Chemistry Letters Vol.35, No.1 (2006)
23
Table 4. The new Friedel–Crafts reaction for some substrates
Table 2. The Friedel–Crafts reaction in the presence of diethyl
sulfate
O
4
(1.4 mol )
Ethyl(E)-4-(4-ethoxy-3-methoxy-
phenyl)- 4-oxo-2-butenoate
R
O
3
, 4, AlCl3
3 (1.75 mol), AlCl3 (1.3 mol)
2
1
Substrate
1 mol)
+
OEt
(
(
1 mol)
C H Cl, 50 °C, 1 h
6 5
C H Cl, 10−15 °C, 1 h
6
5
(8)
Entry
3/mol
4/mol
AlCl3/mol
2/%a
1/%a
8/%a
Yield/%a
Entry
Substrate
1
2
3
4
5
6
7
1.2
1.5
1.2
1.2
1.2
1.4
1.6
1.4
1.4
1.2
1.2
1.2
1.2
1.2
1.3
1.1
10
20
71
62
70
74
67
76
71
11
1
2
3
4
Methoxybenzene
63
41
58
28
9.8
8.9
12
1,2,3-Trimethoxybenzene
1,4-Benzodioxan
1,2-Methylenedioxybenzene
2.0
13
1.75
2.0
6.1
16
8.7
11
aIsolated yield.
1.75
1.75
5.6
9.8
11
ring, so 2 would react with 3 very slowly. On the other hand, in
the presence of 4, the acylium ion (A) and/or (B) could react
with 4 smoothly to produce the esterified acylium ion (C) as
an irreversible reaction. Consequently, the equilibrium among
aThe ratio of 2/1/8 was determined by HPLC.
Table 3. Effect of temperature on the Friedel–Crafts reaction in
the presence of diethyl sulfate
3
, A, and B would be moved one-sidedly to ethoxycarbonyl ac-
3
(1.75 mol), 4 (1.4 mol), AlCl3 (1.3 mol)
C H Cl, Temp, 1 h
ylium ion (C) leading to the desired (E)-compound (1) as a major
product in good yield. Thus, it was clarified that (EtO)2SO2 (4)
plays an indispensable role in the present new reaction.
Thus, a new and efficient method has been presented for the
preparation of ꢀ-aroylacrylic acid ethyl ester such as ethyl (E)-4-
2
1
+
8
(
1 mol)
6
5
ꢀ
2/%a
1/%a
8/%a
Entry
Temp/ C
1
2
3
4
5
5–10
10–15
15–20
20–30
50
31
21
19
15
5.6
68
78
77
77
76
0.1
0.6
1.5
3.0
11
(
3,4-dimethoxyphenyl)-4-oxo-2-butenoate (1) in good yield and
ꢀ
9
excellent purity at 10–15 C in 1 h. In this Friedel–Crafts
reaction, it is important that the key reagent, (EtO)2SO2,
works as an agent trapping acylium ion produced from maleic
anhydride and AlCl3 by an ethyl source and not allowed to
revert to the starting material and serves as a trigger so that
the following Friedel–Crafts reaction proceeded smoothly.
Further study on this type of Friedel–Crafts reaction is now in
progress in our laboratory.
aThe ratio of 2/1/8 was determined by HPLC.
except in the case of AlCl3.
Thus, AlCl3 was chosen as the preferable Lewis acid for this
Friedel–Crafts reaction.
The suitable temperature conditions were then examined for
the reaction under the above-mentioned molar ratios (Table 3).
ꢀ
When the reaction was carried out at 10–15 C, the desired ester
1
References and Notes
was obtained in 78% relative yield along with 8 (0.6% relative
1
2
W. S. Johnson, Org. React. 1994, 2, 114.
yield; Table 3, Entry 2). In higher temperatures, the yield of 8
was increased relatively by way of demethylation followed by
ethylation with 4 (Table 3, Entries 3, 4, and 5).
a) M. Yamada, N. Nagashima, J. Hasegawa, S. Takahashi,
Tetrahedron Lett. 1998, 49, 9019. b) K. Ozeki, Y. Ishizuka,
M. Sawada, H. Shimamura, T. Ichikawa, M. Sato, H.
Yaginuma, Yakugaku Zasshi 1987, 107, 268.
The Friedel–Crafts reaction in the presence of diethyl sulfate
for several compounds having oxygen atoms on benzene ring
was tried; the results are summarized in Table 4. The ethyl ester
of 5a could be obtained directly from methoxybenzene in fairly
good yield (Table 4, Entry 1); also, the desired esters could be
prepared respectively from 1,2,3-trimethoxybenzene, 1,4-benzo-
dioxan, and 1,2-methylenedioxybenzene within 1 h (Table 4,
Entries 2, 3, and 4). Although it was assumed that 1,2-dime-
thoxybenzene (2) would form an intermediate 5c at first,
followed by the effective esterification with 4 in this reaction
3
4
P. Clawson, P. M. Lunn, D. A. Whiting, J. Chem. Soc.,
Perkin Trans. 1 1990, 159.
a) D. Papa, E. Schwenk, F. Villani, E. Klingsberg, J. Am.
Chem. Soc. 1948, 70, 3356. b) R. E. Lutz, P. S. Bailey, C.
Dien, J. W. Rinker, J. Am. Chem. Soc. 1953, 75, 5039.
E. Butkus, B. Bieliryte, J. Prakt. Chem./Chem.-Ztg. 1992, 3,
285.
M. Bianchi, A. Butti, Y. Christidis, J. Perronnet, F. Barzaghi,
Eur. J. Med. Chem. 1988, 23, 45.
E. N. Alesso, D. G. Tombari, G. Y. M. Iglesias, J. M.
Aguirre, Can. J. Chem. 1987, 65, 2568.
I. Itoh, T. Shintou, Patent WO 2003097568.
5
6
7
system, the esterification did not take place in the case of 5c with
ꢀ
4
and AlCl3 in chlorobenzene at 10–15 C within 2 h.
Based on these results, the Friedel–Crafts reaction by use of
, 3, and AlCl3 in the presence of 4 is assumed to proceed as our
8
9
2
Procedure of the Friedel–Crafts reaction in the presence
of diethyl sulfate: Into a stirred solution of 3 (34.3 g, 0.35
mol) and 4 (43.2 g, 0.28 mol) in chlorobenzene (78 mL)
was added AlCl3 (34.7 g, 0.26 mol) and 2 (28.0 g, 0.20
working hypothesis shown in Scheme 1. It was considered that,
in the absence of 4, an excess amount of AlCl3 would generally
be assumed to be coordinated with the carbonyl oxygen atoms of
ꢀ
3
to form initially a ring-opened acylium (Z)-intermediate (A) as
mol) at 10–15 C under N2 atmosphere. The reaction mixture
ꢀ
a counter ion. While A would be preferential to the ring-closed
system (3), only a small amount of A would be isomerized to E-
isomer (B), which could be a good accepter of the Friedel–Crafts
reaction. In addition, the nucleophilicity of 2 would be decreased
owing to coordination of AlCl3 to the oxygen atoms on benzene
was stirred at 10–15 C for 1 h and poured into 150 mL of
ꢀ
0.03 M HCl (aq) at 10–30 C. The organic layer was separat-
ed, washed with 0.03 M HCl (aq) followed with 5% Na2CO3
aq, and then concentrated in vacuo. The desired compound
was purified by recrystallization from ethanol (8 mL).