Stereoselective synthesis of 2-[1-methylpyridin-2(1H)-ylidene]malononitrile derivatives

Article abstract of DOI:10.1055/s-2008-1072578

An efficient synthesis of 2-[1-methylpyridin-2(1H)-ylidene]malononitrile derivatives have been identified, the reactions have been proved to be stereoselective; the spatial location of substituents has been determined. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072578

PAPER
1541
Stereoselective Synthesis of 2-[1-Methylpyridin-2(1H)-ylidene]malononitrile
Derivatives
2
-[1-Methylpyridin
e
-2(
1
H
)-yli
n
dene]malono
n
nitrile
D
eriv
a
a
tive
s
diy Khoroshilov,* Ivan Demchak, Tatjana Saraeva
Luhansk Taras Shevchenko National Pedagogical University, Oboronnaya 2, 91011 Luhansk, Ukraine
E-mail: demchak@mail.ru
Received 23 January 2008; revised 15 February 2008
Abstract: An efficient synthesis of 2-[1-methylpyridin-2(1H)-
ylidene]malononitrile derivatives have been identified, the reac-
tions have been proved to be stereoselective; the spatial location of
substituents has been determined.
CN
Et3N
Z
+
N
Cl
N
R
I
Z
R
CN
3a–j
2
1a,b
Key words: 1-alkyl-2-chloropyridinium iodide, CH-acids, nitrile
group, hydrogen bond, stereoselectivity
Scheme 1
2-(Dicyanomethylene)-1-methyl-1,2-dihydropyridines
have specific synthetic abilities, for example, they can re-
act with maleic acid derivatives (Diels–Alder reaction)
and form the isoquinuclidine skeleton in comparatively
high yield.1
NC
CN
Ph
Et3N
CN
+
N
Cl
N
R
I
R
1a,b
CN
3a,b
4
During our investigations of the reactions and synthetic
abilities of 2-chloropyridinium salts,2,3 we have studied
the nucleophilic substitution of chlorine in N-alkyl deriv-
atives salts 1a,b by various CH-acids, such as malononi-
trile derivatives. We have shown that 1-alkyl-2-
chloropyridinium iodides 1a,b react with various malono-
nitrile derivatives 2 in the presence of two equivalents of
a tertiary base to give 1-alkyl-1,2-dihydropyridines 3a–j
(Scheme 1, Table 1); the reactions occur under mild con-
ditions.
Scheme 2
It is well known6 that if there is a possibility to form a hy-
drogen bond between H3 in a pyridine ring and an elec-
tron-withdrawing atom (O, N) of the Z substituent then
H3 shifts to lower field. The degree of shift depends on the
strength of the hydrogen bond. In compounds 3a,b, where
there is no possibility to form a hydrogen bond, the dou-
blets of H3 appear in the range d = 7.16 and d = 7.20–7.25,
respectively. In compounds 3d,e, where the amides of the
sp2 hybrid carbon atom can take part in forming a hydro-
gen bond, H3 appears in the range d = 7.56–7.62. In com-
pound 3c, where the oxygen atom of the ester group
functions as an electron-donor component for hydrogen
bond formation, the shift is more intensive: H3 appears in
the range of d = 8.01–8.05. The most intensive shifts occur
in the compounds that contain a thiazole ring, where a ni-
trogen atom of the heterocycle functions as an electron-
donor component for hydrogen bond formation: H3 for
3f–j appears in range d = 8.33–8.76. Thus, we can con-
clude that the compounds 3c–j are formed with high ste-
reoselectivity. The spatial location of substituents is
shown for the compounds 3c,d,f (Figure 1).
The structure of 3a was first synthesized and character-
ized by Kröhnke and Pauls.4 According to the literature
the first synthesis of 3c was performed by Boyd and
Ezekiel,5a however, this report involves the presence of a
strong nucleophilic reagent, such as the hydroxide ion,
and it lacks physicochemical data. The method reported
by Zagulyaeva and co-workers5b is more realistic.
