10.1002/ejoc.201900722
European Journal of Organic Chemistry
FULL PAPER
2-Azido-1-(2,5-dimethoxyphenyl)ethanone (2d). Pale yellow solid;
yield 84%; m.p. 67-68°C. 1H NMR (400 MHz, CDCl3, 25 °C) δ= 7.48–
7.47 (m, 1H), 7.13–7.11 (m, 1H), 6.96–6.94 (m, 1H), 4.54 (s, 2H), 3.91 (s,
3H), 3.83 (s, 3H). 13C NMR (150 MHz, CDCl3, 25 °C) δ= 194.0, 153.9,
153.8, 124.7, 122.2, 113.7, 113.1, 59.5, 56.0, 55.9. FT-IR (film, cm-1) ṽ=
3391, 2921, 2101, 1675, 1501, 1267, 1013. GC-MS (EI, 70 eV) m/z (%):
221 (M+, 11), 165 (100), 107 (16), 92 (7), 77 (11). HRMS (ESI) m/z calcd
for C10H11N3O3 [M+Na]+: 244.0693; found: 244.0708.
sequentially added to the ChCl/Gly (1:2 molꢀmol−1) (2.0 g) eutectic
mixture. The reaction mixture was stirred at RT in air for 3–6 h until
complete consumption of the starting material. Then, the mixture was
transferred to a Parr autoclave, and Pd/C (1 mol%, 16 mg) was added.
The autoclave was closed, and 3 atm of H2 was charged. The mixture
was kept under stirring at RT for 6–24h until complete consumption of
the starting material. After carefully releasing the hydrogen, the reaction
mixture was diluted with AcOEt (MeOH in the case of pyrazines 4d and
4h) (10 mL), and filtered through a Celite pack. Then, water was added,
and the mixture was extracted with AcOEt (3 x 10 mL). The collected
organic layers were dried using anhydrous Na2SO4, filtered, and the
volatile evaporated under reduced pressure to afford the crude product,
which was purified by column chromatography on silica gel
(hexane/EtOAc10:1) to provide pyrazine 4 (4a, 4b, 4d or 4h) (64–95%
yield; see Table 3).
2-Azido-1-[4-(diethylamino)phenyl]ethanone (2e). Yellow oil, yield
80%. 1H NMR (400 MHz, CDCl3, 25°C) δ= 7.77 (d, J = 9.0 Hz, 2H), 6.62
(d, J = 9.0 Hz, 2H), 4.44 (s, 2H), 3.42 (q, J = 7.0 Hz, 4H), 1.20 (t, J = 7.0
Hz, 6H). 13C NMR (150 MHz, CDCl3, 25 °C) δ= 190.6, 151.8, 130.5,
121.4, 110.4, 54.1, 44.6, 12.4. FT-IR (film, cm-1) ṽ= 332, 2974, 2102,
1596, 1409, 1187. GC-MS (EI, 70 eV) m/z (%): 232 (M+, 5), 176 (100),
133 (12), 77 (7). HRMS (ESI) m/z calcd for C12H16N4O [M+Na]+:
255.1222; found: 255.1217.
2,5-Diphenylpyrazine (4a).[6] Pale yellow oil; yield 87%. 1H NMR (600
MHz, CDCl3, 25 °C) δ= 9.09 (s, 2H); 8.08–8.07 (m, 4H), 7.55–7.47 (m,
6H). 13C NMR (150 MHz, CDCl3, 25 °C) δ= 150.8, 141.3, 136.4, 129.8,
129.1, 126.9. FT-IR (KBr, cm-1) ṽ= 3060, 2929, 1694, 1620, 1450, 1288,
757, 698. GC-MS (EI, 70 eV) m/z (%): 232 (M+, 100), 204 (5), 129 (6),
102 (86), 76 (16), 51 (5). HRMS (ESI) m/z calcd for C16H12N2 [M+Na]+:
255.0893; found: 255.0895.
