The Journal of Organic Chemistry
ARTICLE
NMR (200 MHz, DMSO-d6) δ 6.16 (d, J = 4.6 Hz, 1H), 6.49 (d, J = 4.8
Hz, 1H), 7.41ꢀ7.59 (m, 5H), 7.75ꢀ7.86 (m, 3H), 8.58 (s, 1H);
13C NMR (50 MHz, CDCl3) δ 65.0, 119.7, 120.5, 127.6, 128.9, 128.9,
129.2, 129.7, 132.7, 134.2, 136.7, 138.0, 150.0; ESI-MS (m/z) calcd for
C15H12N3OCl2 [M þ H]þ 320.0352, found 320.0357.
Hz), 133.4, 150.4, 162.0 (d, J = 245 Hz); ESI-MS m/z calcd for
C10H11N3F [M þ H]þ 192.0932, found 192.0935.
4-Ethyl-1-(4-methoxyphenyl)-1H-1,2,3-triazole (17): pale
yellow solid (100%); mp = 63 °C (n-hexane; colorless fine crystals);
1H NMR (200 MHz, CDCl3) δ 1.22 (t, J = 7.5 Hz, 3H), 2.70 (q, J = 7.6
Hz, 2H), 3.72 (s, 3H), 6.86 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H),
7.60 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 13.4, 18.8, 55.3, 114.3,
118.5, 121.6, 130.4, 150.0, 159.2; ESI-MS m/z calcd for C11H14N3O
[M þ H]þ 204.1131, found 204.1137.
General Procedure for Synthesis of Triazoles 7ꢀ11,
15ꢀ17, 19, and 21. L-Proline (16 mg, 20 mol %, 0.14 mmol),
CuSO4 5H2O (17 mg, 10 mol %, 0.068 mmol), sodium ascorbate (27
3
mg, 20 mol %, 0.14 mmol), NaN3 (67 mg, 1.5 equiv, 1.0 mmol), K2CO3
(114 mg, 1.20 equiv, 0.825 mmol), alkynoic acid (1.0 equiv, 0.69 mmol),
aryl (alkenyl) iodide (1.0 equiv, 0.69 mmol), DMSO (2.25 mL), and
water (0.25 mL) were sequentially added to a 4 mL vial. The vial was
closed with a screw-cap containing a once-perforated septum, enabling
release of overpressure. The mixture was stirred slowly (250 rpm) at
65 °C for 20ꢀ24 h and then added to a mixture of concd NH4OH
(5 mL), water (10 mL), and ethyl acetate (40 mL). The aqueous phase
was extracted with ethyl acetate (20 mL), and the combined organic
extracts were washed with brine (4 ꢁ 10 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford the corre-
sponding triazole.
4-(4-Ethyl-1H-1,2,3-triazol-1-yl)-2-fluoroaniline (19): brown
oil (94%); 1H NMR (200 MHz, CDCl3) δ 1.31 (t, J = 7.6 Hz, 3H), 2.80
(q, J = 7.6 Hz, 2H), 3.95 (bs, 2H), 6.84 (dd, J = 8.8, 8.8 Hz, 1H), 7.21ꢀ7.27
(m, 1H), 7.39 (dd, J = 2.4, 11.4 Hz, 1H), 7.59 (s, 1H) ; 13C NMR (50 MHz,
CDCl3) δ 13.4, 18.8, 108.5 (d, J = 23.0 Hz), 116.5 (d, J = 5.0 Hz), 116.6 (d,
J = 3.0 Hz), 118.5, 127.9 (d, J = 9.0 Hz), 135.1 (d, J = 12.5 Hz), 150.1, 150.7
(d, J = 240 Hz); ESI-MS m/z calcd for C10H12N4F [M þ H]þ 207.1041,
found 207.1044.
(E)-4-Ethyl-1-(oct-1-enyl)-1H-1,2,3-triazole (21): yellow li-
1
quid (99%); H NMR (200 MHz, CDCl3) δ 0.88 (m, 3H), 1.27 (m,
9H), 1.45 (m, 2H), 2.20 (ddt, J = 1.4, 7.2, 7.2 Hz, 2H), 2.75 (q, J = 7.6 Hz,
2H), 6.13 (dt, J = 7.4, 14.2 Hz, 1H), 7.07 (dt, J = 1.4, 14.4 Hz, 1H), 7.46
(s, 1H); 13C NMR (50 MHz, CDCl3) δ 13.4, 13.8, 18.8, 22.3, 28.5, 28.7,
29.4, 31.4, 117.2, 122.3, 124.1, 149.6; ESI-MS m/z calcd for C12H22N3
[M þ H]þ 208.1808, found 208.1817.
