Synthesis of substituted 7,8-di(propylsulfonyl)pyrrolo[1,2-a]pyrazines

Article abstract of DOI:10.1007/s11172-008-0069-9

Heating of pyrazinium salts with E-1,2-dichloro-1,2-di(propylsulfonyl) ethene in chloro-form in the presence of three-fold excess of Et₃N regiospecifically gives rise to substituted 7,8-di(propylsulfonyl)pyrrolo[1,2-a] pyrazines in high yields.

Full text of DOI:10.1007/s11172-008-0069-9

Russian Chemical Bulletin, International Edition, Vol. 57, No. 2, pp. 434—436, February, 2008
434
Synthesis of substituted 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines
N. E. Dontsova,ꢀ A. M. Shestopalov, and V. P. Litvinov†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 8804. Eꢀmail: gsv@ioc.ac.ru
Heating of pyrazinium salts with Eꢀ1,2ꢀdichloroꢀ1,2ꢀdi(propylsulfonyl)ethene in chloroꢀ
form in the presence of threeꢀfold excess of Et3N regiospecifically gives rise to substituted 7,8ꢀ
di(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines in high yields.
Key words: 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines, pyrazinium salts, Eꢀ1,2ꢀdichloroꢀ
1,2ꢀdi(propylsulfonyl)ethene, pyrazinium ylides.
Scheme 1
Substituted pyrrolopyrazines and their hydrogenated
analogs attract a growing attention of chemists and bioloꢀ
gists as potential class of biologically active substances.1
For example, an intensive study of substituted pyrroloꢀ
thienopyrazines revealed their high antiꢀtumor activity.2,3
Alkaloids, such as brevianamide, barretin, cambines, etc.,
contain fragments of substituted hydrogenated pyrroloꢀ
pyrazines.1 It is known4—6 that many of these compounds
have antiꢀmicrobial and antiꢀviral activity, including
activity against the human immunodeficiency virus.
Specific phytotoxins and selective herbicides1 are also
found among these substances.
However, so far this class of heterocycles remains
poorly studied, apparently, because of a limited number
of methods for their synthesis. The Chichibabin reaction,
viz., intramolecular condensation of 1ꢀcarbonylmethylꢀ
2ꢀmethylpyrazinium salts under action of bases, is often
used for the preparation of substituted pyrrolopyrazines.7—9
In addition, a few examples for the construction of
pyrrolopyrazine system by the reaction of 1,3ꢀdipolar cyꢀ
cloaddition of pyrazinium ylides with unsaturated comꢀ
pounds are known.10,11 It should be noted that the yield
of target compounds is not high because of formation of
byꢀproducts.
The reaction of 1,3ꢀdipolar cycloaddition of sulfonylꢀ
substituted unsaturated compounds with pyrazinium ylides
has not been used for the synthesis of substituted
pyrrolopyrazines. In continuation of our works on the
synthesis of sulfonylꢀsubstituted bicyclic azines with
the bridgehead nitrogen atom,12,13 we investigated the
reaction of pyrazinium ylides with Eꢀ1,2ꢀdichloroꢀ
1,2ꢀdi(propylsulfonyl)ethene for the first time (Scheme 1).
Pyrazinium salts 1 were treated with threeꢀfold excess
of Et3N in CHCl3 to generate pyrazinium ylides 2 folꢀ
2—5: R = 4ꢀMeC6H4 (a), 4ꢀEtC6H4 (b), 2,4ꢀMe2C6H3 (c),
4ꢀMeOC6H4 (d), 3,4ꢀ(MeO)2C6H3 (e), 4ꢀFC6H4 (f),
4ꢀClC6H4 (g), 4ꢀBrC6H4 (h)
lowed by addition of Eꢀ1,2ꢀdichloroꢀ1,2ꢀdi(propylsulfonyl)ꢀ
ethene (3). The reaction mixture was refluxed for 40 min
and substituted 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]ꢀ
pyrazines 5 were isolated in good yield (63—85%) (Table 1).
Earlier,13 we suggested a plausible mechanism for the
1,3ꢀdipolar cycloaddition of Eꢀ1,2ꢀdi(alkylsulfonyl)ꢀ
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 424—426, February, 2008.
1066ꢀ5285/08/5702ꢀ0434 © 2008 Springer Science+Business Media, Inc.

