Facile synthesis of benzothiadiazine 1,1-dioxides, a precursor of RSV inhibitors, by tandem amidation/ intramolecular aza-Wittig reaction

Article abstract of DOI:10.3762/bjoc.9.54

Reaction of o-azidobenzenesulfonamides with ethyl carbonochloridate afforded the corresponding amide derivatives, which gave 3-ethoxy-1,2,4- benzothiadiazine 1,1-dioxides through an intramolecular aza-Wittig reaction. The reaction was found to be general

Full text of DOI:10.3762/bjoc.9.54

Supporting Information
for
Facile synthesis of benzothiadiazine-1,1-dioxides, a
precursor of RSV inhibitors, by tandem amidation/
intramolecular Aza-Wittig reaction
Krishna C. Majumdar*,§ and Sintu Ganai
Address: Department of Chemistry, University of Kalyani, Kalyani 741235, W.B India
§Tel.: +91-33-2582 8750; Fax: +91-33-2582 8282
Email: Krishna C. Majumdar - kcm@klyuniv.ac.in
*Corresponding author
Experimental part
General information
Melting points were determined in open capillaries and are uncorrected. Silica gel (60–
120 mesh) was used for chromatographic separation. Silica gel G was used for TLC.
Petroleum ether (Pet) refers to the fraction boiling between 60 °C and 80 °C. IR spectra were
recorded on a Perkin-Elmer L 120-000A spectrometer (max in cm−1) on KBr disks and neat.
1H NMR and 13C spectra were recorded in CDCl3 and DMSO (chemical shifts in ) with TMS
as internal standard. MS were recorded on a Q-TOF microTM instrument at the Indian
S1

Institute of Chemical Biology (Kolkata). CHN analyses were recorded on a Perkin-Elmer
2400 series II CHN analyzer. HRMS were recorded on a Q-TOF Micro YA263 instrument at
the Indian Association for the Cultivation of Science (Kolkata).
General procedure for the preparation of o-azidobenzenesulfonic acid (11) [1]:
2-Aminobenzenesulfonic acid (11.57 g, 66.8 mmol) was dissolved in a water (45 mL) and
conc. H2SO4 (15 mL) mixture and cooled to 0 °C. A solution of NaNO2 (6 g, 86.8 mmol) in
water (30 mL) was added dropwise to it and the reaction mixture was stirred at 0 °C for
30 min. Then a cold solution of NaN3 (8.68 g, 133.6 mmol) in water (30 mL) was added
slowly. The reaction mixture was stirred at room temperature for a period of 12 h. The
resulting precipitate was filtered off and washed with ice-cold water (10 mL) and dried under
reduced pressure to give o-azidobenzenesulfonic acid (6.8 g, 34.1 mmol, 51%). Mp 152–
154 °C (lit. 153–155 °C); IR (KBr): 1108, 1270, 1465, 1609, 2135 cm−1 (lit. 2134 cm−1).
General procedure for the preparation of 2-azido-N-phenylbenzenesulfonamide (10a):
To a suspension of o-azidobenzenesulfonic acid (500 mg, 2.510 mmol) in dichloromethane
(30 mL) was added a solution of 2 M oxalyl chloride in CH2Cl2 (6.280 mmol) and DMF
(4 drop). The resulting mixture was heated under reflux for 3 h and then evaporated under
reduced pressure. This crude o-azidobenzenesulfonyl chloride was added in small portions
to a vigorously stirred mixture of the corresponding amine (here aniline 350 mg, 3.765 mmol)
and NaOAc (310 mg, 3.765 mmol) in 50% aq MeOH (15 mL) over a period of 30 min. The
mixture was then stirred at 60 °C for 1 h, cooled to room temperature, diluted with water
(30 mL) and acidified to pH 2 with conc. HCl. The precipitate was filtered off, washed
thoroughly with water and recrystallized from EtOAc to afford the grey solid product 10a
(571 mg, 2.084 mmol, 83%) [Found: C, 52.71; H, 3.86; N, 20.18 %. C12H10N4O2S requires C,
52.54; H, 3.67; N, 20.43 %] Rf (15% EtOAc/Pet) 0.48; Mp 255–257 °C; IR (KBr): 1155, 1472,
1
2130, 3254 cm−1; H NMR (400 MHz, CDCl3) δH 7.05-7.12 (m, 4H, ArH), 7.16-7.24 (m, 3H,
ArH), 7.28 (s, 1H, NH), 7.53 (t, J = 8.0 Hz, 1H, ArH), 7.90 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
S2

(100 MHz, CDCl3) δC 119.4, 121.2, 124.8, 125.5, 128.9, 129.3, 131.3, 134.4, 136.1, 137.7;
HRMS-ESI m/z found 275.0610 (MH+), C13H10N4O2S requires 275.0607 (MH+).
