B(C 6 F 5 ) 3 -catalysed C3 alkylation of indoles and oxindoles Laura Winfrey , Shyam Basak, Ana Alvarez-Montoya, Rebecca L. Melen, Louis C. Morrill
and Alexander P. Pulis University of Leicester, 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. 1 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. 2 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. 3 Furthermore, substrates such as 1-methyl indole and 1,2-dimethyl indole 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 borohydrides (e.g. 5 ) has come to light. 4 We have used this unique reactivity to mediate unusual catalytic transformations, such as in the selective C3 alkylation of indoles and oxindoles 1 . Our approach uses commercially available catalyst B(C 6 F 5 ) 3 and readily available amine based alkylating agents 2 . 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 pyrrolidines 2b as alkylating agents. The reaction generated indolebutylamines scaffolds 4 , which are substructures of serotonergic/dopaminergic drug molecules. 5
Exploiting the hydride abstraction capabilities of B(C 6 F 5 ) 3 has provided a metal-free alternative to the direct C3 alkylation of indoles and oxindoles. We are using this reactivity to solve synthetic challenges, including the synthesis of tetrahydroquinolines and the dehydrogenation of pyrrolidines... References 1. Chadha, N.; Silakari, O. J. Med. Chem., 2017 , 134 , 159–184 2. Wander, P. A.; Verma, V. A.; Paxton T. J.; Pillow, T. H.; Chem. Res ., 2008 , 41 , 40–49 3. Ciszewski, L. W.; Durka, K.; Gryko, D. Lett. 2019 , 21 , 7028–7032 4. Basak, S.; Winfrey, L.; Kustiana, B. A.; Melen, R. L.; Morrill, L. C.; Pulis, A. P. Soc. Rev . 2021 , 50 , 3720–3737 5. Schwartz, T. L.; Siddiqui, U. A.; Stahl, S. M. Adv. Psychopharmacol . 2011 , 1 , 81–87 6. University of Leicester, UK Cardiff University, UK
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