January 2011
Synthesis of Bis-pyrrole Tetra Esters and Alcohols As Novel Mimetics
of the Anticancer Mitomycin
47
white solid. A sample of the product 1a was recrystallized
4H, CH2N), 6.6 (s, 2H, CHCN), 7.2–7.6 (bs, 20H, ArH). Anal.
Calcd. for C33H28N4O2 (512.61); C, 77.32; H, 5.50; N, 10.93.
Found: C, 77.27; H, 5.37; N, 10.87.
from aqueous methanol. mp 167–169ꢁC; IR: 2950, 2246,
1
1646, 1452 cmꢀ1; H NMR (CDCl3): d 0.9 (t, 6H, J ¼ 7 Hz,
2,20-[1,3-Propanediyl-{N,N0-(4,40-dimethoxy)-dibenzoyl}]bis-
benzenemethane nitrile (1n). The compound was obtained in
59% yield from the reaction of 7d (3 g, 0.01 mol) p-methoxy
benzoyl chloride (3.6 g, 0.021 mol) and an aqueous sodium
hydroxide solution (30%; 8 mL) as a white solid mp 152ꢁC
CH3CH2), 1.4–2.2 (m, 4H, CH3CH2), 3.7 (s, 4H, NCH2), 4.8
(bt, 2H, CHCN), 7.5 (s, 10H, ArH). Anal. Calcd for
C24H26N4O2 (402.5): C, 71.62; H, 6.51; N, 13.92. Found: C,
71.58; H 6.46; N 13.98.
2,20-[1,2-Ethanediyl-{N,N0-(4,40-dichloro-dibenzoyl}]bis-butane
nitrile (1b). The compound 1b was obtained in 78% yield from
7a (9.5 g, 0.05 mol) p-chlorobenzoyl chloride (15 g, 0.11 mol)
and aqueous sodium hydroxide (30%, 20 mL) as a white solid.
mp 178–179ꢁC; IR: 2950, 2255, 1705, 1650, 1410, 1300,
1100; 1H NMR (CDCl3): d 1.0 (t, 6H, J ¼ 7 Hz, CH2CH3),
1.6-2.2 (m, 4H, CH2CH3), 3.7 (s, 4H, CH2N) 4.7 (t, 2H,
CHCN), 7.4 (s, 8H, ArH). Anal. Calcd. for C24H24N4O2Cl2
(471.38): C, 61.15; H, 5.13; N, 11.89. Found: C, 61.35; H,
5.02; N, 11.71.
IR: 2325, 1620, 1460, 1100, 820 cmꢀ1 1H NMR (CDCl3): d
.
1.67 (m, 2H, CH2CH2CH2), 2.93 (m, 4H, CH2N), 3.73 (s, 6H,
ArOCH3), 6.4 (s, 2H, CHCN), 6.7–7.46 (m, 18H, ArH). Anal.
Calcd. for C35H32N4O4 (572.67): C, 73.40; H, 5.63; N, 9.78.
Found: C, 73.28; H, 5.57; N, 9.63.
Preparation of selected bis-oxazolium salts
3,30-Ethylene-bis(2-phenyl 4-ethyl-5-aminooxazolium per-
chlorate) (8a). To the bis-Reissert analog 1a (1.6 g, 4 mmol)
was added 8 mL of perchloric acid (70%) slowly and with
cooling to 10ꢁC. The reaction mixture was stirred vigorously
for 15 min and the resulting yellow precipitate was filtered
and washed with dry ether. The crude salt was crystallized
from acetonitrile-dry ether to get 1.25 g (50%) of the salt 8a.
mp 196–198ꢁC (dec.); IR: 3400, 3300, 3200, 1680, 1620,
2,20-[1,2-Ethanediyl-{N,N0-(4,40-dimethyl)-dibenzoyl}]bis-
butane nitrile (1c). The compound was obtained in 39% yield
from 7a (9.5g, 0.05 mol) p-tolyl chloride (17 g, 0.11 mol) and
aqueous sodium hydroxide (30%, 20 mL) as a white solid. mp
162ꢁC; IR: 2980, 2240, 1640, 1400, 1300, 1060 cmꢀ1 1H
;
1570, 1420, 1070, 765 cmꢀ1 1H NMR (DMSO-d6): d 1.0 (t,
;
NMR (CDCl3): d 0.9 (t, 6H, J ¼ 7 Hz, CH2CH3), 1.7 (m, 4H,
CH2CH3), 2.4 (s, 6H, ArCH3), 3.6 (bs, 4H, CH2N), 4.8 (t, 2H,
J ¼ 6 Hz, CHCN), 7.3 (s, 8H, ArH). Anal. Calcd for
C26H30N4O2 (430.56): C, 72.53; H, 7.02; N, 13.01. Found: C,
72.67; H, 7.14; N, 13.23.
6H, J ¼ 7 Hz, CH3CH2), 2.1–2.7 (m, 4H, CH3CH2), 4.6 (s,
4H, CH2N), 6.8 (bs, 4H, D2O exchangeable, NH2), 7.8 (s,
10H, ArH). Anal. Calcd. for C24H28N4O10Cl2 (603.4): C,
47.80; H, 4.70; N, 9.30. Found: C, 48.20; H, 4.60; N, 9.40.