7,8ꢀDi(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 2, February, 2008
435
Table 1. Physicoꢀchemical characteristics of substituted 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]ꢀ
pyrazines 5
Comꢀ M.p./°С
pound (solvent)
Yield
(%)
Found
Calculated
Molecular
formula
(%)
C
H
N
S
5a
5b
5c
5d
5e
5f
166—167
(CHCl3)
154
(MeCOMe)
174
(CHCl3)
124
(CHCl3)
176—177
(CHCl3)
166
73
54
73
85
64
74
65
63
55.03
55.28
56.89
57.12
56.85
57.12
54.41
54.29
53.11
53.43
52.91
53.08
51.39
51.22
46.55
46.79
5.01
5.10
5.61
5.67
5.58
5.67
5.29
5.21
5.15
5.30
4.64
4.68
4.57
4.51
4.09
4.12
6.27
14.93
14.76
13.99
13.86
14.03
13.86
13.61
13.80
12.87
12.96
14.33
14.17
13.45
13.67
12.71
12.49
C20H22N2O5S2
C22H26N2O5S2
C22H26N2O5S2
C21H24N2O6S2
C22H26N2O7S2
C20H21FN2O5S2
C20H21ClN2O5S2
C20H21BrN2O5S2
6.45
5.95
6.06
5.91
6.06
6.11
6.03
5.51
5.66
6.10
6.19
5.89
5.97
5.37
5.46
(MeCOMe)
191
(MeOH)
182
5g
5h
(MeOH)
Table 2. Spectroscopic characteristics of substituted 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines 5
Comꢀ
pound
IR, ν/cm–1
1H NMR, δ (J/Hz)
MS, m/z
(Irel (%))
C=O
SO2
5a
5b
5c
1670
1668
1668
1324,
1148
0.88, 1.00 (both t, 3 H each, Ме, J = 7.35); 1.61, 1.78 (both m, 2 H each, CH2);
2.42 (s, 3 H, Mе); 3.59 (m, 4 H, 2 CH2SO2); 7.39, 7.74 (both d, 2 H each, H(3),
H(5), Н(2), Н(4) (C6H4), J = 8.09); 7.94 (d, 1 H, C(3)H, J = 4.41); 8.05 (d, 1 H,
C(4)H, J = 5.15); 9.57 (s, 1 H, C(1)H)
0.95, 1.07 (both t, 3 H each, Me, J1 = 7.15, J2 = 7.70); 1.27 (t, 3 H, Me (4ꢀEt),
J = 7.70); 1.66, 1.83 (both m, 2 H each, CH2); 2.75 (q, 2 H, CH2 (4ꢀEt), J = 7.15);
3.58 (m, 4 H, 2 CH2SO2); 7.38, 7.72 (both d, 2 H each, H(3), H(5), H(2), H(6)
(C6H4), J = 7.70); 7.92 (m, 2 H, C(3)Н, С(4)Н); 9.59 (s, 1 H, C(1)H)
0.92, 1.07 (both t, 3 H each, Me, J = 7.32); 1.68, 1.86 (both m, 2 H each, CH2); 2.39,
2.67 (both s, 3 H each, Me); 3.40, 3.62 (both m, 2 H each, CH2SO2); 7.01 (m, 2 H,
H(3), H(5) (C6H3)); 7.22 (m, 1 H, Н(6) (C6H3)); 7.80 (d, 1 H, C(3)H, J = 4.89);
7.93 (d, 1 H, C(4)H, J = 4.88); 9.80 (s, 1 H, C(1)H)
0.98, 1.07 (both t, 3 H each, Me, J1 = 7.15, J2 = 7.70); 1.70, 1.85 (both m, 2 H each, CH2); 469 [M]+
3.55 (m, 4 H, 2 CH2SO2); 3.95 (s, 3 H, OMe); 7.05, 7.78 (both d, 2 H each, H(3), H(5) (54)
and H(2), Н(4) (C6H4), J = 8.80); 7.95 (m, 2 H, C(3)H, C(4)H); 9.55 (m, 1 H, C(1)H)
1.03 (m, 6 H, 2 Me); 1.83 (m, 4 H, 2 CH2); 3.61 (m, 4 H, 2 CH2SO2); 3.94, 3.97
(both s, 3 H each, MeO); 6.83 (d, 1 H, H(5) (C6H3), J = 8.74); 7.02 (d, 1 H, H(6)
(C6H3), J = 8.01); 7.62 (m, 2 H, H(2) (C6H3), C(3)H); 7.89 (d, 1 H, C(4)H,
J = 5.25); 9.78 (s, 1 H, C(1)H)
0.89, 1.00 (both t, 3 H each, Me, J = 7.35); 1.60, 1.78 (both m, 2 H each, CH2);
3.59 (m, 4 H, 2 CH2SO2); 7.41 (t, 2 H, H(3), H(5) (C6H4), J = 8.83); 7.96 (m, 3 H,
H(2), H(4) (C6H4) + C(3)H); 8.15 (d, 1 H, C(4)H, J = 4.42); 9.58 (s, 1 H, C(1)H)
0.96, 1.06 (both t, 3 H each, Me, J1 = 7.70, J2 = 7.15); 1.65, 1.83 (both m, 2 H each,
CH2); 3.55 (m, 4 H, 2 CH2SO2); 7.58, 7.86 (both d, 2 H each, H(3), H(5) and Н(2),
Н(6) (C6H4), J = 8.8); 7.94, 8.06 (both d, 1 H each, C(3)H, C(4)H, J = 4.95);
9.58 (s, 1 H, C(1)H)
0.97, 1.08 (both t, 3 H each, Me, J = 7.35); 1.66, 1.83 (both m, 2 H each, CH2);
3.55 (m, 4 H, 2 CH2SO2); 7.73, 7.78 (both d, 2 H each, H(3), H(5) and H(2), H(4)
(C6H4), J = 8.09); 7.94, 8.06 (both d, 1 H each, C(3)H, C(4)H, J = 5.15);
9.59 (s, 1 H, C(1)H)
434 [M]+
(46)
1320,
1150
462 [M]+
(44)
1318,
1140
462 [M]+
(42)
5d
5e
1660
1660
1328,
1140
1328,
1144
494 [M]+
(55)
5f
—
—
—
—
452 [M]+
(44)
5g
468 [M]+
(40)
5h
—
—
513 [M]+
(42)

