Stereochemical features of addition of O- and C-nucleophiles to 5-(Het)aryl-2,3-dicyano-1-ethylpyrazinium salts

Article abstract of DOI:10.1007/s11178-008-2019-2

Stable σ^H-adducts of O- and C-nucleophiles were obtained with cations of 5-(het)aryl-2,3-dicyano-1-ethylpyrazinium, and their structure was investigated by X-ray diffraction analysis. Analytical separation was performed of 1,2-dihydropyrazines

Full text of DOI:10.1007/s11178-008-2019-2

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 2, pp. 302−310. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © E.V. Verbitskii, G.L. Rusinov, P.A. Slepukhin, A.N. Grishakov, M.A. Ezhikova, M.I. Kodess, V.N. Charushin, 2008, published in
Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 2, pp. 305−312.
Dedicated to the Full Member of the Russian Academy of Sciences
G.A. Tolstikov on occasion of his 75th anniversary
Stereochemical Features of Addition of O- and C-Nucleophiles
to 5-(Het)aryl-2,3-dicyano-1-ethylpyrazinium Salts
E. V. Verbitskii, G. L. Rusinov, P. A. Slepukhin, A. N. Grishakov, M. A. Ezhikova,
M. I. Kodess, and V. N. Charushin
Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
Yekaterinburg, 620041 Russia
e-mail: rusinov@ios.uran.ru
Received July 27, 2007
H
Abstract—Stable σ -adducts of O- and C-nucleophiles were obtained with cations of 5-(het)aryl-2,3-dicyano-1-
ethylpyrazinium, and their structure was investigated by X-ray diffraction analysis. Analytical separation was
performed of 1,2-dihydropyrazines into individual enantiomers by means of HPLC on columns with chiral sorbents.
DOI: 10.1134/S107042800802019X
stability of the monoadducts is not sufficient for their
isolation in the crystalline state.
2,3-Dicyanopyrazines are known to be precursors in
the synthesis of tetrapyrazinoporphyrazines, aza analogs
of phthalocyanines that are of interest as dyes, optical
sensors, and also as photosensitive compounds used in
the photodynamic therapy of cancer [1–5]. One of the
general methods of pyrazines modification is applying
the reactions of nucleophilic substitution. For instance,
in a series of publications a substitution of chlorine in
5,6-dichloro-2,3-dicyanopyrazine under stringent
conditions was described [1, 6, 7].
On the other hand, an interest grew recently to the
synthesis of individual stereoisomers of biologically
active aza heterocycles. In this connection much
attention is given to the stereoselective reactions of
nucleophilic addition to C=N and also C=C bonds of
nitroalkenes and to the other multiple bonds [16, 17]. In
particular, a diastereoselective synthesis was described
H
[18] of σ -adducts in the series of 1,2,4-triazin-5(4H)-
one, but no such studies were reported in the series of
1,4-diazines.
At the same time published data exist [8, 9] on easy
exchange of cyano groups of cyanopyrazines and their
salts for nucleophiles residues; in the other cases the
cyano groups in the dicyanopyrazines are transformed
under the action of nucleophiles [10] yielding, for
instance, cyclic products resulting from the attack of
a dinucleophile on both cyano groups [10, 11].
We report here on the investigation of reactions of
5-(het)aryl-2,3-dicyano-1-ethylpyrazinium salts with
O- (water and alcohols) and C-nucleophiles (enolates of
dicarbonyl compounds, indole etc.). It was presumed that
the bulky aryl sybstituent would block the diadducts
formation, and the presence of two cyano groups would
We previously [12] reported on reactions of 2,3-di-
cyano-1-ethylpyrazinium tetrafluoroborate with C- and
O-nucleophiles leading to the formation of cyclic and
H
provide for enhanced stability of the σ -adducts and
would permit their characterization by the spectral and
crystallographic methods.
H
acyclic σ -diadducts at the unsubstituted positions of the
pyrazine ring; the products were characterized by X-ray
diffraction analysis. Published data exist [13–15] on
equilibrium mixtures of mono- and diadducts of 1,4-di-
azinium salts with methoxide anion and water, but the
In order to obtain 1-ethyl-5-(het)aryl-pyrazinium salts
IIa–IIc 2,3-dicyanopyrazines Ia–Ic were subjected to
the treatment of the Meerwein reagent, Et3O+BF4–, in
CHCl3 at 20°C (Scheme 1). The structure of compounds
302

STEREOCHEMICAL FEATURES OF ADDITION OF O- AND C-NUCLEOPHILES
303
dihydropyrazin-2,3-dicarbonitriles IV and V whose struc-
ture was proved by H NMR spectrum and X-ray dif-
IIa–IIc was confirmed by X-ray diffraction analysis by
an example of IIb salt (Fig. 1). We did not observe a
forma-tion of possible isomers, namely, other 6-(het)aryl-
2,3-dicyano-1-ethylpyrazinium salts (1H NMR data);
they apparently did not form due to steric reasons.
1
fraction analysis by an example of compound IV (Fig. 3).
Under similar conditions [12] unsubstituted 2,3-dicyano-
pyrazinium salt (IX) formed the product of cyano group
substitution in the position 2, namely pyrazinone X, or
diadducts XIa–XIc (Scheme 2).
