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Synlett 2020; 31(01): 41-44
DOI: 10.1055/s-0039-1690187
cluster – 9th Pacific Symposium on Radical Chemistry
© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Radical Bis(trifluoromethylation) of Alkynes and 1,3-Enynes

Haigen Shen
a   Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: zhulin@mail.ustc.edu.cn   Email: clig@mail.sioc.ac.cn
,
Hawen Xiao
a   Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: zhulin@mail.ustc.edu.cn   Email: clig@mail.sioc.ac.cn
,
Lin Zhu∗
a   Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: zhulin@mail.ustc.edu.cn   Email: clig@mail.sioc.ac.cn
,
Chaozhong Li∗
a   Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: zhulin@mail.ustc.edu.cn   Email: clig@mail.sioc.ac.cn
b   School of Materials and Chemical Engineering, Ningbo University of Technology, No. 201 Fenghua Road, Ningbo 315211, P. R. of China
› Author Affiliations
Subject Editor: David Nicewicz and Corey Stephenson

This project was supported by the Natural Science Foundation of Shanghai (Grant Number 16ZR1443700), by the National Natural Science Foundation of China (Grant Numbers 21421002, 21532008, 21602239, and 21871285), by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant Number XDB20020000), and by the Shanghai Scientific and Technological Innovation Project (Grant Number 18JC1410600).
Further Information

Publication History

Received: 12 July 2019

Accepted after revision: 05 August 2019

Publication Date:
15 August 2019 (online)

 
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Published as part of the Cluster 9th Pacific Symposium on Radical Chemistry

Abstract

The copper-catalyzed radical bis(trifluoromethylation) of alkynes and 1,3-enynes is described. With Cu(CH3CN)4BF4 as the catalyst, the reaction of arylalkynes with Togni reagent II and (bpy)Zn(CF3)2at room temperature affords the corresponding 1,2-bis(trifluoromethylated) alkenes in good yields with excellent E-stereoselectivity. Under similar conditions, the reaction of 1,3-enynes provides the corresponding 1,4-bis(trifluoromethylated) allenes exclusively in satisfactory yields. The protocol exhibits broad substrate scope and excellent functional group compatibility.


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Key words

copper - trifluoromethylation - radicals - alkynes - 1,3-enynes

Trifluoromethylated molecules have found increasingly important applications in pharmaceuticals and agrochemicals.[1] As a consequence, various trifluoromethylating reagents[2] and trifluoromethylation methods[3] have been developed in the past decades. In this aspect, a number of vinylic CF3-containing compounds possess important biological activities such as herbicides, insecticides, and aminotransferase inhibitors. Representative examples are shown in Figure [1]. The construction of Cvinyl–CF3 bonds has thus attracted a considerable attention, and several methods have been reported. A typical strategy is the trifluoromethylation of vinyl derivatives (e.g., vinyl halides, vinyl carboxylic acids, or vinylboronates) with trifluoromethylating reagents in the presence of various transition metals (Scheme [1, a]).[3e] While this method allows the introduction of CF3 groups in site-selective manner, it requires prefunctionalized alkenes as substrates. An alternative strategy is the addition of CF3 radicals to alkynes to give vinyl radicals, which are then intercepted by various functionalities other than CF3 groups (Scheme [1, b]).[4] However, the method typically provides products with CF3 as the end group. It is certainly desirable to develop new methods for Cvinyl–CF3 bond formations. Herein, we report the copper-catalyzed trifluoromethylation of alkenyl radicals, rendering the facile bis(trifluoromethylation) of alkynes and 1,3-enynes under mild conditions (Scheme [1, c]).

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Figure 1 Examples of Cvinyl–CF3-containing pharmaceuticals and agricultural chemicals
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Scheme 1 Construction of Cvinyl–CF3 bonds

We recently introduced radical trifluoromethylation of alkyl halides and proposed the mechanism of CF3 group transfer from Cu(II)–CF3 intermediates to alkyl radicals.[5] This concept was then successfully applied to a number of reactions including decarboxylative trifluoromethylation of aliphatic acids and C(sp3)–H trifluoromethylation by us[6] and by the groups of Liu,[7] Cook,[8] Gong,[9] and MacMillan.[10] We also developed the C(sp2)–H trifluoromethylation of aldehydes via acyl radicals.[11] In the meantime, the trifluoromethylation of aryl C(sp2) radicals was also developed with arene diazonium salts[12] or aryl halides[13] as aryl radical precursors. However, to date, there is no example of trifluoromethylation of alkenyl radicals. In continuation of our interest in radical trifluoromethylation, we speculated that alkenyl radicals might also undergo trifluoromethylation via CF3 group transfer from Cu(II)–CF3 intermediates. This would allow 1,2-bis(trifluoromethylation) of alkynes to occur.[14] With this idea in mind, we carried out the following investigations.

