5-alkyl-l-pyrazinecarboxamides, 5-alkyl-2-pyrazinecarbonitriles and 5-alkyl-2-acetylpyrazines as synthetic intermediates for antiinflammatory agents

Article abstract of DOI:10.1135/cccc19961093

2-Pyrazinecarbonitrile, 2-acetylpyrazine, 5-alkyl-2-pyrazinecarboxamides, 5-alkyl-2-pyrazinecarbonitriles and 5-alkyl-2-acetylpyrazines were prepared as intermediates for use in synthesis of potential antiinflammatory agents. The results of the homolytic alkylation of pyrazinecarboxamide were compared with published data. 2-Acetylpyrazine and its 5-(1,1-dimethylethyl) derivative were screened for biological activity, but no interesting effect was found.

Full text of DOI:10.1135/cccc19961093

Pyrazine Derivatives
1093
5-ALKYL-2-PYRAZINECARBOXAMIDES, 5-ALKYL-2-PYRAZINECARBO-
NITRILES AND 5-ALKYL-2-ACETYLPYRAZINES AS SYNTHETIC
INTERMEDIATES FOR ANTIINFLAMMATORY AGENTS
a1
b
c
a
Veronika OPLETALOVA , Asmita PATEL , Michael BOULTON , Alice DUNDROVA ,
a
a
a
Eva LACINOVA , Marta PREVOROVA , Martina APPELTAUEROVA
a
and Milada COUFALOVA
a Department of Pharmaceutical Chemistry and Drug Control, Charles University,
500 05 Hradec Kralove, Czech Republic; e-mail: 1 opletalo@faf.cuni.cz
b School of Pharmacy and Biomedical Science, University of Portsmouth, King Henry I Street,
Portsmouth PO1 2DZ, United Kingdom; e-mail: patela@sci1.sci.port.ac.uk
c Department of Biomolecular Screening, Glaxo Wellcome Medicines Research Centre, Stevenage,
Hertfordshire SG1 2NY, United Kingdom
Received December 13, 1995
Accepted April 7, 1996
2-Pyrazinecarbonitrile, 2-acetylpyrazine, 5-alkyl-2-pyrazinecarboxamides, 5-alkyl-2-pyrazinecarbo-
nitriles and 5-alkyl-2-acetylpyrazines were prepared as intermediates for use in synthesis of potential
antiinflammatory agents. The results of the homolytic alkylation of pyrazinecarboxamide were com-
pared with published data. 2-Acetylpyrazine and its 5-(1,1-dimethylethyl) derivative were screened
for biological activity, but no interesting effect was found.
Key words: Pyrazinecarboxamide; Pyrazinecarbonitrile; Homolytic alkylation; 5-Alkyl-2-acetyl-
pyrazines; Antiinflammatory agents intermediates.
Homolytic substitution reactions are suitable for preparation of various derivatives of
heteroaromatic bases. In the pyrazine series, homolytic alkylation1–3, alkoxycarbonylation4,
carbamoylation4,5, acylation6–9, and aroylation10 have been studied. In this paper, prepa-
ration of 5-alkyl-2-pyrazinecarboxamides 1b–1e, 2-pyrazinecarbonitrile 2a and 5-alkyl-
2-pyrazinecarbonitriles 2b–2e is described. The mixture of a carboxylic acid, ammonium
peroxydisulfate and silver nitrate was used as a source of the alkyl radical. Pyrazine-
carbonitrile 2a and its 5-alkylated analogues 2b–2e were then converted to the corres-
ponding acetyl derivatives 3a–3e via the Grignard reaction (Scheme 1).
