A facile access to biologically important scaffolds from bifunctional alkynenitriles

Abstract

The development of new and efficient strategies for constructing aliphatic/aromatic heterocyclic structural compounds specifically containing N, O and S heteroatoms has received tremendous attention owing to their ubiquitous presence in variety of natural products, agrochemicals, pharmaceuticals, dyes, cosmetics etc. Many are of fundamental importance to living systems and essential to life. Classical approaches to variously substituted heterocyclic and acyclic scaffolds mainly rely on the transition metal-catalyzed reactions. Reports on transition metal-catalyzed addition/cyclization reactions, coupling reactions, asymmetric synthesis, C-H bond activation/functionalization reactions, olefin metathesis reactions, etc. describes the dominance of transition metals in modern organic synthesis. However, the organic compounds which are synthesized using metal catalysts often suffer from severe contamination with residual metal impurities. In most of the cases, the expensive nature, tedious synthesis of the catalysts, cumbersome product isolation procedures, low sensitivity towards moisture and oxygen, toxicity, etc., limits the use of metal-catalyzed processes. The limitations of transition metal catalysis have encouraged chemists worldwide to bend towards metal-free chemistry. Therefore, our aim was to develop new methodologies for synthesizing diversely functionalized heterocyclic and acyclic scaffolds using transition metal-free appropriate milder reaction conditions. After successful exploration of alkynenitriles and alkynethiocyanates (potent bifunctional compounds containing both an alkyne-π system and a nitrile group) to develop cycloaddition methodologies to synthesize fused cyanoarenes, 2-alkynyl pyridines, aryl thiocyanates, and propargylic cyclic imines under mild reaction conditions, we switched our interest to exploit these bifunctional alkynenitriles in our laboratory to carry out a diverse range of transition metal-free chemical transformations especially the transition metal-free intermolecular nucleophilic additions. The thesis entitled “A Facile Access to Biologically Important Scaffolds from Bifunctional Alkynenitriles” has been described in the form of six chapters which cover discussions on four efficient transition metal-free approaches, developed by us, to access biologically important heterocyclic and acyclic scaffolds from bifunctional alkynenitriles and heteronucleophiles. Chapter 1: Introduction Heterocyclic compounds constitute nearly 50% of known organic compounds and nearly 90% of active pharmaceuticals. Cyclocondensation, multicomponent, cycloaddition, and ring expansion/contraction reactions are some of the efficient protocols to obtain a variety of heterocyclic adducts from various unsaturated substrates like alkynes, alkenes, etc. For the last couple of decades, bifunctional compounds like alkynenitriles possessing nitrile and acetylene functionalities have been exploited for the synthesis of various biologically and chemically important carbo- and heterocycles. In this chapter, heterocyclic compounds, their importance and general routes to synthesize has been concisely discussed. In addition, alkynenitriles and their use in nucleophilic conjugate addition reactions have been briefly documented. Chapter 2: Access to 5-Substituted 3-Aminofuran/thiophene-2-carboxylates from Bifunctional Alkynenitriles Five-membered heterocycles furans, thiophenes, and pyrroles and their derivatives are found as core structural motifs in various natural products, pharmaceuticals, and complex organic compounds. 3-amino substituted five-membered heterocycles are necessary scaffolds embedded in many molecules having potential biological activities. A majority of strategies include the reduction of 3-azido/3-nitro, rearrangements of furan-3-carboxylate derivatives, the cross-coupling of 3-halo/3 ylboronate derivatives with a nitrogen source, and so on. In addition, the strong base assisted Thorpe-Ziegler cyclization of cyanovinyl ethers has become an efficient and atom-economical tool for synthesizing 3-amino furans. Thus, we can see that all these above mentioned protocols require pre-functionalized substrate that itself has to be prepared, often in multiple steps using undesirable reagents. In this chapter, we have described how alkynenitriles could act as suitable candidates to react with heteronucleophiles having EWG at α-position to construct 3-amino substituted five membered heterocycles (Scheme 1). 