Synthesis of 6- or 8-Carboxamido Derivatives of Imidazo[1,2- a]pyridines via a Heterogeneous Catalytic Aminocarbonylation Reaction

Abstract

Imidazo[1,2-a]pyridines and especially their amide derivatives exhibit a wide range of favourable pharmacological properties. In this work, Pd-catalysed carbonylation was used for the first time for the introduction of the carboxamide moiety into positions 6 or 8. A recyclable Pd catalyst, with palladium immobilised on a supported ionic liquid phase decorated with pyridinium ions, was used efficiently for the conversion of 6- or 8-iodo derivatives to the products. In the case of 6-iodo derivatives, a competing mono- and double carbonylation could be observed in the reactions of aliphatic amines as nucleophiles, but under the proper choice of reaction conditions, good-to-excellent selectivities could be achieved towards either the corresponding amides or α-ketomides. The heterogeneous catalyst showed excellent recyclability and low Pd-leaching.

Keywords: amide; palladium catalyst; supported ionic liquid; α-ketoamide.

Figure 1

Marketed drugs and potential drug candidates incorporating the imidazo[1,2-a]pyridine core and an amide functionality.

Scheme 1

Synthesis of iodoimidazo[1,2-a]pyridine derivatives 1–3.

Figure 2

The structure of pyridinium SILP support used for the immobilisation of palladium.

Figure 3

General mechanism of mono- and double carbonylation of aryl halides in the presence of nucleophiles.

Figure 4

Recycling experiments in aminocarbonylation of 6-iodoimidazo[1,2-a]pyridine (1) and morpholine (4a) (Reaction conditions: 0.2 mmol 1, 0.5 mmol 4a, 0.25 mmol Et₃N, catalyst SILP-Pd (with 2.8 μmol Pd-content), 2 mL DMF, 100 °C, 30 bar, 7 h).

Figure 5

Recycling experiments in aminocarbonylation of 6-iodoimidazo[1,2-a]pyridine (1) and morpholine (4a) (Reaction conditions: 0.2 mmol 1, 0.5 mmol 4a, 0.25 mmol DBU, catalyst SILP-Pd (with 2.8 μmol Pd-content), 2 mL toluene (left) or 1,4-dioxane (right), 100 °C, 30 bar, 7 h).

Figure 6

Recycling experiments in aminocarbonylation of 6-iodoimidazo[1,2-a]pyridine (1) and morpholine (4a) (Reaction conditions: 0.2 mmol 1, 0.5 mmol 4a, 0.25 mmol DBU, catalyst SILP-Pd (with 2.8 μmol Pd-content), 2 mL toluene, 120 °C, 5 bar, 7 h).

Figure 7

Products obtained by the aminocarbonylation of 8-iodoimidazo[1,2-a]pyridines 2 and 3. (Reaction conditions: 0.2 mmol 2 or 3, 0.5 mmol amine (4a or 4f), 0.25 mmol Et₃N, catalyst SILP-Pd (with 2.8 μmol Pd-content), 2 mL DMF, 100 °C, 30 bar, 7 h). In parenthesis: yields after column chromatography.

Figure 8

Assumed coordination of Pd to N(1) of 8-iodoimidazo[1,2-a]pyridine (3) in the acyl complex formed during carbonylation.