An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl- 1,3‑dielectrophiles and 1,2-Azole Derivatives

Valéria D. O. Bareño, Daiane S. Santos, Leandro M. Frigo, Debora L. de Mello, Juliana L. Malavolta, Rogerio F. Blanco, Lucas Pizzuti, Darlene C. Flores and Alex F. C. Flores * Escola de Química e Alimentos, Universidade Federal do Rio Grande, 96203-900 Rio Grande-RS, Brazil Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil Faculdade de Ciências Exatas e Tecnologia, Universidade Federal da Grande Dourados, 79804-970 Dourados-MS, Brazil


An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives
in a less-substituted enolate by irreversible kinetic control, whereas those reactions under thermodynamic control usually yield the more substituted product.In more favorable cases, one regioisomer can greatly predominate the equilibrium mixture, but often the equilibrium constant is not sufficiently high to achieve an acceptable regioselectivity.Furthermore, even if one prepares a regiodefined enolate, problems may occur with proton-transfer isomerization. 29,30On the other hand, the trichloromethyl group has attracted the attention of new material researchers in different fields of chemistry.For example, in the course of screening fungal extracts for new metabolites that induce morphological and physiological differentiation in human HL-60 cells, Becker and Anke 31 isolated and characterized pinicoloform, attributed as (2Z, 5Z, 7E)-1,1,1-trichloro-2-hydroxy-2,5,7-undecatrien-4-one, from fermentations of Risinicium pinicola (Figure 2).Synthetic compounds containing a trichloromethyl group have demonstrated high relevance as biological agents and synthetic intermediates; among them, apcin derivatives (Figure 2) have the ability to block mitotic exit, inducing tumor cell death. 32Penclomedine, 3,5-dichloro-2,4-dimethoxy-6-trichloromethyl pyridine (Figure 2) is presently in clinical trials by the United States National Institutes of Health for treating patients with unspecified solid tumors and lymphoma. 33 u r t h e r m o r e , s o m e s p e c i m e n s o f s p o n g e (Dysidea herbacea) contain 5,5,5-trichloroleucine derivatives, including dysidenin, barbamide, herbacic acid, and herbamide (Figure 2).Interest in natural products that contain the trichloromethyl group found in sponges has been stimulated by biosynthetic observations that the pro-S methyl group of leucine, or an unidentified leucine derivative, is the origin of the trichloromethyl group in a compound produced by the marine cyanobacterium Lyngbya majuscule.This is important in the context that two independent groups have provided evidence that another cyanobacterium, the symbiotic Oscillatoria spongeliae, which lives in association with D. herbacea, is the source of chlorinated metabolites extracted from D. herbacea.34,35   The trichloromethyl group also has attracted attention in crystallographic studies, as well, due to potential sigma effects on chlorine halogen bonding.36 Therefore, the acylation process of acetals is important, particularly for trichloromethyl derivatives, because of the wide scope of the method and consequent diversification of 1,3-dielectrophilic precursors.To the best of our knowledge, acylation of acetals is the only method to date that has been useful to systematically obtain trichloromethyl-substituted 1,3-dielectrophiles. 37,38

Acetal acylation methodology
Acetal synthesis was conducted using an adaptation of the Wohl method. 37Ketones 1a-j were reacted with one mol-equivalent of trimethyl orthoformate under p-toluenesulfonic acid catalysis; after 8 to 24 h, the acid was neutralized with K 2 CO 3 .For levulinic acid (1m) and 5-oxohexanoic acid (1n), reacting one mol-equivalent of trimethyl orthoformate led to methyl 4-oxopentanoate and methyl 5-oxohexanoate, respectively, demonstrating that esterification occurred before the ketalization.To perform esterification and ketalization, 2.5 mol-equivalents of trimethyl orthoformate were added and the mixture was maintained without stirring for 48 h.Distilled acetals 2a-n were reacted with two mol-equivalents of trifluoroacetyl anhydride or trichloroacetyl chloride in a pyridine/ CHCl 3 mixture at -5 to 10 o C, leading to kinetic enol ether, an unsubstituted enol, via O-acylation (Scheme 1).According to the literature and our own experience, this enol ether derived from asymmetrically substituted dimethoxy acetals is readily acylated, through the lower activation energy intermediary, favored by steric factors.Although theoretically there is a higher concentration of thermodynamic enol ether, its acylation requires a higher activation energy, probably due to steric hindrance from the substituent on the β-carbon.Our results demonstrate that the presence of the substituents in the enol ether precursor makes it difficult to form the C-C bond to obtain the enolone push-pull system; thus, experimentally, we can control the regioselectivity by controlling the reaction temperature of trihaloacetylation. 38sing this method, it was possible to obtain a large and diversified series of 1,3-dielectrophiles, as 1,1,1-trialo-4-methoxy-3-alken-2-ones 2,3a-n.In the process of acylating the dimethoxy acetal from raspberry ketone (1i), the hydroxyl substituent of the aromatic ring competed for the acylating agent, making it necessary to increase the quantity of this reagent for complete C-acylation of the enol ether; the proper stoichiometry was 1:3.5 between dimethoxy ketal 2i and trifluoroacetic anhydride.The synthesis and reactivity of the acetal precursor is key to the successful application of this method; for example, the presence of only one α-halogen substituent in the starting ketone facilitates the formation of the ketal precursor, but dramatically reduces its reactivity for enol ether formation.Thus, even when reacting the 1-chloro-2,2-dimethoxypropane and 1,1,1-trifluoro-2,2-dimethoxypropane with trichloroacetyl chloride for 24 h at toluene reflux temperature, it does not form any detectable amount of trichloroacetylation product, indicating that intermediate reactive enol ethers do not form during the process (Scheme 2).In addition, no acylated products were obtained in the acetal acylation reaction starting from dimethoxy acetals derived from 2-acetylpyrrol, 2-acetylpyridine, 3-acetylpyridine, and 4-acetylpyridine.Furthermore, the reaction of hydroxybutanone and trimethyl orthoformate produced 2-methoxy-2-methyloxirane (2q), which was unreactive in trichloroacylation medium under toluene reflux (Scheme 2).This demonstrates the complementarity between the acylation methods for some substrates since, for example, the 1,1,1-trifluoro-4-(pyridinyl)-butan-2,4-dione derivatives are easily obtained following the Claisen method. 39,40he acylation of acetals is particularly important in the case of trichloromethyl-substituted derivatives because of the scarce information available in the literature on the diversification of methods for the production of 1,3-dielectrophilic precursors containing this group.That is why we have concentrated our efforts on these in this study and have previously disclosed some individual results now discussed in this report. 38,41Therefore, if the ketal precursor is formed and isolated in sufficient amounts, it is also possible to vary the trihaloacetylating agent, as demonstrated using chlorodifluoroacetic anhydride for the acylation of methyl 4,4-dimethoxypentanoate (Scheme 3).
On the other hand, Claisen condensation of aldehyde precursors has not been reported in the literature as far as we have been able to confirm; in fact, auto-condensation between aldehydes in basic medium, or aldol condensation, competes with and is preferential over acylation with an ester. 42,43In this case, acetal acylation with trihaloacetylating agents is also an attractive alternative.Obtaining acetals from aldehydes is preferred over obtaining them from ketones.In addition, for steric reasons in the acylated product, 44,45 it allows the use of triethyl orthoformate instead of the more expensive trimethyl orthoformate.Therefore, we reacted lauric aldehyde and triethyl orthoformate under tosylic acid (TsOH) catalysis to obtain 1,1-diethoxydodecane.This aldehyde-derived precursor was reacted with two molar equivalents of trifluoroacetic anhydride in chloroformpyridine solution at 50 o C.After 24 h under stirring, the consumption of all precursor acetal was observed and the reaction was quenched.The product obtained was attributed as 3-(ethoxymethylene)-1,1,1-trifluorotridecan-2-one.In addition, with this precursor, acylation was performed with chlorodifluoroacetic anhydride in chloroform-pyridine solution, leading to 1-chloro-3-(ethoxymethylene)-1,1-difluorotridecan-2-one (Scheme 4).
