Synthesis, crystal structures, and properties of 5-(het)aryl-3-cyano-1- ethyl-2(1H)-pyrazinones

Article abstract of DOI:10.1007/s11172-011-0142-7

A simple method for the synthesis of 5-(het)aryl-3-cyano-1-ethyl-2(1H)- pyrazinones was proposed. The method is based on the hydrolysis of the corresponding 2,3-dicyanopyrazinium salts. The spectral properties of pyrazinones were studied and their crystal

Full text of DOI:10.1007/s11172-011-0142-7

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 906—913, May, 2011
906
Synthesis, crystal structures, and properties
of 5ꢀ(het)arylꢀ3ꢀcyanoꢀ1ꢀethylꢀ2(1H)ꢀpyrazinones
E. V. Verbitskiy, M. V. Berezin, P. A. Slepukhin, O. N. Zabelina, G. L. Rusinov, and V. N. Charushin
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620990 Ekaterinburg, Russian Federation.
Fax: +7 (343) 369 3058. Eꢀmail: Verbitsky@ios.uran.ru
A simple method for the synthesis of 5ꢀ(het)arylꢀ3ꢀcyanoꢀ1ꢀethylꢀ2(1H)ꢀpyrazinones was
proposed. The method is based on the hydrolysis of the corresponding 2,3ꢀdicyanopyrazinium
salts. The spectral properties of pyrazinones were studied and their crystallographic investigaꢀ
tion was carried out. The possibility of introduction of 5ꢀ(het)arylꢀ3ꢀcyanoꢀ1ꢀethylꢀ2(1H)ꢀ
pyrazinones into the [2+4] cycloaddition under the microwave activation conditions was shown.
Key words: pyrazinium salts, 5ꢀarylꢀ3ꢀcyanoꢀ2(1H)ꢀpyrazinones, 1,2ꢀdihydropyrazines,
microwave irradiation, cycloaddition reactions.
Scheme 1
2(1H)ꢀPyrazinones are known as substances widely
used in syntheses of biologically active compounds,1—9
since the 2(1H)ꢀpyrazinone fragment makes it possible to
introduce into molecules a whole series of pharmacologiꢀ
cally active groups capable of purposefully interacting with
biological targets.10—13
The traditional method for the synthesis of 2(1H)ꢀ
pyrazinones is the condensation of αꢀaminocarboxamides
with 1,2ꢀdicarbonyl compounds; however, the formation
of a mixture of regioisomers is a substantial drawback
of this method.14 Multicomponent reactions involving
primary amines, aldehydes, and cyanide are also used for
the synthesis of pyrazinones. These reactions lead to
αꢀaminonitriles, whose subsequent cyclization affords the
corresponding pyrazinones.3,4,10 A possibility of preparing
3ꢀcyanoꢀ1ꢀethylꢀ2(1H)ꢀpyrazinone by the reaction of
2,3ꢀdicyanoꢀ1ꢀethylpyrazinium tetrafluoroborate with
water was shown.15 However, the reactions of salts of
5ꢀ(het)arylꢀ2,3ꢀdicyanoꢀ1ꢀethylpyrazinium 1a—c with
water under the basic catalysis conditions lead to comparꢀ
atively stable 6ꢀhydroxyadducts 2а—с (Scheme 1).16
In the present work, we show that the hydrolysis
of salts 1 in an acidic medium (reflux in a mixture of
MeCN—H2O—HCl(conc.), 5 : 10 : 1) affords 6ꢀ(het)arylꢀ
4ꢀethylꢀ3ꢀoxoꢀ3,4ꢀdihydropyrazineꢀ2ꢀcarbonitriles 3а—с
(see Scheme 1) in high yields. Their structures were deterꢀ
mined by Xꢀray diffraction analysis for compounds 3а,c as
an example (Figs 1 and 2).
1—3: Ar = Ph (a), 4ꢀFC6H4 (b); Het = thiophenꢀ3ꢀyl (c)
oroborate17,18) afforded 6ꢀ(het)arylꢀ4ꢀethylꢀ3ꢀoxoꢀ3,4ꢀdiꢀ
hydropyrazineꢀ2ꢀcarbonitriles 3а—с (Scheme 2).
The reaction of compound 3с with molecular bromine
gives 6ꢀ(2,5ꢀdibromothiophenꢀ3ꢀyl)ꢀ4ꢀethylꢀ3ꢀoxoꢀ
3,4ꢀdihydropyrazineꢀ2ꢀcarbonitrile (5) (Scheme 3), whose
structure was unambiguously proved by Xꢀray diffraction
analysis (Fig. 3). Note that the obtained bifunctional diꢀ
bromothiophene 5 can be interesting as a component for
copolycondensation and synthesis of polythiophenes with
specified optical properties.
