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K. Mori, C.Y. Yang / Tetrahedron xxx (2017) 1e4
3
4.3. 3-Chloro-2,5-dimethylpyrazine (5)
The N-oxide (7, 15.0 g, 121 mmol) and POCl3 (55.1 g, 360 mmol)
were mixed, and the mixture was stirred and heated at 60 ꢀC for
30 min (CAUTION: In one occasion, an explosion took place upon
mixing 7 with POCl3). After cooling, the mixture was poured por-
tionwise in ice and water, made alkaline with 20% aqueous NaOH,
and extracted with Et2O. The extract was washed with water and
brine, dried (MgSO4), and concentrated in vacuo. The residue was
distilled to give 12.2 g (71%) of 5 as a pale yellow oil, bp 98e100 ꢀC/
40 Torr; nmax (film): 3045 (w), 2999 (w), 2962 (w), 2925 (w), 1567
(w), 1519 (w), 1454 (s), 1377 (m), 1329 (s), 1313 (s), 1248 (m), 1168
(m), 1088 (s), 968 (m), 456 (m); dH(CDCl3): 2.49 (3H, s), 2.59 (3H, s),
8.23 (1H, s); dC(CDCl3): 21.2, 22.3, 142.1, 148.3, 150.1, 151.7.
4.4. 2,5-Dimethyl-3-vinylpyrazine (1)
Potassium vinyltrifluoroborate (2.07 g, 15.4 mmol), K2CO3
(5.40 g, 39.1 mmol) and PEPPSI® (Aldrich, 187 mg, 0.275 mmol)
were added to a solution of 5 (1.85 g, 13.0 mmol) in MeOH (45 mL)
under argon. The mixture was stirred and heated under reflux for
1 h. The color of the mixture was first yellow, then yellowish green
and finally dark, and metallic Pd precipitated out. After cooling, the
mixture was diluted with water, and extracted with Et2O. The
extract was washed with water and brine, dried (MgSO4), and
concentrated under atmospheric pressure (with a Vigreux column).
The residue (2.15 g) was chromatographed over SiO2 (30 g). Elution
with pentane/EtOAc (6:1) gave 1, which was distilled in the pres-
ence of TBC (4-t-butylcatechol, 20 mg) as a polymerization inhibi-
tor to give 1.28 g (74%) of 1 as a pale yellow oil, bp 71e72 ꢀC/7 Torr;
n2D2 ¼ 1.5128. In another run starting from 3.00 g of 5, the yield of 1
was 1.54 g (55%), when no TBC was added. The rest remained as a
Scheme 3. Synthesis of the trialkylpyrazines 2, 3 and 4.
3. Conclusion
Four tri-substituted pyrazines isolated from the female Korean
apricot wasp Eurytoma maslovskii were identified as 1e4 by their
MS comparison with the synthetic samples. Synthesis of 1e4 was
carried out in gram-scale by employing transition metal-catalyzed
cross-coupling reactions. The first reliable and scalabe method for
the synthesis of 2,5-dimethyl-3-vinylpyrazine (1) was established.
Regrettably, males of Eurytoma maslovskii were not attracted to
lures with pyrazines 1e4 (field test in Korea in April and May, 2017),
although they showed strong EAG activities.
