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Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

Hannah E. Askey, James D. Grayson, Joshua D. Tibbetts, Jacob C. Turner-Dore, Jake M. Holmes, Gabriele Kociok-Kohn, Gail L. Wrigley and Alexander J. Cresswell*

*Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K., Email:

H. E. Askey, J. D. Grayson, J. D. Tibbetts, J. C. Turner-Dore, J. M. Holmes, G. Kociok-Kohn, G. L. Wirgley, A. J. Cresswell, J. Am. Chem. Soc., 2021, 143, 15936-15945.

DOI: 10.1021/jacs.1c07401 (free Supporting Information)

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Organophotoredox catalysis enables an intermolecular hydroaminoalkylation (HAA) of styrenes with unprotected primary alkylamines to provide pharmacologically relevant γ-arylamines. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow.

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proposed mechanism



All batch photoreactions were conducted in commercially-available EvoluChem PhotoRedOx Box reactors purchased from HepatoChem Inc. An EvoluChem 18 W LED lamp (425 nm) was used for all reactions.

General Procedure for Hydroaminoalkylation with Primary Alkylamines

A 20-mL scintillation vial equipped with a stirrer bar was transferred to a nitrogen-filled purge box. In the case of solid or viscous oil substrates, the requisite amine (1.0 equiv or 3.0 equiv) or styrene (1.0 equiv) was weighed into the empty vial at this point, and the stirrer bar was replaced. The vial was then charged with stock solutions of 3DPA2FBN (2.80 mM in DMF, 1 mol%), tetrabutylammonium azide (70.3 mM in DMF, 20 mol%) and additional anhydrous DMF was added to give a total concentration of 0.15 M wrt the styrene. For liquid amines, the requisite amine (1.0 equiv or 3.0 equiv) was transferred into the vial by microlitre syringe. For liquid styrenes, the requisite styrene (1.0 equiv) was added into the vial by microlitre syringe and the vial was sealed using a B24 rubber septa. It was then removed from the purge box and transferred to a photoreactor, and irradiated (with stirring) for 20 h at 425 nm. Fan cooling was used to maintain an external temperature of 25-26 C. Following irradiation, the reaction mixture was concentrated in vacuo on a spiral evaporator.

Notes on tetrabutylammonium azide (Bu4NN3):

Bu4NN3 (CAS# 993-22-6) is extremely hygroscopic and best handled under inert atmosphere. It can be conveniently prepared in situ by stirring Bu4NCl with NaN3 in MeCN, followed by filtration of NaCl. We found that the commercial material (Sigma-Aldrich) is contaminated with NaCl, such that dissolution in MeCN is visibly incomplete, leading to a slightly cloudy solution. Upon standing, the NaCl residues will settle and the clear supernatant solution can be used. Whilst Bu4NN3 should be treated with the same precautions taken for sodium azide (NaN3) (e.g., not ingested/inhaled, and exposure to acids or low pH avoided), it has no impact sensitivity and a decomposition temperature of 196 C (see: Shalibor, A.; Modarresi-Alam, A. R. A Green and Simple Process for Preparation of Tetraalkylammonium Azide with Excellent Environmental Factor: Comparison of Batch and Flow Column Reactor. Org. Proc. Res. Dev. 2018, 22, 1753-1760).

Key Words

amines, photochemistry, organocatalysis

ID: J48-Y2021