Synthesis of pyrimidinones by action of benzamidine on a benzocycloheptenic β-keto ester

Article abstract of DOI:10.1002/jhet.5570380630

The synthesis of a polycyclic heterocyclic ring system compound, ethyl 7-hydroxy-4-oxo-2-phenyl-4,5-dihydro-3H-benzo[6,7]cyclohepta[ 1,2-d]pyrimidine-6-carboxylate was carried out by condensation of benzamidine on diethyl 5,9-dihydroxy-7H-benzo[a]cycloheptene-6,8-dicarboxylate, after opening and then closure of the seven membered ring.

Full text of DOI:10.1002/jhet.5570380630

Nov-Dec 2001
Synthesis of Pyrimidinones by Action of Benzamidine on a
Benzocycloheptenic β-Keto Ester
1447
Nadine Muller, Robert Granet, Lucette Lepage, Pierre Krausz
Laboratoire de Chimie des Substances Naturelles
Faculté des Sciences, 123, Avenue Albert Thomas, 87060 Limoges Cedex. (France)
Jean-Paul Laval
SPCTS,UMR n° 6638
Faculté des Sciences, 123, Avenue Albert Thomas, 87060 Limoges Cedex. (France)
Received December 30, 1998
The synthesis of a polycyclic heterocyclic ring system compound, ethyl 7-hydroxy-4-oxo-2-phenyl-4,5-
dihydro-3H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-6-carboxylate was carried out by condensation of benz-
amidine on diethyl 5,9-dihydroxy-7H-benzo[a]cycloheptene-6,8-dicarboxylate, after opening and then
closure of the seven membered ring.
J. Heterocyclic Chem., 38, 1447 (2001).
A large number of benzocycloheptene derivatives con-
Starting from commercially available diethyl phthalate 1
(Scheme1), Β-keto ester 2 is obtained by Dieckmann method
[11] after reaction of compound 1 with diethyl glutarate in the
presence of sodium ethoxide. The infrared spectrum of the
bicyclic compound 2 shows C=O ester bands at 1610-1640
taining additional heterocycles were reported to possess
interesting biological properties such as antitumour [1],
antihypertensive, antithrombotic [2-3] or anticytokine
activity [4]. On the other hand, pyrimidine base derivatives
have been investigated due to their potential for medicinal
activity [5-6]. Benzocycloheptene derivatives containing
pyrimidine bases are also compounds of pharmacological
interest [3,7]. In connection with our investigations for
novel benzocycloheptene derivatives [8-10], we have been
interested in the reaction of benzamidine hydrochloride
with β-keto ester-benzocycloheptene 2 (Scheme 1) and we
describe in this paper the synthesis of a novel family of
pyrimidinones after an original ring opening of a seven
membered cycle by retro-Claisen condensation.
-1
cm . We already assume that the presence of strong hydrogen
bonding, between the hydroxyl group at the 5 and 9-position
and the ester group at the 6 and 8-position, favour the enol
1
13
form of this compound. The H nmr as well the C nmr spec-
tra strongly supports this enol form (δ 12.6 ppm s OH; δ 166.5
ppm C-enol) and the symmetry of the molecule 2.
The attempted condensation of 2 with benzamidine does
not allow isolation of the expected benzocycloheptenopy-
rimidine 3 but rather gives predominantly the pyrimidinone
4 in 56% yield. The structure of the pyrimidinone 4 can be

1448
N. Muller, R. Granet, L. Lepage, P. Krausz, and J.-P. Laval
Vol. 38
Table 1
Yield, Melting Points and Elemental Analyses of Compounds 2-7
Compound
No
Yield
(%)
Mp
°C
Formula
Calcd.%
H
Found.%
H
C
N
C
N
2
3
4
5
6
7
55
31
56
73
92
80
87
C
C
C
C
C
C
H
O
64.15
67.33
67.33
67.96
65.74
65.93
5.66
5.14
5.14
5.46
5.98
4.43
-----
7.14
7.14
6.89
6.39
7.69
63.99
67.86
67.37
67.72
66.06
65.85
5.73
5.48
5.46
5.35
5.50
4.55
-----
7.47
7.37
7.10
6.43
7.57
15 18
6
238
220
175
140
262
H
O N H O
22 18
4
2,
2
2
H
O N
22 20
5
H
O N
24 22
5
2
H
O N H O
24 24
5
2,
2
2
H
O N
20 16
5
established from its elemental (Table 1) and spectral analy-
intermediate addition product. However, simultaneously, the
strongly basic environment leads to a retro-Claisen conden-
sation on the seven membered ring.
