Regiocontrolled Microwave Assisted Bifunctionalization of 7,8-Dihalogenated Imidazo[1,2-a]pyridines: A One Pot Double-Coupling Approach

The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2-a]pyridines 1a–e diversely substituted on the 2 position, towards Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig cross-coupling reactions as well as cyanation was evaluated. Various methodologies are proposed to introduce aryl, heteroaryl, alkyne, amine or cyano groups in the two positions depending on the nature of the substituent present in position 2. In both series, the substitution of the iodine atom was totally regioselective and the difficulty was to substitute the chlorine atom in a second step. Until now, only hetero(aryl) groups could be introduced though Suzuki-Miyaura cross-coupling. We overcame this problem evaluating both regioisomers in parallel. The double coupling approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/Sonogashira and cyanation/Buchwald reactions leading to polyfunctionnalized imidazo[1,2-a]pyridines.


Introduction
Over the last decades, the imidazo[1,2-a]pyridine ring has been considered an important scaffold for biomolecules in medicinal chemistry, with a broad spectrum of potential therapeutic properties such as, for example, antibacterial [1], HIV inhibitory [2], anti-inflammatory [3] and anticancer [4] properties. Moreover, several drug formulations containing imidazo [1,2-a]pyridine derivatives, are marketed in the anxiolytic/hypnotic area (zolpidem, alpidem) and GDR/peptic ulcer therapy (zolimidine). Therefore, convergent, rapid, and easy to implement functionalization routes are still needed to introduce various modulations on this skeleton, in order to complete the putative biological activities evaluation of these series of compounds.
In the course of our work evaluating the chemical and pharmacological properties of the imidazo[1,2-a]pyridine series, we further pursued investigations on methods of functionalization which would allow the rapid preparation of a number of structural variants. We thus became interested in the regiocontrolled substitution of 7,8-dihalogenated imidazo[1,2-a]pyridine derivatives. The introduction of various substituents such as aryl, heteroaryl, cyano and amino groups was studied and our results in this area are the subject of this manuscript. Analogous works on double-coupling approach in positions 3 and 6, or positions 6 and 8 of this scaffold were already presented by other groups [5,6].

Results and Discussion
In order to control the regioselectivity of the disubstitution pattern in positions 7 and 8 of the imidazo[1,2-a]pyridine scaffold, we chosen as starting materials the 7-chloro-8-iodo-and 8-chloro-7iodoimidazo[1,2-a]pyridines 1a-e diversely substituted on the 2 position. Both series were studied concomitantly in order to offer the largest scope of functionalization. To our knowledge, the analogous 7-bromo-8-iodo-and 8-bromo-7-iodoimidazo[1,2-a]pyridines are still not described in the literature.
Compounds 1a-e were obtained in 71-100% yields by condensation of 2-amino-3-chloro-4iodopyridine or 2-amino-4-chloro-3-iodopyridine, with the corresponding α-halogenoketones. Different groups (phenyl, ethyl carboxylate, methyl) were considered in position 2 to overview the influence of this position on the reactivity of the 7 and 8 positions of the imidazo[1,2-a]pyridine series towards various cross-coupling reactions. Indeed, such an influence of the 2-substituent on the reactivity of not only position 3 [12], but also of position 6 [13], was previously noticed by our group.

Regioselective Substitution of the Iodine Atom of Compounds 1a-e
Initial work focused on the regioselective substitution of iodine atom of compounds 1a-e. Three classical cross-coupling reactions were studied: Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig reactions, as well as cyanation reactions (Schemes 1-4).

Sonogashira Cross-Coupling on Compounds 1a-e
Optimization of Sonogashira cross-coupling conditions was conducted in position 8 of compound 1d using 4-ethynyltoluene (3 equiv.), PdCl 2 (dppf) (0.05 equiv.), TEA (5 equiv.) and CuI (0.1 equiv.) in DMF at 90 °C for 1 h under microwave irradiation [14]. A partial conversion was observed (NMR yield of 29%) and a large amount of starting material was recovered, that could not be separated from the attempted product. A methodology developed in our laboratory using 4-ethynyltoluene (1.3 equiv.), Pd(PPh 3 ) 4 (0.1 equiv.), PCy 3 HBF 4 (0.3 equiv.) in the presence of t-BuONa (3 equiv.) and CuI (0.4 equiv.) in DMF at 100 °C for 20 min under microwave irradiation was then tested. A total dehalogenation occurred in position 8. Thus, we decided to work at lower temperature (90 °C), to change the base to Et 3 N (5 equiv.) and to lower the amount of CuI (0.2 equiv.). Under these conditions, a total conversion was observed allowing the purification of the attempted compounds 7 and 8 in moderate yields (60 and 50%, respectively) (Scheme 2). The position 7 appeared to be more reactive towards these Sonogashira conditions than position 8, leading to compounds 5 and 6 in 71% and 77% yields respectively (Scheme 2). The presence of N 1 in close vicinity of position 8 may explain its lower reactivity. Moreover, the 2-ester function seems to lower the reactivity of the 8 position towards the Sonogashira cross-coupling. Scheme 2. Sonogashira cross-coupling reaction on compounds 1a, 1b, 1d, 1e (isolated yields).