436
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 2, February, 2008
Dontsova et al.
1,2ꢀdichloroethenes with pyridinium ylides through the
formation of hydrogenated intermediates 4, the subseꢀ
quent double dehydrochlorination of which, in case of
the reaction of ethenes 1 with pyrazinium ylides, leads to
substituted 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines
5 (see Scheme 1).
This work was partially financially supported by the
Russian Academy of Sciences (Program Pꢀ8 (2007)).
References
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1
elemental analysis data, H NMR and IR spectroscopy,
and mass spectrometry data (Tables 1 and 2). The IR
spectra of compounds 5 contain absorption bands correꢀ
sponding to the stretching vibrations of the carbonyl group
(1712—1688 cm–1) and the sulfonyl group14 (1324—1308
and 1145—1140 cm–1). A molecular ion peak [M]•+ is
presented in the mass spectra of all the compounds synꢀ
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1
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the proton signals of the pyrazine fragment reveal
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IR spectra of compounds were recorded on a PerkinꢀElmerꢀ
577 and Specord M82 spectrometers in CHCl3 with d = 0.078
mm (a NaCl cuvette). 1H NMR spectra were recorded on a
Bruker DRXꢀ500 (500 MHz) and Bruker WMꢀ250 (250 MHz)
spectrometers for 5—12% solutions in DMSOꢀd6 with Me4Si
as the internal standard. Mass spectra were recorded on a
FINNIGAN MAT INCOS 50 quadruple mass spectrometer with
the energy of ionization 70 eV. Monitoring of the course of the
reaction and the individuality of compounds synthesized were
performed by TLC on Silufol UVꢀ254 plates (eluent hexane—
acetone, 2 : 1) with visualization in iodine vapors.
Eꢀ1,2ꢀDichloroꢀ1,2ꢀdi(propylsulfonyl)ethene (3) was synꢀ
thesized by the method described earlier.14
14. E. N. Prilezhaeva, N. E. Dontsova, N. P. Petukhova, V. S.
Bogdanov, Gazz. Chim. Ital., 1990, 120, 235.
Substituted 7,8ꢀdi(propylsulfonyl)pyrrolo[1,2ꢀa]pyrazines
5a—h (general procedure). Triethylamine (0.003 mol) was added
to a stirred solution of compound 1 (0.001 mol) in CHCl3, then
a solution of sulfone 3 was added dropwise. The reaction mixture
was refluxed for 40 min (monitoring by chromatography). Then
the reaction mixture was diluted with CHCl3, washed with water,
and dried with MgSO4. After the solvent was evaporated, the
solid residue was recrystallized. Characteristics of compounds
5a—h are given in Tables 1 and 2.
Received November 21, 2007