Thiolene and thiolane 1,1-dioxides are convenient precursors for the preparation of practically valuable compounds,1,2,3,4,–5 including polycyclic sulfolane-containing systems, some of which have been characterized as histamine receptor blockers,6 have shown neuroleptic, sedative, analgesic, and anticonvulsant activity7,8 and can inhibit the neuraminidase of influenza virus.1,9

Convenient substrates for the construction of sulfolaneand sulfolene-containing polycyclic structures include s-trans-nitrosulfodienes of thiolene 1,1-dioxide series – 2-benzylidene-3-methyl-4-nitro-3-thiolene 1,1-dioxides 1a–f, which are capable of rapid reactions with binucleophiles.10,11,12,–13 Thus, the reactions with cyclic β-diketones (dimedone, dihydroresorcinol) resulted in polycyclic structures containing a nitrosulfolane ring fused with chromane system,11 while the reactions with N,N-binucleophiles – phenylhydrazine and semicarbazide – served as a foundation for the development of effective methods for the synthesis of bicyclic nitrosulfolane derivatives containing a pyrazolidine ring.12,13 It should be noted that our proposed procedures for the formation of pyrazolidine structures were performed under mild conditions12,13 (room temperature, without catalysts), in contrast to the traditional synthesis of pyrazolidines through dipolar cycloaddition reactions.14

For the purpose of extending this method to the construction of structurally related sulfolane-containing bicyclic systems, we studied the reactions of 2-benzylidene- 3-methyl-4-nitro-3-thiolene 1,1-dioxides 1a–f with N,O-binucleophiles – hydroxylamine (2а) and N-methylhydroxylamine (2b) (Scheme 1). The synthesis of target compounds containing a fused isoxazolidine system is of interest due to the fact that the isoxazole ring and its hydrogenated derivatives are present as structural motifs in a range of natural compounds,15 β-lactam antibiotics,16 as well as in biologically active compounds with antibacterial17 and cytotoxic18 properties.

scheme 1

Scheme 1

The previously used conditions12,13 for the synthesis of pyrazolidine-containing bicyclic nitrosulfolane derivatives (ethanol, 18°С, 24 h) were found to be ineffective for the reaction between nitrosulfodienes 1а–f and hydroxylamine (2а), since the bicyclic target compounds 3а–f formed in these reactions were isolated as 1:6 mixtures of two diastereomers. Performing the reaction in DMSO led to a different ratio of stereoisomers 3a–f (10:1 according to the data of 1Н NMR spectroscopy), allowing to isolate the major diastereomers as individual compounds in 43–75% yields. The highly electron-deficient nature of nitrosubstituted diene 1e was the reason why it was the most reactive toward hydroxylamine (2a), giving the maximum yield of bicyclic product 3e. In the case of bicyclic derivatives 3c,f that were obtained on the basis of benzylidenenitrothiolene 1,1-dioxides 1c,f containing electrondonating substituents (4-MeC6H4, furan-2-yl), the yields did not exceed 55% (Scheme 1, Table 1).

Table 1. Yields of products 3, 4 a–f
Full size table

The reaction of dienes 1a–f with N-methylhydroxylamine (2b) proceeded in ethanol (18°С, 72 h) with the formation of bicyclic compounds 4а–f, which were isolated in the form of individual diastereomers in 25–56% yields (Scheme 1, Table 1).

It can be logically assumed that the formation of products 3, 4 a–f, similarly to the case of pyrazolidinecontaining analogs,12,13 resulted from a tandem process that included the initial nucleophilic addition step of the reagent at positions 1 and 4 of dienes and subsequent heterocyclization via secondary addition step involving the ОН group. The proposed role of Δ3-isomeric form in the latter transformation was supported by the preference for 5-exotrig-cyclization19 and the pronounced lability of the multiple bond in nitrothiolene dioxides in the presence of polar solvents.10

Compounds 3, 4 a–f were isolated as colorless crystals that were stable during storage at room temperature. Their structures were confirmed by IR spectroscopy, one-dimensional 1Н and 13С NMR spectroscopy, as well as 1Н–13С HMQC and 1H–13C HMBC experiments. It should be noted that the spectral characteristics of the synthesized isoxazolidine-containing nitrosulfolane derivatives 3, 4 a–f were in agreement with the properties of the previously obtained pyrazolidine-containing analogs.12,13

IR spectra of the bicyclic products 3, 4 a–f showed absorption bands due to an unconjugated nitro group (1350−1373, 1548−1569 cm–1) and sulfonyl group (1122−1145, 1309−1339 cm–1), while the spectra of products 3a–f additionally contained absorption bands due to NH bond vibrations (3219−3303 cm–1).

