Three-component assembly of structurally diverse 2-aminopyrimidine-5- carbonitriles

Article abstract of DOI:10.1021/co4000503

An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.

Full text of DOI:10.1021/co4000503

Research Article
pubs.acs.org/acscombsci
Three-Component Assembly of Structurally Diverse
2‑Aminopyrimidine-5-carbonitriles
Cristina Val,†,‡ Abel Crespo,†,‡ Vicente Yaziji,†,‡ Alberto Coelho,*,†,‡ Jhonny Azuaje,†,‡
Abdelaziz El Maatougui,†,‡ Carlos Carbajales,†,‡ and Eddy Sotelo*,†,‡
†Center for Research in Biological Chemistry and Molecular Materials (CIQUS) and ‡Department of Organic Chemistry, Faculty of
Pharmacy, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
S
* Supporting Information
ABSTRACT: An expedient route for the synthesis of libraries
of diversely decorated 2-aminopyrimidine-5-carbonitriles is
reported. This approach is based on a three-component
reaction followed by spontaneous aromatization.
KEYWORDS: Multicomponent reactions, Biginelli Reaction, 2-aminopyrimidine
Significant advances in both transformations have been made
through the use of nonconventional heating modes (e.g.,
microwave irradiation)22,23 and the progress in cross-coupling
chemistry24−28 (e.g., the development of more active catalysts).
However, there are still limitations associated with these
methods. In particular, the introduction of aromatic amines has
not been fully addressed and these reactions generally give
moderate or low yields and usually require prolonged heating at
high temperatures with a large excess of amine. In addition, the
multistep nature of these strategies make it difficult to
implement parallel synthesis techniques and, consequently, to
produce large numbers of analogs rapidly. Given this scenario,
the discovery of robust synthetic strategies that enable the one-
pot convergent assembly of 2-aminopyrimidines remains a
vibrant research area.
INTRODUCTION
■
The pyrimidine core is a ubiquitous structural motif in natural
products.1,2 The diverse pharmacological activities exhibited by
this highly versatile template have been extensively exploited in
drug discovery (Figure 1),3,4 as well as in the optimization of
molecular probes for the study of chemical/biological
interfaces.5,6 In addition, pyrimidine derivatives constitute
invaluable synthetic precursors in a variety of organic
transformations and in coordination chemistry.7−9 The pursuit
of protein kinase inhibitors,10−13 an emerging therapeutic class
that has provided conceptually new therapeutic approaches for
diseases that challenge the medical community, has triggered
renewed interest in molecular architectures that incorporate the
pyrimidine core. In particular, the role of the 2-amino-
pyrimidine template as a key binding fragment toward these
targets has been extensively documented.14,15 Furthermore, this
unit is one of a number of diverse molecular entities that exhibit
protein kinase inhibitory activity, with the bcr-Abl kinase
inhibitor Imatinib16,17 the first drug of this family to enter
clinical trials.
The importance of the 2-aminopyrimidine chemotype
notwithstanding, prevailing synthetic strategies to access these
derivatives are rather limited in their scope and generality,
being based either on the functionalization of an appropriately
substituted pyrimidine ring or de novo construction thereof.
Most approaches of the latter type rely on the cyclo-
condensation of 1,3-dicarbonyl compounds (or synthetic
equivalents, such as enaminones, β-ketoenolethers, or ynones)
and guanidines (e.g., Bredereck or Pinner pyrimidine
syntheses).18−21 Densely substituted 2-aminopyrimidines are
commonly obtained by the introduction of amino groups into a
previously decorated pyrimidine ring18−21 by displacement of
halides or other leaving groups at C-2 in nucleophilic aromatic
substitution or metal-catalyzed C−N bond forming reactions.
The Biginelli synthesis29−31 is one of the classical multi-
component reactions32−35 and it enables rapid access to diverse
pharmacologically active36 collections of pyrimidine derivatives
from commercially available precursors. Whereas the use of
ureas and thioureas as reactive partners in the Biginelli reaction
is well documented,29−31 similar transformations that employ
guanidine derivatives are comparatively much less well
developed.37−45 The reaction of guanidines (1) and benzyli-
dene-3-oxoalkanoates (2) provided a proof of concept to access
these heterocyclic derivatives (Figure 2), although the
corresponding 2-amino-5-alkoxycarbonyl-1,4-dihydropyrimi-
dines (3) were generally obtained in low to moderate
yields.37,38 The concomitant formation of bicyclic compounds
(e.g., diethyl 2,4,6,8-tetraaryl-4,6-dihydro1H-pyrimido[1,2-a]-
pyrimidine-3,7-dicarboxylates, compounds 4, Figure 2), which
Received: April 18, 2013
Revised: May 20, 2013
© XXXX American Chemical Society
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Figure 1. Representative bioactive structures that incorporate the 2-aminopyrimidine template.
Figure 2. Biginelli-based approaches to 2-amino-3,4-dihydropyrimidines.
arise from Michael-type condensation of two ketoester
molecules on the guanidine backbone, has been documented
during the transformation.39 An alternative approach29−31,40,41
has also been described and this is based on the aminolysis of
Biginelli adducts containing alkyloxy- or alkylthio residues at
position 2 of the heterocyclic backbone (7) for the synthesis of
2-amino-1,4-dihydropyrimidines (8) (Figure 2). The mecha-
nistic rationalization of the available experimental data
prompted Kappe to propose a three-component approach
[by reacting guanidine (1), ethyl benzoylacetate (6) and
carboxaldehydes (5)] to access diverse 2-amino-5-alkoxycar-
bonyl-3,4-dihydropyrimidines, although the method was
unsuccessful with ethyl acetoacetate.42 The Biginelli-like
approach, in addition to suppress the side-product formation,
provided additional evidence for the advantages derived from
the multicomponent approach. Incisive work by Overman43
enabled the successful exploitation of acetoacetates as reactive
partners in the Biginelli-based 2-amino-5-alkoxycarbonyl-3,4-
dihydropyrimidine synthesis (Figure 2). An exhaustive
experimental optimization validated the convenience of
guanidine surrogates [e.g., N-pyrazole carboxamidine or 1,3,5-
triazin-4-one carboxamidine (9)] as part of an expedient
synthesis of guanidine alkaloid-like complex structures
(batzelladine F-like derivatives (11), Figure 2). The one-pot
base-catalyzed condensation of guanidine, carboxaldehydes and
ketoesters has recently been employed during a diversity-
oriented branching synthetic strategy that enabled the
identification of Emmacin (Figure 1), the prototype of a new
family of antibacterial agents.44,45
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Figure 3. Retrosynthetic scheme to access targeted structures.
Scheme 1. Three-Component Synthesis of Pyrimidine-5-carbonitriles
vs inert atmosphere) did not prove to be particularly influential
on the reaction behavior at either the qualitative (compound
isolated) or quantitative (yields) level. The best results were
obtained in DMF using 3 equivalents of Na2CO3 at 80 °C
during 6−12 h. The analytical and spectroscopic data obtained
for compounds 14 unequivocally support the assigned
structures and these were confirmed by X-ray crystallography
data obtained on a monocrystal of 2-(ethylamino)-4,6-
diphenylpyrimidine-5-carbonitrile 14{3,1,1} (Figure 4).46
Although the mechanism of the transformation [and
particularly the intermediacy of 1,4-dihydropyrimidine-5-
carbonitriles (13)] has not been experimentally established, a
RESULTS AND DISCUSSION
■
In the context of a medicinal chemistry program on the 2-
aminopyrimidine chemotype, we needed to experimentally
validate in silico bioactivities predicted for virtually generated
new ligands that incorporated a cyano group at position 5 of
the heterocyclic core. Given the limitations of published
methods to access the target structures, we decided to assess
the feasibility of a Biginelli-inspired approach (Figure 3). It was
envisioned that the reaction of α-cyanoketones (12),
carboxaldehydes (5), and guanidines (1) would enable the
rapid assembly of 2-amino-1,4-dihydropyrimidine-5-carbon-
itriles (13) that could be subsequently aromatized to afford
14 (Figure 3).29−31
To the best of our knowledge, α-cyanoketones and
guanidines have not previously been employed in such a
transformation. Following previous reports,42−45 we opted to
apply a base-catalyzed experimental protocol (Scheme 1). A
preliminary study to evaluate the feasibility of the method was
developed employing benzoylacetonitrile (12{1}), benzalde-
hyde (5{1}), and five guanidines (1{1−5}) as model substrates
(Scheme 1). All of the experiments were performed in either
DMF or dioxane as the solvents, while the effects of different
inorganic bases (Na2CO3, K2CO3, and NaHCO3), temper-
atures (70−100 °C), and reaction times (4−18 h) on reaction
behavior were screened. From preliminary experimentation
(Scheme 1) it became clear that the isolated products from the
base-catalyzed reaction of benzoylacetonitrile, benzaldehyde,
and guanidines 1{1−5} were not the corresponding 2-amino-
1,4-dihydropyrimidine-5-carbonitriles (13) but rather the
desired 2-aminopyrimidine-5-carbonitriles 14.
These experiments not only demonstrated the feasibility of
the transformation in a shorter sequence, but also enabled the
identification of a set of optimal conditions (Scheme 1) to
prepare 14 in moderate to satisfactory yields. Preliminary
screening of the experimental conditions evidenced the
superior effectiveness of DMF as the solvent while confirming
the key role exerted by catalysis. The other experimental
conditions screened (e.g., temperatures and aerobic conditions
Figure 4. Plot showing the crystal structure and atomic numbering
scheme for 2-(ethylamino)-4,6-diphenylpyrimidine-5-carbonitrile
(14{3,1,1}) (CCDC 917600).46.
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Scheme 2. Three-Component Synthesis of 2-Aminopyrimidine-5-carbonitriles
Figure 5. Diversity elements employed during library synthesis. Guanidines 1{1−5}, aldehydes 5{1−13} or dimethyl acetals {14−15}, and α-
cyanoketones 12{1−3}.
rational reaction sequence would involve a Biginelli-like
heterocyclization mechanism47 followed by a spontaneous
aromatization process. It should be noted that, in contrast to
Hantzsch-type 1,4-dihydropyridines (where the aromatization
to pyridines is typically facile) the dehydrogenation of
dihydropyrimidines is known to be nontrivial30,48,49 [usually
requiring stoichiometric reagents (DDQ, CAN, Pd/C, CuCl2),
harsh reaction conditions, or both]. A comparative analysis of
herein documented results with the experiments reported by
Kappe (employing β-keto esters) suggests the presence of a
cyano group at position 5 of the heterocyclic core (instead an
ester function) facilitate the aromatization process.
