ACS Chemical Neuroscience
Research Article
80 °C under stirring for 1−3 h (until completion followed by TLC).
The solvent was removed by distillation under reduced pressure and
the residue was dissolved in a small volume of methanol. The addition
to this stirred solution of an equal volume of distilled water led to the
precipitation of the title compound, which was collected by filtration,
washed with water, and dried (yields: 80−90%).
The non-4-alkylated compound 7-chloro-2,3-dimethyl-3,4-dihydro-
2H-1,2,4-benzothiadiazine 1,1-dioxide 7a was also obtained by means
of the same synthetic procedure starting from the reference compound
5a.
R/S-7-Chloro-2,3-dimethyl-3,4-dihydro-2H-1,2,4-benzothiadia-
zine 1,1-Dioxide (7a). White solid; m.p.: 178−180 °C; 1H NMR
(DMSO-d6) δ 1.45 (d, J = 6.4 Hz, 3H, CHCH3), 2.46 (s, 3H, NCH3),
5.25 (q, J = 6.4 Hz, 1H, CHCH3), 6.87 (d, J = 9.0 Hz, 1H, 5-H), 7.39
(dd, J = 8.9 Hz/2.5 Hz, 1H, 6-H), 7.42 (bs, 1H, NH), 7.50 (d, J = 2.5
Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ 17.5 (CHCH3), 27.5 (NCH3),
64.7 (CHCH3), 117.8 (C-5), 118.4 (C-7), 120.2 (C-8a), 124.2 (C-8),
133.3 (C-6), 141.9 (C-4a). Anal. (C9H11ClN2O2S) theoretical: C,
43.81; H, 4.49; N, 11.35; S, 12.99. Found: C, 43.41; H, 4.28; N, 11.24;
S, 12.78.
Compound 6a devoid of an alkyl substituent at the 4-position is a
known chemical substance30 that was prepared according to the
general synthetic pathway reported for compounds 6d−g but using the
commercially available 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide (3a) as the starting material.
Compounds 6b and 6c were obtained as previously described.15
7-Chloro-2-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-
1
Dioxide (6a). White solid; m.p.: 195−198 °C; H NMR (DMSO-
d6) δ 2.62 (s, 3H, NCH3), 4.80 (s, 2H, 3−CH2), 6.88 (d, J = 9.0 Hz,
1H, 5-H), 7.38 (dd, J = 9.0 Hz/2.5 Hz, 1H, 6-H), 7.44 (s, 1H, NH),
7.49 (d, J = 2.5 Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ 34.3 (NCH3),
60.4 (C-3), 118.0 (C-5), 118.3 (C-7), 120.0 (C-8a), 124.1 (C-8),
133.4 (C-6), 141.8 (C-4a). Anal. (C8H9ClN2O2S) theoretical: C,
41.29; H, 3.90; N, 12.04; S, 13.78. Found: C, 41.08; H, 4.03; N, 12.23;
S, 13.65.
7-Chloro-4-(2-fluoroethyl)-2-methyl-3,4-dihydro-2H-1,2,4-benzo-
thiadiazine 1,1-Dioxide (6d). White solid; m.p.: 112−114 °C; 1H
NMR (DMSO-d6) δ 2.68 (s, 3H, NCH3), 3.80 (dt, J = 27.1 Hz/4.8
Hz, 2H, NCH2), 4.62 (dt, J = 47.4 Hz/4.8 Hz, 1H, CH2F), 4.97 (s, 2H,
3−CH2), 7.07 (d, J = 9.2 Hz, 1H, 5-H), 7.48 (dd, J = 9.2 Hz/2.6 Hz,
1H, 6-H), 7.57 (d, J = 2.6 Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ 34.4
(NCH3), 49.0 (d, J = 20 Hz, NCH2), 67.4 (C-3), 82.0 (d, J = 165 Hz,
CH2F), 115.9 (C-5), 119.4 (C-7), 120.4 (C-8a), 124.8 (C-8), 133.6
(C-6), 141.0 (C-4a). Anal. (C10H12ClFN2O2S) theoretical: C, 43.09;
H, 4.34; N, 10.05; S, 11.50. Found: C, 43.06; H, 4.35; N, 10.09; S,
11.45.
R/S-7-Chloro-2,3,4-trimethyl-3,4-dihydro-2H-1,2,4-benzothiadia-
zine 1,1-Dioxide (7b). White solid; m.p.: 126−128 °C; 1H NMR
(DMSO-d6) δ 1.55 (d, J = 6.7 Hz, 3H, CHCH3), 2.63 (s, 3H, NCH3),
2.96 (s, 3H, NCH3), 5.14 (q, J = 6.7 Hz, 1H, CHCH3), 6.98 (d, J = 9.2
Hz, 1H, 5-H), 7.50 (dd, J = 9.1 Hz/2.5 Hz, 1H, 6-H), 7.56 (d, J = 2.5
Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ 17.8 (CHCH3), 32.9 (NCH3),
34.6 (NCH3), 72.8 (CHCH3), 116.4 (C-5), 120.3−120.5 (C-7/C-8a),
124.5 (C-8), 133.5 (C-6), 141.9 (C-4a). Anal. (C10H13ClN2O2S)
theoretical: C, 46.06; H, 5.03; N, 10.74; S, 12.30. Found: C, 45.57; H,
5.03; N, 10.73; S, 11.61.
