Evaluation of Efficient and Practical Methods for the Preparation of Functionalized Aliphatic Trifluoromethyl Ethers.

The "chlorination/fluorination" technique for aliphatic trifluoromethyl ether synthesis was investigated and a range of products with various functional groups was prepared. The results were compared with oxidative desulfurization-fluorination of xanthates with the same structure.

1. Introduction

Fluorine is one of the most favorite heteroatoms for incorporation into small molecules in life science-oriented research. In particular, commercial pharmaceuticals and agrochemicals frequently contain single fluorine atoms or trifluoromethyl groups [1,2,3,4]. Nevertheless, growing interest in emergent fluorinated substituents, like α-fluorinated ethers, has been observed within recent years [5,6,7,8].

While aromatic trifluoromethyl ethers, since their first publication [9] in 1955, have been extensively studied and widely used as pharmaceuticals and crop protection agents, as well as critical components for liquid crystals design [3,4,5,6,10], aliphatic trifluoromethyl ethers are less studied. Only a few practical methods for the synthesis of such compounds have been developed. Fluorination of fluoroformates with SF4 leads to aliphatic trifluoromethyl ethers. For instance, methyl(trifluoromethoxy) acetate was obtained by this method [11]. Nucleophilic substitution of benzylic halogen or α-halogen atoms in acetophenones with perfluoroalcoholate anions is a suitable method for aliphatic ether preparation [12].

Oxidative desulfurization-fluorination of xanthates is now the most attractive method for primary alkyl trifluoromethyl ether synthesis. At least 42 publications concerning this reaction are cited in Reaxys. N-Bromo- [13] or N-iodosuccinimide [14], dibromodimethylhidantoine [15,16], and IF5 [17] are suitable oxidants in this reaction. Complexes pyridine-HF or NEt3-HF are commonly used as fluorine atom sources. Bromine trifluoride [18] or p-nitrophenylsulfur chlorotetrafluoride [19] were used as oxidants and fluorinating agents.

A number of new methods for trifluoromethyl ether synthesis were developed over the past ten years. The progress in this field was well summarized in the [6]. It is also worth noting the recent publication concern to asymmetric bromotrifluoromethoxylation of alkenes [8].

Surprisingly, and to the best of our knowledge, common for aromatic and revisited for heterocycles [20] trifluoromethyl ether synthesis “chlorination/fluorination” technique was not investigated enough for aliphatic substrates in order to compare existing methods due to the necessity to choose the most effective ones leading to the best yields and the lowest percentage of byproducts. It was reported that only 1,1,1-trifluoro-2-(trichloromethoxy)propane fluorination with anhydrous HF yielded the corresponding trifluoromethyl ether [21]. The aim of this work was to answer the question “is a “chlorination/fluorination” technique suitable for the aliphatic trifluoromethoxy-containing compound preparation as it is for aromatic ones” and to compare results of this method with oxidative desulfurization-fluorination at the same substrates.

2. Results and Discussion

We based our research on hydroxyacetic and β-hydroxypropionic acid derivatives, and alcohols containing two and three carbon atoms, including branched structures with phtalimido end groups as model objects.

Xanthates 1a–g were prepared in a one-pot procedure starting from n class="Chemical">sodium alcoholates of ω-hydroxysubstituted aliphatic esters, nitriles, and N-protected alkanolamines by the action of carbon disulfide and methyliodide. Target products were obtained with high yields in all cases (Scheme 1).

Scheme 1

Synthesis and structures of methylxanthates.

Chlorination of xanthates 1a–g readily occurred with elemental n class="Chemical">chlorine to produce trichloromethylethers 2a–g, which were isolated with almost quantitative yields (Scheme 2). Chloroderivatives 2a–g can be stored in a fridge and they are extremely sensitive to moisture.

Scheme 2

Syntheses of trifluoromethoxiderivatives.

Antimony trifluoride (method A) and hydrogen fluoride (method B) were used for chlorine-fluorine exchange because they are the cheapest for this reaction. Antimonium pentachloride was used as catalyst in both cases. Pyridine-HF70% and dibromodimethylhidantoine (DBH) (method C) were used for oxidative desulfurization-fluorination. It must be added that xanthates 1a–g were converted to trifluoromethyl ethers by the last method in the one-pot synthesis (Scheme 2).

In the case of trichloromethoxyacetate 2a fluorination by both methods A and B failed. The desired compound 3a was prepared with low yield only by oxidative desulfurization-fluorination of xanthate 1a (Table 1, Entry 1). On the contrary, fluorination of trichloromethoxypropanecarboxylic acids derivatives 2b–c and xanthates 1b–c was successfully performed by all three methods (Table 1, entry 2,3). In the case of nitrile 2c reaction with SbF3 (method A) lead to low yield of trifluoromethylether 3c (Table 1, Entry 4). Thus, the presence of electron-withdrawing carboxylic group close to the reaction center prevented successful fluorination processes.

Table 1

Structures and yields of chlorinated and fluorinated products.