3-aminofurans/thiophenes have been synthesized using K2CO3/DMF base solvent combination from cheap and readily available substrates in good to high yields. Chapter 3: A Facile Transition Metal-free Ionic Liquid [BMIM]OH Mediated Regio- and Stereoselective Hydrocarboxylation of Alkynenitriles Enol esters are versatile synthons in various elegant synthetic transformations. They have been used in multicomponent reactions, hydroformylation, epoxidation, aldol reactions, cycloaddition reactions, α-functionalization reactions, Mannich type reactions and asymmetric hydrogenations reactions. Therefore, several methods have been developed to synthesize substituted enol esters. Among different approaches, the direct addition of carboxylic acids to alkynes is the most widely used atom-economical approach. However, it is very challenging to control the regio- and stereoselecivity during the addition process especially in the case of unsymmetrically substituted internal alkynes. Therefore, specific reagents and catalysts, transition metal complexes of ruthenium, palladium, rhodium, iridium, cobalt, rhenium, silver, iron, copper, gold and mercury are utilized for the hydrocarboxylation of the alkynes to synthesize substituted enol esters. In addition, a lot of efforts have been employed in literature to tailor the synthesis of metal complexes and ligands to achieve the required regio- and stereoselectivity. Thus, most of approaches are assisted by either toxic or expensive metal salts, drastic reaction conditions, poisonous reagents or costly ligands, while reports on metal-free hydrocarboxylation reactions are rather limited. In this chapter, we have presented highly efficient, transition metal-free, ionic liquid [BMIM]OH mediated synthesis of nitrile substituted enol esters in Z-stereoselection fashion with the reusability of the ionic liquid up to ten runs without loss of activity (Scheme 2). Chapter 4: Ionic Liquid Mediated One-Pot 3-Acylimino-3H-1,2-dithioles Synthesis from Thiocarboxylic Acids and Alkynenitriles via in situ Generation of Disulfide Intermediates Functionalized 1,2-dithiol heterocyclic structural motifs are frequently found in various natural products and pharmaceuticals and show a broad spectrum of biological and pharmacological activity, like antioxidant, antibiotic, chemotherapeutic, antitumor and anti HIV etc. In addition, they are being used as building blocks for synthesizing novel sulfur or nitrogen atom(s) containing heterocycles. As a result, several synthetic methodologies are being developed for their preparation. However, 3-acylimino-1,2 dithiole derivatives another class of 1,2-dithiols remained underexplored and further development is much needed to widen the access to this class of compounds. So far, all the existing protocols rely on the already inbuilt 1,2-dithiole core containing substrates and are associated with the drawback of the limited availability and multistep synthesis of the pre-decorated precursors. In this context, we have developed the first quantitative one-pot ionic liquid [BMIM]Br-mediated synthesis of 3-acylimino-3H-1,2-dithiols from readily available thiocarboxylic acids and bifunctional alkynenitriles in the presence of K2CO3 as a base (Scheme 3). Chapter 5: Tetra Substituted Chromanone Synthesis via a Tandem Michael/oxa Michael Addition between 2-Hydroxyacetophenones and Alkynenitriles Polyfunctionalized Chroman-4-ones are widespread oxygen-based heterocycles with numerous applications in medicinal chemistry. They have been identified as an active core in many biologically active natural products and pharmaceuticals and are of great interest to organic chemists owing to their diverse biological activities. As a result, numerous elegant synthetic strategies have been developed to build up their fundamental cores. After successfully developing straightforward routes to five-membered N, O and S containing heterocycles utilizing bifunctional alkynenitriles, we paid our attention to further exploit these bifunctional substrates to develop a protocol to synthesize six membered oxygen-based heterocycles. Scheme 4 Tetra substituted chromanone synthesis via Michael/oxa-Michael addition between 2-hydroxyacetophenones and alkynenitriles. In this context, we have developed a transition metal-free, one-pot, NaH-mediated Michael/intramolecular oxo-Michael addition process to synthesize C2, tetrasubstituted chroman-4-ones from readily accessible starting materials 2-hydroxyacetophenones and alkynenitriles under mild reaction conditions (Scheme 4). The protocol proceeds via a sequence of 1,4-conjugate addition of enolate to alkynenitrile, followed by subsequent intramolecular oxa-Michael addition. This strategy provides a convenient method for accessing a broad range of tetrasubstituted chromanones in good to excellent yields with good functional-group tolerance. Chapter 6: Conclusions In this chapter, the summary of the whole work has been described (Scheme 5).