A route to dicyanomethylene pyridines and substituted benzonitriles utilizing malononitrile dimer as a precursor

Article abstract of DOI:10.3390/molecules16010298

The conditions of the reaction of malononitrile dimer with enaminones and arylidenemalononitrile could be adapted to yield either pyridines or benzene derivatives. A new synthesis of pyrido[1,2-a]pyrimidines from the reaction of malononitrile dimer 1 and

Full text of DOI:10.3390/molecules16010298

Molecules 2011, 16, 298-306; doi:10.3390/molecules16010298
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Route to Dicyanomethylene Pyridines and Substituted
Benzonitriles Utilizing Malononitrile Dimer as a Precursor
Noha M. Helmy 1,*, Fatma E. M. El-Baih 1, Monirah A. Al-Alshaikh 1 and Moustafa S. Moustafa 2
1
Women Students-Medical Studies & Sciences Sections, Chemistry Department, College of Science,
King Saud University, Riyadh, KSA, P.O. Box 22452, Riyadh 11495, Saudi Arabia
2
Department of Chemistry, Faculty of Science, University of Kuwait, Safat 13060, Kuwait
* Author to whom correspondence should be addressed; E-Mail: Elnagdinoha@yahoo.com;
Tel.: +966-500432102; Fax: +966-1 477-2245.
Received: 12 October 2010; in revised form: 20 December 2010 / Accepted: 22 December 2010 /
Published: 4 January 2011
Abstract: The conditions of the reaction of malononitrile dimer with enaminones and
arylidenemalononitrile could be adapted to yield either pyridines or benzene derivatives. A
new synthesis of pyrido[1,2-a]pyrimidines from the reaction of malononitrile dimer 1 and
2-phenyl-3-piperidin-1-yl-acrylonitrile (11) is described. Compound 1 condensed with
DMFDMA to yield an enaminonitrile that reacted with hydrazine hydrate to yield N',4,6-
triamino-2H-pyrazolo[3,4-b]pyridine-5-carboxamidine (17).
Keywords: malononitrile dimer; arlymethylenemalononitrile; benzylidenemalononitrile;
pyrazolopyridine
1. Introduction
Polyfunctionally substituted nitriles are versatile reagents that have been extensively utilized in the
past as precursors to polyfunctionally substituted heteroaromatics [1-4]. Interest in further developing
the synthetic potential of these compounds has been revived [5-7]. 2-Aminoprop-1-ene-1,1,3-
tricarbonitrile (1) has proved to be an excellent precursor to condensed pyridines, pyridazines, and
pyrazoles [8-10]. However, to our knowledge the utility of 1 as a precursor to polyfunctional aromatics
has received little attention. Elnagdi et al. have noted the formation of 3 as a side product from the
reaction of 2 with 1, while compound 4 was obtained as the main product [11] (Scheme 1). In

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connection to results reported earlier [11] we were able to react 1 with 5a,b to afford either pyridines
or benzene derivatives after changing the reaction conditions.
Scheme 1. Malononitrile dimer as precursor to heterocycles and substituted benzenes [11].
Ar
O
CN
H2N
CN
CN
Ar
H2N
NC
NH2
NH
+
+
CN
Me2N
Ar
CN
1
CN
CN
2
O
3 a
4 a-c
2,4 a, Ar = C6H5
b
, Ar = 4-CH3-C6H4
c, Ar = 4-CH3OC6H4
2. Results and Discussion
Thus reaction of 1 with 2a,b in ethanolic piperidine has afforded 4a,d as a sole product. On the
other hand, when the reaction was conducted in acetic acid in the presence of ammonium acetate and
refluxing for 4 hrs only 3a was formed via intermediate 5 (Scheme 2) The 1H-NMR of 4a, in addition
to phenyl proton signals, showed two doublets at δ = 7.16 ppm and δ = 7.86 ppm with J = 8 Hz, typical
for pyridine H-5 and H-4, respectively. A D2O exchangeable one proton signal for a NH group
appeared at δ = 9.42 ppm.
Scheme 2. Synthesis of pyridine 3a and substituted benzenes 4a,d.
Ar
EtOH/pip
NH
O
CN
reflux
4 hrs
H2N
CN
CN
Ar
+
CN
CN
Me2N
4 a,d
2
CN
a
d
Ar = Ph
Ar = 2-thienyl
1
AcOH
NH4OAc
reflux
CN
H2N
CN
CN
CN
NH2
H2N
NH2
H2N
-NMe2
NC
O
O
NC
NC
Ar
O
Me2N
Ar
3 d
Ar
3 a
5 a

