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gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu4NBF4 or electrogenerated acid

  1. 1 ,
  2. 1 ,
  3. 1 ,
  4. 2 ,
  5. 1 and
  6. 1
1Department of Chemistry, School of Science and Engineering, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
2Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
  1. Corresponding author email
This article is part of the thematic issue "Synthetic electrochemistry".
Guest Editor: K. Lam
Beilstein J. Org. Chem. 2024, 20, 2261–2269. https://doi.org/10.3762/bjoc.20.194
Received 15 Apr 2024, Accepted 08 Jul 2024, Published 06 Sep 2024
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Abstract

gem-Difluorination of carbon–carbon triple bonds was conducted using Brønsted acids, such as Tf2NH and TfOH, combined with Bu4NBF4 as the fluorine source. The electrochemical oxidation of a Bu4NBF4/CH2Cl2 solution containing alkyne substrates could also give the corresponding gem-difluorinated compounds (in-cell method). The ex-cell electrolysis method was also applicable for gem-difluorination of alkynes.

Keywords: carbon–carbon triple bonds; chemical method; electrochemistry; gem-difluorination

Introduction

Organofluorine compounds have attracted great attention in various fields, such as organic materials and pharmaceuticals [1-3], because fluorinated compounds sometimes show specific properties [4]. So far, several methods have been developed for the synthesis of fluorinated compounds. Using nucleophilic fluorinating reagents, such as diethylaminosulfur trifluoride (DAST), HF, CsF, and AgF has been established as a reliable method. Electrophilic fluorinating reagents, such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-fluorobenzenesulfonimide, and fluorobenziodoxole, are also utilized as F+ equivalents to introduce fluorine atoms into organic molecules. In addition, various trifluoromethylation reagents have been developed so far [5-18]. Transition-metal-catalyzed fluorination and trifluoromethylation methods have also been proposed [19,20]. Thus, the synthesis of fluorinated compounds is an active research field. Among these compounds, skeletons bearing CF2 units are important [21-24], because such molecules can change the physical properties and biological activity. They can also serve as building blocks for further transformations.

We have focused on the investigation of gem-difluorination of carbon–carbon triple bonds, because this procedure is one of the most simple but powerful and straightforward methods. In addition, there have been a few reports in the literature that seem to mainly rely on the use of HF or its complexes as a reagent. These reactions seem to proceed via the formation of the vinyl fluoride as the intermediate [25-28].

In the first example, Olah and co-workers reported the reaction of terminal alkynes with HF/pyridine (Olah reagent) (Figure 1, reaction 1) [29-32], although the original work was developed by Linn and Plueddeman using HF [33-35]. As another example, Renoux and co-workers developed the utility of SbF5/HF (Figure 1, reaction 2) [36]. In 2014, the HF/N,N’-dimethylpropyleneurea (DMPU) complex in the presence of an Au catalyst was found to be a good reagent for the gem-difluorination of alkynes, reported by Hammond and Xu (Figure 1, reaction 3) [37]. HF/DMPU is easy to handle under experimental conditions. In addition, they recently reported the utilization of a combination of KHSO4·13HF and DMPU·12HF under neat conditions for the gem-difluorination of alkynes (Figure 1, reaction 4) [38]. In 2020, the utility of 2,6-dichloropyridinium tetrafluoroborate was nicely demonstrated for the gem-difluorination by Liu and Wang (Figure 1, reaction 5) [39].

Although some procedures have been reported, the use of hazardous reagents such as HF is still inevitable [40,41]. Quite recently, Crimmin and co-workers reported gem-difluorination by shuttling between fluoroalkanes and alkynes, in which catalytic HF played a key role [42]. In the course of our study on the fluorination reaction, we have envisioned that the combination of a Brønsted acid, such as Tf2NH and TfOH, with Bu4NBF4 might be effective to promote the gem-difluorination of alkynes because of the in situ generation of HF equivalents (Figure 1, reaction 6, chemical method). In addition, the electrogenerated acid (EGA) [43-52] from a solution of Bu4NBF4/CH2Cl2 containing substrates might also promote the same reactions (Figure 1, reaction 6, electrochemical method). Currently, electrochemistry can be regarded as a promising technique in organic synthesis, because heavy-metal reagents can be avoided for the oxidation or reduction of organic molecules. Herein, we wish to report that the combination of the excess amount of Brønsted acid and Bu4NBF4 or the use of an EGA in Bu4NBF4/CH2Cl2 can serve as suitable reagents for the gem-difluorination of alkynes. These procedures are practical, simple and environmentally friendly, because HF or its equivalent is indirectly prepared and utilized in only solution phase.