Spectral studies of 2(1H)ꢀpyrazinones. The synthesized
pyrazinones 3а—с have extended πꢀconjugation and an
intramolecular system of chromophores. Due to this,
compounds 3а—с possess yellowꢀgreen fluorescence both
Attempts of oxidative aromatization of 6ꢀhydroxyadꢀ
ducts 2а—с to pyrazinones 4а—с under the action of oxiꢀ
dants (such as air oxygen and 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ
1,4ꢀbenzoquinone) were unsuccessful. The reactions with
the Barluenga reagent (bis(pyridinium)iodonium tetrafluꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 886—892, May, 2011.
1066ꢀ5285/11/6005ꢀ906 © 2011 Springer Science+Business Media, Inc.

Synthesis and properties of 2(1H)ꢀpyrazinones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
907
Scheme 2
Ar = Ph (a), 4ꢀFC6H4 (b); Het = thiophenꢀ3ꢀyl (c)
Scheme 3
in solutions and in the solid state. At the same time,
2(1H)ꢀpyrazinone 5, having a large Stokes shift, exhibits
weak yellow luminescence, which can be caused by both
a change in the electronic structure and changes in its
crystal packing due to the presence of two bromine atoms.
The results of spectral studies of compounds 3а—с and 5
are given in Table 1.
Xꢀray diffraction study of 2(1H)ꢀpyrazinones. Crystals
of compound 3а are formed by two crystallographically
independent molecules of close configurations (I and II),
which crystallize in the centrosymmetric space group Р–1
of the triclinic crystal system. The general view of the
structure and the atomic numbering scheme in the Xꢀray
diffraction experiment are presented in Fig. 1 for molecule
I as an example; atoms of molecule II are marked with
additional index "A." The corresponding bond lengths and
bond angles in the both molecules are close, but there are
some differences in their conformations. For example, the
phenyl substituent of molecule I lies almost in the pyrꢀ
azine ring plane and the deviation of atoms through the
rootꢀmeanꢀsquare plane drawn through the atoms of these
cycles is <0.03 Å, whereas the substituent in molecule II is
unfolded relatively to the pyrazine cycle at an angle of
13.3°. The bond lengths in the pyrazine cycle are equalꢀ
ized to a considerable extent and are close in value to the
bond lengths in aromatic systems. The exception is the
bond С(2)—С(3) equal to 1.446(3) Å (С(2А)—С(3А),
1.460(3) Å), whose length more corresponds to the ordiꢀ
nary bond length in the system of conjugation of multiple
N(3)
C(13)
C(12)
N(2)
C(5)
C(1)
C(4)
C(3)
C(2)
C(11)
C(9)
O(1)
C(10)
C(6)
N(1)
C(7)
C(8)
Fig. 1. Xꢀray crystal structure of compound 3a.
C(10A)
S(1A)
N(3A)
C(7)
Br(2)
C(9A)
N(2)
C(11)
C(8)
C(4A)
N(2A)
N(1A)
N(4)
C(5)
C(8A)
C(3A)
C(10)
C(3)
C(7A)
S(1)
C(5A)
C(6A)
C(2A)
O(1A)
C(9)
C(6)
C(2)
N(1)
Br(1)
O(1)
C(1A)
C(1)
C(4)
Fig. 3. Xꢀray crystal structure of compound 5.
C(11A)
Fig. 2. Xꢀray crystal structure of compound 3с.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Verbitskiy et al.
Table 1. Data of the IR, UV, and fluorescence spectra of compounds 3а—с and 5
MeCN b
Comꢀ
pound
IR,a
ν/cm–1
UV, λmax/nm (ε)
Fmax
SSc
MeCN
solid state
nm
3a
693 (C—H arom., C—Carom.),
767 (C—H arom., C—C arom.),
780 (C—H arom.), 1596 (C—C arom.),
1653 (C=O), 2227 (C≡N), 3073 (C—H arom.)
779 (C—H arom., C—C arom.),
821 (C—H arom., C—C arom.),
853 (C—H arom., C—C arom.),
1515 (C—C arom.), 1652 (C=O),
2230 (C≡N), 3062 (C—H arom.)
