Utility of bis(methylthio)methylene malononitrile as a synthon in the synthesis of new poly-functionalized cyanoiminopyrimidines

Article abstract of DOI:10.1007/s00706-017-2037-2

Abstract: A new series of 4-(alkyl/arylamino)-6-amino-5-cyano-2-cyanoimino-1H-pyrimidine was obtained via one-pot three-component reaction of bis(methylthio)methylene malononitrile, primary amines, and cyanoguanidine using sodium ethoxide as basic catalys

Full text of DOI:10.1007/s00706-017-2037-2

Monatsh Chem
DOI 10.1007/s00706-017-2037-2
ORIGINAL PAPER
Utility of bis(methylthio)methylene malononitrile as a synthon
in the synthesis of new poly-functionalized cyanoiminopyrimidines
Amr Hassan Moustafa1 Amer Anwar Amer1
•
Received: 28 May 2017 / Accepted: 10 July 2017
Ó Springer-Verlag GmbH Austria 2017
Abstract A new series of 4-(alkyl/arylamino)-6-amino-5-
cyano-2-cyanoimino-1H-pyrimidine was obtained via one-
pot three-component reaction of bis(methylthio)methylene
malononitrile, primary amines, and cyanoguanidine using
sodium ethoxide as basic catalyst. The same new products
were prepared by classical route via reaction of (alkyl/
Graphical abstract
OH
H2N
NHR
N
R
NH
R
N
O
NC
H2
R1
NC
NC
SMe
SMe
NC
NC
RNH2
R1
+
H2
N
N
H
N
N
H
N
N
H
N
EtONa
arylamino)(methylthio)methylene
malononitrile
with
OEt
OEt
NC
H2
NC
H2
PhCH2CH2NH2
Ph
PhCH2CH2NH2
N
cyanoguanidine in presence of sodium ethoxide. In absence
of amines, bis(methylthio)methylene malononitrile reacts
directly with cyanoguanidine in presence of sodium
ethoxide to give 4-ethoxy-2-cyanoimino-1H-pyrimidine.
On the other hand, multicomponents reaction of
bis(methylthio)methylene malononitrile with cyanoguani-
dine and binucleophilic b-hydroxyamines and/or ortho-
phenylenediamine gave perspective 4-methyl- and/or
5-methyl-1,3-oxazolidin-2-ylidenemalononitrile and 1,3-
dihydro-2H-benzimidazol-2-ylidenemalononitrile, which
are inactive compounds toward reaction with cyanoguani-
dine to give the expected 4-(alkyl/arylamino)-2-
cyanoimino-1H-pyrimidines.
N
NH
N
N
N
N
N
N
N
H
N
H
H
Keywords Bis(methylthio)methylene malononitrile Á
Amines Á Cyanoguanidine Á Cyanoiminopyrimidine Á
Multicomponent reaction Á Cycloadditions
Introduction
Bis(methylthio)methylene malononitrile is an attractive
synthon extensively utilized as reactant or reaction inter-
mediate, where the dimethylthio and/or the dicyano groups
in its structure are suitably situated to enable reactions with
various binucleophilic reagents to form a diverse of hete-
rocyclic compounds [1–9]. Literature survey showed that
the pyrimidine scaffold has been identified as a central
structure element in a number of biological active com-
pounds and has broad application in drug development for
the treatment of bacterial infection [10], cancer [11],
tuberculosis [12], leukemia [13], malaria parasite infection
[14], HIV-1 infection [15], leishmaniasis [16], and
inflammations [17]. We here envisioned that the multi-
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-2037-2) contains supplementary
material, which is available to authorized users.
& Amer Anwar Amer
amer_chem@yahoo.com
component
reaction
of
bis(methylthio)methylene
malononitrile, primary aliphatic/aromatic amines, and
cyanoguanidine would be utilized in pyrimidine syntheses.
