The Journal of Organic Chemistry
Note
(complex, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.1, 156.1,
80.6, 66.0, 59.4, 50.4, 40.1, 28.4, 25.0, 23.2, 22.2, 13.9, 3.8, 3.3; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H31N2O4, 315.2283; found
315.2280.
6-Benzyl-3-isopropylpyrazin-2(1H)-one (Phevalin, 1a).
Known compound.2Yield 46% (30 mg) over two steps from 4a
(100 mg). White solid, mp 179−181 °C; Rf = 0.32 (40% EtOAc/
hexanes); IR 3360, 1647 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.54
(br s, 1H), 7.35−7.24 (complex, 6H), 3.83 (s, 2H), 3.42 (septet, J =
6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.2, 157.5, 136.8, 136.1, 129.3, 129.0, 127.5, 122.5, 36.8,
30.2, 20.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H17N2O,
229.1341; found 229.1333.
6-(4-Hydroxybenzyl)-3-isopropylpyrazin-2(1H)-one (tyrva-
lin, 1b). Known compound.3,4,8Yield 45% (30 mg) over two steps
from 4b (100 mg). Yellow solid, mp 207−210 °C; Rf = 0.68 (EtOAc);
IR 3253 (broad peak), 1640, 1615 cm−1; 1H NMR (400 MHz,
CD3OD) δ 7.09−7.05 (complex, 3H), 6.76−6.72 (complex, 2H),
3.72 (s, 2H), 3.34 (septet, J = 6.8 Hz, 1H, partially obscured), 1.18 (d,
J = 6.9 Hz, 6H); 13C{1H} NMR (100 MHz, CD3OD) δ 162.5, 157.9,
157.7, 140.0, 130.9, 128.4, 123.1, 116.6, 36.2, 31.0, 20.4; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C14H17N2O2, 245.1290; found
245.1283.
6-Isobutyl-3-isopropylpyrazin-2(1H)-one (leuvalin, 1c).
Known compound.8Yield 52% (32 mg) over two steps from 4c
(100 mg). White solid, mp 135−138 °C; Rf = 0.48 (40% EtOAc/
hexanes); IR 3364, 1645 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.89
(br s, 1H), 7.18 (s, 1H), 3.40 (septet, J = 6.8 Hz, 1H), 2.38 (d, J = 7.2
Hz, 2H), 2.05 (m, 1H), 1.25 (d, J = 6.9 Hz, 6H), 0.98 (d, J = 6.6 Hz,
6H); 13C{1H} NMR (CDCl3, 100 MHz) δ 161.3, 158.0, 137.6, 123.1,
39.6, 30.4, 28.4, 22.4, 20.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C11H19N2O, 195.1497; found 195.1495.
mp 150−154 °C; Rf = 0.35 (40% EtOAc/hexanes); IR 2951, 1648
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35−7.24 (complex, 6H), 3.82
(s, 2H), 2.65 (d, J = 7.0 Hz, 2H), 2.22 (m, 1H), 0.97 (d, J = 6.6 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 136.8, 135.8, 129.3,
129.1, 127.6, 122.5, 41.8, 36.8, 26.9, 22.8; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C15H19N2O, 243.1497; found 243.1490.
(S)-6-Benzyl-3-(sec-butyl)pyrazin-2(1H)-one (1i). Known com-
pound.13Yield 53% (35 mg) over two steps from 4i (100 mg). White
solid, mp 146−150 °C; [α]D22 14.6 (c 0.70, CHCl3); Rf = 0.39 (40%
EtOAc/hexanes); IR 2962, 1633 cm−1; 1H NMR (400 MHz, CDCl3)
δ 12.35 (br s, 1H), 7.35−7.24 (complex, 6H), 3.83 (s, 2H), 3.25
(sextet, J = 6.9 Hz, 1H), 1.82 (m, 1H), 1.55 (m, 1H, partially
obscured by water signal), 1.21 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.5, 158.1, 137.0,
136.3, 129.3, 128.9, 127.4, 122.7, 36.8, 27.6, 17.8, 12.2; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H19N2O, 243.1497; found
243.1488.
3-Cyclopropyl-6-isobutylpyrazin-2(1H)-one (1j). Yield 33%
(20 mg) over two steps from 4j (100 mg). White solid, mp 173−176
°C; Rf = 0.39 (40% EtOAc/hexanes); IR 2957, 1648 cm−1; 1H NMR
(400 MHz, CDCl3) δ 13.05 (br s, 1H), 7.07 (s, 1H), 2.57 (m, 1H),
2.38 (d, J = 7.2 Hz, 2H), 2.05 (m, 1H), 1.07−0.95 (complex, 10H);
13C{1H} NMR (100 MHz, CDCl3) δ 158.7 157.9, 136.2, 123.3, 39.5,
28.4, 22.3, 11.4, 10.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H17N2O, 193.1341; found 193.1334.
