Alkynyl trifluoromethyl selenide synthesis via oxidative trifluoromethylselenolation of terminal alkynes

Abstract

The synthesis of alkynyl trifluoromethyl selenides by Cu-mediated oxidative trifluoromethylselenolation of terminal alkynes is reported. Treatment of [(bpy)Cu(SeCF₃)]₂ with various terminal alkynes in the presence of an oxidant, Dess–Martin periodinane, led to the formation of trifluoromethylselenolated acetylenes bearing sensitive moieties such as alkoxy, halogens, trifluoromethyl, and heterocyclic groups.

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The importance of organofluorine compounds in the fields of agricultural, medicinal, and materials chemistry has inspired chemists to continue developing mild and efficient methods for their synthesis.^1–8 Among such compounds trifluoromethyl thioethers have attracted a great deal of attention in the past few years owing to their strong electron-withdrawing effects and high lipophilicity.^9–12 The development of new synthetic routes to trifluoromethyl thioethers thus represents an important area of research in organic chemistry.^13–18 Recently, the development of new trifluoromethylthiolating reagents^19–30 and transition-metal-catalyzed or -mediated trifluoromethylthiolation has found many applications for assembling aryl and alkyl trifluoromethyl thioethers.^{24,28,31–41} Various methodologies have also been developed for introducing the trifluoromethanesulfenyl group into acetylenes. These include oxidative trifluoromethylthiolation of terminal alkynes with CF₃SiMe₃, and elemental sulphur⁴² or later with AgSCF₃,⁴³ copper-catalyzed trifluoromethylthiolation of terminal alkynes with a novel thioperoxy reagent,²⁵ base-catalyzed trifluoromethylthiolation of terminal alkynes with a trifluoromethanesulfenamide reagent,⁴⁴ and bismuth(III)-promoted trifluoromethylthiolation of trimethyl(alkynyl)silane with a trifluoromethanesulfanylamide reagent.⁴⁵

Despite these seminal contributions made in trifluoromethylthiolation, to our knowledge, there are no examples in the literature for the construction of C_sp–SeCF₃ bonds. This is probably because the starting materials and reagents are either highly toxic, unstable, commercially unavailable, or require elaborate preparative methods.^46–52

The organoselenium compounds also display significant potential as antioxidant, antitumor, antimicrobial, and antiviral agents.⁵³ Therefore, development of efficient procedures for the synthesis of alkynyl trifluoromethyl selenides is of much importance.

In our continuing efforts aimed at developing simple and efficient synthesis of trifluoromethylselenolated compounds by using the copper reagent [(bpy)Cu(SeCF₃)]₂ (1),⁵⁴ we recently described the nucleophilic trifluoromethylselenolation of aryl and alkyl halides,⁵⁴ α- or β-halo-α,β-unsaturated carbonyl compounds,^55,56 propargylic chlorides, and allylic bromides.⁵⁷ These organic halides were reacted smoothly with 1 to furnish the corresponding trifluoromethylselenolated products in good yield (Scheme 1). We further developed a method for the trifluoromethylselenolation of aryl, heteroaryl and alkyl halides by the Cu(I) catalyst.⁵⁸ Since no method is available in the literature for the synthesis of trifluoromethylselenolated acetylenes, we developed a novel method to access them. Herein, we report the first example of copper-mediated oxidative trifluoromethylselenolation of terminal alkynes.

Scheme 1 Examples of copper-mediated/-catalyzed trifluoromethylselenolation.

Our efforts to develop Cu-mediated methods for oxidative trifluoromethylselenolation of terminal alkynes were initiated with 4-ethynyltoluene (2b) as the substrate. Treatment of 2b with [(bpy)Cu(SeCF₃)]₂ (1) in CH₃CN at 25 °C for 16 h gave (p-tolylethynyl)(trifluoromethyl)selane (3b) in 5% yield (Table 1, entry 1). These results encouraged us to optimize the other reaction parameters. After considerable efforts, we found that the yield of 3b (69%) could be enhanced in the presence of 2.0 equiv. of DMP as the oxidant and 3.0 equiv. of KF as the base (Table 1, entry 2). Of the solvents investigated, DMF was determined to be the optimal solvent for the trifluoromethylselenolation and the yield of 3b could be improved to 87% (Table 1, entry 8). Other solvents such as CH₃CN, toluene, THF, dioxane, CH₂Cl₂, and DMSO gave inferior results (Table 1, entries 2–7). Among a set of oxidants, DMP gave the highest yield for this oxidative trifluoromethylselenolation (Table 1, entry 8). Other oxidants such as PhI(OAc)₂, PIFA, DDQ, K₂S₂O₈, air, DTBP and CuSO₄ showed less or no efficiency (Table 1, entries 9–15). Further screening revealed that the amount of DMP affected the reaction, thus 1.0 equiv. of DMP offered the desired product 3b in a lower yield (80%; Table 1, entry 16). We also explored various bases in this reaction, and observed that KF was the most efficient base (Table 1, entries 17–20).

