Synthesis and application of well-defined [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex as a versatile pentafluoroethylating reagent

Abstract

We herein describe the preparation and application of a new bispentafluoroethylated organocuprate [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻. This complex has demonstrated a remarkable range of reactivities towards carboxylic acids, diazonium salts, organic halides, boronic esters, terminal alkynes and (hetero)arenes as a versatile pentafluoroethylating reagent. The construction of C(sp³)–/C(sp²)–/C(sp)–CF₂CF₃ bonds can therefore be achieved using a single reagent.

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Introduction

Perfluoroalkylated molecules represent a significant portion of existing pharmaceutical compounds or drug candidates owing to their desirable biological and chemophysical properties.¹ Consequently, methods for introducing perfluoroalkyl groups into organic molecules have become increasingly important.² Trifluoromethylation, the introduction of the smallest perfluoroalkyl group CF₃, has reached a certain level of maturity.³ In contrast, the development of analogous pentafluoroethylation for introducing the CF₂CF₃ group has been lagging drastically behind.⁴ Biologically active compounds containing the pentafluoroethyl group do exist including the angiotensin II receptor antagonist DuP 532,^5a antihypertensive potassium channel opener KC-515 (ref. 5b) and fulvestrant for treating breast cancer.^5c The number of marketed drugs containing CF₂CF₃, however, is much lower than that of the CF₃-containing drugs, despite some evidence pointing to the superior biological activities of the pentafluoroethylated congeners.⁶ Thus, new methods for synthesizing pentafluoroethylated molecules with diverse structures will be crucial for their future applications as therapeutic agents.⁷

The identification of accessible and easy-to-handle pentafluoroethylating reagents has been the bottleneck for developing pentafluoroethylation reactions. In this regard, pioneering works on the preparation and applications of transition-metal-based reagents (MCF₂CF₃; M = Cu,⁸ Zn,⁹ Ag,¹⁰ Pd,¹¹ Ir¹²) have significantly broadened the reaction scope. Yet, with few exceptions, many of these reagents were not well-characterized and often in situ generated. For instance, Hu et al.^8i,j,n,p and Ogoshi et al.^8k reported the in situ generation of CuCF₂CF₃ using TMSCF₃ and tetrafluoroethylene (TFE), respectively, and studied their reactions with aryl iodides. In terms of well-defined CuCF₂CF₃ complexes, several examples can be found in the literature (Scheme 1). Daugulis et al. first described the synthesis of [K(DMPU)₃]⁺[(CF₂CF₃)CuCl]⁻ from CuCl, KF and TMSCF₃ in DMPU/THF (14% yield), which was characterized by NMR spectroscopy and X-ray crystallography (Scheme 1a).^8q This anionic complex was a temperature and moisture sensitive solid that decomposed at room temperature under argon over few hours. Subsequently, Hartwig et al. reported the preparation of [(phen)CuCF₂CF₃] from [Cu(Mesityl)]₅, t-BuOH, 1,10-phenanthroline (phen) and TMSCF₂CF₃ (Scheme 1b).^8b This complex was effective for the pentafluoroethylation of arylboronate esters and heteroaryl bromides.^8e Grushin et al. described the cupration of pentafluoroethane (HCF₂CF₃) gas with [K(DMF)][(t-BuO)₂Cu] to generate the [K(DMF)₂][(t-BuO)CuCF₂CF₃] complex with X-ray structural proof (Scheme 1c).^8c A broad scope of pentafluoroethylation of aryl/vinyl iodides and bromides was demonstrated with this complex.^8g Moreover, the same group prepared four [L_nCuCF₂CF₃] complexes bearing different ligands (L) using [K(DMF)₂][(t-BuO)CuCF₂CF₃] and obtained their X-ray crystal structures (Scheme 1d).^8f The [(Ph₃P)Cu(phen)CF₂CF₃] complex was shown to be useful for the pentafluoroethylation of acid chlorides.

Scheme 1 Preparation of well-defined [CuCF₂CF₃] complexes.

We herein describe the synthesis of a novel bispentafluoroethylated organocuprate [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ 1 (Scheme 1e). This complex can be prepared on gram-scale and is a stable solid at room temperature under argon for months. More importantly, 1 has demonstrated a broad spectrum of reactivity as a versatile pentafluoroethylating reagent that is superior than previous CuCF₂CF₃ complexes. For instance, 1 was highly reactive towards not only aryl diazonium salts and iodides, but also difficult substrates such as aryl bromides and chlorides. In addition, 1 could be applied in challenging decarboxylative pentafluoroethylation, oxidative pentafluoroethylation of aryl pinacol boronic esters/alkynes, or even direct C–H bond pentafluoroethylation.

Results and discussion

We have recently reported the first preparation of [Ph₄P]⁺[Cu(CF₃)₂]⁻ complex^13a from TMSCF₃ and its usage in trifluoromethylation of organic halides with detailed mechanistic investigation.^13b,c Subsequently, [Ph₄P]⁺[Cu(CF₂H)₂]⁻ was synthesized using TMSCF₂H and proved to be a powerful difluoromethylating reagent.¹⁴ However, the pentafluoroethylated analogue remained unknown. We decided to use TESCF₂CF₃ as a potential pentafluoroethyl source for the synthesis of CuCF₂CF₃ complex (Scheme 2). The TESCF₂CF₃ was conveniently prepared from the low-cost pentafluoroethane (HFC-125, fire suppression agent/ozone-friendly refrigerant) and triethylchlorosilane on 350 mmol scale (Scheme 2a).¹⁵ When initially applying the original protocol for the preparation of [Ph₄P]⁺[Cu(CF₃)₂]⁻ complex^13a using TESCF₂CF₃, only trace product was detected. By increasing the equivalents of TESCF₂CF₃ and KF with prolonged reaction time, the product formation was significantly improved. Thus, a two-step procedure was followed (Scheme 2b): (1) reacting CuCl with TESCF₂CF₃ (4.0 equiv.) and KF (8.0 equiv.) in THF at room temperature overnight; (2) adding tetraphenylphosphonium chloride Ph₄P⁺Cl⁻ (1.0 equiv.) at room temperature and stirring for 2 h. To our delight, the [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex 1 was successfully isolated in 92% yield (5.86 g, white solid) on 10 mmol scale. This complex was fully characterized by ¹H, ¹⁹F and ³¹P NMR spectroscopy as well as high-resolution mass spectrometry. The structure was unambiguously confirmed by X-ray crystallography.

Scheme 2 Synthesis of bispentafluoroethylated organocuprate [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ 1.

Carboxylic acids are naturally abundant materials that are readily available, inexpensive and stable. As a result, decarboxylative cross-coupling of carboxylic acids has drawn tremendous attention in the synthetic community in recent years.¹⁶ The conversion of CO₂H group to CF₃ via decarboxylative trifluoromethylation has emerged as a viable perfluoroalkylation strategy.¹⁷ To the best of our knowledge, decarboxylative pentafluoroethylation remains unknown. Li et al. pioneered the decarboxylative trifluoromethylation of aliphatic carboxylic acids using a Cu(III) complex (bpy)Cu(CF₃)₃ as the reagent.^17a In their proposed mechanism, (bpy)Cu(CF₃)₃ reacts with ZnMe₂ to generate the [Cu(CF₃)₃Me]⁻ anion, which undergoes reductive elimination to form the key [Cu(CF₃)₂]⁻ anion (Scheme 3a). In the presence of an oxidant, [Cu^I(CF₃)₂]⁻ anion becomes Cu^II(CF₃)₂. Decarboxylation of carboxylic acid 2 would lead to the alkyl radical, in Li's report a silver(II) salt was employed for this purpose. This radical can react with the Cu^II(CF₃)₂ species to generate product 3 with the formation of a C–CF₃ bond (Scheme 3b). We envisioned that our Cu(I) complex [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ 1 can intercept this reaction pathway bypassing the reductive elimination from the Cu(III) anion to achieve decarboxylative pentafluoroethylation. However, the reactivity and compatibility of this complex in the decarboxylation conditions were unclear to us at the outset.

Scheme 3 Initial investigation of decarboxylative pentafluoroethylation of aliphatic carboxylic acids using 1.

An initial attempt using Li's conditions (A)^17a with 1 and 2a failed to provide any products (Scheme 3c). However, we were delighted to find that by using the photocatalyst 9-mesityl-10-methylacridinium tetrafluoroborate [Mes-Acr-Me][BF₄] under blue light irradiation (condition B), the desired product 3a could be obtained in 80% yield. Although visible-light-induced decarboxylative functionalization of carboxylic acids has been well-studied,^18a its application to perfluoroalkylation is limited.^18b,c Extensive screening of reaction parameters including photocatalysts, oxidants, additives and solvents was carried out to improve the yield.¹⁹ It was found that adding a hypervalent iodine(III) reagent PhIO (iodosylbenzene)²⁰ could enhance the yield to 96% (condition C).

