Recent Development of Trifluoromethyl Reagents: A Review

Organic molecules having fluorine atom are very important since it increases the lipophilicity that is essential for drug development and additionally strong carbon-fluorine (C-F) bond makes the material unique, especially for material chemistry. Instead of elemental fluorine, recently trifluoromethylated materials (CF3) have drawn considerable attention in the agrochemical and pharmaceutical industries. In the continuous development of the trifluoromethylated reagents, over the last few decades, some trifluoromethylated reagents have been well developed and the efficiency of these reagents for incorporating CF3 group on different types of substrates are also studied. In this article, all types of available trifluoromethylated reagents and their effectiveness on suitable substrates are summarized. Additionally, the methods of synthesizing trifluoromethylated substrates are discussed. Finally, the scopes of the development of new reagents after focusing on the shortcomings of the current reagents are also discussed.

It is worth mentioning that incorporating trifluoromethyl (CF 3 ) on organic molecules changes their properties and, in this way, fluorinated substrates are very important for the material's chemistry [24][25][26] for designing some smart materials such as semiconductor in organic light-emitting diode (OLED) [27] and organic field-effect transistor (OFET) [28]. It is also well known that handling fluorinated materials need extra precaution since they produce toxic chemicals [29] during chemical reaction with substrates. That is why there is still a big challenge working with fluorinated reagents [30]. Further, current trifluoromethylating reagents have some limitations such as toxicity, moisture sensitivity, and explosiveness [31]. Considering the following facts, researchers are trying to develop a facile method of synthesizing trifluoromethylated reagents and measuring their effectiveness for preparing trifluoromethylated substrates.

Aim of the Review
There is a wide variety of review articles for explaining the trifluoromethyl (CF 3 ) reagents for developing trifluromethylated organic molecules. A few of them are concentrated on specific areas such as Umemoto's reagent [21], reactions in aqueous media [31], hypervalent iodine reagents [32], CF 3 -S transfer agents [33] and photolytic reactions [34]. Further, a few reviews have been discussed fluorine effect on chemical reactions [35] and in some reviews, it is described some selective trifluoromethylated reactions [36][37][38][39]. Although, a good number of review articles are available, sometimes it is difficult to extract important ideas from the vast amount of discussion. Besides, it is not known any review article that summarized all available trifluoromethylated reagents with highlighting the specific type of substrates scopes where most of them concentrated on one specific reagent and its substrate scopes. That is why a short review incorporating all types of available reagents is very essential especially for young researchers for getting incite and developing new trifluoromrthylated organic substrates. Considering this, here, the review has been concentrated on all types of the current development of trifluoromethyl (CF 3 ) reagents up to 2020 and depending on these reagents probable target products are being discussed. So, it is believed that the reader will find a summary of all efficient reagents with their suitability on different organic targets and further, this will help researchers to identify easily suitable reagents/methods during the synthesis of trifluoromethylated materials. Also, it is well known that although a lot of methods are available all methods are not good for organic synthesis due to their low yield. Hence, some selective methods are described in this review that will be helpful to identify effective methods to prepare a gram scale of substrates during organic synthesis since reaction yields are discussed along with substrate scopes. It will also be beneficial having incite of the area needs to develop further after reading this review (section 3.11.). The review discusses very briefly all types of trifluoromethylated reagents, which is a benefit of this review to readers.

Light mediated trifluoromethylation using Ag-salts
It was used anatase TiO 2 powder, arene, silver trifluoroacetate, trifluoroacetic acid, and the solvent was used dry acetonitrile. The reaction was stirred under an inert condition with a 500 W Hg lamp for 24 h. This method easily helped to incorporate the trifluoromethyl (CF 3 ) group on aromatic systems. Even substituted aromatic systems (Ar-R, R = H, X, CH 3 , CO 2 R, CH 2 NO 2, etc.) worked very smoothly. The demerit of the method is that reaction yields were mentioned moderate 10-50 % [40].

Hydrotrifluoromethylation of alkene
To a dry Schlenk line tube, silane and t-BuONa was added. The reaction was stirred at 100 C for 1 h in dry DMF. Later (Py)Cu(CF 3 ) 3 and alkyne were added and again it was stirred for 12 h. In this way, trifluoromethylation happens by Cu catalyst [42] (Scheme 3). Scheme 3. Trifluoromethylation of arylalkyne by the copper catalyst.
Synthesis of (Py)Cu(CF 3 ) 3 catalyst: It was stirred a mixture of CuI, AgF, pyridine, and TMSCF 3 in dry DMF for 21 h at room temperature under the inert condition to get the final catalyst (Py)Cu(CF 3 ) 3 [43].

