One-step synthesis of aminopyrimidines from 5-oxo-4H-benzopyrans

Article abstract of DOI:10.1002/jhet.5570410406

Novel 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitriles have been prepared in one step procedure from the readily available 4-aryl-2-amino-3-cyano-5,6,7,8- tetrahydro-7,7-dimethyl-5-oxo-4H-benzopyrans. The mass spectroscopy study under EI conditions shows

Full text of DOI:10.1002/jhet.5570410406

Jul-Aug 2004
509
One-Step Synthesis of Aminopyrimidines from
5-Oxo-4H-Benzopyrans
Esperanza Salfrán, Margarita Suárez,a* Yamila Verdecia,a Amaury Alvarez,a
Estael Ochoa,a Roberto Martínez-Alvarez,b Carlos Seoaneb* and Nazario Martínb*
[a]
Laboratorio de Síntesis Orgánica, Facultad de Química.
Universidad de La Habana,
10400 Ciudad Habana, Cuba
Departamento de Química Orgánica. Facultad de Química.
[b]
Universidad Complutense,
E-28040 Madrid, Spain
Received November 7, 2003
Novel 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitriles have been prepared in one step procedure from
the readily available 4-aryl-2-amino-3-cyano-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-benzopyrans. The
mass spectroscopy study under EI conditions shows molecular peaks with high intensity corresponding to
the loss of benzonitrile from the C2 position of the pyrimidine ring. Semiempirical (AM1 and PM3) and ab
initio HF/6-31G* calculations reveal a favored distorted geometry where the three rings are not in the same
plane.
J. Heterocyclic Chem., 41, 509 (2004).
Introduction.
hydrochloride has been previously reported [21,22].
Although very early we have reported the synthesis of
aminocyano substituted pyrimidines from the correspond-
ing 4H-pyrans [23], the procedure now reported is, to the
best of our knowledge, a new approach to the synthesis of
a pyrimidine ring with a different substitution pattern. The
pyrimidine ring is a skeleton of particular interest provided
that it is present in many compounds exhibiting biological
and pharmaceutical activity [24]. The present methodol-
ogy allows preparing new pyrimidine derivatives in two
steps from acyclic readily available starting materials
involving: i) formation of 5-oxo-4H-benzopyrans and ii)
further ring transformation to the pyrimidine system by
reaction with benzamidine.
The synthesis of 1,4-dihydropyridines (1,4-DHPs) 1 has
attracted much attention along the last three decades due
the calcium modulator effect they display [1]. It is well-
established that the pharmacological activity of this family
of compounds is determined by their structural features [2-
4], and major efforts have been devoted to the preparation
of novel derivatives and to the definition of the structure-
activity relationship based on crystallographic studies.
Related structures with more pharmacological interests [5-
8] and 1,4-DHP sub-structures fused to one carbocyclic
ring as 2 [9] were also reported and evaluated.
The 4H-pyran ring 3 can be considered as the oxa-ana-
logue of the biologically active 1,4-dihydropyridine sys-
tem. Therefore, we have reported the synthesis of a wide
variety of 4H-pyran derivatives [10-12] as well as their
study by mass spectrometry [13,14] and NMR spec-
troscopy [15,16]. In addition, the X-ray crystal structure of
some monocyclic 4H-pyran derivatives showed that their
geometrical features were similar to those found for the
biologically active 1,4-DHPs [17-19].
Chart 1
In order to determine the influence of the presence of a
fused carbocyclic ring on the structure of the 4H-pyran
ring, we reported an X-ray crystallographic study of sub-
stituted tetrahydrobenzo-4H-pyrans 4 [20].
As a part of our studies aimed at determining the reactiv-
ity of 2-amino-3-cyano-5-oxo-4H-benzopyran derivatives
(4), in this paper we report on the reaction of these com-
pounds with benzamidine. The reaction yielded the respec-
tive 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitrile
derivatives.
The synthesis of substituted aryl pyrimidines from
α-substituted cinnamonitrile derivatives and benzamidine
Some representative 1,4-DHPs and 4H-pyrans.

510
E. Salfrán, M. Suárez, Y. Verdecia, A. Alvarez, E. Ochoa,
R. Martínez-Alvarez, C. Seoane and N. Martín
Vol. 41
Discussion.
164 ppm) and C4a (δ= 110-118 ppm) in compounds 4 a - g,
clearly showing the presence of a push-pull effect which is
responsible for the δ values found for these olefinic carbon
atoms. This finding has been previously observed in other
related molecules [25-28]. All signals were unambiguously
2-Amino-4-aryl-3-cyano-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydrobenzo-4H pyrans (4 a - g) were synthesized by
following the general procedure from dimedone (5) and
the corresponding arylidenmalononitrile (6a-g) by an 6-
exo-dig cyclization of δ-oxonitriles firstly reported by our
group [11,20] (See Scheme 1).
.
assigned by DEPT 90° and 135° and HMQC experiments
A further support to the spectroscopic assignment was
Scheme 1
Compounds 4a-g were obtained as crystalline solids after
recrystallization from ethanol and their structures were
confirmed by spectroscopic methods (see Experimental
part). Thus, compounds 4a-g show in the FTIR spectra the
bands corresponding to the C≡N and C=O groups at 2220
based on the HMBC, NOE and COSY experiments (see
Experimental section).
Further reaction of the corresponding 5-oxobenzopyran
(4a-g) with an excess of benzamidine (7), prepared from
benzamidine hydrochloride immediately before its use by
treatment under basic conditions, led to the respective 4-
amino-6-aryl-2-phenylpyrimidine-5-carbonitrile (8a-g)
(See Scheme 1).
