A one-step radical synthesis of pyrrol-2-acetic acids

Article abstract of DOI:10.1016/S0040-4039(03)01714-3

Pyrrol-2-acetic acids were generated following a procedure involving I-transfer radical addition of iodoacetic acids to pyrrole with spontaneous loss of HI. This procedure also allows for efficient syntheses of 2-alkyl pyrroles through subsequent thermolytic decarboxylation.

Full text of DOI:10.1016/S0040-4039(03)01714-3

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TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6853–6855
A one-step radical synthesis of pyrrol-2-acetic acids
Jeffrey H. Byers,* Michael P. Duff and Gregory W. Woo
Department of Chemistry and Biochemistry, Middlebury College, Middlebury, VT 05753, USA
Received 12 June 2003; revised 7 July 2003; accepted 12 July 2003
Abstract—Pyrrol-2-acetic acids were generated following a procedure involving I-transfer radical addition of iodoacetic acids to
pyrrole with spontaneous loss of HI. This procedure also allows for efficient syntheses of 2-alkyl pyrroles through subsequent
thermolytic decarboxylation.
© 2003 Elsevier Ltd. All rights reserved.
Pyrrol-2-acetic acids constitute an important class of
compounds due to their use in a wide variety of
molecules of pharmaceutical interest, most notably
non-steroidal anti-inflammatory drugs such as tolmetin1
and ketorolac.2 There currently exist several modestly
successful routes to esters of pyrrol-2-acetic acid (1),
shown in Eq. (1). Friedel–Crafts acylation of pyrrole
with ethoxalyl chloride,3 followed by reduction of the
resulting glyoxalate ester4 led to generation of ester 1,
which could be alternatively generated upon treatment
of pyrrole with ethyl diazoacetate in the presence of
Cu(acac)2.5 More recently, radical methods have been
used to synthesize these pyrrole acetate esters.
Baciocchi6 has utilized oxidative radical aromatic sub-
stitution methods (BEt3, DMSO) to generate 1 in 47%
yield.
to generate substitution product 1. Curran8 has shown
that a substoichiometric quantity of Bu3SnSnBu3 is
required in I-transfer radical addition reactions in order
to consume I2, a radical chain suppressant which is
generated as a byproduct of these reactions. In the
course of our work,7 we found that the addition of
Na2S2O3 as an I2 reductant in the presence of the
phase-transfer catalyst Bu4N+I− to aid in thiosulfate
solubility provided an effective alternative to the use of
distannanes. We also found that propylene oxide served
as an effective HI trap.
Hydrolysis of ester 1 with aqueous NaOH has been
reported to generate pyrrol-2 acetic acid (2, Eq. (1)) in
56% yield upon reacidification.4 We were initially inter-
ested in seeing if our I-transfer radical aromatic substi-
tution conditions would be amenable to the direct
synthesis of 2, negating the need for this low-yielding
hydrolysis. Under our conditions, photolysis of
iodoacetic acid in the presence of 15 equiv. of pyrrole
led to formation of 2 in 72% yield (Eq. (3)). As in our
previous work, the significant excess of pyrrole was
necessary in order to minimize the formation of dialkyl-
ated products. Regioselectivities in this and all other
radical reactions reported herein were outstanding, with
barely detectable (by GC/MS) and non-isolable quanti-
ties of other isomeric products being formed.
(1)
We have previously reported atom-transfer radical
addition methodology leading to formation of ester 1 in
90% yield.7 In this methodology, CꢀC bond formation
is proposed to occur in the course of I-transfer radical
addition, as shown in Eq. (2). The putative addition
product 3 spontaneously undergoes elimination of HI
(2)
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01714-3

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6854
J. H. Byers et al. / Tetrahedron Letters 44 (2003) 6853–6855
(3)
Table 1.
through flash chromatography on silica gel or extrac-
tion with aqueous base. The yields listed are for iso-
lated and fully characterized products.10
It is also important to note that the known facile
thermal decarboxylation of pyrrole-2-acetic acids9,11
allows this methodology to serve as a highly regioselec-
tive synthesis of 2-alkyl pyrroles. This decarboxylation
does, however, lead to the necessity of limiting the
exposure of the acids to all but the mildest heat.
Attempted GC/MS analysis of these acids also resulted
in only the detection of the decarboxylated products,
with the decarboxylation occurring due to the high
temperature (250°C) in the injection port.
The successful generation of 2 was dependent on care-
ful control of the reaction temperature in the course of
the photolysis. If the reaction temperature was allowed
to warm above approximately 30°C, the major product
obtained was acid 4, presumably arising from nucle-
ophilic attack of one of several possible carboxylic acid
intermediates on iodoacetic acid, in addition to the
desired radical substitution.
Attempted addition of malonate monoester 8 led to
formation of ester 9 in 65% yield, presumably through
a sequence of events involving radical substitution fol-
lowed by decarboxylation, as shown in Eq. (4). Not
surprisingly, the carboxylic acid functionality present in
the intermediate is further labilized by the additional
ester functionality. Acid 8 was generated by treatment
of dimethyl methylmalonate with 1 equiv. of KOH in
methanol. Purification of the saponification product
was simplified by recrystallization of the sodium salt
from MeOH with hot filtration prior to reacidification.
Conversion of the monoacid to 8 was carried out by
treatment with Br2 in CH2Cl2.
More highly substituted pyrrol-2-acetic acids have pre-
viously only been synthesized through the generation of
the trianion of 2 with excess t-BuLi, followed by
monoalkylation with an alkyl halide.9 Thus, we were
(4)
interested in seeing if our methodology would allow for
direct generation of these alkylated acids. The modest
variety of a-iodoacids in Table 1, generated upon treat-
ment of commercially available a-bromoacids with NaI
and catalytic Bu4N+I− in acetone, were successfully
added to pyrrole under these conditions, leading to the
products shown. Iodophenylacetic acid, on the other
hand, failed to yield any substitution product, pre-
sumably due to the diminished reactivity of the benzylic
radical. A typical procedure for the reaction is as
follows: Pyrrole (2.02 g, 30 mmol), Na2S2O3 (0.32 g, 2
mmol), propylene oxide (0.58 g, 10 mmol), Bu4N+I−
(0.0074 g, 0.02 mmol) and 2.0 mmol of the desired
iodoacid were dissolved in 4 ml of methyl tert-butyl
ether (MTBE, distilled from CaH2) in a screw-cap
Pyrex test tube. The solution was cooled in an ice bath
and deoxygenated with bubbling Ar for 10 min. Photoly-
sis with an efficiently-cooled 450-W Hanovia lamp for
36 h resulted in complete consumption of the limiting
iodoacid. Pyrrol-2-acetic acids could be isolated
In conclusion, we have demonstrated a convenient one-
step synthesis of pyrrol-2-acetic acids, which also serves
as an efficient entry into 2-alkyl pyrroles through subse-
quent thermal decarboxylation.
Acknowledgements
We thank the National Science Foundation (Grant
CHE-9732600) and the Petroleum Research Fund of
the ACS (Grant 33156-B1) for their support of this
project. Purchase of the NMR spectrometer used in this
work was supported through the Kresge Foundation.
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J. H. Byers et al. / Tetrahedron Letters 44 (2003) 6853–6855
6855
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