HOMOLYTIC ACETYLATION OF 2,5-DIMETHYLPYRAZINE

Article abstract of DOI:10.1135/cccc19951551

2,5-Dimethylpyrazine prepared by the method described in the literature was acetylated by means of acetaldehyde, tert-butylhydroperoxide and ferrous sulfate. 2,5-Diacetyl-3,6-dimethylpyrazine and 2-acetyl-3,5,6-trimethylpyrazine were obtained.The structure of the products was confirmed by NMR and mass spectral data, and the compounds were screened for biological activity using 20 different screens.No interesting biological activity was found.

Full text of DOI:10.1135/cccc19951551

Short Communication
1551
HOMOLYTIC ACETYLATION OF 2,5-DIMETHYLPYRAZINE
a
a
b
c
Veronika OPLETALOVA , Jiri HARTL , Asmita PATEL and Michael BOULTON
a Department of Pharmaceutical Chemistry and Drug Control,
Faculty of Pharmacy, Charles University, 500 05 Hradec Kralove, Czech Republic
b School of Pharmacy and Biomedical Science,
University of Portsmouth, King Henry I Street, Portsmouth PO1 2DZ, United Kingdom
c Department of Biomolecular Screening,
Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
Received June 15, 1995
Accepted July 18, 1995
2,5-Dimethylpyrazine prepared by the method described in the literature was acetylated by means of
acetaldehyde, tert-butylhydroperoxide and ferrous sulfate. 2,5-Diacetyl-3,6-dimethylpyrazine and
2-acetyl-3,5,6-trimethylpyrazine were obtained. The structure of the products was confirmed by NMR
and mass spectral data, and the compounds were screened for biological activity using 20 different
screens. No interesting biological activity was found.
The inductive effect of the ring nitrogen atoms and the resonance structures cause a
positive charge on the ring carbon atoms, and thus pyrazine does not undergo direct
substitution by electrophilic reagents. Various ring substituted pyrazine derivatives can,
however, be obtained by homolytic substitution reactions1–7. Homolytic acylation of
pyrazine has been studied by Caronna et al.5. Acyl radicals were generated from an
aldehyde using redox system tert-butylhydroperoxide/ferrous sulfate. The reaction was
carried out in water containing acetic and sulfuric acids, and the corresponding diacyl
derivative was formed as the main product. Houminer and co-workers1 used a slightly
modified procedure eliminating acetic acid from the reaction mixture, and obtained the
monoacyl pyrazine as the major product. In addition, small amounts of the correspond-
ing diacyl and alkylated products were also detected. Acyl radicals can also be genera-
ted by Ag-catalyzed decarboxylation of α-keto acids by persulfate6,7. In this paper, we
report on the results of homolytic acetylation of 2,5-dimethylpyrazine, which to our
knowledge has not been studied so far.
A modification of Charrier’s method8,9 was used to prepare the starting material 2-oxo-
propanal-1-oxime (I). 2,5-Dimethylpyrazine (II) was obtained according to Kastron et
al.10 and acetylated using the procedure described by Houminer and co-workers1,2. An
equivalent amount of 80% tert-butylhydroperoxide in di-tert-butylhydroperoxide was
used. The addition of tert-butylhydroperoxide and ferrous sulfate to the reaction mix-
ture required 75 min instead of 15 min as mentioned in the literature1,2. The reaction
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Opletalova, Hartl, Patel, Boulton:
mixture contained unreacted 2,5-dimethylpyrazine and three new products. Two of
them reacted positively with 2,4-dinitrophenylhydrazine. These two compounds were
separated by means of column chromatography and identified as 2,5-diacetyl-3,6-di-
methylpyrazine (III) and 2-acetyl-3,5,6-trimethylpyrazine (IV, Scheme 1).
Both substances were described in the literature previously. Compound III was iso-
lated during studies aimed at the synthesis of pyrroles11–13 and guanidino-β-diketones14.
Condensation of the pyrazine ring from aliphatic precursors was used in these studies.
Compound IV was prepared by the Grignard reaction between 3,5,6-trimethyl-2-py-
razinecarbonitrile and methylmagnesium bromide15. NMR spectroscopy and mass spec-
trometric data of these compounds have not been reported previously.
1
The H NMR spectra of compounds III and IV show absence of signals between δ
6–10 ppm indicating substitution on carbons 2 and 5 of both compounds. The symmetry
of structure III is reinforced by the observation of only half the number of expected
proton and carbon signals in the 1H and 13C NMR spectra, respectively. The assignment