The formation of compounds 8a-g is not straightforward
and can be accounted for by assuming the reaction steps
depicted in Scheme 2. A nucleophilic attack by the benza-
midine to the C2 of the benzopyran ring in 4a-g promotes
a ring opening, leading to intermediate 9. Elimination of a
1
and 1680 cm-1, respectively. The H nmr spectra of com-
pounds 4 show the proton on C4 as a singlet at δ=4.6–4.0
ppm. The two protons on C6 appear as an AB system with
a coupling constant of J = 16 Hz, indicating that these two
geminal protons are not equivalents. The protons on C8
appear as a broad singlet at δ=2.4–2.5 ppm. The 13C nmr
spectra show two olefinic double bonds between C2
(δ=156-159 ppm) and C3 (δ=57-68 ppm), and C8a (δ=159-
Scheme 2

Jul-Aug 2004
One-Step Synthesis of Aminopyrimidines from 5-Oxo-4H-Benzopyrans
511
dimedone molecule generates 10, the cyclization of which
affords the final products 7a-g, that are obtained as stable
crystalline solids in good yields (69 to 79%) after a simple
work-up.
ions [29-32]; however, for these compounds these frag-
ments were not detected. Cleavage of the N1-C2 bond
causes no change in mass, producing only a distonic radi-
cal ion (11). Subsequent cleavage of the N3-C4 with con-
comitant elimination of benzonitrile yields the most char-
acteristic fragment of these compounds, the corresponding
[M-C6H5CN]+ (12) which is stabilized by the effect of the
amino group.
It is important to note that the homologous elimination
of 4-substituted benzonitrile was not observed. This differ-
ence can be explained because the cyano group is not able
to stabilize the corresponding odd-electron ion. On the
other hand, no fragments from a retro Diels-Alder reaction
were detected. The stability of the possible diazodiene
formed in the RDA process is too low and the reaction
does not take place. This fragmentation pattern is similar
to that previously found in the mass spectra of cycloalkane
fused pyrimidines [33].
The FTIR spectra of compounds 8a-g show the NH2
group as two bands at around 3470 and 3380 cm-1, the
conjugated cyano group at ca. 2200 cm-1 and several
bands in the aromatic region. The 1H nmr spectra show the
NH2 protons as a singlet at δ=7.9–7.7 ppm and the
expected signals corresponding to the protons of the
monosubstituted and disubstituted benzene ring. The 13C
nmr spectra of these compounds (8a-g) exhibit signals cor-
responding to the cyano and aromatic regions (see Table
1). In order to assign unequivocally the signals corre-
sponding to the heterocyclic ring, we used 1D and 2D
techniques: DEPT(135°), HMQC and HMBC. The cyano
group appears at δ=116–18 ppm. As shown in Table 1, the
signals corresponding to the heterocyclic system (C2, C4,
C5, C6) are relatively insensitive to the nature of the sub-
stituent on the aryl ring. The rest of the signals are in
agreement with the nature of the aromatic carbon atoms
(see Experimental part).
In order to gain a better understanding of the novel com-
pounds, we have calculated their structures at ab initio and
semiempirical levels.
Scheme 3
Table 1
13
C nmr Spectroscopic Data of Compounds 8a-g
Compound
C6
C4
C2
CN
C5
8a
8b
8c
8d
8e
8f
168.0
167.4
167.2
167.6
168.0
168.1
168.6
164.5
164.9
164.8
165.9
165.5
165.3
166.7
163.9
164.2
164.0
164.4
164.7
164.7
164.8
116.2
117.2
116.7
118.3
117.6
118.2
118.5
84.3
84.3
83.3
82.5
84.2
83.4
82.5
8g
In order to establish the fragmentation pathway of com-
pounds 8a-g, we have recorded the mass spectra generated
under EI conditions. The principal peaks are listed in Table 2.
Table 2
Significant Peaks in the Mass Spectra (EI) of Pyrimidines 8a-g
.+
Compound
M
M – C H CN (12)
6 5
8a (X = H)
8b (X = 2-CH )
8c (X = 4-OCH
8d (X = 4-N(CH ) )
272 (100)
286 (100)
302 (100)
315 (100)
378 (15)
169 (68)
183 (55)
199 (63)
212 (15)
3
3
3 2
Mass spectrometry fragmentation pattern of pyrimidines 8a-g.
+
8e (X = 4-OCH C H )
91 (C H , 100)
2
6
5
7 7
8f (X = 4-NHCOCH
329 (100)
317 (100)
Not detected
214 (46)
3
8g (X 4-NO )
2
In previous works we have widely used theoretical calcu-
lations for determining the conformational features of 1,4-
DHPs and 3,4-dihydropyridone derivatives [34-36] and we
have proved that ab initio and semiempirical calculations
(at AM1 level) reproduce adequately the geometry of this
type of compounds.
The molecular peaks of pyrimidines 8a-g were detected
at high intensity (See Scheme 3) with exception of com-
pound 8e, where the base peak was the tropilium ion (m/z
= 91). It is known that pyrimidine forms easily [M-H]+

512
E. Salfrán, M. Suárez, Y. Verdecia, A. Alvarez, E. Ochoa,
R. Martínez-Alvarez, C. Seoane and N. Martín
Vol. 41
In the case of model compound 8 a, calculations were
Table 3 shows the most relevant bond distances, valence
angles and dihedral angles predicted for the minimum
energy conformation of 8a calculated by AM1, PM3 and
HF/6-31G* methods.
performed using both semiempirical AM1 and PM3 meth-
ods and ab initio HF/6-31G* method for comparison sake.
Figure 1 shows the most stable conformation of 8a calcu-
lated by semiempirical AM1 and HF/6-31G* ab initio
method.
Theoretical calculations show that the system formed by
these three aromatic rings is not fully planar, due to the
steric interaction of phenyl rings with the pyrimidine ring.
Torsion angle C2''-C1''-C2-N3 is -39.0º, -26.8º and 3.4º by
mean of AM1, PM3 and ab initio HF/6-31G* methods,
respectively; while C2'-C1'-C4-N3 is 50.2º, 89.7º, 38.5º by
AM1, PM3 and HF/6-31G*, respectively. Taking ab initio
HF/6-31G* results as a reference, phenyl ring at C2 is
nearly planar with respect to the pyrimidine ring, while
phenyl group at C6 shows a clear loss of planarity and
hence, the loss of electronic delocalization between both
aromatic rings. The high deviation from coplanarity of the
phenyl at C6 compared to coplanarity of the phenyl at C2
is due to the presence of the cyano group on C5 position.
AM1 and PM3 methods overestimate the steric repulsion
between both the phenyl and the pyrimidine rings.
Nevertheless, AM1 method appears to be slightly closer to
the HF/6-31G* results than PM3.
a
b
Figure 1. Most stable conformation for compound 8a calculated by (a)
AM1 and (b) HF/6-31G* showing the atomic numbering scheme.
