Where Does the Fluorine Come From? A Review on the Challenges Associated with the Synthesis of Organofluorine Compounds

Abstract

Fluorinated organic molecules are increasingly being prepared for a variety of applications, including pharmaceutical products. However, the supply chain to access the necessary raw materials, which originate primarily from calcium fluoride, is often not considered, may be difficult to access at commercial scale, and has become destabilized as more stringent environmental policies are justifiably enforced. This manuscript presents an overview of the preparation and use of simple organofluorinated intermediates and reagents and the challenges associated with them.

Monofluoromethyl‐Substituted Sulfonium Ylides: Preparation, Structure‐Reactivity Study and Substrate Scope†

“…Classic methods for the introduction of monofluoromethyl group generally involve two different strategies. [4] In the first strategy, a primary alcohol was treated with a fluorinating reagent such as DAST or its derivatives to afford the monofluoromethylated compounds. [5] Alternatively, in the second strategy, an alkyl electrophile such as alkyl halide or tosylate was nucleophilically replaced by a fluoride to generate the corresponding monofluoromethylated compounds.…”

“…Carefully monitoring the reaction by F NMR spectroscopy disclosed that the reaction occurred rather fast since full conversion was observed when the reactants and the solvent were mixed and rushed for NMR acquisition within 5 min (Scheme 4, entry 3). A quick screening of the solvents showed reactions in CH 2 Cl 2 and dioxane occurred in high yields, while reactions in other polar solvents such as DMF, DMSO or CH 3 CN did not give the monofluoromethylated product at all (Scheme 4, entries [2][3][4][5][6]. Considering that the solubility of the inorganic base in dioxane is higher than that in CH 2 Cl 2 , we next chose dioxane as the solvent to examine the effect of the inorganic bases.…”

“…Eluent: ethyl acetate/petroleum ether (1 : 10, R f = 0.7). 4,162.2,141.7,139.5,128.8,127.0,124.2,121.0,115.8,104.1 (d,J = 221.3 Hz),67.7,35.9,22.0. 2, 162.5, 159.4, 140.5, 134.0, 125.0, 116.6, 115.8, 104.9, 04.0 (d, J = 221.4 Hz), 55.6, 51.5, 35.1.…”

“…1. IR (KBr) ν: 3480, 3373, 1693, 1600, 1560, 1520, 1246, 1198, 1155, 1104 4,147.9,141.0,135.4,132.1,131.9 (q,J = 32.2 Hz),123.0,125.3,120.2 (q,J = 3.9 Hz),118.8 (q,J = 3.8 Hz),118.3,114.1,110.8,93.5 (d,J = 221.3 Hz). IR (KBr) ν: 3316,3003,1701,1605,1529,1337,1258,1116,997,749 1,137.6,127.3,126.3,125.3,122.9,121.2,112.1,111.0,93.7 (d,J = 221.8 Hz) 3099, 3000, 1759, 1384, 1281, 1242, 1139, 1015, 916, 769, 683 cm 1, 145.4, 145.2, 1226, 1213, 118.4, 116.6, 93.5 (d, J = 221.8 Hz), 76.7, 30.3, 25.0, 20.6, 12.1, 11.7, 11.11.…”

“…, CDCl 3 , 293 K, TMS) δ:7.51-7.28 (m, 5H),5.18 (s, 1H),5.09 (s, 1H),4.34 (q, J = 7.1, 2H), 4.31 (q, J = 7.1, 2H), 1.31 (t, J = 7.1 Hz, 6H); 19 F NMR (471 MHz, CDCl 3 ) δ: -223.77 (t, J = 46.7 Hz, 1F); 13 C NMR (126 MHz, CDCl 3 ) δ: 168.1 (d, J = 5.7 Hz), 134.4, 128.5, 128.2, 128.0, 84.7 (d, J = 177.7 Hz), 63.7 (d, J = 19.2 Hz), 62.2, 14.0. General procedure for O-selective monofluoromethylation of β-ketoesters with reagent 3 Into a 10 mL Schlenk tube equipped with a magnetic stirring bar was added β-ketoester (0.3 mmol), BTPP (0.6 mmol), reagent 3 (0.3 mmol) and anhydrous dichloromethane (1.0 mL).…”