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Herein, we provide a brief overview of the synthesis and applications of trifluoromethylpyridine (TFMP) and its derivatives in the agrochemical and pharmaceutical industries. Currently, the major use of TFMP derivatives is in the protection of crops from pests. Fluazifop-butyl was the first TFMP derivative introduced to the agrochemical market, and since then, more than 20 new TFMP-containing agrochemicals have acquired ISO common names. Several TFMP derivatives are also used in the pharmaceutical and veterinary industries; five pharmaceutical and two veterinary products containing the TFMP moiety have been granted market approval, and many candidates are currently undergoing clinical trials. The biological activities of TFMP derivatives are thought to be due to the combination of the unique physicochemical properties of the fluorine atom and the unique characteristics of the pyridine moiety. It is expected that many novel applications of TFMP will be discovered in the future.
These unique properties of fluorine mean that substitution with a fluorine or fluorine-containing moiety can have a large impact on the conformation, acid dissociation constant, metabolism, translocation, and biomolecular affinity of a compound. This has meant that bioisosteric replacement of hydrogen with fluorine has become a useful means of designing compounds with unique biological properties. For similar reasons, much effort has been made to develop synthetic methods for introducing trifluoromethyl groups into aromatic rings. The first synthesis of an aromatic compound bearing a trifluoromethyl group was reported in by Swarts, 6 ) who treated benzotrichloride with antimony trifluoride to afford benzotrifluoride; the same transformation using hydrogen fluoride was subsequently achieved under liquid-phase reaction conditions in the s. 7 ) In , the introduction of a trifluoromethyl group into a pyridine ring to afford trifluoromethylpyridine (TFMP) using a synthetic procedure similar to that used for benzotrifluoride but involving chlorination and fluorination of picoline ( Scheme 1 ) was first reported. 8 ) Comparing the physicochemical properties of TFMP and benzotrifluoride, there is a significant difference in the hydrophobic constant (e.g., 3-(trifluoromethyl)pyridine 1.7 versus benzotrifluoride 3.0), which can be expected to provide TFMP-containing compounds with many advantages, such as novel biological activity, lower toxicity, and advanced systemic and/or good selectivity; therefore, many efforts have been made to achieve the synthesis of TFMP. However, to make enough TFMP for use as a raw material for industrial production, it is important to establish a practical large-scale industrial manufacturing process. Details of the industrial manufacturing of TFMP and its use in the manufacture of various agrochemicals and pharmaceuticals are discussed in this review.
In the crop protection industry, more than 50% of the pesticides launched in the last two decades have been fluorinated. In addition, around 40% of all fluorine-containing pesticides currently on the market contain a trifluoromethyl group, making these compounds an important subgroup of fluorinated compounds. 1 ) The biological activities of fluorine-containing compounds are considered to be derived from the unique physicochemical properties of fluorine (van der Waals radius, 1.47 Å), 2 ) which, sterically, is the next smallest atom after hydrogen (van der Waals radius, 1.20 Å) 2 ) but the atom with the largest electronegativity (3.98). 3 ) In addition, because the carbon&#;fluorine bond is relatively short (1.38 Å) compared with the other carbon&#;halogen bonds, the bond has strong resonance. As a result, the Hammett constant (σ p ) of fluorine is 0.06, 4 ) which is similar to that of hydrogen. Interestingly, the electronegativity of the trifluoromethyl group is 3.46, 5 ) and its Hammett constant is 0.54, 4 ) indicating that, unlike fluorine, the trifluoromethyl group is strongly electron withdrawing. Therefore, during compound development, the trifluoromethyl group can be treated as a purely electron-withdrawing group.
Many recent advances in the agrochemical, pharmaceutical, and functional materials fields have been made possible by the development of organic compounds containing fluorine. Indeed, the effects of fluorine and fluorine-containing moieties on the biological activities and physical properties of compounds have earned fluorine a unique place in the arsenal of the discovery chemist. As the number of applications for these compounds continues to grow, the development of fluorinated organic chemicals is becoming an increasingly important research topic.
Research and development activities (i.e., the outputs of scientific papers and patents) involving TFMP derivatives from to were examined using data obtained through crossover analysis of the STN International Registry 9 ) and HCAplus databases 10 ) (CAS, Columbus, Ohio, USA, and FIZ Karlsruhe, Eggenstein-Leopoldshafen, Germany). Since the development of economically feasible processes for the synthesis of several TFMP intermediates from 3-picoline in the early s, research and development activity involving TFMP derivatives has rapidly and consistently increased each year ( Fig. 2 ).
Every year from to , the demand was greatest for β-TFMP, followed by α-TFMP and γ-TFMP. In addition, the demand for each of the three TFMP isomers increased each year. Examining the sales of the pesticides individually, globally in , fluazinam and haloxyfop were the two top-selling pesticides possessing the β-TFMP moiety. In addition, the total sales volumes of fluopicolide and fluopyram, which also contain the β-TFMP moiety, have gradually increased from to and are now around 1,000 tons/year. Picoxystrobin is the only pesticide manufactured using the α-TFMP intermediate with sales of more than 2,000 tons/year. However, sales of bicyclopyrone have markedly increased in the last few years, which has increased demand for α-TFMP. Around 500 tons/year of pesticides containing the γ-TFMP intermediate are manufactured; therefore, the demand for γ-TFMP is relatively small.
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The production volume of each TFMP isomer ( Fig. 1 ) was estimated based on the following data sources: the sales volume of each formulated agrochemical, which was obtained from i-map Sigma (https://kynetecwebsc.com/documentation/i-map/3.29.0/), a database for the crop protection market provided by the market research company Kynetec (Newbury, UK); the concentration of each active ingredient in the formulated product; and the synthetic yield described in the patent for each agrochemical containing a TFMP moiety.
For lutidines, the reaction proceeds under similar conditions, but the reaction temperature needs to be higher than that for picolines. Several novel compounds with two trifluoromethyl groups, such as chloro-bis(trifluoromethyl)pyridine, can be synthesized in 60 to 80% yield ( Table 2 ).
The vapor&#;phase reactor used for this approach includes two phases: a catalyst fluidized-bed phase and an empty phase ( Fig. 3 ). In the fluidized-bed phase, fluorination proceeds immediately after chlorination of the methyl group of 3-picoline, resulting in the production of 3-TF. In the next step, further nuclear chlorination of the pyridine ring is performed in the empty phase to give 2,5-CTF as the major product, which can be subsequently converted to 2,3,5-DCTF. At the same time, 2-chloro-3-(trifluoromethyl)pyridine (2,3-CTF), which can be used to produce several commercial products, as discussed in sections 3 and 4, is also obtained as a minor product.
Another well-known approach is simultaneous vapor&#;phase chlorination/fluorination at a high temperature (>300°C) with transition metal-based catalysts such as iron fluoride ( Scheme 4 ). 17 , 18 ) The simultaneous vapor&#;phase reaction has the advantage that 2-chloro-5-(trifluoromethyl)pyridine (2,5-CTF), a key intermediate for the synthesis of fluazifop, can be obtained in good yield via a simple one-step reaction. The number of chlorine atoms introduced to the pyridine ring can be controlled by changing the molar ratio of chlorine gas and the reaction temperature; however, the formation of some multi-chlorinated by-products is unavoidable. Fortunately, these unwanted by-products can be reduced to 3-(trifluoromethyl)pyridine (3-TF) by catalytic hydrogenolysis and then fed back into the reactor to reduce overall production costs.
Among TFMP derivatives, 2,3-dichloro-5-(trifluoromethyl)pyridine (2,3,5-DCTF), which is used as a chemical intermediate for the synthesis of several crop-protection products, is in the highest demand (production data estimated from the i-map Sigma database). Various methods of synthesizing 2,3,5-DCTF have been reported. For example, 2-chloro-5-methylpyridine or 2-chloro-5-(chloromethyl)pyridine can be chlorinated under liquid-phase conditions to afford the intermediate 2,3-dichloro-5-(trichloromethyl)pyridine (2,3,5-DCTC); subsequent vapor&#;phase fluorination of 2,3,5-DCTC produces 2,3,5-DCTF ( Scheme 2 ). 12 &#; 14 )
There are three main methods for preparing TFMP derivatives: chlorine/fluorine exchange using trichloromethylpyridine; construction of a pyridine ring from a trifluoromethyl-containing building block; or direct introduction of a trifluoromethyl group using a trifluoromethyl active species such as trifluoromethyl copper, which undergoes substitution reactions with bromo- and iodopyridines. 11 ) The first two methods are currently the most commonly used; therefore, the discussion below focuses on those two methods.
The ISO common names for 22 agrochemicals containing a TFMP moiety, listed in the Compendium of Pesticide Common Names (http://www.alanwood.net/pesticides/index.html), are shown in Table 3. Prior to , all compounds except dithiopyr employed 3- or 5-trifluoromethyl-substituted pyridines as a partial structure. These compounds are synthesized from 2,5-CTF or 2,3,5-DCTF derived from 3-picoline. However, since , other substitution patterns, mainly 6-trifluoromethyl-substituted pyridine derivatives, have increased. A 4-trifluoromethyl-substituted pyridine moiety is adopted in relatively few agrochemicals, and only flonicamid and pyroxsulam have been commercialized.
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