Characterization of ethyl 2-azidophenylsulfonyl-(4-chlorophenyl)-carbamate (9b):
White gummy liquid; Rf (15% EtOAc/Pet) 0.58; IR (neat): 1158, 1332, 1510, 1711, 2134 cm−1;
1H NMR (400 MHz, CDCl3) δH 1.08 (t, J = 7.2 Hz, 3H, COOCH2CH3), 4.09 (q, J = 7.2 Hz, 2H,
COOCH2CH3), 7.32-7.36 (m, 2H, ArH), 7.40-7.46 (m, 4H, ArH), 7.68 (td, J = 6.4, 1.6 Hz, 1H,
ArH), 8.22 (dd, J = 8.0, 1.6 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC 13.9, 63.8, 119.8,
124.6, 129.3, 129.4, 131.5, 133.4, 133.5, 135.2, 135.4, 138.5, 151.9.
2-azido-N-(4-chlorophenyl)benzenesulfonamide (10b):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and p-chloroaniline (480 mg, 3.765 mmol), compound 10b was isolated as a
gummy liquid (627 mg, 2.035 mmol, 81%); Rf (15% EtOAc/Pet) 0.51; IR (neat): 1160, 1331,
1
2136, 3251 cm−1; H NMR (400 MHz, CDCl3) δH 7.04-7.07 (m, 3H, ArH), 7.17-7.19 (m, 2H,
ArH), 7.22 (s, 1H, NH), 7.27 (d, J = 8.0 Hz, 1H, ArH), 7.56 (t, J = 7.6 Hz, 1H, ArH), 7.88 (d, J
= 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC 118.5, 121.8, 124.8, 125.4, 129.0, 129.1,
129.5, 132.5, 133.0, 136.5. 136.9; HRMS-ESI m/z found 331.0042 (MNa+), C12H9ClN4O2SNa
requires 331.0032 (MNa+).
Characterization of iminophosphorane intermediate (12b):
White solid; Rf (15% EtOAc/Pet) 0.45; Mp 128–130 °C; IR (KBr): 1158, 1332, 1548,
1
1711 cm−1; H NMR (400 MHz, CDCl3) δH 1.12 (t, J = 6.8 Hz, 3H, COOCH2CH3), 4.03-4.15
(m, 2H, COOCH2CH3), 6.41 (d, J = 8.0 Hz, 1H, ArH), 6.66 (t, J = 7.6 Hz, 1H, ArH), 6.70-6.78
(m, 1H, ArH), 6.81 (d, J = 8.4 Hz, 1H, ArH), 6.99 (t, J = 7.6 Hz, 1H, ArH), 7.14 (d, J = 8.0 Hz,
1H, ArH), 7.33-7.38 (m, 7H, ArH), 7.47-7.54 (m, 3H, ArH), 7.63-7.68 (m, 5H, ArH), 7.72 (d,
J = 8.0 Hz, 1H, ArH), 8.08 (d, J = 7.6 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC 14.0,
63.7, 115.4, 116.9, 117.7, 119.4, 122.8, 122.9, 128.1, 128.7, 128.8, 129.0, 129.4, 130.0,
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131.4, 131.7, 132.0, 132.1, 132.7, 132.8, 133.8, 134.1, 134.5, 134.9, 135.3, 135.4, 146.9,
151.7, 152.3, 152.5.
