Journal of Medicinal Chemistry
Article
All protocols requiring the use of mice were approved by the animal care
committee of Beijing Normal University.
though a SN2 reaction between hydroquinone and 1-(bromomethyl)-4-
iodobenzene).
1-Iodo-4-((4-nitrophenoxy)methyl)benzene (1). To a solution of
4-nitrophenol (695.6 mg, 5.0 mmol) and 1-(bromomethyl)-4-iodobenzene
(1.48 g, 5.0 mmol) in anhydrous DMF (5 mL) was added K2CO3 (1.38 g,
10.0 mmol). The resulting mixture was stirred at 90 °C for 2 h; after
cooling to room temperature, 50 mL of water was added and a white
precipitate was formed. The precipitate was collected by filtration,
washed with 50 mL of water, and recrystallized from methanol to give 1
as a white solid (1.69 g, 95.2%). HPLC: 7.51 min, 99.8%; mp 147.4−
148.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 9.2 Hz, 2H), 7.75
(d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H),
5.10 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 163.37, 141.85, 137.91,
135.19, 129.24, 125.94, 114.84, 94.10, 69.97. MS (EI): m/z calcd for
C13H10INO3 355; found 355 M+.
3-(4-Iodobenzyloxy)phenol (8). The procedure described above for
the preparation of 7 was employed to afford 8 as a white solid (93.1 mg,
28.5%). HPLC: 3.95 min, 98.6%; mp 109.9−110.6 °C. 1H NMR
(400 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H),
7.16−7.09 (m, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.46−6.44 (m, 2H), 4.98
(s, 2H), 4.74 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 159.87, 156.65,
137.67, 136.59, 130.24, 129.23, 108.32, 107.39, 102.55, 93.45, 69.36. MS
(EI): m/z calcd for C13H11IO2 326; found 326 M+.
2-(4-Iodobenzyloxy)phenol (9). The procedure described above for
the preparation of 7 was employed to afford 9 as yellow oil (109.8 mg,
33.7%). HPLC: 4.25 min, 99.9%; mp 62.1−63.4 °C. 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.98−6.95 (m,
1H), 6.93−6.88 (m, 2H), 6.85−6.81 (m, 1H), 5.62 (s, 1H), 5.06 (s, 2H).
13C NMR (101 MHz, CDCl3) δ 145.91, 145.56, 137.88, 136.09, 129.54,
122.13, 120.20, 114.98, 112.30, 93.99, 70.44. MS (EI): m/z calcd for
C13H11IO2 326; found 326 M+.
1-(4-Iodobenzyloxy)-3-nitrobenzene (2). The procedure described
above for the preparation of 1 was employed to afford 2 as a white solid
1
(345.5 mg, 97.3%). HPLC: 8.53 min, 99.9%; mp 75.2−75.9 °C. H
NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.74
(d, J = 8.2 Hz, 2H), 7.45 (t, J = 8.2 Hz, 1H), 7.30−7.26 (m, 1H), 7.19
(d, J = 8.1 Hz, 2H), 5.09 (s, 2H). 13C NMR (101 MHz, CDCl3) δ
158.91, 149.19, 137.84, 135.41, 130.06, 129.29, 121.84, 116.18, 109.21,
93.99, 69.88. MS (EI): m/z calcd for C13H10INO3 355; found 355 M+.
1-(4-Iodobenzyloxy)-2-nitrobenzene (3). The procedure described
above for the preparation of 1 was employed to afford 3 as a yellow solid
1-Fluoro-4-(4-iodobenzyloxy)benzene (10). The procedure de-
scribed above for the preparation of 1 was employed to afford 10 as a
white solid (253.1 mg, 77.1%). HPLC: 8.92 min, 98.0%; mp 62.3−62.8
°C. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.17 (d, J =
8.2 Hz, 2H), 7.00−6.95 (m, 2H), 6.91−6.85 (m, 2H), 4.97 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 157.49 (d, J = 238.9 Hz, 1C), 154.61 (d, J =
2.1 Hz, 1C), 137.71, 136.58, 129.23, 115.95 (d, J = 12.3 Hz, 2C), 115.88
(d, J = 18.8 Hz, 2C), 93.51, 70.00. MS (EI): m/z calcd for C13H10FIO
328; found 328 M+.
1-Chloro-4-(4-iodobenzyloxy)benzene (11). The procedure de-
scribed above for the preparation of 1 was employed to afford 11 as a
white solid (136.2 mg, 79.0%). HPLC: 12.86 min, 99.6%; mp 107.5−
108.1 °C. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.24
(d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H),
4.98 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 157.06, 137.72, 136.30,
129.40, 129.19, 126.08, 116.15, 93.59, 69.60. MS (EI): m/z calcd for
C13H10ClIO 344; found 344 M+.
1-Bromo-4-(4-iodobenzyloxy)benzene (12). The procedure de-
scribed above for the preparation of 1 was employed to afford 12 as a
white solid (302.5 mg, 77.8%). HPLC: 14.61 min, 99.3%; mp 122.6−
123.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.37
(d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H),
4.97 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 157.58, 137.74, 136.26,
132.35, 129.20, 116.68, 113.39, 93.62, 69.53. MS (EI): m/z calcd for
C13H10BrIO 388; found 388 M+ (compared with the method in ref 46,
the reaction was carried out in DMF instead of acetone and gave
1-bromo-4-(4-iodobenzyloxy)benzene in a higher yield of 77.8%).
1-Iodo-4-(4-iodobenzyloxy)benzene (13). The procedure described
above for the preparation of 1 was employed to afford 13 as a white solid
(436.0 mg, 89.3%). HPLC: 17.49 min, 98.2%; mp 135.0−135.9 °C. 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.7 Hz,
2H), 7.15 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 4.97 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 158.33, 138.29, 137.72, 136.21, 129.17,
117.25, 93.60, 83.31, 69.37. MS (EI): m/z calcd for C13H10I2O 436;
found 436 M+.
1
(238.9 mg, 67.3%). HPLC: 6.03 min, 99.5%; mp 70.6−71.5 °C. H
NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8.1, 1.4 Hz, 1H), 7.73 (d, J =
8.2 Hz, 2H), 7.56−7.46 (m, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.09−7.04 (m,
2H), 5.18 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 151.62, 140.23,
137.80, 135.27, 134.07, 128.78, 125.73, 120.90, 115.03, 93.80, 70.45.
1-Iodo-4-((4-methoxyphenoxy)methyl)benzene (4). The proce-
dure described above for the preparation of 1 was employed to afford
4 as a white solid (255.3 mg, 75.1%). HPLC: 8.28 min, 99.5%; mp
1
128.9−130.2 °C. H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz,
2H), 7.17 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 6.83 (d, J =
9.2 Hz, 2H), 4.96 (s, 2H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
154.18, 152.68, 137.63, 137.08, 129.25, 115.92, 114.72, 93.30, 70.07, 55.72.
HRMS (EI): m/z calcd for C14H13IO2 339.9960; found 339.9966 M+.
1-(4-Iodobenzyloxy)-3-methoxybenzene (5). The procedure de-
scribed above for the preparation of 1 was employed to afford 5 as a white
solid (211.7 mg, 62.2%). HPLC: 8.68 min, 98.5%; mp 77.4−78.7 °C. 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 2H), 7.21−7.17 (m, 3H),
6.57−6.50 (m, 2H), 4.99 (s, 2H), 3.79 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 160.87, 159.75, 137.65, 136.71, 129.94, 129.26, 106.93, 106.73,
101.44, 93.42, 69.30, 55.27. MS (EI): m/z calcd for C14H13IO2 340; found
340 M+.
1-(4-Iodobenzyloxy)-2-methoxybenzene (6). The procedure de-
scribed above for the preparation of 1 was employed to afford 6 as a
white solid (288.1 mg, 84.7%). HPLC: 6.63 min, 98.7%; mp 110.4−
110.8 °C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.1 Hz, 2H), 7.19
(d, J = 8.0 Hz, 2H), 6.97−6.91 (m, 2H), 6.85 (d, J = 3.8 Hz, 2H), 5.10
(s, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.78, 147.89,
137.58, 137.00, 129.11, 121.76, 120.78, 114.41, 112.03, 93.25, 70.41,
55.92. MS (EI): m/z calcd for C14H13IO2 340; found 340 M+.
4-(4-Iodobenzyloxy)phenol (7). To a solution of hydroquinone
(110.1 mg, 1.0 mmol) and 1-(bromomethyl)-4-iodobenzene (296.9 mg,
1.0 mmol) in anhydrous DMF (5 mL) was added K2CO3 (276.4 mg,
2.0 mmol). The resulting mixture was stirred at 90 °C for 2 h; after
cooling to room temperature, 50 mL of water was added and extracted
by CH2Cl2 (3 × 10 mL). Combined organic layers were dried over
MgSO4, filtered, and concentrated under a vacuum. The crude mixture
was purified by silica gel chromatography (petroleum ether/AcOEt =
4/1) to give 7 as a white solid (49.3 mg, 15.1%). HPLC: 3.75 min,
99.3%; mp 152.2−153.7 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J =
8.3 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.85−6.81 (m, 2H), 6.78−6.74
(m, 2H), 4.95 (s, 2H), 4.41 (s, 1H). 13C NMR (101 MHz, CDCl3) δ
152.75, 149.83, 137.65, 137.00, 129.27, 116.09, 115.91, 93.35, 70.11.
MS (EI): m/z calcd for C13H11IO2 326; found 326 M+ (different
from the procedure in ref 45, 4-(4-iodobenzyloxy)phenol was gained
1-Iodo-4-(phenoxymethyl)benzene (14). The procedure described
above for the preparation of 1 was employed to afford 14 as a white solid
1
(310.1 mg, 72.1%). HPLC: 9.59 min, 99.2%; mp 96.7−97.6 °C. H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.32−7.27 (m,
2H), 7.19 (d, J = 8.1 Hz, 2H), 6.99−6.94 (m, 3H), 5.02 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 158.49, 137.64, 136.81, 129.51, 129.22,
121.15, 114.84, 93.37, 69.20. MS (EI): m/z calcd for C13H11IO 310;
found 310 M+ (different from the procedure in ref 47, 1-iodo-4-
(phenoxymethyl)benzene was gained though a SN2 reaction between
phenol and 1-(bromomethyl)-4-iodobenzene).
1-tert-Butyl-4-(4-iodobenzyloxy)benzene (15). The procedure
described above for the preparation of 1 was employed to afford 15 as
a white solid (366.2 mg, 87.4%). HPLC: 27.14 min, 98.3%; mp 91.9−
93.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.31
(d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H),
4.99 (s, 2H), 1.30 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 156.28,
I
dx.doi.org/10.1021/jm5004396 | J. Med. Chem. XXXX, XXX, XXX−XXX