Trifluoromethylation of aromatic and heteroaromatic systems
A successful method of incorporating trifluoromethyl was developed by Buchwald et al. [52] where it was used flow method. Shortly, CuI, pyridine, CF 3 COOK, Nmethylpyrrolidone (NMP), and 4-iodobiphenyl were injected in a preheated (200 C) stainless steel tube reactor for 16 min. After isolating the target compound the yield was found 87 % (Scheme 5). It was mentioned that ester-, nitro-, amide-, sulfonamide-and chloro-substituted compounds gave good yield and were tolerated under flow temperature. The method was found also efficient for a variety of heterocyclic compounds such as indole, pyridines, pyrazine, pyrimidine, isoquinoline, quinoline, pyrrolopyridine, and imidazopyridine. Using this method two grams of trifluoromethylated product were isolated from 4-iodobenzoate.

Synthesis of Togni reagents 2
A beaker was cooled in ice-salt mixtures with a magnetic stir bar at 0 C. Next, it was added H 2 SO 4 in the beaker. In this cooled acid, it was added methyl anthranilate (17) and sodium nitrite that was dissolved in water. This mixture was heated (40 C) and added sequentially potassium iodide, H 2 SO 4 , sodium hydrosulfite. Finally, methyl-2iodobenzoate (18) is collected and purified (Scheme 3.5). This reaction mixture was added to dry ether with methylmagnesium iodide and the reaction was stirred at -30 C for 6 h and 2-(2-iodophenyl)propan-2-ol (19) is formed and purified. This material was heated at 75 C in dry acetonitrile and trichloroisocyanuric acid and 1-Chloro-3,3-dimethyl-1,2benziodoxole (20) formed and purified. The chloro product was stirred with dry potassium fluoride in dry acetonitrile and added TMSCF 3 with stirring at -30 C for 6 h. Later, it was stirred at -10 C for 12 h leads to Togni reagent 2 (21) with 85-91 % yield [14] (Scheme 6). Scheme 6. Synthesis of Togni reagent 2.

Synthesis of Togni reagents 1
One-pot synthesis of Togni reagent 1 was done from the reaction of 2-iodobenzoic acid, KOAc, and trichloroisocyanuric acid heating at 75 C for 2 h in dry acetonitrile. Later, this was stirred with TMSCF 3 and gave Togni reagent 1 with a 75 % yield [14] (Scheme 7). Scheme 7. One-pot synthesis of Togni reagent.

Deoxyfluorination of aliphatic acids
Different types of aliphatic trifluoromethyl derivatives have been prepared from aliphatic acids almost as same as shown in section 3.4.1 (Scheme 9) [62]. The reactions went smoothly in gram scale for different types of primary, secondary, tertiary, and α-halogeno acids, cyclic amines, and α-amino acids with retaining stereo and absolute configuration of chiral centers. The method is developed by Engelhardt [60], Li [48], and MacMillan [63], however, the following method is better since it does not need liquid hydrofluoric acid (HF) and, also, chiral centers remain unaltered. Scheme 9. Deoxyfluorination of aliphatic carboxylic acid.

Trifluoromethylation of aryliodide
In a reaction vial, CuI, t-BuONa, and NMP (N-methylpyrolidone) were stirred at room temperature for 10 min. Later, N, N'-dimethylenendiamine was added to the above reaction mixture. After 2 min AgF and Me 3 SiCF 3 were added to the reaction mixture. Fitted with a teflon screw cap, the reaction heated at 90 C for 30 min. After cooling, a few more portions of Me 3 SiCF 3 were added and, finally, the reaction was stirred for 5 h at 90 C (Scheme 10). In this method, different types of iodoarenes were used and yields were noted 47-98 %. It is said that Cu and Ag both played a role in this type of transformation.

