Pyrrolo[2,1-c][1,4]benzodiazepine DNA Cross-Linking Agents
J . Org. Chem., Vol. 61, No. 23, 1996 8145
Meth od B: DMF (2 drops) was added to a stirred suspen-
sion of oxalyl chloride (3.1 g, 24.4 mmol, 2.4 equiv) and the
appropriate bis(4-carboxy-2-methoxyphenoxy)alkane (10 mmol)
in dry THF (25 mL), and stirring was continued for 6 h. The
THF was removed by evaporation in vacuo, and the resultant
solid dissolved in dry MeOH (60 mL). After stirring for a
further 2 h, the MeOH was removed in vacuo and the residue
triturated with water (30 mL). The resultant solid was
collected by filtration:
121.9, 149.5, 152.8, 167.0; IR (KBr) 2940, 1710, 1600, 1575,
1520, 1420, 1355, 1280, 1250, 1210, 1175, 1140, 1045, 990, 960,
870, 830, 750 cm-1; EIMS m/ z (relative intensity) 494 (M+•
,
94), 463 (14), 449 (8), 404 (3), 285 (3), 268 (28), 267 (29), 240
(32), 236 (68), 222 (94), 207 (6) 194 (45), 164 (19), 151 (15),
122 (14), 109 (9), 86 (47), 84 (73), 75 (12), 59 (29), 49 (100), 41
(73); EIHRMS m/ z Calcd for 494.1173 (C21H22N2O12). Found
494.1170.
1′,4′-Bis[2-m et h oxy-4-(m et h oxyca r b on yl)-5-n it r op h e-
n oxy]bu ta n e (8b). Mp 180-182 °C; Yield ) 3.45 g (68% from
4.18 g of 7b); 1H NMR (CDCl3): δ 2.10-2.14 (m, 4H), 3.91 (s,
6H), 3.96 (s, 6H), 4.23 (t, 4H, J ) 10.9 Hz), 7.03 (s, 2H), 7.44
(s, 2H); 13C NMR (CDCl3): δ 25.6, 53.2, 56.5, 69.2, 107.3, 110.8,
121.5, 141.1, 149.6, 152.7, 166.3; IR (KBr) 2940, 1720, 1590,
1520, 1450, 1425, 1570, 1340, 1280, 1210, 1140, 1040; EIMS
m/ z (relative intensity) 508 (M+•, 12), 476 (2), 445 (1), 281 (63),
250 (3), 240 (14), 196 (24), 182 (6), 55 (45), 44 (7); EIHRMS
m/ z Calcd for 508.1329 (C22H24N2O12). Found 508.1326.
1′,5′-Bis[2-m et h oxy-4-(m et h oxyca r b on yl)-5-n it r op h e-
n oxy]p en ta n e (8c). Mp 147-149 °C; Yield ) 3.90 g (75%
from 4.3 g of 7c); 1H NMR (CDCl3): δ 1.71-1.76 (m, 2H), 1.93-
2.04 (m, 4H), 3.91 (s, 6H), 3.96 (s, 6H), 4.10-4.16 (m, 4H), 7.08
(s, 2H), 7.44 (s, 2H); 13C NMR (CDCl3): δ 22.5, 28.5, 53.2, 56.5,
69.3, 107.9, 110.9, 121.5, 141.2, 149.8, 152.8, 166.4; IR (KBr)
2920, 1430, 1720, 1600, 1580, 1530, 1350, 1280, 1260, 1130,
1040; EIMS m/ z (relative intensity) 522 (M+•, 17), 491 (30),
296 (39), 264 (75), 251 (27), 196 (55), 182 (35), 69 (12), 55 (92),
44 (12), 41 (58); EIHRMS m/ z Calcd for 522.1486 (C23H26N2O12).
Found 522.1486.
1′,3′-Bis[2-m eth oxy-4-(m eth oxyca r bon yl)p h en oxy]p r o-
p a n e (7a ). Mp 153-155 °C; Yield ) 3.8 g (94% from 3.76 g
1
of 6a ); H NMR (CDCl3): δ 2.39-2.43 (m, 2H), 3.89 (s, 6H),
3.90 (s, 6H), 4.30 (t, 4H, J ) 6.1 Hz), 6.93 (d, 2H, J ) 8.5 Hz),
7.54 (d, 2H, J ) 2.0 Hz), 7.64 (dd, 2H, J 1 ) 8.5 Hz, J 2 ) 2.0
Hz); 13C NMR (CDCl3): δ 28.9, 52.0, 56.0, 65.4, 111.7, 112.3,
122.8, 123.5, 148.9, 152.2, 166.9; IR (KBr) 2940, 1710, 1600,
1510, 1460, 1435, 1410, 1340, 1290, 1270, 1215, 1180, 1130,
1100, 1060, 1025, 975, 870, 760, 720 cm-1; EIMS m/ z (relative
intensity) 404 (M+•, 92), 373 (19), 256 (3), 223 (100), 195 (49),
191 (58), 171 (18), 164 (39), 151 (51), 135 (12), 119 (20), 107
(11), 85 (61), 83 (90), 59 (23), 43 (24); EIHRMS m/ z Calcd for
404.1472 (C21H24O8). Found 404.1457.
1′,4′-Bis[2-m eth oxy-4-(m eth oxyca r bon yl)p h en oxy]bu -
ta n e (7b). Mp 151-152 °C; Yield ) 5.98 g (92% from 6.06 g
1
of 6b); H NMR (CDCl3): δ 2.06-2.10 (m, 4H), 3.89 (s, 6H),
3.91 (s, 6H), 4.16-4.20 (m, 4H), 6.89 (d, 2H, J ) 10.4 Hz),
7.52 (d, 2H, J ) 2.0 Hz), 7.64 (d, 2H, J ) 8.4 Hz); 13C NMR
(CDCl3): δ 25.8, 52.0, 68.5, 111.4, 112.2, 122.5, 123.5, 148.8,
152.4, 166.9; IR (KBr) 2920, 2900, 1720, 1580, 1520, 1390,
1370, 2840, 1270, 1250, 1220, 1150, 1125, 1085; EIMS m/ z
(relative intensity) 418 (M+•, 7), 237 (55), 205 (2.33), 195 (22),
151 (12), 135 (2), 55 (29), 44 (7), 41 (4); EIHRMS m/ z Calcd
for 418.1661 (C22H26O8). Found 418.1695.
1′,6′-Bis[2-m et h oxy-4-(m et h oxyca r b on yl)-5-n it r op h e-
n oxy]h exa n e (8d ). Mp 132-134 °C; Yield ) 3.44 g (65% from
1
4.40 g of 7d ); H NMR (CDCl3): δ 1.55-1.58 (m, 4H), 1.89-
1.93 (m, 4H), 3.91 (s, 6H), 3.96 (s, 6H), 4.11 (t, 4H, J ) 13.2
Hz), 7.07 (s, 2H), 7.44 (s, 2H); 13C NMR (CDCl3): δ 25.5, 28.6,
53.3, 56.6, 69.4, 107.8, 110.9, 121.4, 141.1, 149.9, 152.7, 166.4;
EIMS m/ z (relative intensity) 537 (M+•, 22), 507 (14), 505 (20),
477 (27), 257 (17), 254 (24), 252 (15), 240 (16), 210 (28), 198
(98), 112 (32), 107 (38), 85 (100), 81 (99); EIHRMS m/ z Calcd
for 536.1653 (C24H28N2O12). Found 536.1642.
1′,5′-Bis[2-m eth oxy-4-(m eth oxyca r bon yl)p h en oxy]p en -
ta n e (7c). Mp 127-128 °C; Yield ) 6.12 g (90% from 7.27 g
1
of 6c); H NMR (CDCl3): δ 2.06-2.10 (m, 4H), 3.89 (s, 6H),
3.91 (s, 6H), 4.18 (m, 4H), 6.89 (d, 2H, J ) 10.4 Hz), 7.52 (d,
2H, J ) 2.0 Hz), 7.65 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3):
δ 22.5, 28.7, 52.0, 56.0, 68.9, 111.4, 112.3, 122.5, 123.5, 148.9,
152.5, 166.9; IR (KBr) 2920, 1720, 1600, 1510, 1435, 1410,
1290, 1270, 1210, 1175, 1130, 1000 cm-1; EIMS m/ z (relative
intensity) 432 (M+•, 34), 401 (76), 354 (49), 251 (48), 216 (75),
195 (100), 182 (63), 151 (32), 69 (56), 44 (77), 41 (40); EIHRMS
m/ z Calcd for 432.1833 (C23H28O8). Found 432.1881.
Bis(4-ca r boxy-2-m eth oxy-5-n itr op h en oxy)a lk a n es 9a-
d . A suspension of the appropriate methyl ester 8a -d
(approximately 1.0 g) in a mixture of THF (20 mL) and
aqueous NaOH (1 M, 20 mL) was stirred at 40 °C for 6 h until
TLC (ethyl acetate/hexane, 1:1) indicated that reaction was
complete. The THF was removed by evaporation in vacuo, and
the remaining aqueous solution adjusted to pH 1 with concd
HCl. The resulting precipitate was collected by filtration and
dried to afford the nitro acid as a yellow solid:
1′,6′-Bis[2-m eth oxy-4-(m eth oxyca r bon yl)p h en oxy]h ex-
a n e (7d ). Mp 126-127 °C; Yield ) 4.06 g (91% from 4.18 g of
1
6d ); H NMR (CDCl3): δ 1.56 (m, 4H), 1.90 (m, 4H), 3.89 (s,
6H), 3.91 (s, 6H), 4.09 (m, 4H), 6.87 (d, 2H, J ) 8.4 Hz), 7.63
(d, 2H, J ) 2.0 Hz), 7.66 (d, 2H, J ) 2.0 Hz); 13C NMR
(CDCl3): δ 25.7, 28.9, 51.9, 56.0, 68.7, 111.4, 112.3, 122.4,
123.5, 148.8, 152.5, 166.9; IR (KBr) 2925, 2860, 1430, 1700,
1595, 1500, 1410, 1340, 1290, 1270, 1220, 1180, 1130, 1000;
EIMS m/ z (relative intensity) 446 (M+•, 100), 432 (9), 415 (20),
391 (20), 282 (25), 251 (9), 211 (11), 182 (155), 151 (73), 85
(28), 69 (4), 55 (39), 44 (5); EIHRMS m/ z Calcd for 446.1995
(C24H30O8). Found 446.2049.
