Solvent-free synthesis of cyclic ethers from dihalo compounds in the presence of alumina

Article abstract of DOI:10.1055/s-2002-33536

Facile synthesis of cyclic ethers from dihalo compounds on alumina has been accomplished in good yields. The reactions proceeded smoothly both in refluxing hexane and by microwave irradiation in the absence of solvent. In addition to being an organic-solvent-free operation, it also entails a short reaction time.

Full text of DOI:10.1055/s-2002-33536

1
526
LETTER
Solvent-Free Synthesis of Cyclic Ethers from Dihalo Compounds in the
Presence of Alumina
a
a
b
b
S
M
olvent-Free Synthesis
a
of
C
yclic
E
s
thers from
a
D
ihalo C
t
ompou
o
nds shi Mihara, Yoshio Ishino,* Satoshi Minakata, Mitsuo Komatsu*
a
Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax +81(6)69638049; E-mail: ishino@omtri.city.osaka.jp
b
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
Fax +81(6)68797402; E-mail: komatsu@chem.eng.osaka-u.ac.jp
Received 8 July 2002
With this in mind, we attempted a novel and convenient
synthesis of cyclic ethers from dihalo compounds on alu-
mina under solvent-free conditions.
Abstract: Facile synthesis of cyclic ethers from dihalo compounds
on alumina has been accomplished in good yields. The reactions
proceeded smoothly both in refluxing hexane and by microwave ir-
radiation in the absence of solvent. In addition to being an organic-
solvent-free operation, it also entails a short reaction time.
Initially, the intramolecular cyclization of , -dichloro-
o-xylene (1a) on alumina was examined in an organic sol-
vent (Scheme1). Treatment of 1a (1 mmol) with an excess
Key words: cyclic ethers, dichlorides, alumina, microwave, sol-
vent-free
of alumina (10 g) in hexane at reflux for 1 h gave phthalan
9
(
2a) in 64% yield (Table 1, entry 1). The use of an exces-
sive amount of alumina (namely 1a/Al O = 1 mmol/10 g)
2
3
Considerable attention has been devoted to heterogeneous caused a smooth reaction to afford the intramolecular cy-
organic reactions utilizing inorganic oxides such as alumi- clization product 2a in good yield, while a decrease in the
na, silica gel, zeolite, and clay, because such reactions amount of alumina from 10 g to 2 g led to the recovery of
have the advantage of high selectivity, mild conditions, the starting material even when the reaction time was pro-
1
and simplicity of operation. A number of heterogeneous longed (entry 3). The reaction proceeded in a similar man-
2
3
4
syntheses of ethers, sulfides, and amines from alkyl ha- ner to give 2a in good yield under milder conditions, such
lides have been already reported. In addition, solvent-free as at 30 °C (entry 4).
synthesis using solid-supported reagents in combination
with microwave irradiation is a subject that has been ac-
Al2O3
Cl
tively studied because of the reduced reaction time, ease
in work-up procedure, and enhanced selectivity and reac-
O
Cl
Hexane
1
a
2a
5
tivity. Recently, we described an inorganic porous solid-
(
1 mmol)
6
7
promoted synthesis of oxathiane and dithiane deriva-
tives from dichloro sulfides which were readily prepared
by the addition of sulfur dichloride to olefins. The result
Scheme 1
revealed that an inorganic oxide-promoted reaction is a Table 1 Intramolecular Cyclization of , -Dichloro-o-xylene (1a)
powerful tool for the synthesis of heterocyclic compounds on Alumina
via intramolecular cyclization. Herein we wish to report
Entry
Al O
Hexane
(mL)
Temp
(°C)
Time
(h)
Yielda
(%)
2
3
the facile synthesis of cyclic ethers by intramolecular
cyclization on alumina in hexane and its extension to an
organic-solvent-free system by using microwave irradia-
tion.
(
g)
1
2
3
10
5
20
10
4
reflux
reflux
reflux
30
1
91 (64)b
89
3.5
8.5
2
Phthalan, a cyclic ether, is known to be useful as a raw
material for preparing resins and is a precursor of func-
tional compounds such as phthalide. Several methods for
2
32c
4
10
20
92
8
preparing this compound have been reported. However,
a 1
H NMR yields.
these methods suffer from drawbacks such as the require-
ment of basic conditions, high temperature, and an aque-
ous work-up. Kabalka and coworkers also reported on the
conversion of benzyl halide to dibenzyl ether on alumina
b
c
An isolated yield.
Recovery of 1a: 63%.
but some difficulties such as recovery of the starting ma- With regard to alternate promoters instead of alumina, sil-
terial and the limitation of substrates were encountered.2d ica gel, montmorillonite K10, a 30% aqueous solution of
sodium hydroxide,8 and calcium oxide were evaluated,
c
but the reaction of 1a with these acids or bases resulted in
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1526,1528,ftx,en;U01702ST.pdf.
poor yields. On the other hand, the use of alumina with
acid-base bifunctional catalysis gave the best result for the
intramolecular cyclization.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Solvent-Free Synthesis of Cyclic Ethers from Dihalo Compounds
1527
Organic-solvent-free reactions were next performed using of an amount of water in excess of 2 equiv led to the re-
microwave irradiation. A variety of cyclic ethers 2 were covery of the starting material (Table 3, entries 4 and 5).
effectively obtained in moderate to good yields from the Therefore, the formation of 2a is remarkably dependent
corresponding dichloro- and dibromo-compounds 1 on on the amount of water present in the reaction mixture.
alumina under microwave irradiation (Scheme 2 and
1
0
Table 2, Method A ) as well as when the mixture was re-
Al2O3 (10 g) / H2O
9
1a
2a
fluxed in hexane (Scheme 2, Method B ). Organic-sol-
Hexane (20 mL), r.t.
vent-free conditions eliminate toxicity and flammability
of solvents and the use of alumina in combination with
microwave accelerated the rate of the reaction. Conse-
quently, the method of choice for the synthesis of cyclic
ethers constitutes a convenient and environmentally To investigate the oxygen source of the cyclic ether, we
friendly alternative to conventionally used procedures. On
the other hand, treatment of 1,5-dichloropentane, a
(1 mmol)
Scheme 3
carried out the reaction of 1a in the presence of H218
O
straight chain dichloride, with alumina afforded tetrahy- Table 3 The Effect of Water on the Cyclization
dropyran in rather low yield (ca.10%).
Entry
Al O
H O
Time
(h)
Yielda
(%)
2
3
2
The effect of water in alumina on the cyclization was ex-
amined by the addition of water to alumina that had previ-
(
equiv)
1
2
3
4
Not dry
dry
0
0
2
6
2
6
3
96 (4)b
78 (13)
Method A or B
X
O
X
100 (0)b
dry
2
1
2
dry
10
80 (20)
5
dry
100
17 (79)b
Scheme 2 Conditions of Method A: substrates (1 mmol), Al O (10
2
3
g), 5~15 min, microwave irradiation (300~500 W) [except for 1,8-
bis(bromomethyl)naphthalene: 0.3 mmol scale]. Conditions of Me-
thod B: substrates (1 mmol), Al O (10 g), hexane (20 mL), 20~90
a 1
H NMR yields. In parentheses, 1a recovered (%).
b
By glc analysis.
2
3
min, r.t. to reflux.
(
95 atom%, 2 equiv) on dried alumina (Scheme 4). The re-
ously been dried by heating at 180 °C for 2 h in vacuo
Scheme 3). The reaction of 1a on the dried alumina af-
forded 2a together with the starting material and the use
of dried alumina and 2 equiv of water gave 2a in quantita-
tive yield (Table 3, entries 2 and 3). However, the addition
16
sulting product was a mixture of O-phthalan (2a) and
(
1
8
11
O-phthalan (2a ) (2a/2a = ca. 3:1). This suggests that
phthalan was formed by the nucleophilic attack of a
hydroxy group, derived from both the surface layer of alu-
mina and water added to the alumina, to 1a. Consequent-
Table 2 Alumina- or Alumina/Microwave-Promoted Synthesis of Cyclic Ethers
1
Power (W), Time (min)
Method A
Temp, Time (min)
Method B
2
Yield (%)
Method A/B
X
X
O
X = Cl = Br
500
10
6
reflux
r.t.
60
90
69/64
60/60
5
00
Cl
Cl
5
00
5
reflux
reflux
30
20
O
59/49
73/98
Br Br
O
3
5
00
00
15
Br
Br
10
reflux
20
82/97
O
Synlett 2002, No. 9, 1526–1528 ISSN 0936-5214 © Thieme Stuttgart · New York