It was established that salts IIa–IIc readily reacted
with C- and O-nucleophiles under mild conditions
H
The formation of monoalkoxy adducts in reactions
of N-alkylazinium salts with alcohols formerly was only
detected in the NMR spectra [15].
(CH3CN, NEt3, 20°C) giving σ -adducts at the position
6. For instance, in the reaction of salts IIa and IIb with
water in the presence of Na2CO3 formed stable 5-aryl-6-
hydroxy-1-ethyl-1,6-dihydropyrazine-2,3-dicarbonitriles
IIIa and IIIb (Scheme 1) as proved by the presence in
Reactions with C-nucleophiles also have specific
features. In the reactions of 2,3-dicyano-1-ethyl-pyr-
azinium tetrafluoroborate with enolates of 1,3-dicarbonyl
compounds it was observed formerly the fusion of a furan
ring (Scheme 2): therewith the 1,3-dicarbonyl compounds
behaved as O,C-dinucleophiles [12]. Naturally, the reac-
tion of salts IIa–IIc with the enolates of 1,3-dicarbonyl
compounds occurs at the unsubstituted C6 position of
the heterocycle providing stable C-adducts VI–VIII
1
the H NMR spectra of a characteristic doublet due to
the coupling of the proton at C6 with the OH group with
a constant ~8 Hz, and also by the X-ray diffraction data
obtained for the first time for a monohydrated azinium
cataion, namely for compound IIIa (Fig. 2).
Similarly salts IIa and IIb reacted with alcohols
yielding the corresponding 6-alkoxy-5-aryl-1-ethyl-1,6-
Scheme 1.
Ar
NC
NC
N
H
N
Et
O
H
Ph
O
NC
NC
N
IIIà, IIIb
R
N
Et
IV, V
H
ROH,
NEt3
H2O,
Na2CO3
_
Et3O+BF4
CHCl3
NC
NC
N
Ar
NC
NC
N
Ar
BF4_
+
N
O
O
N
Ià_Ic
Et
,
IIà_IIc
NEt3
CH3CN
Li
O
O
CH3CN
Me
R
Ph
NC
NC
N
+
O
HNEt3
NC
NC
N
Ar
H
_
N
Et
H
O
O
N
Et
R
Me
VI
O
VIIà_VIIc, VIIIà_VIIIc
R = Me (IV, VII), Et (V), OEt (VIII); Ar = Ph (a), p-FC6H4 (b), 3-thienyl (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

VERBITSKII et al.
304
Scheme 2.
H
N
H
H
NC
OR
NC
O
N
NC
N
OR
N
Et
Et
X
XIà_XIc
ROH, NEt3
CH3CN
H2O NEt3
N
NC
NC
NC
NC
N
ROH, NEt3
+
N
N
OR
H
Fig. 1. Geometry of molecule IIb in a crystal.
BF4_
H
Et
IX
Et
H
O
O
O
O
CH3CN
NEt3
Me
R'
R'
Me
R'
NEt3
O
H
O
H
H
N
R'
H
H
AcOH
Me
NC
NC
N
NC
NC
Me
O
O
N
OR
N
H
Et
Et
XIIà, XIIb
XIIIà, XIIIb
R = Me (a), Et (b), i-Pr (c); R' = Me (a), OEt (b).
1
(Scheme 1) as proved by the presence in the H NMR
spectra of compounds VIIa–VIIc and VIIIa–VIIIc of
doublets with vicinal coupling constants J 9.2–9.6 Hz,
and also by the X-ray diffraction data for compound VIIc
(Fig. 4).
Fig. 2. Geometry of molecule IIIa in a crystal.
were isolated in pure form and characterized by the
X-ray diffraction analysis (Fig. 5).
In the 1H NMR spectra of products VIIIa–VIIIc of
ethyl acetoacetate addition to salts II signals were
observed belonging to two diastereomers present in
a ~ 1:1 ratio and distinguished by the configuration of
chiral centers Cexo and C6 (Scheme 1). The diastereomers
formation originated from the appearance of a new chiral
center, the carbon atom of the CH-active compound after
the formation of its C–C bond with the pyrazine ring.
The stereoisomers mixture was by means of flash
chromatography first enriched to the ratio 9:1–11:1, and
then the major (S,R/R,S) stereoisomers VIIIa and VIIIb
Using arylamines and indoles as C-nucleophiles in
reactions with salts IIa and IIc we also succeeded to
obtain stable C-adducts XIVa and XIVc, and XV
(Scheme 3).
Indol added to salts IIa and IIc by its C3' atom as
confirmed by the existence of the vicinal coupling
between protons NH1' and H2' of the indole fragment in
1
the H NMR spectra of compounds XIVa and XIVc
registered in DMSO-d6, and N,N-dimethylaniline formed
a C-adduct XV at the para-position of the aryl substituent
(Scheme 1).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

STEREOCHEMICAL FEATURES OF ADDITION OF O- AND C-NUCLEOPHILES
305
In order to investigate the enantiomeric composition of
the obtained 1,2-dihydropyrazines we attempted their
separation into individual enantiomers by means of
HPLC on chromatographic columns with chiral sorbents,
Chiralcel OD-H and Chiralpak AD. We selected as
objects of the chromatographic study compounds VIIb
and VIIc, and also previously prepared 1-ethyl-6-(2,2,6,6-
tetramethylpiperidin-1-oxyl-4-ylideneaminoxyl)-5-
phenyl-1,6-dihydropyrazine-2,3-dicarbonitrile (XVI)
[19]. The results of the study with the use of HPLC are
presented in the table.