6-Benzyl-3-isopropyl-5,6-dihydropyrazin-2(1H)-one (6). To
a microwave vial equipped with a stir bar, the compound 5a (130 mg,
0.37 mmol) was added, followed by HFIP (3 mL) and sealed. This
reaction mixture was then heated in a microwave reactor at 140 °C for
2h. The solvent was removed under reduced pressure and the crude
was then purified on a semiautomated purification system using a
normal phase silica flash column (100% hexanes to 60% ethyl acetate
over 18 min). The product 6 was obtained was an oil (28 mg, 33%
yield) along with 13 mg of 1a (15% yield). [α]2D2 −16.5 (c 1.0,
CHCl3); Rf = 0.24 (40% EtOAc/hexanes); IR 3200, 1683, 1633 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.37−7.27 (complex, 3H), 7.18−7.16
(complex, 2H), 5.76 (br s, 1H), 3.97 (m, 1H), 3.76 (m, 1H), 3.51
(ddd, J = 16.3, 10.2, 1.6 Hz, 1H), 3.27 (septet, J = 6.8 Hz, 1H), 2.94
(dd, J = 13.7, 5.0 Hz, 1H), 2.65 (dd, J = 13.7, 9.5 Hz, 1H), 1.14 (d, J
= 6.8 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 170.4, 157.7, 135.8, 129.27, 129.23, 127.5, 53.1, 51.1, 39.6,
30.7, 20.2, 19.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H19N2O, 231.1497; found 231.1490.
3,6-Diisopropylpyrazin-2(1H)-one (1d). Known compoun-
d.28Yield 50% (30 mg) over two steps from 4d (100 mg). White
solid, mp 131−134 °C; Rf = 0.64 (40% EtOAc/hexanes); IR 2965,
1
2870, 1636, 1607 cm−1; H NMR (400 MHz, CDCl3) δ 13.10 (br s,
1H), 7.22 (s, 1H), 3.41 (septet, J = 6.9 Hz, 1H), 2.84 (septet, J = 7.0
Hz, 1H), 1.33 (d, J = 7.0 Hz, 6H), 1.24 (d, J = 6.8 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 161.7, 157.6, 143.4, 120.4, 30.3, 30.2,
21.3, 20.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H17N2O,
181.1341; found 181.1331.
3-Isopropyl-6-methylpyrazin-2(1H)-one (1e). Yield 43% (24
mg) over two steps from 4e (100 mg). White solid, mp 145−148 °C;
Rf = 0.16 (40% EtOAc/hexanes); IR 2962, 1640 cm−1; 1H NMR (400
MHz, CDCl3) δ 13.1 (br s, 1H), 7.21 (s, 1H), 3.41 (septet, J = 6.8
Hz, 1H), 2.28 (s, 3H), 1.22 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 161.1, 158.0, 134.4, 123.0, 30.0, 20.2, 16.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C8H13N2O, 153.1028; found
153.1021.
ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
(S)-6-(sec-Butyl)-3-isopropylpyrazin-2(1H)-one (1f). Yield
55% (34 mg) over two steps from 4f (100 mg). White solid, mp
145−148 °C; [α]2D2 35.5 (c 0.80, CHCl3); Rf = 0.64 (40% EtOAc/
1
Copies of H and 13C NMR spectra for compounds
prepared by the present method (PDF)
1
hexanes); IR 2965, 1638 cm−1; H NMR (400 MHz, CDCl3) δ 7.29
(s, 1H), 3.41 (septet, J = 6.7 Hz, 1H), 2.57 (sextet, J = 7.1 Hz, 1H),
1.80−1.60 (complex, 2H), 1.32 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 6.8
Hz, 6H), 0.90 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 161.3, 157.7, 142.7, 122.2, 37.4, 30.4, 28.6, 20.1, 19.0, 12.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H19N2O, 195.1497; found
195.1488.
AUTHOR INFORMATION
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Corresponding Author
ORCID
3-Isopropyl-6-phenylpyrazin-2(1H)-one (1g). Yield 52% (33
mg) over two steps from 4g (100 mg). White solid, mp 197−200 °C;
Notes
1
Rf = 0.42 (40% EtOAc/hexanes); IR 2960, 1636, 1574 cm−1; H
The authors declare no competing financial interest.
NMR (400 MHz, CDCl3) δ 12.93 (br s, 1H), 7.80−7.70 (complex,
3H), 7.54−7.46 (complex, 3H), 3.47 (septet, J = 6.8 Hz, 1H), 1.30 (d,
J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.6, 157.6,
136.4, 131.2, 130.3, 129.3, 126.7, 121.8, 30.7, 20.1; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C13H15N2O, 215.1184; found
215.1175.
ACKNOWLEDGMENTS
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We acknowledge financial support from the University of
Kansas and the University of North Carolina at Chapel Hill.
We thank Dr. Brandie Ehrmann (UNC Chapel Hill) for
HRMS analysis.
6-Benzyl-3-isobutylpyrazin-2(1H)-one (1h). Known compoun-
d.13Yield 53% (35 mg) over two steps from 4h (100 mg). White solid,
D
J. Org. Chem. XXXX, XXX, XXX−XXX