Synthesis, Structure, and Cyclocondensation of the 4,4,4-Trifluoro-3,3-dihydroxy-2-methyl-1-(thien-2-yl)-1- butanone with Hydroxylamine and Hydrazine

The synthesis of 4,4,4-trifluoro-3,3-dihydroxy-2-methyl-1-(thien-2-yl)butan-1-one (3) through acylation of 1,1-dimethoxy-1(thien-2-yl)propane (1) with trifluoroacetic anhydride and its reactions with hydroxylamine and hydrazine was investigated. X-ray structural analysis of new trifluoromethyl-substituted dielectrophile 3 revealed that this hydrate exists as a racemate with interand intramolecular O-H·O bonds. The crystal structure shows alignment along axis b of pair molecules with the same configuration of the O2-H·O1 bond. For 5(3)-trifluoromethyl-4-methyl-3(5)-(thien-2-yl)-1H-pyrazole (4), obtained via cyclocondensation of precursor 2 and hydrazine hydrochloride, X-ray structural analysis indicated that its rings are almost planar (torsion angle N2-C5-C6-C7–5.4°) and that S1 at the thienyl moiety is anti-periplanar to N2 (torsion angle N2-C5-C6-S1 176.01); no disorder effect was observed for the thienyl ring.

In this work, we report the application of an acetal acylation method to 1,1-dimethoxy-1-(thien-2-yl)-propane 1 and the cyclocondensation of dielectrophilic products obtained using the dinucleophiles hydrazine and hydroxylamine.
In the 1 H NMR spectrum of the mixture obtained after acid work-up, a quartet at 3.75 ppm with J HH 6.8 Hz was assigned to H-2 of product 2, and one at 3.85 ppm with J HH 6.8 Hz was assigned to H-2 of hydrate 3; in addition, multiplet signals from the thien-2-yl ring at δ 7.43 and 7.75 ppm were observed.In the 13 C{ 1 H} NMR spectrum, quartet signals at 187.6 ppm with J CF 36 Hz and at 95 ppm with J CF 32 Hz were compatible with a mixture of acylated products 2 and 3.
The infrared absorption spectra of compound 3 are presented (Figure 2) and show the O-H stretching at 3383 cm −1 , attributable to the linear vibration of O-H bonds; in this region C-H stretching is also observed, 3074 and 3016 cm −1 .The C=O stretching is observed at 1662 cm −1 , and an intense absorption is observed at 1448 cm −1 attributable to bending of CF 3 group.The absorption peaks at the region of 2300-2400 cm −1 indicated the carbon dioxide of normal air.
Hydrate compound 3 crystallizes in the P2 1 /n space group (Table 1).Figure 1 shows the molecular structure with the atom-numbering scheme, and Figure 2 shows the unit cell packing.Molecule 3 in a solid state consists of a pseudoring with an intramolecular O-H…O hydrogen bond (Figures 2 and 3).The bond distances and angles of the thienyl and trifluoromethyl hydrate moieties in the structure are in an acceptable range.The dihedral angle O3C5C6S1 1.1 °indicates coplanarity between the thienyl ring and the carbonyl group, and the refinement indices do not suggest disorder on the thienyl ring.In the crystal structure, the molecules are linked together by pairs of intermolecular O-H…O hydrogen bonds to form dimers (Table 2; Figures 3 and 4); there are also π-π interactions between antiparallel thienyl rings, which yield an infinite 3D arrangement of layers.
The 1 H NMR spectra of the mixture 4a/4b in CDCl 3 contain two signals assigned to the methyl at position 4 of the isoxazole ring.A doublet at 1.48 ppm with 3 J HH 7.6 Hz was attributed to a 4a (4R,5R)/(4S,5S) enantiomer pair.And assuming that the spin-spin coupling between the hydrogen from the methyl group and the fluorine from the trifluoromethyl group occurs through space, then the doublet of quartets at 1.45 ppm with 3 J HH 8.0 Hz and J FH 2.0 Hz was attributed to a 4b (4S,5R)/(4R,5S) enantiomer pair.The quartet at 3.89 ppm with J HH 6.8 Hz was assigned to H-4 of an isoxazole isomer of 4a, and one at 3.78 ppm with J HH 6.8 Hz was assigned to H-4 of a minor isoxazole isomer of 4b.The spectrum also has multiplet signals between δ 7.0 and 7.50 ppm from the thien-2-yl ring.The signals corresponding to OH were assigned to 2.35 (4a) and 2.31 ppm (4b); although the ratio between the integrals of the signal areas corresponding to H-4 and that assigned to OH, for each product 4a or 4b, is not 1 : 1, they maintain the same ratio between these areas in both products, in both 4a and 4b; the ratio between the area of the signal around 3.8-3.9ppm and the area of the signal around 2.3 is equal to 3.5.
In the 13 C{ 1 H} NMR spectra, the quartet signals at 103.8 and 104.1 ppm with J CF 33 Hz were assigned to C-5 of isoxazole rings of 4a/4b, and signals from a CF 3 group were observed at 121.8 and 122.2 ppm with J CF 285 Hz.The signals originating from CH 3 at position 4 of the diastereoisomeric isoxazoles of 4 presented a difference of 2 ppm, a singlet signal at 10.8 ppm was assigned to 4a, and a quartet signal at 12.8 ppm with J CF 2.9 Hz was compatible with 4b; therefore, this coupling between the methyl and the trifluoromethyl groups through space indicates the cis relationship [11].The condensation of 3 with hydrazine hydrochloride was carried out in ethanol under reflux for 6 h, producing 4methyl-3( 5)-(thien-2-yl)-5(3)-trifluoromethyl-1H-pyrazole (5) as a crystalline solid at 85-89% yield (Scheme 3).Unlike of the hydroxylamine dinucleophile, [3 + 2] cyclocondensations of unsubstituted hydrazine with trifluoromethyl- 2 Journal of Spectroscopy substituted dielectrophiles lead to an aromatic 1H-pyrazole product [12] without isolating the intermediate 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazol.The aromatic 1H-pyrazole product is isolated as a tautomeric form depending on the substituents and other parameters [13]; here, we attributed the 1,5-tautomer form from NMR CDCl3 solution analysis data and 1,3-tautomer form from the crystal X-ray diffraction data (Tables 3 and 4; Figures 5 and 6).
The 1 H NMR spectrum of the 5(3)-trifluoromethyl-4methyl-3(5)-thien-2-yl-1H-pyrazole (5) in CDCl 3 contains only one signal set: a singlet at 2.29 ppm assigned to the methyl at position 4 of the 1H-pyrazole ring and multiplet signals between δ 7.0 and 7.50 ppm from the thien-2-yl ring.In the 13 C{ 1 H} NMR spectra, a quartet signal at 141.2 ppm with J CF 36 Hz corresponded to C-5, a simple signal at 137.4 ppm was assigned to C-3, and a signal from the C-4 of the 1H-pyrazole ring was displayed at 112.3 ppm.The signal of the CF 3 group appeared as a characteristically large quartet at 121.6 ppm with J CF 268 Hz.

Refinement method
Full-matrix least-squares on (5 mmol, 1.27 g), and ethanol (10 mL) were stirred at reflux for 2 h.After the solvent was evaporated, a yellowish waxy residue was obtained.This residue was dissolved in chloroform (10 mL) and washed with water (2 × 10 mL), and then the organic layer was dried over Na 2 SO 4 .After the chloroform was evaporated, a yellow wax was obtained at 91% yield.

Table 3 :
Crystallographic data and structure refinement parameters of 5.