Competitive condensation and tandem cyclization reactions of 2-cyano-3-ferrocenylacrylonitrile with amidines in an aqueous medium

Article abstract of DOI:10.3987/COM-12-12540

The synthesis of a series of ferrocenyl-substituted 2-aminopyridineand 6-amino-4,5-dihydropyridine-3,5-dicarbonitriles, 4-aminopyrimidine- and 3,4-dihydropyrimidine-5-carbonitriles by reactions of 2-cyano-3- ferrocenylacrylonitrile with amidines in aqueous medium is described. New fused 6-amino-2-ethoxy-4-ferrocenyl-5-ferrocenylmethyl-5-ferrocenyl methyl-4,5- dihydropyridine-3,5-dicarbonitrile was prepared in a tricomponent cyclodimerization from 2-cyano-3-ferrocenylacrylonitrile in presence of ethanol. The structures of the obtained compounds were established by IR, 1H and 13C NMR spectroscopy, mass-spectrometry and X-ray diffraction analysis.

Full text of DOI:10.3987/COM-12-12540

HETEROCYCLES, Vol. 85, No. 10, 2012
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HETEROCYCLES, Vol. 85, No. 10, 2012, pp. 2505 - 2514. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 6th July, 2012, Accepted, 29th August, 2012, Published online, 11th September, 2012
DOI: 10.3987/COM-12-12540
COMPETITIVE CONDENSATION AND TANDEM CYCLIZATION
REACTIONS OF 2-CYANO-3-FERROCENYLACRYLONITRILE WITH
AMIDINES IN AN AQUEOUS MEDIUM
Elena I. Klimova,* Marcos Flores-Alamo, José M. Méndez Stivalet, and
Tatiana Klimova
Faculty of Chemistry, National Autonomous University of México, Cd.
Universitaria,
Coyoacán,
México
D.F.,
04510,
México.
E-mail:
klimova@unam.mx
Abstract –The synthesis of a series of ferrocenyl-substituted 2-aminopyridine-
and 6-amino-4,5-dihydropyridine-3,5-dicarbonitriles, 4-aminopyrimidine- and
3,4-dihydropyrimidine-5-carbonitriles by reactions of 2-cyano-3-ferrocenyl-
acrylonitrile with amidines in aqueous medium is described. New fused
6-amino-2-ethoxy-4-ferrocenyl-5-ferrocenylmethyl-5-ferrocenyl
dihydropyridine-3,5-dicarbonitrile was prepared in
methyl-4,5-
a
tricomponent
cyclodimerization from 2-cyano-3-ferrocenylacrylonitrile in presence of ethanol.
1
The structures of the obtained compounds were established by IR, H and 13C
NMR spectroscopy, mass-spectrometry and X-ray diffraction analysis.
Ferrocenyl-substituted organic molecules have been immensely exploited for their potential applications
in diverse fields, such as organic synthesis,1 medicinal chemistry,2,3 supramolecular chemistry,4 chemo-
and biosensors,5 materials science,6 etc. The stability and non toxicity of ferrocenyl group in aqueous and
aerobic media has made it an ideal candidate for use in drug designing. Heterocyclic derivatives of
ferrocene are the most interesting from the point of view of the biological activity.6-9 Many
ferrocenyl-substituted nitrogen heterocycles, such as pyrazole, triazole, pyridazine, pyrimidine,
quinuclidine, pyridine, etc., were reported to pertain to biologically active compounds.9-14 Their activity
depends on the nature of functional groups and of the heterocycle in the molecules. This stimulates the
research on new heterocyclic compounds of the ferrocene series with potential practically useful
properties. Therefore, the interest in the synthesis of novel ferrocenyl-containing heterocycles is quite
justified. The past years have seen a boost in the synthesis of functionalized ferrocenyl-pyrimidines and

