Developing New Reagents for Advanced Fluorination Chemistry

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Access to simpler and more direct methodologies for the incorporation of fluorinated substituents remains an unmet need in pharmaceutical synthesis. An analysis of recent trends in fluorination chemistry.

Fluorine offers real benefits

Although fluorinated compounds are not generally observed in natural biological systems, the benefits of incorporating fluorine into APIs have been recognized for some time. With a size similar to that of hydrogen, fluorine can be substituted for hydrogen atoms in various ways within complex pharmaceutical compounds. Fluorine has a high ionization potential, high electron affinity, and high electronegativity, and thus forms much stronger bonds with carbon than hydrogen and acts as a strong electron-withdrawing group. The changes in polarity resulting from the incorporation of fluorine atoms can affect not only the reactivity of neighboring groups, but also modify the acidity, basicity, protein-binding affinity, and lipophilicity, and therefore most importantly, the bioavailability of the drug compound (1-4). As an added benefit, analyses using


F nuclear magnetic resonance imaging (MRI) and positron emission tomography (PET) of


F radiolabeled substances can provide invaluable information on drug performance. These advantages are reflected in the fact that nearly a quarter of drugs on the market today contain fluorine to some extent (5).

Harsh conditions pose problems
Initially developed fluorinating reagents, such as potassium fluoride, hydrogen fluoride, and antimony trifluoride, are still widely used for basic fluorination reactions, but have somewhat limited applications directly in pharmaceutical synthesis because they typically require harsh reaction conditions. Even those fluorinating reagents that have been commonly used, such as bis (2-methoxyethyl) aminosulfur trifluoride, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis(tetrafluoroborate), (diethylamino) difluorosulfonium tetrafluoroborate, poly [4-vinylpyridinium poly(hydrogen fluoride)], 1-fluoro-2,4,6-trimethylpyridinium triflate, cyanuric fluoride, and tetrabutylammonium hydrogen difluoride, present handling issues, can be quite costly, and may also still require conditions that are detrimental to many functional groups.

As a result, fluorine groups have conventionally been incorporated into pharmaceutical compounds in the early stages of a synthesis when little functionality is present and loss of expensive intermediates is not a concern. There is a growing trend, however, toward the use of convergent synthesis, which requires the introduction of fluorine substituents much later in the synthetic sequence. In addition, many new small-molecule drug candidates require the use of fluorination techniques for the direct introduction of the fluorine moiety. In fact, the rising interest in the direct introduction of fluorine was readily reflected in the large number of presentations discussing the topic at the recent (January, 2013) 21st Winter Fluorine Conference organized by the American Chemical Society Division of Fluorine Chemistry.

New alkylating reagent
As a supplier of a wide range of basic and advanced organofluorine raw materials and reagents, Halocarbon is exploring various methods and reagents for the direct introduction of fluorine into complex organic substrates.

One compound that has been attracting attention is the alkylating agent trifluoroethyliodide (CF3CH2I). At INFORMEX USA, which was held in Anaheim, California, in February 2013, Halocarbon received numerous inquiries on the availability of this fluorinated halide. The drug lomitapide, which is a microsomal triglyceride transfer protein (MTP) inhibitor, is one example of an API that could be synthesized using this reagent.

Traditionally, the trifluoroethyl group has been introduced using trifluoroethylamine. This amine, however, is a very weak base and requires strongly acidic reaction conditions to enable the alkylation to occur, which limits its use to substrates that can tolerate exposure to strong acids. Trifluoroethyliodide, on the other hand, is a much more reactive alkylating agent and does not require harsh conditions. Alkylation using an iodide is, in fact, a commonplace transformation that can be employed even at later stages in the synthesis of complex pharmaceutical intermediates.

Specific reactions of trifluoroethyliodide have been reported in the literature. This iodide has been demonstrated by Hu to be useful in the Pd-catalyzed 2,2,2-trifluoromethylation of organoboronic acids and esters (6). Prakash et al., meanwhile, used this trifluoro substituted iodide in the synthesis of β-trifluoromethylstyrenes via a domino Heck coupling reaction (7).

Furthermore, trifluoroethyliodide is a cost-effective alternative that does not require special handling, which provides further advantages and meets the critical need in the pharmaceutical and other industries for practical alternatives to existing fluorinating reagents. It is also just one example of the types of organofluorine compounds that Halocarbon is exploring. The company is also receiving inquiries for brominated difluoro compounds from customers in the pharmaceutical, electronic, and other industries.

Growing interest in HFA and HFIP
Separately, interest is growing in the use of hexafluoroacetone (HFA) and hexafluoroisopropanol (HFIP), which is made from HFA, and other HFA derivatives for use in synthesis. For example, some of the products prepared with these reagents are used for magnetic resonance imaging (MRI). Fluorinated amino acids manufactured using HFA/HFIP chemistry find their way into diagnostic applications. HFA, meanwhile, has been used to introduce geminal trifluoromethyl groups into aromatic compounds in two steps using (8) and has served as a coreactant in regio- and stereoselective alkene epoxidations with H2O2 as a key step in the synthesis of steroids that contain multiple sites of unsaturation (9). The regioselective [2+3]-cycloaddition of diazoalkanes with N-arylmines of HFA at –60 °C to room temperature afford 4,5-dihydro-1H-[1,2,3]-triazoles, which thermally degrade to the corresponding aziridines bearing two trifluoromethyl groups (10).

Trifluoroacetone (TFA), with an acidity greater than that of acetone, can readily form the corresponding enolate, thus enabling the introduction of the trifluoromethyl group under relatively mild basic conditions. Like HFIP, TFA has also been used for the synthesis of amino acids. In this case, TFA is reacted with 2,6-dihalopyridines to produce chiral 2-trifluoromethyl-7-azaindoles, which are then converted to enantiopure α-trifluoromethyl alanines and diamines via a Strecker reaction followed by either nitrile hydrolysis or reduction (11).


Pursuing other opportunities
Clearly, while advances in the technology for the direct introduction of fluorine into complex organic compounds has significantly advanced in recent years, there are still plenty of opportunities for the development of novel reagents that can enable the introduction of various fluorine-containing groups and do so cost-effectively with multiple levels of selectivity under mild reaction conditions and tolerate a wide range of functionalities within the substrate. At Halocarbon, we are actively pursuing such activities and welcome suggestions and inquiries in this area.


1. S. Purser et al., Chem. Soc. Rev. 37 (2), 320-330 (2008).

2. R. Filler and R. Saha, Future Med. Chem. 1 (5), 777-791 (2009).

3. K. Müller et al., Science 317 (5846), 1881-1886 (2007).

4. J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, (Wiley-VCH, Weinheim, Germany, 2008).

5. G.K. S. Prakash and F.Wang, chim. oggi/Chem. Today 30 (5), 30-36 (2012).

6. Y. Zhao and J.Hu, Angew. Chem. Int. Ed. Engl. 51 (4), 1033-6 (2012).

7. G.K. Prakash at al., Org. Lett. 14(4), 1146-1149 (2012).

8. J. P. Amara and T. M. Swager, Macromolecules, 39 (17), 5753-5759 (2006).

9. The Fluorine Boom Continues as Benefits Become More Widespread, Halocarbon Products Corporation,, accessed April 3, 2010.

10. G. Mlostona et al., Polish J. Chem. 81 (5-6), 631-641 (2007).

11. F. Huguenot and T. Brigaud. J. Org. Chem. 71(18), 7075-7078 (2006).

Anthony Nigro is Account Manager - Inert Lubricants and Fluorochemicals and Joel Swinson is a Senior Research Chemist with Halocarbon Corp.