Julie-Ann A. Grant et al. / Bioorg. Med. Chem. 18 (2010) 909–921
919
ꢀ
max 1708, 3467 cm , 1H NMR (DMSO-d
ꢀ1
1
675, 3427 cm 1; 1H NMR d = 2.41 (s, 3H, –CH
OCH ), 5.28 (s, 2H, –CH Cl), 6.93 (dd, J = 2 and 5 Hz, 1H, H-5),
.99 (d, J = 2 Hz, 1H, H-7) 7.03 (d, J = 5 Hz, 1H, H-4), 7.71 (dd,
3
) 3.90 (s, 3H, –
IR
m
6
+
) d = 2.42 (s, 3H, –
3
2
3 3 2
CH ), 3.90 (s, 3H, –OCH ), 6.12 (s, 3H, –CH N ), 6.97 (dd, J = 2 and
9 Hz, 1H, H-2), 7.00 (d, J = 2 Hz, 1H, H-4), 7.23 (dd, J = 5 and 8 Hz,
1H, H-10), 7.58 (d, J = 9 Hz, 1H, H-1), 7.76 (d, J = 8 Hz, 1H, H-9),
8.64 (d, J = 5 Hz, 1H, H-11), 11.94 (s, 1H, –NH), C NMR (DMSO-
6
d ) d = 18.6, 50.0, 55.9, 95.8, 113.0, 121.3, 121.7, 123.3, 124.8,
6
0
0
0
J = 2 and 7 Hz, 1H, H-5 ), 8.19 (m, 2H, H-3 and H-6 ), 8.97 ppm (s,
1
3
13
1
1
1
H, –NH); C NMR d = 21.8, 35.3, 56.2, 96.0, 114.3, 115.1, 121.1,
21.8, 122.3, 124.5, 142.3, 148.1, 150.4, 151.1, 153.3, 155.3,
61.3 ppm.
128.5, 139.8, 141.8, 146.2, 149.0, 155.2, 158.0, 160.9 ppm.
6
.1.3.3. 3-(Chloromethyl)-6-methoxy-N-(6-methylpyridin-2-yl)
6.1.4.3. 3-Methoxy-9-methyl-6-oxo-7,13-dihydro-6H-benzofuro
[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8c). Chloro-
methyl amide 7c (0.074 g, 0.23 mmol) in 1,4-dioxane (4 mL) for
3 days gave 8c (0.036 g, 49%) as a cream solid, mp 283–285 °C; IR
benzofuran-2-carboxamide (7e). Bromomethyl amide 6e (0.55 g,
.47 mmol) reacted in chloroform (40 mL) for 12 h to give 7e
0.41 g, 88%) as beige crystals, mp 143–144 °C (EtOH); IR
1
(
1
3
7
m
max
ꢀ1
1
ꢀ1 1
544, 1664, 3413 cm
H, –OCH ), 5.28 (s, 2H, –CH
.69 (m, 2H, H-4 and H-5 ), 8.17 (d, J = 8 Hz, 1H, H-3 ), 8.94 ppm
;
H NMR d = 2.51 (s, 3H, –CH
3
) 3.90 (s,
m
max 1711, 3485 cm , H NMR (DMSO-d
6
) d = 2.52 (s, 3H, –CH
3
),
+
3
2
Cl), 7.00 (m, 3H, H-4, H-5 and H-7),
3.85 (s, 3H, –OCH ), 5.90 (s, 2H, –CH N ), 7.13 (dd, J = 2 and 9 Hz,
3
2
0
0
0
1H, H-2), 7.38 (d, J = 2 Hz, 1H, H-4), 7.54 (s, 1H, H-8), 7.62 (d,
J = 6, 1H, H-10), 8.01 (d, J = 9 Hz, 1H, H-1), 8.85 (d, J = 6 Hz, 1H,
1
3
(
s, 1H, –NH); C NMR d = 24.5, 35.4, 56.2, 96.0, 111.4, 114.3,
1
3
1
1
20.2, 122.4, 123.9, 125.5, 139.1, 142.1, 151.8, 155.3, 157.7,
58.7, 161.3 ppm.
H-11), 12.13 ppm (s, 1H, –NH); C NMR (DMSO-d
6
) d = 22.2,
49.9, 56.9, 80.0, 97.0, 115.4, 118.6, 122.0, 123.4, 123.9, 143.0,
1
C
44.5, 148.5, 157.5, 158.6, 159.7, 161.9 ppm; Anal. Calcd for
Cl: C, 61.73; H, 4.57; N, 8.47. Found: C, 61.56; H,
6
.1.3.4. 3-Chloromethyl-N-(5-chloropyridin-2-yl)-6-methoxybe
17 15 2 3
H N O
nzofuran-2-carboxamide (7f). Bromomethyl amide 6f (0.55 g,
.47 mmol) reacted in chloroform (40 mL) for 4 h to give 7f
0.41 g, 88%) as beige crystals, mp 207–208 °C (EtOH); IR
4.50; N, 8.25.
1
(
m
max
6.1.4.4. 3-Methoxy-10-methyl-6-oxo-7,13-dihydro-6H-benzof-
uro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium
(8d). Crude chloromethyl amide 7d (0.20 g) in 1,4-dioxane
(2 mL) for 3 days gave 8d (0.05 g, 24%) as a pale gray solid, mp
ꢀ
1
1
1
2
4
9
1
1
549, 1666, 3398 cm ; H NMR d = 3.90 (s, 3H, –OCH
3
), 5.26 (s,
chloride
H, –CH
2
Cl), 7.01 (m, 2H, H-5 and H-7), 7.73 (m, 2H, H-4 and H-
0
0
0
), 8.30 (d, J = 6 Hz, 1H, H-6 ), 8.36 (d, J = 9 Hz, 1H, H-3 ),
.01 ppm (s, 1H, –NH); 13C NMR d = 34.8, 55.8, 95.6, 114.0, 114.9,
20.6, 122.0, 125.1, 127.3, 138.1, 141.4, 146.7, 149.1, 155.8,
57.5, 161.4 ppm.
ꢀ1
1
>300 °C; IR
6
mmax 1716, 3465 cm , H NMR (DMSO-d ) d = 2.41 (s,
+
3H, –CH ), 3.88 (s, 3H, –OCH ), 6.05 (s, 2H, –CH N ), 7.17 (dd,
3
3
2
J = 2 and 9 Hz, 1H, H-2), 7.42 (d, J = 2 Hz, 1H, H-4), 7.76 (d,
J = 9 Hz, 1H, H-1), 8.05 (d, J = 9 Hz, 1H, H-9), 8.37 (d, J = 9, 1H, H-
1
3
6
.1.3.5. 3-(Chloromomethyl)-5,6-dimethoxy-N-(pyridin-2-yl)be
8), 9.03 (s, 1H, H-11), 12.12 ppm (s, 1H, –NH); C NMR (DMSO-
) d = 17.9, 50.6, 56.9, 97.0, 115.5, 118.6, 121.8, 123.6, 124.2,
133.8, 142.9, 144.1, 146.6, 148.2, 157.7, 158.4, 162.1; Anal. Calcd
for C17 Cl: C, 61.73; H, 4.57; N, 8.47. Found: C, 61.56; H,
4.58; N, 8.41.
nzofuran-2-carboxamide (7h). Bromomethyl amide 6h (0.13 g,
d
6
0
6
1
.33 mmol) reacted in chloroform (12 mL) to give 7h (0.41 g,
8%) as beige crystals, mp 207–208 °C (EtOH); IR max 1557,
), 4.01 (s, 3H, –
Cl), 6.99 (s, 1H, H-7), 7.00 (s, 1H, H-4),
m
15 2 3
H N O
ꢀ
1
1
669, 3403 cm ; H NMR d = 4.00 (s, 3H, –OCH
3
OCH
3
), 5.14 (s, 3H, –CH
2
0
0
0
7
6
1
1
.13 (m, 1H, H-4 ), 7.80 (m, 1H, H-5 ), 8.40 (m, 2H, H-3 and H-
6.1.4.5. 3-Methoxy-11-methyl-6-oxo-7,13-dihydro-6H-benzof-
uro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride
(8e). Chloromethyl amide 7e (0.38 g, 1.20 mmol) in 1,4-dioxane
(2 mL) for 5 days gave 8e (45 mg, 12%) as a cream solid, mp 260–
0
13
), 8.98 ppm (s, 1H, –NH), C NMR d = 35.6, 56.8, 56.9, 95.4,
01.9, 114.6, 119.9, 120.6, 125.2, 139.1, 142.0, 147.9, 148.0,
49.0, 151.5, 151.9, 157.8 ppm.