400 (8060),
272 (24060),
216 (15200),
206 (13960)
400 (9600),
270 (29000)
401,
269
465
466
65
66
3b
407,
277
3c
5
795 (C—H of thiophene), 1451 (thiophene cycle), 410 (8460),
411,
277
491
479
81
88
1534 (thiophene cycle), 1652 (C=O),
2232 (C≡N), 3073 (C—H of thiophene),
3088 (C—H of thiophene)
277 (28460),
231 (11760),
210 (14540)
391 (5800),
280 (12300),
248 (21200),
208 (15900)
781, 841, 851 (C—H of thiophene),
1066 (CHet—Br), 1442, 1475 (thiophene cycle),
1540 (thiophene cycle), 1668 (C=O),
2234 (C≡N), 3064 (C—H of thiophene)
396,
251
a The bands were assigned on the basis of the published data.19
b Fluorescence maximum at λ
.
MeCN
max
c Stokes shift, SS = λ MeCN – Fmax
.
MeCN
max
bonds. It is most likely this is related to the influence of
the electronꢀwithdrawing substituents (conjugated carbonyl
and cyano groups). In the molecular packing molecules
I form piles oriented along the axis а. Molecules II are
arranged at an angle between the pile to form rather loosꢀ
ened structure. No shortened intermolecular π—πꢀconꢀ
tacts are observed in the packing, but there is the strongly
shortened intermolecular contact С—Н...О=С close in
value to the intermolecular hydrogen bond: d(C(6)...O(1A)
[x, –1 + y, z]) = 3.159 Å, d(C(6А)...O(1)) = 3.188 Å (by
0.061 and 0.032 Å shorter than the sum of van der Waals
radii), d(H(6A)...O(1A) [x, –1 + y, z]) = 2.271 Å,
d(O(1)...H(6AA)) = 2.309 Å (by 0.449 and 0.411 Å shortꢀ
er than the sum of van der Waals radii). Taking into acꢀ
count these contacts, the molecular packing takes the
shape of convex ribbons oriented along the axis b and
formed by alternating molecules I and II.
The crystals of compound 3с are formed by two crysꢀ
tallographically independent molecules (I and II), which
crystallize in the centrosymmetric space group Р–1 of triꢀ
clinic crystal system, and the unit cell parameters deterꢀ
mined by the molecular crystal packing differ sharply from
the unit cell parameters of compound 3а. The general
view of molecules I and II and the atomic numbering
scheme in the Xꢀray diffraction experiment are presented
in Fig. 2, and the corresponding atoms of molecule II are
marked by additional index "A." The corresponding bond
lengths and bond angles in the both molecules are close
between each other, and the differences are observed in
the orientation of the thienyl substituent relatively to
the atoms of the pyrazine cycle: the torsional angle
N(2)—C(5)—C(8)—C(7) is 0.0° and N(2A)—C(5A)—
C(8A)—C(7A) is 175.5°. In the both cases, the thienyl
substituent lies almost in the pyrazine cycle plane, and the
deviation of atoms from the rootꢀmeanꢀsquare plane drawn
through the atoms of these cycles for molecule I is <0.015 Å
and that for molecule II is <0.05 Å. The bond length
distribution in pyrazine cycle 3с is analogous to the
bond length distribution in molecules 3а, in particular,
d(С(2)—С(3)) = 1.456(3) Å, d(С(2А)—С(3А)) = 1.449(3) Å.
The molecular packing is layered, and the planes of the
layers are parallel to the crystallographic plane [110]. The
interlayer shortened π—πꢀcontacts are observed for the
pyrazine and thiophene cycles. The distances between the
centroids of the pyrazine cycle of molecule II and the
thiophene cycle of molecule I is 3.456 Å, whereas that
between the centroids of the pyrazine cycle of molecule I
and the thiophene cycle of molecule II is 3.578 Å. Thus, in
molecular packing 3с the conjugation of the thiophene
cycle with the pyrazine ring is a rigidly fixed system of
intermolecular contacts, which probably favors the enꢀ
hancement of luminescence properties of the compound
due to a decrease in energy losses on thermal vibrations.
The crystals of compound 5 are triclinic, and the subꢀ
stance crystallizes in the centrosymmetric space group Р–1.
The general view of the molecule and the atomic numberꢀ
ing scheme in the Xꢀray diffraction experiment are shown
in Fig. 3. The thienyl substituent is unfolded relatively to
the pyrazine plane at an angle of 44.25°. The bond length
between the cyano and keto groups of the pyrazine cycle

Synthesis and properties of 2(1H)ꢀpyrazinones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
909
Scheme 5
(d(С(2)—С(3)) = 1.446(3) Å) coincides with the correꢀ
sponding bond lengths in compounds 3а,c. The molecular
packing has no a pronounced geometric motive. The shortꢀ
ened π—πꢀcontact between the carbon atoms of the pyrꢀ
azine cycle bearing the CN group (d(C(3)...C(3) [–x, 2 – y,
3 – z]) = 3.324 Å) should be mentioned.