The scope of aliphatic carboxylic acids 2 in the decarboxylative pentafluoroethylation using 1 was subsequently studied (Scheme 4). Under the optimized conditions, a variety of carboxylic acids containing benzylic CO₂H group could be converted to the corresponding pentafluoroethylated products 3a–j. The reaction tolerated electron-donating (3d) and electron-withdrawing (3j) aryl substituents. Halogens including fluoro (3f), chloro (3g), bromo (3h) and iodo (3i) groups were also compatible. A ɣ-keto acid was suitable substrate in the reaction (3k). Moreover, the anti-inflammatory agent Isoxepac could be pentafluoroethylated in excellent yield (3l). However, a secondary carboxylic acid only gave a low yield.

Scheme 4 Scope of decarboxylative pentafluoroethylation using 1.^{a a}General conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Mes-Acr-Me][BF₄] (3 mol%), K₂S₂O₈ (0.4 mmol), PhIO (0.2 mmol), MeCN (2.0 mL), blue LEDs, rt for 12 h under argon. Isolated yields based on 1.

Based on literature evidence,^18c the following plausible reaction mechanism is proposed for the decarboxylative pentafluoroethylation of 2 with reagent 1 (see the ESI† for proposed mechanisms and control experiments). The photocatalyst [Mes-Acr-Me]⁺ is activated by visible light, which then undergoes single-electron oxidation of carboxylate R–CH₂–COO⁻ (from 2) to give acyloxyl radical R–CH₂–COO˙ and generate the [Mes-Acr-Me]˙ species. Decarboxylation of R–CH₂–COO˙ leads to alkyl radical. Meanwhile, [Cu^I(CF₂CF₃)₂]⁻ 1 is oxidized to Cu^II(CF₂CF₃)₂ which then reacts with the radical to form the R–CH₂–CF₂CF₃ product 3 (cf. Scheme 3b).^17a Finally, [Mes-Acr-Me]˙ is oxidized via SET to regenerate the catalyst [Mes-Acr-Me]⁺. Adding PhIO can lead to the formation of phenyliodine(III) dicarboxylates (RCH₂COO)₂IPh, which are known to undergo decarboxylation in the presence of copper(I) complexes to generate alkyl radical.²⁰ It is possible that both pathways contributed to the formation of 3 from 2.

Arenediazonium salts are useful substrates for Sandmeyer-type trifluoromethylation and can be made from inexpensive aromatic amines.²¹ However, the corresponding pentafluoroethylation is far less explored. One report in the literature by Hu et al.⁸ⁿ described the copper-mediated pentafluoroethylation of arenediazonium tetrafluoroborates with in situ generated tetrafluoroethylene (TFE) from TMSCF₃ and NaI. By adding CuSCN and CsF to TFE, the “CuCF₂CF₃” species is formed which can react with the diazonium salt.²² We found that 1 was remarkably reactive with arenediazonium salts 4 even at −20 °C (Scheme 5).²³ Within 30 min, various arenediazonium tetrafluoroborates could be converted directly to pentafluoroethyl arenes 5 in good yields. The reaction exhibited good functional group tolerability towards halo (5b, 5c), amine (5d), sulfone (5e), nitro (5f), ketone (5g), ester (5h) and heteroaryl (5i) groups. This protocol was operationally straightforward without the use of separate reagents/additives and the conditions were mild and fast.

Scheme 5 Pentafluoroethylation of arenediazonium tetrafluoroborates using 1.^{a a}General conditions: 1 (0.2 mmol), 4 (0.2 mmol), MeCN (2.0 mL), under argon. Isolated yields.

(Hetero)aryl halides could be pentafluoroethylated using 1 based on analogous trifluoromethylation conditions^13a (Scheme 6). Aryl iodides were quite reactive within 12 h to provide products 5a, 5j–l in good yields. An example of alkenyl iodide in pentafluoroethylation was also demonstrated (5m). Aryl and heteroaryl bromides gave products 5a, 5n–q in good yields after 24 h. In contrast, aryl chlorides were much less reactive than aryl iodide and aryl bromide, often were inert in previously reported pentafluoroethylation protocols.²⁴ Actually, reaction of unactivated 4-biphenyl chloride with 1 did not generate compound 5a at all. However, activated heteroaryl chlorides containing isoquinoline (5r), quinoline (5s), quinoxaline (5t), pyrimidine (5u), triazine (5q), nicotinate (5v–x), benzothiazole (5y) and benzoxazole (5z) cores did react with reagent 1 to afford pentafluoroethylated heteroarenes in 73–92% yields. Intriguingly, an acid chloride (2-naphthoyl chloride) was able to generate the pentafluoroethylated ketone 5aa at lower temperature (60 °C) without the CuI additive.^8f

Scheme 6 Pentafluoroethylation of (hetero)aryl halides using 1.^{a a}General conditions: 1 (0.3 mmol), 6 (0.2 mmol), CuI (0.2 mmol), DMF (2.0 mL), under argon. Isolated yields. ^bdr = 17 : 1 from starting alkenyl iodide. ^cConditions: 2-naphthoyl chloride (0.2 mmol), 1 (0.3 mmol), THF (2.0 mL), 60 °C for 12 h, under argon.

Furthermore, reagent 1 was effective in oxidative pentafluoroethylation of aryl boronic esters 7 and terminal alkynes 8 under mild conditions (Scheme 7).²⁵ Thus, pentafluoroethylated arenes 5 were synthesized from the corresponding aryl-Bpin tolerating aldehyde, ester, amide, nitro and nitrile groups. An alkenyl-Bpin substrate also gave the product (5ah). Readily available terminal alkynes were directly converted to pentafluoroethylated internal alkynes 9a–g showing good functional group tolerance. The simple operations (open to air) and the use of air as a green oxidant were the advantages of these reactions.

Scheme 7 Aerobic pentafluoroethylation of boronic esters and terminal alkynes using 1.^{a a}General conditions using boronic esters: 1 (0.3 mmol), 7 (0.2 mmol), KOAc (0.3 mmol), DMF (2.0 mL), open to air, 12 h. Isolated yields. General conditions using terminal alkynes: 1 (0.24 mmol), 8 (0.2 mmol), KOAc (0.3 mmol), DMF (2.0 mL), open to air, 12 h. Isolated yields. ^bYield determined by ¹⁹F NMR using benzotrifluoride as the internal standard.

The direct conversion of C–H bonds to C–R_f bonds bypassing the requirement of prefunctionalized substrates is a very desirable strategy. Trifluoromethylation of arene C–H bonds has been reported by Zhang et al. using a high-valent Cu(III)-CF₃ complex.²⁶ However, to the best of our knowledge, the corresponding pentafluoroethylation using copper-based reagents is unknown. In the literature, the C–H bond pentafluoroethylation has been achieved by employing nickel catalysts,^27a,b cobalt complexes^27c and photocatalytic methods.^27d,e We discovered that our CuCF₂CF₃ complex 1 was capable of pentafluoroethylating arenes and heteroarenes in the presence of an oxidant (Scheme 8). Different oxidants including K₂S₂O₈, PIDA, Selectfluor, Oxone and NFSI were screened and NFSI showed the best reactivity.¹⁹ Thus, at room temperature, aromatic C–H bonds could be converted to C–CF₂CF₃ bonds (5ag, 5ai–5al). Heteroaromatic C–H bonds including pyrazine (5am), pyridine (5an), thiophene (5ao) and furan (5ap) were also reactive. Interestingly, the C–H bond of caffeine could be smoothly functionalized to afford the pentafluoroethylated caffeine 5aq. Moreover, the alkenyl C–H bond pentafluoroethylation was achieved to give compound 5ar and an uracil derivative 5as. It was found that the electron-rich arenes were more reactive than the electron-poor ones. In comparison with 1,4-dimethoxybenzene (5ai, 65%), 1,4-dibromobenzene (14%) and 1,4-dinitrobenzene (<5%) gave low yields even at elevated temperature (60 °C in DCE). This is likely due to the electrophilic nature of the pentafluoroethyl radical generated in situ, which is more reactive towards the electron-rich arenes.

Scheme 8 Oxidative pentafluoroethylation of (hetero)aromatic C–H bond using 1.^{a a}General conditions: 1 (0.2 mmol), 10 (1.0 mmol), NFSI (0.6 mmol), CH₂Cl₂ (2.0 mL), under argon, 12 h. Isolated yields.