Compounds 3, 4 а–f had generally similar 1Н NMR spectra that contained all of the expected proton signals of the structural parts in these molecules. For example, the methyl group protons in 1H NMR spectrum of bicyclic compound 3b appeared as a singlet at 1.35 ppm; the 5-CH2 methylene protons and the nitromethine proton (6-СН) formed a strongly coupled three-spin АВХ system observed as three double doublets at 3.94, 4.13, and 5.40 ppm (2JAB = 13.7, 3JAX = 6.6, 3JBX = 11.5 Hz). The proton at the С-3 atom gave a double doublet at 5.09 ppm, forming an АМХ system (3JAМ = 2.1, 3JМX = 5.5 Hz) with the methine proton at the С-3а atom (4.14 ppm) and the proton bonded to the nitrogen atom (7.01 ppm). The downfield region (7.33, 7.52 ppm) contained two doublets that were assigned to the protons of benzene ring. Identical 1Н NMR characteristics were also observed in the case of bicyclic products 3a,d,e.

1Н NMR spectra of compounds 3c,f, 4а–f had several distinguishing features pointing to a different spatial arrangement compared to bicyclic products 3a,b,d,e. The spectra of compounds 3c,f showed a characteristic downfield shift of methyl group protons to 1.80−1.82 ppm, as well as the presence of a remote coupling between the 5-СНА methylene group proton and the 3а-СН methine group proton (4J = 1.8 Hz). In the case of bicyclic products 4a–f, the downfield appearance of methyl group protons (1.81−1.86 ppm) was accompanied by an upfield shift of the 3-СН proton signal to 4.09−4.18 ppm.

According to the results of X-ray structural analysis, all chiral centers in the molecule of product 3b had (R)-configuration. The close similarity of 1Н NMR spectra of compounds 3a,b,d,e allow to logically propose that compounds 3а,d,e were also isolated as 3R*,3aR*,6R*,6aR*-isomers. Analogously, by taking into account the data of X-ray structural analysis and 1Н NMR spectroscopy, 3R*,3aR*,6S*,6aR* configuration was assigned to products 3c,f and 3R*,3aS*,6R*,6aS* configuration to bicyclic compounds 4а–f.

According to the data of X-ray structural analysis, the unit cells in the crystal structure of all three compounds 3b,f, 4c contained a single bicyclic molecule (Fig. 1a–c). All of the molecules had similar bond lengths, valence and torsion angles, but certain spatial structure features could be distinguished in each case. The most distinct structure was that of compound 4с, with (S,S)-configuration of the С-3а,6а atoms.

Figure 1.
figure 1

The molecular structures of compounds a) 3b, b) 3f, and c) 4c with atoms represented by thermal vibration ellipsoids of 50% probability.

Full size image

The molecular packing of all bicyclic products (Fig. 2 а,b, 3 a–c) was realized by a network of intermolecular hydrogen bonds involving the hydrogen atoms of methyl and methylene groups, as well as the oxygen atoms of sulfonyl and nitro groups. It should be noted that an additional π–π interaction of furan rings occurred between the molecules of compound 3f (Fig. 3c).

Figure 2.
figure 2

a) The molecular packing in crystal of compound 3b, b) hydrogen bonding pattern in the structure of compound 3b.

Full size image
Figure 3.
figure 3

The hydrogen bonding network in the structures of compounds a) 3f and b) 4c; c) π–π interaction between the furan rings in the structure of compound 3f.

Full size image

Thus, we have demonstrated that the reactions of nitrosulfodienes of thiolene 1,1-dioxide series with hydroxylamine and N-methylhydroxylamine at room temperature provided good yields of bicyclic structures combining fused isoxazolidine and nitrosulfolane rings.

Experimental

IR spectra were recorded on a Shimadzu IRPrestige-21 FTIR spectrometer in KBr pellets. 1Н, 13С, 1Н–13С HMQC, and 1Н–13С НМВС NMR spectra were acquired on a Jeol ECX400A spectrometer at 400 MHz for 1H nuclei and 100 MHz for 13С nuclei in CD3CN solution. Residual nondeuterated solvent signals (1.92 ppm for 1Н NMR spectra) and deuterated solvent signals (0.42 ppm for 13С NMR spectra) were used as internal standards. Elemental analysis was performed on a Eurovector EuroEA3000 analyzer (CHN Dual mode). Melting points were determined on a PTP(M) apparatus (specification TU 92-891.001-90).