ses. Thus the IR of 4 shows a major absorption at 3350-3150
-1
cm that can be attributed to NH and OH groups. The
-1
strong band that appears at 1625 cm corresponds to the
Treatment of 4 with sulfuric acid in methanol or ethanol
1
13
1
pyrimidine carbonyl. The assignment of its H and C nmr
spectra was also accomplished by utilising two dimensional
give the diesters 5 and 6 respectively. The H nmr spec-
trum of 5 shows clearly the two different ester functions.
1
13
1
nmr methods: H- C HMQC (Heteronuclear Multiple
For the compounds 5 and 6 the H nmr shows also the two
1
1
1
Quantum Coherence), and H- H COSY. In the H nmr
CH as two distinct multiplets. Saponification of 4 with
2
spectrum of 4 in DMSO-d , a four protons multiplet cen-
potassium hydroxide in methanol gives the diacid 7.
Reaction of 5 and 6 with sodium ethoxide in dry toluene
affords the benzocycloheptenopyrimidinone 3. The struc-
ture of 3 is assigned by chemical (Table 1) and spectral
analyses. The infrared spectrum shows the stretching fre-
quencies which are characteristic of the NH (3400-3200
6
tered at δ 2.49 ppm was observed. (The HMQC correlation
proton-carbon allows us to establish the presence of two
neighbouring methylene groups -δ 22.4-31.4 ppm- in the
same multiplet at δ 2.49 ppm). This result demonstrates that
the seven membered ring has been converted to an other
compound which contains not one, but two methylene
-1
-1
-1
cm ), C=O (1630 cm ) and C=N (1600 cm ) groups of
1
1
13
groups. On the other hand the H nmr reveals a broad signal
the pyrimidine nucleus. The H and C nmr show the
methylene group of the seven membered ring at δ 3.32
ppm (as a singlet) and δ17.2 ppm respectively (Scheme 2).
It is interesting to observe over all the compounds 3-6, the
tautomeric properties of the phenyl-pyrimidinone. The
infrared and nmr spectra of these compounds show both the
NH and the C=O bands and therefore the predominant tau-
tomeric form of this phenylpyrimidinone should be the lac-
tam pyrimidine which is the usual form in pyrimidinones.
at δ 11.0-10.5 ppm (NH+OH) which disappears upon
deuteration. The spectrum shows multiplets in the region of
δ 8.07-7.20 ppm that can be ascribed to the aromatic pro-
tons. We propose a reaction pathway for the formation of
this ring showed in Scheme 2. Initially, the condensation of
free benzamidine with compound 2 leads to the formation of
the pyrimidinone [12] resulting from addition of the NH
2
group to the ketone group followed by a cyclisation of the

Nov-Dec 2001
Synthesis of Pyrimidinones by Action of Benzamidine
1449
Table 2
Single Crystal X-Ray Crystallographic Analysis of 5
Table 2 (continued)
A) Crystal Parameters
formula
B) Refinement Parameters
Index ranges
C
H
N O (406.4)
-11<h<1; -14<k<14; -18<l<18
23 22
2 5
crystallization medium
Crystal Size (mm)
méthanol
0.2 X 0.2 X 0.15
Collected Reflections
Observed Reflections
6026
3073
Crystal System and Space Group
