Synthetic Utilization of 2H-Heptafluoropropane: Ionic 1,4-Addition to Electron-Deficient Carbon–Carbon Unsaturated Bonds

Abstract

We have found a novel method for introducing heptafluoro-2-propyl CF(CF₃)₂ groups into carbon–carbon unsaturated bonds via a nucleophilic reaction using 2H-heptafluoropropane as the source of CF(CF₃)₂ groups. The reaction involves the nucleophilic addition of a heptafluoro-2-propyl anion, generated by treating 2H-heptafluoropropane with a fluoride ion, to various electron-deficient unsaturated compounds. This allows the easy synthesis of various aliphatic compounds containing heptafluoro-2-propyl groups.

1. Introduction

Many fluorine-containing organic compounds have been developed, including pharmaceuticals, agrochemicals, electronic materials, and polymer materials with fluorine functional groups.¹ Accordingly, reactants and synthetic methods have been developed to introduce various fluorine-containing functional groups.² In particular, much effort has been devoted to the development of chemical reactions to introduce relatively small fluorine-containing functional groups, such as trifluoromethyl CF₃, difluoromethyl CHF₂, and pentafluoroethyl C₂F₅ groups.² Despite the expectation that increasing the number of fluorine atoms in a fluoroalkyl group will lead to improved functionality and new physical properties due to the unique electronic and steric effects of fluorine, little attention has been paid to this issue. Only recently have methods been developed to introduce the simplest secondary fluoroalkyl group, heptafluoro-2-propyl, (CF₃)₂FC, into aliphatic chains. These methods use heptafluoro-2-iodopropane or hexafluoropropene as the reagent and introduce it into a carbon–carbon unsaturated bond (Scheme 1A). Heptafluoro-2-iodopropane can be added to unsaturated carbon–carbon bonds when exposed to light or one-electron reducing agents as part of a reaction.³⁻⁵ Treatment of hexafluoropropene with metal fluorides followed by oxidation with one-electron oxidizing reagents produces a key intermediate for addition to unsaturated bonds.⁶ However, the conventional method faces the problem of homocoupling between radical species, where the heptafluoro-2-propyl group is introduced in the form of a radical species.⁷ As a result, valuable resources are wasted for the introduction of the heptafluoro-2-propyl radical species.

Scheme 1. Heptafluoro-2-propyl Group Introduction to Carbon–Carbon Unsaturated Bond.

We therefore set out to develop a chemical reaction to introduce anionic (CF₃)₂FC species into an aliphatic chain. Here, we present the first incorporation of anionic (CF₃)₂FC species into carbon–carbon unsaturated bonds (Scheme 1B).⁸ 2H-Heptafluoropropane, which possesses an acidic proton,⁹ was chosen as the source of the heptafluoro-2-propyl group.

2. Results and Discussion

Fluoroalkyl anion species are typically unstable and tend to decompose to form carbene species by α-F elimination or a fluoroalkene by β-F elimination.¹⁰ These decomposition processes are reversible. To incorporate the (CF₃)₂FC anion into a chemical reaction, we planned to use a fluoride ion that exhibits strong basicity [HF, pK_a 15 (DMSO)]^11a under nonaqueous conditions and expected it to also act as a regenerator of a fluoroalkyl anion, thereby prolonging the lifetime of the anion species (Scheme 1C). Following the above strategy, the reaction between the electrophile adamantyl acrylate 1a and 2H-heptafluoropropane was investigated. 1a (0.25 mmol) and 2H-heptafluoropropane (20 mL, 0.88 mmol) were reacted with tetramethylammonium fluoride tetrahydrate, Me₄NF·4H₂O (TMAF·4H₂O) (0.25 mmol) in dimethylformamide (DMF) (2 mL) at 30 °C for 5 h. This gave the fluoroalkylated product 2a with a heptafluoro-2-propyl group added to the β-carbon of 1a in a 49% yield (Table 1, entry 1).¹² In this reaction, the starting material 1a was recovered in a 41% yield, accompanied by a small amount of 1/2 adduct of (CF₃)₂CHF/1a. Although changing the base to anhydrous TMAF under similar reaction conditions resulted in a comparable yield of product 2a, only a small amount of 1a was recovered (entry 2). The results of entries 1 and 2 support our strategy that the use of fluoride ions under nonaqueous conditions is effective in activating 2H-heptafluoropropene. When other tetramethylammonium halides [HCl, pK_a −2.0 (DMSO);^11b HBr, pK_a −6.8 (DMSO);^11b and HI, pK_a −10.9 (DMSO)^11b were used as bases, the reaction did not proceed and the starting material was recovered quantitatively (entries 3–5). On the other hand, 2a was formed in a low yield using more basic tetramethylammonium hydroxide [H₂O, pK_a 32 (DMSO)^11a (entry 6). Furthermore, the reactions were investigated with several organic bases widely used in organic synthesis, but no formation of 2a was observed in any case (entries 7–11). For example, the use of LDA, KHMDS, and t-BuOK, which are reported to deprotonate fluoroform (HCF₃), did not affect the reaction of 2H-heptafluoropropane.¹³ In the past, some reports have shown that the use of bases paired with a metal countercation promotes the rapid decomposition of the (CF₃)₂FC anion species.^13c Next, reactions with other ammonium fluorides were then investigated. The use of tetrabutylammonium fluoride trihydrate (TBAF·3H₂O) gave the desired product 2a in a 60% yield with a satisfactory material balance (entry 11). Although the conditions were favorable from the point of view of the raw material/product balance, a significant amount of tributylamine was found to be produced by the Hoffman elimination of TBAF.¹⁴ Therefore, the reactions were carried out using benzyltrimethylammonium fluoride and adamantyltrimethylammonium fluoride, which are less susceptible to Hoffman elimination. The results were comparable to those obtained using the TMAF (entries 2 vs 12 and 13). Finally, the reaction was carried out using cesium fluoride as a base to obtain the desired product 2a in a 17% yield (entry 14).