Having established the viability of the method (Scheme 1),
we wondered if it would be possible to improve these results
(e.g., yields, reaction times) by performing the three-
component reaction under a nonconventional energy source,
such as microwave irradiation. Preliminary experimentation on
model compounds revealed that only slight modifications of
optimized conditions (Scheme 1) were required to obtain
target molecules in analogous yields (40−85%), while
drastically shortening reaction times (<1 h). Optimal
experimental conditions are depicted in Scheme 2.
commercially available starting materials [e.g., α-cyanoketones
(12), aldehydes (5), and guanidines (1)] (Figure 5). These
inputs were selected to address the generality of the
transformation, while simultaneously expecting to modify the
electronic, steric, and lipo-/hydrophilic features of the scaffold
itself.
It was gratifyingly to observe that most of the tested
substrates exhibited satisfactory reactivity profiles, in all cases
leading to a smooth heterocyclization/aromatization sequence
that readily afforded the target structures (Table 1). It can be
seen that the transformation enables the rapid assembly of 2-
aminopyrimidines that incorporate diverse residues at the
heterocyclic core, a characteristic that is particularly valuable in
the context of medicinal chemistry programs. As observed, the
method is broadly robust with a variety of components and is
not influenced by the electronic or steric variations in the
reactants. Significant structural variation is well tolerated for
aryl and heteroaryl aldehyde partners (including some sterically
hindered derivatives), while the reaction generally failed during
the introduction of aliphatic moieties (entries 20−25), which
required the use of dimethyl acetals instead of the
corresponding carbaldehydes to afford moderated yields (34−
55%) of targeted compounds. Excellent reactivity profile was
found for all guanidines (1), which proved successful for the
introduction of diverse amine residues in the heterocyclic
backbone (Table 1). The optimized conditions probed to be
Encouraged by the general interest of this convergent and
experimentally simple transformation, we decided to evaluate
its scope and efficiency in the generation of 2-aminopyrimidine-
5-carbonitrile arrays by recourse to a diverse range of
D
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a
Table 1. Structure, Time, and Yields of 2-Aminopyrimidine-5-carbonitriles Assembled
b
entry
1
5
12
product
time (min)
yield (%)
1
{1}
{2}
{3}
{4}
{5}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{2}
{2}
{4}
{4}
{5}
{5}
{1}
{2}
{4}
{1}
{2}
{4}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{2}
{1}
{1}
{1}
{1}
{3}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
{1}
14{1,1,1}
14{2,1,1}
14{3,1,1}
14{4,1,1}
14{5,1,1}
14{1,2,1}
14{1,3,1}
14{1,4,1}
14{1,5,1}
14{1,6,1}
14{1,7,1}
14{1,8,2}
14{2,9,1}
14{2,10,1}
14{2,6,1}
14{4,9,1}
14{4,11,3}
14{5,12,1}
14{5,13,1}
14{1,14,1}
14{2,14,1}
14{4,14,1}
14{1,15,1}
14{2,15,1}
14{4,15,1}
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
45
45
45
45
45
45
47
80
35
49
86
65
58
66
74
57
45
64
71
76
78
70
73
81
75
34
48
55
37
46
2
{1}
3
{1}
4
{1}
5
{1}
6
{2}
7
{3}
8
{4}
9
{5}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
{6}
{7}
{8}
{9}
{10}
{6}
{9}
{11}
{12}
{13}
{14}
{14}
{14}
{15}
{15}
{15}
51
a
b
Reaction conditions: 1 (1.2 mmol), 5 (1.0 mmol), 12 (1.0 mmol), Na2CO3 (3.0 mmol), DMF (4 mL), MW heating 120 °C. Isolated yields.
general, with only slight differences in the required reaction
times (Table 1).
structures of the obtained compounds were characterized by
nuclear magnetic resonance spectroscopy (1H and 13C) and
high-resolution mass spectra (HRMS). Unless otherwise
quoted, NMR spectra were recorded in CDCl3. Chemical
shifts are given as δ values against tetramethylsilane as internal
standard and J values are given in hertz (Hz). Microwave-
assisted syntheses were performed in a Monowave 300 oven
(Anton-Paar), reaction temperature was measured by surface
sensor.
In summary, a convergent and robust three-component
approach that enables the assembly of 2-aminopyrimidine-5-
carbonitriles from simple starting materials has been developed.
By virtue of its operational simplicity, efficiency, and wide
scope, the herein documented methodology constitutes a very
attractive protocol addressing the access to diversely substituted
pyrimidine derivatives in a cost- and time-effective manner.
