Synthesis of Imidazo[1,2- a ]pyridines via Multicomponent GBBR Using α -isocyanoacetamides

: Six novel imidazo[1,2- a ]pyridines were synthesized by Groebke–Blackburn–Bienaymé reactions (GBBRs) under eco-friendly conditions (10 mol% ammonium chloride catalyst in EtOH at room temperature) with moderate to good yields (76–44%) using 2-isocyano-1-morpholino-3-phenylpropan-1-one. This is the first successful use of this type of α -isocyanoacetamide in a GBBR, as these reactive isonitriles readily undergo ring-chain tautomerization, as reported in other IMCRs (isonitrile-based multicomponent reactions). The product structures contain a peptidomimetic imidazo[1,2- a ]pyridine scaffold linked to an α -aminomorpholide and are of interest to medicinal chemists.

The most common methodologies for the synthesis of imidazo [1,2-a]pyridines are (i) the condensation of 2-aminopyridines with α-halo carbonyl compounds [8], which suffers from limitations such the scarcity of commercially available α-halo carbonyl compounds and their lachrymatory properties; (ii) copper-catalyzed three-component reactions of 2-aminopyridines, aldehydes, and alkynes [9]; and (iii) Grobke-Blackburn-Bienaymé reactions (GBBRs) between an aldehyde, a 2-aminoazine, and an isocyanide [10][11][12].In modern synthetic chemistry, there is an urgent need to design and develop new green and efficient methodologies to synthesize complex molecules from simple materials with high atom economy.The isocyanide-based multicomponent reaction (IMCR) is a powerful tool that plays a central role in the synthesis of heterocycles [13].The GBBR is one of the most common and efficient methodologies to synthesize imidazole analogues and the method of choice to synthesize imidazo[1,2-a]pyridine-3-amines.Normally, this reaction requires a solvent and a catalyst [5,6].Various GBBR procedures have been reported, using catalysts such as Lewis acids, Bronsted acids, solid supports, organic bases, and inorganic salts [14].Each of these methodologies has drawbacks such as high temperature, low yields, expensive catalysts, and/or non-green solvents.The design and development of improved GBBR procedures using green solvents and catalysts at room temperature is an underexplored field.There are few GBBR reports available towards imidazo[1,2-a]pyridine-3amines describing the use of green catalysts [15,16].For these reasons, it is necessary to increase efforts to develop new, efficient, mild methodologies using green, inexpensive, and readily available catalysts and solvents.
α-isocyanoacetamides present exceptional reactivity because they can undergo intramolecular ring closure.For this reason, they have been extensively explored in certain IMCRs as an Ugi three component reaction [17].On the other hand, the use of this type of isonitrile in GBBRs is practically unexplored; in fact, there is only one such previous report, by Bienaymé in 1998 (see Scheme 1) [12].
The methodology described here allows the one-pot synthesis of new imidazo[1,2-a]pyridine-3amines that incorporate a peptidomimetic amide fragment in the isonitrile reactant.To the best of our knowledge, the only other published method for access to this type of compound uses a synthesis strategy of GBBR followed by deprotection and peptide coupling steps (Scheme 1, Valakirev, M.Y. et al.) [7].Therefore, the methodology described here is attractive due to the use of green reaction conditions and access to the final products in a single stage.

Results and Discussion
In order to develop green conditions for the GBBR, we started the synthesis of imidazo[1,2a]pyridine-3-amine analogue 6a by reacting equimolar amounts of 2-aminopyridine (7), benzaldehyde (8a), and 2-isocyano-1-morpholino-3-phenylpropan-1-one (9).In concordance with our main line of research, green conditions were studied to optimize the reaction.Initially we performed the GBBR under neat conditions at room temperature, generating product 6a in poor yield (10%) after 5 h (Entry 1, Table 1) [18].When the reaction was performed in water as solvent (Entry 2), only 8% of compound 6a was obtained.Changing the solvent to EtOH (Entry 3) increased the yield to 46%.Seeking a green, inexpensive, and easily available catalyst, we decided to try the reaction with a catalytic amount of NH4Cl at room temperature [19].This raised the product yield to 72% (Entry 4).The use of iodine and montmorillonite (K-10) as catalysts in GBBR is well-documented [20][21][22][23][24], so we decided to try those catalysts in our methodology.Unfortunately, catalytic iodine or montmorillonite at room temperature resulted in lower yields of 49% and 66%, respectively (Entries 5-6).We then tested phenyl phosphinic acid, which is not a known catalyst for the GBBR, but this catalyst did not result in an improved yield (67%, Entry 7).Performing the NH4Cl-catalyzed reaction at 60 °C lowered the yield of product 6a to 49% (Entry 8, Table 1), which can be attributed to the low stability of this isocyanide in acidic media at elevated temperatures.Indeed, we detected the corresponding oxazole 13, resulting from chain-ring tautomerization of isocyanide 9, as a by-product.a All reactions were carried out using equimolar amounts of 7, 8a, and 9 for 12 h.b [1.0 M] c Isolated yield.rt = room temperature.In all reactions, oxazole 13 was detected as a by-product.
Figures 2 and 3 show the 1 H and 13 C NMR spectra for the representative imidazo[1,2-a]pyridine 6a.In the 13 C NMR, the carbonyl carbon signal appears at 172.1 ppm, which confirms the formation of the GBBR product and not the formation of the oxazole by an intramolecular ring closure in the isonitrile.All of the other key signals are readily observed in these spectra.

General Information, Instrumentation, and Chemicals
1 H and 13 C NMR spectra were acquired on Bruker Avance III spectrometers (500 or 400 MHz).The solvent used was deuterated chloroform (CDCl3).Chemical shifts are reported in parts per million (δ/ppm).The internal reference for 1 H NMR spectra is trimethylsilane at 0.0 ppm.The internal reference for 13 C NMR spectra is CDCl3 at 77.0 ppm.Coupling constants are reported in Hertz (J/Hz).Multiplicities of the signals are reported using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).NMR spectra were analyzed using the MestreNova software version 10.0.1-14719.IR spectra were acquired on a Perkin Elmer 100 spectrometer using an Attenuated Total Reflectance (ATR) method with neat compounds.The absorbance peaks are reported in reciprocal centimeters (υmax/cm −1 ).Reaction progress was monitored by Thin-Layer Chromatography (TLC) on precoated silica-gel 60 F254 plates and the spots were visualized under UV light at 254 or 365 nm.Mixtures of hexane with ethyl acetate (EtOAc) were used to run TLC and for measuring retention factors (Rf).Flash column chromatography was performed using silica gel (230-400 mesh) and mixtures of hexane with EtOAc in different proportions (v/v) as the mobile phase.All reagents were purchased from Sigma-Aldrich and were used without further purification.Chemical names and drawings were obtained using the ChemBioDraw Ultra 13.0.2.3020 software package.The purity for all the synthesized products (up to 99%) was assessed by NMR.

Scheme 1 .
Scheme 1.Previous reports and our work.