Abstract
As a versatile intermediate, difluorocarbene is an electron-deficient transient species, meaning that its oxidation would be challenging. Herein we show that the oxidation of difluorocarbene could occur smoothly to generate carbonyl fluoride. The oxidation process is confirmed by successful trifluoromethoxylation, 18O-trifluoromethoxylation, the observation of AgOCF3 species, and DFT calculations.
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Introduction
Due to the unique properties of fluorine element such as strong electronegativity and small atomic radius, the incorporation of fluorine atom(s) into organic molecules could usually lead to profound changes of the latter’s physical, chemical, and biological properties1. Therefore, significant efforts have been directed towards the development of efficient methods for introducing fluorine or fluorinated moieties into organic compounds2,3. Difluorocarbene (:CF2) has served as a versatile intermediate and the transformations of difluorocarbene has proved to be quite efficient for fluorine incorporation4,5. Typical difluorocarbene conversions, including insertions into X-H bonds (X=O, N, S, etc.)4,6,7, [2 + 1] cycloadditions with multi-bonds8,9, and coupling with other carbenes10,11,12, can conveniently construct various fluorinated functionalities, such as difluoromethyl, gem-difluorocyclopropyl and gem-difluoroalkenyl groups. However, these typical reactions are limited to the incorporation of a -CF2- moiety. We have previously found that difluorocarbene is so reactive that it can be readily trapped by a suitable sulfur13,14,15, selenium16, or nitrogen source17 to generate thiocarbonyl fluoride (CF2=S), selenocarbonyl fluoride (CF2=Se), and cyanide anion (CN−), respectively (Fig. 1a–c). On the basis of these findings, which offers more possibilities for difluorocarbene chemistry, it is reasonable to conceive that the oxidation of difluorocarbene with a suitable oxygen source may proceed to afford carbonyl fluoride (CF2=O) (Fig. 1d). Usually, oxidation reactions could proceed smoothly to oxidize electron-rich substrates, but not to electron-deficient substrates18,19. Since difluorocarbene is an electron-deficient transient intermediate20, its oxidation would be a challenging task. Furthermore, because CF2=O is a highly reactive gas and thus hard to detect, it cannot be determined simply by spectroscopic monitoring of the reaction whether the oxidation process occurs or not.
The transformations of difluorocarbene. a The transformation of difluorocarbene into thiocarbonyl fluoride. b The transformation of difluorocarbene into selenocarbonyl fluoride. c The transformation of difluorocarbene into cyanide anion. d The transformation of difluorocarbene into carbonyl fluoride.
Herein we describe the oxidation of difluorocarbene by using diphenyl sulfoxide (Ph2S=O) as the oxidant to provide carbonyl fluoride, a process which is confirmed by successful trifluoromethoxylation and 18O-trifluoromethoxylation reactions, the observation of AgOCF3 species, and DFT calculations. A late-stage trifluoromethoxylation for the synthesis of a Trioxsalen derivative is shown to further demonstrate the synthetic utility of this trifluoromethoxylation protocol.
Results
Optimization of the trifluoromethoxylation conditions
Ph3P+CF2CO2−, developed by us recently21, and AgF were used as a difluorocarbene reagent and the fluoride source, respectively, in our efforts to ascertain the oxidation process via the trifluoromethoxylation of benzyl bromide 1-1 (Table 1). AgF was used to convert CF2=O into AgOCF3, which may be experimentally observed22 to support the oxidation process. The oxidants were initially screened, but no desired trifluoromethoxylation product was detected in most cases (Table 1, entries 1–5). To our delight, the use of DMSO (dimethyl sulfoxide) as the oxidant afforded the expected product in 9% yield (Table 1, entry 6), suggesting that sulfoxides may be a suitable class of oxidants. We then examined other sulfoxides (Table 1, entries 7–8) and diphenyl sulfoxide was found to be a superior choice (Table 1, entry 8). Other fluoride sources, including inorganic (Table 1, entries 9–11) and organic (Table 1, entry 12, TBAF=tetra-n-butylammonium fluoride) fluoride salts, were examined, but they were all ineffective. This indicates that the Ag ion may play an important role in the reaction. A brief survey of reaction solvents (Table 1, entries 13–17) showed that THF (tetrahydrofuran) or DCM (dichloromethane) was the suitable solvent for this conversion (Table 1, entries 15 and 16). The use of 2,2′-bipyridine or a crown ether as a ligand (Table 1, entries 18 and 19) significantly increased the product yield. A 67% yield was obtained if both bipyridine and the crown ether were present (Table 1, entry 20). The concentration affected the reaction slightly, and the yield increased with increasing concentration (Table 1, entry 21 vs entry 20). At this concentration, the yield decreased if either the crown ether or 2,2′-bipyridine was not used (Table 1, entries 22−23).
Mechanistic investigations
Further experimental evidence was collected to support the difluorocarbene oxidation process. The use of other difluorocarbene reagents such as FSO2CF2CO2TMS23 and TMSCF2Br8 could also give the desired trifluoromethoxylation product, albeit in a low yield, suggesting that difluorocarbene is a key intermediate (Fig. 2a). CF2=O could not be detected in the reaction mixtures, because it is a highly electrophilic species and would be rapidly attacked by AgF to provide AgOCF3. Even stirring the mixture of Ph3P+CF2CO2− and Ph2S=O alone could not lead to the observation of CF2=O, because CF2=O would easily react with the nucleophile, Ph3P generated from Ph3P+CF2CO2−9. Ph2S=O should be the oxygen source to oxidize difluorocarbene to generate CF2=O, since 18O-labeled diphenyl sulfoxide afforded the CF318O product (Fig. 2b), and diphenyl sulfoxide underwent deoxygenation to afford diphenyl sulfide (Ph2S) in a high yield based on Ph2S=O consumed (39% of Ph2S=O was recovered) (Fig. 2c) (Supplementary Methods). A stepwise reaction was performed to confirm the generation of the AgOCF3 complex (Fig. 2d). Without the presence of a substrate, heating a mixture of Ph3P+CF2CO2−/Ph2S=O/AgF with ligands at 60 °C for 0.5 h led to the formation of a number of unkonwn species, as detected by 19F NMR spectroscopy (Supplementary Fig. 2). Two broad signals, appearing at −21.66 and −21.94 ppm in the 19F NMR spectrum, respectively, may correspond to two different ligand-coordinated AgOCF3 complexes22. Subsequent addition of substrate 1–1 afforded the desired trifluoromethoxylation product, further supporting that AgOCF3 was generated from the Ph3P+CF2CO2−/Ph2S=O/AgF system (Fig. 2d). In addition to the trifluoromethoxylation product, a fluorination byproduct was observed (Fig. 2d). However, almost no fluorination byproduct was observed under the optimal conditions (Table 1, entry 21), which suggests that AgOCF3 was too reactive and decomposed easily.
Mechanistic investigation. a The use of other difluorocarbene reagents for trifluoromethoxylation. b The identification of the oxygen source by 18O-labeling. c The identification of the oxygen source by isolating Ph2S. d The confirmation of the AgOCF3 complex. aThe optimal conditions are shown as Table 1, entry 21: substrate 1 (0.2 mmol), Ph3P+CF2CO2− (2.5 equiv), Ph2S=O (2.5 equiv), AgF (2 equiv), 2,2′-bipyridine (1.5 equiv), and 2,3,11,12-dibenzo-18-crown-6 (0.5 equiv) in THF (1.5 mL) at 60 °C for 0.5 h; bYields were determined by 19F NMR spectroscopy. cThe 18O content was determined by EI-MS. dIsolated yield calculated based on substrate 1–1. eIsolated yield based on Ph2S=O consumed.
DFT calculations at the M062X//6–31 + + G(d,p)/LANL2DZ level provided insights into the mechanism of the oxidation of difluorocarbene and the subsequent trifluoromethoxylation. We have previously demonstrated that Ph3P+CF2CO2− is an efficient difluorocarbene precursor, and has proposed that difluorocarbene is generated via a decarboxylation process, i.e., Ph3P+CF2CO2− → Ph3P+CF2− → :CF214,15,24. Calculations revealed that the activation energy for this process is quite low (10.12 kcal mol−1) (Supplementary Fig. 3 and Supplementary Data 1), supporting the mechanistic proposal. As an electron-deficient species, difluorocarbene can be attacked by Ph2S=O to form an O–CF2 bond (Fig. 3, INT-1). The formation of this bond weakens the S–O bond in Ph2S=O, as shown by the increasing S–O bond length from TS-1 to INT-1. Back donation of the carbon lone pair strengthens the O–CF2 bond and further weakens the S–O bond (Fig. 3, TS-2). Complete cleavage of the S–O bond releases Ph2S and carbonyl fluoride (CF2=O), a process which is thermodynamically favored. CF2=O is electrophilic and is therefore trapped by AgF to generate AgOCF3, which can readily convert the substrates to the final products. The Ag ion can activate the substrates by precipitating the AgBr salt. Identification of transition state TS-2 enabled us to calculate the overall activation energy, i.e., 17.60 kcal mol−1; this value is low and in agreement with the rapid process.
Relative free energies for difluorocarbene-oxidation-based trifluoromethoxylation. All calculations were performed in Gaussian 09 D01 package.
The introduction of CF3O installation
The above results revealed that difluorocarbene could indeed be oxidized to give carbonyl fluoride. The oxidation of difluorocarbene and the subsequent trifluoromethoxylation provides an efficient protocol for CF3O incorporation. CF3O incorporation has received increasing attention because the CF3O group is a common structural motif in pharmaceuticals25,26, agrochemicals27,28, and functional materials29,30. A number of effective trifluoromethoxylation methods have been developed, including nucleophilic31,32,33,34,35,36,37, radical38,39,40, and transition-metal-promoted41,42,43,44 reactions. As the use of a CF3O-containing reagent is required, these approaches cannot be directly applied to 18O-labeling trifluoromethoxylation. Furthermore, the CF3O-containing reagents used are usually volatile, expensive, or difficult to prepare. In contrast, in the above protocol, CF3O moiety was formed from a reagent system consisting of Ph3P+CF2CO2−, which could be easily prepared and easy-to-handle, an oxygen source and fluoride anion. Apparently, this reaction provides a strategy for 18O-labeling trifluoromethoxylation, which may be achieved by replacing the oxygen source with 18O-source. 18O-trifluoromethoxylation may show great value as 18O-labeling has found widespread application in various research areas such as proteomics45,46,47 and synthetic chemistry48,49,50.
The substrate scope of trifluoromethoxylation
Since difluorocarbene could be oxidized and the subsequent trifluoromethoxylation proceeded smoothly (Table 1, entry 21), we then investigated the substrate scope of trifluoromethoxylation. Figure 4 shows that electron-deficient, -neutral, and -rich benzyl bromides were all converted to the desired products in moderate to good yields (5–1 ~ 5–17). Various functional groups were tolerated, e.g., halide, ketone, ester, alkene, cyano, nitro, ether, and various heterocycles. Heterocycles usually have interesting physicochemical properties, and therefore the easy access to CF3O-containing heterocycles could be useful in the life sciences (5–15 ~ 5–17). Transformation of secondary benzyl bromides gave moderate yields (5–18 ~ 5–22). The diphenyl substituted product (5–22) was unstable, and a heterolytic cleavage of the C–OCF3 bond readily occurred to form a diphenyl-stabilized methyl cation, hydrolysis of which led to an alcohol by product (Ph2CH-OH) in 35% isolated yield. In addition to benzyl bromides, allyl bromides were also converted under these conditions (5–23 ~ 5–28). The reactivity of alkyl bromide (5–29) was much lower than that of benzyl bromides. Alkyl iodides (5–30 ~ 5–33) underwent the desired reaction smoothly to give the expected products in moderate yields. A method for achieving direct access to a flavone derivative was developed (5–34) and a moderate yield was obtained for a large-scale reaction (5–4), demonstrating the synthetic utility of this trifluoromethoxylation protocol.
Difluorocarbene-oxidation-based trifluoromethoxylation. Isolated yields are shown. Reaction conditions: substrate 1 (0.8 mmol), Ph3P+CF2CO2− (2.5 equiv), Ph2S = O (2.5 equiv), AgF (2 equiv), 2,2′-bipyridine (1.5 equiv), and 2,3,11,12-dibenzo-18-crown-6 (0.5 equiv) in THF (6 mL) at 60 °C for 0.5 h. aThe yields in parentheses were determined by 19F NMR spectroscopy. b0.2 mmol of substrate was used. c8 mmol of substrate was used.
Trioxsalen, a furanocoumarin and a psoralen derivative obtained from plants, can be used for phototherapy treatment of vitiligo and hand eczema51. A convenient route to the CF3O-containing Trioxsalen derivative (8) was developed to further show the synthetic utility of this trifluoromethoxylation strategy. The trifluoromethoxylation of the precursor (7), prepared from the commercially available m-benzenediol by a reported procedure (Supplementary Fig. 1)52,53, occurred smoothly to give the Trioxsalen derivative in a moderate yield (Fig. 5).
The synthesis of CF3O-containing Trioxsalen derivative. The derivative was synthesized by a late-stage trifluoromethoxylation reaction.
18O-Trifluoromethoxylation
18O-Labeling trifluoromethoxylation is challenging, because all reported trifluoromethoxylation methods have to use a CF3O-containing reagent and the corresponding CF318O-reagents are difficult to prepare. Recently, Tang used an 18O-labeled reagent, ArSO2–18OCF3, to explore and elucidate the mechanism of the trifluoromethoxylation reaction; only a 33% 18O content was obtained in the desired product37. They proposed that the low 18O-content was because of the 16O-18O exchange in the SO2–18OCF3 moiety from the reagent. We employed 18O-labeled diphenyl sulfoxide (Ph2S=18O, 18O content: 89%) as the oxygen source in this difluorocarbene-oxidation-based trifluoromethoxylation reaction. Since the reagent, Ph2S=18O, did not contain any 16O atom, no 16O-18O exchange would occur and therefore the expected products were obtained with high 18O contents (Fig. 6).
Difluorocarbene-oxidation-based 18O-trifluoromethoxylation. Isolated yields. Reaction conditions: substrate 1 (0.2 mmol), Ph3P+CF2CO2− (2.5 equiv), Ph2S=18O (2.5 equiv), AgF (2 equiv), 2,2′-bipyridine (1.5 equiv), and 2,3,11,12-dibenzo-18-crown-6 (0.5 equiv) in THF (1.5 mL) at 60 °C for 0.5 h. The 18O contents were determined by EI-MS.
Discussion
In summary, we have shown that difluorocarbene could be oxidized to afford carbonyl fluoride. This process was confirmed by the successful trifluoromethoxylation, 18O-trifluoromethoxylation, the observation of AgOCF3 species, and DFT calculations. It is worth noting that the 18O-products were obtained with high 18O-contents. A CF3O-containing Trioxsalen derivative was synthesized by this trifluoromethoxylation protocol. The oxidation of difluorocarbene may provide more possibilities for difluorocarbene chemistry.
Methods
Typical procedure for trifluoromethoxylation
Into a 20 mL sealed tube were added benzyl bromide 1–1 (0.8 mmol, 197.7 mg, 1.0 equiv), Ph3P+CF2CO2− (2.0 mmol, 712.0 mg, 2.5 equiv), Ph2S=O (2.0 mmol, 404.6 mg, 2.5 equiv), AgF (1.6 mmol, 203.2 mg, 2.0 equiv), 2,2′-bipyridine (1.2 mmol, 187.4 mg, 1.5 equiv), 2,3,11,12-dibenzo-18-crown-6 (0.4 mmol, 144.2 mg, 0.5 equiv), and THF (6 mL) under a N2 atmosphere. The tube was sealed and the reaction mixture was stirred at 60 °C for 30 min. After the mixture was cooled to room temperature, the pure product was isolated by flash column chromatography.
Typical procedure for 18O-trifluoromethoxylation
Into a 10-mL sealed tube were added benzyl bromide 1–1 (0.2 mmol, 49.4 mg, 1.0 equiv.), Ph3P+CF2CO2− (0.5 mmol, 178.0 mg, 2.5 equiv), Ph2S=18O (0.5 mmol, 102.1 mg, 2.5 equiv), AgF (0.4 mmol, 51.0 mg, 2.0 equiv), 2,2′-bipyridine (0.3 mmol, 47.0 mg, 1.5 equiv), 2,3,11,12-dibenzo-18-crown-6 (0.1 mmol, 36.0 mg, 0.5 equiv), and THF (1.5 mL) under a N2 atmosphere. The tube was sealed and the reaction mixture was stirred at 60 oC for 30 min, and the mixture was cooled to room temperature. The pure product was isolated by flash column chromatography, and the 18O contents were determined by GC-MS (EI) spectroscopy.
For the preparation of starting materials and the characterization data of the products, see Supplementary Methods. For the NMR spectra of the compounds, see Supplementary Figs. 5–184. For EI spectra of the 18O-products, see Supplementary Figs. 185–214. For DFT calculations, see Supplementary Figs. 3 and 4 and Supplementary Data 1 and 2.
Data availability
The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files or from the corresponding author on reasonable request.
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Acknowledgements
We thank the National Natural Science Foundation (21421002, 21672242, 21971252), Key Research Program of Frontier Sciences (CAS) (QYZDJSSW-SLH049), the Fujian Institute of Innovation, Chinese Academy of Sciences (FJCXY18040102) for financial support. Computing resources were provided by the National Supercomputing Center of China in Shenzhen.
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J.Y. performed the experiments. D.Y. performed the DFT calculations. R.D. analyzed the data. J.-H.L. analyzed the data and wrote the manuscript. J.-C.X. designed the experiments and wrote the manuscript.
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Yu, J., Lin, JH., Yu, D. et al. Oxidation of difluorocarbene and subsequent trifluoromethoxylation. Nat Commun 10, 5362 (2019). https://doi.org/10.1038/s41467-019-13359-z
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DOI: https://doi.org/10.1038/s41467-019-13359-z
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