1
Department of Chemistry, Faculty of Science, Sohag
ˆ
University, Sohag 82524, Egypt
123

A. H. Moustafa, A. A. Amer
signals at 172.2, 137.1, 135.4, 135.0, 134.6, 131.2, 128.8,
128.0, 127.4, 127.2, 117.0, 59.6 ppm, which are assigned
to carbons of aromatic and two nitrile groups, while CH3 is
characterized by signal at 17.9 ppm.
Results and discussion
Herein, we reported a new method for the synthesis of
poly-functionalized 4-(alkyl/arylamino)-2-cyanoimino-1H-
pyrimidine (4-alkyl/arylamino-CIPMs). The target
4-(alkyl/arylamino)-6-amino-5-cyano-2-cyanoimino-1H-
pyrimidines 5a–5g were prepared via one-pot multicom-
ponent reaction of bis(methylthio)methylene malononitrile
(1), primary aliphatic/aromatic amines 2a–2g namely:
aniline, 4-chloro-, 2-methyl-, 3-methyl-, 4-methyl-aniline,
2-aminopropane, and b-phenylethylamine, respectively,
and cyanoguanidine (3) in the presence of sodium ethoxide
as basic catalyst (method A). The same products 5a–5g
were also prepared through two-component reaction of
(alkyl/arylamino)(methylthio)methylene malononitrile 4a–
4g with cyanoguanidine in presence of sodium ethoxide
(method B). The reaction mechanism for the formation of
product 5 was assumed to proceed via nucleophilic sub-
stitution of the first methylthio group by primary amine, in
absence of catalyst [18] to give the (un)separated products
4a–4g, followed by another nucleophilic substitution of the
second methylthio group by amino group of cyanoguani-
dine, in the presence of strong base (sodium ethoxide) to
give intermediate I, which underwent intramolecular
cyclization through nucleophilic addition of NH2 group on
C:N group (Scheme 1).
IR spectrum of 6 showed characteristic absorption bands at
3376, 3327, 3197 cm-1 for NH2 and NH groups, 2993,
2940 cm-1 for the aliphatic C–H, 2226, 2187 cm-1 for two
C:N groups. The 1H NMR spectrum of 6 showed the pres-
ence of two broad singlet signals at 11.51 and 7.71 ppm,
which are characteristic of NH and NH2, respectively, quartet
and triplet signals at 4.42 and 1.32 ppm with coupling con-
stant J = 7.0 Hz attributed to methylene and methyl of
ethoxy group, respectively. Its 13C NMR spectrumshowed six
signals at 171.5, 163.6, 159.9, 114.2, 112.3, 66.7 ppm, which
are assigned to carbons of aromatic and two nitrile groups,
while two sp3 carbons of ethoxy group are characterized by
two signals at 64.1 and 14.6 ppm. The NOESY spectrum of 6
showed a correlation peak between a proton of NH at
11.51 ppm and two protons of the NH2 group at 7.71 ppm,
which confirmed the cyanoimino form of product 6.
One-pot multicomponents reaction of bis(methylthio)-
methylene malononitrile (1), cyanoguanidine (3), and
bifunctional nucleophiles like b-hydroxyamines and ortho-
phenylenediamine afforded oxazolines 8a, 8b and 1,3-di-
hydro-2H-benzoimidazole 9 [20], respectively, instead of
expected products 4h–4j or 5h–5j (Scheme 2).
The chemical structure of products 8 and 9 was fully
characterized using 1H, 13C NMR, and IR spectroscopy and
elemental analysis. IR spectrum of 8b showed character-
istic absorption bands at 3259 cm-1 for NH group, 2991,
2904 cm-1 for C–H aliphatic, 2216, 2194 cm-1 for cyano
groups. Its 1H NMR spectrum showed the presence of
broad singlet signal at 9.94 ppm for NH; multiplet signal at
5.17–5.10 ppm for CH, two triplet signals at 3.88 and
3.37 ppm with coupling constant J = 8.8 and 8.4 Hz,
respectively, due to CH2 protons, and doublet signal at
1.43 ppm with coupling constant J = 4.5 Hz, which is
characteristic of methyl group. The 13C NMR spectrum of
8b showed three signals at 172.4, 116.2, and 81.5, which
are assigned to olefin and cyano groups; in addition to three
signals at 50.3, 31.7, and 19.6 ppm attributed to CH, CH2,
and CH3 carbons, respectively.
On the other hand, one-pot multicomponents reaction of
bis(methylthio)methylene malononitrile with cyanoguani-
dine in sodium ethoxide, then followed by addition of
primary aliphatic/aromatic amines 2a–2g afforded on hot
the corresponding 6-amino-5-cyano-2-cyanoimino-4-
ethoxy-1H-pyrimidine (4-ethoxy-CIPM, 6) instead of 5a–
5g. The inactivity of product 6 to react with primary
amines may be attributed to its precipitation through the
reaction. However, reaction of 4-ethoxy-CIPM with b-
phenylethylamine took place by refluxing them in DMF to
give product 7 instead of expected product 5g (Scheme 1).
The chemical structures of the new pyrimidines 5a–5g,
6, and 7 were proved by 1H, 13C NMR, and IR spec-
troscopy and elemental analysis. The IR spectra of 5a–5g
and 6 showed formation of cyanoimino =N– C:N group,
in which an absorption band of cyano group is given at
2180–2194 cm-1 [19]. For example the IR spectrum of 5c
showed characteristic absorption bands at 3229,
3137 cm-1 for NH2 and NH groups, 3055 cm-1 for the
aromatic C–H, 2927 cm-1 for the aliphatic C–H, 2215,
Conclusion
1
2189 cm-1 for two C:N groups. Its H NMR spectrum
In conclusion, we have demonstrated that a new series of
4-(alkyl/arylamino)-6-amino-5-cyano-2-cyanoimino-1H-
pyrimidines 5a–5g can be synthesized via one-pot three-
showed the presence of singlet signal at 10.18 ppm char-
acteristic of NH, multiplet signal at 7.30–7.26 ppm due to
aromatic protons, three singlet signals at 4.08, 2.63,
2.25 ppm characteristic of NH, NH2, and methyl groups,
respectively. The 13C NMR spectrum of 5c showed twelve
component
reaction
of
bis(methylthio)methylene
malononitrile with primary amines and cyanoguanidine
using sodium ethoxide as basic catalyst.
123

Utility of bis(methylthio)methylene malononitrile as a synthon in the synthesis of new…
Scheme 1
NH
NHR
N
N
NC
H
RNH2
2a-2g
H2N
N
H
N
N
SMe
CN
R
NC
NC
SMe
SMe
3
N
N
H
NH2
..
NC
EtONa / EtOH
EtOH
4a-4g
1
I
NH
N
EtONa
/ EtOH
H2N
N
H
3
NHR
N
RNH2
2a-2g
OEt
NC
NC
N
N
N
H2N
N
H
N
EtONa / EtOH
H2N
N
H
N
5a-5g
6
2a, 4a, 5a; R = Ph
PhCH2CH2NH2
DMF
2b, 4b, 5b; R = 4-ClC6H4
2c, 4c, 5c; R = 2-MeC6H4
2d, 4d, 5d; R = 3-MeC6H4
2e, 4e, 5e; R = 4-MeC6H4
2f, 4f, 5f; R = CH(Me)2
2g, 4g, 5g; CH2CH2Ph
OEt
NC
N
NH
Ph
H2N
N
H
N
N
H
7
Scheme 2
OH
R
O
H2N
R
NC
NC
NC
NC
NHR
SMe
R1
R1
, EtOH
i)
N
H
8a, 8b
ii) H2NC(=NH)NHCN, EtONa
4h-4j
8a, R = H, R1 = Me
8b, R = Me, R1 = H
OR
NOT
NC
NC
SMe
SMe
NHR
NH2
NC
H2N
N
H
1
i)
, EtOH
NC
NC
N
CN
NH2
N
H
N
N
H
ii) H2NC(=NH)NHCN, EtONa
5h-5j
9
123

A. H. Moustafa, A. A. Amer
6-Amino-4-[(4-chlorophenyl)amino]-2-cyanoimino-1,2-di-
hydropyrimidine-5-carbonitrile (5b, C12H8ClN7)
Experimental
Yield: method A 62%, method B 69%; m.p.: 252–254 °C;
FT-IR: mꢀ = 3219, 3123, 3069, 3010, 2208, 2194,
Melting points were detected with a Kofler melting
points apparatus. Infrared spectra were recorded with a
FT-IR-ALPHBROKER-Platinum-ATR spectrometer. 1H
NMR and 13C NMR spectra for all compounds were
recorded in DMSO-d6 on a Bruker Bio Spin AG spec-
trometer at 400 MHz and 100 MHz, respectively.
