Synthesis and reactions of 1,2-bis[3-cyano-4-(2-fluorophenyl)-6-oxo-1,4,5, 6-tetrahydropyridin-2-yl]diselane

Article abstract of DOI:10.1007/s10593-012-1092-1

The interaction of 2-fluorobenzaldehyde, cyanoselenoacetamide and Meldrum's acid in the presence of N-methylmorpholine gives 1,2-bis[3-cyano-4-(2- fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]di-selane, which also is the product of the reaction of cyanoselenoacetamide with 5-(2-fluorobenzylidene)-2, 2-dimethyl-1,3-dioxane-4,6-dione. The diselane obtained interacts with alkyl halides in the presence of a base, forming the corresponding 4-(2-fluorophenyl)-2-(2-R-methylselanyl)-6-oxo-1,4,5,6-tetra-hydropyridine-3- carbonitriles.

Full text of DOI:10.1007/s10593-012-1092-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS AND REACTIONS OF
1,2-BIS[3-CYANO-4-(2-FLUOROPHENYL)-6-OXO-
1,4,5,6-TETRAHYDROPYRIDIN-2-YL]DISELANE
K. A. Frolov1*, V. V. Dotsenko1, and S. G. Krivokolysko1
The interaction of 2-fluorobenzaldehyde, cyanoselenoacetamide and Meldrum's acid in the presence of
N-methylmorpholine gives 1,2-bis[3-cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]di-
selane, which also is the product of the reaction of cyanoselenoacetamide with 5-(2-fluorobenzylidene)-
2,2-dimethyl-1,3-dioxane-4,6-dione. The diselane obtained interacts with alkyl halides in the presence of
a base, forming the corresponding 4-(2-fluorophenyl)-2-(2-R-methylselanyl)-6-oxo-1,4,5,6-tetra-
hydropyridine-3-carbonitriles.
Keywords: cyanoselenoacetamide, diselane, Meldrum's acid, 1,2,3,4-tetrahydropyridin-2-one,
cyclocondensation.
Partially hydrogenated pyridine chalcogenones are a well-investigated group of heterocyclic
compounds. The most studied among substituted tetrahydropyridine chalcogenones are sulfur-containing
compounds [1, 2]. They display various forms of biological activity [1]. At the same time, in view of the
currently limited choice of methods for obtaining substituted tetrahydropyridine selenones, they remain a little
studied group of organic compounds and are represented in the literature by isolated examples [3, 4].
We have shown previously that a multicomponent reaction of aromatic aldehydes with
cyanoselenoacetamide, Meldrum's acid, and N-methylmorpholine leads to the formation of the corresponding
Michael adduct, N-methylmorpholinium 5-(2-cyanoethyl-1-hetaryl-2-selenocarbamoyl)-2,2-dimethyl-6-oxo-1,3-di-
oxa-4-cyclohexen-4-olate, which is transformed upon heating into N-methylmorpholinium 6-amino-4-aryl-3,5-di-
cyanopyridine-2-selenolate [5]. Since the sulfur-containing analogs, N-methylmorpholinium 5-(2-cyanoethyl-
1-hetaryl-2-thiocarbamoyl)-2,2-dimethyl-6-oxo-1,3-dioxa-4-cyclohexen-4-olates under similar conditions
undergo cyclocondensation with the formation of 1,2,3,4-tetrahydropyridin-2-one derivatives [2, 5, 6], we
decided to study this reaction in detail.
It was established that 2-fluorobenzaldehyde (1) reacts with cyanoselenoacetamide (2) [7], Meldrum's acid
(3), and N-methylmorpholine under an argon atmosphere at room temperature with the formation of Michael
adduct 4. Subsequent heating of the adduct 4 leads to a previously unknown 1,2-bis[3-cyano-4-(2-fluorophenyl)-
6-oxo-1,4,5,6-tetrahydropyridin-2-yl]diselane (5) in 63% yield (Method A). Compound 5 may also be obtained on
interacting cyanoselenoacetamide (2) with 5-(2-fluorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6)
______
*To whom correspondence should be addressed, e-mail: ka.frolov@inbox.ru.
1"ChemEx" Laboratory, Vladimir Dal' East-Ukrainian National University, 20-A Molodyozhny Kv., Lugansk
91034, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 7, pp. 1083-1087, July, 2012. Original
article submitted July 27, 2011.
1006
0009-3122/12/4807-1006©2012 Springer Science+Business Media New York

[8] in the presence of N-methylmorpholine in 69% yield (Method B). Cyclocondensation of the Michael adduct
4 hypothetically proceeds through the formation of N-methylmorpholinium 3-cyano-4-(2-fluorophenyl)-6-oxo-
1,4,5,6-tetrahydropyridine-2-selenolate (7). Obviously, the selenolate 7 is oxidized to the stable diselane 5 in the
presence of even trace amounts of oxygen (reaction proceeds under a constant stream of argon with a purity of
99.98%).
O
CN
O
O
F
Method A
Method B
B, EtOH
O
2 +
+
+
F
O
Me
Me
Se
NH2
O
3
O
CHO
1
2
Me
Me
O
6
F
O
O
F

CN
CN
Se
O
Se
NH2
Me
Me
O
O
N
+
BH
+
BH
H
4
7
[O]

F
CN
NC
Se
F
Se
N
NH
O
H
5
B = N-methylmorpholine
O
Brief heating of compound 5 with an equimolar quantity of alkyl halides 8a-d in the presence of an
excess of aqueous KOH solution led to the formation of the previously unknown 4-(2-fluorophenyl)-2-(2-R-me-
thylselanyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles 9a-d in 38-70% yield.
F
F
HalCH2R
8a–d
HCHO
4-MeC6H4NH2
CN
Se
CN
Se
5
KOH, EtOH
KOH, EtOH
R
O
N
N
H
O
Me2CO
EtOH
9a–d
CH2(CN)2
N
10
NH2
Me
F
Me
N
CN
Se
11
O
N
H
8 a Hal = I, b Hal = Br, c,d Hal = Cl;
8, 9 a R = Me, b R = 4-MeC6H4CO, c R = PhNHCO, d R = 4-MeC6H4NHCO
1007

