Reactions of σh-adducts of 1-ethyl-1,4-diazinium salts with arylalkynes as a one-step approach to pyrrolo[1,2-a]pyrazine derivatives

Article abstract of DOI:10.1007/s11172-009-0169-1

The O-and C-adducts of 5-aryl and 5-hetaryl-2,3-dicyano-1-ethylpyrazinium salts are hidden sources of ylides, which can be used for the cyclization with arylacetylenes giving rise to pyrrolo[1,2-a ]pyrazines. ; 2009 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s11172-009-0169-1

Russian Chemical Bulletin, International Edition, Vol. 58, No. 6, pp. 1291—1293, June, 2009
1291
H
Reactions of σ ꢀadducts of 1ꢀethylꢀ1,4ꢀdiazinium salts with arylalkynes
as a oneꢀstep approach to pyrrolo[1,2ꢀa]pyrazine derivatives*
E. V. Verbitskiy, P. A. Slepukhin, M. A. Ezhikova, M. I. Kodess, 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, 620041 Ekaterinburg, Russian Federation.
Eꢀmail: rusinov@ios.uran.ru
The Oꢀ and Cꢀadducts of 5ꢀaryl and 5ꢀhetarylꢀ2,3ꢀdicyanoꢀ1ꢀethylpyrazinium salts are
hidden sources of ylides, which can be used for the cyclization with arylacetylenes giving rise to
pyrrolo[1,2ꢀa]pyrazines.
H
Key words: Nꢀalkylpyrazinium ylides, 1,2ꢀdihydropyrazines, σ ꢀadducts, hidden 1,3ꢀdipoles,
phenylacetylene, 4ꢀbromophenylacetylene, pyrrolo[1,2ꢀa]pyrazines.
Azoloazines containing a bridging nitrogen atom are
uncommon in nature; however, the synthesis of these comꢀ
pounds has attracted great attention with the main aim
to design biologically active compounds.1 Thus, pyrroloꢀ
[1,2ꢀa]pyrazine derivatives, viz., azaindolizines, have a wide
spectrum of physiological activities, such as antihypoxic,2
psychotropic,3 antimalarial,2,4 antidiabetic,5,6 etc.
Azaindolizines 1 can be synthesized from ylides of
pyrazinium salts 2 through the 1,3ꢀdipolar [3+2]ꢀcycloadꢀ
dition7 (Scheme 1).
Scheme 2
Scheme 1
NuH = Cꢀ and Oꢀnucleophiles
A convincing evidence for the generation of ylides 3 as
a result of dissociation of σHꢀadducts 4—6 was obtained
by studying the reactions of the latter compounds
with phenylꢀ (8a) or 4ꢀbromophenylacetylenes (8b) in
boiling orthoꢀxylene. These reactions afforded 8ꢀphenylꢀ,
8ꢀ(4ꢀbromophenyl)ꢀ3ꢀarylꢀ, and 8ꢀ(4ꢀbromophenyl)ꢀ
3ꢀhetarylꢀ6ꢀmethylpyrrolo[1,2ꢀa]pyrazineꢀ1ꢀcarbonitriles
9a—d (Scheme 3). The structures of compounds 9a—d
In the present study, we showed that ylides 3 can be
synthesized starting from σHꢀadducts 4—6 of 1,4ꢀdiazines
of different nature. These adducts are formed by the reacꢀ
tions of 5ꢀarylꢀ and 5ꢀhetarylꢀ2,3ꢀdicyanoꢀ1ꢀethylpyraziꢀ
nium salts 7 with Oꢀ (water and alcohols) and Cꢀnucleoꢀ
philes (enolates of dicarbonyl compounds, indoles, etc.)8
(Scheme 2).
1
were established by H and 13C NMR spectroscopy and
by the Xꢀray diffraction study of 6ꢀmethylꢀ3,8ꢀdiphenylꢀ
pyrrolo[1,2ꢀa]pyrazineꢀ1ꢀcarbonitrile 9a (Fig. 1).
It should be noted that the reaction of hydroxy adduct
6 with phenylacetylene affords cyclization product 9a in a
substantially lower yield (15%) and is accompanied by
strong resinification, which is apparently attributed
to lower stability of hydroxy compound 6 compared to
Cꢀadducts 4 and 5. This fact can be a consequence of
* Dedicated to Academician O. N. Chupakhin on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1255—1257, June, 2009.
1066ꢀ5285/09/5806ꢀ1291 © 2009 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Verbitskiy et al.
Scheme 3
Starting
compound
Substituents
Product
Yield
(%)
R
Ar
R´
4a, 8a
4b, 8a
4a, 8b
4b, 8b
5, 8a
Me
Me
Me
Me
OEt
—
Ph
3ꢀthienyl
Ph
3ꢀthienyl
Ph
Ph
Ph
4ꢀBrC6H4
4ꢀBrC6H4
Ph
9a
9b
9c
9d
9a + 5
9a
46
54
44
40
14 + 44
15
6, 8a
Ph
Ph
Scheme 4
the lower strength of the C—O bond compared to the
C—C bond.9
failed because of the formation of complex multicompoꢀ
nent mixtures (TLC data).
