1262
A. Ambroꢀak and M. Gütschow
Vol 44
(CH2-cyclohexyl), 29.97 (CH2CH3), 54.09 (CH-cyclohexyl), 63.10
(C-5), 150.01 (C-2), 169.36, 169.96, 170.45 (CO), signals of 2a: ꢀ
9.25 (CH3), 25.00, 25.79, 27.40, 28.09 (CH2-cyclohexyl), 54.84
(CH-cyclohexyl), 67.99 (C-5), 123.91 (C-4', C-7'), 130.50 (C-3a',
C-7a'), 135.73 (C-5', C-6'), 149.40 (C-2), 167.35, 167.96, 168.44
(CO). One signal for CH2-cyclohexyl and the signal for CH2CH3
are missing. Signals of phthalic anhydride: ꢀ 125.49 (C-3, C-6),
131.39 (C-1, C-2), 136.32 (C-4, C-5), 163.40 (C=O), signals of
6a: ꢀ 7.64 (CH3), 29.06 (CH2-cyclohexyl), 30.24 (CH2CH3), 54.13
(CH-cyclohexyl), 63.29 (C-5'), 128.59 (C-3), 128.93 (C-6), 130.33
(C-CO2H), 130.70 (C-4), 132.45 (C-5), 134.83 (C-2), 150.17 (C-
2'), 168.26, 168.32, 168.95, 170.03 (CO). Four signals for CH2-
cyclohexyl are missing.
propyl)-N'-ethylcarbodiimide hydrochloride (0.72 g, 3.75
mmoles) in dry tetrahydrofuran (5 ml), a suspension of 1-
hydroxy-7-azabenzotriazole (0.37 g, 2.75 mmoles) in dry
tetrahydrofuran (6 ml) and N-ethyldiisopropylamine (0.48 ml,
0.36 g, 2.75 mmoles) were added successively. The resulting
mixture was stirred for 20 minutes at room temperature.
Afterwards, the suspension of 5-amino-5-ethyl-1-phenyl-
barbituric acid 1b (0.62 g, 2.5 mmoles) in dry dimethylforma-
mide (12 ml) was added and the stirring was continued for 24
hours at room temperature. The solution was poured into water
(120 ml) and adjusted to pH 2 by dropwise addition of 4 M
hydrochloric acid. After extraction with ethyl acetate (5 ꢁ 40
ml), the combined organic layers were washed with saturated
sodium hydrogen carbonate solution (2 ꢁ 100 ml) and with brine
(100 ml). The organic layer was dried over sodium sulfate,
filtrated and evaporated in vacuo. The crude product was
recrystallized from methanol to give 0.58 g (57 %) of 4b as
white crystals; mp 250-256 °C; ir (potassium bromide): ꢂ 3327,
33210 (NH), 1705, 1667 cm-1 (C=O); 1H nmr (DMSO-d6): ꢀ
1.03 (t, 3H, J = 7.5 Hz, CH2CH3), 2.15 (q, 2H, J = 7.5 Hz, CH2),
3.66 (s, 3H, OCH3), 7.21-7.74 (m, 9H, arom. H), 9.78 (s, 1H,
NH), 11.94 (s, 1H, N(3')-H); 13C nmr (DMSO-d6): ꢀ 7.89
(CH2CH3), 29.86 (CH2CH3), 52.40 (OCH3), 63.46 (C-5'),
128.47, 128.79, 129.24, 130.63, 130.79, 131.50, 134.96, 135.15
(arom. C, two signals are missing), 149.94 (C-2'), 167.52,
168.85, 169.27, 169.98 (CO); ms: 409 (6 %, M+), 317 (34 %, M+
– C6H5 – CH3), 163 (100 %, M+ – C6H5 – CH3 – C6H6N2O3), 77 (6
N-(1-Cyclohexyl-5-ethyl-hexahydro-2,4,6-trioxo-5-pyrim-
idinyl)phthalamic acid tert-butyl ester (5a). To a suspension
of phthalic acid mono-tert-butyl ester (1.22 g, 5.5 mmoles, 1.1
equiv) in dry tetrahydrofuran (16 ml), a solution of N-(3-
dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.44
g, 7.5 mmoles, 1.5 equiv) in dry tetrahydrofuran (16 ml), a
suspension of 1-hydroxy-7-azabenzotriazole (0.75 g, 5.5
mmoles, 1.1 equiv) in dry terahydrofuran (20 ml) and N-ethyl-
diisopropylamine (0.95 ml, 0.71 g, 5.5 mmoles, 1.1 equiv) were
added successively. The resulting mixture was stirred for 20
min at room temperature. Afterwards, the suspension of 5-
amino-5-ethyl-1-phenylbarbituric acid 1a (1.26 g, 4.07 mmoles)
in dry DMF (30 ml) was added, and the stirring was continued
for 24 h at room temperature. After this time, the resulting
solution was poured into water (300 ml) and the basic mixture
was adjusted to pH 2 by dropwise addition of HCl (4 M). After
extraction with ethyl acetate (5 ꢁ 100 ml), the combined organic
+
%, C6H5 ). Anal. Calcd. for C21H19N3O6: C, 61.61; H, 4.68; N,
10.26. Found: C, 61.73; H, 4.98; N, 10.22.
N-(5-Ethyl-hexahydro-2,4,6-trioxo-1-phenyl-5-pyrimidin-
yl)phthalamic acid tert-butyl ester (5b). Compound 1b (0.62 g,
2.5 mmoles) was reacted with phthalic acid mono-tert-butyl
ester (0.61 g, 2.75 mmoles), N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride, 1-hydroxy-7-azabenzotriazole
and N-ethyldiisopropylamine in tetrahydrofuran/dimethyl-
formamide according to the aforementioned procedure.
Recrystallization from methanol gave 0.49 g (43 %) of 5b as
colorless crystals; mp 212-217 °C; ir (potassium bromide): ꢂ
3303, 3113 (NH), 1738 (br), 1694 (C=O); 1H nmr (DMSO-d6): ꢀ
1.04 (t, 3H, J = 7.6 Hz, CH2CH3), 1.44 (s, 9H, (CH3)3), 2.18 (q,
2H, J = 7.6 Hz, CH2CH3), 7.20-7.65 (m, 9H, arom. H), 9.72 (s,
1H, NH), 11.95 (s, 1H, N(3')-H); 13C nmr (DMSO-d6): ꢀ 7.93
(CH2CH3), 27.57 ((CH3)3), 30.05 (CH2CH3), 63.53 (C-5'), 81.52
(C(CH3)3), 128.41, 128.77, 128.82, 128.91, 129.13, 130.09,
131.07, 132.99, 134.56, 134.88 (arom. C), 149.91 (C-2'), 167.11,
167.98, 169.33, 169.99 (CO). Anal. Calcd. for C24H25N3O6: C,
63.85; H, 5.58; N, 9.31. Found: C, 63.24; H, 5.90; N, 9.24.
5-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-5-ethyl-1-phen-
ylbarbituric acid (2b). A mixture of trifluoroacetic acid (10 ml)
and anhydrous dichloromethane (6 ml) was added in portions at
0 °C to the phthalamic acid mono-tert-butyl ester 5b (0.17 g,
0.38 mmoles). When a clear solution was obtained, the mixture
was allowed to warm to room temperature and stirred for
additional 90 minutes. The solution was evaporated to give a
white solid to which anhydrous dichloromethane (5 ml) and
trifluoroacetic acid anhydride (13 ml) were added. The resulting
solution was stirred at 40 °C for 5 hours until no starting
material was detectable by thin-layer chromatography. The
mixture was evaporated to dryness to give 0.14 g (98 %) of 2b
as a white solid; mp 236-239 °C, ref 212-214 °C [2]; ir
layers were washed with saturated NaHCO solution (2 ꢁ 220
3
ml) and with brine (220 ml). The organic layer was dried over
sodium sulfate, filtrated and evaporated in vacuo to give a crude
product which was recrystallized from methanol to give 0.68 g
(30 %) of 5a as white crystals; mp 230-233 °C; ir (potassium
bromide): ꢂ 3297, 3179 (NH), 1735, 1672, 1643 cm-1 (C=O); 1H
nmr (DMSO-d6): ꢀ 0.89 (t, 3H, J = 7.6 Hz, CH2CH3), 1.08-2.23
(m, 10H, CH2-cyclohexyl), 1.43 (s, 9H, (CH3)3), 2.02 (q, 2H, J =
7.6 Hz, CH2CH3), 4.48 (tt, 1H, J = 12.3, 3.6 Hz, CH-
cyclohexyl), 7.49-7.65 (m, 4H, arom. H), 9.56 (s, 1H, NH),
11.61 (s, 1H, N(3')-H); 13C nmr (DMSO-d6): ꢀ 7.70 (CH2CH3),
25.08, 25.91, 27.47, 28.44, 29.35 (CH2-cyclohexyl), 25.99
(C(CH3)3), 30.31 (CH2CH3), 54.13 (CH-cyclohexyl), 63.54 (C-
5'), 81.43 (C(CH3)3), 128.32, 128.93, 129.98, 130.99, 133.07,
134.63 (arom. C), 150.02 (C-2'), 167.20, 167.54, 169.04, 170.23
(CO). Anal. Calcd. for C24H31N3O6: C, 63.01; H, 6.83; N, 9.18.
Found: C, 62.53; H, 7.14; N, 9.12.
Reaction of N-(1-cyclohexyl-5-ethyl-hexahydro-2,4,6-trioxo-
5-pyrimidinyl)phthalamic acid tert-butyl ester (5a) with
trifluoroacetic acid. A mixture of trifluoroacetic acid (26 ml)
and anhydrous dichloromethane (5.5 ml) was added in portions at
0 °C to the phthalamic acid mono-tert-butyl ester 5a (0.46 g, 1.00
mmol). When a clear solution was obtained, the mixture was
allowed to warm to room temperature and stirred for additional
150 minutes. The solution was evaporated to give 0.39 g (97 %)
of N-(1-cyclohexyl-5-ethyl-hexahydro-2,4,6-trioxo-pyrimidin-5-
yl)phthalamic acid (6a) as a white solid. The material was pure
and identical (mp, nmr) to that obtained from 1a.
N-(5-Ethyl-hexahydro-2,4,6-trioxo-1-phenyl-5-pyrimidin-
yl)phthalamic acid methyl ester (4b). To a suspension of
phthalic acid mono-methyl ester (0.5 g, 2.75 mmoles) in dry
tetrahydrofuran (5 ml), a solution of N-(3-dimethylamino-
1
(potassium bromide): ꢂ 3243 (NH), 1707 cm-1 (br, C=O); H
nmr (DMSO–d6): ꢀ 1.10 (t, 3H, J = 7.3 Hz, CH3), 2.87 (q, 2H, J