Reactions of 5-(het)aryl-1-ethyl-2(1H )-pyrazinones with terminal arylacetylenes promoted by microwave radiation

Article abstract of DOI:10.1007/s10593-011-0824-y

The reaction of 5-(het)aryl-1-ethyl-2(1H)-pyrazinones with terminal arylacetylenes, leading to a mixture of two isomeric 4-aryl- and 5-aryl-substituted 2(1H)-pyridones has been investigated. The regioselectivity of this reaction has been shown on the basi

Full text of DOI:10.1007/s10593-011-0824-y

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
REACTIONS OF 5-(HET)ARYL-1-ETHYL-
2(1H )-PYRAZINONES WITH TERMINAL
ARYLACETYLENES PROMOTED
BY MICROWAVE RADIATION
E. V. Verbitskiy1*, E. M. Cheprakova1, P. A. Slepuhin1,
M. G. Pervova1, M. A. Samorukova1, O. N. Zabelina1,
G. L. Rusinov1, and V. N. Charushin1
The reaction of 5-(het)aryl-1-ethyl-2(1H)-pyrazinones with terminal arylacetylenes, leading to a mixture
of two isomeric 4-aryl- and 5-aryl-substituted 2(1H)-pyridones has been investigated. The regio-
selectivity of this reaction has been shown on the basis of reaction mixtures study by chromato-mass
spectrometry. A crystallographic investigation of the synthesized 2(1H)-pyridones and also a forecast of
their potential biological activity have been carried out.
Keywords: ꢀH-adducts, arylacetylenes, 1,2-dihydropyrazines, ionic liquid, 2(1H)-pyrazinones,
2(1H)-pyridones, microwave radiation.
The readily available and widely functionalized 2-azadiene system of 2(1H)-pyrazinones allow unique
possibilities for intra- and intermolecular cycloaddition reactions with both electron-rich and electron-deficient
dienophiles [1–3]. However the described reactions of pyrazinones 1 with acetylenes are restricted to several
examples of intramolecular cycloaddition reactions when alkyne is one of the substituents in the pyrazinone
fragment, and also to the interaction with the dimethyl ester of acetylenedicarboxylic acid 2 [3–5].
These Diels-Alder reactions usually lead to a mixture of pyridone 4 and pyridine 5 adducts due to two
competing spontaneous routes of the initially formed bicyclic cycloadducts 3 fragmentation by a retro Diels–
Alder reaction. Depending on the substituents R and R1, the ratio of compounds 4 and 5 vary significantly.
When R = Ph, R1 = Cl the main product of the reaction is pyridine 5, but at R = Et, R1 = (Het)Ar pyridone 4
predominates.
The aim of the present study was the investigation of the cycloaddition reaction of 5-(het)aryl-1-ethyl-
2(1H)-pyrazinones with terminal acetylenes on microwave irradiation in comparison to the usual thermal con-
_______________
*To whom correspondence should be addressed, e-mail: Verbitsky@ios.uran.ru.
1I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22
S. Kovalevskoi/20 Akademicheskaya St, Yekaterinburg 620041, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 860–870, June, 2011. Original
article submitted March 3, 2011.
0009-3122/11/4706-0710©2011 Springer Science+Business Media, Inc.
710
ꢀ

