Bromotrifluoromethane, a Useful Synthon for Trifluoromethylation
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PRODUCT FOCUS Chimica Oggi - Chemistry Today customer's publication Bromotrifluoromethane, a useful synthon for trifluoromethylation Why trifluoromethylation? - CF3I and BTFM have similar reactivity. Although CF3I is A large percentage of the new active molecules in often used in laboratories due to its ease of use, it is less pharmaceutical and agrochemical industry contain available industrially and more expensive than BTFM. fluorine atoms (1,2,3). In many cases, the trifluoromethyl group shows interesting properties that make it desirable A variety of uses in biologically active compounds(4) and introducing BTFM can react with organic substrates in a variety of ways: trifluoromethyl groups is a valuable addition to the organic • through an ionic mechanism chemist’s toolbox. • in a catalytic system • through a free-radical mechanism, when used in Why bromotrifluoromethane (BTFM)? conjunction with a free radical initiator The trifluoromethyl group is often added by the use of a fluorinated synthon. One classical way to affect Reaction on carbon, oxygen, nitrogen or sulphur atoms yields trifluoromethylation is by fluorination of a trichloromethyl, different functions presented in figure 1: carboxyl or carbonyl group, although drastic process conditions are generally required which makes this method inconvenient and limited in scope due to the availability of chemically robust synthons. Milder reactants have been proposed to perform direct trifluoromethylations: • Trifluoroacetic acid and its derivatives are convenient for the synthesis of heterocycles, but the scope of use is narrower than with other reagents. • The Ruppert-Prakash reagent, CF3Si(CH3)3 and its analogues (e.g., Togni and Umemoto reagents) are versatile and reactive but can be unstable, difficult to handle and expensive. • Activated forms of fluoroform, an easily available compound, Figure 1 References: 1. PCT 20015787 01/25/2001 have been a recent focus: 2. CN 10253040 07/4/2012 3. By Klemmensen, Per Dausell, from PCT Int. Appl.; 2005044806, 19 May 2005 - CF3Cu is the most reactive but has to be 4. CN 103664904/ 09/07/2012 5. From Angwandte Chemie, International Edition, 55(8), 2782-2786; 2016 generated in-situ. 68 Chimica Oggi - Chemistry Today - vol. 35(5) September/October 2017 Other kinds of reaction are presented in figure 2: • Trifluoromethylation of aromatic or heteroaromatic cycles by a catalytic activation system • Addition to electron-poor olefins, substitution on other kinds of olefins • Reaction with a carbonyl group to provide a trifluoromethylated alcohol, followed by elimination to provide an olefin. • BTFM can also be used to prepare CF3ZnBr in situ (by reacting BTFM with Zn). This reagent reacts with a carbonyl group to form an alcohol and a vicinal -CF3 group with moderate yields (40% to 60%). BTFM history Bromotrifluoromethane (BTFM) Figure 2. was developed in the sixties as a fire extinguishing agent for planes. It has been produced by Arkema in very large REFERENCES: quantities ever since. 1. Jeanmart S. and all; Bioorg.Med.Chem.; 2016,24, pp 317-341 Its emissive use is controlled by the Montreal Protocol due 2. Ding H.X. and al; Bioorg.Med.Chem.; 2015, 23, pp1895-1922 to its significant ozone depletion potential. With proper 3. Ding H.X. and al; Bioorg.Med.Chem.; 2014,22,pp2005-2032 handling to minimise emissions and reporting, its use as 4. Jiang Wang et al, Chem. Rev.,2014, 114, pp2432-2506 feedstock is permitted where its properties shine: it is a readily available, easy to handle gas and performs as a versatile The following review and articles give overview of some trifluoromethylation reagent, either as is or through an easy classical reactions with BTFM, as well as newer examples of in-situ derivatization. BTFM-based chemistry: “Bromotrifluoromethane” by Rozen S; and Hagooly A; From One such historical use is the industrial preparation of the well- e-EROS Encyclopedia of Reagents for Organic Synthesis, no known pest-control molecule Fipronil (Fig.1, 3). pp given, 2001 Trifluoromethylzinc Bromide By Hein, M and Miethchen, R; From e-EROS Encyclopedia of Reagents for Organic Synthesis, No pp. given; 2001 Natte K. and al; Angew.Chem.Int.Ed;,2016,55, pp2782-86 BTFM information Formula: CF3Br CAS No.: 75-63-8 Molecular Weight : 148,91 Contact our experts: Boiling point :-57,8°C [email protected] Vapour pressure: • 1,43 MPa , at 20 °C • 1,63 MPa , at 25 °C • 2,83 MPa , at 50 °C Non toxic, non flammable Regulated under the Montréal protocol – restrictions in use may apply, contact us for information [email protected] Chimica Oggi - Chemistry Today - vol. 35(5) September/October 2017 69.