Table 1. Investigation of Base Effects^a.

entry	base	2a (%)a	1a (%)b
1	Me4N+F–·4H2O	49	41
2	Me4N+F–	46	2
3	Me4N+Cl–	0	99
4	Me4N+Br–	0	99
5	Me4N+I–	0	99
6	Me4N+OH–·5H2O	2	93
7	LDA	0.2	69
8	KHMDS	0	99
9	tBuOK	0	82
10	NaNH2	1	83
11	Bu4N+F–·3H2O	60	30
12	BnN+Me3F–	46	5
13	AdN+Me3F–	47	24
14	CsF	17	81

^aThe reaction of 1a (0.25 mmol) with (CF₃)₂CHF [20 mL (gas), 0.88 mmol] was carried out in the presence of base (0.25 mmol) in DMF (2 mL) at 30 °C in 5 h.

^bGC yield with heptadecane as the internal standard.

The effect of the solvent in this reaction was then investigated. The reaction of 1a with 2H-heptafluoropropane proceeded only in aprotic polar solvents, with DMSO giving the 1,4-adduct in the highest yield (Table 2, entries 1–4). On the other hand, no product 2a was observed in solvents of lower polarity such as dichloromethane, THF, toluene, and 1,4-dioxane (Table 2, entries 5–8). The effect of the polarity of the solvents is deduced as follows: (a) activation of the base and (b) inhibition of degradation and stabilization of the anionic intermediate. (a) The fluoride ion in TMAF·4H₂O is fixed in the strong hydrogen bonding network with hydrated water molecules.¹⁵ It is thought that the polar solvent disrupts this network to isolate the free fluoride ion to act as a base. In addition, (b) the heptafluoro-2-propyl anion formed from 2H-heptafluoropropane probably prevents the decomposition process by reducing the desorption of the fluoride ion by solvation via electrostatic interaction. In addition, DMAc and DMF were thought to capture the heptafluoro-2-propyl anion with their carbonyl groups, preventing its degradation.¹⁶ The above consideration of the effect of polar solvents supports the working hypothesis that the heptafluoro-2-propyl anion is formed from 2H-heptafluoropropane in the present reaction.

Table 2. Investigation of Solvent Effects^a.

entry	solvent	εr	2aa	1ab
1	DMSO	47.0	71% (66%)	13% (5%)
2	DMAc	37.8	26%	72%
3	MeCN	37.5	2%	88%
4	DMF	36.7	49%	41%
5	DCM	9.1	0%	87%
6	THF	7.6	0%	79%
7	Toluene	2.4	0%	96%
8	1,4-dioxane	2.2	0%	87%

^aConditions: 1a (0.25 mmol), 2H-heptafluoropropane [20 mL (gas), 0.88 mmol], TMAF·4H₂O (0.25 mmol), DMSO (2 mL), −40 to 30 °C, 5 h.

^bGC yield with heptadecane as the internal standard (isolated yield). ε_r: relative permittivity.

Interestingly, the results in Table 1 (entries 1 and 2) show that while there is no significant difference in the yield of 1,4-adduct 2a when using TMAF tetrahydrate or anhydride under nonaqueous reaction conditions, almost all of the starting material 1a is consumed when using anhydride. Mass spectrometric analysis of the reaction mixture after 5 h of reaction with anhydrous TMAF (Table 1, entry 2) showed the formation of oligomers with 2–29 molecules of 1a inserted, in addition to the 1:1 adduct of 1a with 2H-heptafluoropropane (Figure 1). This indicates that anionic polymerization of 1a takes place with the (CF₃)₂FC anion as the initiator, originating initially from 2H-heptafluoropropane and fluoride ions.

Figure 1.

Mass spectra of the reaction mixture under anhydrous TMAF conditions.