The synthesis of compounds 3a,b was also carried out by
synthesis using 1-alkyl-2-chloropyridinium salts and 2-
(phenylmethylene)malononitrile (4) (Scheme 2).
The compounds 3a–j have similar stretching vibrations
for the cyano groups (2160–2172 cm–1), which is evidence
for these compounds having the cyano group in identical
positions.
In 1H NMR spectrum of compounds 3a–j the most char-
Thus,
a
convenient
2-[1-methylpyridin-2(1H)-
acteristic peaks are the doublets of H3 and H6 in the pyri-
ylidene]malononitrile derivatives as been found, further-
more the reactions proved to be stereoselective. The spa-
tial location of substituents has been determined.
3
dine ring (by CSSI); J = 8.4–9.2 Hz is typical for H3,
while J = 5.8–7.2 Hz is typical for H6: compound 3a has
H3 3J = 8.5 Hz and H6 3J = 7 Hz.4
SYNTHESIS 2008, No. 10, pp 1541–1544
x
x.
x
x
.
2
0
0
8
Advanced online publication: 07.04.2008
DOI: 10.1055/s-2008-1072578; Art ID: Z02708SS
© Georg Thieme Verlag Stuttgart · New York

1542
G. Khoroshilov et al.
PAPER
Table 1 Substituents, Melting Points, Solvent of Crystallization, and Yields for 3a–j
Compd R
Z
Product
Mp (°C) [Lit.]
204 [2054]
Solvent for crystallization
EtOH
Yielda (%)
65 (67)
3a
3b
Me CN
CN
CN
N
Me
CN
Et
CN
120–121
EtOH
24 (52)
25b
N
Et
CN
O
3c
3d
3e
Me CO2Et
124–125 [127–1285a] MeOH
N
O
Me
Me
CN
NH2
NH2
Me
256–266
232–234
EtOH
EtOH
59
CN
CN
CN
CN
N
CN
NH2
Me
CN CN
NH2
Et
57
N
CN
Et
CN
CN
EtOH–H2O
(1:1)
3f
Me
129–130
61
56
N
N
S
S
N
Me
CN
Cl
Cl
EtOH–H2O
(1:1)
3g
Me
N
133
N
S
S
N
Me
CN
N
3h
Me
Me
OMe
148–149
207–210
EtOH
75
68
N
S
MeO
S
N
Me
CN
O
N+
O–
EtOH–AcOH
(4:1)
N
3i
O
N+
–O
N
S
S
N
Me
CN
Cl
Cl
3j
Et
N
193–195
EtOH
60
N
S
S
N
Et
CN
a Yield from method B given in parentheses.
b Yield in ref 5a = 24.5%.
Synthesis 2008, No. 10, 1541–1544 © Thieme Stuttgart · New York

PAPER
2-[1-Methylpyridin-2(1H)-ylidene]malononitrile Derivatives
1543
1H NMR: d = 8.31 (d, J = 7.2 Hz, 1 H, H6), 7.66 (t, J = 9.2 Hz, 1 H,
H4), 7.22 (d, J = 9.2 Hz, 1 H, H3), 6.86 (t, J = 7.2 Hz, 1 H, H5), 4.39
(dd, J1 = J2 = 7.3 Hz, 2 H, CH2), 1.38 (t, J = 7.3 Hz, 3 H, Me).
H
H
H
NH2
O
N
Anal. Calcd for C10H9N3: C, 70.16; H, 5.30; N, 24.54. Found: C,
70.15; H, 5.34; N, 24.51.
