Journal of Medicinal Chemistry
ARTICLE
not as cytotoxic as the 1,2-dialkynylimidazoles 1a,d, and e, the
N-ethynylimidazole 6b is at least as cytotoxic as the other 1,2-
dialkynylimidazoles examined. Interestingly, the N-ethynyl group
of the 1,2-dialkynylimidazole 1a was found to react selectively with
thiophenol, and this addition abrogates the cytotoxicity of this
compound. This unexpected electrophilic nature of the imidazole
N-ethynyl group bears further study, as it stands in contrast
with the established role of related N-alkynyl heterocycles and
N-alkynylamides as electron-rich, nucleophilic species.51 In light of
this reactivity and the lack of DNA cleavage ability, the 1,2-
dialkynylimidazoles and 1-alkynylimidazoles may have more in
commonwith otherheterocyclic, thiol-reactive anticancer agents52
than the enediyne natural products or recently reported DNA-
cleaving cytotoxic lysineꢀacetylene conjugates.53 Interestingly,
certain 1,2-dialkynylimidazoles such as 1a and 1e are notably
more cytotoxic against A549 cells than thiol-reactive heterocycles
currently in clinical trials.54 Thus, the potential of N-ethynylimi-
dazoles to react with biological thiols deserves further investiga-
tion, and studies exploring this possibility are ongoing.
EtOAc/hexane), 128 mg of 1b (75%) was obtained as a white solid. mp
82ꢀ84 ꢀC; 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 9H), 3.17 (s, 1H),
7.04 (d, 1H, J = 1.4 Hz), 7.14 (d, 1H, J = 1.4 Hz), 7.37 (dt, 2H, J = 8.6,
2.0 Hz), 7.51 (dt, 2H, J = 8.6, 2.0 Hz). 13C NMR (100 MHz, CDCl3)
δ 31.1, 34.9, 61.8, 77.0, 71.1, 94.3, 118.2, 122.3, 125.5, 129.7, 131.9,
135.9, 153.1. IR (KBr) 3296, 2960, 2868, 2216, 2161, 1529, 1464, 1402,
1274, 1106, 835 cmꢀ1; MS (CI) 249 (M+1, 100%). HRMS (CI) calc for
C17 H17 N2 (M + H+) 249.1392; found, 249.1392. Anal. Calcd. for C17
H17 N2: C, 82.22; H, 6.49; N, 11.28. Found: C, 82.31; H, 6.42; N, 11.22.
2-(4-Acetylphenylethynyl)-1-ethynyl-imidazole (1d). Fol-
lowing the general procedure above (flash chromatography; 0ꢀ5% EtOAc/
hexane), 100 mg of 1d (73%) was obtained as a tan solid; mp
1
176ꢀ177 ꢀC; H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H), 3.22 (s,
1H), 7.09 (d, 1H, J = 1.6 Hz), 7.19 (d, 1H, J = 1.6 Hz), 7.66 (d, 2H, J =
8.7 Hz), 7.94 (d, 2H, J = 8.7 Hz. 13C NMR (100 MHz, CDCl3) δ 197.1,
137.2, 135.1, 132.1, 130.1, 128.3, 125.9, 122.8, 92.9, 80.1, 77.2, 62.2, 25;
IR (KBr) 3207, 3153, 2120, 1672, 1400, 1271, 1109, 835 cmꢀ1; MS (CI)
235 (M+1, 100%). HRMS (CI) calc for C15 H11 N2 O (M + H+)
235.0871; found, 235.0874. Anal. Calcd. for C15 H10 N2 O: C, 76.91; H,
4.30; N, 11.96. Found: C, 76.40; H, 4.45; N, 11.60.