Thus we demonstrated that 5-(het)aryl-2,3-dicyano-
H
1-ethylpyrazinium salts formed stable mono-σ -adducts
with C- and O-nucleophiles. The analysis of the
enantiomeric composition and analytical separation of
adduct obtained into individual enantiomers by means
of HPLC was performed.
Fig. 3. Geometry of molecule IV in a crystal.
EXPERIMENTAL
Compounds Ia–Ic were prepared by procedure from
[20]. The solvents were dried and purified as described
in [21].
NMR spectra were registered on a spectrometer
Bruker DRX-400 [400 (1H), 100 MHz (13C)], internal
reference TMS. Mass spectra were measured on
a quadrupole liquid GC-MS instrument Shimadzu
LCMS-2010 in acetonitrile at the scanning rate 0.25 ml/
min on a column Supelco LC-18 (4.6×250 mm). Mass
spectra were obtained in the mode of positive ions scan-
ning usingAPCI, (atmospheric pressure chemical ioniza-
tion), operating voltage 4.5 kV, tuning control by the
autotuning file, carrier gas nitrogen, flow rate 2.5 l/min.
Elemental analysis was carried out on an automatic
analyzer Carlo Erba 1108. Melting points were measured
Fig. 4. Geometry of molecule VIIc in a crystal.
The structure of compound XIVc was confirmed by
1H and 13C NMR spectra. A complete assignment of
proton and carbon signals was carried out with the use
of a combination of 2D spectroscopy procedures HSQC/
HMBC.
..
on combined Boetius heating blocks and are reported
without correction. For the flash-chromatography silica
gel Lancaster 0.040–0.063 mm (230–400 mesh) was
used. The enantiomers mixtures were analyzed by HPLC
As already mentioned, the adducts obtained adduct
III–VIII, XIV, and XV are mixtures of two enantiomers.
Scheme 3.
CH3
H3C
N
NC
NC
N
Ph
NC
NC
N
Ar
5'
N
H
4'
NC
NC
N
Ar
6'
7'
3'
+
N
Et
N
Et
N
Et
CH3CN
CH3CN
H
BF4_
H
CH3
N 1'
H
2'
N
CH3
IIà, IIc
Ar = Ph (a), 3-thienyl (c).
XV
XIVà, XIVc
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VERBITSKII et al.
306
Results of chromatographic separation into enantiomers of compounds VIIb, VIIc, and XVI by HPLC on columns with chiral sorbents
Retention time of
first enantiomer (τ1), second enantiomer
Retention time of
Compound
no.
Column type
Eluent
Enantiomers ratio
min
(τ2), min
Hexane–2-propanol,
10:1
Hexane–2-propanol,
10:1
Hexane–2-propanol,
8:1
Hexane–2-propanol,
20:1
VIIb
VIIb
VIIc
XVI
Chiralcel OD-H
Chiralpak AD
Chiralcel OD-H
Chiralpak AD
26.7
34.6
44.7:55.3
–
13.2
31.6
158
13.2
34.3
17.0
42.0:58.0
48.2:51.8
N 17.35. C14H11N4·ΒF4. Calculated, %: C 52.21; H 3.44;
on a chromatograph Merck-Hitachi (L-6200A Intelligent
Pump, L-4000A UV Detector, D-2500A Chromato-
Integrator) on columns Hibar Pre-packed Column RT250-
4 250×4 mm with a sorbent LiChrosorb Si-60 5 μm, with
chiral sorbents Chiralcel OD-H and Chiralpak AD
250×4.6 mm, produced by Daicel Chemical Industries
Ltd (Japan), mobile phase hexane–2-propanol, 10:1 or
20:1, elution rate 1.0 ml/min, detecting on the wave length
230 nm. The monitoring of reactions progress and
checking of the products purity was carried out by TLC
on Silufol UV-254 plates, development under UV
irradiation or by iodine vapor. X-ray diffraction analysis
on single crystals was performed on an X-ray
diffractometer Xcalibur-3 equipped with a CCD detector
(λMoKα, graphite monochromator). The structure was
solved by the direct method using SHELXS-97 program
and refined applying SHELXL-97 program. The results
of the X-ray structural data were deposited in the
Cambridge Crystallographic Database under the numbers
CCDC 652113 (compound IIb), CCDC 652114 (com-
pound IV), CCDC 652115 (compound IIIa), CCDC
652116 (compound VIIIb), and CCDC 652118
(compound VIIc). The access to these data is free by the
address www.ccdc.cam.ac.uk/data_request/cif.
N 17.40.
In the same way salts IIb and IIc were prepared.
2,3-Dicyano-5-(4-fluorophenyl)-1-ethylpyrazin-
ium tetrafluoroborate (IIb). Yield 340 mg (45%), bright
yellow crystalline powder, mp 180–182°C (decomp.).
1H NMR spectrum (CD3CN), δ, ppm: 1.79 t (3H, CH3,
J 7.4 Hz), 5.00 q (2H, NCH2, J 7.4 Hz), 7.48 d.d (2H,
Hm, J 9.1, 8.7 Hz), 8.39 d.d (2H, H°, J 9.1, 5.2 Hz),
9.66 s (1H, H6). Found, %: C 49.65; H 3.06; N 16.44.
C14H10FN4·ΒF4. Calculated, %: C 49.45; H 2.96; N 16.48.
2,3-Dicyano-5-(3-thienyl)-1-ethylpyrazinium
tetrafluoroborate (IIc) was obtained from 1.87 g
(8.8 mmol) of 2,3-dicyano-5-(thiophen-3-yl)pyrazine and
8.35 g (44.00 mmol) of Et3O+BF4–, reaction time 48 h
without access of air. Yield 2.07 g (72%), orange powder,
1
mp 198–200°C (decomp.). H NMR spectrum (CD3CN),
δ, ppm: 1.78 t (3H, CH3, J 7.2 Hz), 4.00 q (2H, NCH2,
J 7.2 Hz), 7.77 d.d (1H, H5', J 5.2, 2.8 Hz), 7.89 d.d (1H,
2,3-Dicyano-5-phenyl-1-ethylpyrazinium tetra-
fluoroborate (IIa). To a solution of 1.0 g (14.6 mmol)
of 2,3-dicyano-5-phenylpyrazine in 25 ml of CHCl3 was
added 5.52 g (29.1 mmol) of Et3O+BF4–. The reaction
mixture obtained was left standing for 7 days without
access of air. The separated precipitate was filtered off,
washed with 20–30 ml of THF, and dried. Yield 3.55 g
(76%), dark-yellow powder, mp 174–176°C (decomp.).
1H NMR spectrum (CD3CN), δ, ppm: 1.78 br.s (3H, CH3),
5.00 br.s (2H, NCH2), 7.72 br.m (3H, Ph), 8.30 br.s (2H,
Ph), 9.75 br.s (1H, H6). Found, %: C 52.20; H 3.26;
Fig. 5. Geometry of molecule VIIIb in a crystal.
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STEREOCHEMICAL FEATURES OF ADDITION OF O- AND C-NUCLEOPHILES
307
H4', J 5.2, 1.2 Hz), 8.79 d.d (1H, H2', J 2.8, 1.2 Hz),
9.54 s (1H, H6). Found, %: C 43.86; H 2.76; N 17.05.
C12H9N4S·ΒF4. Calculated, %: C 43.93; H 2.76; N 17.08.
5-Phenyl-1-ethyl-6-ethoxy-1,6-dihydropyrazine-
2,3-dicarbonitrile (V) was obtained similarly to
compound IV. Yield 45%, yellow crystalline powder, mp
1
98–100°C (decomp.). H NMR spectrum (CD3CN), δ,
6-Hydroxy-5-phenyl-1-ethyl-1,6-dihydropyrazine-
2,3-dicarbonitrile (IIIa). To a solution of 164 mg
(1.55 mmol) of Na2CO3 in 10 ml of H2O was added
500 mg (1.55 mmol) of salt IIa. The reaction mixture
was stirred for 30 min, the yellow precipitate was filtered
off, washed with 20 ml of H2O, and dried. Yield 365 mg
ppm: 1.10 t [3H, CH3(NEt), J 6.9 Hz], 1.29 t [3H,
CH3(OEt), J 7.3 Hz], 3.54 q (2H, OCH2, J 6.9 Hz),
3.79 d.q (1H, NCHB, J 14.6, 7.3 Hz), 3.86 d.q (1H, NCHA,
J 14.6, 7.3 Hz), 6.12 s (1H, H6), 7.49–7.57 m (3H, Hm,p),
7.98 m (2H, H°). Mass spectrum, m/z (Irel, %): 235 [M –
OEt]+ (100), 276 [M – OEt + CH3CN]+ (38). Found, %:
C 68.61; H 5.65; N 20.02. C16H16N4O. Calculated, %:
C 68.55; H 5.75; N 19.99.
1
(93%), mp 126–128°C (decomp.). H NMR spectrum
(DMSO-d6), δ, ppm: 1.37 t (3H, CH3, J 7.2 Hz), 3.72 d.q
(1H, NCHB, J 14.4, 7.2 Hz), 3.82 d.q (1H, NCHA, J 14.4,
7.2 Hz), 6.24 d (1H, H6, J 8.2 Hz), 7.13 d (1H, OH,
J 8.2 Hz), 7.49–7.55 m (3H, Ph), 7.99 m (2H, Ph). Found,
%: C 66.51; H 4.54; N 22.47. C14H12N4O. Calculated,
%: C 66.65; H 4.79; N 22.21.
N,N,N-Triethyl-2-(5-phenyl-5,6-dicyano-1-ethyl-
1,2-dihydropyrazin-2-yl)-1,3-dioxoindan-2-aminium
(VI). To a solution of 259 mg (0.80 mmol) of salt IIa
and 118 mg (0.80 mmol) 1,3-indandione in 5 ml of
CH3CN was added 123 μl of NEt3, the mixture was stirred
for 1.5 h, the separated precipitate was filtered off,
washed with H2O, and dried. Yield 95 mg (31%), orange
powder, mp 167–169°C (decomp.). 1H NMR spectrum
(DMSO-d6), δ, ppm: 1.19 m (12H, CH3), 3.09 m (6H,
NCH2), 3.34 d.q (1H, NCHB, J 14.2, 7.1 Hz), 3.41 d.q
(1H, NCHA, J 14.2, 7.1 Hz), 5.59 s (1H, H6), 7.08–
7.10 m (2H, indan), 7.23–7.25 m (2H, indan), 7.32–
7.37 m (3H, Ph), 7.97 m (2H, Ph), 8.84 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 381 [M – H – NEt3]+ (6),
276 [M – H – NEt3 – C9H4O2 + CH3CN]+ (36), 235 [M –
H – NEt3 – C9H4O2]+ (100), 102 [NEt3 + H]+. Found, %:
C 71.13; H 6.52; N 14.39. C23H16N4O2·N(C2H5)3·
0.5H2O. Calculated, %: C 71.00; H 6.57; N 14.28.
6-Hydroxy-5-(4-fluorophenyl)-1-ethyl-1,6-di-
hydropyrazine-2,3-dicarbonitrile (IIIb). To a solution
of 62 mg (0.59 mmol) of Na2CO3 in 5 ml of H2O was
added 200 mg (0.59 mmol) of salt IIb. The reaction
mixture was stirred for 30 min, the yellow precipitate
was filtered off, dried and separated on a column packed
with silica gel, eluent acetone–hexane, 1:2. The oily
substance obtained was ground with hexane till the
formation of yellow powder. Yield 120 mg (75%), mp
1
110–112°C (decomp.). H NMR spectrum (DMSO-d6),
δ, ppm: 1.37 t (3H, CH3, J 7.2 Hz), 3.71 d.q (1H, NCHB,
J 14.4, 7.2 Hz), 3.82 d.q (1H, NCHA, J 14.4, 7.2 Hz),
6.24 d (1H, H6, J 8.1 Hz), 7.14 d (1H, OH, J 8.1 Hz),
7.36 t (2H, Hm, J 9.0 Hz), 8.04 d.d (2H, H°, J 9.0,
5.5 Hz). Mass spectrum, m/z (Irel, %): 270 [M]+ (22),
269 [M – H]+ (100). Found, %: C 62.44; H 4.18; N 20.70.
C14H11FN4O. Calculated, %: C 62.22; H 4.10; N 20.73.
6-(1-Acetyl-2-oxoprop-1-yl)-5-phenyl-1-ethyl-1,6-
dihydropyrazine-2,3-dicarbonitrile (VIIa). A mixture
of 1.29 g (4 mmol) of salt IIa and 0.42 g (4 mmol) of
lithium acetylacetonate was dissolved in 25 ml of
CH3CN. The reaction mixture obtained was stirred for
1 h, evaporated, and the residue was subjected to
chromatography on silica gel (eluent acetone–hexane,
1:2). The reaction product was recrystallized from
MeOH. Yield 1.17 g (87%), bright yellow crystalline
6-Methoxy-5-phenyl-1-ethyl-1,6-dihydropyrazine-
2,3-dicarbonitrile (IV). To a solution of 210 mg
(0.65 mmol) of salt IIa in 2 ml of MeOH was added 100
μl of NEt3. The reaction mixture was stirred for 1 h, the
residue was subjected to column chromatography on
silica gel (eluent acetone–hexane, 1:2). The oily
substance obtained was ground with hexane till the
formation of bright yellow powder. Yield 116 mg (67%),
mp 105–107°C (decomp.). 1H NMR spectrum (DMSO-
d6), δ, ppm: 1.28 t (3H, CH3, J 7.2 Hz), 3.28 s (3H,
OCH3), 3.85 d.q (1H, NCHB, J 14.4, 7.2 Hz), 3.90 d.q
(1H, NCHA, J 14.4, 7.2 Hz) 6.41 s (1H, H6), 7.51–7.57 m
(3H, Ph), 8.02 m (2H, Ph). Mass spectrum, m/z (Irel, %):
235 [M – OMe]+ (100), 276 [M – OMe + CH3CN]+ (39).
Found, %: C 67.58; H 5.36; N 21.07. C15H14N4O.
Calculated, %: C 67.65; H 5.30; N 21.04.
1
powder, mp 137–139°C (decomp.). H NMR spectrum
(DMSO-d6), δ, ppm: 1.01 t (3H, CH3, J 7.1 Hz), 2.03 s
(3H, COCH3), 2.22 s (3H, COCH3), 3.59 q (2H, NCH2,
J 7.1 Hz), 4.52 d (1H, H1', J 9.2 Hz), 5.85 d (1H, H6,
J 9.2 Hz), 7.45–7.53 m (3H, Ph), 7.99 m (2H, H°). Mass
spectrum, m/z (Irel, %): 235 [M + H – CH(COMe)2]+
(100), 335 [M + H]+ (90), 376 [M + H + CH3CN]+ (39).
Found, %: C 68.51; H 5.40; N 16.85. C19H18N4O2.
Calculated, %: C 68.25; H 5.43; N 16.76.
Compounds VIIb and VIIc, VIIIa–VIIIc were
similarly obtained.
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VERBITSKII et al.
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(2H, AB-system OCH2, J 10.9, 7.1 Hz), 5.74 d (1H, H6,
J 9.6 Hz), 7.13 d.d (2H, Hm, J 9.0, 8.2 Hz), 8.00 d.d (2H,
H°, J 9.0, 5.2 Hz); isomer Β (RR/SS): 1.00 t [3H,
CH3(OEt), J 7.1 Hz], 1.07 t [3H, CH3(NEt), J 7.2 Hz],
2.12 C (3H, COCH3), 3.55 d.q (1H, NCHB, J 14.4,
7.2 Hz), 3.73 d.q (1H, NCHA, J 14.4, 7.2 Hz), 3.74 d
(1H, H1', J 9.2 Hz), 4.26 d.q, 4.29 d.q (2H, AB-system
OCH2, J 10.9, 7.1 Hz), 5.71 d (1H, H6, J 9.2 Hz),
7.14 d.d (2H, Hm, J 8.9, 8.3 Hz), 8.03 d.d (2H, H°, J 8.9,
5.3 Hz). A:Β ratio 9:1 (after flash-chromatography). Mass
spectrum, m/z (Irel, %): 381 [M – H]+ (100), 383 [M +
H]+ (27), 424 [M + H + CH3CN]+ (32). Found, %: C 62.86;
H 4.97; N 14.95. C20H19FN4O3. Calculated, %: C 62.82;
H 5.01; N 14.65.
6-(1-Acetyl-2-oxoprop-1-yl)-5-(4-fluorophenyl)-1-
ethyl-1,6-dihydropyrazine-2,3-dicarbonitrile (VIIb).
Yield 83%, yellow crystalline powder, mp 142–144°C
1
(decomp.). H NMR spectrum (CDCl3), δ, ppm: 1.05 t
(3H, CH3, J 7.2 Hz), 2.11 s (3H, COCH3), 2.26 s (3H,
COCH3), 3.53 d.q (1H, NCHB, J 14.4, 7.2 Hz), 3.70 d.q
(1H, NCHA, J 14.4, 7.2 Hz), 4.13 d (1H, H1', J 9.2 Hz),
5.76 d (1H, H6, J 9.2 Hz), 7.13 d.d (2H, Hm, J 9.2,
8.2 Hz), 7.97 d.d (2H, H°, J 9.2, 5.3 Hz). Found, %:
C 64.53; H 4.88; N 16.05. C19H17FN4O2. Calculated, %:
C 64.77; H 4.86; N 15.90.
6-(1-Acetyl-2-oxopropyl)-5-(3-thienyl)-1-ethyl-1,6-
dihydropyrazine-2,3-dicarbonitrile (VIIc). Yield 52%,
yellow crystalline powder, mp 151–153°C (decomp.).
1H NMR spectrum (CD3CN), δ, ppm: 1.01 t (3H, CH3,
J 7.2 Hz), 2.04 s (3H, COCH3), 2.18 s (3H, COCH3),
3.51 d.q (1H, NCHB, J 14.4, 7.2 Hz), 3.62 d.q (1H, NCHA,
J 14.4, 7.2 Hz), 4.36 d (1H, H1', J 9.3 Hz), 5.65 d (1H,
H6, J 9.3 Hz), 7.46 d.d (1H, H5", J 5.2, 2.8 Hz), 7.58 d.d
(1H, H4", J 5.2, 1.3 Hz), 8.04 d.d (1H, H2", J 2.8, 1.3 Hz).
Mass spectrum, m/z (Irel, %): 339 [M – H]+ (100). Found,
%: C 60.10; H 4.68; N 16.40. C17H16N4O2S. Calculated,
%: C 59.98; H 4.74; N 16.46.
Ethyl 2-[3-(3-thienyl)-5,6-dicyano-1-ethyl-1,2-di-
hydropyrazin-2-yl]-3-oxobutanoate (VIIIc). Yield
78%, yellow powder, mp 131–133°C (decomp.). 1H NMR
spectrum (CD3CN), δ, ppm, isomer A (RS/SR): 0.95 t
(3H, CH3, J 7.2 Hz), 1.04 t (3H, CH3, J 7.2 Hz), 2.17 s
(3H, COCH3), 3.62 d.q, 3.66 d.q (2H, AB-system NCH2,
J 14.4, 7.2 Hz), 3.74 d.q, 3.78 d.q (2H, AB-system OCH2,
J 10.9, 7.2 Hz), 3.87 d (1H, H1', J 9.6 Hz), 5.66 d (1H,
H6, J 9.6 Hz), 7.46 d.d (1H, H5", J 5.2, 2.8 Hz), 7.59 d.d
(1H, H4", J 5.2, 1.3 Hz), 8.03 d.d (1H, H2", J 2.8, 1.3 Hz);
isomer Β (RR/SS): 1.04 t (3H, CH3, J 7.2 Hz), 1.29 t
(3H, CH3, J 7.2), 2.06 s (3H, COCH3), 3.52 d.q (1H,
NCHB, J 14.4, 7.2 Hz), 3.66 d.q (1H, NCHA, J 14.4,
7.2 Hz), 3.85 d (1H, H1', J 9.1 Hz), 4.20 d.q, 4.24 d.q
(2H, AB-system OCH2, J 10.9, 7.2 Hz), 5.63 d (1H, H6,
J 9.1 Hz), 7.46 d.d (1H, H5", J 5.2, 2.8 Hz), 7.61 d.d (1H,
H4", J 5.2, 1.3 Hz), 8.15 d.d (1H, H2", J 2.8, 1.3 Hz); A:Β
ratio 11:1 (after flash-chromatography). Found, %:
C 58.51; H 4.89; N 14.98. C18H18N4O3S. Calculated, %:
C 58.36; H 4.90; N 15.12.