Conclusions

In conclusion, we have synthesized and characterized a novel [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex 1. This complex proved to be a highly versatile pentafluoroethylating reagent. A diverse array of pentafluoroethylation reactions of carboxylic acids, diazonium salts, organic halides, boronic esters, terminal alkynes and (hetero)arenes were developed using 1. Therefore, one reagent was capable of constructing all C(sp³)–, C(sp²) and C(sp)–CF₂CF₃ bonds. It is worth mentioning that the [Ph₄P]⁺[Cu(CF₂CF₃)₂]⁻ complex 1 has demonstrated superior reactivities than its [Ph₄P]⁺[Cu(CF₃)₂]⁻ counterpart.¹⁹ For instance, pentafluoroethylation of carboxylic acid, diazonium salt, arene C–H bond and heteroaryl chloride using 1 gave significantly higher yields than the corresponding trifluoromethylation with [Ph₄P]⁺[Cu(CF₃)₂]⁻. Further transformations of 1 and studies of reaction mechanisms are ongoing in our laboratories.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Research Grants Council of Hong Kong (NSFC/RGC Joint Research Scheme, N_CUHK403/20), the Chinese University of Hong Kong (Faculty of Science – Direct Grant for Research), the National Key Research and Development Program of China (No. 2021YFF0701700), the National Natural Science Foundation of China (22061160465) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0590000). We also thank the Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences for funding.

Notes and references

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18. A review: (a) J. Xuan, Z. Zhang and W. Xiao, Angew. Chem., Int. Ed., 2015, 54, 15632 ; Trifluoromethylation:; (b) P. Xu, A. Abdukader, K. Hu, Y. Cheng and C. Zhu, Chem. Commun., 2014, 50, 2308 ; Trifluoromethylselenolation:; (c) Q.-Y. Han, K.-L. Tan, H.-N. Wang and C.-P. Zhang, Org. Lett., 2019, 21, 10013.
19. See the ESI† for details.
20. Z. Li, G. Zhang, Y. Song, M. Li, Z. Li, W. Ding and J. Wu, Org. Lett., 2023, 25, 3023.
21. Representative examples: (a) X. Wang, Y. Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2013, 135, 10330; (b) J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu, L. Liu and Y. Fu, J. Am. Chem. Soc., 2013, 135, 8436; (c) A. Lishchynskyi, G. Berthon and V. V. Grushin, Chem. Commun., 2014, 50, 10237; (d) G. Danoun, B. Bayarmagnai, M. F. Grunberg and L. J. Goossen, Angew. Chem., Int. Ed., 2013, 52, 7972.
22. For a related transformation (3 examples) using “NiCF₂CF₃”, see: S. T. Shreiber and D. A. Vicic, Angew. Chem., Int. Ed., 2021, 60, 18162.
23. At higher temperatures, e.g., 0 °C and rt, bis-pentafluoroethylated side products were observed.
24. Pentafluoroethylation of heteroaryl chlorides is very rare. Most literature examples use (het)aryl iodides and bromides, see ref. 8c, 8e and 8j.
25. For related transformations, see ref. 8b and 8p, phen ligand was required for the CuCF₂CF₃ complex for the pentafluoroethylation of boronic esters.
26. H. Zhang, C. Feng, N. Chen and S. Zhang, Angew. Chem., Int. Ed., 2022, 61, e202209029.
27. (a) S. Deolka, R. Govindarajan, T. Gridneva, M. C. Roy, S. Vasylevskyi, P. K. Vardhanapu, J. R. Khusnutdinova and E. Khaskin, ACS Catal., 2023, 13, 13127; (b) S. Deolka, R. Govindarajan, S. Vasylevskyi, M. C. Roy, J. R. Khusnutdinova and E. Khaskin, Chem. Sci., 2022, 13, 12971; (c) H. M. Dinh, R. Govindarajan, S. Deolka, R. R. Fayzullin, S. Vasylevskyi, E. Khaskin and J. R. Khusnutdinova, Organometallics, 2023, 42, 2632; (d) M. Zhang, J. Chen, S. Huang, B. Xu, J. Lin and W. Su, Chem. Catal., 2022, 2, 1793; (e) J. W. Beatty, J. J. Douglas, R. Miller, R. C. McAtee, K. P. Cole and C. R. J. Stephenson, Chem, 2016, 1, 456.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2325717. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc02075h

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