8074 J . Org. Chem., Vol. 62, No. 23, 1997
Elliott et al.
amine (7.1 g, 0.07 mol) and 109 (4.5 g, 0.022 mol) at 4 °C. HgCl2
(6.0 g, 0.022 mol) was added in one portion, and the mixture
was stirred at room temperature overnight. The solvent was
removed in vacuo, and the product was dissolved in EtOAc
(200 mL) and filtered through a short silica gel plug to remove
inorganics. The solvent was removed to give 5.8 g (75%) of
12a . An analytical sample was obtained as colorless needles,
mp 158-60 °C, by recrystallization from MeOH: 1H NMR
(CDCl3) δ 3.70 (s, 3H), 3.80 (s, 3H), 3.83 (s, 5H), 6.44 (d, 1H,
J ) 4.21 Hz), 7.1-7.3 (m, 5H), 9.04 (br s, NH), 9.96 (br s, NH),
(br s, NH); IR (KBr) 3304, 2925, 2852, 1731, 1713, 1647, 1621
cm-1; MS (ES+) 395.2 (MH+). Anal. Calcd for C18H26N4O6:
C, 54.81; H, 6.64; N, 14.20. Found: C, 54.55; H, 6.67; N, 14.07.
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
bon yl)im in o]m eth yl]a m in o]-4-(3-th ien ylm eth yl)-1H-p yr -
r ole-2-ca r boxyla te (12i): 66% yield; colorless needles; mp
1
168-70 °C from toluene; H NMR (CDCl3) 3.71 (s, 3H), 3.81
(s, 3H), 3.84 (s, 3H), 3.86 (s, 2H), 6.55 (d, 1H, J ) 3.10 Hz),
6.88 (m, 1H), 6.94 (m, 1H), 7.22 (m, 1H), 9.25 (br s, NH), 10.08
(br s, NH), 11.74 (br s, NH); IR (KBr) 3277, 1737, 1699, 1648,
11.72 (br s, NH); IR (KBr) 3192, 1730, 1696, 1650, 1614 cm-1
;
1625 cm-1
;
MS (ES+) 395.3 (MH+). Anal. Calcd for
MS (ES+) 389.3 (MH+). Anal. Calcd for C18H20N4O6: C, 55.67;
H, 5.19; N, 14.43. Found: C, 55.74; H, 5.22; N, 14.53. F r om
10 Usin g AcOH Ca ta lysis. The pyrrole 2a (2.3 g, 0.01 mol)
and 10 (2.27 g, 0.011 mol) were stirred together in MeOH (50
mL), and AcOH (3.0 g, 0.05 mol) was added. The mixture was
stirred at room temperature overnight, and the precipitate was
collected by filtration and recrystallized from 2-propanol to give
12a (1.6 g, 41%) identical with the material obtained above.
F r om 11 Usin g AcOH Ca ta lysis. Using 11 in place of 10
above gave similar results.
C16H18N4O6S: C, 48.73; H, 4.60; N, 14.21. Found: C, 48.71;
H, 4.73; N, 14.25.
Gen er a l P r oced u r e for th e Ca r ba m a tes 13. 2-(Ca r -
bom eth oxya m in o)-7-(p h en ylm eth yl)-1,5-d ih yd r o-4H-p yr -
r olo[3,2-d ] p yr im id in -4-on e (13a ). F r om 10. The pyrrole
2a (4.6 g, 0.02 mol) was dissolved in MeOH (20 mL), and 10
(4.5 g, 0.022 mol) was added followed by AcOH (6.0 g, 0.1 mol).
The mixture was stirred at room temperature overnight and
became a thick paste. NaOMe (25%) (26 mL, 0.12 mol) was
added, and stirring was continued at room temperature for 2
h. The mixture was neutralized with AcOH and the solid
collected by filtration and washed well with water. After
drying, 13a (4.2 g, 70%) was obtained as an off-white powder:
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
b on yl)im in o]m et h yl]a m in o]-4-(1-n a p h t h ylm et h yl)-1H -
p yr r ole-2-ca r boxyla te (12b): 32% yield; colorless needles;
mp 180-82 °C from 2-propanol; 1H NMR (CDCl3) δ 3.70 (s,
3H), 3.80 (s, 3H), 3.86 (s, 3H), 4.23 (s, 2H), 6.02 (d, 1H, J )
3.25 Hz), 7.1-8.1 (m, 7H), 8.77 (br s, NH), 10.13 (br s, NH),
mp >250 °C;
1H NMR (360 MHz, DMSO-d6) δ 3.71 (s, 3H),
3.88 (s, 2H), 7.0-7.3 (m, 6H), 11.00 (br s, NH), 11.23 (br s,
NH), 11.80 (br s, NH); IR (KBr) 3355, 1735, 1700, 1608 cm-1
;
11.79 (br s, NH); IR (KBr) 3297, 1735, 1708, 1648, 1623 cm-1
;
MS (ES+) 299.3 (MH+). Anal. Calcd for C15H14N4O3: C, 60.39;
H, 4.73; N, 18.73. Found: C, 60.39; H, 4.80; N, 18.69. F r om
11. The use of 11 in place of 10 gave 4.5 g (76%) of 13a as an
off-white solid identical with that obtained from 10.
