Iron-and ruthenium-catalyzed cycloaddition reactions of alkynylnitriles and alkynylthiocyanates

Abstract

The development of efficient methodologies for the construction of complex aromatic/heteroaromatic molecular structures has received widespread attention because of their ubiquitous presence in various natural products, pharmaceuticals, agrochemicals, cosmetics, dyes etc. Classical approaches to variedly substituted aromatic compounds mainly rely on the electrophilic and nucleophilic substitution reactions of readily available benzene ring, while the condensation reactions under basic and acidic conditions is normally employed for heteroaromatic compounds. Therefore, the development of new reactions for the synthesis of such compounds has always been a prime focal area in synthetic organic chemistry. An expedient approach to highly substituted aromatic/heteroaromatic compounds involves the convergent annulation strategy in which these systems can be assembled from simple acyclic precursors, with all or most substituents pre-installed in place. Therefore, [2+2+2] cycloaddition approach where, three readily available unsaturated partners, such as alkynes and nitriles, combine together, permits the rapid and efficient assembly of highly substituted aromatics/heteroaromatics. Such structures normally require multiple tedious steps for their synthesis using classical substitution methodology. Over the last few years, atom-efficient and group tolerant [2+2+2] cycloaddition reactions between α,ω-diynes and acetylenes/nitriles have been well explored for the synthesis of a variety types of fused substituted benzenes and pyridines, respectively. Keeping this in mind, we explored alkynylnitriles and alkynylthiocyanates (potent bifunctional compounds containing both an alkyne-π system and a nitrile-like lone pair for coordinating to metal centers) to develop a [2+2+2] cycloaddition methodology in which both benzene and pyridine rings could be synthesized in a chemoselective manner. Therefore, we developed the transition metal-catalyzed chemoselective synthesis of fused cyanoarenes, 2- alkynyl pyridines and aryl thiocyanates under mild reaction conditions. The general methodologies to synthesize these compounds mainly encompass the transition metalcatalyzed cyanation of aryl halides, palladium-catalyzed Sonogashira cross-coupling reactions and the metal-catalyzed cyanation of diselenides. Additionally, the transition metal-catalyzed formation of multiple rings via sequential or one-pot cycloaddition reactions is an efficient way to rapidly assemble complex fused polycyclic ring systems. Therefore, the development of such synthetic protocols still remains an attractive goal in synthetic organic chemistry. In this context, employing alkynylthiocyanates, work has been done towards the sequential synthesis of aryl thiopyridines via double intermolecular [2+2+2] cycloaddition reactions and the one-pot synthesis of triazolyl thio-/selenopyridines via [3+2]/[2+2+2] cycloadditions. The title of my thesis is “Iron- and Ruthenium-Catalyzed Cycloaddition Reactions of Alkynylnitriles and Alkynylthiocyanates” and the thesis work has been presented in the form of five chapters as summarized below. Chapter 1: Introduction Cycloaddition reactions, a means to construct several bonds simultaneously in a single step, is a powerful strategy to obtain a variety of cyclic adducts from various unsaturated substrates like alkynes, alkenes, allenes, nitriles, isocyanates etc. These convergent reactions are high in atom-economy and show good functional group tolerance. In spite of these advantages, the use of harsh reaction conditions like heat, light, high pressure, sonication etc. is always an associated problem, which, can be tackled to some extent with the involvement of transition metal catalysts and this has made a tremendous contribution in the field of cycloadditions. In this context, the use of [2+2+2] and [3+2] cycloadditions for the rapid construction of substituted carbo-/heterocyclic ring systems like benzenes, pyridines, triazoles etc. has become a highly effective tool and numerous transition metals have been employed to synthesize these targets. The first thermal induced cyclization of acetylene was discovered by Berthelot in 1866. Later, in 