Characterization of ethyl 2-aminophenylsulfonyl-(4-chlorophenyl)-carbamate (14b):
White solid; Rf (15% EtOAc/Pet) 0.55; Mp 113–115 °C; IR (KBr): 1161, 1336, 1561, 1719,
3382, 3390 cm−1; 1H NMR (400 MHz, CDCl3) δH 1.13 (t, J = 7.2 Hz, 3H, COOCH2CH3), 4.13
(q, J = 7.2 Hz, 2H, COOCH2CH3), 5.08 (m, 2H, NH2), 6.72-6.79 (m, 2H, ArH), 7.28 (d, J =
8.8 Hz, 2H, ArH), 7.33-7.37 (m, 1H, ArH), 7.40 (d, J = 8.8 Hz, 2H, ArH), 7.72 (d, J = 8.0 Hz,
1H, ArH); 13C NMR (100 MHz, CDCl3) δC 13.8, 63.7, 119.7, 124.4, 128.9, 129.3, 131.5,
133.4, 133.5, 135.2, 135.4, 138.3, 151.4.
N-(4-acetylphenyl)-2-azidobenzenesulfonamide (10c):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and 1-(4-aminophenyl)ethanone (508 mg, 3.765 mmol), compound 10c was
isolated as a grey solid (690 mg, 2.183 mmol, 87%); [Found: C, 53.09; H, 3.88; N, 17.92;
C14H12N4O3S requires C, 53.16; H, 3.82; N, 17.71] Rf (15% EtOAc/Pet) 0.46; Mp decomposed
at 200 °C; IR (KBr): 1160, 1339, 1669, 2102, 3208 cm−1; 1H NMR (400 MHz, CDCl3) δH 2.51
(s, 3H, COCH3), 7.19 (t, J = 8.2 Hz, 2H, ArH), 7.25-7,27 (m, 2H, ArH), 7.33 (s, 1H, NH), 7.58
(t, J = 7.8 Hz, 1H, ArH), 7.82 (d, J = 8.4 Hz, 2H, ArH), 7.99 (d, J = 7.6 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δC 26.4, 119.1, 119.6, 124.9, 129.9, 131.4, 133.6, 134.8, 137.8, 140.7,
196.6.
Methyl 4-(2-azidophenylsulfonamido)benzoate (10d):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and methyl 4-aminobenzoate (569 mg, 3.765 mmol), compound 10d was
isolated as a grey solid (700 mg, 2.108 mmol, 84%); [Found: C, 50.71; H, 3.57; N, 16.93;
C14H12N4O4S requires C, 50.60; H, 3.64; N, 16.86] Rf (30% EtOAc/Pet) 0.47; Mp 188–190 °C;
1
IR (KBr): 1165, 1345, 1695, 2106, 3212 cm−1; H NMR (400 MHz, DMSO) δH 3.75 (s, 3H,
COOCH3), 7.20 (d, J = 8.2 Hz, 2H, ArH), 7.31 (m, 1H, ArH), 7.49 (m, 1H, ArH), 7.64 (d, J =
S4

7.6 Hz, 1H, ArH), 7.78 (d, J = 8.2 Hz, 2H, ArH), 7.95 (d, J = 7.0 Hz, 1H, ArH), 10.90 (s, 1H,
NH); 13C NMR (100 MHz, DMSO) δC 52.0, 117.9, 121.3, 124.3, 125.0, 128.6, 130.6, 130.8,
135.0, 137.7, 142.1, 165.7.
2-azido-N-p-tolylbenzenesulfonamide (10e):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and p-methylaniline (403 mg, 3.765 mmol), compound 10e was isolated as a
white solid (636 mg, 2.208 mmol, 88%); [Found: C, 53.91; H, 4.12; N, 19.61 %. C13H12N4O2S
requires C, 54.15; H, 4.20; N, 19.43 %] Rf (15% EtOAc/Pet) 0.47; Mp 138–140 °C; IR (KBr):
1159, 1331, 2134, 3263 cm−1; 1H NMR (400 MHz, CDCl3) δH 2.23 (s, 3H, CH3), 6.98-7.02 (m,
5H, NH and ArH overlapped), 7.14 (dt, J = 8.4, 0.8 Hz, 1H, ArH), 7.26 (d, J = 8.8 Hz, 1H,
ArH), 7.52 (dt, J = 8.4, 1.6 Hz, 1H, ArH), 7.86 (dd, J = 8.0, 1.2 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δC 20.8, 119.4, 121.9, 124.8, 129.0, 129.9, 131.3, 133.4, 134.3, 135.6,
137.6.