The bond angle H-N4-H for amino group is 119.0º and
119.3º for AM1 and ab initio HF/6-31G* optimized
geometries. This fact indicates an sp2 hybridization, due to
the delocalization of the nitrogen lone-pair electrons
through the aromatic pyrimidine ring. PM3 predict and sp3
hybridization for the amine nitrogen since the bond angle
H-N4-H is 113.8º in compound 8a. In this case, PM3 do
not reproduce the possible delocalization of the nitrogen
lone-pair electrons through the aromatic ring, which can be
confirmed by the longer C4-N4 bond distance predicted
for PM3 (1.401 Å), while AM1 and ab initio HF/6-31G*
methods gave 1.373 and 1.339 Å, respectively. For this
particular bond distance, even when both semiempirical
methods seems to overestimate the possible value, AM1
method appears to give more reliable values than PM3.
The remaining synthesized compounds 8b-g were then
studied by using the AM1 semiempirical method which
shows more reliable results and the calculations reveal for
compounds 8b-g similar results. The most relevant geo-
metrical data calculated for these compounds (8 b - g) are
collected in Table 4.
Table 3
Heat of Fortmation and Most Relevant Bond Distances,
Bond Angles and Dihedral Angles for Compound 8a;
Bond Distances are given in Å and Angles in Degrees
AM1
PM3
HF/6-31G*
-868.58669 [b]
°
ΔH
133.0 [a]
121.9 [a]
f
Bond distances
C5-CN
C4-N4
C2-N3
C2-N1
C6-C1'
C2-C1''
1.411
1.373
1.361
1.374
1.476
1.489
1.417
1.401
1.360
1.370
1476
1.432
1.339
1.320
1.325
1.489
1.487
1.474
Bond angles
N1-C2-N3
C2-N1-C6
C4-N3-C2
C4-C5-CN
C5-C4-N4
N1-C6-C1'
N3-C2-C1''
H-N4-H
126.2
117.1
117.0
120.4
120.6
118.2
116.9
119.0
121.9
119.9
119.3
121.0
123.7
117.0
119.1
113.8
125.7
118.3
117.6
118.4
121.8
116.0
117.3
119.3
Conclusions.
Dihedral angles
In summary, we have carried out the one-step synthesis
and characterization of substituted 4-amino-6-aryl-2-
phenylpyrimidine-5-carbonitriles from the readily avail-
able 2-amino-4-aryl-3-cyano-5,6,7,8-tetrahydro-7,7-
dimethyl-5-oxo-4H-benzopyrans. The structure of the
compounds have been calculated by theoretical methods at
the semiempirical and ab initio levels. Structural charac-
terization has been completed by means of the fragmenta-
tion pattern of these heterocyclic compounds by mass
spectrometric study under EI conditions.
N3-C2-N1-C6
C2-N1-C6-C5
N1-C6-C5-C4
C6-C5-C4-N3
C5-C4-N3-C2
C4-N3-C2-N1
C2'-C1'-C6-N1
C2''-C1''-C2-N3
N3-C4-C5-CN
C6-C5-C4-N4
0.1
-0.6
1.0
-0.9
0.5
-0.1
50.2
-39.0
178.1
177.7
-0.1
0.3
0.3
-1.2
1.4
-0.7
89.7
-26.8
178.6
173.8
-0.2
-1.3
1.7
-0.7
-0.7
1.2
38.5
3.4
176.7
179.4
[a] Energy in kcal/mol; [b] Electronic energy in Hartree.

Jul-Aug 2004
One-Step Synthesis of Aminopyrimidines from 5-Oxo-4H-Benzopyrans
513
Table
4
Synthesis of 3-Arylidenemalononitriles (6a-g).
Most Relevant Bond Distances, Bond Angles Dihedral Angles for
Compound 8b-g Calculated by AM1 Semiempirical Method; Bond
Distances are Given in Å and Angles in Degrees
These compounds were obtained by following the method pre-
viously reported in the literature [43].
General Procedure for Synthesis of 2-Amino-4-aryl-3-cyano-
5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-benzopyrans (4a-g).
8b
127.0
8c
94.6
8d
141.1
8e
123.7
8f
96.0
8g
137.4
°
ΔH [a]
f
A mixture of dimedone (5,5-dimethyl-1,3-cyclohexanedione)
(40 mmol), the appropriate arylidenemalononitrile (40 mmol)
and catalytic amount of piperidine in ethanol (40 mL) was stirred
at room temperature. After 1 h, a precipitate was formed. The
solid was collected by filtration. Further purification was accom-
plished by recrystallization from ethanol.
Bond distances
C5-CN
C4-N4
C2-N3
C2-N1
C6-C1'
C2-C1''
1.410 1.410
1.41
1.411
1.371
1.361
1.374
1.474
1.489
1.411
1.371
1.361
1.374
1.475
1.489
1.411
1.369
1.360
1.376
1.479
1.488
1.373 1.371 1.372
1.361 1.361 1.361
1.375 1.373 1.373
1.479 1.474 1.472
1.489 1.489 1.489
2-Amino-3-cyano-4-phenyl-5,6,7,8-tetrahydro-7,7-dimethyl-5-
oxo-4H-benzopyran (4a).