CO2Me
CO2Me
NC
O
–R1CN
N
R
CO2Me
CO2Me
R1
N
NC
O
N
C
CO2Me
4
+
O
N
N
R
CO2Me
R1
NC
MeO2C
N
N
R1
R
–RNCO
1
2
3
CO2Me
5
ditions. The commercially available phenylacetylene (7), 4-bromophenylacetylene (8), and 4-dimethylamino-
phenylacetylene (9) were used as alkynes. Reactions of pyrazinones 6a,b with terminal arylacetylenes 7–9 pro-
ceeded, according to data of both chromato-mass spectrometry and 1H NMR spectrometry, regioselectively and
led to a mixture of only two regioisomeric 2(1H)-pyridones, the major were 4-aryl-1-ethyl-2-oxo-1,2-dihydropy-
ridine-3-carbonitriles 12, 14, and 16, and the minor were 5-aryl-1-ethyl-2-oxo-1,2-dihydropyridine-3-carbo-
nitriles 13 and 15.
[4+2] Cycloaddition reactions were carried out under conditions of microwave irradiation in the pres-
ence of the ionic liquid bmimPF6. The experimentally found (by TLC reaction progress control) optimum time
for carrying out these reactions was 90 min at 195oC. For comparison the same reactions were carried out under
thermal conditions on boiling (178–180oC, 90 min) in 1,2-dichlorobenzene in the absence of any additives
(Table 1).
The obtained results indicate the absolute advantage of microwave syntheses. At one and the same time
in reactions proceeding under the usual thermal conditions, incomplete conversion of the initial
2(1H)-pyrazinones 6a,b and the formation of resinous products was observed. When promoted by microwave
radiation, reactions proceed with complete conversion of the starting compounds and the formation of a mixture
of the regioisomerically substituted 2(1H)-pyridones 12–16.
TABLE 1. Yields and Ratios of 2(1H)-Pyridines 12–17
Conversion of compound 6a
or 6b, %*
Yield,
%
Product ratio*
Reac-
tion
MW
Boiling
MW
Boiling
–*2
Compound
MW
6ꢀ+7
6b+7
94
39
–*2
12
13
55
7
82
28
55
–*2
–*2
12
13
68
11
6ꢀ+8
100
100
100
100
14 : 15
6.1 : 1
14 : 15
6.9 : 1
14
15
60
4
6b+8
32
14 : 15
7.3 : 1
14 : 15
5.4 : 1
14
15
–
98
–
6ꢀ+9
100
95
16 : 17
1 : 0
16 : 17
1 : 0
16
6b+9
16 : 17
1 : 0
16 : 17
1 : 0
16
_______
*According to GLC-MS data.
*2Ratio not established due to closeness of retention time in GLC-MS da-
ta and overlap of signals in 1H NMR spectra of reaction mixtures.
711
ꢀ

R
N
R
N
C
NC
O
–ArCN
O
N
N
Me
Ar
NC
O
Ar
N
N
Me
major
minor
MW, bmimPF6
10a,b
12, 14, 16
+
R
1.2-Dichlorobenzene
7–9
Me
N
NC
O
R
6a,b
C
R
–ArCN
O
N
N
N
Me
Me
Ar
13, 15, 17
11a,b
6a Ar = Ph, b Ar = 3-Thienyl;
7, 12, 13 R = Ph; 8, 14, 15 R = 4-BrC6H4; 9, 16, 17 R = 4-(Me2N)C6H4
The structures of the obtained 2(1H)-pyridones 12 and 14–16 were established by X-ray structural ana-
lysis (XSA). Data of XSA agree well with the data of 1H NMR spectra in which J5,6 = 7.0–7.2 for 4-aryl-1-ethyl-
2-oxo-1,2-dihydropyridine-3-carbonitriles 12, 14, and 16, while J4,6 = 2.6–2.7 Hz for 5-aryl-1-ethyl-2-oxo-
1,2-dihydropyridine-3-carbonitriles 13 and 15.
According to the data of XSA the investigated compounds are crystallized in centrosymmetric space
groups (compounds 12, 14, and 16 are monoclinic, 15 is orthorhombic). The distribution of bond lengths and
valence angles is fairly typical for such a series of compounds. The distribution of bond lengths in the
heterocycle indicates clearly the formation of a conjugated dienone system.
Fig. 1. Geometry of the compounds 14 (a) and 15 (b) molecules in the crystal.
712
ꢀ