Elemental analyses were obtained on a Perkin-Elmer
CHN-analyzer model.
1
1588 cm-1; H NMR (400 MHz, DMSO-d6): d = 10.55
(s, 1H, NH), 7.47 (d, J = 7.2 Hz, 2H, CHarom), 7.33 (d,
J = 7.2 Hz, 2H, CHarom), 4.08 (s, 1H, NH), 2.56 (s, 2H,
NH2) ppm; 13C NMR (100 MHz, DMSO-d6): d = 172.2,
137.9, 135.6, 131.2, 129.6, 128.3, 126.6, 126.1, 121.0,
62.6 ppm.
6-Amino-2-cyanoimino-1,2-dihydro-4-[(2-
methylphenyl)amino]pyrimidine-5-carbonitrile
(5c, C13H11N7)
General procedure for the synthesis of compounds
5a–5g
Yield: method A 62%, method B 67%; m.p.: 237–239 °C;
Method A (three components)
ꢀ
FT-IR: m = 3229, 3137, 3055, 3003, 2927, 2215, 2189,
Equimolar amounts (3 mmol) of bis(methylthio)methylene
malononitrile (1) and primary amine 2 namely: aniline,
4-chloro-, 2-methy-, 3-methy-, 4-methy-aniline, 2-amino-
propane or b-phenylethylamine in 40 cm3 ethanol were
stirred with reflux for about 8 h, then 3 mmol of
cyanoguanidine (3) in freshly prepared sodium ethoxide
solution (4 mmol of sodium in 20 cm3 absolute ethanol)
was added and the reaction mixture was refluxed for about
5 h. After completion of reaction (monitored with TLC),
the reaction mixture was cooled to RT and poured in ice-
cold water and neutralized to pH 7.0 with diluted HCl. The
formed precipitate was collected by filtration, washed
several times with distilled water, dried, and recrystallized
from ethanol.
1
1586 cm-1; H NMR (400 MHz, DMSO-d6): d = 10.18
(s, 1H, NH), 7.30–7.26 (m, 4H, CHarom), 4.08 (s, 1H, NH),
2.63 (s, 2H, NH2), 2.25 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 172.2, 137.1, 135.4, 135.0,
134.6, 131.2, 128.8, 128.0, 127.4, 127.2, 117.0, 59.6,
17.9 ppm.
6-Amino-2-cyanoimino-1,2-dihydro-4-[(3-
methylphenyl)amino]pyrimidine-5-carbonitrile
(5d, C13H11N7)
Yield: method A 69%, method B 70%; m.p.: 234–235 °C;
ꢀ
FT-IR: m = 3299, 3148, 3089, 3010, 2960, 2206, 2193,
1
1600 cm-1; H NMR (400 MHz, DMSO-d6): d = 10.45
(s, 1H, NH), 7.29 (s, 1H, CHarom), 7.09 (m, 3H, CHarom),
4.05 (s, 2H, NH2), 2.52 (s, 1H, NH), 2.33 (s, 3H, CH3)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 171.9, 139.1,
136.5, 129.4, 127.9, 125.2, 124.7, 121.8, 121.4, 120.1,
116.7, 62.6, 21.3 ppm.