2-azido-N-(4-methoxyphenyl)benzenesulfonamide (10f):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and p-methoxyaniline (463 mg, 3.765 mmol), compound 10f was isolated as a
grey solid (649 mg, 2.134 mmol, 85%); [Found: C, 51.03; H, 4.10; N, 18.57 %. C13H12N4O3S
requires C, 51.31; H, 3.97; N, 18.41 %] Rf (15% EtOAc/Pet) 0.48; Mp 116–118 °C; IR (KBr):
1
1163, 1311, 2139, 3277 cm−1; H NMR (400 MHz, CDCl3) δH 3.72 (s, 3H, OCH3), 6.72 (dd,
J = 6.8, 2.0 Hz, 2H, ArH), 6.87 (s, 1H, NH), 7.01 (dd, J = 7.6, 2.0 Hz, 2H, ArH), 7.14 (t, J =
7.6 Hz, 1H, ArH), 7.29 (d, J = 8.0 Hz, 1H, ArH), 7.54 (dt, J = 8.0, 1.6 Hz, 1H, ArH), 7.80 (dd,
J = 8.0, 1.6 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC 55.4, 114.5, 119.3, 124.7, 124.8,
124.9, 128.6, 129.0, 131.3, 134.2, 137.6.
2-azido-N-benzylbenzenesulfonamide (10g):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and benzylamine (403 mg, 3.675 mmol), compound 10g was isolated as a light
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tan solid (579 mg, 2.010 mmol, 80%); [Found: C, 53.81; H, 4.06; N, 19.65 %. C13H12N4O2S
requires C, 54.15; H, 4.20; N, 19.43 %] Rf (15% EtOAc/Pet) 0.50; Mp 80–82 °C; IR (KBr):
1165, 1327, 2142, 3292 cm−1; 1H NMR (400 MHz, CDCl3) δH 4.10 (d, J = 6.0 Hz, 2H, NCH2),
5.28 (brs, 1H, NH), 7.16-7.23 (m, 7H, ArH), 7.55 (t, J = 7.2 Hz, 1H, ArH), 7.98 (d, J = 7.6 Hz,
1H, ArH); 13C NMR (100 MHz, CDCl3) δC 47.6, 119.3, 124.8, 127.9, 128.0, 128.4, 128.5,
130.0, 130.6, 134.0, 136.0, 137.5.
2-azido-N-methylbenzenesulfonamide (10h):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and methylamine solution (10 mL), compound 10h was isolated as a colourless
solid (442 mg, 2.084 mmol, 83%); [Found: C, 39.86; H, 4.05; N, 26.17 %. C7H8N4O2S
requires C, 39.62; H, 3.80; N, 26.40 %] Rf (15% EtOAc/Pet) 0.53; Mp 136–138 °C; IR (KBr):
1
1161, 1326, 2142, 3305 cm−1; H NMR (400 MHz, CDCl3) δH 2.61 (d, J = 5.2 Hz, 3H, CH3),
4.94 (d, J = 4.8 Hz, 1H, NH), 7.27 (d, J = 8.0 Hz, 1H, ArH), 7.31 (d, J = 8.4 Hz, 1H, ArH),
7.60 (dt, J = 8.8, 0.8 Hz, 1H, ArH), 7.99 (d, J = 7.6 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3)
δC 29.4, 119.4, 124.9, 128.4, 131.1, 134.1, 137.6.
2-azido-N-(2-oxo-2H-chromen-6-yl)benzenesulfonamide (10i):
Using the general procedure (as 10a) starting from o-azidobenzenesulfonic acid (500 mg,
2.510 mmol) and 6-aminocoumarine (605 mg, 3.765 mmol), compound 10i was isolated as a
brown solid (773 mg, 2.260 mmol, 90%); [Found: C, 52.78; H, 3.15; N, 16.11%. C15H10N4O4S
requires C, 52.63; H, 2.94; N, 16.37%.] Rf (30% EtOAc/Pet) 0.50; Mp 194–196 °C
1
decomposed; IR (KBr):1160, 1310, 2128, 1711, 3282 cm−1; H NMR (400 MHz, DMSO) δH
6.43 (d, J = 9.6 Hz, 1H, =CH of coumarin), 7.26-7.35 (m, 3H, ArH), 7.43 (d, J = 2.4 Hz, 1H,
ArH), 7.52 (d, J = 8.0 Hz, 1H, ArH), 7.64 (t, J = 7.6 Hz, 1H, ArH), 7.84 (d, J = 8.0 Hz, 1H,
ArH), 8.00 (d, J = 9.6 Hz, 1H, =CH of coumarin), 10.48 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3 + DMSO) δC 116.9, 117.3, 118.7, 119.0, 119.8, 124.4, 124.6, 129.0, 131.0, 133.8,
134.3, 137.8, 143.2, 150.6, 160.4.
