Aminophenyl Functionalized Ureidopyrimidinones
HRMS calcd for C17H24O2N5 (MH)+ 330.19299, found 330.19288;
m/z (ES+) 352 ([MNa]+, 100).
(CH2Ar C-4), 154.5 (NHCONH), 152.1 (C-2), 148.4 (C-4′), 142.3
(C-1′), 130.7 (CH2Ar C-1), 128.9 (CH2Ar C-2, C-6), 127.9 (C-2′,
C-6′), 123.7 (C-3′, C-5′), 114.5 (CH2Ar C-3, C-5), 104.2 (C-5),
71.3 (CH2OAr), 69.9, 69.8, 69.6, 68.9, 67.1, 58.1 (OCH3), 42.4
(NHCH2Ar); m/z HRMS calcd for C25H29N5O8Na 550.19083,
found 550.19059; m/z (+FAB) 550 ([MNa]+, 10).
1-{6-[4-(4-Dimethylaminophenylazo)phenyl]-4-oxo-1,4-
dihydropyrimidin-2-yl}-3-hexylurea (5). The amino com-
pound 2 (0.10 g, 0.30 mmol) was dissolved in a mixture of acetic
acid (2 mL) and concd HCl (0.7 mL). The solution was then
cooled to 5 °C. To this was added a solution of sodium nitrite
(0.03 g, 0.03 mmol) in water (0.6 mL) at 0 °C, resulting in the
formation of a yellow solution. The reaction was stirred for 15
min at 0 °C. A solution of N,N-dimethylaniline (0.036 g, 0.30
mol) in acetic acid (0.1 mL) at 0 °C was then added to give a
red solution, and the mixture was stirred for 30 min at rt. A
saturated sodium acetate solution was then added to the
mixture in order to increase the pH close to 6, resulting in
the precipitation of the azo compound. Recrystallization from
methanol afforded 5 (0.030 g, 20%): (pyrimidin-4-ol DADA
tautomer C) 1H NMR δ (400 MHz; DMSO-d6) 10.21 (1H, s,
NHCONHCH2), 7.96 (2H, d, J 7.9 Hz, 2′-H, 6′-H), 7.80 (2H,
d, J 9.1 Hz, NMe2Ar 2-H 6-H), 7.78 (2H, d, J 7.9 Hz, 3′-H,
5′-H), 6.83 (2H, d, J 9.1 Hz, NMe2Ar 3-H 5-H), 6.04 (1H, s,
5-H), 3.18 (2H, m, NHCH2CH2), 3.06 (6H, s, NMe2), 1.51 (2H,
m, NHCH2CH2), 1.34 (2H, m, NH(CH2)2CH2), 1.26 (4H, m, NH-
(CH2)3CH2CH2), 0.82 (3H, m, CH2CH3); 13C NMR δ (75 MHz;
DMSO-d6) 175.5 (C-4), 159.5 (C-6), 158.7 (C-2), 155.8 (NH-
CONH), 153.0, 152.97, 143.1, 140.1, 127.1, 125.1, 122.2, 112.0,
102.0 (C-5), 39.0 (NHCH2), 30.0, 26.7, 22.4, 14.2 (CH2CH3); m/z
(ES+) 484 ([MNa]+, 100), 461 (MH+, 30).
1-[2-(2-Methoxyethoxymethyl]-3-(1,4-dihydro-4-oxo-6-
p-nitrophenyl-2-pyrimidinyl)urea (7). A suspension of 6-(p-
nitrophenyl)isocytosine 3 (150 mg, 0.645 mmol) and 6 (2.80
mmol) in dry pyridine (10 mL) and DMF (15 mL) was heated
at 90 °C for 16 h. The solvent was removed in vacuo and the
product purified using flash silica chromatography (chloroform/
methanol, 35:1) to give 7 as a solid (32 mg, 28%): 1H NMR
(6[1H]-pyrimidinone monomeric A) δ (300 MHz; DMSO-d6)
11.92 (1H, s, 3-H), 10.30 (1H, s, NHCONHCH2), 8.32 (2H, d,
J 9.1 Hz, 3′-H), 8.23 (2H, d, J 9.1 Hz, 2′-H), 7.86 (1H, br s,
CONHCH2), 6.72 (1H, s, 5-H), 4.67 (2H, d, J 6.6 Hz, NHCH2O),
3.48-3.55 (6H, m, CH2O), 3.42 (2H, m, CH2O), 3.21 (3H, s,
OCH3); 13C NMR δ (100 MHz; DMSO-d6) 164.6 (C-4), 155.2
(NHCONH), 148.5 (C-4′), 142.4 (C-1′), 128.1 (C-2′), 123.8 (C-
3′), 104.8 (C-5), 74.6 (NHCH2O), 71.3, 69.7, 69.6, 67.0, 58.0
(OCH3); m/z (ES+) 430 ([MNa]+, 90), 408 (MH+, 10).
1-(4-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}benzyl)-3-
[6-(4-aminophenyl)-4-oxo-1,4-dihydropyrimidin-2-
yl]urea (11). Tin(II) chloride (0.857 g, 3.80 mmol) was added
to a solution of 9 (0.334 g, 0.634 mmol) in concd HCl (7.5 mL)
and absolute ethanol (3.75 mL). The solution was heated at
90 °C for 2 h. The yellow solution was then poured into ice
and the pH adjusted to 8-9 by addition of sodium hydrogen
carbonate. The aqueous layer was then extracted with chlo-
roform (5 × 10 mL) and the organic phase washed with
saturated sodium chloride solution (10 mL) and dried (MgSO4).