The starting nitrosulfodienes 1а–f were obtained according to published procedures.10,20

(3 R *,3a R *,6 R *,6a R *)-6а-Methyl-6-nitro-3-phenylhexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (3а). Aqueous 1 M NaOH solution (2 ml) was added to hydroxylamine hydrochloride (2а) (140 mg, 2 mmol). The obtained solution was poured into a stirred solution of nitrosulfodiene 1а (265 mg, 1 mmol) in DMSO (10 ml). The reaction mixture was stirred for 24 h at room temperature, then poured onto crushed ice (20 ml). The obtained precipitate contained a mixture of diastereomers (3R*,3aR*,6aR*,6R*) in 9:1 ratio according to the data of 1H NMR spectra. The product was collected on a Schott filter, washed with distilled water, ethanol, and air-dried. Yield 208 mg (70%), white powder, mp 160–162°С (EtOH). IR spectrum, ν, cm–1: 1134, 1309 (SO2), 1369, 1555 (NO2), 3279, 3296 (NH). 1H NMR spectrum, δ, ppm (J, Hz): major diastereomer: 1.37 (3Н, s, СН3); 3.95 (1Н, dd, 2J = 13.7, 3J = 6.7, 5-CH2); 4.04 (1Н, dd, 2J = 13.7, 3J = 11.6, 5-СН2); 4.14 (1H, d, 3J = 2.1, 3а-СН); 5.09 (1H, dd, 3J = 5.9, 3J = 2.1, 3-СН);

5.40 (1Н, dd, 3J = 11.6, 3J = 6.7, 6-СН); 6.97 (1H, d, 3J = 5.9, NH); 7.28–7.43 (5H, m, H Ph); minor diastereomer: 1.52 (3Н, s, СН3); 3.67–3.69 (1Н, m, 5-СН2); 3.90–3.92 (1Н, m, 5-СН2); 4.54 (1H, br. s, 3а-СН); 5.00–5.02 (1H, m, 3-СН); 5.41–5.43 (1Н, m, 6-СН); 6.98 (1H, br. s, NH); 7.28–7.43 (5H, m, H Ph). 13C NMR spectrum, δ, ppm: 19.6 (СН3); 53.4 (С-5); 65.9 (С-3); 75.2 (С-3а); 86.6 (С-6); 93.3 (С-6а); 126.9 (C Ph); 127.8 (2C Ph); 128.6 (2C Ph); 133.4 (C Ph). Found, %: С 48.17; H 4.88; N 9.23. C12H14N2O5S. Calculated, %: С 48.32; Н 4.73; N 9.39.

(3 R *,3a R *,6 R ,*6a R *)-3-(4-Bromophenyl)-6а-methyl-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (3b) was obtained analogously to compound 3а from nitrosulfodiene 1b (344 mg, 1 mmol) and hydroxylamine hydrochloride (2а) (140 mg, 2 mmol). Yield 274 mg (70%), white powder, mp 183–185°С (EtOH). IR spectrum, ν, cm–1: 1123, 1318 (SO2), 1368, 1551 (NO2), 3272, 3302 (NH). 1H NMR spectrum, δ, ppm (J, Hz): 1.35 (3Н, s, СН3); 3.94 (1Н, dd, 2J = 13.7, 3J = 6.6, 5-СН2); 4.13 (1Н, dd, 2J = 13.7, 3J = 11.5, 5-СН2); 4.14 (1H, d, 3J = 2.1, 3а-СН); 5.09 (1H, dd, 3J = 5.5, 3J = 2.1, 3-СН); 5.40 (1Н, dd, 3J = 11.5, 3J = 6.6, 6-СН); 7.01 (1H, d, 3J = 5.5, NH); 7.33 (2Н, d, 3J = 8.2, H Ar); 7.52 (2H, d, 3J = 8.2, H Ar). 13C NMR spectrum, δ, ppm: 19.4 (СН3); 53.5 (С-5); 65.8 (С-3); 75.2 (С-3а); 86.4 (С-6); 93.6 (С-6а); 122.2 (C Ar); 130.2 (2C Ar); 131.3 (2C Ar); 132.3 (C Ar). Found, %: C 38.51; H 3.13; N 7.65. C12H13BrN2O5S. Calculated, %: C 38.21; H 3.47; N 7.43.