R/S-7-Chloro-4-ethyl-2,3-dimethyl-3,4-dihydro-2H-1,2,4-benzo-
thiadiazine 1,1-Dioxide (7c). White solid; m.p.: 70−71 °C; 1H NMR
(DMSO-d6) δ 1.10 (t, J = 7 Hz, 3H, CH2CH3), 1.58 (d, J = 6.7 Hz,
3H, CHCH3), 2.60 (s, 3H, NCH3), 3.47 (m, 2H, NCH2CH3), 5.17 (q,
J = 6.7 Hz, 1H, CHCH3), 7.01 (d, J = 9.3 Hz, 1H, 5-H), 7.47 (dd, J =
9.2 Hz/2.6 Hz, 1H, 6-H), 7.54 (d, J = 2.6 Hz, 1H, 8-H); 13C NMR
(DMSO-d6) δ 12.1 (CH2CH3), 18.3 (CHCH3), 32.8 (NCH3), 40.5
(NCH2CH3), 71.7 (CHCH3), 116.1 (C-5), 119.9−120.1 (C-7/C-8a),
124.7 (C-8), 133.6 (C-6), 140.5 (C-4a). Anal. (C11H15ClN2O2S)
theoretical: C, 48.08; H, 5.50; N, 10.20; S, 11.67. Found: C, 48.06; H,
5.51; N, 10.36; S, 11.02.
7-Chloro-4-(2,2-difluoroethyl)-2-methyl-3,4-dihydro-2H-1,2,4-
benzothiadiazine 1,1-Dioxide (6e). White solid; m.p.: 143−145 °C;
1H NMR (DMSO-d6) δ 2.70 (s, 3H, NCH3), 3.97 (td, J = 15.9 Hz/3.3
Hz, 2H, NCH2), 5.00 (s, 2H, 3−CH2), 6.30 (tt, J = 54.9 Hz/3.4 Hz,
1H, CHF2), 7.15 (d, J = 9.2 Hz, 1H, 5-H), 7.52 (dd, J = 9.2 Hz/2.6 Hz,
1H, 6-H), 7.60 (d, J = 2.6 Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ 34.4
(NCH3), 50.4 (t, J = 24 Hz, NCH2), 67.7 (C-3), 115.0 (t, J = 241 Hz,
CHF2), 116.4 (C-5), 120.0 (C-7), 121.3 (C-8a), 124.7 (C-8), 133.6
(C-6), 141.1 (C-4a). Anal. (C10H11ClF2N2O2S) theoretical: C, 40.48;
H, 3.74; N, 9.44; S, 10.80. Found: C, 40.33; H, 4.12; N, 9.55; S, 10.98.
7-Chloro-4-cyclopropyl-2-methyl-3,4-dihydro-2H-1,2,4-benzo-
thiadiazine 1,1-Dioxide (6f). White solid; m.p.: 134−136 °C; 1H
NMR (DMSO-d6) δ 0.70 (m, 2H, CH(CH2)2), 0.93 (m, 2H,
CH(CH2)2), 2.59 (m, 1H, CH(CH2)2), 2.62 (s, 3H, NCH3), 4.90 (s,
2H, 3−CH2), 7.33 (d, J = 9.0 Hz, 1H, 5-H), 7.55 (dd, J = 9.0 Hz/2.6
Hz, 1H, 6-H), 7.57 (d, J = 2.4 Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ
8.3 (CH(CH2)2), 29.7 (NCH3), 34.0 (CH(CH2)2), 66.8 (C-3), 116.6
(C-5), 120.4 (C-7), 121.3 (C-8a), 124.4 (C-8), 133.3 (C-6), 142.2 (C-
4a). Anal. (C11H13ClN2O2S) theoretical: C, 48.44; H, 4.80; N, 10.27;
S, 11.75. Found: C, 48.16; H, 4.87; N, 10.42; S, 11.36.
7-Chloro-4-cyclopropylmethyl-2-methyl-3,4-dihydro-2H-1,2,4-
benzothiadiazine 1,1-Dioxide (6g). White solid; m.p.: 90−92 °C; 1H
NMR (DMSO-d6) δ 0.31 (m, 2H, CH(CH2)2), 0.48 (m, 2H,
CH(CH2)2), 1.06 (m, 1H, CH(CH2)2), 2.68 (s, 3H, NCH3), 3.33 (m,
2H, NCH2), 4.97 (s, 2H, 3−CH2), 7.10 (d, J = 9.2 Hz, 1H, 5-H), 7.47
(dd, J = 9.2 Hz/2.6 Hz, 1H, 6-H), 7.55 (d, J = 2.6 Hz, 1H, 8-H); 13C
NMR (DMSO-d6) δ 3.1 (CH(CH2)2), 8.7 (CH(CH2)2), 34.5
(NCH3), 52.9 (NCH2), 67.1 (C-3), 115.8 (C-5), 119.1 (C-7), 119.9
(C-8a), 124.8 (C-8), 133.6 (C-6), 141.1 (C-4a). Anal.
