Syntheses of Some New N-Linked Pyrimidine-2-amines with Pyrazinopyrimidines, Thienopyrimidines, and Benzazoles via Reactions of Various Nucleophiles with Cyanamides

Article abstract of DOI:10.1002/jhet.2972

New heterocycles containing 2-aminopyrimidine moiety linked with pyrazino[1,2-c]pyrimidines, thieno[2,3-d]pyrimidines, benzimidazoles, benzothiazoles, and benzoxazoles have been prepared by an efficient method starting from N-(pyrimidin-2-yl)cyanamides.

Full text of DOI:10.1002/jhet.2972

Month 2017
Syntheses of Some New N-Linked Pyrimidine-2-amines with
Pyrazinopyrimidines, Thienopyrimidines, and Benzazoles via Reactions of
Various Nucleophiles with Cyanamides
*
Amr Hassan Moustafa,
Walaa Wefki Ahmed, and Ahmed Khodairy
Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt
*
E-mail: amr_hassanegypt@ymail.com
Received January 21, 2017
DOI 10.1002/jhet.2972
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
New heterocycles containing 2-aminopyrimidine moiety linked with pyrazino[1,2-c]pyrimidines,
thieno[2,3-d]pyrimidines, benzimidazoles, benzothiazoles, and benzoxazoles have been prepared by an effi-
cient method starting from N-(pyrimidin-2-yl)cyanamides.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
2-aminopyrimidines via heterocyclization reaction of
N-(pyrimidin-2-yl)cyanamides with some reagents
containing both nucleophile and electophile and/or
binucleophiles.
2-Aminopyrimidine is an interesting structural element
present in a large number of both natural compounds
(folic acid, guanine, and meridianins) [1,2] and
synthetic
drugs
(zovirax
“acyclovir”,
curantil
“dipyridamole”, icotidine, methotrexate, piribedil,
trimethoprim, etc.) [3,4]. Its derivatives possess diverse
biological activities, for example, cardioprotective [5],
antipsychotic [6], antitubercular [7], antimalarial [8,9],
and antitumor [10,11]. Mostly, the formation of
heterocyclic 2-aminopyrimidine system was pursued via
reactions of nucleophilic substituted guanidine with
diverse bi-electrophiles, such as β-dicarbonyl, β-
ketoester, enone, and enaminone derivatives [4,11–13].
RESULTS AND DISCUSSION
The starting materials, N-(pyrimidin-2-yl)cyanamides 1
and 2, were prepared according to the published
procedure described earlier [18,19]. Cyanamide 6 has not
yet been reported in the literature and was obtained via
one-pot multicomponent reaction of ethyl 3-oxo-3-
phenylpropanoate 4, dimethylformamide dimethylacetal 5
(DMF-DMA 5), and inexpensive commercially available
cyanoguanidine 3, (Method A, Scheme 1); or via two-
component reaction of enaminone 7 with cyanoguanidine
3, (Method B, Scheme 1).
The starting cyanamide 6 has been synthesized by
heating of ethyl 3-oxo-3-phenylpropanoate 4 with DMF-
DMA 5 for 1 h in solvent-free condition; then an
equimolecular amount of cyanoguanide 3 in ethanol was
added, and the reaction mixture was further refluxed for
5 h in the presence of sodium ethoxide as basic catalyst.
As
a result of the limited available numbers of
substituted guanidines, this approach is of restricted use
for the preparation of targeted heterocyclic 2-
aminopyrimidines. So the most appropriate method to
introduce 2-aminopyrimidine moiety can be achieved by
using N-(pyrimidin-2-yl)cyanamides [14]. Some of these
cyanamides have anti-inflammatory [15], antifungi [16],
and anticancer [17] activities. Herein, we will describe
a detailed synthesis for a number of N-heterocyclic
© 2017 Wiley Periodicals, Inc.

A. H. Moustafa, W. W. Ahmed, and A. Khodairy
Vol 000
Scheme 1. Starting material cyanamides 1, 2, and 6.
The plausible mechanism for the formation of product 6
was assumed to proceed via production of enaminone 7
[20] by reaction between 3-oxo-3-phenylpropanoate 4
and DMF-DMA 5, then its interaction with
cyanoguanidine 3 in the presence of sodium ethoxide
takes place at carbon atom in 3-position with elimination
of dimethylamine. It was shown that nucleophilicity of
the guanidine fragment was reduced by electron-adjacent
nitrile group, and it cannot complete reaction without a
strong nucleophile ethoxide anion [19]. Thus, the first
step is apparently formed intermediate I, which is reacted
with cyanoguanidine 3 by elimination of ethanol to give
intermediate II in tautomer with enol form III in basic
medium. The resulting intermediate undergoes
intramolecular cyclization in two possible ways by
elimination of water to give cyanamide 6 (route A) or by
elimination of ethanol to give cyanamide 60 (route B,
Scheme 2).