CN
S
N
N
O
N
Me
CN
CN
Me
CN
Me
CN
Ethyl (E)-2-Cyano-2-[1-methylpyridin-2(1H)-ylidene]acetate
3c
3f
(3c)
3d
IR: 2172, 1652 cm–1.
amplification intensity of hydrogen bond
1H NMR: d = 8.19 (d, J = 6.6 Hz, 1 H, H6), 8.03 (d, J = 9.0 Hz, 1 H,
H3), 7.78 (t, J = 9.0 Hz, 1 H, H4), 7.47 (t, J = 6.6 Hz, 1 H, H5), 4.05
(dd, J1 = J2 = 7.2 Hz, 2 H, CH2), 3.89 (s, 3 H, NMe), 1.18 (t, J = 7.2
Hz, 3 H, Me).
Figure 1 Intramolecular hydrogen bonding
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.64; H, 5.96; N, 13.70.
1
The structures of compounds have been confirmed by IR and H
NMR spectroscopy, and elemental analysis. IR spectra were mea-
1
sured with an IKS-40 spectrophotometer (mineral oil mull). H
(Z)-2-{1-Amino-2-cyano-2-[1-methylpyridin-2(1H)-
ylidene]ethylidene}malononitrile (3d)
NMR spectra were recorded with a Varian VRX-200 (199.9969
MHz, internal standard TMS). Commercial DMSO-d6 was used as
solvent without further purification. The purity of the products was
monitored by TLC performed on Silufol UV-254 plates (acetone–
hexane, 3:5). Elemental analysis was carried out on a Perkin-Elmer
CHN analyzer. Melting points were determined on a Kofler hot
stage.
IR: 3406, 3324, 3164, 2202, 2183, 2162 cm–1.
1H NMR: d = 8.38 (d, J = 6.4 Hz, 1 H, H6), 7.91 (t, J = 8.4 Hz, 1 H,
H4), 7.58 (d, J = 8.4 Hz, 1 H, H3), 7.30 (s, 2 H, NH2), 7.22 (t,
J = 6.4 Hz, 1 H, H5), 3.82 (s, 3 H, Me).
Anal. Calcd for C12H9N5: C, 64.56; H, 4.06; N, 31.37. Found: C,
64.49; H, 4.11; N, 31.35.
2-Chloro-1-methylpyridinium Iodide (1a)
A mixture of 2-chloropyridine (1.7 g, 15 mmol) and MeI (6.39 g, 45
mmol) was heated on a water bath for 2 h and then it was left to
stand at r.t. overnight. Then acetone (15 mL) was added and the
mixture was allowed to stand at r.t. After 3 d the sediment was fil-
tered off and washed (acetone); yield: 1.4 g (37%).
(Z)-2-{1-Amino-2-cyano-2-[1-ethylpyridin-2(1H)-ylidene]eth-
ylidene}malononitrile (3e)
IR: 3386, 3308, 3192, 2204, 2194, 2166 cm–1.
1H NMR: d = 8.43 (d, J = 6.4 Hz, 1 H, H6), 7.92 (t, J = 8.6 Hz, 1 H,
H4), 7.59 (d, J = 8.6 Hz, 1 H, H3), 7.29 (t, J = 6.4 Hz, 1 H, H5), 7.22
(s, 2 H, NH2), 4.34 (dd, J1 = J2 = 7.0 Hz, 2 H, CH2), 1.42 (t, J = 7.0
Hz, 3 H, Me).
Anal. Calcd for C6H7NClI: C, 28.21; H, 2.76; N, 5.48. Found: C,
28.27; H, 2.86; N, 5.39.
Anal. Calcd for C13H11N5: C, 65.81; H, 4.67; N, 29.52. Found: C,
65.83; H, 4.72; N, 29.49.
2-Chloro-1-ethylpyridinium Iodide (1b)
A mixture of 2-chloropyridine (4.97 g, 43.75 mmol) and EtI (20.75
g, 131.25 mmol) was heated on a water bath for 2.5 h. When the re-
action was complete, the mixture was allowed to cool to r.t., acetone
(20 mL) was added and the mixture was allowed to stand overnight
at 25 °C. Then residue was filtered off and washed (acetone); yield:
8.3 g (70%).