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HETEROCYCLES, Vol. 85, No. 10, 2012
pyridines.15,16 However, the approaches to the synthesis of these compounds and their properties remain
largely unexplored so far. Among methods used for the synthesis of such kind of compounds, the most
common are reactions of ferrocenyl--enones (1) (Schemes 1 and 2a) or acetylferrocene (3) (Scheme
2b) with amidine derivatives (for synthesis of ferrocenylpyrimidines 2)15-17 or with malononitrile, ethyl
cyanoacetate, or with arylcarboxaldehydes in the presence NH4OAc (for synthesis of ferrocenylpyridines
4a,b).18,19
Scheme 1
Schemes 2a,b
Since the synthetic approach used for obtaining heteryl-ferrocenes plays an important role and is crucial
for their possible future application, the aim of our work was to develop a new convenient method of the
synthesis of aminocyano(ferrocenyl)pyrimidine and pyridine derivatives by reactions of
2-cyano-3-ferrocenylacrylonitrile with amidines. To the best of our knowledge, the use of
2-cyanoacrylonitniles for the preparation of pyrimidine and pyridine derivatives has not hitherto been
documented.
The starting 2-cyano-3-ferrocenylacrylonitrile (7) was prepared in 76% yield by condensation of
1
ferrocenecarbaldehyde (5) with malononitrile (6) (Scheme 3). The physical and H NMR spectroscopic
characteristics of compound 7 were well in line with the literature data.20

HETEROCYCLES, Vol. 85, No. 10, 2012
2507
Scheme 3
The reaction of 2-cyano-3-ferrocenylacrylonitrile (7) with acetamidine hydrochloride (8a) and
benzamidine hydrochloride (8b) was performed in aqueous EtOH in presence of Na2CO3 at ca. 80-85 °C.
It was found that this reaction affords ferrocenecarboxaldehyde(5) (9-10%), 2-amino-6-ethoxy-4-ferro-
cenylpyridine-3,5-dicarbonitrile (9) (23-27%), 4-amino-2-methyl(or phenyl)-6-ferrocenylpyrimi-dine-
5-carbonitriles (10a) and (10b) (9-10%), 6-amino-2-ethoxy-4-ferrocenyl-5-ferrocenylmethyl-4,5-
dihydropyridine-3,5-dicarbonitrile (11a) (12-15%), 6-amino-4-ferrocenyl-4-ferrocenyl-2-methyl(or
phenyl)-3,4-dihydropyrimidine-5-carbonitriles (12a) and (12b) (32-33%) (Scheme 4).
R
Fc
NC
EtO
NH2
CN
N
N
HN
Fc
H
CN
CN
C
C
FcCHO
C
R
+
+
+
Fc
R
NH2
N
NH2
H2N
5
7
CN
9
8a-c
R= Me (a); R= Ph (b); R= -N(Me)2 (c)
10a-c
Fc
N
NH
N
NC
Fc
+
OEt
Fc
NH2
CN
CN
12a,b, [12c]
11a
Scheme 4
Further we found that the reaction of 2-cyano-3-ferrocenylacrylonitrile (7) with 1,1-dimethylguanidinium
sulfate (8c) under analogous conditions affords, in contrast to condensations of 7 with 8a and 8b, only
four compounds: 5, 9, 10c, 11a (Scheme 4), and the product 12c was not formed in detectable amount.
Compounds 5, 9, 10a-c, 11a, and 12a,b were isolated by column chromatography on alumina and their
structures were established based on the data from IR and NMR sprctroscopy, mass spectrometry, and
elemental analysis (see experimental section). The spatial structures of compounds 9, 11a, and 12b were
determined by X-ray diffraction analysis of their single crystals.21 Crystals of 9 and 12b were obtained by
crystallization from CHCl3, and crystals of 11a were obtained by crystallization from CH2Cl2 - MeOH
(1:1). The general views of molecules 9, 11a, and 12b are shown in Figures 1-3, respectively. The data
from X-ray diffraction analysis confirmed the aromatic pyridine and dihydropyridine structures for

