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Organic Process Research & Development
Technology Report
Sinha et al.10 have found a new decarboxylation method
during their search for alternative decarboxylation catalysts.
They were attracted by the catalytic ability of basic ionic liquids
as basic conditions have been known to favor the
decarboxylation process. Consequently, 1 was irradiated with
ionic liquid 1-butyl-3-methylimidazolium hydroxide [bmim]-
OH under microwave conditions. The authors found that the
expected indole (2) was obtained in 60% yield at the optimized
temperature of 240 °C and thereafter screened a number of
ionic liquids. From this study they found that the best ionic
liquid was the neutral 1-hexyl-3-methylimidazolium bromide
which increased the yield of indole (2) up to 79% at 240 °C.
The yield could be further improved through the addition of a
small amount of water to the ionic liquid (6 equiv in
comparison to the substrate). The obtained yield of indole
(2) was, after 15 min at 240 °C, 88%.
new homogeneous decarboxylation method involving the use of
an organic base, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU),
and a high-boiling polar aprotic solvent, N,N-dimethylaceta-
mide (DMAC). Also for this method microwave heating was
utilized. The decarboxylation was carried out at 200 °C for 1 h
in a sealed microwave vessel (Scheme 4). The authors found
Scheme 4. DBU-promoted decarboxylation with microwave
heating
this method to be more convenient as both the base and the
solvent could be easily washed away. Based on the substituents
in the benzothiophene, yields between 54 and 100% were
obtained.
The main obstacle with microwave technology is still the
very limited scale-up possibilities; this limits the use of
microwave heating for process development with the intention
for large-scale manufacture. To mimic microwave heating with
conventional heating, the fast heatup, and the ability for super
heating, the amount of material heated has to be very small.
One way of doing this is in a plug-flow tube reactor with
pressure control. This reactor can be heated and cooled very
rapidly to any temperature independent of the boiling point of
the solvent.
Trainer et al.11 reported that in a simple procedure, indole-2-
carboxylic acid (1) was quantitatively decarboxylated after 20
min at 255 °C in water in a microwave batch reactor. 2-
Carbethoxyindole (3) could not be decarboxylated under these
conditions. The authors found only the 2-indole carboxylic
acid. They also found that an excess of base prohibits the
decarboxylation of 2-carbethoxyindole (3). Changing the
conditions from pure water or an excess of base to
substoichiometric amounts of base n(0.2 mol %) in 0.05 M
sodium acetate solutions gave within 60 min at 265 °C indole
(2) in a 95% yield (Scheme 2). From their findings, the authors
Scheme 2. Microwave-assisted hydrolysis and
decarboxylation in aqueous sodium hydroxide
RESULTS AND DISCUSSION
■
We have assembled and used a continuous reactor setup for
process development and scale-up of high-pressure, high-
temperature, continuous processes that has been used in
various projects. The reactor consists of ISCO high-pressure
syringe pumps, a mixing device (either micro mixer or T-joint),
coiled tubing (stainless steel, PTFE, Hasteloy) coiled in a GC
oven, and at the outlet of the reactor, a cooling zone, a pressure
gauge, and a backpressure valve controlling the conditions to
prevent evaporation or off gassing in the hot zone.
suggest that the decarboxylation is going through an arenium
ion mechanism with H+ as the electrophile and CO2 as the
leaving group. The authors back up their discussion with several
references.
Rao et al.12 reported the decarboxylation of indole derivative
4 with copper oxide in sulfolane at 185−200 °C with
conventional heating to obtain 5 an intermediate for the
synthesis of an active pharmaceutical ingredient (Scheme 3).
We have, in a way similar to that of Kappe et al.,14 also
looked at the potential to transfer processes that are run under
microwave heating to continuous plug flow reactor protocols
with convection heating. The microwave-assisted decarbox-
ylation of indole-2-carboxylic acid from Jones and Chapman9 is
an interesting reaction as the reaction delivered indole in high
yield under microwave heating in quinoline or neat. However,
the reaction was found to be successful only on very small scale.
The transfer to a tube reactor would be ideal as in this type of
reactor there is a very small amount of reactants in the hot zone
at any given time. In combination with the report of Sinha10 on
the decarboxylation of indole-2-carboxylic acid in an ionic
liquid with a small amount of water and the process developed
by Trainer11 with a decarboxylation of the same substrate under
high-temperature aqueous conditions, it seems possible to
decarboxylate indole-2-carboxylic acid in solution in a tube
reactor under various conditions. The microwave-mediated
decarboxylation of the benzo[b]thiophene-2-carboxylic acid
with 5 equiv of DBU in DMAC at 200 °C from Allen13 is also
interesting as part of this concept. On the basis of these reports
we thought that it would be worthwhile to screen for a new
protocol for the decarboxylation of indole-2-carboxylic acid and
for other heteroaromatic and aromatic carboxylic acids in a tube
Scheme 3. Copper oxide-catalyzed decarboxylation in
sulfolane
Allen13 reported an improved decarboxylation method for
substituted benzothiophenes by using microwave heating. They
first developed a copper-mediated reaction in quinoline. The
reaction was run on a 170 mmol scale in the CEM MARS
microwave oven at 200 °C. Under these conditions they
obtained an isolated yield of 6-cyano benzothiophene of 93% in
comparison to 53% with conventional heating. The authors
commented that, although the reaction was successful, the
reaction mixture was heterogeneous and the workup problem-
atic. To circumvent these problems the authors developed a
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dx.doi.org/10.1021/op300125p | Org. Process Res. Dev. 2012, 16, 1449−1454