Method B (two components)
Equimolar
amounts
(3 mmol)
of
(alkyl/ary-
lamino)(methylthio)methylene malononitile 4a–4g and
cyanoguanidine (3) were added to a freshly prepared
sodium ethoxide solution (4 mmol of sodium in 60 cm3 of
absolute ethanol). The resulting mixture was heated under
reflux for about 5 h. After completion of reaction (moni-
tored with TLC), the reaction mixture was cooled to RT
and poured in ice-cold water and neutralized to pH 7.0 with
diluted HCl. The formed precipitate was collected by fil-
tration, washed several times with distilled water, dried,
and recrystallized from ethanol.
6-Amino-2-cyanoimino-1,2-dihydro-4-[(4-
methylphenyl)amino]pyrimidine-5-carbonitrile
(5e, C13H11N7)
Yield: method A 64%, method B 67%; m.p.: 242–244 °C;
ꢀ
FT-IR: m = 3215, 3119, 3054, 3003, 2951, 2209, 2188,
1
1587 cm-1; H NMR (400 MHz, DMSO-d6): d = 10.43
(s, 1H, NH), 7.22 (d, J = 6.8 Hz, 2H, CHarom), 7.16 (d,
J = 7.6 Hz, 2H, CHarom), 4.05 (s, 3H, NH2 ? NH), 2.32
(s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 171.9, 136.7, 133.9, 130.1, 129.0, 124.9, 124.5, 123.4,
119.6, 60.3, 21.0 ppm.
6-Amino-4-anilino-2-cyanoimino-1,2-dihydropyrimidine-5-
carbonitrile (5a, C12H9N7)
Yield: method A 69%, method B 74%; m.p.: 228–229 °C;
6-Amino-2-cyanoimino-1,2-dihydro-4-(2-propyl-
amino)pyrimidine-5-carbonitrile (5f, C9H11N7)
Yield: method A 58%, method B 62%; m.p.: 218–219 °C;
ꢀ
FT-IR: m = 3240, 3116, 3067, 3012, 2210, 2183,
1
1598 cm-1; H NMR (400 MHz, DMSO-d6): d = 10.52
(s, 1H, NH), 7.44–739 (m, 2H, CHphenyl), 7.31–7.27 (m,
3H, CHphenyl), 4.06 (s, 2H, NH2), 2.53 (s, 1H, NH) ppm;
13C NMR (100 MHz, DMSO-d6): d = 172.0, 136.6, 129.6,
128.6, 127.2, 124.8, 124.4, 121.5, 119.5, 62.6 ppm.
ꢀ
FT-IR: m = 3269, 3187, 3096, 3073, 2972, 2935, 2208,
2191, 1567 cm-1 1H NMR (400 MHz, DMSO-d6):
;
d = 8.52 (s, 1H, NH), 4.01 (m, 4H, CH ? NH2 ? NH),
1.21 (d, J = 5.8 Hz, 6H, 2CH3) ppm; 13C NMR
123

Utility of bis(methylthio)methylene malononitrile as a synthon in the synthesis of new…
(100 MHz, DMSO-d6): d = 171.5, 163.0, 124.2, 117.4,
40 cm3 ethanol were stirred with reflux for about 8 h, then
117.2, 60.2, 46.4, 22.8 ppm.
3 mmol of cyanoguanidine (3) in freshly prepared sodium
ethoxide solution (4 mmol of sodium in 20 cm3 absolute
ethanol) was added and the reaction mixture was refluxed
for about 5 h. After completion of reaction (monitored with
TLC), the reaction mixture was cooled to RT and poured in
ice-cold water and neutralized to pH *7.0 with diluted
HCl. The formed precipitate was collected by filtration,
washed several times with distilled water, dried, and
recrystallized from dioxane.
