Zero Hunger (SDG 2), Good Health & Well-being (SDG 3) Shaunté Cotterell, Nadale Downer-Riley, Ainka Brown Department of Chemistry, The University of the West Indies, Mona, Kingston 7, Jamaica email : shaunte.cotterell@mymona.uwi.edu A more versatile sulfur-mediated multicomponent synthesis of thioamides Shaunté Cotterell*, Nadale Downer-Riley, Ainka Brown Department of Chemistry, The University of the West Indies, Mona, Kingston, Jamaica Thioamides are typically accessed via smelly, multi-step protocols with poor atom economy and cumbersome clean-up. Thus, the resurgence of interest in the Willgerodt-Kindler and related multicomponent reactions that use elemental sulfur to prepare thioamides in one step, provides a path to more attractive alternatives. However, many of the protocols reported to date have limited substrate scope and lack cross-applicability. 1-2 We have identified a base-catalysed, efficient and operationally simple method for the synthesis of thioamides that can accommodate a range of starting materials (Scheme 1). This three-component one-pot protocol can facilitate the reaction of nitroarenes, anilines, or aliphatic amines as the N -coupling partner, with aromatic and heteroaromatic aldehydes, cinnamic acids and active methylenes. No bias is shown towards mono- or multi-substitution on either ring. The reaction also demonstrated good tolerance towards ortho - substitution, which is vastly underrepresented in the literature. Electronic effects favour electron-donating groups, whereas electron-withdrawing groups are poorly tolerated. The reaction is robust and scalable for the synthesis of thioamides. Thioamides are versatile tools that are used both as synthetic precursors to complex heterocyclic compounds, and also commercially due to their range of bioactive properties. 1-2 These include antimicrobial, antioxidant and most notably antithyroid activities among others. 1 Thioamides are typically accessed via smelly, multi-step protocols with poor atom economy and cumbersome clean-up. Thus, the resurgence of interest in the Willgerodt-Kindler and related multicomponent reactions that use elemental sulfur to prepare thioamides in one step, provides a path to more attractive alternatives. However, many of the protocols reported to date have limited substrate scope and lack cross-applicability. 1-2 We have identified a base-catalysed, efficient and operationally simple method for the synthesis of thioamides that can accommodate a range of starting materials (Scheme 1). This three-component one- pot protocol can facilitate the reaction of nitroarenes, anilines, or aliphatic amines as the N-coupling partner, with aromatic and heteroaromatic aldehydes, cinnamic acids and active methylenes. No bias is shown towards mono- or multi-substitution on either ring. The reaction also demonstrated good tolerance towards ortho- substitution, which is vastly underrepresented in the literature. Electronic effects favour electron-donating groups, whereas electron-withdrawing groups are poorly tolerated. The reaction is robust and scalable for the synthesis of thioamides. Thioamides are versatile tools that are used both as synthetic precursors to complex heterocyclic compounds, and also commercially due to their range of bioactive properties. 1-2 These include antimicrobial, antioxidant and most notably antithyroid activities among others. 1
Scheme 1 References 1. Kale, A.; Tayade, Y.; Mahale, S.; Patil, R.; Dalal, D., Tetrahedron Lett. 2019, 75 , 130575-130587. 2. Do, N.; Tran, K.; Phan, H.; To, T.; Nguyen, T.; Phan, N., Org. Biomol. Chem 2019, 17 , 8987-8991. Scheme 1 References 1. Kale, A.; Tayade, Y.; Mahale, S.; Patil, R.; Dalal, D.,Tetrahedron Lett. 2019, 75, 130575-130587. 2. Do, N.; Tran, K.; Phan, H.; To, T.; Nguyen, T.; Phan, N., Org. Biomol. Chem 2019, 17, 8987-8991.
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