Cell Dimensions : (Å and °)
triclinic P -1
a: 8.037(2) alpha: 98.31(2)
b: 10.362(2) beta: 101.97(2)
c: 13.146(2) gamma: 99.81(2)
1036.8(4)
2
1.302
0.093
P3
Absorption Correction Method
Structure Solution Program
Structure Refinement Program
Extinction Coefficient
Number of l.s. Parameters
Residuals (observed data)
Residuals (all data)
psi-scan
SHELXS-97 (Sheldrick, 1997)
SHELXL-97 (Sheldrick, 1997)
0.009(3)
3
Cell Volume (Å )
361
Z (formula units/cell)
R1 = 0.0642: wR2 = 0.1358
R1 = 0.1403: wR2 = 0.1698
S= 1.0120
Density (calculated) (g/ml)
Absorption Coefficient µ(mm-1)
Diffractometer
Radiation Source and Wavelength (Å)
Data Collection Temperature (K)
Two-theta range (°)
Goodness-of-fit (all data)
Largest e-Density Peak and
-3
MoKα = 0.7107
293(2)
4.06 to 60.00
Hole (e.Å )
0.303: -0.218
Table 3
Bond Lengths (Å), Bond Angles (°) and Symmetry
N(1)-C(2)
N(1)-C(6)
N(3)-C(2)
N(3)-C(4)
C(4)-O(4)
C(4)-C(5)
C(5)-C(6)
C(2)-C(7)
C(7)-C(8)
C(7)-C(12)
C(8)-C(9)
C(9)-C(10)
C(10)-C(11)
C(11)-C(12)
C(5)-C(13)
C(13)-C(14)
C(14)-C(15)
C(15)-O(15)
1.306(2)
C(15)-C(16)
C(16)-O(16)
C(16)-C(17)#
C(6)-C(18)
1.308(3)
1.458(3)
1.483(4)
1.497(3)
1.404(3)
1.393(3)
1.398(3)
1.375(3)
1.374(4)
1.385(3)
1.494(3)
1.199(2)
1.340(3)
1.441(3)
1.375(3)
1.374(4)
1.483(4)
1.199(2)
1.379(2)
1.364(2)
1.383(3)
1.243(2)
1.431(3)
1..368(3)
1.488(3)
1.389(3)
1.392(3)
1.389(3)
1.374(4)
1.374(4)
1.384(3)
1.507(3)
1.526(4)
1.503(4)
1.189(3)
#1: x+1,y,z
C(18)-C(19)
C(18)-C(23)
C(19)-C(20)
C(20)-C(21)#
C(21)-C(22)#
C(22)-C(23)
C(19)-C(24)
C(24)-O(24)#
C(24)-O(25)
O(25)-C(25)
C(21)-C(20)#
C(22)-C21)#
C(17)-C(16)#
O(24)-C(24)#
#1: x+1,y,z
#1: x-1,y,z
#1: x,y+1,z
#1: x-1,y,z
#1: x+1,y,z
#1: x-1,y,z
#1: x,y-1,z
C(6)-N(1)-C(2)
C(2)-N(3)-C(4)
C(18)-C(23)-C(19)
C(23)-C(18)-C(6)
C(19)-C(18)-C(6)
C(5)-C(6)-N(1)
C(18)-C(6)-C(5)
N(1)-C(6)-C(18)
C(12)-C(7)-C(8)
C(8)-C(7)-C(2)
C(12)-C(7)-C(2)
C(18)-C(19)-C(20)
C(20)-C(19)-C(24)
C(24)-C(19)-C(18)
N(1)-C(2)-N(3)
N(1)-C(2)-C(7)
N(3)-C(2)-C(7)
C(4)-C(5)-C(6)
C(6)-C(5)-C(13)
C(4)-C(5)-C(13)
O(4)-C(4)-N(3)
O(4)-C(4)-C(5)
117.4(2)
123.3(2)
118.9(2)
117.0(2)
124.1(2)
124.1(2)
121.4(2)
114.4(2)
118.7(2)
122.7(2)
118.6(2)
119.0(2)
120.3(2)
120.8(2)
122.0(2)
119.2(2)
118.8(2)
118.0(2)
124.3(2)
117.7(2)
120.2(2)
124.5(2)
N(3)-C(4)-C(5)
C(7)-C(8)-C(9)
115.3(2)
120.2(2)
121.1(2)
112.0(2)
120.7(2)
123.3(2)
125.3(2)
111.4(2)
121.1(2)
120.2(2)
120.1(2)
119.9(2)
120.3(2)
119.8(2)
122.6(3)
124.2(3)
113.1(3)
107.1(3)
111.4(3)
117.1(2)
118.7(2)
C(21)-C(20)#1-C(19)
C(5)-C(13)-C(14)
C(16)-C(11)-C(3)
O(24)-C(24)-O(25)#1
O(24)-C(24)-C(19)
O(25)-C(24)#1-C(19)
C(22)-C(23)-C(18)
C(20)-C(21)#1-C(22)#1
C(9)-C(10)-C(11)
C(10)-C(11)-C(12)
C(10)-C(9)-C(8)
C(21)-C(22)#1-C(23)
O(15)-C(15)-O(16)
O(15)-C(15)-C(14)
O(16)-C(15)-C(14)
O(16)-C(16)-C(17)#1
C(15)-C(14)-C(13)
C(24)-O(25)#1-C(25)
C(16)-O(16)-C(15)
#1: x+1,y,z
#1: x,y+1,z
# 1: x,y+1,z
#1: x-1,y,z
#1: x+1,y,z
#1: x+1,y,z
#1: x,y-1,z
Estimated standard deviations are given in parenthesis.

