5040
G. Keglevich et al. / Tetrahedron Letters 49 (2008) 5039–5042
The alkylation of phenol and 4-substituted phenols with
ated species 3a were formed, while in the presence of 5% of the
catalyst, the relative quantities of 2a and 3a were 84% and 4%,
respectively (Table 2, entries 2 and 3). The cresol was not, however,
consumed on further heating. At room temperature, without the
use of TEBAC, the O-benzylation was significantly selective, but
the reaction was slow (Table 2, entry 4). For the above reasons,
thermal heating is not a good alternative to MW heating in the
PT catalyzed alkylation under discussion.
1.2 equiv of benzyl bromide or benzyl chloride in the presence
(or in a few cases, in the absence) of 1.0 equiv of K2CO3 under
solvent-free conditions served as the model reaction. The benzyl-
ations were carried out in the range of 80–120 °C isothermally,
under MW irradiation in the presence of 0–5% of triethylbenzyl-
ammonium chloride (TEBAC)14 and the reactions were monitored
by GC and GC–MS.
Carrying out the alkylation of cresol with benzyl bromide at
100 °C without the use of K2CO3 and TEBAC, the reaction was reluc-
tant but selective with regard to C-alkylation, as mostly 2-benzyl-
cresol 3a was formed (Table 1, entry 1). In the presence of K2CO3 at
80 °C, 45% of the expected benzyl cresyl ether 2a, 27% of 2-benzyl-
cresol 3a,15 4% and 7% of doubly benzylated derivatives 4a16 and
5a,17 along with 17% of unreacted cresol were present in the reac-
tion mixture according to GC–MS (Table 1, entry 2). The composi-
tion did not change after 50 min. At 120 °C, the situation was
similar (55% of 2a and 27% of 3a were present), but no cresol
remained in the mixture (Table 1, entry 4). The experiment carried
out at 100 °C represented an intermediate case (Table 1, entry 3).
The addition of 5% of TEBAC to the reaction mixture resulted in a
dramatic change in favour of benzyl aryl ether 2a: 94% and 96%
of product 2a was formed after 45 min at 80 °C or 35 min at
100 °C, respectively (Table 1, entries 5 and 6). The isolated yield
of 2a18 was 86% after column chromatography. The reaction with
benzyl chloride led to rather similar results (Table 1, entries 7
and 8). It can be seen that the MW promoted, solvent-free, S–L
phase benzylation of cresol takes place chemoselectively only in
the absence of K2CO3 or in the case of the combined use of K2CO3
and a PT catalyst. In the latter instance, MW irradiation and the
presence of the onium salt result in a synergic effect. 2-Benzylcre-
sol 3a must be formed by aromatic electrophilic substitution, as
benzyl cresyl ether 2a cannot undergo rearrangement to 3a. This
was proved by separate experiments. It is, however, known that
alkenyl aryl ethers undergo the Claisen rearrangement at 180–
240 °C to furnish a 2-alkenylphenol.19–22
The directing role of the reaction components such as K2CO3 and
quaternary onium salt is noteworthy. It seemed to be interesting to
investigate if the chemoselectivity (O-alkylation versus C-alkyl-
ation) observed is of general value or not. For this, reactions were
carried out with additional model compounds, such as 4-chloro-
phenol (1b) and 4-tert-butylphenol (1c) without and with K2CO3
and TEBAC, using the conditions established for the alkylation of
cresol (1a) using benzyl bromide. Carrying out the alkylation of
1b with BnBr in the absence of K2CO3 and in the presence of
K2CO3 and 5% of TEBAC at 120 °C for 35 min, the proportion of the
O- (2) and C-alkylated (3) products was 0/43 and 96/0, respectively
(Table 3, entries 1 and 3). Repeating the latter benzylation in the ab-
sence of TEBAC, the above ratio was 73/14 (Table 3, entry 2). It was
found that the benzylation of 4-tert-butylphenol at 120 °C in the
absence of K2CO3 yielded only C-alkylated products 3c and 5c
(44% combined) (Table 3, entry 4). In the presence of K2CO3, the
ratio of 2c and 3c was 59:20 (Table 3, entry 5). It is noteworthy that
the use of TEBAC resulted in an even slower reaction (only a 71%
conversion and selective formation of the C-benzylated products
(3c and 5c, 62% combined) (Table 3, entry 6). In all the three cases,
the reaction was reluctant to proceed. The increased proportion of
the C-alkylated product (3a) is due to the tert-butyl group activat-
ing the phenyl ring to aromatic electrophilic substitution. With
the lack of a suitably acidic hydroxy group in 4-tert-butylphenol,
formation of the potassium salt is suppressed and as a consequence
of the lipophilicity due to the tert-butyl group on the aromatic ring,
the salt formed and anchored on the surface of K2CO3 can enter the
organic phase without the assistance of the phase transfer catalyst.
Moreover, the presence of TEBAC in the organic phase prevents the
transfer of the phenolate from the surface of K2CO3 as the onium
salt content may result in decreased solubity.
Control experiments carried out by traditional heating at 100 °C
for 45 min also revealed the effect of K2CO3 and a PT catalyst on the
chemoselectivity of the alkylation. In the absence of K2CO3 the
benzylation became C-selective, but the reaction was reluctant
(Table 2, entry 1). In the presence of K2CO3 and in the absence of
TEBAC, 52% of the O-alkylated product (2a) and 26% of the C-alkyl-
Finally, the S–L phase benzylation of phenol was investigated.
Three products, benzyl phenyl ether (7) along with 4- and 2-
benzylphenol (8 and 9, respectively) may be formed as a result
Table 1
The reaction of cresol with benzyl halides under MW irradiation
MW
T °C
OH
OBn
OH
OBn
OH
TEBAC
K2CO3
Bn
Bn
Bn
+
+
+
+
BnX
1.2 eq.
no solvent
Bn
Me
Me
Me
Me
Me
1a
2a
3a
4a
5a
Entry
X
K2CO3 (equiv)
TEBAC (%)
T (°C)
t (min)
1aa (%)
2aa (%)
3aa (%)
4aa (%)
5aa (%)
b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Cl
Cl
—
1
1
1
1
1
1
1
—
—
—
—
5
5
—
5
100
80
100
120
80
100
120
100
35
50
40
35
45
35
40
40
58
17c
9c
0
0
45
52
55
94
96
53
91
32
27
27
27
0
0
22
4
0
4
6
9
6
4
4
5
7
7
6
9
0
0
4
0
0
0
17c
0
a
Determined by GC–MS or GC.
3% others.
Does not disappear on further irradiation.
b
c
Keglevich, Gy?rgy
