Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) Recyclization of 2-amino- and 2-methylamino-2-trifluoromethyl-5,5-dimethyltetrahydro- 4-pyrone oximes to 5-amino- and 5-methylamino-5-trifluoromethyl- 3-(2-hydroxy-1,1-dimethylethyl)- 2-isoxazolines Vyacheslav Ya. Sosnovskikh,* Mikhail Yu. Mel’nikov and Andrei V. Zaitsev Department of Chemistry, A. M. Gor’ky Urals State University, 620083 Ekaterinburg, Russian Federation.Fax: +7 343 261 5978; e-mail: Vyacheslav.Sosnovskikh@usu.ru The reactions of hydroxylamine with 2-amino- and 2-methylamino-2-trifluoromethyl-5,5-dimethyltetrahydro-4-pyrones yield 2-aminoand 2-methylamino-2-trifluoromethyl-5,5-dimethyltetrahydro-4-pyrone oximes, which can be converted to 5-amino- and 5-methylamino- 5-trifluoromethyl-3-(2-hydroxy-1,1-dimethylethyl)-D2-isoxazolines, respectively, by heating in ethanol.Previously1 we described the interaction of 6-trifluoromethyl- 3,3-dimethyl-2,3-dihydro-4-pyrone 1 with hydroxylamine hydrochloride and hydroxylamine base. We found that the reaction with NH2OH·HCl in the presence of Et3N in methanol proceeded at the C(6) atom and was accompanied by ring opening to form monoxime 2.This compound exists as cyclic isoxazoline species 3 in the solid state and in CDCl3 solution or as a mixture of monoxime 2 and isoxazoline 3 (in the ratio 40:60) in DMSO solution. Dihydropyrone 1 with an excess of hydroxylamine base yielded 5-hydroxyamino-D2-isoxazoline 4. To explain the formation of 4, we suggested that the reaction proceeds simultaneously at two electrophilic sites via a step of formation of 2-trifluoromethyl-2-hydroxyamino-5,5-dimethyltetrahydro- 4-pyrone oxime 5, which immediately undergoes recyclization to isoxazoline 4 under the reaction conditions.To test this hypothesis, we decided to examine the interaction of hydroxylamine with 2-amino- and 2-methylamino-2-trifluoromethyl- 5,5-dimethyltetrahydro-4-pyrones 6a,b prepared by reactions of dihydropyrone 1 with ammonia2 and methylamine.† Because tetrahydropyrone 6a is a cyclic form of 5-amino-6,6,6-trifluoro-1-hydroxy-2,2-dimethylhex-4-en-2-one 7, which was synthesised previously by condensation of 4-hydroxy-3,3-dimethyl-2-butanone with trifluoroacetonitrile,2 it was also of interest to compare the behaviour of aminoenone 7 and its cyclic isomer 6a in reactions with hydroxylamine.Note that 7 cannot transform into 6a either spontaneously or in the presence of bases. We found that tetrahydropyrones 6a,b with hydroxylamine base in methanol at room temperature formed oximes 8a,b‡ in high yields. These oximes undergo recyclization to thermodynamically more stable 5-amino- and 5-methylamino-D2-isoxazolines 9a,b§ on heating in ethanol.The transformation 8 ® 9 † 2-Trifluoromethyl-2-methylamino-5,5-dimethyltetrahydro-4-pyrone 6b: yield 84%, mp 87–88 °C. 1H NMR (250 MHz, CDCl3) d: 1.01 (s, 3H, Me), 1.30 (s, 3H, Me), 1.58 (br. s, 1H, NH), 2.27 (d, 1H, CHeH, JAX 15.0 Hz), 2.42 (s, 3H, NMe), 2.97 (d, 1H, CHHa, JAX 15.0 Hz), 3.72 (AB system, Dd 0.22, 2H, CH2–O, JAB 11.0 Hz). IR (Vaseline oil, n/cm–1): 3390 (NH), 1720 (C=O).Found (%): C 48.00; H 6.49; N 6.14. Calc. for C9H14F3NO2 (%): C 48.00; H 6.27; N 6.22. supports a scheme that was suggested previously1 for the formation of isoxazoline 4 and makes it possible