1
528
M. Mihara et al.
LETTER
Al O (dry)
Cl
Cl
2
3
H218O
O16
+
O18
+
Hexane
(
2 equiv)
1a
2a
2a'
Scheme 4
2d
(6) Minakata, S.; Mihara, M.; Sugoh, N.; Komatsu, M.
ly, alumina can be considered to function as a reagent as
well as a promoter. That is to say, the reaction might pro-
ceed smoothly owing to the activation of chloride atoms
of 1a and an oxygen atom of water as the result of the
acid-base bifunctional property of alumina.
Heterocycles 1998, 47, 133.
(
(
7) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. Synthesis
001, 2397.
2
8) (a) Willstätter, R.; Veraguth, H. Chem. Ber. 1907, 40, 957.
(b) Weinheimer, A. J.; Kantor, S. W.; Hauser, C. R. J. Org.
Chem. 1953, 18, 801. (c) Nippon Shokubai Kagaku Kogyo
Co. Ltd. Jpn.; Kokai Tokkyo Koho, 1984, 139375; Chem.
Abstr. 1985, 102, 6189q
9) Method B: A typical procedure is as follows: A suspension
of neutral activated alumina (10 g) in hexane (20 mL) and
, -dichloro-o-xylene (1a) (1 mmol) was stirred for 1 h at
reflux temperature. The alumina was then removed from the
reaction mixture by filtration and washed with ether (100
mL). After the combined filtrate was concentrated in vacuo
and purified by distillation, phthalan (2a) was isolated in
In conclusion, the method presented herein, using dihalo
compounds and alumina provides a convenient route to a
variety of cyclic ethers. The reaction involves simple op-
erations, mild conditions and provides good yields of
products. Furthermore, the alumina-microwave promoted
reaction proceeds smoothly in a short time without the
need for any organic solvent.
(
1
References
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(
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(
(
10) Method A: A typical procedure is as follows: A mixture of
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,
(
was placed in a beaker (200 mL) and irradiated by micro-
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(
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(
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(
2a) in 69% yield. The final temperatures after microwave
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(
(
3) Czech, B.; Quici, S.; Regen, S. L. Synthesis 1980, 113.
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(
11) Mass spectrometric analysis was performed on a Varian
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16
+
follows: O-phthalan; MS (EI): m/z (%) = 121 (3), 120 (M ,
(
5) (a) Caddick, S. Tetrahedron 1995, 51, 10403. (b) Loupy,
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16
1
0), 119 (40), 118 (2), 117 (1); a mixture of O-phthalan
18
and O-phthalan; MS (EI): m/z (%) = 123 (1), 122 (3)
18
+
16
+
(
O – M ), 121 (12), 120 (8) ( O – M ), 119 (29), 118 (1),
17 (1), 116 (1).
1
Synlett 2002, No. 9, 1526–1528 ISSN 0936-5214 © Thieme Stuttgart · New York