2-(4-Nitrophenylethynyl)-1-ethynylimidazole (1e). Follow-
ing the general procedure above (flash chromatography; 0ꢀ5% EtOAc/
hexane), 77 mg of 1e (71%) was obtained as a yellow solid; mp
160ꢀ162 ꢀC; 1H NMR (400 MHz, CDCl3) δ 3.24 (s, 1H), 7.10
(d, 1H, J = 1.2 Hz), 7.21 (d, 1H, J = 1.2 Hz), 7.37 (d, 2H, J = 9.0 Hz), 7.51
(d, 2H, J = 9.0 Hz). 13C NMR (100 MHz, CDCl3) δ 62.4, 70.6, 81.8,
91.6, 123.2, 123.7, 127.9, 130.4, 132.7, 134.5, 147.8. IR (KBr) 3244,
2360, 1593, 1511, 1456, 1402, 1275, 1107, 856 cmꢀ1; MS (CI) 238
(M+1, 100%). HRMS (CI) calc for C13 H8 N3 O2 (M + H+) 238.0617;
found, 238.0617. Anal. Calcd. for C13 H7 N3 O2: C, 65.82; H, 2.97; N,
17.71. Found: C, 65.65; H, 2.94; N, 17.66.
2-(3,5-Bis(trifluoromethyl)phenylethynyl)-1-ethynyl-imi-
dazole (1g). Following the general procedure above (flash chroma-
tography; 0ꢀ5% EtOAc/hexane), 124 mg of 1g (68%) was obtained as a
tan solid; mp 73.2ꢀ74.1 ꢀC; 1H NMR (400 MHz, CDCl3) δ 3.26 (s,
1H), 7.11 (d, 1H, J = 1.6 Hz), 7.21 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.98
(s, 2H). 13C NMR (100 MHz, CDCl3) δ 7134.3, 132.3 (q, 2C, J = 34
Hz), 131.9, 130.4 (2C), 123.2, 123.0 (q, 2C, J = 270 Hz), 122.9 (q, J =
5 Hz), 90.3, 80.3, 70.5, 62.4. IR (KBr) 2913, 2856, 2164, 1525, 1408,
1369, 1281, 1180, 1136, 899 cmꢀ1; MS (CI) 329 (M+1, 100%). HRMS
(CI) calc for C15 H7 N2 F6 (M+H+) 329.0513; found, 329.0513. Anal.
Calcd. for C15 H6 N2 F6: C, 54.89; H, 1.84; N, 8.54. Found: C, 54.68; H,
1.76; N, 8.56.
3-(1-(3-Hydroxypropyn-1-yl)-1H-imidazol-2-yl)-prop-2-yn-
1-ol (1j). The general procedure above was followed at room tempera-
ture, and the reaction mixture was quenched after 3 h with H2O (0.2 mL).
After removal of the solvent under reduced pressure, the crude was
subjected to flash chromatography without extraction (flash chromatog-
raphy; 0ꢀ2% MeOH/EtOAc) to afford 36 mg of 1j (41%) as a white
solid. mp 105ꢀ107 ꢀC; 1H NMR (400 MHz, MeOD-d4) δ 7.40 (1H, d,
J = 1.5 Hz), 7.02 (1H, d, J = 1.5 Hz), 4.45 (2H, s), 4.40 (2H, s). 13C NMR
(100 MHz, MeOD-d4) δ 136.1, 129.9, 124.8, 95.3, 73.8, 73.4, 73.0, 50.9,
50.4. IR (KBr) 3322, 3148, 3125, 2358, 2273, 1525, 1471, 1420, 1303,
1130, 1034 cmꢀ1; MS (ESI) 375 (2M+23, 100%). HRMS (ESI) calc for
C9 H9 N2 O2 (M + H+) 177.0654; found, 177.0658.
1,2-Diethynyl-4-phenyl-1H-imidazole (1k). Following the
general procedure above (flash chromatography; 0ꢀ5% EtOAc/hexane),
76 mg of 1k (79%) was obtained as a white solid. mp 62ꢀꢀ64 ꢀC; 1H
NMR (400 MHz, CDCl3) δ 7.77ꢀ7.75 (2H, m), 7.42ꢀ7.37 (3H, m),
7.33ꢀ7.28 (1H, m), 3.44 (1H, s), 3.24 (1H, s). 13C NMR (100 MHz,
CDCl3) δ 142.1, 134.3, 131.8, 128.7 (2C), 128.1, 125.4 (2C), 117.6, 82.6,
71.6, 70.5, 62.2. IR (KBr) 3389, 3294, 3141, 2598, 2163, 2113, 1494, 1450,
1394, 1189, 1151, 748, 691 cmꢀ1; MS (CI) 193 (M+1, 100%). HRMS
(CI) calc for C13 H9 N2 (M + H+) 193.0768; found, 193.0766. Anal. calcd
’ EXPERIMENTAL SECTION
General. All reactions were carried out under argon in oven-dried
glassware with magnetic stirring. Unless otherwise noted, all materials
were obtained from commercial suppliers and were used without further
purification. THF was distilled from sodium/benzophenone prior to
use. Flash chromatography was performed with EM Reagent silica gel
(230ꢀ400 mesh) using the mobile phase indicated. Melting points
(open capillary) are uncorrected. Unless otherwise noted, 1H and 13
C
NMR spectra were determined in CDCl3 on a spectrometer operating at
400 and 100 MHz, respectively, and are reported in ppm using solvent as
the internal standard (7.26 ppm for 1H and 77.0 ppm for 13C in CDCl3).
Mass spectra were obtained in the positive mode either by chemical
ionization using methane as the ionizing gas or by electrospray ioniza-
tion. The purity of all test compounds was determined to by >95%
by HPLC.
Typical Procedure for the Synthesis of 1,2-Dialkynylimi-
dazoles: 1-Ethynyl-2-(2-(4-methoxyphenyl)-ethynyl)-1H-ben-
zimidazole (1p). To a solution of 2-iodo-1-(2-triisopropylsilylethyn-
yl)-1H-benzimidazole 4g (212 mg, 0.5 mmol) in Et3N (10 mL) under
argon was added 4-ethynylanisole (0.075 mL, 0.55 mmol), Pd(PPh3)4
(30 mg, 0.026 mmol), and CuI (10 mg, 0.05 mmol). The reaction
mixture was stirred at 50 ꢀC until complete consumption of 4g. The
solvent was removed under reduce pressure, and the residue was purified
by flash chromatography (0ꢀ5% EtOAc/hexane) to afford 210 mg
(98%) of the TIPS-protected compound as a yellow crystalline solid. To
this material in THF (10 mL) at ꢀ78 ꢀC was added TBAF (0.5 mL of
1 M solution in THF, 0.5 mmol), and the mixture was stirred at ꢀ78 ꢀC
until completion. The reaction mixture was quenched at ꢀ78 ꢀC with
10 mL of water and extracted with CH2Cl2 (3 ꢁ 25 mL). The organic
layers were combined and dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The residue was purified by flash
chromatography (0ꢀ20% EtOAc/hexane) to afford 122 mg (92%) of
compound 1p as a white solid. mp 140.1ꢀ141.3 ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7 75 (d, J = 7.4 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.50 (d, J =
8.8 Hz, 2H), 7.37 (p, J = 7.6 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 3.81 (s,
3H), 3.46 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 160.9, 141.7, 138.8,
134.6, 134.0, 125.2, 124.6, 120.4, 114.2, 112.5, 110.7, 96.6, 79.9, 69.7,
64.4, 55.3. MS (CI) 273 (M+1, 100%). HRMS calc for C18H13N2O
(M+H+) 273.1028, found 273.1028. Anal. Calcd. for C18H12N2O: C,
79.39; H, 4.44; N, 10.20. Found: C, 79.35; H, 4.27; N, 10.18
2-(4-tert-Butylphenylethynyl)-1-ethynylimidazole (1b).
Following the general procedure above (flash chromatography; 0ꢀ5%
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dx.doi.org/10.1021/jm200289j |J. Med. Chem. 2011, 54, 5059–5069