Bis[2-m eth oxy-4-(m eth oxyca r bon yl)-5-n itr op h en oxy]-
a lk a n es 8a -d . A freshly prepared mixture of SnCl4 (6.48 g,
24.9 mmol) and fuming nitric acid (2.0 g, 31.7 mmol) in CH2Cl2
(5 mL) was added dropwise over 5 min to a stirred solution of
the appropriate methyl ester 7a -d (4.0 g, 10.0 mmol) in CH2-
Cl2 (60 mL) at -25 °C (dry ice/CCl4). The mixture was
maintained at the same temperature for a further 10 min,
quenched with water (150 mL), and then allowed to return to
room temperature. The organic layer was separated and the
aqueous phase extracted with ethyl acetate (2 × 100 mL). The
combined organic phase was dried (Na2SO4) and evaporated
in vacuo to afford the corresponding nitroaryl ester as a brown
gum which was crystallized from ethyl acetate/hexane to afford
yellow prisms:
1′,3′-Bis(4-ca r b oxy-2-m e t h oxy-5-n it r op h e n oxy)p r o-
p a n e (9a ). Mp 243-246 °C; Yield ) 0.91 g (95% from 1.02 g
1
of 8a ); H NMR (DMSO-d6): δ 2.25 (t, 2H, J ) 5.9 Hz), 3.90
(s, 6H), 4.27 (t, 4H, J ) 5.9 Hz), 7.29 (s, 2H), 7.62 (s, 2H), 13.6
(bs, 2H); 13C NMR (DMSO-d6): δ 28.0, 56.3, 65.7, 108.0, 111.2,
121.1, 141.3, 149.1, 151.7, 165.9; IR (KBr) 3620-2280, 1700,
1595, 1570, 1515, 1460, 1415, 1350, 1270, 1210, 1180, 1135,
1045, 930, 880, 810, 750, 730, 645 cm-1; EIMS m/ z (relative
intensity) 467 (MH+•, 1), 450 (1), 436 (3), 423 (8), 378 (4), 268
(1), 255 (4), 236 (4), 210 (7), 194 (2), 182 (7), 164 (14), 153 (2),
123 (3), 91 (6), 77 (3), 55 (5), 44 (100); EIHRMS m/ z Calcd for
466.0860 (C19H18N2O12). Found 466.0871.
1′,4′-Bis(4-ca r b oxy-2-m e t h oxy-5-n it r op h e n oxy)b u -
ta n e (9b). Mp 282-284 °C; Yield ) 0.967 g (93% from 1.10 g
of 8b); 1H NMR (DMSO-d6): δ 1.93-1.96 (m, 2H), 3.89 (s, 6H),
4.18-4.25 (m, 4H), 7.27 (s, 2H), 7.56 (s, 2H); 13C NMR (DMSO-
d6): δ 24.9, 56.3, 68.6, 107.7, 111.1, 120.9, 141.3, 149.3, 151.7,
166.0; IR (KBr) 3620-2280, 1700, 1595, 1570, 1515, 1460,
1415, 1350, 1270, 1210, 1180, 1135, 1045, 930, 880, 810, 750,
730, 645 cm-1
.
1′,5′-Bis(4-ca r b oxy-2-m e t h oxy-5-n it r op h e n oxy)p e n -
ta n e (9c). Mp 283-285 °C; Yield ) 826 mg (90% from 0.97 g
1
of 8c); H NMR (DMSO-d6): δ 1.56-1.59 (m, 2H), 1.81-1.86
1′,3′-Bis[2-m et h oxy-4-(m et h oxyca r b on yl)-5-n it r op h e-
n oxy]p r op a n e (8a ). Mp 165-168 °C; Yield ) 3.52 g (72%
(m, 4H), 3.92 (s, 6H), 4.11-4.15 (m, 4H), 7.29 (s, 2H), 7.58 (s,
2H); 13C NMR (DMSO-d6): δ 21.9, 27.9, 56.3, 68.9, 107.7, 111.1,
120.8, 141.4, 149.4, 151.7, 165.9; IR (KBr) 3620-2280, 1700,
1595, 1570, 1515, 1460, 1415, 1350, 1270, 1210, 1180, 1135,
1
from 4.0 g of 7a ); H NMR (CDCl3): δ 2.43 (m, 2H), 3.90 (s,
6H), 3.95 (s, 6H), 4.32 (t, 4H, J ) 6.0 Hz), 7.06 (s, 2H), 7.49 (s,
2H); 13C NMR (CDCl3): δ 28.6, 53.3, 56.6, 65.6, 108.1, 110.9,
1045, 930, 880, 810, 750, 730, 645 cm-1
.