This regioselectivity has been unambiguously
1
substantiated through the H, 13C NMR, and elemental
analyses.
The IR spectrum of compound 6 showed absorption
peaks at 1620 cmꢀ1 for C═N, 1705 cmꢀ1 for C═Oester
,
2261 cmꢀ1 for C☰N, 2897, 2932, 2980 cmꢀ1 for C─H
aliphatic, 3045 cmꢀ1 for C─H aromatic, and 3116 cmꢀ1
for NH group. 1H NMR spectrum of compound 6
showed presence of triplet and quartet signals at δ 1.06
and 4.12 characteristic of CH3 and CH2 groups,
respectively, two singlet signals at δ 8.91 and 12.59 for
CHpyrimidine and NH group, respectively, and multiplet
Scheme 2. The reaction mechanism for the synthesis of cyanamide 6. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2017
Syntheses of Some New N-Linked Pyrimidine-2-amines
signals at δ 7.49–7.56 ppm for phenyl protons. Its 13C
NMR spectrum showed 10 signals at δ 168.6, 165.0,
160.1, 137.0, 130.9, 129.7, 129.1, 128.6, 117.1, and
111.9, which are assigned to carbonyl, cyano, and
aromatic carbons, while the methyl and methylene carbon
atoms of ester group are characterized by signals at δ
14.0 and 61.7 ppm, respectively.
presence of three singlet signals at δ 3.85, 8.35, and
12.73 characteristic of OCH3, CONH, and exo NH
group, respectively; also, it exhibited two doublet
signals at δ 7.08 and 8.09 for phenyl group, two
doublet signals at δ 7.49 and 8.59 for pyrimidine
protons, doublet and doublet of doublets signals at δ
4.45–4.58 for two protons of CH2 at position 4 of
pyrazinopyrimidine ring, and two multiplet signals in
aliphatic region at δ 2.82–2.97 and 3.34–3.58 ppm for
protons of 2CH2 and CH at positions 9, 3, and 9a of
pyrazinopyrimidine ring, respectively. Its 13C NMR
spectrum showed 11 signals at δ 167.6, 167.0, 164.7,
163.9, 162.2, 158.6, 150.3, 129.1, 129.0, 114.9, and
109.7, which are assigned to two carbonyl groups and
aromatic carbons, while the aliphatic carbons of
pyrazinopyrimidine ring are characterized by signals at
δ 66.8, 55.9, 53.0, 39.5, and 34.0 ppm.
N-(Pyrimidin-2-yl)cyanamides
can
react
with
compounds containing both electrophilic and nucleophilic
centers, namely, ethyl (3-oxopiperazin-2-yl)acetate (8)
[21]
benzothiophene-3-carboxylate (10) [22] to give the
corresponding pyrazinopyrimidines 9a,b and
thienopyrimidines 11a–c, respectively, Scheme 3.
and
ethyl
2-amino-4,5,6,7-tetrahydro-1-
Reaction of hetarylcyanamides 2 or 6 with ethyl (3-
oxopiperazin-2-yl)acetate (8) was carried out by
nucleophilic addition of NH group to C☰N group to
form guanidine intermediate IV, which is easy to cyclize
via elimination of ethanol to give 3,4,9,9a–tetrahydro-2H-
pyrazino[1,2-c]pyrimidine-1,8-diones (9a,b). Thiophene
10 was reacted with cyanamides 1, 2, or 6 in the presence
of HCl. Presumably, the use of hydrochloric acid
enhances the electrophilicity of cyanamides and converts
them into chloroformamidines V [23], which are easy to
react with 10 via intermediate VI, which undergoes
intramolecular cyclization with elimination of ethanol to
produce 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-
4(3H)-ones (11a–c) (Scheme 3).
The IR spectrum of compound 11a showed
disappearance of cyano group while exhibited
characteristic absorption bands at 1624 cmꢀ1 for C═N,
1654 cmꢀ1 for C═O, 2850 and 2926 cmꢀ1 for C─H
aliphatic, 3044 cmꢀ1 for C─H aromatic and 3235 and
1
3374 cmꢀ1 for 2N─H. Its H NMR spectrum showed the
presence of four singlet signals at δ 2.43, 6.97, 11.07, and
13.24 characteristic of two CH3, CH pyrimidine ring,
CONH, and exo NH groups, respectively, two triplet
signals at δ 2.68 and 2.84 for two CH2 groups at position
5 and 8 of tetrahydrobenzothieno[2,3-b]pyrimidine, and
the other two methylene groups appeared as multiplet
signals at δ 1.77–1.80 ppm. Its 13C NMR spectrum
showed nine signals at δ 168.2, 158.2, 157.4, 148.7,
130.9, 128.3, 117.1, 115.4, and 114.7, which are assigned
to carbonyl group and aromatic carbons, one signal at δ
23.8 for symmetrical carbon of two methyl groups, and
four signals in aliphatic region of methylene groups at δ
25.7, 24.7, 23.1 and 22.3 ppm.
