Trifluoromethyl-substituted selenium ylide: a broadly applicable electrophilic trifluoromethylating reagent

Hangming Ge and Qilong Shen*
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China. E-mail:

Received 16th November 2018 , Accepted 3rd January 2019

First published on 5th January 2019

The preparation of an easily available, air/moisture insensitive electrophilic reagent, trifluoromethyl-substituted selenium ylide 1a, and its reactions with a variety of nucleophiles including β-ketoesters and silyl enol ethers, aryl/heteroaryl boronic acids, electron-rich heteroarenes and sulfinates were described. These results suggest that reagent 1a is a broadly applicable electrophilic trifluoromethylating reagent.


Nowadays, the trifluoromethyl group (–CF3) is generally considered as a privileged structural motif in new drug discovery1 because of its unique steric and electronic properties that might dramatically improve the lead compound's pharmacokinetics and pharmacodynamics.2 Development of efficient methods for the incorporation of the trifluoromethyl groups has thus become an emerging challenge in the field of organofluorine chemistry. Consequently, in the past several decades, a number of elegant methods3 have been developed, which allows to site-specifically introduce the trifluoromethyl group into substrates that are of high interests in pharmaceutical/agrochemical industry.

Often, the development of efficient trifluoromethylating methodologies that could be conducted under mild conditions relied heavily on the invention of new trifluoromethylating reagents.4 In this respect, the discovery of the first electrophilic trifluoromethylating reagent Ar2S+CF3 SbF6 by Yagupolskii and co-workers in 1984 opened a new era for the field of trifluoromethylation, even though its electrophilicity and reactivity is not high.5 Subsequently, Umemoto,6 Adachi/Ishihara,7 Shibata,8 Togni9 and Wang10 reported several new electrophilic trifluoromethylating reagents with higher reactivities (Fig. 1). Among them, the Umemoto's reagent B and Togni's reagent F are two of the most studied trifluoromethylating reagents with broad substrate scopes. Nevertheless, development of new electrophilic trifluoromethylating reagents that could react with both hard and soft nucleophiles are still urgently needed.

image file: c8qo01249k-f1.tif
Fig. 1 Electrophilic trifluoromethylating reagents.

In 2015, we discovered that a trifluoromethyl-substituted sulfonium ylide, which was highly efficiently synthesized in one step from easily available starting materials in the presence of 100 ppm of Rh2(esp)2 (esp = tetramethyl m-benzenediproprionate), can serve as an electrophilic trifluoromethylating reagent to react with β-ketoesters or aryl iodides to give the trifluoromethylated products in high yields.11 Previously, sulfonium ylides were generally reported as nucleophiles that could react with aldehydes, imines and α,β-unsaturated esters to give epoxides, aziridines and cyclopropane derivatives.12 The umpolung reactivity of the trifluoromethyl-substituted sulfonium ylides and their ease in the preparation have thus led us to discover two analogous electrophilic reagents – difluoromethyl- and monofluoromethyl-substituted sulfonium ylides – with unprecedented high reactivity.13,14 Despite these findings, the electrophilic and reactivity of the original trifluoromethyl-substituted sulfonium ylides were not as high as that of the Umemoto's and Togni's reagents.

Selenium, as one of chalcogens, has similar chemical properties with sulfur.15 Yet, it is generally known that the Se–C bond is much weaker than S–C bond. We, therefore, questioned ourselves whether a trifluoromethyl-substituted selenium ylide could act as a more reactive electrophilic trifluoromethylating reagent. The trifluoromethyl-substituted selenium ylides 1a–f were then prepared and further studies showed that the ylide with an electron-withdrawing nitro group exhibited high reactivity toward a variety of different nucleophiles under mild conditions. Herein, the invention of reagent 1a and its reactions with various nucleophiles were described.

The preparation of trifluoromethyl-substituted selenium ylides 1a–f were straightforward using trifluoromethylselenium ethers as the starting materials, which were readily prepared from the corresponding aryl diazonium salt with KSeCN in the presence of a copper catalyst, followed by replacing the cyano group by TMSCF3.16 Treatment of the trifluoromethylselenium ether with dimethyl diazomalonate in the presence of 0.1 mol% of Rh2(esp)2 at 40 °C for 1.0 h afforded compound 1a–f in 45–91% yields (on 10 mmol scale) (Scheme 1). These crystalline air and moisture insensitive solids can be easily purified by recrystallization and were fully characterized by 1H, 13C and 19F NMR, MS and IR spectroscopies and elemental analyses. Single crystal of compound 1a was obtained by layering a CH2Cl2 solution of compound with petroleum ether and X-ray diffraction further confirmed its structure (see ESI for details).

image file: c8qo01249k-s1.tif
Scheme 1 Preparation of trifluoromethyl-substituted selenium ylides 1a–f. Reaction conditions: Dimethyl diazomalonate (12.0 mmol), trifluoromethylselenoether (10.0 mmol Rh2(esp)2 (0.1 mol%) in CH2Cl2 (0.1 M) at 40 °C for 1 h; isolated yields.