1
of H and 13C absorptions was assisted by the use of 2D H,C-COSY spectra, and also
from comparison of the reported16 13C NMR chemical shifts of pyrazine and methylpy-
1
razine. The H NMR spectrum of IV showed the presence of four methyl signals (δ 2.69,
2.74, 2.56 and 2.57 ppm). From the 2D H,C-COSY spectrum only one of these (δ 2.69 ppm)
corresponds to that for an acetyl methyl group. Hence, the second group substituted
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Short Communication
1553
onto the pyrazine ring must be methyl. Further confirmation was obtained from MS
analysis which gave a molecular ion of 164.0989 (M+).
The absence of 2-acetyl-3,6-dimethylpyrazine (V) in the reaction mixture obtained
under the conditions described in the present paper is rather surprising. It may be possible
to obtain this compound by homolytic acetylation using α-keto acid as a source of the acyl
radical6,7.
The compounds obtained are pyrazine analogues of ring substituted acetophenone.
As some acetophenone derivatives show antirheumatic17 and antiasthmatic18 activity,
both the isolated products were screened against a variety of different therapeutic tar-
gets. The final assay concentrations ranged from 2–40 µg/ml. None of the compounds
exhibited any activity.
EXPERIMENTAL
The analytical TLC was carried out on silica gel plates Silufol UV 254 (Kavalier, Votice) using pe-
troleum ether–ethyl acetate mixture 80 : 20 (v/v) as eluent. Silpearl (Kavalier, Votice) was used for
flash column chromatography. Melting points were determined with Boetius apparatus and are uncor-
rected. Elemental analyses were performed with CHN analyzer (Laboratory Instruments, Prague). In-
frared spectra were measured in KBr pellets with Perkin–Elmer 577 IR Spectrophotometer;
1
wavenumbers are given in cm–1. H and 13C NMR spectra (δ, ppm) were recorded at room tempera-
ture in CDCl3 in 5 mm tubes with 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 Me4Si as internal stand-
ard. The 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) and computer memory 32 K. Mass spectra were measured on a JEOL JMS-DX303
mass spectrometer.
Homolytic Acetylation of 2,5-Dimethylpyrazine
To a stirred mixture of 2,5-dimethylpyrazine (7.4 g, 0.07 mol) and freshly distilled acetaldehyde
(18.5 g, 0.42 mol) in 35 ml 3.4 M sulfuric acid at 5 °C, 80% tert-butylhydroperoxide (33.1 g, 0.294 mol)
and a solution of ferrous sulfate heptahydrate (116.9 g, 0.42 mol) in 350 ml water were added con-
currently over 75 min. The resulting mixture was stirred for an additional 1 h. During this time the
temperature increased to 15 °C. A saturated solution of sodium sulfite was added until a test with
starch-iodide paper was negative. The mixture was then continually extracted with dichloromethane.
The organic extract was washed with water, dried (anhydrous Na2SO4) and evaporated under reduced
pressure. From the residue, two compounds were isolated by means of repeated column chromato-
graphy on silica gel using petroleum ether–ethyl acetate mixture 80 : 20 (v/v) as the eluent.
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Opletalova, Hartl, Patel, Boulton:
2,5-Diacetyl-3,6-dimethylpyrazine (III). Crystallization from ethanol, sublimation at 60–70 °C/1.73 kPa
afforded yellow needles, RF 0.82, yield 1 g (7.6%), m.p. 98.5–99.5 °C (refs13,14 97–98 °C or refs11,12
101 °C). For C10H12N2O2 (192.2) calculated: 62.49% C, 6.29% H, 14.57% N; found: 62.05% C,
5.92% H, 14.97% N. IR spectrum: 3 015, 2 945 (CH aliph.); 1 690 (CO); 1 420, 1 390, 1 365, 1 265,
1
1 200, 1 125, 970. H NMR spectrum: 2.72 s, 6 H (OCCH3); 2.80 s, 6 H (CH3). 13C NMR spectrum:
27.7 (OCCH3), 201.7 (OCCH3), 22.9 (CH3), 146.6 (C-2 and C-5), 149.9 (C-3 and C-6). Mass spec-
trum, m/z (%): 192.9854 (M+, C10H12N2O2, 100), 149.97290(40).
2-Acetyl-3,5,6-trimethylpyrazine (IV). Sublimation at 45–55 °C/1.73 kPa gave cream coloured leaflets, RF
0.43, yield 1 g (8.9%), m.p. 57–60 °C (ref.15 61–62 °C). IR spectrum: 2 990, 2 950 (CH-aliph.); 1 685
1
(CO); 1 535, 1 417, 1 365, 1 305, 1 250, 1 200, 1 180, 1 120, 970. H NMR spectrum: 2.69 s, 3 H
(OCCH3); 2.74 s, 3 H (3-CH3); 2.56 and 2.57 s, 2 × 3 H (5- and 6-CH3). 13C NMR spectrum: 27.8
(OCCH3), 201.7 (OCCH3), 23.0 (3-CH3), 21.5 and 22.2 (5- and 6-CH3), 143.5 (C-2), 148.4 (C-3),
154.4 (C-5), 150.4 (C-6). Mass spectrum, m/z (%): 164.0989 (M+, C9H12N2O, 100), 121.0873 (96).
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