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General procedure for the preparation of 2-N-phenyl-3-ethoxy-1,2,4-benzothiadiazine
1,1-dioxide (13a):
2-azido-N-phenylbenzenesulfonamide (150 mg, 0.547 mmol) and Et3N (1.094 mmol) in 5 mL
xylene was taken in a sealed tube and ethyl carbonochloridate (89 mg, 0.820 mmol) was
added dropwise and stirred at room temperature for 30 minutes. Then Ph3P (215 mg,
0.820 mmol) was added to it and it was sealed with the cap tightly and the reaction was
heated at 135 °C. After completion of the reaction as monitored by TLC, the reaction mixture
was cooled, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 ×
30 mL). The ethyl acetate extract was washed with water (2 × 40 mL), followed by brine
(30 mL). The organic layer was dried (over Na2SO4), and the solvent was evaporated to give
a crude product. This was purified by column chromatography over silica gel (230–
400 mesh) using petroleum ether and ethyl acetate (4:1) as an eluent. The product 13a was
isolated as a white solid (149 mg, 0.493 mmol, 90%); Rf (20% EtOAc/Pet) 0.47; Mp 116–
118 °C; IR (KBr): 1155, 1306, 1338, 1579, 1610 cm−1; 1H NMR (300 MHz, CDCl3) δH 1.26 (t,
J = 6.9 Hz, 3H, OCH2CH3), 4.45 (q, J = 6.9 Hz, 2H, OCH2CH3), 7.33-7.56 (m, 7H, ArH), 7.66
(td, J = 7.5, 3.0 Hz, 1H, ArH), 7.89 (d, J = 7.2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC
14.0, 65.1, 122.0, 124.7, 126.1, 126.7, 129.3, 129.6, 129.8, 131.4, 133.8, 141.8, 150.7;
HRMS-ESI m/z found 303.0801 (MH+), C15H15N2O3S requires 303.0803 (MH+).
2-N-(4-chlorophenyl)-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13b):
Using
the
general
procedure
(as
13a)
starting
from
2-azido-N-(4-
chlorophenyl)benzenesulfonamide (150 mg, 0.487 mmol), compound 13b was isolated as a
white solid (154 mg, 0.458 mmol, 94%); Rf (20% EtOAc/Pet) 0.55; Mp 102–104 °C; IR (KBr):
1
1186, 1310, 1338, 1577, 1610 cm−1; H NMR (300 MHz, CDCl3) δH 1.25 (t, J = 7.2 Hz, 3H,
OCH2CH3), 4.43 (q, J = 6.9 Hz, 2 , OCH2CH3), 7.34-7.38 (m, 3H, ArH), 7.44 (d, J = 8.4 Hz,
3H, ArH), 7.65 (t, J = 7.8 Hz, 1H, ArH), 7.86 (d, J = 8.0 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δC 14.0, 65.3, 122.0, 124.9, 125.9, 126.8, 129.6, 129.8, 131.1, 134.0, 135.8, 141.7,
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150.3; HRMS-ESI m/z found 337.0409 (MH+), 339.0380 (MH++2), C15H14ClN2O3S requires
337.0414 (MH+), 339.0384 (MH++2).