(3 R *,3a R *,6 S *,6a R *)-6а-Methyl-3-(4-methylphenyl)-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (3c) was obtained analogously to compound 3a from nitrosulfodiene 1c (279 mg, 1 mmol) and hydroxylamine hydrochloride (2а) (140 mg, 2 mmol). Yield 172 mg (55%), white powder, mp 185–189°С (EtOH). IR spectrum, ν, cm–1: 1122, 1318 (SO2), 1364, 1556 (NO2), 3219, 3243 (NH). 1H NMR spectrum, δ, ppm (J, Hz): 1.80 (3Н, s, СН3); 2.31 (3Н, s, СН3 Ar); 3.77 (1Н, ddd, 2J = 13.7, 3J = 6.7, 4J = 1.8, 5-СН2); 3.93 (1H, dd, 3J = 6.4, 4J = 1.8, 3а-СН); 4.19 (1Н, dd, 2J = 13.7, 3J = 12.2, 5-СН2); 4.92 (1H, dd, 3J = 10.7, 3J = 6.4, 3-СН); 5.28 (1Н, dd, 3J = 12.2, 3J = 6.7, 6-СН); 6.51 (1H, d, 3J = 10.7, NH); 7.20 (2Н, d, 3J = 8.2, H Ar); 7.31 (2H, d, 3J = 8.2, H Ar). 13C NMR spectrum, δ, ppm: 22.5 (СН3); 20.2 (CH3 Ar); 49.6 (С-5); 68.6 (С-3); 80.1 (С-3а); 83.8 (С-6); 90.5 (С-6а); 126.7 (C Ar); 127.7 (2C Ar); 129.6 (2C Ar); 138.8 (C Ar). Found, %: C 50.29; H 5.33; N 8.83. C13H16N2O5S. Calculated, %: C 49.99; H 5.16; N 8.97.

(3 R *,3a R *,6 R *,6a R *)-3-(4-Chlorophenyl)-6а-methyl-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (3d) was obtained analogously to compound 3а from nitrosulfodiene 1d (300 mg, 1 mmol) and hydroxylamine hydrochloride (2а) (140 mg, 2 mmol). Yield 242 mg (73%), white powder, mp 165–167°С (EtOH). IR spectrum, ν, cm–1: 1125, 1319 (SO2), 1364, 1548 (NO2), 3272, 3303 (NH). 1H NMR spectrum, δ, ppm (J, Hz): major diastereomer: 1.35 (3Н, s, СН3); 3.95 (1Н, dd, 2J = 13.8, 3J = 6.7, 5-СН2); 4.04 (1Н, dd, 2J = 13.8, 3J = 11.6, 5-СН2); 4.13 (1H, d, 3J = 1.8, 3а-СН); 5.10 (1H, dd, 3J = 5.3, 3J = 1.8, 3-СН); 5.40 (1Н, dd, 3J = 11.6, 3J = 6.7, 6-СН); 7.02 (1H, d, 3J = 5.3, NH); 7.30 (2Н, d, 3J = 7.9, H Ar); 7.36 (2H, d, 3J = 7.9, H Ar); minor diastereomer: 1.52 (3Н, s, СН3); 3.68–3.70 (1Н, m, 5-СН2); 3.89–3.91 (1Н, m, 5-СН2); 4.52 (1H, br. s, 3а-СН); 4.95–4.97 (1H, m, 3-СН); 5.40–5.43 (1Н, m, 6-СН); 6.98 (1H, br. s, NH); 7.30 (2Н, d, 3J = 7.9, H Ar), 7.36 (2H, d, 3J = 7.9, H Ar). 13C NMR spectrum, δ, ppm: 19.6 (СН3); 53.5 (С-5); 65.9 (С-3); 75.1 (С-3а); 86.6 (С-6); 93.4 (С-6а); 125.5 (C Ar); 131.2 (2C Ar); 133.4 (2C Ar); 137.5 (C Ar). Found, %: C 43.79; H 4.04; N 8.26. C12H13ClN2O5S. Calculated, %: C 43.31; H 3.94; N 8.42.

