An efficient and catalyst-free synthesis of N-arylidene-2-arylimidazo[1,2-a]pyridine-3-ylamine derivatives via Strecker reaction under controlled microwave heating

1 Introduction

Imidazo[1,2-a]pyridine derivatives are highly potent heterocyclic scaffolds because of their biological activity and are found in numerous drugs, such as Zolpidem, Alpidem, Zolimidine, Alprinone, Saripidem, and Necopidem [1], [2], [3], [4], [5], [6], [7], [8], [9]. Imidazo[1,2-a]pyridines possess a variety of biological activities such as anticancer [10], antiviral [11], antimicrobial [12], antiparkinson [13], antimutagenics [14], antihypoxia [15], and antinflammatory effects [16]. The synthesis of such scaffold has been extensively studied. Among these, the multicomponent reaction of 2-aminopyridine, aldehydes, and alkynes is one of the most common methods for their synthesis utilizing transition metal catalyst such as palladium [17], copper [18], silver [19], and gold [20]. Transition metal salts such as Ag (I), Au (III), and Cu (II) in combination with either p-toluenesulfonic acid (PTSA) or copper (I) complex have been utilized to catalyze such three-component reactions [21], [22]. Indium (III) bromide has also been used for the synthesis of imidazo[1,2-a]pyridines [23]. Multicomponent synthesis strategies to prepare a series of imidazo[1,2-a]pyridines have also been reported, however, the most utilized methodology to prepare such scaffold is the Grobke-Blackburn-Bienayme reaction [24], [25], [26], and its recent modifications [27], [28], [29], [30] that mainly afforded 3-amino-imidazo[1,2-a]pyridines. It is worth to mention that other few protocols for the synthesis of 3-amino substituted products are reported such as nitration of C-3 and subsequent reduction [31]; multicomponent reaction of 2-aminopyridines aromatic aldehydes and imidazoline-2,4,5-trione [32]; as well as Strecker reaction using trimethylsilyl cyanide (TMSCN) or cyanohydrins as the source of cyanide ion utilizing either silica sulfuric acid or (bromo dimethylsulfonium)bromides catalysts [33] with reaction time ranging from 2–3 days to 10–20 h, the use of MCM-41 supported boron trifloride (BF3MCM-41) as a nanosaturated solid acid catalyst with reaction time ranging from 40 to 240 min [34] or Ugi-type multicomponent reaction in water utilizing KF for activation of TMSCN [35]. Although these methods afford good to excellent yields, TMSCN or cyanohydrin is known to be highly toxic and thus an environmental pollutant. Only one recent protocol utilizing polymer-bound scandium triflate as a catalyst under microwave heating has been reported [36]. Though, these protocols are useful, many of these have some demerits such as the use of expensive and excess amount of catalyst, longer reaction times, difficult work-up procedures, and harsh reaction conditions. Extensive efforts have been invested in utilizing green technologies in synthetic organic chemistry. One such technology involves microwave heating with its advantageous features such as operational simplicity, enhanced reaction rates with short reaction times, high yields, and purity of production [37], [38]. In continuation of our interest and others [39], [40], [41], [42], [43], [44], [45] in performing reactions utilizing microwave heating we have developed an efficient catalyst-free multicomponent reaction for the synthesis of N-arylidene-2-arylimidazo[1,2-a]pyridine derivatives under controlled microwave heating.

2 Materials and methods

3 Results and discussion

With the initial aim of optimizing the experimental reaction conditions we explored the reaction of 2-aminopyridine (1), aromatic aldehyde (2a), and either benzoyl cyanide (3a) or cyanamide (3b) under both acidic and basic conditions. The reaction was promoted by microwave heating over 30 min (Scheme 1). When ethanol in the presence of 10 mol% PTSA was used, the process led to a low yield (36%) of the target imidazo[1,2-a]pyridine derivatives 4a. Pyridine was also examined and found to be very convenient for such a reaction with a higher yield (88%). To determine the role of the reaction medium, other solvents were examined such as water, methanol, or ethanol without any catalyst. In this case 4a was not formed even after prolonged microwave irradiation. Finally irrespective of the aryl substituent reactions took place in reasonable yields (Table 1).

Scheme 1:

Synthesis of imidazo[1,2-a]pyridine derivatives 4a–j.

The structure of products could be established based on the analytical and spectral data. Mass spectra of 4a showed M⁺ peak at 365 (100%). ¹H NMR showed peaks assigned for aromatic protons and a singlet at δ=8.94 ppm for CH=N function. ¹³C NMR was in agreement with the proposed structure.

In order to determine the effect of the reactants molar ratio on the overall yield we started our protocol by mixing the reactants 2-aminopyridine, aromatic aldehydes, and cyanating agent in the ratio 1:1:1 all dissolved in 10 ml pyridine and heated under reflux in a microwave lab station for 30 min. The products were obtained in almost 40% yield as a maximum. However, with a ratio of 1:2:1 of the reactants under the same reaction conditions, the yields increased as shown in Table 1.

To evaluate the advantages of performing the reaction under microwave heating, a control experiment was conducted under conventional heating. It was observed that lower amounts of the products were obtained after 3–4 h. The use of microwave irradiation provided a more efficient and clear reaction.

A suggested mechanism for the formation of compound 4 displayed in Scheme 2 involves the formation of Schiff’s base 5 from the reaction of 2-aminopyridine with aldehydes which undergoes Strecker reaction by the cyanide ion to form the corresponding aminonitrile adduct 6. Attack of the pyridine nitrogen ion pair to the CN function would result in the formation of the bicyclic imine product 7. 1,3-Proton shift followed by aromatization led to the formation of the corresponding 3-aminoimidazo[1,2-a]pyridine 8 which react with another molecule of aromatic aldehyde to afford final isolable product.

Scheme 2:

Proposed mechanism for the synthesis of imidazo[1,2-a]pyridine derivatives 4a–j.

In support of this mechanism, when 2-aminopyridine and aromatic aldehydes in pyridine were allowed to react first for 10 min followed by addition of cyanide ion source and another molecule of aldehyde and microwave heating continued for additional 20 min, compounds 4a–d were obtained in lower yields (cf. Table 1) than method A. Although, method B is a one-pot synthesis it includes two steps. Accordingly, method A is much desired because it saves time while increasing chemical yields. This is contrary to the previously reported formation of the corresponding cyanohydrin [33] from the reaction of aldehydes with TMSCN followed by the reaction with 2-aminopyridine.

4 Conclusion

In conclusion, we have reported a catalyst-free, one-pot three component, general high yielding method for the synthesis of N-arylidene-2-arylimidazo[1,2-a]pyridine-3-ylamine derivatives under microwave heating. Only one article, which describes using microwave heating with polymer-bound scandium triflate as a catalyst and trimethylsilyl cyanide as a cyanide ion source, has been reported. Our protocol was developed to avoid the use of both the hazardous reagents and expensive catalysts, with the advantages of the short microwave-assisted reaction time.