Attempts to obtain the selenium analog 10 of the condensed 1,3,5-thiadiazine [9, 10] by
aminomethylation of the diselane 5 by the action of p-toluidine and HCHO were unsuccessful. Previously on
interacting a series of pyridine-2-thiolates with malononitrile and acetone, we obtained a series of
dipyridothiophene derivatives [11, 12]. It was established that bis(pyridin-2-yl) disulfides were involved as
intermediates in this cascade reaction [13]. On attempting to obtain the dipyridoselenophene analog 11 by the
reaction of diselane 5 with acetone and malononitrile, the starting diselane 5 was isolated.
The structures of compounds 5 and 9a-d were confirmed by spectral data. In the IR spectra of
compounds 5 and 9a-d, absorption bands were present corresponding to the stretching vibrations of the
functional groups in the ranges 3196-3345 (NH), 2180-2215 (CN), and 1683-1713 cm-1 (C=O). In the 1H NMR
spectra of compounds 5 and 9a-d, signals of the tetrahydropyridone ring 5-CH2 protons were detected as two
double doublets in the region of 2.58-2.64 ppm (3J = 6.0-6.1 Hz) and 2.87-2.94 ppm (3J = 7.3-7.5 Hz), the signal
of the H-4 proton appeared as a double doublet in the region of 4.19-4.24 ppm (3J = 6.1 and 7.3-7.5 Hz), while the
signal of the NH proton of the tetrahydropyridone ring was identified as a singlet in the 10.50-10.95 ppm
region. A molecular ion [M]+ peak with a mass of 588 was present in the mass spectrum of compound 5.
The spectral data of compounds 9 were in good agreement with the results described in [2, 5, 6, 13-15]
for the corresponding sulfur-containing analogs.
Two methods of obtaining 1,2-bis[3-cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]-
diselane are proposed: 1) multicomponent condensation of cyanoselenoacetamide, Meldrum's acid, and 2-fluoro-
benzaldehyde in the presence of N-methylmorpholine and 2) a reaction of the 2-fluorobenzylidene derivative of
Meldrum's acid with cyanoselenoacetamide. The obtained diselane interacts with alkyl halides with the
formation of 4-(2-fluorophenyl)-2-(2-R-methylselanyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles.
EXPERIMENTAL
1
The IR spectra were recorded on an IKS-29 spectrophotometer in nujol. The H NMR spectra were
recorded on a Bruker Avance II 400 (400 MHz) in DMSO-d6, internal standard was TMS. HPLC-MS analysis
was carried out on an Agilent 1100 liquid chromatograph with DAD, ELSD Sedex 75 detectors, connected to an
Agilent LC/MSD VL mass spectrometer, ionization by electrospray. Elemental analysis was carried out on a
Carlo Erba 1106 Elemental Analyzer (compounds 9c,d) and a Perkin Elmer CHN Analyzer (remaining
compounds). Monitoring of the purity of the obtained compounds was carried out by TLC on Silufol UV-254
plates, eluent was acetone–hexane, 1:1, visualizing with iodine vapor and a UV detector. Melting points of
substances were determined on a Kofler hot stage and are not corrected. All syntheses were carried out under an
argon atmosphere.
1,2-Bis[3-cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]diselane (5). A. A mixture
of 2-fluorobenzaldehyde (1) (1.44 ml, 13.6 mmol), freshly prepared cyanoselenoacetamide (2) [7] (2.00 g,
13.6 mmol), and N-methylmorpholine (3 drops) in EtOH (30 ml) was stirred until dissolution of the starting
materials, then Meldrum's acid (1.96 g, 13.6 mmol) and N-methylmorpholine (2.08 ml, 20.4 mmol) were added.
The obtained mixture was stirred for 10 min, refluxed for 1.5 h, and stored for 72 h. The solid formed was
filtered off, washed with EtOH and with hexane. The corresponding diselane 5 was obtained as fine beige
crystals. Yield 2.52 g (63%).
B. A mixture of freshly prepared cyanoselenoacetamide (2) (1.53 g, 10.4 mmol), 5-(2-fluoro-
benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6) [8] (2.60 g, 10.4 mmol), and N-methylmorpholine
(1.60 ml, 15.6 mmol) was stirred in EtOH (20 ml) for 10 min, and refluxed for 1 h. The reaction mixture was
stored for 72 h. The solid formed was filtered off, washed with EtOH and hexane, and the diselane 5 (2.11 g,
69%) was obtained. The physicochemical and spectral characteristics of the compounds obtained by methods A
and B were identical. Mp 141-143oC. IR spectrum, , cm-1: 1684, 1695 (sh) (2C=O), 2180 (2C≡N), 3241
1
2
3
2
(2NH). H NMR spectrum, δ, ppm (J, Hz): 2.63 (2H, dd, J = 16.4, J = 6.0) and 2.93 (2H, dd, J = 16.4,
1008

