Synthesis of chalcogenated compounds via various protocols

Abstract

Organochalcogen compounds have been widely studied as they often exhibit biological activities, including anticancer, antimicrobial, and antioxidant. More specifically, the chalcogenocyanates and chalcogenated ethers are important structural constituents that are present in biologically active reagents and functional materials. Many chalcogen containing molecules such as Crizotinib and Lorlatinib have been witnessed as blockbuster drugs in recent decades. By considering the biological roles of these compounds, the development of new and efficient routes for the synthesis of chalcogenocyanates is a tempting research area. Classical approaches to thiocyanates rely on the reaction of various alkyl or aryl substrates that do not contain sulfur with a thiocyanating agent and reaction of a substrate bearing electrophilic or nucleophilic sulfur with a cyanating agent, while selenocyanates are obtained by employing selenocyanate salts such as potassium selenocyanate, triselenium dicyanide (TSD), dicyanodiselenide, selenocyano-benziodoxolone, and a combination of elemental selenium and TMSCN in organic synthesis. However, most of these cyanation methods are confronted with various drawbacks and limitations, including the utilization of highly poisonous and notorious cyanating agents, the pre-functionalization or pre-activation of substrates and harsh reaction conditions. Therefore, the development of new reactions for the synthesis of such compounds has always been a prime focal area in synthetic organic chemistry.Keeping this in mind, various chalcogenocyanate salts have been investigated to access the alkyl/aryl chalcogenocyanates. The obtained chalcogenocyanates further explored to achieve chalcogenated ethers. For this purpose, various methods including metal-free and metal catalyzed [2+2+2] cycloaddition are developed. The transition metal-catalyzed formation of multiple rings via 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 aryl cyanates, aryl thio-/selenocyanates, work has been done towards the synthesis of aryloxypyridines, aryl thio-/selenopyridines via intermolecular [2+2+2] cycloaddition reactions. After obtaining macrocyclic aryl chalcogenated-pyridine derivatives, chalcogenocyanates were probed with electron-rich arenes and indoles under metal-free conditions. In this regard, HFIP was explored as a solvent for the decyanation of chalcogenocyanates. The title of my thesis is “Synthesis of chalcogenated compounds via various protocols” and my thesis-work has been presented in the form of five chapters as summarized below. Chapter 1: A brief introduction to aryl chalcogenocyanates and their applications in synthetic chemistry The group 16 elements are named as chalcogens and their coupling with nitrile group have a dramatic impact on the physical, chemical and biological properties. Thus coupled molecules, aryl chalcogenocyanates have the general formula ArXCN (X = O, S, Se or Te), which demonstrates the potential of getting converted into other interesting functional groups. Moreover, they have the capability to introduce both the chalcogen atom and nitrile group simultaneously into organic molecules depending on the reaction conditions. They have mainly exploited for the formation of tetrazoles via [3+2] cycloadditions with azides. Interestingly, depending on the reaction conditions they can either act as a source of ArX or CN group. Such interesting properties have prompted us to explore the chemistry of aryl chalcogenocyanates. Literature studies revealed that they act as catalytic poison for the transition-metal due to their coordinating properties with metals. In this context, [2+2+2] cycloaddition for utilizing them as an ideal precursor has become an efficient tool and numerous transition-metals are employed for the said purpose. The pioneering studies in the direction of [2+2+2] cycloadditions to pyridine synthesis was done by Wakatsuki and Yamazaki in 1973, which involved stoichiometric reactions of cobaltacyclopentadienes (formed from two acetylenes) with nitriles to produce pyridines (Scheme 1). Since then a number of catalytic and stoichiometric cyclocotrimerizations have been developed using various transition metal complexes involving Fe, Ru, Co, Rh, Ir, Ni, Au, Au, Nb, Ti and Zr. In the [2+2+2] cocycloadditions of alkynes and nitrile, the latter is generally used in excess so as to avoid any alkyne cyclotrimerizations which is generally a favoured process. Additionally, the incorporation of more than one nitrile does not occur since such a dimerization or trimerization of nitriles is thermally and kinetically non-favorable in the presence of alkynes. However, [2+2+2] cycloaddition strategy has never been explored for the reaction of diyne and aryl chalcogenocyanates till the publication of our group. Keeping this in mind, a variety of transition-metal are investigated for the [2+2+2] cycloaddition of diynes and aryl chalcogenocyanates. It is important to mention that the chalcogenocyanates are less studied for decyanative purpose. Encouraged by the interesting applications of chalcogenocyanates in the area of [2+2+2] cycloadditions, we further embarked to probe them under metal-free conditions. Foe the decyanation purpose, HFIP was chosen as a solvent due to its H-bonding capability. In this connection, we have synthesized various chacogenocyanates, and further utilized them for chalcogenated ethers using both metal-free conditions and metal catalyzed [2+2+2] cycloaddition, and has been documented in second, third and fourth chapter of the thesis. Chapter 2: Novel Reactivities of KXCN (X = O, S, Se) Towards Aryl Sulfonyl Chlorides: Temperature Controlled Chemoselective Synthesis of