Development of an S_NAr Reaction: A Practical and Scalable Strategy To Sequester and Remove HF

Abstract

A simple and operationally practical method to sequester and remove fluoride generated through the S N Ar reaction between amines and aryl fluorides is reported. Calcium propionate acts as an inexpensive and environmentally benign in situ scrubber of the hydrofluoric acid byproduct, which is simply precipitated and filtered from the reaction mixture during standard aqueous workup. The method has been tested from 10 to 100 g scale of operation, showing >99.5% decrease in fluoride content in each case. Full mass recovery of calcium fluoride is demonstrated at both scales, proving this to be a general, efficient, and robust method of fluoride abstraction to help prevent corrosion of glass-lined reactors.

NaBHT Generated In Situ from BHT and NaOtBu: Crystallographic Characterization and Applications in Buchwald–Hartwig Amination

“…1 H NMR (600 MHz, CDCl 3 ) δ 7.86 (dt, J = 8.8, 2.2 Hz, 2H, 2-CH), 7.30 (t, J = 8.0 Hz, 4H, 3′-CH), 7.14 (d, J = 8.0 Hz, 4H, 2′-CH), 7.11 (t, J = 8.0 Hz, 2H, 4′-CH), 6.99 (dt, J = 8.8, 2.2 Hz, 2H, 3-CH), 4.35 (q, J = 7.2 Hz, OCH 2 ), 1.36 (t, J = 7.2 Hz, CH 2 CH 3 ) ppm; 13 C­{ 1 H} NMR (150 MHz, CDCl 3 ) δ 166.5 (CO 2 ), 152.0 (4-CN), 146.9 (1′-CN), 130.9 (2-CH), 129.7 (3′-CH), 125.9 (2′-CH), 124.5 (4′-CH), 122.7 (1-C), 120.3 (3-CH), 60.7 (OCH 2 ), 14.6 (CH 2 CH 3 ) ppm; 15 N NMR ( 1 H– 15 N HMBC projection, 60 MHz, CDCl 3 ) δ 99.9 ppm. The spectral data are consistent with those reported in the literature …”

“…The spectral data are consistent with those reported in the literature. 75 tert-Butyl 4-(diphenylamino)benzoate was isolated as byproduct with 4 in procedures when NaBHT was generated from BHT and NaOtBu, as described in procedures above.…”

From Milligram to Kilogram Manufacture of AZD4573: Making It Possible by Application of Enzyme-, Iridium-, and Palladium-Catalyzed Key Transformations

“…On 100 g scale in a steel vessel at 100 °C and using aqueous ammonia (13 equiv) in NMP as solvent, fluoropyridine 7 underwent ammonolysis to give, after extraction and concentration, aminopyridine 8 in 93% assayed yield by 1 H NMR as a highly discolored solid. Although we initially were concerned about the generation of HF and its corrosive/etching properties, we did not visually observe any damage to the reaction vessel, probably due to the large excess of ammonia used . To avoid the need for chromatography for purification of 8 , a quick screen of suitable solvents for crystallization was performed.…”

Palladium-Catalyzed Enantioselective Three-Component Synthesis of alpha-Arylglycine Derivatives from Glyoxylic Acid, Sulfonamides and Aryl Trifluoroborates

“…the Pbf-protected product 10a) and safety issues, we decided to investigate the influence of various fluoride scavengers as additives in our three-component process. [24][25] An extensive study (not shown), revealed, that most common scavengers either led to a decreased yield, a decreased stereoselectivity or a combination of both. Yet a combination of CaCO3, tartaric acid and molecular sieves 4Å, each already employed a HF scavenger by itself, did afford the desired arylglycine in high yields and enantioselectivities (entry 11).…”