General Procedure for the Conventional Synthesis of
2,4,6-Substituted Pyrimidine-5-carbonitriles. Guanidine
salt (1.2 mmol) and sodium carbonate (3 mmol) were added to
an equimolecular (1.0 mmol) mixture of the α-cyanoketone
and the corresponding aldehyde (or dimethyl acetal) in DMF
(4 mL), and the mixture was heated at 80 °C until the starting
materials had been consumed (6−12 h). The mixture was
cooled to room temperature, and the solvent was evaporated to
dryness to give an oily residue, which was poured into water.
After extraction with ethyl acetate, the organic phase was dried
(Na2SO4) and evaporated under reduced pressure. The oily
residue was precipitated by the addition of MeOH and the
isolated solid was purified by column chromatography (silica
gel) and then recrystallized.
EXPERIMENTAL PROCEDURES
■
Commercially available starting materials and reagents were
purchased and used without further purification from freshly
opened containers. All solvents were purified and dried by
standard methods. Organic extracts were dried with anhydrous
Na2SO4. The reactions were monitored by TLC and purified
compounds showed a single spot. Unless stated otherwise, UV
light or iodine vapor were used for the detection of compounds.
The synthesis and purification of all compounds were
accomplished using the equipment routinely available in
organic chemistry laboratories. Most of the preparative
experiments were performed in coated vials on an organic
synthesizer with orbital stirring. Purification of isolated
products was carried out by column chromatography.
Compounds were routinely characterized by spectroscopic
and analytical methods. Melting points were determined on a
melting point apparatus and are uncorrected. The chemical
General Procedure for the Microwave-Assisted Syn-
thesis of 2,4,6-Substituted Pyrimidine-5-carbonitriles.
Guanidine salt (1.2 mmol) and sodium carbonate (3 mmol)
were added to an equimolecular (1.0 mmol) mixture of the α-
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cyanoketone and the corresponding aldehyde (or dimethyl
acetal) in DMF (4 mL). The mixture was heated at 120 °C by
irradiation in a microwave synthesizer (surface sensor) until the
starting materials had been consumed (30−60 min). The
mixture was cooled to room temperature, and the solvent was
evaporated to dryness to give an oily residue, which was poured
into water. After extraction with ethyl acetate, the organic phase
was dried (Na2SO4) and evaporated under reduced pressure.
The oily residue was precipitated by the addition of MeOH,
and the isolated solid was purified by column chromatography
(silica gel) and then recrystallized.
MeOH = 8:2) and then recrystallized (EtOH); mp 245−246
°C (EtOH); white solid; yield 58% (168 mg); 1H NMR
(DMSO-d6, 300 MHz) δ (ppm) 7.96 (bs, 2H), 7.89−7.85 (m,
2H), 7.73−7.54 (m, 6H), 7.53−7.40 (m, 1H); 13C NMR
(DMSO-d6, 75.5 MHz) δ (ppm) 170.7, 169.4, 163.8, 162.8,
159.9, 138.9, 136.5, 131.0, 128.8, 128.5, 125.1, 118.4, 117.9,
115.9, 91.2; HRMS-ESI m/z calcd. for C17H11FN4 [M + H]+
291.1046, found 291.1041.
2-Amino-4-(3-hydroxyphenyl)-6-phenylpyrimidine-5-car-
bonitrile 14{1,4,1}: Purified by flash chromatography (DCM/
MeOH = 8:2) and then recrystallized (EtOH); mp 249−251
°C (EtOH); white solid; yield 66% (190 mg); 1H NMR
(DMSO-d6, 300 MHz) δ (ppm) 9.75 (s, 1H, OH), 7.85−7.82
(m, 4H), 7.55−7.52 (m, 3H), 7.36−7.32 (m, 3H), 6.96−6.93
(m, 1H); 13C NMR (DMSO-d6) δ (ppm) 170.8, 170.7, 162.8,
157.3, 137.8, 136.6, 130.9, 129.5, 128.8, 128.4, 119.5, 118.6,
117.8, 115.6, 91.0; HRMS-ESI m/z calcd. for C17H12N4O [M +
H]+ 289.1089, found 289.1084.
2-Amino-6-phenyl-4-(thiophen-3-yl)pyrimidine-5-carboni-
trile 14{1,5,1}: Purified by flash chromatography (DCM/
MeOH = 8:2) and then recrystallized (EtOH); mp 181−182
°C (EtOH); white solid; Yield 74% (205 mg); 1H NMR
(DMSO-d6, 300 MHz) δ (ppm) 8.64 (dd, J = 1.6 Hz, J = 1.0
Hz, 1H), 7.91−7.88 (m, 3H), 7.55−7.51 (m, 3H), 7.44−7.41
(m, 1H, aromatic), 5.60 (bs, 2H); 13C NMR (DMSO-d6, 75.5
MHz) δ (ppm) 171.1, 164.4, 162.9, 138.1, 136.6, 130.9, 130.1,
128.8, 128.4, 127.8, 127.1, 119.1, 89.8; HRMS-ESI m/z calcd.
for C15H10N4S [M + H]+ 279.0704, found 279.0699.
