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128.5, 128.3, 127.9, 127.1, 126.7, 126.4, 125.2, 118.2,
105.8, 53.7, 35.3; IR (KBr) 3244, 2239, 1715 cmK1; Ms m/z
317 (MC). Anal. Calcd for C20H15NO3: C 75.70, H 4.76, N
4.41, O 15.12. Found: C 75.68, H 4.93, N 4.40, O 14.99.
3.95 (s, 3H), 3.76 (s, 3H); 13C NMR (CDCl3): d 170.1,
153.0, 148.7, 141.2, 132.5, 131.5, 130.4, 128.5, 127.0,
126.3, 117.0, 116.8, 112.8, 55.8, 52.9, 34.0; IR (neat) 3384,
1719 cmK1; Ms m/z 272 (MC); HRMS (EI) Calcd for
C16H16O4: 272.1049. Found: 272.1061.
4.3.6. 4-Bromo-2-[(1-methoxycarbonyl-2-naphthyl)-
methyl]phenol (1f). Colorless oil; 1H NMR (CDCl3): d
7.89–7.79 (m, 3H), 7.58–7.41 (m, 3H), 7.41 (s, 1H), 7.43 (d,
1H, JZ8.6 Hz), 7.24 (d, 1H, JZ8.4 Hz), 6.68 (d, 1H, JZ
8.4 Hz), 4.14 (s, 3H), 4.05 (s, 2H); 13C NMR (CDCl3): d
171.9, 154.4, 135.4, 133.6, 132.1, 131.3, 131.1, 129.8,
128.4, 128.2, 127.4, 127.1, 126.3, 124.9, 118.5, 111.7, 53.2,
35.0; IR (neat) 3371, 1700 cmK1; Ms m/z 372 (MC). Anal.
Calcd for C19H15O3Br: C 66.88, H 4.43. Found: C 67.04, H
4.31.
4.4.2. 2-(1-Methoxycarbonyl-2-phenyl)methylphenol
(2b). Colorless oil; H NMR (CDCl3): d 7.93 (s, 1H), 7.83
1
(d, 1H, JZ7.4 Hz), 7.45–7.36 (m, 2H), 7.28–7.22 (m, 2H),
7.17–7.11 (m, 1H), 6.89–6.83 (m, 2H), 4.24 (s, 2H), 3.98 (s,
3H); 13C NMR (CDCl3): d 170.5, 154.9, 141.3, 132.5, 131.5,
131.0, 128.4, 128.2, 126.3, 126.0, 119.9, 116.6, 53.0, 33.8;
IR (neat) 3368, 1698 cmK1; Ms m/z 242 (MC). Anal. Calcd
for C15H14O3: C 74.36, H 5.83. Found: C 74.70, H 5.84.
4.4.3.
4-Phenyl-2-[(1-methoxycarbonyl-2-phenyl)-
methyl]phenol (2c). Colorless crystals; mp 103 8C; 1H
NMR (CDCl3): d 8.14 (s, 1H), 7.85 (d, 1H, JZ7.7 Hz),
7.61–7.24 (m, 10H), 6.94 (d, 1H, JZ8.2 Hz), 4.32 (s, 2H),
4.00 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3): d 170.1,
152.4, 141.1, 133.0, 132.6, 130.3, 129.8, 128.6, 128.4,
127.0, 126.7, 126.5, 126.4, 126.2, 117.0, 53.2, 34.1; IR
(KBr) 3324, 1696 cmK1; Ms m/z 318 (MC). Anal. Calcd for
C21H18O3: C 79.22, H 5.70. Found: C 78.92, H 5.54.
4.4. General procedure for the preparation of 2
1-Bromo-2-methylbenzene was added to a solution of NBS
in CCl4 containing BPO, and the mixture was refluxed for
5 h. The mixture is filtrated, concentrated, and recrystallized
to give 1-bromo-2-bromomethylbenzene (94%). 1-Bromo-
2-bromomethylbenzene was etherified by the 4-substituted
phenols with K2CO3. Then the ethers in CH2Cl2 were added
by TiCl4 under argon atmosphere. The mixture was stirred
at room temperature, and quenched by water. The products
were extracted, dried (Na2SO4), concentrated, and purified
by column chromatography on silica gel (eluent: hexane and
ethyl acetate) to give ortho-rearranged phenols. The amount
of TiCl4, reaction time, and product yields were dependent
on the substituent at 4-position. In the case of 1e having an
electron-withdrawing group (cyano group), the CH2Cl2
solution (200 ml) containing 1-bromo-2-[(4-cyano-
phenoxy)methyl]benzene (4.5 g, 15.7 mmol) and 5 equiv
of TiCl4 (8.6 ml, 78.5 mmol) was stirred for 24 h at room
temperature under argon atmosphere, quenched by water,
and purified to give 1e in very low yield (2%). On the other
hand, the CH2Cl2 solution (50 ml) containing the other
ethers (10 mmol) and 1 equiv of TiCl4 (10 mmol) was
stirred for 3 h at room temperature, quenched by water, and
purified to give 1a–d in moderate yields (ca. 20–40%).
4.4.4.
4-Methyl-2-[(1-methoxycarbonyl-2-phenyl)-
1
methyl]phenol (2d). Colorless oil; H NMR (CDCl3): d
7.83 (d, 1H, JZ7.7 Hz), 7.71 (s, 1H), 7.46–7.27 (m, 2H),
7.28–7.22 (m, 1H), 7.06 (s, 1H), 6.94 (d, 1H, JZ8.2 Hz),
6.74 (d, 1H, JZ8.2 Hz), 4.21 (s, 2H), 3.97 (s, 3H), 2.29 (s,
3H); 13C NMR (CDCl3): d 170.3, 152.6, 141.4, 132.4, 131.5,
131.4, 130.2, 128.9, 128.7, 128.4, 126.2, 125.7, 116.4, 53.0,
33.8, 20.6; IR (neat) 3371, 1700 cmK1; Ms m/z 256 (MC);
HRMS (EI) Calcd for C16H16O3: 256.1099. Found:
256.1074.
4.4.5.
4-Cyano-2-[(1-methoxycarbonyl-2-phenyl)-
1
methyl]phenol (2e). Colorless oil; H NMR (CDCl3): d
9.20 (s, 1H), 7.85 (d, 1H, JZ7.5 Hz), 7.60 (s, 1H), 7.51–
7.42 (m, 2H), 7.36–7.26 (m, 2H), 6.88 (d, 1H, JZ8.4 Hz),
4.21 (s, 2H), 4.01 (s, 3H); 13C NMR (CDCl3): d 171.0,
159.3, 140.0, 135.1, 133.6, 132.9, 132.7, 131.5, 130.4,
128.3, 127.2, 126.9, 119.5, 117.8, 53.4, 33.5; IR (neat) 3315,
2225, 1718 cmK1; Ms m/z 267 (MC); HRMS (EI) Calcd for
C16H13O3N: 267.0895. Found: 267.0858.
These phenols (4 mmol) were protected by benzyl chloride
(5 mmol) in the presence of K2CO3 (4 g) to give the ethers
(O90%). n-BuLi (15 wt% in n-hexane solution, 14.6 ml,
22.8 mmol) was added drop-wise to the ethers (19 mmol) in
THF (100 ml) at K60 8C. The mixture was stirred for 2 h at
K60 8C under argon atmosphere, and ClCO2CH3 (1.8 ml,
23 mmol) in THF (15 ml) was added. Then the mixture was
stirred for 1 h at room temperature, and 3 N HCl was added.
The product was extracted with ether, washed with H2O,
dried (Na2SO4), and concentrated. Purification by column
chromatography on silica gel (eluent: hexane and ethyl
acetate) gave the corresponding ester derivatives in
moderate yields (ca. 60%). Then, the esters (3.5 mmol) in
ethanol (150 ml) were stirred for 8 h with 10% Pd/C
(140 mg) under hydrogen atmosphere to afford 2a–e,
respectively (90%).
4.5. General procedure for the preparation of 3–5
The amide derivative 3 was synthesized by the amidation of
the corresponding bromo derivative according to a similar
method of esterification (by ClCON(CH3)2, 30% yield).
The cyano derivative 4 was also obtained by the cyanation
according to the method described in the literature, followed
by deprotection. A mixture of the bromo derivatives
(1.1 mmol), CuCN (5.5 mmol), and N-methyl-2-pyrroli-
done (10 ml) was heated at 180 8C for 20 min under argon.
After cooling to room temperature, 10% aqueous ammonia
solution (50 ml) and dichloromethane (50 ml) were added to
the solution and filtered. The filtrate was combined with
Et2O, washed with H2O, and dried (Na2SO4). After removal
of N-methyl-2-pyrrolidone in vacuo, column chromato-
graphy on silica gel (eluent: hexane and ethyl acetate)
4.4.1. 4-Methoxy-2-[(1-methoxycarbonyl-2-phenyl)-
methyl]phenol (2a). Colorless oil; H NMR (CDCl3): d
1
7.85 (d, 1H, JZ7.9 Hz), 7.46–7.36 (m, 3H), 7.28–7.23 (m,
1H), 6.80–6.77 (m, 2H), 6.71–6.67 (m, 1H), 4.22 (s, 2H),