TABLE 2. Main Crystallographic Parameters and Results of the Refine-
ment of Structural Experiments
Compound
12
14
15
16
Empirical formula
ꢁ
C14H12N2O
224.26
C14H11BrN2O
303.16
C14H11BrN2O
303.16
C16H17N3O
267.33
ꢂ, K
295(2)
295(2)
295(2)
295(2)
System
Monoclinic
P21/n
Orthorhombic
Pbca
Monoclinic
P21/n
Monoclinic
P21/ꢀ
Space group
Parameters of unit cell
13.0840(6)
13.9098(13)
14.3560(14)
90
a, Å
d, Å
7.8184(8)
13.1383(16)
11.7049(14)
100.244(10)
9.5290(4)
11.3804(11)
12.1323(14)
101.047(7)
13.9250(8)
10.9721(6)
9.4267(5)
98.061(5)
c, Å
ꢃ, deg
V, Å3
1183.2(2)
4
2612.7(4)
8
1291.3(2)
4
1426.04(14)
4
Z
D
calc., g/cm3
ꢄ, mm–1
F(000)
1.259
0.081
472
1.541
3.135
1216
1.559
3.172
608
1.245
0.080
568
ꢁmin
ꢁmax
–
–
0.403
0.546
0.439
0.729
–
–
Scanning angle,
ꢅ, deg
3.07 < ꢅ < 28.28 3.11 < ꢅ < 28.28 2.82 < ꢅ < 28.28 2.87 < ꢅ < 28.28
Reflections total
5509
8893
10151
8779
Independent
reflections
2839
(Rint = 0.0177)
3070
(Rint = 0.0369)
3184
(Rint = 0.0332)
3495
(Rint = 0.0259)
Reflections with
1511
97.9
1207
97.1
1586
99.8
1669
99.0
[I>2ꢀ(I)]
Complexity, %,
for ꢅ 26.00°
S on F2
1.010
0.0354
0.0733
0.0877
0.0933
1.010
0.0389
0.0594
0.1233
0.0627
1.010
0.0303
0.0505
0.0843
0.0531
1.008
0.0408
0.0843
0.0967
0.0903
R1 [I>2ꢀ(I)]
wR2[I>2ꢀ(I)]
R1 (all data)
wR2 (all data)
ꢆꢇmin, eꢈÅ–3
0.127
–0.123
0.555
–0.655
0.440
–0.379
0.193
–0.168
ꢆꢇmax, eꢈÅ–3
The length of the C=O bond in the investigated series lies within 1.222–1.236 Å, the length (provision-
ally) of the double bonds varies from 1.343 to 1.383 Å. Provisionally the single bonds vary from 1.405 to
1.449 Å. The aromatic substituent is turned relative to the plane of the pyridine ring. The respective dihedral
angles were 43.5(2)o (compound 12), 48.3(2)o (compound 14), 28.2(2)o (compound 15), and 36.7(2)o (compound
16). As we see, for compounds 12, 14, and 16 the angle of turn is reduced according to the increase in electron-
donating properties of the aromatic substituent, which is probably caused by the conjugation increase in the
rings ꢉ-systems due to the transfer of electrons from the ꢉ-donor to the ꢉ-accepting pyridine ring. In the case of
compound 15 the reduction in the angle of turn of the substituent may be explained by the reduction of CN
group steric factor influence.
A special feature of the molecular packing of the investigated compounds is the formation of shortened
contacts between the carbonyl oxygen atom and the proton at C(6) of the pyridine ring: d{O(1)ꢊꢊꢊH(6A)
[–1/2+x, y, 1.5–z]} = 2.500 (compound 14), d{O(1)ꢊꢊꢊH(6A)[1.5–x, –1/2+y, 2.5–z]} = 2.431 (compound 15),
713
ꢀ