2-Amino-4,6-diphenylpyrimidine-5-carbonitrile 14{1,1,1}:
Purified by flash chromatography (DCM/MeOH = 8:2) and
then recrystallized (EtOH); mp 227−228 °C (EtOH); white
1
solid; yield 47% (168 mg); H NMR (CDCl3, 300 MHz) δ
(ppm) 7.94−7.91 (m, 4H), 7.57−7.49 (m, 6H), 5.93 (s, 2H);
13C NMR (CDCl3, 75.5 MHz) δ (ppm) 171.0, 162.0, 135.9,
131.1, 128.7, 128.5, 117.8, 71.6; HRMS-EI m/z calcd. for
C17H12N4 [M]+ 272.1056, found 272.1056.
2-(Methylamino)-4,6-diphenylpyrimidine-5-carbonitrile
14{2,1,1}: Purified by flash chromatography (DCM/MeOH =
9:1) and then recrystallized (EtOH); mp 214−216 °C (EtOH);
white solid; yield 80% (228 mg); 1H NMR (CDCl3, 300 MHz)
δ (ppm) 8.05−7.89 (m, 4H), 7.54−7.52 (m, 6H), 5.86 (bs,
1H), 3.11 (d J = 5.1 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz) δ
(ppm) 171.0, 161.7, 136.3, 131.0, 128.9, 128.6, 118.5, 91.7,
28.1; HRMS-ESI m/z calcd. for C18H14N4 [M + H]+ 287.1296,
found 287.1291.
2-Amino-6-phenyl-4-(pyridin-3-yl)pyrimidine-5-carboni-
trile 14{1,6,1}: Purified by flash chromatography (DCM/
MeOH = 8:2) and then recrystallized (EtOH); mp 243−244
°C (EtOH); white solid; yield 57% (155 mg); 1H NMR
(DMSO-d6 300 MHz) δ (ppm) 9.17 (d, J = 1.6 Hz, 1H), 8.75−
8.70 (m, 1H), 8.25 (m, 1H), 8.01 (m, 2H), 7.90−7.86 (m, 2H),
7.62−7.55 (m, 4H); 13C NMR (DMSO-d6, 75.5 MHz) δ
(ppm) 187.9, 170.6, 168.5, 162.9, 151.5, 149.2, 136.4, 132.5,
131.1, 128.8, 128.5, 123.5, 118.4, 91.5; HRMS-ESI m/z calcd.
for C16H11N5 [M + H]+ 274.1093, found 274.1087.
2-Amino-4-cyclohexyl-6-phenylpyrimidine-5-carbonitrile
14{1,7,1}: Purified by flash chromatography (DCM/MeOH =
8:2) and then recrystallized (EtOH); mp 186−187 °C (EtOH);
white solid; yield 45% (125 mg); 1H NMR (CDCl3, 300 MHz)
δ (ppm) 7.98−7.87 (m, 2H), 7.50−7.22 (m, 3H), 5.62 (s, 2H),
3.11−2.99 (m, 1H), 1.85−1.20 (m, 10H); 13C NMR (CDCl3,
75.5 MHz) δ (ppm) 180.4, 162.3, 136.5, 172.5, 169.5, 130.9,
128.4, 117.2, 93.7, 44.3, 30.9, 25.8, 25.6; HRMS-ESI m/z calcd.
for C17H18N4 [M + H]+ 279.1610, found 279.1604.
2-(Ethylamino)-4,6-diphenylpyrimidine-5-carbonitrile
14{3,1,1}: Purified by flash chromatography (DCM/MeOH =
9:1) and then recrystallized (EtOH); mp 178−180 °C (EtOH);
1
yield 35%; H NMR (CDCl3, 300 MHz) δ (ppm) 8.02−7.90
(m, 4H), 7.50−7.25 (m, 6H), 5.86 (t, 1H, J = 4.63), 3.58 (m,
2H, CH2), 1.26 (t, 3H, J = 7.2, CH3); HRMS m/z calcd. for
C19H16N4 (M+) 300.3571, found 300.3567.
4,6-Diphenyl-2-(phenylamino)pyrimidine-5-carbonitrile
14{4,1,1}: Purified by flash chromatography (DCM/MeOH =
9:1) and then recrystallized (EtOH); mp 165−167 °C (EtOH);
white solid; yield 49% (191 mg); 1H NMR (CDCl3, 300 MHz)
δ (ppm) 8.04−8.02 (m, 4H), 7.72 (m, 3H), 7.60−7.55 (m,
6H), 7.38 (t J = 7.5 Hz, 2H), 7.13 (t J = 7.5 Hz, 1H); 13C NMR
(CDCl3, 75.5 MHz) δ (ppm) 171.1, 158.9, 138.0, 136.0, 131.2,
128.9, 128.8, 128.5, 123.8, 119.8, 118.0, 93.9; HRMS-ESI m/z
calcd for C23H16N4 [M + H]+ 349.1453, found 349.1448.
