PAPER
Chemoselective and Rapid Chlorination of Benzyl Alcohols
3923
reaction was monitored by TLC until the complete disappearance of
4-methoxybenzyl alcohol occurred (5 h). Then, the reaction mixture
was diluted with Et2O (50 mL), and the organic phase was washed
with H2O (2 × 30 mL), dried over anhyd Na2SO4 and concentrated
under reduced pressure to give the crude product which was then fil-
tered through a silica gel pad with petroleum ether to afford 4-meth-
oxybenzyl chloride; yield: 270 mg (79%).
Anal. Calcd for C9H10ClNO4: C, 46.67; H, 4.35; N, 6.05. Found: C,
46.49; H, 4.36; N, 6.05.
2-[4-(Chloromethyl)-2-methoxyphenoxy]ethanol (Table 2,
Entry 4)
From 4-(2-hydroxyethoxy)-3-methoxybenzyl alcohol (200 mg,
1.01 mmol).
Yield: 154 mg (70%).
2-[4-(Chloromethyl)phenoxy]ethanol (Table 2, Entry 1); Typi-
cal Procedure for the Chemoselective Chlorination of Benzylic
Hydroxy Groups in the Presence of Aliphatic Hydroxy Groups
The procedure for the chemoselective chlorination of 4-(2-hydroxy-
ethoxy)benzyl alcohol (Table 2, entry 1) is representative. To a soln
of 4-(2-hydroxyethoxy)benzyl alcohol (200 mg, 1.19 mmol) in an-
hyd DMSO (5 mL) was added TCT (121 mg, 0.65 mmol) portion-
wise. The mixture was stirred at r.t. and the reaction was monitored
by TLC until completion (30 min). Then, the mixture was added to
CH2Cl2 (50 mL), and the organic phase was washed with H2O
(5 × 30 mL), dried over anhyd Na2SO4 and concentrated under re-
duced pressure to give the crude product which was then purified by
silica gel chromatography (petroleum ether–EtOAc, 3:1) to afford
2-[4-(chloromethyl)phenoxy]ethanol; yield: 140 mg (63%).
IR (KBr): 3549, 2940, 1608, 1519, 1460, 1268, 1238, 1167, 1139,
1089, 1035, 687 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.92 (m, 2 H), 6.88 (m, 1 H), 4.57
(s, 2 H), 4.13 (d, J = 4.5 Hz, 2 H), 3.95 (d, J = 4.5 Hz, 2 H), 3.88 (s,
3 H).
13C NMR (125 MHz, CDCl3): d = 149.6, 148.1, 130.8, 121.2, 113.8,
112.0, 71.0, 61.1, 55.8, 46.5.
MS (EI): m/z (%) = 218 (11) [M + 2]+, 216 (33) [M]+, 181 (20), 172
(13), 137 (100), 122 (10).
Anal. Calcd for C10H13ClO3: C, 55.44; H, 6.05. Found: C, 55.51; H,
6.07.
IR (KBr): 3398, 2929, 2870, 1612, 1590, 1513, 1249, 1082 cm–1.
2-[5-(Chloromethyl)-2-methoxyphenoxy]ethanol (Table 2,
Entry 5)
From 3-(2-hydroxyethoxy)-4-methoxybenzyl alcohol (200 mg,
1.01 mmol).
1H NMR (500 MHz, CDCl3): d = 7.32 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.6 Hz, 2 H), 4.57 (s, 2 H), 4.09 (t, J = 4.5 Hz, 2 H), 3.97 (t,
J = 4.5 Hz, 2 H), 2.17 (br s, 1 H).
Yield: 175 mg (80%).
13C NMR (125 MHz, CDCl3): d = 158.6, 130.09, 130.06, 114.7,
69.2, 61.3, 46.1.
IR (KBr): 3507, 3367, 2954, 1605, 1520, 1428, 1267, 1238, 1169,
1139, 1077, 1024, 680 cm–1.
MS (EI): m/z (%) = 188 (3) [M + 2]+, 186 (9) [M]+, 151 (42), 107
(100).
1H NMR (500 MHz, CDCl3): d = 6.98 (m, 2 H), 6.85 (d, J = 8.7 Hz,
1 H), 4.55 (s, 2 H), 4.15 (t, J = 4.5 Hz, 2 H), 3.96 (t, J = 4.5 Hz, 2
H), 3.87 (s, 3 H), 2.70 (br s, 1 H).
Anal. Calcd for C9H11ClO2: C, 57.92; H, 5.94. Found: C, 58.03; H,
5.92.
13C NMR (125 MHz, CDCl3): d = 149.7, 148.0, 130.1, 122.0, 114.7,
111.4, 71.1, 61.1, 55.8, 46.4.
2-[2-(Chloromethyl)phenoxy]ethanol (Table 2, Entry 2)
From 2-(2-hydroxyethoxy)benzyl alcohol (200 mg, 1.19 mmol).
MS (EI): m/z (%) = 218 (5) [M + 2]+, 216 (15) [M]+, 181 (35), 172
(13), 137 (100), 122 (14).
Yield: 158 mg (71%).
Anal. Calcd for C10H13ClO3: C, 55.44; H, 6.05. Found: C, 55.54; H,
6.04.
IR (KBr): 3282, 2945, 1603, 1598, 1496, 1451, 1252, 1051, 752,
660 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.32 (m, 2 H), 6.96 (t, J = 7.4 Hz,
1 H), 6.90 (d, J = 8.2 Hz, 1 H), 4.67 (s, 2 H), 4.17 (t, J = 4.5 Hz, 2
H), 3.99 (m, 2 H), 2.36 (br s, 1 H).
Competitive Intermolecular Experiment between Benzyl Alco-
hols and Aliphatic Alcohols: 4-Chlorobenzyl Chloride (Table 2,
Entry 6); Typical Procedure
13C NMR (125 MHz, CDCl3): d = 156.6, 130.6, 130.3, 125.8, 121.0,
112.0, 69.7, 61.3, 42.3.
The competitive intermolecular experiment between 4-chloroben-
zyl alcohol and 2-phenoxyethanol (Table 2, entry 6) is representa-
tive. To a soln of 4-chlorobenzyl alcohol (444 mg, 3.12 mmol) and
2-phenoxyethanol (431 mg, 3.12 mmol) in anhyd DMSO (5 mL)
was added TCT (316 mg, 1.71 mmol) portionwise. The reaction
mixture was stirred at r.t. for 25 min and then Et2O (50 mL) was
added. The organic phase was washed with H2O (5 × 30 mL), dried
over anhyd Na2SO4 and concentrated under reduced pressure. The
mixture was separated by silica gel chromatography with petroleum
ether to give 4-chlorobenzyl chloride [yield: 380 mg (76%)] and
then with petroleum ether–EtOAc (3:1) to recover 2-phenoxyetha-
nol (431 mg, 100%).
MS (EI): m/z (%) = 188 (11) [M + 2]+, 186 (33) [M]+, 151 (15), 142
(20), 133 (20), 107 (100), 91 (35), 78 (25).
Anal. Calcd for C9H11ClO2: C, 57.92; H, 5.94. Found: C, 58.12; H,
5.95.
2-[2-(Chloromethyl)-4-nitrophenoxy]ethanol (Table 2, Entry 3)
From 2-(2-hydroxyethoxy)-5-nitrobenzyl alcohol (250 mg, 1.17
mmol).
Yield: 217 mg (80%).
IR (KBr): 3309, 3229, 2931, 2873, 1614, 1595, 1504, 1358, 1273,
1095, 1045 cm–1.
Monochlorogastrodin by the Chemoselective Chlorination of
Gastrodin (Table 2, Entry 8)
1H NMR (500 MHz, CDCl3): d = 8.29 (d, J = 2.8 Hz, 1 H), 8.25 (dd,
J = 2.8, 9.0 Hz, 1 H), 7.00 (d, J = 9.0 Hz, 1 H), 4.68 (s, 2 H), 4.29
(t, J = 4.5 Hz, 2 H), 4.07 (t, J = 4.5 Hz, 2 H).
To a soln of gastrodin (150 mg, 0.52 mmol) in anhyd DMSO (1 mL)
was added TCT (53 mg, 0.29 mmol) portionwise. The mixture was
stirred at r.t. and the reaction was monitored by TLC until comple-
tion (15 min). Then, DMSO was removed via bulb-to-bulb distilla-
tion under reduced pressure. The residue was taken up in anhyd
MeCN (15 mL), filtered, and the filtrate was concentrated and puri-
fied by silica gel chromatography (Et2O–EtOH, 25:1) to give
monochlorogastrodin; yield: 134 mg (84%).
13C NMR (125 MHz, CDCl3): d = 161.4, 141.1, 126.8, 126.2, 126.1,
111.4, 70.6, 60.9, 40.8.
MS (EI): m/z (%) = 233 (2) [M + 2]+, 231 (6) [M]+, 187 (17), 152
(75), 77 (42), 51 (40), 45 (100).
Synthesis 2008, No. 24, 3919–3924 © Thieme Stuttgart · New York