The structures of the newly synthesized compounds
9a,b and 11a–c were confirmed by their spectral IR,
1H, 13C NMR, and elemental analyses (see Supporting
Information). For example, in IR spectrum of
compound 9a, C☰N absorption band disappeared while
exhibited
a
characteristic absorption bands at
1608 cmꢀ1 for C═N, 1658 and 1708 cmꢀ1 for C═O
groups, 2840, 2915, and 2972 cmꢀ1 for C─H aliphatic,
3058 cmꢀ1 for C─H aromatic, and 3321 and
It has been reported that heating of some
hetarylcyanamides with ortho-phenylenediamines in
3222 cmꢀ1 for 2NH. Its H NMR spectrum showed the
1
Scheme 3. Synthesis of 2-aminopyrimidines 9a,b and 11a–c.
Journal of Heterocyclic Chemistry
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A. H. Moustafa, W. W. Ahmed, and A. Khodairy
Vol 000
cellosolve/conc. HCl [24] or in abs. EtOH [25] gave
benzimidazoles in low yield. Herein, we found that
interaction of cyanamides 1, 2, and 6 with ortho-
phenylenediamines or ortho-aminothiophenol in iso-
propanol/conc. HCl gave 2-aminobenzimidazoles and
2-aminobenzothiazoles 12a–h in good yield (Scheme 4).
Seemingly, using of iso-propanol/conc. HCl can
improve the electrophilicity of cyanamides and turning
them into chloroformamidines V, which are possible to
interact with amino or thiol groups to result guanidine or
thiocarbamide intermediates VII. Intermediates VII
undergo intramolecular cyclization via removal of
ammonia to give 12a–h. In contrast, reaction of
cyanamides 2 or 6 with ortho-aminophenol in iso-
propanol/conc. HCl gave low yield of 2-
aminobenzoxazoles 13a,b, respectively, while heating
them in DMF gave the same product 13a,b in a moderate
yield (Scheme 4).
group and exhibited five absorption peaks at 1604 cmꢀ1
for C═N, 2958 cmꢀ1 for C─H aliphatic, 3019 and
3082 cmꢀ1 for C─H aromatic, and 3170 cmꢀ1 for NH
1
group. Its H NMR spectrum showed two singlet signals
at δ 3.90 and 11.82 characteristic of OCH3 and NH
groups, respectively, three pairs of doublet signals: two
doublet signals at δ 7.59 and 8.66 with coupling constant
(J) 4.3 Hz due to CHpyrimidine, two doublet signals at δ
7.17 and 8.32 with coupling constant (J) 7.6 Hz for four
protons of phenylene group and two doublet signals at δ
7.69 and 7.96 with coupling constant (J) 7.4, 7.3 Hz due
to protons at position 4 and 7 of benzothiazole, and two
triplet signals at δ 7.26 and 7.42 ppm with coupling
constant (J) 7.3 and 7.4 Hz for two protons at position 5
and 6 of benzothiazole ring. Its 13C NMR spectrum
showed one signal at δ 55.9 because of methoxy carbon
atom, and the other aromatic carbons are characterized by
15 signals at δ 109.9, 114.9, 120.1, 121.7, 122.9, 126.3,
128.7, 129.6, 132.4, 150.1, 157.8, 159.4, 159.8, 162.5,
and 164.2 ppm.
The IR spectrum of compound 12d showed the
disappearance of absorption band corresponding to cyano
Scheme 4. Synthesis of compounds 12a–h and 13a,b.
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DOI 10.1002/jhet

Month 2017
Syntheses of Some New N-Linked Pyrimidine-2-amines
CONCLUSIONS
vacuum. The residual was dissolved in 100-mL distilled
water and acidified by addition of dilute HCl. The crude
product was filtered, washed with cold distilled water,
dried, and recrystallized from ethanol.
In summary, the three starting materials of N-(pyrimidin-
2-yl)cyanamides have been prepared. One of them is newly
synthesized via one-pot three-component reaction.
