoles. Deoxyfluorination of the resulting 5-(hydroxymethyl)isoxazoles morph-DAST gave the corresponding fluoromethyl derivatives in low yields (6–31%). Meanwhile, deoxofluorination of the corresponding aldehydes (obtained by oxidation of the CH₂OH derivatives with the Parikh – Doering reagent or PCC) was more efficient and gave 5-(difluoromethyl)isoxazoles in 23–61% overall yield (method B).

More efficient method for the synthesis of 5-fluoromethyl-substituted derivatives included nucleophilic substitution in the corresponding 5-bromomethyl derivatives (91–98% yield), in turn prepared by [3+2] cycloaddition of halogenoximes and propargyl bromide (61–71% yield) (method C). 5-(β,β,β-Trifluoro-α-hydroxyethyl)isoxazoles were prepared by reaction of isoxazole-5-carbaldehydes with the Ruppert – Prakash reagent (44–95% yield) (method D). Oxidation of the resulting N-Boc-protected amino alcohols led to the corresponding 5-(trifluoroacetyl)isoxazoles, which were obtained as hydrates.

Experimental part

The solvents were purified according to the standard procedures.⁶⁴ The starting materials 1a–p, 2, 4, 44–47, 54 and 55 were purchased from commercial sources. Melting points were measured on an automated melting point system. Analytical TLC was performed using silica gel plates. Column chromatography was performed using silica gel (230–400 mesh) as the stationary phase. ¹H and ¹³C NMR spectra were recorded on a NMR spectrometer at 500 MHz for Protons and 126 MHz for Carbon-13 or at 400 MHz for protons and 101 MHz for Carbon-13. 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, National Taras Shevchenko University of Kyiv. Mass spectra were recorded on an LCMS instrument (chemical ionization (CI)) and GCMS instrument (electron impact ionization (EI)). Preparative flash chromatography was performed on chromatograph using 40 g columns. Optical rotations were measured on polarimeter in MeOH (for amine hydrochlorides) or CHCl₃ (in all other cases) using 1-dm cell; optical rotation values are given in 10⁻¹ deg cm² g⁻¹; concentrations (c) are given in mmol/L, wavelength 589 nm at 20 °C. The enantiomeric excess and retention time (t_R) was determined for major signal by HPLCs. CCDC 1945950 (3h) 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.

Calculation methods.

All calculations were carried out using TURBOMOLE program package (versions 6.4).^65,66 Geometry optimization and calculation of total energy values were made using DFT (RI-BP86) approximation with the TZVP basis sets, the implemented into the TURBOMOLE set of programs polarized Ahlrich’s “triple-zeta” TZV basis sets.⁶⁷ The structures corresponding to local minima were re-optimized using Grimme’s RI-B97-D, having a dispersion correction.^68–70 For structure 5a a manual conformational analysis was performed searching the most favorable conformation. The found total energy variation for the four conformational isomers was quite small (within few tenths kcal/mol, see the SI for more detail). For locating transition state structures, force constants were calculated and the standard procedure for location of the transition state structures, implemented into the TURBOMOLE set of program, were used. Vibration frequencies and corrections for calculation of relative energies and relative free Gibbs energies were derived analytically (RI-BP86) or numerically (RI-B97-D). For the structures corresponding to local energy minima no imaginary frequencies were found, whereas for every TS structure only one imaginary frequency was detected. For computing relative energies, the corresponding corrections on vibrations at 0 K (ZPE) were added to the total energies. For deriving relative free Gibbs energy values, chemical potential magnitudes calculated at the standard conditions (pressure: 0.1 MPa, temperature: 298.15 K) with the default scaling coefficient (0.9914) were used as corrections for the both DFT methods. Frontier molecular orbitals (FMO) were presented graphically using the Chemissian program.⁵⁷ Corresponding single-point density matrices and NBO atomic charges^58,59 were derived for the isolated molecules of 1,3-dipoles and dipolarophile using the GAUSSIAN-09 set of programs.⁷¹

General procedure for the preparation of isoxazoles 3a–o.

The corresponding halogenoxime 1a–o (40.2 mmol, 1 eq) was dissolved in EtOAc (100 mL, 0.4 M solution of 1a–o) (NOTE: in the case of 1j, EtOAc – THF (100 mL, 1:1, v/v) was used), and 2-bromo-3,3,3-trifluoro-1-propene (2, 21.1 g, 121 mmol, 3 eq) and NaHCO₃ (11.1 g, 133 mmol, 3.3 eq) were added to the vigorously stirred homogeneous solution at rt. The resulting mixture was stirred overnight. The completion of the reaction was monitored by ¹H NMR spectroscopy. Then, the resulting mixture was filtered through a plug of silica gel and evaporated in vacuo.

Ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3a).⁵³

The compound was purified by distillation in vacuo. Yield 5.81 g (69%, can be scaled up to 95.2 g by using 1a (100 g, 0.660 mol) and 2 (346 g, 1.98 mol)); colorless oil; bp 39–40 °C / 8.5 mmHg. ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (d, J = 1.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 159.1 (q, J = 42.7 Hz), 158.3, 117.8 (q, J = 270 Hz), 108.0 (q, J = 2.3 Hz), 62.9, 14.1. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −64.0. LC/MS (CI): m/z = 210 [M+H]⁺. Anal. Calcd. for C₇H₆F₃NO₃: C, 40.20; H, 2.89; N, 6.70. Found: C, 40.59; H, 3.28; N, 6.84.

3-Phenyl-5-(trifluoromethyl)isoxazole (3b).^72,73

The compound was purified by distillation in vacuo. Yield 3.77 g (44%); colorless powder; mp 76–78 °C; sublimation 55–57 °C / 0.8 mmHg. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.99 – 7.93 (m, 2H), 7.60 – 7.53 (m, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 163.2, 157.9 (q, J = 41.7 Hz), 131.6, 129.7, 127.4, 127.2, 118.3 (q, J = 270 Hz), 105.9 (d, J = 2.4 Hz). ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −63.9. GC/MS (EI): m/z = 77 [Ph]⁺, 144 [M–CF₃]⁺, 194 [M–F]⁺, 213 [M]⁺.Anal. Calcd. for C₁₀H₆F₃NO: C, 56.35; H, 2.84; N, 6.57. Found: C, 56.57; H, 2.60; N, 6.29.

3-(4-Methoxyphenyl)-5-(trifluoromethyl)isoxazole (3c).

The compound was purified by column chromatography on silica gel (40 g RediSep column; run length: 89.2 CV; flow rate: 60 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent. Yield 7.23 g (74%); beige powder; mp 72–75 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.95 – 7.83 (m, 2H), 7.17 – 7.07 (m, 2H), 3.83 (s, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 162.7, 161.9, 157.6 (q, J = 41.6 Hz), 129.0, 119.5, 118.4 (q, J = 270 Hz), 115.1, 105.6, 105.6, 55.7. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ –63.9. GC/MS (EI): m/z = 76 [C₆H₄]⁺, 107 [C₆H₄OMe]⁺, 174 [M–CF₃]⁺, 224 [M–F]⁺, 243 [M]⁺. Anal. Calcd. for C₁₁H₈F₃NO₂: C, 54.33; H, 3.32; N, 5.76. Found: C, 54.25; H, 2.99; N, 5.81.

3-(4-Fluorophenyl)-5-(trifluoromethyl)isoxazole (3d).

The compound was purified by column chromatography on silica gel (40 g RediSep column; run length: 63.0 CV; flow rate: 60 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent. Yield 6.88 g (73%); colorless powder; mp 45–47 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 8.01 (dd, J = 8.9, 5.3 Hz, 2H), 7.40 (t, J = 8.9 Hz, 2H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 164.2 (d, J = 249 Hz), 162.2, 157.9 (q, J = 41.8 Hz), 129.8 (d, J = 8.9 Hz), 123.7 (d, J = 3.3 Hz), 118.3 (q, J = 270 Hz), 116.7 (d, J = 22.1 Hz), 105.7 (q, J = 2.3 Hz). ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −64.1, −109.9 (tt, J = 8.9, 5.3 Hz). GC/MS (EI): m/z = 162 [M–CF₃]⁺, 212 [M–F]⁺, 231 [M]⁺. Anal. Calcd. for C₁₀H₅F₄NO: C, 51.96; H, 2.18; N, 6.06. Found: C, 51.97; H, 2.31; N, 6.01.

3-(Thiophen-2-yl)-5-(trifluoromethyl)isoxazole (3e).

The compound was purified by column chromatography on silica gel (40 g RediSep column; run length: 74.0 CV; flow rate: 60 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – CHCl₃ (4:1) as eluent. Yield 3.52 g (40%); colorless powder; mp 112–113 °C; sublimation 50–52 °C / 0.4 mmHg. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.89 – 7.82 (m, 2H), 7.27 (dd, J = 5.1, 3.7 Hz, 1H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 158.7, 157.6 (q, J = 41.5 Hz), 131.4, 130.7, 128.8, 128.1, 118.2 (q, J = 271 Hz), 105.9 (d, J = 2.4 Hz). ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −63.8. LC/MS (CI): m/z = 220 [M+H]⁺. Anal. Calcd. for C₈H₄F₃NOS: C, 43.84; H, 1.84; N, 6.39; S, 14.63. Found: C, 43.56; H, 1.65; N, 6.09; S, 14.46.

tert-Butyl ((5-(trifluoromethyl)isoxazol-3-yl)methyl)carbamate (3f).

The compound was purified by column chromatography on silica gel using hexanes – CHCl₃ (4:1) as eluent. Yield 9.52 g (89%); colorless powder; mp 62–64 °C. In the case of using 1f (160 g, 0.767 mol), the reaction was performed with 2 (335 g, 1.92 mol) and NaHCO₃ (128 g, 1.53 mol), which gave 148 g (73%) of 3f. ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (t, J = 5.9 Hz, 1H), 7.24 (s, 1H), 4.27 (d, J = 5.6 Hz, 2H), 1.39 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 163.6, 156.8 (q, J = 41.6 Hz), 155.7, 117.9 (q, J = 270 Hz), 106.2, 78.5, 35.6, 28.1. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −63.9. GC/MS (EI): m/z = 57 [t-Bu]⁺, 150 [M–NHCO₂t-Bu]⁺, 166 [M-CO₂–H₂C=C(CH₃)₂]⁺, 193 [M–Ot-Bu]⁺, 210 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₀H₁₃F₃N₂O₃: C, 45.12; H, 4.92; N, 10.52. Found: C, 45.22; H, 4.69; N, 10.89.

(S)-tert-Butyl (1-(5-(trifluoromethyl)isoxazol-3-yl)ethyl)carbamate (3g).

The compound was purified by column chromatography on silica gel (125 g RediSep column; run length: 14.2 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent. Yield 8.11 g (72%); colorless powder; mp 86–88 °C. [α]²⁰_D = –55.3 (с = 35.7, CHCl₃), 98% ee, t_R = 9.53 min. ¹H NMR (500 MHz, DMSO-d₆) δ 7.52 (d, J = 6.6 Hz, 1H), 7.28 (s, 1H), 4.89 – 4.78 (m, 1H), 1.40 (s, 3H), 1.38 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 167.4, 156.7 (q, J = 41.6 Hz), 154.9, 117.9 (q, J = 270 Hz), 105.4, 78.4, 42.9, 28.0, 19.7. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −63.1. GC/MS (EI): m/z = 57 [t-Bu]⁺, 164 [M–NHCO₂t-Bu]⁺, 180 [M–CO₂–H₂C=C(CH₃)₂]⁺, 207 [M–Ot-Bu]⁺, 224 [M–H₂C=C(CH₃)₂]⁺, 265 [M–CH₃]⁺. Anal. Calcd. for C₁₁H₁₅F₃N₂O₃: C, 47.14; H, 5.40; N, 10.00. Found: C, 47.44; H, 5.57; N, 10.27.

(R)-tert-Butyl (1-(5-(trifluoromethyl)isoxazol-3-yl)ethyl)carbamate (3h).

The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent. Yield 8.56 g (76%); colorless powder; mp 86–88 °C. [α]²⁰_D = +53.2 (с = 35.7, CHCl₃), 96% ee, t_R = 10.4 min. The spectral data are analogous to that of S-isomer 3g. LC/MS (CI): m/z = 165 [M–NHCO₂t-Bu+H]⁺, 181 [M–CO₂–H₂C=C(CH₃)₂]⁺, 208 [M–Ot-Bu+H]⁺, 225 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₁H₁₅F₃N₂O₃: C, 47.14; H, 5.40; N, 10.00. Found: C, 46.85; H, 5.64; N, 10.11.

tert-Butyl (2-(5-(trifluoromethyl)isoxazol-3-yl)propan-2-yl)carbamate (3i).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–9.5 min; H₂O – MeCN; flow rate 30mL / min) or by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent. Yield 10.1 g (85%); colorless powder; mp 79–81 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.46 – 7.33 (m, 1H), 7.30 (s, 1H), 1.53 (s, 6H), 1.32 (s, 9H). ¹H NMR (400 MHz, CDCl₃) δ 6.68 (s, 1H), 4.96 (s, 1H), 1.66 (s, 6H), 1.37 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 169.8, 158.3 (q, J = 42.3 Hz), 154.3, 117.9 (q, J = 270 Hz), 103.8, 80.1, 51.4, 28.2, 27.9. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −64.2. GC/MS (EI): m/z = 57 [t-Bu]⁺, 178 [M–NHCO₂t-Bu]⁺, 194 [M–CO₂–H₂C=C(CH₃)₂]⁺, 221 [M–Ot-Bu]⁺, 238 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₂H₁₇F₃N₂O₃: C, 48.98; H, 5.82; N, 9.52. Found: C, 49.01; H, 6.07; N, 9.52.

tert-Butyl 3-(5-(trifluoromethyl)isoxazol-3-yl)azetidine-1-carboxylate (3j).

The compound was purified by column chromatography on silica gel (80 g RediSep column; run length: 20.7 CV; flow rate: 60 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent. Yield 4.93 g (42% if the reaction was performed in EtOAc) or 9.51 g (81% if the reaction was performed in EtOAc – THF); colorless powder; mp 57–58 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.64 (s, 1H), 4.23 (d, J = 6.8 Hz, 2H), 4.04 – 3.93 (m, 3H), 1.39 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 166.0, 157.5 (d, J = 41.5 Hz), 155.9, 117.0 (q, J = 276 Hz), 106.9, 54.1, 28.5, 25.3. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −63.7. GC/MS (EI): m/z = 57 [t-Bu]⁺, 192 [M–CO₂–H₂C=C(CH₃)₂]⁺, 219 [M–Ot-Bu]⁺, 236 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₂H₁₅F₃N₂O₃: C, 49.32; H, 5.17; N, 9.59. Found: C, 49.62; H, 5.43; N, 9.46.

(S)-tert-Butyl 2-(5-(trifluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (3k).

The compound; purified by column chromatography on silica gel (125 g RediSep column; run length: 18.2 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent; existed as ca. 5:4 mixture of rotamers. Yield 11.6 g (94%); white crystals; mp 55–58 °C; bp 82–84 °C / 1 mmHg. [α]²⁰_D = −60.3 (с = 32.7, CHCl₃), 99% ee, t_R =6.93 min. ¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (d, J = 44.6 Hz, 1H), 5.02 – 4.86 (m, 1H), 3.53 – 3.37 (m, 2H), 2.33 (s, 1H), 1.90 (d, J = 5.2 Hz, 3H), 1.39 (s, 4H), 1.20 (s, 5H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 168.2 and 167.5, 157.0 (q, J = 41.5 Hz), 154.1 and 153.3, 118.4 (q, J = 270 Hz), 106.2 and 105.9, 79.5 and 79.3, 53.4, 46.9 and 46.7, 33.2 and 31.9, 28.5 and 28.2, 24.0 and 23.4. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −63.6 and −63.8. GC/MS (EI): m/z = 57 [t-Bu]⁺, 206 [M–CO₂–H₂C=C(CH₃)₂]⁺, 233 [M–Ot-Bu]⁺, 250 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₃H₁₇F₃N₂O₃: C, 50.98; H, 5.59; N, 9.15. Found: C, 50.67; H, 5.86; N, 8.86.

(R)-tert-Butyl 2-(5-(trifluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (3l).

tert-Butyl 4-(5-(trifluoromethyl)isoxazol-3-yl)piperidine-1-carboxylate (3m).