2-(Dimethylamino)-4,6-diphenylpyrimidine-5-carbonitrile
14{5,1,1}. Purified by flash chromatography (DCM/MeOH =
9:1) and then recrystallized (EtOH); mp 233−234 °C (EtOH);
1
2-Amino-6-(3-chlorophenyl)-4-(3,5-dichlorophenyl)-
pyrimidine-5-carbonitrile 14{1,8,2}: Purified by flash chroma-
tography (DCM/MeOH = 8:2) and then recrystallized
(EtOH); mp 274−275 °C (EtOH); white solid; yield 64%
(239 mg); 1H NMR (DMSO-d6) δ (ppm) 8.11 (s, 2H), 7.93−
7.84 (m, 5H), 7.66−7.59 (m, 2H); 13C NMR (DMSO-d6) δ
(ppm) 169.1, 167.9, 162.8, 139.6, 138.3, 134.3, 133.3, 130.9,
130.6, 130.4, 128.6, 127.6, 127.5, 118.0, 91.5; HRMS-ESI m/z
calcd. for C17H9Cl3N4 [M + H]+ 374.9971, found 374.9966.
4-(4-Hydroxyphenyl)-2-(methylamino)-6-phenylpyrimi-
dine-5-carbonitrile 14{2,9,1}: Purified by flash chromatography
(DCM/MeOH = 9:1) and then recrystallized (EtOH); mp
white solid; yield 86% (258 mg); H NMR (DMSO-d6, 300
MHz) δ (ppm) 7.92 (m, 4H), 7.58 (m, 6H), 3.49 (s, 6H); 13
C
NMR (DMSO-d6,75.5 MHz) δ (ppm) 169.8, 136.8, 131.1,
129.0, 128.5, 123.5, 107.0, 93.1, 36.9; HRMS-ESI m/z calcd. for
C19H16N4 [M + H]+ 301.1453, found 301.1448.
2-Amino-6-phenyl-4-p-tolylpyrimidine-5-carbonitrile
14{1,2,1}: Purified by flash chromatography (DCM/MeOH =
8:2) and then recrystallized (EtOH); mp 192−193 °C (EtOH);
white solid; yield 65% (185 mg); 1H NMR (CDCl3, 300 MHz)
δ (ppm) 7.93 (m, 2H), 7.85 (d J = 8.0 Hz, 2H), 7.54 (m, 3H),
7.33 (m, 2H), 5.73 (s, 2H), 2.48 (s, 3H); 13C NMR (CDCl3,
75.5 MHz) δ (ppm) 171.1, 170.8, 163.1, 141.3, 137.0, 134.1,
132,4, 131.2, 129.3, 129.2, 128.7, 119.1, 91.2, 21.4; HRMS-ESI
m/z calcd for C18H14N4 [M + H]+ 287.1297; found 287.1291.
2-Amino-4-(3-fluorophenyl)-6-phenylpyrimidine-5-car-
bonitrile 14{1,3,1}: Purified by flash chromatography (DCM/
1
307−308 °C (EtOH); white solid; yield 71% (214 mg); H
NMR (CDCl3, 300 MHz) δ (ppm) (DMSO-d6) 10.15 (bs, 1H,
OH), 8.23 (bs, 1H, −NH), 7.92−7.78 (m, 4H), 7.56−7.52 (m,
3H), 6.93−6.88 (m, 2H), 2.95 (d J = 3.8 Hz, 3H); 13C NMR
F
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(CDCl3, 75.5 MHz) δ (ppm) 170.3, 169.6, 161.5, 160.5, 137.0,
130.9, 129.0, 128.4, 127.4, 127.1, 119.3, 115.2, 89.8, 28.0;
HRMS-ESI m/z calcd. for C18H14N4O [M + H]+ 303.1246,
found 303.1240.
NMR (DMSO-d6, 300 MHz) δ (ppm) 7.94−7.86 (m, 4H),
7.66−7.52 (m, 5H), 3.27 (s, 6H); (DMSO-d6 75.5 MHz) δ
(ppm) 170.1, 168.7, 160.5, 139.1, 137.0, 133.6, 131.5, 131.2,
130.8, 129.3, 129.0, 128.9, 128.0, 119.0, 90.3, 37.3; HRMS-ESI
m/z calcd. for C19H15ClN4 [M + H]+ 335,1063, found
335.1058.
2-Amino-6-methyl-4-phenylpyrimidine-5-carbonitrile
14{1,14,1}: Purified by flash chromatography (DCM/MeOH =
8:2) and then recrystallized (EtOH); mp 170−172 °C (EtOH);
white solid; yield 34% (71 mg); 1H NMR (CDCl3, 300 MHz) δ
(ppm) 7.91−7.88 (m, 2H), 7.52−7.50 (m, 3H), 5.70 (bs, 2H),
2.62 (s, 3H); 13C NMR (CDCl3, 75.5 MHz) δ (ppm) 173.3,
162.0, 135.5, 131.1, 128.5, 128.4, 117.1, 107.5, 95.5, 23.5;
HRMS-EI m/z calcd. for C12H10N4 [M]+ 210.0905, found
210.0910.