Bond angles
This compound was obtained in 78 % yield, mp 224-225°; ir
(KBr): 3396 and 3325 (NH ), 2196 (CN), 1679 (C=O), 1660 and
N1-C2-N3
C2-N1-C6
C4-N3-C2
C4-C5-CN
C5-C4-N4
N1-C6-C1''
N3-C2-C1''
H-N4-H
126.2 126.2 126.3
117.0 117.1 117.2
117.0 117.0 116.8
120.6 120.3 120.2 120.27 120.4
120.6 120.6 120.6 120.64 120.7
118.6 118.2 118.2
117.0 116.9 116.9
119.2 119.7 119.6
126.2
117.1
116.9
126.2
117.1
116.9
126.1
117.0
117.1
120.5
120.7
117.9
117.1
119.6
2
1604 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 7.29-7.09
-1
1
6
(m, 5H, H2', H3', H4', H5', H6'), 6.99 (s, 2H, NH ), 4.14 (s, 1H,
2
H4), 2.38 (br s, 2H, H8), 2.24 (d, 1H, H6a, J=16.1 Hz), 2.14 (d,
118.1
116.9
119.7
118.2
117.0
119.7
13
1H, H6b, J=16.1 Hz), 1.01 (s, 3H, CH ), 0.92 (s, 3H, CH );
C
nmr (dimethylsulfoxide-d ): δ 195.7 (C5), 162.5 (C8a), 158.6
3
3
6
(C2), 144.8 (C1'), 128.4 (C2', C6'), 127.2 (C3', C5'), 126.6 (C4'),
119.8 (CN), 112.8 (C4a), 58.2 (C3), 50.1 (C6), 9.6 (C8), 5.6 (C4),
+
31.8 (C7), 28.5 (CH ), 26.8 (CH ); ms: m/z 294 (M , 66), 293
Dihedral angles
N3-C2-N1-C6
C2-N1-C6-C5
N1-C6-C5-C4
C6-C5-C4-N3
C5-C4-N3-C2
C4-N3-C2-N1
C2'-C1'-C6-N1
C2''-C1''-C2-N3 -38.2
N3-C4-C5-CN
C6-C5-C4-N4
0.0
-0.1
0.4
-0.3
-0.5
1.1
-0.3
-0.8
1.1
-0.3
-0.5
1.1
-0.8
0.0
0.3
0.6
-0.9
0.5
0.0
-0.5
0.6
-0.2
-0.3
0.4
3
([M –H] , 25), 217 ([M –C H ] , 100), 161 (5).
3
+
+
+
+
6
5
Anal. Calcd. C H N O (294.35): C, 73.45; H, 6.16; N, 9.52.
18 18 2 2
Found: C, 73.53; H, 6.31; N, 9.47.
-0.7
0.6
-0.2
64.7
-0.8
0.0
0.6
47.9
39.1
-0.4
-0.5
1.0
46.8
39.3
0.2
2 - A m i n o - 3 - c y a n o - 5 , 6 , 7 , 8 - t e t r a h y d r o - 7 , 7 - d i m e t h y l - 4 - ( 2 ' -
methylphenyl)-5-oxo-4H-benzopyran (4b).
0.6
-0.6
-48.1
-39.2
-178.2 178.8
-179.5 179.9
47.9
39.1
178.0
178.9
51.4
38.7
This compound was obtained in 88 % yield, mp 205-206°; ir
(KBr): 3400 and 3330 (NH ), 2194 (CN), 1679 (C=O), 1660 and
178.8 177.9 178.1
178.1 178.8 179.8
2
1620 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 7.16-7.05
-1
1
6
(m, 3H, H4', H5', H6'), 6.97 (d, 1H, H3' J=8.1 Hz), 6.93 (s, 2H,
NH ), 4.50 (s, 1H, H4), 2.56 (s, 3H, CH ), 2.44 (br s, 2H, H8),
[a] Energy in kcal/mol.
2
3
2.21 (d, 1H, H6a, J=16.3 Hz), 2.14 (d, 1H, H6b, J=16.3 Hz), 1.05
EXPERIMENTAL
13
(s, 3H, CH ), 0.94 (s, 3H, CH ); C nmr (dimethylsulfoxide-d ):
3
δ 195.7 (C5), 162.4 (C8a), 158.2 (C2), 143.5 (C1'), 134.7 (C2'),
3
6
Melting points were determined in a capillary tube in an
Electrothermal C14500 apparatus and are uncorrected. The NMR
spectra were recorded on a Bruker DPX300 spectrometer (300
129.8 (C3'), 127.8 (C6'), 127.2 (C4'), 126.7 (C5'), 119.7 (CN),
113.4 (C4a), 58.2 (C3), 49.9 (C6), 39.4 (C8), 32.7 (C4), 31.8
+
(C7), 28.3 (CH ), 26.7 (CH ), 20.9 (CH ); ms: m/z 308 (M , 90),
3
3
293 ([M –CH ] 30), 217 ([M –C H -CH ] , 80); 161 (20).
3
1
13
+
+
+
+
MHz- H and 75.47 MHz- C). Chemical shifts are given as δ
values against tetramethylsilane as the internal standard and J
values are given in Hz. The IR spectra were measured with a
Shimadzu FTIR 8300 instrument as potassium bromide pellets.
Mass spectra were obtained with a Hewlett Packard 5989A spec-
trometer. Microanalyses were performed in a Perkin Elmer 2400
CHN by the Servicio de Microanálisis of Universidad
Complutense de Madrid. The reactions were monitored by TLC
3
Anal. Calcd. C
Found: C, 74.36; H, 6.92; N, 9.43.
6
4
3
H N O (308.38): C, 74.00; H, 6.54; N, 9.08.
19 20 2 2
2 - A m i n o - 3 - c y a n o - 5 , 6 , 7 , 8 - t e t r a h y d r o - 7 , 7 - d i m e t h y l - 4 - ( 4 ' -
methoxyphenyl)-5-oxo-4H-benzopyran (4c).
This compound was obtained in 82 % yield, mp 207-208°; ir
(KBr): 3398 and 3317 (NH ), 2187 (CN), 1683 (C=O), 1654 and
2
1606 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 7.03 (d, 2H,
-1 1
performed on silica-gel plates (Merck 60F ) and using
2 5 0
6
H2', H6', J=8.6 Hz), 6.92 (s, 2H, NH ), 6.82 (d, 2H, H3', H5',
hexane:ethyl acetate (8:2) as eluent. Commercially available
starting materials and reagents were purchased from commercial
sources (BDH and Fluka) and were used without further purifica-
tion. Semiempirical calculations (AM1 [37] and PM3 [38]) were
carried out using the MOPAC 6.0 molecular orbitals set [39].
Previously, the molecular geometry was optimized by means of
the Allinger´s Molecular Mechanics [40] with PCMODEL pro-
gram [41]. Ab initio calculations were carried out with Gaussian
98 program [42]. Calculations were performed on an IBM-
RS6000.