The effect of H₂O was also investigated by performing the reaction of 2H-heptafluoropropane with 1a under basic conditions using DMSO as the solvent and various amounts of H₂O added to anhydrous TMAF (Figure 2). As the amount of H₂O added was increased from 0, the yield of 2a was the highest when 4 equiv of H₂O was added, and the results were comparable to those obtained with commercial tetrahydrate. As summarized in Scheme 2, the presence of H₂O in the reaction system can easily affect not only the deprotonation ability (basicity) of fluoride ions but also the inhibition of anionic polymerization. It can be easily concluded that up to a certain amount, the presence of H₂O does not reduce the basicity of the fluoride ion enough to act as a base for the deprotonation of 2H-heptafluoropropane to produce the heptafluoro-2-propyl anion (intermediate A). After the addition of A to 1a, the first adduct, intermediate B, is formed and hydrolysis of B by H₂O present in the reaction system eventually yields the 1,4-adduct 2a, while less H₂O promotes the anionic polymerization. In the above reaction, where 1a is an acceptor for the (CF₃)₂FC anion, about 4 equiv can be considered a reasonable amount for the addition of H₂O.

Figure 2.

Influence of the addition of H₂O.

Scheme 2. Outline of the Addition Reaction of 2H-Heptafluoropropane to 1a.

Based on the above results, the reaction of 2H-heptafluoropropane with various electron-deficient unsaturated compounds was investigated by using TMAF as the base. The effects of the water addition described above varied from substrate to substrate. For highly reactive substrates, including polymerizable substrates, the use of DMF as a solvent resulted in decreased reactivity of the heptafluoro-2-propyl anion and produced a product with a higher material balance. Specific reaction conditions for each substrate are reviewed in the Supporting Information. The desired product 2b was not obtained when adamantyl methacrylate (1b) had a methyl group in the α-position and only the starting material was recovered quantitatively (Table 3, entry 1), while the reaction with benzyl methacrylate (1c) gave adduct 2c in a 20% yield (entry 2). In addition, crotonate ester 1d and cinnamate ester 1e did not react probably due to the presence of substituents on the β-position carbon (entries 3–4). This may be due to steric repulsion between the sterically large heptafluoro-2-propyl anion and the substituent, which inhibits the reaction. This problem can be solved by introducing substituents with stronger electron-withdrawing properties to the alkene. The introduction of an additional ester group at the α-position of the cinnamate ester 1f, while activating the alkene, increased the reactivity of the substrate, resulting in the progression of the 1,4-addition reaction (2f, 36%) (entry 5). This result indicates that the introduction of a (CF₃)₂FC group at the β-position is possible as long as the reaction site is not disturbed by an extremely large steric hindrance. The reaction is also applicable to alkenes with various electron-withdrawing substituents. The reaction of electron-deficient alkenes with sulfonyl (1g), sulfinyl (1h), phosphoryl (1i), and cyano (1j) groups afforded the corresponding 1,4-addition products (2g–2j) (entries 6–7). In particular, acrylonitrile (1j) showed a high reactivity, and even nitrile cinnamate (1k) with the β-position phenyl group, which did not react with cinnamate ester, proceeded to 1,4-addition (2k) (entry 10). Not only electron-deficient alkenes but also alkynes could be heptafluoro-2-propylated in this reaction. The reaction of dimethyl acetylenedicarboxylate (1l) with 2H-heptafluoropropane at −40 °C in the presence of 1 equiv of TMAF and 4 equiv of H₂O afforded CF(CF₃)₂ group-substituted maleic acid ester derivative 2l in a 52% yield as a single product (entry 11). ¹H–¹⁹F HOESY analysis of the isolated reaction product showed a nuclear Overhauser effect between H and CF and between H and CF₃. These indicate clearly that the H and CF(CF₃)₂ groups are introduced in the cis-manner to the triple bond of dimethyl acetylenedicarboxylate (1l). No further heptafluoro-2-propylation by 1,4-addition to 2l was observed. Finally, the reaction was carried out with dehydroamino acid (1m) to give the leucine derivative 2m in a 68% yield (entry 12).

Table 3. Reactions of Various C–C Unsaturated Compounds^a.

^aThe reaction of 1 (0.25 mmol), H₂O (X mmol) with (CF₃)₂CHF [20 mL (gas), 0.88 mmol] was carried out in the presence of TMAF (0.25 mmol) in DMF or DMSO (2 mL) at 30 °C in 5 h.

^bIsolated yield.

^c1HNMR yield with mesitylene as the internal standard.

^dReaction was carried out at −40 °C.

3. Conclusions

In conclusion, we have developed a novel method for the incorporation of (CF₃)₂FC groups into carbon-unsaturated compounds using 2H-heptafluoropropane as the starting material. The present approach successfully suppresses the formation of byproducts after the homocoupling reaction, which have been casting critical drawbacks to the previous radical-based reaction systems. Use of 2H-heptafluoropropane, which is a byproduct of the manufacture of fluorine-containing materials, is currently limited to applications such as a refrigerant and fire extinguishing agent.¹⁷ The results of the present study shed light on 2H-heptafluoropropane as a useful source of organic fluorine.

