Metal-free C–H arylation of imidazoheterocycles with aryl hydrazines

A simple and efficient metal-free arylation of imidazo[1,2-a]pyridines at the C-3 position with arylhydrazine has been achieved at room temperature under ambient air conditions. Various 2,3-disubstituted imidazopyridines and imidazothiazoles were synthesized with high yields. The present methodology demonstrates the usefulness of commercially available aryl hydrazine as an arylating agent.


Introduction
The development of efficient methodologies for the arylation of biological active heterocycles has been of great importance over the years. 1 Traditionally, arylation is achieved via transitionmetal-catalyzed cross-coupling reactions. 2 In the last decade, transition-metal-catalyzed direct C-H arylation has emerged as an alternative to the conventional cross-coupling reaction. 3 However, use of a metal catalyst, ligand, and additives limits the application of these methodologies. As such, it is desirable to develop transition-metal-free methods for the arylation of bioactive heterocycles. 4 Arylhydrazine has recently been used as an arylating agent due to its ready availability. 5 Few methodologies have been developed using arylhydrazine for the arylation of various heterocycles. 5b,d,f,i,j Imidazo[1,2-a]pyridine has attracted much interest due to its wide range of applications in pharmaceuticals and material science. 6 The pharmacological activity of this moiety is dependent on its substituents. Several bioactive compounds such as g-secretase modulators (GSMs) (1), liver X receptor (LXR) agonists (2), positive allosteric modulators (PAMs) of metabotropic glutamate 2 receptor (3), GABA A a2/a3 agonists (4), antileishmanial agents (5 and 6), and kinase inhibitors (7) contain the arylimidazo[1,2-a]pyridine moiety as the core structure ( Fig. 1). 7 As a consequence, a number of methodologies have been developed for the synthesis and functionalization of this moiety. 8 Conventionally, arylation of imidazo[1,2-a]pyridine is carried out by transition-metal-catalyzed cross-coupling reactions using aryl halide/tosylate/mesylate as the aryl source. 9 Despite these advances in the functionalization of this moiety, to the best of our knowledge, there is no metal-free protocol for the arylation of imidazo[1,2-a]pyridines. This prompted us to develop a transition-metal-free method for the arylation of imidazo[1,2-a]pyridines. Herein, we report a direct C-H arylation of imidazo[1,2-a]pyridines using easily accessible arylhydrazine hydrochloride in the presence of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) at room temperature under ambient air (Scheme 1).

Results and discussion
We commenced our study by taking 2-phenylimidazo[1,2-a] pyridine (1a) and phenyl hydrazine hydrochloride (2a) as the model substrates for the arylation of imidazopyridines. Initially we carried out the reaction using Et 3 N (4 equiv.) as a base in MeCN. Gratifyingly, the expected 2,3-diphenyl imidazo[1,2-a] pyridine was obtained in 56% yield within 4 h (Table 1, entry 1). On screening with other organic bases such as Et 2 NH, i Pr 2 NH, DBU and 1,4-diazabicyclo[2.2.2]octane (DABCO), it was found that DBU was the optimal base, affording the desired product in 83% yield (Table 1, entries 2-5). Inorganic bases (K 2 CO 3 , Cs 2 CO 3 , K 3 PO 4 and KO t Bu) were also tested, but none were as effective (  [10][11][12][13][14][15][16][17]. Increment of base loading did not improve the yield, whereas decrement of base loading diminished the yield signicantly (Table 1, entries 18 and 19). The reaction did not occur in the absence of base, which suggests a signicant role for the base in this arylation reaction (Table   1, entry 20). When the reaction was carried in an oxygen atmosphere, no further improvement in yield was observed (Table 1, entry 21); however, in an inert atmosphere, only a trace amount of the product was obtained (Table 1, entry 22). Thus, the optimum yield was obtained by carrying out the reaction using 4 equiv. of DBU in MeCN in ambient air (Table  1, entry 4).
To assess the general applicability of the protocol, different arylhydrazine hydrochlorides were also reacted with 2-phenylimidazo[1,2-a]pyridine, as shown in Scheme 4. Different arylhydrazines bearing substituents such as -Me, -Cl, -Br afforded the corresponding arylated products (3ab-3ae) with good to excellent yields. However, arylhydrazines with strong electronwithdrawing groups such as -NO 2 and -CN were unable to produce the desired products under the present reaction conditions.
A number of control experiments were performed to investigate the reaction pathway. The reactions were carried out in the presence of radical scavengers such as 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) and benzo-1,4-quinone (BQ). The formation of a trace amount only of the products indicates that the reaction probably proceeds through a radical pathway (Scheme 7, eqn (A)). Furthermore, the formation of a trace amount of the product in an argon atmosphere suggests that aerial oxygen plays a vital role in this reaction (Scheme 7, eqn (B)).
On the basis of the control experiments and literature reports, 5b,f,i the probable mechanism of the reaction is outlined in Scheme 8. Initially the phenyl radical is formed from the phenyl hydrazine in the presence of base under aerobic conditions. The generated phenyl radical reacts with the imidazo[1,2a]pyridine moiety to afford the radical intermediate A. Intermediate A is oxidized into the intermediate B under aerobic conditions. Finally, the product is obtained from the intermediate B via elimination of a proton.

Conclusions
In summary, we have developed a metal-free convenient methodology for the arylation of imidazo[1,2-a]pyridines employing arylhydrazine as an arylating agent at room temperature. The present methodology offers a practical route for the synthesis of various 2,3-disubstituted imidazo[1,2-a] pyridines with a wide range of functional groups. Imidazo[2,1-b] thiazole and benzo [d]imidazo [2,1-b]thiazole were also arylated under the present reaction conditions in good yields. We believe our present protocol for arylation will nd useful applications in organic synthesis, the pharmaceutical industry, and material science.

General information
Reagents were purchased from commercial sources and used without further purication. 1 H and 13 C{ 1 H} nuclear magnetic resonance (NMR) spectra were determined on a 400 MHz spectrometer. 1 H NMR spectra were determined on a 400 MHz spectrometer as solutions in CDCl 3 . Chemical shis are expressed in parts per million (d) and the signals are reported as s (singlet), d (doublet), t (triplet), m (multiplet), dd (double doublet), and coupling constants (J) are given in Hz. 13 C{ 1 H} NMR spectra were recorded at 100 MHz in CDCl 3 solution. Chemical shis as internal standard are referenced to CDCl 3 (d ¼ 7.26 for 1 H and d ¼ 77.16 for 13 C{ 1 H} NMR) as the internal standard. Thin layer chromatography (TLC) was performed on a silica gel-coated glass slide. Commercially available solvents were freshly distilled before the reaction. All reactions involving moisture-sensitive reactants were executed using oven-dried glassware. X-ray single crystal data were collected using MoKa (l ¼ 0.71073Å) radiation with Charged Coupled Device (CCD) area. All the imidazoheterocycles were prepared by our reported methods. 8e,f General experimental procedure for the arylation of imidazo [1,2-a]pyridines (3) A mixture of imidazo[1,2-a]pyridine (1, 0.20 mmol, 1 equiv.) and arylhydrazine hydrochloride (2, 0.26 mmol, 1.3 equiv.) was dissolved in 3 mL MeCN at room temperature (rt) in a reaction tube. Then, 4 equiv. of DBU (120 mL) was added to the reaction mixture and stirred in air for 4 h unless otherwise mentioned. Aer completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed with water. The organic phase was dried over anhydrous Na 2 SO 4 . The crude residue was obtained aer evaporating the solvent under reduced pressure and was nally puried by column chromatography on silica gel (60-120 mesh) using petroleum ether and ethylacetate as an eluent to afford the pure product. 2