1450
N. Muller, R. Granet, L. Lepage, P. Krausz, and J.-P. Laval
Vol. 38
Table 4
Atomic Coordinates (x 10 ) and Equivalent Isotropic Displacement
4
2
3
Parameters (Å x 10 )
x
y
z
U(eq)
N(1)
N(3)
C(18)
C(6)
C(7)
C(19)
C(2)
C(5)
C(4)
C(8)
C(20)
C(13)
C(12)
C(24)
C(23)
C(21)
C(10)
C(11)
C(9)
C(22)
C(15)
C(16)
C(25)
C(14)
C(17)
O(4)
4192(2)
1794(2)
6727(2)
4921(2)
1790(3)
7112(2)
2653(3)
4135(3)
2468(3)
13(3)
8852(3)
4920(3)
2802(3)
5692(3)
8092(3)
177(3)
6253(2)
5391(2)
7764(2)
6978(2)
4729(2)
9029(2)
5491(2)
6941(2)
6076(2)
4212(2)
9657(2)
7736(2)
4554(2)
9713(2)
7185(2)
9063(3)
3392(2)
3885(2)
3546(3)
7833(3)
2763(1)
1338(1)
2596(2)
2106(2)
3058(2)
3246(2)
2366(2)
1072(2)
637(2)
39(1)
40(1)
36(1)
36(1)
37(1)
35(1)
35(1)
38(1)
40(1)
46(1)
44(1)
45(1)
49(1)
40(1)
50(1)
51(1)
54(1)
56(1)
53(1)
54(1)
71(1)
62(1)
60(1)
65(1)
72(1)
57(1)
60(1)
55(1)
63(1)
162(2)
2809(2)
3675(2)
351(2)
4004(2)
3455(2)
2387(2)
3461(2)
4436(2)
4688(2)
3501(2)
2814(2)
-1189(2)
-1664(2)
4364(3)
-409(2)
-1217(3)
-297(1)
3089(1)
4129(1)
-997(1)
-1891(2)
284(4)
2051(4)
-731(4)
9806(3)
6306(4)
8783(4)
5098(4)
5678(4)
688(4)
1641(2)
4167(2)
6329(2)
8001(2)
5376(3)
7655(3)
8791(3)
1670(3)
6883(3)
9101(4)
5915(2)
9285(2)
878(2)
O(24)
O(25)
O(16)
O(15)
7984(2)
7980(4)
U(eq) is defined as 1/3 of the trace of the orthogonalized Uij tensor.
In order to prove the structure of this heterocycle in
solid state, a X-ray structural determination of com-
pound 5 was performed on a single crystal grown from
methanol (mp 175 °C). The structure has been solved by
direct methods using ShelXs-97 [13] and refined with
ShelXl-97 [14] under the experimental conditions gath-
ered on Table 2. All atoms, including hydrogen atoms
have been localised and refined with isotropic thermal
vibration factors. Then, anisotropy of the thermal vibra-
tions has been introduced for all atoms except H. The
Figure 1. X-Ray crystallographic structure of 5.
refinement converges to satisfying R values (R = 0.064
tively correspond to an aliphatic chain with two neigh-
bouring methylene groups. The second feature to note is
that the C(4) - O(4) and N(1) - C(2) bond lengths are
short [1.243(2) and 1.306(2) Å ] and correspond to C=O
and N=C respectively. In addition, N(3) - C(2) and N(3)
- C(4) bond lengths are longer at 1.364(2)Å and
1.383(3)Å respectively, corresponding to single bonds.
X-ray diffraction shows that in the crystalline state,
compound 5 exists in the lactam form.