The solvents were evaporated in vacuo, and the product was
purified using flash silica chromatography (chloroform/metha-
nol, 7:1) to give 11 as an oil (200 mg, 63%): IR (KBr) 3448,
3363, 3219, 2937, 2879, 1693, 1667, 1623, 1600, 1573, 1512
cm-1; (4[1H]-pyrimidinone tautomer B) 1H NMR δ (500 MHz;
CDCl3) 13.66 (1H, s, 1-H), 12.17 (1H, s, NHCONHCH2), 10.89
(1H, s, CONHCH2), 7.45 (2H, d, J 7.3 Hz, CH2Ar 2-H, 6-H),
7.31 (2H, d, J 8.2 Hz, 2′-H), 6.87 (2H, d, J 7.3 Hz, CH2Ar
3-H, 5-H), 6.73 (2H, d, J 8.2 Hz, 3′-H), 6.21 (1H, s, 5-H), 4.46
(2H, s, CONHCH2), 4.16-3.44 (12H, m, CH2O), 3.36 (3H, s,
OMe); (pyrimidin-4-ol DADA tautomer C) 1H NMR δ (400
MHz; CDCl3) 13.24 (1H, s, OH), 11.41 (1H, s, NHCONHCH2),
10.19 (1H, s, CONHCH2), 7.37 (2H, d, J 8.2 Hz, 2′-H), 7.13
(2H, d, J 7.4 Hz, CH2Ar 2-H, 6-H), 6.96 (2H, d, J 7.4 Hz, CH2-
Ar 3-H, 5-H), 6.54 (1H, s, 5-H), 6.35 (2H, d, J 8.2 Hz, 3′-H),
4.43 (2H, s, CONHCH2), 4.16-3.44 (12H, m, CH2O), 3.41 (3H,
s, OMe); (4[1H]-pyrimidinone tautomer B) 13C NMR δ (125
MHz; CDCl3) 173.1 (CdO), 157.9 (CH2Ar C-4), 157.0 (NH-
CONH), 149.7 (C-4′), 131.3 (CH2Ar C-1), 128.7 (CH2Ar C-2,
C-6), 127.1 (C-2′, C-6′), 120.0 (C-1′), 115.2 (C-3′, C-5′), 114.6
(CH2Ar C-3, C-5), 101.7 (C-5), 67.4-71.9 (signal overlap), 38.7-
60.4 (several signals not assignable to each tautomer); (pyri-
midin-4-ol DADA tautomer C); 13C NMR δ (100 MHz; DMSO-
d6) 165.5 (COH), 161.0 (C-6), 157.7 (CH2Ar C-4), 154.6
(NHCONH), 153.2 (C-2), 151.0 (C-4′), 131.0 (CH2Ar C-1), 129.0
(CH2Ar C-2, C-6), 127.7 (C-2′, C-6′), 123.2 (C-1′), 114.5 (CH2-
Ar C-3, C-5), 113.3 (C-3′, C-5′), 98.0 (C-5), 71.3, 67.0, 69.8, 69.6,
69.0, 67.2, 58.1 (OCH3), 42.6 (NHCH2); m/z HRMS calcd for
C15H22O6 (MH)+ 498.23471, found 498.23376.
1-(4-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}benzyl)-
3-[6-(4-nitrophenyl)-4-oxo-1,4-dihydropyrimidin-2-yl]-
urea (10). The isocyanate 9 (3.30 mmol) was added to a
solution of the amine 3 (0.255 g, 1.10 mmol) in dried pyridine
(10 mL). The mixture was then heated at reflux for 18 h. The
product was precipitated by the addition of hexane, and
filtration afforded 10 as a colorless solid (0.469 g, 81%): mp
238-240 °C (hexane); IR (KBr) 3216, 3133, 3079, 2931, 2876,
Acknowledgment. We thank the AWE for a stu-
dentship to V.G.H.L. Dr. B. R. Peterson (Pennsylvania
State University) is thanked for providing the Associate
program used in this work for the analysis of the
concentration-dependent diffusion rates.
1
1667, 1613, 1559 cm-1; (6[1H]-pyrimidinone tautomer A) H
NMR δ (400 MHz; DMSO-d6) 11.92 (1H, s, 3-H), 10.07 (1H, s,
NHCONHCH2), 8.25 (2H, d, J 8.8 Hz, 3′-H), 8.13 (2H, d, J 8.8
Hz, 2′-H), 7.74 (1H, br s, CONHCH2), 7.26 (2H, d, J 8.5 Hz,
CH2Ar 2-H, 6-H), 6.93 (2H, d, J 8.5 Hz, CH2Ar 3-H, 5-H), 6.67
(1H, s, 5-H), 4.31 (2H, d, J 5.4 Hz, CONHCH2), 4.06 (2H, m,
CH2OAr), 3.73 (2H, m, CH2O), 3.56 (2H, m, CH2O), 3.51 (4H,
m, 2 × CH2O), 3.42 (2H, m, CH2O), 3.35 (3H, s, OCH3); 13C
NMR δ (125 MHz; DMSO-d6) 161.6 (C-4), 159.1 (C-6), 157.7
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 4, 6, 8, 9, and 12
and copies of NMR spectra for compounds 2, 4, 5, 7, 8, and
10-12 (and intermediates). This material is available free of
JO048223L
J. Org. Chem, Vol. 70, No. 7, 2005 2707