2-Azido-1-(4-fluorophenyl)ethanone (2f).[14a] Orange solid; yield 93%;
m.p. 54-55 °C. 1H NMR (600 MHz, CDCl3, 25 °C) δ= 7.96–7.93 (m, 2H),
7.19–7.16 (m, 2H), 4.54 (s, 2H). 13C NMR (100 MHz, CDCl3, 25 °C) δ=
191.7, 166.1 (d, 1JC-F = 257 Hz), 130.9 (d, 4JC-F = 5 Hz), 130.8 (d, 3JC-F
=
9 Hz), 116.3 (d, JC-F = 22 Hz), 54.9. FT-IR (film, cm-1) ṽ= 3031, 2102,
1689, 1595, 1226, 1216, 832. GC-MS (EI, 70 eV) m/z (%): 151 [(M-28)+,
2], 123 (100), 95 (52), 75 (19), 69 (5), 50 (4). HRMS (ESI) m/z calcd for
C8H6N3FO [M+Na]+ 202.0387; found 202.0387.
2
2,5-Di-p-tolylpyrazine (4b).[6] Brown solid; yield 54%; m.p. 182-183 °C.
1H NMR (600 MHz, CDCl3, 25 °C) δ= 9.04 (s, 2H), 7.97 (d, J = 8.1 Hz,
4H), 7.34 (d, J = 8.1 Hz, 4H). 13C NMR (150 MHz, CDCl3, 25 °C) δ=
151.7, 140.2, 139.4, 134.0, 129.9, 127.0, 21.4. FT-IR (KBr, cm-1) ṽ=
3029, 2920, 1679, 1606, 1477, 1269, 1180, 819. GC-MS (EI, 70 eV) m/z
(%): 260 (M+, 100), 259 (15), 245 (4), 143 (2), 130 (4), 116 (37), 115 (46),
90 (3), 89 (6), 65 (2), 63 (2). HRMS (ESI) m/z calcd for C18H16N2
[M+Na]+: 283.1206; found: 283.1210.
2-Azido-1-(2-hydroxyphenyl)ethanone (2g).[28] Pale yellow solid; yield
95%; m.p. 75-76 °C. 1H NMR (400 MHz, CDCl3, 25 °C) δ= 11.61 (s, 1H),
7.55–7.49 (m, 2H), 7.03–7.01 (m, 1H), 6.94–6.90 (m, 1H), 4.58 (s, 2H).
13C NMR (100 MHz, CDCl3, 25 °C) δ= 198.5, 162.2, 137.2, 128.4, 119.3,
118.7, 117.1, 54.0. FT-IR (film, cm-1) ṽ= 3429, 2115, 1651. GC-MS (EI,
70 eV) m/z (%): 177 (M+, 3), 149 (9), 121 (100), 94 (18), 65 (23). HRMS
(ESI) m/z calcd for C8H7N3O2 [M+H]+: 178.0611; found: 178.0618.
2,5-Di(4-chlorophenyl)pyrazine (4c).[6] Orange solid; yield 55%; m.p.
173-174 °C. 1H NMR (600 MHz, CDCl3, 25 °C) δ= 9.05 (s, 2H), 8.04–
8.02 (m, 4H), 7.52–7.51 (m, 4H). 13C NMR (150 MHz, CDCl3, 25 °C) δ=
149.7, 140.9, 136.2, 134.5, 129.3, 128.0. FT-IR (KBr, cm-1) ṽ= 2922,
2852, 1466, 1409, 1159, 1098, 1017, 836, 825. GC-MS (EI, 70 eV) m/z
(%): 304 [(M+4)+, 11], 302 [(M+2)+, 65], 300 (M+, 100), 265 (13), 138 (27),
137 (17), 136 (78), 101 (18), 75 (12), 51 (4). HRMS (ESI) m/z calcd for
C16H10N2Cl2 [M+Na]+: 323.0113; found 323.0114.
2-Azido-1-(naphthalen-2-yl)ethanone (2h).[29] Pale yellow solid; yield
73%; m.p. 62-64 °C. 1H NMR (600 MHz, CDCl3, 25 °C) δ= 8.43–8.41 (m,
1H), 7.98–7.89 (m, 4H), 7.66–7.56 (m, 2H), 4.71 (s, 2H). 13C NMR (100
MHz, CDCl3, 25 °C) δ= 193.0, 135.9, 132.2, 131.5, 129.7, 129.5, 129.0,
128.9, 127.8, 127.1, 123.1, 54.9. FT-IR (film, cm-1) ṽ= 3062, 2980, 2905,
2099, 1676, 1624, 1466, 1355, 1274, 1215, 1003, 898, 850, 816, 772.