1
wR = 0.136 for all observed data) after introduction of
2
an extinction correction and of a weighting scheme. A
last Fourier-difference calculation does not show any
significant residual electronic density. The atomic coor-
dinates are reported in Table 4 and the main interatomic
distances and angles in Table 3. Figure 1 presents the
molecular structure of the pyrimidinone 5. The most
salient feature of the structure of the heterocycle is that
the C(5) - C(13), C(13) - C(14) and C(14) - C(15) bond
lengths of 1.507(3)Å, 1.526(4)Å and 1.503(4)Å respec-
Molecular ion peaks are observed in the mass spectra of
all these compounds.

Nov-Dec 2001
General Methods.
Synthesis of Pyrimidinones by Action of Benzamidine
1451
EXPERIMENTAL
ml of MeOH. The resulting solution was refluxed for 12 hours,
evaporated to dryness and the residue was dissolved in water. The
solution was neutralised with sodium hydrogen carbonate and
extracted with chloroform. The organic layer was washed with
water, dried over anhydrous sodium sulfate, and evaporated to
All melting points were determined on an Electrothermal
IA9000 apparatus in glass capillary tubes or a Kofler hot-stage and
are uncorrected. Infrared spectra were recorded on a Perkin Elmer
afford crystals which were recrystallised from MeOH, to give 405
1
mg (1 mmole) (73%) of 5; H NMR (CD OD): δ 1.16 (3H, t, J
3
-1
1000 FTIR instrument and the frequencies are expressed in cm .
=7.1, CH ester), δ 2.49 (2H, m, CH β), δ 2.67 (2H, m, CH α),δ
3
2
2
1
13
The H and C nmr spectra were acquired using a Brücker spec-
3.71 (3H, s, O-CH ), δ 4.02 (2H, q, J = 7.1, CH ester) δ 7.43 (1H,
d, J = 7.5, H-3), δ 7.50 (2H, m, H-3'', H-5''), δ 7.54 (1H, d, J = 7.2,
3
2
1
13
trometer operating at 400 MHz for H and 100 MHz for C.
Chemical shifts are given in ppm (δ) and J in Hz and the signals are
designated as follows; s singlet, d doublet, t triplet, m multiplet.
The IC-mass on a R10-10 Nermag apparatus and microanalyses
are realised at the University Pierre et Marie Curie, Paris VI.
H-4''), δ 7.57 (1H, t, J = 7.7, H-5), δ 7.67 (1H, t, J = 7.1, H-4), δ
7.95 (2H, d, J = 7.3, H-2'', H-6''), δ 8.03 (1H, d, J = 7.7, H-6);
13
C
NMR (CD OD): δ 14.5 (CH ester), δ 23.5 (CH α), δ 33.2
3
3
2
(CH β), δ 52.7 (O-CH ), δ 61.6 (CH ester), δ 117.1 (C-5'), δ
2
3
2
122.7 (C-1), δ 128.9 (C-2'',C-6''), δ 130.0 (C-3'', C-5''), δ 130.2 (C-
3), δ 130.8 (C-5), δ 131.5 (C-2), δ 131.5 (C-3), δ 131.6 (C-6), δ
132.9 (C-4''), δ 133.9 (C-1'') δ 133.4 (C-4), δ 140.6 (C-4'), δ 156.5
(C-2'), δ 168.8 (C-6'), δ 174.6 (C=O); IR (KBr): 3350-3100 (NH),
Diethyl 5,9-dihydroxy-7H-benzo[a] cycloheptene-6,8-dicar-
boxylate (2).
To a mixture of 7.2 g (105 mmoles) of sodium ethoxide and 12
ml (60 mmoles) of diethylphtalate 1, 10 ml (53 mmoles) of
diethylglutarate was added. The mixture was heated at 130 °C for
3 hours and then cooled; ethanol formed was eliminated by using
a Dean Stark apparatus. The product was poured into 10 N aque-
ous solution of hydrochloric acid (0.5 L). The precipitate formed
was filtered and washed with water. The residue was crystallized
from ethanol and gives 10.49 g (33 mmoles) (55%) of the benzo-
2990-2930 (CH CH ), 1735-1730 (C=O ester), 1634 (C=O
2,
3
+
pyrimidine); IC-ms: m/z 407 (MH ).
Ethyl 2-[5-(-3Ethoxy-3-oxopropyl)-2-phenyl-1,6-dihydro-4-
pyrimidyl]benzoate (6).