Transformation of 2(1H)ꢀpyrazinones. It has earlier20,21
been shown that 2(1Н)ꢀpyrazinones 3а,с undergo the
[4+2] cycloaddition reaction with 9ꢀallylcarborane (6),
yielding the corresponding cyclic adducts 7а,b (Scheme 4).
Scheme 4
Ar = Ph (3a, 8a, 9a); Het = thiophenꢀ3ꢀyl (3c, 8b, 9b)
i. MW, 195 °C, 200 W, 15 min, bmimPF6, 1,2ꢀdichlorobenzene.
5—7 times and a decrease in the amount of resinificaꢀ
tion products.
The GLC/MS study of the reaction mixtures also inꢀ
dicates that the reaction is accelerated at the same duraꢀ
tion (15 min) and the formation of 2(1H)ꢀpyridone 10 is
preferential. The results of studying the cycloaddition reacꢀ
tion by GLC/MS are generalized in Table 3.
Ar = Ph (3a, 7a); Het = thiophenꢀ3ꢀyl (3c, 7b)
The synthesized dimethyl 6ꢀ(het)arylꢀ2ꢀcyanopyriꢀ
dineꢀ3,4ꢀdicarboxylate 9а,b and dimethyl 5ꢀcyanoꢀ1ꢀethylꢀ
6ꢀoxoꢀ1,6ꢀdihydropyridineꢀ3,4ꢀdicarboxylate (10) were
isolated using preparative HPLC. The structure of the latꢀ
ter was unambiguously established on the basis of Xꢀray
diffraction data (Fig. 4).
i. MW, 195 °C, 250 W, 300 min, 1,2ꢀdichlorobenzene.
In this work, the reactions of cycloaddition of В 2(1Н)ꢀ
pyrazinones 3а,с with acetylenic dienophiles attracted our
attention. These Diels—Alder reactions were shown to give
a mixture of pyridines 9a,b and pyridone 10 because of the
competitive routes of retrodecomposition of primarily
formed bicyclic adducts 8а,b (Scheme 5).
Using 2(1H)ꢀpyrazinone precursors 3а,с as model subꢀ
strates, we studied the cycloaddition of dimethyl acetyꢀ
lenedicarboxylate under the microwave (MW) irradiation
conditions and the use of 1ꢀbutylꢀ3ꢀmethylimidazolium
hexafluorophosphate (bmimPF6) as the ionic liquid (see
Scheme 5). For comparison the same reactions were carꢀ
ried out under thermal conditions on reflux (178—180 °С,
100 min) in 1,2ꢀdichlorobenzene in the absence of addiꢀ
tives. The results are given in Table 2.
Table 2. Conditions of the reaction of 2(1H)ꢀpyrazinones 3а,с
with dimethyl acetylenedicarboxylate and their influence of the
yields of pyridines 9а,b and pyridone 10
Initial
Reaction conditions
Yield of
compound
products (%)
9
10
3а
3с
MW*, 195 °С, 15 min
Reflux**, 178—180 °С, 100 min
MW*, 195 °С, 15 min
5 (9а) 83
3 (9а) 74
6 (9b) 88
4 (9b) 78
The results (see Table 2) indicate that the yield and
the ratio of products are close regardless of the reacꢀ
tion conditions. In this case, advantages of microꢀ
wave synthesis are in the acceleration of the reaction by
Reflux**, 178—180 °С, 70 min
* Microwave irradiation.
** With reflux condenser.

910
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Verbitskiy et al.
Table 3. Ratio of products in the reactions of 2(1H)ꢀpyrazinones
3а,с with dimethyl acetylenedicarboxylate (according to the
GLC/MS data)
The instrument is equipped with an autosampler (900 μL),
a diodeꢀmatrix detector (chosen analytical wavelength 280 nm),
and a collector of fractions; column: ZORBAX Eclipse XDBꢀC18
PrepHT (21.2 mm × 150 mm), particle size 5 μm (Agilent Techꢀ
nologies, USA), room temperature of the column. An acetoniꢀ
trile—water (50 : 50) mixture was used as a mobile phase, the
flow rate of the mobile phase was 20 mL min–1, and the elution
regime was isocratic.
