K.S. Sharath Kumar, H. Ananda, S. Rangappa et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. Synthesis of pyrrole derivative 4a.
tiarybutoxide, DBU and potassium carbonate under different reac-
tion conditions (Table 1 Entry 1–9). In all the cases we found b-
enaminone as a major byproduct.
The generality of the protocol was explored using suitable reac-
tion condition for the preparation of other structurally diversified
pyrroles 4a-o (Scheme 3) from the corresponding monothio-1,3-
diketones 1a-m and ethyl glycine ester/amino acetonitrile 2a-b
as shown in the Table 2. The ethyl glycine ester and amino acetoni-
monothio-1,3-diketones with the moderate product yield, we
became interested in isolating b-enaminones intermediate and to
perform a base catalysed cyclocondensation reaction stepwise to
compare efficiency in terms of product yield. Based on the opti-
mization study for one pot synthesis of pyrroles, it is clear that
sodium acetate in ethanol at room temperature is the better reac-
tion condition to prepare b-enaminones (Table 1, Entry 12). Both,
ethyl glycine ester and aminoacetonitrile 2a-b undergo facile con-
densation reaction with 1,3-monothio-b-diketones 1a-m to afford
corresponding enaminones 3a-o in good yields (See supplemen-
tary file Scheme S1 and Table S1). The chemical shift value of
˃11.0 corresponds to NH confirmed that the enaminones exists
in more stable intra-molecularly hydrogen bonded Z configuration
form. In further, to optimize the cyclocondenstaion reaction of b-
enaminones to generate pyrroles, enaminone 3b was selected as
a model reactant for the synthesis of pyrrole 4b in the presence
of various bases and solvents in different reaction conditions
(Scheme S2 and Table S2). Thus, the condensation of 3b with differ-
2 3
trile underwent cyclocondensation smoothly in presence of CS CO
in DMF at reflux condition. Thus, the monothio-1,3-diketones bear-
ing various electron donating substituents on the different position
of aryl ring such as methoxy, chloro, bromo and trimethoxy groups
gave the desired product in good yield (Table 2, Entry 2, 6, 8 & 11).
Similarly, the monothio-1,3-diketones bearing electron withdraw-
ing substituents on the different position of aryl ring such as nitro,
cyano and trifluoromethyl groups have also gave the considerable
product yield (Table 2, Entry 4, 5 & 9). On the other hand, the pyr-
roles bearing 2-furyl/2-thienyl/4-pyridyl groups at 3rd and 5th
positions were obtained in appreciable yields from the correspond-
ing monothio-1,3-diketones (Table 2, Entry 3, 7 and 10). Expect-
edly cyclocondenstaion of amino acetonitrile with monothio-1,3-
diketones gave considerably high yields compare to ethyl glycine
ester because of more electron withdrawing ability of cyano group,
which makes the methylene protons more acidic (Table 2, Entry 12,
2 3
ent bases like K CO , NaH and sodium ethoxide doesn’t gave the
desired product 4b in appreciable yield (Table S2, Entry 1, 4 & 5).
When the reaction was performed in presence of potassium ter-
tiary butoxide, only trace amount of desired product was observed
(Table S2, Entry 3). When the condensation reaction was per-
formed with the triethyl amine as a base in DMF solvent, the reac-
tion doesn’t yield the product 4b (Table S2, Entry 6). However,
dramatic increase in the yield (70% & 72%) of pyrrole 4b was
observed when cesium carbonate and DBU was used as a base
respectively in DMF solvent at 120 °C (Table S2, Entry 2 & 7), prob-
ably due to enhanced base strength of cesium carbonate and DBU.
Similarly, pyrrole 4b was obtained in an improved yield, when the
reaction was conducted in toluene as solvent and DBU as a base
(Table S2, Entry 8). Attempt to further improvement of the product
yield of 4b by varying the reaction time was not successful
(Table S2, Entry 9). Interestingly, there was an increase in yields
via step-wise procedure but not an appreciable improvement in
the formation of pyrrole derivatives 4a-o on comparison with
one-pot protocol (Scheme S3 and Table S3).
1
3, 14 and 15). It is noteworthy to mention that, it was possible to
regioselectively install two different heterocyclic rings at 3rd and
th position of pyrrole which may display NLO properties because
5
of the push–pull chromophores i.e., electron donating substituents
at 3rd & 5th position and electron withdrawing carboxylate/car-
bonitrile group at 2nd position on pyrrole moiety, which was evi-
dent while TLC monitoring showing fluorescent spots. Therefore,
three different heterocycles with extended
p-conjugation could
become useful fluorophores in optoelectronic devices [58–59].
We have synthesized a good number of pyrrole derivatives with
most of the possible (Scheme 4) substituents on 2nd, 3rd and 5th
positions in one pot operation. The present method showed wide
functional group tolerance with product yield ranging from 60 to
8
0% and also, we found the expected b-enaminone byproduct in
Next, we have diverged our interest in substituting aryl/hetero-
aryl groups on second position of pyrrole ring by using different
aryl/heteroaryl methylene amines. Condensation of 2-furfury-
lower yields. Having established the regioselective route for 3,5-
bis(het)arylpyrrole-2-carboxylates/carbonitriles generation from
Scheme 3. Synthesis of 3,5-bis(het)arylpyrrole-2-carboxylates/carbonitriles (4a-o) from monothio-1,3-diketones.
3
Sharath Kumar, Kothanahally S.