4-(2-Methoxyphenyl)-2-(methylamino)-6-phenylpyrimi-
dine-5-carbonitrile 14{2,10,1}: Purified by flash chromatog-
raphy (DCM/MeOH = 9:1) and then recrystallized (EtOH);
mp 229−230 °C (EtOH); white solid; yield 76% (240 mg); 1H
NMR (DMSO-d6, 300 MHz) δ (ppm) 8.32−8.30 (m, 1H),
7.94−7.90 (m, 1H), 7.85−7.81 (m, 1H), 7.57−7.35 (m, 5H),
7.28−7.27 (d J = 4.1 Hz, 1H), 7.20−7.04 (m, 1H), 3.81 (s,
3H), 2.95 (d J = 4.7 Hz, 3H); 13C NMR (DMSO-d6, 75.5
MHz) δ (ppm) 171.2, 168.7, 162.0, 156.6, 136.7, 131.8, 131.1,
130.2, 129.9, 128.8, 126.1, 120.6, 118.1, 111.9, 93.3, 55.7, 28.1;
HRMS-ESI m/z calcd. for C19H16N4O [M + H]+ 317.1402,
found 317.1397.
6-Methyl-2-(methylamino)-4-phenylpyrimidine-5-carboni-
trile 14{2,14,1}: Purified by flash chromatography (DCM/
MeOH = 8:2) and then recrystallized (EtOH); mp 174−176
°C (EtOH); white solid; yield 48% (107 mg); 1H NMR
(CDCl3, 300 MHz) δ (ppm) 8.00−7.86 (m, 2H), 7.51−7.49
(m, 3H), 5.88 (bs, 1H), 3.01 (d J = 8.3 Hz, 3H), 3.14 (s, 3H);
13C NMR (CDCl3, 75.5 MHz) δ (ppm) 177.1, 169.8, 161.7,
136.1, 130.8, 128.6, 128.4, 117.5, 28.1, 23.9, 23.5; HRMS-EI m/
z calcd. for C13H12N4 [M]+ 224.1062, found 224.1068.
6-Methyl-4-phenyl-2-(phenylamino)pyrimidine-5-carboni-
trile 14{4,14,1}: Purified by flash chromatography (DCM/
MeOH = 8:2) and then recrystallized (EtOH); mp 168−169
°C (EtOH); white solid; yield 55% (157 mg); 1H NMR
(CDCl3, 300 MHz) δ (ppm) 8.02−7.99 (m, 2H), 7.67−7.52
(m, 6H), 7.12 (m, 2H), 7.12 (m, 1H), 2.69 (s, 3H); 13C NMR
(CDCl3, 75.5 MHz) δ (ppm) 173.0, 169.0, 158.8, 137.9, 135.7,
131.2, 128.9, 128.7, 128.6, 123.7, 119.9, 117.3, 95.6, 23.8.
HRMS-ESI m/z calcd. for C18H14N4 [M + H]+ 287.1297, found
287.1291.
2-Amino-4-ethyl-6-phenylpyrimidine-5-carbonitrile
14{1,15,1}: Purified by flash chromatography (DCM-MeOH:
8:2) and then recrystallized (EtOH); mp 123−125 °C (EtOH);
white solid; yield 37% (82 mg); 1H NMR (CDCl3, 300 MHz) δ
(ppm) 7.90−7.86 (m, 2H), 7.52−7.46 (m, 3H), 5.75 (bs, 2H),
2.93 (d J = 7.5 Hz, 2H), 1.34 (d J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 75.5 MHz) δ (ppm) 173.0, 169.8, 162.2, 135.8, 131.0,
128.5, 128.4, 117.1, 111.0, 30.1, 12.1; HRMS-EI m/z calcd. for
C13H12N4 [M]+ 224.1062, found 224.1068.
2-(Methylamino)-6-phenyl-4-(pyridin-3-yl)pyrimidine-5-
carbonitrile 14{2,6,1}: Purified by flash chromatography
(DCM/MeOH = 9:1) and then recrystallized (EtOH); mp
1
248−249 °C (EtOH); white solid; yield 78% (223 mg); H
NMR (DMSO-d6, 300 MHz) δ (ppm) 9.11−9.01 (bs, 1H),
8.78−8.74 (m, 1H), 8.44 (m, 1H), 8.34−8.23 (m, 1H), 7.97−
7.85 (m, 2H), 7.62−7.54 (m, 4H), 2.96 (d J = 4.7 Hz, 3H); 13
C
NMR (DMSO-d6, 75.5 MHz) δ (ppm) 187.9, 170.3, 168.9,
161.6, 151.7, 149.4, 136.4, 132.7, 131.2, 128.9, 123.5, 118.6,
112.3, 91.3, 28.0; HRMS-ESI m/z calcd. for C17H13N5 [M +
H]+ 288.1249, found 288.1244.
4-(4-Hydroxyphenyl)-6-phenyl-2-(phenylamino)-
pyrimidine-5-carbonitrile 14{4,9,1}: Purified by flash chroma-
tography (DCM/MeOH = 9:1) and then recrystallized
(EtOH); mp 286−287 °C (EtOH); white solid; yield 70%
(254 mg); 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 10.51 (m,
1H), 10.24 (s, 1H), 7.96−7.90 (m, 4H), 7.83−7.80 (d J = 7.6
Hz, 2H), 7.60−7.57 (m, 3H), 7.34 (m, 2H), 7.04−7.01 (m,
1H), 6.95 (d J = 7.6 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz) δ
(ppm) 170.7, 169.7, 160.6, 159.0, 139.3, 136.6, 131.1, 129.1,
129.0, 128.8, 128.6, 126.9, 123.2, 120.4, 118.8, 115.4, 92.2;
HRMS-ESI m/z calcd. for C23H16N4O [M + H]+ 365.1402,
found 365,1397.
