Chemistry Letters Vol.33, No.7 (2004)
941
Table 2. Optimization trials of the reaction conditions
nBu Cl (2b)(1.1 equiv.)
refluxed for 8 h. The reaction mixture was diluted with aq NaOH,
and extracted with 3 times of dichloromethane. The combined
organic layer was washed with aq NaOH, water, 2M aq
HCl, water, and saturated aq NaHCO3. After drying with anhy-
drous magnesium sulfate, the filtrate was concentrated in the
reduced pressure to give 1.48 g (93%) of n-butyl phenyl ether
as colorless oil.
K CO (1.2 mol equiv.)
2
3
HO
n
Bu NCl (0.2 equiv.) nBu O
4
Na SO
N
H
O
2
3
N
H
O
Solvent
Additive
reflux, 8 h
1
3b
In summary, we have developed the 2,6-lutidine-assisted
etherification of phenol derivatives with alkyl chloride. The re-
action proceeded in good yield in water. Further studies of the
reaction including the investigation on the reaction mechanism
K CO
mol equiv.
2,6-Lutidine nBu NCl
Solvent
H O−tolueneb
Yield
/ %
Entry
2
3
4
a
/
/ equiv.
/ equiv.
7
are on-going.
1
2
1.2
1.2
0
0.2
0.2
2
2
1.1
H O−tolueneb 35
2
References and Notes
1
H O−tolueneb
1
R. C. Larock, in ‘‘Comprehensive Organic Transforma-
tions,’’ 2nd ed., John Wiley & Sons, Inc., New York
3
4
5
0
2.3
1.1
0.2
0.2
0
2
H O−tolueneb
1.2
1.2
2
2
(
1999), p 889.
H O−tolueneb 21
0.2
2
For examples, see: a) T. Nobori, S. Fujiyoshi, I. Hara,
T. Hayashi, A. Shibahara, K. Funaki, K. Mizutani, and S.
Kiyono, Presented at the 81st Annual Meeting of the Chemi-
cal Sociaty of Japan, Tokyo, March 2002, Abstr., No. 1F9-
27. b) T. Nobori, S. Fujiyoshi, I. Hara, T. Hayashi, A.
Shibahara, K. Funaki, K. Mizutani, and S. Kiyono WO01,
2
H O−tolueneb
6
7
8
1.2
1.2
1.1
1.1
1.1
0.4
0.2
0.4
70
84
89
2
H2Oc
H2Oc
1.2
a
b
Isolated yield. The co-solvent of five-fold volume of water
and three-fold volume of toluene to the weight of 1 was used.
Five-fold volume of water to the weight of 1 was used.
8
1274 (2001). c) H. K. Yoo, D. M. Davis, Z. Chen, L.
Echegoyen, and G. W. Gokel, Tetrahedronn Lett., 31, 55
1990). d) M. R. V. Sahyun and D. J. Cram, Org. Synth.,
c
(
Coll. Vol. V, 926 (1973).
3
For examples, see: a) J. J. V. Eynde and I. Mailleux, Synth.
Commun., 31, 1 (2001). b) H. H. Freedman and R. A. Dubois,
Tetrahedron Lett., 38, 3251 (1975). c) A. McKillop, J.-C.
Fiaud, and R. P. Hug, Tetrahedron, 30, 1379 (1974).
The order of reactivity of the alkylating agents was reported
as R-I > R-OMs > R-Br ꢀ R-Cl; see: G. Gelbard, Synthesis,
Table 3. Etherification reaction of phenol derivatives with
butyl chloride
nBu Cl (2b)(1.1 equiv.)
4
5
K CO (1.2 mol equiv.)
HO
2
3
nBu O
n
Bu NCl
(
0.2 equiv.)
X
4
X
1
977, 113.
2,6-lutidine (1.1 equiv.)
The similar enhancement of the methylation reactions of
phenols using dimethylcarbonate (DMC) as an alkylating
agent, 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), and
tetra-n-butyl-ammonium iodide, was reported. However the
reaction was necessary to use an excess amount of DMC
as a solvent, see: W. Shieh, S. Dell, and O. Repi cˇ , Org. Lett.,
H O (x 5V)
reflux, 8 h
2
4
5
a
Entry
X
Yield / % : 2,6-Lutidine
1
.1 equiv.
0 equiv.
1
2
H
93
97
77
92
3
, 4279 (2001).
o-OMe
6
7
S. Aki, M. Kurimura, T. Nishi, M. Tominaga, J.
Minamikawa, A. Yamamoto, and N. Fukuyama, Jpn.
Kokai Tokkyo Koho JP2001, 213,877; Chem. Abstr., 135,
3
4
5
p-OMe
p-Me
94
92
84
88
75
20
1
37510s (2002).
p-NHAc
The reaction using N-n-butylpyridinium chloride as the alky-
lating agent did not proceed. Although we do not have cer-
tain evidence to explain the mechanism on etherification ac-
celerated by 2,6-lutidine, we speculate it as follows: 1) The
intermolecular interaction between 2,6-lutidine and 1-chlo-
robutane accelerates at the C–Cl bond cleavage step without
forming the corresponding pyridinium salt. 2) The formation
of 2,6-lutidine salt with phenols increases the solubility of
the phenols in water to enhance the initial formation of po-
tassium phenoxide derivatives of the phenols with the potas-
sium carbonate. In addition, 2,6-lutidine accelerates the
phase-transfer of tetra-n-butylammonium phenoxide deriva-
tives, which form in the following step, from a water phase to
an organic phase.
6
7
8
9
p-Cl
p-CN
p-NO2
74
46
28
97
48
13
16
78
b
OH
a
b
Isolated yield. Instead of phenols, 2-naphthol was used.
Entry 1): The suspension of phenol (1.00 g, 10.6 mmol), 1-chlo-
robutane (1.22 mL, 11.7 mmol), potassium carbonate (1.76 g,
12.8 mmol), tetra-n-butylammonium chloride (0.59 g, 2.1
mmol), and 2,6-lutidine (1.36 mL, 11.7 mmol) in water was
Published on the web (Advance View) June 26, 2004; DOI 10.1246/cl.2004.940