2
J=8.6 Hz), 4.10 (s, 1H, H4), 3.86 (s, 3H, OCH ), 2.44 (br s, 2H,
3
H8), 2.23 (d, 1H, H6a, J=16.3 Hz), 2.06 (d, 1H, H6b, J=16.3 Hz),
13
1.01 (s, 3H, CH ), 0.93 (s, 3H, CH ); C nmr (dimethylsulfox-
3
ide-d ): δ 195.7 (C5), 162.2 (C8a), 158.4 (C4'), 157.9 (C2), 136.8
3
6
(C1'), 128.2 (C2', C6'), 119.8 (CN), 113.7 (C4a), 113.0 (C3', C5'),
58.7 (C3), 55.0 (OCH ), 50.0 (C6), 40.7 (C8), 34.3 (C4), 32.8
+
3
(C7), 28.4 (CH ), 26.8 (CH ); ms: m/z 324 (M , 100), 293
3
3
([M –OCH ] ,43), 217 ([M –C H -OCH ], 73), 161 (25).
+
+
+
3
Anal. Calcd. C
6
4
3
H N O (324.38): C, 70.35; H, 6.21; N, 8.64.
19 20 2 3

514
E. Salfrán, M. Suárez, Y. Verdecia, A. Alvarez, E. Ochoa,
R. Martínez-Alvarez, C. Seoane and N. Martín
Vol. 41
-1
1637 (C=C), 1525 and 1350 (NO ) cm ; H nmr (dimethylsul-
1
Found: C, 70.76; H, 6.52; N, 8.43.
2
foxide-d ): δ 8.16 (d, 2H, H3', H5', J=8.0 Hz), 7.43 (d, 2H, H2',
6
H6', J=8.0 Hz), 7.19 (s, 2H, NH ), 4.35 (s, 1H, H4), 2.52 (br s,
2-Amino-3-cyano-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4'-N,N-
dimethylaminophenyl)-5-oxo-4H-benzopyran (4d).
2
2H, H8), 2.25 (d, 1H, H6a, J=16.0 Hz), 2.08 (d, 1H, H6b, J=16.0
13
Hz), 1.02 (s, 3H, CH ), 0.94 (s, 3H, CH ); C nmr (dimethylsul-
This compound was obtained in 83 % yield, mp 216-217°; ir
(KBr): 3388 and 3320 (NH ), 2197 (CN), 1685 (C=O), 1650 and
3
foxide-d ): δ 195.7 (CO), 163.2 (C8a), 158.6 (C2), 152.3 (C1'),
3
2
1604 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 6.93 (d, 2H,
6
146.3 (C4'), 128.7 (C3', C5'), 123.7 (C2', C6'), 119.4 (CN), 111.7
(C4a), 57.0 (C3), 49.7 (C6), 39.5 (C8), 35.5 (C4), 31.8 (C7), 28.3
-1 1
6
H2', H6', J=8.5 Hz), 6.87 (s, 2H, NH ), 6.62 (d, 2H, H3', H5',
2
J=8.5 Hz), 4.04 (s, 1H, H4), 2.52 (d, 1H, H8a, J=18.0 Hz), 2.42
(d, 1H, H8b, J=18.0 Hz), 2.83 (s, 6H, 2CH ), 2.23 (d, 1H, H6a,
+
(CH ), 27.9 (CH ); ms: m/z 339 (M , 65), 293 ([M -NO ] , 18),
+
+
3
3
217 ([M –C H -NO ] , 100), 161 (25).
2
+
+
3
J=16.1 Hz), 2.06 (d, 1H, H6b, J=16.1 Hz), 1.04 (s, 3H, CH ),
13
6
Anal. Calcd. C
4
2
H
N O (339.35): C, 63.71; H, 5.05; N,
3
0.94 (s, 3H, CH ); C nmr (dimethylsulfoxide-d ): δ 195.7
18 17 3 4
12.38. Found: C, 63.86; H, 5.33; N, 12.51.
3
6
(CO), 161.9 (C8a), 158.4 (C2), 149.3 (C4'), 132.6 (C1'), 127.8
(C2', C6'), 120.0 (CN), 113.3 (C4a), 112.4 (C3', C5'), 59.0 (C3),
50.1 (C6), 43.1 (CH ), 42.9 (CH ), 40.0 (C8), 34.3 (C4), 31.8
General Procedure of Synthesis of 4-Amino-6-aryl-2-
phenylpyrimidine-5-carbonitrile (8a-g).
3
3
+
(C7), 28.6 (CH ), 26.8 (CH ); ms: m/z 337 (M , 100), 293
3
A solution of 144 mg (0.0063 at-g) sodium metallic in 20 mL
dry ethanol was cooled with ice-water and benzamidine
hydrochloride was added 0.889 g (5.7 mmol) with stirring during
15 minutes. The sodium chloride that precipitated was filtered
off, and to the resulting solution 1.9 mmol of the corresponding
tetrahydro-4H-benzopyran was added. The mixture was refluxed
during 72 hours and the solid was collected by filtration. Further
purification was accomplished by recrystallization from ethanol.
3
+
([M –N(CH ) ] , 22), 217 ([M –C H -N(CH ) ] , 10), 161 (3).
+
+
+
3 2
Anal. Calcd. C
12.45. Found: C, 71.46; H, 6.52; N, 12.53.
6
4
3 2
H N O (337.42): C, 71.19; H, 6.87; N,
20 23 3 2
2-Amino-4-(4'-benzyloxyphenyl)-3-cyano-5,6,7,8-tetrahydro-
7,7-dimethyl-5-oxo-4H-benzopyran (4e).
This compound was obtained in 86 % yield, mp 224-226°; ir
(KBr): 3380 and 3310 (NH ), 2189 (CN), 1688 (C=O), 1660 and
2
1610 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 7.45-7.33
4-Amino-2,6-diphenylpyrimidine-5-carbonitrile (8a) [21].
