Friedel-Crafts Benzylation and Phenethylation Reactions Using Benzyl and Phenethyl Benzothiazol-2-yl Carbonate Derivatives

Article abstract of DOI:10.1246/cl.2003.814

Friedel-Crafts benzylation and phenethylation reactions of several aromatic compounds with benzyl and phenethyl benzothiazol-2-yl carbonate derivatives were carried out in the presence of scandium triflate (Sc(OTf) ₃) as a catalyst. Suitable combinations of the leaving group of carbonates and acid promoters that generate cationic alkyl species were examined.

Full text of DOI:10.1246/cl.2003.814

8
14
Chemistry Letters Vol.32, No.9 (2003)
Friedel–Crafts Benzylation and Phenethylation Reactions
Using Benzyl and Phenethyl Benzothiazol-2-yl Carbonate Derivatives
ꢀ
y;yy
y;yy y;yy
and Hiroyuki Yamanaka
Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
Teruaki Mukaiyama,
Hiroaki Kamiyama,
y
yy
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641
(Received June 6, 2003; CL-030510)
Friedel–Crafts benzylation and phenethylation reactions of
Table 1. Friedel–Crafts benzylation with benzyl carbonate 1a
several aromatic compounds with benzyl and phenethyl benzo-
thiazol-2-yl carbonate derivatives were carried out in the pres-
ence of scandium triflate (Sc(OTf)3) as a catalyst. Suitable com-
binations of the leaving group of carbonates and acid promoters
that generate cationic alkyl species were examined.
Sc(OTf)3
(5 mol%)
O
O
+
R2
OR1
Solvent
Temp., Time
R2
1
a-c
1
1
1
1
a:R =4-nitrophenyl; 1b:R =benzothiazol-2-yl; 1c:R =6-nitro-
Friedel–Crafts alkylation reactions are very useful tools for
introducing alkyl groups into aromatic compounds. A standard
benzothiazol-2-yl
1
R2
Temp. Time Yield /%
°C
Entry
1
Solvent
Friedel–Crafts alkylation is generally carried out by using an al-
kyl halide and a Lewis acid catalyst such as aluminum chloride.
In some cases, however, undesirable side reactions such as
poly-alkylations and skeletal rearrangements take place to de-
crease their yields. Therefore, various methods for catalytic
Friedel–Crafts alkylations which proceed under mild and con-
/
/ h
(o:p)
b
1
1a OMe
1b OMe
CH Cl2
reflux
reflux
reflux
120
1
1
1
N. R.
trace
2
b
2
CH Cl2
2
3b,c 1c
OMe
CH Cl2
55 (22:33)
2
4
5
1a OMe
anisole
anisole
0.5 98 (45:53)
0.5 95 (38:57)
2
trolled conditions have been studied extensively.
In the meantime, the use of esters for alkylating agents has
1c
OMe
120
1,3
been reported as the alternatives of alkyl halides. These esters
were dialkyl carbonates and alkyl sulfates, sulfites, phosphates,
silicates, and borates which were activated by using more than a
stoichiometric amount of a Lewis acid. Then the carbonates
having one alkyl and one good leaving group which were acti-
vated by acids were considered. The carbonates having one al-
kyl and one benzothiazol-2-yl group would generate active spe-
cies and react with nucleophiles such as aromatic compounds to
form the alkylated products along with synchronous formation
of CO2 and benzothiazolinone by the application of acids.
These carbonates are prepared via alkyl chloroformates formed
from alcohols and COCl2, and subsequent treatment of the
chloroformates with benzothiazolinones in the presence of Et3N
or pyridine.
6
7
1a
1c
Me
Me
toluene
toluene
reflux
reflux
2
1
88(36:52)
82 (33:49)
8
9
1a 1,3-diMe m-xylene
1c 1,3-diMe m-xylene
120
120
1.5 91 (72:19)d
d
0.5 92 (73:19)
1
1
0
1c
1c
H
benzene
reflux
1.5 85 (77:8)e
1.5 69 (23:46)
f
1
Cl chlorobenzene reflux
aA mixture of 1 (0.2 mmol), an aromatic compound (0.8 mL),
and Sc(OTf)3 (5 mol%) was stirred unless otherwise noted.
Anisole (1.0 equiv.) was used. 2,4-Dibenzyl-1-methoxyben-
b
c
d
zene was also obtained in 29% yield. Ratio of (2,4-dimethyl-
phenyl)phenylmethane : (2,6-dimethylphenyl)phenylmethane.
Ratio of diphenylmethane : dibenzylbenzene. Sc(OTf)3
e
f
(
3 mol%) was used.
First, benzylation of an aromatic compound with benzyl
carbonates 1a–c in the presence of Sc(OTf)3, one of the active
Lewis acid catalysts, was chosen as a model reaction in order
4
though the phenethylation of anisole with 2 in the presence of
20 mol% of TfOH resulted in incomplete consumption of 2 (En-
tries 1–8), thiocarbonate 2h gave the best yield of the desired
product (Entry 8). The combined use of 2h and at least
3
50 mol% of TfOH or Sc(OTf) completed the reaction to pro-
duce phenethylated anisoles in good yields (Entries 11 and
to find a suitable carbonate which has an excellent leaving
group (Table 1). In the case of the benzylation of anisole (1.0
equiv.) in dichloromethane, benzyl 6-nitrobenzothiazol-2-yl
carbonate 1c gave mono-benzylated anisole in 55% yield along
with dibenzylated anisole in 29% yield (Entry 1) while benzyl
4
-nitrophenyl carbonate 1a and benzothiazol-2-yl carbonate
13) without any skeletal rearrangements, probably by the SN1
type reaction via a non-aromatic symmetrical intermediate as
mentioned by McMahon et al. The result indicated that the
1b were not reactive enough to give benzylated products (En-
5
tries 2 and 3). When the reaction was carried out in a large ex-
cess amount of anisole, however, mono-benzylated products
were obtained in high yields without accompanying dibenzylat-
ed products (Entries 4 and 5).
present phenethylation reaction was completed by using less
stoichiometric but rather catalytic amounts of the acid. The
use of 16 mol% of Sc(OTf) , however, again resulted in incom-
3
Next, Friedel–Crafts phenethylation of an aromatic com-
pound with phenethyl carbonate derivatives 2 having similar
structures to benzyl carbonate 1c was examined (Table 2). Al-
plete consumption of 2h after the reaction mixture was stirred at
ꢁ
120 C for 4 h. In this case, additional refluxing for 5 h caused
formation of a side-product of 2-phenethyloxybenzothiazole in
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.9 (2003)
815
Table 2. Effects of substituents of phenethyl carbonate 2 on the
a
Table 3. Effects of Lewis acids on the Friedel–Crafts phene-
thylation of anisole with 2h
Friedel–Crafts phenethylation of anisole
TfOH or
Sc(OTf)3
OMe
Additive
OMe
O
O
O
O
(100 mol%)
X
N
Y
S
N
+
+
120 °C, 5 h
Temp., Time
S
Z
OMe
OMe
2
2h
TfOH Sc(OTf)3 Yield /%
mol% / mol%
Entry
2
X
Y
Z
Temp. Time
°C
Yield /%
(o:p)
/
(o:p)
Entry
Additive
/
/ h
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
O
O
O
O
S
O
O
S
NO2
H
20
20
20
20
20
20
20
20
trace
10 (5:5)
trace
1
2
3
4
5
6
TfOH
120
120
5
1
3
5
3
3
73(35:38)
84(42:42)
43(17:26)
N. R.
N. R.
28(14:14)
Sc(OTf)3
Sn(OTf)2
Zn(OTf)2
CuOTf
Cu(OTf)2
a
NO2
100-150
120
100
100
S
H
NO2
H
22 (10:12)
10 (5:5)
N. R.
O
O
S
S
b
7
8
AgOTf
AgB(C F )
80-120
80-120b
5
5
30(15:15)
47(31:16)
2g
2h
S
NO2
33 (14:19)
39 (19:20)
6
5 4
S
S
H
a
ꢁ
The reaction mixure was stirred at 100 C for 1h and then
at 150 C for 2 h. The reaction mixure was stirred at 80 C
for 2 h and then at 120 C for 3 h.
9
2g
2h
2h
S
S
S
S
S
S
NO2
H
100
100
50
63 (34:29)
73 (35:38)
71 (34:37)
ꢁ
b
ꢁ
ꢁ
1
0
1
1
H
ture of 1c (66.0 mg, 0.20 mmol) and Sc(OTf)3 (4.9 mg, 5 mol%)
was added anisole (0.66 mL) at room temperature. The mixture
was stirred at 120 C for 0.5 h and then was cooled down to
room temperature. Then, it was poured into 10% of aqueous so-
dium hydrogencarbonate solution and was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over anhydrous sodium sulfate, filtrated, and concentrated
in vacuo. The crude product was purified by preparative TLC to
give 2-benzyl-1-methoxybenzene (15.2 mg, 38%) and 4-benzyl-
1-methoxybenzene (22.7 mg, 57%).
2b 2h
3c 2h
4d 2h
1
1
1
S
S
S
S
S
S
H
H
H
100
50
84 (42:42)
83 (40:43)
31 (16:15)
ꢁ
16
a
A mixture of 2 (0.2 mmol), anisole (0.8 mL), and TfOH or
Sc(OTf)3 was stirred at 120 C for 5 h unless otherwise noted.
Reaction time was 1h. Reaction time was 2 h. The reaction
mixure was stirred at 120 C for 4 h and then under reflux for
h. 2-Phenethyoxybenzothiazole was obtained as a by-prod-
uct in 26% yield.
ꢁ
b
c
d
ꢁ
5
This study was supported in part by the Grant of the 21st
Century COE Program from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT), Japan.
2
6% yield, which was apparently the result of decomposition of
2h. It seems that the generation of a phenethyl cation is much
more difficult than the benzyl one due to its lower cationic sta-
bility. For instance, according to the conventional Friedel–
Crafts reaction conditions using aluminum chloride (1.0
References
6
1a) G. A. Olah, in ‘‘Friedel–Crafts and Related Reactions,’’
John Wiley and Sons, New York (1964), Vol. II. b) R. M.
Roberts and A. A. Khalaf, in ‘‘Friedel–Crafts Alkylation
Chemistry,’’ Marcel Dekker, Inc., New York (1984).
ꢁ
ꢁ
equiv.) in anisole (at 50 C for 2 h and then at 80 C for
.5 h), phenethylated anisoles were obtained in only 16% com-
3
5
bined yield (ortho:para = 1:1) via McMahon’s intermediate.
The effects of Lewis acids on the model phenethylation re-
action of anisole with 2h are shown in Table 3. Among the
Lewis acids examined, Sc(OTf)3 gave the best result.
Thus, the use of the above mentioned active carbonate de-
rivatives in the presence of a catalytic amount of Sc(OTf)3 ef-
fectively worked in Friedel–Crafts benzylation and phenethyla-
tion reactions of aromatic compounds to give the corresponding
alkylated products in good yields.
2
S. Sebti, R. Tahir, R. Nazih, and S. Boulaajaj, Appl. Catal.,
A, 218, 25 (2001), and references cited therein.
a) H. L. Kane and A. Lowy, J. Am. Chem. Soc., 58, 2605
3
(1936). b) J. F. Norris and B. M. Sturgis, J. Am. Chem.
Soc., 61, 1413 (1939).
4
a) T. Tsuchimoto, K. Tobita, T. Hiyama, and S. Fukuzawa,
J. Org. Chem., 62, 6997 (1997). b) A. Kawada, S. Mitamura,
J. Matsuo, T. Tsuchiya, and S. Kobayashi, Bull. Chem. Soc.
Jpn., 73, 2325 (2000).
Further investigations to develop more effective systems of
catalytic Friedel–Crafts alkylations are now in progress.
A typical experimental procedure for the Friedel–Crafts
benzylation of anisole is as follows (Table 1, Entry 5): to a mix-
5
6
M. A. McMahon and S. C. Bunce, J. Org. Chem., 29, 1515
(1964).
C. C. Lee, A. G. Forman, and A. Rosenthal, Can. J. Chem.,
35, 22 (1957).
Published on the web (Advance View) August 11, 2003; DOI 10.1246/cl.2003.814