Two synthetic procedures were used for the preparation of 5-alkyl-2-pyrazinecar-
bonitriles. In method A, 2-pyrazinecarboxamide (1a) is first alkylated to give 5-alkyl-2-
pyrazinecarboxamides 1b–1e. These components are then dehydrated to the
corresponding 5-alkyl-2-pyrazinecarbonitriles 2b–2e. Alkylation of the amide was per-
formed using the method of Nalepa3. The results were only satisfactory and comparable
with reported data1–3 in the case of alkylation with pivalic acid. In all other prepara-
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1094
Opletalova et al.:
tions, separation of the 5-alkyl derivative from the reaction mixture was found to be
difficult. Crystallization had to be repeated several times, and the yields were conse-
quently low (Table I).
Dehydration of the amides 1b–1e to the corresponding nitriles 2b–2e proceeded
without problems. Total yields of method A (Table II) were, however, low due to the
low yields of the first reaction step.
It was, therefore, decided to try method B in which 2-pyrazinecarboxamide (1a) is
first dehydrated to 2-pyrazinecarbonitrile (2a), and the nitrile is then alkylated to give
the corresponding 5-alkyl-2-pyrazinecarbonitriles 2b–2e. Dehydration with phosphoryl
chloride is widely used for the preparation of 2-pyrazinecarbonitrile11–15 (2a) and gave
a high yield (Table II). Alkylation of nitrile 2a gave a mixture in each case from which
the 5-alkyl derivative was separated by means of flash column chromatography on
silica gel using petroleum ether–ethyl acetate 80 : 20 as the eluent. Since alkylation of
nitrile 2a gave better yields (40 to 80%) than alkylation of amide 1a, total yields of
method B were higher compared to method A (Table II).
The pyrazinecarbonitriles 2a–2e were converted to the acetyl derivatives 3a–3e by
the Grignard reaction13,15
.
N
CONH
N
CN
2
b
N
N
1a
2a
a
c
c
a
O
C
N
CONH
N
N
CN
N
2
CH
b
3
R
N
R
R
N
1b-1e
2b-2e
3a-3e
1-3
a
R
H
b
(CH ) C
3 3
c
(CH ) CHCH
3 2
2
d
CH CH CH CH
3
2
2
2
e
CH CH CH
3
2
2
a) R-COOH, AgNO , (NH ) S O ; b)POCl , ∆; c) CH MgI, ether
3
4 2
2
8
3
3
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Pyrazine Derivatives
1095
Infrared spectra (Tables I, II and III) of unsubstituted 2-pyrazinecarbonitrile (2a) and
2-acetylpyrazine (3a) conformed to literature data16. Infrared spectra of alkylated products
1b–1e, 2b–2e and 3b–3e were compared with available data of various pyrazine deri-
vatives17. Weak to medium intensity bands between 1 529–1 542 cm–1 and 1 550–1 590 cm–1,
which are usually present in all spectra of pyrazine derivatives, except in those of tetra-
substituted pyrazines17, were observed in the spectra of all the prepared pyrazine deri-
vatives. 2,5-Disubstituted pyrazines usually show a characteristic absorption in the
region 1 033–1 040 cm–1 (ref.17). In contrast, a strong absorption band only occurred
between 1 050–1 060 cm–1 in the infrared spectra of the products described in this
1
paper. 2,5-Disubstitution was, however, confirmed from H NMR spectroscopic ana-
lysis where the magnitude of the coupling constant extracted for the pyrazine ring
protons (H-3 and H-6) for all the compounds examined is consistently 1.5 Hz, which is
comparable with literature values5 (J(3,6) = 1.33–1.45 Hz).
TABLE I
Characteristic data, infrared and mass spectra of amides 1b–1e
–1
~
Calculated/Found
% C % H % N
ν , cm
Com-
pound
M.p., °C
Yield, %
Formula
M.w.
m/z, %
NH2 CH-aliph. C=O
1b 155–157.5, sublim.a C9H13N3O 60.32 7.31 23.45 3 440 2 985 1 670 179 (M+, 34)
50
179.2
60.25 7.08 23.09 3 290 2 960
3 220 2 895
164 (100)
137 (41)
121 (6)
1c 158–178, sublim.b C9H13N3O 60.32 7.31 23.45 3 420 2 975 1 670 179 (M+, 17)
20
179.2
60.03 7.46 22.89 3 280 2 950
3 180 2 890
164 (19)
137 (100)
121 (13)
1d 141–150, sublim.c C9H13N3O 60.32 7.31 23.45 3 430 2 980 1 670 179 (M+, 34)
20
179.2
60.33 7.20 22.88 3 290 2 950
3 200 2 890
164 (8)
137 (100)
121 (28)
1e 152–165, sublim.d C8H11N3O 58.17 6.71 25.44 3 410 2 975 1 670 165 (M+, 29)
20
165.2
58.43 6.66 25.07 3 280 2 950
3 240 2 890
150 (23)
137 (100)
121 (16)
a Crystallized from ethanol–water; ref.1 155–157 °C. b Crystallized from water; ref.2 155–156 °C, ref.3
171–174 °C. c Crystallized from water; refs1,2 150–152 °C. d Crystallized from water; ref.1 154–156 °C,
ref.2 154–155 °C.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1096
Opletalova et al.:
1H and 13C NMR chemical shift assignments were assisted by the use of the DEPT
technique. In addition, 2D hetero (1H, 13C) nuclear correlation studies were carried out
on compounds 2b, 3b and 3e. Both 1H and 13C NMR chemical shifts (Tables IV and V)
of the pyrazine nuclei are similar for all the compounds except those (1b, 2b, 3b)
substituted by a tert-butyl group. In these compounds the 13C NMR signals for C-5
(167.7, 168.0 and 167.9, respectively) are shifted relatively downfield and those for C-6
(139.4, 142.5 and 140.1, respectively) are shifted relatively more upfield compared to
1
compounds with other alkyl chains. In the H NMR spectra of compounds 2b and 3b,
the signal for H-6 (8.78 and 8.71, respectively) is shifted downfield compared to that
obtained from substitution with other alkyl groups. The respective signal for 1b (8.37)
is surprisingly unaffected and follows the trend set by the related amide analogues.
The mass spectra of the pyrazine derivatives (Tables I, II and III) showed that com-
pounds such as 1c, 1d and 1e which have alkyl groups with a methylene group directly
bonded to the pyrazine ring, gave a characteristic base peak (m/z 137, 100%). This
results from fragmentation of the alkyl chain from the penultimate carbon (for
TABLE II
Characteristic data, infrared and mass spectra of nitriles 2a–2e
~
ν, cm–1
Distillation
temperature
°C/kPa
M.p., °C
Yield, %
Formula
M.w.
Compound
m/z, %
CH-aliph.
–
CN
2a
2b
–
90–91/1.99a
–
C5H3N3
105.1
2 280
–
85
59–61b
C9H11N3
161.2
2 985
2 280
2 280
2 280
2 280
161 (M+, 24)
42c
2 925
2 890
146 (100)
119 (12)
69d
2c
2d
2e
–
94–96/0.33
127–128/0.40
114–115/0.33
C9H11N3
161.2
2 970
161 (M+, 9)
17c
2 940
2 890
146 (13)
119 (100)
47d
–
C9H11N3
161.2
2 970
161 (M+, 3)
17c
2 940
2 880
146 (5)
119 (100)
47d
–
C8H9N3
147.2
2 980
147 (M+, 34)
17c
2 950
2 890
132 (33)
119 (100)
33d
a Refs11,15 87 °C/0.79 kPa; ref.12 96–100 °C/1.99 kPa. b Crystallized from ethanol. c Method A, related
to pyrazinecarboxamide 1a. d Method B, related to pyrazinecarboxamide 1a.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Pyrazine Derivatives
1097
1c, 1d and 1e; M+ – CnH2n = m/z 137). Branching by substitution of the hydrogens of
the methylene group (e.g. 2b and related analogues) alters the fragmentation pattern as
reflected by the observed base peak (2b gave M+ – CH3 = m/z 146).
Structurally, 2-acetylpyrazines may be considered to be related to acetophenone and
since acetophenone derivatives show antirheumatic18 and antiasthmatic19 activity, some
of the pyrazine derivatives (3a and 3b) were tested for biological activity. The final
concentrations ranged from 2–40 µg/ml. None of the compounds exhibited any activity.
They can, however, be used as intermediates for the synthesis of other potential anti-
inflammatory agents.
EXPERIMENTAL
Pyrazinecarboxamide, granted by Bracco s.p.a., Milano, was used as the starting material. Alkylation
was carried out with pivalic acid (Merck), isovaleric acid (Aldrich), valeric acid (Fluka) and butyric
TABLE III
Characteristic data, infrared and mass spectra of acetylpyrazines 3a–3e
–1
~
ν, cm
Distillation
temperature
°C/kPa
M.p., °C
Yield, %
Formula
M.w.
Compound
m/z, %
CH-aliph.
C=O
3a
3b
74–76.5a
79/1.87
C6H6N2O
122.1
–
1 695
–
40
45–47
51
108–110.5/1.47 C10H14N2O
178.2
2 980
1 690
1 690
1 690
1 690
178 (M+, 26)
2 920
2 885
163 (100)
136 (55)
121 (17)
3c
3d
3e
–
115–120/1.47
125–130/1.99
118–122/1.99
C10H14N2O
178.2
2 970
178 (M+, 10)
58
2 945
2 890
163 (19)
136 (100)
121 (28)
–
C10H14N2O
178.2
2 970
178 (M+, 6)
56
2 940
2 880
163 (6)
136 (100)
121 (54)
–
C9H12N2O
164.2
2 980
164 (M+, 33)
64
2 950
2 890
149 (25)
136 (100)
121 (49)
a Ref.13 74–76 °C, ref.15 76–78 °C.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1098
Opletalova et al.:
TABLE IV
1H NMR spectra (δ, ppm; J, Hz) of the compounds 1, 2 and 3
Compound
1H NMR spectrum
1b
1c
1.44 s, 9 H ((CH3)3C); 5.84 and 7.62 (CONH2); 9.31 d, 1 H, J = 1.5 (H-3); 8.37 d,
1 H, J = 1.5 (H-6)
0.96 d, 6 H, J = 6.8 ((CH3)2CH–CH2); 2.16 m, 1 H, J = 6.8 and 7.2 ((CH3)2CH–CH2);
2.77 d, 2 H, J = 7.2 ((CH3)2CH–CH2); 5.97 and 7.62 (CONH2); 9.32 d, 1 H, J = 1.5
(H-3); 8.37 d, 1 H, J = 1.5 (H-6)
1d
1e
0.96 t, 3 H, J = 7.3 (CH3–CH2–CH2–CH2); 1.41 m, 2 H, J = 7.3 and 7.7
(CH3–CH2–CH2–CH2); 1.77 m, 2 H, J = 7.7 and 7.7 (CH3–CH2–CH2–CH2); 2.91 t, 2
H, J = 7.7 (CH3–CH2–CH2–CH2); 6.56 and 7.67 (CONH2); 9.31 d, 1 H, J = 1.5 (H-3);
8.40 d, 1 H, J = 1.5 (H-6)
1.00 t, 3 H, J = 7.3 (CH3–CH2–CH2); 1.80a m, 2 H (CH3–CH–CH2); 2.88a m,
(CH3–CH2–CH2); 7.15 and 7.75 (CONH2); 9.27 d, 1 H, J = 1.5 (H-3); 8.42 d, 1 H,
J = 1.5 (H-6)
2b
2c
1.43 s, 9 H ((CH3)3C); 8.84 d, 1 H, J = 1.6 (H-3); 8.78 d, 1 H, J = 1.6 (H-6)
0.99 d, 6 H, J = 6.6 ((CH3)2CH–CH2); 2.19 m, 1 H, J = 6.6 and 7.3 ((CH3)2CH–CH2);
2.82 d, 2 H, J = 7.3 ((CH3)2CH–CH2); 8.88 d, 1 H, J = 1.5 (H-3); 8.58 d, 1 H, J = 1.5
(H-6)
2d
2e
0.96 t, 3 H, J = 7.3 (CH3–CH2–CH2–CH2); 1.41 m, 2 H, J = 7.3 and 7.3
(CH3–CH2–CH2–CH2); 1.77 m, 2 H, J = 7.3 and 7.7 (CH3–CH2–CH2–CH2); 2.94 t,
2 H, J = 7.7 (CH3–CH2–CH2–CH2); 8.84 d, 1 H, J = 1.5 (H-3); 8.59 d, 1 H, J = 1.5 (H-
6)
1.01 t, 3 H, J = 7.3 (CH3–CH2–CH2); 1.83 m, 2 H, J = 7.3 and 7.6 (CH3–CH–CH2);
2.92 t, 2 H, J = 7.6 (CH3–CH2–CH2); 8.85 d, 1 H, J = 1.5 (H-3); 8.59 d, 1 H, J = 1.5
(H-6)
3b
3c
1.44 s, 9 H ((CH3)3C); 2.71 s, 3 H (COCH3); 9.15 d, 1 H, J = 1.6 (H-3); 8.71 d, 1 H,
J = 1.6 (H-6)
0.96 d, 6 H, J = 6.8 ((CH3)2CH–CH2); 2.16 m, 1 H, J = 6.8 and 7.2 ((CH3)2CH–CH2);
2.77 d, 2 H, J = 7.2 ((CH3)2CH–CH2); 2.71 s, 3 H (COCH3); 9.15 d, 1 H, J = 1.5
(H-3); 8.46 d, 1 H, J = 1.5 (H-6)
3d
3e
0.96 t, 3 H, J = 7.3 (CH3–CH2–CH2–CH2); 1.40 m, 2 H, J = 7.3 and 7.3
(CH3–CH2–CH2–CH2); 1.76 m, 2 H, J = 7.3 and 7.7 (CH3–CH2–CH2–CH2); 2.93 t,
2 H, J = 7.7 (CH3–CH2–CH2–CH2); 2.71 s, 3 H (COCH3); 9.13 d, 1 H, J = 1.5 (H-3);
8.48 d, 1 H, J = 1.5 (H-6)
1.01 t, 3 H, J = 7.5 (CH3–CH2–CH2); 1.81 m, 2 H, J = 7.5 and 7.3 (CH3–CH2–CH2);
2.89 t, 2 H, J = 7.3 (CH3–CH2–CH2); 2.71 s, 3 H (COCH3); 9.14 d, 1 H, J = 1.5 (H-3);
8.50 d, 1 H, J = 1.5 (H-6)
a Non-first order.
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Pyrazine Derivatives
1099
acid (Fluka). Purity of the products was checked by TLC on Silufol UV 254 plates (Kavalier, Votice).
The following solvent systems were used: toluene–acetone 50 : 50 (v/v), petroleum ether–ethyl ace-
tate 25 : 75 (v/v), and petroleum ether–ethyl acetate 80 : 20 (v/v). Silpearl (Kavalier, Votice) was
used for flash column chromatography. Melting points were determined with a Boetius apparatus and
are uncorrected. Elemental analyses were performed with CHN Analyzer (Laboratorni pristroje,
Prague). Infrared spectra of the amides were recorded in KBr pellets with an IR spectrophotometer
Perkin–Elmer 577. Infrared spectra of the nitriles and acetyl derivatives were recorded in chloroform
solution with the same apparatus. 1H and 13C NMR spectra were recorded at room temperature in
CDCl3 in 5 mm tubes using a JEOL GSX-270 (1H, 13C) FT spectrometer at 270.16 (1H) and 67.97
(13C) MHz, using the deuterium signal of the solvent as the lock and TMS as internal standard. The
TABLE V
13C NMR spectra (δ, ppm) of the compounds 1, 2 and 3
Compound
13C NMR spectrum
1b
1c
1d
29.7 ((CH3)3C), 37.0 ((CH3)3C), 166.0 (CONH2), 141.2 (C-2), 142.3 (C-3), 167.7
(C-5), 139.4 (C-6)
22.3 ((CH3)2CH–CH2), 29.2 ((CH3)2CH–CH2), 44.6 ((CH3)2CH–CH2), 165.3 (CONH2),
141.6 (C-2), 142.7 (C-3), 160.5 (C-5), 143.7 (C-6)
13.8 (CH3–CH2–CH2–CH2), 22.4 (CH3–CH2–CH2–CH2), 31.4 (CH3–CH2–CH2–CH2),
35.4 (CH3–CH2–CH2–CH2), 166.1 (CONH2), 141.7 (C-2), 142.3 (C-3), 161.3 (C-5),
143.6 (C-6)
1e
2b
2c
2d
13.7 (CH3–CH2–CH2), 22.4 (CH3–CH2–CH2), 37.4 (CH3–CH2–CH2), 166.0 (CONH2),
142.0 (C-2), 142.3 (C-3), 160.7 (C-5), 143.4 (C-6)
29.5 ((CH3)3C), 37.4 ((CH3)3C), 115.9 (CN), 127.7 (C-2), 146.8 (C-3), 168.0 (C-5),
142.5 (C-6)
22.3 ((CH3)2CH–CH2), 29.0 ((CH3)2CH–CH2), 44.7 ((CH3)2CH–CH2), 115.8 (CN),
128.0 (C-2), 147.5 (C-3), 161.1 (C-5), 145.7 (C-6)
13.8 (CH3–CH2–CH2–CH2), 22.4 (CH3–CH2–CH2–CH2), 31.0 (CH3–CH2–CH2–CH2),
35.6 (CH3–CH2–CH2–CH2), 115.8 (CN), 127.9 (C-2), 147.5 (C-3), 161.8 (C-5),
145.3 (C-6)
2e
3b
3c
3d
13.7 (CH3–CH2–CH2), 22.3 (CH3–CH2–CH2), 37.8 (CH3–CH2–CH2), 115.8 (CN),
127.9 (C-2), 147.5 (C-3), 161.6 (C-5), 145.3 (C-6)
29.7 ((CH3)3C), 37.0 ((CH3)3C), 199.3 (COCH3), 25.8 (COCH3), 145.1 (C-2),
142.0 (C-3), 167.9 (C-5), 140.1 (C-6)
22.4 ((CH3)2CH–CH2), 29.1 ((CH3)2CH–CH2), 44.7 ((CH3)2CH–CH2),
199.4 (COCH3), 25.8 (COCH3), 145.5 (C-2), 142.8 (C-3), 160.8 (C-5), 143.5 (C-6)
13.8 (CH3–CH2–CH2–CH2), 22.4 (CH3–CH2–CH2–CH2), 31.4 (CH3–CH2–CH2–CH2),
35.5 (CH3–CH2–CH2–CH2), 199.4 (COCH3), 25.9 (COCH3), 145.5 (C-2), 142.8 (C-3),
161.7 (C-5), 143.0 (C-6)
3e
13.8 (CH3–CH2–CH2), 22.6 (CH3–CH2–CH2), 37.6 (CH3–CH2–CH2), 199.3 (COCH3),
25.8 (COCH3), 25.8 (COCH3), 145.5 (C-2), 142.7 (C-3), 161.4 (C-5), 143.1 (C-6)
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1100
Opletalova et al.:
parameters were: spectral width 3 kHz (1H) and 18 kHz (13C), pulse width 3 µs (1H) and 4.2 µs (13C)
(ca 40 and 45° flip angle, respectively), acquisition time 5.46 or 0.90 s, number of scans 16 (1H) and
600 (13C). Mass spectra were determined on a JEOL JMS-DX303 mass spectrometer.
Alkylated Pyrazinecarboxamides 1b–1e. General Procedure
To a solution of pyrazinecarboxamide 1a (12.3 g, 0.1 mol) in water (300 ml) heated to 80 °C, silver
nitrate (1.7 g, 0.01 mol) and the corresponding carboxylic acid (0.1 mol) were added. Ammonium
peroxydisulfate (25.1 g, 0.11 mol) in water (70 ml) was then added dropwise whilst stirring and tem-
perature maintained between 75–80 °C. The reaction mixture was stirred for 1 h. After cooling, the
pH was adjusted to 9 with 10% solution of sodium hydroxide, and the mixture continuously extracted
with 1,2-dichloroethane. The organic extract was dried over anhydrous sodium sulfate before evapo-
rating to dryness. Crystallization of the residue yielded amides 1b–1e. Their characteristic data, in-
frared and mass spectra are given in Table I, their NMR spectra in Tables IV and V.
Pyrazinecarbonitrile 2a
Pyrazinecarboxamide 1a (6.15 g, 0.05 mol) was stirred with phosphorylchloride (31.2 ml) for 90 min
in a bath heated to 100 °C. Excess phosphoryl chloride was then removed in mild vacuo and water
aspirated. The residue was dropped to ice, the pH adjusted to 9 with saturated solution of sodium
carbonate, and the mixture continuously extracted with ether. The organic portion was dried over
anhydrous sodium sulfate, and the solvent evaporated. Distillation of the residue gave pyrazinecar-
bonitrile 2a. Its characteristic data and infrared spectra are given in Table II.
Alkylated Pyrazinecarbonitriles 2b–2e. General Procedure
Method A. Alkylated pyrazinecarboxamides 1b–1e were first prepared as described above, and
then dehydrated under the same conditions as the unsubstituted pyrazinecarboxamide 1a.
Method B. Pyrazinecarbonitrile 2a was first prepared and then alkylated using the procedure simi-
lar to that of preparation of alkylated amides 1b–1e. Reaction products were extracted with ether and
then separated chromatographically. Nitrile 2b was purified by crystallization, nitriles 2c–2e were
distilled. Their characteristic data, infrared and mass spectra are given in Table II, their NMR spectra
in Tables IV and V.
2-Acetylpyrazines 3a–3e. General Procedure
The nitriles 2a–2e (0.064 mol) in 25 ml (in case of the nitrile 2b 110 ml) absolute ether were added
dropwise to methylmagnesium iodide (24.9 g, 0.15 mol) in 100 ml absolute ether whilst stirring at
–10 to +10 °C. The reaction mixture was stirred at the same temperature for 1 h and then poured on
cracked ice. Dilute hydrochloric acid (25 ml, 1 : 1, v/v) was then added and the mixture extracted
continuously with ether. The organic portion was dried over anhydrous sodium sulfate, and solvent
removed. Distillation of the respective residues yielded acetyl derivatives 3a–3e. Their characteristic
data, infrared and mass spectra are given in Table III, their NMR spectra in Tables IV and V.
This study was supported by the Internal Grant Agency of Charles University (No. 40/93). The
authors thank Mrs D. Karlickova (Department of Pharmaceutical Chemistry and Drug Control, Faculty
of Pharmacy, Charles University) for elemental analyses, Mrs J. Zizkova (Department of Inorganic and
Organic Chemistry of the same faculty) for the IR spectra, Dr L. Canfield for NMR spectroscopic
analysis and Mr N. Armstrong for MS analysis (both situated in the NMR/MS unit, University of
Portsmouth).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Pyrazine Derivatives
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