-1
1
6
(m, 5H, H2", H3", H4", H5", H6"), 7.05 (d, 2H, H3', H5', J=8.7
Hz), 6.95 (s, 2H, NH ), 6.91 (d, 2H, H2', H6', J=8.7 Hz), 4.11 (s,
This compound was obtained in 79 % yield, mp 158-159°; ir
(KBr) 3470 and 3380 (N-H), 2202 (CN), 1660 and 1580 (C=C)
2
1H, H4), 3.32 (s, 2H, CH ), 2.46 (br s, 2H, H8), 2.24 (d, 1H, H6a,
-1
cm ; H nmr (dimethylsulfoxide-d ): δ 8.31(m, 2H, H2" H6"),
1
2
J=16.1 Hz), 2.08 (d, 1H, H6b, J=16.1 Hz), 1.02 (s, 3H, CH ),
13
6
7.92 (s, 2H, NH ), 7.84 (m, 2H, H2', H6'), 7.45 (m, 6H, H3', H4',
13
3
0.93 (s, 3H, CH ); C nmr (dimethylsulfoxide-d ): δ 195.4 (C5),
2
H5', H3", H4", H5"); C nmr (dimethylsulfoxide-d ): δ 168.0
3
6
6
(C6), 164.5 (C4), 163.9 (C2), 136.4 (C1''), 131.6 (C), 130.9(C),
128.6 (3C), 128.5 (3C), 128.4 (2C), 128.2 (C1'), 116.2 (CN), 84.3
(C5); ms: m/z 272 (100), 271 (72), 169 (76), 142 (15), 104 (27),
77 (26).
Anal. Calcd. C H N (272.31): C, 74.98; H, 4.44; N, 20.57.
17 12 4
Found: C, 74.88; H, 4.21; N, 20.32.
162.0 (C8a), 158.3 (C2), 156.9 (C4'), 137.0 (C1'), 136.9 (C1"),
128.2 (C3', C5'), 128.1 (C2", C6"), 127.6 (C3", C5"), 127.5 (C2',
C6'), 119.6 (CN), 114.4 (1C), 112.8 (C4a), 69.1 (CH ), 58.4 (C3),
2
49.9 (C6), 39.6 (C8), 34.7 (C4), 31.6 (C7), 28.2 (CH ), 26.7
+
3
(CH ); ms: m/z 400 (M , 20), 293 ([M –OCH C H ] 4), 217
+
+
3
2
([M –C H - OCH C H ] , 10), 161 (5), 91 (100).
6
5
,
+
+
6
4
Anal. Calcd. C
2 6 5
H N O (400.48): C, 79.98; H, 6.04; N, 7.00.
25 24 2 3
4-Amino-6-(2´-methylphenyl)-2-phenylpyrimidine-5-carboni-
trile (8b).
Found: C, 79.48; H, 6.41; N, 7.43.
4-(4'-Acetamidophenyl)-2-amino-3-cyano-5,6,7,8-tetrahydro-
7,7-dimethyl-5-oxo-4H-benzopyran (4f).
This compound was obtained in 75 % yield, mp 201-202°; ir
(KBr) 3450 and 3340 (N-H), 2200 (CN), 1650 and 1580 (C=C)
-1
cm ; H nmr (dimethylsulfoxide-d ): δ 8.28-8.05 (m, 2H, H2",
1
This compound was obtained in 86 % yield, mp 250-251°; ir
(KBr): 3382 and 3303 (NH ), 2191 (CN), 1683 (C=O), 1654 and
6
H6"), 7.90 (s, 2H, NH ), 7.44–7.32 (m, 3H, H3'', H4'', H5''), 7.21-
2
1606 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 9.87 (s, 1H,
2
7.11 (m, 3H, H3', H4', H5'), 7.01 (d, 1H, H3', J= 7.3 Hz), 2.47 (s,
-1 1
6
NH), 7.44 (d, 2H, H3', H5', J=8.0 Hz), 7.03 (d, 2H, H2', H6',
J=8.0), 6.97 (s, 2H, NH ), 4.10 (s, 1H, H4), 2.47 (s, 2H, H8), 2.25
13
3H, CH ); C nmr (dimethylsulfoxide-d ): δ 167.4 (C6), 164.9
3
6
(C4), 164.2 (C2), 138.2 (C1'), 136.7 (C1''), 135.2 (C2'), 129.6
(2C), 129.2 (2C), 128.8 (2C), 128.6 (2C), 128.4 (C), 117.2 (CN),
84.3 (C5), 20.9 (CH ); ms: m/z 286 (100), 285 (62), 242 (15),
2
(d, 1H, H6a, J=16.0 Hz), 2.07 (d, 1H, H6b, J=16.0 Hz), 1.99 (s,
13
3H, CH ), 1.02 (s, 3H, CH ), 0.93 (s, 3H, CH ); C nmr
3
3
(dimethylsulfoxide-d ): δ 195.4 (C5), 167.8 (C=O), 161.9 (C8a),
3
3
183 (55), 104 (25), 91 (10).
6
158.2 (C2), 139.1 (C1'), 137.5 (C4'), 127.1 (C3', C5'), 119.5
(CN), 118.8 (C2', C6'), 112.5 (C4a), 58.1 (C3), 49.7 (C6), 39.8
(C8), 34.7 (C4), 31.5 (C7), 28.1 (CH ), 26.3 (CH ), 23.6 (CH );
Anal. Calcd. C H N (286.33): C, 75.50; H, 4.93; N, 19.57.
18 14 4
Found: C, 75.62; H, 4.81; N, 19.72.
3
+
3
3
4-Amino-6-(4´-methoxyphenyl)-2-phenylpyrimidine-5-carboni-
trile (8c).
+
+
ms: m/z 351 (M , 76), 293 ([M – N H C O C H ] , 14), 217
3
+
+
([M –C H -NHCOCH ] , 100), 161 (15).
6
Anal. Calcd. C
4
3
H N O (351.41): C, 68.36; H, 6.02; N,
This compound was obtained in 69 % yield, mp 215-216°; ir
(KBr) 3375 and 3344 (N-H), 2118 (CN), 1639 and 1608 (C=C)
20 21 3 3
11.96. Found: C, 68.48; H, 6.33; N, 11.65.
-1
cm ; H nmr (dimethylsulfoxide-d ): δ 8.40-8.29 (m, 2H, H2",
1
6
H6"), 8.03-7.90 (d, 2H, H2', H6', J=11.3 Hz), 7.91 (s, 2H, NH ),
2-Amino-3-cyano-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4'-nitro-
phenyl)-5-oxo-4H-benzopyran (4g).
2
7.53 (m, 3H, H3", H4", H5"), 7.14 (d, 2H, H6', H2', J=11.3 Hz),
13
3.87 (s, 3H, OCH ); C nmr (dimethylsulfoxide-d ): δ 167.2
This compound was obtained in 81 % yield, mp 209-210°; ir
(KBr): 3392 and 3327 (NH ), 2198 (CN), 1685 (C=O), 1670 and
3
(C6), 164.8 (C4), 164.0 (C2), 161.5 (C4'), 136.6 (C1''), 131.4
6
2

Jul-Aug 2004
One-Step Synthesis of Aminopyrimidines from 5-Oxo-4H-Benzopyrans
515
(C4''), 130.4 (C2', C6'), 128.7 (C1'), 128.4 (C3'', C5''), 128.3
(C2'', C6''), 116.7 (CN), 113.8 (C5', C3'), 83.3 (C5), 55,4 (OCH );
13
H4'', H5''); C nmr (dimethylsulfoxide-d ): δ 168.6 (C6), 166.7
6
3
(C4), 164.8 (C2), 150.2 (C4'), 145.8 (C1'), 139.2 (C1''), 129.5
(C4''), 130.3 (C5'', C3''), 129.2 (C2'', C6''), 128.9 (C2', C6'), 125.2
(C3', C5'), 118.5 (CN), 82.5 (C5); ms: m/z 317 (100), 316 (63),
283 (15), 214 (46), 104 (12).
ms: m/z 302 (100), 301 (52), 258 (15), 199 (55), 104 (20).
H N O (302.34): C, 71.51; H, 4.67; N,
18 14 4
Anal. Calcd. C
18.53. Found: C, 71.68; H, 4.55; N, 18.37.
Anal. Calcd. C
H N O (317.30): C, 64.35; H, 3.49; N:
17 11 5 2
22.07. Found: C, 64.61; H, 3.80; N, 22.36.
4-Amino-6-(4'-N,N-dimethylaminophenyl)-2-phenylpyrimidine-
5-carbonitrile (8d) [22].
Acknowledgement.
This compound was obtained in 72 % yield, mp 234-235°; ir
(KBr) 3475 and 3305 (N-H), 2202 (CN), 1635 and 1616 (C=C)
Supports of this work by Proyectos Alma Mater (CUBA) and
MCyT of Spain (BQU2002-00855 and BQU2000-0790) are
gratefully acknowledged.
-1
1
cm ; H nmr (dimethylsulfoxide-d ): δ 8.39-8.21 (m, 2H, H2",
6
H6"), 8.02 (d, 2H, H2', H6', J=8.9 Hz), 7.72 (s, 2H, NH ), 7.53-
2
7.42 (m, 3H, H3", H4", H5"), 6.84 (d, 2H, H3', H5', J=8.9 Hz),
13
3.02 (s, 6H, 2CH ); C nmr (dimethylsulfoxide-d ): δ 167.6
3
6
REFERENCES AND NOTES
(C6), 165.9 (C4), 164 4 (C2), 153.1 (C4'), 137.8 (C1''), 132.2
(C4''), 130.8 (C2', C6'), 129.3 (C5'', C3''), 129.2 (C2'', C6''), 123.7
(C1'), 118.3 (CN), 112.0 (C5', C3'), 82.5 (C5), 40.5 (CH ), 40.4
[1a] W. G. Mayler, Calcium Antagonist, Academic Press: London,
1989; [b] D. J. Triggle, Mini Rev. Med. Chem., 3, 215 (2003).
[2] D. J. Triggle, D. A. Langs and R. A. Janis, Med. Res. Rev., 9,
123 (1989).
3
(CH ); ms: m/z 315 (100), 314 (63), 298 (12), 212 (16), 157 (10),
3
104 (14).
Anal. Calcd. C
H N (315.38): C, 72.36; H, 5.43; N, 22.21.
19 17 5
Found: C, 72.65; H, 5.22; N, 22.32.
[3] S. Mehdi and K. Ravikumar, Acta Cryst., C48, 1627 (1992).
[4] K. R. Rowan and M. E. Holt, Acta Cryst., C52, 2207 (1996).
[5a] J. Breitenbucher and G. Figliozzi, Tetrahedron Lett., 41, 4311
(2000); [b] W. H. Correa and J. L. Scott, Green Chem., 3, 296 (2001); [c]
L. M. Yagupolskii, I. Maletina, K. I. Petko, D. V. Fedyuk, R. Handrock, S.
S. Shavaran, B. M. Klebanov and S. Herzig, J. Fluorine Chem., 109, 87
(2001); [d] S. Balalaie and E. Kowsari, Monatsh. Chem., 1 3 2, 1551
(2001); [e] G. Cave, C. Raston and J. Scott, Chem. Commun., 2159
(2001); [f] H. Novoa, N. M. Blaton, O. M. Peeters, C. De Ranter, M.
Suarez, E. Ochoa, Y. Verdecia and E. Salfrán, J. Chem. Crystall., 30, 237
(2000); [g] M. Suárez, E. Salfrán, E. Ochoa, Y. Verdecia, L. Alba, N.
Martín, C. Seoane, R. Martínez-Alvarez, H. Novoa, N. M. Blaton, O. M.
Peeters and C. De Ranter, J. Heterocyclic Chem., 40, 269 (2003).
[6a] M. Epstein, Heart Dis., 3, 398 (2001); [b] S. Gullapalli and P.
Ramarao, Neuropharmacology, 42, 467 (2002); [c] F. Crespi, E.
Vecchiato, C. Lazzarini, M. Andreli and G. Gaviraghi, J. Cardiovasc.
Pharmacol., 39, 471 (2002); [d] M. Lohn, U. Muzzulini, K. Essin, S. Y.
Tsang, T. Kirsch, J. Litteral, P. Waldron, H. Conrad, N. Klugbauer, F.
Hofmann, H. Haller, F.C. Luft, Y. Huang and M.Gollasch, J. Hypertens.,
20, 885 (2002).
4-Amino-6-(4´-benzyloxiphenyl)-2-phenylpyrimidine-5-car -
bonitrile (8e).
This compound was obtained in 76 % yield, mp 265-266°; ir
(KBr): 3385 and 3308 (N-H), 2190 (CN), 1660 and 1610 (C=C)
-1
cm ; H nmr (dimethylsulfoxide-d ): δ 8.42-8.24 (m, 2H, H2",
1
6
H6"), 8.15 (d, 2H, H2', H6', J=9.7 Hz), 7.86 (s, 2H, NH ), 7.58-
2
7.38 (m, 8H, H3'', H4'', H5'', Ph-CH ), 7.22 (d, 2H, H3', H5',
13
2
J=9.7 Hz), 5.23 (s, 2H, CH ); C nmr (dimethylsulfoxide-d ): δ
2
6
168.0 (C6), 165.5 (C4), 164.7 (C2), 161.5 (C4'), 141.9 (C), 137.5
(C1''), 132.2 (2C), 131.3 (C), 129.7 (C), 129.4 (C), 129.3 (C2',
C6'), 128.9 (C), 128.7 (2C), 128.4 (C1'), 128.1 (C), 127.8 (C),
117.6 (CN), 115.6 (C3', C5'), 84.2 (C5), 70.3 (CH ); ms: m/z 378
2
(40), 377 (12), 353 (15), 319 (21), 275 (12), 104 (10), 91 (100).
Anal. Calcd. C H N O (378.43): C, 76.17; H, 4.79; N,
24 18 4
14.80. Found: C, 76.83; H, 4.86; N, 14.58.
[7] I. T. Mak, J. Zhang and W. B. Weglicki, Pharmacol. Res., 45,
27 (2002).
[8] D. Boschi, G. Caron, S. Visentin, A. Di Stilo, B. Rolando, R.
Fruttero and A. Gasco, Pharm. Res., 18, 987 (2001).
[9] M. Suárez, Y. Verdecia, E. Ochoa, N. Martín, R. Martínez-
Alvarez, M. Quinteiro, C. Seoane, J. L. Soto, H. Novoa, N. Blaton, O.
Peeters and C. De Ranter, J. Heterocyclic Chem., 37, 735 (2000).
[10] M. Quinteiro, C. Seoane and J. L. Soto, Tetrahedron Lett., 18,
1835 (1977).
4-Amino-6-(4´-acetamidophenyl)-2-phenylpyrimidine-5-car -
bonitrile (8f).
This compound was obtained in 74 % yield, mp 243-244°; ir
(KBr): 3930 and 3310 (N-H), 2202 (CN); 1680 (C=O), 1640 and
-1
1620 (C=C) cm ; H nmr (dimethylsulfoxide-d ): δ 8.40-8.31
1
6
(m, 2H, H2", H6"), 7.92 (d, 2H, H3', H5', J=8.7 Hz), 7.81 (s, 2H,
NH ), 7.51 (d, 2H, H2', H6', J=8.7 Hz), 7.18-7.06 (m, 3H, H3",
13
2
H4", H5"), 2.20 (s, 3H, CH ); C nmr (dimethylsulfoxide-d ): δ
3
6
[11] N. Martín, M. Quinteiro, C. Seoane and J. L. Soto, Liebigs
Ann. Chem., 101 (1990).
169.1 (C=O), 168.1 (C6), 165.3 (C4), 164.7 (C2), 143.2 (C4'),
138.9 (C1''), 132.7 (C1'), 128.9 (C4''), 129.5 (C5'', C3''), 127.7
(C2', C6'), 128.8 (C2'', C6''), 118.2 (CN), 122.1 (C3', C5'), 83.4
(C5), 20.5 (CH ); ms: m/z 329 (100), 328 (60), 203 (12), 104
3
(18).
[12] N. Martín, A. Martinez-Grau, C. Seoane, J. L. Marco, A.
Albert and F. H. Cano, J. Heterocyclic Chem., 33, 27 (1996).
[13] A. de Lucas, J. Fernández, N. Martín, R. Martínez-Alvarez,
and C. Seoane, Rapid Commun. Mass Spectrom., 14, 1783 (2000).
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Salfrán, Y. Verdecia and N. Kayali, Rapid Commun. Mass Spectrom., 15,
20 (2001).
Anal. Calcd. C H N O (329.36): C, 69.29; H, 4.59; N,
19 15 5
21.26. Found: C, 69.42; H, 4.70; N, 21.32.
4-Amino-6-(4´-nitrophenyl)-2-phenylpyrimidine-5-carbonitrile
(8g).
[15] C. Pascual, N. Martín, C. Seoane, Magn. Reson. Chem., 23,
793 (1985).
[16] M. Suárez, D. Molero, E. Salfrán, N. Martín, Y. Verdecia R.
Martínez-Alvarez, E. Ochoa, L. Alba, M. Quinteiro and C. Seoane,
Magn. Reson. Chem., 39, 105 (2001).
[17] J. Bellanato, F. Florencio, S. García Blanco, N. Martín and C.
Seoane, J. Mol. Struct., 162, 19 (1987).
This compound was obtained in 76 % yield, mp 215-216°; ir
(KBr): 3478 and 3300 (N-H), 2200 (CN); 1640, 1620 (C=C),
-1
1540 and 1350 (NO ) cm ; H nmr (dimethylsulfoxide-d ): δ
1
2
8.41 (m, 2H, H2'', H6''), 8.14 (d, 2H, H3', H5', J = 7.9 Hz), 7.67
6
[18] J. Bellanato, F. Florencio, S. García Blanco, N. Martín and C.
(s, 2H, NH ), 7.62 (d, 2H, H2', H3', J=7.9 Hz), 7.28 (m, 3H, H3'',
2

516
E. Salfrán, M. Suárez, Y. Verdecia, A. Alvarez, E. Ochoa,
R. Martínez-Alvarez, C. Seoane and N. Martín
Vol. 41
Seoane, J. Mol. Struct., 172, 63 (1988).
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F. H. Cano, Tetrahedron Lett., 33, 3809 (1992).
[33] R. Martínez-Alvarez, A. Herrera, A. Sanchez Vazquez, J.
Aladro Maroto, M. Chioua and R. Chioua, Rapid Commun. Mass
Spectrom., 13, 79 (1999).
[20] M. Suárez, E. Salfrán, Y.Verdecia, E. Ochoa, L. Alba, N.
Martín, R. Martínez-Alvarez, M. Quinteiro, C. Seoane, H. Novoa, N.
Blaton, O. Peeters and C De Ranter, Tetrahedron, 58, 953 (2002).
[21] A. M. Abd-Elfattah, S. M. Hussain and A. M. El-Reedy,
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