1-Phenyl-1H-1,2,3-triazole (7):7 pale brown solid (61%);
1
mp =53 °C (n-hexane; colorless fine crystals); H NMR (200 MHz,
CDCl3) δ 7.39ꢀ7.56 (m, 3H), 7.72ꢀ7.76 (m, 2H), 7.84 (s, 1H), 8.00 (s,
1H); 1H NMR (200 MHz, DMSO-d6) δ 7.45ꢀ7.64 (m, 3H), 7.89ꢀ7.93
(m, 2H), 7.98 (s, 1H), 8.83 (s, 1H); MS (EI) m/z 145.04 [Mþ]; ESI-MS
(m/z) calcd for C8H8N3 [M þ H]þ 146.0713, found 146.0712.
4-Methyl-1-phenyl-1H-1,2,3-triazole (8):25 yellow solid
(95%); mp = 69ꢀ71 °C (petroleum ether; colorless needles); 1H
NMR (200 MHz, CDCl3) δ 2.44 (s, 3H), 7.37ꢀ7.54 (m, 3H),
7.69ꢀ7.73 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 10.7, 119.3,
120.2, 128.3, 129.5, 137.0, 143.9; MS (EI) m/z 159.05 [Mþ]; ESI-MS
(m/z) calcd for C9H10N3 [M þ H]þ 160.0869, found 160.0867.
4-Ethyl-1-phenyl-1H-1,2,3-triazole (9): yellow liquid (97%);
1H NMR (200 MHz, CDCl3) δ 1.34 (t, J = 7.6 Hz, 3H), 2.84 (q, J = 7.6
Hz, 2H), 7.37ꢀ7.54 (m, 3H), 7.68ꢀ7.74 (m, 3H); 13C NMR (50 MHz,
CDCl3) δ 13.5, 18.9, 118.4, 120.1, 128.2, 129.5, 137.1, 150.3; MS (EI)
m/z 173.09 [Mþ]; ESI-MS m/z calcd for C10H12N3 [M þ H]þ
174.1026, found 174.1028.
1-Phenyl-1H-1,2,3-triazole-4-carboxylic acid (13). CuSO4
3
5H2O (20 mg, 5 mol %, 0.081 mmol), sodium ascorbate (32 mg, 10 mol
%, 0.16 mmol), water (0.5 mL), azidobenzene (207 mg, 1.0 equiv, 1.63
mmol; 94% purity), t-BuOH (0.5 mL), and propiolic acid (127 μL, 1.2
euiv., 1.96 mmol; 95% purity) were sequentially added to a 4 mL vial.
The vial was closed with a screw-cap containing a septum. The mixture
was mildly stirred (250 rpm) at rt for 21 h. It was then quenched with
satd NaHCO3 (25 mL), washed with diisopropyl ether (20 mL),
acidified with 0.5 M aq solution of H2SO4 ,and extracted with ethyl
acetate (80 mL and 2 ꢁ 40 mL). The combined organic solutions were
dried over Na2SO4, filtered, and concentrated under reduced pressure to
afford acid 13 as a pale yellow solid (309 mg, 100%): mp = 132ꢀ134 °C
1
(toluene/n-hexane); H NMR (200 MHz, DMSO-d6) δ = 7.48ꢀ7.65
(m, 3H), 7.97 (d, J = 7.6 Hz, 2H), 9.40 (s, 1H), 13.34 (s, 1H); 13C NMR
(50 MHz, acetone-d6) δ = 122.4, 128.4, 131.0, 131.6, 138.5, 142.3,
162.7; ESI-MS m/z calcd for C9H8N3O2 [M þ H]þ 190.0611, found
190.0620.
4-Propyl-1-phenyl-1H-1,2,3-triazole (10): pale brown amor-
phous solid (96%); 1H NMR (200 MHz, CDCl3) δ 0.95 (t, J = 7.4 Hz,
3H), 1.76 (sextet, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 7.29ꢀ7.46
(m, 3H), 7.64ꢀ7.72 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 13.6, 22.4,
27.4, 118.7, 120.0, 128.1, 129.4, 137.0, 148.7; MS (EI) m/z = 187.08
[Mþ]; ESI-MS m/z calcd for C11H14N3 [M þ H]þ 188.1182, found
188.1186.
