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D. Innes et al.
Ethyl 3-Diethylamino-5H-benzo[4,5]imidazo[1,2-b][1,2,6]
thiadiazine-4-carboxylate 1,1-Dioxide 9b
(600 MHz, d6-DMSO) 13.13 (1H, br. s, NH), 7.73–7.67 (3H,
m, ArH), 7.55 (1H, d, J 8.1, ArH), 7.44–7.34 (2H, m, ArH), 7.30
(2H, d, J 8.0, ArH), 3.55 (4H, q, J 7.0, N(CH2CH3)2), 2.31 (3H, s,
ArCH3), 1.05 (6H, t, J 7.0, N(CH2CH3)2). dC (150 MHz,
d6-DMSO) 160.08, 149.77, 143.12, 140.42, 129.76, 129.27,
126.19, 126.17, 125.81, 124.45, 112.96, 112.54, 82.01, 45.94,
20.90, 12.69.
Method A: The combined precipitate and EtOAc extract residue
were purified by column chromatography (10 % EtOAc in
CH2Cl2) to provide the title compound 9b (65 mg, 22 %) as a
white solid.
Method D: Extraction with CH2Cl2 and EtOAc and purifica-
tion by column chromatography (5 % EtOAC in CH2Cl2)
provided the title compound 9b (229 mg, 39 %) as a white solid.
Recrystallization from CH2Cl2 gave fine white needles, mp
137–1398C. m/z 387.1094 [M þ Na]þ; C16H20N4O4SNa
requires 387.1103 [M þ Na]þ. dH (600 MHz, d6-DMSO) 12.55
(1H, s, NH), 7.72 (1H, d, J 7.7, ArH), 7.60 (1H, d, J 7.7, ArH),
7.40 (1H, t, J 7.7, ArH), 7.34 (1H, t, J 7.7, ArH), 4.26 (2H, q, J
6.9, OCH2CH3), 3.45 (4H, q, J 6.9, N(CH2CH3)2), 1.30 (3H, t, J
6.9, OCH2CH3), 1.16 (6H, t, J 6.9, N(CH2CH3)2). dC (150 MHz,
d6-DMSO) 164.49, 161.17, 151.87, 131.58, 126.85, 125.72,
124.09, 112.90, 112.52, 75.21, 60.24, 40.05, 14.37, 12.87.
dH (600 MHz, CDCl3) 10.55 (1H, s, NH), 7.98–7.89 (1H, m,
ArH), 7.81 (1H, d, J 8.1, ArH), 7.65 (2H, dd, J 16.5, 8.0, ArH), 7.48
(2H, d, J 8.1, ArH), 7.43–7.32 (5H, m, ArH), 7.19 (1H, d, J 8.1,
ArH), 7.11 (2H, d, J8.0, ArH), 5.97 (1H, s, CHSO2), 4.25 (1H, dd, J
15.2, 7.4, 1H from NCH2 of CH tautomer), 4.12 (1H, dd, J 13.6,
7.0, 1H from NCH2 of CH tautomer), 3.68–3.60 (4H, m, 1H from
NCH2 of CH tautomer and 2 ꢀ NCH2 of NH tautomer), 3.44 (1H,
dd, J 13.6, 7.0, 1H from NCH2 of CH tautomer), 2.33 (3H, s,
ArCH3, NH tautomer), 2.30 (3H, s, ArCH3, CH tautomer), 1.41
(3H, t, J 7.2, NCH2CH3 of CH tautomer), 1.37 (3H, t, J 7.2,
NCH2CH3 of CH tautomer), 1.12 (6H, t, J 7.1, N(CH2CH3)2 of NH
tautomer). dC (150, CDCl3) 161.55, 152.49, 151.09, 147.22,
144.03, 141.33, 140.37, 140.32, 132.06, 131.42, 130.24, 129.99,
129.92, 129.67, 127.53, 126.37, 126.18, 125.83, 125.07, 124.90,
120.24, 114.43, 113.55, 111.50, 83.17, 63.45, 47.27, 45.70, 45.54,
29.85, 21.85, 21.66, 14.05, 13.11, 11.91.
Ethyl 3-(Piperidin-1-yl)-5H-benzo[4,5]imidazo[1,2-b]
[1,2,6]thiadiazine-4-carboxylate 1,1-Dioxide 9c
Method D: Extraction with CH2Cl2 and purification by column
chromatography (20 % EtOAc in hexanes) provided the title
compound 9c (60 mg, 11 %) as a white solid. Recrystallization
from acetone gave clear colourless prisms, mp 2108C (dec.). m/z
399.1103 [M þ Na]þ; C17H20N4O4SNa requires 399.1103 [M
þ Na]þ. dH (600 MHz, d6-DMSO) 12.62 (1H, s, NH), 7.73 (1H,
d, J 7.8, ArH), 7.61 (1H, d, J 7.8, ArH), 7.41 (1H, td, J 7.8, 1.2,
ArH), 7.36 (1H, td, J 7.8, 1.2, ArH), 4.28 (2H, q, J 7.2,
OCH2CH3), 3.47 (4H, br. s, 2 ꢀ NCH2), 1.55–1.66 (6H, m,
3 ꢀ CCH2), 1.31 (3H, t, J 7.2, OCH2CH3). dC (150 MHz,
d6-DMSO) 164.37, 160.56, 151.91, 131.50, 125.56, 123.99,
123.99, 112.88, 112.36, 74.80, 60.08, 50.08, 25.57, 23.62,
14.37.
