Org. Synth. 2002, 79, 204
DOI: 10.15227/orgsyn.079.0204
3-(4-BROMOBENZOYL)PROPANOIC ACID
[
Bromobutanoic acid, 4-bromo-γ-oxo-
]
Submitted by Alexander J. Seed, Vaishali Sonpatki, and Mark R. Herbert
1
.
Checked by Ayako Ono and Koichi Narasaka.
1. Procedure
A 500-mL, three-necked, round-bottomed flask
(Note 1)
equipped with an overhead mechanical stirrer, is charged with
powdered
succinic anhydride (10.01
g, 0.1000 mol)
(Note 2) and
bromobenzene (96.87 g,
0.6170 mol)
(Note 2) under dry argon.
The resulting white mixture is cooled to 0°C before anhydrous
aluminum chloride (26.67 g, 0.2000 mol)
(Note 2) is added in one portion (Note 3).
The reaction conditions are maintained over a period of 4 hr before the reaction mixture
is allowed to warm to room temperature. The reaction mixture is stirred for 96 hr
at room temperature (completion of the reaction is indicated by cessation of the evolution
of hydrogen chloride gas) and is then poured into cooled (0°C),
mechanically stirred
hydrochloric acid
(250 mL, 37%)
(Note 4)
and stirred for 1 hr. The white precipitate is filtered off, washed well with water
(1 L) and dried overnight on a Büchner funnel. The crude
product (24.81 g, 97%) is crystallized from dry
toluene
(Note 5) and dried under
reduced pressure (P2O5, CaCl2, 18 hr) to afford a
white crystalline product (first fraction, 20.76
g, second fraction, 3.47 g);
yield is 24.23 g (94%) (Note 6).
2. Notes
1.
The glassware was dried in an oven at 130°C, assembled while
still hot, and alternately evacuated and flushed with
argon.
2.
The checkers purchased
succinic
anhydride, bromobenzene
and
aluminum
chloride from Wako Pure Chemical Industries, Ltd, Tokyo Chemical
Industry Co., and Kanto Chemical Co.
respectively, and used
them as received.
3.
Upon the addition of the
aluminum
chloride
the reaction progressively turned from a yellow suspension
to a clear yellow to a clear orange-red solution.
4.
The checkers used
35-37%
hydrochloric acid (340 mL) purchased from Kokusan
Chemial Works, Ltd.
5.
The
toluene was
dried over sodium metal.
6.
The product showed the following physical and spectroscopic characteristics:
mp 147-148°C (lit.
2
149.5-150.2°C).
1H NMR (500 MHz,
DMSO-d
6) δ: 2.59 (2 H, t,
3J = 6.5), 3.21
(2 H, t,
3J = 6.5), 7.88 (2 H, d,
3J = 8.8),
7.96 (2 H, d,
3J = 8.8), 12.19 (1 H, s)
;
13C NMR (126
MHz, DMSO-d
6) δ: 28.3, 33.6, 127.7,
130.3, 132.2, 135.9, 174.1, 198.2;
IR (KBr) cm
−1: 3400-2600,
1730, 1670, 1585, 1479, 1447,
1410, 1332, 1281, 1241, 1198,
1105, 1074, 990, 905, 840,
791. MS m/z 256.2(M+),
185.1, 183.1(100%), 157.1, 155.1,
76.1, 75.1. Anal. Calcd for C
10H
9BrO
3:
C, 46.72; H, 3.53. Found: C, 46.69; H, 3.49.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
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3. Discussion
Recently we have reported the first highly efficient synthesis of ferroelectric
liquid crystals bearing the 2-alkoxythiophene unit via Lawesson's reagent-mediated
cyclization of γ-keto esters.
3
4 The requisite γ-keto
acids were initially targeted through acylation of appropriately substituted aryl
compounds using the procedure described by Fieser et al.
5
A literature search reveals that acylation of aryl units with
succinic
anhydride
is almost always carried out using this procedure
which requires elevated temperatures. Recent studies have shown that the acylation
of bromophenyl systems using this procedure results in problematic debromination
2 and considerably lower yields.
6 In repeating the method of Fieser it was found that
acylation of
bromobenzene
gave lower yields and a substantial quantity (
8%
by
1H NMR) of the ortho product as well as the desired para isomer.
Our improved methodology uses low temperatures and extended reaction times, and
has been shown to give consistently high yields of purified materials combined with
complete regioselectivity in a variety of aryl systems (see Table I). The procedure
is the first reliable, simple and general method for acylation of aryl systems using
succinic anhydride
. In addition,
it was noted that the reaction conditions also gave the highest reported yield (previous
yields range from
55-63%
7) for acylation of
bromothiophene
with
succinic anhydride. Of particular interest was the fact
that we did not observe any ring opening that is so often reported in reactions involving
combinations of
aluminum chloride
and thiophene derivatives.
8
The methodology may also be applicable to the synthesis of pharmacodynamic agents
based on the alkoxythiophene core.
9 Such materials
should be readily accessible via our new cyclization methodology
3,
4,
10
which utilizes the γ-keto acid precursors.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
3-(4-Bromobenzoyl)propanoic acid
:
Benzenebutanoic acid, 4-bromo-γ-oxo- (9); (6340-79-0).
Succinic anhydride (8):
2,5-Furandione, dihydro-
(9); (108-30-5).
Bromobenzene:
Benzene, bromo-
(8,9); (108-86-1).
Aluminum chloride (8,9); (7446-70-0).
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