(C12H15ClN2O2S) theoretical: C, 50.26; H, 5.27; N, 9.77; S, 11.18.
Found: C, 49.67; H, 5.22; N, 9.76; S, 11.36.
R/S-7-Chloro-4-(2-fluoroethyl)-2,3-dimethyl-3,4-dihydro-2H-
1,2,4-benzothiadiazine 1,1-Dioxide (7d). White solid; m.p.: 118−120
°C; 1H NMR (DMSO-d6) δ 1.59 (d, J = 6.7 Hz, 3H, CHCH3), 2.63 (s,
3H, NCH3), 3.80 (m, 2H, NCH2), 4.61 (dt, J = 47.5 Hz/4.9 Hz, 1H,
CH2F), 5.23 (q, J = 6.7 Hz, 1H, CHCH3), 7.09 (d, J = 9.3 Hz, 1H, 5-
H), 7.48 (dd, J = 9.2 Hz/2.6 Hz, 1H, 6-H), 7.59 (d, J = 2.6 Hz, 1H, 8-
H); 13C NMR (DMSO-d6) δ 18.2 (CHCH3), 32.5 (NCH3), 46.4 (d, J
= 20 Hz, NCH2), 72.1 (CHCH3), 82.0 (d, J = 166 Hz, CH2F), 116.7
(C-5), 120.8−120.9 (C-7/C-8a), 124.8 (C-8), 133.4 (C-6), 140.8 (C-
4a). Anal. (C11H14ClFN2O2S) theoretical: C, 45.13; H, 4.82; N, 9.57;
S, 10.95. Found: C, 45.07; H, 4.75; N,9.65; S, 10.71.
R/S-7-Chloro-4-(2,2-difluoroethyl)-2,3-dimethyl-3,4-dihydro-2H-
1,2,4-benzothiadiazine 1,1-Dioxide (7e). White solid; m.p.: 119−121
°C; 1H NMR (DMSO-d6) δ 1.59 (d, J = 6.7 Hz, 3H, CHCH3), 2.66 (s,
3H, NCH3), 3.96 (m, 2H, NCH2), 5.24 (q, J = 6.7 Hz, 1H, CHCH3),
6.29 (tt, J = 55.0 Hz/3.7 Hz, 1H, CHF2), 7.18 (d, J = 9.3 Hz, 1H, 5-
H), 7.52 (dd, J = 9.2 Hz/2.6 Hz, 1H, 6-H), 7.62 (d, J = 2.6 Hz, 1H, 8-
H); 13C NMR (DMSO-d6) δ 18.0 (CHCH3), 32.8 (NCH3), 48.2 (t, J
= 25 Hz, NCH2), 72.6 (CHCH3), 115.0 (t, J = 242 Hz, CHF2), 117.2
(C-5), 121.4−121.7 (C-7/C-8a), 124.7 (C-8), 133.4 (C-6), 140.9 (C-
4a). Anal. (C11H13ClF2N2O2S) theoretical: C, 42.52; H, 4.22; N, 9.01;
S, 10.32. Found: C, 42.68; H, 4.21; N,9.09; S, 10.73.
R/S-7-Chloro-4-cyclopropyl-2,3-dimethyl-3,4-dihydro-2H-1,2,4-
benzothiadiazine 1,1-Dioxide (7f). White solid; m.p.: 135−136 °C;
1H NMR (DMSO-d6) δ 0.66 (m, 2H, CH(CH2)2), 0.97 (m, 2H,
CH(CH2)2), 1.57 (d, J = 6.9 Hz, 3H, CHCH3), 2.51 (m, 1H,
CH(CH2)2), 2.67 (s, 3H, NCH3), 4.99 (q, J = 6.8 Hz, 1H, CHCH3),
7.32 (d, J = 9.1 Hz, 1H, 5-H), 7.54 (dd, J = 9.1 Hz/2.6 Hz, 1H, 6-H),
7.57 (d, J = 2.5 Hz, 1H, 8-H); 13C NMR (DMSO-d6) δ 7.7
(CH(CH2)2), 10.1 (CH(CH2)2), 17.4 (CHCH3), 28.3 (NCH3), 35.1
(CH(CH2)2), 73.9 (CHCH3), 117.6 (C-5), 121.4−121.8 (C-7/C-8a),
124.2 (C-8), 133.2 (C-6), 141.3 (C-4a). Anal. (C12H15ClN2O2S)
theoretical: C, 50.26; H, 5.27; N, 9.77; S, 11.18. Found: C, 50.30; H,
5.26; N, 9.97; S, 11.18.
Synthetic Pathway to 4-Alkyl-7-chloro-2,3-dimethyl-3,4-dihydro-
2H-1,2,4-benzothiadiazine 1,1-Dioxides 7. The 4-alkyl-7-chloro-2,3-
dimethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides 7b−g
were obtained by methylation of the corresponding 4-alkyl-7-chloro-
3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides 5b−g by
means of methyl iodide in the experimental conditions used for the
synthesis of compounds 6 (see above).
J
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX