Phosphine-Free Palladium-Catalyzed Direct C-3 Arylation of 2-Phenylimidazo [ 1 , 2-a ] pyridine Using Silver ( I ) Carboxylate

Phosphine-free palladium-catalyzed direct arylation of 2-phenyl-imidazo[1,2-a]pyridine has been developed with the concept of using silver(I) carboxylate. This protocol efficiently catalyzes the C-H arylation of 2-phenyl-imidazo[1,2-a]pyridine with aryl iodides to afford the corresponding 2-phenyl-3-aryl-imidazo[1,2-a]pyridines in moderate to-good yields.


Introduction
Syntheses of several heterocycles via palladium-catalyzed direct C-H bond activation using aryl halides are of great importance in recent years along with time-honored coupling reactions where expensive and toxic phosphines are widely used [1][2][3][4][5][6].Hence, there are signi�cant efforts to perform reactions without using any phosphines for the same reasons.In this aspect, phosphine-free palladium-catalyzed synthesis of free (N-H) as well as substituted indole and pyrroles are reported in the literature [7][8][9].In 2008, Igor Larosa reported the intrinsic idea of using the several different types of Ag(I) carboxylate salts (generated in situ by the combination of Ag 2 O/differently substituted benzoic acids) along with Pd(OAc) 2 to undergo C-H bond activation under very mild conditions to afford C-2 arylated indoles with different functionalities [9].is paper prompted us to use the same approach for the highly demanding arylation for the C3 position of imidazo [1,2-a]pyridine, a heterocycle with outstanding biological activities [10][11][12][13][14][15].e most well known drugs like zolimidine (A, antiulcer), alpidem (B, anxiolytic), and zolpidem (C, hypnotic) [14] (Figure 1) also bear this imidazo[1, 2-pyridine skeleton.
It is to be noted that, in 2007, the research group of Dalibor reported the phosphine-free Pd(OAc) 2 catalyzed direct C-arylation of free (-NH) indoles and pyrroles in the presence of CsOAC [8].Recently there are few reports on the Pd-catalyzed direct C-3 arylation of imidazo[1, 2-pyridines using phosphines as ligands [16][17][18][19] along with the traditional coupling reactions where the starting material should be 3-haloimidazo [1, 2-𝑎𝑎𝑎pyridines [20-23].During the preparation of our paper, Fu and collaborators published the phosphine-free Pd-catalyzed direct arylation of imidazo [1,2-a]pyridine using KOAc as base [24].However, prior to the work published by Fu et al. to the best of our knowledge, there was no report on the phosphine-free direct arylation of imidazo[1, 2-pyridine using palladium as catalyst.In this present work, we describe a new convenient methodology for the phosphine-free direct C3 alkylation of 2-phenylimidazo[1, 2-pyridine by the reaction of aryl iodides in the presence of Pd(OAc) 2 as catalyst with silver(I) carboxylate which is assumed to increase the rate of the palladation step in the catalytic cycle along with its basic nature needed at the reductive elimination step [9].is methodology also offer a new route for the direct arylation of 2-phenylimidazo[1, 2-pyridine with aryl iodides.

Results and Discussion
Using Pd(OAc) 2 as catalyst and several different types of silver(I) acetates or carboxylates, we have begun phosphinefree reactions of 2-phenylimidazo[1,2-a]pyridines (1) with phenyl iodide to afford the direct C-3 arylated product 2,3diphenyl imidazo[1,2-a]pyridine (2a) (Scheme 1).We have taken this reaction as a model to optimize the yield by changing different combinations of Ag(I) carboxylate (generated in situ from Ag 2 O and different carboxylic acids) along with other bases and solvents (Table 1).Indeed, compound 1 is a very stable starting material that could be synthesized in a convenient way by the reaction of cheap commercially available 2-aminopyridine and 2-bromoacetophenone.Moreover, 2-phenylimidazo[1, 2-]pyridine derivatives are well established as potent and selective ligands for peripheral benzodiazepine receptor [10].ere was no progress of this reaction at room temperature.e highly coordinating dimethylformamide (DMF) was the best choice as a solvent for the different combination of Ag(I) salt.e more acidic o-nitro benzoic acid was more effective combination than other acids with Ag 2 O for the above reaction to afford compound 2a with high yield in DMF at 120 ∘ C under nitrogen.To �nd out the extent of this reaction, we have used several aryl iodides substituted with both electron withdrawing and donating groups for this reaction.e products and yields are pointed out in Table 2.
It is experiential that the percentages of yields do not vary considerably (entries 2, 4, 5, and 6) with the type of substiutents present (or absent; entry 1) in the phenyl ring of aryl iodides.Both, electron-withdrawing (entries 4, 5, 8, and 10) and electron-donating substitutents (entries 2, 3, 6, 7, and 9) show the same result.As expected, the more hindered ortho-substituted aryl iodides react considerably more slowly than the meta-and para-counterparts to afford slightly lower yields (entries 7 and 10).Further, we also have checked the reactivity of 2-iodothiophene as a heteroaryl iodide under the same reaction condition which affords the compound 3k with 66% yield.All the compounds (3a-k) were characterized by IR, NMR, mass spectroscopy, and elemental analysis.In the 1 H-NMR spectra all aromatic protons resonate in the  All reactions were carried out using 5 mol% Pd(OAc) 2 , 1.5 equiv (entries 1-3), or 0.75 equiv (entries 4-8) of base, 1.5 equiv of acid, 1.0 equiv of 1, and 2.0 equiv of phenyl iodide in a 0.5 M solution, for 12 h at 120 ∘ C. region 6.66-8.42Hz.Finally the structure for one of these compounds 3c is proven by X-ray crystallography (Figure 2).(X-ray data was collected on a Bruker AXS-SMART diffractometer using Mo-K  ( = 0.71073 Å) radiation.e structure was solved and re�ned by standard methods.

Conclusions
In conclusion, we have applied the catalytic Pd(OAc) 2 and Ag(I) carboxylate combination to develop a successful methodology for this challenging direct C-3 arylation of 2-phenylimidazo[1, 2-pyridine with differently substituted aryl iodides without the presence of phosphines or other ligands to give 3-aryl-2-phenyl imidazo[1, 2-pyridines with moderate to-high-yield.e structure of one of these compounds has been characterized by X-ray crystallography.