(3 R *,3a R *,6 R *,6a R *)-6а-Methyl-6-nitro-3-(4-nitrophenyl) hexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (3e) was obtained analogously to compound 3а from nitrosulfodiene 1e (310 mg, 1 mmol) and hydroxylamine hydrochloride (2а) (69.5 mg, 1 mmol). Yield 257 mg (75%), white powder, mp 180–184°С (EtOH). IR spectrum, ν, cm–1: 1129, 1314 (SO2), 1350, 1558 (NO2), 3276, 3315 (NH). 1H NMR spectrum, δ, ppm (J, Hz): 1.33 (3Н, s, СН3); 3.99 (1Н, dd, 2J = 13.8, 3J = 6.7, 5-СН2); 4.20 (1Н, dd, 2J = 13.8, 3J = 12.5, 5-СН2); 4.30 (1H, d, 3J = 6.7, 3а-СН); 5.14 (1H, dd, 3J = 8.2, 3J = 6.7, 3-СН); 5.31 (1Н, dd, 3J = 12.5, 3J = 6.7, 6-СН); 7.13 (1H, d, 3J = 8.2, NH), 7.53–7.56 (2H, m, H Ar); 8.14–8.22 (2H, m, H Ar). 13C NMR spectrum, δ, ppm: 19.8 (СН3); 53.7 (С-5); 66.1 (С-3); 76.3 (С-3а); 86.6 (С-6); 93.4 (С-6а); 127.4 (C Ar); 131.3 (2C Ar); 132.9 (2C Ar); 133.5 (C Ar). Found, %: С 41.65; H 3.73; N 12.56. C12H13N3O7S. Calculated, %: С 41.98; Н 3.82; N 12.24.

(3 R *,3a R *,6 S *,6a R *)-3-(Furan-2-yl)-6а-methyl-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (3f) was obtained analogously to compound 3а from nitrosulfodiene 1f (255 mg, 1 mmol) and hydroxylamine hydrochloride (2а) (350 mg, 5 mmol). Yield 124 mg (43%), white powder, mp 162–164°С (EtOH). IR spectrum, ν, cm–1: 1130, 1318 (SO2), 1371, 1555 (NO2), 3225 (NH). 1H NMR spectrum, δ, ppm (J, Hz): 1.82 (3Н, s, СН3); 3.79 (1Н, ddd, 2J = 13.7, 3J = 6.7, 4J = 1.8, 5-СН2); 4.05 (1H, dd, 3J = 5.2, 4J = 1.8, 3а-СН); 4.15 (1Н, dd, 2J = 13.7, 3J = 12.2, 5-СН2); 5.05 (1H, dd, 3J = 9.3, 3J = 5.2, 3-СН); 5.31 (1Н, dd, 3J = 12.2, 3J = 6.7, 6-СН); 6.42 (1Н, dd, 3J = 3.4, 3J = 1.8, H furan); 6.50 (1H, d, 3J = 3.4, H furan); 6.55 (1H, d, 3J = 9.3, NH); 7.52 (1Н, d, 3J = 1.8, H furan). 13C NMR spectrum, δ, ppm: 22.5 (СН3); 50.1 (С-5); 68.1 (С-3); 80.2 (С-3а); 84.1 (С-6); 90.4 (С-6а); 110.2 (С furan); 110.6 (С furan); 143.5 (С furan); 145.1 (С furan). Found, %: C 41.31; H 3.80; N 9.49. C10H12N2O6S. Calculated, %: C 41.67; H 4.20; N 9.72.