We commenced our study by using 4-(tert-butyl)phenylacetylene (1a) as the model substrate. With Cu(OTf)2 as the catalyst and 4,4′-dimethoxy-2,2′-bipyridine as the ligand, the reaction of 1a with a typical trifluoromethylating reagent such as Ruppert–Prakash reagent (TMSCF3)[2a] or Umemoto reagent[2c] in CH3CN at room temperature resulted in either no reaction or a very low (<10%) yield of the expected product 2a. However, with the combination of Umemoto reagent and Ruppert–Prakash reagent, the reaction of 1a under similar conditions afforded the 1,2-bis(trifluoromethylated) alkene 2a in 50% yield with a high E/Z ratio (ca. 93:7 determined by 19F NMR spectroscopy). Encouraged by the result, we went on to optimize the reaction conditions (see Tables S1–S4 in the Supporting Information). We were pleased to find that the Cu(CH3CN)4BF4 (20 mol%) catalyzed reaction of 1a with the combination of Togni reagent[2e] (1.7 equiv) and (bpy)Zn(CF3)2 (1.5 equiv, bpy = 2,2′-bipyridine)[15] at room temperature provided product 2a in 81% isolated yield with excellent stereoselectivity (E/Z > 95:5). No extra ligand was required.

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Scheme 2 1,2-Bis(trifluoromethylation) of alkynes. a Conditions: 1 (0.30 mmol), Togni (0.51 mmol), (bpy)Cu(CF3)3 (0.45 mmol), Cu(CH3CN)4BF4(0.06 mmol), CH3CN (6.0 mL), rt, 12 h. b Isolated yield based on 1. c DCM (6.0 mL) was used in place of CH3CN as the solvent.

With the optimized conditions in hand, we then examined the scope of the method. As shown in Scheme [2, a] wide range of arylacetylenes with either electron-donating or electron-withdrawing substituents on the aromatic ring were converted smoothly into the corresponding 1,2-bis(trifluoromethylated) alkenes 2a–j in good to high yields. Interestingly, an excellent chemoselectivity was observed in the reaction of 1j bearing two triple bonds, and 1,2-bis(trifluoromethylation) occurred exclusively at the aryl-conjugated triple bond to produce 2j while the internal triple bond remained intact. Heterocyclic arylacetylenes were also suitable substrates for the transformation, as exemplified by the synthesis of 2k and 2l in satisfactory yields. A variety of functional groups were well tolerated, including ethers, ketones, esters, and nitriles. The wide functional group compatibility enabled late-stage modification of complex molecules. For example, alkynyl-containing steroids, carbohydrates, and vitamin E derivatives underwent bis(trifluoromethylation) to provide the corresponding products 2n–q in acceptable yields. In all cases, an excellent E-stereoselectivity (E/Z > 95:5 determined by crude 19F NMR spectroscopy) was observed. Nevertheless, the extension of the method to alkyl-substituted alkynes resulted in a low efficiency and poor stereoselectivity, as evidenced by the synthesis of 1,2-bis(trifluoromethylated) alkene 2r in 17% yield with almost no stereoselectivity. Instead, a significant amount (ca. 50%) of the hydrotrifluoromethylated byproduct was obtained.

The above method can be extended to the 1,2-bis(trifluoromethylation) of unactivated alkenes.[16] For example, the reaction of alkene 3 under the above optimized conditions furnished the corresponding product 4 in 78% yield (Scheme [3]).

