Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)3 catalyst in the reaction selectivity

Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)3 catalyst in the reaction selectivity Natividad Herrera Cano1, Jorge G. Uranga1, Mónica Nardi2, Antonio Procopio3, Daniel A. Wunderlin4 and Ana N. Santiago*1,§ Full Research Paper Address: 1INFIQC-CONICET and Facultad de Ciencias Químicas, Departamento de Química Orgánica, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, 5000 Argentina, 2Dipartimento di Chimica, Università della Calabria Cubo 12C, 87036-Arcavacata di Rende (CS), Italia, 3Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa, 88100-Germaneto (CZ), Italia and 4ICYTAC-CONICET and Facultad de Ciencias Químicas, Departamento de Química Orgánica, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, 5000 Argentina Email: Ana N. Santiago* - Open Access Beilstein J. Org. Chem. 2016, 12, 2410–2419. doi:10.3762/bjoc.12.235 Received: 18 July 2016 Accepted: 28 October 2016 Published: 16 November 2016 This article is part of the Thematic Series "Green chemistry". Guest Editor: L. Vaccaro © 2016 Herrera Cano et al.; licensee Beilstein-Institut. License and terms: see end of document. * Corresponding author § Tel: +54 351 5353867, extension 53314 Keywords: catalysis; charge density; condensation; erbium(III) trifluoromethanesulfonate; green procedure; heterocycle Abstract An improved and greener protocol for the synthesis of benzimidazole derivatives, starting from o-phenylenediamine, with different aldehydes is reported. Double-condensation products were selectively obtained when Er(OTf)3 was used as the catalyst in the presence of electron-rich aldehydes. Conversely, the formation of mono-condensation products was the preferred path in absence of this catalyst. One of the major advantages of these reactions was the formation of a single product, avoiding extensive isolation and purification of products, which is frequently associated with these reactions. Theoretical calculations helped to understand the different reactivity established for these reactions. Thus, we found that the charge density on the oxygen of the carbonyl group has a significant impact on the reaction pathway. For instance, electron-rich aldehydes better coordinate to the catalyst, which favours the addition of the amine group to the carbonyl group, therefore facilitating the formation of double-condensation products. 2410 Beilstein J. Org. Chem. 2016, 12, 2410–2419. Reactions with aliphatic or aromatic aldehydes were possible, without using organic solvents and in a one-pot procedure with short reaction time (2–5 min), affording single products in excellent yields (75–99%). This convenient and eco-friendly methodology offers numerous benefits with respect to other protocols reported for similar compounds. Introduction The formation of heterocyclic compounds is a very important task in organic synthesis, mainly because they are present in numerous biologically active compounds and in several natural products [1]. Among them the presence of benzimidazole [2-7] or benzothiazole [8,9] rings in numerous compounds is an important structural element for their biological and medical applications. For example benzimidazoles are widely spread in antiulcer, antihypertensive, antiviral, antifungal, anticancer, and antihistaminic medicines, among others [10-12]. One frequently used protocol for the synthesis of benzimidazole derivatives is the coupling of o-phenylenediamines with carboxylic acids [13,14]. Another widely used procedure for the same synthesis represents the condensation of o-phenylenediamine with aldehydes. The latter approach has become more widely accepted, because of the easy access to a variety of substituted aldehydes. For instance, the reaction between o-phenylenediamine and benzaldehyde readily affords benzimidazole derivatives (Scheme 1). However, the reaction is not selective, affording both 2-substituted (a) and 1,2-disubstituted benzimidazoles (b). Therefore, the main drawbacks of current protocols for the synthesis of benzimidazoles include the use of expensive reagents, difficulties in the preparation of the catalyst, long reaction times, a narrow scope of substrates, tedious work-up procedures, the use of hazardous organic solvents and lack of selectivity [15-21]. Rare earth metals are economical and readily available from commercial sources and represent useful catalysts in organic synthesis [22]. In particular, erbium(III) promotes environmentally friendly reactions [23-25], and has been successfully applied to the synthesis of natural products [26-28]. For instance, an efficient method for the synthesis of a wide range of 3,3-dimethyl-11-alkyl, or aryl 2,3,4,5-tetrahydro-1Hdibenzo[b,e][1,4]diazepin-1-ones was reported using erbium(III) trifluoromethanesulfonate, Er(OTf)3 as catalyst. The reaction comprises a one-pot condensation between o-phenylenediamine and 5,5-dimethylcyclohexane-1,3-dione, followed by a Er(OTf) 3 -catalyzed cyclization with diverse alkyl- or arylcarbonyl chlorides [29,30]. In view of these previous applications, our main goal was the development of an environmentally friendly synthetic method, to obtain different derivatives containing the benzimidazole core by a one-pot reaction. Additionally, Er(OTf)3 was selected as the catalyst to achieve the selective formation of products in order to avoid tedious work-up and product separation procedures. Moreover, differences in reactivity were investigated by by means of theoretical calculations. Results and Discussion The benzimidazole core was obtained by air oxidative cyclocondensation of o-phenylenediamine with benzaldehyde under different conditions. In water and in the presence of Er(OTf)3, the diamine and benzaldehyde (1:2 ratio) selectively afforded 1-benzyl-2-phenyl-1H-benzimidazole (1b) (72% yield), using both microwave irradiation and conventional heating for 15 minutes (Table 1, entries 1 and 3). In the absence of the catalyst, the same reaction afforded a mixture of products 1a and 1b using both conditions. Namely, under microwave irradiation, 41% of 1a and 51% of 1b were formed (Table 1, entry 2). While, using conventional heating, 52% of 1a and 40% of 1b were formed (Table 1, entry 4). To shorten the reaction time, the catalyzed reaction was carried out during 5 minutes at room temperature. Using these last conditions, the reaction afforded selectively 1b in 62% yield (Table 1, entry 5). On the other hand, when the reaction was Scheme 1: Formation of the benzimidazole core. 2411 Beilstein J. Org. Chem. 2016, 12, 2410–2419. Table 1: Comparison of the efficiency of various catalysts, solvents and temperatures in the reaction of o-phenylenediamine with benzaldehyde.a Entry Catalyst Solvent Temperature (°C) Time (min) Yield (%) References 1 2 Er(OTf)3 – H2O H2O MW/120b MW/120b 15 15 this work this work 3 4d Er(OTf)3 – H2O H2O 120b 120b 15 15 5 6 7 Er(OTf)3 Er( (...truncated)