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HETEROCYCLES, Vol. 85, No. 10, 2012
compounds 9 and 11a, respectively, and the dihydropyrimidine structure for compound 12b. The central
fragment of the molecule 9 is a flat six-membered ring with one nitrogen atom. Data from the X-ray
analysis show that the N(1)-C(15) bond in the
compound 9 is somewhat shorter [d = 1.320(4)
Å] than the standard value of 1.338 Å.22 The
C(15)-C(14), C(11)-C(12) and C(12)-C(13)
bond lengths are somewhat longer [d =
1.413(4) Å, d = 1.413(5) Å and d = 1.414(5) Å,
respectively] than the standard value of 1.339
Å.23 The lengths of the C-Fe and C-C bonds in
the ferrocenyl substituents, as well as the
Figure 1. X-Ray crystal structure of compound 9
geometric parameters of the ferrocene san-
dwiches are close to standard values.24 The central nonplanar fragment of the molecule 11a is a
six-membered ring with one nitrogen atom in the half-chair conformation. The N(1)-C(25), N(1)-C(26),
C(23)-C(24) and C(24)-C(25) bond lengths are equal to d = 1.377(3) Å, d = 1.315(3) Å, d = 1.516(3) Å,
and d = 1.362(3) Å, respectively. The ferrocenyl and ferrocenylmethyl substituents at C-4 and C-5 have
trans-orientation.
Figure 2. X-Ray crystal structure of compound
Figure 3. X-Ray crystal structure of
11a
dihydropyrimidine 12b
The central nonplanar fragment of the molecule 12b is a six-membered ring with two nitrogen atoms in
the half-chair conformation. Data from the X-ray analysis show that the N(1)-C(17), N(2)-C(17) and
N(3)-C(20) bonds in the dihydropyrimidine are somewhat shorter [d = 1.335(5) Å, d = 1.318(4) Å and d =

HETEROCYCLES, Vol. 85, No. 10, 2012
2509
1.361 Å, respectively] than the corresponding standard values of d = 1.387 Å, d = 1.355 Å and d = 1.394
Å.23
a)
R
R
C
C
NH
CN
CH2
R
C
H2N
NH
H
N
NH
CN
CN
Fc CH N
+
CN
CH
CH
CN
CN
H2O
O
Fc
Fc CH C
6
13a-c
Fc
C
H
5
b)
c)
NC
Fc
C
N
CH
CH
CN
Na2CO3
Fc
H
CN
CN
+
C
C
C
N
CH2
CN
EtOH/H2O
CH
7
6
CN
14
HOEt
NH
Fc
NC
NC
CN
[O]
N
Fc
OEt
EtO
N
NH2
CN
9
15
Schemes 5a-c
Although the detailed mechanism of the reaction shown in Scheme 4 requires to be fully clarified, the
formation of ferrocenylcarboxaldehyde 5, 2-amino-6-ethoxy-4-ferrocenylpyridine-3,5-dicarbonitrile 9,
4-amino-6-ferrocenylpyrimidine-5-carbonitriles 10a-c and 12a,b can be explained by possible reaction

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HETEROCYCLES, Vol. 85, No. 10, 2012
sequence presented in Schemes 5a-c. Compound 5 may be formed via sequential addition of the amidines
8a-c at the double bond FcCH=C of the inicial compound 7 (the Michael addition) resulting in
intermediate products 13a-c, further fragmentation of which can lead to aldehyde 5 and malononitrile 6
(Scheme 5a). This type of fragmentation of CC bonds in the ferrocenyl--dicarbonilic compouds was
well documented in previous publications.35 The intramolecular cyclization of (13a-c) gives
dihydropyrimidines 12a,b and aromatic pyrimidines 10a-c (Scheme 5b). The addition between
malononitrile 6 and 2-cyano-3-ferrocenylacrylonitrile 7 affords intermediate (14), which upon
intramolecular cyclization in the presence of EtOH gives rise to (15) and 9 (Scheme 5c). This type of
cyclization represents, in reality, a tricomponent reaction.
Tentative mechanism for the formation of the diferrocenyl(dihydro)pyridine-3,5-dicarbonitriles 11a,b is
represented in Scheme 6.
Fc
Fc
Fc
Fc
N
N
N
C
C
C
H
H
CN
NH
+
C
N
C
N
RO
N
R
O
H
16
R= Et (a)
R= iPr (b)
Fc
Fc
NC
CN
11a,b
RO
N
NH
2
17
Scheme 6
To prove the mechanism described above, the cyclodimerization of 2-cyano-3-ferrocenylacrylonitrile 1
was carried out under identical conditions in isopropyl alcohol in presence of water and Na2CO3. The
product of the cyclodimerization, 6-amino-4-ferrocenyl-5-ferrocenylmethyl-2-isopropoxy-4,5-
dihydropyridine-3,5-dicarbonitrile 4b, was obtained with  27% yield. Thus, this cyclodimerization of
compound 1 represents a novel type of the three-component anomalous reaction of [4+2]-cycloadition,
absolutely different from the reaction of Diels-Alder.
Thus, in the present work, a convenient method of obtaining of 6-alkoxy-2-amino-4-ferrocenylpyridine-
3,5-dicarbonitriles,
2-alkoxy-6-amino-4-ferrocenyl-5-ferrocenylmethyl-4,5-dihydropyridine-3,5-
dicarbonitriles, 6-amino-4-ferrocenyl-2-(alkyl or aryl)-3,4-dihydropyrimidine-5-carbonitriles and
4-amino-6-ferrocenyl-2-(alkyl or aryl)pyrimidine-5-carbonitriles based on accessible 2-cyano-