Ethyl 2-(3-phenyl-5,6-dicyano-1-ethyl-1,2-
dihydropyrazin-2-yl)-3-oxobutanoate (VIIIa) was
obtained analogously to compound VIIa. Yellow
crystalline powder. Yield 90%, mp 170–172°C
1
(decomp.). H NMR spectrum (CDCl3), δ, ppm, isomer
A (RS/SR): 0.94 t (3H, CH3, J 7.2 Hz), 1.07 t (3H, CH3,
J 7.2 Hz), 2.26 s (3H, COCH3), 3.62 d.q (1H, NCHB,
J 14.5, 7.2 Hz), 3.73 d.q (1H, NCHA, J 14.5, 7.2 Hz),
3.74 d (1H, H1', J 9.5 Hz), 3.77 m (2H, AB-system OCH2),
5.78 d (1H, H6, J 9.5 Hz), 7.42–7.50 m (3H, Ph), 7.96 m
(2H, H°); isomer Β (RR/SS): 1.08 t [3H, CH3(NEt),
J 7.2 Hz], 1.34 t [3H, CH3(OEt), J 7.1 Hz], 2.10 s (3H,
COCH3), 3.56 d.q (1H, NCHB, J 14.4, 7.2 Hz), 3.73 d
(1H, H1', J 8.9 Hz), 3.74 d.q (1H, NCHA, J 14.4, 7.2 Hz),
4.25 d.q and 4.29 d.q (2H, AB-system OCH2, J 11.0,
7.1 Hz), 5.76 d (1H, H6, J 8.9 Hz), 7.42–7.50 m (3H,
Ph), 7.99 m (2H, H°). A:Β ratio 9:1 (after flash-chromato-
graphy). Found, %: C 66.05; H 5.49; N 15.66.
C20H20N4O3. Calculated, %: C 65.92; H 5.53; N 15.38.
6-(1H-Indol-3-yl)-5-phenyl-1-ethyl-1,6-dihydro-
pyrazine-2,3-dicarbonitrile (XIVa). To a solution of
117 mg (1 mmol) of indole in 2 ml of CH3CN was added
at stirring 322 mg (1 mmol) of salt IIa in 5 ml of CH3CN.
The reaction mixture was stirred for 50 min, evaporated,
and the residue was subjected to chromatography on
silica gel (eluent acetone–hexane, 1:2). The dark-yellow
resinous substance obtained was reprecipitated with H2O
from MeOH. Yield 212 mg (61%), bright yellow powder,
mp 67–69°C (decomp.). 1H NMR spectrum (DMSO-d6),
δ, ppm: 1.19 t (3H, CH3, J 7.2 Hz), 3.72 d.q (1H, NCHB,
J 14.4, 7.2 Hz), 3.81 d.q (1H, NCHA, J 14.4, 7.2 Hz),
6.59 s (1H, H6), 7.11–7.17 m (2H, H5', H6'), 7.24 d (1H,
H2', J 2.7 Hz), 7.38–7.49 m (4H, H7', Ph), 7.84 m (1H,
H4'), 7.96 m (2H, H°), 11.31 br.d (1H, NH, J 2.7 Hz).
Mass spectrum, m/z (Irel, %): 352 [M + H]+ (100), 393
Ethyl 2-[3-(4-fluorophenyl)-5,6-dicyano-1-ethyl-
1,2-dihydropyrazin-2-yl]-3-oxobutanoate (VIIIb).
Yield 76%, yellow crystalline powder, mp 178–180°C
(decomp.). 1H NMR spectrum (CDCl3), δ, ppm, isomer
A (RS/SR): 1.00 t [3H, CH3(OEt), J 7.1 Hz], 1.06 t [3H,
CH3(NEt), J 7.2 Hz], 2.27 s (3H, COCH3), 3.59 d.q (1H,
NCHB, J 14.4, 7.2 Hz), 3.71 d.q (1H, NCHA, J 14.4,
7.2 Hz), 3.75 d (1H, H1', J 9.6 Hz), 3.83 d.q, 3.86 d.q
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STEREOCHEMICAL FEATURES OF ADDITION OF O- AND C-NUCLEOPHILES
309
[M + H + CH3CN]+ (45). Found, %: C 74.99; H 5.12;
N 19.87. C22H17N5. Calculated, %: C 75.19; H 4.88;
N 19.93.
31.68 ≥ θ ≥ 3.00. Intensities were measured of
5012 reflections, 2390 of which with I > 2σ. Final values
of divergence factors R 0.0687, Rw 0.1965.
Compound IIIa. Crystals were obtained from hot
MeOH, monoclinic, space group C2/C. Cell parameters
at 295 K: a 15.400(3), b 14.2785(9), c 13.545(3) Å,
α 90.00, β 119.549(19), γ 90.00°, V 2590.9(7) Å3, Z 8,
ω- and ö-scanning, 31.75 ≥ θ ≥ 2.85. Intensities were
measured of 3983 reflections, 1593 of which with I >
2σ. Final values of divergence factors R 0.0398,
Rw 0.0602.