to prepare 5-amino derivatives of 5-trifluoromethyl-D2-isoxazolines. This transformation can be considered as a new example of ring–ring isomerisation (see ref. 3 and references therein) that proceeds via unstable open-chain imino-oxime species 10, which cannot be detected in 1H NMR spectra. Note that a mixture of compounds 8b and 9b in the ratio 55:45 was formed when deuterioacetic acid was added to an oxime 8b solution in CDCl3, whereas oxime 8a remained unchanged under similar conditions (according to 1H NMR spectral data). Tetrahydropyrone 6a reacted with NH2OH at the carbonyl group with the retention of the cyclic structure; this fact suggests that this compound is reasonably stable despite the hemiaminal character of the C–O bond.In contrast, open-chain species 7 exhibited a much different behaviour in this reaction. Aminoenone 7 underwent a nucleophilic attack on the carbon atom adjacent to the CF3 group and, via a transamination step, resulted in monoxime 2, which exists predominantly as isoxazoline 3, which was prepared previously from dihydropyrone 1.1 Judging from the 1H NMR spectral data for oximes 8a,b (only a single set of signals was observed in the spectra), the reaction resulting in these compounds is highly stereoselective and leads to products with the E-configuration of the C=N bond.A comparison between the 1H NMR spectra for compounds 6b and 8b indicates that replacing a carbonyl oxygen by an oxime functional group primarily affected the positions of doublets of ‡ 2-Amino-2-trifluoromethyl-5,5-dimethyltetrahydro-4-pyrone oxime 8a: yield 63%, mp 126–127 °C. 1H NMR (250 MHz, CDCl3) d: 1.11 (s, 3H, Me), 1.29 (s, 3H, Me), 1.80 (s, 2H, NH2), 2.43 (d, 1H, CHeH, JAX 15.0 Hz), 3.34 (d, 1H, CHHa, JAX 15.0 Hz), 3.46 (d, 1H, CHH–O, JAX 11.2 Hz), 3.93 (d, 1H, CHH–O, JAX 11.2 Hz), 8.43 (s, 1H, OH).IR (Vaseline oil, n/cm–1): 3425, 3385, 3280 (br.), 3120 (OH, NH2), 1660, 1625 (C=N, NH2). Found (%): C 42.40; H 5.82; N 12.09. Calc. for C8H13F3N2O2 (%): C 42.48; H 5.79; N 12.38. 2-Trifluoromethyl-2-methylamino-5,5-dimethyltetrahydro-4-pyrone oxime 8b: yield 70%, mp 129–130 °C. 1H NMR (250 MHz, CDCl3) d: 1.08 (s, 3H, Me), 1.28 (s, 3H, Me), 1.58 (br. s, 1H, NH), 2.39 (d, 1H, CHeH, JAX 15.1 Hz), 2.41 (s, 3H, NMe), 3.31 (d, 1H, CHHa, JAX 15.1 Hz), 3.56 (AB system, Dd 0.22, 2H, CH2–O, JAB 11.2 Hz), 8.49 (s, 1H, OH). IR (Vaseline oil, n/cm–1): 3420, 3250 (br.), 3150 (OH, NH), 1675 (C=N). Found (%): C 44.82; H 6.43; N 11.64. Calc.for C9H15F3N2O2 (%): C 45.00; H 6.29; N 11.66. § 5-Amino-5-trifluoromethyl-3-(2-hydroxy-1,1-dimethylethyl)-D2-isoxazoline 9a: yield 74%, mp 73–74 °C. 1H NMR (250 MHz, CDCl3) d: 1.17 (s, 3H, Me), 1.19 (s, 3H, Me), 2.54 (br. s, 3H, NH2, OH), 2.90 (dq, 1H, CHH, JAB 18.3 Hz, 4JH,F 1.1 Hz), 3.33 (d, 1H, CHH, JAB 18.3 Hz), 3.58 (AB system, Dd 0.02, 2H, CH2–O, JAB 11.0 Hz). IR (Vaseline oil, n/cm–1): 3465, 3390, 3320 (OH, NH), 1615 (C=N).Found (%): C 42.56; H 6.02; N 12.04. Calc. for C8H13F3N2O2 (%): C 42.48; H 5.79; N 12.38. 