Troublesome Alkoxythiophenes
Sch em e 3a
J . Org. Chem., Vol. 66, No. 22, 2001 7285
anhydride (10.01 g, 0.1000 mol) in bromobenzene (96.87 g,
0.6170 mol) at -5 °C, under dry argon. The reaction temper-
ature was maintained at -5 °C for 4 h and was then allowed
to warm to room temperature. The reaction mixture was
stirred at room temperature for 96 h (ceasing of HCl gas
evolution indicated a complete reaction). The reaction mixture
was poured onto a mechanically stirred solution of dilute
hydrochloric acid (250 mL, 18%) at 0 °C, and the mixture was
stirred for a further 30 min while the solution was allowed to
warm to room temperature. The yellowish white solid was
filtered off, washed with water, and dried in vacuo (CaCl2,
P2O5, 20 h). The crude product was purified by crystallization
from toluene to afford a white crystalline solid, which was
dried in vacuo (CaCl2, P2O5, 24 h): yield 24.23 g (94%); mp
147-148 °C (lit.34 mp 149.5-150.2 °C); 1HNMR (500 MHz,
DMSO-d6) δ 2.59 (2H, t, 6.35 Hz), 3.21 (2H, t, 6.35 Hz), 7.88
(2H, d, J ) 8.79 Hz), 7.96 (2H, d, J ) 8.79 Hz), 12.19 (1H, s);
IR (KBr) νmax 2600-3400, 1730, 1670, 1585, 1479, 1447, 1410,
1105, 1074, 840 cm-1; MS m/z 256.2 (M+), 185.1, 183.1 (100),
157.1, 155.1, 76.1, 75.1. Anal. Calcd for C10H9BrO3: C, 46.72;
H, 3.53. Found: C, 46.69; H, 3.49.
a
Key: (a) dodecan-1-ol, N,N′-dicyclohexylcarbodiimide, 4-(N,N-
dimethylamino)pyridine; (b) Lawesson’s reagent, dry toluene.
Ta ble 1. Syn th esis of Alk oxy- a n d Ar yloxyth iop h en es
via Cycliza tion of γ-Keto Ester s
4-(5-Br om oth ien -2-yl)-4-oxobu ta n oic Acid (2). γ-keto
acid 2 was prepared as described for the preparation of
compound 1 except that nitrobenzene was used as solvent, and
the reaction mixture was stirred at -5 to -10 °C for 5 h before
workup, using the quantities stated: anhydrous aluminum
chloride (1.32 g, 9.90 mmol), succinic anhydride (0.45 g, 4.5
mmol), and 2-bromothiophene (0.733 g, 4.50 mmol). After
treatment with hydrochloric acid, a semisolid was observed
to settle at the bottom of the flask. The top layer was discarded,
and water was added before the mixture was extracted with
diethyl ether. The organic layer was washed with potassium
hydroxide (5% aqueous), and the aqueous layer was separated
and brought to pH 2-3 by the addition of hydrochloric acid
(10%). A cream-orange solid was filtered off, washed with
water, and dried (CaCl2, P2O5, 20 h). The crude product was
purified by crystallization from water to afford a white
crystalline solid, which was dried in vacuo (CaCl2, P2O5, 24
γ-keto ester
reaction time (h)
product (yield,a %)
3
4
11.3
16
12 (47)
13 (52)
14 (86)
15 (62)
16 (83)
17 (94)
18 (94)
19 (75)
20 (74)
22 (35)
5
20
6
22
7
24
8
25
9
48
10
11
21
22
29
1.5
a
Yields refer to isolated purified products.
produced in each reaction. Initially, we thought that the
product alkoxythiophenes might be reacting with Lawes-
son’s reagent, and this was disproved by heating 18 under
reflux with Lawesson’s reagent for 10 days without any
significant reaction being observed. Clearly, the oxidized
form of Lawesson’s reagent (produced during the cycliza-
tion) must be responsible for the side reactions observed;
all of the reactions were stopped once byproduct forma-
tion was observed (even if cyclization was not complete,
as was the case for alkoxythiophenes 3-6). Analysis of
the results shows that there is a clear trend in the
reaction time required to effect optimum cyclization. The
shorter is the alkyl chain on the γ-keto esters (3-9), the
shorter is the time required for observation of the
unwanted byproducts.
1
h): yield 1.12 g (95%); mp 141-142 °C (lit.37 mp 141 °C); H
NMR (CDCl3) δ 2.80 (2H, t, J ) 6.56 Hz), 3.20 (2H, t, J ) 6.56
Hz), 7.20 (1H, d, J ) 3.9 Hz), 7.50 (1H, d, J ) 3.9 Hz), the
carboxylic acid proton was not detected; IR (KBr) νmax 3079,
-1
2761, 1703, 1651, 1526, 1413, 1332, 1278, 1247, 979 cm
.
Gen er a l P r oced u r e for th e Syn th esis of γ-Keto Ester s
3-11 a n d 21. N,N′-Dicyclohexylcarbodiimide (8.53 g, 41.3
mmol) was added in one portion to a stirred solution of the
appropriate alcohol (1.588 g, 34.47 mmol), γ-keto acid (7.38 g,
28.7 mmol), and 4-(N,N-dimethylamino)pyridine (1.68 g, 13.8
mmol) in dry dichloromethane (250 mL) under dry argon at
room temperature. The reaction mixture was stirred at room
temperature overnight (TLC analysis revealed a complete
reaction), and the N,N′-dicyclohexylurea was filtered off. The
filtrate was washed successively with potassium hydroxide (5%
aqueous), water, acetic acid (5% aqueous), and water and dried
(MgSO4). The drying agent was filtered off, and the solvent
was removed in vacuo before being purified as described.
Gen er a l P r oced u r e for th e Syn th esis of Τh iop h en es
12-20 a n d 22. The method described by Shridar et al.25 was
employed with minor modifications to the reaction time.
Lawesson’s reagent (5.11 g, 12.6 mmol) was added in one
portion to a stirred solution of the appropriate γ-keto ester
(3.00 g, 10.5 mmol) in dry toluene (100 mL) under dry argon.
The reaction mixture was heated under reflux (see Table 1
for the appropriate reaction times) before the reaction mixture
was cooled to room temperature and the solvent was removed
in vacuo. The crude products were purified as described.
Derivatives having chain lengths in excess of 12 carbon
atoms were not evaluated as the use of such long chains
in thermotropic liquid crystals results in increases in
viscosity that are not compatible with fast responding
electrooptic materials.
Con clu sion s
We have demonstrated the first reliable and highly
efficient synthesis of alkoxythiophenes from γ-keto ester
precursors. The described procedure represents the first
synthetic methodology that provides a general entry into
functional alkoxythiophene derivatives that may, for
example, be used in the synthesis of thermotropic liquid
crystals. The methodology is a significant addition to the
currently available literature and may also be used in
the synthesis of precursors for materials used in medical
applications.
Ack n ow led gm en t. The authors would like to ex-
press their gratitude to Kent State University for
financial assistance. Our grateful thanks are also given
to Dr. Mahinda Gangoda for assistance in obtaining
Exp er im en ta l Section
4-(4-Br om op h en yl)-4-oxobu ta n oic Acid (1). Anhydrous
aluminum chloride (26.67 g, 0.2000 mol) was added in one
portion to a mechanically stirred mixture of powdered succinic
(37) Badger, G. M.; Rodda, H. J .; Sasse, W. H. F. J . Chem. Soc. 1954,
4162-4168.