Facile Microwave Synthesis of Pd-Catalyzed Suzuki Reaction for Bis-6-Aryl Imidazo[1,2-a]Pyridine-2-Carboxamide Derivatives with PEG3 Linker

Abstract An efficient and facile synthetic procedure has been developed for the synthesis of novel series of Bis-6-aryl-imidazo[1,2-a]pyridine-2-carboxamide containing 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) derivatives (6a-6j). An application of the Palladium catalyzed Suzuki reaction on amine-(CH2)3-PEG3-(CH2)3-amine linked 6-bromo imidazo[1,2-a]pyridine-2-carboxamide was reported and their products are discussed. The reaction was optimized through numerous catalytic conditions for this strategy, and it was fixed with the best approach having advantages of less reaction time, higher degree of yield, most consumption of starting material, and selection of best catalyst for the success of the reaction. The ideal spectroscopic characterization (PMR, CMR, IR and MS) have been utilized for the finalization of the synthesized adducts.

The impact of the cross-coupling reactions, particularly the Suzuki reaction on the pharmaceutical industry has been profound: an analysis of the types of molecules synthesized within the pharmaceutical industry noted that there had been an increase in the "flatness" of molecules since the 1970s and that this correlates with the availability of chemistry facilitating sp 2 -sp2 coupling. [14][15][16][17] It served in scientific society by generating various clinical candidates in the last few decades like abemaciclib, preclamol, niraparib, isoanabasine and many more. 18 It should be taken into consideration that small modifications in the bioactive molecular targeting vectors can influence their biodistribution pattern. Polyethylene glycols (PEG) and polypropylene glycols (PPG) are coming underclass of polyether's and are used in pharmaceuticals, cosmetics and other industries. 19 It inhibits bacterial growth, is active as an antibacterial effect and can act as a disinfecting agent, also significant delivering anticancer, anti-HIV, antiviral activity in clinical trials. Hence, modification in the length of the spacer moiety might influence the in vivo kinetics in biological processes and modify its medicinal potency. 20 Because of the significance of the Suzuki reaction and the imidazo[1,2-a]pyridine core, the further development of new palladium catalyzed approach for the efficient synthesis of novel PEG fused imidazo[1,2-a]pyridines is highly desirable. So moving forward to work on new N-based heterocycles, [21][22][23][24][25] we report herein our recent efforts in the development of a Pd-catalyzed Suzuki reaction for the synthesis of diverse -CONH-(CH 2 ) 3 -PEG 3 -(CH 2 ) 3 -CONHfused imidazo[1,2a]pyridines (Scheme 1) and reaction optimization was discussed through varying in catalytic conditions.

Materials and method
All the chemicals and solvents for the synthesis were purchased from Sigma-Aldrich Chemicals, Spectrochem and Merck Chemicals. Reactions were continuously monitored by thin-layer chromatography (TLC) on silica gel-(G60 F254 (Merck)) of 0.5 mm thickness, visualizing with ultraviolet light (254 and 365 nm) or with iodine vapor. Melting points were determined using a Buchi B-540 capillary apparatus. NMR spectra were recorded on a Bruker Advance 400 MHz spectrometer (400 MHz for 1 H NMR and 101 MHz for 13 C NMR) respectively in DMSO-d 6 solvent and tetramethylsilane as reference. Elemental analysis was carried out on Euro EA 3000 elemental analyzer. Mass spectra were recorded on a Shimadzu GC-MS-QP-2010 mass spectrometer in EI (70 eV) model using the direct inlet probe technique. IR spectra of all compounds were recorded on the IR Affinity 1S spectrometer (Shimadzu). Microwave synthesizer Antonpaar 300 was used for microwave irradiation. Ultrasonic Sonicator PCI USB-01 (30 KHz) was used for the sonication. The solvent was evaporated using a Buchi rotary evaporator.
Yield ¼ 85% (  Procedure for the synthesis of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid (4) To a stirred solution of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (3) (13.0 g, 48.30 mmol, 1.0 eq.) in a mixture of methanol (60 mL): water (30 mL), the aqueous solution of lithium hydroxide monohydrate (LiOH.H 2 O) (2.23 g,53.14 mmol. 1.1 eq.) in 10 mL water was added and was stirred at room temperature (RT) for overnight. The reaction progress was monitored by TLC. After the competition of the reaction, it was concentrated under a vacuum to reduce methanol content in the reaction mixture. The reaction mixture was acidified with dilute HCl to adjust PH 6.0. The precipitated product was filtered out and dried under a vacuum to obtain the desired product (4).
The entire compounds of the series were isolated under the above-stated procedure and confirmed by various spectroscopic techniques.
The endeavor for the synthesis of compounds 6a-6j for the C-C coupling was carried out by using palladium catalyzed through Suzuki reaction between key intermediate 5 and various aryl boronic acid. [30][31][32][33] Here, we had chosen 4-pyridyl boronic acid (6b) for the optimization of the process using varying the catalyst. We have not obtained the desired product in sufficient amount even after 24 h of stirring at 80 C using Tetrakis Pd(PPh 3 ) 4 as a catalyst under 1,4-dioxane media. Due to this, we had tried different reaction conditions like the solvent, catalyst, temperature to set an approach for better yield. Among the set of reactions, we noticed upliftment in the yield and a satisfactory result was found under PdCl 2 dppf.DCM as a catalyst. Furthermore, we had chosen the combination of solvent in all the reactions but higher incremental product conversion was found in 1,4-dioxane: water combinations than the other polar/non-polar media. This process required more catalysts along with the use of other reagents as well. So, that we were applied different mole percentages of catalyst and reagents in reaction with 1,4-dioxane: water (9:1) as a solvent (Table 1).
For the preparation of N,N'-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(propane-3,1-diyl))bis(6-(pyridin-4-yl)imidazo[1,2-a]pyridine-2-carboxamide) (6b), firstly we tried with Tetrakis Pd(PPh 3 ) 4 , K 3 PO 4 and 1,4-dioxane solvent but didn't get exemplary reaction conversion. Then we also tried to reduce the mole percentage of catalyst and other reagents ( Table 1) and found that the reaction conversion remains unchanged. So, our focus moved on temperature parameters and the application of microwave reactor. The desired outcome concerning catalyst and yield were satisfied through microwave reaction conditions. For the comparison purpose, we have tried reaction with 100 C in a conventional heating mode and the reaction time reduced to 8.0 h means almost 1/3 of the previously used reaction conditions (time and temperature). Simultaneously, we also tried to perform it at 100 C by microwave irradiation in a microwave reactor. Surprisingly, there is a much higher conversion of the reaction to the desired product as described in Table 2.
For the accuracy purpose, the above method was applied in 6a and 6d and we got the same results. Hence, MW based reactions to synthesized 6a-6j are best than the conventional reaction conditions and the same protocol was used to synthesize the entire series of the compounds.