Reactions of N-(pyrimidin-2-yl)cyanamides with different
reagents having nucleophile–electrophile and di-
nucleophile centers have been studied, and all new
products were characterized by melting points and IR,
1H, and 13C NMR spectral analyses.
Method B: Two-component synthesis.
A mixture of
ethyl 2-benzoyl-3-(dimethylamino)acrylate (7) (0.01 mol,
2.47 gm) and cyanoguanidine (0.01 mol, 0.84 gm) in
sodium ethoxide solution (0.1 M, 50 ml) was refluxed
for 5 h. The mixture was cooled, and the solvent was
evaporated under vacuum. The residual was dissolved in
100-mL distilled water and acidified by addition dilute
HCl. The crude product was filtered, washed with cold
distilled water, dried, and recrystallized from ethanol.
Ethyl 2-(cyanoamino)-4-phenylpyrimidine-5-carboxyl-
EXPERIMENTAL
General.
All commercially available reagents were
ate (6).
yellow solid; mp 158–160°C; IR (ATR) νmax 3116, 3045,
2980, 2932, 2897, 2261, 1705, 1620 cmꢀ1 1H NMR
(400 MHz, DMSO-d6) δ 12.59 (br. s, 1H, NH), 8.91 (s,
1H, CHpyrimidine), 7.56–7.49 (m, 5H, CHarom.), 4.12 (q,
J = 7.1 Hz, 2H, CH2); 1.06 (t, J = 7.1 Hz, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6) δ 168.6, 165.0, 160.1,
137.0, 130.9, 129.7, 129.1, 128.6, 117.1, 111.9, 61.7,
14.0. Anal. Calcd for C14H12N4O2 (268): C, 62.68; H,
Yield (Method A 79%, Method B 89%);
purchased from Merck, Aldrich, and Fluka (Trading
Dynamic Company, Giza City, Egypt) and were used
without further purification. All reactions were
monitored by thin-layer chromatography using precoated
plates of silica gel G/UV-254 of 0.25 mm thickness
(Merck 60F254) using UV light (254/365 nm) for
visualization. Melting points were detected with a
Kofler melting points apparatus and uncorrected. IR
spectra were recorded with a Fourier transform infrared-
ALPHBROKER-Platinum-ATR spectrometer (Bruker,
Germany) and are given as cmꢀ1 using the attenuated
;
4.51; N, 20.88. Found: C, 62.34; H, 4.63; N, 20.54.
Procedure for synthesis of compounds 9a,b. A mixture of
ethyl (3-oxopiperazin-2-yl)acetate (8) (0.01 mol,
1.86 gm) and cyanamides 2 or 6 (0.01 mol) in 60 mL
dioxane was heated at 80°C for 3 h. After completion
total reflection (ATR) method. H NMR and 13C NMR
spectra for all compounds were recorded in DMSO-d6
on a Bruker Bio Spin AG spectrometer (Bruker,
Switzerland) at 400 and 100 MHz, respectively. For H
1
of
the
reaction
(monitored
with
thin-layer
1
chromatography), the products 9a,b were formed after
cooling, collected by filtration, and recrystallized from
iso-propanol-DMF (3:1).
6-{[4-(4-Methoxyphenyl)pyrimidin-2-yl]amino}-
1,3,4,8,9,9a-hexahydro-2H-pyrazino[1,2-c]pyrimidine-
NMR, chemical shifts (δ) were given in parts per
million (ppm) with reference to tetramethylsilane as an
internal standard (δ = 0); coupling constants (J) were
given in hertz (Hz), and data are reported as follows:
chemical shift, integration, and multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doublet of doublets). For 13C NMR, tetramethylsilane
(δ = 0) or DMSO (δ = 39.51) was used as internal
standard, and spectra were obtained with complete
proton decoupling. Elemental analyses were obtained on
a Perkin-Elmer CHN-analyzer model (Perkin Elmer,
Waltham, MA). The starting materials, N-(Pyrimidin-2-
yl)cyanamides 1 and 2, were prepared according to the
published procedure described earlier [18,19].
1,8-dione (9a).