A decrease in the yield of product 9a in the reaction of
adduct 5 with phenylacetylene can be associated with the
lower reactivity of 5 than that of adducts 4a,b and, as a
consequence, with a lower degree of completion of the
reaction under analogous conditions. Nevertheless, this
question is still debated.
Attempts to generate ylides directly from Nꢀethylꢀ
pyrazinium salts 7 in the presence of bases and the inꢀ
volvement of the latter in the reaction with arylacetylenes
The reaction under consideration proceeds apparently
as the 1,3ꢀdipolar cycloaddition of the generated ylides 3
with arylacetylenes followed by the aromatization of
cycloadducts 10 through the elimination of hydrocyanic
acid (Scheme 4).
To sum up, we showed that the σHꢀadducts that are
formed as a result of the addition of nucleophiles to
1ꢀethylꢀ5ꢀarylꢀ and 1ꢀethylꢀ5ꢀhetarylꢀ2,3ꢀdicyanopyraziꢀ
nium salts can be used as hidden 1,3ꢀdipoles for the synꢀ
thesis of pyrrolo[1,2ꢀa]pyrazine derivatives.
C(18)
N(3)
Experimental
C(9)
N(2)
C(17)
C(2)
C(16)
C(1)
C(14)
C(13)
C(19)
C(21)
C(15)
C(3)
C(4)
C(5)
The solvents and reagents were dried and purified according
to known procedures.10 The starting compounds 4—6 were
synthesized according to a procedure described previously.8
N(1)
The H and 13C NMR spectra were recorded on a Bruker
1
C(20)
C(10)
C(12)
C(11)
DRXꢀ400 instrument (400 and 100 MHz, respectively) with
Me4Si as the internal standard. The APCI (atmospheric presꢀ
sure chemical ionization) and ESI (electrospray ionization)
mass spectra were obtained on a Shimadzu LCMSꢀ2010
quadrupole LCꢀmass spectrometer in CH3CN at a scanning rate
of 0.25 mL min–1 with the use of a Supelco LCꢀ18 column
(4.6×250 mm) operating in the positive or negative ion mode;
C(6)
C(8)
C(7)
Fig. 1. Molecular structure of 9a in the crystals.

Syntheses of pyrrolopyrazines from σHꢀadducts
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1293
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 Perkin—Elmer PEꢀ2400 analyzer.
The melting points were determined on combined Boetius hot
stages and are uncorrected. The flash chromatography was perꢀ
formed with the use of silica gel Lancaster 0.040—0.063 mm
(230—400 mesh).
The course of the reactions was monitored and the purity of
the products was checked by TLC on Sorbfil plates; spots were
visualized under UV light or by spraying with I2 vapor.
The Xꢀray diffraction study of compound 9a was carried out
on a Xcalibur 3 diffractometer equipped with a CCD detector at
295(2) К (λMoꢀKα, graphite monochromator, ϕꢀ and ωꢀscanꢀ
ning technique). All structures were solved by direct methods
with the use of the SHELXSꢀ97 program package and refined
using the SHELXLꢀ97 program package with anisotropic disꢀ
placement parameters (isotropic displacement parameters for H
atoms). The results of the Xꢀray diffraction study were deposited
with the Cambridge Crystallographic Data Centre* (CCDC
730052).
8ꢀ(4ꢀBromophenyl)ꢀ6ꢀmethylꢀ3ꢀ(3ꢀthienyl)pyrrolo[1,2ꢀa]ꢀ
pyrazineꢀ1ꢀcarbonitrile (9d). Orange crystalline powder,
m.p. 246—247 °C (decomp.). 1H NMR (CDCl3), δ: 2.61 (s,
3 H, CH3); 6.86 (s, 1 H, C(7)H); 7.40 (d, 2 H, Ph, J = 8.5 Hz);
7.44 (dd, 1 H, H(5″) 3ꢀthienyl, J = 5.0 Hz, J = 3.0 Hz); 7.54
(dd, 1 H, H(4″) 3ꢀthienyl, J = 5.0 Hz, J = 1.3 Hz); 7.59 (d, 2 H,
Ph, J = 8.5 Hz); 7.90 (dd, 1 H, H(2І) 3ꢀthienyl, J = 3.0 Hz,
J = 1.3 Hz); 8.01 (s, 1 H, C(4)H). Found (%): C, 57.62; H, 3.01;
N, 10.69. C19H12N3SBr. Calculated (%): C, 57.88; H, 3.07;
N, 10.66. LC/MS, m/z (I (%)): 394 [M]+ (56), 395 [M + H]+
(15), 396 [M + 2 H]+ (55), 435 [M + CH3CN]+ (98), 436
[M + H + CH3CN]+ (27), 437 [M + 2 H + CH3CN]+ (100).
