Tetrahedron Letters
On water direct arylation of imidazo[1,2-a]pyridines with aryl halides
Saradhi Kalari a, Dattatraya A. Babar a,b, Uttam B. Karale a,b, Vitthal B. Makane a,b, Haridas B. Rode a,b,
⇑
a Department of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
Introduction
reported.12 Kwong et al. studied the direct arylation of 1a with aryl
tosylates and mesylate using K3PO4 base at 120 °C in presence of
SPhos ligand in t-BuOH12c whereas, Doucet et al. reported the
direct arylation using aryl bromide in DMA at 150 °C with KOAc
as base.12b Lee et al. reported the direct arylation of 1a and aryl
bromide in DMA at 140 °C with Pd(II) complexes having
monodentate abnormal and normal carbene ligands.12d Sames
et al. reported the direct arylation of 1a and aryl iodide in DMA
at 125 °C with palladium complexes (L1L2PdX2 wherein L1 = N-
heterocyclic carbene (NHCs) and L2 = phosphine).12a All the above
methods are reported in organic solvents and at high
temperature. Additionally, three of the methods need ligand,
either added during reaction or in the form of palladium
precatalyst; while ligandless method reported by Doucet et al. is
carried out at 150 °C in DMA. This suggests that there is a need
for a general arylation protocol under mild reaction condition.
Herein, we report the first example of palladium-catalysed
direct arylation of imidazo[1,2-a]pyridines on water. This ligand-
free method is a simple, mild and ecofriendly protocol for the
direct arylation.
CAC bond formation constitutes an important strategy for the
synthesis of chemically diverse compounds.1 Some of the promi-
nent strategies include, for instance, Suzuki, Kumada, Stille,
Negishi and Hiyama cross-coupling reactions.1c,2 Despite the
large applicability of these reactions, most of them proceed via
stoichiometric organometallic reagents.3 In such cases, the prepa-
ration of such organometallic reagents becomes troublesome and
their instability may jeopardise these reactions. Large amount of
metallic salts, as by-products, are generally produced in these reac-
tions.3b,4 In such a scenario, metal catalysed direct arylation
method is advantageous, since it leads to a reduced/limited
amount of byproducts as well as no prior preparation of
organometallic reagents is required.5 Hence, strategies for direct
functionalization of sp2 CAH bond are becoming more attractive
in recent times.6 The direct arylation holds a significant place in
medicinal chemistry and drug discovery as many pharmaceutical
companies uses this strategy to synthesize the drug molecules.7
Solvents including, DMSO, NMP, dioxane, DMAc, xylene and
toluene have been reported to effect the palladium catalysed direct
arylation reactions, more so at higher temperature (>100 °C) and
requiring sterically demanding phosphine ligands.8 These two fac-
tors limit the applicability of metal catalysed direct arylation reac-
tions in industry. In view of these factors, water as a solvent in
organic transformations has attracted much interest due to its
low cost, easy availability; nontoxic and non-flammable nature.9
In addition, simple work-up procedures and mild reaction condi-
tion may signify its role as solvent in such reactions. Continuing
our efforts to generate heterocycle based inhibitors as antibacterial
agents, we became interested in 3-aryl imidazo[1,2-a]pyridines.
The imidazo[1,2-a]pyridines are biologically important class of
molecule and have shown wide variety of pharmacological effects
including anticancer, antiapoptotic, anxiolytic, analgesic, anti-
inflammatory, antiviral, antituberculosis.10 Recently we have
shown antibacterial activity of 3-aryl imidazo[1,2-a]pyridines
against Staphylococcus aureus.11 The imidazo[1,2-a]pyridine scaf-
fold (1a) is present in commonly used drugs such as, olprinone,
zolmidine, zolpidem, alpidem, necopidem and saripidem.10 As a
result, direct arylations on 1a and its analogues have been
Results and discussion
The 1a undergoes arylation at 3 position. This regioselectivity
may be due to
p-excessive nature of the fused five membered
ring.8,13 The bromination occurs exclusively at 3-position of 1a
suggesting potential of high regioselectivity in arylation reaction.14
We began initial optimization of direct arylation between 1a with
4-iodoanisole (2a) in the presence of catalytic amount of Pd(OAc)2
at 100 °C as a model reaction. The results are summarized in
Table 1. Keeping in mind, the cost factor and water based protocol;
KOH was selected as the base for conducting this reaction. A reac-
tion between 1a, (1 equivalent) 2a, (1.5 equivalent) and KOH (3
equivalent) using palladium(II)acetate (5 mol%) in dioxane, ace-
tonitrile, DMSO, DMF, DMA, and toluene at 100 °C for 24 h was
investigated (entry 1 to 6, Table 1). Reaction in DCE was carried
out at 80 °C. In DMA, 70% yield of 3a was observed while other
organic solvents gave lower yields. In case of acetonitrile, only
trace amount of product was formed, while no product was
observed in case of DCE. When the reaction was carried out in
water (entry 8, Table 1), we were pleased to observe that LCMS
based yield of product was 94% and isolated yield was 85%. Further
reduction in the amount of catalyst to 2 and 1 mol% afforded lower
yields of product 3a (entry 10 and 11, Table 1). Change in base from
⇑
Corresponding author at: Department of Natural Product Chemistry, CSIR-
Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Kalari, Saradhi
