An organophotocatalytic late-stage N-CH 3 oxidation of trialkylamines with O 2 in continuous flow Mark John Mandigma 1,2 , Jonas Žurauskas 1 , Callum I. MacGregor 3 , Lee J. Edwards 3 , Ahmed Shahin 1,4 , Ludwig d’Heureuse 1 , Philip Yip 5 , David J. S. Birch 5 , Thomas Gruber 1 , J rg Heilmann 1 , Matthew P. John 3 , Joshua P. Barham 1 2 University of Bristol, UK, 1 Universität Regensburg, Germany. 3 GlaxoSmithKline Medicines Research Centre, UK, 4 Benha University, Egypt, 5 University of Strathclyde, UK Direct access to N -formyl groups from tertiary amines is typically achieved by transition metal 1 or carbene reagents. 2 However, these reagents are either incompatible with redox sensitive functionalities that are ubiquitous in alkaloids and pharmaceuticals, or are used in excess. Direct use of molecular oxygen is a more benign and sustainable alternative, but issues of O 2 solubility in typical organic solvents and safety remain as challenges in its applicability. 3 Herein, we report a gas-liquid flow photocatalytic selective oxidation of N -methyl groups of alkylamines using a novel, modified 9,10-dicyanoanthracene (DCA) organophotocatalyst. 4 Back-pressure promoted O 2 solubility while the small (2.7 mL) continuous reacting volume at any time allowed safe handling of O 2 . Electron-withdrawing and solubilizing 2,6-substituents on the catalyst benefited the chemistry by: i) increasing catalyst solubility in polar aprotic media; ii) promoting an 1 O 2 sensitization mechanism vs. parent DCA. This rare photochemical mechanistic switchover induced by covalent modification on the organophotocatalyst was revealed by extensive spectroscopic and computational investigations. A range of N -methyl alkylamine natural products, drug molecules and API fragments were transformed into N -formyl products in moderate to very good yields with excellent selectivities (vs. N -CH 2 positions). Functional groups such as alcohols, epoxides, and esters were tolerated. Productivities of up to 0.65 g / day were achieved, and the succinct synthesis of Confoline and other related formyl tropanoids were demonstrated. References 1. a) R. Perrone, G. Carbonara and V. Tortorella, Arch. Pharm. ,1984, 317 , 635–639; b) R. Perrone, G. Carbonara and V. Tortorella, Arch. Pharm. , 1984, 317 , 21–27; c) S. W. Pelletier, H. K. Desai, J. Finer-Moore and N. V. Mody, Tetrahedron Lett. , 1982, 23 , 4229–4232. d) S. Nakai, T. Yatabe, K. Suzuki, Y. Sasano, Y. Iwabuchi, 2. J. Y. Hasegawa, N. Mizuno and K. Yamaguchi, Angew. Chem., Int. Ed. , 2019, 58 , 16651–16659. 3. J. Su, X. Ma, Z. Ou and Q. Song, ACS Cent. Sci. , 2020, 6 , 1819–1826. 4. J. Santamaria, R. Ouchabane and J. Rigaudy, Tetrahedron Lett. , 1989, 30 , 3977–3980. 5. M. J. P. Mandigma, J. Zurauskas, C. I. MacGregor, L. J. Edwards, A. Shahin, L. d'Heureuse, P Yip, D. J. S. Birch, T.Gruber, J. Heilmann, M. P. John and J. P. Barham. Chem. Sci. , 2022, 13 , 1912-1924.
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