[1860-5397-20-194-1]

Figure 1: gem-Difluorination of carbon–carbon triple bonds. Selected examples from (1) to (5), and this work of (6).

Results and Discussion

First, we have chosen hex-5-yn-1-ylbenzene (1a) as the model substrate in the reaction optimization (Table 1, method A). The reaction was carried out as follows: Hex-5-yn-1-ylbenzene (1a, 0.5 mmol) was reacted with the Brønsted acid (X equiv) and the fluorine source (Y equiv) in the solvent (4 mL) at temperature of T (°C) for Z hours. The chemical yield of the desired product, (5,5-difluorohexyl)benzene (2a), was evaluated for reaction optimization by using the 19F nuclear magnetic resonance (NMR) yield, in which trifluorotoluene (CF3C6H5) was used as an internal standard. The use of Tf2NH (5 equiv or 10 equiv) and Bu4NBF4 (5 equiv) in CH2Cl2 at room temperature gave the corresponding product 2a in up to 83% yield (Table 1, entries 1–5). The use of CF3COOH did not yield 2a at all (Table 1, entry 6), but TfOH gave the product 2a in 72% yield (Table 1, entry 7). As for the solvent, CH3CN slightly afforded 2a, although N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) were not suitable for the reactions (Table 1, entries 8–10). A fluorine source, such as Bu4NF or BF3·Et2O, instead of Bu4NBF4 was not effective (Table 1, entries 11 and 12). Finally, investigations of the amount of Bu4NBF4 and the reaction temperature demonstrated that conditions including Bu4NBF4 (9 equiv) and room temperature gave the best result (Table 1, entries 13–17). Based on the above investigation, we decided to use the optimized conditions in entry 2, because reducing the amount of Bu4NBF4, for example, to 5 equiv is important from the viewpoint of eco-friendly chemical synthesis. The reaction time of 16 h also seems to be suitable for the investigation. Thus, the combination of Tf2NH and Bu4NBF4 might generate HBF4 in the solution.

Table 1: Optimization of the gem-difluorination of hex-5-yn-1-ylbenzene (1a) to form difluorinated compound 2a (method A).

[Graphic 1]
Entry Brønsted
acid 		X
(equiv) 		Fluorine
source 		Y
(equiv) 		Solvent Reaction
time
Z (h) 		T (°C) % Yielda
1 Tf2NH 5 Bu4NBF4 5 CH2Cl2 8 rt 83
2 Tf2NH 5 Bu4NBF4 5 CH2Cl2 16 rt 83 (72)b
3 Tf2NH 5 Bu4NBF4 5 CH2Cl2 24 rt 82
4 Tf2NH 3 Bu4NBF4 5 CH2Cl2 16 rt 75
5 Tf2NH 10 Bu4NBF4 5 CH2Cl2 16 rt 46
6 CF3COOH 5 Bu4NBF4 5 CH2Cl2 16 rt n.r.c
7 TfOH 5 Bu4NBF4 5 CH2Cl2 16 rt 72
8 Tf2NH 5 Bu4NBF4 5 CH3CN 16 rt 6
9 Tf2NH 5 Bu4NBF4 5 DMF 16 rt n.r.c
10 Tf2NH 5 Bu4NBF4 5 DMSO 16 rt n.r.c
11d Tf2NH 5 Bu4NF 5 CH2Cl2 16 rt n.r.c
12 Tf2NH 5 BF3·Et2O 5 CH2Cl2 16 rt n.d.e
13 Tf2NH 5 Bu4NBF4 3 CH2Cl2 16 rt 50
14 Tf2NH 5 Bu4NBF4 9 CH2Cl2 16 rt 89
15 Tf2NH 5 Bu4NBF4 9 CH2Cl2 16 0 31
16 Tf2NH 5 Bu4NBF4 9 CH2Cl2 16 −40 n.r.c
17 Tf2NH 5 Bu4NBF4 9 CH2Cl2 16 40 82

a19F NMR yields. Trifluorotoluene (CF3C6H5) was used as an internal standard. bIsolated yield after silica gel column chromatography of crude product. cn.r. = no reaction. dA solution of Bu4NF/THF underwent vacuum drying to prepare Bu4NF without THF. Then, CH2Cl2 was added to Bu4NF to prepare a solution. en.d. = not detected.