Cyanation on Compounds 1a-e
Then, we considered the cyanation of compounds 1 (Scheme 3). According to a literature procedure, reaction of 1a with CuCN (1.6 equiv.) in acetonitrile at 160 °C for 30 min under microwaves irradiation led to 9 in 32% yield [8]. We then changed the solvent to DMF and reaction of 1a or 1b with CuCN (1.3 equiv.) at 200 °C for 15 min under microwave irradiation, afforded 9 and 10 in respective yields of 72 and 63%. Applying the same conditions to compounds 1d-e led to formation of dehalogenated compounds. The 8-cyano compounds 11 and 12 were obtained after reaction at 150 °C for 15 min in 69% and 46% yields, respectively. Again, the 2-ester function seems to lower the reactivity of the 8 position towards the cyanation reaction.  Finally, we carried out a short study of Buchwald-Hartwig amination to optimize the aniline cross-coupling conditions, depending on the substituent present in position 2 of the imidazo[1,2-a]pyridine ring (Scheme 4). A nucleophilic substitution was first attempted following the procedure described by Tresadern et al. for the coupling of alkylpiperazine to 7-iodo-8-cyanoimidazo[1,2-a]pyridine derivatives [9]. Treatment of 1a with N-methylpiperazine (3 equiv.), DIPEA (4 equiv.) in acetonitrile at 180 °C for 1 h under microwave irradiation led exclusively to a mixture of starting material and deiodinated compound. The 8-cyano group appears to greatly increase the reactivity of the adjacent position, allowing a nucleophilic substitution.  In view to study one-pot heterogeneous double-coupling of aryl and amine groups in positions 7 and 8, Pd(PPh 3 ) 4 was preferred as catalyst in a first attempt. Thus, the reaction was achieved using aniline (1 equiv.), Pd(PPh 3 ) 4 (0.1 equiv.), Xantphos (0.3 equiv.), K 2 CO 3 (10 equiv.) in dioxane, but only starting material was recovered after 90 min at 100 °C under microwave irradiation. In the same way, only traces of the attempted compounds 13 were obtained using the following conditions: aniline (3 equiv.), Pd(PPh 3 ) 4 (0.1 equiv.), rac-BINAP (0.3 equiv.), t-BuONa (3 equiv.) in DME at 85 °C after 2 h 30 min under microwave irradiation. Therefore, we attempted these last conditions but with a catalytic amount of CuI (0.2 equiv.). We noticed that the reaction was completed after 45 min at 85 °C under microwaves and we obtained 13 in 48% yield. Under the same conditions, we synthesized 15 in 51% yield (Scheme 4).
The presence of the ester group in compounds 1b and 1e prevented us from using t-BuONa as base for the amination reaction. The different approaches evaluated to introduce the aniline were unsuccessful. We then decided to work with cyclohexylamine. The coupling reaction was first conducted on 1b using cyclohexylamine (2 equiv.), Pd(PPh 3 ) 4 (0.1 equiv.), Xantphos (0.2 equiv.), K 2 CO 3 (15 equiv.) in DMF at 160 °C during 1 h under microwave irradiation. This reaction did not afford the expected product 14. The reaction was then attempted on 1e using cyclohexylamine (13 equiv.), Pd 2 dba 3 (0.04 equiv.), Xantphos (0.12 equiv.), K 2 CO 3 (15 equiv.) in dioxane for 1 h 15 min at 150 °C under microwaves, leading to 16 in 66% yield ( Table 2). These last conditions applied to 1b led to 14 in 40% yield (Scheme 4).

Substitution of the Chlorine Atom in Position 7 of Compounds 7-8, 11, 15
Using the previously established experimental conditions, four examples of 7-arylimidazo[1,2a]pyridines 31-34 were obtained presenting an alkyne, cyano or amino group in position 8 (44 to 69% yields) ( Table 3). For compound 34, we noticed the formation of a dehalogenated compound during the Suzuki cross-coupling reaction, and a higher amount of boronic acid was then required to complete the reaction.