6-Amino-2-cyanoimino-1,2-dihydro-4-[(2-
phenylethyl)amino]pyrimidine-5-carbonitrile
(5g, C14H13N7)
Yield: method A 61%, method B 64%; m.p.: 241–242 °C;
ꢀ
FT-IR: m = 3281, 3127, 3077, 3025, 2953, 2933, 2208,
2180, 1591 cm-1 1H NMR (400 MHz, DMSO-d6):
;
d = 8.74 (s, 1H, NH), 7.35–7.19 (m, 5H, CHphenyl), 3.88
(s, 3H, NH2 ? NH), 3.57 (q, J = 7.2 Hz, 2H, CH2), 2.88
(t, J = 7.2 Hz, 2H, CH2) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 172.4, 138.5, 129.2, 129.0, 128.9, 128.8,
126.9, 126.5, 116.9, 59.9, 44.7, 35.5 ppm.
(4-Methyl-1,3-oxazolidin-2-ylidene)malononitrile
(8a, C7H7N3O)
ꢀ
Yield 81%; m.p.: 128–130 °C; FT-IR: m = 3230, 3173,
1
2981, 2940, 2217, 2195, 1601 cm-1; H NMR (400 MHz,
6-Amino-2-cyanoimino-1,2-dihydro-4-ethoxypyrimidine-5-
carbonitrile (6, C8H8N6O)
DMSO-d6): d = 9.97 (br. s, 1H, NH), 4.77 (m, 1H, CH),
4.25 (m, 2H, CH2), 1.26 (d, J = 5.8 Hz, 3H, CH3) ppm;
13C NMR (100 MHz, DMSO-d6): d = 172.4, 116.2, 115.8,
77.3, 52.9, 31.8, 19.4 ppm.
A mixture of bis(methylthio)methylene malononitrile (1,
0.51 g, 3 mmol) and cyanoguanidine (3, 0.25 g, 3 mmol)
in freshly prepared sodium ethoxide solution (4 mmol of
sodium in 50 cm3 absolute ethanol) was refluxed for about
5 h. After completion of the reaction, the formed precip-
itate was filtered on hot and recrystallized from DMF.
(5-Methyl-1,3-oxazolidin-2-ylidene)malononitrile
(8b, C7H7N3O)
ꢀ
Yield 84%; m.p.: 140–142 °C; FT-IR: m = 3259, 2991,
2904, 2216, 2194, 1602 cm-1 1H NMR (400 MHz,
;
ꢀ
Yield: 77%; m.p.:[300 °C; FT-IR: m = 3376, 3327, 3197,
2993, 2940, 2226, 2187, 1593 cm-1; H NMR (400 MHz,
1
DMSO-d6): d = 9.94 (br. s, 1H, NH), 5.17–5.10 (m, 1H,
CH), 3.88 (t, J = 8.8 Hz, 1H, CH2), 3.37 (t, J = 8.4 Hz,
1H, CH2), 1.43 (d, J = 4.5 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 172.4, 116.2, 81.5, 50.3, 31.7,
19.6 ppm.
DMSO-d6): d = 11.51 (br. s, 1H, NH), 7.71 (br. s, 2H,
NH2), 4.42 (q, J = 7.0 Hz, 2H, CH2), 1.32 (t, J = 7.0 Hz,
3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 171.5, 163.6, 159.9, 114.2, 112.3, 66.7, 64.1,
14.6 ppm.
1-[6-Amino-5-cyano-4-ethoxypyrimidin-2(1H)-ylidene]-3-
(2-phenylethyl)guanidine (7, C16H19N7O)
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malononitrile (1) and bidentate amine namely: 2-amino-
propan-1-ol, 1-aminopropan-2-ol or o-phenylenediamine in
123

A. H. Moustafa, A. A. Amer
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