4. Experimental Section

4.1. General Conditions

¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were recorded on a JEOL JNM-ECX500 instrument (¹H NMR: 500 MHz, ¹³C NMR: 126 MHz, ¹⁹F NMR: 471 MHz). The chemical shift value by nuclear magnetic resonance (NMR) measurement was adjusted based on the chloroform solvent signal (¹H NMR: δ 7.26, ¹³C NMR: δ 77.0), the tetramethylsilane solvent signal (TMS, ¹H NMR: δ 0.00), or the hexafluorobenzene solvent signal (¹⁹F NMR: δ −162.9). Coupling constants in NMR spectra are abbreviated as s (singlet), d (doublet), t (triplet), q (quartet), sep (septet), or m (complex multiplet). The infrared (IR) absorption spectra were measured using a JASCO FT/IR-4200 spectrometer with the following relative intensities: s (strong), m (medium), and w (weak). Mass spectra were measured using a JEOL JMS-700 MStation or JMS-T100LP AccuTOF LC-plus 4G, DART/ESI/CSI/APCI. The melting point was measured with MP-500D. Analytical gas chromatography (GC) was performed on a SHIMADZU GC-2025 gas chromatograph with a GL-Science capillary column (InterCap CHIRAMIX, id 0.25 mm × length 30 m, df 0.25 μm), equipped with a flame ionization detector. MERCK Silica gel 60 was used for flash column chromatography. X-ray crystallographic analysis was performed using a Rigaku VariMax RAPID RA-Micro7HFM.

4.2. Materials

2H-Heptafluoropropane was provided by Daikin Industries, Ltd. All other reagents were purchased from Sigma-Aldrich, Wako Pure Chemicals, Tokyo Kasei, Kanto Chemical, and Nacalai Tesque. All anhydrous solvents, purchased from Wako Pure Chemicals, were stored in a glovebox to avoid moisture and used directly without further purification. Tetramethylammonium fluoride tetrahydrate (TMAF·4H₂O) was purchased from Tokyo Kasei and was used directly without further purification. Tetramethylammonium fluoride anhydrate (TMAF, containing 1.8% water) was purchased from Sigma-Aldrich and stored in the glovebox to avoid moisture. Chloroform-d (99.8 atom % D), DMF-d₇ (99.5 atom % D), and DMSO-d₆ (99.9 atom % D) were purchased from Cambridge Isotope Laboratories, Inc. Acrylonitrile 1j was purchased from Wako Pure Chemicals and used directly without further purification. Benzyl methacrylate 1c, diethyl benzylidenemalonate 1f, diethyl vinylphosphonate 1i, cinnamonitrile 1k, and dimethyl acetylenedicarboxylate 1l were purchased from Tokyo Kasei and used directly without further purification. Phenyl vinyl sulfone 1g and phenyl vinyl sulfoxide 1h were purchased from Sigma-Aldrich and used directly without further purification.

Note: The moisture content of TMAF anhydrate varies by supplier and lot.

4.3. Preparation and Characterization Date of Substrate: Synthesis of Vinyl Esters 1a, 1b, 1d, and 1e

Substrates 1a, 1b, 1d, and 1e were synthesized according to a reported literature procedure.¹⁸ A 300 mL three-necked flask equipped with a stirring bar was charged with 1-adamantyl alcohol (50 mmol, 7.61 g), triethylamine (75 mmol, 10 mL), and dichloromethane (100 mL) in a N₂ atmosphere. After cooling the solution to 0 °C, acyl chloride (75 mmol) was added dropwise to the stirred solution over a period of 30 min, and the reaction mixture was stirred for 1 h at 0 °C. The reaction vessel was placed in an oil bath preheated at 40 °C. The reaction was monitored by GC and thin-layer chromatography (TLC). After complete consumption of 1-adamantyl alcohol, the reaction mixture was filtrated, then washed with NaHCO₃ solution, water, and brine, and dried over MgSO₄. After the filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (n-hexane/Et₂O = 100/1) to give 1a–d in 69–98% yield.

4.3.1. (3s,5s,7s)-Adamantan-1-yl Acrylate (1a)

Spectral data are in accordance with those reported in the literature.^18a Yield 72% (7.31 g); white solid; R_f 0.4 (n-hexane/Et₂O = 100/1); ¹H NMR (500 MHz, CDCl₃): δ 6.28 (dd, J = 17.2, 1.7 Hz, 1H), 6.02 (dd, J = 17.2, 10.3 Hz, 1H), 5.71 (dd, J = 10.3, 1.7 Hz, 1H), 2.17 (s, 3H), 2.14 (s, 6H), 1.67 (s, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 165.2, 130.5, 129.2, 80.6, 41.3, 36.2, 30.8; LRMS (EI) m/z (relative intensity, %): 206 (17, M⁺), 135 (37), 134 (100), 93 (31), 92 (70), 91 (14), 79 (22), 78 (10), 77 (10), 67 (10), 55 (43); HRMS (EI): exact mass for C₁₃H₁₈O₂ [M⁺], 206.1307; found, 206.1307.