Attempts to hydrolyze the isolated 1,1,1-trifluoro(chloro)-4-methoxyalk-3-en-2-ones 3,4a-g were not successful even under conditions using acetonitrile to homogenize the reaction medium.Table 1 shows the reaction media used in the attempt to obtain the 1,1,1-trifluoro(chloro) undecan-2,4-dione derivatives 5,6a from 1,1,1-trihalo-4-methoxyundec-3-en-2-ones 3,4a.These reaction media worked well for phenethyl-like derivatives 3,4h-j and for the derivatives substituted with the thiomethyl group 3,4k.For strongly acid-sensitive functional groups containing 1,1,1-trihalo-4-methoxyalk-3-en-2-ones (3,4g,m,n), this process was not successful, forming in general, polymeric products without reproducibility.It is worth mentioning that one-pot hydrolysis of methyl 8,8,8-trifluoro-5-methoxy-7-oxooct-5-enoate (3n) obtained 3-(4-oxo-2,6-bis(trifluoromethyl)-4H-pyran-3-yl) propanoic acid, derived from condensation between the hydrolyzed product, 8,8,8-trifluoro-5,7-dioxooctanoic acid, and the methyl trifluoroacetate present in the reaction medium (Scheme 6). 47 1 , 13 C, and 19 F nuclear magnetic resonance (NMR) attribution The molecular structures of the alkoxy alkenones were characterized based on NMR spectroscopy and mass spectrometry (MS) data.The electron impact ionization (EI) MS or exact mass recorded by high-resolution measurements as well as the signal pattern of NMR spectra confirmed the products obtained.In the case of trifluoroacylated ketones, the 1,1,1-trifluoro-4-methoxyalk-3-en-2-ones 3a-n, the 1 H NMR spectra showed common characteristics including singlet signals from vinylic H-3 (H-5 for ester 3m, and H-6 for ester 3n) at d 5.6 to 5.7 ppm and the methoxy group at d 3.78-3.79ppm; other signals were due to alkyl from the starting ketone.The 13 C NMR spectra included signals from methoxyenone carbons C-1 to C-4 (C-4 to C-7 to ester 3m, and C-5 to C-8 to ester 3n), and a signal from the methoxy group.C-1 and C-2 appeared as quartets at d 116-117 ppm with 1 J CF 292 Hz, and d 178-179 ppm with 2 J CF 34 Hz, respectively; C-3 appeared at d 91-92 ppm; and C-4 appeared at d 182 to 185 ppm, with spectra obtained for 1,1,1-trifluoro-4-methoxy-8-methyl non-3,7-dien-2-one (3g) (Figure 3).The 19 F NMR data were compatible with already observed chemical shift values for α,β-unsaturated trifluoromethyl ketones or enolized trifluoromethyl-β-diketones ranging from -78 to -76 ppm to trifluoromethyl substituted series 3 and 5. 48 Trichloromethyl-substituted derivative 4 also showed a set of characteristic signals for the nuclei of the constituent atoms of the enone entity, in addition to the characteristic signals for each substituent coming from the precursor methyl ketones.In these compounds, the 1 H NMR spectra showed common characteristics including singlet signals from vinylic H-3 (H-5 for ester 4m, and H-6 for ester 4n) at high-field d 5.9 to 6.0 ppm and the methoxy group at d 3.8-4.0ppm; both were more deshielded than the respective trifluoromethyl-substituted derivatives, and the other signals were due to the alkyl from the starting ketone.Further support for acylated products was provided by the 13  The 1 H NMR spectra for 3-(ethoxymethylene)-1,1,1-trihalotridecan-2-one showed characteristic signals of the enone system, including a signal from vinylic hydrogen at d 7.5 to 8.0 ppm, one from the ethoxy group at d 1.39 (t, J HH 6.8 Hz) and 4.2 ppm (q, J HH 6.8 Hz), and the pattern signal set of a ten-carbon fatty chain (see SI section). 13C NMR data indicated that the enone C-2 was the more deshielded signal at d 179.7 ppm with 2 J CF 34 Hz; the signal from C-4 at d 164.2 ppm was a quartet with 4 J CF 5 Hz; and the signals from CF 3 and C-3 appeared at d 117.0 and 117.1 ppm, respectively, forming an interesting set, a large quartet with J CF 291 Hz and an intense signal almost in the middle (see SI section).One-pot procedure; b after isolation of oily precursor 3a or 4a.
