B(C6F5)3-catalysed C3 alkylation of indoles and oxindoles Laura Winfrey 1 , Shyam Basak 2 , Ana Alvarez-Montoya 1 , Laura Winfrey 1 , Dr. Rebecca L. Melen 2 , Dr. Louis C. Morrill 2 , Dr. Alexander P. Pulis 1 1 University of Leicester, UK, 2 Cardiff University, UK Indoles and oxindoles are both heterocyclic ring systems found in many pharmacologically active agents, with the former also present in various naturally occurring alkaloids. 3 New approaches to their functionalisation that are operationally simple, have high step-economy and use readily available materials and commercially available catalysts, are of significant interest to synthetic chemists and the wider pharmaceutical industry. 4 Despite the seemingly well-established chemistry for the C3 functionalisation of indoles and oxidindoles, there remains significant challenges involved in their selective C3 alkylation, which includes C - vs N -alkylation and over-alkylation. 5 Furthermore, substrates such as 1-methyl indole and 1,2-dimethylindole are unreactive when methyl iodide is used as a methylating agent. A single protocol that addresses these issues would therefore be of synthetic value. In classical Lewis acid chemistry, a borane typically activates polarised bonds by interaction with a lone pair of a heteroatom. Recently the ability of boranes to heterolytically cleave normally unreactive α- N C( sp 3 )–H bonds to form iminium borohydrideshas come to light. 6 We have used this unique reactivity to mediate unusual catalytic transformations, such as in the selective C3 alkylation of indoles and oxindoles. Our approach uses commercially available catalyst B(C 6 F 5 ) 3 and readily available amine based alkylating agents. Functional groups such as halides, ether, nitro and ester groups were well tolerated, as well as NH bearing indoles, where no N -alkylation was observed. The reaction is user friendly and doesn’t necessitate the use of a glove box or specialised glassware, as commercially available H 2 O·B(C 6 F 5 ) 3 is used as received and weighed in air on an open bench. H 2 O·B(C 6 F 5 ) 3 is dried in situ using triethysilane and therefore strictly anhydrous reagents and solvents are not required. We discovered a novel alkylation ring-opening cascade when applying cyclic pyrrolidinesas alkylating agents. The reaction generated indolebutylamines scaffolds, which are substructures of serotonergic/dopaminergic drug molecules. 7 References 1. Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main Building, Cardiff, CF10 3AT, UK 2. School of Chemistry, University of Leicester, Leicester, LE1 7RH, UK 3. Chadha, N.; Silakari, O. J. Med. Chem., 2017 , 134 , 159–184 4. Wander, P. A.; Verma, V. A.; Paxton T. J.; Pillow, T. H.; Chem. Res ., 2008 , 41 , 40–49 5. Ciszewski, L. W.; Durka, K.; Gryko, D. Lett. 2019 , 21 , 7028–732 6. Basak, S.; Winfrey, L.; Kustiana, B. A.; Melen, R. L.; Morrill, L. C.; Pulis, A. P. Soc. Rev . 2021 , 50 , 3720–3737 7. Schwartz, T. L.; Siddiqui, U. A.; Stahl, S. M. Adv. Psychopharmacol . 2011 , 1 , 81–87
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