A solution of 1 g (2.74 mmoles) of 4 in 20 ml of EtOH was
added to a solution of 3 ml of concentred sulfuric acid in 20 ml of
EtOH. The resulting solution was refluxed for 24 hours, cooled
and neutralised with 1 N aqueous sodium hydroxide. The precipi-
tate formed was isolated by filtration and washed with diethylox-
ide. Crystals were recrystallised from ethyl acetate to give 1.06 g
1
cycloheptene 2. H NMR (DMSO-d6): δ 1.32 (6H, t, J =7.1,
2xCH ester), δ 3.29 (2H, s, CH ), δ 4.28 (4H, q, J = 7.2, 2xCH
3
2
2
ester), δ 7.68 (2H, dd, J = 3.4, 5.9, H-2, H-3), δ 7.93 (2H, dd, J =
13
3.4, 5.9, H-1, H-4), δ 12.52 (2H, s, OH); C NMR (DMSO-d6):
1
δ 14.5 (CH ) δ 18.7 (C-7), δ 61.2 (CH ), δ 104.8 (C-6, C-8), δ
(2.52 mmoles) (92%) of compound 6; H NMR (DMSO-d6): δ
3 ,
2
128.1-130.11 (C-1, C-2, C-3, C-4), δ 134.2 (C-9a, C-4a), δ 166.5
(C-5, C-9), δ 171.7 (C=O); IR (KBr): 2990-2960 (CH , CH ),
0.98 (3H, t, J =7.1, CH ester), δ 1.11 (3H, t, J =7.1, CH ester), δ
3
3
2.43 (2H, br t, J = 7.0, CH β), δ 2.57 (2H, br t, J = 7.3, CH α), δ
2
3
2
2
+
1640-1610 (C=O ester); IC-ms: m/z 319 (MH ).
3.97 (2H, q, J = 7.1, CH ester), δ 4.04 (2H, q, J = 7.1, CH ester),
2
2
δ 7.48 (1H, m, H-3), δ 7.49 (1H, m, H-4''), δ 7.54 (2H, m, H-3'', H-
5''), δ 7.59 (1H, dt , J = 1.0-7.4, H-5), δ 7.69 (1H, dt, J = 0.95-7.4,
2-[5-(3-Ethoxy-3-oxopropyl)-6-oxo-2-phenyl-1,6-dihydro-4-
pyrimidinyl]benzoic Acid (4).
H-4), δ 7.92 (1H, d, J = 7.5, H-6), δ 8.02 (2H, d, J = 7.5, H-2'',
13
To a mixture of 1.085 g (6.9 mmoles) of benzamidine
hydrochloride hydrate and 1 g (3.14 mmoles) of diester 2 in 20 ml
of ethanol 38 mg (6.9 mmoles) of potassium hydroxide dissolved
in 20 ml of ethanol was added. The solution was refluxed for 24
hours. Ethanol was distilled under vacuum. The product was then
washed thoroughly with water and crystallized from methanol to
H-6''), δ 12.89 (1H,br s, NH); C NMR (DMSO-d ): δ 13.4 (CH
6
3
ester), δ 13.45 (CH ester), δ 22.1 (CH α), δ 31.5 (CH β), δ 59.8
3
2
2
(CH ester), δ 60.6 (CH ester), δ 120.6 (C-5), δ 127.4 (C-2'',
2
2
C-6''), δ 127.5 (C-1), δ 128.6 (C-3'', C-5''), δ 129.2 (C-3), δ 129.8
(C-5), δ 130.2 (C-6), δ 131.4 (C-2), δ 131.5 (C-4), δ 131.8 (C-4''),
δ 132.2 (C-1''), δ 138.9 (C-4'), δ 163.2 (C-2'), δ 166.6 (C-4), δ
1
give 670 mg (1.76 mmoles) (56%) of the pyrimidinone 4; H
172.0 (C=O); IR (KBr): 3470-3060 (NH), 2980 (CH , CH ), 1712
2
3
+
NMR (DMSO-d6): δ 1.10 (3H, t, J =7.1, CH ester), δ 2.49 (4H,
(C=O ester), 1638 (C=O pyrimidine); IC-ms: m/z 421 (MH ).
3
m, CH α,CH β), δ 3.96 (2H, q, J = 7.1, CH ester), δ 7.20 (1H, m,
H-3), δ 7.40 (1H, m, H-5), δ 7.45 (2H, m, H-3'', H-5''), δ 7.54 (1H,
2
2
2
2-[5-(2-Carboxyethyl)-6-oxo-2-phenyl-1,6-dihydro-4-pyrim-
idinyl]benzoic Acid (7).
t, J = 7.8, H-4''), δ 7.66 (1H, t, J = 7.4, H-4), δ 7.87 (1H, m, H-6),
13
δ 8.07 (2H, d, J = 7.00, H-2'', H-6'') δ 10.6 (1H, br s, NH);
C
A solution of 1 g (2.74 mmoles) of compound 4 in 30 ml of 1 N
methanolic potassium hydroxide was stirred at room temperature
for 12 hours. The resulting solution was poured into a 10 N aque-
ous solution of hydrochloric acid (5 ml). The precipitate formed
was isolated by filtration and crystallised from methanol-water
NMR (DMSO-d6): δ 14.0 (CH ester), δ 22.4 (CH α), δ 31.4
3
2
(CH β), δ 59.7 (CH ester), δ 119.5 (C-5'), δ 127.45 (C-3), δ
2
2
127.5 (C-2'',C-6''), δ 128.4 (C-5), δ 128.8 (C-3'', C-5''), δ 129.1 (C-
1), δ 129.4 (C-6), δ 131.0 (C-4''), δ 132.2 (C-4), δ 132.9 (C-1''), δ
138.1 (C-2), δ 138.8 (C-4'), δ 153.2 (C-2'), δ 165.9 (C-6'), δ 172.2
(C=O ester), δ 172.4 (C=O acid); IR (KBr): 3350-3150 (OH, NH),
1
(80-20) giving 795 mg (2.2 mmoles) (80%) of compound 7; H
NMR (DMSO-d6): δ 2.37 (2H, m, CH β), δ 2.45 (2H, m, CH α),
2
2
2980-2930 (CH , CH ), 1715 (C=O ester), 1660 (C=O acid), 1625
(C=O pyrimidine); IC-ms: m/z 393 (MH ).
δ 7.42 (1H, d, J = 7.4, H-3), δ 7.49 (2H, m, H-3'', H-5''), δ 7.54 (1H,
m, H-4''), δ 7.56 (1H, m, H-5), δ 7.65 (1H, br t, J = 7.3, H-4), δ 7.92
2
3
+
(1H, d, J = 7.5, H-6), 8.04 (2H, d, J = 7.3, H-2'', H-6''), δ 12.57 (4H,
Methyl 2-[5-(-3ethoxy-3-oxopropyl)-6-oxo-2-phenyl-1,6-dihydro-
4-pyrimidinyl] benzoate (5).
13
br s, NH+OH); C NMR (DMSO-d6): δ 22.4 (CH α), δ 31.5
2
(CH β), δ 120.6 (C-5), δ 127.6 (C-2'',C-6''), δ 128.6 (C-3'', C-5''), δ
2
A solution of 500 mg (1.37 mmoles) of 4 in 20 ml of MeOH
was added to a solution of 3 ml of concentrated sulfuric acid in 20
128.64 (C-3), δ 129.3 (C-4'), δ 129.9 (C-6), δ 130.9 (C-1), 131.4
(C-4''), δ 131.5 (C-4), δ 132.4 (C-1''), δ 139.2 (C-2), δ 153.6 (C-4'),

1452
N. Muller, R. Granet, L. Lepage, P. Krausz, and J.-P. Laval
Vol. 38
REFERENCES AND NOTES
δ 161.7 (C-2'), δ 163.4 (C-6'), δ 167.9 (C=O), δ 173.8 (C=O); IR
(KBr): 3400-3050 (OH, NH), 2980-2930 (CH ), 1715-1735 (C=O
2
+
acid), 1638 (C=O pyrimidine); IC-ms: m/z 365 (MH ).
[1] J. McLean, V. Peesapati, andG. R. Proctor, J. Chem. Soc.,
Perkin Trans. I, 98 (1979).
[2] G. Cignarella, D. Barlocco, G. A. Pinna, M. Loriga, M. M.
Curzu, O. Tofanetti, M. Germini, P. Gazzulani and E. Cavalletti, J.