15a: Recrystallization from acetone gave clear colourless
blocks, mp 129–1308C. m/z 505.0768 [M þ Na]þ;
C20H23N4O4S2ClNa requires 505.0747 [M þ Na]þ. dH
(600 MHz, d6-DMSO) 7.81 (1H, d, J 7.7, ArH), 7.71 (2H, d, J
8.0, ArH), 7.66 (1H, d, J 7.7, ArH), 7.46 (2H, d, J 8.0, ArH), 7.43
(1H, ddd, J 7.7, 7.7, 1.3, ArH), 7.36 (1H, ddd, J 7.7, 7.7, 1.3,
ArH), 5.31 (2H, s, CH2S), 3.60 (4H, sxt, J 7.5, N(CH2CH3)2),
2.43 (3H, s, ArCH3), 1.11 (6H, t, J 7.5, N(CH2CH3)2). dC
(150 MHz, CDCl3) 149.48, 145.27, 142.57, 141.48, 136.42,
134.23, 129.85, 128.99, 125.34, 124.16, 120.38, 114.66,
56.17, 47.83, 47.31, 21.88, 12.94, 11.99.
3-Diethylamino-4-tosyl-4a,5-dihydro-4H-benzo[4,5]
imidazo[1,2-b][1,2,6]thiadiazine 1,1-Dioxide 14a
(4-Chlorophenyl)(3-dimethylamino-1,1-dioxido-5H-benzo
[4,5]imidazo[1,2-b][1,2,6]thiadiazin-4-yl)methanone 12
Et3N (110 mL, 0.8 mmol) was added at 08C to a stirred solution
of 15a (194 mg, 0.4 mmol) in ClCH2CH2Cl (1 mL). The reaction
mixture was stirred at 408C for 4 days. The reaction mixture was
diluted with water (,10 mL) and extracted with EtOAc
(2 ꢀ 10 mL) and CH2Cl2 (2 ꢀ 10 mL). The combined organic
extracts were dried (Na2SO4) and the solvent was removed to
give a yellow solid. Column chromatography (silica gel, 40 %
EtOAc in hexanes) returned the starting material 15a (17 mg,
9 %) and the title compound 14a (86 mg, 48 %) as white solids.
Method D: Extraction with CH2Cl2, purification by column
chromatography (10 % EtOAc in CH2Cl2) provided the title
compound 12 (100 mg, 22%) as a yellow solid. Recrystallization
from EtOH gave clear colourless blocks; mp 254–2558C. m/z
425.0452 [M þ Na]þ; C18H15N4O3ClSNa requires 425.0451
[M þ Na]þ. dH (600 MHz, d6-DMSO) 13.25 (1H, br. s, NH), 7.74
(1H, d, J 8.4, ArH), 7.70 (2H, d, J 8.4, ArH), 7.64 (1H, d, J 7.5,
ArH), 7.51 (2H, d, J 8.4, ArH), 7.45 (1H, t, J 7.5, ArH), 7.37 (1H,
t, J 7.5, ArH), 2.89 (6H, s, N(CH3)2). dC (150 MHz, d6-DMSO)
184.79, 150.06, 149.27, 139.95, 135.05, 131.77, 129.39, 127.74,
126.56, 126.26, 123.26, 115.41, 113.08, 96.11, 40.81.
3-(Piperidin-1-yl)-4-tosyl-4H-benzo[4,5]imidazo[1,2-b]
[1,2,6]-thiadiazine 1,1-Dioxide 14b and N-((2-Tosylmethyl-
1H-benzo[d]imidazol-1-yl)sulfonyl) piperidine-1-
carbimidoyl Chloride 15b
Method D: The combined precipitate and the residue from
evaporation of the CH2Cl2 and EtOAc extracts were purified by
column chromatography (50 % EtOAc in hexanes) to provide
the title compounds 14b (210 mg, 21 %) and 15b (330 mg, 30 %)
as yellow solids.
3-Diethylamino-4-tosyl-4a,5-dihydro-4H-benzo[4,5]
imidazo[1,2-b][1,2,6]thiadiazine 1,1-dioxide 14a and N,N-
diethyl-N0-((2-(tosylmethyl)-1H-benzo[d]imidazol-1-yl)
sulfonyl)carbamimidic Chloride 15a
Method D: Extraction with CH2Cl2 and purification by column
chromatography (silica gel, 30 % EtOAc in hexanes) provided
the title compounds 14a (175 mg, 17 %) and 15a (660 mg, 60 %)
as white solids.
14a: Recrystallization from CH2Cl2 gave clear, colourless
blocks, mp 1608C (dec.). m/z 469.0968 [M þ Na]þ;
C20H22N4O4S2Na requires 469.0980 [M þ Na]þ. dH
14b: A small sample was recrystallized from acetone to give
clear colourless blocks, mp 1708C (dec.). m/z 481.0993 [M þ
Na]þ; C21H22N4O4S2Na requires 481.0980 [M þ Na]þ. dH
(600 MHz, d6-DMSO) 13.09 (1H, br. s, NH), 7.64–7.75 (3H,
m, ArH), 7.53 (1H, br. s, ArH), 7.38 (2H, br. s, ArH), 7.27 (2H,
br. s, ArH), 3.55 (4H, br. s, 2 ꢀ NCH2), 2.30 (3H, s, ArCH3), 1.59
(6H, br. s, 3 ꢀ CH2). dC (150 MHz, d6-DMSO) 159.93, 149.64,