(E)-2-[1-Methylpyridin-2(1H)-ylidene]-2-(4-phenylthiazol-2-
yl)acetonitrile (3f)
IR: 2164 cm–1.
1H NMR: d = 8.57 (d, J = 9.2 Hz, 1 H, H3), 8.01 (d, J = 6.0 Hz, 1 H,
H6), 7.89 (d, J = 6.8 Hz, 2 H, Ar), 7.65 (s, 1 H, Hthiazolyl), 7.63 (t,
J = 8.1 Hz, 1 H, H4), 7.34 (m, 3 H, Ar), 6.80 (dt, J1 = 6.8 Hz,
J2 = 1.4 Hz, 1 H, H5), 3.92 (s, 3 H, Me).
Anal. Calcd for C7H9NClI: C, 31.20; H, 3.37; N, 5.20. Found: C,
31.12; H, 3.43; N, 5.29.
2-[1-Alkylpyridin-2(1H)-ylidene]acetonitriles 3a–j; General
Procedures
Anal. Calcd for C17H13N3S: C, 70.08; H, 4.50; N, 14.42. Found: C,
70.15; H, 4.46; N, 14.47.
Method A: To a stirred mixture of 1a,b (2.5 mmol) and CH-acid (2.5
mmol) in EtOH (10–15 mL) was added Et3N (2 equiv). When the
reagents had dissolved, the mixture was filtered (fold filter) and al-
lowed to stand overnight at 25 °C. The residue was filtered off,
washed (EtOH and hexane), and crystallized (solvent, see Table 1)
(E)-2-[4-(4-Chlorophenyl)thiazol-2-yl-2-[1-methylpyridin-
2(1H)-ylidene]acetonitrile (3g)
IR: 2162 cm–1.
1H NMR: d = 8.57 (d, J = 9.0 Hz, 1 H, H3), 8.02 (d, J = 6.6 Hz, 1 H,
H6), 7.91 (d, J = 8.4 Hz, 2 H, Ar), 7.71 (s, 1 H, Hthiazolyl), 7.64 (t,
J = 8.8 Hz, 1 H, H4), 7.45 (d, J = 8.4 Hz, 2 H, Ar), 6.81 (t, J = 6.7
Hz, 1 H, H5), 3.92 (s, 3 H, Me).
Method B: To a stirred mixture of 1a,b (2.5 mmol) and (phenyl-
methylene)malononitrile (2.5 mmol) was added Et3N (2 equiv). The
mixture was then treated as for Method A.
Anal. Calcd for C17H12N3ClS: C, 62.67; H, 3.71; N, 12.90. Found:
C, 62.73; H, 3.69; N, 12.93.
2-[1-Methylpyridin-2(1H)-ylidene]malononitrile (3a)
IR: 2166, 2194 cm–1.
1H NMR: d = 7.93 (d, J = 7.0 Hz, 1 H, H6), 7.62 (dd, J1 = J2 = 7.0
Hz, 1 H, H4), 7.16 (d, J = 8.5 Hz, 1 H, H3), 6.79 (dd, J1 = J2 = 7.0
Hz, 1 H, H5), 3.98 (s, 3 H, Me).
(E)-2-[4-(2-Methoxyphenyl)thiazol-2-yl-2-[1-methylpyridin-
2(1H)-ylidene]acetonitrile (3h)
IR: 2160 cm–1.
1H NMR: d = 8.56 (d, J = 9.2 Hz, 1 H, H3), 8.02 (dd, J1 = 6.9 Hz,
J2 = 14.2 Hz, 2 H), 7.69 (s, 1 H, Hthiazolyl), 7.61 (t, J = 8.0 Hz, 1 H,
H4), 7.29 (t, J = 7.5 Hz, 1 H, Ar), 7.1 (d, J = 7.4 Hz, 1 H), 7.0 (t,
J = 7.4 Hz, 1 H), 6.77 (t, J = 6.6 Hz, 1 H, H5), 3.90 (s, 6 H, OMe,
Me).