Next, the electrochemical method was studied for gem-difluorination. In a previous report by us, we found that the electrogenerated acids of “H+BF4−” equivalents can actually serve as H+ equivalents [51,52]. We have envisioned that electrogenerated acids such as ’’H+BF4−’’ equivalents might serve as good reagents for the gem-difluorination of alkynes. Thus, we have examined the electrochemical oxidation of a solution of Bu4NBF4/CH2Cl2 containing 1a (0.5 mmol) in a divided cell using 8 mA or 16 mA (Scheme 1, method B, in-cell method). In-cell method means that EGA was generated in the presence of the substrate. The total electricity of 3.0 F/mol vs 1a was passed to the solution. Interestingly, the result gave the corresponding difluorinated compound 2a in 29% yield in the case of 8 mA, as shown by 19F NMR analysis. In addition, 2a was obtained in 42% yield by 19F NMR analysis in the case of 16 mA [53].

[1860-5397-20-194-i1]

Scheme 1: gem-Difluorination promoted by electrogenerated acids (method B).

With the successful formation of (5,5-difluorohexyl)benzene (2a) by the chemical (method A) and electrochemical oxidation (method B) methods in hand, we have investigated the scope and limitations of gem-difluorination for various alkynes (Table 2). Electrochemical oxidation of method B was conducted by using 8 mA. The reaction of but-3-yn-1-ylbenzene (1b) in method A gave the corresponding compound 2b in 21% isolated yield (Table 2, entry 1). The 19F NMR result indicated 63% yield. Because of the low molecular weight of 2b, the isolated yield might be somewhat lower. In contrast, method B produced 2b in 6% isolated yield (Table 2, entry 2). The 19F NMR result indicated 29% yield. As for the internal carbon–carbon triple bonds, diphenylacetylene (1c) was tested, but the desired product 2c was not obtained in any of the two methods (Table 2, entries 3 and 4). In the case of an aliphatic terminal alkyne, such as dec-1-yne (1d), the 19F NMR study indicated 46% yield with method A (Table 2, entry 5), but it was difficult to purify and isolate product 2d because of the low molecular weight. Scale up conditions of method A, for the purpose of the isolation, led to the formation of the corresponding product 2d in 40% yield as the 19F NMR analysis (Table 2, entry 6), but the isolation of 2d was difficult [54]. Method B gave 2d in 35% yield, as shown by the 19F NMR analysis (Table 2, entry 7). Another alkyne, namely, octadec-1-yne (1e), was found to be a nice substrate for gem-difluorination to yield the difluorinated compound 2e (Table 2, entries 8 and 9). Interestingly, terminal alkynes bearing –OH and –O– functional groups, such as 1f and 1g, were used for reactions, and the corresponding products 2f and 2g were obtained by both methods (Table 2, entries 10–13). In addition, 2-(pent-4-yn-1-yl)isoindoline-1,3-dione (1h) was utilized for the construction of the CF2 unit under the same conditions to give 2h (Table 2, entries 14 and 15). The substrate bearing a halogen, such as 10-iododec-1-yne (1i) in method A, produced the corresponding 2i in 60% isolated yield (Table 2, entry 16). Likewise, method B also gave 2i in 21% yield, as shown by the 19F NMR analysis (Table 2, entry 17), but it was difficult to purify and isolate the product 2i in this case. Finally, the internal aliphatic alkyne such as dodec-6-yne (1j) was found to be effective for the gem-difluorination. Method A gave 2j in 38% isolated yield, and method B produced 2j in 10% isolated yield (Table 2, entries 18 and 19).

Table 2: Scope and limitations.