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The 1H-NMR spectrum of 3a revealed a singlet at δ = 8.29 ppm for H-6 and two D2O exchangeable
amino signals at δ = 7.08 ppm and δ = 7.77 ppm, in addition to the phenyl protons (see Experimental).
The 13C-NMR clearly indicated the carbonyl carbon at δ = 190.23 ppm and two CN signals at
δ = 114.13 and 113.85 ppm.
In an attempt to generate further examples of the synthesis of substituted benzenes 3, malononitrile
dimer 1 was reacted with 2d in acetic acid/ammonium acetate, and a product with molecular formula
C13H8N4OS (M+ at m/z = 268) which we think to be 3d was isolated after reflux for 1/2 hrs; prolonged
1
heating did not change the identity of the compound. The H-NMR under D2O exchange of the
presumed structure 3d; showed, along with three thienyl protons, two amino group singlets at
δ = 7.1 ppm and δ = 7.9 ppm, and a doublet at δ = 8.2 ppm with J = 8 Hz, that could not be explained
or assigned to any proton in the suggested structure.
Repeating the same reaction using sodium acetate instead of ammonium acetate, and refluxing for 3
hrs, a whole new set of data were obtained. A compound with molecular formula C20H12N4O2S2 (M+
1
404) was obtained. H-NMR of this compound showed two singlets at δ= 7.47 ppm and δ= 8.98 ppm
each for one proton of C-5 and C-2 of the pyridine ring, respectively, in addition to six thienyl protons
and two amino signals. The 13C-NMR spectrum showed the presence of 19 different carbon atoms with
two carbonyl carbons at δ = 184.7 ppm. These data can be interpreted as corresponding to structure 7
that is assumed to result from initial reaction of the active methylene moiety and the amino function in
1 with 2d to yield the intermediate 6 that then cylizes to 7 (Scheme 3).
Scheme 3. Synthesis of 4,7-diamino-3,6-di(thiophene-2-carbonyl)quinoline-8-carbonitrile (7).
O
O
H2N
CN
CN
Ar
+
Ar
NH
CN
CN
AcOH
NaOAc
Me2N
CN
reflux
3 hrs
2d
Ar = 2-thienyl
1
NC
O
6
Ar
O
Ar
N
CN
H2N
NH2
Ar
O
7

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Like the recently reported formation of 9 from reaction of 1 and 8a,b in ethanolic chitosan,
compound 1 reacted with 8a,b to yield dihydropyridine 9a,b. However in refluxing acetic acid in the
presence of ammonium acetate, the benzene derivative 10 was obtained as indicated by the spectral
data (Scheme 4).
Scheme 4. Synthesis of 6-amino-2-dicyanomethylene-4-aryl-2,3-dihydropyridine-3,5-
dicarbonitriles 9a,b and 3,5-diaminobiphenyl-2,4,6-tricarbonitrile (10).
NH2
NC
EtOH/pip
NH
reflux 4 hrs
CN
Ar
CN
CN
Ar
1
+
CN
CN
9 a,b
8
a, Ar = Ph
b, Ar = CH3OC6H4
H2N
CN
AcOH / NH4OAc
reflux 3 hrs
NC
CN
CN
8a
Ph
CN
CN
H2N
CN
H2N
NH2
CN
-HCN
NC
NH
NC
Ph
10
CN
CN
Ph
The reaction of 1 with 11, which was recently obtained by reacting benzyl cyanide with triethyl
orthoformate and piperidine [12], afforded 14 via intermediates 12 and 13. Attempts to isolate 13 have
failed (cf. Scheme 5). The reaction of 1 with DMFDMA afforded 16 which may exist in E or Z forms.
1
Isomeric structure 15 was ruled out based on H NMR that revealed the D2O exchangeable amino
13
signal at δ = 7.19 ppm. In addition, the C NMR did not reveal any signals for the sp3 carbons other
than those of the dimethylamino moiety. Reacting 16 with hydrazine hydrate afforded 4,6-diamino-
2H-pyrazolo[3,4-b]pyridine-5-carboxamide hydrazone 17 (cf. scheme 6).

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Scheme 5. Synthesis of 2-(4-amino-7-cyano-3,9-diphenyl-pyrido[1,2-a]pyrimidin-6-
ylidene)-malononitrile (14).
NH2
Ph
H2N
CN
CN
NH
NC
Ph
N
dioxan
+
CN
reflux 4 hrs
CN
CN
CN
11
1
12
Ph
Ph
HN
N
CN
Ph
Ph
NH
N
NH2
CN
CN
CN
CN
CN
CN
14
13
Scheme 6. Synthesis of 4,6-diamino-2H-pyrazolo[3,4-b]pyridine-5-carboxamide hydrazone (17).
Me2N
CN
CN
H2N
CN
CN
CN
15
DMF DMA
dioxan, stirring
4 hrs
CN
H2N
CN
1
CN
H2N
Me2N
CN
16
N
EtOH reflux
4 hrs
H2N
NH2
NH2NH2
H2N
N
N
N
H
17

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3. Experimental
3.1. General
All melting points are uncorrected and were determined on a Sanyo (Gallenkamp) instrument.
Infrared spectra were recorded from KBr discs on a Perkin-Elmer 2000 FT–IR system.1H-NMR and
13C-NMR spectra were determined on a Bruker DPX spectrometer operating at 400 MHz for 1H-NMR
and 100 MHz for 13C-NMR using DMSO-d6 as solvent and TMS as internal standard; chemical shifts
are reported in δ (ppm). Mass spectra were measured on VG Autospec Q MS 30 and MS 9 (AEI)
spectrometers, with EI at 70 eV'. Elemental analyses were measured by means of LEOCHNS-932
Elemental Analyzer. General purpose silica gel on polyester 20 x 20 cm TLC plates with UV indicator
were used in TLC experiments to monitor completion of reactions, in which ethyl acetate-petroleum
ether (1:1) was used as eluent.
3.2. 2,4-Diamino-5-benzoyl-isophthalonitrile (3a)
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and enaminone 2a
(0.01 mol) in AcOH (10 cm) and 0.2 gm of NH4OAc, was kept at reflux temperature for 4 hrs. The
mixture was cooled and then poured onto ice-water. The solid, so formed, was collected by filtration
and recrystallized from EtOH to give yellow crystals; Yield 83%; m.p. 298–299 °C; Anal. Calcd. for
C15H10N4O (262.27): C, 68.69; H, 3.84; N, 21.36%. Found: C, 68.53; H, 3.92; N, 21.34%; IR (KBr,
cm−1): 3,443, 3,352 (NH2), 3,322, 3,209 (NH2), 2,210, 2,206 (2CN); 1H-NMR: δ, ppm = 7.08 (br s, 2H,
NH2, D2O exchangeable) 7.50–7.57 (3H, m, H-3',4',5'), 7.77 (2H, br. s, NH2, D2O exchangeable), 8.22
3
4
13
(2H, dd, J = 8.0, J = 1.6, H-2',6'), 8.29 (1H, s, H-6); C-NMR: δ, ppm = 190.23, 159.85, 159.62,
157.90, 154.44, 154.12, 143.65, 136.01, 130.21 (2C), 127.32 (2C), 115.89, 114.13, 113.85; MS: m/z
(%) 262 (M+, 100), 234 (15), 217 (5), 192 (5), 164 (25), 131 (10).
3.3. General procedure for the synthesis of compounds 4a,d
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and enaminone 2a,b
(0.01 mol) in EtOH (10 mL) was treated with piperidine (5 drops). The reaction mixture was refluxed
for 4 h. The mixture was cooled and then poured onto ice-water. The solid, so formed, was collected
by filtration and recrystallized from EtOH to give yellow crystals.
2-(3-Cyano-6-phenyl-1H-pyridin-2-ylidene)malononitrile (4a). Yield 80%; m.p. 257–259 °C; Anal.
Calcd. for C15H8N4 (244.26): C, 73.76; H, 3.30; N, 22.94%. Found: C, 73.94; H, 3.52; N, 23.04%; IR
1
(KBr, cm−1): 3,097 (NH), 2,210, 2,182 (3CN); H-NMR: δ, ppm = 7.16 (1H, d, J = 8.0 Hz, H-5),
7.48–7.51 (3H, m, H-3',4',5'), 7.86 (1H, d, J = 8.0 Hz, H-4), 8.01 (2H, m, H-2',6'), 9.42 (1H, br. s, NH,
D2O exchangeable); 13C-NMR: δ, ppm = 180.88, 160.54, 159.45, 155.50, 136.89, 132.09, 128.31 (2C),
127.32 (2C), 114.72, 113.88 (2C), 91.82, 63.25; MS: m/z (%) 243 (M+, 100), 217 (25), 152 (25), 128
(15), 105 (100), 77 (10).
2-(3-Cyano-6-thiophen-2-yl-1H-pyrid in-2-ylidene)malononitrile (4d). Yield 75%; m.p. 200–202 °C;
Anal. Calcd. for C13H6N4S (250.28): C, 62.93; H, 2.42; N, 22.39; S, 12.81%. Found: C, 63.06; H, 2.54;