MS (ES+) 439.4 (MH+). Anal. Calcd for C22H22N4O6: C, 60.27;
H, 5.06; N, 12.78. Found: C, 60.19; H, 5.08; N, 12.75.
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
b on yl)im in o]m et h yl]a m in o]-4-(2-n a p h t h ylm et h yl)-1H -
p yr r ole-2-ca r boxyla te (12c): 54% yield; colorless needles;
mp 196-7 °C from EtOAc; 1H NMR (DMSO-d6) δ 3.55 (s, 3H),
3.68 (s, 3H), 3.71 (s, 3H), 3.89 (s, 2H), 6.75 (d, 1H, J ) 3.20
Hz), 7.2-7.9 (m, 7H), 9.58 (br s, NH), 11.41 (br s, NH), 11.81
(br s, NH); IR (KBr) 3322, 1728, 1697, 1641 cm-1; MS (ES+)
439.0 (MH+). Anal. Calcd for C22H22N4O6: C, 60.27; H, 5.06;
N, 12.78. Found: C, 60.39; H, 5.13; N, 12.74.
Generally, the carbamates (13) were not characterized but
were converted directly to the pyrrolopyrimidines (1).
Gen er a l Met h od for t h e P yr r olop yr im id in es 1.
2-Am in o-7-(ph en ylm eth yl)-1,5-dih ydr o-4H-pyr r olo[3,2-d]-
p yr im id in -4-on e (1a ). 13a (4.54 g, 0.15 mol) was added to
1 N NaOH (46 mL), and the mixture was heated at 55 °C for
3 h. The mixture was cooled and neutralized with acetic acid,
and the solid was collected by filtration. After being washed
well with water and drying at 110 °C, 1a (3.6 g, 97%) was
obtained as an off-white solid: mp 276-8 °C (lit.1 mp 269-70
°C); 1H NMR (DMSO-d6) δ 3.81 (s, 2H), 5.85 (s, NH2), 6.91 (d,
J ) 2.9 Hz, 2H), 7.1-7.3 (m, 5H), 10.39 (br s, NH), 11.25 (br
s, NH); IR (KBr) 3176, 1678, 1635 cm-1; MS (ES+) 241.0 (MH+).
Anal. Calcd for C13H12N2O2: C, 67.81; H, 6.13; N, 12.16.
Found: C, 67.82; H, 6.16; N, 12.16.
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
bon yl)im in o]m eth yl]a m in o]-4-[(4-p h en ylp h en yl)m eth yl]-
1H-pyr r ole-2-car boxylate (12d): 87% yield; colorless needles;
mp 196-7 °C from MeOH-EtOAc; 1H NMR (DMSO-d6) δ 3.55
(s, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.78 (s, 2H), 6.75 (d, 1H, J )
3.00 Hz), 7.2-7.7 (m, 9H), 9.65 (br s, NH), 11.45 (br s, NH),
11.80 (br s, NH); IR (KBr) 3320, 1733, 1698, 1623 cm-1; MS
(ES+) 465.1 (MH+). Anal. Calcd for C24H24N4O6: C, 62.06;
H, 5.20; N, 12.06. Found: C, 62.14; H, 5.20; N, 12.10.
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
b on yl)im in o]m et h yl]a m in o]-4-[(4-isop r op ylp h en yl)m e-
th yl]-1H-p yr r ole-2-ca r boxyla te (12e): 72% yield; colorless
2-Am in o-7-(1-n aph th ylm eth yl)-1,5-dih ydr o-4H-pyr r olo-
[3,2-d ]p yr im id in -4-on e (1b): 74% yield; off-white solid; mp
1
290-2 °C; H NMR (DMSO-d6) δ 4.24 (s, 2H), 5.87 (s, NH2),
6.73 (d, J ) 2.9 Hz, 2H), 7.2-8.2 (m, 7H), 10.41 (br s, NH),
11.22 (br s, NH); IR (KBr) 3416, 1674 cm-1; MS (ES+) 291.3
(MH+). Anal. Calcd for C17H14N4O‚0.5H2O: C, 68.21; H, 5.05;
N, 18.72. Found: C, 68.02; H, 5.16; N, 18.60.
