Abstract
The synthesis of gem-difluoroethylene compounds remains a difficult task in organic synthesis. Here, the direct difluoroethylation reactions of N- and O-nucleophiles including amides and acids were realized with a hypervalent iodine reagent: gem-difluorovinyl iodonium salt (DFVI). The reactions were accomplished via a neighbouring group rearrangement. The gem-difluorovinyl iodonium salt was found to display diverse reactivity due to its unique electronic effect and was applied to the incorporation of difluoroethylene group, including difluorovinylation of carboxylic acids, difluorovinylation and 1,3-cyclic fluorovinylation of amides and 1,1-cyclic difluoroethylation of amines.
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Introduction
The incorporation of fluorine has been known to change the organic molecules’ physical, chemical and biological properties significantly. Therefore, organofluorine compounds have attracted widespread attention in various fields such as agricultural chemistry1, medicinal chemistry2,3,4, and material sciences5,6,7. As an important component of fluorine-containing groups, gem-difluoroethylene moiety (CH2CF2) is considered as stable bioisostere for metabolically susceptible keto group in drug research8,9,10. The replacement of a carbonyl group with a gem-difluoroethylene moiety improves the in vivo absorption rate and reduce the in vivo metabolism (Fig. 1)8,11. As a valuable building block in organic synthesis, it has been applied to a multitude of organic transformations, including defluorosilylation12, defluoroborylation13,14, defluoro cross-coupling with alkyl halides15, [3 + 2] annulation16,17,18, hydrothiolation to access α,α-difluoroalkylthioethers and so on.
gem-Difluoroethylene moieties present in natural products and potential therapeutic compounds.
More recently, many efficient methods for the introduction of gem-difluoro olefin group into small molecules have been developed, but these methods are often limited to some specific substrates. For example, classic synthetic methods for the incorporation of gem-difluorovinyl moiety include gem-difluoroolefination of carbonyl compounds19,20,21,22 such as the Wittig reaction, the Julia–Kocienski reaction, and the Horner–Wadsworth–Emmons reaction. α-trifluoromethyl substituted alkene or carbene surrogates are also found to be efficient precursors via the C-X (X = C, B, O) bond formation subsequently C-F elimination23,24,25,26,27,28,29. Apart from this, the strategy that cross-coupling reaction of difluorocarbene with other carbene precursors has been successfully demonstrated30,31,32. Undoubtedly, the most convenient and direct way to introduce gem-difluoro olefin is to employ gem-difluorovinyl reagent. But until now, gem-difluorovinyl reagents are too rare to meet the needs of organic synthesis from the synthetic chemist. To the best of our knowledge, the electrophilic gem-difluorovinyl reagents reported hitherto are mainly limited to gem-difluorovinyl iodide and gem-difluorovinyl sulfonate. The gem-difluorovinyl iodide is gaseous leading to operation with difficulty and usually needs to be prepared as an organometallic reagent in advance to improve reactivity33,34,35. The gem-difluorovinyl sulfonate suffers from harsh reaction conditions or limited substrate scope36,37,38,39.
As a continuation of our interest in both hypervalent iodine reagents and fluorine-containing chemistry40,41,42,43,44,45,46,47,48, herein we like to report a new type of gem-difluorovinyl hypervalent iodine reagent (DFVI). Different from usual alkenyl groups, gem-difluorovinyl iodonium salt has strong electrophilicity due to the strong induction of fluorine atom and trivalent iodonium ion, thus it can react with O- and N-nucleophiles such as carboxylic acid and amide to afford gem-difluorovinyl ester and amide which are otherwise hardly accessible (Fig. 2). Furthermore, the increase of the amounts of silver carbonate in the reaction, the resulting difluorovinyl amide could perform intramolecular ring closure to generate fluorine-substituted oxazole with amide acting as 1,3-N,O-binucleophiles and gem-difluorovinyl iodonium salt acting as 1,2-bielectrophiles. By analogy, replacing the amides by amines (1,1-N,N-binucleophiles), gem-difluoro aziridine rings could be constructed. The above results have enriched the reaction mode of alkenyl iodonium salts49,50 and provided a novel method for introducing gem-difluorovinyl group.
a gem-Difluorovinyl iodonium salt acted as electrophiles. b gem-Difluorovinyl iodonium salt acted as bielectrophiles.
Results and discussion
Synthesis of gem-difluorovinyl iodonium salt
In an attempt to prepare the electrophilic gem-difluorovinyl iodonium salt 1, we initially tried the reaction of cyano(aryl)-λ3-iodanyl trifluoromethanesulfonate with tributyl(2,2-difluorovinyl)stannane51 in DCM from −40 °C to room temperature. we were pleased to find that versatile gem-difluorovinyl iodonium salt 1a–1c were successfully synthesized with corresponding Stang’s reagents (Fig. 3). It was worth mentioning that in the preparation of gem-difluorovinyl iodonium salt 1a, the proposal that cyano(phenyl)-λ3-iodanyl trifluoromethanesulfonate intermediate was purified by employing a catheter tied with filter paper to drain the solvent below 0 °C was adopted due to the instability of the corresponding Stang’s reagent52. The desired gem-difluorovinyl iodonium salt 1a–1c were obtained in 58–68% yield, as determined by 1H, 13C, 19F NMR spectroscopy. The gem-difluorovinyl iodonium salt structure was unambiguously confirmed by single crystal X-ray diffraction analysis of 1a (Supplementary Table S1). The preparation method could be scaled up to 20 mmol scale without decreasing the yield. In addition, iodonium salt 1a could be stored at 0 °C in the refrigerator for at least 1 year without degradation (characterized by 1H NMR spectroscopy). The calculation revealed the neat charge of −0.28 on Cα and 0.23 on Cβ in 1a. The substitution of CF3 group on the aryl ring of DFVI would significantly change the neat charge of double bond and reached to −0.68 on Cα and 0.37 on Cβ in 1c (Fig. 3). This unique charge distribution could affect the reactivity of DFVI (vide infra).
X-ray structure of 1a (CCDC No.: 2141360). The counter anion is omitted for clarity.
gem-Difluorovinylation of carboxylic acid
With this new DFVI reagent in hand, we then explored its application in the incoporation of CHCF2 moiety with a variety of nucleophiles. Oxygen nucleophiles such as carboxylic acid compounds, were found to react smoothly with 1a to give the corresponding gem-difluorovinyl esters when Ag2CO3 was used as the base (Fig. 4). Generally, aryl-, alkenyl- and benzyl-substituted carboxylic acid reacted gently to give gem-difluorovinyl carboxylate 2 in moderate to good yields. The electron-withdrawing groups substituted on the phenyl ring, such as phenyl, bromine, carbonyl, iodine groups, even strong electron-withdrawing nitro group had no significant effects on the yields. Besides, electron-donating groups substituted on the phenyl ring gave the desired product in good yield (2g). 3,5-dichlorobenzoic acid, 1-naphthoic acid were also excellent substrates, leading to gem-difluorovinyl carboxylate (2i, 2j). To illustrate potential utility, the methodology was applied to the gem-difluorovinylation of selected drug. For instance, flurbiprofen, an anti-inflammatory drug used to treat rheumatoid arthritis, osteoarthritis, could also be converted to the corresponding gem-difluorovinyl carboxylate product 2k in 69% yield. Although para-bienol esters 2l were obtained in relatively low yield, they were valuable starting materials in polymer chemistry. Considering the alkyl and aryl carboxylic acid pKa was ~4.2, and the carbonate pKa1 was 6.2, we envisioned whether the reaction underwent silver carboxylate intermediate. To verify this, we combined silver benzoate with gem-difluorovinyl iodonium salt 1a at 1:1 molar ratio, 2,2-difluorovinyl benzoate was achieved in 63% yield [Eq. (3)].
Reaction conditions: carboxylic acid (0.2 mmol), 1a (0.8 mmol), Ag2CO3 (0.8 mmol) in CH3CN (2.0 ml) at room temperature for 12 h. Yields shown are of isolated products.
gem-Difluorovinylation of amide
Enamides are versatile building blocks for the synthesis of nitrogen-containing molecules. As stable and electron-rich olefins, they participate in diverse transformations such as asymmetric hydrogenation53, cycloaddition54,55, and C–H activation56,57. Inspired by the successful results with carboxylic acid, we next studied reactions with amides, as so far there was a still no-good method to synthesize gem-difluoro enamides. Under the reaction conditions similar to carboxylic acid, however there was no gem-difluorovinyl amide generated. Fluorine-substituted oxazole was the major product which would be described in the following text. Gratifyingly, when we used the catalytic amount of Ag2CO3, main product of gem-difluorovinyl amide was observed accompanied by starting materials. Nevertheless, the conversion rate of 1a was very low, ~50%. When we attempted to use bases (e.g. Na2CO3 and DTBPy) to capture the trifluoromethanesulfonic acid produced in the system to improve the conversion rate, yet the yield of desired product did not increase, and side product trifluoroethyl amide was produced much. In view of the weak alkalinity of amide, we tried to make amide itself as base and increased its amount to twice that of the gem-difluoro iodonium salt. To our delight, we found that gem-difluorovinyl iodonium salt was converted completely thus the yield of title compound was increased to 68%. Further screening of the amount of amide led to the yield of the desired product reaching to 82%. Under the optimized reaction conditions, the substrate scope was studied.
As shown in Fig. 5, both electron-rich and electron-deficient amides reacted to give the corresponding products in high yields. Various functional groups, including methyl, fluorine, tert-butyl, chlorine, trifluoromethoxy groups, were all tolerated under the standard conditions. Notably, polycyclic aryl and benzyl amide were also compatible with reaction conditions (3a–3b, 3j). Reactions of heteroaryl amide occurred smoothly to give the gem-difluorovinyl products in moderate yields (3k). NMR spectra obtained from the mixture of amide with gem-difluorovinyl iodonium salt in CD2Cl2 showed a significant upfield shift (0.19 ppm) of the F resonance in iodonium salt 1a and simultaneously a downfield shift (0.34 ppm) of the active N proton signal in amide (see SI). Both observations provided evidence for weak interaction between iodonium salt and nucleophile reagent amide. The gem-difluorovinyl structure was unambiguously confirmed by single crystal X-ray diffraction analysis of 3a (Supplementary Table S2).
Reaction conditions: amide (0.8 mmol), 1a (0.2 mmol), Ag2CO3 (0.02 mmol) in CH2Cl2 (2.0 ml) at room temperature for 12 h. Yields shown are of isolated products. CCDC No.: 2141364.
Fluorovinylation of amide
As mentioned above, due to the leaving ability of fluorine atom in gem-difluorovinyl group, 1,1 gem-difluorovinyl amides could be further transformed into oxazoles through intramolecular ring closure. After a quick screening of the reaction conditions, it turned out that reactions conducted with Ag2CO3 (200% mol) in DCM resulted in full conversion of amides into fluoro oxazoles (Fig. 6). After establishing the optimum reaction conditions, we set out to evaluate the substrate scope. To our delight, both electron-donating and -withdrawing groups were well tolerated and the corresponding products 4a–4u were furnished in good to high yields. Excellent compatibility of various functionalities including alkyl, methoxy, ester, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, iodine, nitro was observed (4d–4s). In addition, this protocol was also applicable for bisubstituted and polycyclic aryl amides as starting materials affording the products (4a–4b, 4t–4u) with good efficiency. The fluorine-substituted oxazole structure was unambiguously confirmed by single crystal X-ray diffraction analysis of 4j (Supplementary Table S3). To gain insight into the reaction mechanism, gem-difluorovinyl amide 3j was treated with Ag2CO3 in DCM at 100 °C for 12 h, which led to 4v in 44% yield as detected by 19F NMR analysis of the crude reaction mixture [Eq. (4)]. The observation supported our hypothesis that fluorovinylation of amide via the intermediate gem-difluorovinyl amide, so the silver carbonate acted both as a catalyst in the difluorovinylation process and as a base leading to further ring closure.
Reaction conditions: amide (0.2 mmol), 1a (0.24 mmol), Ag2CO3 (0.4 mmol) in CH2Cl2 (2.0 ml) at room temperature for 12 h. Yields shown are of isolated products. CCDC No.: 2141361.
Difluoroethylation of amines
Finally, the reaction of DFVI with amines was examined. Initially, para-bromoaniline was chosen as the template substrate with 1a for our optimization studies. However, the target product aziridine 5a was obtained in only 4% yield, along with 9% of the side product trifluoroethyl amine 5a’ employing Et3N base (Fig. 7). It probably arose from the gem-difluorovinylation of amine (α position of alkene reacted with nitrogen atom) subsequently HF generated in the system addition to the double bond. In order to solve the problem of regioselectivity, we tried reagent 1c with CF3 groups on the phenyl ring to make amine attack β-C in priority and indeed the yield of gem-difluoro aziridine was improved to 69%. In addition to this, naphthyl amine was also proved reactive partners, affording the product in moderate yield (5b). Both benzyl and biphenyl amine were transformed to generate 5c and 5d (43% and 43%) in decreased yield might owing to the instability of difluoro aziridines58. However, gem-difluorovinyl ethers and thioethers could not be obtained when combining gem-difluorovinyl iodonium salt with corresponding substrates, and undetermined polymer was detected.
Reaction conditions: amine (0.2 mmol), 1 (0.24 mmol), Na2CO3 (0.4 mmol) in CH2Cl2 (2.0 ml) at room temperature for 12 h. Yields shown are of isolated products.
Proposed mechanism
To gain more insight into the reaction mechanism, density functional theory calculations were conducted. Figure 8 shows the free energy profile of the route leading to the construction of the enamide in a simple model reaction of amide and 1a. Our computations reveal that the reaction is initiated by a weak interaction between the iodonium cation and the silver salt to form IM1. This interaction increases the electrophilicity of the C=CF2 bond, and a subsequent Michael Addition of amide to IM1 renders the formation of IM2, proceeding with a low activation barrier of 6.3 kcal/mol. Then, the reaction becomes a little bit endergonic in the deprotonation process using triflate anion. The resulting species IM3 undergoes five-membered cyclic transition state (TS2) when it is transformed into the appropriate conformation IM3’. Final product 3a is obtained upon ring cleavage of IM4 via TS3. This is the rate-determining step with a moderate free energy barrier of 15.0 kcal/mol.
The energies are given in kcal/mol.
Based on the above results and previous researcher’s work59, a plausible reaction mechanism for the ring-closure of amine is proposed in Fig. 9. In which amine attacks the β-C of the alkenyl group to generate the iodonium yield I under the basic reaction conditions, subsequently elimination of iodobenzene from II upon proton migration from nitrogen to carbon to afford the aziridine salt. Following deprotonation with Na2CO3, the resultant difluoro aziridine 5 is formed.
The reaction proceeds via iodonium yield intermediate.
Conclusions
In summary, a bench-stable crystalline of gem-difluorovinyl iodonium salt (DFVI) was developed via the ligand exchange of Stang’s reagent with tributyl(2,2-difluorovinyl)stannane and served as a diverse gem-difluorovinyl reagent. The direct difluoroethylation reactions of N- and O-nucleophiles including amides and acids were realized for the first time with DFVI. Moreover, a number of applications of DFVI were explored, especially in the construction of various fluorinated heterocycles. Considering the unique properties and advantages of this gem-difluorovinyl iodonium salt (DFVI), the reagent might have wider applications in fluorination chemistry and remarkable transformations to investigate.
Methods
General procedure for gem-difluorovinylation of carboxylic acid with reagent 1a
Carboxylic acid (0.2 mmol 1.0 equiv.), Ag2CO3 (4.0 equivalent/1.0 equivalent carboxyl group) and reagent 1a (4.0 equivalent/1.0 equivalent carboxyl group) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 ml of freshly distilled CH3CN was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.
General procedure for gem-difluorovinylation of amide with reagent 1a
Amide (0.8 mmol 4.0 equiv.), Ag2CO3 (10% mol) and reagent 1a (0.2 mmol 1.0 equiv.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 ml of freshly distilled CH2Cl2 was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.
General procedure for fluorovinylation of amide with reagent 1a
Amide (0.2 mmol 1.0 equiv.), Ag2CO3 (0.4 mmol 2.0 equiv.) and reagent 1a (0.24 mmol 1.2 equiv.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 ml of freshly distilled CH2Cl2 was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.
General procedure for difluoroethylation of amine with reagent 1c
Amine (0.2 mmol 1.0 equiv.), Na2CO3 (0.4 mmol 2.0 equiv.) and reagent 1c (0.24 mmol 1.2 equiv.) were placed into an oven-dried Schlenk tube that is equipped with a stirring bar under N2. The tube was quickly sealed with a rubber stopper and 2 ml of freshly distilled CH2Cl2 was added. The reaction was stirred at room temperature for 12 h. Then the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel.
Data availability
The data supporting the findings of this study are available within the article and its Supplementary Information. Supplementary Methods includes the details of manipulation, isolation and characterization of all new compounds obtained this study. Supplementary Data 4 includes XYZ coordinates for all optimized structures. Supplementary Data 5 includes 1H, 13C, 19F NMR spectra. In addition, the X-ray crystallographic data are included in Supplementary Data 1–3. The X-ray crystallographic coordinates for the structure reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under CCDC deposition numbers 2141360 (1a), 2141364 (3a) and 2141361 (4j). These data can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/data_request/cif. Experimental procedures and characterization of the new compounds are available in the Supplementary Information
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (2016YFB0401400), the National Natural Science Foundation of China (22071129, 21871158).
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C.C. and C.G. conceived the project and co-wrote the manuscript. C.G. and B.W. performed the experiments and analyzed the data. Y.J. designed and performed the DFT calculations.
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Ge, C., Wang, B., Jiang, Y. et al. Diverse reactivity of the gem-difluorovinyl iodonium salt for direct incorporation of the difluoroethylene group into N- and O-nucleophiles. Commun Chem 5, 167 (2022). https://doi.org/10.1038/s42004-022-00772-7
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DOI: https://doi.org/10.1038/s42004-022-00772-7
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