Table 1 Optimization of the Cu-mediated oxidative trifluoromethylselenolation of 4-ethynyltoluene (2b)^a

Entry	Base	Oxidant (equiv.)	Solvent	Yield^b [%]
a Reaction conditions: 1 (0.060 mmol), 2b (0.10 mmol), base (0.30 mmol), solvent (1.0 mL), under N2 atmosphere, DMP = Dess–Martin periodinane, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. PIFA = [bis(trifluoroacetoxy)iodo]benzene, DTBP = di-tert-butyl peroxide, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide; the equiv. of oxidant is based on 2b. b Yields were determined by ^19F NMR spectroscopy with PhOCF3 as internal standard.
1	—	—	CH3CN	5
2	KF	DMP (2.0)	CH3CN	69
3	KF	DMP (2.0)	Toluene	28
4	KF	DMP (2.0)	THF	52
5	KF	DMP (2.0)	Dioxane	28
6	KF	DMP (2.0)	CH2Cl2	43
7	KF	DMP (2.0)	DMSO	16
8	KF	DMP (2.0)	DMF	87
9	KF	PhI(OAc)2 (2.0)	DMF	40
10	KF	PIFA (2.0)	DMF	62
11	KF	DDQ (2.0)	DMF	65
12	KF	K2S2O8 (2.0)	DMF	51
13	KF	Air	DMF	27
14	KF	DTBP (2.0)	DMF	5
15	KF	CuSO4 (2.0)	DMF	5
16	KF	DMP (1.0)	DMF	80
17	NaF	DMP (2.0)	DMF	80
18	K2CO3	DMP (2.0)	DMF	26
19	NaOH	DMP (2.0)	DMF	28
20	KOH	DMP (2.0)	DMF	17

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To explore the scope of the oxidative trifluoromethylselenolation, various substituted terminal alkynes were examined under the optimized reaction conditions (Table 2). Variation of the 3-alkyl- or 4-alkyl-substituted phenylacetylenes underwent the reaction with 1 to afford trifluoromethylselenolated acetylenes 3a–g in good yields (74–87%). (4-Phenylphenyl)ethyne also efficiently participated in the trifluoromethylselenolation to furnish the desired product 3h in 74% yield. Notably, the electronic effects of the substituents on the aromatic units had no significant influence on the outcome of the reaction. Indeed, both 4-alkoxy-substituted phenylacetylenes and 4-trifluoromethyl-substituted phenylacetylene produced the desired products 3i–l in good yields (68–81%). Interestingly, the reaction was also tolerated in the presence of a halogen atom on the aromatic rings such as fluorine, chlorine and bromine, affording the corresponding products 3m–q in good yields (71–82%). In addition, even more challenging and highly valuable heteroaromatic-substituted alkynes such as pyridines and thiophenes were readily transformed into the corresponding trifluoromethylselenolated products 3r–u in synthetically useful yields (67–73%). Additionally, the scope of the reaction was not limited to aromatic substrates and was successfully expanded to aliphatic alkyne (3v), thus showcasing the effectiveness of the reaction.

Table 2 Trifluoromethylselenolation of terminal alkynes by [(bpy)Cu(SeCF₃)]₂1^a

a 1 (0.18 mmol), 2 (0.30 mmol), DMP (0.60 mmol), KF (0.90 mmol), DMF (2.5 mL), 25 °C, 16 h, N₂. All reported yields are isolated yields.

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To demonstrate the practical utility, the reaction of 1 and 2b was conducted on a 9.0 mmol scale. As shown in Scheme 2, 2b underwent the oxidative trifluoromethylselenolation without any loss in effectiveness and the corresponding product 3b was obtained in 84% yield (1.99 g).

Scheme 2 Scalability of the trifluoromethylselenolation of 2b.

In an effort to understand the mechanistic details of the transformation, a series of experiments were undertaken. First, the trifluoromethylselenolation of 2b was conducted in the presence of 1.0 equiv. of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical scavenger, and the desired product 3b was obtained in 65% yield (Scheme 3). This observation suggests against the fact that the reaction proceeds via a radical pathway.

Scheme 3 Radical scavenger experiments.

To examine whether any reactive species is involved in the oxidative trifluoromethylselenolation, the progress of the reaction was monitored by ¹⁹F NMR (see ESI†). The results revealed that a copper intermediate (I) is formed immediately in 75% yield during the reaction of 1 with DMP in the presence of KF. The amount of copper in I was determined by ICP, which gave Cu 8.18 wt%. In addition, the oxidative state of copper in I was verified by using X-ray photoelectron spectroscopy (XPS). The binding energy for Cu 2p_3/2 is 934.2 eV, which is characteristic of a Cu(II) state⁵⁹ (see ESI†). The ¹⁹F NMR spectrum of intermediate I showed a peak at −37.1 ppm. When 2b was added to this mixture, the resonances for intermediate I decreased and, instead, a new peak at −36.8 ppm was increased corresponding to the product (p-tolylethynyl)(trifluoromethyl)selane (3b).

Based on aforementioned experimental evidence, a plausible preparation mechanism for the alkynyl trifluoromethyl selenides (3) is proposed: the copper reagent 1 undergoes oxidation by DMP in the presence of KF to form an intermediate I. The subsequent electrophilic trifluoromethylselenolation of terminal alkynes 2 with I under copper-mediated conditions would produce the corresponding products 3 (Scheme 4).

Scheme 4 Proposed mechanism of oxidative trifluoromethylselenolation of terminal alkynes.

Conclusions

In conclusion, we have discovered a new copper-mediated oxidative trifluoromethylselenolation of terminal alkynes. This reaction readily converts a variety of terminal alkynes to the corresponding alkynyl trifluoromethyl selenides in good yields. Importantly, several synthetically valuable functional groups, such as alkoxy, halides, trifluoromethyl, and heterocyclic groups, were tolerated under the developed reaction conditions. Further applications of this method to the synthesis of other related compounds are in progress.

Acknowledgements

Financial support from the National Natural Science Foundation of China (NSFC) (grant number 21372044), the Research Fund for the Doctoral Program of Higher Education of China (grant number 20123514110003), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, P. R. China (grant number 2012-1707), the Science Foundation of the Fujian Province, China (grant number 2013J01040), and Fuzhou University (grant numbers 022318, 022494) is gratefully acknowledged.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical data for all new compounds. See DOI: 10.1039/c5qo00045a

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