(3 R *,3a S *,6 R *,6a S *)-2,6а-Dimethyl-6-nitro-3-phenylhexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (4а). Aqueous 1 M NaOH solution (1 ml) was added to N-methylhydroxylamine hydrochloride (2b) (84 mg, 1 mmol). The obtained solution was poured into a suspension of nitrosulfodiene 1а (265 mg, 1 mmol) in ethanol (10 ml). The reaction mixture was stirred for 72 h at room temperature, the obtained precipitate was collected on a Schott filter, washed with ethanol, and air-dried. Yield 162 mg (52%), white powder, mp 157–160°С (EtOH). IR spectrum, ν, cm–1: 1134, 1332 (SO2), 1373, 1569 (NO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.83 (3Н, s, СН3); 2.54 (3H, s, NCH3); 3.66 (1Н, ddd, 2J = 12.9, 3J = 6.7, 4J = 2.1, 5-СН2); 3.99 (1H, dd, 3J = 7.2, 4J = 2.1, 3а-СН); 4.15 (1H, d, 3J = 7.2, 3-СН); 4.18 (1Н, dd, 2J = 12.9, 3J = 12.2, 5-СН2); 5.18 (1Н, dd, 3J = 12.2, 3J = 6.7, 6-СН); 7.29–7.34 (5H, m, H Ph). 13C NMR spectrum, δ, ppm: 24.5 (СН3); 42.5 (NCH3); 52.8 (С-5); 73.9 (С-3); 76.3 (С-3а); 83.9 (С-6); 85.8 (С-6а); 128.2 (3C Ph); 128.6 (2C Ph); 131.9 (C Ph). Found, %: С 49.89; H 5.26; N 8.67. C13H16N2O5S. Calculated, %: С 49.99; Н 5.16; N 8.97.

(3 R *,3a S *,6 R *,6a S *)-3-(4-Bromophenyl)-2,6а-dimethyl-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (4b) was obtained analogously to compound 4а from nitrosulfodiene 1b (344 mg, 1 mmol) and N-methylhydroxylamine hydrochloride (2b) (84 mg, 1 mmol). Yield 156 mg (40%), white powder, mp 165–170°С (EtOH). IR spectrum, ν, cm–1: 1145, 1339 (SO2), 1368, 1557 (NO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.83 (3Н, s, СН3); 2.53 (3H, s, NCH3); 3.69 (1Н, ddd, 2J = 13.0, 3J = 6.8, 4J = 2.2, 5-СН2); 3.99 (1H, dd, 3J = 7.2, 4J = 2.2, 3а-СН); 4.12 (1H, d, 3J = 7.2, 3-СН); 4.14 (1Н, dd, 2J = 13.0, 3J = 12.2, 5-СН2); 5.18 (1Н, dd, 3J = 12.2, 3J = 6.8, 6-СН); 7.27 (2H, d, 3J = 8.4, H Ar); 7.51 (2H, d, 3J = 8.4, H Ar). 13C NMR spectrum, δ, ppm: 24.5 (СН3); 42.4 (NCH3); 52.9 (С-5); 73.2 (С-3); 76.0 (С-3а); 84.0 (С-6); 85.7 (С-6а); 121.6 (C Ar); 130.6 (2C Ar); 131.2 (2C Ar); 131.5 (C Ar). Found, %: C 39.43; H 3.96; N 7.02. C13H15BrN2O5S. Calculated, %: C 39.91; H 3.86; N 7.16.

(3 R *,3a S *,6 R *,6a S *)-2,6а-Dimethyl-3-(4-methylphenyl)-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (4c). Aqueous 1 M NaOH solution (2 ml) was added to N-methylhydroxylamine hydrochloride (2b) (167 mg, 2 mmol). The obtained solution was poured into a suspension of nitrosulfodiene 1c (279 mg, 1 mmol) in ethanol (10 ml). The reaction mixture was maintained for 72 h at room temperature, the obtained precipitate was collected on a Schott filter, washed with ethanol, and air-dried. Yield 133 mg (41%), white powder, mp 153–157°С (EtOH). IR spectrum, ν, cm–1: 1132, 1324 (SO2), 1370, 1556 (NO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.83 (3Н, s, СН3); 2.31 (3H, s, CH3 Ar); 2.53 (3H, s, NCH3); 3.65 (1Н, ddd, 2J = 12.8, 3J = 6.7, 4J = 2.1, 5-СН2); 3.94 (1H, dd, 3J = 7.2, 4J = 2.1, 3а-СН); 4.09 (1H, d, 3J = 7.2, 3-СН); 4.17 (1Н, dd, 2J = 12.8, 3J = 12.2, 5-СН2); 5.18 (1Н, dd, 3J = 12.2, 3J = 6.7, 6-СН); 7.16 (2H, d, 3J = 7.9, H Ar); 7.21 (2H, d, 3J = 7.9, H Ar). 13C NMR spectrum, δ, ppm: 20.3 (CH3 Ar); 24.5 (СН3); 42.5 (NCH3); 52.8 (С-5); 73.9 (С-3); 76.2 (С-3а); 83.9 (С-6); 85.8 (С-6а); 128.5 (C Ar); 128.8 (2C Ar); 128.9 (2C Ar); 138.1 (C Ar). Found, %: C 51.20; H 5.90; N 8.32. C14H18N2O5S. Calculated, %: C 51.52; H 5.56; N 8.58.