1948, Reppe reported that transition metals can catalyze the cycloaddition of alkynes into substituted benzenes. In 1973, Yamazaki and his co-worker documented the application of [2+2+2] cycloaddition to synthesize pyridines from the combination of two acetylenes and one nitrile moiety in the presence of cobalt catalyst. Similarly, in the field of [3+2] cycloadditions, in 1963, Huisgen reported the thermal [3+2] cycloaddition approach leading to 1,4- and 1,5-disubstituted triazoles while, the first transition metal-catalyzed azide-alkyne cycloaddition was reported in 2002 by Sharpless and Meldal, independently, in the presence of copper-catalyst to produce 1,4-disubstituted regioisomer. Scheme 1 depicts the aforementioned pioneering works in the field of [2+2+2] and [3+2] cycloaddition reactions. These discoveries led to a paradigm shift, moving beyond the available standard methods and since then, these transition metal-catalyzed cycloadditions have become essential tools in modern synthesis owing to their atom-economical construction of various aromatic/heteroaromatic molecules which were otherwise difficult to be accessed. A number of transition metal complexes of cobalt, rhodium, ruthenium, nickel, iron, iridium, palladium, gold and niobium have been well explored for the synthesis of a variety of functionalized benzene and pyridine derivatives using [2+2+2] cycloadditions while, rhodium, ruthenium, nickel, copper and iridium are available for [3+2] cycloadditions. In the similar manner, we have synthesized various biologically relevant structures involving benzene, pyridine and triazole rings and it has been documented in second, third and fourth chapter of the thesis. Scheme 1. Pioneering studies in the field of [2+2+2]- and [3+2] cycloadditions. Chapter 2: An Atom Economic Route to Cyanoarenes and 2,2'-Dicyanobiarenes via Iron Catalyzed Chemoselective [2+2+2] Cycloaddition Reactions of Diynes and Tetraynes with Alkynylnitriles Owing to the biological prevalence of nitrile group and its tendency to be converted to various other functionalities, the synthesis of cyanoarenes has garnered a lot of attention. All the methods available in literature starting from the transition metal-catalyzed cyanations of aromatic halides with inorganic metal salts to the use of methodologies involving organic precursors bearing a cyano functionality, deal with the introduction of a cyano group on the already available benzene ring. In this regard, the use of transition metal-catalyzed [2+2+2] cycloaddition between 1,6-diynes and alkynylnitriles for the creation of aromatic rings with a pre-installed cyano group is a valuable alternative. In this chapter, an efficient route for the synthesis of cyanoarenes in good to excellent yields has been developed via iron-catalyzed chemoselective [2+2+2] cycloaddition reactions between diynes and alkynylnitriles. The reaction utilizes the catalytic combination of FeCl2·4H2O as a metal source, 2-(2,6- diisopropylphenyl)iminomethylpyridine (dipimp) as a ligand, and Zn as a reducing agent in DME solvent. The protocol exhibited remarkable regio- and chemoselectivity. This methodology was also extended to the construction of 2,2′-dicyanobiarenes from the reaction of tetraynes with alkynylnitriles. The work done has been depicted in the schematic diagram (Scheme 2). Scheme 2. Chemoselective iron-catalyzed approach to cyanoarenes and 2,2'-dicyanobiarenes. Chapter 3: Additive Controlled Switchable Selectivity from Cyanobenzenes to 2- Alkynylpyridines: Ruthenium(II)-Catalyzed [2+2+2] Cycloadditions of Diynes and Alkynylnitriles The [2+2+2] cycloadditions between diynes and acetylenes/nitriles has been well explored for the synthesis of fused benzenes/pyridines and a number of transition metals are available for the same. We aimed at employing a bifunctional reactant i.e alkynylnitrile, containing both acetylene and nitrile functionalities, for the development of a [2+2+2] cycloaddition protocol in which by simple modification in the reaction conditions such as solvent, temperature, additive, catalyst etc., keeping the reactants and catalyst unchanged, both cyanoarenes and 2-alkynylpyridines could be constructed in a chemoselective manner. These compounds are generally prepared via the transition metal-catalyzed cyanation