A simple scale-up strategy for organolithium chemistry in flow mode: From feasibility to kilogram quantities

Synthesis of 2-Trifluoromethyl-4-fluorophenylboronic acid (2a)
2a: 2-Trifluoromethyl-4-fluorophenylboronic acid After reaching steady-state, the outcoming stream was quenched for 25 min (765 mmol) on 797 mL citric acid (10% in water) at 0 °C. After full addition, the mixture was stirred for 30 min at 0 °C and then warmed up to r.t. and stirred for another hour. The phases were separated and the water phase was extracted twice with 1.8 L isopropyl acetate. The organic phases were combined, washed with 20% NaClsolution (1.8 L) and dried in vacuum to yield the final product. The product was obtained as a slightly yellow solid. 146.1 g (HPLC purity at 210 nm = 97.4%). Yield = 89%.

1H NMR (400 MHz, DMSO-d6): δ = 8.00 (dd, J = 8.3, 6.6 Hz, 1H, Ar-H), 7.52 (dd, J = 9.9, 2.5 Hz, 1H, Ar-H), 7.55−7.45 (m, 1H, Ar-H) ppm.

13C NMR (100 MHz, DMSO-d6): δ = 162.6 (d, J = 247.0 Hz, CF), 138.1 (d, J = 7.9 Hz), 134.8 (dq, J = 31.6, 7.7 Hz), 133.8, 124.5 (dq, J = 274.8, 3.00 Hz, CF3), 118.4 (d, J = 19.2 Hz), 113.3 (dq, J = 24.2, 6.1 Hz) ppm.

 19F NMR (376 MHz, DMSO-d6): δ = −57.8 (s, 3F, CF3), −111.2 (s, 1F, CF) ppm. 11B-NMR (128 MHz, DMSO-d6): δ = 13.8 ppm. Analytical data is identical with the literature.1 [1] A. Hafner, M. Meisenbach, J. Sedelmeier, Org. Lett. 2016, 18, 3630-3633.

A simple scale-up strategy for organolithium chemistry in flow mode: From feasibility to kilogram quantities Andreas Hafner, Paolo Filipponi, Lorenzo Piccioni, Mark Meisenbach, Berthold Schenkel, Francesco Venturoni and Joerg Sedelmeier* Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland Joerg.Sedelmeier@novartis.com