(Hetero)Arylation of 6-Halogenoimidazo[1,2-a]pyridines Differently Substituted at C(2): Influence of the 2-Substituent on theSuzuki Cross-Coupling Reaction

Abstract

We previously reported that reactivity towards the Suzuki cross-coupling reaction of 3-iodoimidazo[1,2a]pyridines substituted at C(2) is largely influenced by the nature of this 2-substituent. Hence, with the aim to expand the scope of this coupling process to the 6-position of this series, it seemed important to similarly determine the influence of the nature of the 2-substituent (H, alkyl, or aryl) on the rate of coupling. From this work, the Suzuki-type cross-coupling was shown to proceed efficiently on 6-bromo-2-methyl-and 2-(4fluorophenyl)imidazo[1,2-a]pyridines, whereas the 6-Br derivative unsubstituted at C(2) appeared to be poorly reactive. By modifying the reaction conditions in terms of catalyst and base, and the nature of the halogen, the reactivity of the unsubstituted series was largely enhanced. Finally, this work led us to establish efficient and convenient Suzuki reaction conditions for the 6-(hetero)arylation of 6-halogenoimidazo[1,2-a]pyridines depending on the nature of the 2-substituent and boronic acid.Introduction. ± As part of our continuing efforts to develop rapid pharmacomodulation methods of N-bridgehead heterocycles containing a fused imidazole ring, we turned our interest to the application of the Suzuki-type cross-coupling reaction [1] [2]. We previously reported the good reactivity of the 2-substituted 3-iodoimidazo[1,2a]pyridine series toward boronic acids, a reactivity largely influenced by the nature of the substituent present at C(2) [1]. Hence, we were interested in extending this coupling process to the pyridine part of the imidazo[1,2-a]pyridine ring system and, in a first approach, to the C(6) position. The poor reactivity towards traditional nucleophilic substitutions of 6-halogeno derivatives is now well-established. Only few examples of functionalization have been reported to date (see, e.g., [3]). Thus, correct pharmacomodulation is generally required to be performed on the starting aminopyridines (see, e.g., [4]) in contrast to a general and convenient synthetic approach. Generalization of the Suzuki coupling process could then provide an easy and convergent access to 6-(hetero)arylimidazo[1,2-a]pyridines with potential synthetic application as serotonin 5-HT 1 agonists [5]. To the best of our knowledge, application of this reaction has only been reported by Tenbrink [6] and Momose [7] on 6-bromo-2-(substituted-methyl)imidazo[1,2-a]pyridines with PhB(OH) 2 acid under different reaction conditions, leading to 6-Ph derivatives in 78 and 30% yields, respectively. The lack of a general

A novel method for the synthesis of 6-bromo-2-(3,4-dichlorophenyl)imidazo[1,2-a]pyridine using microwave irradiation

“…by the reaction between 5-bromo-2-aminopyridine (1) and 2-bromo-1-(3,4-dichlorophenyl)ethanone (2) using different methods [1][2][3][4]. In the usual methods, bases like sodium bicarbonate or potassium carbonate were employed in polar solvents such as methanol or ethanol under reflux for 4-6 hours.…”

Identification of the Privileged Position in the Imidazo[1,2-a]pyridine Ring of Phosphonocarboxylates for Development of Rab Geranylgeranyl Transferase (RGGT) Inhibitors

“…For their synthesis, appropriate 2-aminopyridine analogues were used in the reaction with bromomalonaldehyde . Apart from commercially available halogen and methyl substituted 2-aminopyridine, phenyl substituted analogues had to be first synthesized either from halogen-containing 2-aminopyridines or from the corresponding halogen-substituted aldehydes 3 , in the Suzuki–Miyaura coupling with phenylboronic acid . Polyphenyl aldehydes 3u , 3w , 3y , 3z (Figure ) were synthesized according to literature procedures (see Supporting Information for experimental details). , …”

New Calcineurin Inhibiting 3‐Dimethylaminopropyl Substituted Diarylheterocycles by Sonogashira Reactions and Catalytic Hydrogenation

“…This new compound was prepared adopting a reported procedure [40]. A 50 ml flask was charged with 3-amino-6-chloropyridazine (1.30 g, 10 mmol), 2-bromo-2-phenyl-acetophenone (desyl bromide) (3.40 g, 12 mmol), NaHCO 3 (982 mg, 12 mmol) and i-PrOH (30 ml).…”