HETEROCYCLES, Vol. 85, No. 10, 2012
2511
3-ferrocenylacrylonitrile 7 was developed. This method can be widely used in the synthesis of various
ferrocene derivatives. The reactions described in this study will be of interest to synthetic, theoretical and
practical organic chemists looking for obtaining functionalized ferrocenylheterocycles.
EXPERIMENTAL
1
Column chromatography was carried out on alumina (Brockmann activity III). The H and 13C NMR
spectra were recorded on a Unity Inova Varian spectrometer (300 and 75 MHz) for solutions in CDCl3,
with Me4Si as the internal standard. The IR spectra were measured on a Spectrofotometer FT-IR
(Spectrum RXI Perkin Elmer instruments) using KBr pellets. The mass spectra were obtained on a Varian
MAT CH-6 instrument (EI MS, 70 eV). Elementar Analysensysteme LECO CHNS-900 was used for
elemental analyses. The unit cell parameters and the X-ray diffraction intensities were recorded on a
Gemini (detector AtlasCCD, Cryojet N2) diffractometer. The structures of compounds 9, 11a and 12b
were solved by the direct method (SHELXS-9725).
Tipical procedure of the reactions of 2-cyano-3-ferrocenylacrylonitrile (7) with acetamidine (8a),
benzamidine (8b) and 1,1-dimethylguanidine (8c). A mixture of compound 7 (2.26 g, 10 mmol),
acetamidine hydrochloride 8a (1.4 g, 15 mmol), benzamidine hydrochloride 8b (2.34 g, 15 mmol) or
1,1-dimethylguanidinium sulfate 8c (2.05 g, 15 mmol), EtOH (100 mL), H2O (10 mL) and 2.0 g Na2CO3
was stirred for 8 h at 80 C. The solvents were removed in vacuo and the residue was dissolved in CH2Cl2
(50 mL). The solution was mixed with Al2O3 (activity III) (20 g) and the solvent was evaporated in air.
This sorbent was applied onto a column with Al2O3 (the height of alumina is ca. 20 cm) and the reaction
products were eluted from the column first with petroleum ether, then with a 1:2 CH2Cl2 - petroleum ether
and 1:10 CH2Cl2 - MeOH solvent system to give compounds 5 (0.09g, 9% from 8a; 0.11g, 11% from 8b);
0.1g, 10% from 8c), 9, 10a-c, 11a and 12a,b.
2-Amino-6-ethoxy-4-ferrocenylpyridine-3,5-dicarbonitrile (9): yield 0.5g (27.5%, from 8a), 0.4g (22%,
from 8b) and 0.42g (23%, from 8c), red crystals, mp 168-169 °C. IR 499, 817, 1006, 1109, 1483, 1555,
1611, 2202, 2218, 2978, 3105, 3226, 3369cm-1; 1H NMR  1.43 (t, J = 7.08 Hz, 3H), 4.43 (q, J = 7.08 Hz,
2H), 4.28 (s, 5H), 4.58 (m, 2H), 5.21 (m, 2H), 5.58 (bs, 2H);13C NMR  14.43, 59.10, 64.12, 70.99, 69.62,
69.85, 70.89, 71.10, 84.99, 116.32, 117.68, 160.12, 161.54, 164.88, 167.18, 170.09; MS: mz 372 M.
Anal. Calcd for C19H16FeN4O: C, 61.32; H, 4.33; N, 15.05. Found: C, 61.39; H, 4.42; N, 15.07.
4-Amino-6-ferrocenyl-2-methylpyrimidine-5-carbonitrile (10a): yield 0.32 g (10%), red crystals,
1
182-183 °C. IR 485, 822, 1000, 1100, 1494, 1568, 1595, 1655, 2167, 2930, 3135, 3323, 3377 cm-1; H
13
NMR  2.53 (s, 3H), 4.18 (s, 5H), 4.56 (m, 2H), 5.32 (m, 2H), 5.52 bs, 1H); C NMR  26.00, 69.95,
69.21, 71.06, 79.06, 117.09, 164.28, 168.25, 169.21, 171.45; MS: mz 318 M. Anal. Calcd. for

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HETEROCYCLES, Vol. 85, No. 10, 2012
C16H14FeN4: C, 60.40; H, 4.44; N, 17.60. Found: C, 60.31; H, 4.53; N, 17.58.
4-Amino-6-ferrocenyl-2-phenylpyrimidine-5-carbonitrile (10b): yield 0.34g (9%), red crystals, mp
197-198 °C. IR 483, 821, 1001, 1106, 1461, 1485, 1531, 1615, 2208, 3093, 3223, 3331 cm-1; 1H NMR 
13
4.18 (s, 5H), 4.58 (m, 2H), 5.44 (m, 2H), 5.63 (bs, 2H), 7.32-7.72 (m, 5H); C NMR  70.51, 70.04,
71.92, 79.22, 117.50, 128.55, 128.96, 131.65, 137.01, 137.54, 164.42, 164.70,170.83; MS: mz 380 M.
Anal. Calcd for C21H16FeN4: C, 66.33; H, 4.24; N, 14.73. Found: C, 66.42; H, 4.17; N, 14.65.
4-Amino-2-dimethylamino-6-ferrocenylpyrimidine-5-carbonitrile (10c): yield 1.46 g (42%), red
crystals, mp 156-157 °C. IR 483, 818, 1000, 1104, 1557, 1612, 1633, 2160, 2927, 3094, 3322, 3467 cm-1;
1H NMR  3.21 (bs, 6H), 4.17 (s, 5H), 4.46 (m, 2H), 5.22 (m, 2H), 5.25 (m, 2H); 13C NMR  36.95, 70.29,
69.65, 71.02, 80.31, 119.44, 164.81, 170.06, 178.67, 189.72; MS: mz 347 M. Anal. Calcd For
C17H17FeN5: C, 58.81; H, 4.93; N, 20.16. Found: C, 58.75; H, 4.81; N, 20.23.
6-Amino-2-ethoxy-4-ferrocenyl-5-ferrocenylmethyl-4,5-dihydropyridine-3,5-dicarbonitrile
(11a):
yield 0.19g (14%, from 8a), 0.16g (12%, from 8b), 0.2 g (15%, from 8c), yellow crystals, mp dec. ca.
273 °C. IR 482, 1001, 1106, 1553, 1595, 1638, 1665, 2194, 2245, 3098, 3325 cm-1; 1H NMR  1.40 (t, J
= 6.9 Hz, 3H), 2.92 (d, J = 14.1 Hz, 1H), 3.11 (d, J = 14.1 Hz, 1H), 3.43 (s, 1H), 4.33 (q, J = 6.9 Hz, 2H),
4.15 (s, 5H), 4.28 (s, 5H), 3.87 (m, 1H), 4.09 (m, 1H), 4.13 (m, 1H), 4.17 (m, 2H), 4.24 (m, 2H), 4.43 (m,
1H), 5.56 (bs, 2H); 13C NMR  15.53, 37.01, 63.55, 41.42, 69.09, 69.60, 66.98, 68.24, 68.60, 68.91, 68.95,
69.17, 69.87, 70.29, 79.33, 83.64, 119.22, 120.51, 51.30, 160.54, 164.30, 165.68, 165.98; MS: mz 572
M. Anal. Calcd for C30H28Fe2N4O: C, 62.96; H, 4.93; N, 9.79. Found: C, 62.97; H, 4.62; N, 9.55.
6-Amino-4-ferrocenyl-2-methyl-3,4-dihydropyrimidine-5-carbonitrile (12a): yield 1.02 g (32%),
yellow crystals, mp 203-204 °C. IR 485, 822, 1000, 1100, 1494, 1568, 1595, 1655, 2167, 2930, 3323,
1
3377 cm-1; H NMR  1.75 (s, 3H), 3.92 (m, 1H), 3.97 (m, 3H), 4.04 (s, 5H), 4.71 (d, J = 3.0 Hz, 1H),
13
5.55 (bs, 1H), 5.64 (bs, 2H); C NMR  22.01, 52.87, 69.12, 65.74, 65.84, 67.51, 67.99, 95.29, 122.99,
148,94, 159.50, 160.14; MS: mz 320 M. Anal. Calcd for C16H16FeN4: C, 60.02; H, 5.04; N, 17.50.
Found: C, 59.91; H, 4.89; N 17.51.
6-Amino-4-ferrocenyl-2-phenyl-3,4-dihydropyrimidine-5-carbonitrile (12b): yield 1.26 g (33%),
yellow crystals, mp 218-219 °C. IR 499, 812, 998, 1105, 1573, 1596, 1635, 2168, 3073, 3135, 3255 cm-1;
1H NMR  4.13 (m, 3H), 4.19 (m, 1H), 4.21 (s, 5H), 4.97 (d, J = 2.8 Hz, 1H), 5.74 (bs, 1H), 6.01 (bs, 2H),
7.49-7.55 (m, 3H), 7.87 (d, J = 6.0 Hz, 2H); 13C NMR  54.14, 69.17, 65.73, 65.95, 67.62, 68.24, 95.25,
122.82, 127.88, 128.87, 131.99, 133.93, 157.57, 159.9, 162.41; MS: mz 382 M. Anal. Calcd. for
C21H18FeN4: C, 66.00; H, 4.74; N, 14.65. Found: C, 65.97; H, 4.58; N, 14.78.
Tipical procedure of the cyclodimerization of 2-cyano-3-ferrocenylacrylonitrile 7 in the presence
2-PrOH, H2O and Na2CO3. A mixture of compound 7 (1.13 g,5 mmol), 2-PrOH (60 mL), H2O (10 mL)

HETEROCYCLES, Vol. 85, No. 10, 2012
2513

and 1.0 g Na2CO3 was stirred for 12 h at 80 C. The reaction mixture was worked up as described above,
subsequent chromatography on Al2O3 gave 6-amino-4-ferrocenyl-5-ferrocenylmethyl-2-isoprpoxy-4,5-
dihydropyridine-3,5-dicarbonitrile 11b, yield 0.4g (27%), yellow crystals, mp ca. 302 °C (decomp). IR
483, 821, 1001, 1106, 1294, 1316, 1355, 1423, 1585, 1629, 2191, 2230, 3095, 3241, 3335 cm-1; 1H NMR
 1.39 (d, J = 6.0 Hz, 6H), 2.90 (d, J = 13.8 Hz, 1H), 3.09 (d, J = 13.8 Hz, 1H), 3.81 (s, 1H), 4.13 (s, 5H),
4.28 (s, 5H), 4.08 (m, 1H), 4.16 (m, 2H), 4.23 (m, 2H), 4.28 (m, 2H), 4.42 (m, 1H), 5.07 (m, J = 6.0 Hz,
1H), 5.54 (bs, 2H); 13C NMR  21.94, 36.96, 41.40, 66.96, 69.04, 69.56, 68.20, 68.54, 68.90, 68.94, 69.09,
69.84, 70.38, 71.52, 79.25, 83.68, 119.16, 120.49, 51.28, 160.43, 161.54, 165.37, 166.82; MS: mz 586
M. Anal. Calcd for C31H30Fe2N4O: C, 63.51; H, 5.16; N, 9.55. Found: C, 63.67; H, 5.03; N 9.41.
ACKNOWLEDGEMENTS
This work was supported by CONACyT (Mexico, grant 100970) and DGAPA-UNAM Mexico, grant
IN-211112.
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