3,30-Ethylene-bis[2-(4-chlorophenyl)-4-ethyl-5-aminooxazo-
lium perchlorate] (8b). This salt was obtained from 1b (2 g,
4.25 mmol) and 70% perchloric acid (8 mL) in a similar proce-
dure described for 8a yielded 1.65 g (60 %) yield. mp 213ꢁC
2,20-[1,2-Ethanediyl-(N,N0-dibenzoyl)]bis-benzene methane
nitrile (1f). The compound was obtained in 80% yield from
the reaction of 7b (14.5, 0.05 mol), benzoyl chloride (15.5 g;
0.11 mol), and aqueous sodium hydroxide (30%, 20 mL). mp
211ꢁC; IR: 2210, 1970, 1900, 1640, 1290 cmꢀ1 1H NMR
;
(dec); IR: 3450, 2990, 1700, 1500, 1100 cmꢀ1 1H NMR
;
(CDCl3): d 3.4 (m, 4H, CH2N), 6.3 (bs, 2H, CHCN), 7.3–7.5
(m, 20H, ArH). Anal. Calcd for C32H26N4O2 (498.59): C,
77.08; H, 5.25; N, 11.23. Found: C, 77.12; H, 5.01; N, 11.19.
2,20-[1,2-Ethanediyl-{N,N0-(4,40dimethoxy)-dibenzoyl}]bis-
benzene methane nitrile (1i). The compound was obtained in
87% yield from the reaction of 7b (5.8 g, 0.02 mol) p-methoxy
benzoyl chloride (7 g, 0.041 mol), aqueous sodium hydroxide
(30%, 15 mL) mp 205–6ꢁC; IR: 2990, 2215, 1620, 1420,
(DMSO-d6): d 1.07 (t, 6H, J ¼ 7 Hz, CH3CH2), 2.49 (q, 4H, J ¼
7 Hz, CH3CH2), 4.6 (s, 4H, CH2N), 6.6–7.3 (bs, 4H, D2O
exchangeable, NH2), 7.7 (s, 8H, ArH). Anal. Calcd. for
C24H26N4O10Cl4 (672.3): C, 42.88; H, 3.89; N, 8.33; Found: C,
43.19; H, 3.92; N, 8.34.
Reaction of oxazolium salt 8a with DMAD
1,10-(1,2-Ethanediyl)-bis[dimethyl 2-ethyl, 5-phenyl pyrrole-
3,4-dicarboxylate] (2a). The perchlorate salt 8a (605 mg, 1
mmol) was heated with DMAD (0.5 mL, 4 mmol) at 80–85ꢁC
for 72 h. The reaction mixture turned brown and became a ho-
mogeneous hard mass. Chloroform was added to the cooled
reaction mixture and warmed to 45ꢁC and was filtered to sepa-
rate the solid, presumably a polymer of isocyanuric acid. The
chloroform solution was washed with saturated sodium bicar-
bonate solution followed by water and dried over anhydrous
sodium sulfate. The solvent was removed in vacuo and 5 mL
methanol was added to the mixture, stirred for 15 min and fil-
tered. The crystals, after washing with cold methanol and dry-
ing, afforded 170 mg (28%) of 2a. mp 268ꢁC; IR (KBr): 2970,
1310, 1260, 845 cmꢀ1 1H NMR (CDCl3): d 2.9–3.5 (m, 4H,
;
CH2N) 3.8 (s, 6H, OCH3) 6.3 (bs, 2H, CHCN) 6.8–7.5 (m,
18H, ArH); Anal. Calcd for C34H30N4O4 (558.63): C, 73.10;
H, 5.41; N, 10.02. Found: C, 73.02; H, 5.38; N, 10.13.
2,20-[1,3-Propanediyl-{N,N0-(4,40-dichloro)-dibenzoyl}]bis-
butane nitrile (1l). The analog could be obtained in 61% yield
from the reaction of 7c (2 g, 0.01 mol) p-chloro benzoyl chlo-
ride (3.7 g, 0.02 mol) and an aqueous sodium hydroxide solu-
tion (30%, 8 mL) as a viscous liquid. IR: 2250, 1640, 1400,
1
1290, 1070 cmꢀ1. H NMR (CDCl3): d 0.9 (t, 6H, J ¼ 7 Hz,
CH2CH3), 1.6–2.23 (m, 6H, CH2CH3, CH2CH2CH2), 3.23 (t,
4H, J ¼ 10 Hz, CH2N), 4.73 (t, 2H, J ¼ 10 Hz, CHCN) 7.03–
7.4 (m, 8H, ArH). Anal. Calcd for C25H26N4O2Cl2 (485.42):
C, 61.85; H, 5.39; N, 11.54. Found: C, 61.73; H, 5.27; N,
11.63.
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1720, 1710, 1610 cmꢀ1; H NMR (CDCl3): d 0.9 (t, 6H, J ¼
7 Hz, CH2CH3), 2.0 (q, 4H, J ¼ 7 Hz, CH2CH3), 3.5 (s, 6H,
COOCH3), 3.7 (s, 4H, CH2N), 3.8 (s, 6H, COOCH3), 7.1–7.6
(m, 10H, ArH). Anal. Calcd. for C34H36N2O8 (600.6): C,
67.98; H, 6.04; N, 4.66. Found: C, 68.13; H, 5.93; N, 4.98.
Conversion of bis-Reissert analog 1 to bis-pyrrole tetra
esters 2—The in situ procedure
2,20-[1,3-Propanediyl-{N,N0-dibenzoyl}]bis-benzenemethane
nitrile (1m). The compound was obtained in 78% yield from
the reaction of 7d (3 g, 0.01 mol) benzoyl chloride (3.7 g,
0.02 mol) and an aqueous sodium hydroxide solution (30%, 8
mL) as a white solid. mp 139ꢁC; IR: 2215, 1650, 1460, 1380
General procedure using TFA. The bis-Reissert analog 1 (3
mmol), DMAD (7.5 mmol) and TFA (15 mmol) were added to
dry dichloromethane (20 mL) and refluxed for 3 days and kept
1
cmꢀ1; H NMR (CDCl3): d 1.9 (m, 2H, CH2CH2CH2), 3.2 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet