Transformations of C-adducts of 1,4-diazinium salts with dicarbonyl compounds into polycyclic systems

Article abstract of DOI:10.1007/s11172-008-0102-z

C-Adducts of 5-(het)aryl-2,3-dicyano-1-pyrazinium salts containing a residue of a 1,3-dicarbonyl compound at position 6 can be involved in the cyclization with hydrazine hydrate giving rise to pyrazino[2,3-c]pyridazines along with the expected pyrazole derivatives. The reactions of the same σ^H-adducts with hydroxylamine unexpectedly afforded triazacyclopenta[a]indene derivatives. The crystallographic data on the three-dimensional structures of new polycyclic compounds were obtained.

Full text of DOI:10.1007/s11172-008-0102-z

Russian Chemical Bulletin, International Edition, Vol. 57, No. 3, pp. 652—656, March, 2008
652
Transformations of Cꢀadducts of 1,4ꢀdiazinium salts
with dicarbonyl compounds into polycyclic systems

E. V. Verbitskiy, P. A. Slepukhin, G. L. Rusinov, and V. N. Charushin
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Еꢀmail: rusinov@ios.uran.ru
CꢀAdducts of 5ꢀ(het)arylꢀ2,3ꢀdicyanoꢀ1ꢀpyrazinium salts containing a residue of a 1,3ꢀdicarboꢀ
nyl compound at position 6 can be involved in the cyclization with hydrazine hydrate giving rise to
pyrazino[2,3ꢀc]pyridazines along with the expected pyrazole derivatives. The reactions of the same
H
σ ꢀadducts with hydroxylamine unexpectedly afforded triazacyclopenta[a]indene derivatives.
The crystallographic data on the threeꢀdimensional structures of new polycyclic compounds were
obtained.
H
Key words: 1,2ꢀdihydropyrazines, σ ꢀadducts with Cꢀnucleophiles, nucleophiles, polycyclic comꢀ
pounds, 3a,3b,4,7,7a,8aꢀhexahydroꢀ1,8ꢀdioxaꢀ2,4,7ꢀtriazacyclopenta[a]indene, 1,4,4a,5,8,8aꢀheꢀ
xahydropyrazino[2,3ꢀc]pyridazine.
In recent years, methods for the modification of
ethanol to form pyrazino[2,3ꢀc]pyridazine derivatives
3a,b and 4a,b (Scheme 1). The reaction with the acetylacꢀ
etone derivative is accompanied by elimination of one
acetyl group, whereas this is not the case in the reactions
with compounds 2a,b. In addition, the reactions of comꢀ
pounds 4a,b with hydrazine produce the expected pyraꢀ
zole derivatives 5a,b. The structures of compounds 3a
and 4a were established by Xꢀray diffraction (Figs 1 and 2).
The reactions of compounds 1a,b with hydroxylamine
proceed in a more complex way to give 3a,3b,4,7,7a,8aꢀ
hexahydroꢀ1,8ꢀdioxaꢀ2,4,7ꢀtriazacyclopenta[a]indene
derivatives 6a,b (Scheme 2).
πꢀdeficient azaaromatic systems, in particular, of 1,2ꢀ
and 1,4ꢀdiazines, have been extensively developed. These
methods involve the nucleophilic attack on one Csp2—H
fragment or two adjacent carbon atoms in the aromatic
ring. The use of ANH—ANH, SNH—SNH, and other tandem
reactions allows the synthesis of a wide range of fused
azaheterocycles.1—8 These reactions afford σHꢀadducts as
intermediates, whose stability varies in a wide range.9—13
As a rule, the presence of electronꢀwithdrawing groups in
the starting azines imparts stability to σHꢀadducts, as can
be judged from pKR+, NMR spectroscopic data, electroꢀ
chemical parameters, etc.11 Actually, pyrazines containꢀ
ing alkoxycarbonyl, aminocarbonyl, or cyano groups in
the ring can form stable monoꢀ and diꢀσHꢀadducts.12—14
The properties of these adducts remained unknown. Genꢀ
erally, the functionalization involved the aromatization
of these adducts via the vicarious or oxidative nucleoꢀ
philic substitution.15—17
Earlier,18,19 we have demonstrated that 1ꢀalkylꢀ2,3ꢀ
dicyanoꢀ6ꢀmethoxyꢀ5ꢀnitromethylꢀ1,4,5,6ꢀtetrahydroꢀ
pyrazines react with azinium salts to form polycyclic
derivatives. The aim of the present study was to examine
the possibilities of further modifications of Cꢀmonoadꢀ
ducts 1a—c and 2a—c, which were prepared by the reacꢀ
tions of 5ꢀ(het)arylꢀ2,3ꢀdicyanoꢀ1ꢀethylpyrazinium tetꢀ
rafluoroborates with acetylacetone or acetoacetic ester.20
These compounds bear reactive carbonyl groups and can
react with nucleophiles at the azine ring. It was found that
1,2ꢀdihydropyrazines 1a,b and 2a,b are involved in
the cyclization with hydrazine hydrate under reflux in
C(12)
C(13)
C(11)
C(14)
C(10)
C(9)
N(6)
N(2)
C(5)
C(2)
N(4)
N(3)
C(3)
C(4)
C(1)
C(16)
C(8)
N(1)
C(7)
C(6)
C(17)
C(15)
N(5)
Fig. 1. Molecular structure of 3a in crystals.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 639—643, March, 2008.
1066ꢀ5285/08/5703ꢀ652 © 2008 Springer Science+Business Media, Inc.

Transformation of Cꢀadducts of pyrazinium salts
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
653
Scheme 1
Scheme 2
The structures of products 6a,c were established by Xꢀ
ray diffraction study based on the data for compound 6a
(Fig. 3) and were confirmed by elemental analysis and
1
mass spectrometry. It should be noted that the H NMR
spectra show a complex set of multiplets, whose assignꢀ
ment to particular functional groups presents difficulties.
The complexity of the interpretation of the 1H NMR
spectra can be attributed to the ringꢀchain tautomerism,
as well as to the formation of a mixture of diastereomers.
The proposed reaction mechanism involves the formation
of the dihydrooxazole derivative as the first step followed
by the closure of the tetrahydrofuran ring as a result of the
attack on the C(5) atom of the dihydropyrazine ring.
R = Me (1), OEt (2); Ar = Ph (a),
(b), 4ꢀFC6H4 (c)
C(12)
C(11)
C(13)
C(10)
N(6)
N(4)
C(14)
C(19)
C(9)
N(2)
N(5)
O(1)
C(12)
C(10)
C(2)
C(2)
C(5)
N(2)
C(3)
C(3)
C(18)
C(19)
C(5)
C(1)
O(2)
C(9)
N(1)
C(20)
C(7) C(6)
C(8)
C(17)
C(4)
C(15)
C(4)
C(1)
C(11)
C(8)
C(7)
O(1)
C(6)
N(4)
C(16)
N(3)
N(5)
N(1)
C(16)
O(2)
C(18)
C(13)
C(15)
C(17)
C(14)
Fig. 2. Molecular structure of 4a in crystals.
Fig. 3. Molecular structure of 6a in crystals.

654
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
Verbitskiy et al.
The reactions of adducts 2a,b with hydroxylamine
afford complex multicomponent mixtures (TLC data).
Attempts to isolate anyone individual product from these
mixtures failed.
dicyanoꢀ1ꢀethylpyrazinium salts can be used for the synꢀ
thesis of polycyclic systems due to their involvement
in further cyclization reactions.
Experimental
Attempts to isolate products of the reactions of comꢀ
pounds 1c and 2c (Ar = 4ꢀFC6H4) with hydrazine hydrate
and hydroxylamine performed under analogous condiꢀ
tions were unsuccessful. These reactions gave (TLC data)
complex multicomponent mixtures as a result of the side
reactions at the fluorine atom in the benzene ring.
Urea, thiourea, thiosemicarbazide, and derivatives of
the latter compound either did not react in refluxing
EtOH with compounds 1 and 2 or gave mixtures, which
were difficult to separate.
The refluxing of adducts 1a,b in ethanol with 1,2ꢀethylꢀ
enediamine (7a) or 1,2ꢀpropylenediamine (7b) led to
elimination of one acetyl group giving rise to 5ꢀ(het)arylꢀ
1ꢀethylꢀ6ꢀ(2ꢀoxopropyl)ꢀ1,6ꢀdihydropyrazineꢀ2,3ꢀdicarꢀ
bonitriles 8a,b (Scheme 3). The structures of these prodꢀ
ucts were established by Xꢀray diffraction based on
the data for compound 8a (Fig. 4). Under analogous
conditions, the reactions of adducts 2a,b afforded comꢀ
plex multicomponent mixtures (TLC data).