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1
N, 22.54; S, 12.98%; IR (KBr, cm−1): 3,189 (NH), 2,230, 2,210 (3CN); H-NMR: δ, ppm = 7.04 (1H,
d, J = 8.0, H-5), 7.14 (1H, t, J = 4.0, thienyl H-4'), 7.66–7.68 (2H, m, H-4, thienyl H-3'), 7.76 (1H, d,
J = 4.0, thienyl H-5'), 8.06 (1H, br. s, NH, D2O exchangeable); MS: m/z (%) 250 (M+, 100), 223 (20),
185 (30), 158 (15), 141 (20), 114 (25), 82 (10), 69 (15).
3.4. Synthesis of 4,7-diamino-3,6-di(thiophene-2-carbonyl)quinoline-8-carbonitrile (7).
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and enaminone 2d
(0.01 mol) in AcOH (10 cm) and 0.2 gm of NH4OAc, was kept at reflux temperature for 3 hrs. The
mixture was cooled and then poured onto ice-water. The solid so formed was collected by filtration
and recrystallized from EtOH to give yellow crystals; Yield 88%; m.p. 330–332 °C; Anal. Calcd. for
C20H12N4O2S2 (404): C, 59.40; H, 2.97; N, 13.86; O, 7.92; S, 15.84%. Found: C, 59.50; H, 2.78; N,
1
13.96; O, 7.87; S, 15.89%.; H-NMR: δ, ppm = 7.05 (br. s, 2H, NH2), 7.27 (t, J = 4.0, 1H, thienyl
H-4'), 7.31 (t, J = 4.0, 1H, thienyl H-4''), 7.47 (s, 1H, H-5), 7.79 (d, 1H, J = 3.2, thienyl H-3'), 7.85 (d,
3H, J = 3.2, thienyl H-3''& NH2), 7.93 (d, 1H, J = 5.2, H-5'), 8.17 (d, 1H, J = 5.2, H-5''), 8.98 (s, 1H,
H-2); 13C-NMR: δ, ppm = 128.9, 154.0 (2C), 184.7 (2 C=O), 77.1, 98.3, 103.9, 115.85, 118.0,
129.2,131.6, 134.0, 135.7, 136.1, 140.6, 143.67, 156.1, 157.1, 160.4, 162.0; MS: m/z (%) 404 (M+,
100), 373 (10), 358 (5), 319 (20), 187 (5), 11 (20).
3.5. General procedure for the synthesis of compounds 9a,b
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and enaminone 8a,b
(0.01 mol) in EtOH (10 mL) as a solvent was treated with piperidine (5 drops). The reaction mixture
was refluxed for 4 hr. The mixture was cooled and then poured onto ice-water. The solid so formed
was collected by filtration and recrystallized from EtOH to give yellow crystals.
6-Amino-2-dicyanomethylene-4-phenyl-2,3-dihydro-pyridine-3,5-dicarbonitrile (9a). Yield 82%; m.p.
195–197 °C; Anal. Calcd. for C16H8N6 (284.28): C, 67.60; H, 2.84; N, 29.56%. Found: C, 67.43; H,
1
2.61; N, 29.33%; IR (KBr, cm−1): 3,467, 3,323 (NH2), 3,222 (NH), 2,314, 2,219 (4CN); H-NMR: δ,
ppm = 7.52–7.61 (7H, m, Ar-H, NH2, D2O exchangeable), 8.19 (1H, br. s, NH, D2O exchangeable);
13C-NMR: δ, ppm = 160.35, 158.81, 158.71, 133.82, 130.47, 128.76 (2C), 128.67, 128.36 (2C),
116.10, 114.60, 113.5, 95.29, 89.17; MS: m/z (%) 284 (M+, 100), 257 (25), 219 (10), 165 (25), 127
(10), 77 (5).
2-[6-Amino-3-aminoethynyl-5-cyano-4-(4-methoxy-phenyl)-1H-pyridin-2-ylidene]malononitrile (9b).
Yield 82%; m.p. 248–250 °C; Anal. Calcd. for C17H10N6O (314.31): C, 64.96; H, 3.21; N, 26.74%.
Found: C, 65.01; H, 3.22; N, 26.44%; IR (KBr, cm−1): 3,423, 3,327 (NH2), 3,212 (NH), 2,187, 2,150
1
(3CN); H-NMR: δ, ppm = 3.82 (s, 3H, OCH3), 6.86 (br, 2H, NH2, D2O exchangeable), 7.04 (2H, d,
13
J = 8.0, H-3',5'), 7.35 (2H, d, J = 8.0, H-2',6'), 8.22 (1H, br. s, NH, D2O exchangeable); C-NMR: δ,
ppm = 162.95, 160.23, 159.47, 158.97, 133.45, 130.19 (2C), 127.80, 121.39, 117.24, 116.92, 113.82
(2C), 85.26, 80.48, 55.31; MS: m/z (%) 284 (M+, 100), 257 (25), 219 (10), 165 (25), 127 (10), 77 (5).

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3.6. Synthesis of 3,5-Diaminobiphenyl-2,4,6-tricarbonitrile (10)
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and benzylidene-
malononitrile (8, 0.01 mol)in AcOH (10 cm) and 0.2 gm of NH4OAc, was kept under reflux
temperature for 3 hr. The mixture was cooled and then poured onto ice-water. The solid so formed was
collected by filtration and recrystallized from EtOH to give yellow crystals; yield 80%; m.p. 290–292 °C;
Anal. Calcd. for C15H9N5 (259.27): C, 69.49; H, 3.50; N, 27.01%. Found: C, 69.62; H, 3.34; N,
27.17%; IR (KBr, cm−1): 3,371, 3,305 (NH2), 3,265, 3,213 (NH2), 2,218 (3CN); 1H NMR: δ, ppm = 4.51
13
(br. s, 4H, 2NH2, D2O exchangeable), 7.41–7.44 (2H, m, H-3',5'), 7.50–7.53 (3H, m, H-2',4',6'); C
NMR: δ, ppm = 160.92 (2C), 157.07, 135.08, 129.92, 128.49 (2C), 128.21 (2C), 115.61 (2C), 85.65,
81.06, 75.95, 66.31; MS: m/z (%) 259 (M+, 100), 234 (20), 205 (15), 165 (20), 127 (10), 77 (50).
3.7. Synthesis of 2-(4-Amino-7-cyano-3,9-diphenylpyrido[1,2-a]pyrimidin-6-ylidene)-malononitrile (14)
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and 2-phenyl-3-
piperidin-1-yl-acrylonitrile (11, 0.01 mol) in dioxane (10 mL) was kept under reflux temperature for 3-
4 hrs. The mixture was cooled and then poured onto ice-water. The solid so formed was collected by
filtration and recrystallized from AcOH to give yellow crystals; yield 85%; m.p. 270–272 °C; Anal.
Calcd. for C24H14N6 (386.42): C, 64.60; H, 3.65; N, 21.75%. Found: C, 64.48; H, 3.55; N, 21.90%; IR
1
(KBr, cm−1): 3,383, 3,186 (NH2), 2,237, 2,196 (3CN); H-NMR: δ, ppm = 6.82 (2H, br. s, NH2, D2O
exchangeable), 7.24–7.52 (m, 12H, Ar-H); MS: m/z (%) 386 (M+, 10), 379 (40), 337 (70), 319 (100),
278 (95), 259 (35), 251 (30), 210 (20), 179 (20), 155 (10), 140 (25), 115 (15), 140 (25), 115 (10), 77
(15), 59 (20).
3.8. Synthesis of 2-amino-4-(dimethylamino)buta-1,3-diene-1,1,3-tricarbonitrile (16)
A mixture of 2-aminoprop-1-ene-1,1,3-tricarbonitrile (1, 1.32 g, 0.01 mol) and DMFDMA (1.19 g,
