Journal of Natural Products
Article
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title compound as a pale yellow oil (191 mg, 0.8 mmol, 67%): H
NMR (400 MHz) δ 5.15 (s, 2H), 2.48 (s, 3H), 2.47 (s, 3H), 2.46 (s,
3H), 2.21 (d, J = 7.6 Hz, 2H), 2.09 (m, 1H), 0.92 (d, J = 8.0 Hz, 6H);
13C NMR (100 MHz) δ 172.6, 151.1, 148.85, 148.82, 144.8, 64.7, 43.1,
25.6, 22.3 (2 × C), 21.6, 21.3, 20.4; EIMS m/z (%) 236(4), 208(10),
152(50), 151(100), 135(20), 121(10), 94(10), 53(20); HREIMS
found 236.1528 (C13H20N2O2 calcd 236.1525).
The mixture was extracted three times with DCM, and the organic
phases were combined and then washed with saturated brine, before
being dried with MgSO4 and concentrated to give 2.51 g of the crude
product as a yellow oil. The crude material was purified by silica gel
chromatography (eluent: 50% EtOAc/petroleum ether) to give the
title compound as a pale yellow solid (1.66 g, 10 mmol, 50%).
Spectroscopic data were in agreement with those previously
published.24
2,3,6-Trimethylpyrazine 1-Oxide and 2,3,5-Trimethylpyrazine 1-
Oxide. These compounds were prepared according to the method
described for 2,3,5,6-tetramethylpyrazine 1-oxide using 2,3,5-trime-
thylpyrazine (6.17 g, 50.0 mmol), glacial HOAc (20 mL), and H2O2
(30%, 20 mL + 20 mL). After 16 h, water was added and the mixture
was concentrated under vacuum. This process was repeated three
times. A saturated aqueous solution of K2CO3 was added until the
mixture reached pH 9, at which point a yellow precipitate formed and
the solution was extracted four times with DCM. The organic phases
were combined and washed with saturated brine, dried with MgSO4,
and concentrated to give the title compounds as a mixture in a ratio of
3:2 as a white, crystalline solid (4.61 g, 33.4 mmol, 67%). The derived
spectroscopic data agreed with those reported.24
2-Hydroxymethyl-3,5-dimethylpyrazine (4) and 3-Hydroxymeth-
yl-2,5-dimethylpyrazine (5). These compounds were prepared from
1.38 g (10 mmol) of the mixture of 2,3,6-trimethylpyrazine 1-oxide,
2,3,5-trimethylpyrazine 1-oxide, and acetic anhydride (1.1 mL, 12
mmol) followed by the hydrolysis procedure described for 1. Upon
workup, the crude products were recovered as a brown oil (1.58 g),
which was purified by silica gel chromatography (eluent: 60% EtOAc/
petroleum ether) to give a mixture of the title compounds (267 mg,
2.0 mmol, 20%). Partial separation of the two isomers on silica gel
allowed a small amount of each alcohol to be isolated for analysis.
Compound 4 crystallized as the hydrate upon standing, allowing the
crystal structure to be determined. Compound 4: 1H NMR (400
MHz) δ 8.21 (s, 1H), 4.70 (s, 2H), 4.14 (s, 1H), 2.52 (s, 3H), 2.44 (s,
3H); 13C NMR (100 MHz) δ 151.2, 149.8, 148.6, 139.5, 61.2, 21.0,
19.9; EIMS m/z (%) 138(95), 137(35), 120(40), 109(100), 107(30)
and 138(95), 137(35), 120(40), 109(100), 107(30); HREIMS found
138.0795 (C7H10N2O calcd 138.0793). Compound 5: δ 8.25 (s, 1H),
4.70 (s, 2H), 4.32 (s, 1H), 2.53 (s, 3H), 2.42 (s, 3H); 13C NMR δ
150.4, 149.1, 147.5, 141.6, 61.0, 20.8, 19.3; EIMS m/z (%) 138(95),
137(35), 120(40), 109(100), 107(30) and 138(95), 137(35), 120(40),
109(100), 107(30); HREIMS found 138.0797 (C7H10N2O calcd
138.0793).
2-(3-Methylbutyl)-3,5,6-trimethylpyrazine (8). 1,3-Bis-
(diphenylphosphino)propane]nickel(II) chloride (dppp-NiCl2, 20
mg) and 2-chloro-3,5,6-trimethylpyrazine (200 mg, 1.3 mmol) were
added to dry Et2O (5 mL) to form a suspension, to which freshly
prepared 3-methylbutylmagnesium bromide (4 M) in Et2O (0.5 mL,
2.0 mmol) was added. Upon addition of the Grignard reagent, the
solution turned orange, then red, before darkening to deep brownish-
red. The solution was refluxed for 2 h before being poured on ice and
acidified with HCl (1 M) in the presence of Et2O. The organic layer
was removed and replaced before the solution was basified to pH 9
with saturated aqueous K2CO3 solution. The basic aqueous phase was
extracted three times with Et2O. The combined organic phase was
dried and evaporated under reduced pressure to give the crude
product as a dark yellow oil (247 mg). The product was purified on a
silica column eluted with 15% EtOAc/DCM to give the purified
1
product (41 mg, 0.2 mmol, 16%): H NMR (400 MHz) δ 2.72 (m,
2H), 2.48 (s, 3H), 2.46 (s, 3H), 2.45 (s, 3H), 1.65 (thept, J = 6.8, 6.8
Hz, 1H), 1.48−1.54 (m, 2H), 0.96 (d, J = 6.8 Hz, 6H); 13C NMR (100
MHz) δ 152.2, 148.3, 148.0, 147.5, 37.9, 32.8, 29.7, 28.3, 22.5 (2 × C),
21.4, 20.9; EIMS data were consistent with published data;25 HREIMS
found 192.1605 (C12H20N2 calcd 192.1628).
X-ray Crystal Structure of Compound 4. Diffraction data were
collected at 100(2) K on an Oxford Diffraction Xcalibur diffractometer
fitted with Mo Kα radiation. Following multiscan absorption
corrections and solution by direct methods, the structure was refined
against F2 with full-matrix least-squares using the program SHELXL-
97.25 The hydrogen atoms of the water molecule were located and
refined with geometries restrained to ideal values. All remaining
hydrogen atoms were added at calculated positions and refined by use
of a riding model with isotropic displacement parameters based on
those of the parent atoms. All non-hydrogen atoms were refined with
anisotropic displacement parameters. Atomic parameters for 4 have
been deposited with the Cambridge Crystallographic Data Centre with
deposition number 880008. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge, CB2
(3,5-Dimethylpyrazin-2-yl)methyl 3-Methylbutanoate (6) and
(2,5-Dimethylpyrazin-3-yl) 3-Methylbutanoate (7). These com-
pounds were prepared from 3-methylbutanoic acid (72 mg, 0.74
mmol) and a mixture of 4 and 5 (100 mg, 0.7 mmol) obtained in the
previous step, according to the procedure outlined for 2 and 3. Upon
workup, the crude products obtained (183 mg) were purified by silica
gel chromatography (eluent: 20% EtOAc/petroleum ether) to return 7
(60 mg, 0.3 mmol, 40%) and 6 (40 mg, 0.2 mmol, 26%) as pale yellow
oils. The two products were differentiated by confirmation of GC
retention times of the corresponding products from microscale
reactions of the purified fractions of 4 and 5.
Compound 4: C7H10N2O, H2O, MW = 156.19. Orthorhombic,
space group Pbca, a = 14.8674(5) Å, b = 7.0370(2) Å, c = 15.2699(6)
Å, V = 1597.57(9) Å3, Z = 8, ρ = 1.299 Mg·m−3, μ = 0.096 mm−1,
crystal size = 0.46 × 0.23 × 0.06 mm3. Total no. of reflections = 17
484, no. unique reflections = 2705 (Rint = 0.0366), R1 = 0.056, wR2 =
0.125 [I > 2σ(I)], R1 = 0.066, wR2 = 0.130 (all data); |Δρmax| = 0.49
1
−3
́
Compound 6: H NMR (600 MHz) δ 8.26 (s, 1H), 5.22 (s, 2H),
e·Å .
2.57 (s, 3H), 2.52 (s, 3H), 2.26 (d, J = 7.2 Hz, 2H), 2.12 (m, 1H), 0.95
(d, J = 6.6 Hz, 6H); 13C NMR (150 MHz) δ 172.7, 152.6, 151.8,
145.8, 141.2, 64.6, 43.1, 25.9, 22.4 (2 × C), 21.3, 21.1; EIMS m/z (%)
180(20), 138(100), 137(50), 121(20); HREIMS found 222.1365
(C12H18N2O calcd 222.1368).
ASSOCIATED CONTENT
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S
* Supporting Information
NMR spectra (1H and 13C) of the semiochemicals 1−3, 7, and
8 are provided. This material is available free of charge via the
1
Compound 7: H NMR (600 MHz) δ 8.26 (s, 1H), 5.22 (s, 2H),
2.55 (s, 3H), 2.52 (s, 3H), 2.26 (d, J = 7.2 Hz, 2H), 2.14 (m, 1H), 0.95
(d, J = 6.6 Hz, 6H); 13C NMR (150 MHz) δ 172.7, 150.5, 149.5,
147.7, 143.1, 64.8, 43.1, 25.7, 22.4 (2 × C), 21.0, 20.6; EIMS m/z (%)
222(4), 180(20), 138(100), 137(50), 121(20), 80(15), 53(15);
HREIMS found 222.1362 (C12H18N2O calcd 222.1368).
2-Chloro-3,5,6-trimethylpyrazine. A mixture of 2,3,6-trimethylpyr-
azine 1-oxide and 2,3,5-trimethylpyrazine 1-oxide (2.76 g, 20 mmol)
was added slowly to freshly distilled POCl3 (24.8 mL) containing 1
drop of concentrated H2SO4 at 70 °C. The mixture was stirred for 5 h
before being poured on ice and basified with 5 M NaOH to a pH of 9.
AUTHOR INFORMATION
■
Corresponding Author
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/np300388y | J. Nat. Prod. 2012, 75, 1589−1594