A. Wróblewska et al. / Tetrahedron: Asymmetry 26 (2015) 1448–1452
1451
1459m, 1410m, 1274m, 1016m, 911m, 785m, 756m, 701m. 1H
NMR (CDCl3): d 7.50–7.42 (m, 3H, HC(arom.)), 7.32–7.29 (m, 2H,
HC(arom.)), 3.79–3.74 (m, 2H, H2C); 2.19 (s, 3H, H3C); 2.14 (s,
3H, H3C); 1.65–1.58 (m, 2H, H2C); 1.42–1.34 (m, 2H, H2C); 0.99–
0.94 (m, 3H, H3C). 13C NMR (CDCl3): d 137.2, 132.8 (C(5), C(4));
130.3 (2HC(arom.)); 129.2 (C(arom.)); 129.9, 128.9 (3HC(arom.));
90.4 (C–I); 47.8 (CH2); 32.4 (CH2); 19.6 (CH2); 13.4 (Me); 12.6
(Me). HR-ESI-MS (MeOH): 341.05092 (calcd 341.05239 for
(CH2); 13.6 (Me); 12.8 (Me); 8.9 (Me). HR-ESI-MS (MeOH):
177.13848 (calcd 177.13863 for C11H17N2, [M+1]+).
4.5.5. 1-Butyl-2-ethynyl-4-methyl-5-phenyl-1H-imidazole 6e
Yield: 0.099 g (42%). Pale yellow oil (Al2O3, AcOEt/hexane 3:7).
IR (film):
m 3336br, 2959m, 2123m, 1489m, 1460m, 1405m,
1377m, 1315m, 761m, 702m, 610m, 596m, 508m, 454m. 1H
NMR (CDCl3): d 7.47–7.43 (m, 2H, HC(arom.)); 7.41–7.38 (m, 1H,
HC(arom.)); 7.29–7.26 (m, 2H, HC(arom.)); 3.98–3.94 (m, 2H,
H2C); 3.34 (s, 1H, HC); 2.16 (s, 3H, Me); 1.55–1.49 (m, 2H, H2C);
1.19–1.12 (m, 2H, H2C); 0.77 (t, J = 7.2 Hz, 3H, Me). 13C NMR
(CDCl3): d 136.3, 130.1, 129.7, 129.5 (C(arom.), 3C(imid.)); 129.9,
128.7, 128.2 (5HC(arom.)); 80.9, 74.0 (C„C); 44.9 (CH2); 32.5
(CH2); 19.5 (CH2); 13.4 (Me); 13.2 (Me). HR-ESI-MS (MeOH):
239.15403 (calcd 239.15428 for C16H19N2, [M+1]+).
C
14H18N2I, [M+1]+).
4.5. General procedure for the synthesis of compounds 6
To a solution of the corresponding iodoimidazole 5 (1 mmol), Pd
(PPh3)4 (0.2 mmol), and CuI (0.4 mmol) in dry Et3N (5 mL),
trimethylsilylacetylene (1.2 mmol) was added dropwise. The mix-
ture was heated at 50 °C until the substrate was consumed (ca.
30 min). Next, the precipitate was filtered and washed with Et2O.
The solvent was evaporated and the crude product was purified
by column chromatography (Al2O3, AcOEt/hexane 1:9). The
obtained product was dissolved in dry THF and TBAF (1.5 equiv)
was added to the solution at À78 °C. After 20 min, H2O was added
to the mixture, which was then extracted with CH2Cl2 (3 Â 15 mL).
The organic layers were combined and dried over Na2SO4. After fil-
tration, the solvent was evaporated. Product 6 was purified by col-
umn chromatography (AcOEt/hexane 3:7).