3J = 7.5, 5,5'-CH2); 4.29-4.32 (2H, m, H-4,4'); 7.12-7.34 (8H, m, H Ar); 10.82 (2H, br. s, 2NH). Mass spectrum,
m/z (Irel, %): 588 [M]+ (100). Found, %: C 48.57; H 2.77; N 9.43. C24H16F2N4O2Se2. Calculated, %: C 49.00;
H 2.74; N 9.52.
4-(2-Fluorophenyl)-2-(2-R-methylselanyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles 9a-d
(General Method). A mixture of diselane 5 (0.30 g, 0.5 mmol) and 10% aqueous KOH solution (0.57 ml,
1.0 mmol) was stirred until dissolution of the starting reactant (2-3 min) in 70% aq. EtOH (30 ml). Then alkyl
halide 8a-d (1 mmol) was added, the obtained solution was refluxed for 1-2 min, and rapidly filtered through a
folded paper filter. The reaction mixture was stored for 24 h at 20oC. The precipitate formed was filtered off,
washed with EtOH and hexane. Compounds 9a-d were obtained in analytically pure form.
6-(Ethylselanyl)-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitrile (9a). Yield
0.11 g (70%). Fine, light-yellow crystals, mp 173-175oC. IR spectrum, , cm-1: 1683 (C=O), 2195 (C≡N), 3196
(NH). 1H NMR spectrum, δ, ppm (J, Hz): 1.49 (3H, t, 3J = 7.4, CH2CH3); 2.63 (1H, dd, 2J = 16.4, 3J = 6.1) and
2.90 (1H, dd, 2J = 16.4, 3J = 7.5, 5-CH2); 3.12 (2H, q, 3J = 7.4, CH2CH3); 4.20 (1H, dd, 3J = 6.1, 3J = 7.5, H-4);
7.09-7.32 (4H, m, H Ar); 10.50 (1H, s, NH). Found, %: C 51.71; H 4.07; N 8.59. C14H13FN2OSe. Calculated, %:
C 52.02; H 4.05; N 8.67.
4-(2-Fluorophenyl)-2-{[2-(4-methylphenyl)-2-oxoethyl]selanyl}-6-oxo-1,4,5,6-tetrahydropyridine-
3-carbonitrile (9b). Yield 0.11 g (53%). Fine, light-gray crystals, mp 147-149oC. IR spectrum, , cm-1: 1697
1
(2C=O), 2205 (C≡N), 3252 (NH). H NMR spectrum, δ, ppm (J, Hz): 2.44 (3H, s, 4-CH3C6H4); 2.58 (1H, dd,
2J = 16.4, 3J = 6.1) and 2.87 (1H, dd, 2J = 16.4, 3J = 7.3, 5-CH2); 4.19 (1H, dd, 3J = 6.1, 3J = 7.3, H-4); 4.69 (1H,
2
2
d, J = 14.2) and 4.74 (1H, d, J = 14.2, SeCH2); 7.11-7.92 (8H, m, H Ar); 10.54 (1H, s, NH). Found, %:
C 58.64; H 4.04; N 6.62. C21H17FN2O2Se. Calculated, %: C 59.02; H 4.01; N 6.56.
2-[3-Cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-ylselanyl]-N-phenylacetamide (9c).
Yield 0.08 g (38%). Fine, white crystals, mp 179-181oC. IR spectrum, , cm-1: 1712 (2C=O), 2204 (C≡N), 3345
1
2
3
2
(2NH). H NMR spectrum, δ, ppm (J, Hz): 2.64 (1H, dd, J = 16.4, J = 6.1) and 2.94 (1H, dd, J = 16.4,
3J = 7.3, 5-CH2); 3.89 (1H, d, J = 13.2) and 3.95 (1H, d, J = 13.2, SeCH2); 4.24 (1H, dd, J = 6.1, J = 7.3,
H-4); 7.04-7.61 (9H, m, H Ar); 10.32 (1H, s, NHPh); 10.88 (1H, s, NH). Found, %: C 55.91; H 3.80; N 9.76.
C20H16FN3O2Se. Calculated, %: C 56.08; H 3.77; N 9.81.
2
2
3
3
2-[3-Cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-ylselanyl]-N-(4-methylphenyl)-
acetamide (9d). Yield 0.11 g (51%). Fine, light-gray crystals, mp 205-207oC. IR spectrum, , cm-1: 1713
(2C=O), 2215 (C≡N), 3333 (2NH). 1H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s, 4-CH3C6H4); 2.64 (1H, dd,
3
2
3
2
2J = 16.4, J = 6.1) and 2.94 (1H, dd, J = 16.4, J = 7.3, 5-CH2); 3.85 (1H, d, J = 13.2) and 3.92 (1H, d,
2J = 13.2, SeCH2); 4.24 (1H, dd, J = 6.1, J = 7.3, H-4); 7.08 (2H, d, J = 8.3) and 7.48 (2H, d, J = 8.3,
4-MeC6H4); 7.11-7.34 (4H, m, H Ar); 10.24 (1H, s, NHAr); 10.95 (1H, s, NH). Found, %: C 56.89; H 4.14;
N 9.46. C21H18FN3O2Se. Calculated, %: C 57.02; H 4.10; N 9.50.
3
3
3
3
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