For the series of 6-aryl-1,1,1-trifluorohexan-2,4-diones 5h-j obtained from acid hydrolysis of the 6-aryl-1,1,1-trifluoro-4-methoxyhex-3-en-2-ones 3h-j, in which the substituents were not susceptible to the acid medium used, the spectrum pattern for 1 H NMR showed, as the most remarkable characteristic, the disappearance of the signal due to the methoxy group.The H-3 signal was slightly deshielded to 5.9 ppm, and the enolic OH was not clearly observed due to fast exchange with residual water in the CDCl 3 .The 13 C NMR spectra presented very evident differences in chemical shifts, C-F coupling constants, and multiplicity of the signals from the enone system carbons.For example, the signal for C-2 in enone 3h appeared at d 178.9 ppm with 3 J CF 33 Hz, whereas in the diketone 5h the signal for C-2 was shielded by 4 ppm appearing at d 174.8 ppm with 2 J CF 36 Hz .The C-4 in enone 3h appeared at d 184.4 ppm while the C-4 in the diketone 5h was deshielded by 12 ppm at d 196.5 ppm.
The signals for CF 3 carbon appeared at d 117.1 ppm for both enone and diketone, nevertheless the J CF values differed by 10 Hz, with 292 Hz for CF 3 in enone 3h and 282 Hz in diketone 5h.Also important was the chemical shift variance and coupling constant 3 J CF of C-3 in the diketone product relative to enone, as it appeared at 91.7 ppm without CF coupling for 3h and was deshielded at d 96.2 ppm with 3 J CF 2 Hz for diketone 5h.The trifluoromethyl-β-diketones showed a remarkable preference for keto-enol forms in CDCl 3 , with the intramolecular hydrogen bond.
When R = alkyl groups, as the series synthesized here, the dynamic equilibrium constant between forms A and B (Figure 4) is near unity. 6However, considering the correlation between CF coupling constants and alkene configuration described by Bégué et al. 45 for trifluoromethylated vinyl compounds, we can conclude that the keto-enol form preferred is A, because we observed a 3 J CF around 2.0 Hz for isolated product 5.The methoxy group in enone 3 fixed the resonant push-pull system and caused the adoption of a geometry that does not favor coupling between C-3 and the F atoms of the trifluoromethyl group.
For trichloromethyl-β-diketones, the 1 H NMR spectrum showed signals from H-3 as a singlet at 6.0 ppm for 6h, together with methylene multiplets at 2.71 and 2.98 ppm and phenyl hydrogens as a broad multiplet at 7.18-7.30ppm, demonstrating the presence of an enone (keto-enol) form in CDCl 3 solution.The 1 H NMR spectrum from 6k showed that this hydrolyzed product exists in an enone form as well as in a diketo form when in CDCl 3 solution.The signal from vinylic H-3 was a singlet at d 6.28 ppm, and doublet signals at d 4.28 and 4.43 ppm were attributed to diastereotopic methylene between the two carbonyls of the diketo form, with a geminal coupling constant of J HH 16.4 Hz.Besides the two quartets from H-5 at d 3.39 and 3.51 ppm with J HH 7.0 Hz, at a 3:1 ratio between the enone and keto forms, the spectrum showed two singlet signals from the thiomethyl group and two doublets from the terminal CH 3 .