The solvents and reagents were dried and purified according to
standard procedures.21
1
The H NMR spectra were recorded on a Bruker DRXꢀ400
instrument with SiMe4 as the internal standard. The APCI (atmoꢀ
spheric pressure chemical ionization) LC/MS spectra were meꢀ
asured on a Shimadzu LCMSꢀ2010 quadrupole LCꢀmass spectromꢀ
eter in MeCN at a scanning rate of 0.25 mL min–1 using a Supelco
LCꢀ18 column (4.6×250 mm) in either the positive or negative ion
mode; the working voltage was 4.5 kV; nitrogen was used as
the carrier gas; the flow rate was 2.5 L min–1. The elemental analysis
was carried out on an automated Carlo Erba 1108 analyzer.
The melting points were determined on combined Boetius stages
and are uncorrected. Flash chromatography was performed with
the use of silica gel Lancaster 0.040—0.063 mm (230—400 mesh).
The progress of the reactions was monitored and the purity of
the products was checked by TLC on Sorbfil plates; spots were
visualized with UV light or I2 vapor.
Xꢀray diffraction study was carried out on a Xcaliburꢀ3 diffracꢀ
tometer equipped with a CCD detector at 295(2) К (λꢀMoꢀKα,
graphite monochromator, ϕꢀ and ωꢀscanning technique). The strucꢀ
tures of all compounds were solved by direct methods using
the SHELXSꢀ97 program package and refined with anisotropic
(isotropic for hydrogen atoms) displacement parameters with
the use of the SHELXLꢀ97 program package. The results of Xꢀray
diffraction study (Table 1) were deposited with the Cambridge
Structural Database.*
Scheme 3
Reaction of 6ꢀ(1ꢀacetylꢀ2ꢀoxopropyl)ꢀ1ꢀethylꢀ5ꢀphenylꢀ1,6ꢀ
dihydropyrazineꢀ2,3ꢀdicarbonitrile (1a) with hydrazine hydrate.
Hydrazine hydrate (19 µL, 0.39 mmol) was added to a suspension of
compound 1a (120 mg, 0.36 mmol) in EtOH (7 mL). The reaction
mixture was refluxed for 1 h, the solvent was distilled off in vacuo,
and the residue was separated on silica gel using elution with an ethyl
acetate—hexane mixture (1 : 2). Two products were isolated and
identified as 5ꢀethylꢀ3ꢀmethylꢀ8aꢀphenylꢀ1,4,4a,5,8,8aꢀhexahydroꢀ
pyrazino[2,3ꢀc]pyridazineꢀ6,7ꢀdicarbonitrile (3a) and 6ꢀ(3,5ꢀdiꢀ
methylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ1ꢀethylꢀ5ꢀphenylꢀ1,6ꢀdihydropyrazineꢀ
2,3ꢀdicarbonitrile (5a).
R = H (7a), Me (7b)
To summarize, we showed that the σHꢀadducts proꢀ
duced by the nucleophilic addition to 5ꢀ(het)arylꢀ2,3ꢀ
C(17)
Product 3a was obtained as a beige powder (Rf = 0.6, TLC data,
acetone—hexane (1 : 1)). The yield was 33 mg (30%), m.p.
191—195 °C (decomp.). Found (%): C, 66.39; H, 5.94; N, 27.26.
C17H18N6. Calculated (%): C, 66.65; H, 5.92; N, 27.43. 1H NMR
(CDCl3), δ: 0.66 (t, 3 H, Me, J = 7.2 Hz); 1.93 (m, 4 H, C(3)Me,
C(4)HA); 2.38 (dd, 1 H, C(4)HB, J = 19.2 Hz, J = 7.6 Hz); 2.79
(dq, 1 H, NCHB, J = 14.4 Hz, J = 7.2 Hz); 3.00 (dq, 1 H, NCHA,
J = 14.4 Hz, J = 7.2 Hz); 3.76 (m, 1 H, C(4a)H); 4.19 (br.s, 1 H,
N(8)H or N(1)H); 5.75 (br.s, 1 H, N(8)H or N(1)H); 7.26—7.41
(br.m, 5 H, Ph). MS (LC/MS), m/z (I (%)): 305 [M – H]+ (100),
306 [M]+ (23), 347 [M + CH3CN]+ (2).
O(1)
C(16)
C(15)
C(11)
C(10)
C(12)
C(2)
C(7)
C(1)
N(1)
C(13)
Product 5a was isolated as a yellow powder (Rf = 0.3, TLC data,
acetone—hexane (1 : 1)). The yield was 69 mg (55%), m.p.
201—203 °C. Found (%): C, 68.63; H, 5.56; N, 25.24. C19H18N6.
N(2)
C(9)
C(4)
C(6)
C(8)
N(3)
C(3)
C(14)
C(5)
* These data can be obtained, free of charge, on application to
the Cambridge Crystallographic Data Centre, www.ccdc.cam.ac.uk/
data_request/cif.
N(4)
Fig. 4. Molecular structure of 8a in crystals.

Transformation of Cꢀadducts of pyrazinium salts
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
655
Table 1. Principal Xꢀray diffraction data collection statistics for compounds 3a, 4a, 6a, and 8a
Parameter
3a
4a
6a
8a
Solvent for crystallization
Molecular formula
Molecular formula
Space group
Acetone—hexane (1 : 2)
МеОН
C20H22N6О2
Monoclinic
P21/с
МеОН
C19H19N5O2
Triclinic
P–1
МеОН
C17H16 N4O
Triclinic
P–1
C17H18N6
Monoclinic
P21/n
Unit cell parameters
а/Å
b/Å
с/Å
α/deg
12.726(2)
9.3642(15)
14.673(3)
90.00
105.069(15)
90.00
8.1488(5)
12.7554(6)
19.3254(11)
90.00
98.618(5)
90.00
8.5904(7)
9.6357(6)
12.0390(8)
87.846(5)
87.459(6)
66.471(7)
912.56(11)
2
7.8140(17)
8.3935(14)
12.293(2)
87.933(14)
79.626(17)
81.731(16)
784.8(3)
β/deg
γ/deg
V/Å3
1688.5(5)
4
1986.03(19)
4
Z
2
Completeness of scanning (%)
96.3
99.2
97.4
99.1
(26.37 > θ > 2.61)
(26.37 > θ > 2.66) (26.37 > θ > 2.69)
(26.00 > θ > 2.68)
86.5 (31.71 > θ > 2.68)
Total number of reflections
Number of reflections with I > 2σ
3323
1534
4013
2128
3627
2283
4613
1649
S
1.001
0.0372
0.0559
1.002
0.0444
0.0911
1.002
0.0369
0.0909
0.985
0.0375
0.0492
R(I > 2σ)
Rw(I > 2σ)
Calculated (%): C, 69.07; H, 5.49; N, 25.44. 1H NMR (CDCl3), δ:
1.26 (t, 3 H, Me, J = 7.2 Hz); 2.30 (s, 6 H, Me); 3.45 (dq, 1 H,
NCHB, J = 14.4 Hz, J = 7.2 Hz); 3.62 (dq, 1 H, NCHA, J = 14.4 Hz,
J = 7.2 Hz); 5.75 (s, 1 H, C(6)H); 7.26—7.44 (m, 3 H, Ph); 7.74
(m, 2 H, Ph). MS (LC/MS), m/z (I (%)): 331 [M + H]+ (19), 372
[M + H + CH3CN]+ (100).
Reaction of 6ꢀ(1ꢀacetylꢀ2ꢀoxopropyl)ꢀ1ꢀethylꢀ5ꢀ(thiophenꢀ3ꢀ
yl)ꢀ1,6ꢀdihydropyrazineꢀ2,3ꢀdicarbonitrile (1b) with hydrazine hyꢀ
drate. Products 3b and 5b were synthesized analogously to comꢀ
pounds 3b and 5b.
5ꢀEthylꢀ3ꢀmethylꢀ8aꢀ(thiophenꢀ3ꢀyl)ꢀ1,4,4a,5,8,8aꢀhexaꢀ
hydropyrazino[2,3ꢀc]pyridazineꢀ6,7ꢀdicarbonitrile (3b) (Rf = 0.6,
TLC data, acetone—hexane (1 : 1)) was obtained as a beige powder.
The yield was 19%, m.p. 218—219 °C (decomp.). Found (%):
C, 57.63; H, 5.16; N, 26.71. C15H16N6S. Calculated (%): C, 57.67;
H, 5.16; N, 26.90. 1H NMR (CDCl3), δ: 0.74 (t, 3 H, Me, J = 7.2 Hz);
1.92 (m, 4 H, C(3)Me and C(4)HA); 2.38 (dd, 1 H, C(4)HB,
J = 19.4 Hz, J = 7.8 Hz); 2.91 (dq, 1 H, NCHB, J = 14.4 Hz,
J = 7.2 Hz); 3.08 (dq, 1 H, NCHA, J = 14.4 Hz, J = 7.2 Hz); 3.72
(m, 1 H, C(4a)H); 4.07 (br.s, 1 H, N(8)H or N(1)H); 5.76 (br.s,
1 H, N(8)H or N(1)H); 7.02 (dd, 1 H, H(4´), J = 5.0 Hz, J = 1.3 Hz);
7.27 (dd, 1 H, H(2´), J = 3.0 Hz, J = 1.3 Hz); 7.35 (dd, 1 H, H(5´),
J = 5.0 Hz, J = 1.3 Hz). MS (LC/MS), m/z (I (%)): 311 [M – H]+
(100), 312 [M]+ (19), 353 [M – H + CH3CN]+ (45).
6ꢀ(3,5ꢀDimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ1ꢀethylꢀ5ꢀ(thiophenꢀ3ꢀ
yl)ꢀ1,6ꢀdihydropyrazineꢀ2,3ꢀdicarbonitrile (5b) (Rf = 0.3, TLC data,
acetone—hexane (1 : 1)) was obtained as a yellow powder. The yield
was 55%, m.p. 212—214 °C. Found (%): C, 60.62; H, 4.98;
N, 24.32. C17H16N6S. Calculated (%): C, 60.69; H, 4.79; N, 24.98.
1H NMR (CDCl3), δ: 1.26 (t, 3 H, Me, J = 7.2 Hz); 2.31 (s, 6 H, Me);
3.40 (dq, 1 H, NCHB, J = 14.4 Hz, J = 7.2 Hz); 3.57 (dq, 1 H,
NCHA, J = 14.4 Hz, J = 7.2 Hz); 5.63 (s, 1 H, C(6)H); 7.31 (dd, 1 H,
H(5´), J = 5.2 Hz, J = 2.8 Hz); 7.49 (dd, 1 H, H(2´), J = 2.8 Hz,
J= 1.2 Hz); 7.53 (dd, 1 H, H(5´), J = 5.2 Hz, J= 1.2 Hz). MS (LC/MS),
m/z (I (%)): 335 [M – H]+ (100), 336 [M]+ (23), 337 [M + H]+ (63).
Ethyl 6,7ꢀdicyanoꢀ5ꢀethylꢀ3ꢀmethylꢀ8aꢀphenylꢀ1,4,4a,5,8,8aꢀ
hexahydropyrazino[2,3ꢀc]pyridazineꢀ4ꢀcarboxylate (4a). Product
4a was synthesized analogously to compounds 3a and 5a as a beige
crystalline powder. The yield was 51%, m.p. 187—189 °C (deꢀ
comp.). Found (%): C, 63.43; H, 5.98; N, 22.31. C20H22N6O2.
Calculated (%): C, 63.48; H, 5.86; N, 22.21. 1H NMR (CDCl3), δ:
0.46 (t, 3 H, NCH2CH3, J = 7.2 Hz); 1.35 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 1.95 (d, 3 H, Me, J = 1.2 Hz); 2.75 (dq, 1 H, NCHB,
J = 14.4 Hz, J = 7.2 Hz); 2.86 (dq, 1 H, NCHA, J = 14.4 Hz,
J = 7.2 Hz); 2.96 (dd, 1 H, C(4)H, J = 9.6 Hz, J = 1.2 Hz); 4.08
(br.s, 1 H, N(8)H or N(1)H); 4.16 (dd, 1 H, C(4a)H, J = 9.6 Hz,
J = 1.2 Hz); 4.27 (m, 1 H, OCH2); 5.90 (br.s, 1 H, N(8)H or
N(1)H); 7.41 (br.m, 5 H, Ph). MS (LC/MS), m/z (I (%)): 377
[M + H]+ (100), 378 [M]+ (25), 418 [M + CH3CN]+ (14).
Ethyl 6,7ꢀdicyanoꢀ5ꢀethylꢀ3ꢀmethylꢀ8aꢀ(thiophenꢀ3ꢀyl)ꢀ
1,4,4a,5,8,8aꢀhexahydropyrazino[2,3ꢀc]pyridazineꢀ4ꢀcarboxylate
(4b). Product 4b was synthesized analogously to compounds 3a and 5a
as a beige crystalline powder. The yield was 56%, m.p. 167—168 °C
(decomp.). Found (%): C, 56.28; H, 5.47; N, 21.66. C18H20N6O2S.
Calculated (%): C, 56.23; H, 5.24; N, 21.86. 1H NMR (CDCl3), δ:
0.59 (t, 3 H, NCH2CH3, J = 7.2 Hz); 1.39 (t, 3 H, OCH2CH3,
J = 7.2 Hz); 1.93 (d, 3 H, Me, J = 0.8 Hz); 2.88 (m, 3 H, NCH2,
C(4)H); 4.12 (m, 2 H, OCH2, N(8)H or N(1)H); 4.27 (m, 2 H,
OCH2, C(4a)H); 5.95 (br.s, 1 H, N(8)H or N(1)H); 7.09 (dd, 1 H,
H(4´), J = 5.2 Hz, J = 1.6 Hz); 7.30 (dd, 1 H, H(2´), J = 3.2 Hz,
J = 1.6 Hz); 7.37 (dd, 1 H, H(5´), J = 5.2 Hz, J = 3.2 Hz).
4ꢀEthylꢀ3,8aꢀdimethylꢀ7aꢀphenylꢀ3a,3b,4,7,7a,8aꢀhexahyꢀ
droꢀ1,8ꢀdioxaꢀ2,4,7ꢀtriazacyclopenta[a]indeneꢀ5,6ꢀdicarbonitrile
(6a). A mixture of 6ꢀ(1ꢀacetylꢀ2ꢀoxopropyl)ꢀ1ꢀethylꢀ5ꢀphenylꢀ1,6ꢀ
dihydropyrazineꢀ2,3ꢀdicarbonitrile (1a) (334 mg, 1.00 mmol), hyꢀ
droxylamine hydrochloride (76 mg, 1.10 mmol), and potassium
tertꢀbutoxide (123 mg, 1.10 mmol) was dissolved in ЕtOH (10 mL).
The reaction mixture was refluxed for 1 h, the solvent was distilled
off in vacuo, and the residue was separated on silica gel using elution
with an ethyl acetate—hexane mixture (1 : 2). Product 6a was obꢀ

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Verbitskiy et al.
tained as a resin, which was triturated with hexane until a yellow
powder was obtained. The yield was 195 mg (56%), m.p. 169—175 °C
(decomp.). Found (%): C, 65.15; H, 5.29; N, 19.90. C19H19N5O2.
Calculated (%): C, 65.32; H, 5.48; N, 20.04. 1H NMR (CD3CN),
δ: 0.78—2.17 (m, 9 H, NCH2CH3, CH3); 3.02—3.96 (m, 4 H,
NCH2, C(3a)H, C(3b)H); 7.36—7.52 (m, 5 H, Ph). MS (LC/MS),
m/z (I (%)): 330 [M + H – H2O]+ (47), 348 [M – H]+ (100).
4ꢀEthylꢀ3,8aꢀdimethylꢀ7aꢀ(thiophenꢀ3ꢀyl)ꢀ3a,3b,4,7,7a,8aꢀ
hexahydroꢀ1,8ꢀdioxaꢀ2,4,7ꢀtriazacyclopenta[a]indeneꢀ5,6ꢀdicarꢀ
bonitrile (6b). Product 6b was synthesized analogously to comꢀ
pound 9a as a brightꢀyellow powder. The yield was 43%, m.p.
68—71 °C (decomp.). Found (%): C, 57.61; H, 4.99; N, 19.83.
C17H17N5O2S. Calculated (%): C, 57.45; H, 4.82; N, 19.71.
1H NMR (CD3CN), δ: 0.77—2.39 (m, 9 H, NCH2CH3, CH3);
3.21—3.69 (m, 4 H, NCH2, C(3a)H, C(3b)H); 7.04—7.76
(m, 3 H, H(5´), H(4´), H(2´)). MS (LC/MS), m/z (I (%)): 336
[M + H – H2O]+ (55), 354 [M – H]+ (100), 355 [M]+ (26).
5ꢀ(Het)arylꢀ1ꢀethylꢀ6ꢀ(2ꢀoxopropyl)ꢀ1,6ꢀdihydropyraziꢀ
neꢀ2,3ꢀdicarbonitriles 8a,c (general procedure). 1,2ꢀDiamine
(3.3 mmol) was added to a solution of compound 1a or 1b (3 mmol)
in ЕtOH (10 mL). The resulting reaction mixture was refluxed for
1 h, the solvent was distilled off in vacuo, and the residue was
separated on silica gel using an ethyl acetate—benzene mixture
(1 : 3) as the eluent.
1ꢀEthylꢀ6ꢀ(2ꢀoxopropyl)ꢀ5ꢀphenylꢀ1,6ꢀdihydropyrazineꢀ2,3ꢀ
dicarbonitrile (8a) was obtained as a yellow crystalline powder. The
yields were 27% (in the reaction with 1,2ꢀethylenediamine) and
32% (in the reaction with 1,2ꢀdiaminopropane), m.p. 132—134 °C
(decomp.). Found (%): C, 69.67; H, 5.54; N, 19.32. C17H16N4O.
Calculated (%): C, 69.85; H, 5.52; N, 19.16. 1H NMR (CDCl3), δ:
1.16 (t, 3 H, NCH2CH3, J = 7.2 Hz); 2.19 (s, 3 H, C(O)CH3); 2.29
(dd, 1 H, CHAC(O), J = 18.7 Hz, J = 2.6 Hz); 2.91 (dd, 1 H,
CHBC(O), J = 18.7 Hz, J = 9.2 Hz); 3.67 (m, 2 H, NCH2); 5.45
(dd, 1 H, C(6)H, J = 9.2 Hz, J = 2.6 Hz); 7.46—7.51 (m, 3 H, Ph);
7.88—7.90 (m, 2 H, Ph).
2. V. N. Charushin, O. N. Chupakhin, Mendeleev Commun., 2007,
17, 249.
3. A. V. Gulevskaya, A. F. Pozharskii, Adv. Heterocycl. Chem.,
2007, 93, 57.
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Geterotsikl. Soedin., 2000, 1403 [Chem. Heterocycl. Compd.,
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5. A. V. Gulevskaya, A. F. Pozharskii, Khim. Geterotsikl. Soedin.,
2001, 1611 [Chem. Heterocycl. Compd., 2001, 37, 1461
(Engl. Transl.)].
6. A. V. Gulevskaya, D. V. Besedin, A. F. Pozharskii, Z. A.
Starikova, Tetrahedron Lett., 2001, 42, 5981.
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Besedin, Tetrahedron, 2003, 59, 7669.
8. V. N. Charushin, O. N. Chupakhin, H. Van der Plas, Adv.
Heterocycl. Chem., 1988, 43, 301.
9. O. N. Chupakhin, V. N. Charushin, A. R. Chernyshev, Progr.
Nucl. Magn. Reson. Spectrosc., 1988, 20, 95.
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Sidorov, I. M. Sosonkin, Khim. Geterotsikl. Soedin., 1985, 669
[Chem. Heterocycl. Compd., 1985, 21, No. 5 (Engl. Transl.)].
11. V. N. Charushin, I. V. Kazantseva, M. G. Ponizovskii, L. G.
Egorova, E. O. Sidorov, O. N. Chupakhin, Khim. Geterotsikl.
Soedin., 1986, 1380 [Chem. Heterocycl. Compd., 1986, 22
(Engl. Transl.)].
12. P. A. Slepukhin, G. L. Rusinov, V. N. Charushin, V. I. Filyakꢀ
ova, N. S. Karpenko, D. B. Krivolapov, I. A. Litvinov, Izv.
Akad. Nauk, Ser. Khim., 2004, 1 [Russ. Chem. Bull., Int. Ed.,
2004, 53, 1].
13. E. V. Verbitskiy, G. L. Rusinov, P. A. Slepukhin, A. I. Matern,
Yu. N. Shvachko, D. V. Starichenko, V. N. Charushin, O. N.