272°C; IR (ATR) νmax 3321, 3222, 3058, 2972, 2915,
2840, 1708, 1658, 1608 cmꢀ1 1H NMR (400 MHz,
DMSO-d6) 12.73 (s, 1H, NHexo), 8.59 (d,
J = 5.3 Hz, 1H, CHpyrimidine), 8.35 (s, 1H, CONH),
8.09 (d, 8.7 Hz, 2H, CHarom.), 7.49 (d,
Yield 65%; white solid; mp 270–
;
δ
J
=
J = 5.3 Hz, 1H, CHpyrimidine), 7.08 (d, J = 8.7, 2H,
CHarom.), 4.58 (d, J = 12.5 Hz, 1H, NCH2CH2NH),
4.45 (dd, J = 4.9, 12.6 Hz, 1H, NCH2CH2NH), 3.85
(s, 3H, OCH3), 3.58–3.34 (m, 3H, NCH2CH2NH, CH),
2.97–2.82 (m, 2H, COCH2CH). 13C NMR (100 MHz,
DMSO-d6) δ 167.6, 167.0, 164.7, 163.9, 162.2, 158.6,
150.3, 129.1, 129.0, 114.9, 109.7, 66.8, 55.9, 53.0, 39.5,
34.0. Anal. Calcd for C18H18N6O3 (366): C, 59.01; H,
4.95; N, 22.94. Found: C, 59.28; H, 4.84; N, 22.75.
Ethyl 2-[(1,8-dioxo-1,3,4,8,9,9a–hexahydro-2H-pyrazino
[1,2-c]pyrimidin-6-yl)amino]-4-phenylpyrimidine-5-
Typical experimental procedures. Preparation of ethyl 2-
(cyanoamino)-4-phenylpyrimidine-5-carboxylate (6). Method
A: One-pot three-component synthesis.
ethyl 3-oxo-3-phenylpropanoate 4 (0.01 mol, 1.73 mL)
and DMF-DMA 5 (0.011 mol, 1.46 mL) was heated at
90–95°C for 1 h; then, a solution of cyanoguanidine
(0.01 mol, 0.84 gm) in sodium ethoxide (0.1 M, 50 ml)
was added. The reaction mixture was refluxed for 5 h and
was cooled, and the solvent was evaporated under
A mixture of
carboxylate (9b).
Yield 61%; white solid; mp 248–
250°C; IR (ATR) νmax 3227, 3193, 3054, 2978, 2921,
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A. H. Moustafa, W. W. Ahmed, and A. Khodairy
Vol 000
2852, 1726, 1693, 1677, 1607 cmꢀ1; 1H NMR (400 MHz,
DMSO-d6) δ 12.16 (s, 1H, NHexo), 8.94 (s, 1H,
CHpyrimidine), 8.41 (s, 1H, CONH), 7.54–7.48 (m, 5H,
CHarom.), 4.55–4.48 (m, 2H, NCH2CH2NH), 4.12 (q,
J = 7.1 Hz, 2H, CH2), 3.38–3.36 (m, 3H, NCH2CH2NH,
CH), 2.95–2.84 (m, 2H, COCH2CH), 1.06 (t, J = 7.1 Hz,
3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 167.5,
166.9, 166.7, 165.9, 165.1, 160.5, 151.1, 138.3, 130.2,
128.9, 128.5, 116.6, 61.3, 52.9, 41.0, 39.3, 33.8, 14.1.
Anal. Calcd for C20H20N6O4 (408): C, 58.82; H, 4.94; N,
20.58. Found: C, 58.53; H, 4.99; N, 20.72.
δ 12.81 (s, 1H, NHexo), 11.74 (s, 1H, NHendo), 9.06 (s,
1H, CHpyrimidine), 7.64–7.54 (m, 5H, CHarom.), 4.15 (q,
J = 7.1 Hz, 2H, CH2), 2.83 (t, J = 5.3 Hz, 2H, CH2), 2.69
(t, J = 5.3 Hz, 2H, CH2), 1.81–1.76 (m, 4H, 2CH2), 1.08
(t, J = 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-
d6) δ 165.4, 164.6, 161.1, 158.9, 157.3, 147.9, 137.4,
131.0, 130.9, 129.2, 129.1, 128.9, 128.8, 117.9, 117.8,
61.7, 25.6, 24.8, 23.1, 22.3, 14.0. Anal. Calcd for
C23H21N5O3S (447): C, 61.73; H, 4.73; N, 15.65. Found:
C, 61.63; H, 4.93; N, 15.55.
5-Chloro-N-(4,6-dimethylpyrimidin-2-yl)-1H-benzimidazol-
2-amine (12a).
Yield 64%; beige solid; mp > 300°C;
General procedure for synthesis of 11a–c and 12a–h.
A
IR (ATR) νmax 3258, 3166, 3064, 3007, 2917,
mixture of cyanamides 1, 2, or 6 (0.01 mol) and ethyl 2-
amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
(10), ortho-phenylenediamines or ortho-aminothiophenol
(0.01 mol) in 40 mL iso-propanol and 0.91 mL conc.
HCl was refluxed for 3 h. After cooling, the reaction
mixture was neutralized by sodium hydroxide solution
(0.5 gm in 50-mL distilled water). The formed crude
product was filtered, washed with distilled water, dried,
and recrystallized from iso-propanol-DMF.
1
1637 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 12.02 (s,
1H, NHexo), 11.18 (br. s, 1H, NHendo), 7.56–7.52 (m, 2H,
CHarom.), 7.07 (d, J = 7.4 Hz, 1H, CHarom.), 6.85 (s, 1H,
CHpyrimidine), 2.47 (s, 6H, 2CH3). Anal. Calcd for
C13H12ClN5 (273): C, 57.04; H, 4.42; N, 12.95. Found:
C, 57.36; H, 4.51; N, 12.65.
N-(4,6-Dimethylpyrimidin-2-yl)-5-methoxy-1H-
benzimidazol-2-amine (12b).
Yield 69%; pale brown
solid; mp 278–280°C; IR (ATR) νmax 3236, 3072, 2994,
2-(4,6-Dimethylpyrimidin-2-ylamino)-5,6,7,8-tetrahydro
1
1636 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 11.82 (br.
[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (11a).
83%; beige solid; mp 250–251°C; IR (ATR) νmax 3374,
3235, 3044, 2926, 2850, 1654, 1624 cmꢀ1 1H NMR
Yield
s, 1H, NHexo), 11.03 (br. s, 1H, NHendo), 7.37 (d,
J = 8.5 Hz, 1H, CHarom.), 7.08 (s, 1H, CHarom.), 6.81 (s,
1H, CHpyrimidine), 6.68 (d, J = 8.5 Hz, 1H, CHarom.), 3.77
(s, 3H, CH3), 2.45 (s, 6H, 2CH3). Anal. Calcd for
C14H15N5O (269): C, 62.44; H, 5.61; N, 26.01. Found:
C, 62.15; H, 5.75; N, 26.27.
;
(400 MHz, DMSO-d6) δ 13.24 (s, 1H, NHexo), 11.07 (s,
1H, NHendo), 6.97 (s, 1H, CHpyrimidine), 2.84 (t, J = 5.1 Hz,
2H, CH2), 2.68 (t, J = 5.1 Hz, 2H, CH2), 2.43 (s, 6H,
2CH3), 1.80–1.77 (m, 4H, 2CH2); 13C NMR (100 MHz,
DMSO-d6) δ 168.2, 158.2, 157.4, 148.7, 130.9, 128.3,
117.1, 115.4, 114.7, 25.7, 24.7, 23.8, 23.1, 22.3. Anal.
Calcd for C16H17N5OS (327): C, 58.70; H, 5.23; N, 21.39.
Found: C, 58.54; H, 5.35; N, 21.49.
N-[4-(4-Methoxyphenyl)pyrimidin-2-yl]-1H-benzimidazol-
2-amine (12c).
Yield 59%; beige solid; mp 294–296°C;
IR (ATR) νmax 3329, 3192, 3052, 2961, 1636 cmꢀ1; H
NMR (400 MHz, DMSO-d6) δ 11.99 (br. s, 1H, NHexo),
10.87 (br. s, 1H, NHendo), 8.62 (d, J = 4.3 Hz, 1H,
CHpyrimidine), 8.19 (d, J = 8.1 Hz, 2H, CHarom.), 7.52 (d,
J = 4.4 Hz, 1H, CHpyrimidine), 7.46 (m, 2H, CHarom.), 7.13
(d, J = 8.3 Hz, 2H, CHarom.), 7.08 (m, 2H, CHarom.), 3.88
(s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ 164.7,
164.1, 162.4, 159.2, 158.7, 149.0, 141.9, 129.4, 128.9,
120.9, 114.9, 109.4, 55.9. Anal. Calcd for C18H15N5O
(317): C, 68.13; H, 4.76; N, 22.07. Found: C, 68.32; H,
4.58; N, 22.34.
1
2-[4-(4-Methoxyphenyl)pyrimidin-2-ylamino]-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]-pyrimidin-4(3H)-one
(11b).
Yield 92%; yellow solid; mp 222–224°C; IR
(ATR) νmax 3322, 3245, 3066, 2925, 2838, 1680,
1
1623 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 13.21 (s,
1H, NHexo), 11.24 (s, 1H, NHendo), 8.67 (d, J = 5.4 Hz,
1H, CHpyrimidine), 8.16 (d, J = 8.8 Hz, 2H, CHarom.), 7.66
(d, J = 5.4 Hz, 1H, CHpyrimidine), 7.12 (d, J = 8.8 Hz, 2H,
CHarom.), 3.87 (s, 3H, OCH3), 2.85 (t, J = 5.5 Hz, 2H,
CH2), 2.68 (t, J = 5.5 Hz, 2H, CH2), 1.81–1.77 (m, 4H,
2CH2); 13C NMR (100 MHz, DMSO-d6) δ 165.0, 164.0,
162.7, 158.9, 158.6, 157.4, 148.7, 130.9, 129.4, 129.2,
128.3, 127.9, 114.9, 110.6, 55.9, 25.7, 24.7, 23.1, 22.3.