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Scheme 3

Encouraged by the successful 1,2-bis(trifluoromethylation) of arylalkynes and unactivated alkenes, we went on to examine the behaviors of 1,3-enynes. We anticipated that 1,3-enynes would undergo alkene 1,2-bis(trifluoromethylation), given that (1) CF3 radicals are electrophilic in nature and thus alkenes are more reactive than alkynes towards CF3 radical addition, and (2) the resulting propargyl radicals are more stable than their resonant structures as short-lived allenyl radicals. Indeed, only a few examples[17] of 1,4-radical addition of 1,3-enynes have been reported. To our surprise, the reaction of 1,3-enynes 5 under the above optimized conditions led to the exclusive formations of the corresponding allenes 6 while no 1,2-addition products could be detected. As summarized in Scheme [4], the method was applicable not only to aryl-substituted 1,3-enynes (to give 6a–f) but also to alkyl-substituted 1,3-enynes (to give 6g–i). The protocol was efficient and exhibited good functional group tolerance. It is worth mentioning that previous methods for the synthesis of trifluoromethylated allenes typically require the use of propargyl halides, esters, or tosylates as the substrates and often suffer from the generation of 3-CF3-substituted 1-alkynes as the byproducts.[18] Thus, the above 1,4-bis(trifluoromethylation) of easily available 1,3-enynes offers a nice complement to the literature methods.

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Scheme 4 Bis(trifluoromethylation) of 1,3-enynes. a Conditions: 5 (0.30 mmol), Togni reagent (0.51 mmol), (bpy)Cu(CF3)3 (0.45 mmol), Cu(CH3CN)4BF4 (0.06 mmol), CH3CN (6.0 mL), rt, 12 h. b Isolated yield based on 5.

To gain more insight into the mechanism of the bis(trifluoromethylation) of alkynes and 1,3-enynes, the radical capture experiment was conducted. When a stoichiometric amount of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) was added into the reaction of arylalkyne 1h under the standard conditions, the yield of the desired product 2h decreased to 27% while TEMPO–CF3 was obtained in 80% yield. This result indicated that a CF3 radical was involved in the reaction.

On the basis of the above results and literature reports,[5] [6] [14] a plausible mechanism is proposed (Scheme [5]). Transmetalation of the CF3 anion from (bpy)Zn(CF3)2 to the Cu catalyst generates a Cu(I)–CF3 species that undergoes single-electron transfer with the Togni reagent to form a CF3 radical and a Cu(II)–CF3 intermediate. The addition of the CF3 radical to the alkyne or 1,3-enynes gives the corresponding alkenyl radical A or propargyl radical B. Radical B is in equilibrium with its tautomer allenyl radical C. Finally, radical A or C is intercepted by Cu(II)–CF3 to afford the corresponding bis(trifluoromethylation) product 2 or 6 and regenerate the Cu(I) catalyst. The formation of allene 6 seems to indicate that allenyl radical C is more reactive than propargyl radical B towards the Cu(II)–CF3 intermediate. More mechanistic studies are certainly required to have a clear understanding on the mechanism.

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Scheme 5 Proposed mechanism of bis(trifluoromethylation)

In summary, we have successfully developed a copper-catalyzed 1,2-bis(trifluoromethylation) of alkynes, providing a practical and efficient approach to 1,2-bis(trifluoromethylated) alkenes with excellent E-stereoselectivity. This reaction can be extended to 1,3-enynes, leading to the efficient synthesis of 1,4-bis(trifluoromethylated) allenes. The protocol exhibits broad substrate scope and excellent functional group compatibility. As the procedure is catalytic in copper and operationally simple,[19] [20] the method should find important applications in the synthesis of trifluoromethylated molecules.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690187.
  • Supporting Information


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Figure 1 Examples of Cvinyl–CF3-containing pharmaceuticals and agricultural chemicals
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Scheme 1 Construction of Cvinyl–CF3 bonds
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Scheme 2 1,2-Bis(trifluoromethylation) of alkynes. a Conditions: 1 (0.30 mmol), Togni (0.51 mmol), (bpy)Cu(CF3)3 (0.45 mmol), Cu(CH3CN)4BF4(0.06 mmol), CH3CN (6.0 mL), rt, 12 h. b Isolated yield based on 1. c DCM (6.0 mL) was used in place of CH3CN as the solvent.
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Scheme 3
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Scheme 4 Bis(trifluoromethylation) of 1,3-enynes. a Conditions: 5 (0.30 mmol), Togni reagent (0.51 mmol), (bpy)Cu(CF3)3 (0.45 mmol), Cu(CH3CN)4BF4 (0.06 mmol), CH3CN (6.0 mL), rt, 12 h. b Isolated yield based on 5.
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Scheme 5 Proposed mechanism of bis(trifluoromethylation)