4-Pentyl-1-phenyl-1H-1,2,3-triazole (11): yellow oil (95%);
1H NMR (200 MHz, CDCl3) δ 0.91 (t, J = 6.9 Hz, 3H), 1.35ꢀ1.42 (m,
4H), 1.74 (m, 2H), 2.79 (t, J = 7.7 Hz, 2H), 7.37ꢀ7.54 (m, 3H),
7.70ꢀ7.75 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 13.8, 22.2, 25.4,
28.9, 31.2, 118.7, 120.1, 128.2, 129.4, 137.0, 148.9; MS (EI) m/z =
215.12 [Mþ]; ESI-MS m/z calcd for C13H18N3 [M þ H]þ 216.1495,
found 216.1501.
General Procedure for Synthesis of Triazoles 18 and 20.
The reaction was setup as above, but 2.20 equiv (208 mg, 1.51 mmol) of
K2CO3 was used. Workup: the mixture was added to a solution of 0.5 M
H2SO4 (6 mL), brine (9 mL), and ethyl acetate (40 mL). The aqueous
phase was extracted with ethyl acetate (20 mL), and the combined
organic extracts were washed with brine (4 ꢁ 10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure to afford the
corresponding triazole.
4-(4-Ethyl-1H-1,2,3-triazol-1-yl)benzoic acid (18): pale
brown solid (98%); mp = 280ꢀ284 °C (EtOH; sublimation upon
heating); 1H NMR (200 MHz, DMSO-d6) δ 1.27 (t, J = 7.6 Hz, 3H),
2.74 (q, J = 7.6 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H),
8.70 (s, 1H), 13.21 (bs, 1H); 13C NMR (50 MHz, DMSO-d6) δ 13.3,
18.5, 119.3, 119.7, 130.2, 131.0, 139.7, 149.9, 166.4; ESI-MS m/z calcd
for C11H12N3O2 [M þ H]þ 218.0924, found 218.0920.
4-Ethyl-1-(2-methylphenyl)-1H-1,2,3-triazole (15): pale
1
green oil (97%); H NMR (200 MHz, CDCl3) δ 1.35 (t, J = 7.5 Hz,
3H), 2.21 (s, 3H), 2.85 (q, J = 7.6 Hz, 2H), 7.30ꢀ7.39 (m, 4H), 7.47 (s,
1H); 13C NMR (50 MHz, CDCl3) δ 13.4, 17.6, 18.7, 121.7, 125.6, 126.4,
129.3, 131.1, 133.3, 136.5, 149.3; ESI-MS m/z calcd for C11H14N3 [M þ
H]þ 188.1182, found 188.1186.
4-Ethyl-1-(4-fluorophenyl)-1H-1,2,3-triazole (16): pale yel-
low solid (100%); mp =74ꢀ75 °C (n-hexane; pale brown needles); 1H
NMR (200 MHz, CDCl3) δ 1.26 (t, J = 7.6 Hz, 3H), 2.75 (q, J = 7.6 Hz,
2H), 7.11 (m, 2H), 7.59ꢀ7.66 (m, 2H), 7.68 (s, 1H); 13C NMR (50
MHz, CDCl3) δ 13.4, 18.8, 116.3 (d, J = 25 Hz), 118.6, 122.1 (d, J = 10
5-(4-Ethyl-1H-1,2,3-triazol-1-yl)-2-hydroxybenzoic acid
1
(20): pale brown solid (91%); mp = 229ꢀ234 °C (EtOH/H2O); H
NMR (200 MHz, DMSO-d6) δ 1.22 (t, J = 7.6 Hz, 3H), 2.67 (q, J = 7.6
Hz, 2H), 7.08 (d, J = 9.0 Hz, 1H), 7.92 (dd, J = 2.6, 8.8 Hz, 1H), 8.17
(d, J = 2.6 Hz, 1H), 8.44 (s, 1H), 11.76 (bs, 2H); 13C NMR (50 MHz,
DMSO-d6): δ = 13.5, 18.6, 113.9, 118.4, 119.7, 121.4, 127.1, 128.8,
149.5, 160.7, 171.2; ESI-MS m/z calcd for C11H12N3O3 [M þ H]þ
234.0873, found 234.0885.
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dx.doi.org/10.1021/jo1024927 |J. Org. Chem. 2011, 76, 2613–2618