The GLC/MS analysis of all samples was carried out using
an Agilent GC 7890A MS 5975C Inert XL EI/CI GC/MS
spectrometer with a quadrupole massꢀspectrometric detector with
electron ionization (70 eV) and scan over the total ionic current
in the range m/z 20—1000 and a quartz capillary column
HPꢀ5MS (30 m × 0.25 mm, film thickness 0.25 μm). Helium
served as a carrier gas, the split ratio of the flow was 1 : 50, and
the consumption through the column was 1.0 mL min–1; the
initial temperature of the column was 40 °С (storage 3 min),
programming rate was 10 °С min–1 to 290 °С (storage 20 min),
the temperature of the evaporator was 250 °С, the temperature
of the source was 230 °С, the temperature of the quadrupole was
150 °С, and the temperature of the transition chamber was 280 °С.
Solutions of the samples with a concentration of 3—4 mg mL–1
were prepared in acetonitrile. Samples of 1 μL of the obtained
solutions were analyzed.
Initial
Reaction
Ratio
pyrazinone
conditions
of products (%)
3а
3с
MW, 195 °С
Reflux, 178—180 °С
MW, 195 °С
85 : 11 : 4 (10 : 9а : 3а)
57 : 11 : 32 (10 : 9а : 3а)
79 : 7 : 14 (10 : 9b : 3c)
83 : 6 : 11 (10 : 9b : 3c)
Reflux, 178—180 °С
C(10)
O(4)
C(7)
C(9)
O(5)
O(2)
O(3)
C(1)
C(3)
C(4)
C(6)
C(5)
N(1)
C(12)
Flash chromatography was carried out using silica gel Lanꢀ
caster 0.040—0.063 mm (230—400 mesh).
The reaction course and purity of the products were moniꢀ
tored by TLC on plates Sorbfil (UV development).
All microwave experiments were carried out in a CEMꢀDisꢀ
cover monomode microwave apparatus (USA) operating at
a frequency of 2.45 GHz and with continuous irradiation power
from 0 to 300 W. with utilization of the standard absorbance
level of 200 W maximum power. The reactions were carried out
in microwave process vials (10 mL) with sealed Teflon crimp
top, which can be exposed to 250 °C and 20 bar external presꢀ
sure. The temperature was measured with an IR sensor on the
outer surface of the process vial.
C(2)
C(11)
C(8)
N(2)
O(1)
Fig. 4. Xꢀray crystal structure of compound 10.
Thus, the simple method for the synthesis of 5ꢀ(het)ꢀ
arylꢀ3ꢀcyanoꢀ1ꢀethylꢀ2(1H)ꢀpyrazinones was proposed in
the work. 5ꢀ(Het)arylꢀ3ꢀcyanoꢀ1ꢀethylꢀ2(1H)ꢀpyrazinoꢀ
nes exhibit pronounced luminescence properties and can
be used as the initial compounds in cycloaddition reactions.
Synthesis of 6ꢀ(het)arylꢀ4ꢀethylꢀ3ꢀoxoꢀ3,4ꢀdihydropyrazineꢀ
2ꢀcarbonitriles 3а—с from 5ꢀ(het)arylꢀ2,3ꢀdicyanoꢀ1ꢀethylꢀ
pyrazinium tetrafluoroborates 1а—с (general procedure). Salt 1а—с
(1 mmol) was dissolved in MeCN (5 mL), and Н2О (10 mL) and
concentrated hydrochloric acid (1 mL) were added to the obꢀ
tained solution. The reaction mixture was refluxed for 0.5 h, the
solvent was distilled off in vacuo, and the residue was separated
on silica gel eluting with an ethyl acetate—hexane (1 : 3) mixꢀ
ture. The obtained product was recrystallized from MeOH.
4ꢀEthylꢀ3ꢀoxoꢀ6ꢀphenylꢀ3,4ꢀdihydropyrazineꢀ2ꢀcarbonitrile
(3а). Yellow crystalline powder. The yield was 61%, m.p.
191—193 °С. 1H NMR (CD3CN), δ: 1.39 (t, 3 H, Me, J = 7.2 Hz);
4.08 (q, 2 H, NCH2, J = 7.2 Hz); 7.40—7.42 (m, 1 H, Ph);
7.46—7.50 (m, 2 H, Ph); 7.78—7.81 (m, 2 H, Ph); 8.23 (s, 1 H,
C(5)H). Found (%): C, 69.29; H, 5.02; N, 18.68. C13H11N3O.
Calculated (%): C, 69.32; H, 4.92; N, 18.66. GLC: tR = 25.465 min.
MS (EI, 70 eV), m/z (Irel (%)): 225 [М]+ (100).