Thiosulfonates and Thiocyanates with KSeCN Organosulfurs, with a wide spectrum of biological and pharmaceutical applications, have fascinated many synthetic chemists. Among them, thiosulfonates and thiocyanates have drawn considerable attention in the past decades. Inspite of having many methods in the literature, the synthesis of thiosulfonates and thiocyanates through single reaction strategy has become a research hotspot in organic synthesis. During the reactivity studies of potassium chalcogenocyanates towards aryl sulfonyl chlorides, thiosulfonates and thiocyanates are obtained chemoselectively from the treatment of aryl sulfonyl chlorides with potassium selenocyanate. Analogously, thiosulfonates were obtained as sole products when sulfonyl chlorides treated with KSCN. In this chapter, chemoselective route to access the thiosulfonates and thiocyanates has been developed just by tuning the amount the temperature and amount of potassium selenocyanates. Furthermore, the synthesis of α- carbonyl selenocyanates was accomplished via the reaction of substituted acetophenone with the white salt obtained during thiocyanation reaction as a side product. The work done has been depicted in the schematic diagram (Scheme 2). Chapter 3: An Atom-Economical Approach to 2-Aryloxypyridines, 2,2'/2,3'- Diaryloxybipyridines and 2-Aryl Selenopyridines via Ruthenium-Catalyzed [2+2+2]- Cycloadditions Chapter 3A: An Atom-Economical Approach to 2-Aryloxypyridines and 2,2’/2,3’- Diaryloxybipyridines via Ruthenium-Catalyzed [2+2+2] Cycloadditions In this chapter, synthesis of 2-aryloxy pyridines via ruthenium (II)-catalyzed [2+2+2] cycloadditions has been achieved. Among the various transition-metal-based catalysts known for cycloaddition reactions for the synthesis of pyridine derivatives, chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) was found to be one of the best catalyst in this category. Over the past decade, 2-aryloxy pyridine skeletons have been synthesized by Pd- and Cu-catalyzed C-O cross-coupling reactions of 2-halopyridines with phenols, all of which involve the derivatization of the already available pyridine ring, elevated temperatures and large reaction times. Herein, using [2+2+2] cycloadditions, we have presented a facile and novel approach for the construction of pyridines with the concomitant introduction of aryloxy group under mild reaction conditions. The protocol presented in this chapter provides ruthenium (II)-catalyzed [2+2+2] cycloadditions reactions of diynes with phenyl cyanates to give access to multisubstituted 2-aryloxy pyridines. The protocol was further utilized for the synthesis of 2,2'- and 2,3'-diaryloxybipyridines by the reaction of tetraynes with aryl cyanates. It was observed that in the case of malonate tethered tetraynes, 2,3'-diaryloxybipyridines were regioselectively produced, while in the case of O-tethered tetraynes, 2,2'-diaryloxybipyridines were the exclusive regioisomers obtained. The schematic diagram of 2-aryloxypyridine derivatives has been disclosed below. Chapter 3B: An Expeditious and Environmentally-Benign Approach to 2-Aryl/Heteroaryl Selenopyridines via Ruthenium (II)-Catalyzed [2+2+2] Cycloaddition Reactions of Diynes with Aryl Selenocyanates In this chapter, a highly efficient, protocol for the synthesis of 2-aryl selenopyridines via Ru(II)-catalyzed [2+2+2] cycloaddition reaction of 1,6-diynes with aryl/heteroaryl selenocyanates has been developed. The protocol enables the transformation of various aryl/heteroaryl selenocyanates into 2-aryl/heteroarylpyridines in the presence of Cp*Ru(COD)Cl as a catalyst in ethanol with good to excellent yields. The traditional method is based on the the nucleophilic substitution of 2-halopyridines with salts of selenols or transition metal catalyzed cross-coupling reactions of diselenides with aryl boronic acids or 2-halopyridines. In this section, we presented an expeditious and environmentally-benign approach to 2- aryl/heteroaryl selenopyridine derivatives via [2+2+2] cycloaddition reaction of 1,6-diynes with aryl/heteroaryl selenocyanatates ambient temperature with lower catalyst loading. The work done has been described below in schematic diagram (Scheme 4). Chapter 4: An Efficient Transition Metal-free HFIP-Mediated Organo Chalcogenylation Reactions of Arenes/Indoles with Thio-/Selenocyanates In this section, an efficient metal-free protocol for the synthesis of diaryl thio- /selenoethers by the reaction of aryl thio-/selenocyanates with electron rich arenes/hetero arenes via HFIP promoted C-H activation has been developed. Over the decades, unsymmetrical chalcogenated-ethers have been obtained by transition-metal-catalyzed coupling reaction. Due to requisite need of toxic and expensive transition-metals, metal-free approaches are highly desired. To achieve more efficient C–H activation, we focused on highly acidic hexafluoro iso-propanol (HFIP), which is almost exclusively involved as a solvent or an additive in stabilizing cationic intermediates due to its high polarity and low nucleophilicity. The chapter presents the efficient metal-free strategy for the formation of C-X (X = S, Se) bonds through the C-H activation of arenes/indoles with aryl/heteroaryl selenocyanates utilizing the H-bonding ability of HFIP. The protocol can also be utilized for the large scale synthesis of aryl (hetero)aryl thio-/selenoethers. The work done has been disclosed below in schematic diagram (Scheme 5). Chapter 5: Conclusion In this chapter, summary of the whole work has been described. In addition, potential future aspects of the thesis are indicated. The aforementioned pieces of work on the chalcogenocyanation and their use for chalcogenated-ethers is shown below in a schematic diagram to have a quick look (Scheme 6).