2-N-(4-acetylphenyl)-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13c):
Using the general procedure (as 13a) starting from N-(4-acetylphenyl)-2-
azidobenzenesulfonamide (150 mg, 0.474 mmol), compound 13c was isolated as a white
solid (150 mg, 0.436 mmol, 92%); Rf (20% EtOAc/Pet) 0.48; Mp 143–145 °C; IR (KBr): 1159,
1
1311, 1585, 1615, 1682 cm−1; H NMR (400 MHz, CDCl3) δH 1.25 (t, J = 6.8 Hz, 3H,
OCH2CH3), 2.65 (s, 3H, COCH3), 4.45 (q, J = 6.8 Hz, 2H, OCH2CH3), 7.36 (t, J = 7.6 Hz, 1H,
ArH), 7.46-7.51 (m, 3H, ArH), 7.66 (t, J = 7.8 Hz, 1H, ArH); 7.86 (d, J = 8.0 Hz, 1H, ArH),
8.05 (d, J = 8.4 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3) δC 12.0, 26.7, 65.4, 122.0, 125.0,
126.0, 126.9, 129.3, 129.7, 134.0, 135.8, 137.7, 141.7, 151.1, 197.0; HRMS-ESI m/z found
345.0903 (MH+), C17H17N2O4S requires 345.0909 (MH+).
2-N-(p-methoxycarbonylphenyl)-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13d):
Using
the
general
procedure
(as
13a)
starting
from
methyl
4-(2-
azidophenylsulfonamido)benzoate (150 mg, 0.451 mmol), compound 13d was isolated as a
white solid (154 mg, 0.429 mmol, 95%); Rf (20% EtOAc/Pet) 0.45; Mp 160–162 °C; IR (KBr):
1
1179, 1312, 1583, 1619, 1718 cm−1; H NMR (400 MHz, CDCl3) δH 1.24 (t, J = 7.2 Hz, 3H,
OCH2CH3), 3.95 (s, 3H, COOCH3), 4.44 (q, J = 7.2 Hz, 2H, OCH2CH3), 7.36 (td, J = 7.6,
0.8 Hz, 1H, ArH), 7.45-7.48 (m, 3H, ArH), 7.65 (td, J = 8.4, 1.4 Hz, 1H, ArH), 7.86 (dd, J =
8.0, 1.2 Hz, 1H, ArH), 8.14 (dd, J = 8.4, 1.6 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3) δC
14.0, 52.4, 65.3, 122.0, 125.0, 126.1, 126.9, 129.6, 130.6, 131.2, 134.0, 135.7, 141.7, 150.2,
166.1; HRMS-ESI m/z found 361.0849 (MH+), C17H17N2O5S requires 361.0858 (MH+).
2-N-p-tolyl-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13e):
Using the general procedure (as 13a) starting from 2-azido-N-p-tolylbenzenesulfonamide
(150 mg, 0.520 mmol), compound 13e was isolated as a white solid (132 mg, 0.417 mmol,
80%); Rf (20% EtOAc/Pet) 0.53; Mp 108–110 °C; IR (KBr): 1156, 1305, 1340, 1580,
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1611 cm−1; 1H NMR (300 MHz, CDCl3) δH 1.25 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.41 (s, 3H, p-
ArCH3), 4.43 (q, J = 7.2 Hz, 2H, OCH2CH3), 7.25-7.32 (m, 4H, ArH), 7.33 (t, J = 7.6 Hz, 1H,
ArH), 7.44 (d, J = 8.0 Hz, 1H, ArH), 7.62 (t, J = 7.6 Hz, 1H, ArH), 7.86 (d, J = 7.6 Hz, 1H,
ArH); 13C NMR (75 MHz, CDCl3) δC 14.1, 21.3, 65.1, 122.0, 124.7, 126.1, 126.7, 128.6,
129.6, 130.1, 133.8, 139.9, 142.0, 150.9; HRMS-ESI m/z found 317.0965 (MH+),
C16H17N2O3S requires 317.0960 (MH+).
2-N-(4-methoxyphenyl)-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13f):
Using
the
general
procedure
(as
13a)
starting
from
2-azido-N-(4-
methoxyphenyl)benzenesulfonamide (150 mg, 0.493 mmol), compound 13f was isolated as
a white solid (136 mg, 0.409 mmol, 83%); Rf (20% EtOAc/Pet) 0.50; Mp 148–150 °C; IR
1
(KBr): 1167, 1334, 1581, 1611 cm−1; H NMR (300 MHz, CDCl3) δH 1.27 (t, J = 6.9 Hz, 3H,
OCH2CH3), 3.87 (s, 3H, OCH3), 4.44 (q, J = 6.9 Hz, 2H, OCH2CH3), 6.98 (d, J = 8.7 Hz, 2H,
ArH), 7.28-7.37 (m, 3H, ArH), 7.45 (d, J = 7.8 Hz, 1H, ArH), 7.63 (td, J = 8.4, 1.5 Hz, 1H,
ArH), 7.88 (d, J = 7.8 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC 14.0, 55.5, 65.0, 114.6,
122.1, 123.4, 124.6, 126.0, 126.7, 131.1, 133.8, 141.8, 150.9, 160.5; HRMS-ESI m/z found
333.0911 (MH+), C16H17N2O4S requires 333.0909 (MH+).