Chupakhin, Izv. Akad. Nauk, Ser. Khim., 2006, 2035 [Russ.
Chem. Bull., Int. Ed., 2006, 55, 2114].
14. V. N. Charushin, M. G. Ponizovskii, O. N. Chupakhin, Khim.
Geterotsikl. Soedin., 1985, 1011 [Chem. Heterocycl. Compd.,
1985, 21, No. 8 (Engl. Transl.)].
1ꢀEthylꢀ6ꢀ(2ꢀoxopropyl)ꢀ5ꢀ(thiophenꢀ3ꢀyl)ꢀ1,6ꢀdihydropyraꢀ
zineꢀ2,3ꢀdicarbonitrile (8b) was isolated as a yellow crystalline
powder. The yields were 53% (in the reaction with 1,2ꢀethylenediꢀ
amine) and 52% (in the reaction with 1,2ꢀdiaminopropane), m.p.
146—148 °C (decomp.). Found (%): C, 60.46; H, 4.66; N, 18.72.
C15H14N4OS. Calculated (%): C, 60.38; H, 4.73; N, 18.78.
1H NMR (CDCl3), δ: 1.17 (t, 3 H, NCH2CH3, J = 7.2 Hz); 2.19
(s, 3 H, C(O)CH3); 2.37 (dd, 1 H, CHAC(O), J = 18.8 Hz, J= 3.2 Hz);
2.85 (dd, 1 H, CHBC(O), J = 18.8 Hz, J = 8.4 Hz); 3.63 (m, 2 H,
NCH2); 5.26 (dd, 1 H, C(6)H, J = 8.4 Hz, J = 3.2 Hz); 7.39
(dd, 1 H, H(5´), J = 5.2 Hz, J = 2.8 Hz); 7.63 (dd, 1 H, H(4´),
J = 5.2 Hz, J = 1.2 Hz); 7.81 (dd, 1 H, H(2´), J = 2.8 Hz, J = 1.2 Hz).
MS (LC/MS), m/z (I (%)): 297 [M – H]+ (100), 298 [M]+ (16).
15. M. Makosza, K. Wojciechowski, Chem. Rev., 2004, 104, 2631.
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philic Aromatic Substitution of Hydrogen, Academic Press, San
Diego, New York, 1994, 376 pp.
17. A. I. Matern, V. N. Charushin, O. N. Chupakhin, Usp. Khim.,
2007, 76, 27 [Russ. Chem. Rev., 2007, 76 (Engl. Transl.)].
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achenko, O. N. Kazheva, A. N. Chekhlov, E. V. Verbitsky, M. I.
Kodess, O. N. Chupakhin, Mendeleev Commun., 2006, 16, 26.
19. P. A. Slepukhin, N. N. Mochul´skaya, L. P. Sidorova, G. L.
Rusinov, M. A. Ezhikova, M. I. Kodess, O. N. Kazheva, A. N.
Chekhlov, O. A. D´yachenko, V. N. Charushin, Izv. Akad.
Nauk, Ser. Khim., 2005, 2132 [Russ. Chem. Bull., Int. Ed.,
2005, 54, 2197].
20. E. V. Verbitskiy, G. L. Rusinov, P. A. Slepukhin, A. N. Grishaꢀ
kov, M. A. Ezhikova, M. I. Kodess, V. N. Charushin, Zh. Org.
Khim., 2008, 305 [Russ. J. Org. Chem., 2008, No. 2].
21. L. F. Tietze und T. Eicher, Reaktionen und Synthesen im
organishꢀchemischen Praktikum und Forschugslaboratorium,
Georg Thieme Verlag, Stuttgart—New York, 1991.
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos 06ꢀ03ꢀ
08141ꢀofi, 07ꢀ03ꢀ12112ꢀofi, 07ꢀ03ꢀ96113ꢀr_ural_a, and
07ꢀ03ꢀ96123ꢀr_ural_a) and the Council on Grants of
the President of the Russian Federation (Program for
State Support of Leading Scientific Schools of the Rusꢀ
sian Federation, Grant NSh 9178.2006.3).
References
1. V. N. Charushin, O. N. Chupakhin, Pure Appl. Chem., 2004,
76, 1621.
Received December 25, 2007