GC-MS (EI, 70 eV) m/z (%): 211 (M+, 5), 183 (11), 155 (92), 127 (100).
HRMS (ESI) m/z calcd for C12H9N3NO [M+Na]+ 234.0638; found
234.0631.
2,5-Di(2,5-dimethoxyphenyl)pyrazine (4d). Pale yellow solid; yield
84%; m.p. 208-210 °C. 1H NMR (400 MHz, CDCl3, 25 °C) δ= 9.28 (s, 2H),
7.53–7.52 (m, 2H), 6.99–6.97 (m, 4H), 3.87 (s, 6H), 3.86 (s, 6H); 13C
NMR (150 MHz, CDCl3, 25 °C) δ= 154.0, 151.5, 148.6, 145.3, 126.3,
116.7, 115.3, 112.9, 56.2, 55.8. FT-IR (KBr, cm-1) ṽ= 2998, 2937, 2832,
1584, 1505, 1476, 1462, 1313, 1262, 1210, 1177, 1048, 1018, 881, 806,
733. GC-MS (EI, 70 eV) m/z (%): 352 (M+, 100), 351 (38), 338 (11), 337
(57), 335 (23), 322 (12), 321 (32), 307 (34), 305 (12), 161 (21), 147 (14).
HRMS (ESI) m/z calcd for C20H20N2O4 [M+Na]+ 375.1315; found
375.1318.
General Procedure for the Synthesis of 2,5-Diarylpyrazines 4a–h. In
a 100 mL beker, Pd/C (1 mol%, 15 mg) was added to a suspension of α-
azido ketone 2 (1.5 mmol) in the ChCl/Gly (1:2 molꢀmol−1) (2.0 g) eutectic
mixture in a Parr autoclave. The autoclave was closed, and 3 atm of H2
was charged. The mixture was kept under stirring at RT for 6–24 h until
complete consumption of the starting material (monitored by thin layer
chromatography). After carefully releasing the hydrogen, the reaction
mixture was diluted with AcOEt (MeOH in the case of pyrazines 4d and
4h) (10 mL), and filtered through a Celite pack. Then, water was added,
and the mixture was extracted with AcOEt (3 x 10 mL). The collected
organic layers were dried using anhydrous Na2SO4, filtered, and the
volatile evaporated under reduced pressure to afford the crude product,
which was crystallised from EtOAc (compounds 4d, 4h) or purified by
column chromatography on silica gel (hexane/EtOAc 15:1) (compounds
4a–c, 4e–g) to afford pyrazine 4 (40–87% yield; see Table 2 and
Scheme 3).
2,5-Di[4-(N,N-diethylamino)phenyl]pyrazine (4e). Yellow waxy solid;
yield 71%. 1H NMR (600 MHz, CDCl3, 25 °C) δ= 8.90 (s, 2H), 7.92 (d, J
= 8.5 Hz, 4H), 6.78 (d, J = 8.5 Hz, 4H), 3.44 (q, J = 6.4 Hz, 8H) 1.23 (t, J
= 6.4 Hz, 12H); 13C NMR (150 MHz, CDCl3, 25 °C) δ= 149.1, 148.6,
139.7, 127.6, 123.4, 111.7, 44.4, 12.6. FT-IR (KBr, cm-1) ṽ= 2921, 1607,
1527, 1468, 1198, 817. GC-MS (EI, 70 eV) m/z (%): 374 (M+, 100), 359
(79), 315 (80), 253 (15), 172 (35), 158 (13). HRMS (ESI) m/z calcd for
C24H30N4 [M+Na]+: 397.2363; found 397.2366.
General Procedure for the One-pot, Two-step Synthesis of 2,5-
Diarylpyrazines 4a, 4b, 4d, and 4h. α-Halo carbonyl compound 1 (1a,
1c, 1e or 1i) (1.5 mmol) and NaN3 (107 mg, 1.65 mmol) were
2,5-Di(4-fluorophenyl)pyrazine (4f).[6] Brown orange solid; yield 87%;
m.p. 232-235 °C. 1H NMR (600 MHz, CDCl3, 25 °C) δ= 9.03 (s, 2H),
8.09–8.06 (m, 4H), 7.25–7.22 (m, 4H). 13C NMR (150 MHz, CDCl3,
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