Introduction

Imidazo[1,2-a]pyridines are an important class of heterocyclic compounds possessing a wide range of biological and pharmacological activity,1 such as antiviral,2 antibacterial,3 anticancer,4 antiprotozoal,5 antiinflammatory,6 antiepileptic,7 antiparasitic,8 antituberculosis,9 etc. Therefore, significant strides have been made in the synthesis of imidazo[1,2-a]pyridines in the last decade employing various synthetic strategies such as multicomponent reactions, tandem reaction sequences, metal and organocatalysis.10 Among others, the use of α,β-unsaturated aldehydes as starting materials is a widely employed strategy for the synthesis of imidazo[1,2-a]-pyridines.

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Synthesis of imidazo[1,2- a ]pyridines from 2-alkenals

In 2013, 3-hydroxy-2-methylimidazo[1,2-a]pyridine (3) was obtained by us via the reaction of 2-alkoxypropenals 1 with an equimolar amount of 2-aminopyridine (2) in the presence of an acid.11 The reaction mechanism is based on the facile conversion of 2-alkoxypropenals into methylglyoxal as a result of Markovnikov addition of water to their vinyloxy group in acidic aqueous medium.

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Jørgensen et al. have demonstrated the possibility of enantioselective accessing hydroxyalkyl- or aminoalkylsubstituted imidazopyridines 6 by organocatalytic annulation of 2-aminopyridines 5 with propenals 4.12

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Natalia Afanas'evna Keiko defended her candidate of sciences (1965) and doctor of sciences (1985) theses at the A. E. Favorsky Irkutsk Institute of Chemistry of the Siberian Branch of the Russian Academy of Sciences. She is currently professor and leading scientist at the same Institute. Her research interests include synthesis and properties of unsaturated carbonyl and heterocyclic compounds.

Nadezhda Viktorovna Vchislo was born in 1984 in Irkutsk, Russia. In 2012, she defended her candidate thesis, written under the supervision of Professor Dr. Natalia Keiko, at the A. E. Favorsky Irkutsk Institute of Chemistry of the Siberian Branch of the Russian Academy of Sciences. Her research interests include synthesis of heterocycles from α,β-alkenals.

Synthesis of imidazo[1,2- a ]pyridines from 2-alkynals

In 2008, it was shown by Medvedeva et al. that the acid-catalyzed (5 mol % HCl) reaction of phenylpropynal (7) with 2 equiv of 2-aminopyridine (2) in acetonitrile at room temperature for 7 days leads to 3-[(2-pyridylamino)(phenyl)-methyl]imidazo[1,2-a]pyridine (8), the self-assembled cascade reaction product, in 64% yield.13

Among the three-component methods of synthesis of imidazo[1,2-a]pyridines, the reaction of 2-aminopyridines 5 with alkynals 9 and aromatic isocyanides 10 in the presence of perchloric acid should be noted. This work also demonstrated the possibility of further intramolecular cyclization of imidazo[1,2-a]pyridines 11 into the corresponding polycyclic compounds 12 by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Continuing their work in 2015, these authors have expanded the number of synthesized 3-aminoimidazo[1,2-a]pyridines by the use of tert-butylisocyanide instead of aromatic isocyanides 10 in the above reaction.15 The yields of the products amounted to 30–80%.

Another example of using propynals in the synthesis of imidazo[1,2-a]pyridines is a three-component reaction between alkynals 9, substituted 2-aminopyridines 5, and an alcohol, amine, or thiol. For example, the desired products 13 were obtained in 70–87% yields at 80°C in acetonitrile after 8 h in the presence of 2.5 mol % of acetic acid as the catalyst.16

Recently, the proposed use of microwave irradiation lead to significantly reduced (16–30 times) reaction times for a similar reaction. Thus, the reaction is complete in 30 min under microwave irradiation in the presence of 2 mol % of trifluoroacetic acid at 130°C in DMF,17 and in 15 min in the presence of 5 mol % of toluenesulfonic acid at 100°C without using solvent.18 This method allowed to improve the yields of the desired imidazo[1,2-a]pyridines (81–92% and 76–89%, respectively).

Lewis acids (Pd(OAc)2, CuI) were successfully used for the synthesis of imidazo[1,2-a]pyridines 14 and 15 in a twocomponent reaction of aromatic and aliphatic alkynals 9 with substituted 2-aminopyridines 5.19 Similar results were obtained when complex Ph3PAu–AgSbF6 was used as the catalyst.20 According to the supplied data, the metal catalytic synthesis of functionalized imidazo[1,2-a]pyridines 14 proceeds by oxidation of the metal carbene complex with atmospheric oxygen.

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