Harnessing Strained Systems: Arynes, Donor Acceptor Cyclopropanes, and Bicyclobutanes in Annulations, Multicomponent Couplings and Insertion Reactions

Abstract

More than a century ago, the discovery of aryne intermediates proved to be a valuable addition to the toolkit of organic chemists, enabling the synthesis of a diverse range of molecules using these electrophilic intermediates as building blocks. The intrinsic electrophilicity and kinetic instability of aryne intermediates arise from the presence of a carbon-carbon triple bond within a six-membered ring, leading to a strained structure, and this is the reason for the exceptional reactivity of arynes. Chapter 2 The synthetic utility of NaN3 as the inorganic azide component in the [3+2] annulation with arynes generated from 2-(trimethylsilyl)aryltriflates resulting in the transition-metal-free synthesis of N H and N-aryl benzotriazoles has been demonstrated in this Chapter. Using CsF as the fluoride source in CH3CN, the N-H benzotriazoles are formed in high selectivity instead of the expected azidobenzene. Interestingly, N-aryl benzotriazoles are formed using KF and THF as solvent in an open-flask reaction. Moreover, a method for the N1-arylation of benzotriazole has also been uncovered. Chapter 3 A transition-metal-free, three-component and diastereoselective [6+3] annulation reaction employing tropone, imino esters and arynes allowing the synthesis of bridged azabicyclo[4.3.1] decadienes is disclosed in this Chapter. The key nitrogen ylides for the [6+3] annulation was generated by the addition of imino esters to the arynes followed by a proton transfer. The nitrogen ylides undergo a regioselective addition to tropone to furnish the desired products in moderate to good yields with good functional group tolerance under mild conditions. The present reaction is operationally simple, advance smoothly under mild conditions and can tolerate various functional groups. Experiments were carried out to get insight into the possible course of the reaction and the product were transformed into other bridged azabicycles Chapter 4 The direct C2-functionalization of pyridines via a transition-metal-free protocol using aryne multicomponent coupling is demonstrated in this Chapter. The reaction allowed a broad scope synthesis of C2 substituted pyridine derivatives bearing the -CF3 group in good yields engaging α,α,α‐ trifluoroacetophenones as the third component. Activated keto esters could also be employed as the third component in this formal 1,2-di(hetero)arylation of ketones. Performing the reaction under dilute conditions inhibited the competing pyridine-aryne polymerization pathway. The nucleophilic pyridylidene intermediate generated from pyridine and aryne adds to the activated carbonyls in an SNAr process (similar to the Smiles rearrangement) to afford the desired products. Detailed mechanistic studies were performed to get insight into the mechanism of the reaction. The present aryne coupling is not limited to -CF3 containing ketones as electrophilic third components but instead -ketoesters can also be used to intercept the pyridylidene intermediates generated from pyridine and aryne. Chapter 5 The advancement of novel reactive molecular entities plays a crucial role in enhancing the toolkit of synthetic organic chemists for constructing intricate architectures. Among these entities, donor acceptor (D-A) cyclopropanes have emerged as particularly significant. This strained but kinetically stable intermediate can be further activated through various methods, including Lewis acid activation, organocatalysis, radical activation, and electrochemical activation. These activation processes enable a range of reactions, such as cycloaddition, ring-opening reactions, and 1,3-bisfunctionalization. This Chapter presents an overview of the progress in this field, the distinctive characteristics of D-A cyclopropanes, their potential modes of reactivity, and other notable advancements. Additionally, this Chapter also provides an introduction to highly strained bicyclobutane (BCB), which has gained popularity in recent years Chapter 6 In this Chapter, the Yb(OTf)3 catalyzed mild and regioselective ring-opening 1,3- aminothiolation of donor-acceptor (D-A) cyclopropanes using sulfenamides has been demonstrated. The insertion of the C-C σ-bond of D-A cyclopropanes into the S-N σ-bond of sulfenamides allows the synthesis of diverse -aminated -thiolated malonic diesters in moderate to good yields (up to 87%) with good functional group compatibility. Complete regioselectivity was observed in the ring-opening of DACP with sulfonamides. The stereospecificity of the reaction was demonstrated using enantiopure D-A cyclopropanes Chapter 7 Ring-opening 1,3-carbothiolation of donor-acceptor (D-A) cyclopropanes employing alkyl halides and in situ generated dithiocarbamates (from amines and CS2) has been demonstrated under mild conditions. The reaction is operationally simple and works with good functional group compatibility. Three new bonds including C-N, C-S and C-C are formed in this 1,3-bifunctionalization strategy. Electron-poor olefins can also be used as electrophiles instead of alkyl halides. The use of enantiomerically pure D-A cyclopropane afforded enantiopure 1,3-carbothiolated product thus demonstrating the stereospecificity of the reaction Chapter 8 Traditional radical-mediated ring-opening of bicyclo[1.1.0]butanes (BCBs) for cyclobutane synthesis suffers from poor diastereoselectivity. Although few reports on BCB ring-opening via polar mechanisms are available, the Lewis acid-catalyzed diastereoselective ring-opening of BCBs using carbon nucleophiles is still underdeveloped. Herein, we report a mild and diastereoselective Bi(OTf)3- catalyzed ring-opening of BCBs employing 2-naphthols. The anticipated carbofunctionalized trisubstituted cyclobutanes were obtained via the bicoordinated bismuth complex and the products are formed in good to excellent yields with high regio- and diastereoselectivity. The scope of the reaction was further extended using electron-rich phenols and naphthylamine. The functionalization of the synthesized trisubstituted cyclobutanes shows the synthetic utility of the present method.