With an efficient and robust method for the preparation of trifluoromethyl-substituted selenium ylide in hand, we next set to probe whether these compounds can serve as the electrophilic trifluoromethylating reagents. We chose the reaction of cyclic β-ketoesters with compounds 1a–f as a model reaction to evaluate these compounds’ reactivity and the effect of different substituents on selenium ylides. A quick screening of the reaction conditions disclosed that reaction of β-ketoester derived from indanone with reagent 1a containing a 4-nitro group occurred in good conversion to give the corresponding trifluoromethylated β-ketoester in good yields, while reactions with selenium ylides 1b–c with nitro group at ortho or meta position were less effective (0–94% yields, see ESI for details). Likewise, meta-chloro-substituted selenium ylide 1f was much less reactive. In addition, reactions with selenium ylides bearing an electron-donating group such as phenyl or methoxy group were not effective at all. Under these conditions, various β-ketoesters derived from indanone, tetralone, or 1-benzosuberone reacted with reagent 1a in DMSO when DBU was used as the base to give the corresponding 2a–k in high yields. Particularly, sterically-hindered β-ketoester also reacted to generate trifluoromethylated compound 2h in 98% yield (Scheme 2, 2h). Notably, under the optimized conditions, reactions of non-phenyl fused β-ketoesters or open-chain β-ketoesters were much slower and the formation of the trifluoromethylated compounds were not observed, even though a combination of different bases in different solvents were examined.

image file: c8qo01249k-s2.tif
Scheme 2 Scope for reaction of β-ketoesters with reagent 1a. Reaction conditions: β-Ketoester (0.5 mmol), reagent 1a (0.6 mmol), DBU (0.6 mmol) in DMSO (3.0 mL) at room temperature for 2 h; isolated yields.

To further expand the scope of the reaction with soft carbon nucleophile, we next studied the reaction of silyl enol ethers with reagent 1a. It was found that in the presence of 10 mol% CuSCN, reactions of various silyl enol ethers with reagent 1a in DMAc after 16 h at 40 °C to afford the α-trifluoromethyl ketone in high yields (Scheme 3). Common functional groups such as halogens (Cl, Br), nitro or ester groups were compatible. In addition, α-substituted silyl enol ethers also reacted to give the corresponding trifluoromethylated products in high yields (Scheme 3, 3g–i, 3k). These results indicate that reagent 1a is a good electrophilic trifluoromethylating reagent for not only β-ketoesters but also silyl enol ethers.

image file: c8qo01249k-s3.tif
Scheme 3 Scope for reaction of silyl enol ethers with reagent 1a. Reaction conditions: Silyl enol ether (0.5 mmol), reagent 1a (0.75 mmol), CuSCN (0.05 mmol) in DMAc (10.0 mL) at 40 °C for 16 h; isolated yields.

Previously, it has been reported that in the presence of a copper catalyst, electrophilic trifluoromethylating reagents such as Umemoto's reagent B, Shibata's reagent C or Togni's reagent F were able to couple with aryl boronic acids to give trifluoromethylarenes in high yields.17 To probe whether reagent 1a could react with aryl boronic acids, we investigated this reaction in detail. After several rounds of optimization of the conditions, it was found that reaction of aryl boronic acids with reagent 1a in DMF in the presence of 1.2 equivalents of CuCl occurred in high yield after 16 h at room temperature (see ESI for details about optimization of the reaction conditions). Both electron-rich or electron-poor aryl boronic acids reacted to give the trifluoromethylarenes in high yields (Scheme 4, 4a–e). More importantly, heteroaryl boronic acids also reacted to give the trifluoromethylated heteroarenes that are important structural units in many agrochemicals in high yields (Scheme 4, 4f–m). Furthermore, trifluoromethylated derivatives of a few drug molecules such as Pterostilbene (4n), Meclozine (4p), Estrone (4o), Fenoxaprop-P-ethyl (4q) and Desloratadine (4r) can all be synthesized under the standard conditions. These results indicate the potential applicability of the reagent 1a in the preparation of drug molecules.

image file: c8qo01249k-s4.tif
Scheme 4 Scope of the copper-mediated reactions of aryl/heteroaryl boronic acids with reagent 1a. Reaction conditions: Arylboronic acid (0.5 mmol), reagent 1a (0.75 mmol), Cs2CO3 (0.4 mmol), CuCl (0.6 mmol) in DMF (5.0 mL) at room temperature for 16 h; isolated yields.