of aryl halides and palladium-catalyzed Sonogashira cross-coupling reactions. Therefore, in this chapter, an atom-economical and straight forward access to cyanoarenes and 2-alkynylnitriles has been presented via silver triflate controlled and Cp*Ru(COD)Cl catalyzed [2+2+2] cycloaddition reactions between diynes and alkynylnitriles. The addition of AgOTf in catalytic amounts as an additive to the reaction mixture, resulted in an explicit shift in the product formation from cyanoarenes to 2-alkynylpyridines. DFT calculations indicated that the neutral Ru-complex is responsible for the formation of cyanobenzenes, whereas, cationic Ru-complex generated insitu using AgOTf was responsible for the 2-alkynylpyridines formation. The general applicatibility of the protocol was confirmed by the successful cycloadduct formations in case of non-conjugated alkynylnitriles. The work done has been shown in Scheme 3. Scheme 3. Silver-triflate controlled, ruthenium(II)-catalyzed approach to cyanoarenes and 2- alkynylpyridines. Chapter 4: Ruthenium(II)-Catalyzed Sequential and One-Pot Double Cycloadditions Chapter 4A: Chemoselective Ru(II)-Catalyzed Synthesis of Aryl Thiocyanates and Sequential Double [2+2+2] Cycloaddition to 2-Aryl Thiopyridines Owing to the easy transformations of the thiocyanate group to various other functional groups, these are interesting targets for synthetic organic chemists. The general techniques to synthesize these compounds mainly rely on the nucleophilic and electrophilic substitution reactions at the aromatic ring using inorganic thiocyanate salts. In this chapter, efficient, chemoselective, solvent-free synthesis of aryl thiocyanates via Cp*Ru(COD)Cl catalyzed [2+2+2] cycloaddition reaction of 1,6-diynes with 1-alkynyl thiocyanates has been developed. We aimed at utilizing the isolated aryl thiocyanate derivatives by combining the initial [2+2+2] cycloaddition with another [2+2+2] cycloaddition for making complex structures with the incorporation of both benzene and pyridine rings. Therefore, this chapter also involves the sequential ruthenium(II)-catalyzed chemoselective double [2+2+2] cycloadditions for the synthesis of 2-aryl thiopyridines. Over the past few years, the 2-aryl thiopyridine skeleton has generally been synthesized by transition metal-catalyzed cross-coupling reactions. The work done has been depicted in Scheme 4. Scheme 4. Sequential ruthenium(II)-catalyzed chemoselective double [2+2+2] cycloadditions to 2-aryl thiopyridines. Chapter 4B: An Atom-Economical Approach to 2-Triazolyl Thio-/Seleno Pyridines via Ruthenium-Catalyzed One-Pot [3+2]/[2+2+2] Cycloadditions Transition metal-catalyzed [2+2+2] and [3+2] cycloadditions are highly efficient and straightforward routes to the synthesis of variety of fused carbo-/heterocycles and substituted triazoles. We anticipated that bifunctional 1-alkynyl thiocyanates could lead to the possibility of development of a transition metal-catalyzed double [3+2]/[2+2+2] cycloaddition protocol in which both triazole and pyridine rings could be constructed in a one-pot manner. Therefore, in this chapter, we documented the synthesis of 2-triazolyl thio-/selenopyridines with good to Scheme 5. One-pot Ru(II)-catalyzed [3+2]/[2+2+2] cycloaddition reactions to 2-triazolyl thio-/selenopyridines. excellent regioselectivites using one-pot Cp*Ru(COD)Cl catalyzed [3+2]/[2+2+2] cycloaddition reactions between 1,6-diynes, alkyl/aryl azides and 1-alkynyl thio- /selenocyanate under mild reaction conditions. An unpredented access to 3,3'-bis(triazolyl thio- /seleno)-2,2'-bipyridines by the reaction of tetraynes with 1-alkynyl thio-/selenocyanates in the presence of aryl/alkyl azides has also been presented to extend the applicability of this protocol. In addition, the chapter also describes an access to a wide range of thio-/selenocyanate substituted triazoles in good regioselectivities. The work developed is illustrated in Scheme 5. The aforementioned pieces of work on the iron and ruthenium-catalyzed cycloadditions using bifunctional reagents is shown below in a schematic diagram to have a quick look (Scheme 6). Scheme 6. Iron and ruthenium-catalyzed cycloadditions using bifunctional reagents. Chapter 5. Conclusions In this chapter, the summary of the whole work has been described.