Document N4oNR4zxvpVzz7g268dbjnpD

ELSEVIER Journal of Fluorine Chemistry 257-258 (2022) 109978 Contents lists available at ScienceDirect Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor Successful trifluoromethoxy-containing pharmaceuticals and agrochemicals Jiang Liu a, Weikang Lin b, Alexander E. Sorochinsky C'*, Greg Butler d, Aitor Landa e, Jianlin Han a,*, Vadim A. Soloshonok e' f,** a Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China b Suqian Keylab Biochemical Co., Ltd, Suqfrui, Jiangsu 223800, China The National Academy of Sciences of Ukraine, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, 1 Murmanska sir., Kyiv 02094, Ukraine d Oakwood Chemical, Inc. 730 Columbia Hwy. N, Estill, SC 29918, USA Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizabal 3, San Sebastian 20018, Spain f IKERBASQUE, Basque Foundation for Science, Maria Diaz de Haro 3, Plaza Bizkaia, Bilbao 48013, Spain ARTICLE INFO Keywords: Drugs Agrochemicals Fluorine Synthesis Trifluoromethoxylation Fluorination ABSTRACT Trifluoromethoxy-containing molecules represent still underdeveloped, but highly promising group of biologically active compounds. The first part of this review profiles five known pharmaceuticals Riluzole (myotrophic sclerosis), Delamanid (tuberculosis), Sonidegib (cancer), Pretomanid (tuberculosis), and Celikalim (blood pressure). The second part of this article covers five marketed agrochemicals featuring trifluoromethoxy group. These include pesticides No-valuron and Flometoquin; herbicides Flucarbazone-sodium and Flurprimidol; and fungicide Thifluzamide. For each compound, we discuss the detailed chemical synthesis and general aspects of biological activity. 1. Introduction Over the last 20 years, organo-fluorine molecules represent one of the most fast-growing classes of organic compounds [1-15]. In particular, the essential role of fluorine in the design of pharmaceutical drugs [16-26], agrochemicals, and specialty materials [27-29] is well-recognized. Historically, the major research effort in the area of fluorine synthetic methodology has been heavily focused on the development of approaches for the preparation of aromatic and aliphatic C-F and C-CF3 compounds [30-34]. Consequently, other types of fluorine substitution, for example, trifluoromethoxylated compounds possessing an intriguing combination of physicochemical properties, are relatively less studied [35-47] and only about 1.5% and 2.5% of the fluorine-containing pharmaceutical drugs and agrochemicals contain this unit [48]. The OCF3 group is specially interested from the biochemical point of view to pharmaceutical and agrochemicals research due to its high electronegativity (x = 3.7), lipophilicity (z = +1.04), and metabolic stability as well as unique orthogonal conformation relatively to arene ring [48]. Beside pharmaceuticals and agrochemicals containing the OCF3 group often show diminished side effects [48b]. Nevertheless, it is generally recognized that access to convenient approaches for the preparation of structurally novel fluorinated scaffolds is of critical importance in the discovery of new generation pharmaceuticals and agrochemicals. In this work, we profile five known (Fig. 1) pharmaceutical drugs Riluzole 1, Delamanid 2, Sonidegib 3, Pretomanid 4, and Celikalim 5. Therapeutic areas include cancer (3), tuberculosis (2 and 4), myotrophic sclerosis (1), and blood pressure (5). This review article also covers five marketed agrochemicals (Fig. 2) featuring trifluoromethoxy group. These include pesticides Novaluron 6 and Flometoquin 7; herbicides Flucarbazone-sodium 8 and Flurprimidol 10; and fungicide Thifluzamide 9. For each compound, we discuss the chemical synthesis and general aspects of biological activity. 2. Trifluoromethoxy-containing drugs 2.1. Riluzole Riluzole (2-amino-6-trifluoromethoxy benzothiazole, 1) is a drug for the treatment of people with amyotrophic lateral sclerosis (ALS) [49], which is a terrible disease with quite poorly understood pathogenesis * Corresponding author. "" Corresponding author at: Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizabal 3, San Sebastian 20018, Spain. E-mail addresses: gmail.com (A.E. Sorochinsky),.@njfu.edu.cn (J. Han), @ehu.es (V.A. Soloshonok). https://doi.org/10.1016/j.jfluchem.2022.109978 Received 2 February 2022; Received in revised form 10 April 2022; Accepted 11 April 2022 Available online 14 April 2022 0022-1139/ 2022 Elsevier B.V. All rights reserved. J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Fig. 1. CF3-O-containing pharmaceutical drugs 1-5. Fig. 2. CF3-O-containing agrochemicals 6-10. Fig. 3. Structures of benzothiazolamine-containing compounds. and unknown cure. It was developed by Rhone Poulenc Rorer and approved by FDA in 1995 with the trade name RilutekTM, which has proved to be the first drug possessing some neuroprotective effects on survival in patients with ALS. As a small molecular, riluzole could inhibit excitatory amino acid release and actions with stimulation of excitatory amino acid receptors, as well as keep the inactivated level of voltage-dependent sodium channels at low micromolar concentrations [50]. It has disclosed neuroprotective effects both in vitro and in vivo. 50 M of riluzole can reduce INaT amplitude by 51.6%. It provides a single IC50 value of 34.2 M along with a nHill value of 0.82 [51]. Substituents in the 6-position of 2-benzothiazolamines were found to be of crucial importance for the anticonvulsant activity against administration of glutamic acid [52]. The ED50 value of 2-amino benzothiazole (11, R = H) is > 10 mg/kg i.p. as well as 2-amino-6-methoxy benzothiazole (12, R = OCH3) (Fig. 3). While the substituent is OCF3 (1, riluzole), the ED50 value decreases to 3.2 mg/kg i.p.. Although the effect is modest, riluzole has shown some insight into the pathogenesis of ALS and afforded some inspirations for further investigation. Synthesis of riluzole was reported by Jordan group as illustrated in Scheme 1 [53], which was based on their previous method via a direct reaction of substituted anilines with tetrabutylammonium thiocyanate [53b]. As a stable organic ammonium tribromide, benzyltrimethylammonium tribromide (PhCH2NMe3Br3) is a very good choice for the electrophilic bromine source. The trifluoromethoxy benzene was 2 J. Liu et al. Fig. 4. Structures of delamanid and related compounds. prepared via fluorination by anhydrous HF of the trichloromethoxy benzene at 80 C, which then underwent nitration and reduction by Fe/HCl affording 4-trifluoromethoxyaniline [53c]. Subsequently, a one-pot reaction of 4-trifluoromethoxyaniline with ammonium thiocyanate in the presence of PhCH2NMe3Br3 could directly afford rulizole. The reaction was performed in acetonitrile as solvent at ambient temperature and the target product 1 was obtained in 71% yield after 24 h as an off-white crystalline solid. In this procedure, tetrabutylammonium thiocyanate could be employed instead of ammonium thiocyanate, but the yield was a little bit lower (61%). PhCH2NMe3Br3 is crystalline and quite easy to handle compared with Br2, so that brominated side products were avoided in this transformation. 2.2. Delamanid As a derivative of bicyclic nitroimidazole bearing an OCF3 group, delamanid (2) is a drug for the treatment of multidrug-resistant tuberculosis, which is still a major serious public health problem in the world (Fig. 4) [17]. It was developed by the company Otsuka Pharmaceutical showing mycobacteria-specific antibacterial activity in vitro. Delamanid got its first global approval on 28 April 2014 in the European Union with the trade name DeltybaTM [54]. As a new therapy for tuberculosis, delamaind meets most of the crucial requirements, such as short treatment duration, no potential tuberculosis infection, low toxicity profiles, poor interaction with other relevant drugs, good activity against drug-resistant tuberculosis. It could prevent the biosynthesis of mycolic acid to stop the generation of mycobacterial cell envelope. The OCF3 group has proved to be crucial for the in vitro antituberculosis activity against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis H37Rv and for short-term in vivo efficacy [55]. For example, delamanid (2, R = OCF3) displayed excellent in vivo efficacy (> Journal of Fluorine Chemistry 257-258 (2022) 109978 3.8 log CFU reduction), while 13 (R = H) was normal (2.8 log CFU reduction). In contrast, 14 (R = OCH3) did not show efficacy in vivo screening (Fig. 4). In general, delamanid is a safe, orally bioavailable and cost-effective drug. Access to the chiral structure of delamanid is reported by the Fair- lamb group in five steps as shown in Scheme 2 [56]. First, chiral epoxyethane 15 underwent a nucleophilic ring-opening addition with 1H-imidazole 16 in the presence of Et3N as a base at 60-65 C to generate the intermediate 17. Second, 1,2-diol 18 was obtained via hydrolysis to cleave the p-nitrobenzoate unit of 17 catalyzed by potas- sium carbonate at room temperature. Then, the terminal hydroxyl group of 1,2-diol 18 was selectively protected by methanesulfonyl chloride to afford intermediate 19, which was further converted to epoxyethane 20 by intramolecular cyclization with DBU. Finally, a nucleophilic ring-opening addition was performed between epoxyethane 20 and phenol 21 promoted by sodium hydride in DMF at 50 C, and the target product delamanid 2 was achieved via subsequent in situ ring-closure reaction as a pale yellow solid in 49% yield [56a]. The key intermediate 21 was prepared according to the following strategy with 4-trifluoromethoxyaniline as the starting material (Scheme 3). First, 4-trifluoromethoxyaniline was transferred into 4- (trifluoromethoxy)phenol via the treatment of NaNO2 in the presence of 9 N sulfonic acid [53b]. Then, condensation reaction between (tri- fluoromethoxy)phenol and tert-butyl 4-hydroxypiperidine-1-carboxy- late with the use of PPh3 and diisopropyl azodicarboxylate (DIAD) and followed by removal of Boc protecting group afforded the 4-(4-(tri- fluoromethoxy)phenoxy)piperidine [56b]. Pd-catalyzed coupling reac- tion of 4-(4-(trifluoromethoxy)phenoxy)piperidine with 2-(4-bromophenoxy)tetrahydro-2H-pyran gave the coupling product, which was then subjected to the reaction with pyridinium ptol- uenesulfonate generating the desired intermediate 21 [56c]. 2.3. Sonidegib Sonidegib 3, with the trade name OdomzoTM, is a drug for the treatment of locally advanced basal cell carcinoma (BCC), which remains the most common human nonmelanoma skin cancer caused by abnormal activation of the hedgehog signal pathway [57]. Patients with BCC are usually treated by surgical resection, as well as selectively radiation. As an orally available small molecule, sonidegib was developed by the company Novartis for patients no longer amenable to curative surgery or radiation therapy. Novartis also carried out the SAR studies, which disclose the introduction of trifluoromethoxyl group leads to improved bioactivity. Compound 3A featuring a methoxyl group resulted in the TM3-Gli-Luc IC50 values of 0.6 and 10 nM at two different concentrations (1 and 25 nM), respectively. While a lower IC50 value of 8 nM was found for Sonidegib 3 at 25 nM (Fig. 5) [57b]. It received the first global approval on 30 June 2015 in Switzerland, which also received approval in the United States and European Union in the same year [58]. By binding to smoothened receptors and inhibiting the transmembrane protein, sonidegib could disrupt the hedgehog pathway, which is a major factor in BCC pathogenesis [32]. The potential adverse events of sonidegib are dysgeusia, alopecia, fatigue, muscle spasms, nausea, and decreased weight. Particularly, it may cause embryo-feal Fig. 5. Structures of sonidegib and related compounds. 3 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Fig. 6. Structures of pretomanid and related compounds. Fig. 7. Structure of antihypertensive compounds. Scheme 1. Synthesis of riluzole 1. death and severe birth defects, which should be announced to both male and female patients before treatment [58]. A green and efficient synthetic route of sonidegib was recently reported by the Takale group in 2019 as described in Scheme 4 [59]. First, SNAr reaction was carried out between chiral dimethyl-substituted morpholine 22 and chlorinated pyridine 23. This reaction employed Scheme 2. Synthesis of delamanid 2. 