4.3.2. (3s,5s,7s)-Adamantan-1-yl Methacrylate (1b)

Spectral data are in accordance with those reported in the literature.^18b Yield 98% (10.63 g); pale yellow oil; R_f 0.35 (n-hexane/Et₂O = 100/1); ¹H NMR (500 MHz, CDCl₃): δ 5.99 (t, J = 1.4 Hz, 1H), 5.46–5.45 (m, 1H), 2.17 (s, 3H), 2.14 (s, 6H), 1.89 (s, 3H), 1.66 (dd, J = 16.3, 13.5 Hz, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.5, 138.0, 124.2, 80.4, 41.2, 36.2, 30.9, 30.8, 30.7, 18.3; LRMS (EI) m/z (relative intensity, %): 220 (48, M⁺), 135 (88), 134 (100), 93 (33), 92 (65), 91 (13), 79 (25), 69 (25), 67 (10); HRMS (EI): exact mass for C₁₄H₂₀O₂ [M+], 220.1463; found, 220.1455.

4.3.3. (3s,5s,7s)-Adamantan-1-yl Crotonate (1d)

Yield 69% (7.48 g); colorless oil; R_f 0.40 (n-hexane/Et₂O = 100/1); ¹H NMR (500 MHz, CDCl₃): δ 5.93–5.85 (m, 1H), 5.14–5.09 (m, 2H), 2.98 (dt, J = 6.9, 1.4 Hz, 2H), 2.14 (s, 3H), 2.09 (s, 6H), 1.64 (t, J = 14.0 Hz, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 170.6, 131.0, 117.8, 80.6, 41.3, 40.5, 36.1, 30.8; LRMS (EI) m/z (relative intensity, %): 220 (0.5, M⁺), 136 (11), 135 (100), 134 (11), 93 (15), 79 (13); HRMS (EI): exact mass for C₁₄H₂₀O₂ [M⁺], 220.1463; found, 220.1460.

4.3.4. (3s,5s,7s)-Adamantan-1-yl Cinnamate (1e)

Spectral data are in accordance with those reported in the literature.^18c Yield 82% (11.30 g); pale yellow solid; R_f 0.38 (n-hexane/Et₂O = 100/1); ¹H NMR (500 MHz, CDCl₃): δ 7.58 (d, J = 16.0 Hz, 1H), 7.50 (dd, J = 6.9, 2.3 Hz, 2H), 7.41–7.33 (m, 3H), 6.37 (d, J = 16.0 Hz, 1H), 2.20 (s, 9H), 1.70 (dd, J = 21.2, 12.6 Hz, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 165.9, 143.4, 134.6, 129.8, 128.7, 127.9, 120.3, 80.5, 41.4, 36.2, 30.8; LRMS (EI) m/z (relative intensity, %): 282 (40, M⁺), 254 (10), 237 (10), 236 (20), 222 (11), 135 (84), 134 (86), 131 (100), 103 (53), 93 (33), 92 (59), 91 (15), 79 (26), 78 (11), 77 (35), 67 (10); HRMS (EI): exact mass for C₁₉H₂₂O₂ [M⁺], 282.1620; found, 282.1616.

4.3.5. Synthesis of Dehydroamino Acid 1m

Substrate 1m was synthesized according to the reported procedure, and the spectral data were consistent with those reported in the literature.¹⁹ A 100 mL two-necked flask equipped with a stirring bar was charged with phthalimide (36 mmol, 5.250 g), Ph₃P (14.4 mmol, 3.777 g), and 1,4-dioxane (20 mL). The mixture was placed in a water bath at room temperature. Methyl propiolate (36 mmol, 3.027 g) in 1,4-dioxane (30 mL) was added dropwise over a period of 30 min to a magnetically stirred mixture. The water bath was removed, and the reaction mixture was stirred at room temperature. The reaction was monitored by GC and TLC. After 2 h, the reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (n-hexane/AcOEt = 3/2) to give 1m in a 67% yield.

4.3.6. Methyl 2-(1,3-Dioxoisoindolin-2-yl)acrylate (1m)

Yield 67% (5.57 g); white solid; R_f 0.43 (n-hexane/AcOEt = 3/2); ¹H NMR (500 MHz, CDCl₃): δ 7.73 (dd, J = 5.5, 3.5 Hz, 2H), 7.63 (dd, J = 5.5, 3.0 Hz, 2H), 6.53 (s, 1H), 5.87 (s, 1H), 3.66 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.0, 162.4, 134.3, 131.4, 128.7, 127.9, 123.6, 52.5; LRMS (EI) m/z (relative intensity, %): 231 (78, M⁺), 203 (11), 173 (13), 172 (100), 132 (13), 104 (48), 76 (34); HRMS (EI): exact mass for C₁₂H₉O₄N [M⁺], 231.0532; found, 231.0531.

4.4. General Experimental Procedure; Reaction of 1a with 2H-Heptafluoropropane in the Presence of TMAF·4H₂O (Tables 1–3)

TMAF·4H₂O (0.25 mmol, 23.3 mg) was placed in a dry 10 mL test tube equipped with a three-way stopcock under a N₂ atmosphere. The tube was sealed with a rubber septum; 2.0 mL of DMSO was added through the rubber septum using a syringe, and the mixture was stirred at room temperature for 30 min. After the mixture was cooled (solidified) to −40 °C, the tip of a gastight syringe filled with 2H-heptafluoropropane [20 mL (gas), 0.88 mmol] was inserted into the cold mixture and slowly added while the gas was liquefied. Substrate 1 (0.25 mmol) was then added by a syringe. The rubber septum was replaced with a screw cap, and the reaction tube was sealed with a screw cap in the cold state. The tube was placed in an oil bath preheated to 30 °C. After 5 h, 5 mL of toluene was added to homogenize the entire mixture, and heptadecane was added as an internal standard. The mixture was analyzed directly by GC, and the GC yield was calculated. The reaction mixture was extracted three times (first: NaHCO₃ aq. 10 mL, second: 10 mL water, and third: 10 mL brine) and dried over MgSO₄. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (n-hexane/Et2O) to give 2.

4.5. Characterization Data of Products

4.5.1. (3s,5s,7s)-Adamantan-1-yl 4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentanoate (2a)

GC yield 71%, isolated yield 66% (62.1 mg); Colorless oil; R_f 0.23 (n-hexane/Et₂O = 10/1); ¹H NMR (500 MHz, CDCl₃): δ 2.52–2.49 (m, 2H), 2.43–2.35 (m, 2H), 2.15 (s, 3H), 2.08 (s, 6H), 1.64 (s, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 170.0, 121.0 (dq, J = 283, 31 Hz), 91.1 (dsep, J = 203.7, 32 Hz), 81.5, 41.2, 36.0, 30.9, 27.6, 27.6, 23.9, 23.7; ¹⁹F NMR (471 MHz, CDCl₃): δ −77.9 (d, J = 7.0 Hz, 6F), −186.6––186.8 (m, 1F); IR (neat, cm^–1) 2914 s, 2857 m, 1734 s, 1458 w, 1354 w, 1222 s, 1159 m, 1089 m, 1054 m; HRMS (DRAT): exact mass DART for C₁₆H₂₃NO₂F₇, 394.1612 [M + NH₄]; found, 394.1614.

4.5.2. Benzyl 4,5,5,5-Tetrafluoro-2-methyl-4-(trifluoromethyl)pentanoate (2c)

Yield 20% (17.3 mg); colorless oil; R_f 0.25 (n-hexane/AcOEt = 10/1); ¹H NMR (500 MHz, CDCl₃): δ 7.39–7.34 (m, 5H), 5.14 (d, J = 2.0 Hz, 2H), 2.94–2.90 (m, 1H), 2.86–2.78 (m, 1H), 2.08–2.00 (ddd, J = 21.5, 15.5, 4 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 174.5, 135.4, 128.6, 128.4, 128.2, 121.0 (dq, J = 285, 35 Hz), 91.1 (dsep, 207, 30 Hz), 66.9, 33.8 (d, J = 4.8 Hz), 31.3 (d, J = 19 Hz), 19.2; ¹⁹F NMR (471 MHz, CDCl₃): δ −78.11 (dq, J = 18.0, 7.2 Hz, 6F), −187.0––187.2 (m, 1F); IR (neat, cm^–1) 2922 w, 2257 w, 1715 w, 1450 w, 1354 w, 1325 m, 1300 m, 1226 s, 1159 s, 1087 m, 989 w, 954 w, 913 w, 762 w, 719 m, 676 w; LRMS (EI) m/z (relative intensity, %): 388 (6, M⁺), 211 (11), 108 (77), 91 (100), 79 (10), 77 (10), 65 (15); HRMS (EI+): exact mass for C₁₄H₁₃O₂F₇, 346.0804 [M⁺]; found, 346.0809.

4.5.3. Diethyl 2-(2,3,3,3-Tetrafluoro-1-phenyl-2-(trifluoromethyl)propyl)malonate (2f)

Yield 20% (17.3 mg); colorless oil; R_f 0.15 (n-hexane/AcOEt = 5/1); ¹H NMR (500 MHz, CDCl₃): δ 7.31 (m, 5H), 4.73–4.70 (m, 1H), 4.36 (d, J = 12 Hz, 1H), 4.31–4.21 (m, 2H), 3.84–3.74 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.8, 165.7, 130.7 (d, J = 25 Hz), 128.9, 128.2, 120.7 (ddq, J = 285, 35 Hz), 92.8 (dsep, 207, 30 Hz), 62.3, 61.9, 53.3, 45.7 (d, J = 18 Hz), 13.7, 13.3; ¹⁹F NMR (471 MHz, CDCl₃): δ −70.6 (dq, J = 19, 8.5 Hz, 3F), −74.8 (dq, J = 19.5, 9.0 Hz, 3F), −175.2––175.3 (m, 1F); IR (neat, cm^–1) 2986 w, 1763 s, 1741 s, 1499 w, 1456 w, 1369 w, 1296 m, 1257 s, 1229 s, 1178 m, 1159 m, 1138 m, 1119 m, 1082 w, 1031 w, 977 w, 928 w, 951 w, 928 w, 865 w, 727 m, 703 m; LRMS (EI) m/z (relative intensity, %): 418 (20, M⁺), 345 (32), 344 (9), 327 (33), 326 (22), 325 (14), 300 (15), 299 (100), 298 (28), 132 (52), 103 (29), 77 (19); HRMS (EI+): exact mass for C₁₇H₁₇O₄F₇, 418.1015 [M⁺]; found, 418.1018.

4.5.4. ((3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butyl)sulfonyl)benzene (2g)

Yield 56% (46.7 mg); white solid; melting point 74.9–75.2 °C; R_f 0.33 (n-hexane/AcOEt = 10/1); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J = 6.9 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.7 Hz, 2H), 3.31–3.27 (m, 2H), 2.62–2.55 (m, 2H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 137.9, 134.5, 129.7, 128.1, 120.5 (dq, J = 288.4, 27.8 Hz), 90.5 (dsep, J = 206.8, 32.5 Hz), 48.9, 22.2 (d, J = 25.2 Hz); ¹⁹F NMR (471 MHz, CDCl₃): δ −77.6 (d, J = 7 Hz, 6F), −185.6 (dsep, J = 25.0, 7.0 Hz, 1F); IR (KBr, cm^–1) 3000 w, 2951 w, 1585 w, 1449 m, 1320 m, 1285 m, 1245 m, 1220 m, 1145 s, 1087 m, 1076 m, 1036 m, 972 m, 939 m; LRMS (EI) m/z (relative intensity, %): 338 (5, M⁺), 141 (60), 78 (11), 77 (100), 51 (25); HRMS (EI+): exact mass for C₁₁H₉O₂F₇S, 338.0211 [M⁺]; found, 338.0212. The crystallographic data have been deposited at the Cambridge Crystallographic Data Centre with deposition number 2310581.

4.5.5. ((3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butyl)sulfinyl)benzene (2h)

Yield 10% (8.1 mg); colorless oil; R_f 0.25 (n-hexane/AcOEt = 4/1); ¹H NMR (500 MHz, CDCl₃): δ 7.61–7.52 (m, 5H), 3.15 (td, J = 12.7, 4.5 Hz, 1H), 2.82 (td, J = 12.7, 4.5 Hz, 1H), 2.69–2.59 (m, 1H), 2.27–2.16 (m, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 141.8, 131.6, 129.5, 123.8, 120.8 (dq, J = 253.0, 45.1 Hz), 90.9 (dsep, J = 205.8, 31.6 Hz), 47.5, 20.8 (d, J = 21 Hz); ¹⁹F NMR (471 MHz, CDCl₃): δ −77.5 (dq, J = 8.3, 8.0 Hz, 3F), −77.7 (dq, J = 8.3, 8.0 Hz, 3F), −185.1––185.3 (m, 1F); IR (neat, cm^–1) 2926 w, 1478 w, 1444 w, 1343 w, 1308 m, 1221 s, 1150 m, 1086 m, 1032 m, 970 w, 970 w, 746 m, 692 m; LRMS (EI) m/z (relative intensity, %): 322 (40, M+), 125 (100), 77 (35), 51 (15); HRMS (EI+): exact mass for C₁₁H₉OF₇S, 322.0262 [M⁺]; found, 322.0260.

4.5.6. Diethyl (3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butyl)phosphonate (2i)

Yield 10% (8.1 mg); colorless oil; R_f 0.25 (n-hexane/AcOEt = 4/1); ¹H NMR (500 MHz, CDCl₃): δ 4.16–4.08 (m, 4H), 2.37 (dq, J = 9.0, 2H), 1.99–1.91 (m, 2H), 1.33 (t, J = 7.0 Hz, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 120.9 (dq, J = 161, 29 Hz), 91.0 (dsep, J = 185, 18 Hz), 62.3 (d, J = 6 Hz), 22.6 (d, J = 21 Hz), 19.0 (dd, J = 143, 5 Hz), 17.9 (d, J = 6 Hz), 16.4 (d, J = 21 Hz); ¹⁹F NMR (471 MHz, CDCl₃): δ −77.4 (d, J = 24 Hz, 6F), −186.1–186.2 (m, 1F); IR (neat, cm^–1) 2987 w, 2361 w, 1446 w, 1348 w, 1315 m, 1291 m, 1061 s, 1157 m, 1034 s, 968 m, 790 w; LRMS (EI) m/z (relative intensity, %): 335 (12, M+), 331 (13), 57 (100); HRMS (CI+): exact mass for C₉H₁₅O₃F₇P, 335.0647 [M⁺]; found, 335.0645.

4.5.7. 4,5,5,5-Tetrafluoro-4-(trifluoromethyl)pentanenitrile (2j)

¹H NMR yield 87%, isolated yield 18% (10.5 mg); colorless oil; boiling point; 60 °C/35 kPa; ¹H NMR (500 MHz, CDCl₃): δ 2.69–2.66 (m, 2H), 2.57–2.50 (m, 2H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 121.6 (dq, J = 291, 24 Hz), 116.9, 91.1 (dsep, J = 200, 32 Hz), 25.0 (d, J = 21 Hz), 10.9; ¹⁹F NMR (471 MHz, CDCl₃): δ −77.6 (d, J = 7.5 Hz, 6F), −187.3–187.5 (m, 1F); IR (neat, cm^–1) 2921 m, 2258 w, 1450 w, 1354 m, 1325 s, 1231 s, 1160 s, 1087 s, 1045 s, 990 m, 954 m, 913 m, 761 w, 719 s; HRMS (DRAT): exact mass for C₆H₅NF₇, 224.0305 [M + H⁺]; found, 224.0307.

4.5.8. 4,5,5,5-Tetrafluoro-3-phenyl-4-(trifluoromethyl)pentanenitrile (2k)

Yield 9% (6.7 mg); colorless oil; R_f 0.20 (n-hexane/AcOEt = 9/1); ¹H NMR (500 MHz, CDCl₃): δ 7.46–7.42 (m, 3H), 7.34–7.32 (m, 2H), 3.90–3.8 (m, 1H), 3.18–3.10 (m, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 131.1, 129.6, 129.4, 129.0, 181.7 (dq, J = 289, 38 Hz), 116.2, 91.5–90.7 (m), 43.6 (d, J = 22 Hz), 19.5 (d, J = 7.6 Hz); ¹⁹F NMR (471 MHz, CDCl₃): δ −72.3 (dq, J = 17, 7.5 Hz, 3F), −73.6 (dq, J = 17, 7.5 Hz, 3F), −178.6–178.7 (m, 1F); IR (neat, cm^–1) 3039 w, 2922 m, 2851 w, 1725 w, 1500 w, 1459 w, 1439 w, 1296 m, 1229 s, 1162 m, 1145 m, 1120 m, 1083 m, 1052 w, 1035 w, 1022 w, 985 w, 772 m, 723 m; LRMS (EI) m/z (relative intensity, %): 299 (66, M⁺), 259 (98), 239 (10), 190 (20), 130 (100); HRMS (EI+): exact mass for C₁₂H₈NF₇, 299.0545 [H⁺]; found, 299.0543.

4.5.9. Dimethyl 2-(Perfluoropropan-2-yl)maleate (2l)

Yield 52% (41 mg); colorless oil; R_f 0.20 (n-hexane/AcOEt = 95/5); ¹H NMR (500 MHz, CDCl₃): δ 6.48 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 162.9 (d, J = 2.0 Hz), 162.0 (d, J = 20 Hz), 136.0 (d, J = 24 Hz), 127.0 (d, J = 12 Hz),119.6 (dq, J = 289, 26 Hz), 89.9 (dsep, J = 208, 34 Hz), 53.5, 52.8; ¹⁹F NMR (471 MHz, CDCl₃): δ −76.2 (d, J = 7.5 Hz, 6F), −180.7 (sep, J = 7.5 Hz, 6F); IR (neat, cm^–1) 2921 m, 1752 s, 1438 m, 1367 m, 1243 s, 1101 m, 968 m, 894 w, 732 w, 670 w; HRMS (CI+): exact mass for C₉H₈O₄F₇, 313.0311 [M + H⁺]; found, 313.0302.

4.5.10. Methyl 2-(1,3-Dioxoisoindolin-2-yl)-4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentanoate (2m)

Yield 68% (68.2 mg); colorless oil; R_f 0.23 (n-hexane/AcOEt = 5/1); ¹H NMR (500 MHz, CDCl₃): δ 7.94–7.87 (m, 2H), 7.81–7.77 (m, 2H) 5.28 (dd, J = 9.8, 3 Hz, 1H), 3.76 (s, 3H), 3.33–2.17 (m, 2H).; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ168.1, 167.1, 134.7, 131.6, 124.0, 121.9 (dq, J = 287, 15 Hz), 90.8 (dsep, J = 207, 32 Hz), 53.9, 46.3 (d, J = 3 Hz), 27.0 (d, J = 18 Hz).; ¹⁹F NMR (471 MHz, CDCl₃): δ −77.6 (dq, J = 8.0, 8.5 Hz, 3F), −78.8 (dq, J = 8.0, 8.5 Hz, 3F), −189.7–189.8 (m, 1F); IR (NaCl, cm^–1) 3491 w, 3009 w, 2960 m, 2851 w, 1756 s, 1730 s, 1613 m, 1469 m, 1439 m, 1391 s, 1344 s, 1318 s, 1227 b, 1163 s, 1122 s, 1086 s, 1053 s, 1022 m, 990 m, 941 m, 910 s; LRMS (EI) m/z (relative intensity, %): 401 (5, M⁺), 343 (14), 342 (100), 322 (40), 302 (56), 151 (22), 130 (14), 104 (51), 77 (11), 76 (31), 66 (11), 50 (13); HRMS (EI+): exact mass for C₁₅H₁₀O₄NF₇, 401.0498 [M⁺]; found, 401.0500.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02798.

• Details of the experimental procedures, references not included in the body of the paper, and spectroscopic (NMR, IR, and mass) and X-ray crystallographic data (PDF)

The authors declare no competing financial interest.