4,6-Bis(4-methoxyphenyl)-2-(phenylamino)pyrimidine-5-
carbonitrile 14{4,11,3}: Purified by flash chromatography
(DCM/MeOH = 9:1) and then recrystallized (EtOH); mp
1
210−211 °C (EtOH); white solid; yield 73% (297 mg); H
NMR (CDCl3, 300 MHz) δ (ppm) 10.50 (bs, 1H), 7.97 (d J =
8.7 Hz, 4H), 7.82 (d J = 7.6 Hz, 2H), 7.33 (m, 2H), 7.13 (d J =
8.7 Hz, 4H), 7.05 (t J = 7.6 Hz, 1H), 3.85 (s, 6H); 13C NMR
(CDCl3, 75.5 MHz) δ (ppm) 169.7, 161.8, 159.0, 139.3, 131.0,
128.8, 123.1, 120.3, 119.0, 114.0, 91.8, 55.6; HRMS-ESI m/z
calcd. for C25H20N4O2 [M + H]+ 409.1665, found 409.1659.
2-(Dimethylamino)-4-(4-fluorophenyl)-6-phenylpyrimi-
dine-5-carbonitrile 14{5,12,1}. Purified by flash chromatog-
raphy (DCM/MeOH = 9:1) and then recrystallized (EtOH);
mp 237−238 °C (EtOH); white solid; yield 81% (257 mg); 1H
NMR (DMSO-d6, 300 MHz) δ (ppm) 8.04−8.01 (m, 2H),
7.99−7.91 (m, 2H), 7.57−7.55 (m, 3H), 7.43−7.37 (m, 2H),
3.32 (s, 6H); 13C NMR (DMSO-d6, 75.5 MHz) δ (ppm) 170.2,
169.7, 160.6, 137.1, 133.6, 132.0, 131.5, 129.3, 128.9, 119.2,
116.1, 115.8, 90.3, 37.3; HRMS-ESI m/z calcd. for C19H15N4F
[M + H]+ 319.1359, found 319.1354.
6-Ethyl-2-(methylamino)-4-phenylpyrimidine-5-carboni-
trile 14{2,15,1}. Purified by flash chromatography (DCM/
MeOH = 8:2) and then recrystallized (EtOH); mp 143−144
°C (EtOH); white solid; yield 46% (109 mg); 1H NMR
(CDCl3, 300 MHz) δ (ppm) 7.99−7.85 (m, 2H), 7.51−7.49
(m, 3H), 5.65 (bs, 1H), 3.07 (s, 3H), 2.91 (q J = 7.2 Hz, 2H),
1.23 (t J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz) δ
(ppm) 176.7, 169.3, 162.0, 136.5, 130.8, 128.7, 128.5, 117.8,
92.8, 30.0, 28.2, 12.1; HRMS-EI m/z calcd. for C14H14N4 [M]+
238.1218, found 238.1228.
4-Ethyl-6-phenyl-2-(phenylamino)pyrimidine-5-carboni-
trile 14{4,15,1}. Purified by flash chromatography (DCM/
MeOH = 9:1) and then recrystallized (EtOH); mp 151−152
°C (EtOH); white solid; yield 51% (153 mg); 1H NMR
(CDCl3, 300 MHz) δ (ppm) 8.01−7.98 (m, 2H), 7.71−7.68
(m, 2H), 7.57−7.51 (m, 4H), 7.37 (m, 2H), 7.12 (m, 1H), 3.07
(t J = 7.5 Hz, 2H), 1.41 (t J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz) δ (ppm) 169.1, 159.0, 138.1, 135.9, 133.5, 131.1,
128.9, 128.6, 128.5, 123.6, 119.7, 117.1, 95.0, 30.1, 11.8;
4-(3-Chlorophenyl)-2-(dimethylamino)-6-phenylpyrimi-
dine-5-carbonitrile 14{5,13,1}: Purified by flash chromatog-
raphy (DCM/MeOH = 9:1) and then recrystallized (EtOH);
mp 178−179 °C (EtOH); white solid; yield 75% (250 mg); 1H
G
dx.doi.org/10.1021/co4000503 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

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HRMS-EI m/z calcd. for C19H16N4 [M]+ 300.1375, found
300.1367.
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(19) Brown, D. J. The Pyrimidines, Supplement II; Wiley Interscience:
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds and
crystallographic information files (CIF) of compound
14{3,1,1}. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E.S.: Tel. +34881815732; fax +34-881815704; e-mail e.
sotelo@usc.es. A.C.: Tel. +34881815739; fax +34-881815704;
e-mail albertojose.coelho@usc.es.
■
New York, 1985.
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Funding
This work was financially supported by the Fondo Europeo de
Desarrollo Social (FEDER) and the Galician Government
(Project: 09CSA016234PR). E.S. is the recipient of a
Consolidation Group Research Grant from the Conselleria de
Educacion
Notes
́
(Xunta de Galicia).
The authors declare no competing financial interest.
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