resin in the distillation flask. Properties of 1: nmax (film): 3099 (w),
3033 (m), 2991 (m), 2958 (m), 2924 (m), 2861 (w), 1628 (w), 1561
(w), 1529 (w), 1445 (s), 1375 (m), 1350 (s), 1275 (m), 1250 (w), 1177
(m), 1122 (s), 1034 (w), 984 (m), 934 (s), 894 (w), 792 (w), 766 (w),
703 (w), 676 (m); dH(CDCl3): 2.48 (3H, s), 2.52 (3H, s), 5.53 (1H, dd,
J ¼ 2, 13 Hz), 6.38 (1H, d, J ¼ 18 Hz), 6.87e6.95 (1H, m), 8.17 (1H, s);
dC(CDCl3): 21.1, 21.3, 121.3, 132.0, 142.3, 147.6, 147.7, 150.7; GC-MS
[column: HP-5 ms, 5% phenylmethylsiloxane, 0.25 mm i.d. x
30 m; carrier gas, He; press, 61 kPa; temp: 70e230 ꢀC (þ10 ꢀC/
min)]: tR 6.28 min (97.9%); MS (70 eV, EI): m/z: 135 (6) [(Mþ1)þ],
134 (87) [Mþ], 133 (100) [(M-1)þ], 81 (4), 66 (7), 65 (5), 54 (12), 42
(27), 40 (7), 39 (15). HRMS calcd for C8H10N2: 134.0844, found:
134.0834.
4. Experimental
4.1. General
Refractive indices were measured on an Atago EMF-1 refrac-
tometer. IR spectra were measured on a Jasco FT/IR-410 spec-
trometer. 1H NMR spectra (400 MHz, TMS at
d
¼ 0.00 as the internal
4.5. 2,5-Dimethyl-3-(2-methylpropyl)pyrazine (2)
standard) and 13C NMR spectra (100 MHz, CDCl3 at
d
¼ 77.0 as the
internal standard) were recorded on a Jeol JNM-ECZ 400S/L1
spectrometer. GC-MS were measured on Agilent Technologies 5975
inert XL. HRMS were recorded on Jeol JMS-T100GCV. Column
chromatography was carried out on Merck Kieselgel 60 Art 1.00734.
A Grignard reagent was prepared from 2-methylpropyl bromide
(6.8 g, 50 mmol) and Mg (1.2 g, 50 mmol) in dry THF (30 mL). After
cooling, the Grignard reagent was added dropwise over 15 min to a
stirred and ice-cooled solution of 5 (3.00 g, 21.1 mmol) and Fe(a-
cac)3 (200 mg, 0.559 mmol) in a mixture of THF and NMP (10:1,
40 mL) at 5e20 ꢀC. After the addition, the solution was stirred for
2 h at 0e5 ꢀC. The color of the mixture was initially red and turned
to dark red or black. The reaction was then quenched by pouring
the mixture into ice and water, and the aqueous mixture was
extracted with Et2O. The Et2O extract was washed successively with
water and brine, dried (MgSO4), and concentrated in vacuo. The
residue (3.93 g) was chromatographed over SiO2 (35 g). Elution
with hexane removed hydrocarbon impurities. Further elution with
hexane/EtOAc (6:1) gave 3.68 g of crude 2, which was distilled to
give 2.85 g (82%) of 2 as a colorless oil, bp 115e116 ꢀC/40 Torr;
4.2. 2,5-Dimethylpyrazine-1-oxide (7)
2,5-Dimethylpyrazine (6, 21.8 g, 200 mmol) in AcOH (400 mL)
was oxidized with NaBO3$4H2O (37.0 g, 240 mmol) by stirring and
heating at 80 ꢀC for 6 h. The mixture was concentrated in vacuo. The
residue was made alkaline by the addition of 2 M NaOH in water,
and extracted with Et2O. The extract was concentrated in vacuo,
and the residue was chromatographed over SiO2 (100 g). Elution
with hexane/EtOAc (4:1e1:1) gave 15.0 g (60%) of 7 as a solid, nmax
(nujol): 3090 (w), 3065 (w), 1605 (m), 1514 (w), 1377 (m), 1352 (m),
1310 (m), 1287 (m), 1222 (m), 1011 (m), 744 (m).
n2D4 ¼ 1.4886;
nmax (film): 3041 (w), 2956 (s), 2926 (s), 2869 (s),
1571 (w), 1536 (w), 1449 (s), 1370 (s), 1169 (m),1074 (m); dH(CDCl3):
Please cite this article in press as: Mori K, Yang CY, Pheromone synthesis. Part 261: Synthesis of four pyrazines produced by females of the