2-N-benzyl-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13g):
Using the general procedure (as 13a) starting from 2-azido-N-benzylbenzenesulfonamide
(150 mg, 0.520 mmol), compound 13g was isolated as a white solid (143 mg, 0.452 mmol,
87%); Rf (20% EtOAc/Pet) 0.54; Mp 85–87 °C; IR (KBr): 1152, 1327, 1584, 1613 cm−1;
1H NMR (400 MHz, CDCl3) δH 1.28 (t, J = 7.2 Hz, 3H, OCH2CH3), 4.40 (q, J = 7.2 Hz, 2H,
OCH2CH3), 5.04 (s, 2H, NCH2Ph), 7.25-7.36 (m, 7H, ArH), 7.57 (td, J = 8.0, 1.2 Hz, 1H, ArH),
7.86 (d, J = 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δC 14.0, 45.2, 65.1, 121.7, 124.6,
125.5, 126.6, 127.9, 128.3, 128.5, 133.7, 135.9, 141.7, 150.9; HRMS-ESI m/z found
317.0967 (MH+), C16H17N2O3S requires 317.0960 (MH+).
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2-N-methyl-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13h):
Using the general procedure (as 13a) starting from 2-azido-N-methylbenzenesulfonamide
(150 mg, 0.707 mmol), compound 13h was isolated as a white solid (134 mg, 0.558 mmol,
79%); Rf (20% EtOAc/Pet) 0.45; Mp 136–138 °C; IR (KBr): 1156, 1305, 1340, 1580,
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1611 cm−1; H NMR (400 MHz, CDCl3) δH 1.42 (t, J = 7.2 Hz, 3H, OCH2CH3), 3.38 (s, 3H,
NCH3), 4.49 (q, J = 7.2 Hz, 2H, OCH2CH3), 7.28 (t, J = 7.8 Hz, 1H, ArH), 7.35 (d, J = 8.0 Hz,
1H, ArH), 7.58 (td, J = 7.8, 1.2 Hz, 1H, ArH), 7.82 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δC 14.2, 27.1, 65.0, 121.6, 124.4, 124.7, 126.4, 133.7, 141.8, 151.3;
HRMS-ESI m/z found 241.0639 (MH+), C10H13N2O3S requires 241.0647 (MH+).
2-N-(2-oxo-2H-chromen-6-yl)-3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13i):
Using the general procedure (as 13a) starting from 2-azido-N-(2-oxo-2H-chromen-6-
yl)benzenesulfonamide (150 mg, 0.438 mmol), compound 13i was isolated as a white solid
(144 mg, 0.390 mmol, 89%); Rf (25% EtOAc/Pet) 0.40; Mp 193–195 °C; IR (KBr): 1186,
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1339, 1592, 1629, 1733 cm−1; H NMR (300 MHz, CDCl3) δH 1.27 (t, J = 6.9 Hz, 3H,
OCH2CH3), 4.46 (q, J = 6.9 Hz, 2H, OCH2CH3), 6.51 (d, J = 9.6 Hz, 1H, =CH of coumarin),
7.35-7.55 (m, 4 H, ArH), 7.63-7.68 (m, 2H, ArH), 7.73 (d, J = 9.6 Hz, 1H, =CH of coumarin),
7.88 (d, J = 8.1 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) δC 14.1, 65.5, 117.7, 118.1, 119.4,
122.1, 125.0, 125.8, 127.0, 127.3, 129.3, 133.2, 134.2, 141.6, 142.7, 154.5, 160.0; HRMS-
ESI m/z found 371.0710 (MH+), C18H15N2O5S requires 371.0702 (MH+).