4 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Scheme 3. Synthesis of the intermediate 21. K3PO4 as the base and water as the solvent. Brij-30 was found to be the best surfactant with quantitative conversion to afford the intermediate 24, which subsequently underwent a reduction of the nitro group to the amnio group. Particularly, carbonyl iron powder was utilized as a reductant in this step instead of traditional Pd/C. On the other hand, Suzuki-Miyaura cross-coupling was conducted between bromobenzene 26 and phenylboronic acid 27, considered as the key and likely costly step in the synthesis of sonidegib due to the expensive catalyst. The desired coupling product 28 could be easily obtained using the combination of Pd(OAc)2 with PPh3 in a 1:3 ratio by the loading amount of only 5000 ppm in water at 45 C. Hydrolysis of 28 smoothly proceeded with NaOH at 75 C to furnish intermediate 29. It should be noted that both the reduction step giving amine 25 and the hydrolysis step affording benzoic acid 29 could be performed in the same pot, without the need of isolating intermediates 24 and 28, respectively. The final step is also a coupling reaction of amine 25 and acid 29 to generate the target product 3 in the presence of DCC and DMAP with good chemical yield. In a word, sonidegib could be synthesized in three-pot, five-step all performed in water at room temperature with ppm levels of a Pd catalyst [59a]. The key intermediate (4-(trifluoromethoxy)phenyl)boronic acid (27) was synthesized via the following strategy (Scheme 5). Bromination of (trifluoromethoxy)benzene catalyzed by iron at 100 C for 16 h gave 1bromo-4-(trifluoromethoxy)benzene [59b], which was converted into the key intermediate boronic acid 27 via the treatment by triisopropyl borate in the presence of nbutyl lithium [59c]. 2.4. Pretomanid Another derivative of bicyclic nitroimidazole bearing an OCF3 group, pretomanid 4 is a drug similar to delamanid 2 for the treatment of patients with tuberculosis caused by Mycobacterium tuberculosis infection. It was developed by the Global Alliance for Tuberculosis Drug Development with the license from Novartis. The key role of OCF3 substituent has been demonstrated by the SAR studies. As shown in Fig. 6, The IC50 values of pretomanid 4 for inhibition of the growth of L. don and L. inf were 0.39 and 4.0 M respectively. When the OCF3 group was replaced by OBn, decreased activities were observed with IC50 values of 1.1 and 5.9 M respectively [60]. Pretomanid was first approved on 14 August 2019 in the USA, and was specifically indicated as part of a combination regimen with bedaquiline, linezolid and pyrazinamide optionally for treating extensively drug-resistant or treatment-intolerant or non-responsive multidrug-resistant tuberculosis [61]. By the elimination of ketoymycolates and the accumulation of hydroxymycolates, pretomanid could act on the mycolic acid biosynthetic pathway thus leading to the inhibition of mycobacterial activity in replicative bacteria [62]. With the minimum inhibitory concentration values of 0.015-0.25 mol/L, it can serve as an efficient inhibitor of both actively replicating bacteria and hypoxic Mycobacterium tuberculosis without damage of any intracellular macromolecules [62b]. The synthetic method of pretomanid is shown in Scheme 6 [63]. Initially, chiral epoxyethane 31 underwent a ring-opening reaction with dinitro imidazole 30 at 70 C to generate intermediate 32. It should be mentioned that this step was a solventless protocol different from the previous reports. Protection of the hydroxy group was conducted subsequently by adding dihydropyran (DHP), pyridinium p-toluenesulfonate (PPTS) and toluene to the mixture of the ring-opening reaction without isolation of 32. The nitro imidazooxazine 34 was obtained via cyclization of intermediate 33 in the presence of tetrabutylammonium fluoride (TBAF) in THF at room temperature. Deprotection then proceeded smoothly by employing 12N HCl and THF/MeOH as a combined solvent to detach the THP group. The final step was the nucleophilic substituted reaction of alcohol 35 with trifluoromethoxylated benzyl bromide 36 promoted by sodium hydride to furnish the desired pretomanid [63a]. It should be mentioned that 1-(bromomethyl)-4-(trifluoromethoxy) benzene (36) could be easily obtained via the bromomethylation reaction of (trifluoromethoxy)benzene with the use of paraformaldehyde and sodium bromide in the presence of sulfonic acid and acetic acid [63b]. 2.5. Celikalim Celikalim 5, also named way-120,491, is a potent potassium channel opener (KCO) in human airway smooth muscles, which was developed by Wyeth-Ayerst Research as an antihypertensive drug [64]. As shown in Fig. 7, celikalim 5 is a chiral compound and contains a trifluoromethoxy substituted chromene key structural unit, a vicinal amino alcohol moiety and an isoindolone unit. SAR studies disclosed that the C-6 substituent shows a key determination of antihypertensive potency. 5 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Scheme 4. Synthesis of sonidegib 3. Scheme 5. Synthesis of the intermediate 27. For example, replacement of the C-6 cyano by trifluoromethoxy group and introduction of an isoindolone unit to the C-4 lactam led to a ten-fold better potency, as well as a slower onset and longer duration of action compared to cromakalim 37 [65]. In particular, OCF3 substituent on C-6 is more important, as celikalim 5 discloses an enhanced antihypertensive effect compared with compound 38 [66]. A multigram scale synthetic route for the preparation of celikalim is presented in Scheme 8, which was developed by Wyeth-Ayerst Research 6 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Scheme 6. Synthesis of pretomanid 4. Scheme 7. Synthesis of the key intermediate 36. Scheme 8. Synthesis of celikalim 5. 7 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Scheme 9. Synthesis of novaluron 6. in 1991 [67]. The synthesis started from diazotization of p-trifluoromethoxyaniline via the treatment of NaNO2 in the presence of sulfonic acid at 0 C, which was followed by heating with 9N sulfonic acid at 105-110 C to generate the 4-(trifluoromethoxy)phenol. Then, alkylation reaction between 4-(trifluoromethoxy)phenol and 3-chloro-3-methyl-1-butyne (39) with K2CO3 as a base in the presence of KI afforded the alkylated intermediate which was directly subjected to intramolecular cyclization at 185 C for 45 min. Thus, the key chromene intermediate 40 was successfully obtained. Epoxidation of chromene 40 with MCPBA as an oxidant in a buffered two-phase system generated epoxide 41. Subsequent ring-opening by ammonium hydroxide occuring in ethanol at room temperature for 96 h gave the racemic aminoalcohol 42 in moderate yield. Then, reductive amination of aminoalcohol 42 with methyl 2-formylbenzoate and combination of NaBH3CN/ZnCl2 (2:1) afforded the aminoalcohol intermediate 43, which then underwent isoindolone formation by heating in toluene resulting in the racemic celikalim 5. Finally, resolution of racemic 5 was achieved via the formation of a diastereomeric carbamates by reaction with (S)-(+)-1-(1-naphthyl)ethyl isocyanate (44), followed by separation and trichlorosilane cleavage to give the desired optical pure celikalim 5. 3. Trifluoromethoxy-containing agrochemicals 3.1. Novaluron Novaluron 6, with the chemical name as N-((3-chloro-4-(1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy)phenyl)carbamoyl)-2,6-difluorobenzamide (Fig. 2), was developed as an effective type of insect growth regulator. Novaluron belongs to a type of urea, which contains eight fluorine atoms in the molecule, in particular, there is a key trifluoromethoxy group. Novaluron showed an inhibitory against the synthesis of chitin, an essential component of insect exoskeleton. Thus, Novaluron has been demonstrated to be high activity against agricultural pests [68,69]. The synthesis of novaluron 6 was presented in Scheme 9, which used 2-chloro-4-aminophenol (45) and perfluoro methyl vinyl ether (46) as the starting materials [70]. Perfluoro methyl vinyl ether (46) was synthesized via the reaction between carbonyl fluoride and Scheme 10. Synthesis of flometoquin 7. 8 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Scheme 11. Synthesis of flucarbazone-sodium 8. chlorotrifluoroethylene in the presence of HF and trimethylamine [71]. The first step was the addition of phenol 45 to perfluoro-vinyl ether 46 in the presence of potassium hydroxide under nitrogen atmosphere, which afforded the key substituted aniline 47. Then addition of the aniline 47 to 2,6-difluorobenzoyl isocyanate (48) under reflux for 12 h successfully generated the desired novaluron 6. 3.2. Flometoquin Flometoquin 7 was discovered and developed by Meiji Seika Kaisha and Nippon Kayaku in 2004, which was used a new type of insecticide. Flometoquin was environmental-friendly and active for control of lepidoptera, diptera, thysanoptera, acari, hemiptera, and other related insect pests with fast knockdown and little influence on beneficial organisms [72,73]. The chemical structure of flometoquin contains a quinolone heterocyclic unit, a key trifluoromethoxy substituted phenyl group and a carbonate group [72,73]. Nippon Kayaku and Meiji Seika Kaisha also reported a method for the preparation of flometoquin, which could be applied to manufacture (Scheme 10) [74,75]. Sandmeyer reaction of isopropyl 5-amino-4-methyl-2-nitrobenzoate (49) afforded the key chloride intermediate 50. Then, the intermediate 50 underwent a substitution reaction with 4-(trifluoromethoxy)phenol in the presence of potassium carbonate resulting in the ether intermediate 51. Reduction of the ether 51 by iron under acidic conditions gave the amine 52. Finally, cyclization reaction of the amine intermediate 52 with 3-pentanone catalyzed by benzenesulfonic acid in mesitylene as a solvent afforded the target compound flometoquin 7. 3.3. Flucarbazone Flucarbazone 8, also named as flucarbazone-sodium, is a kind of highly efficient and broad-spectrum sulfonylurea herbicide. It was firstly developed by Bayer in 1996 [76], and then Arysta acquried the right to develop it in 2002. The chemical name of flucarbazone is sodium (3-methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carbonyl) ((2-(trifluoromethoxy)phenyl)sulfonyl)-amide, which contains a sulfonylurea key structural unit, a triazol-3-one heterocyclic moiety and a OCF3-substituted phenyl group (Fig. 2). Flucarbazone-sodium showed high bioactivity even at low concentrations, which could be as low as 1 g kg-1 in the oriental mustard root inhibition [77]. The synthesis of flucarbazone usually used 5-methoxy-4-methyl-2,4dihydro-3H-1,2,4-triazol-3-one (53) as starting reagent and was patented previously by Bayer in 1996 [76], which provided a conventional strategy to obtain flucarbazone-sodium. Very recently, Jiangsu Rotam Chemistry Co., Ltd reported a revised method for the synthesis of this agrochemical, which provided a new crystal form of flucarbazone-sodium [78]. Scheme 11 described the synthetic method for this compound [79]. The first step is the protection of 5-methoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (53) by phenyl carbonochloridate in the presence of sodium hydroxide and 4-dimethylaminopyridine (DMAP) at 10-15 C. The protected triazol-3-one 54 was obtained in 85% yield and subjected to the reaction with 2-(trifluoromethoxy)benzenesulfonamide in the presence of sodium hydroxide as a base in methyl isobutyl ketone, successfully affording the target flucarbazone-sodium 8 in 90% yield. The key 2-(trifluoromethoxy)benzenesulfonamide intermediate could be synthesized with 2-(trifluoromethoxy)aniline as the starting material (Scheme 12) [80]. Treatment of 2-(trifluoromethoxy)aniline by NaNO2 in the presence of sulfur dioxide and copper dichloride afforded 2-(trifluoromethoxy)benzenesulfonyl chloride [80a], which was converted into 2-(trifluoromethoxy)benzenesulfonamide via the reaction with ammonia in acetonitrile [80b]. Scheme 12. Synthesis of 2-(trifluoromethoxy)benzenesulfonamide. 9 J. Liu et al. Journal of Fluorine Chemistry 257-258 (2022) 109978 Scheme 13. Synthesis of thifluzamide 9. 3.4. Thifluzamide Thifluzamide 9 was developed by Monsanto and used as a fungicide. The structure of thifluzamide 9 was shown in Fig. 2, which features a trifluoromethyl substituted thiazole and a trifluoromethoxyl substituted aniline moiety. Notably, as thifluzamide was widely used in controlling crop diseases, residual levels and dietary risk assessment to the environment of thifluzamide attracted much attention [81,82]. Monsanto Company also patented a synthetic method for the preparation of thifluzamide with 2,6-dibromo-4-(trifluoromethoxy)aniline (55) and 2-methyl-4-(trifluoromethyl)thiazole-5-carbonyl chloride (59) as the key intermediates (Scheme 13) [83]. Initially, bromination of 4-(trifluoromethoxy)aniline by bromine in the presence of sodium acetate in acetic acid gave one key intermediate 2,6-dibromo-4-(trifluoromethoxy)aniline (55). The synthesis of another key intermediate 59 started from a cyclization reaction between ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (56) and thioacetamide in DMF under reflux. The thiazole intermediate 57 was obtained in a 38% yield, which underwent hydrolysis process by sodium hydroxide to give the carboxylic acid 58 in 93% yield. Then, treatment of carboxylic acid 58 with thionyl chloride under reflux afforded the acyl chloride 59. Finally, condensation reaction between aniline 55 and acyl chloride 59 in xylene under reflux for 24 h successfully generated the target thifluzamide 9. Scheme 14. Synthesis of flurprimidol 10. 10 J. Liu et al. 3.5. Flurprimidol Acknowledgments Journal of Fluorine Chemistry 257-258 (2022) 109978 Flurprimidol 10, was developed by Eli Lily and Company as a plant growth regulator many years ago. It belongs to the nitrogen-containing heterocycle compound which features a key pyrimidine moiety and a trifluoromethoxy substituted phenyl group. Flurprimidol 10 was registered as Cutless for turf use in the U.S. and commercially used for greenhouse crops in Europe [84]. It has been demonstrated that flurprimidol plays an important role in plant metabolism, flowering and plant productivity. For example, fluorprimidol is effective at height control of `Star Gazer' oriental lily [85]. It also shows effects on Kentucky bluegrass under reduced irradiance, and significantly reduced clipping yields for a minimum of six weeks [86]. Eli Lilly also patented a synthetic route for the preparation of flurprimidol 10 in 1976, which used 4-bromophenyltrilfuoromethyl ether (60) as the starting material (Scheme 14) [87]. The first step was the formation of Grignard reagent via the treatment of 4-bromophenyltrilfuoromethyl ether (60) by magnesium turnings. Then, the obtained Grignard reagent was subjected to the reaction with isobutyronitrile under reflux for 10 h, resulting in the isopropyl 4-trilfuoromethyoxyphenyl ketone intermediate 61. Subsequently, the ketone intermediate 61 underwent the nucleophilic addition reaction by the lithium reagent generated from 5-bromopyrimidine and n-butyl lithium at -70 C, which completed the synthesis and afforded the corresponding flurprimidol 10 in moderate yield. 4. Conclusions It should be noted that trifluoromethoxy-containing compounds constitute only about 1.5% and 2.5% of the corresponding fluorinecontaining pharmaceutical drugs and agrochemicals, respectively. This relatively low number is not a reflection of the impact of trifluoromethoxy moiety on biological properties. As highlighted in this review article, CF3-O-containing compounds show a wide range of useful bio-properties and are considered as highly promising class of compounds. The key reason for the low representation is a lack of convenient synthetic methods and, therefore, high cost of preparation of trifluoromethoxy derivatives. As one can see from the structures of drugs 1-5 and agrochemicals 6-10, profiled in this work, virtually all of the compounds 1-10 are aromatic CF3-O-Ar derivatives. Furthermore, the large-scale synthesis of the starting CF3-O-containing building blocks relies on the chlorine-fluorine exchange, the methodology developed approach by L. Yagupolskii in 1955 [88-90]. Some other industrial approaches include fluorination of fluoroformates (FCO-O- to CF3-O-) [91], desulfurization (RS-CS-O- to CF3-O-) [92-94]. By contrast, more recent approaches, such as direct trifluoromethylation of OH group, are based on highly expensive electrophilic Umemoto [95] and Togni [96, 97] reagents and, therefore, unpractical for large-scale preparations [48]. Another general observation is an absence of data on self-disproportionation of enantiomers (SDE)-properties [98,99] of chiral enantiomerically enriched compounds containing trifluoromethoxy group. It could be expected that similar to other fluorine-containing compounds [100-102], CF3-O-group should increase magnitude of the SDE manifestation. Studying of SDE-properties of chiral molecules is an important issue in laboratory practice and drug development [103-105]. As one can see, three out of the five pharmaceutical drugs profiled in this work, are chiral and are supposed to be administered as pure enantiomers, underscoring the importance of the SDE phenomenon in the preparation of trifluoromethoxy-containing chiral bioactive compounds [106,107]. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21761132021). The Qinlan Project of Jiangsu Province, and IKERBASQUE, the Basque Foundation for Science are also acknowledged. 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