(3 R *,3a S *,6 R *,6a S *)-3-(4-Chlorophenyl)-2,6а-dimethyl-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (4d) was obtained analogously to compound 4а from nitrosulfodiene 1d (300 mg, 1 mmol) and N-methylhydroxylamine hydrochloride (2b) (84 mg, 1 mmol). Yield 104 mg (30%), white powder, mp 164–166°С (EtOH). IR spectrum, ν, cm–1: 1144, 1339 (SO2), 1367, 1563 (NO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.83 (3Н, s, СН3); 2.54 (3H, s, NCH3); 3.69 (1Н, ddd, 2J = 13.1, 3J = 6.7, 4J = 2.1, 5-СН2); 4.00 (1H, dd, 3J = 7.1, 4J = 2.1, 3а-СН); 4.14 (1H, d, 3J = 7.1, 3-СН); 4.16 (1Н, dd, 2J = 13.1, 3J = 12.2, 5-СН2); 5.20 (1Н, dd, 3J = 12.2, 3J = 6.7, 6-СН); 7.32 (2H, d, 3J = 8.8, H Ar); 7.36 (2H, d, 3J = 8.8, H Ar). 13C NMR spectrum, δ, ppm: 24.4 (СН3); 42.5 (NCH3); 52.8 (С-5); 73.2 (С-3); 76.2 (С-3а); 84.1 (С-6); 85.7 (С-6а); 128.3 (C Ar); 130.7 (2C Ar); 133.3 (2C Ar); 137.1 (C Ar). Found, %: C 44.57; H 3.98; N 7.59. C13H15ClN2O5S. Calculated, %: C 45.03; H 4.36; N 8.08.

(3 R *,3a S *,6 R *,6a S *)-2,6а-Dimethyl-6-nitro-3-(4-nitrophenyl) hexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (4e) was obtained analogously to compound 4а from nitrosulfodiene 1e (310 mg, 1 mmol) and N-methylhydroxylamine (2b) (84 mg, 1 mmol). Yield 200 mg (56%), white powder, mp 145–148°С (EtOH). IR spectrum, ν, cm–1: 1134, 1336 (SO2), 1367, 1563 (NO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.86 (3Н, s, СН3); 2.58 (3H, s, NCH3); 3.70 (1Н, ddd, 2J = 13.1, 3J = 6.7, 4J = 2.1, 5-СН2); 4.11 (1H, dd, 3J = 7.3, 4J = 2.1, 3а-СН); 4.14 (1H, d, 3J = 7.3, 3-СН); 4.17 (1Н, dd, 2J = 13.1, 3J = 12.2, 5-СН2); 5.21 (1Н, dd, 3J = 12.2, 3J = 6.7, 6-СН); 7.60 (2H, d, 3J = 8.8, H Ar); 8.17 (2H, d, 3J = 8.8, H Ar). 13C NMR spectrum, δ, ppm: 24.4 (СН3); 42.3 (NCH3); 52.9 (С-5); 74.0 (С-3); 76.3 (С-3а); 83.9 (С-6); 85.8 (С-6а); 127.3 (2C Ar); 130.3 (C Ar); 133.0 (2C Ar); 133.7 (C Ar). Found, %: C 44.17; H 4.72; N 12.05. C13H15N3O7S. Calculated, %: C 43.70; H 4.23; N 11.76.