ꢀ1 1
2
61 °C; IR
mmax 1707, 3458 cm
6
, H NMR (DMSO-d ) d = 2.82 (s,
+
6
.1.4. Preparation of tetracyclic salts (8a–f, 8h)
3H, –CH ), 3.76 (s, 3H, –OCH ), 5.81 (s, 2H, –CH N ), 7.05 (dd,
3
3
2
In a round-bottomed flask fitted with a reflux condenser and
J = 2 and 9 Hz, 1H, H-2), 7.32 (d, J = 2 Hz, 1H, H-4), 7.63 (dd, J = 2
and 8 Hz, 2H, H-8 and H-10), 8.04 (d, J = 9 Hz, 1H, H-1), 8.56 (t,
J = 8 Hz, 1H, H-9), 12.07 ppm (s, 1H, –NH); C NMR (DMSO-d )
6
d = 21.7, 45.0, 56.4, 96.6, 115.2, 117.9, 119.5, 122.9, 123.8, 124.6,
144.8, 145.8, 149.0, 152.9, 157.3, 158.0, 161.5 ppm; Anal. Calcd
calcium chloride guard tube, was placed a solution (10–20%) of
chloromethyl amide in 1,4-dioxane. This was heated at reflux for
several days. The resultant precipitate was collected by filtration
and was washed with hot acetone to give the respective tetracyclic
chloride salt.
1
3
for C17
15 2 3
H N O Cl: C, 61.73; H, 4.57; N, 8.47. Found: C, 61.37; H,
4
.51; N, 7.91.
6
.1.4.1. 3-Methoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]py
rido[1,2-a][1,3]diazepin-12-ium chloride (8a). Chloromethyl
amide 7a (0.35 g, 1.11 mmol) in 1,4-dioxane (2 mL) for 3 days gave
6.1.4.6. 10-Chloro-3-methoxy-6-oxo-7,13-dihydro-6H-benzof-
uro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride
8
3
–
4
a (0.15 g, 43%) as a pale gray solid, mp 285–287 °C; IR
m
max 1721,
), 6.10 (s, 2H,
N ), 7.17 (dd, J = 1 and 9 Hz, 1H, H-2), 7.43 (d, J = 1 Hz, 1H, H-
), 7.83 (dd, J = 2 and 8 Hz, 2H, H-8 and H-9), 8.07 (d, J = 9 Hz, 1H,
(8f). Chloromethyl amide 7f (0.10 g) in 1,4-dioxane (0.5 mL) for
3 days gave 8f (0.052 g, 50%) as a pale gray solid, mp 204–
ꢀ
1 1
6 3
430 cm , H NMR (DMSO-d ) d = 3.88 (s, 3H, –OCH
+
ꢀ1
1
CH
2
206 °C; IR
3H, –OCH
m
max 1720, 3431 cm
6
, H NMR (DMSO-d ) d = 3.88 (s,
+
3
), 5.75 (s, 2H, –CH
2
N ), 7.08 (dd, J = 2 and 9 Hz, 1H, H-
H-1), 8.49 (dt, J = 2 and 6 Hz, 1H, H-10), 9.1 (d, J = 6 Hz, 1H, H-11),
2), 7.28 (d, J = 2 Hz, 1H, H-4), 7.80 (d, J = 9 Hz, 1H, H-1), 8.00 (dd,
J = 2 and 9 Hz, 1H, H-9), 8.19 (d, J = 9 Hz, 1H, H-8), 8.48 (d,
J = 2 Hz, 1H, H-11), 10.61 ppm (s, 1H, –NH); C NMR (DMSO-d )
6
d = 55.4, 56.3, 96.5, 114.4, 116.3, 120.4, 122.5, 124.0, 126.7, 138.5,
142.6, 147.1, 149.1, 150.1, 155.0, 157.9, 161.0 ppm; Anal. Calcd
1
1
1
6
2.21 ppm (s, 1H, –NH); 13C NMR (DMSO-d
15.0, 118.1, 121.9, 122.9, 123.1, 123.6, 143.6, 143.7, 146.8,
48.4, 157.2, 157.8, 161.6 ppm; Anal. Calcd for C16 Cl: C,
0.67; H, 4.14; N, 8.84. Found: C, 60.49; H, 4.21; N, 8.82.
6
) d = 50.2, 56.4, 96.5,
1
3
13
H N
2
O
3
12 2 3 2
for C16H N O Cl : C, 54.72; H, 3.44; N, 7.98. Found: C, 54.40; H,
6
.1.4.2. 3-Methoxy-8-methyl-6-oxo-7,13-dihydro-6H-benzofuro
3.48; N, 8.01.
[
2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8b). Crude
chloromethyl amide 7b (0.44 g) in 1,4-dioxane (4 mL) for 3 days
gave 8b (0.019 g, 2% from amide) as a brown solid, mp >300 °C;
6.1.4.7. 2,3-Dimethoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-
e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8h). Chloro-