coupling sequence.6 However, the sequence operated only
when a nitrogroup at the ortho-position to the carboxylate
group inthe arene ring waspresent, whereas, inthe absence
of the nitro group, the same catalytic condition drove the
reaction via the imination/CꢀH activation sequence. This
result was in line with Goossen’s bimetallic approach
which hypothesizes that due to its strong coordinating
property, the presence of the nitro group ortho to the
carboxylate in aromatic system enhances the copper-ligat-
ing quality of the carboxylate.2b In contrast, for hetero-
aromatic carboxylic acids, the decarboxylative coupling
was shown to be successful with the Pd-catalyst only.4a,c
Forgione et al. proposed that delocalization of the lone
pair of electrons of the heteroatom in the ring induces
nucleophilicity in the heteroaromatic partner which then
undergoes a reaction with the in situ generated electrophile
ArꢀPd(X)(L). This hypothesis gained support by the
theoretical studies performed by Liu et al. toward under-
standing the Pd-catalyzed decarboxylative couplings.7 With
this background it became imperative to investigate the
feasibility of transition-metal promoted tandem imination/
decarboxylative coupling between potassium 2-amino-
(hetero)benzoates and 2-haloarylaldehydes. Herein, we
report results of our studies in this direction using potassium
5-amino-1-phenyl-1H-pyrazole-4-carboxylates and 3-amino-
thiophene-2-carboxylate as the heterocyclic substrates.
preparing fused pyrazoles,11 we were prompted to initially
establish the conditions for arylation in pyrazoles via
decarboxylative coupling. In this context first we prepared
1-(2-chlorophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid
1 and 1,5-diphenyl-1H-pyrazole-4-carboxylic acid 3 and
their respective potassium salts and subjected them to
coupling with bromobenzene in the presence of a Pd-
catalyst and Cs2CO3 as reported by Forgione et al.
(condition A) and in the presence of a PdꢀCu cocatalyst
as reported by us (condition B). It was gratifying to note
that the reactions were successful under both conditions to
afford the respective coupling products 2 and 4 in compar-
able yields (Scheme 1). Subsequently in a modification of
condition A, the reactions of potassium salts of 1 and 3
were performed in the presence of 1,10-phenanthroline in
place of Cs2CO3 (condition C). Under this condition
though 2 was isolated in58% yields, the yield of4 increased
to 92%. Thus it was apparent that as reported for other
5-member heterocyclic carboxylic acids, the decarboxyla-
tive coupling in pyrazole carboxylic acids can be achieved
in the presence of the Pd-catalyst only.
Next in our objective to establish cascade imination/
decarboxylative coupling in pyrazole-based substrates,
we embarked on studying the reaction of potassium
5-amino-1-phenyl-1H-pyrazole-4-carboxylate (5a) with
2- bromobenzaldehyde (6A). Successful implementation
of the protocol was anticipated to afford pyrazolo-fused-
pyridine, a core unit represented in several bioactive
compounds endowed with antidepressant, antianxiolytic,
and platelet aggregation inhibitory activities.12 Although
the synthesis of such a system via a PictetꢀSpengler
reaction of 4-(3,4-dimethoxyphenyl)-5-aminopyrazoles
with different aldehydes is reported,13 its scope remains
limited due to the necessity for the presence of electron
donating groups on the aromatic ring. In a pilot experi-
ment therefore, the reaction of 5a with 6A was investigated
in the presence of Pd(PPh3)2Cl2 (condition C), but the
required product 7aA could be isolated in 47% yields only
(Table 1, entry 1). Performing the same reaction in the
presence of Cs2CO3 instead of 1,10-phenanthroline failed
to yield any product (entry 2). This impelled us to screen
other Pd-sources including PdCl2, Pd(TFA)2, and Pd(OAc)2
for the reaction, but the yields of the product were only
moderate (entries 3ꢀ6). To improve the yield of 7aA, we
next examined the PdꢀCu cocatalyst system (condition B),
and to our delight the yield improved to 90% (entry 7).
Further we discovered that reducing the catalyst load to
Pyrazoles are considered to be important heteroarenes
due to their frequent presence in pharmaceuticals and
herbicides.8,9 In particular, the significance of pyrazole
bi(heteroaryl) has resulted in the formulation of effi-
cient protocols for direct C-3, C-4, and C-5 arylations of
pyrazoles.10 Arylations in pyrazoles can also be achieved
via decarboxylative coupling, but to the best of our knowl-
edge there is no previous report by this route. Therefore in
order to investigate the implementation of cascade imination/
decarboxylative coupling/arylation in pyrazoles for
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