Takuma
Tagami‡
a,
Yuma
Aoki‡
a,
Shintaro
Kawamura
*ab and
Mikiko
Sodeoka
*ab
aCatalysis and Integrated Research Group, RIKEN Center for Sustainable Resource Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. E-mail: sodeoka@riken.jp
bSynthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
First published on 15th September 2021
A novel, Cu-mediated protocol toward the 1,2-bis-perfluoroalkyaltion of alkenes/alkynes was developed. The method proceeded with perfluorocarboxylic anhydrides as inexpensive and readily available perfluoroalkyl sources. Diacyl peroxide was generated in situ from the perfluorocarboxylic anhydrides and H2O2. The key step in this reaction is the formation of a stable perfluoroalkylcopper intermediate that is achieved with the aid of a bipyridyl ligand. Subsequent reaction of the intermediate with perfluoroalkyl-containing alkyl or vinyl radicals affords the desired products.
In an attempt to remedy this disadvantage of perfluoroalkylation reactions, our group has been investigating the use of perfluorocarboxylic anhydrides as inexpensive and readily available perfluoroalkyl sources for these processes.13,14 We have realised the efficient radical perfluoroalkylation of alkenes by the in situ generation of diacyl peroxides from the reaction of the acid anhydrides and urea·H2O2 (Scheme 1a). The key step in successfully conducting these reactions was the taming of a highly reactive alkyl radical intermediate containing a perfluoroalkyl group, which was transformed into the corresponding carbocation by single-electron transfer (SET) with a Cu(II) species. As part of our interest in perfluoroalkylations driven by perfluorocarboxylic anhydrides, we envisaged a novel protocol for the 1,2-bis-perfluoroalkylation of alkenes and alkynes using perfluorocarboxylic anhydrides (Scheme 1b), which is described herein.
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Scheme 1 Perfluoroalkylation by using perfluorocarboxylic anhydrides (a) previous work (b) this work. |
According to recent literature,9–12 a similar process, 1,2-bis-trifluoromethylation, requires not only electrophilic CF3 reagents but also CF3 nucleophiles or CF3–Cu(II) coupling partners to introduce a second CF3 group. In 2019, Han and Lee achieved the 1,2-bis-trifluoromethylation of alkenes using the Umemoto reagent and CF3SiMe3 as the electrophilic and nucleophilic reagents, respectively, in the presence of a copper catalyst and a stoichiometric amount of silver fluoride.9 Zhu and Li performed the 1,2-bis-trifluoromethylation of alkynes using the Togni reagent and (bpy)Zn(CF3)2 (bpy = 2,2′-bipyridine) with a copper catalyst in 2020.10 Tsui developed a protocol for the 1,2-bis-trifluoromethylation of arynes with Cu(I)CF3 in the presence of an oxidant to afford unique 1,2-bis-trifluoromethylarenes.11 In this reaction, a CF3–Cu(II) intermediate was postulated to be formed and was thought to be responsible for the formation of CF3-containing aryl radicals; a second equivalent of CF3–Cu(II) then reacts with these radicals and affords the products. Cook developed an elegant method for the 1,2-bis-trifluoromethylation of terminal alkynes with (bpy)Cu(III)(CF3)3, where the photolysis of the latter simultaneously generated a CF3 radical and a CF3–Cu(II) intermediate.12 Inspired by these previous works, we designed a methodology for the Cu-mediated 1,2-bis-perfluoroalkylation of alkenes and alkynes with perfluorodiacyl peroxides. This unprecedented approach involves the generation of a perfluoroalkylcopper(II) intermediate (Rf–Cu(II)) that occurs through the capturing of perfluoroalkyl radicals with a Cu(I) salt (Scheme 1b, concept).15 However, there are a few, formidable challenges to this approach. First, the same Cu(I) species must contribute to two different processes simultaneously: the formation of perfluoroalkyl radicals with diacyl peroxide by SET and the formation of the Rf–Cu(II) intermediate through the capturing of the perfluoroalkyl radical. The second disadvantage of the proposed method is that the concentration balance between the Rf–Cu(II) and alkyl/vinyl radical intermediates, generated from perfluoroalkyl radicals reacting with the alkene/alkyne, must be precisely tuned to introduce a second perfluoroalkyl group. This balance is required because in the absence of the Rf–Cu(II) intermediate the alkyl/vinyl radicals, which are highly reactive, can participate in undesirable side reactions. To solve these issues, we envisioned the use of a ligand to control the reactivity and stability of the copper species.
Entry | Ligandb | Yieldc (%) |
2a![]() ![]() |
|
---|---|---|---|---|
2a | 3a (E/Z) | |||
a Run on a 0.2 mmol scale. b 4.0 equiv. of ligand were used unless otherwise noted. c The yields were determined by NMR analysis. d Isolated yield was 58% yield. e PMDTA = N,N,N′,N′′,N′′-pentamethyldiethylenetriamine. | ||||
1 | Pyridine (8 equiv.) | 2 | 27 (90/10) | 7/93 |
2 | 2,2′-Bipyridine (bpy) | 75d | 4 (91/9) | 94/6 |
3 | 4,4′-Dimethyl-2,2′-bipyridine | 64 | 7 (91/9) | 90/10 |
4 | 1,10-Phenanthroline | 51 | 1 (n.d.) | 98/2 |
5 | TMEDA | 5 | 36 (88/12) | 12/88 |
6 | PMDTAe | 1 | 5 (88/12) | 17/83 |
7 | PPh3 (8.0 equiv.) | n.d. | n.d. | — |
8 | DPPE | n.d. | n.d. | — |
With the optimal conditions (Table 1, entry 2) in hand, the substrate scope was then investigated, as shown in Scheme 3.16,17 The functional group tolerance was confirmed by the reaction of several alkenes, which afforded the desired products bearing esters (2a,b), ketones (2c), phthalimides (2d), amides (2e), and sulphonamides (2f). A cyclic internal alkene could also be employed in the reaction, and the corresponding product (2g) was obtained. N-Tosyl allylamine, which was found to induce intramolecular amino- and carbo-trifluoromethylations in our previous work,13b successfully provided the 1,2-bis-trifluoromethylated product 2h in the present study. Perfluorocarboxylic anhydrides bearing longer alkyl chains were also employed in place of TFAA, providing the corresponding 1,2-bis-perfluoroalkylated molecules 2i and 2j. In addition, the reactions of terminal alkynes (4) smoothly proceeded to give 1,2-bis-perfluoroalkylated alkenes 5a–g with complete E-selectivity. The reaction also showed sufficient reactivity toward internal alkynes, affording the corresponding tetrasubstituted alkenes (5h–5k). To the best of our knowledge, the only other example of a 1,2-bis-perfluoroalkylation of an internal alkyne is that of arynes reported by Tsui's group.11 In all cases of the present study, E-selectivity was preferred; however, both the type of perfluoroalkyl group and the substituents on the triple bond of the alkyne were found to affect the stereoselectivity.
Finally, the reaction mechanism was investigated using the 1,2-bis-trifluoromethylation of alkynes as a model reaction. We assumed that a stable, cationic copper(I) complex ligating two bpy ligands (A) is formed under the optimal conditions.18,19 At the beginning of the reaction, SET between bis(trifluoroacetyl) peroxide (BTFAP) and A generates a CF3 radical and [(bpy)2Cu(O2CCF3)]+ (B) (Scheme 4).13,20 The CF3 radicals react with the alkyne to afford a vinyl radical intermediate.21 Simultaneously, [(bpy)2Cu(II)CF3]+ (C) can be formed by the reaction of a CF3 radical with A. The free energies of activation obtained by density functional theory (DFT) calculations (M06(CPCM = DCM)/6-311+G(d,p), SDD for Cu) indicated that the capturing of CF3 radicals by A is kinetically preferable to vinyl radical formation (ΔG‡Cu(II) = +5.5 kcal mol−1vs. ΔG‡vinyl = +9.4 kcal mol−1). Furthermore, the bpy ligand was found to remarkably stabilize intermediate C; the free energy change for the formation of intermediate C (ΔGCu(II)) was −16.1 kcal mol−1, whereas the free energy changes for the formation of bpy-free Cu(II)–CF3 complexes [Cu(CH3CN)4(CF3)]+ and (CH3CN)2Cu(O2CCF3)(CF3) (ΔGCu(II)) were −2.8 and −8.8 kcal mol−1, respectively.19 The reversibility of this step would lead to an imbalance between the concentrations of the vinyl radical and the Cu(II)–CF3 species, which is due to the high thermodynamic stability of the former (ΔG‡vinyl = −31.9 kcal mol−1). Thus, bpy was considered to play a crucial role in controlling the selectivity of the reaction by stabilising intermediate C and suppressing this reverse reaction.