Sodium trifluoromethanesulfinate as CF 3 source
In this method, sodium trifluoromethanesulfinate is used and tert-butyl hydroperoxide is used as a source of oxidizer. A catalytic amount of Cu(OSO 2 CF 3 ) 2 was used and the reaction was done in acetonitrile at 20 C. This reagent helps to introduce CF 3 on a wide variety of substituted aromatic systems (Scheme 11) with the highest yield up to 90 % [18]. Scheme 11. Trifluoromethylation of aromatic compounds by using Langlois reagent.
A big advantage of this reagent is that it is very cheap compare to other available reagents and triflinate salt is air stable. Triflinate salt is also easy to prepare by using bromotrifluoromethane and sodiumdithionite or zinc/SO 2 . Later, different research groups prepared different types of trifluoromethylated compounds by using this reagent. Wang's group [66] prepared different types of trifluoromethylated oxindoles from activated alkenes with a 94 % yield where he used K 2 S 2 O 8 as oxidant (Scheme 12). Scheme 12. Langlois reagent for trifluoromethylation of arylboronic acids.
Sanford group [68] used t-BuOOH, Langlois reagent, and different types of arylboronic acids. It is also noted that aryl boronic acids having electron-donating groups such as alkyl, alkoxy, and phenoxy, and the presence of NaHCO 3 and (MeCN) 4 CuPF 6 lead to excellent yield. Liu's group [69] studied alkene in dimethyl sulfoxide (DMSO) and found a good yield of up to 95 % (Scheme 14). Scheme 14. Hydroxytrifluormethylation of an alkene by Langlois reagent.

Electrosynthesis of arenes and heteroarenes
Alternating current electrolysis (ACE) is a technique where an alternating voltage (± v) is applied to push the redox transformations. In an electrochemical method, first, triflyl chloride generates trifluoromethyl (CF 3 ) radical (Scheme 17) under negative electrode potential and, next, this trifluoromethyl (CF 3 ) reacts with the aromatic system (2acetylpyrrole) and forms a radical intermediate. When the voltage is reversed, the intermediate is oxidized to allylic cation, and subsequent deprotonation results in the final product. Instead of paired electrolysis, the ACE method gives a better yield of up to 84% [77]. This method successfully prepares trifluoromethylated pyrroles, arenes, furans, thiophenes, and imidazole with moderate to high yield. Since the intermediate involves the loss of aromaticity, electrosynthesis gave a low yield. Scheme 17. Electrosynthesis of aromatic arenes.
Studer's research group [78] has also published an electrochemical method for the synthesis of trifluoromethylated phenanthridine by using Togni reagent with the highest yield up to 77 %.

Types of Umemoto reagents
Umemoto and coworkers [95,96] have developed some reagents (Scheme 19) that are used to incorporate trifluoromethyl (CF 3 ) on different types of aromatic systems as an electrophile. S-(trifluoromethyl)dibenzothiophenium triflate (35) is used in synthesis due to its better reactivity. This reagent (35) has a better yield during synthesis than others. Scheme 19. Umemoto reagents.
2-mercaptobiphenyl was placed in dry dimethylformamide (DMF) and cooled in an ice bath. It was added NaH, and when hydrogen gas evolution is ceased, it was added CF 3 Br gas and irradiated by Hg lamp for 2 h. Finally, an oily product was formed (82 %). Next, F 2 and N 2 were introduced (1:9 mixture) with the addition of TfOH in CCl 3 F at 0 C. The reaction warmed to room temperature and after the addition of Et 2 O, white precipitate of S -(trifluoromethyl)dibenzothiophenium triflate (35)  Gouverneur et al. [100] focused on inactivated alkene with Ru(bpy) 3 Cl 2 as photocatalyst in MeOH and light-driven product with a moderate yield of 64 %. CF 3 H is added to alkene where Umemoto reagent acts as trifluoromethyl CF 3 donor and methanol as hydrogen donor with maintaining regioselectivity.

Future direction
Trifluoromethylating reagents still have some problems like air and moisture sensitivity. It is also noted that a few reagents are very expensive. Besides, one reagent is not effective for all types of substrates, like trifluromethylation of alkene, amine, amide, arene, heteroarene, etc. So, a common reagent that will be very cheap, stable, and effective for all types of substrates may open a new window for the development of trifluoromethylated substrates. Currently, non-metallic reagents are very important for developing new drugs. During the development of new materials, it may consider following solvents such as MeCN, DMF, DMSO. It is seen in literature that a few groups did the reaction in MeOH and used water as a solvent. Since toxic chemicals may generate during the reaction, a facile route is still necessary to develop in the future.

Conclusion
This review is illustrating clearly some important trifluoromethylated reagents and their effectiveness for different types of substrates. Although a lot of reviews exist, this review will be very effective for getting knowledge about the CF 3 reagents, as here everything is mentioned very briefly to make it interesting to the reader. Additionally, it will be very helpful as a practical guide if anyone wants to develop some new materials either reagent or substrates. The synthetic methods of the reagents are discussed citing their original articles as reference.