(3 R *,3a S *,6 R *,6a S *)-3-(Furan-2-yl)-2,6а-dimethyl-6-nitrohexahydrothieno[2,3- d ]isoxazole 4,4-dioxide (4f). Aqueous 1 M NaOH solution (5 ml) was added to N-methylhydroxylamine hydrochloride (2b) (417 mg, 5 mmol). The obtained solution was poured into a suspension of nitrosulfodiene 1f (255 mg, 1 mmol) in ethanol (10 ml). The reaction mixture was maintained for 72 h at room temperature, the obtained precipitate was collected on a Schott filter, washed with ethanol, and air-dried. Yield 76 mg (25%), white powder, mp 149–153°С (EtOH). IR spectrum, ν, cm–1: 1133, 1317 (SO2), 1372, 1559 (NO2). 1H NMR spectrum, δ, ppm (J, Hz): 1.81 (3Н, s, СН3); 2.54 (3H, s, NCH3); 3.67 (1Н, ddd, 2J = 13.1, 3J = 6.7, 4J = 2.4, 5-СН2); 3.92 (1H, dd, 3J = 7.9, 4J = 2.4, 3а-СН); 4.18 (1H, d, 3J = 7.9, 3-СН); 4.21 (1Н, dd, 2J = 13.1, 3J = 12.0, 5-СН2); 5.17 (1Н, dd, 3J = 12.0, 3J = 6.7, 6-СН); 6.37 (1H, d, 3J = 3.2, H furan); 6.40 (1H, dd, 3J = 3.2, 3J = 2.1, H furan); 7.51 (1Н, d, 3J = 2.1, H furan). 13C NMR spectrum, δ, ppm: 24.3 (CH3); 42.6 (NCH3); 52.6 (С-5); 68.3 (С-3); 74.2 (С-3а); 84.4 (С-6); 86.0 (С-6а); 110.2 (C furan); 110.7 (C furan); 143.3 (C furan); 145.0 (C furan). Found, %: C 43.26; H 4.87; N 9.72. C11H14N2O6S. Calculated, %: C 43.71; H 4.67; N 9.27.

X-ray structural analysis of compounds 3b,f, 4c was performed at 100 K on Rigaku Oxford Diffraction Xcalibur Eos (monochromatic microfocus MoKα radiation, compound 3b), Rigaku Oxford Diffraction SuperNova Atlas (monochromatic microfocus CuKα radiation, compound 3f), and Bruker Kappa Apex II DUO (monochromatic microfocus MoKα radiation, compound 4с) diffractometers that were equipped with planar CCD detectors.

The obtained data were integrated with corrections for Lorentz background and polarization effects using the CrysAlisPro software suite21 (for compounds 3f,b) or Bruker APEX2 and XPREP software (for compounds 4c). The correction for absorption in the case of compounds 3f,b was introduced empirically with CrysAlisPro software suite, using spherical harmonics implemented with the SCALE3 ABSPACK scaling algorithm or the SADABS program for compound 4c.22 The structures were solved by direct methods and refined by using the SHELX program23 within the OLEX2 software suite.24 The hydrogen atom positions were calculated by algorithms incorporated in the SHELX software suite where Uiso(H) was set as 1.5Ueq(C) and C–H bond length was 0.96 Å for CH3 groups, Uiso(H) was set as 1.2Ueq(C) and C–H bond length was 0.97 Å for CH2 groups, Uiso(H) was set as 1.2Ueq(C) and C–H bond length was 0.93 Å for CH groups in cyclic moieties, Uiso(H) was set as 1.2Ueq(C) and C–H bond length was 0.98 Å for tertiary CH groups, and Uiso(H) was set as 1.2Ueq(N) and N–H bond length was 0.86 Å for NH groups.

Compounds 3b,f and 4c crystallized in monoclinic syngony, space group P21/c. Compound 3b: a 5.8141(3), b 32.9213(14), c 7.3228(4) Å; β 100.376(5)°; V 1378.72(12) Å3; Z 4, 2θ 5.79–60.00°, R1 0.040, wR2 0.078 (for 3431 reflections with |Fo| ≥ 4σ F ); S 1.099. Compound 3f: a 17.7558(11), b 5.2441(3), c 13.6905(9) Å; β 109.448(7)°; V 1202.04(14) Å3; Z 4, 2θ 10.57–145.00°, R1 0.038, wR2 0.102 (for 2178 reflections with |Fo| ≥ 4σ F ); S 1.048. Compound 4c: a 14.9756(15), b 11.7644(13), c 8.5652(9) Å; β 95.443(2)°; V 1502.2(3) Å3; Z 4; 2θ 4.41–60.00°, R1 0.033, wR2 0.086 (for 3458 reflections with |Fo| ≥ 4σ F ); S 1.056.

The complete crystallographic datasets for compounds 3b,f and 4c were deposited at the Cambridge Crystallographic Data Center (deposits CCDC 1576187, CCDC 1559533, CCDC 1559534, respectively).

A Supplementary information file containing 1H and 13C NMR spectra of all synthesized compounds, as well as 1H–13C HMQC and 1H–13C HMBC spectra of compounds 3c, 4a–c is available at the journal website at http://springerlink.bibliotecabuap.elogim.com/journal/10593.