General procedure for the preparation of 2-N-substituted-1,2,4-benzothiadiazine-3-one
1,1-dioxide derivatives (15):
50 mg 3-ethoxy-1,2,4-benzothiadiazine 1,1-dioxide (13) was taken in a round bottomed flask
in ethanol (4 mL) and HCl (1 mL) was added to it. The reaction mixture was heated at 80 °C
for 4 h. After completion of the reaction as monitored by TLC the solvent was evaporated and
saturated NaHCO3 solution (10 mL) was added to it and extracted with ethyl acetate (3 ×
10 mL). The ethyl acetate extract was washed with water (2 × 15 mL), followed by brine
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(10 mL). The organic layer was dried (over Na2SO4), and the solvent was evaporated and
passed through a short column to yield solid product 15.
2-N-(4-acetylphenyl)-1,2,4-benzothiadiazine-3-one 1,1-dioxide (15c):
Using the general procedure starting from compound 13c (50 mg, 0.145 mmol), compound
15c was isolated as a white solid (43 mg, 0.136 mmol, 94%); Rf (30% EtOAc/Pet) 0.42; Mp
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123–125 °C; IR (KBr): 1181, 1340, 1608, 1686, 1698, 3076 cm−1; H NMR (400 MHz,
CDCl3 + DMSO) δH 2.49 (s, 3 H, COCH3), 7.25-7.34 (m, 2H, ArH), 7.58-7.62 (m, 3H, ArH),
7.84 (d, J = 7.6 Hz, 1H, ArH), 8.08 (d, J = 8.0 Hz, 2H, ArH), 11.19 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3 + DMSO) δC 26.8, 117.7, 122.7, 123.0, 123.3, 129.4, 130.8, 134.6, 134.8,
135.1, 137.8, 150.1, 197.1; HRMS-ESI m/z found 317.0591 (MH+), C15H13N2O4S requires
317.0596 (MH+).
2-N-p-tolyl-1,2,4-benzothiadiazine-3-one 1,1-dioxide (15e):
Using the general procedure starting from compound 13e (50 mg, 0.158 mmol), compound
15e was isolated as a white solid (44 mg, 0.152 mmol, 96%); Rf (30% EtOAc/Pet) 0.47; Mp
250–252 °C; IR (KBr): 1187, 1345, 1360, 1602, 1708, 3089 cm−1; 1H NMR (400 MHz, CDCl3)
δH 2.43 (s, 3H, p-ArCH3), 7.01 (d, J = 8.0 Hz, 1H, ArH), 7.28-7.37 (m, 5H, ArH), 7.58 (td, J =
8.4, 1.0 Hz, 1H, ArH), 7.89 (d, J = 8.0 Hz, 1H, ArH), 9.01 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3) δC 21.4, 117.3, 123.1, 123.2, 123.8, 127.6, 130.2, 130.4, 134.0, 134.5, 140.4, 151.3;
HRMS-ESI m/z found 289.0651 (MH+), C14H13N2O3S requires 289.0647 (MH+).
2-N-methyl-1,2,4-benzothiadiazine-3-one 1,1-dioxide (15h):
Using the general procedure starting from compound 13h (50 mg, 0.208 mmol), compound
15h was isolated as a white solid (43 mg, 0.202 mmol, 97%); Rf (30% EtOAc/Pet) 0.53; Mp
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158–160 °C; IR (KBr): 1180, 1333, 1600, 1693, 3061 cm−1; H NMR (400 MHz, CDCl3) δH
3.42 (s, 3H, NCH3), 7.18 (d, J = 8.0 Hz, 1H, ArH), 7.29 (t, J = 7.8 Hz, 1H, ArH), 7.61 (t, J =
7.8 Hz, 1H, ArH), 7.85 (d, J = 7.6 Hz, 1H, ArH), 10.34 (s, 1H, NH); 13C NMR (100 MHz,
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CDCl3) δC 26.5, 117.1, 122.0, 122.8, 123.9, 134.0, 134.6, 152.0; HRMS-ESI m/z found
213.0331 (MH+), C15H15N2O3S requires 213.0334 (MH+).
Reference
1. Blackburn, C.; Achab, A.; Elder, A.; Ghosh, S.; Guo, J.; Harriman, G.; Jones, M. J.
Org. Chem. 2005, 70, 10206-10209. doi: 10.1021/jo051843h
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