Med. Chem., 32, 2277 (1989).
[3] K. Sasaki, Y. Arimoto, H. Ohtomo, T. Nakayama and T.
Hirota, J. Heterocyclic Chem., 30, 989 (1993).
[4] P. C. Ting, J. F. Lee, D. M. Solomon, S. R. Smith, C. A.
Terminelli, J. P. Jakway and D. N. Zambas, Bioorg. Med. Chem. Lett.,
5, 2749 (1995).
[5] D. J. Brown, R. F. Evans, W. B. Cowden, and M. D. Fenn,
The Pyrimidines, ed, E. C. Taylor, Ed, John Wiley & Sons, New York
(1994).
[6] E. C. Taylor, P. Zhou and C. M. Tice, Tetrahedron Lett.,
38, 4343 (1997).
[7] R. Nimura, N. Ishida, and K. Imafuku, J. Heterocyclic
Chem., 29, 795 (1992).
[8] J. El Youssoufi, R. Granet, P. Krausz, and L. Lepage, Bull.
Soc. Chim. Fr., 134, 571 (1997).
[9] N. Muller, J. El Youssoufi, L. Lepage, R. Benhaddou, R.
Granet, P. Krausz and M. Guilloton, C. R. Acad. Sci. Paris, t. 323,
série IIb, 781 (1996).
Ethyl 7-hydroxy-4-oxo-2-phenyl-4,5-dihydro-3H-benzo[6-7]-
cyclohepta[1,2-d]pyrimidine-6-carboxylate (3).
A solution of 1 g (2.38 mmoles) of 6 in 15 ml of dry toluene
was added dropwise to 970 mg (15 mmoles) dry powdered
sodium ethoxide. The mixture was heated at 120 °C for 4 hours
(ethanol formed was eliminated by using a Dean Stark appara-
tus). After addition of water, the resulting mixture was acidified
with 10 N acetic acid and extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous
sodium sulfate, and evaporated to afford crystals which were
recrystallised from propanol to give 275 mg (0.74 mmole) (31%)
1
of compound 3; H NMR (DMSO-d6): δ 1.33 (3H, t, J =7.0, CH
3
ester), δ 3.32 (2H, br s, CH ), δ 4.32 (2H, q, J = 7.0, CH ester), δ
2
2
7.53 (1H, m, H-11), δ 7.55 (2H, m, H-3',H-5'), δ 7.68 (1H, m,
H-4'), δ 7.73 (1H, br t, J = 6.6, H-9), δ 7.95 (1H, br d, J = 7.2,
H-10), δ 8.16 (2H, d, J = 7.3, H-2', H-6'), δ 8.23 (1H, d, J = 7.4,
13
H-8) δ 12.70 (1H, br s, NH), δ 12.88 (1H, br s, OH); C NMR
(DMSO-d6): δ 13.8 (CH ester), δ 17.2 (C-5), δ 60.8 (CH ester),
3
2
δ 102.7 (C-6), δ 127.2 (C-4a), δ 127.4 (C-2', C-6'), δ 128.3 (C-3',
C-5'), δ 129.8-129.3 (C-8, C-11), δ 131.0 (C-9, C-10), δ 131.3
(C-1'), δ 132.1 (C-4'), δ 133.1 (C-8a), δ 136.7 (C-11a), δ 154.3
(C-1a), δ 161.1 (C-2), δ 166.0 (C-7), δ 168.4 (C=O ester), δ 170.6
[10] J. El Youssoufi and L. Lepage, Bull. Soc. Chim. Fr., 131,
48 (1994).
[11] W. Dieckmann, Chem. Ber., 32, 2227 (1899).
[12] N. R. El-Rayyes, and H. M. Ramadan, J. Heterocyclic
Chem., 24, 1141 (1987).
(C-4); IR (KBr): 3400-3200 (NH, OH), 2980 (CH , CH ), 1710
2
3
+
(C=O ester), 1634 (C=O pyrimidine); IC-ms: m/z 375 (MH ).
[13] G. M. Sheldrick, SHELXS-97 Program for Crystal
Structure Solution (1997). University of Göttingen, Germany.
[14] G. M. Sheldrick, SHELXL-97 Program for Crystal
Structure Refinement (1997) ibid.
Acknowledgments.
The authors are greatly indebted to Regional Council of
Limousin for financial support.