Multi-component solvent-free versus stepwise solvent mediated reactions: Regiospecific formation of 6-trifluoromethyl and 4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridines (original) (raw)

2012, Journal of Fluorine Chemistry

Multicomponent reactions (MCRs) are special type of synthetically useful organic reactions, in which three or more simple reactants are consumed in a single chemical step to produce a product that incorporates substantial portions of all the reactants. Generally multicomponent reactions, being one-pot process, afford good yields. They are fundamentally different from two component stepwise reactions in several ways such as: the simplicity of one-pot procedure, possible structural variation, complicated synthesis and large number of accessible compounds. Organic reactions under solvent-free conditions have gained much attention due to several advantages over the conventional methods in terms of enhanced selectivity, cleaner reaction profile, ease of manipulation and relatively benign conditions [1-6]. Among the condensed heterocyclic systems, pyrazolo[3,4b]pyridines are an important class of heterocyclic systems being part of therapeutically interesting compounds that display significant activity such as antimicrobial [7], antiviral [8], antiinflammatory [9], antitumor agents [10] and as potent PDE4B inhibitors [11]. In addition, pyrazolo[3,4-b]pyridines with a trifluoromethyl group are known to possess multidrug function with antimalarial activity [12]. The foregoing observations prompted us to undertake the preparation of trifluoromethyl substituted pyrazolo[3,4-b]pyridines. Generally, the synthesis of such heterocycles is accomplished by two distinct routes. The first one (Route A, Fig. 1) involves formation of a pyrazole ring on a 3acetyl/cyanopyridine bearing a good leaving group in 2-position, but this method lacks versatility in terms of substitution, as only pyridines containing, methyl, aryl, hydroxyl and amino groups at position-3 can be attained. The second route uses the condensation reaction of 5-amino-1H-pyrazoles with bifunctional electrophiles to form the pyridine moiety (Route B, Fig. 1), and offers a great diversity and flexibility in terms of substitution at pyrazole and pyridine rings. Nevertheless, this method is disadvantageous due to multiple step synthesis, large reaction times and low/moderate yields. Moreover, formation of different regioisomers has been reported in the literature i.e. in the reaction of 5-amino-1H-pyrazoles with trifluoromethyl-b-diketones under similar reaction conditions [13,14]. In view of these observations and our ongoing interest to develop greener protocols for the synthesis of heterocyclic compounds [15-18], we report here a mild and efficient MCR providing a regiospecific synthesis of 6-trifluoromethyl-1Hpyrazolo[3,4-b]pyridines under solvent-free conditions. At the same time, and in order to compare the results obtained by MCR with those using a multistep solvent mediated process, regioisomeric 4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridines will also be described.