F. Clerici et al. / Tetrahedron 59 (2003) 9399–9408
9407
(C-4), 147.1 (C-5), 159.2 (C-3). Calcd for C5H7ClN2O2S
(194.64) C 30.85 H 3.62 N 14.39, found C 30.56 H 3.78 N
14.13.
7.18 (d, 2H, J¼8.4 Hz, arylH), 7.24 (d, 2H, J¼8.4 Hz,
arylH), 7.72 (d, 1H, J¼5.8, H5). 13C NMR 22.0 (CH3), 46.0
(CH2), 122.0 (C-4), 128.0, 130.0 (arCH), 134.0, 138.0,
146.0 (arC, C-5), 160.0 (C-3). Calcd for C11H11ClN2O2S
(270.74) C 48.80 H 4.10 N 10.35, found C 48.95 H 3.95 N
10.01.
4.5.8. 4,5-Dichloro-N-ethylisothiazol-3-amine 1,1-dioxide
13c. Yield 60%. Mp 189–1928C (white powder from Et2O).
IR 3321 cm21. 1H NMR 1.40 (t, 3H, J¼7.3 Hz, CH3), 3.65
(m, 2H, CH2), 6.25 (bs, 1H, NH). 13C NMR (CD3OD) 12.5
(CH3), 38.3 (CH2), 125.5 (C-4), 142.4 (C-5), 157.1 (C-3).
Calcd for C5H6Cl2N2O2S (229.08) C 26.21 H 2.64 N 12.23,
found C 26.34 H 2.98 N 12.02.
4.5.15. 5-Chloro-N-(4-nitrobenzyl)isothiazol-3-amine
1,1-dioxide 12h. Yield 70%. Mp 2188C dec. (white powder
from Et2O). IR 3266 cm21. 1H NMR (CD3COCD3) 4.92 (s,
2H, CH2), 7.12 (s, 1H, H4), 7.75 (d, 2H, AB syst., J¼8.8 Hz,
arylH), 8.28 (d, 2H, AB syst., J¼8.8 Hz, arylH), 8.99 (bs,
1H, NH). 13C NMR 45.8 (CH2), 123.3, 129.2 (arCH), 120.4
(C-4), 144.4, 147.0, 148.0 (arC, C-5), 161.1 (C-3). Calcd for
C10H8ClN3O4S (301.71) C 39.81 H 2.67 N 13.93, found C
39.56 H 2.90 N 13.90.
4.5.9. N-Cyclohexylisothiazol-3-amine 1,1-dioxide 11d.
Yield 74%. Mp 183–1868C (white powder from Et2O). IR
3282 cm21
.
1H NMR (CD3OD)1.27–1.49, 1.65–2.85,
2.02–2.06 (3m, 10H, CH2), 3.72–3.82 (m, 1H, CH), 6.83
(d, 1H, J¼5.6 Hz, H4), 7.70 (d, 1H, J¼5.6 Hz, H5). 13C
NMR (CD3COCD3) 24.1, 24.9, 31.5 (CH2), 52.1 (CH),
125.2 (C-4), 143.8 (C-5), 160.0 (C-3). Calcd for
C9H14N2O2S (214.29) C 50.44 H 6.59 N 13.07, found C
50.76 H 6.43 N 12.89; m/z 215 (Mþþ1).
4.5.16. Ethyl [(1,1-dioxidoisothiazol-3-yl)amino]acetate
11i. Yield 56%. Yellow oil. IR 3300 (NH), 1730
1
(CO) cm21. H NMR (CD3COCD3) 1.28 (t, 3H, J¼7 Hz,
CH3), 4.25 (q, 2H, J¼7 Hz, CH2), 4.29–4.33 (m, 2H, CH2),
7.13 (d, 1H, J¼5.5 Hz, H4), 7.75 (d, 1H, J¼5.5 Hz, H5),
8.30–8.40 (bs, 1H, NH). 13C NMR (CD3COCD3) 13.7
(CH3), 44.4 (CH2), 61.4 (OCH2), 125.1 (C-4), 145.0 (C-5),
162.2 (C-3), 168.3 (CO). Calcd for C7H10N2O4S (218.23) C
38.53 H 4.62 N 12.84, found C 38.76 H 4.60 N 12.76.
4.5.10. 5-Chloro-N-cyclohexylisothiazol-3-amine 1,1-
dioxide 12d. Yield 77%. Mp 155–1588C (white powder
1
from Et2O). IR 3438 cm21. H NMR (CD3OD) 1.27–2.05
(m, 10H, CH2), 3.79–3.81 (m, 1H, CH), 6.80 (s, 1H, H4).
13C NMR (CD3COCD3) 23.5, 24.3, 30.8 (CH2), 51.4
(CH), 119.4 (C-4), 146.9 (C-5), 158.3 (C-3). Calcd for
C9H13ClN2O2S (248.73) C 43.46 H 5.27 N 11.26, found C
43.35 H 5.18 N 11.09.
4.5.17. Methyl 2-[(1,1-dioxidoisothiazol-3-yl)amino]-3-
phenylpropanoate 11l. Yield 78%. Mp 153–1548C
(white powder from Et2O). IR 3300 (NH), 1745
1
(CO) cm21. H NMR 3.27–3.49 (m, 2H, CH2), 3.85 (s,
4.5.11. N-Phenylisothiazol-3-amine 1,1-dioxide 11e.
3H, CH3), 5.02 (m, 1H, CH), 6.21 (bs, 1H, NH), 6.63 (d, 1H,
J¼5.5 Hz, H4), 7.04–7.32 (m, 5H, arylH), 7.49 (d, 1H,
J¼5.5 Hz, H5). 13C NMR 37.2 (CH2), 53.2, 57.1
(CH3þCH), 125.2, 127.8, 129.1, 129.5 (arCHþC-4),
134.9 (arC), 144.5 (C-5), 161.0 (C-3), 171.3 (CO). Calcd
for C13H14N2O4S (294.33) C 53.05 H 4.79 N 9.52, found C
53.16 H 4.56 N 9.45; m/z 294 (Mþ).
Yield 82%. Mp 174–1768C dec. (Et2O). IR 3226 cm21
.
1H NMR (DMSO-d6) 7.11 (d, 1H, J¼5.7 Hz, H4), 7.24–
7.79 (m, 5H, arylH), 8.15 (d, 1H, J¼5.7 Hz, H5). 13C NMR
(CD3OD) 121.1 (C-4), 125.9, 126.9, 129.2 (arCH), 137.9
(arC), 142.6 (C-5), 158.5 (C-3). Calcd for C9H8N2O2S
(208.24) C 51.91 H 3.87 N 13.45, found C 51.74 H 3.98 N
13.23; m/z 208 (Mþ).
4.5.18. N-Benzyl-4-bromoisothiazol-3-amine 1,1-dioxide
15. Compound 11a (500 mg, 2.25 mmol) was dissolved in a
mixture of CH2Cl2 (25 mL) and CCl4 (5 mL) under stirring
and Br2 (356 mg, 2.25 mmol) in 3 mL di CCl4 was slowly
dropped into the solution. The reaction was checked by TLC
until disappearance of the starting material (15 h, cyclohex-
ane/AcOEt 6:4). At the end of the reaction, TEA (227 mg,
2.25 mmol) was added and stirring was continued for
additional 15 h. The reaction was quenched with diluted
HCl (10% solution, 10 mL) and transferred to a separatory
funnel and the organic layer separated. This last was washed
twice with water (10 mL) and then with a saturated solution
of Na2S2O5. The organic layer was separated, dried with
Na2SO4 and the solvent evaporated at reduced pressure. The
residue was chromatographed on silica gel (eluent:
cyclohexane/AcOEt 100:0 to 0:100) and 15 crystallized
with Et2O. Yield 77%. Mp 185–1878C (white powder from
Et2O). IR 3313 cm21 (NH). 1H NMR (CD3COCD3) 4.74 (d,
2H, CH2; J¼6.2 Hz), 7.32–7.47 (m, 5H, arylH), 8.19 (s, 1H,
H-5), 8.56(bs,1H, NH). 13CNMR(CD3COCD3)47.63(CH2),
119.73 (C-4), 128.11, 128.49, 128.95 (arCH), 137.17 (arC),
143.79 (C-5), 15.51 d (C-3). Calcd for C10H9BrN2O2S
(301.16) C 39.88, H 3.01, N 9.30, S 10.65, found C 39.66
H 2.89, N 9.35, S 10.62
4.5.12. 5-Chloro-N-phenylisothiazol-3-amine 1,1-dioxide
12e. Yield 35%. Mp 2008C dec. (white powder from Et2O).
1
IR 3292 (NH) cm21. H NMR (CD3COCD3) 7.19 (s, 1H,
H4), 7.20–7.40, 7.40–7.60, 7.80–7.90 (3m, 5H, arylH),
10.30–10.50 (bs, 1H, NH). 13C NMR (CD3COCD3) 121.4,
121.5, 126.2, 129.5 (C-4þarCH), 137.5 (arC), 147.3 (C-5),
157.5 (C-3). Calcd for C9H7ClN2O2S (242.68) C 44.54 H
2.91 N 11.54, found C 44.76 H 2.98 N 11.20.
4.5.13. N-(4-Methylbenzyl)isothiazol-3-amine 1,1-dioxide
11f. Yield 50%. Mp 159–1628C (white powder from Et2O).
1
IR 3092 cm21. H NMR (CD3OD) 2.25 (s, 3H, CH3), 4.68
(CH2), 6.85 (d, 1H, J¼5.8 Hz, H4), 7.24 (d, 2H, J¼8 Hz,
arylH), 7.27 (d, 2H, J¼8 Hz, arylH), 7.72 (d, 1H, J¼5.8 Hz,
H5). 13C NMR (CD3OD) 19.9 (CH3), 46.7 (CH2), 125.7 (C-4),
128.1, 129.3 (arCH), 133.4, 137.8 (arC), 143.8 (C-5), 161.8
(C-3). Calcd for C11H12N2O2S (236.29) C 55.91 H 5.12 N
11.86, found C 55.75 H 5.18 N 11.73; m/z 236 (Mþ).
4.5.14. 5-Chloro-N-(4-methylbenzyl)isothiazol-3-amine
1,1-dioxide 12f. Yield 65%. Mp 148–1508C (white powder
1
from Et2O). IR 3200 (NH) cm21. H NMR 2.40 (s, 3H,
CH3), 4.60 (CH2), 6.45–6.60 (bs, 1H, NH), 6.56 (s, 1H, H4),