European Journal of Medicinal Chemistry xxxxx
137.4 (C), 136.5 (C), 134.0 (C), 131.8 (C), 128.9 (C), 128.6
3
= 14.2, 3.4 Hz, 1H, N-CH ), 4.04 (dd, J = 14.1A, 7C.1 CHzE, 1PHT, EN-D MANUSCRIPT
2
CH2). 13C NMR: (75.4 MHz, DMSO-D6) δ = 138.61 (C),
137.68 (C), 132.69 (C-Cl), 131.75 (C-Cl), 129.33 (C), 128.36
(C), 127.91 (C), 127.40 (C), 119.96 (C), 68.65 (CH-OH), 51.58
(CH2) ppm. MS [EI+] m/z (%): 257 (M+), 239 (2), 221 (56),
175 (58), 147 (13), 113 (8), 108 (54), 82 (100), 69 (81), 54
(39), 52 (8).
(C), 127.8 (C), 127.5 (C), 127.0 (C), 126.2 (C), 123.9 (C),
123.1 (C), 120.8 (C), 113.5 (C), 69.4 (CH), 64.6 (CH2-O), 60.3
(CH2-OH), 52.9 (CH2-N) ppm. MS [EI+] m/z (%): 376 (M+),
257 (78), 220 (43), 203 (24), 176 (64), 167 (16), 147 (85), 139
(34), 125 (27), 112 (94), 89 (34), 80 (100), 57 (40), 43 (65), 41
(60).
6.2.3 1-(2-(2,4-dichlorophenyl)-2-(3,4-dimethoxyphenethoxy)
ethyl)-1H-imidazole (8).
6.2.6.
2-(2-chlorophenyl)-2-(1-(2,4-dichlorophenyl)-2-(1H-
imidazol-1-yl)ethoxy)acetic acid (11)
To a solution of alcohol 3 (0.257 g, 1.0 mmol) in anhydrous
DMF (3.0 mL) was added NaH (2.0 mmol, 0.048 g, 60% in
mineral oil) at room temperature under nitrogen atmosphere,
and the reaction mixture was stirred for 20 min. Then, alkyl
halide 4 (0.292 g, 1.0 mmol) dissolved in 2 mL of anhydrous
DMF was added dropwise and the reaction mixture was stirred
for 24 h at room temperature, at which time TLC indicated the
disappearance of the starting materials. Brine ( 40 mL) was
added to the reaction mixture, which was washed with EtOAc
(3×10 mL). The organic layer was dried over (anhydrous
Na2SO4) and the solvent evaporated under reduced pressure.
Flash column chromatography afforded the yellow oil 8 (0.282
g, 67%). Rf: 0.77 (EtOAc/Hex 3/7). 1H NMR: (300 MHz,
CDCl3) δ = 7.72 (d, J = 1.7 Hz, 1H, N=CH-N), 7.57-7.55 (m,
3H), 7.21-6.96 (m, 5H), 5.20 (t, J = 3.54 Hz, 1H, CH-O), 4.27
(dd, J = 3.1, 13.9 Hz, 1H, CH-O), 4.12 (dd, J = 7.0, 13.9 Hz,
1H, CH2-N), 3.90 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.45 (s,
2H, CH2), 2.62 (t, J = 1.8 Hz, 2H, CH2) ppm. 13C NMR: (75.4
MHz, CDCl3) δ = 148.8 (C), 147.4 (C), 139.7 (C), 137.6 (C),
136.3 (C), 135.7 (C), 133.8 (C), 131.8 (C), 130.6 (C), 128.7
(C), 127.4 (C), 122.6 (C), 119.3 (C), 111.6 (C), 111.0 (C), 75.0
(CH-O), 69.3 (CH2-O), 55.8 (CH2-N), 53.4 (OCH3), 52.7
(OCH3), 36.3 (CH2) ppm. MS [EI+] m/z (%): 420 (M+), 256
(23), 223 (94), 222 (85), 203 (19), 176 (81), 147 (93), 112 (96),
91 (58), 84 (100), 63 (43), 51 (90), 41 (59).
Following the synthetic procedure for 8, compound 3 (0.257
g, 1.0 mmol) and 7 (0.249 g, 1 mmol) were coupled. The crude
exctract was purified by column chromatography eluting with
AcOEt/hexane 3/7 to afford the yellow solid 11 (0.154 g,
41%). m.p. 116-118 °C. 1H NMR: (300 MHz, CDCl3) δ = 7.55
(dd, J = 8.5, 3.1 Hz, 3H), 7.44-7.43 (m, 1H), 7.38 (d, J = 2.0
Hz, 3H), 7.30-7.24 (m, 3H), 5.30 (s, 1H, CH), 5.26–5.25 (m,
1H, CH-C=O), 4.18 (dd, J = 3.0, 15.0 Hz, 1H), 3.91 (dd, J =
7.5, 14.1 Hz, 1H) ppm. 13C NMR: (77 MHz, CDCl3) δ = 172.8
(C=O), 142.9 (C), 141.8 (C), 138.3 (C), 137.4 (C), 135.6 (C),
134.7 (C), 133.1 (C), 132.2 (C), 131.9 (C), 130.4 (C), 128.6
(C), 128.5 (C), 128.3 (C), 127.5 (C), 125.2 (C), 72.6 (CH-
C=O), 69.5 (CH-O), 53.3 (CH2-N) ppm. MS [EI+] m/z (%):
424 (M+), 257 (51), 220 (44), 203 (23), 176 (63), 147 (92), 112
(94), 89 (34), 80 (85), 57 (66), 43 (100), 41 (84).
Acknowledgments
Financial support from UAEMex (project No.
3804/2014/CID) and CONACYT-Mexico (postgraduate
scholarship 273644) is gratefully acknowledged. The authors
would like to thank the referee for valuable comments and
suggestions, Signa S.A. de C.V. for some graciously donated
solvents and reagents, M.N. Zavala-Segovia and L. Triana-
Cruz (CCIQS UAEMex‒UNAM) for technical support, and
Dr. E. Díaz-Torres for his helpful advice.
6.2.4. Methyl 4-((1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)
ethoxy)methyl)benzoate (9).
Supplementary Material
Following the synthetic procedure for 8, compound 3 (0.257
g, 1.0 mmol) and 5 (0.229 g, 1 mmol) were coupled. The crude
extract was purified by column chromatography eluting with
AcOEt/hexane 3/7 to afford the yellow oil 9 (0.121 g, 53%).
Supplementary material associated with this article
(determination of sensitivity to synthesized antifungal
compounds, characterization data for all compounds and
1
Rf: 0.48 (EtOAc/Hex 3/7). H NMR: (300 MHz, CDCl3) δ =
1
copies of H–NMR and 13C–NMR spectra) can be found in the
8.14 (s, 1H, N=CH-N), 7.75-7.65 (m, 3H), 7.54 (s, 2H), 7.48-
7.41 (m, 4H), 5.41 (d, J = 7.7 Hz, 1 H, CH-O), 4.41-4.34 (m,
2H, O-CH2), 4.26 (dd, J = 13.4, 7.2 Hz, 1H), 4.09-4.02 (m,
1H), 3.02 (s, 3H, CH3) ppm. 13C NMR: (75.4 MHz, CDCl3) δ =
162.4 (C=O), 143.3 (C), 142.0 (C), 139.4 (C), 139.2 (C), 138.1
(C), 136.9 (C), 134.2 (C), 132.3 (C), 131.8 (C), 130.7 (C),
128.9 (C), 128.4 (C), 127.6 (C), 123.3 (C), 118.7 (C), 74.6
(CH-O), 69.5 (CH2-O), 56.2 (CH2-N), 53.1 (CH3) ppm.
MS [EI+] m/z (%): 404 (M+), 279 (8), 221 (22), 175 (26), 167
(21), 149 (65), 113 (26), 111 (56), 81 (100), 57 (86), 43 (81) 41
(55).
online version.
References and notes
(1) Grudzien, M.; Król, A.; Paterek, G.; Stepien, K.; Plucinski, F.;
Mazurek, A. P. Eur. Med. Chem. 2009, 44, 1978–1981.
(2) (a) Ji, H.; Zhang, W.; Zhang, M.; Kudo, M.; Aoyama, Y.;
Yoshida, Y.; Sheng, C.; Song, Y.; Yang, S.; Zhou, Y.; Lü, J.; Zhu,
J. J. Med. Chem.. 2003, 46, 474–485. (b) Yao, B.; Ji, H.; Cao, Y.;
Zhou, Y.; Zhu, J.; Lü, J.; Li, Y.; Chen, J.; Zheng, C.; Jiang, Y.;
Liang, R.; Tang, H. J. Med. Chem. 2014, 50, 5293–5300.
(3) Cao, X.; Sun, Z.; Cao, Y.; Wang, R.; Cai, T.; Chu, W.; Hu, W.;
Yang, Y. J. Med. Chem. 2014, 57, 3687–3706.
6.2.5. (4-((1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy)
methyl)phenyl)methanol (10).
(4) (a) Moraca, F.; De Vita, D.; Pandolfi, F. Di Santo, R.; Costi, R.;
Cirilli, R.; D’Auria, F. D.; Panella, S.; Palamara, A. T.; Simonetti,
G.; Botta, M.; Scipione. L. Eur. J. Med. Chem. 2014, 83, 665–
673. (b) Jalil, M. A.; Masum, S. M. Tetrahedron Lett. 2012, 53,
3049–3051. (c) Pericherla, K.; Khedar, P.; Khungar, B.; Kumar,
A. Tetrahedron Lett. 2012, 53, 6761–6764. (d) Silvestri, R.;
Artico, M.; La Regina, G.; Di Pasquali, A.; De Martino, G.;
D’Auria, F. D.; Nencioni, L.; Palamara. A. T. J. Med. Chem.
2004, 47, 3924-3926. (e) Cuevas-Yañez, E.; Canul-Sánchez, A.;
Serrano-Becerra, J. M.; Muchowski, J. M.; Almanza, R. C. Rev.
Soc. Quím. Méx. 2004, 48, 49–52. (f) Tortolani, D. R.; Biller, S.
A. Tetrahedron Lett. 1996, 37, 5687–5690.
Following the synthetic procedure for 8, compound 3 (0.257
g, 1.0 mmol) and 6 (0.201 g, 1 mmol) were coupled. The crude
extract was purified by column chromatography eluting with
AcOEt/hexane 3/7 to afford the yellow solid 10 (0.157 g,
1
42%). Rf: 0.51 (EtOAc/Hex 3/7). m.p. 105-107 °C. H NMR:
(300 MHz, CDCl3) δ = 7.53-7.16 (m, 10H), 5.31 (s, 1H), 5.30-
5.21 (m, 2H), 4.30-4.16 (dd, J = 2.2, 14.0 Hz, 2H, CH2-OH),
4.12 (q, J = 7.14 Hz, 1H), 3.97 (dd, J = 7.7, 14.1 Hz, 1H), 1.28
(s, 1H, OH) ppm. 13C NMR: (75.4 MHz, CDCl3) δ = 139.9 (C),