4ꢀEthylꢀ6ꢀ(4ꢀfluorophenyl)ꢀ3ꢀoxoꢀ3,4ꢀdihydropyrazineꢀ2ꢀ
carbonitrile (3b). Yellow crystalline powder. The yield was 60%,
m.p. 219—220 °С. 1H NMR (CD3CN), δ: 1.39 (t, 3 H, Me,
J = 7.2 Hz); 4.07 (q, 2 H, NCH2, J = 7.2 Hz); 7.20—7.24 (m, 2 H,
Ph); 7.79—7.83 (m, 2 H, Ph); 8.20 (s, 1 H, C(5)H). Found (%):
C, 64.00; H, 4.36; N, 17.48. C13H10FN3O. Calculated (%):
C, 64.19; H, 4.14; N, 17.28.
Experimental
Solvents and reagents were dried and purified according to
described procedures.22 Compounds 1a—c were synthesized acꢀ
cording to the known procedure,16 and bis(pyridinium)iodonium
tetrafluoroborate was synthesized according to the published proꢀ
cedure.17
1H NMR spectra were recorded on a Bruker DRXꢀ400 inꢀ
strument (400 MHz) using Me4Si as an internal standard. Eleꢀ
mental analysis was carried on a Perkin—Elmer PEꢀ2400 autoꢀ
mated analyzer. IR spectra were recorded on an FTꢀIR Specꢀ
trometer Spectrum One instrument (Perkin—Elmer) in Nujol.
UV spectra were measured on a UVꢀ2401 PC instrument (Shiꢀ
madzu) for solutions of the compounds in acetonitrile with
a concentration of 10–5 mol L–1. UV spectra in the solid state
were obtained by mixing a sample of compound 3а—с with
BaSO4 using the "integrating sphere" attachment. Emission specꢀ
tra were recorded on a Varian Cary Eclipse spectrofluorimeter
for solutions of the compounds in acetonitrile with a concentraꢀ
tion of 10–5 mol L–1. Melting points were determined on Boetꢀ
ius combined heating stages and were not corrected. Preparative
HPLC was carried out using an Agilent 1200 Series semiꢀpreꢀ
parative liquid chromatograph (Agilent Technologies, USA).

Synthesis and properties of 2(1H)ꢀpyrazinones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
911
4ꢀEthylꢀ3ꢀoxoꢀ6ꢀ(thiophenꢀ3ꢀyl)ꢀ3,4ꢀdihydropyrazineꢀ2ꢀ
carbonitrile (3с). Yellow crystalline powder. The yield was 57%,
m.p. 166—167 °С. 1H NMR (CD3CN), δ: 1.38 (t, 3 H, Me,
J = 7.2); 4.05 (q, 2 H, NCH2, J = 7.2 Hz); 7.46 (dd, 1 H, H(4´)
of thiophenꢀ3ꢀyl, J = 5.2 Hz, J = 1.2 Hz); 7.52 (dd, 1 H, H(5´)
of thiophenꢀ3ꢀyl, J = 5.2 Hz, J = 3.2 Hz); 7.73 (dd, 1 H, H(2´)
of thiophenꢀ3ꢀyl, J = 3.2 Hz, J = 1.2 Hz); 8.16 (s, 1 H, C(5)H).
Found (%): C, 57.309; H, 4.12; N, 18.43. C11H9N3OS. Calcuꢀ
lated (%): C, 57.13; H, 3.92; N, 18.17. GLC: tR = 25.714 min.
MS (EI, 70 eV), m/z (Irel (%)): 231 [М]+ (100).
Me, J = 7.2 Hz); 4.05 (q, 2 H, NCH2, J = 7.2 Hz); 7.10 (s, 1 H,
H(4´) of thiophenꢀ3ꢀyl); 8.20 (s, 1 H, C(5)H). Found (%):
C, 33.80; H, 1.64; Br, 40.82; N, 10.68. C11H7Br2N3OS. Calcuꢀ
lated (%): C, 33.96; H, 1.82; Br, 41.07; N, 10.80.
Synthesis of dimethyl 6ꢀ(het)arylꢀ2ꢀcyanopyridineꢀ3,4ꢀdicarbꢀ
oxylates 9а,b and dimethyl 5ꢀcyanoꢀ1ꢀethylꢀ6ꢀoxoꢀ1,6ꢀdihydroꢀ
pyridineꢀ3,4ꢀdicarboxylate (10) (general procedure A). A solution
of 2(1H)ꢀpyrazinone 3а,c (0.60 mmol), dimethyl acetylenediꢀ
carboxylate (0.72 mmol), and bmimPF6 (15 μL, 0.15 mmol) in
1,2ꢀdichlorobenzene (3 mL) was irradiated with microwave
radiation (250 W) at 195 °С for 15 min, the solvent was distilled
off in vacuo, and the residue was separated on silica gel eluting
with an ethyl acetate—hexane (1 : 1) mixture or was isolated by
HPLC. The yields of the products and reaction conditions are
given in Table 2.
General procedure B. A solution of 2(1H)ꢀpyrazinone 3a,c
(0.60 mmol) and dimethyl acetylenedicarboxylate (0.72 mmol)
in 1,2ꢀdichlorobenzene (3 mL) was refluxed with a reflux
condenser until the initial pyrazinone disappeared (TLC moniꢀ
toring), the solvent was distilled off in vacuo, and the residue
was separated on silica gel eluting with an ethyl acetate—hexꢀ
ane (1 : 1) mixture or was isolated by preparative HPLC.
6ꢀ(2,5ꢀDibromothiophenꢀ3ꢀyl)ꢀ4ꢀethylꢀ3ꢀoxoꢀ3,4ꢀdihydropyrꢀ
azineꢀ2ꢀcarbonitrile (5). Bromine Br2 (153 μL, 3 mmol) was addꢀ
ed to a solution of compound 3с (231 mg, 1 mmol) in anhydrous
THF (5 mL). The reaction mixture was stirred for 30 min at
room temperature, the solvent was distilled off in vacuo, and the
residue was treated with an aqueous solution of Na2CO3 and
extracted with 10—20 mL of CHCl3. The extract was dried with
anhydrous Na2SO4, the solvent was distilled off in vacuo, and
the residue was separated on silica gel eluting with an ethyl aceꢀ
tate—hexane (1 : 1) mixture. The obtained product was recrysꢀ
tallized from EtOH. The yield was 230 mg (59%), m.p. 145—147 °С.
1
Yellow crystalline powder. H NMR (CD3CN), δ: 1.37 (t, 3 H,
Table 4. Selected parameters of Xꢀray diffraction experiments for compounds 3a,c, 5, and 10
Compound
3а
3с
5
10
Formula
Molecular weight
C13H11N3O
225.25
C11H9N3OS
231.27
C11H7Br2N3OS
389.08
C12H12N2О5
264.24
T/K
295(2)
130(2)
295(2)
295(2)
Crystal system
Space group
Triclinic
Triclinic
Triclinic
Monoclinic
C2/c
–
–
P–1
P1
P 1
a/Å
b/Å
c/Å
α/deg
7.3234(11)
11.818(3)
13.626(3)
89.900(17)
81.249(14)
88.071(14)
1164.8(4)
4
10.0725(7)
10.4250(9)
10.7356(4)
110.186(7)
91.764(6)
94.049(7)
1053.58(12)
4
8.5161(7)
9.5480(7)
10.0678(7)
106.279(7)
105.992(7)
109.823(7)
674.14(9)
2
17.5631(16)
12.7613(12)
11.6843(11)
90
98.960(8)
90
2586.8(4)
8
1.357
β/deg
γ/deg
V/Å3
Z
dcalc/g cm–3
1.284
0.085
1.458
0.287
1.917
6.157
μ/mm–1
0.107
Scan range on θ/deg
Number of measured
reflections
2.82 < θ < 26.37
8159
2.78 < θ < 29.13
10107
2.60 < θ < 28.28
3694
2.77 < θ < 28.28
5833
Number of independent
4526
(0.0356)
1611
5569
(0.0175)
3980
3259
(0.0218)
1649
3167
(0.0193)
1539
reflections (Rint
)
Number of reflection
with I > 2σ(I)
Completeness of experiꢀ
ment (%) (for θ/deg)
Number of refined
parameters
95.5
(26.00)
307
98.7
(26.00)
321
97.5
(28.28)
164
99.3
(26.00)
180
S
1.000
0.0433
0.0917
0.1295
0.0972
1.002
0.0337
0.0901
0.0511
0.0948
1.003
0.0301
0.0479
0.0703
0.0495
1.006
0.0378
0.0884
0.0849
0.0945
R1 (on I > 2σ(I))
wR2 (on I > 2σ(I))
R1 (on all reflections)
wR2 (on all reflections)
Δe/e Å–3
0.177/–0.173
0.364/–0.226
0.367/–0.458
0.197/–0.174

912
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Verbitskiy et al.
The yields of the products and reaction conditions are given
in Table 2.
gram for Support of Leading Scientific Schools of the
Russian Federation, Grant NShꢀ65261.2010.3), and the
Ministry of Education and Science of the Russian Federaꢀ
tion (State Contract No. 02.740.11.0260).
Dimethyl 2ꢀcyanopyridineꢀ6ꢀphenylꢀ3,4ꢀdicarboxylate (9а).
1
Yellow oil. Н NMR (CDCl3), δ: 3.98 (s, 3 H, COOMe); 4.07
(s, 3 H, COOMe); 7.53—7.56 (m, 3 H, Ph); 8.09—8.11 (m, 2 H,
Ph); 8.34 (s, 1 H, C(5)H). Found (%): C, 64.75; H, 4.05; N, 9.66.
C16H12N2O4. Calculated (%): C, 64.86; H, 4.08; N, 9.45.
Rf 0.60 (Sorbfil, ethyl acetate—hexane, 1 : 1). HPLC: tR
8.5—9.5 min. GLC: tR 25.389 min. MS (EI, 70 eV), m/z (Irel (%)):
296 [М]+ (100).
Dimethyl 2ꢀcyanopyridineꢀ6ꢀ(thiophenꢀ3ꢀyl)ꢀ3,4ꢀdicarboxylꢀ
ate (9b). Yellow oil. 1Н NMR (CDCl3), δ: 3.99 (s, 3 H, COOMe);
4.06 (s, 3 H, COOMe); 7.47 (dd, 1 H, H(5´) of thiophenꢀ3ꢀyl,
J = 5.1 Hz, J = 3.0 Hz); 7.73 (dd, 1 H, H(4´) of thiophenꢀ3ꢀyl,
J = 5.1 Hz, J = 1.3 Hz); 8.14 (dd, 1 H, H(2´) of thiophenꢀ3ꢀyl,
J = 1.4 Hz, J = 3.0 Hz); 8.15 (s, 1 H, C(5)H). Found (%):
C, 55.75; H, 3.37; N, 9.15. C14H10N2O4S. Calculated (%):
C, 55.62; H, 3.33; N, 9.27. Rf 0.63 (Sorbfil, ethyl acetate—hexane,
1 : 1). GLC: tR 25.725 min. MS (EI, 70 eV), m/z (Irel (%)): 302
[М]+ (100).
Dimethyl 5ꢀcyanoꢀ1ꢀethylꢀ6ꢀoxoꢀ1,6ꢀdihydropyridineꢀ3,4ꢀdiꢀ
carboxylate (10). Light yellow crystalline powder. M.p.
183—184 °С. 1Н NMR (CDCl3), δ: 1.44 (t, 3 H, Me, J = 7.2 Hz);
3.87 (s, 3 H, COOMe); 4.03 (s, 3 H, COOMe); 4.11 (q, 2 H,
NCH2, J = 7.2 Hz); 8.40 (s, 1 H, C(2)H). Found (%): C, 54.48;
H, 4.33; N, 10.57. C12H12N2O5. Calculated (%): C, 54.55;
H, 4.58; N, 10.60. Rf 0.25 (Sorbfil, ethyl acetate—hexane, 1 : 1).
HPLC: tR 1.7—3.0 min. GLC: tR 24.326 min. MS (EI, 70 eV),
m/z (Irel (%)): 264 [М]+ (100).
Xꢀray diffraction experiments were carried out on an Xcaliꢀ
burꢀ3 Xꢀray diffractometer with a CCD detector according to
a standard procedure (λ(MoꢀKα), graphite monochromator,
ω scan mode). Pieces of yellow crystals 0.51 × 0.39 × 0.23 mm
(3а), 0.49 × 0.41 × 0.35 mm (3с), 0.33 × 0.21 × 0.05 (5), and
0.25 × 0.12 × 0.08 mm (10) in size were used for analysis. The
data were collected and processed using the CrysAlis program
package.23 No absorption correction was applied for samples
3а,с and for sample 5 a correction was applied analytically by
the crystal model.24 The structures of all compounds were deterꢀ
mined by a direct method using the SHELXSꢀ97 program and
refined using the SHELXLꢀ97 program25 in the anisotropic
(isotropic for hydrogen atoms) approximation. Hydrogen atoms
were partially resolved and refined independently and were
partially included into refinement in the riding model with
dependent thermal parameters. Selected crystallographic paramꢀ
eters and the results of Xꢀray diffraction experiments are preꢀ
sented in Table 4.
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This work was financially supported by the Ural Branch
of the Russian Academy of Sciences (Program of Support
of Young Scientists and PostꢀGraduates No. 10ꢀ3ꢀNPꢀ81;
Grants 09ꢀIꢀ3ꢀ2004, 09ꢀPꢀ3ꢀ1015, and 09ꢀTꢀ3ꢀ1022), the
Russian Foundation for Basic Research (Project Nos 09ꢀ03ꢀ
12242ꢀofi_m and 10ꢀ03ꢀ96078ꢀr_ural_a), the Council on
Grants at the President of the Russian Federation (Proꢀ

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Received January 17, 2011