Encouraged by the excellent reactivity of reagent 1a, we next studied whether it is also capable of being a trifluoromethyl radical precursor. Interestingly, under irradiation of blue LED light, reagent 1a reacted with electron-rich indole or pyrrole derivatives in the presence of 1.5 equivalents of DABCO (1,4-diazabicyclo[2.2.2]octane) to regioselectively give the 3-trifluoromethylated indoles or 2-trifluoromethylated pyrroles in high yields (Scheme 5). Similar reactions with electron-rich arenes were less successful. However, 1,3,5-trimethoxybenzene reacted with reagent 1a to give 1-trifluoromethyl-2,4-6-trimethoxybenzene in 80% yield (Scheme 5, 5h). Because of the mild conditions, a range of common functional groups such as fluoride (5b, 5n and 5p), chloride (5c, 5o–p), bromide (5g), iodide (5d), ester (5f, 5i, and 5k–l) and enolizable ketone (5j). The addition of DABCO played a key role in promoting the reaction since the yield decreased significantly to 40% in the absence of DABCO. It was proposed that a donor–acceptor complex between DABCO and reagent 1a was initially formed. Under irradiation of visible light, this charge-transfer complex was excited. Consequently, the Se–CF3 bond was homolytically cleaved to generate CF3˙ which further attacked the arene to give trifluoromethylated arene. Similar phenomena have previously been observed by Yu and coworkers for the generation of trifluoromethyl radical from Umemoto's or Togni's reagents in the presence of different amine donors.18

image file: c8qo01249k-s5.tif
Scheme 5 Visible light-promoted trifluoromethylation of arene C–H bond with reagent 1a. Reaction conditions: Arene (0.5 mmol), reagent 1a (0.6 mmol), DABCO (0.75 mmol) in CH2Cl2 (10.0 mL) under irradiation of blue LED light at room temperature for 12 h; isolated yields.

Additionally, we found that in the presence of sodium benzenesulfinate derivatives, the trifluoromethyl radical could be generated in the absence of amine donors. Likely, the sulfinate anion can also be used as the donor to interact with reagent 1a to form a charge-transfer complex. Upon irradiation with visible light, the complex collapsed to generate the trifluoromethyl radical, which then reacted with sulfinate radical cation to form the trifluoromethylated sulfone derivatives.19 Under these conditions, various benzenesulfinate derivatives were trifluoromethylated to give trifluoromethylated sulfones 6a–f in excellent yields (Scheme 6).

image file: c8qo01249k-s6.tif
Scheme 6 Visible light-promoted trifluoromethylation of sulfinates with reagent 1a. Reaction conditions: Arene (0.5 mmol), reagent 1a (0.6 mmol), in DMSO (5.0 mL) under irradiation of blue LED light at room temperature for 12 h; isolated yields.

In summary, we have successfully developed an easily available, air/moisture insensitive and highly reactive electrophilic trifluoromethylating reagent 1a. The selenium ylide based electrophilic trifluoromethylating reagent exhibited higher reactivity and broader scope than its analog based on the sulfonium ylide skeleton. Under mild conditions, this reagent reacted with soft carbon nucleophiles β-ketoester and silyl enol ethers to give the α-trifluoromethylated ketone derivatives in high yields. In the presence of a copper catalyst, reagent 1a reacted with a wide range of aryl or heteroaryl boronic acids to give trifluoromethylated arenes in high yields. In addition, a donor–acceptor charge-transfer complex was formed between reagent 1a and DABCO or sulfonate. Under irradiation of visible light, a trifluoromethyl radical can be easily generated, which can further react with electron-rich arenes or sulfinates to afford the corresponding trifluoromethylated arenes or sulfones in high yields. Because these reactions were conducted under mild conditions, various common functional groups such as fluoride, chloride, bromide, iodide, trifluoromethyl, and ester group were compatible. Further expanding the scope of the reaction, for example, the difunctionalization of alkenes and reaction with phenol derivatives for the preparation of trifluoromethoxylated arenes are currently undergoing in our laboratory.

Conflicts of interest

There are no conflicts to declare.


The authors gratefully acknowledge the financial support from National Natural Science Foundation of China (21625206, 21632009, 21572258, 21421002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000) for financial support.

Notes and references

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Electronic supplementary information (ESI) available: NMR data of compounds 1a–f, 2a–k, 3a–k, 4a–r, 5a–q and 6a–f. CCDC 1879465. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8qo01249k

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