Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

Bis(trimethylsilyl)ketene acetals readily react with activated N -triflyl isoxazoles to selectively afford novel isoxazoline or isoxazolidine derivatives. The regioselectivity of the reaction strongly depends on the substrate substituents. When the isoxazole is substituted at the 5-position by a methyl or phenyl group, the lactonization product, i

Herein, we report a methodology to selectively obtain novel 4-isoxazoline carboxylic acid or isoxazolidineδ-bicyclic lactone derivatives via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles.To promote the reaction, we decided to activate the substrate by introducing the strongly electron-withdrawing triflyl group at the 2-position of isoxazole.Additionally, the CF3SO2 group could confer potential biological activity to the product. 40,41

Results and Discussion
We started our study with the activation of isoxazole 1 with triflic anhydride (1.2 equiv), followed by the addition of bis(trimethylsilyl)ketene acetal 2 at -78 o C in CH2Cl2 as the solvent (Scheme 1).

Scheme 1. Synthesis of 4-isoxazoline derivatives (3).
If substrate 1 is not activated with triflic anhydride, the carbon at the 3-position is not electrophilic enough and the reaction does not proceed (Table 1, entry 1).
As shown in Table 1, after triflic anhydride is added, the activation time has an important impact on the overall reaction effectiveness.When 1 was reacted with triflic anhydride for 1 h, and then 2 is added and stirred for 24 h, the 4-isoxazoline carboxylic acid derivative 3 is obtained in 50% yield (Table 1, entry 2).However, if the reaction is activated for 3 h, the yield increases to 81% (Table 1, entry 3).After 4 h activation, there is not a significant change in the yield (Table 1, entries 4 and 5).In order to explore the scope of this reaction, we decided to examine the reaction of oxazole 1 with different bis(trimethylsilyl) ketene acetals 2 (Table 2).As expected, the nucleophilic addition reaction showed strong dependence on steric effects.When the bis(trimethylsilyl) ketene acetals are substituted by R 2 and R 3 substituents larger than methyl groups, i.e., cyclobutyl, cyclopentyl and cyclohexyl groups, the yields decreased dramatically as the steric-hindrance effects increased (Table 2).This result can be attributed to the presence of the voluminous -SO2CF3 group at the 2-position of the isoxazole, increasing the steric strain in the compound which led to product degradation.
Compounds 3a-d were fully characterized using spectroscopic techniques.As a representative example, for compound 3a, the presence of the carboxylic acid was clearly observed in the IR spectrum by two absorption bands: a broad band between 2800 and 3200 cm -1 (ν(OH)), and a sharp band at 1771 cm -1 (ν(C=O)).The 1 H-NMR spectrum showed a broad singlet at 10.54 ppm corresponding to the hydrogen of the -COOH group, and a signal at 5.23 ppm (m, 1H) corresponding to the proton at the 3-position of the isoxazoline (the site of the nucleophilic addition by the bis(TMS)ketene acetal).In the 13 C-NMR spectrum, a signal at 181.3 ppm is observed for the carboxylic carbon, and introduction of the triflyl group is confirmed by a quartet signal at 121.74 ppm (JCF 323. 2  Hz).Moreover, the molecular structure of compound 3c was unambiguously confirmed by X-ray diffraction analysis (Figure 1).The molecular structure shows the carboxylic acid in an anti-conformation with respect to the triflyl group.Interestingly, when the isoxazole is substituted at the 5-position by a methyl group (Scheme 2), the lactonization product 4 was isolated as the main product (Table 3, entries 1 and 2), and only some trace amounts of carboxylic acid 3' were observed.