The compound; purified by column chromatography on silica gel (40 g RediSep column; run length: 47.0 CV; flow rate: 55 mL / min; rack: 16 mm × 150 mm tubes) using gradient CH₂Cl₂ – MeCN or hexanes – t-BuOMe (7:3) as eluent. Yield 7.34 g (57%); colorless powder; mp 78–79 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, J = 2.8 Hz, 1H), 3.98 (d, J = 11.0 Hz, 2H), 3.10 – 2.99 (m, 1H), 2.88 (s, 2H), 1.89 (d, J = 12.8 Hz, 2H), 1.61 – 1.47 (m, 2H), 1.40 (d, J = 3.7 Hz, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 168.1, 157.0 (q, J = 41.4 Hz), 154.3, 118.4 (q, J = 270 Hz), 106.3, 79.1, 43.3, 33.7, 30.3, 28.5. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −63.8. GC/MS (EI): m/z = 57 [t-Bu]⁺, 220 [M–CO₂–H₂C=C(CH₃)₂]⁺, 247 [M–Ot-Bu]⁺, 264 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₄H₁₉F₃N₂O₃: C, 52.50; H, 5.98; N, 8.75. Found: C, 52.16; H, 6.18; N, 8.54.

tert-Butyl (S)-2,2-dimethyl-4-(5-(trifluoromethyl)isoxazol-3-yl)oxazolidine-3-carboxylate (3n).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeOH; flow rate 30mL / min); existed as ca. 5:4 mixture of rotamers. Yield 5.41 g (40%); colorless solid; mp 43–45 °C. [α]²⁰_D = −66.2 (с = 29.7, CHCl₃), 99% ee, t_R = 7.33 min. ¹H NMR (400 MHz, CDCl₃) δ 6.65 (s, 1H), 5.22 – 4.97 (m, 1H), 4.26 (d, J = 13.5 Hz, 2H), 1.69 (s, 1H), 1.57 (s, 5H), 1.48 (s, 4H), 1.33 (s, 5H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 165.2 and 164.6, 158.8 (q, J = 46.2, 44.6 Hz), 152.1 and 151.2, 117.7 (q, J = 270 Hz), 104.4 and 103.5, 94.8 and 94.3, 81.3 and 80.8, 67.9 and 67.1, 53.6 and 53.3, 28.1 and 28.1, 27.0 and 26.1, 24.2 and 23.2. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −64.8 and −64.9. LC/MS (CI): m/z = 223 [M–CH₃–CO₂–H₂C=C(CH₃)₂+H]⁺, 237 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 322 [M–CH₃+H]⁺. Anal. Calcd. for C₁₄H₁₉F₃N₂O₄: C, 50.00; H, 5.69; N, 8.33. Found: C, 50.01; H, 5.43; N, 8.11.

tert-Butyl (R)-2,2-dimethyl-4-(5-(trifluoromethyl)isoxazol-3-yl)oxazolidine-3-carboxylate (3o).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeOH; flow rate 30mL / min); existed as ca. 5:4 mixture of rotamers. Yield 5.68 g (42%); colorless solid; mp 43–45 °C. [α]²⁰_D = +70.8 (с = 29.7, CHCl₃), 100% ee, t_R = 6.45 min. The spectral data are analogous to that of S-isomer 3n. Anal. Calcd. for C₁₄H₁₉F₃N₂O₄: C, 50.00; H, 5.69; N, 8.33. Found: C, 50.22; H, 5.64; N, 8.59.

3,5-Dibromo-5-(trifluoromethyl)-4,5-dihydroisoxazole (5).

Hydroxycarbonimidic dibromide (4, 8.15 g, 40.2 mmol) was dissolved in CH₂Cl₂ (100 mL), and 2-bromo-3,3,3-trifluoro-1-propene (2, 21.1 g, 121 mmol) and NaHCO₃ (11.1 g, 133 mmol) were added to the vigorously stirred homogeneous solution at rt. The resulting mixture was stirred overnight. The completion of the reaction was monitored by ¹H NMR spectroscopy. Then, the resulting mixture was filtered through a plug of silica gel and evaporated in vacuo. The compound was purified by distillation in vacuo. Yield 7.52 g (63%); yellowish oil; bp 57–59 °C / 17 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 4.08 (d, J = 19.3 Hz, 1H), 3.83 (d, J = 19.3 Hz, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 140.3, 120.6 (q, J = 281 Hz), 92.3 (q, J = 37.3 Hz), 56.2. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −78.3. GC/MS (EI): m/z = 216/218 [M–Br]⁺, 295/297/299 [M]⁺. Anal. Calcd. for C₄H₂Br₂F₃NO: C, 16.18; H, 0.68; N, 4.72; Br, 53.83. Found: C, 16.30; H, 0.69; N, 4.77; Br, 53.92.

3-Bromo-5-(trifluoromethyl)isoxazole (6).

Method A: Hydroxycarbonimidic dibromide (4, 8.15 g, 40.2 mmol) was dissolved in EtOAc (100 mL), and 2-bromo-3,3,3-trifluoro-1-propene (2, 21.1 g, 121 mmol) and NaHCO₃ (30.3 g, 363 mmol) were added to the vigorously stirred homogeneous solution at rt. The resulting mixture was stirred overnight. The completion of the reaction was monitored by ¹H NMR spectroscopy. Then, the mixture was filtered through a plug of silica gel and evaporated in vacuo. Method B: The corresponding dihydroisoxazole 5 (7.00 g, 23.6 mmol) was dissolved in EtOAc (100 mL) and NaHCO₃ (5.94 g, 70.8 mol) was added. The resulting mixture was stirred at rt overnight, the solvent was evaporated in vacuo. The compound was purified by distillation in vacuo. Yield 5.29 g (61% from 4 via Method A) or 2.91 g (57% from 5 via Method B); colorless oil; bp 33–35 °C / 94 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 6.78 (s, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.0 (q, J = 43.6 Hz), 140.5, 116.9 (q, J = 271 Hz), 108.9 (q, J = 2.2 Hz). ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −65.3. GC/MS (EI): m/z = 146/148 [M–CF₃]⁺, 215/217 [M]⁺. Anal. Calcd. for C₄HBrF₃NO: C, 22.25; H, 0.47; N, 6.49; Br, 37.00. Found: C, 22.24; H, 0.38; N, 6.49; Br, 36.92.

General procedure for the preparation of carboxylic acid 10 and 29

A solution of the corresponding ester 3a or 28 (0.335 mol, 1 eq) in MeOH (700 mL, 0.5 M solution of ester) was cooled to 0 °C, and pre-cooled absolute solution of NaOH (14.0.g, 0.351 mol, 1.05 eq) in MeOH (61 mL, 5.75 M solution of NaOH) was added dropwise (NOTE: the reaction is highly exothermic). After addition, the mixture was stirred for 1 h at 0 °C to rt, and evaporated in vacuo to dryness. Then, 6 M aq HCl (50 mL) was added in portions, and the reaction mixture was stirred for 10 min at rt (NOTE: MeOH traces led to formation of the corresponding methyl esters via the trans-esterification reaction). Most of solvents was evaporated in vacuo, the residue was diluted with CH₂Cl₂ (500 mL), dried over Na₂SO₄, and evaporated in vacuo.

5-(Trifluoromethyl)isoxazole-3-carboxylic acid (10).

The compound; purified by column chromatography on silica gel (330 g RediSep column; run length: 14.7 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe. Yield 41.2 g (68%); white crystals; mp 109–111 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.59 (br s, 1H), 7.17 (s, 1H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 162.6, 160.9 (q, J = 43.8 Hz), 155.8, 117.2 (q, J = 271 Hz), 106.2 (q, J = 2.2 Hz). ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −64.5. LC/MS: m/z = 136 [M–CO₂–H]⁻. Anal. Calcd. for C₅H₂F₃NO₃: C, 33.17; H, 1.11; N, 7.74. Found: C, 33.30; H, 0.86; N, 7.52.

5-(Difluoromethyl)isoxazole-3-carboxylic acid (29).

Yield 39.9 g (73%); gray powder; mp 121–122 °C. ¹H NMR (400 MHz, D₂O) δ 6.97 (s, 1H), 6.87 (t, J = 52.0 Hz, 1H). ¹³C{¹H} NMR (126 MHz, D₂O) δ 165.0 (t, J = 30.4 Hz), 161.9, 157.4, 107.1 (t, J = 238 Hz), 105.1 (t, J = 2.7 Hz). ¹⁹F{¹H} NMR (376 MHz, D₂O) δ −119.5. LC/MS: m/z = 118 [M–CO₂–H]⁻. Anal. Calcd. for C₅H₃F₂NO₃: C, 36.83; H, 1.85; N, 8.59. Found: C, 37.20; H, 1.95; N, 8.43.

(5-(Trifluoromethyl)isoxazol-3-yl)methanol (11).⁷⁴

A solution of ester 3a (10.0 g, 47.8 mmol) in CH₂Cl₂ (150 mL) was cooled to −5 °C, and DIBAL (17.8 mL, 14.2 g, 0.100 mol) was added dropwise. After addition, the resulting mixture was stirred at 0 °C for 1 h, and 6 M aq HCl (ca. 50 mL) was added in small portions until pH = 4 was reached (NOTE: extensive gas evolution was observed). The precipitate formed was filtered off, the filtrate was evaporated in vacuo. Yield 6.47 g (81%); colorless liquid. 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). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 165.6, 156.8 (q, J = 41.7 Hz), 118.1 (q, J = 270 Hz), 106.2, 54.7. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −64.2. GC/MS (EI): m/z = 167 [M]⁺. Anal. Calcd. for C₅H₄F₃NO₂: C, 35.94; H, 2.41; N, 8.38. Found: C, 35.91; H, 2.49; N, 8.26.

3-(Chloromethyl)-5-(trifluoromethyl)isoxazole (12).

Method A: The halogenoxime 1p (146 g; 1.14 mol) was dissolved in EtOAc (3000 mL), and 2-bromo-3,3,3-trifluoro-1-propene (2, 600 g; 3.43 mol) and NaHCO₃ (316 g, 3.76 mol) were added to the vigorously stirred homogeneous solution at rt. The resulting mixture was stirred overnight. The completion of the reaction was monitored by ¹H NMR spectroscopy. The, the reaction mixture was filtered through a plug of silica gel and evaporated in vacuo. Method B: A solution of alcohol 11 (4.60 g, 27.5 mmol) in CH₂Cl₂ was cooled to −5 °C, and a drop of DMF (5.00 μL, 4.74 mg) was added. Then, SOCl₂ (2.29 mL, 3.76 g, 31.6 mmol) was added dropwise. The completion of reaction was monitored by ¹H NMR (ca. 10 h). Then, the reaction mixture was evaporated in vacuo. The compound was purified by distillation in vacuo. Yield 97.3 g (46% from 1p via Method A) or 3.28 g (64% from 11 via Method B); colorless liquid; bp 39–41 C / 60 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 6.83 (s, 1H), 4.63 (s, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 161.4, 159.6 (q, J = 42.9 Hz), 117.7 (q, J = 270 Hz), 105.2, 34.8. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −65.4. GC/MS (EI): m/z = 185/187 [M]⁺. Anal. Calcd. for C₅H₃ClF₃NO: C, 32.37; H, 1.63; N, 7.55; Cl, 19.11. Found: C, 32.35; H, 1.42; N, 7.70; Cl, 18.96.

General procedure for the preparation of amines 13f–m·HCl, 13i, 20i–l·HCl and 21g–l·HCl.

The corresponding N-Boc-amine 3f–m, 18i–l or 19g–l (4.80 mmol, 1 eq) was dissolved in MeOH (9 mL, 0.53 M solution of 3, 18 or 19) and the solution was cooled to −1 °C. Acetyl chloride (412 μL, 455 mg, 5.80 mmol, 1.2 eq) was added dropwise at −1 °C. The completion of the reaction was monitored by NMR. Then, most of MeOH was evaporated in vacuo (NOTE: if necessary, the resulting solid was recrystallized from MeCN (ca. 1 mL) unless other is specified).

(5-(Trifluoromethyl)isoxazol-3-yl)methanamine hydrochloride (13f·HCl).

Yield 924 mg (95%); colorless powder; mp 95–97 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (br s, 3H), 7.63 (s, 1H), 4.28 (s, 2H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 159.6, 156.9 (q, J = 42.0 Hz), 117.7 (q, J = 270 Hz), 107.4, 34.1. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −64.2. LC/MS (CI): m/z = 167 [M–HCl+H]⁺. Anal. Calcd. for C₅H₆ClF₃N₂O: C, 29.65; H, 2.99; N, 13.83; Cl, 17.50. Found: C, 29.43; H, 2.99; N, 13.76; Cl, 17.39.

(S)-1-(5-(Trifluoromethyl)isoxazol-3-yl)ethan-1-amine hydrochloride (13g·HCl).

Yield 936 mg (93%); beige powder; mp 93–96 °C. [α]²⁰_D = −4.02 (с = 46.2, MeOH). ¹H NMR (400 MHz, DMSO-d₆): δ 9.11 (br.s, 3H), 7.79 (s, 1H), 4.71 (dd, J = 13.2, 6.5 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 163.7, 157.2 (q, J = 42.4 Hz), 117.7 (q, J = 270 Hz), 106.5, 42.9, 17.9. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ –63.8. LC/MS (CI): m/z = 181 [M–HCl+H]⁺. Anal. Calcd. for C₆H₈ClF₃N₂O: C, 33.27; H, 3.72; N, 12.93; Cl, 16.37. Found: C, 32.95; H, 3.98; N, 12.59; Cl, 16.60.

(R)-1-(5-(Trifluoromethyl)isoxazol-3-yl)ethan-1-amine hydrochloride (13h·HCl).

Yield 956 mg (92%); beige powder; mp 94–96 °C. [α]²⁰_D = +4.61 (с = 46.2, MeOH). The spectral data are analogous to that of S-isomer 13g·HCl. LC/MS (CI): m/z = 181 [M–HCl+H]⁺. Anal. Calcd. for C₆H₈ClF₃N₂O: C, 33.27; H, 3.72; N, 12.93; Cl, 16.37. Found: C, 33.04; H, 4.10; N, 12.80; Cl, 16.32.

2-(5-(Trifluoromethyl)isoxazol-3-yl)propan-2-amine (13i).

The resulting 13i·HCl (864 mg, 78% yield) was dissolved in MeOH (5 mL), and NaOH (196 mg, 4.90 mmol) in MeOH (1 mL) was added at rt. The resulting mixture was stirred for 2 h, the filtered and evaporated in vacuo. The compound was purified by distillation in vacuo. Yield 475 mg (51%); beige powder; mp 146–149 °C (as a hydrochloride); bp 54–56 °C / 9 mmHg (as a base). ¹H NMR (400 MHz, DMSO-d₆): δ 7.51 (s, 1H), 2.24 (s, 2H), 1.40 (s, 6H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 173.2, 156.3 (q, J = 41.4 Hz), 118.0 (q, J = 270 Hz), 105.3, 49.4, 29.5. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −64.4. LC/MS (CI): m/z = 195 [M+H]⁺. Anal. Calcd. for C₇H₉F₃N₂O: C, 43.30; H, 4.67; N, 14.43. Found: C, 43.26; H, 4.84; N, 14.52

3-(Azetidin-3-yl)-5-(trifluoromethyl)isoxazole hydrochloride (13j·HCl).

Yield 1.04 g (95%); beige powder; mp 106–109 °C ¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (br. s, 2H), 7.79 (s, 1H), 4.34 – 4.26 (m, 5H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 164.5, 157.4 (q, J = 41.9 Hz), 118.3 (q, J = 270 Hz), 107.2, 49.4, 28.2. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −63.9. LC/MS (CI): m/z = 193 [M–HCl+H]⁺. Anal. Calcd. for C₇H₈ClF₃N₂O: C, 36.78; H, 3.53; N, 12.25; Cl, 15.51. Found: C, 36.94; H, 3.61; N, 12.28; Cl, 15.15.

(S)-3-(Pyrrolidin-2-yl)-5-(trifluoromethyl)isoxazole hydrochloride (13k·HCl).

Yield 1.13 g (97%); beige powder; mp 96–98 °C. [α]²⁰_D = −16.2 (с = 41.2, MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (d, J = 281 Hz, 2H), 7.80 (s, 1H), 4.88 (t, J = 7.5 Hz, 1H), 3.40 – 3.26 (m, 2H), 2.47 – 2.39 (m, 1H), 2.24 – 1.95 (m, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 161.7, 157.6 (q, J = 42.0 Hz), 118.1 (q, J = 270 Hz), 107.6 (d, J = 2.1 Hz), 53.9, 45.1, 29.6, 23.3. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ –63.9. LC/MS (CI): m/z = 207 [M–HCl+H]⁺. Anal. Calcd. for C₈H₁₀ClF₃N₂O: C, 39.60; H, 4.15; N, 11.55; Cl, 14.61. Found: C, 39.52; H, 3.86; N, 11.36; Cl, 14.84.

(R)-3-(Pyrrolidin-2-yl)-5-(trifluoromethyl)isoxazole hydrochloride (13l·HCl).

Yield 1.14 g (98%); beige powder; mp 97–99 °C. [α]²⁰_D = +16.7 (с = 41.2, MeOH). The spectral data are analogous to that of S-isomer 13k·HCl. LC/MS (CI): m/z = 207 [M–HCl+H]⁺. Anal. Calcd. for C₈H₁₀ClF₃N₂O: C, 39.60; H, 4.15; N, 11.55; Cl, 14.61. Found: C, 39.92; H, 4.52; N, 11.27; Cl, 14.42.

3-(Piperidin-4-yl)-5-(trifluoromethyl)isoxazole hydrochloride (13m·HCl).

Yield 1.14 g (92%); colorless powder; mp 153–155 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 2H), 7.49 (s, 1H), 3.29 (s, 2H), 3.19 (t, J = 11.4 Hz, 1H), 3.01 (t, J = 12.3 Hz, 2H), 2.14 (d, J = 13.3 Hz, 2H), 1.87 (qd, J = 15.1, 3.8 Hz, 2H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 167.2, 157.2 (q, J = 41.5 Hz), 118.4 (q, J = 270 Hz), 106.5 (d, J = 2.0 Hz), 42.7, 31.5, 26.8. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −63.8. LC/MS (CI): m/z = 221 [M–HCl+H]⁺. Anal. Calcd. for C₉H₁₂ClF₃N₂O: C, 42.12; H, 4.71; N, 10.92; Cl, 13.81. Found: C, 41.74; H, 4.37; N, 10.59; Cl, 13.49.

2-(5-(Fluoromethyl)isoxazol-3-yl)propan-2-amine hydrochloride (20i·HCl).

Yield 859 mg (92%); yellow powder, mp 154–155 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (br.s, 3H), 7.08 (d, J = 3.2 Hz, 1H), 5.61 (d, J = 47.0 Hz, 2H), 1.65 (s, J = 37.0 Hz, 6H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 167.2 (d, J = 18.8 Hz), 166.2 (d, J = 2.6 Hz), 103.6 (d, J = 4.5 Hz), 74.0 (d, J = 163 Hz), 51.7, 25.7. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −215.0 (td, J = 47.0, 3.3 Hz). LC/MS (CI): m/z = 159 [M–HCl+H]⁺. Anal. Calcd. for C₇H₁₂ClFN₂O: C, 43.20; H, 6.21; N, 14.39; Cl, 18.21. Found: C, 42.85; H, 5.85; N, 14.54; Cl, 18.54.

(S)-5-(Fluoromethyl)-3-(pyrrolidin-2-yl)isoxazole hydrochloride (20k·HCl).

Yield 768 mg (94%); yellow powder; mp 166–167 °C. [α]²⁰_D = −21.2 (с = 48.4, MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (d, J = 353 Hz, 2H), 7.05 (d, J = 3.2 Hz, 1H), 5.63 (d, J = 47.0 Hz, 2H), 4.82 – 4.69 (m, 1H), 3.34 – 3.24 (m, 2H), 2.40 (dt, J = 14.4, 5.8 Hz, 1H), 2.09 – 2.02 (m, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 167.6 (d, J = 18.7 Hz), 160.7 (d, J = 2.7 Hz), 105.4 (d, J = 4.5 Hz), 74.4 (d, J = 164 Hz), 54.4, 45.0, 29.7, 23.2. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −215.0 (t, J = 47.0 Hz). LC/MS (CI): m/z = 171 [M–HCl+H]⁺. Anal. Calcd. for C₈H₁₂ClFN₂O: C, 46.50; H, 5.85; N, 13.56; Cl, 17.15. Found: C, 46.20; H, 6.18; N, 13.54; Cl, 17.20.

(R)-5-(Fluoromethyl)-3-(pyrrolidin-2-yl)isoxazole hydrochloride (20l·HCl).

Yield 760 mg (95%); yellow powder; mp 166–167 °C. [α]²⁰_D = +24.3 (с = 48.4, MeOH). The spectral data are analogous to that of S-isomer 20k·HCl. LC/MS (CI): m/z = 171 [M–HCl+H]⁺. Anal. Calcd. for C₈H₁₂ClFN₂O: C, 46.50; H, 5.85; N, 13.56; Cl, 17.15. Found: C, 46.54; H, 5.68; N, 13.47; Cl, 17.22.

(S)-1-(5-(Difluoromethyl)isoxazol-3-yl)ethanamine hydrochloride (21g·HCl).

Yield 915 mg (96%); beige powder; mp 99–101 °C. [α]²⁰_D = −7.59 (с = 50.4, MeOH). ¹H NMR (400 MHz, DMSO-d₆): δ 9.01 (s, 3H), 7.44 (t, J = 52.5 Hz, 1H), 7.33 (s, 1H), 4.66 (dd, J = 13.3, 6.5 Hz, 1H), 1.58 (d, J = 6.7 Hz, 3H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 163.8 (t, J = 28.7 Hz), 163.5, 108.0 (t, J = 237 Hz), 105.0, 43.5, 18.6. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ –118.7 (d, J = 52.5 Hz). LC/MS (CI): m/z = 163 [M–HCl+H]⁺. Anal. Calcd. for C₆H₉ClF₂N₂O: C, 36.29; H, 4.57; N, 14.11; Cl, 17.85. Found: C, 36.42; H, 4.65; N, 13.97; Cl, 17.89.

(R)-1-(5-(Difluoromethyl)isoxazol-3-yl)ethanamine hydrochloride (21h·HCl).

Yield 906 mg (95%); beige powder; mp 99–101 °C. [α]²⁰_D = +8.23 (с = 50.4, MeOH). The spectral data are analogous to that of S-isomer 21g·HCl. LC/MS (CI): m/z = 163 [M–HCl+H]⁺. Anal. Calcd. for C₆H₉ClF₂N₂O: C, 36.29; H, 4.57; N, 14.11; Cl, 17.85. Found: C, 36.04; H, 4.27; N, 14.27; Cl, 18.20.

2-(5-(Difluoromethyl)isoxazol-3-yl)propan-2-amine hydrochloride (21i·HCl).

Yield 949 mg (93%); colorless powder; mp 107–109 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (br.s, 3H), 7.43 (t, J = 52.6 Hz, 1H), 7.40 (s, 1H), 1.67 (s, 6H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.3, 163.5 (t, J = 29.0 Hz), 107.6 (t, J = 237 Hz), 103.7, 51.8, 25.6. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −118.8. LC/MS (CI): m/z = 177 [M–HCl+H]⁺. Anal. Calcd. for C₇H₁₁ClF₂N₂O: C, 39.54; H, 5.21; N, 13.18; Cl, 16.67. Found: C, 39.25; H, 4.92; N, 13.58; Cl, 16.52.

3-(Azetidin-3-yl)-5-(difluoromethyl)isoxazole hydrochloride (21j·HCl).

Yield 920 mg (91%); orange powder; mp 83–86 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 2H), 7.42 (t, J = 52.6 Hz, 1H), 7.33 (s, 1H), 4.43 – 4.19 (m, 3H), 4.14 – 4.03 (m, 2H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 163.4, 163.3 (t, J = 28.8 Hz), 107.7 (t, J = 236 Hz), 104.7 (t, J = 3.4 Hz), 49.2, 27.8. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −118.6 (d, J = 52.6 Hz). LC/MS (CI): m/z = 175 [M–HCl+H]⁺. Anal. Calcd. for C₇H₉ClF₂N₂O: C, 39.92; H, 4.31; N, 13.30; Cl, 16.83. Found: C, 40.25; H, 4.12; N, 13.60; Cl, 16.55.

(S)-5-(Difluoromethyl)-3-(pyrrolidin-2-yl)isoxazole hydrochloride (21k·HCl).

Yield 1.04 g (96%); beige powder; mp 133–135 °C. [α]²⁰_D = −18.6 (с = 44.5, MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (d, J = 298 Hz, 2H), 7.44 (t, J = 52.5 Hz, 1H), 7.32 (s, 1H), 4.91 – 4.77 (m, 1H), 2.49 – 2.30 (m, 2H), 2.19 – 1.97 (m, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 163.9 (t, J = 28.9 Hz), 161.1, 108.0 (t, J = 237 Hz), 105.6 (d, J = 3.2 Hz), 54.1, 45.1, 29.6, 23.3. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −118.7 (dd, J = 52.4, 1.2 Hz). LC/MS (CI): m/z = 189 [M–HCl+H]⁺. Anal. Calcd. for C₈H₁₁ClF₂N₂O: C, 42.77; H, 4.94; N, 12.47; Cl, 15.78. Found: C, 42.86; H, 5.25; N, 12.82; Cl, 15.95.

(R)-5-(Difluoromethyl)-3-(pyrrolidin-2-yl)isoxazole hydrochloride (21l·HCl).

Yield 1.06 g (98%); beige powder; mp 133–135 °C. [α]²⁰_D = +18.9 (с = 44.5, MeOH). The spectral data are analogous to that of S-isomer 21k·HCl. LC/MS (CI): m/z = 189 [M–HCl+H]⁺. Anal. Calcd. for C₈H₁₁ClF₂N₂O: C, 42.77; H, 4.94; N, 12.47; Cl, 15.78. Found: C, 42.71; H, 5.27; N, 12.13; Cl, 15.65.

General procedure for the preparation of alcohols 16f–m, 23, and 24.

The corresponding halogenoxime 1a, 1f–m, or 4 (40.2 mmol, 1 eq) was dissolved in EtOAc (100 mL, 0.4 M solution of 1 or 4). Propargyl alcohol (2.93 g, 52.3 mmol, 1.3 eq) and NaHCO₃ (5.74 g, 68.3 mmol, 1.7 eq) were added to the vigorously stirred homogeneous solution at rt. The resulting mixture was stirred overnight; the completion of reaction was monitored by ¹H NMR spectroscopy. Next, the solution was filtered through a plug of silica gel and evaporated in vacuo.

tert-Butyl ((5-(hydroxymethyl)isoxazol-3-yl)methyl)carbamate (16f).

The compound; purified by column chromatography on silica gel (24 g RediSep column; run length: 33.5 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. Yield 8.63 g (94%); yellowish powder; mp 58–60 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.50 – 7.33 (m, 1H), 6.21 (s, 1H), 5.61 (t, J = 6.4 Hz, 1H), 4.52 (d, J = 3.3 Hz, 2H), 4.12 (d, J = 4.4 Hz, 2H), 1.38 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 173.0, 162.4, 155.8, 100.8, 78.3, 54.8, 35.6, 28.2. GC/MS (EI): m/z = 57 [t-Bu]⁺, 112 [M–NHCO₂t-Bu]⁺, 128 [M–CO₂–H₂C=C(CH₃)₂]⁺, 155 [M–Ot-Bu]⁺, 172 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₀H₁₆N₂O₄: C, 52.62; H, 7.07; N, 12.27. Found: C, 53.01; H, 6.82; N, 12.50.

(S)-tert-Butyl (1-(5-(hydroxymethyl)isoxazol-3-yl)ethyl)carbamate (16g).

The compound; purified by column chromatography on silica gel (220 g RediSep column; run length: 26.0 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. Yield 9.35 g (96%); colorless powder; mp 83–85 °C. [α]²⁰_D = −72.3 (с = 41.3, CHCl₃), 96% ee, t_R = 12.21 min. ¹H NMR (400 MHz, DMSO-d₆): δ 7.41 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 5.60 (t, J = 6.0 Hz, 1H), 4.78 – 4.67 (m, 1H), 4.52 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H), 1.34 (d, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 172.7, 166.3, 154.9, 99.8, 78.1, 54.8, 42.8, 28.2, 20.2. GC/MS (EI): m/z = 57 [t-Bu]⁺, 126 [M–NHCO₂t-Bu]⁺, 142 [M–CO₂–H₂C=C(CH₃)₂]⁺, 169 [M–Ot-Bu]⁺, 186 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₁H₁₈N₂O₄: C, 54.53; H, 7.49; N, 11.56. Found: C, 54.51; H, 7.42; N, 11.82.

(R)-tert-Butyl (1-(5-(hydroxymethyl)isoxazol-3-yl)ethyl)carbamate (16h).

The compound; purified by column chromatography on silica gel (220 g RediSep column; run length: 26.0 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. Yield 9.25 g (95%); colorless powder; mp 82–84 °C. [α]²⁰_D = +66.1 (с = 41.3, CHCl₃), 93% ee, t_R = 8.29 min. The spectral data are analogous to that of S-isomer 16g. GC/MS (EI): m/z = 57 [t-Bu]⁺, 126 [M–NHCO₂t-Bu]⁺, 142 [M–CO₂–H₂C=C(CH₃)₂]⁺, 169 [M–Ot-Bu]⁺, 186 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₁H₁₈N₂O₄: C, 54.53; H, 7.49; N, 11.56. Found: C, 54.79; H, 7.21; N, 11.44.

tert-Butyl (2-(5-(hydroxymethyl)isoxazol-3-yl)propan-2-yl)carbamate (16i).

Yield 9.79 g (91%); colorless powder; mp 84–86 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (s, 1H), 6.18 (s, 1H), 5.59 (t, J = 6.0 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 1.48 (s, 6H), 1.34 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ 172.5, 170.2, 154.7, 100.1, 78.3, 55.2, 51.1, 28.6, 28.2. GC/MS (EI): m/z = 57 [t-Bu]⁺, 140 [M–NHCO₂t-Bu]⁺, 200 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₂H₂₀N₂O₄: C, 56.24; H, 7.87; N, 10.93. Found: C, 55.98; H, 8.23; N, 10.58.

tert-Butyl 3-(5-(hydroxymethyl)isoxazol-3-yl)azetidine-1-carboxylate (16j).

The compound; purified by column chromatography on silica gel (40 g RediSep column; run length: 27.6 CV; flow rate: 40 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. Yield 8.59 g (84%); yellowish oil. ¹H NMR (400 MHz, DMSO-d₆): δ 6.45 (s, 1H), 5.61 (d, J = 5.7 Hz, 1H), 4.54 (d, J = 5.4 Hz, 2H), 4.21 (s, 2H), 3.87 (s, 3H), 1.38 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ 174.0, 164.6, 156.0, 100.8, 79.3, 55.3, 54.4, 28.5, 25.5. GC/MS (EI): m/z = 57 [t-Bu]⁺, 154 [M–CO₂–H₂C=C(CH₃)₂]⁺, 181 [M–Ot-Bu]⁺, 197 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₂H₁₈N₂O₄: C, 56.68; H, 7.14; N, 11.02. Found: C, 56.66; H, 7.49; N, 10.86.

(S)-tert-Butyl 2-(5-(hydroxymethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (16k).

The compound existed as ca. 5:4 mixture of rotamers .Yield 9.71 g (90%); colorless oil. [α]²⁰_D = −80.2 (с = 37.3, CHCl₃), 98% ee, t_R = 18.8 min. ¹H NMR (400 MHz, DMSO-d₆) δ 6.24 (s, 1H), 5.60 (t, J = 6.0 Hz, 1H), 4.89 – 4.81 (m, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.46 – 3.37 (m, 2H), 2.25 – 2.17 (m, 1H), 1.91 – 1.84 (m, 3H), 1.40 (s, 4H) and 1.25 (s, 5H). ¹³C{¹H} NMR (126 MHz, DMSO) δ 172.8, 166.1 and 165.7, 153.6 and 153.2, 100.3 and 99.7, 78.8 and 78.7, 54.8, 53.3 and 53.2, 46.4 and 46.1, 32.6 and 31.4, 28.2 and 28.0, 23.7 and 23.0. GC/MS (EI): m/z = 57 [t-Bu]⁺, [M–CO₂–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₃H₂₀N₂O₄: C, 58.19; H, 7.51; N, 10.44. Found: C, 58.36; H, 7.86; N, 10.59.

(R)-tert-Butyl 2-(5-(hydroxymethyl)isoxazol-3-yl)pyrrolidine-1-carbo-xylate (16l).

The compound existed as ca. 5:4 mixture of rotamers. Yield 9.92 g (92%); colorless oil. [α]²⁰_D = +65.9 (с = 37.3, CHCl₃), 98% ee, t_R = 11.5 min. The spectral data are analogous to that of S-isomer 16k. GC/MS (EI): m/z = 57 [t-Bu]⁺, [M–CO₂–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₃H₂₀N₂O₄: C, 58.19; H, 7.51; N, 10.44. Found: C, 58.34; H, 7.56; N, 10.65.

tert-Butyl 4-(5-(hydroxymethyl)isoxazol-3-yl)piperidine-1-carboxy-late (16m).

The compound; purified by column chromatography on silica gel (80 g RediSep column; run length: 24.2 CV; flow rate: 60 mL / min; rack: 16 mm × 150 mm tubes) using gradient CHCl₃ – t-BuOMe as eluent. Yield 7.15 g (85%); colorless powder; mp 57–59 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 6.35 (s, 1H), 5.58 (t, J = 6.0 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 3.97 (d, J = 12.0 Hz, 2H), 2.96 – 2.75 (m, 3H), 1.85 (d, J = 12.5 Hz, 2H), 1.57 – 1.44 (m, 2H), 1.41 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 172.7, 166.5, 154.0, 100.2, 78.7, 54.9, 43.3, 33.3, 30.4, 28.1. LC/MS (CI): m/z = 183 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 227 [M– H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₄H₂₂N₂O₄: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.24; H, 8.20; N, 10.04.

Ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (23).

The compound was purified by column chromatography on silica gel using hexanes – EtOAc (1:1) as eluent. Yield 3.92 g (57%); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 6.63 (s, 1H), 4.79 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.96 (s, 1H), 1.37 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 173.5, 159.9, 156.3, 102.5, 62.3, 56.3, 14.1. LC/MS (CI): m/z = 172 [M+H]⁺. Anal. Calcd. for C₇H₉NO₄: C, 49.12; H, 5.30; N, 8.18. Found: C, 49.00; H, 5.60; N, 7.99.

(3-Bromoisoxazol-5-yl)methanol (24).

The compound was purified by distillation in vacuo. Yield 4.87 g (68%); colorless liquid; bp 53–55 °C / 1 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 6.33 (s, 1H), 4.73 (s, 2H), 2.87 (s, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 173.4, 140.5, 105.6, 56.3. GC/MS (EI): m/z = 177/179 [M]⁺. Anal. Calcd. for C₄H₄BrNO₂: C, 26.99; H, 2.27; N, 7.87; Br, 44.89. Found: C, 26.73; H, 2.01; N, 8.02; Br, 44.85.

General procedure for the preparation of aldehydes 17g–m, and 25.

Method A: Pyridinium chlorochromate (12.1 g, 55.9 mmol, 1.5 eq), SiO₂ (ca. 20 g) were suspended in CH₂Cl₂ (100 mL, 0.56 M solution of PCC). The resulting mechanically stirred solution was cooled to –10 °C and the corresponding alcohol 16g–m or 23 (37.3 mmol, 1 eq) in CH₂Cl₂ (100 mL, 0.37 M solution of 16 or 23) was added dropwise at −10 °C (NOTE: the temperature should not exceed −5 °C). The resulting mixture was stirred overnight at rt, then filtered through a plug of silica gel, and the filtrate was evaporated in vacuo.

Method B: The corresponding alcohol 16g–m or 23 (37.3 mmol, 1 eq) was dissolved in CH₂Cl₂ (100 mL, 0.37 M solution of 16 or 23), then Et₃N (16.4 mL, 11.9 g, 0.117 mol, 3.15 eq) and DMSO (HPLC grade, 13.2 mL, 14.6 g, 0.187 mol, 5 eq) were added under argon atmosphere. The resulting solution was cooled to 0 °C, and Py·SO₃ (17.8 g, 0.112 mol, 3 eq) was added (NOTE: in the case of 23, 6-fold excess Py·SO₃ (35.6 g, 0.224 mol, 6 eq) was used). The resulting mixture was warmed up to rt, stirred for 1 h; the completion of the reaction was monitored by ¹H NMR. The mixture was poured onto ice (125 g), organic phase was separated and most of CH₂Cl₂ evaporated in vacuo. The aqueous phase was extracted with EtOAc (3×100 mL), combined extracts were added to the residue obtained after CH₂Cl₂ evaporation. The resulting solution was washed with saturated aq NaHSO₃ (3×100 mL), brine (3×75 mL), dried over Na₂SO₄, and evaporated in vacuo.

(S)-tert-Butyl (1-(5-formylisoxazol-3-yl)ethyl)carbamate (17g).

The compound was purified by column chromatography on silica gel (330 g RediSep column; run length: 20.0 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent. Yield 5.91 g (66% from 22j via method A) or 6.98 g (78% via method B); colorless powder; mp 77–79 °C. [α]²⁰_D = −61.6 (с = 41.6, CHCl₃). ¹H NMR (500 MHz, DMSO-d₆) δ 9.89 (s, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.26 (s, 1H), 4.83 (dt, J = 14.9, 7.5 Hz, 1H), 1.40 (s, 3H), 1.39 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 179.9, 167.6, 165.3, 155.0, 109.8, 78.4, 43.0, 28.2, 20.0. GC/MS (EI): m/z = 57 [t-Bu]⁺, 124 [M–NHCO₂t-Bu]⁺, 167 [M–Ot-Bu]⁺, 184 [M–H₂C=C(CH₃)₂]⁺, 225 [M–CH₃]⁺. Anal. Calcd. for C₁₁H₁₆N₂O₄: C, 54.99; H, 6.71; N, 11.66. Found: C, 54.71; H, 7.09; N, 12.04.

(R)-tert-Butyl (1-(5-formylisoxazol-3-yl)ethyl)carbamate (17h).

The compound was purified by column chromatography on silica gel gel (330 g RediSep column; run length: 20.0 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent. Yield 6.00 g (67% via method A) or 6.81 g (76% via method B); colorless powder; mp 77–79 °C. [α]²⁰_D = +58.7 (с = 41.6, CHCl₃). The spectral data are analogous to that of S-isomer 17g. GC/MS (EI): m/z = 57 [t-Bu]⁺, 124 [M–NHCO₂t-Bu]⁺, 167 [M–Ot-Bu]⁺, 184 [M–H₂C=C(CH₃)₂]⁺, 225 [M–CH₃]⁺. Anal. Calcd. for C₁₁H₁₆N₂O₄: C, 54.99; H, 6.71; N, 11.66. Found: C, 55.07; H, 6.34; N, 11.84.

tert-Butyl (2-(5-formylisoxazol-3-yl)propan-2-yl)carbamate (17i).

Yield 7.59 g (80% via method A) or 7.87 g (83% via method B); gray powder; mp 85–86 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.89 (s, 1H), 7.38 (br.s, 1H), 7.25 (s, 1H), 1.53 (s, 6H), 1.33 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 179.9, 171.1, 164.9, 154.4, 110.0, 78.2, 50.7, 28.2, 27.6. GC/MS (EI): m/z = 57 [t-Bu]⁺, 138 [M–NHCO₂t-Bu]⁺, 154 [M–CO₂–H₂C=C(CH₃)₂]⁺, 181 [M–Ot-Bu]⁺, 198 [M–H₂C=C(CH₃)₂]⁺, 239 [M–CH₃]⁺. Anal. Calcd. for C₁₂H₁₈N₂O₄: C, 56.68; H, 7.14; N, 11.02. Found: C, 56.65; H, 7.49; N, 11.32.

tert-Butyl 3-(5-formylisoxazol-3-yl)azetidine-1-carboxylate (17j).

Yield 4.05 g (43% via method A) or 1.41 g (14% via method B); yellowish oil. ¹H NMR (400 MHz, DMSO-d₆): δ 9.91 (s, J = 26.1 Hz, 1H), 7.55 (s, 1H), 4.26 (t, J = 7.4 Hz, 2H), 4.06 – 3.91 (m, 3H), 1.40 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ 180.1, 166.2, 165.9, 156.0, 110.7, 79.3, 54.5, 28.5, 25.5. GC/MS (EI): m/z = 57 [t-Bu]⁺, 152 [M–CO₂–H₂C=C(CH₃)₂]⁺, 179 [M–Ot-Bu]⁺, 196 [M–H₂C=C(CH₃)₂]⁺, 237 [M–CH₃]⁺. Anal. Calcd. for C₁₂H₁₆N₂O₄: C, 57.13; H, 6.39; N, 11.10. Found: C, 57.31; H, 6.60; N, 11.27.

(S)-tert-Butyl 2-(5-formylisoxazol-3-yl)pyrrolidine-1-carboxylate (17k).

The compound was purified by column chromatography on silica gel (330 g RediSep column; run length: 20.0 CV; flow rate: 125 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent; existed as ca. 5:4 mixture of rotamers. Yield 7.75 g (78% via method A) or 8.05 g (81% via method B); colorless oil. [α]²⁰_D = −78.7 (с = 37.6, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 7.33 (d, J = 27.3 Hz, 1H), 4.96 (d, J = 11.5 Hz, 1H), 3.59 – 3.43 (m, 1H), 3.43 – 3.35 (m, 1H), 2.37 – 2.20 (m, 1H), 2.00 – 1.78 (m, 3H), 1.40 (s, 4H) and 1.23 (s, 5H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 179.6, 167.6 and 167.0, 165.2, 153.7 and 153.0, 110.1 and 109.7, 79.0 and 78.9, 53.2, 46.5 and 46.2, 32.7 and 31.4, 28.5 and 27.9, 23.7 and 23.0. GC/MS (EI): m/z = 57 [t-Bu]⁺, 166 [M–CO₂–H₂C=C(CH₃)₂]⁺, 193 [M–Ot-Bu]⁺. Anal. Calcd. for C₁₃H₁₈N₂O₄: C, 58.63; H, 6.81; N, 10.52. Found: C, 58.88; H, 6.68; N, 10.20.

(R)-tert-Butyl 2-(5-formylisoxazol-3-yl)pyrrolidine-1-carboxylate (17l).

The compound existed as ca. 5:4 mixture of rotamers. The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (3:2) as eluent. Yield 6.33 g (75% via method A) or 6.75 g (80% via method B); colorless oil. [α]²⁰_D = +74.9 (с = 37.6, CHCl₃). The spectral data are analogous to that of S-isomer 17k. GC/MS (EI): m/z = 57 [t-Bu]⁺, 166 [M–CO₂–H₂C=C(CH₃)₂]⁺, 193 [M–Ot-Bu]⁺. Anal. Calcd. for C₁₃H₁₈N₂O₄: C, 58.63; H, 6.81; N, 10.52. Found: C, 58.94; H, 7.21; N, 10.40.

tert-Butyl 4-(5-formylisoxazol-3-yl)piperidine-1-carboxylate (17m).

Yield 5.75 g (55% via method A) or 7.21 g (69% via method B); colorless powder; mp 55–57 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 7.44 (s, 1H), 3.99 (d, J = 11.9 Hz, 2H), 3.08 – 3.01 (m, 1H), 2.89 (s, 2H), 1.91 (d, J = 11.5 Hz, 2H), 1.54 (qd, J = 12.3, 4.1 Hz, 2H), 1.41 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ 180.1, 168.1, 165.6, 154.3, 110.3, 79.1, 43.7, 33.7, 30.6, 28.5. GC/MS (EI): m/z = 57 [t-Bu]⁺, 180 [M–CO₂–H₂C=C(CH₃)₂]⁺, 207 [M–Ot-Bu]⁺, 224 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₄H₂₀N₂O₄: C, 59.99; H, 7.19; N, 9.99. Found: C, 59.95; H, 7.42; N, 9.92.

Ethyl 5-formylisoxazole-3-carboxylate (25).

Yield 4.92 g (78% via method A) or 820 mg (13% via method B); pinkish solid; mp 24–27 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 7.32 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 177.6, 166.8, 158.7, 157.1, 108.9, 62.8, 14.1. GC/MS (EI): m/z = 169 [M]⁺. Anal. Calcd. for C₇H₇NO₄: C, 49.71; H, 4.17; N, 8.28. Found: C, 49.93; H, 3.86; N, 8.55.

General procedure for the preparation of fluoromethyl oxazoles 18a, 18f–l.

Method A: The corresponding alcohol 16f–l (18.6 mmol, 1 eq) was dissolved in CH₂Cl₂ (50 mL, 0.37 M solution of 16f–l) and the solution was cooled to –15 °C under argon atmosphere. Morpholinosulfur trifluoride (3.49 g, 19.9 mmol, 1.07 eq) in CH₂Cl₂ (15 mL) was added dropwise (NOTE: the temperature shouldn’t exceed –10 °C.). Reaction mixture was stirred at −10 °C for 1.5 h. Then, the reaction mixture was poured into brine – ice (2 mL – 2 g, 1/1, v/m) and NaHCO₃ was added to ca. pH = 7–8. Most of CH₂Cl₂ was evaporated in vacuo and water phase was extracted with EtOAc (3×15 mL). Combined organic phases were washed with brine (2×10 mL) dried over Na₂SO₄ and evaporated in vacuo.

Method B: KHF₂ (176 mg, 22.5 mmol, 1.5 eq) and 18-crown-6 (19.6 mg, 75.0 μmol, 0.005 eq) were added to a solution of the corresponding bromide 22a, 22f–l, 22j or 22m (15.0 mmol, 1 eq) in MeCN (10 mL, 1.5 M solution of bromide 22) at rt. The completion of reaction was monitored by ¹H NMR (ca. 10 h). Then, the reaction mixture was evaporated in vacuo, the residue was dissolved in EtOAc (10 mL), the precipitate was filtered off, washed with EtOAc (5 mL) and the combined filtrates were evaporated in vacuo.

Ethyl 5-(fluoromethyl)isoxazole-3-carboxylate (18a).

The compound was purified by column chromatography on silica gel using heptane – EtOAc (3:2) or CH₂Cl₂ – hexanes (9:1) as eluent. Yield 169 mg (65% from 22a via method B); colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 6.81 (d, J = 2.8 Hz, 1H), 5.46 (d, J = 47.1 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.5 (d, J = 21.2 Hz), 158.8, 156.0 (d, J = 2.7 Hz), 104.5 (d, J = 4.0 Hz), 73.2 (d, J = 170 Hz), 61.8, 13.5. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −217.4. GC/MS (EI): m/z = 173 [M]⁺. Anal. Сalcd. for C₇H₈FNO₃: C, 48.56; H, 4.66; N, 8.09. Found: C, 48.72; H, 4.26; N, 8.04.

tert-Butyl ((5-(fluoromethyl)isoxazol-3-yl)methyl)carbamate (18f).

The compound; purified by column chromatography on silica gel (24 g RediSep column; run length: 27.6 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (7:3) and then CHCl₃ – MeCN (4:1) as eluent. Yield 257 mg (6% from 16f via method A) or 3.21 (93% from 22f via method B); yellowish oil. ¹H NMR (500 MHz, DMSO-d₆): δ 7.49 – 7.42 (m, 1H), 6.57 (s, 1H), 5.52 (d, J = 47.3 Hz, 2H), 4.18 (d, J = 5.5 Hz, 2H), 1.39 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.3 (d, J = 18.3 Hz), 162.9, 155.8, 104.7 (d, J = 4.1 Hz), 78.4, 73.9 (d, J = 163 Hz), 35.6, 28.2. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −214.0 (td, J = 47.1, 2.6 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 114 [M–NHCO₂t-Bu]⁺, 130 [M–CO₂–H₂C=C(CH₃)₂]⁺, 157 [M–Ot-Bu]⁺, 174 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₀H₁₅FN₂O₃: C, 52.17; H, 6.57; N, 12.17. Found: C, 51.78; H, 6.80; N, 12.45.

(S)-tert-Butyl (1-(5-(fluoromethyl)isoxazol-3-yl)ethyl)carbamate (18g).

The compound; purified by column chromatography on silica gel (125 g RediSep column; run length: 24.5 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent; existed as ca. 2:1 mixture of rotamers. Yield 454 mg (10% from 16g via method A) or 3.55 (97% from 22g via method B); colorless powder; mp 81–83 °C. [α]²⁰_D = −82.2 (с = 40.9, CHCl₃), 96% ee, t_R = 13.0 min. ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 5.54 (d, J = 47.3 Hz, 2H), 4.79 – 4.74 (m, 1H), 1.39 (s, 6H), 1.37 (s, 3H), 1.35 (s, 3H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.9, 166.2 (d, J = 18.4 Hz), 155.0, 103.8, 78.2, 74.0 (d, J = 163 Hz), 42.9, 28.2, 20.0. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −213.0 (t, J = 47.3 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 128 [M–NHCO₂t-Bu]⁺, 144 [M–CO₂–H₂C=C(CH₃)₂]⁺, 171 [M–Ot-Bu]⁺, 188 [M–H₂C=C(CH₃)₂]⁺, 229 [M–CH₃]⁺. Anal. Calcd. for C₁₁H₁₇FN₂O₃: C, 54.09; H, 7.02; N, 11.47. Found: C, 53.77; H, 6.87; N, 11.31.

(R)-tert-Butyl (1-(5-(fluoromethyl)isoxazol-3-yl)ethyl)carbamate (18h).

The compound; purified by column chromatography on silica gel (80 g RediSep column; run length: 19.6 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent; existed as ca. 2:1 mixture of rotamers. Yield 545 mg (12% method A; from 16h via method A) or 3.59 (98% from 22h via method B); colorless powder; mp 81–83 °C. [α]²⁰_D = +47.1 (с = 40.9, CHCl₃), 86% ee, t_R = 12.3 min. The spectral data are analogous to that of S-isomer 18g. GC/MS (EI): m/z = 57 [t-Bu]⁺, 128 [M–NHCO₂t-Bu]⁺, 144 [M–CO₂–H₂C=C(CH₃)₂]⁺, 171 [M–Ot-Bu]⁺, 188 [M–H₂C=C(CH₃)₂]⁺, 229 [M–CH₃]⁺. LC/MS (CI): m/z = 145 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₁H₁₇FN₂O₃: C, 54.09; H, 7.02; N, 11.47. Found: C, 54.16; H, 6.78; N, 11.65.

tert-Butyl (2-(5-(fluoromethyl)isoxazol-3-yl)propan-2-yl)carbamate (18i).

The compound; purified by column chromatography on silica gel (220 g RediSep column; run length: 20.0 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent. Yield 1.44 g (30% from 16i via method A) or 3.60 (93% from 22i via method B); colorless powder; mp 82–84 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.27 (br.s, 1H), 6.55 (d, J = 3.1 Hz, 1H), 5.52 (d, J = 47.4 Hz, 2H), 1.50 (s, 6H), 1.33 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 170.7, 165.9 (d, J = 18.2 Hz), 154.7, 104.1 (d, J = 4.9 Hz), 78.4, 74.3 (d, J = 163 Hz), 51.1, 28.6, 28.0. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −213.5 (t, J = 46.5 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 158 [M–CO₂-H₂C=C(CH₃)₂]⁺, 185 [M–Ot-Bu]⁺, 202 [M–H₂C=C(CH₃)₂]⁺. LC/MS (CI): m/z = 143 [M–NHCO₂t-Bu+H]⁺, 203 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₂H₁₉FN₂O₃: C, 55.80; H, 7.41; N, 10.85. Found: C, 55.54; H, 7.79; N, 11.04.

tert-Butyl 3-(5-(fluoromethyl)isoxazol-3-yl)azetidine-1-carboxylate (18j).

The compound; purified by column chromatography on silica gel (80 g RediSep column; run length: 44.0 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent. Yield 727 mg (16% from 16j via method A) or 3.69 (96% from 22j via method B); yellowish oil. ¹H NMR (400 MHz, DMSO-d₆): δ 6.84 (d, J = 3.4 Hz, 1H), 5.54 (d, J = 47.2 Hz, 2H), 4.23 (s, 2H), 3.91 (s, 3H), 1.38 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.8 (d, J = 18.5 Hz), 164.7 (d, J = 2.9 Hz), 155.6, 104.4 (d, J = 4.6 Hz), 78.9, 74.0 (d, J = 163 Hz), 53.7, 28.1 and 25.0. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −214.4 (td, J = 47.2, 3.3 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 156 [M–CO₂–H₂C=C(CH₃)₂]⁺, 183 [M–Ot-Bu]⁺, 200 [M–H₂C=C(CH₃)₂]⁺. LC/MS (CI): m/z = 157 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 201 [M–H₂C=C(CH₃)₂+H]⁺, 255 [M–H]⁺. Anal. Calcd. for C₁₂H₁₇FN₂O₃: C, 56.24; H, 6.69; N, 10.93. Found: C, 56.48; H, 6.37; N, 10.64.

(S)-tert-Butyl 2-(5-(fluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (18k).

The compound; purified by column chromatography on silica gel (80 g RediSep column; run length: 20.6 CV; flow rate: 50 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent; existed as ca. 5:4 mixture of rotamers. Yield 1.56 g (31% from 16k via method A); colorless powder; mp 71–73 °C. [α]²⁰_D = −79.6 (с = 37.0, CHCl₃), 99% ee, t_R = 8.33 min. ¹H NMR (400 MHz, DMSO-d₆) δ 6.63 (d, J = 13.9 Hz, 1H), 5.53 (d, J = 47.2 Hz, 2H), 4.95 – 4.84 (m, 1H), 3.47 – 3.35 (m, 2H), 2.32 – 2.20 (m, 1H), 1.96 – 1.80 (m, 3H), 1.39 (s, 4H), 1.23 (s, 5H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.8, 166.1 (d, J = 18.3 Hz), 153.6 and 153.2, 104.2 and 103.7, 78.9 and 78.77, 73.9 (d, J = 163 Hz), 53.2, 46.5 and 46.2, 32.7 and 31.4, 28.2 and 27.9, 23.7 and 23.0. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −213.5 (t, J = 46.9 Hz), −213.9 (t, J = 48.1 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 170 [M–CO₂-H₂C=C(CH₃)₂]⁺, 197 [M–Ot-Bu]⁺, 214 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₃H₁₉FN₂O₃: C, 57.77; H, 7.09; N, 10.36. Found: C, 58.06; H, 7.23; N, 10.71.

(R)-tert-Butyl 2-(5-(fluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxy-late (18l).

The compound; purified by column chromatography on silica gel (125 g RediSep column; run length: 35.8 CV; flow rate: 85 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent; existed as ca. 5:4 mixture of rotamers. Yield 1.26 g (25% from 16l via method A); colorless powder; mp 72–73 °C. [α]²⁰_D = +77.9 (с = 37.0, CHCl₃), 100% ee, t_R = 6.98 min. The spectral data are analogous to that of S-isomer 18k. GC/MS (EI): m/z = 57 [t-Bu]⁺, 170 [M–CO₂–H₂C=C(CH₃)₂]⁺, 197 [M–Ot-Bu]⁺, 214 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₃H₁₉FN₂O₃: C, 57.77; H, 7.09; N, 10.36. Found: C, 58.10; H, 6.84; N, 10.22.

General procedure for the preparation of difluoromethyl oxazoles 19g–l, 27, and 38.

The corresponding aldehyde 17a, 17g–l, 25 or 37 (26.3 mmol, 1 eq) was dissolved in CH₂Cl₂ (70 mL, 0.38 M solution of aldehyde) and the solution was cooled to −4 °C under argon atmosphere. Morpholinosulfur trifluoride (5.06 g, 28.9 mmol, 1.1 eq) in CH₂Cl₂ (25 mL) was added dropwise (internal temperature was between –40 to –35 °C.). The resulting mixture was stirred at –10 °C for 1.5 h. Then, the reaction mixture was poured into brine–ice (ca. 4 mL – 4 g, 1/1, v/m) and NaHCO₃ was added until pH = 7–8. Most of CH₂Cl₂ was evaporated in vacuo, and aqueous phase was extracted with EtOAc (3×30 mL). Combined organic phases were washed with brine (2×50 mL) and dried over Na₂SO₄ and the solvent was evaporated in vacuo.

(S)-tert-Butyl (1-(5-(difluoromethyl)isoxazol-3-yl)ethyl)carbamate (19g).

The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (3:2) and then using CHCl₃ – MeCN (19:1) as eluent. Yield 1.74 g (23%); colorless powder; mp 86–88 °C. [α]²⁰_D = −61.0 (с = 38.1, CHCl₃), 97% ee, t_R = 14.6 min. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 – 7.46 (m, 1H), 7.32 (t, J = 52.9 Hz, 1H), 6.86 (s, 1H), 4.80 (s, 1H), 1.39 (s, 9H), 1.35 (s, 3H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.9, 162.6 (t, J = 28.3 Hz), 155.0, 107.6 (t, J = 236 Hz), 103.8, 78.4, 42.9, 28.2, 19.9. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −118.43 (d, J = 52.7 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 146 [M–NHCO₂t-Bu]⁺, 162 [M–CO₂–H₂C=C(CH₃)₂]⁺, 189 [M–Ot-Bu]⁺, 206 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₁H₁₆F₂N₂O₃: C, 50.38; H, 6.15; N, 10.68. Found: C, 50.55; H, 6.39; N, 10.52.

(R)-tert-Butyl (1-(5-(difluoromethyl)isoxazol-3-yl)ethyl)carbamate (19h).

The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (3:2) and then using CHCl₃ – MeCN (19:1) as eluent. Yield 1.89 g (25%); colorless powder; mp 86–88 °C. [α]²⁰_D = +43.4 (с = 38.1, CHCl₃), 81% ee, t_R = 13.6 min. The spectral data are analogous to that of S-isomer 19g. GC/MS (EI): m/z = 57 [t-Bu]⁺, 146 [M–NHCO₂t-Bu]⁺, 162 [M–CO₂–H₂C=C(CH₃)₂]⁺, 189 [M–Ot-Bu]⁺ , 206 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₁H₁₆F₂N₂O₃: C, 50.38; H, 6.15; N, 10.68. Found: C, 50.28; H, 6.14; N, 10.41.

tert-Butyl (2-(5-(difluoromethyl)isoxazol-3-yl)propan-2-yl)carbamate (19i).

The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent. Yield 2.24 g (28%); colorless powder; mp 88–89 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.32 (br.s, 1H), 7.31 (t, J = 52.8 Hz, 1H), 6.80 (s, 1H), 1.51 (s, 6H), 1.32 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 170.4, 162.0 (t, J = 28.2 Hz), 154.3, 107.7 (t, J = 236 Hz), 103.7, 78.2, 50.7, 28.1, 27.5. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −118.2 (d, J = 52.8 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 160 [M–NHCO₂t-Bu]⁺, 176 [M–CO₂–H₂C=C(CH₃)₂]⁺, 203 [M–Ot-Bu]⁺, 220 [M–H₂C=C(CH₃)₂]⁺, 261 [M–CH₃]⁺. Anal. Calcd. for C₁₂H₁₈F₂N₂O₃: C, 52.17; H, 6.57; N, 10.14. Found: C, 52.37; H, 6.58; N, 9.93.

tert-Butyl 3-(5-(difluoromethyl)isoxazol-3-yl)azetidine-1-carboxylate (19j).

The compound was purified by column chromatography on silica gel using CHCl₃ – t-BuOMe (4:1) as eluent. Yield 2.77 g (35%); yellowish crystals; mp 53–55 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.34 (t, J = 52.7 Hz, 1H), 7.16 (s, 1H), 4.24 (t, J = 7.6 Hz, 2H), 3.95 (q, J = 6.4, 6.0 Hz, 3H), 1.39 (s, 9H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 165.2, 163.7 (t, J = 28.8 Hz), 156.0, 108.1 (t, J = 236 Hz), 104.7, 79.3, 54.3, 28.4, 25.4. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −118.6 (dd, J = 53.0, 1.2 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 174 [M–CO₂–H₂C=C(CH₃)₂]⁺, 201 [M–Ot-Bu]⁺ , 218 [M–H₂C=C(CH₃)₂]⁺, 259 [M–CH₃]⁺. Anal. Calcd. for C₁₂H₁₆F₂N₂O₃: C, 52.55; H, 5.88; N, 10.21. Found: C, 52.68; H, 5.63; N, 10.61.

(S)-tert-Butyl 2-(5-(difluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (19k).

The compound existed as ca. 5:4 mixture of rotamers. The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent. Yield 4.42 g (53%); colorless powder; mp 30–33 °C. [α]²⁰_D = −70.5 (с = 34.7, CHCl₃), 82% ee, t_R =7.59 min. ¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (t, J = 52.9 Hz, 1H), 6.93 (d, J = 23.0 Hz, 1H), 4.98 – 4.86 (m, 1H), 3.49 – 3.44 (m, 1H), 3.41 – 3.36 (m, 1H), 2.35 – 2.22 (m, 1H), 1.96 – 1.84 (m, 3H), 1.39 (s, 4H), 1.22 (s, 5H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 167.4 and 166.8, 163.0 (t, J = 28.6 Hz), 154.1 and 153.5, 108.1 (t, J = 236 Hz), 104.4 and 104.0, 79.3, 53.5, 46.9 and 46.7, 33.1 and 31.8, 28.5 and 28.3, 24.1 and 23.4. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −118.3 (dd, J = 52.4, 8.4 Hz), –118.4 (d, J = 52.7 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 188 [M–CO₂–H₂C=C(CH₃)₂]⁺, 215 [M–Ot-Bu]⁺. Anal. Calcd. for C₁₃H₁₈F₂N₂O₃: C, 54.16; H, 6.29; .N, 9.72. Found: C, 54.02; H, 6.40; N, 9.52.

(R)-tert-Butyl 2-(5-(difluoromethyl)isoxazol-3-yl)pyrrolidine-1-arboxylate (19l).

The compound existed as ca. 5:4 mixture of rotamers. The compound was purified by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent. Yield 5.08 g (61%); colorless powder; mp 30–33 °C. [α]²⁰_D = +69.9 (с = 34.7, CHCl₃), 99% ee, t_R = 6.59 min. The spectral data are analogous to that of S-isomer 19k. GC/MS (EI): m/z = 57 [t-Bu]⁺, 188 [M–CO₂–H₂C=C(CH₃)₂]⁺, 215 [M–Ot-Bu]⁺. Anal. Calcd. for C₁₃H₁₈F₂N₂O₃: C, 54.16; H, 6.29; N, 9.72. Found: C, 54.03; H, 6.63; N, 9.37.

Ethyl 5-(difluoromethyl)isoxazole-3-carboxylate (27).

The compound was purified by distillation in vacuo. Yield 3.67 g (73%); colorless oil; mp 46–49 °C / 0.68 mmHg. 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). 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. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −119.2. GC/MS (EI): m/z = 191 [M]⁺. Anal. Calcd. for C₇H₇F₂NO₃: C, 43.99; H, 3.69; N, 7.33. Found: C, 43.80; H, 3.44; N, 7.20.

3-(Chloromethyl)-5-(difluoromethyl)isoxazole (38).

The compound was purified by distillation in vacuo or by column chromatography on silica gel (220 g RediSep column; run length: 21.8 CV; flow rate: 100 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. Yield 1.63 g (37%); colorless liquid; bp 24–26 °C / 1 mmHg;. bp 47–49 °C / 17 mmHg.¹H NMR (500 MHz, CDCl₃) δ 6.72 (t, J = 53.5 Hz, 1H), 6.67 (s, 1H), 4.59 (s, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 164.3 (t, J = 30.9 Hz), 161.1, 107.1 (t, J = 239 Hz), 103.8 (t, J = 2.6 Hz), 35.0. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −118.7. GC/MS (EI): m/z = 167/169 [M]⁺. Anal. Calcd. for C₅H₄ClF₂NO: C, 35.85; H, 2.41; N, 8.36; Cl, 21.16. Found: C, 35.83; H, 2.75; N, 8.52; Cl, 21.21.

General procedure for the preparation of bromomethyl isoxazoles 22a, 22f–h, 22j and 22m.

The corresponding chloroxime 1a, 1f–h, 1j or 1m (2.23 mmol) was dissolved in EtOAc (10 mL), then freshly distilled propargyl bromide (343 mg, 2.90 mmol) and NaHCO₃ (318 mg, 3.71 mmol) were added to the solution at rt. The resulting mixture was stirred overnight; the completion of reaction was monitored by ¹H NMR spectroscopy. Next, the solution was filtered through a plug of silica gel and evaporated in vacuo.

Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (22a).

The compound was purified by column chromatography on silica gel using heptane – EtOAc (3:2) as eluent. Yield 355 mg (68%); yellow crystals; mp 37–40 °C. ¹H NMR (500 MHz, CDCl₃) δ 6.73 (d, J = 2.3 Hz, 1H), 4.51 – 4.49 (m, 2H), 4.44 (dd, J = 6.8, 1.8 Hz, 2H), 1.41 (dd, J = 8.8, 6.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 168.9, 158.9, 156.2, 103.8, 61.8, 17.5, 13.6. GC/MS (EI): m/z = 233/235 [M]⁺. Anal. Calcd. for C₇H₈BrNO₃: C, 35.92; H, 3.45; N, 5.98; Br, 34.14. Found: C, 36.03; H, 3.65; N, 6.25; Br, 34.32.

tert-Butyl ((5-(bromomethyl)isoxazol-3-yl)methyl)carbamate (22f).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 396 mg (61%); beige powder; mp 50–53 °C. ¹H NMR (400 MHz, CDCl₃) δ 6.30 (s, 1H), 4.99 (s, 1H), 4.41 (s, 2H), 4.35 (d, J = 6.0 Hz, 2H), 1.44 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.8, 162.3, 155.8, 103.1, 80.1, 36.4, 28.3, 18.5. LC/MS (CI): m/z = 191/193 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 235/237 [M–H₂C=C(CH₃)₂+H]⁺, 314/316 [M+Na]⁺. Anal. Calcd. for C₁₀H₁₅BrN₂O₃: C, 41.25; H, 5.19; N, 9.62; Br, 27.44. Found: C, 41.34; H, 5.21; N, 9.53; Br, 27.72.

(S)-tert-Butyl (1-(5-(bromomethyl)isoxazol-3-yl)ethyl)carbamate (22g).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 483 mg (71%); beige powder; mp 73–76 °C. [α]²⁰_D = −41.4 (с = 32.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 6.25 (s, 1H), 4.97 – 4.86 (m, 2H), 4.41 (s, 2H), 1.50 (d, J = 6.7 Hz, 3H), 1.43 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.6, 166.2, 155.0, 102.5, 79.9, 43.8, 28.3, 20.3, 18.5. LC/MS (CI): m/z = 205/207 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 328/330 [M+Na]⁺. Anal. Calcd. for C₁₁H₁₇BrN₂O₃: C, 43.29; H, 5.62; N, 9.18; Br, 26.18. Found: C, 43.68; H, 5.85; N, 9.30; Br, 26.27.

(R)-tert-Butyl (1-(5-(bromomethyl)isoxazol-3-yl)ethyl)carbamate (22h).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 491 mg (72%); colorless powder; mp 74–77 °C. [α]²⁰_D = 41.5 (с = 32.8, CHCl₃). The spectral data are analogous to that of S-isomer 22g. LC/MS (CI): m/z = 205/207 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 328/330 [M+Na]⁺. Anal. Calcd. for C₁₁H₁₇BrN₂O₃: C, 43.29; H, 5.62; N, 9.18; Br, 26.18. Found: C, 43.22; H, 5.66; N, 8.81; Br, 26.06.

tert-Butyl 3-(5-(bromomethyl)isoxazol-3-yl)azetidine-1-carboxylate (22j).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 495 mg (70%); colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.35 (s, 1H), 4.43 (s, 2H), 4.29 (t, J = 8.6 Hz, 2H), 4.00 (dd, J = 8.6, 5.8 Hz, 2H), 3.85 – 3.77 (m, 1H), 1.43 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 168.3, 164.7, 156.0, 102.1, 79.7, 54.1, 28.3, 25.5, 18.6. LC/MS (CI): m/z = 217/219 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 243/245 [M–Ot-Bu]⁺, 261/263 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₂H₁₇BrN₂O₃: C, 45.44; H, 5.40; N, 8.83; Br, 25.19. Found: C, 45.48; H, 5.59; N, 8.79; Br, 25.55.

tert-Butyl 4-(5-(bromomethyl)isoxazol-3-yl)piperidine-1-carboxylate (22m).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 547 mg (71%); beige powder; mp 68–70 °C. ¹H NMR (400 MHz, CDCl₃) δ 6.16 (s, 1H), 4.41 (s, 2H), 4.14 (d, J = 13.4 Hz, 2H), 2.86 (q, J = 12.8, 12.2 Hz, 3H), 1.91 (d, J = 12.8 Hz, 2H), 1.61 (qd, J = 12.2, 4.2 Hz, 2H), 1.45 (s, 9H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.3, 167.1, 154.7, 102.0, 79.6, 43.4, 34.1, 30.7, 28.4, 18.7. LC/MS (CI): m/z = 245/247 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 289/291 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₄H₂₁BrN₂O₃: C, 48.71; H, 6.13; N, 8.11; Br, 23.14. Found: C, 48.49; H, 5.74; N, 8.51; Br, 23.34.

3-Bromo-5-(difluoromethyl)isoxazole (28).

Pyridinium chlorochromate (16.2 g, 75.0 mmol), SiO₂ (ca. 25 g) were suspended in CH₂Cl₂ (150 mL). The resulting mechanically stirred solution was cooled to –10 °C and alcohol 24 (8.90 g, 50.0 mmol) in CH₂Cl₂ (150 mL) was added dropwise at −10 (NOTE: the temperature should not exceed −5 °C.). The resulting mixture was stirred overnight at rt, then filtered through a plug of silica gel, and the filtrate was evaporated in vacuo. The corresponding aldehyde 26 was dissolved in CH₂Cl₂ (100 mL) and the solution was cooled to –4 °C under argon atmosphere. Morpholinosulfur trifluoride (9.63 g, 55.0 mmol) in CH₂Cl₂ (50 mL) was added dropwise (internal temperature was between −40 to −35 °C.). The resulting mixture was stirred at −10 °C for 1.5 h. Then, the reaction mixture was poured into brine–ice (ca. 4 mL – 4 g, 1/1, v/m) and NaHCO₃ was added until pH = 7–8. Most of CH₂Cl₂ was evaporated in vacuo, and aqueous phase was extracted with EtOAc (3×45 mL). Combined organic phases were washed with brine (3×50 mL) and dried over Na₂SO₄ and the solvent was evaporated in vacuo. The compound was purified by column chromatography on silica gel (125 g RediSep column; run length: 16.9 CV; flow rate: 85 mL / min; rack: 16 mm × 150 mm tubes) using gradient hexanes – t-BuOMe as eluent. Yield 7.13 g (72% for two steps); colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ 6.74 (t, J = 53.4 Hz, 1H), 6.68 (t, J = 1.7 Hz, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 164.8 (t, J = 31.5 Hz), 140.5 (t, J = 1.7 Hz), 107.6 (t, J = 2.6 Hz), 106.5 (t, J = 240 Hz). ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −119.2. GC/MS (EI): m/z = 197/199 [M]⁺. Anal. Calcd. for C₄H₂BrF₂NO: C, 24.27; H, 1.02; N, 7.08; Br, 40.36. Found: C, 24.13; H, 1.19; N, 6.73; Br, 40.62.

Ethyl 5-acetylisoxazole-3-carboxylate (31).

Chloroxime 1a (1.27 g, 8.39 mmol) was dissolved in EtOAc (15 mL), then methyl ethynyl ketone (600 mg, 8.81 mmol) and NaHCO₃ (775 mg, 9.23 mmol) were added to the solution at rt. The resulting mixture was stirred overnight; the completion of reaction was monitored by ¹H NMR spectroscopy. Next, the solution was dried over Na₂SO₄, filtered through a plug of silica gel and evaporated in vacuo. Yield 1.20 (78%); colorless liquid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.73 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 186.3, 167.4, 159.0, 157.3, 109.3, 62.6, 27.8, 14.2. LC/MS (CI): m/z = 184 [M+H]⁺. Anal. Calcd. for C₈H₉NO₄: C, 52.46; H, 4.95; N, 7.65. Found: C, 52.53; H, 5.17; N, 7.51.

Ethyl 5-(1,1-difluoroethyl)isoxazole-3-carboxylate (32).

Ethyl 5-acetylisoxazole-3-carboxylate (31, 40.0 g, 0.218 mol) was dissolved in CH₂Cl₂ (400 mL) and the solution was cooled to −4 °C under argon atmosphere. Morpholinosulfur trifluoride (40.1 g, 0.229 mol) in CH₂Cl₂ (400 mL) was added dropwise (internal temperature was between −40 to −35 °C.). The resulting mixture was stirred at rt for 1 week. Then, the reaction mixture was poured into brine–ice (ca. 4 mL – 4 g, 1/1, v/m) and NaHCO₃ was added until pH = 7–8. Most of CH₂Cl₂ was evaporated in vacuo, and aqueous phase was extracted with EtOAc (3×300 mL). Combined organic phases were washed with brine (2×100 mL) and dried over Na₂SO₄ and the solvent was evaporated in vacuo. The compound was purified but distillation in vacuo. Yield 37.1 g (83%); colorless liquid; bp 31–33 °C / 3.75 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 6.87 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.02 (t, J = 18.4 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.7 (t, J = 37.4 Hz), 159.0, 156.4, 115.6 (t, J = 238 Hz), 103.3, 62.6, 23.3 (t, J = 26.4 Hz), 14.1. ¹⁹F NMR (376 MHz, CDCl₃) δ −89.5. LC/MS (CI): m/z = 206 [M+H]⁺. Anal. Calcd. for C₈H₉F₂NO₃: C, 46.84; H, 4.42; N, 6.83. Found: C, 46.94; H, 4.74; N, 6.73.

5-(1,1-Difluoroethyl)isoxazole-3-carboxylic acid (33).

A solution of the ester 32 (36.5 g, 0.180 mol) in MeOH (400 mL) was cooled to 0 °C, and pre-cooled absolute solution of NaOH (7.83 g, 0.196 mol) in MeOH (33.2 mL) was added dropwise (NOTE: the reaction is highly exothermic). After addition, the mixture was stirred for 1 h at 0 °C to rt, and evaporated in vacuo to dryness. Then, 6 M aq HCl (35 mL) was added in portions, and the reaction mixture was stirred for 10 min at rt (NOTE: MeOH traces led to formation of the corresponding methyl esters via the tranesterification reaction). Most of solvents was evaporated in vacuo, the residue was diluted with CH₂Cl₂ (400 mL), dried over Na₂SO₄, and evaporated in vacuo. The compound; purified by column chromatography on silica gel using gradient CHCl₃ – THF. Yield 29.0 g (91% from the ester 31); beige crystals; mp 85–86 °C ¹H NMR (400 MHz, CDCl₃) δ 11.25 (s, 1H), 6.95 (s, 1H), 2.05 (t, J = 18.5 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 168.4 (t, J = 37.5 Hz), 163.4, 155.7, 115.5 (t, J = 238 Hz), 103.5 (t, J = 2.2 Hz), 23.3 (t, J = 26.3 Hz). ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ –89.5. LC/MS (CI): m/z = 178 [M+H]⁺. Anal. Calcd. for C₆H₅F₂NO₃: C, 40.69; H, 2.85; N, 7.91. Found: C, 40.96; H, 2.89; N, 8.07.

5-(1,1-Difluoroethyl)isoxazol-3-amine (34).

Carboxylic acid 33 (16.8 g, 95.0 mmol) was suspended in t-BuOH (150 mL), then Et₃N (15.2 mL,11.1 g, 0.109 mol) and DPPA (22.5 mL, 28.8 g, 0.105 mol) were added at rt. The resulting mixture was stirred at 83 °C overnight, then evaporated in vacuo to dryness. The residue was dissolved in EtOAc (250 mL), washed with pre-cooled to 5 °C 10% aq NaOH (3×50 mL), brine (3×50 mL), dried over Na₂SO₄, filtered through a plug of silica gel, and evaporated in vacuo. The residue was suspended in t-BuOMe (75 mL) and filtered through a plug of silica gel, and evaporated in vacuo. The obtained residue was dissolved in MeOH (75 mL), the solution was cooled to cooled to −1 °C and acetyl chloride (7.09 mL, 7.83 g, 99.8 mmol) was added dropwise at −1 °C. The resulting mixture was warmed up to rt, stirred for 1 h, then cooled to 0 °C and NaOH (4.79 g, 0.120 mol) in MeOH (20.3 mL) was added in portions at 0 °C. The solvent was evaporated in vacuo, the residue was dissolved in CH₂Cl₂ (100 mL), filtered through a pad of Na₂SO₄ and evaporated in vacuo. Yield 5.49 g (39%); beige crystals; mp 69–71 °C ¹H NMR (400 MHz, Benzene-d₆) δ 5.35 (s, 1H), 3.43 (s, 2H), 1.48 (t, J = 18.5 Hz, 3H). ¹³C{¹H} NMR (126 MHz, Benzene-d₆) δ 165.4 (t, J = 36.0 Hz), 163.1, 116.3 (t, J = 237 Hz), 95.1, 22.4 (t, J = 26.6 Hz). ¹⁹F{¹H} NMR (376 MHz, Benzene-d₆) δ −89.6. GC/MS (EI): m/z = 148 [M]⁺. Anal. Calcd. for C₅H₆F₂N₂O: C, 40.55; H, 4.08; N, 18.91. Found: C, 40.27; H, 3.85; N, 18.87.

(3-(Chloromethyl)isoxazol-5-yl)methanol (36).

2-Chloroacetaldehyde oxime (35, 207 g, 2.21 mol) was dissolved in DMF (2000 mL) and the solution was cooled to 0 °C. NCS (310 g, 2.32 mol) and then 4 M HCl – 1,4-dioxane (55.3 mL, 0.221 mol) were added to the solution. The resulting mixture was warmed up to rt and stirred overnight. Then, propargylic alcohol (153 mL, 149 g, 2.65 mol) and NaHCO₃ (316 g, 3.76 mol) were added. The resulting mixture was stirred at rt for 48 h, then most of solvents was evaporated in vacuo. The residue was diluted with t-BuOMe (1500 mL), the precipitate was filtered off, and the mother liquor was evaporated in vacuo. The compound was purified but distillation in vacuo. Yield 134 g (41%); colorless liquid; bp 81–83 °C / 0.1 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 6.36 (s, 1H), 4.76 (s, 2H), 4.56 (s, 2H), 2.14 (s, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 172.7, 160.9, 101.7, 56.0, 35.4. GC/MS (EI): m/z = 147/149 [M]⁺. Anal. Calcd. for C₅H₆ClNO₂: C, 40.70; H, 4.10; N, 9.49; Cl, 24.02. Found: C, 40.98; H, 4.39; N, 9.77; Cl, 23.89.

3-(Chloromethyl)isoxazole-5-carbaldehyde (37).

Alcohol 36 (119 g, 0.807 mol) was dissolved in CH₂Cl₂ (1000 mL) and the solution was cooled to 0 C. Then, PCC (261 g, 1.21 mol) and silica gel (261 g) were added. The resulting mixture was warmed up to rt and stirred overnight, the precipitate was filtered through silica gel, and the mother liquor was evaporated in vacuo. The compound was purified by distillation in vacuo. Yield.79.9 g (68%); colorless liquid; bp 35–36 °C / 0.1 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 7.10 (s, 1H), 4.68 (s, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 177.9, 166.4, 161.7, 108.4, 35.0. GC/MS (EI): m/z = 145/147 [M]⁺. Anal. Calcd. for C₅H₄ClNO₂: C, 41.26; H, 2.77; N, 9.62; Cl, 24.36. Found: C, 41.04; H, 2.39; N, 9.91; Cl, 24.68.

General procedure for the preparation of (2,2,2-trifluoro-1-hydroxyethyl)isoxazoles 39 or ketones 43.

The corresponding aldehyde 17g, 17h or 17k–m or Weinreb amides 42a or 42b (40.0 mmol) was dissolved in THF 0.4 M solution of 17 or 42) under argon atmosphere, and the solution was cooled to 0 °C. Then, TMSCF₃ (6.26 g, 44.0 mmol, 1.1 eq) and CsF (608 mg, 4.00 mmol, 0.1 eq) were added, and the resulting mixture was stirred overnight at rt. Then H₂O (15 mL) was added at rt, and the resulting mixture was stirred for 2 h, then evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×25 mL), dried over Na₂SO₄, filtered through a plug of silica gel, and evaporated in vacuo.

tert-Butyl ((1S)-1-(5-(2,2,2-trifluoro-1-hydroxyethyl)isoxazol-3-yl)ethyl)carbamate (39g).

The compound was purified by distillation in vacuo or by column chromatography on silica gel (220 g RediSep column; run length: 41.7 CV; flow rate: 95 mL / min; rack: 16 mm × 150 mm tubes) using hexanes – t-BuOMe as eluent, or by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 5.59 g (44%); colorless powder; mp 88–91 °C. [α]²⁰_D = −37.9 (с = 34.9, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 6.7, 2.0 Hz, 1H), 6.53 (s, 1H), 5.54 (p, J = 6.4 Hz, 1H), 4.80 – 4.69 (m, 1H), 1.38 (s, 9H), 1.34 (s, 3H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.5 (d, J = 33.2 Hz), 155.0, 123.8 (q, J = 283 Hz), 102.6, 79.2, 78.3, 64.8 (q, J = 33.0 Hz), 42.9, 28.2, 20.0. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −76.9 (d, J = 7.1 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 194 [M–NHCO₂t-Bu]⁺, 211 [M–CO₂–H₂C=C(CH₃)₂]⁺, 237 [M–Ot-Bu]⁺, 254 [M–H₂C=C(CH₃)₂]⁺, 310 [M]⁺. Anal. Calcd. for C₁₂H₁₇F₃N₂O₄: C, 46.45; H, 5.52; N, 9.03. Found: C, 46.33; H, 5.28; N, 8.90.

tert-Butyl ((1R)-1-(5-(2,2,2-trifluoro-1-hydroxyethyl)isoxazol-3-yl)ethyl)carbamate (39h).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 6.08 g (49%); yellowish oil. [α]²⁰_D = +38.8 (с = 34.9, CHCl₃). The spectral data are analogous to that of S-isomer 39g. GC/MS (EI): m/z = 211 [M–CO₂–H₂C=C(CH₃)₂]⁺, 237 [M–Ot-Bu]⁺, 254 [M–H₂C=C(CH₃)₂]⁺. Anal. Calcd. for C₁₂H₁₇F₃N₂O₄: C, 46.45; H, 5.52; N, 9.03. Found: C, 46.35; H, 5.33; N, 8.64.

(2S)-tert-Butyl 2-(5-(2,2,2-trifluoro-1-hydroxyethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (39k).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 12.8 g (95%); colorless powder; mp 84–87 °C. [α]²⁰_D = −63.7 (с = 14.9, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 1H), 6.52 (s, 1H), 5.52 (s, 1H), 4.95 – 4.80 (m, 1H), 3.44 – 3.32 (m, 2H), 2.31 – 2.18 (m, 1H), 1.93 – 1.83 (m, 3H), 1.39 (s, 3H) and 1.20 (s, 6H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 167.1 and 167.0 and 166.9, 166.6 and 166.5 and 166.4, 154.1 and 153.5, 124.1 (q, J = 283 Hz), 103.4 and 103.0 and 102.7, 79.3 and 79.1, 65.2 (qd, J = 33.8, 33.3, 11.8 Hz), 53.56, 49.1, 46.8 and 46.6, 33.2 and 31.7, 28.5 and 28.1, 27.2, 24.1 and 23.5. ¹⁹F{¹H} NMR (470 MHz, DMSO-d₆) δ -−76.30 – −76.40 (m), −76.5 (dd, J = 77.7, 7.1 Hz). GC/MS (EI): m/z = 57 [t-Bu]⁺, 237 [M–CO₂–H₂C=C(CH₃)₂]⁺, 263 [M–Ot-Bu]⁺, 280 [M–H₂C=C(CH₃)₂]⁺, 336 [M]⁺. Anal. Calcd. for C₁₄H₁₉F₃N₂O₄: C, 50.00; H, 5.69; N, 8.33. Found: C, 50.09; H, 5.79; N, 8.08.

(2R)-tert-Butyl 2-(5-(2,2,2-trifluoro-1-hydroxyethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (39l).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 12.8 g (95%); colorless powder; mp 84–87 °C. [α]²⁰_D = +63.9 (с = 14.9, CHCl₃). The spectral data are analogous to that of S-isomer 39k. GC/MS (EI): m/z = 57 [t-Bu]⁺, 237 [M–CO₂–H₂C=C(CH₃)₂]⁺, 263 [M–Ot-Bu]⁺, 280 [M–H₂C=C(CH₃)₂]⁺, 336 [M]⁺. Anal. Calcd. for C₁₄H₁₉F₃N₂O₄: C, 50.00; H, 5.69; N, 8.33. Found: C, 49.90; H, 6.09; N, 8.14.

tert-Butyl 4-(5-(2,2,2-trifluoro-1-hydroxyethyl)isoxazol-3-yl)piperi-dine-1-carboxylate (39m).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 10.5 g (75%); yellowish oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.43 – 7.33 (m, 1H), 6.65 (d, J = 4.6 Hz, 1H), 5.50 (p, J = 6.4 Hz, 1H), 3.97 (d, J = 13.1 Hz, 2H), 2.97 – 2.80 (m, 3H), 1.86 (d, J = 13.0 Hz, 2H), 1.55 – 1.46 (m, 2H), 1.40 (s, 9H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 167.2, 166.7, 154.3, 124.1 (q, J = 283 Hz), 103.3, 79.1, 65.2 (q, J = 32.9 Hz), 43.4, 33.7, 30.6, 28.5. ¹⁹F{¹H} NMR (470 MHz, DMSO-d₆) δ −76.5 (d, J = 7.2 Hz). LC/MS (CI): m/z = 251 [M–CO₂-H₂C=C(CH₃)₂+H]⁺, 277 [M–Ot-Bu+H]⁺, 295 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₅H₂₁F₃N₂O₄: C, 51.43; H, 6.04; N, 8.00. Found: C, 51.22; H, 6.42; N, 7.70.

(S)-tert-Butyl 2-(4-(2,2,2-trifluoroacetyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (43a).

The compound was purified by HPLC (SunFire C₁₈ Column, 100 Å, 3.5 μm, 4.6 mm × 150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min); existed as a mixture of ca. 11:9 of rotamers. Yield 9.63 g (72%); yellowish liquid. [α]²¹_D = −33.4 (с = 35.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 0.45H) and 9.03 (s, 0.55H), 5.41 (dd, J = 8.1, 2.0 Hz, 0.55H) and 5.33 (dd, J = 7.7, 2.9 Hz, 0.45H), 3.67 – 3.60 (m, 0.9H) and 3.52 – 3.40 (m, 1.1H), 2.40 – 2.30 (m, 1H), 2.00 – 1.79 (m, 3H), 1.41 (s, 4.95H) and 1.22 (s, 4.05H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 174.1 (q, J = 38.3 Hz), 165.3 and 164.5, 165.0 (q, J = 4.9 Hz) and 164.8 (q, J = 4.9 Hz), 154.1 and 153.5, 115.7 (q, J = 290 Hz), 112.9 and 112.7, 79.9 and 79.7, 53.8 and 53.4, 46.7 and 46.4, 32.2 and 31.2, 28.4 and 28.1, 23.4 and 22.9. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −75.8 and −75.9. LC/MS (CI): m/z = 235 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₄H₁₇F₃N₂O₄: C, 50.30; H, 5.13; N, 8.38. Found: C, 50.32; H, 5.49; N, 8.44.

(R)-tert-Butyl 2-(4-(2,2,2-trifluoroacetyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (43b).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min); existed as a mixture of ca. 11:9 of rotamers. Yield 9.89 g (74%); yellowish liquid. [α]²¹_D = +34.3 (с = 35.5, CHCl₃). The spectral data are analogous to that of S-isomer 43a. Anal. Calcd. for C₁₄H₁₇F₃N₂O₄: C, 50.30; H, 5.13; N, 8.38. Found: C, 50.28; H, 5.03; N, 8.72.

General procedure for the preparation of trifluoromethyl ketones 40.

The corresponding alcohol 39k or 39l (3.36 g, 10.0 mmol, 1 eq) was dissolved in CH₂Cl₂ (35 mL, 0.29 M solution of 39), then Et₃N (4.39 mL, 3.18 g, 31.5 mmol, 3.15 eq) and DMSO (HPLC grade, 3.55 mL, 3.91 g, 50.0 mmol, 5 eq) were added under argon atmosphere. The resulting solution was cooled to 0 °C, and Py·SO₃ (4.77 g, 30.0 mmol, 3 eq) was added. The resulting mixture was stirred overnight at rt, the completion of the reaction was monitored by ¹H NMR. The mixture was poured onto ice (40 g), organic phase was separated and most of CH₂Cl₂ evaporated in vacuo. The aqueous phase was extracted with EtOAc (3×40 mL), combined extracts were added to the residue obtained after CH₂Cl₂ evaporation. The resulting solution was washed with saturated aq NaHSO₃ (3×30 mL), brine (3×30 mL), dried over Na₂SO₄, and evaporated in vacuo.

(S)-tert-Butyl 2-(5-(2,2,2-trifluoro-1,1-dihydroxyethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (40k).

The compound was purified by distillation in vacuo or by column chromatography on silica gel using CHCl₃ – MeCN as eluent; existed as a mixture of ca. 2:1 of rotamers. Yield 1.69 g (48%); colorless powder; mp 72–75 °C. [α]²⁰_D = −38.6 (с = 41.4, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J = 10.9 Hz, 1H), 6.51 (s, 1H), 4.93 – 4.81 (m, 1H), 3.57 – 3.39 (m, 2H), 2.46 – 2.10 (m, 2H), 1.94 – 1.81 (m, 3H), 1.39 (s, 3H), 1.21 (s, 6H). ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 168.7 and 170.0, 154.1 and 153.5, 122.8 (q, J = 289 Hz), 103.8 and 103.2, 90.2 (q, J = 32.4 Hz), 79.2, 53.6, 46.9 and 46.7, 33.2 and 31.7, 28.5 and 28.2, 24.1 and 23.5. ¹⁹F{¹H} NMR (376 MHz, DMSO) δ −83.5, −83.6. LC/MS (CI): m/z = 253 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₄H₁₉F₃N₂O₅: C, 47.73; H, 5.44; N, 7.95. Found: C, 47.66; H, 5.25; N, 7.97.

(R)-tert-Butyl 2-(5-(2,2,2-trifluoro-1,1-dihydroxyethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (40l).

The compound was purified by distillation in vacuo or by column chromatography on silica gel using CHCl₃ – MeCN as eluent; existed as a mixture of ca. 2:1 of rotamers. Yield 1.59 g (45%); colorless powder; mp 72–75 °C. [α]²⁰_D = +39.5 (с = 41.4, CHCl₃). The spectral data are analogous to that of S-isomer 40k. LC/MS (CI): m/z = 253 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₄H₁₉F₃N₂O₅: C, 47.73; H, 5.44; N, 7.95. Found: C, 47.46; H, 5.51; N, 7.61.

General procedure for the preparation of Weinreb amides 42

The corresponding carboxylic acid 41a or 41b (10.0 g; 35.4 mmol, 1 eq) was dissolved in CH₂Cl₂ (100 mL, 0.35 M solution of carboxylic acid 41), and CDI (6.86 g; 42.5 mmol, 1.2 eq) was added in portions at rt. The resulting mixture was stirred at rt for 1 h, and N,O-dimethylhydroxylamine hydrochloride (3.80 g; 38.9 mmol, 1.1 eq) was added in portions at rt. The reaction mixture was stirred overnight, then pre-cooled to 10 °C H₂O (7 mL) was added, and the solution was stirred for 10 min. Organic phase was separated, washed with saturated aq NaHSO₃ (3×30 mL), brine (3×30 mL), dried over Na₂SO₄, and evaporated in vacuo.

(S)-tert-Butyl 2-(4-(methoxy(methyl)carbamoyl)isoxazol-3-yl)pyrroli-dine-1-carboxylate (42a).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; MeCN; flow rate 30mL / min). The compound existed as a mixture of ca. 11:9 of rotamers. Yield 10.7 g (93%); yellowish liquid. [α]²¹_D = −30.1 (с = 30.7, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 0.55H) and 9.34 (s, 0.45H), 5.37 – 5.35 (m, 0.45H) and 5.34 – 5.32 (m, 0.55H), 3.69 (s, 1.35H) and 3.68 (s, 1.65H), 3.48 – 3.41 (m, 1.1H) and 3.40 – 3.34 (m, 0.9H), 3.24 (s, 3H), 2.30 – 2.19 (m, 1H), 1.88 – 1.78 (m, 3H), 1.37 (s, 4.05H) and 1.18 (s, 4.95H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 165.9 and 165.2, 162.2, 160.9, 153.6 and 153.3, 111.1 and 111.0, 78.9 and 78.6, 61.6, 53.9 and 53.8, 46.8 and 46.5, 32.6, 31.8, 28.5 and 28.2, 23.3 and 22.6. LC/MS (CI): m/z = 226 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₅H₂₃N₃O₅: C, 55.37; H, 7.13; N, 12.92. Found: C, 55.60; H, 7.38; N, 12.63.

(R)-tert-Butyl 2-(4-(methoxy(methyl)carbamoyl)isoxazol-3-yl)pyrroli-dine-1-carboxylate (42b).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; MeCN; flow rate 30mL / min). Yield 10.4 (90%); yellowish liquid. [α]²¹_D = +35.8 (с = 30.7, CHCl₃). The spectral data are analogous to that of S-isomer 42a. LC/MS (CI): m/z = 226 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₅H₂₃N₃O₅: C, 55.37; H, 7.13; N, 12.92. Found: C, 55.41; H, 7.27; N, 13.28.

General procedure for the preparation of 1,4,2-oxadioazoles 50–53.

The corresponding chloroxime 1f, 1h–j (24.0 mmol, 1 eq) was dissolved in EtOAc (50 mL, 0.48 M solution of chloroxime 1), then the corresponding fluoromethyl ketone 44–47 (25.2 mmol, 1.05 eq) or enamine 54 or 55 (25.2 mmol, 1.05 eq), and NaHCO₃ (6.04 g, 72.0 mmol, 3 eq) were added to the vigorously stirred solution at rt. The resulting mixture was stirred overnight. The resulting mixture was dried over Na₂SO₄, filtered through a plug of silica gel and evaporated in vacuo.

tert-Butyl 3-(5-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)azetidine-1-carboxylate (50j).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 4.40 g (48% from 44) or 3.30 g (36% from 54); yellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 4.23 – 4.13 (m, 4H), 4.13 – 4.04 (m, 2H), 3.63 – 3.43 (m, 1H), 3.10 (dd, J = 8.3, 2.6 Hz, 2H), 1.41 (s, 9H), 1.24 (td, J = 7.2, 2.4 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 165.3, 160.4, 155.7, 120.5 (q, J = 289 Hz), 108.2 (q, J = 34.2 Hz), 80.1, 61.5, 51.2, 34.9, 28.2, 22.8, 13.9. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −135.2 (dd, J = 293, 54.1 Hz), −137.1 (dd, J = 293, 49.3 Hz). LC/MS (CI): m/z = 283 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₅H₂₁F₃N₂O₆: C, 47.12; H, 5.54; N, 7.33. Found: C, 47.07; H, 5.51; N, 7.03.

(2S)-tert-Butyl 2-(5-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)pyrrolidine-1-carboxylate (50k).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). The compound existed as a mixture of ca. 2:1 of diastereomers and rotamers. Yield 5.04 g (53% from 44) or 4.09 g (43% from 54); yellow oil. [α]²⁰_D = −42.5 (с = 50.6, MeOH). ¹H NMR (400 MHz, CDCl₃) δ 4.76 – 4.67 (m, 0.33H) and 4.67 – 4.56 (m, 0.67H), 4.16 (s, 2H), 3.54 – 3.41 (m, 1.33H) and 3.42 – 3.31 (m, 0.67H), 3.05 (s, 2H), 2.24 – 2.10 (m, 2H), 2.06 – 1.88 (m, 2H), 1.42 (s, 3H) and 1.42 (s, 6H), 1.27 – 1.21 (m, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 165.2 (d, J = 21.9 Hz), 161.1 (d, J = 6.9 Hz), 153.6 (d, J = 18.8 Hz), 120.5 (q, J = 289 Hz) and 120.5 (q, J = 289 Hz), 108.0 (q, J = 33.9 Hz), 80.5 (d, J = 20.4 Hz), 80.1, 61.4 (d, J = 3.5 Hz), 51.4 and 50.8, 46.2 and 45.8, 35.4 and 35.1, 30.2 (d, J = 68.6 Hz) and 29.3 (d, J = 24.8 Hz), 28.3 and 28.1, 24.0 (d, J = 17.6 Hz) and 23.1 (d, J = 65.0 Hz), 14.0. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −85.6 (d, J = 8.4 Hz), −85.7 (d, J = 99.9 Hz). LC/MS (CI): m/z = 297 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₆H₂₃F₃N₂O₆: C, 48.48; H, 5.85; N, 7.07. Found: C, 48.26; H, 6.21; N, 7.44.

(2R)-tert-Butyl 2-(5-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)pyrrolidine-1-carboxylate (50l).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 4.95 g (52% from 44) or 4.09 g (43% from 54); yellow oil. [α]²⁰_D = +41.3 (с = 50.6, MeOH). The spectral data are analogous to that of S-isomer 50k. LC/MS (CI): m/z = 297 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₆H₂₃F₃N₂O₆: C, 48.48; H, 5.85; N, 7.07. Found: C, 48,83; H, 6,14; N, 7,39.

Ethyl 2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-(difluoromethyl)-1,4,2-dioxazol-5-yl)acetate (51f).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 3.17 g (39%); brownish oil. ¹H NMR (400 MHz, CDCl₃) δ 5.96 (t, J = 54.3 Hz, 1H), 4.86 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.10 (s, 2H), 3.04 (s, 2H), 1.43 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 166.6, 158.3, 155.3, 110.9 (t, J = 252 Hz), 109.7 (t, J = 24.9 Hz), 80.5, 61.5, 36.4, 34.2, 28.2, 14.0. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −135.7 (d, J = 294 Hz), −137.2 (d, J = 294 Hz). LC/MS (CI): m/z = 239 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₃H₂₀F₂N₂O₆: C, 46.15; H, 5.96; N, 8.28. Found: C, 46.25; H, 5.62; N, 8.40.

Ethyl 2-(3-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(difluoromethyl)-1,4,2-dioxazol-5-yl)acetate (51g).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 3.81 g (45%); yellow oil. [α]²⁰_D = −31.2 (с = 45.6, MeOH). ¹H NMR (400 MHz, CDCl₃) δ 5.95 (td, J = 54.4, 2.2 Hz, 1H), 4.72 (d, J = 85.7 Hz, 2H), 4.17 (qd, J = 7.2, 2.5 Hz, 2H), 3.03 (s, 2H), 1.44 (s, 3H), 1.42 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 166.6 (d, J = 11.3 Hz), 161.3 (d, J = 16.4 Hz), 154.6, 110.9 (t, J = 252 Hz), 109.6 (t, J = 24.8 Hz), 80.3, 61.5 (d, J = 5.2 Hz), 41.7, 36.4, 28.2, 18.4 (d, J = 8.1 Hz), 14.0. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −134.9 (dd, J = 110, 54.2 Hz), −135.5 (dd, J = 110, 54.2 Hz), −136.6 (dd, J = 54.7, 40.2 Hz), −137.2 (dd, J = 54.7, 40.2 Hz). LC/MS (CI): m/z = 351 [M–H]⁻. Anal. Calcd. for C₁₄H₂₂F₂N₂O₆: C, 47.73; H, 6.29; N, 7.95. Found: C, 47.40; H, 6.06; N, 7.57.

Ethyl 2-(3-((R)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(difluoromethyl)-1,4,2-dioxazol-5-yl)acetate (51h).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 3.64 g (43%); yellow oil [α]²⁰_D = +30.4 (с = 45.6, MeOH). The spectral data are analogous to that of S-isomer 51g. LC/MS (CI): m/z = 351 [M–H]^–. Anal. Calcd. for C₁₄H₂₂F₂N₂O₆: C, 47.73; H, 6.29; N, 7.95. Found: C, 48.12; H, 6.13; N, 8.03.

tert-Butyl 3-(5-(difluoromethyl)-5-(2-ethoxy-2-oxoethyl)-1,4,2-dioxazol-3-yl)azetidine-1-carboxylate (51j).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 4.37 g (50% from 45) or 3.58 g (41% from 55); yellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 5.94 (t, J = 54.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.16 – 4.13 (m, 2H), 4.09 (ddd, J = 8.8, 6.1, 3.0 Hz, 2H), 3.51 (tt, J = 8.8, 6.0 Hz, 1H), 3.05 (s, 2H), 1.42 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 166.4, 160.2, 155.7, 111.0 (t, J = 252 Hz), 109.6 (t, J = 24.5 Hz), 80.1, 61.5, 51.4, 36.5, 28.3, 22.9, 14.0. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −135.2 (ddd, J = 294, 54.2, 5.8 Hz), −137.1 (dd, J = 294, 54.2 Hz). LC/MS (CI): m/z = 265 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 309 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₅H₂₂F₂N₂O₆: C, 49.45; H, 6.09; N, 7.69. Found: C, 49.41; H, 6.45; N, 7.70.

tert-Butyl (2S)-2-(5-(difluoromethyl)-5-(2-ethoxy-2-oxoethyl)-1,4,2-dioxazol-3-yl)pyrrolidine-1-carboxylate (51k).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). The compound existed as a mixture of ca. 2:1 of diastereomers and rotamers. Yield 5.18 g (57% from 45) or 4.00 g (44% from 55); yellow oil. [α]²⁰_D = −81.7 (с = 48.5, MeOH). ¹H NMR (400 MHz, CDCl₃) δ 5.96 (dt, J = 54.6, 7.7 Hz, 1H), 4.58 (dd, J = 8.0, 4.1 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.40 (d, J = 30.4 Hz, 2H), 3.10 – 2.95 (m, 2H), 2.12 (d, J = 21.3 Hz, 2H), 2.02 (dt, J = 12.7, 7.3 Hz, 1H), 1.95 – 1.86 (m, 1H), 1.43 (d, J = 2.7 Hz, 9H)+, 1.24 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 166.7 and 166.5 and 166.4 and 166.4, 161.2 and 161.0 and 160.9, 153.9 and 153.6 and 153.5 and 153.5, 113.2 – 112.4 (m), 111.1 – 110.4 (m), 109.6 – 108.4 (m), 80.5 – 80.3 (m), 80.5 and 80.4 and 80.2 and 80.1, 61.4 and 61.4 and 61.3, 51.1 and 51.0 and 50.9, 46.5 and 46.4 and 46.1 and 46.0, 37.3 and 36.6 and 36.4 and 34.8, 30.6 and 30.4 and 29.7, 28.2, 24.1 and 23.3 and 23.2, 14.0 and 13.9. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −134.6 – −138.5 (m) LC/MS (CI): m/z = 279 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₆H₂₄F₂N₂O₆: C, 50.79; H, 6.39; N, 7.40. Found: C, 50.94; H, 6.04; N, 7.12.

tert-Butyl (2R)-2-(5-(difluoromethyl)-5-(2-ethoxy-2-oxoethyl)-1,4,2-dioxazol-3-yl)pyrrolidine-1-carboxylate (51l).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 4.81 g (53% from 45) or 3.72 g (41% from 55); yellow oil. [α]²⁰_D = 80.4 (с = 48.5, MeOH). The spectral data are analogous to that of S-isomer 51k. LC/MS (CI): m/z = 279 [M–CO₂–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₆H₂₄F₂N₂O₆: C, 50.79; H, 6.39; N, 7.40. Found: C, 50.92; H, 6.04; N, 7.72.

tert-Butyl 3-(5-(bromomethyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)azetidine-1-carboxylate (52j).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 3.46 g (37%); brownish oil. ¹H NMR (400 MHz, CDCl₃) δ 4.21 (t, J = 9.0 Hz, 3H), 4.12 (t, J = 8.0 Hz, 1H), 3.86 (d, J = 12.5 Hz, 1H), 3.78 (d, J = 12.5 Hz, 1H), 3.59 (d, J = 8.5 Hz, 1H), 1.45 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 160.5, 155.7, 119.8 (q, J = 290 Hz), 108.0 (q, J = 33.7 Hz), 80.2, 51.2, 28.2, 27.9, 22.7. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −83.4. LC/MS (CI): m/z = 289/291 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 297 [M–CH₂Br]⁺, 333/335 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₂H₁₆BrF₃N₂O₄: C, 37.04; H, 4.14; N, 7.20; Br, 20.53. Found: C, 37.12; H, 4.01; N, 6.86; Br, 20.45.

tert-Butyl 3-(5-(bromomethyl)-5-(difluoromethyl)-1,4,2-dioxazol-3-yl)azetidine-1-carboxylate (53j).

The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 3.56 g (40%); yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 5.93 (t, J = 53.8 Hz, 1H), 4.24 – 4.17 (m, 2H), 4.15 – 4.12 (m, 1H), 3.76 – 3.70 (m, 1H), 3.56 (s, 1H), 1.57 (s, 2H), 1.44 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 160.37 (d, J = 5.5 Hz), 155.70, 110.37 (td, J = 252.4, 16.1 Hz), 109.17 (d, J = 24.8 Hz), 80.17, 51.35, 41.22, 28.19 (d, J = 8.8 Hz), 22.87 (d, J = 3.4 Hz). ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −135.2 (d, J = 62.0 Hz), −136.0 (d, J = 41.5 Hz). LC/MS (CI): m/z = 271/271 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 315/317 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₂H₁₇BrF₂N₂O₄: C, 38.83; H, 4.62; N, 7.55; Br, 21.53. Found: C, 38.46; H, 4.38; N, 7.55; Br, 21.39.

Ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(difluoromethyl)-isoxazole-4-carboxylate (48f).

The chloroxime 1f (5.00 g, 24.0 mmol) was dissolved in EtOAc (50 mL), then ethyl 4,4-difluoro-3-oxobutanoate (45, 4.19 g, 25.2 mmol), NiCl₂·6H₂O (570 mg, 2.40 mmol), and NaHCO₃ (6.04 g, 72.0 mmol) were added to the vigorously stirred solution at rt. The resulting mixture was stirred overnight. The resulting mixture was dried over Na₂SO₄, filtered through a plug of silica gel and evaporated in vacuo. The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; H₂O – MeCN; flow rate 30mL / min). Yield 999 mg (13%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J = 45.2 Hz, 1H), 5.29 (s, 1H), 4.61 (s, 2H), 4.38 (q, J = 7.2 Hz, 2H), 1.43 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.7, 160.0, 159.0, 155.4, 111.6, 105.7 (t, J = 241 Hz), 80.1, 62.2, 36.7, 28.3, 14.1. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −120.0, −120.1. LC/MS (CI): m/z = 221 [M–CO₂+H₂C=C(CH₃)₂+H]⁺, 265 [M–H₂C=C(CH₃)₂+H]⁺, 343 [M+Na]⁺. Anal. Calcd. for C₁₃H₁₈F₂N₂O₅: C, 48.75; H, 5.66; N, 8.75. Found: C, 48.68; H, 5.44; N, 9.12.

General procedure for the preparation of F₃C-ABT-418 analogues 56

The corresponding amine 13k or 13l (5.14 g, 21.2 mmol) was suspended in dichloroethane (400 mL). Then, MeOH (100 mL), 30% aq CH₂O (20 mL) and NaBH(OAc)₃ (14.0 g, 66.1 mmol) were added. The resulting mixture was stirred overnight at rt, then evaporated in vacuo. The residue was diluted with EtOAc (400 mL), and K₂CO₃ was added until pH = 10 (CAUTION: extensive CO₂ evolution). The reaction mixture was stirred over Na₂SO₄ for ca. 10 min, the precipitate was filtered off, and the filtrate was evaporated in vacuo.

(S)-3-(1-Methylpyrrolidin-2-yl)-5-(trifluoromethyl)isoxazole (56k).

The compound was purified by distillation in vacuo. Yield 4.11 g (88%); colorless powder; mp 56–58 °C; bp 71–73 °C / 0.7 mmHg. [α]²⁰_D = –63.3 (с = 45.4). ¹H NMR (400 MHz, CDCl₃) δ 6.72 (s, 1H), 3.47 (t, J = 8.1 Hz, 1H), 3.19 (t, J = 8.3 Hz, 1H), 2.35 (d, J = 8.9 Hz, 1H), 2.26 (s, 4H), 2.22 (d, J = 8.9 Hz, 2H), 2.00 – 1.93 (m, 1H), 1.85 (td, J = 15.0, 12.8, 5.5 Hz, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.0, 158.6 (q, J = 42.4 Hz), 117.9 (q, J = 270 Hz), 103.6, 61.4, 56.6, 40.3, 32.3, 23.0. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −64.9. LC/MS (CI): m/z = 221 [M+H]⁺. Anal. Calcd. for C₉H₁₁F₃N₂O: C, 49.09; H, 5.04; N, 12.72. Found: C, 48.92; H, 5.36; N, 12.46.

(R)-3-(1-Methylpyrrolidin-2-yl)-5-(trifluoromethyl)isoxazole (56l).

The compound was purified by distillation in vacuo. Yield 4.20 g (90%); colorless powder; mp 56–58 °C; bp 71–73 °C / 0.7 mmHg. [α]²⁰_D = 63.1 (с = 45.4). The spectral data are analogous to that of S-isomer 56k. LC/MS (CI): m/z = 221 [M+H]⁺. Anal. Calcd. for C₉H₁₁F₃N₂O: C, 49.09; H, 5.04; N, 12.72. Found: C, 48.94; H, 4.79; N, 12.49.

N’-(3-Chlorophenyl)-2-oxo-2-(5-(trifluoromethyl)isoxazol-3-yl)aceto-hydrazonoyl cyanide (57).

1.6 M hexanes solution of MeLi (8.96 mL) was added dropwise to the solution of MeCN (1.50 mL) in THF (30 mL) at −78 °C under argon atmosphere. The resulting solution was stirred for −78 to −50 °C for 0.5 h. Then, ester 3a (1.50 g, 7.17 mmol) was added at −78 to −50 °C, and the solution was warmed up to 0 °C for 1 h. After, HOAc (0.82 mL) was added, the reaction mixture was poured into H₂O (25 mL), extracted with EtOAc (50 mL), dried over Na₂SO₄, and evaporated in vacuo. The crude compound 56 was used in the next step without further purification. Next, 1 M aq HCl (1.05 mL) and NaNO₂ (592 mg, 8.58 mmol) in H₂O (2.5 mL) were added to the solution of M–chloroaniline (1.10 g, 8.63 mmol) in H₂O (15 mL) at −5 °C (NOTE: the solution should be homogenous after HCl addition; if the precipitate is formed, additional amount of H₂O should be added). After 30 min, NaOAc·3H₂O (1.94 g, 14.3 mmol) was added, followed by addition of solution of 58 (ca. 1.46 g) in EtOH (15 mL) at 0 °C. After 5 min, the resulting mixture was poured into H₂O (30 mL) at 0 °C, and then extracted with EtOAc (60 mL). The compound was purified by HPLC (SunFire C18 Column, 100 Å, 3.5 μm, 4.6 mm×150 mm, 0–6.5 min; MeCN; flow rate 30mL / min). Yield 2.45 g (46%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 – 7.44 (m, 1H), 7.43 – 7.26 (m, 3H), 7.19 (d, J = 7.1 Hz, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 176.4 and 175.9, 160.1 and 159.9, 159.7 and 159.4, 141.2 and 141.1, 136.2 and 136.0, 131.0, 128.3, 117.5 and 115.6, 116.1 (q, J = 260 Hz) 110.6 and 108.9, 106.3 and 105.5. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −64.4. LC/MS (CI): m/z = 343 [M+H]⁺. Anal. Calcd. for C₁₃H₆ClF₃N₄O₂: C, 45.57; H, 1.77; N, 16.35; Cl, 10.35. Found: C, 45.61; H, 1.41; N, 16.46; Cl, 10.64.

Supplementary Material

SI data

NIHMS1597710-supplement-SI_data.pdf^{(13.7MB, pdf)}

Acknowledgements

The work was funded by Enamine Ltd and NIH grant No. GM133836 (to Prof. John J. Irwin and Y.S.M.). O.O.G. and B.A.V. were also funded by Ministry of Education and Science of Ukraine (Grants No. 19BF037-03 and 19BF037-06, respectively). A.B.R. thanks to the Alexander von Humboldt Foundation (Bonn, Germany) for the financial support by purchasing computer equipment and the license for the Turbomole program used in the current investigation. The authors thank Prof. Dr. Andrey A. Tolmachev for his encouragement and support, Mr. Vasyl V. Skyba for column chromatography purification, and Mr. Oleksandr Liashuk for his help with manuscript preparation.

Footnotes

Supporting Information included copies of ¹H, ¹³C and ¹⁹F NMR spectra, crystallographic information files and computational data. This material is available free of charge at http://pubs.acs.org.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI data

NIHMS1597710-supplement-SI_data.pdf^{(13.7MB, pdf)}

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PERMALINK

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

Bohdan A Chalyk

Kateryna V Hrebeniuk

Yulia V Fil

Dr Konstantin S Gavrilenko

Dr Alexander B Rozhenko

Bohdan V Vashchenko

Dr Oleksandr V Borysov

Dr Angelina V Biitseva

Dr Pavlo S Lebed

Iulia Bakanovych

Dr Yurii S Moroz

Dr Oleksandr O Grygorenko

Abstract

Graphical Abstract

Introduction

Figure 1.

Scheme 1.

Scheme 2.

Results and discussion

Synthesis of 5-(trifluoromethyl)isoxazoles.

Table 1.

Scheme 3.

Figure 2.

Scheme 4.

Table 2.

Figure 3.

Figure 4.

Scheme 5.

Table 3.

Synthesis of other 5-(fluoroalkyl)isoxazoles.

Scheme 6.

Table 4.

Scheme 7.

Scheme 8.

Scheme 9.

Scheme 10.

Scheme 11.

Scheme 12.

Reaction of chloroximes with aliphatic di- and trifluoromethyl ketones.

Scheme 13.

Scheme 14.

Scheme 15.

Synthesis of ABT-418 and ESI-09 analogues.

Scheme 16.

Scheme 17.

Conclusions

Scheme 18.

Experimental part

Calculation methods.

General procedure for the preparation of isoxazoles 3a–o.

Ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3a).53

3-Phenyl-5-(trifluoromethyl)isoxazole (3b).72,73

3-(4-Methoxyphenyl)-5-(trifluoromethyl)isoxazole (3c).

3-(4-Fluorophenyl)-5-(trifluoromethyl)isoxazole (3d).

3-(Thiophen-2-yl)-5-(trifluoromethyl)isoxazole (3e).

tert-Butyl ((5-(trifluoromethyl)isoxazol-3-yl)methyl)carbamate (3f).

(S)-tert-Butyl (1-(5-(trifluoromethyl)isoxazol-3-yl)ethyl)carbamate (3g).

(R)-tert-Butyl (1-(5-(trifluoromethyl)isoxazol-3-yl)ethyl)carbamate (3h).

tert-Butyl (2-(5-(trifluoromethyl)isoxazol-3-yl)propan-2-yl)carbamate (3i).

tert-Butyl 3-(5-(trifluoromethyl)isoxazol-3-yl)azetidine-1-carboxylate (3j).

(S)-tert-Butyl 2-(5-(trifluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (3k).

(R)-tert-Butyl 2-(5-(trifluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (3l).

tert-Butyl 4-(5-(trifluoromethyl)isoxazol-3-yl)piperidine-1-carboxylate (3m).

tert-Butyl (S)-2,2-dimethyl-4-(5-(trifluoromethyl)isoxazol-3-yl)oxazolidine-3-carboxylate (3n).

tert-Butyl (R)-2,2-dimethyl-4-(5-(trifluoromethyl)isoxazol-3-yl)oxazolidine-3-carboxylate (3o).

3,5-Dibromo-5-(trifluoromethyl)-4,5-dihydroisoxazole (5).

3-Bromo-5-(trifluoromethyl)isoxazole (6).

General procedure for the preparation of carboxylic acid 10 and 29

5-(Trifluoromethyl)isoxazole-3-carboxylic acid (10).

5-(Difluoromethyl)isoxazole-3-carboxylic acid (29).

(5-(Trifluoromethyl)isoxazol-3-yl)methanol (11).74

3-(Chloromethyl)-5-(trifluoromethyl)isoxazole (12).

General procedure for the preparation of amines 13f–m·HCl, 13i, 20i–l·HCl and 21g–l·HCl.

(5-(Trifluoromethyl)isoxazol-3-yl)methanamine hydrochloride (13f·HCl).

(S)-1-(5-(Trifluoromethyl)isoxazol-3-yl)ethan-1-amine hydrochloride (13g·HCl).

(R)-1-(5-(Trifluoromethyl)isoxazol-3-yl)ethan-1-amine hydrochloride (13h·HCl).

2-(5-(Trifluoromethyl)isoxazol-3-yl)propan-2-amine (13i).

3-(Azetidin-3-yl)-5-(trifluoromethyl)isoxazole hydrochloride (13j·HCl).

Ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3a).⁵³

3-Phenyl-5-(trifluoromethyl)isoxazole (3b).^72,73

(5-(Trifluoromethyl)isoxazol-3-yl)methanol (11).⁷⁴