0.01 mol) in dioxane (10 mL) was stirred for 3–4 hrs. The mixture then poured onto ice-water. The
solid, so formed, was collected by filtration and recrystallized from EtOH to give yellow crystals; yield
90 % m.p. 189–190 °C. Anal. Calcd. for C9H9N5 (187.2): C, 57.74; H, 4.85; N, 37.41%. Found: C,
1
57.61; H, 4.57; N, 37.19%; IR (KBr, cm−1): 3,344, 3,221 (NH2), 2,208, 2,193 (3CN); H NMR
(400 MHz, DMSO-d6): δ, ppm = 2.50 (3H, s, CH3), 2.57 (3H, s, CH3), 7.19 (br. s, 2H, NH2, D2O
exchangeable), 8.54 (1H, s, olefinic CH); MS: m/z (%) 187 (M+, 100), 172 (30), 159 (35), 144 (25),
122 (60), 117 (20), 97 (15), 95 (15), 81 (20), 67 (20), 57 (30).
3.9. Synthesis of 4,6-diamino-2H-pyrazolo[3,4-b]pyridine-5-carboxamide hydrazone (17)
A mixture of 13 (1.87 g, 0.01 mol) and hydrazine monohydrate (1.00 g, 0.02 mol) in EtOH (20 mL)
was refluxed for 3–4. The mixture then poured onto ice-water. The solid so formed was collected by
filtration and recrystallized from EtOH to give a faint yellow product; yield 87 %; m.p. 210–212 °C;
Anal. Calcd. for C7H10N8 (206.21): C, 40.77; H, 4.89; N, 54.34%. Found: C, 40.58; H, 4.65; N,
1
54.05%; IR (KBr, cm−1): complicated signals from 3,402 to 3,156 for (NH) and (4NH2); H-NMR: δ,
ppm = 5.34 (2H, br. s, NH2, D2O exchangeable), 5.97 (2H, br. s, NH2, D2O exchangeable), 7.10 (2H,
br. s, NH2, D2O exchangeable), 7.29 (2H, br. s, NH2, D2O exchangeable), 8.00 (1H, s, H-3), 8.82 (1H,

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br. s, NH, D2O exchangeable); MS: m/z (%) 106 (M+, 100), 190 (95), 174 (100), 159 (75), 145 (40),
109 (35), 92 (40), 77 (60), 67 (100).
4. Conclusions
We could successfully utilize 1 as precursor to a variety of polyfunctionally substituted
aminoaromatics that seem of value as potential precursors to dyes and pharmaceuticals.
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Sample Availability: Samples of the compounds 3a, 4a-d, 7, 9a-b, 10, 14 and 17 are available from the
authors.
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