Scheme 2. Synthesis of δ-lactones 4.
In fact, it was possible to isolate crystals of compound 3' (R 1 = Me, entry 2), whose structure was confirmed by X-ray diffraction analysis (Figure 2); however, the amount was not sufficient enough to allow its characterization by NMR spectroscopy.When the reaction was carried out with phenyl and para-substituted phenyl groups at the 5-position of the isoxazole, the lactonization product 4 (isoxazolidine derivative) was also obtained instead of the carboxylic acid 3. Products 4c-g were obtained in moderate to good yields (Table 3, entries 1-7).
Notably, derivatives 4 are easily obtained in only one step using this methodology, while the synthesis reported by Miller and co-workers 42 for a structurally similar compound required several steps.The structures of compounds 4a-g were fully characterized by spectroscopic techniques.As a representative example, for compound 4e, in the IR spectrum, the absorption band of the carbonyl group, ν(C=O), was found at 1758 cm -1 , which is in the typical range of wavenumbers expected for a δ-lactone.In the 1 H-NMR spectrum, the clearest evidence of lactone formation were protons H3 and H4; the signal of H3 was observed as a doublet at 4.73 ppm ( 3 JH3-H4 5. 16 Hz), while the signals of the methylene diastereotopic protons H4 and H4' were found at 2.82 ppm (d, 2 JH4-H4' 13.2 Hz) and 2.68 ppm (dd, 2JH4-H4' 13.2 Hz, 3 JH3-H4 5. 16 Hz), respectively.The 13 C spectrum shows the signal of C5 at 109.9 ppm, corroborating the ring closure, and the quartet signal at 120.9 ppm (JCF 320. 25 Hz) confirmed the presence of the triflyl group.Furthermore, the molecular structures for lactones 4c and 4e were unambiguously confirmed by X-ray diffraction analysis (Figures 3 and 4, respectively).To explain the regioselectivity of the reaction, a plausible mechanism is proposed as shown in Scheme 3. In the first step, isoxazole 1 reacts with triflic anhydride to form the electrophilic iminium salt A, then ketene acetal 2 is activated by triflate anion generating the naked enolate which reacts with iminium salt A via the nucleophilic addition at imine carbon to yield adduct B. As described above, when isoxazole 1 is not substituted at the 5position, the reaction affords the corresponding carboxylic acid 3 by hydrolysis of adduct B. In contrast, when the isoxazole is substituted at the 5-position by an electron-donating group like methyl or phenyl, the olefin in adduct B readily undergoes electrophilic addition, promoted by traces of the triflic acid generated in situ, to give the stabilized carbocation C. Finally, lactone 4 is formed through an intramolecular cyclization of intermediate C. In accordance with the stabilization of carbocation C, when the phenyl is substituted at the 4-position by an electron-donating group, e.g., a methoxy group (Table 3, entry 2), the lactonization product 4d was obtained in good yield (70%), while, with less electron donating groups, e.g., halogens, the yield decreases to around 50% (Table 3, entries 3-5).
A variety of methodologies have been reported for the olefinic esters cyclization mediated by Bronsted or Lewis acids, all proposed mechanisms for this kind of reaction involve the formation of carbocationic species by addition of the Bronsted or Lewis acid to the olefin, followed by the intramolecular addition of the nucleophile 43 as shown for transformation B to 4. Although this reaction has been less studied with 2,3-dihidro isoxazol derivatives, a similar reactivity of intermediate C' has been proposed by Campagne et al. 44 Scheme 3. Proposed mechanism for the formation of carboxylic acid 3 and δ-lactone 4.

Conclusions
A straightforward methodology has been developed for the synthesis of highly functionalized 4-isoxazoline and isoxazolidine derivatives, via the addition of the masked dinucleophile bis(trimethylsilyl)ketene acetal to N-trifyl activated isoxazoles.The regioselectivity of the reaction is governed by the ability of the substrate to stabilize the carbocation intermediate at the 5-position of the isoxazole.In this way, when the isoxazole is substituted by methyl or phenyl groups, the lactonization product (isoxazolidine derivative) is afforded.When the isoxazole is not substituted, the reaction stops at carboxylic acid formation (4-isoxazoline derivative).

Experimental Section
General.All substrates and solvents were purchased from specialized suppliers with analytical purity and were used as received without any further purification.Melting points were determined on a Melt Temp II apparatus.The 1 H and 13 C NMR spectra were measured with a Bruker Avance III (300 MHz) and a Bruker Avance III (400 MHz) using CDCl3 or Acetone-d6 as solvent.Chemical shifts are expressed in ppm () relative to TMS.The following abbreviations are used: br=broad signal, s=singlet, d=doublet, t=triplet, dd=double doublet, q=quartet and m=multiplet.Mass spectra were obtained by DART and TOF mass spectrometer.IR spectra were obtained with a Bruker TENSOR 27 spectrophotometer.Suitable X-ray-quality crystals of 3c, 3', 4c, 4e compounds were grown through slow evaporation of solvent.A single white crystal of compounds 3c, 3', 4c, 4e were mounted on a glass fiber at room temperature.The crystal was then placed on a Bruker SMART APEX CCD diffractometer, equipped with MoKa radiation; decay was negligible all cases.Systematic absences and intensity statistics were used in space group determinations.The structures were determined using direct methods. 43Anisotropic structure refinements were achieved using full-matrix, least-squares techniques on all non-hydrogen atoms.All hydrogen atoms were placed in idealized positions, based on hybridization, isotropic thermal parameters fixed at 1.2 times the value of the attached atom.Structure solutions and refinements were performed using SHELXTL v 6.10. 44The bis-(trimethylsilyl)ketene acetals 2 were prepared according to published methods. 45neral procedure for the synthesis of carboxylic acids 3. Trifluoromethane sulfonic anhydride (1.2 equiv, 3.6 mmol) was slowly added by syringe to a solution of isoxazole 1 (3 mmol) in dry dichloromethane (15 mL) at -78 °C and under an inert atmosphere (N2).After 4h at -78 o C, the corresponding bis(trimethylsilyl)ketene acetal 2 (1.2 equiv, 3.6 mmol) was added.Then the temperature was allowed to warm to room temperature and stirred for 20h.The crude was transferred to a separating funnel and washed with water (3 x 20 mL).The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure.The products were purified by silica gel column chromatography, eluted with mixtures of 90:10 hexane/ethyl acetate.

Table 1 .
Activation times of isoxazole 1 and yields