1
needles; mp 157-8 °C from 2-propanol; H NMR (DMSO-d6)
δ 1.15 (d, J ) 6.94 Hz, 6H), 2.81 (m, 1H), 3.54 (s, 3H), 3.68 (s,
3H), 3.71 (s, 3H), 3.77 (s, 2H), 6.68 (d, 1H, J ) 3.20 Hz), 7.00
(d, J ) 8.1 Hz, 2H), 7.07 (d, J ) 8.1 Hz, 2H), 9.61 (br s, NH),
11.44 (br s, NH), 11.75 (br s, NH); IR (KBr) 3286, 2956, 1742,
1702, 1648 cm-1; MS (ES+) 431.4 (MH+). Anal. Calcd for
C21H26N4O6: C, 58.59; H, 6.08; N, 13.01. Found: C, 58.21; H,
6.00; N, 12.75.
2-Am in o-7-(2-n aph th ylm eth yl)-1,5-dih ydr o-4H-pyr r olo-
[3,2-d ]p yr im id in -4-on e (1c): 75% yield; off-white solid; mp
295 °C; 1H NMR (DMSO-d6) δ 3.97 (s, 2H), 5.82 (s, NH2), 6.96
(d, J ) 2.9 Hz, 2H), 7.3-7.9 (m, 7H), 10.36 (br s, NH), 11.26
(br s, NH); IR (KBr) 3323, 3163, 1620 cm-1; MS (ES+) 291.3
(MH+). Anal. Calcd for C17H14N4O‚0.25H2O: C, 69.26; H,
4.96; N, 19.00. Found: C, 69.25; H, 4.96; N, 19.05.
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
bon yl)im in o]m eth yl]a m in o]-4-[[(4-(tr iflu or om eth yl)p h e-
n yl]m eth yl]-1H-p yr r ole-2-ca r boxyla te (12f): 71% yield;
colorless needles; mp 184-5 °C from 2-propanol; 1H NMR
(CDCl3) 3.69 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 3.91 (s, 2H),
6.49 (d, 1H, J ) 3.20 Hz), 7.26 (d, J ) 8.0 Hz, 2H), 7.49 (d, J
) 8.0 Hz, 2H), 9.04 (br s, NH), 9.92 (br s, NH), 11.64 (br s,
NH); IR (KBr) 3303, 1731, 1697, 1652, 1624 cm-1; MS (ES+)
457.7 (MH+). Anal. Calcd for C19H19N4O6F3: C, 50.00; H, 4.20;
N, 12.28. Found: C, 50.10; H, 4.21; N, 12.22.
2-Am in o-7-[(4-p h en ylp h en yl)m eth yl]-1,5-d ih yd r o-4H-
p yr r olo[3,2-d ]p yr im id in -4-on e (1d ): 87% yield; off-white
solid; mp >320 °C; 1H NMR (DMSO-d6) δ 3.85 (s, 2H), 5.83 (s,
NH2), 6.96 (d, J ) 2.7 Hz, 2H), 7.3-7.7 (m, 9H), 10.36 (br s,
NH), 11.25 (br s, NH); IR (KBr) 3406, 3176, 1654, 1623 cm-1
;
MS (ES+) 317.4 (MH+). Anal. Calcd for C19H16N4O: C, 72.13;
H, 5.09; N, 17.71. Found: C, 72.04; H, 5.16; N, 17.77.
2-Am in o-7-[(4-isop r op ylp h en yl)m et h yl]-1,5-d ih yd r o-
4H-p yr r olo[3,2-d ]p yr im id in -4-on e (1e): 48% yield; off-
white solid; mp 164-7 °C; 1H NMR (DMSO-d6) δ 1.15 (d, J )
6.9 Hz, 6H), 2.80 (m, 1H), 3.75 (s, 2H), 5.80 (s, NH2), 6.89 (d,
J ) 2.9 Hz, 2H), 7.09 (d, J ) 8.1 Hz, 2H), 7.13 (d, J ) 8.1 Hz,
2H), 10.34 (br s, NH), 11.20 (br s, NH); IR (KBr) 3325, 3166,
2959, 1678, 1639 cm-1; MS (ES+) 283.5 (MH+). Anal. Calcd
for C16H18N4O‚0.25H2O: C, 66.99; H, 6.50; N, 19.53. Found:
C, 66.73; H, 6.53; N, 19.33.
Meth yl 3-[[[(m eth oxyca r bon yl)a m in o][(m eth oxyca r -
b on yl)im in o]m et h yl]a m in o]-4-(cycloh exylm et h yl)-1H -
p yr r ole-2-ca r boxyla te (12g): 60% yield; colorless needles;
1
mp 171-2 °C from 2-propanol; H NMR (CDCl3) 0.8-1.7 (m,
11H), 2.33 (d, J ) 7.0, 2H), 3.67 (s, 3H), 3.80 (s, 3H), 3.88 (s,
3H), 6.60 (d, 1H, J ) 3.24 Hz), 7.26 (d, J ) 8.0 Hz, 2H), 7.49
(d, J ) 8.0 Hz, 2H), 9.20 (br s, NH), 10.00 (br s, NH), 11.81