Here we also present the 13 C{ 1 H} spectrum of the 4a / 6a mixture to demonstrate that, in the trichloroacetylated derivatives 4 and 6, a different trend was observed for the chemical shifts of the carbon nuclei when comparing enone and diketone trifluoroacetylated derivatives, 3 and 5, respectively.The signal for C-2 in enone 4a appeared at d 179.8 ppm without hydrogen coupling, whereas in the diketone 6a the signal for C-2 was deshielded by 5 ppm appearing at d 185.3 ppm with 2 J CH 3 Hz.The C-4 in enone 4a appeared at d 183.9 ppm while the C-4 in the diketone 6a was deshielded by 6 ppm at d 190.6 ppm.The signals for CCl 3 carbon appeared at d 98 and 94.8 ppm for enone and diketone, respectively.C-3 signals included a doublet at 89.6 ppm with J CH 158 Hz for enone 4a and a doublet of triplets at 92.1 ppm with J CH 170 Hz and 3 J CH 3 Hz in diketone 6a (Figure 3).The experimental procedure for these cyclocondensation reactions is very simple and allows the use of green solvents to an extent.Our experiments showed that the reaction between hydroxylamine hydrochloride and 1,1,1-trihalomethyl-4-alkoxy-3-alken-2-ones 3 or 4, leading to 5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazoles 8 or 9, can be catalyzed by bases or acids.The reaction medium pH is around 7-8 starting from a mixture with equimolar amounts of NaOH and hydroxylamine hydrochloride and dielectrophile precursor (8 or 9) in water, methanol, or ethanol, reacting under neutral conditions.The mixture pH is around 1-2 in water, methanol, or ethanol, when starting from a mixture of only hydroxylamine hydrochloride and dielectrophile precursor, without adding other promoters.All of these reaction media led to prove that, during the process of cyclocondensation, there is an intermediate that allows the closure of the hemicetal entity in the C-5 by Re or Si faces (Figure 5).
The 1 H NMR spectrum of 9g displayed dihydroisoxazole H-4 diasterotopic hydrogens as an AB system, with doublets at d 3.2 and 3.63 ppm and a geminal coupling constant at 2 J 18.8 Hz.The H-4 that is cis to CCl 3 was attributed to the downfield doublet d 3.63 ppm, whereas 4-H, which is cis to the hydroxyl group, was attributed to the upfield doublet d 3.20 ppm.For the 2a-f series, the other 1  The details of the spectroscopic data for 5-hydroxy-3-(4-methyl-3-pentenyl)-5-trichloromethyl-4,5-dihydroisoxazol (9g) are shown in the Experimental section.
The compounds 9a-c,e,f were dehydrated in 98% H 2 SO 4 to produce trichloromethyl-substituted isoxazoles 11a-c,e,f (Scheme 7).Aromatization occurred smoothly at 25 o C, and white needle compounds (9) readily dissolved in concentrated sulfuric acid, forming slightly yellowish solutions.These were maintained under stirring for a further 2 h.Then the reaction was treated with ice water and extracted twice with ethyl acetate.The solvent was evaporated to obtain yellowish oil residues at excellent yields (> 90%); these were assigned as 5-trichloromethylisoxazole 11.The compound was also characterized by its 1 H / 13 C NMR spectra, which displayed a characteristic singlet signal at around d 6.47 ppm; furthermore, the signals for isoxazole carbons C-3, C-4, Scheme 7. Cyclocondensation to trihalomethylisoxazole derivatives.the same products, namely, 5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazole 8 or 9, and at very similar yields.Similar results were obtained when the dielectrophilic precursor in cyclocondensation with hydroxylamine was a trihalomethyl-β-diketone 5 or 6.Caution must be taken not to add NaOH to the trichloromethyl-β-diketone, which causes the haloform reaction. 49he cyclization of trifluoromethyl-1,3-dielectrophiles 3h-l or trichloromethyl-1,3-dielectrophilic precursors 4a-h, 4k-n with hydroxylamine hydrochloride proceeded smoothly in EtOH at 50 o C for 4-8 h.Because ethanol functions with the entire set of trihalomethyl-1,3-dielectrophiles studied in this work, it was chosen as the solvent, although cyclization of 1,1,1-trichloromethyl-4-methoxy-3-alken-2-ones to the isoxazoles has already been done in water. 50After completion of the reaction, the solvent was evaporated, and solid residues were purified by recrystallization from hexane.White solids with a fibrous texture were obtained in isolated yields of 85-90% and attributed as 5-hydroxy-5-trifluoromethyl-4,5-dihydroisoxazoles 8g,h,k-m or 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles 9a-c,f-h,k,m (Scheme 7), which were fully characterized by NMR spectroscopy and electrospray ionization (ESI) high-resolution mass spectrometry (HRMS).