The trifluoromethylation of the vinyl radical was then evaluated and two possible pathways were proposed (Scheme 5a). If SET between Cu(I) intermediate A and the diacyl peroxide is the dominant process over the formation of CF3–Cu(II) intermediate C, the double addition of two CF3 radicals to the triple bond (path b) might proceed instead of a coupling process (path a).6,8,22 Further, when the reaction proceeds via path b, the stereoselectivity outcome would only depend on the substrate structure. We observed that bipyridyl-type ligands such as bpy, 6,6′-dimethyl-2,2′-bipyridine, and 1,10-phenanthroline increased the E-selectivity of the reaction of internal alkyne 4h (Scheme 5b). In particular, sterically demanding 6,6′-dimethyl-2,2′-bipyridine greatly increased the E-selectivity but decreased the product yield. This result confirms that path a involving CF3–Cu(II) intermediate C is the predominant pathway.
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Scheme 5 Mechanistic investigation of the trifluoromethylation of vinyl radicals: (a) proposed mechanism and (b) ligand effect on the stereoselectivity outcome. |
Several attempts were made to detect the CF3–Cu(II) species via spectroscopic analyses of the reaction mixture, but all attempts failed. On the other hand, the 19F NMR analysis of the crude mixture after workup suggested the formation of (bpy)Cu(CF3)3, although its yield (as determined by 19F NMR analysis) was only 5%.23 This result strongly suggests the formation of CF3–Cu species during the reaction. To evaluate the reactivity of (bpy)Cu(CF3)3 under the optimal conditions (Table 1, entry 2), it was used as the reagent instead of a diacyl peroxide; however, no reactivity was observed (Scheme 6a). In addition, the reaction with heptafluorobutyric anhydride in the presence of (bpy)Cu(CF3)3 gave only the 1,2-bis-heptafluoropropylation product, proving that (bpy)Cu(CF3)3 did not participate in the reaction (Scheme 6b). Stable (bpy)Cu(CF3)3 was concluded to be a terminal by-product derived from the reactive CF3–Cu(II) intermediate (C).19
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Scheme 6 Examination of the reactivity of (bpy)Cu(CF3)3 under the optimal conditions (Table 1, entry 2). |
Next, the pathway for the reaction of vinyl radicals with C is discussed. Cook et al. proposed that their photo-induced 1,2-bis-trifluoromethylation of alkynes with (bpy)Cu(CF3)3 proceeds through the capturing of a vinyl radical with (bpy)(L)Cu(II)–CF3 (L = CF3 or OSO3H) and subsequent reductive elimination.12 Thus, as described above, we hypothesized that the coupling process in the present study proceeds in a similar manner: the capturing of the vinyl radical with intermediate C, followed by reductive elimination of Cu(III) intermediate D (Scheme 7, upper arrow).24 In addition to this, we also considered another possible mechanism involving SET between the vinyl radical and intermediate C, in which the resulting vinyl cation and CF3–Cu(I) intermediate E react via nucleophilic addition to give the desired product (Scheme 7, lower arrow).9 The sufficiently small free energy change obtained by DFT calculations suggested that Cu(III) intermediate D is formed by the reaction of C with the vinyl radical (ΔGCu(III) = −2.5 kcal mol−1), which is followed by reductive elimination (ΔG‡RE = +7.3 kcal mol−1). Notably, in the second trifluoromethylation step, no positive effects were induced by bpy on the stability of D and on the rate of the reductive elimination.19 On the other hand, the free energy change for vinyl cation formation by SET (ΔGox) was +28.3 kcal mol−1, suggesting that this process is either very slow or could not proceed.19
Footnotes |
† Electronic supplementary information (ESI) available: Supplementary data, experimental procedures, NMR spectra, computational details. See DOI: 10.1039/d1ob01529j |
‡ These authors equally contributed. |
This journal is © The Royal Society of Chemistry 2021 |