6-(1H-Indol-3-yl)-5-(3-thienyl)-1-ethyl-1,6-di-
hydropyrazine-2,3-dicarbonitrile (XIVc). A solution
of 54 mg (0.46 mmol) of indole and 150 mg (0.46 mmol)
of salt IIc in 5 ml of CH3CN was stirred for 55 min,
evaporated, and the residue was subjected to
chromatography on silica gel (eluent ethyl acetate–
hexane, 1:3). The dark-yellow resinous substance
obtained was ground. Yield 92 mg (66%), yellow powder,
1
mp 84–86°C. H NMR spectrum (DMSO-d6), δ, ppm:
Compound IV. Crystals were obtained from hot
MeOH, monoclinic, space group P21/n. Cell parameters
at 295 K: a 10.0707(5), b 8.3387(11), c 17.0619(15) Å,
α 90.00, β 98.276(6), γ 90.00°, V 1417.9(2) Å3, Z 4,
ω-scanning, 29.69 ≥ θ ≥ 2.72. Intensities were measured
of 3687 reflections, 1468 of which with I > 2σ. Final
values of divergence factors R 0.0418, Rw 0.0749.
1.19 t (3H, CH3, J 7.2 Hz), 3.66 d.q (1H, NCHB, J 14.3,
7.2 Hz), 3.73 d.q (1H, NCHA, J 14.3, 7.2 Hz), 6.46 s
(1H, H6), 7.10–7.17 m (2H, H5', H6'), 7.31 d (1H, H2',
J 2.7 Hz), 7.41 m (1H, H7'), 7.59 d.d (1H, H5", J 5.1,
2.5 Hz), 7.61 d.d (1H, H4", J 5.1, 1.6 Hz), 8.24 d.d (1H,
H2", J 2.5, 1.6 Hz), 11.32 br.d (1H, NH, J 2.7 Hz).
13C NMR spectrum (DMSO-d6), δ, ppm: 14.74 (CH3),
47.92 (NCH2), 50.64 (C6), 107.02, 111.84, 117.40 [C3,
CN(C2), CN(C3)], 110.52 (C3'), 112.11 (C7'), 118.62 (C4'),
118.96 (C2), 119.86, 121.80 (C5', C6'), 124.91 (C3,a),
125.99 (C2'), 126.69 (C4"), 127.71 (C5"), 129.55 (C2"),
136.42 (C7,a), 137.79 (C3"), 145.67 (C5). Mass spectrum,
m/z (Irel, %): 358 [M + H]+ (59), 399 [M + H + CH3CN]+
(100). Found, %: C 67.55; H 4.28; N 19.34. C20H15N5S.
Calculated, %: C 67.21; H 4.23; N 19.59.
Compound VIIc. Crystals were obtained from
a mixture ethyl acetate–hexane, 1:2, monoclinic, space
group P21/n. Cell parameters at 295 K: a 9.296(3),
b 19.292(3), c 11.395(4) Å, α 90.00, β 112.34(3),
γ 90.00°, V 1890.2(9) Å3, Z 4. Intensities were measured
of 3725 reflections, 1338 of which with I > 2σ, ϕ- and
ω-scanning, 26.47 ≥ θ ≥ 2.64. Final values of
divergence factors R 0.0465, Rw 0.0641.
Compound VIIIb. Crystals were obtained from
CH2Cl2, triclinic, space group P-1. Cell parameters at
295 K: a 8.9118(7), b 11.5423(9), c 11.9106(9) Å,
α 61.282(8), β 68.366(7), γ 84.162(6)°, V 994.48(13)
Å3, Z 2. Intensities were measured of 6578 reflections,
3620 of which with I > 2σ, ω-scanning, 33.98 ≥ θ ≥ 2.77.
Final values of divergence factors R 0.0471, Rw 0.1394.
5-Phenyl-6-(4-dimethylaminophenyl)-1-ethyl-1,6-
dihydropyrazine-2,3-dicarbonitrile (XV). To a solution
of 381 mg (1.18 mmol) of salt IIa in 5 ml of CH3CN was
added dropwise at stirring a solution of 150 μl
(1.18 mmol) of N,N-dimethylaniline in 1 ml of CH3CN.
The reaction mixture was stirred for 50 min, evaporated,
and the residue was subjected to chromatography on
silica gel (eluent acetone–hexane, 1:2). Yield 138 mg
(33%), yellow-orange powder, mp 109–111°C (decomp.).
1H NMR spectrum (CD3CN), δ, ppm: 1.22 t (3H, CH3,
J 7.2 Hz), 2.90 s [6H, N(CH3)2], 3.65 d.q (1H, NCHB,
J 14.5, 7.2 Hz), 3.71 d.q (1H, NCHA, J 14.5, 7.2 Hz),
5.90 s (1H, H6), 6.71 d (2H, C6H4, J 8.9 Hz), 7.16 d (2H,
C6H4, J 8.9 Hz), 7.40–7.49 m (3H, Ph), 7.92 m (2H, H°).
Mass spectrum, m/z (Irel, %): 356 [M + H]+ (100), 397
[M + H + CH3CN]+ (64). Found, %: C 74.41; H 6.08;
N 19.51. C22H21N5. Calculated, %: C 74.34; H 5.96;
N 19.70.
The study was carried out under a financial support
of the Russian Foundation for Basic Research ( grants
nos. 06-03-08141-ofi, 07-03-12112-ofi, 07-03-96113-
r_ural_a, 07-03-96123-r_ural_a) and of a grant NSh
9178.2006.3.
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