H. T. Balaydın et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1352–1357
1357
Anal. Calcd for (C15H19BrO3): C 55.06, H 5.85; Found C 55.19, H 5.87.
For 10: Liquid; 1H NMR (400 MHz, CDCl3) d 3.89 (s, OCH3, 3H), 3.88 (s, OCH3,
3H), 3.54 (dd, A part of AB-system, J = 14.27, 3.66 Hz, CH2, 1H), 3.27 (dd, B part
of AB-system, J = 14.27, 10.61 Hz, CH2, 1H), 2.81–2.78 (m, CHCO, 1H), 2.50–2.34
(m, 2H), 2.10–2.03 (m, 1H), 1.91–1.81 (m, 2H), 1.72–1.52 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 211.5 (CO), 150.8 (C), 137.7 (C), 122.9 (C), 121.9 (CH), 121.1
(C), 61.0, 60.9, 50.2, 42.2, 37.7, 33.0, 28.0, 25.5; IR (CH2Cl2, cmꢂ1): 3403, 2936,
2862, 1709, 1558, 1520, 1488, 1451, 1395, 1367, 1329, 1312, 1273, 1218, 1169,
1152, 128, 1074, 1047, 1010; Anal. Calcd for (C15H17Br3O3): C 37.15, H 3.53;
Found C 37.17, H 3.55. For 11 (94%): Liquid; Rf (40%, EtOAc/hexane) 0.82; 1H-
NMR (400 MHz, CDCl3) d 6.90 (s, 1H), 3,86 (s, OCH3, 3H), 3.82 (s, OCH3, 3H),
3,35 (dd, A part of AB-system, J = 13.64, 6.08 Hz, CH2, 1H), 2.73–2.65 (m, OCH,
1H), 2.59 (dd, B part of AB-system, J = 13.64, 6.81 Hz, CH2, 1H), 2.44–0.80 (m,
8H); 13C NMR (100 MHz, CDCl3) d 212.1 (CO), 152.1 (C), 146.0 (C), 137.5 (C),
121.7 (C), 117.5 (C), 114.8 (CH), 60.5, 56.2, 50.8, 42.4, 37.6, 34.3, 28.2, 25.4; IR
(CH2Cl2, cmꢂ1): 3397, 2938, 2861, 2661, 2575, 2392, 2289, 2123, 2012, 1913,
1874, 1741, 1705, 1584, 1549, 1464, 1424, 1379, 1310, 1264, 1224, 1199, 1162,
1128, 1053, 1007; Anal. Calcd for (C15H18Br2O3): C 44.36, H 4.47; Found C
44.19, H 4.45.
1162, 1124, 1102, 1062, 1031, 1007; Anal. Calcd for (C15H20Br2O3): C 44.14, H
4.94; Found C 44.39, H 4.96.
Synthesis of 17: To a cold (0 °C) solution of 16 (0.250 g, 0.61 mmol) in CH2Cl2
(15 mL), triethylamine (5.0 equiv) and 3,5-dinitrobenzoylchloride (4.0 equiv)
were added slowly under N2, respectively. After the mixture was stirred at rt
for 1 day, it was acidified with cold (0 °C) HCl (1%) and then neutralized with
NaOH (1%) and washed with water (20 mL), respectively. Organic phase was
dried over Na2SO4 and the solvent was evaporated. Ester 17 (0.360 g, 98%) was
obtained and crystallized from CH2Cl2/hexane as yellow crystals. Mp 176–
177 °C; 1H NMR (400 MHz, CDCl3) d 3.89 (s, OCH3, 3H), 3.88 (s, OCH3, 3H), 3.54
(dd, A part of AB-system, J = 14.27, 3.66 Hz, CH2, 1H), 3.27 (dd, B part of AB-
system, J = 14.27, 10.61 Hz, CH2, 1H), 2.81–2.78 (m, OCH, 1H), 2.50–2.34 (m,
2H), 2.10–2.03 (m, 1H), 1.91–1.81 (m, 2H), 1.72–1.52 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 211.5 (CO), 150.8 (C), 137.7 (C), 122.9 (C), 121.9 (CH), 121.1
(C), 61.0, 60.9, 50.2, 42.2, 37.7, 33.0, 28.0, 25.5. IR (CH2Cl2, cmꢂ1): 3403, 2936,
2862, 1709, 1558, 1520, 1488, 1451, 1395, 1367, 1329, 1312, 1273, 1218, 1169,
1152, 128, 1074, 1047, 1010; Anal. Calcd for (C15H17Br3O3): C 37.15, H 3.53;
Found C 37.17, H 3.55.
Compound 8 were prepared by known method14a,17 and the method is similar
to that of 17. For 8: mp 98–100 °C; 1H NMR (400 MHz, CDCl3) d 5.52 (s, CH2,
2H), 2.36 (s, CH3, 6H), 2.10 (s, CH3, 3H); 13C NMR (100 MHz, CDCl3) d 170.7
(CO), 167.0 (CO), 166.8 (CO), 143.5 (C), 142.0 (C), 135.0 (CH), 127.2 (C), 122.1
(C), 121.4 (C), 68.1 (CH2), 20.8 (CH3), 20.6 (CH3), 20.5 (CH3); IR (CH2Cl2, cmꢂ1):
3176, 2924, 2857, 1783, 1743, 1645, 1561, 1463, 1418, 1372, 1278, 1235, 1187,
1148, 1050, 1027, 1011.
For natural bromophenol 40or 4 (rasemic): waxy solid; 1H NMR (400 MHz, CDCl3)
d 6.00 (bs, 2OH), 3.48 (dd, A part of AB-system, J = 14.36, 3.85 Hz, CH2, 1H), 3.17
(dd, B part of AB-system, J = 10.61, 14.36 Hz, CH2, 1H), 2.82–2.74 (m, OCH, 1H),
2.50–2.30 (m, 2H), 2.18–2.04 (m, 1H), 1.90–1.47 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 212.0 (CO), 140.9 (C), 140.8 (C), 132.7 (C), 117.7 (C), 113.1 (C), 112.4
(C), 50.3 (CHCO), 50.1, 42.2, 37.1, 32.9, 29.9, 28.0, 25.5.
General procedure for reduction of 11 and 12: For 12; To a cold (0 °C) solution
(30 mL) of 12 (0.5 g, 1.53 mmol) in diethylether/methanol (1:1) NaBH4
(0.018 g) was carefully added over 5 min and the resulting mixture was
stirred at the same temperature for 15 min. After the cold bath was removed, it
was stirred at rt for 1 day. Water (10 mL) was added and then the mixture was
acidified with HCl (5%) until its pH was 3. The mixture was extracted with
CH2Cl2 (2 ꢁ 50 mL). The combined organic layer was dried over Na2SO4 and the
solvent was evaporated. The residue was subjected to column chromatography
on silica gel (SiO2, 50 g) and eluted using EtOAc/hexane (1:95) to give the cis
alcohol 13 (0.196 g, 39%) and trans alcohol 14 (0.292 g, 58%), respectively.
For 13: Liquid; Rf (40%, EtOAc/hexane) 0.74; 1H NMR (400 MHz, CDCl3) d 6.96
(d, J = 0.46 Hz, 1H), 6.68 (d, J = 0.46 Hz, 1H), 3.84 (s, OCH3, 3H), 3.82 (s, OCH3,
3H), 3.79 (s, OCH, 1H), 2.64 (dd, A part of AB-system, J = 13.54, 7.68 Hz, CH2,
1H), 2.45 (dd, B part of AB-system, J = 7.68, 13.54 Hz, CH2, 1H), 1.78–1.21 (m,
8H); 13C NMR (100 MHz, CDCl3) d 153.6 (C), 144.7 (C), 138.6 (C), 125.2 (CH),
117.5 (C), 113.0 (CH), 68.5 (CHO), 60.8, 56.3, 43.6, 38.5, 33.5, 26.6, 25.4, 20.5; IR
(CH2Cl2, cmꢂ1): 3445, 2997, 2932, 2857, 1722, 1596, 1566, 1489, 1464, 1451,
1429, 1413, 1302, 1272, 1235, 1183, 1141, 1102, 1039, 1004; Anal. Calcd for
(C15H21BrO3): C 54.72, H 6.43; Found C 54.42, H 6.40.
17. (a) Menzek, A.; Balci, M. Tetrahedron 1993, 49, 6071; (b) Menzek, A.; Kazaz, C.;
Eryigit, F.; Cengiz, M. J. Chem. Res. 2004, 210; (c) Menzek, A.; Sengül, M. E.;
Cetinkaya, Y.; Ceylan, S. J. Chem. Res. 2005, 209; (d) Sengül, M. E.; Menzek, A.;
Menzek, A.; Balci, M. Turk. J. Chem. 2006, 30, 131; (e) Menzek, A.; Altundas, A.
Tetrahedron 2006, 62, 12318; (f) Sengül, M. E.; Menzek, A.; Sahin, E.; Arik, M.;
Saracoglu, N. Tetrahedron 2008, 64, 7289.
18. X-Ray analysis: For the crystal structure determination, the single-crystal of the
compound 17 was used for data collection on a four-circle Rigaku R-AXIS
RAPID-S diffractometer (equipped with a two-dimensional area IP detector).
The graphite-monochromatized Mo
oscillation scans technique with = 5° for one image were used for data
collection. The lattice parameters were determined by the least-squares
methods on the basis of all reflections with F2 > 2 (F2). Integration of the
Ka radiation (k = 0.71073 Å) and
D
x
r
intensities, correction for Lorentz and polarization effects and cell refinement
was performed using CrystalClear (Rigaku/MSC Inc., 2005) software.22a The
structures were solved by direct methods using SHELXS-9722b and refined by a
full-matrix least-squares procedure using the program SHELXL-97.22b H atoms
were positioned geometrically and refined using a riding model. The final
difference Fourier maps showed no peaks of chemical significance. Crystal data
for 17: C22H22N2O8Br2; crystal system, space group: triclinic, P21/c; (no:14);
unit cell dimensions: a = 13.0170(4), b = 7.8501(3), c = 23.8484(7) Å,
b = 91.94(3)°; volume: 2435.5(2) Å3; Z = 4; calculated density: 1.642 g/cm3;
absorption coefficient: 3.378 mmꢂ1; F(000): 1208; h range for data collection
3.0–26.6°; refinement method: full-matrix least-square on F2; data/
For 14: Liquid; Rf (40%, EtOAc/hexane) 0.56; 1H NMR (400 MHz, CDCl3) d 6.94
(d, J = 0.46 Hz, 1H), 6.66 (s, 1H), 3.84 (s, OCH3, 3H), 3.82 (s, OCH3, 3H), 3.29–
3.23 (m, CHCO, 1H), 3.11 (dd, A part of AB-system, J = 13.54, 3.66 Hz, CH2, 1H),
2.24 (dd, B part of AB-system, J = 9.33, 13.54 Hz, CH2, 1H), 1.99–1.96 (m, 1H),
1.74–1.41 (m, 4H), 1.33–1.24 (m, 2H), 1.2–1.08 (m, 1H), 0.94–0.87 (m, 1H); 13C-
NMR (100 MHz, CDCl3) d 153.6 (C), 144.7 (C), 138.4 (C), 125.5 (CH), 117.4 (C),
113.1 (CH), 74.5 (CHO), 60.8, 56.3, 47.1, 38.8, 36.2, 30.2, 25.6, 25.1; IR (CH2Cl2,
cmꢂ1): 3391, 2997, 2931, 2856, 2006, 1723, 1596, 1566, 1489, 1464, 1449,
1428, 1414, 1298, 1273, 1235, 1182, 1142, 1040, 1005; Anal. Calcd for
(C15H21BrO3): C 54.72, H 6.43; Found C 54.78, H 6.46.
parameters: 5005/307; goodness-of-fit on F2: 1.053; final
R indices
[I > 2
r
(I)]: R1
=
0.066, wR2 = 0.128;
R
indices (all data): R1 = 0.139,
wR2 = 0.158; largest diff. peak and hole: 0.458 and ꢂ0.656 e Åꢂ3
;
Crystallographic data were deposited in CSD under CCDC registration
number 847309. These data can be obtained free of charge from The
For 15: Liquid; Rf (40%, EtOAc/hexane) 0.66; 1H NMR (400 MHz, CDCl3) d 6.82
(s, 1H), 3.84 (s, OCH3, 3H), 3.82 (s, OCH3, 3H), 3.77 (s, OCH, 1H), 2.87 (dd, A part
of AB-system, J = 13.17, 7.68 Hz, CH2, 1H), 2.70 (dd, B part of AB-system,
J = 7.14, 13.17 Hz, CH2, 1H), 1.78–1.24 (m, 8H); 13C NMR (100 MHz, CDCl3) d
152.3 (C), 146.1 (C), 138.1 (C), 122.0 (C), 117.8 (C), 114.5 (CH), 68.5 (CHO), 60.7,
56.4, 41.6, 41.0, 33.5, 26.5, 25.6, 20.3; IR (CH2Cl2, cmꢂ1): 3446, 2997, 2931,
2857, 1745, 1642, 1583, 1548, 1463, 1422, 1377, 1306, 1262, 1222, 1199, 1160,
1133, 1102, 1060, 1007; Anal. Calcd for (C15H20Br2O3): C 44.14, H 4.94; Found C
44.37, H 4.96.
19. (a) Senturk, M.; Kufrevioglu, O. I.; Ciftci, M. J. Enzyme Inhib. Med. Chem 2009, 24,
420; (b) Durdagi, S.; Senturk, M.; Ekinci, D.; Balaydin, H. T.; Goksu, S.;
Kufrevioglu, O. I.; Innocenti, A.; Scozzafava, A.; Supuran, C. T. Bioorg. Med. Chem.
2011, 19, 1381.
20. (a) Supuran, C. T.; Scozzafava, A.; Menabuoni, L.; Mincione, F.; Briganti, F.;
Mincione, G. Eur. J. Med. Chem. 1999, 34, 799; (b) Tas, M. Afr. J. Biotechnol. 2011,
10, 3849; (c) Balaydin, H. T.; Durdagi, S.; Ekinci, D.; Senturk, M.; Goksu, S.;
Menzek, A. J. Enzyme Inhib. Med. Chem. 2011. doi:10.3109/
21. Barrese, A. A.; Genis, C.; Fisher, S. Z.; Orwenyo, J. N.; Kumara, M. T.; Dutta, S. K.;
Phillips, E.; Kiddle, J. J.; Tu, C.; Silverman, D. N.; Govindasamy, L.; Agbandje-
McKenna, M.; McKenna, R.; Tripp, B. C. Biochemistry 2008, 47, 3174.
22. (a) Rigaku/MSC, Inc. 9009 new Trails Drive, The Woodlands, TX 77381.; (b)
Sheldrick, G. M. SHELXS97 and SHELXL97; University of Göttingen: Germany,
1997.
For 16: Liquid; Rf (40%, EtOAc/hexane) 0.50; 1H NMR (400 MHz, CDCl3) d 6.80
(s, 1H), 3.89 (s, OCH3, 3H), 3.86 (s, OCH3, 3H), 3.49 (dd, A part of AB-system,
J = 13.36, 3.24 Hz, CH2, 1H), 3.39–3.37 (m, OCH, 1H), 2.52 (dd, B part of AB-
system, J = 9.76, 13.36 Hz, CH2, 1H), 2.08–2.00 (m, 1H), 1.78–1.62 (m, 4H),
1.38–1.27 (m, 2H), 1.16–0.91 (m, 1H); 13C NMR (100 MHz, CDCl3) d 152.4 (C),
146.1 (C), 138.2 (C), 122.0 (C), 118.0 (C), 114.5 (CH), 75.3 (CHO), 60.7, 56.4,
46.2, 41.1, 36.2, 30.2, 25.6, 25.1; IR (CH2Cl2, cmꢂ1): 3391, 2992, 2931, 2855,
1745, 1717, 1642, 1583, 1549, 1466, 1423, 1374, 1345, 1310, 1262, 1222, 1200,