5-Trifluoromethyl-5-methylamino-3-(2-hydroxy-1,1-dimethylethyl)-D2- isoxazoline 9b: yield 82%, mp 41–42 °C. 1H NMR (250 MHz, CDCl3) d: 1.18 (s, 6H, 2Me), 2.30 (br. s, 2H, NH, OH), 2.40 (s, 3H, NMe), 3.06 (dq, 1H, CHH, JAB 18.6 Hz, 4JH,F 1.1 Hz), 3.18 (d, 1H, CHH, JAB 18.6 Hz), 3.59 (s, 2H, CH2–O).IR (Vaseline oil, n/cm–1): 3435 (br.), 3310 (OH, NH), 1625 (C=N). Found (%): C 44.93; H 6.30; N 11.36. Calc. for C9H15F3N2O2 (%): C 45.00; H 6.29; N 11.66. D O O Me Me CF3 1 N F3C O OH Me Me HO N O F3C O OH Me Me H O NOH Me Me F3C NHOH N O NHOH CF3 OH Me Me NH2OH 2 3 5 4Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) the AX system of CH2(3) group protons, of which a downfield doublet of the axial proton and an upfield doublet of the equatorial proton exhibited paramagnetic shifts by 0.34 and 0.12 ppm, respectively.¶ At the same time, the chemical shifts ¶ According to our unpublished data, in compounds related to tetrahydropyrone 6b, such as 2-trifluoromethyl-2-hydroxy-5,5-dimethyltetrahydro- 4-pyrone and 2-amino-2-trichloromethyl-5,5-dimethyltetrahydro- 4-pyrone, it is the downfield doublet of the AX system of CH2(3) group protons that split into a doublet of doublets and a doublet of triplets with JAX ~ 15.0 Hz and 4J 1.8 and 1.6 Hz, respectively.This is due to longrange spin–spin coupling of a downfield proton with the protons of OH and NH2 groups.This fact is indicative of a rigid chair conformation with the trans-diaxial position of these groups and the downfield proton. At this arrangement, the W-conformation, which is required for the observed stereospecific long-range coupling through four s bonds,6 becomes possible. of methyl groups changed insignificantly: the d values are 1.01 and 1.08 ppm for the equatorial methyl or 1.30 and 1.28 for the axial methyl in compounds 6b and 8b, respectively.4 These data count in favour of the E-configuration such that protons of the CH2(3) group spatially approach the oxime hydroxyl to result in a downfield shift primarily due to an electrostatic deshielding effect5 (this is particularly true for the axial proton).As distinct from the CH2(3) group protons forming the AX system with JAX ~ 15.0 Hz, hydrogen atoms of the CH2(6) group appear as the AB spectrum with JAB ~ 11.0 Hz and are shifted to higher field by 0.16 ppm on going from tetrahydropyrone 6b to oxime 8b.Note that in the 1H NMR spectra of both isoxazolines 9a,b, the upfield signal of the AB quartet due to the CH2 group of the isoxazoline ring (JAB ~ 18.5 Hz) was further split into quartets with 4JH,F = 1.1 Hz.This is due to long-range spin–spin coupling of a proton from this group with fluorine atoms of the trifluoromethyl substituent. This work was supported by the Russian Foundation for Basic Research (grant no. 96-03-33373). References 1 V. Ya. Sosnovskikh, S. A. Pogozhikh and M. Yu. Mel’nikov, Izv. Akad. Nauk, Ser. Khim., in press. 2 V. Ya. Sosnovskikh and M. Yu. Mel’nikov, Zh. Org. Khim., 1998, 34, 303 (Russ. J. Org. Chem., 1998, 34, 280). 3 K. N. Zelenin, Org. Prep. Proced. Int., 1995, 27, 519. 4 S. Bory, M. Fetizon, P. Laszlo and D. H. Williams, Bull. Soc. Chim. Fr., 1965, 2541. 5 B. L. Shapiro, M. D. Johnston, Jr. and T. W. Proulx, J. Am. Chem. Soc., 1973, 95, 520. 6 C. A. Kingsbury, R. S. Egan and T. J. Perun, J. Org. Chem., 1970, 35, 2913. 6a,b NH2 CF3 O OH Me Me O O Me Me F3C NHR N O NHR CF3 OH Me Me NH2OH 2 3 10 7 NH2OH 8a,b O N Me Me F3C NHR OH EtOH D NR F3C NOH OH Me Me 9a,b a R = H b R = Me Received: Moscow, 28th September 1998 Cambridge, 17th November 1998; Com. 8/07880G