Anal. Calcd for C9H7N3: C, 68.78; H, 4.49; N, 26.74. Found: C,
68.72; H, 4.51; N, 26.78.
2-[1-Ethylpyridin-2(1H)-ylidene]malononitrile (3b)
IR: 2160, 2192 cm–1.
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G. Khoroshilov et al.
PAPER
Anal. Calcd for C18H15N3OS: C, 67.27; H, 4.70; N, 13.07. Found:
C, 67.24; H, 4.75; N, 13.02.
Anal. Calcd for C18H14N3ClS: C, 63.62; H, 4.15; N, 12.36. Found:
C, 63.69; H, 4.20; N, 12.31.
(E)-2-[1-Methylpyridin-2(1H)-ylidene]-2-[4-(3-nitrophenyl)thi-
azol-2-yl]acetonitrile (3i)
References
IR: 2168 cm–1.
(1) Tomisawa, H.; Nakano, H.; Hongo, H. Chem. Pharm. Bull.
1988, 5, 1692.
(2) Khoroshilov, G. E. Chem. Heterocycl. Compd. (Engl.
Transl.) 2001, 9, 1141.
(3) Khoroshilov, G. E.; Demchak, I. V. Abstract of Papers,
International Conference Chemistry of Nitrogen Containing
Heterocycles CNCH-2006, Kharkiv, Ukraine, Oct 2–7,
2006; 222; http://cnh2006.iflab.kiev.ua/t/static/
Page223.pdf.
(4) Pauls, H.; Kröhnke, F. Chem. Ber. 1977, 110, 1294.
(5) (a) Boyd, G. V.; Ezekiel, A. D.; Ellis, A. W. J. Chem. Soc. C
1967, 1866. (b) Zagulyaeva, O. A.; Grigorkina, O. A.;
Mamatyuk, V. I.; Mamaev, V. P. Chem. Heterocycl. Compd.
(Engl. Transl.) 1984, 1270.
1H NMR: d = 8.66 (s, 1 H, Ar), 8.57 (d, J = 8.7 Hz, 1 H, H3), 8.35
(d, J = 7.8 Hz, 1 H, H6), 8.18–8.03 (m, 2 H, Ar), 7.97 (s, 1 H,
Hthiazolyl), 7.76–7.61 (m, 2 H, H4, Ar), 6.85 (dt, J1 = 6.8 Hz, J2 = 1.2
Hz, 1 H, H5), 3.94 (s, 3 H, Me).
Anal. Calcd for C17H12N4O2S: C, 60.70; H, 3.60; N, 16.66. Found:
C, 60.78; H, 3.65; N, 16.61.
(E)-2-[4-(4-Chlorophenyl)thiazol-2-yl-2-[1-ethylpyridin-2(1H)-
ylidene]acetonitrile (3j)
IR: 2162 cm–1.
1H NMR: d = 8.74 (d, J = 9.2 Hz, 1 H, H3), 8.03 (d, J = 6.7 Hz, 1 H,
H6), 7.92 (d, J = 8.4 Hz, 2 H, Ar), 7.72 (s, 1 H, Hthiazolyl), 7.61 (t,
J = 8.6 Hz, 1 H, H4), 7.45 (d, J = 8.5 Hz, 2 H, Ar), 6.82 (dt, J1 = 6.8
Hz, J2 = 1.4 Hz, 1 H, H5), 4.45 (dd, J1 = J2 = 7.1 Hz, 2 H, CH2),
1.43 (t, J = 7.1 Hz, 3 H, Me).
(6) Günther, H. NMR Spectroscopy, An Introduction; John
Wiley: Chichester, 1980.
Synthesis 2008, No. 10, 1541–1544 © Thieme Stuttgart · New York