Anal. Calcd for C21H19N5O2S (405): C, 62.21; H, 4.72;
N, 17.27. Found: C, 62.38; H, 4.61; N, 17.19.
N-[4-(4-Methoxyphenyl)pyrimidin-2-yl]-1,3-benzothiazol-
2-amine (12d).
Yield 76%; beige solid; mp > 280°C; IR
(ATR) νmax 3170, 3082, 3019, 2958, 1604 cmꢀ1; 1H NMR
(400 MHz, DMSO-d6) δ 11.82 (br. s, 1H, NH), 8.66 (d,
J = 4.3 Hz, 1H, CHpyrimidine), 8.32 (d, J = 7.6 Hz, 2H,
CHarom.), 7.96 (d, J = 7.3 Hz, 1H, CHarom.), 7.69 (d,
J = 7.4 Hz, 1H, CHarom.), 7.59 (d, J = 4.3 Hz, 1H,
CHpyrimidine), 7.42 (t, J = 7.4 Hz, 1H, CHarom.), 7.26 (t,
J = 7.3 Hz, 1H, CHarom.), 7.17 (d, J = 7.6 Hz, 2H,
CHarom.), 3.90 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6) δ 164.2, 162.5, 159.8, 159.4, 157.8, 150.1,
Ethyl 2-[(4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-
d]pyrimidin-2-yl)amino]-4-phenylpyrimidine-5-carboxylate
(11c).
Yield 75%; yellow solid; mp 248–249°C; IR
(ATR) νmax 3245, 3120, 3077, 2979, 2921, 2860, 2837,
1
1709, 1680, 1613 cmꢀ1; H NMR (400 MHz, DMSO-d6)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Syntheses of Some New N-Linked Pyrimidine-2-amines
132.4, 129.6, 128.7, 126.3, 122.9, 121.7, 120.1, 114.9,
109.9, 55.9. Anal. Calcd for C18H14N4OS (334): C, 64.65;
H, 4.22; N, 16.75. Found: C, 64.37; H, 4.31; N, 16.98.
Ethyl 2-(1H-benzimidazol-2-ylamino)-4-phenylpyrimidine-
Procedure for synthesis of compounds 13a,b. A mixture
of cyanamides 2 or 6 (0.01 mol), ortho-aminophenol
(0.01 mol, 1.09 gm) and 20 mL of DMF was refluxed for
12 h. The formed product upon cooling was filtered and
recrystallized from ethanol.
5-carboxylate (12e).
Yield 67%; beige solid;
mp > 300°C; IR (ATR) νmax 3331, 3260, 3050, 2978,
N-[4-(4-Methoxyphenyl)pyrimidin-2-yl]-1,3-benzoxazol-
1
2920, 1727, 1641 cmꢀ1; H NMR (400 MHz, DMSO-d6)
2-amine (13a).
Yield 59%; gray solid; mp 234–235°C;
IR (ATR) νmax 3140, 3062, 2938, 1654 cmꢀ1; H NMR
(400 MHz, DMSO-d6) δ 11.25 (br. s, 1H, NH), 8.63 (d,
J = 5.1 Hz, 1H, CHpyrimidine), 8.23 (d, J = 8.5 Hz, 2H,
CHarom.), 7.62–7.54 (m, 3H, 2CHarom. + CHpyrimidine),
7.30 (t, J = 7.5 Hz, 1H, CHarom.), 7.24 (t, J = 7.5 Hz, 1H,
CHarom.), 7.12 (d, J = 8.5 Hz, 2H, CHarom.), 3.87 (s, 3H,
OCH3); 13C NMR (100 MHz, DMSO-d6) δ 164.2, 162.4,
159.6, 158.4, 157.1, 148.3, 142.1, 129.3, 128.7, 124.7,
123.1, 118.1, 114.8, 110.5, 110.1, 55.9. Anal. Calcd for
C18H14N4O2 (318): C, 67.91; H, 4.43; N, 17.60. Found:
C, 67.73; H, 4.58; N, 17.75.
1
δ 11.96 (br. s, 2H, 2NH), 9.01 (s, 1H, CHpyrimidine), 7.60
(m, 2H, CHarom.), 7.55–7.48 (m, 5H, CHarom.), 7.10 (m,
2H, CHarom.), 4.14 (q, J = 7.0 Hz, 2H, CH2), 1.07 (t,
J = 7.0 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6)
δ 168.2, 165.7, 160.7, 159.9, 148.3, 138.3, 130.2, 129.0,
128.4, 121.5, 116.7, 114.1, 114.0, 61.3, 14.0. Anal. Calcd
for C20H17N5O2 (359): C, 66.84; H, 4.77; N, 19.49.
Found: C, 66.47; H, 4.92; N, 19.36.
Ethyl
2-[(5-chloro-1H-benzimidazol-2-yl)amino]-4-
Yield 62%;
phenylpyrimidine-5-carboxylate (12f).
beige solid; mp > 300°C; IR (ATR) νmax 3307, 3051,
3027, 2982, 2905, 1727, 1639 cmꢀ1; 1H NMR (400 MHz,
DMSO-d6) δ 12.10–11.75 (br. s, 2H, 2NH), 9.01 (s, 1H,
CHpyrimidine), 7.60 (d, J = 6.9 Hz, 2H, CHarom.), 7.53–7.48
(m, 5H, CHarom.), 7.10 (d, J = 8.4 Hz, 1H, CHarom.), 4.15
(q, J = 7.0 Hz, 2H, CH2), 1.08 (t, J = 7.0 Hz, 3H, CH3);
13C NMR (100 MHz, DMSO-d6) δ 168.2, 165.6, 160.6,
159.4, 149.2, 143.7, 141.8, 138.1, 130.4, 130.2, 129.1,
128.6, 128.4, 121.3, 118.8, 117.1, 61.4, 14.0. Anal. Calcd
for C20H16ClN5O2 (393): C, 60.99; H, 4.09; N, 17.78.
Found: C, 61.26; H, 4.02; N, 17.59.
Ethyl 2-(1,3-benzoxazol-2-ylamino)-4-phenylpyrimidine-
5-carboxylate (13b).
254°C; IR (ATR) νmax 3140, 3093, 3027, 2981, 2921,
1725, 1646 cmꢀ1 1H NMR (400 MHz, DMSO-d6) δ
Yield 53%; gray solid; mp 252–
;
11.96 (br. s, 1H, NH), 9.03 (s, 1H, CHpyrimidine), 7.63–
7.50 (m, 7H, CHarom.), 7.34–7.25 (m, 2H, CHarom.),
4.15 (q, J = 7.1 Hz, 2H, CH2), 1.08 (t, J = 7.1 Hz,
3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 167.6,
165.8, 161.2, 158.9, 156.2, 148.3, 137.8, 130.5,
129.2, 128.5, 124.9, 123.7, 118.5, 118.4, 118.3, 110.3,
61.5, 14.0. Anal. Calcd for C20H16N4O3 (360): C,
66.66; H, 4.48; N, 15.55. Found: C, 66.83; H, 4.32;
N, 15.65.
Ethyl 2-[(5-methoxy-1H-benzimidazol-2-yl)amino]-4-
phenylpyrimidine-5-carboxylate (12g).
Yield 55%;
beige solid; mp > 300°C; IR (ATR) νmax 3328, 3052, 2991,
2898, 1724, 1642 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ
11.90 (br. s, 2H, 2NH), 8.99 (s, 1H, CHpyrimidine), 7.61–7.51
(m, 5H, CHarom.), 7.36 (d, J = 8.6 Hz, 1H, CHarom.), 7.05 (s,
1H, CHarom.), 6.71 (d, J = 8.6 Hz, 1H, CHarom.), 4.13 (q,
J = 7.0 Hz, 2H, CH2), 3.76 (s, 3H, OCH3), 1.06 (t,
J = 7.0 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
168.2, 165.7, 160.7, 159.7, 155.5, 154.6, 148.0, 138.3,
130.5, 130.2, 129.1, 128.9, 128.6, 128.4, 116.4, 109.9,
61.3, 55.9, 14.0. Anal. Calcd for C21H19N5O3 (389): C,
64.77; H, 4.92; N, 17.98. Found: C, 64.39; H, 5.21; N, 17.86.
Ethyl 2-(1,3-benzothiazol-2-ylamino)-4-phenylpyrimidine-
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201°C; IR (ATR) νmax 3147, 3047, 3022, 2984, 2902,
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12.51 (s, 1H, NH), 9.04 (s, 1H, CHpyrimidine), 7.95 (d,
J = 7.9 Hz, 1H, CHarom.), 7.74–7.56 (m, 6H, CHarom.),
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A. H. Moustafa, W. W. Ahmed, and A. Khodairy
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SUPPORTING INFORMATION
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Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet