Communications
Table 1: Two-step ipso substitution of the aromatic carboxylic acids 6 to
The first step of the aromatization is the protonation of
afford the arenes 3.
the carboxylic acid with the stronger mineral acid (Scheme 1).
The intermediate cation 4 can dehydrate to the acylium ion 5,
which after decarbonylation and deprotonation affords the
arenes 3. This mechanism was confirmed by the detection of
carbon monoxide in the gas phase by IR spectroscopy and by
reduction of PdII to Pd0. Therefore, an oxidative decarbox-
ylation can be excluded and the herein described trans-
formation is a formal retro-Koch reaction.[6]
O
CO2H
R
CO2H
R
R
1. Li/NH3
2. RBr
ClSO3H
O
+
–60°C
CH2Cl2, 0°C
R'
R'
R'
R'
6
1
3
7
R’
R
Yield [%][a]
1
3
7
6a
6a
6a
6b
6b
6b
6c
6c
6c
6d
6d
6d
H
H
H
Me
Et
iPr
Me
Et
iPr
Me
Et
iPr
Me
Et
1a [96]
1b [99]
1c [98]
1d [98]
1e [74]
1 f [98]
1g [99]
1h [89]
1i [89]
1j [92]
1k [87]
1l [86]
3a [74]
3b [76]
3c [89]
3d [95]
3e [86]
3 f [98]
3g [32]
3h [38]
3i [35]
3j [81]
3k [87]
3l [93]
7a [0]
7b [0]
7c [0]
7d [0]
7e [0]
7 f [0]
7g [53]
7h [52]
7i [49]
7j [0]
ortho-Me
ortho-Me
ortho-Me
meta-Me
meta-Me
meta-Me
para-Me
para-Me
para-Me
7k [0]
7l [0]
iPr
[a] Yield of isolated product after column chromatography on silica gel,
crystallization, or distillation.
Scheme 1. Proposed mechanism for the acid-catalyzed aromatization
of the cyclohexadienes 1.
O
CO2H
CO2H
R
R
R
We investigated the influence of various acids on the
decarbonylations in order to further improve the yields of the
arenes 3 for synthetic applications. The best results were
obtained with chlorosulfonic acid, since it is not only a strong
mineral acid but exhibits dehydrating properties as well.
Indeed, the desired products 3 could now be isolated in over
90% yield; thus the Birch reduction/protonation reaction
sequence offers a valuable procedure for the highly regiose-
lective synthesis of alkyl-substituted arenes. Such decarbon-
ylations were hitherto unknown for 1,4-cyclohexadienecar-
boxylic acids, but are in accordance with the conversion of
citric acid into acetonedicarboxylic acid.[7]
The applicability of our new methodology was examined
in the reaction of a variety of 1,4-cyclohexadienes 1 with
chlorosulfonic acid (Table 1). In addition to the regioisomeric
benzoic acids 6b–d, unsubstituted benzoic acid (6a) can be
used as the starting material. The advantage of this strategy is
that the Birch reduction/alkylation proceeds very smoothly.[8]
Indeed, the desired arenes 3a–f and 3j–l can be isolated in
high to excellent yields in only two steps from the reaction of 1
with chlorosulfonic acid (Table 1). The slightly lower yields
with the unsubstituted cyclohexadienes 1a–c are attributable
to the higher volatility of the products 3a–c and the resulting
problems during the work-up. Interestingly, meta-toluic acid
(6c) affords lactones 7 as well as the expected arenes 3g–i.
This result can be rationalized in terms of a competing
protonation of the electron-rich double bond on forming the
carbocation 8, which is intramolecularly trapped by the acid
group (Scheme 2).
+
+
- H
H
O
+
CH3
CH3
CH3
1g-i
8g-i
7g-i
Scheme 2. Proposed mechanism for the acid-catalyzed formation of
the lactones 7.
arenes proceeds mechanistically through a protonation,
dehydration, and subsequent decarbonylation reaction. Fur-
thermore, no toxic lead tetraacetate is required. The herein
described formal ipso substitution should be of special
interest for further synthetic applications as it uses simple
and cheap reagents, and offers the possibility of performing
the Birch reduction with various aromatic carboxylic acids
and electrophiles.
Experimental Section
Lithium (1.60 g, 230 mmol) was added in small portions at À608C to a
solution of the carboxylic acid 6 (100 mmol) in liquid ammonia
(400 mL) until a blue color persisted. After 30 min at this temper-
ature, the alkyl halide (400 mmol) was added slowly over a period of
5 min. The ammonia was evaporated overnight and the residue was
dissolved in water (400 mL). Concentrated hydrochloric acid was
then added to give pH1–2 and the solution extracted with tert-butyl
methyl ether (3 200 mL). The combined organic phases were
washed with water (100 mL) and then dried over sodium sulfate.
After removal of the solvent, the 1,4-cyclohexadienecarboxylic acids
1 could be used directly for the next step or were purified by
recrystallization.
In summary, the Birch reduction/protonation reaction
sequence offers a simple and highly regioselective alkylation
of arenes. Excellent yields of ortho- and para-substituted
products are obtained, whereas lactones were isolated as by-
products with 3-methylbenzoic acid. The formation of the
The 1,4-cyclohexadienecarboxylic acid 1 (10 mmol) was dissolved in
dichloromethane (20 mL) and chlorosulfonic acid (1.16 g, 10 mmol)
was added at 08C, which resulted in the evolution of carbon
monoxide. After 10 min the solution was neutralized with a saturated
solution of sodium hydrogen carbonate. The aqueous phase was then
2490
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2003, 42, 2489 – 2491