1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Mechanochemical Synthesis of Functionalized Quinolines by Iodine Mediated Oxidative Annulation Atreyee Halder, Debabrata Maiti, and Suman De Sarkar* [a] Abstract: An iodine-mediated environmentally benign syn- thesis of multi-substituted quinoline derivatives is devel- oped using a solvent-free mechanochemical process. Appropriately designed and easily accessible protecting group-free aniline derivatives were used for the oxidative annulation reaction, and a series of quinoline derivatives with variable functionalities were synthesized up to 89% isolated yield. Importantly, the activator iodine remains in the quinoline molecule and promotes further functionaliza- tions. The present methodology is beneficial with regard to operational simplicity and mild reaction conditions. Quinoline, being a major azaheterocycle, is extensively found in numerous naturally occurring alkaloids and pharmaceuticals. Due to its several biological activities, quinoline derivatives are broadly employed as antimalarial, anticancer, anti-HIV, antibac- terial agents (Figure 1). [1] In addition, quinolines are also used in asymmetric synthesis and preparation of various functional materials with enhanced physical properties. [2] Traditional procedures for the synthesis of quinoline scaffold includes Skraup and Combes synthesis from aniline, and Friedlander synthesis from ortho-acylanilines (Scheme 1a). [3] However, these conventional methods require harsh conditions, prolonged reaction time and show limited functional group tolerance. As an alternative, several mild protocols have been developed using transition metal catalysis via Heck coupling, dehydrogen- ative annulation, C–H activation etc. (Scheme 1b). [4] Peroxide mediated synthesis [5] and transition metal-free radical cation salt catalyzed radical cyclizations have been proven as promising routes for the preparation of quinolines (Scheme 1b). [6] Apart from that, a number of important classes of heterocycles were synthesized efficiently via oxidative annulation processes. [7] Catalytic or stoichiometric amounts of iodine or its derivatives were successfully used for the activation of various functionalities during oxidative cyclization in quinoline synthesis. [8] However, except for a few cases [9] the active iodine component does not get incorporated in the final molecule and released as a byproduct. Considering the bio- logical importance and potential synthetic utilities of iodo- functionalities, [10] it is desirable to develop strategies that will allow heterocycle synthesis via electrophilic activation and will retain the activator iodine as a part of the final molecule for further functionalizations. ‘Mortar and pestle’, the traditional apparatus for mechano- chemical grinding was first used in 1820 when Faraday conducted reduction of silver chloride by other metals. [11] Thereafter, the first documented mechanochemical organic synthesis was by Ling and Baker in 1893. [12] In recent years, [a] A. Halder, D. Maiti, Dr. S. De Sarkar Department of Chemical Sciences Indian Institute of Science Education and Research Kolkata Mohanpur-741246, West Bengal (India) E-mail: sds@iiserkol.ac.in Supporting information for this article is available on the WWW under https://doi.org/10.1002/asia.201901758 This manuscript is part of a special collection in honor of the 2 nd Interna- tional Conference on Organometallics and Catalysis (ICOC-2020). Click here to see the Table of Contents of the special collection. Figure 1. Representative examples of bioactive quinolines. Scheme 1. Synthetic approaches towards quinoline derivatives. Communication DOI: 10.1002/asia.201901758 577 Chem Asian J. 2020, 15,577–580 © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim