550
P. Wang et al. / Chinese Chemical Letters 25 (2014) 549–552
O
O
O
N
N
N
N
Cl
Cl
F
Siramesine
YM-35375
O
O
NC
O
O
O
H
N
O
N
S
H
O
F
OH
N
HO
Phenolphthalein
UK-73093
Escitalopram
Fig. 1. Structures of isobenzofuran drugs.
the solvent was removed under reduced pressure. Ethyl acetate
was added to the residue and filtered over celite. The solvent was
removed under reduced pressure and the residue was purified
by column chromatography to obtain the 2-benzoylbenzaldehyde
as a white solid. (iii) The 2-benzoylbenzaldehyde (1 mmol)
was dissolved in 10 mL methanol at room temperature. NaBH4
(0.5 mmol) was added to the solution followed by 1 drop of
pyridine and then the mixture was stirred 5 h at room tempera-
ture. The solvent was removed under reduced pressure and 0.5 mL
hydrochloric acid was added to the residue. The mixture was
extracted three times with ethyl acetate. The combined organic
phase was distilled under reduced pressure. The residue was used
without further purification. The residue was dissolved in 10 mL
toluene and p-toluenesulfonic acid (0.1 mmol) was added. The
resulting mixture was stirred 3 h under reflux. The solvent was
removed under reduced pressure and the residue was purified by
column chromatography on silica gel to give compound 5a.
1-Phenyl-1,3-dihydroisobenzofuran (5a): 1H NMR (300 MHz,
Anal. calcd. (%) for C14H11NO3: C 69.70, H 4.60, N 5.81; found: C
69.86, H 4.75, N 5.88. MS (ESI): m/z 264 [M+Na]+.
1-(4-Chlorophenyl)-1,3-dihydroisobenzofuran (5d): 1H NMR
(300 MHz, CDCl3):
1H), 5.31 (d, 1H, J = 12.2 Hz), 5.18 (d, 1H, J = 12.2 Hz). 13C NMR
(75 MHz, CDCl3): 141.5, 140.7, 139.0, 133.8, 128.7, 128.3, 127.8,
d 7.25 (m, 7H), 6.99 (d, 1H, J = 7.3 Hz), 6.12 (s,
d
127.6, 122.1, 121.0, 85.4, 73.3. Anal. calcd. (%) for C14H11ClO: C
72.89, H 4.81; found: C 72.76, H 4.93. MS (ESI): m/z 253 [M+Na]+.
1-(4-Nitrophenyl)-1,3-dihydroisobenzofuran (5e): 1H NMR
(300 MHz, CDCl3):
6.24 (s, 1H), 5.35 (d, 1H, J = 12.2 Hz), 5.21 (d, 1H, J = 12.2 Hz). 13C
NMR (75 MHz, CDCl3): 148.5, 145.1, 141.6, 138.1, 132.4, 130.5,
d 8.21 (m, 2H), 7.53 (m, 2H), 7.16 (m, 4H),
d
129.3, 129.2, 128.9, 122.4, 85.1, 73.7. Anal. calcd. (%) for
C14H11NO3: C 69.70, H 4.60, N 5.81; found: C 69.58, H 4.77, N
5.64. MS (ESI): m/z 264 [M+Na]+.
5-Bromo-1-phenyl-1,3-dihydroisobenzofuran (5f): 1H NMR
(300 MHz, CDCl3):
J = 8.0 Hz), 6.09 (s, 1H), 5.28 (d, 1H, J = 12.5 Hz), 5.15 (d, 1H,
J = 12.5 Hz). 13C NMR (75 MHz, CDCl3):
141.6, 141.5, 141.2, 130.6,
d 7.41 (s, 1H), 7.31 (m, 6H), 6.88 (d, 1H,
CDCl3):
1H, J = 12.1 Hz), 5.19 (d, 1H, J = 12.1 Hz). 13C NMR (75 MHz, CDCl3):
142.5, 142.3, 139.5, 129.0, 128.4, 128.0, 127.9, 127.4, 122.4,
d
7.21 (m, 8H), 6.95 (d, 1H, J = 8.0 Hz), 6.09 (s, 1H), 5.27 (d,
d
128.6, 128.3, 126.9, 124.2, 123.8, 121.5, 85.9, 72.6. Anal. calcd. (%)
for C14H11BrO: C 61.11, H 4.03; found: C 61.34, H 3.96. MS (ESI):
m/z 273, 275 [Mꢀ1]ꢀ.
d
121.3, 86.3, 73.4. Anal. calcd. (%) for C14H12O: C 85.68, H 6.16;
found: C 85.79, H 6.08.
5-Bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (5g):
1-(3-Chlorophenyl)-1,3-dihydroisobenzofuran (5b): 1H NMR
1H NMR (300 MHz, CDCl3):
d 7.49 (s, 1H), 7.42 (d, 1H,
(300 MHz, CDCl3):
1H), 5.31 (d, 1H, J = 12.2 Hz), 5.20 (d, 1H, J = 12.2 Hz). 13C NMR
(75 MHz, CDCl3): 144.3, 141.3, 138.9, 134.5, 129.8, 128.1, 127.8,
127.6, 126.9, 124.9, 122.1, 121.0, 85.4, 73.4. Anal. calcd. (%) for
d
7.24 (m, 7H), 7.03 (d, 1H, J = 7.3 Hz), 6.12 (s,
J = 8.1 Hz), 7.32 (m, 2H), 7.10 (t, 2H, J = 8.6 Hz), 6.92 (d, 1H,
J = 8.0 Hz), 6.13 (s, 1H), 5.33 (d, 1H, J = 12.5 Hz), 5.20 (d, 1H,
d
J = 12.5 Hz). 13C NMR (75 MHz, CDCl3):
d 141.6, 141.0, 130.7, 128.9,
128.7, 124.3, 123.8, 121.7, 115.7, 115.4, 85.3, 72.5. Anal. calcd. (%)
for C14H10BrFO: C 57.36, H 3.44; found: C 57.28, H 3.57. MS (ESI):
m/z 291, 293 [Mꢀ1]ꢀ.
C
14H11ClO: C 72.89, H 4.81; found: C 72.80, H 4.95. MS (ESI): m/z
253 [M+Na]+.
1-(3-Nitrophenyl)-1,3-dihydroisobenzofuran (5c): 1H NMR
(300 MHz, CDCl3):
d
8.21 (s, 1H), 8.14 (d, 1H, J = 8.1 Hz), 7.69 (d,
3. Results and discussion
1H, J = 7.6 Hz), 7.51 (m, 1H), 7.32 (m, 2H), 7.24 (m, 1H), 7.03 (d, 1H,
J = 7.6 Hz), 6.25 (s, 1H), 5.38 (d, 1H, J = 12.2 Hz), 5.24 (d, 1H,
In our initial investigation, functional salicylaldehydes were
used to give analogs of intermediate 3 (Scheme 1). This preparation
of N-acylhydrazones of o-hydroxybenzaldehydes proceeded
J = 12.2 Hz). 13C NMR (75 MHz, CDCl3):
d
148.4, 144.5, 140.7, 138.8,
132.7, 129.5, 128.1, 127.7, 122.9, 121.9, 121.6, 121.2, 85.0, 73.6.