4.6. General procedure for the synthesis of compounds 8
To a solution of the corresponding acetylene derivative 6
(1 mmol) and CuI (0.2 mmol) in acetonitrile (3 mL) under an argon
atmosphere, Et3N (3 mL) was added. After 15 min, to the yellow
reaction mixture was added dropwise azide 718 (1 mmol) in ace-
tonitrile (2 mL) and heated at 40 °C for 2 h. Next, H2O was added
and the mixture was extracted with CH2Cl2 (3 Â 15 mL). The
organic layers were combined and dried over Na2SO4. After filtra-
tion, the filtrate was concentrated under reduced pressure. The
residue was diluted in CH2Cl2 (3 mL) and trifluoroacetic acid
(1.5 equiv) in CH2Cl2 (2 mL) was added. After all the intermediate
was consumed (monitored by TLC), the solvent was evaporated
and the residue was dissolved in CH2Cl2 (4 mL). Next, NaHCO3
was added and the mixture was magnetically stirred for 5 h. The
solid was then filtered and the filtrate was concentrated by
evaporation in a rotary evaporator. The crude product 8 was puri-
fied by column chromatography.
4.5.1. 2-Ethynyl-1,4,5-trimethyl-1H-imidazole 6a
Yield: 0.069 g (52%). Pale yellow oil (Al2O3, AcOEt/hexane 3:7).
IR (KBr):
m 3111br, 2984m, 2098m, 1585m, 1466m, 1405m,
1378m, 1162m, 821m, 746m, 729m. 1H NMR (CDCl3): d 3.48 (s,
3H, Me); 3.23 (s, 1H, HC); 2.07 (s, 3H, Me); 2.05 (s, 3H, Me). 13C
NMR (CDCl3): d 134.5, 128.6, 124.6 (3C(imid.)); 80.6, 73.9 (C„C);
31.1 (Me); 12.7 (Me); 8.9 (Me). HR-ESI-MS (MeOH): 135.09162
(calcd 135.09167 for C8H11N2, [M+1]+).
4.6.1. 4-(1,4,5-Trimethyl-1H-imidazol-2-yl)-1-[((S)-pyrrolidin-2-
yl)methyl]-1,2,3-triazole 8a
4.5.2. 2-Ethynyl-1,4-dimethyl-5-phenyl-1H-imidazole 6b
Yield: 0.094 g (48%). Pale yellow oil (Al2O3, AcOEt/hexane 3:7).
Yield: 0.119 g (46%). Pale yellow oil (SiO2, CHCl3/MeOH 9:1). IR
IR (film):
m 3230br, 2918m, 2109m, 1566m, 1487m, 1449m,
1390m, 1018m, 762m, 707m, 655m, 635m. 1H NMR (CDCl3): d
7.48–7.44 (m, 2H, HC(arom.)); 7.41–7.37 (m, 1H, HC(arom.));
7.31–7.27 (m, 2H, HC(arom.)); 3.58 (s, 3H, Me); 3.36 (s, 1H, HC);
2.20 (s, 3H, Me). 13C NMR (CDCl3): d 136.2, 130.2, 130.0, 129.8 (C
(arom.), 3C(imid.)); 129.8, 128.7, 128.2 (5CH(arom.)); 81.3, 73.8
(C„C); 32.3 (Me); 13.4 (Me). HR-ESI-MS (MeOH): 197.10756
(calcd 197.10732 for C13H13N2, [M+1]+).
(film):
m 3399br, 2903m, 2824m, 1646m, 1582m, 1459m, 1289m,
1213m, 1013m, 856m, 748m, 618m. 1H NMR (CDCl3): d 8.22
(s, 1H, HC(triaz.)); 4.46–4.40 (m, 1H, HC); 4.34–4.28 (m, 1H,
H2C); 3.95 (s, 3H, Me); 3.69–3.63 (m, 1H, H2C); 3.04–2.94 (m,
2H, H2C); 2.21 (s, 3H, Me); 2.21 (s, 3H, Me); 2.01–1.94 (m, 1H,
H2C); 1.85–1.72 (m, 2H, H2C); 1.57–1.49 (m, 1H, H2C). 13C NMR
(CDCl3): d 141.2, 136.9, 133.2, 124.5 (3C(imid.), C(triaz.)); 123.1
(CH(triaz.)); 57.9 (CH); 55.3 (CH2); 46.4 (CH2); 32.1 (Me); 29.1
(CH2); 25.3 (CH2); 12.6 (Me); 8.8 (Me). HR-ESI-MS (MeOH):
4.5.3. 2-Ethynyl-1-methyl-4,5-diphenyl-1H-imidazole 6c
261.18240 (calcd 261.18222 for C13H21N6, [M+1]+). [
0.5, CH2Cl2).
a
]
25 = À26 (c
Yield: 0.126 g (49%). Pale yellow oil (Al2O3, AcOEt/hexane 3:7).
D
IR (KBr):
1478m, 1461m, 1447m, 1387m, 1073m, 964m, 778m, 756m,
697m. 1H NMR (CDCl3):
7.53–7.47 (m, 5H, HC(arom.));
m 3299br, 2924m, 2853m, 2118m, 1599m, 1504m,
4.6.2. 4-(1,4-Dimethyl-5-phenyl-1H-imidazol-2-yl)-1-[((S)-
pyrrolidin-2-yl)methyl]-1,2,3-triazole 8b
d
7.38–7.34 (m, 2H, HC(arom.)); 7.24–7.16 (m, 3H, HC(arom.));
3.57 (s, 3H, Me); 3.44 (s, 1H, HC). 13C NMR (CDCl3): d 138.6,
133.9, 130.8, 130.3, 130.2 (2C(arom.), 3C(imid.)); 130.6, 129.1,
128.9, 128.1, 126.9, 126.7 (10CH(arom.)); 81.8, 73.6 (C„C); 32.1
(Me). HR-ESI-MS (MeOH): 259.12283 (calcd 259.12298 for
Yield: 0.197 g (61%). Pale yellow oil (SiO2, CHCl3/MeOH 9:1). IR
(film):
m 3420br, 2925m, 2854m, 2468m, 1683m, 1635m, 1480m,
1312m, 1203m, 1177m, 1131m, 1048m, 1017m, 833m, 801m,
721m, 703m. 1H NMR (CDCl3): d 8.53 (s, 1H, HC(triaz.)); 7.37–
7.30 (m, 3H, HC(arom.)); 7.16–7.13 (m, 2H, HC(arom.)); 4.71–
4.58 (m, 2H, H2C); 4.01–3.94 (m, 1H, HC); 3.52 (s, 3H, Me); 3.32–
3.25 (m, 1H, H2C); 3.16–3.09 (m, 1H, H2C); 2.16 (s, 3H, Me);
2.16–2.08 (m, 1H, H2C); 2.06–1.97 (m, 1H, H2C); 1.94–1.85 (m,
1H, H2C); 1.79–1.69 (m, 1H, H2C). 13C NMR (CDCl3): d 139.8,
138.9, 134.9, 130.6, 130.1, 129.5, 128.8, 128.1 (C(arom.), 3C(imid.),
C(triaz.), 5CH(arom.)); 123.2 (CH(triaz.)); 59.9 (CH); 52.9 (CH2);
45.6 (CH2); 32.9 (Me); 28.7 (CH2); 24.1 (CH2); 12.8 (Me). HR-ESI-
MS (MeOH): 323.19803 (calcd 323.19787 for C18H23N6, [M+1]+).
C
18H15N2, [M+1]+).
4.5.4. 1-Butyl-2-ethynyl-4,5-dimethyl-1H-imidazole 6d
Yield: 0.089 g (51%). Pale yellow oil (Al2O3, AcOEt/hexane 3:7).
IR (film):
m 3428br, 2958m, 2872m, 2112m, 1735m, 1578m,
1467m, 1410m, 1369m, 1214m, 1007m, 830m, 704m. 1H NMR
(CDCl3): d 3.94–3.89 (m, 2H, H2C); 3.28 (s, H, HC); 2.14 (s, 3H,
Me); 2.13 (s, 3H, Me); 1.70–1.64 (m, 2H, H2C); 1.39–1.32 (m, 2H,
H2C); 0.94 (t, J = 7.2 Hz, 3H, Me). 13C NMR (CDCl3): d 134.7, 128.4,
123.9 (3C(imid.)); 80.3, 74.2 (C„C); 44.6 (CH2); 32.6 (CH2); 19.8
[a
]
25 = À19 (c 0.625, CH2Cl2).
D