[Graphic 2]
Entry Substrate Product Method % Yielda
1 [Graphic 3]
1b 		[Graphic 4]
2b 		A 21 (63)
2     B 6 (29)
3 [Graphic 5]
1c 		[Graphic 6]
2c 		A n.d.b
4     B n.d.b
5 [Graphic 7]
1d 		[Graphic 8]
2d 		A –c (46)
6     A 4c (40)d
7     B –c (35)
8 [Graphic 9]
1e 		[Graphic 10]
2e 		A 67 (86)
9     B 50e (45)
10 [Graphic 11]
1f 		[Graphic 12]
2f 		A 47 (59)
11     B 41e (37)
12 [Graphic 13]
1g 		[Graphic 14]
2g 		A 58e (70)
13     B 40e (46)
14f [Graphic 15]
1h 		[Graphic 16]
2h 		A 37 (55)
15     B 15 (13)
16 [Graphic 17]
1i 		[Graphic 18]
2i 		A 60 (81)
17     B –c (21)
18 [Graphic 19]
1j 		[Graphic 20]
2j 		A 38 (62)
19     B 10 (24)

aIsolated yields. Silica gel column chromatography and/or preparative GPC separation were/was conducted for the purification. 19F NMR yields of the crude products are shown in parentheses. bn.d. = not detected. cIt was impossible to purify and isolate the corresponding product, although the product was confirmed by NMR analysis, when the crude product was prepared. The reason might be due to volatility derived from the low molecular weight. dThe reaction was conducted in the fourfold scale. eIsolated products contained a small amount of impurity. fThe conditions such as Bu4NBF4 (9 equiv) and Tf2NH (5 equiv) in CH2Cl2 at 40 °C for 16 h were used.

Another procedure involving electrochemical oxidation was also applied (the ex-cell method) [55,56]. Ex-cell method means that EGA was generated in the absence of the substrate, and the substrate was added to the solution after the electrolysis. Optimized conditions and the result are described in Scheme 2. Namely, the electrochemical oxidation of a 0.3 M Bu4NBF4/CH2Cl2 solution (8 mL) at 0 °C using 32 mA generated and accumulated the EGA as the pool. An electricity of 6.0 F/mol based on 0.5 mmol was passed to the solution. In order to suppress the increase of the solution temperature under the electrolysis, the electrolysis was conducted at 0 oC. Then, the solution containing EGA was allowed to react with 1a (0.5 mmol) at 0 °C for 0.5 h, giving the corresponding product 2a in 61% yield, as demonstrated by the 19F NMR analysis. The result indicated that CH2Cl2 of the solvent might be oxidized and H+ species (or equivalent units) might be generated by the electrolysis in this case. In addition, ex-cell method can avoid the over-oxidation of 2a, although the excess electricity was passed to the solution.

[1860-5397-20-194-i2]

Scheme 2: Generation and accumulation of EGA followed by the reaction with 1a for 2a.

A plausible reaction mechanism for the current reactions is described in Scheme 3. The reaction of carbon–carbon triple bonds and H+ species, which are derived from the Brønsted acid (in method A) or EGA (in method B), gives the vinylic carbocation intermediate A, which can react with BF4− to give fluorinated alkene B [57-60]. In the next step, B can undergo the second addition of H+, followed by the incorporation of F− into the carbocation intermediate C, forming the difluorinated compound 2a. The carbocation adjacent to the F atom might be stabilized by the unshared electron pair of F. Thus, the chemical and electrochemical methods we developed here seem to be superior to the conventional method, because the chemical method requires a usual Brønsted acid and solid Bu4NBF4, which can avoid the use of dangerous HF solutions. The electrochemical method also needs only electricity and solid Bu4NBF4, which realizes in situ formation of “HBF4” equivalents.

[1860-5397-20-194-i3]

Scheme 3: Plausible reaction mechanism.

Conclusion

In summary, we have carried out the gem-difluorination of carbon–carbon triple bonds using Tf2NH/Bu4NBF4 or EGA from Bu4NBF4/CH2Cl2. The feature superiority of these methods is that they do not directly require the use of hazardous HF reagents and expensive metal catalysts. The simple combination of a Brønsted acid with Bu4NBF4 as the fluorine source as well as a simple electrolysis in Bu4NBF4/CH2Cl2 represent new routes to synthesize CF2-incorporated organic molecules from alkynes. Further synthetic applications are in progress in our laboratory.

Supporting Information

Supporting Information File 1: Experimental procedure, characterization data of compounds and copies of spectra of 1H NMR and 13C NMR.
Format: PDF Size: 2.2 MB Download

Acknowledgements

We are grateful for Kindai University Joint Research Center for use of facilities.

Funding

This work was supported in part by JSPS KAKENHI Grants JP20K05588 (Grant-in-Aid for Scientific Research (C)). We appreciate 2021 Kindai University Research Enchancement Grants (KD2106 and KD2104).

Data Availability Statement

All data that supports the findings of this study is available in the published article and/or the supporting information to this article.

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