714
ꢀ

715
ꢀ

d{O(1)ꢊꢊꢊH(6)[–x, 1/2+y, ½–z]} = 2.25(2) Å (compound 16). The values of the contacts (particularly for
compound 16) indicate the possibility of generating specific interactions since they being comparable with an
intermolecular hydrogen bond. In spite of the simplicity of the geometry and the presence of a powerful
ꢉ-system, clearly expressed ꢉ-contacts were absent.
The forecast of the biological activity for the synthesized 2(1H)-pyridones 12–16, and their precursors
2(1H)-pyrazinones 6a,b, has been made in the present work basing on the substance structural formula. It was
carried out by the computer program PASS using the available interactive service PASS INet
(http://www.ibmc.msk.ru/PASS) [6–10]. Biological activity is described in PASS in a qualitative form
(active/inactive) as a list of activities with two probabilities: Pa, to be active and Pi, to be inactive, calculated for
each activity kind. This list is drawn up according to the decrease of the Pa–Pi differences (Table 3). Only
activities with Pa > Pi are considered as probable for a compound being analyzed.
Data on the forecasting of properties for (het)aryl-substituted pyrazinones and pyridines (Table 3) show
that they may display high biological activity over a wide spectrum. This suggests the expediency of
experimental confirmation of biological activity for this class compounds with the aim of searching for new
prospects of physiologically active substances.
A simple and effective way for obtaining 4-aryl- and 5-aryl-substituted 2(1H)-pyridones from reactions
of 5-(het)aryl-1-ethyl-2(1H)-pyrazinones with terminal arylacetylenes promoted by microwave irradiation has
been proposed. Crystallographic investigation of the synthesized 2(1H)-pyridones was carried out and a forecast
of their potential biological activity was made.
EXPERIMENTAL
The 1H NMR spectra were obtained on a Bruker DRX 400 instrument (at 400 MHz) in CDCl3 solution,
internal standard was TMS. Elemental analysis was carried out on an automatic Perkin–Elmer PE 2400 analyzer.
Melting points were determined on a combination Boetius stage and are not corrected. Preparative HPLC was
carried out using a semi-preparative Agilent 1200 Series liquid chromatograph with a diode matrix detector,
analytical wavelength 280 nm. A ZORBAX Eclipse XDB-C18 PrepHT column 21.2 mm × 150 mm, particle
size 5 ꢄm was used at room temperature. Mobile phase was a mixture of acetonitrile–water, 60:40 and 50:50,
flow rate 20 ml/min, elution was isocratic.
GLC–MS analysis of all samples was carried out using a gas chromatograph-mass spectrometer Agilent
GC 7890A MS 5975C Inert XL EI/CI with a quadrupole mass-spectrometric detector and a quartz capillary
column HP 5MS, 30 m × 0.25 mm, film thickness 0.25 ꢄm. The mass spectra were recorded by electron
ionization (70 eV) scanning along the complete ion current in the range m/z 20–1000. Carrier gas was helium,
flow division 1:50, supply through the column 1.0 ml/min. Column temperature was 40oC initially (retention
3 min), programed at 10oC/min to 290oC (retention 20 min), evaporator temperature 250oC, source temperature
230oC, quadrupole 150oC, transfer chamber 280oC. Solutions of samples of concentration 3–4 mg/ml were
prepared in acetonitrile.
X-ray structural analysis (XSA) was carried out on an Xcalibur-3 X-ray diffractometer with a CCD de-
tector by the standard procedure (ꢋMoKꢌ, graphite monochromator, ꢍ-scanning). For analysis fragments of
yellow crystals were used of size 0.26×0.14×0.11 (compound 12), 0.32×0.19×0.07 (compound 14),
0.16×0.09×0.06 (compound 15), and 0.25×0.20×0.15 mm (compound 16). Collection and processing of data
was carried out using the CrysAlis set of programs [12]. No correction for absorption was introduced for sam-
ples of 12 and 16, for samples of 14 and 15 a correction was introduced analytically according to the model for a
polyhedral crystal [12]. The structures of all compounds were solved by the direct method according to program
SHELXS-97 and were refined with the aid of the SHELXL-97 program [13] in an anisotropic approximation
(isotropic for hydrogen atoms). The hydrogen atoms were partially determined and refined independently, and
partially included in the refinement in the rider model with dependent thermal parameters. The XSA data are
recorded in the Cambridge Crystallographic Data Center at www.ccdc.cam.ac. uk/data_request/cif (deposition
716
ꢀ

number CCDC 819354 for compound 12, CCDC 819355 for compound 14, CCDC 819356 for compound 15,
and CCDC 819357 for compound 16).
All microwave experiments were carried out in a single mode CEM Discover system with an operating
frequency of 2.45 GHz. The reactions were carried out in a test tube of 10 ml capacity with a hermetic Teflon
stopper.
Column chromatography was carried out using Lancaster silica gel 0.040–0.063 mm (230–400 mesh),
eluting with ethyl acetate–hexane, 1 : 2.
The progress of reactions and the purity of compounds was checked by TLC on Sorbfil plates, visualiz-
ing with UV light.
Solvents were dried and purified according to procedures taken from literature [11]. The starting com-
pounds 6a,b were obtained according to the known procedure of [5].
4-Aryl-1-ethyl-2-oxo-1,2-dihydropyridine-3-carbonitriles 12, 14, 16, and 5-Aryl-1-ethyl-2-oxo-
1,2-dihydropyridine-3-carbonitriles 13, 15 (General Method). A. Use of microwave radiation. A solution of
the corresponding 2(1H)-pyrazinone 6a,b (0.60 mmol), arylacetylene (0.72 mmol), and bmimPF6 (1-butyl-
3-methylimidazolium hexafluorophosphate) (15 ꢄl, 0.15 mmol) in 1,2-dichlorobenzene (3 ml) was irradiated for
90 min with microwave radiation (250 W) at 195oC, the solvent was distilled at reduced pressure, and the
residue was separated chromatographically on silica gel or isolated by preparative HPLC.
B. Reaction under thermal conditions. A solution of the corresponding 2(1H)-pyrazinone 6a,b
(0.60 mol) and arylacetylene (0.72 mmol) in 1,2-dichlorobenzene (3 ml) was boiled for 90 min. The reaction
mixture was treated analogously to method A.
When investigating the reaction mixtures, the residue after distillation of the solvent was analyzed by
GC–MS without further treatment.
1-Ethyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile (12). Light-yellow crystalline powder;
1
mp 148–150oC. H NMR spectrum, ꢎ, ppm (J, Hz): 1.43 (3H, t, J = 7.2, CH3); 4.01–4.11 (2H, m, CH2); 6.35
(1H, d, J = 7.0, H-6); 7.39–7.53 (3H, m, H Ph); 7.55 (1H, d, J = 7.0, H-5); 7.60–7.63 (2H, m, H Ph). Mass
spectrum, m/z (Irel, %): 224 [M]+ (100). HPLC: tR 2.8–3.6 min. GLC: tR 25.54 min. Found, %: C 74.97; H 5.48;
N 12.51. C14H12N2O. Calculated, %: C 74.98; H 5.39; N 12.49.
1-Ethyl-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (13). Yellow crystalline powder; mp
1
135–137oC. H NMR spectrum, ꢎ, ppm (J, Hz): 1.45 (3H, t, J = 7.2, CH3); 4.13 (2H, q, J = 7.2, NCH2); 7.26–
7.41 (3H, m, H Ph); 7.44–7.48 (2H, m, H Ph); 7.74 (1H, d, J = 2.7, H-6); 8.07 (1H, d, J = 2.7, H-4). Mass
spectrum, (EI, 70 eV), m/z (Irel, %): 224 [M]+ (100). HPLC: tR 3.7–4.6 min. GLC: tR 25.54 min. Found, %:
C 75.12; H 5.23; N 12.50. C14H12N2O. Calculated, %: C 74.98; H 5.39; N 12.49.
4-(4-Bromophenyl)-1-ethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (14). Light-yellow crystalline
1
powder; mp 196–198oC. H NMR spectrum, ꢎ, ppm (J, Hz): 1.43 (3H, t, J = 7.2, CH3); 4.12 (2H, q, J = 7.2,
CH2); 6.31 (1H, d, J = 7.0, H-6); 7.49 (2H, d, J = 8.4, H-3',5'); 7.55 (1H, d, J = 7.0, H-5); 7.65 (2H, d, J = 8.4,
H-2',6'). Mass spectrum, m/z (Irel, %): 302 [M]+ (100) for 79Br, 304 [M]+ (100) for 81Br. HPLC: tR 2.8–3.6 min.
GLC: tR 28.13 min. Found, %: C 55.69; H 3.75; N 9.11. C14H11BrN2O. Calculated, %: C 55.47; H 3.66; N 9.24.
5-(4-Bromophenyl)-1-ethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (15). Light-yellow crystalline
1
powder; mp 193–195oC. H NMR spectrum, ꢎ, ppm (J, Hz): 1.45 (3H, t, J = 7.2, CH3); 4.12 (2H, q, J = 7.2,
CH2); 7.25 (2H, d, J = 8.5, H-3',5'); 7.59 (2H, d, J = 8.5, H-2',6'); 7.72 (1H, d, J = 2.6, H-6); 8.02 (1H, d, J = 2.6,
79
81
H-4). Mass spectrum, m/z (Irel %): 302 [M]+ (100) for Br, 304 [M]+ (100) for Br. HPLC: tR 3.8–4.8 min.
GLC: tR 28.32 min. Found, %: C 55.59; H 3.37; N 9.18. C14H11BrN2O. Calculated, %: C 55.47; H 3.66; N 9.24.
4-(4-Dimethylaminophenyl)-1-ethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (16). Bright-yellow
crystalline powder; mp 187–189oC. 1H NMR spectrum, ꢎ, ppm (J, Hz): 1.40 (3H, t, J = 7.2, CH2CH3); 3.05 (6H,
s, N(CH3)2); 4.03 (2H, q, J = 7.2, CH2CH3); 6.35 (1H, d, J = 7.2, H-6); 6.76 (2H, dd, J = 6.9, J = 2.2, H-3',5');
7.42 (1H, d, J = 7.2, H-5); 7.62 (2H, d, J = 6.9, J = 2.2, H-2',6'). Mass spectrum, m/z (Irel, %): 267 [M]+ (100).
HPLC: tR 2.0–2.5 min. GLC: tR 30.79 min. Found, %: C 71.81; H 6.48; N 15.53. C16H17N3O. Calculated, %:
C 71.89; H 6.41; N 15.72.
717
ꢀ

The work was carried out with the financial support for Programs of the Ural Branch Russian Academy
of Sciences 09-I-3-2004, 09-P-3-1015, 09-T-3-1022, Goscontract No. 02.740.11.0260, and also grants from the
Russian Fund for Fundamental Investigations (RFFI) 10-03-96078-r_ural_a and VNSh-65261.2010.3.
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