Crystallographic data for compound 9a. Crystals of comꢀ
pound 9a, C21H15N3, monoclinic, space group P21/C, were
obtained by recrystallization from a 1 : 3 MeCN—MeOH mixꢀ
ture. The unit cell parameters at 295 K are a = 8.6274(13) Å,
b = 16.470(5) Å, C = 11.6320(9) Å, α = 90.00°, β = 97.721(10)°,
γ = 90.00°, V = 1637.8(5) Å3, Z = 4. 26.36 > θ > 3.03. The
intensities of 3341 reflections were measured, of which 1279
reflections were with I > 2σ. The final R factors are R = 0.0421,
Rw = 0.0742.
Synthesis of 3ꢀarylꢀ and 3ꢀhetarylꢀ6ꢀmethylꢀ8ꢀphenylꢀpyrroloꢀ
[1,2ꢀa]pyrazineꢀ1ꢀcarbonitriles 9a,b (general procedure).
A solution of compound 4a (4b, 5, or 6) (1 mmol) and phenylꢀ
acetylene (1 mmol) in orthoꢀxylene (7 mL) was refluxed for 1 h,
the solvent was distilled off in vacuo, and the residue was
chromatographed on a column using elution with a 1 : 1 CHCl3—
hexane mixture. The reaction product was recrystallized from a
2 : 1 MeCN—MeOH mixture.
This study was financially supported by the Russian
Foundation for Basic Research (Grants Nos 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 Russian Federation, Grant
NShꢀ3758.2008.3).
6ꢀMethylꢀ3,8ꢀdiphenylpyrrolo[1,2ꢀa]pyrazineꢀ1ꢀcarbonitrile
(9a). Redꢀorange crystalline powder, m.p. 158—159 °C.
1H NMR (CDCl3), δ: 2.63 (s, 3 H, CH3); 6.91 (s, 1 H, C(7)H);
7.42—7.56 (m, 8 H, Ph); 7.94—7.97 (m, 2 H, Ph); 8.11 (s, 1 H,
C(4)H). Found (%): C, 81.25; H, 4.74; N, 13.39. C21H15N3.
Calculated (%): C, 81.53; H, 4.89; N, 13.58. LC/MS, m/z
(I (%)): 310 [M + H]+ (70), 352 [M + 2 H + CH3CN]+ (100).
6ꢀMethylꢀ8ꢀphenylꢀ3ꢀ(3ꢀthienyl)pyrrolo[1,2ꢀa]pyrazineꢀ
1ꢀcarbonitrile (9b). Red crystalline powder, m.p. 193—195 °C.
1H NMR (CDCl3), δ: 2.61 (s, 3 H, CH3); 6.88 (s, 1 H, C(7)H);
7.41—7.55 (m, 7 H, Ph and 3ꢀthienyl); 7.89 (dd, 1 H, H(2″)ꢀ
3ꢀthienyl, J = 3.0 Hz, J = 1.3 Hz); 8.11 (s, 1 H, C(4)H).
Found (%): C, 71.97; H, 4.37; N, 13.21. C19H13N3S•0.1H2O.
Calculated (%): C, 71.94; H, 4.19; N, 13.25. LC/MS, m/z
(I (%)): 316 [M + H]+ (100), 358 [M + 2 H + CH3CN]+ (85).
8ꢀ(4ꢀBromophenyl)ꢀ3ꢀarylꢀ and 8ꢀ(4ꢀbromophenyl)ꢀ3ꢀhetarylꢀ
6ꢀmethylpyrrolo[1,2ꢀa]pyrazineꢀ1ꢀcarbonitriles 9c,d were
synthesized from compounds 4a or 4b (1 mmol) and 4ꢀbromopꢀ
henylacetylene (1 mmol) in orthoꢀxylene (7 mL) by analogy
with compounds 9a,b.
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8ꢀ(4ꢀBromophenyl)ꢀ6ꢀmethylꢀ3ꢀphenylpyrrolo[1,2ꢀa]ꢀ
pyrazineꢀ1ꢀcarbonitrile (9c). Red crystalline powder, m.p. 207—
1
208 °C. H NMR (CDCl3), δ: 2.62 (s, 3 H, CH3); 6.88 (s, 1 H,
C(7)H); 7.36—7.61 (m, 7 H, Ph); 7.93—7.96 (m, 2 H, Ph); 8.10
(s, 1 H, C(4)H). Found (%): C, 64.96; H, 3.49; N, 10.93.
C21H14N3Br. Calculated (%): C, 64.96; H, 3.63; N, 10.82.
LC/MS, m/z (I (%)): 388 [M]+ (70), 389 [M + H]+ (20), 390
[M + 2H]+ (74), 429 [M + CH3CN]+ (94), 431 [M + 2 H +
CH3CN]+ (100).
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* These data can be obtained, free of charge, on application to
www.ccdc.cam.ac.uk/data_request/cif.
Received July 18, 2008;
in revised form December 9, 2008