The 1 H NMR spectrum of 5-hydroxy-5-trifluoromethyl-4,5-dihydroisoxazole 8l exhibited only one set of signals: the characteristic two doublets at d 3.0 and 3.22 ppm with germinal 2 J HH 18.4 Hz for the diastereotopic hydrogens at the 4-position of the isoxazole ring.In addition, there were signals from the hydrogens of the methoxy group as a singlet at d 3.86 ppm, from the methylene in the benzyl entity as a singlet at d 3.77 ppm, and from aromatic ring between 6.91 and 7.32 ppm (see SI section).However, the 4,5-dihydroisoxazoles 8k,9k were a mixture of disteroisomers, because we started from 3-thiomethyl-2-butanone as a racemate.For example, the 1 H NMR spectrum for 9k displayed two sets of signals for diastereotopic H-4 with large variation in chemical shifts, four doublets at d 3.37, 3.99, 3.78 and 3.88 ppm.These data and C-5 in compound 11 appeared at d 164, 103, and 168 ppm, respectively.

Conclusions
We demonstrate the wide scope of the acetal acylation method for production of 1,3-dielectrophiles with diverse functionalized substituents, including prenyl.This method allows the formation of C-C bonds through acylation in a mild acidic medium, allowing precursors with groups that are vulnerable to attack by bases.The 1,3-dielectrophilic products (4-alkoxy-1,1,1-trihaloalk-3-en-2-ones or 1,1,1-trihaloalkan-2,4-diones) are important precursors in the preparation of 1,2-azole heterocycles, and herein we report isoxazoles and 1H-pyrazoles with prenyl, phenethyl, and substituted phenethyl entities, and a series with neutral amphiphilic molecular structures.

Experimental
Unless indicated otherwise, all common reagents were used as obtained from commercial suppliers without further purification.Yields listed are of isolated compounds. 1H, 13 C, and 19 F NMR spectra were acquired on a Bruker DPX 200, Bruker DPX 400, or Ascend 400 spectrometer at 300 K, using 5 mm sample tubes, and with a digital resolution of ± 0.01 ppm.CDCl 3 was used as a solvent with tetramethylsilane (TMS) as the internal standard.Chemical shifts are expressed in ppm and coupling constants in Hz.The following NMR abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet.Melting points were determined using open capillaries on a Fisatom 431 apparatus and are uncorrected.HRMS analyses: the compounds were dissolved in acetonitrile (Merck, West Point, USA) and deionized water (50% (v/v) with 0.1% formic acid.The dissolved compounds were injected individually into the ESI source using a syringe pump (Harvard Apparatus) at a flow rate of 150 μL min -1 .ESI(+)-MS and tandem ESI(+)-MS/MS data were acquired using a hybrid high-resolution and high-accuracy (5 μL L -1 ) microTof (quadrupole time of flight (QTOF)) MS (Bruker Scientific).Conditions: cone voltages were set to +3500 and +40 V, respectively, with a de-solvation temperature of 100 o C. For ESI (+)-MS/MS, the energy (between 5 and 40 eV) for collision-induced dissociation (CID) was optimized for each component.Diagnostic ions were identified by comparing the measurements to theoretical ESI(+)-MS/MS data.EI-MS were registered in an HP 5973 MSD connected to an HP 6890 GC and interfaced with a Pentium PC.The GC was equipped with a split-splitless injector and an auto-sampler cross-linked HP-5 capillary column (30 m, 0.32 mm internal diameter), and helium was used as the carrier gas.

3-(Ethoxymethylene)-1,1,1-trihalotridecan-2-ones
To a stirred solution of diethoxy acetal derived from precursor aldehyde 2v (30 mmol) and pyridine (60 mmol, 4.8 g) in CHCl 3 (30 mL) kept at 0 o C, a solution of acylating reagent (60 mmol: 8.4 mL trifluoroacetic anhydride, 10.5 mL chlorodifluoroacetic anhydride or 6.8 mL trichloroacetyl chloride) in CHCl 3 (20 mL) was added dropwise at -5 to 10 o C. Then the mixture was stirred for 12-24 h under reflux (60 o C).After the mixture was quenched with a 2 M HCl solution (20 mL), the organic layer was separated and washed twice with water and dried with Na 2 SO 4 .The solvent was evaporated, and the residue was distilled to remove methyl trihaloacetate byproducts.The products 3v, 4v, and 7v were obtained as reddish to black oil with high purity.

5-Trichloromethylisoxazoles
Compounds 9a-c and 9e,f (3.5 mmol) were efficiently stirred with 98% H 2 SO 4 (2.0 mL) for 5 h.Then cooled water was added and the insoluble residue was filtered and washed with water and a saturated solution of NaHCO 3 , producing 5-trichloromethylisoxazole derivatives 11a-c, and 9e,f in good yields (Table 1).Complete identification data for all isolated 5-trichloromethylisoxazoles are available in the SI section.
C NMR spectra.Pattern 4g showed high-field signals from carbonyl C-2 and enol ether C-4 at d 179.9 and 183.3 ppm, respectively.There was a signal from vinylic C-3 at d 90.2 ppm, a short signal from CCl 3 at d 98.0 ppm, an intense signal from the methoxy group at d 56.2 ppm, signals from methylenes at d 35.3 and 25.7 ppm, and signals at d 132.8, 122.5, 25.6, and 17.6 ppm from the other carbons in the substituent chain (see Supplementary Information (SI) section).
H NMR signals were characteristic of the saturated fatty chain at 3-position of the isoxazole ring, with a triplet from α-methylene at d 2.41 ppm, a quintet from β-methylene at d 1.60 ppm, a broad signal from internal methylenes at d 1.35 ppm, and a triplet from the terminal methyl at d 0.80 ppm.The 13 C NMR spectra of 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles displayed C-3, C-4, and C-5 signals at approximately d 160, 46, and 110.4 ppm, respectively.The CCl 3 carbon displayed a characteristic small signal at approximately d 101 ppm, and the saturated fatty substituent gave rise to a set of signals at a high field, between d 14 and 32 ppm.

3 J
F NMR spectroscopy and by MS.The 1 H NMR spectrum of the 5(3)-trifluoromethyl-3(5)-(2-phenylethyl)-1H-pyrazole (12h) displayed an aromatic H4 at d 6.3 ppm, signals from the ethylene spacer as a coalescent multiplet at d 2.99 ppm, and signals from aromatic hydrogens as multiplets at d 7.17 and 7.29 ppm.The 13 C NMR data also conformed to the structure of 12h, with signals from pyrazole cycle C3 at d 144.7 ppm, C5 at d 143.0 ppm with 2 J CF 38 Hz, and C4 at 102.2 ppm with CF 1.5 Hz, along with signals from a phenyl ring at d 139.9, 128.7, 128.3, and 126.6 ppm, a remarkable quartet from CF 3 at 121.3 ppm with J CF 268 Hz, and signals from an ethylene spacer at d 35.0 and 27.1 ppm.Finally, the

Figure 6 . 1 H
Figure 6. 1 H NMR spectrum of a mixture obtained from a reaction between 4c and NH 2 OH.HCl in 30% H 2 SO 4 .

5 -
H y d r ox y -5 -t r i f l u o r o m e t hy l -3 -( 2 -p h e ny l e t hy l ) -4,5-dihydroisoxazole (8h)