Entry	Chlorinated Product	Yield%	Fluorinated Product	Yield %
				Method A	Method B	Method C
1		87		traces	traces	36
2		89		53	69	63
3		92		22	66	66
4		96		90	93	96
5		95		88	90	95
6		82		60	62	85
7		85		23	34	99

Note: Method A: SbF3 with SbCl5 (cat.), method B: HF with SbCl5 (cat.), method C: Py / HF70 %, DBH.

In general, fluorination of trichloromethylethers 2d–g and xanthates 1d–g with protected amino groups (Table 1, Entry 4–7) results in higher yields of fluorinated products 3d–g as compared with the same reaction of carboxylic acids derivatives. Trifluoromethylethers with linear chains 3d,e were prepared with high yields by all three methods. Oxidative desulfurization-fluorination of xanthate 1f gave a better result than fluorination of chloroderivative 2f with SbF3 or HF (Table 1, entry 6). An essential difference was observed in fluorination of trichloromethylether 2g and xanthate 1g (Table 1, entry 7). Fluorination of compound 2g by methods A and B led to low yields of trifluoromethylether 3g. Nevertheless, oxidative desulfurization-fluorination of xanthate 1g allowed obtaining ether 3g with quantitative yield. It should be noted that both substrates (1g and 2g) are secondary alcohol derivatives.

It must be added that fluorination with pyridine-n class="Chemical">HF complex (method C) requires special polyethylene or polytetrafluoroethylene plastic equipment, fluorination with anhydrous HF (method B) require stainless steel autoclave but fluorination with antimony trifluoride (method A) was performed in common glass equipment. All investigated methods of fluorination (A, B, and C) can be applied for the large-scale experiment. Thus, methyl 3-(trifluoromethoxy)propanoate 3b was prepared in quantity above 25 g at once and protected amine 3d was obtained in ca. 50 g at once by all three methods. The protective phthalimide group can be removed by common methods and was documented in [16].

3. Materials and Methods

1H-NMR spectra were recorded at 300 MHz with a Varian VXR-300 spectrometer (Varian Inc, Palo Alto, CA, USA), at 500 MHz with a Bruker AVANCE DRX 500 instrument (Bruker, Billerica, MA, USA), or at 400 MHz with Varian UNITY-Plus 400 spectrometer (Varian Inc, Palo Alto, CA, USA). 13C-NMR‑spectra (proton decoupled) were recorded on a Bruker AVANCE DRX 500 instrument at 125 MHz, or at 100 MHz with Varian UNITY-Plus 400 spectrometer. 19F-NMR spectra were recorded at 188 MHz with a Varian Geminy-200 instrument (Varian Inc., Palo Alto, CA, USA), or at 376 MHz with Varian UNITY-Plus 400 spectrometer. Chemical shifts are given in ppm relative to Me4Si and CCl3F, respectively, as internal or external standards. 1H-, 13C-, and 19F-NMR spectra of the compounds can be found in Supplementary materials. LC-MS spectra were registered on an “Agilent 1100 Series” instrument with diode-matrix and mass-selective detector “Agilent 1100 LS/MSD SL” (ionization method: chemical ionization at atmospheric pressure; ionization chamber operation conditions: simultaneous scanning of positive and negative ions in the range 80–1000 m/z, Agilent Technologies, Santa Clara, CA, USA). GC-MS spectra were registered on a Hewlett-Packard HP GC/MS 5890/5972 instrument (EI 70 eV) (Philips, Bothell, WA, USA). Melting points were determined in open capillaries using an SMP3 instrument (Stuart Scientific Bibby Sterlin Ltd, Stone, Staffordshire, UK). Elemental analysis was performed in the Analytical Laboratory of the Institute of Organic Chemistry, NAS of Ukraine, Kiev.

Unless otherwise stated, commercially-available reagents were purchased from Enamine Ltd. and were used without purification. Antimony trifluoride was sublimated immediately prior to use. Anhydrous hydrogen fluoride was distilled in the presences of SOCl2. HF70%/pyridine was prepared according to the Olah method [22]. Solvents were dried before use by standard methods. All reactions were performed in an argon atmosphere. For column chromatography, Merck Kieselgel 60 silica gel (Merck, Darmstadt, Germany) was used. Thin-layer chromatography (TLC) was carried out on aluminum-backed plates coated with silica gel (Merck Kieselgel 60 F254, Merck, Darmstadt, Germany).

3.1. Synthesis of Xanthates : General Procedure

Carbon disulfide (18.1 mL, 0.3 mol) was added dropwise at −30 °C to the suspension of sodium hydride (60% in mineral oil) (4.4 g, 0.11 mol) in anhydrous dimethylformamide (DMF) (200 mL). To this mixture the solution of corresponding hydroxyderivatives (0.1 mol) in anhydrous DMF (15 mL) was added dropwise for 3 h with mechanistic stirring at −30 °C. After addition was completed, the mixture was warmed to room temperature and stirred for 3 h. The color of the mixture gradually changed to dark red. The reaction mixture was cooled to −10 °C and methyl iodide (7.8 mL, 0.12 mol) was added dropwise. The mixture was warmed to room temperature, stirred for 3 h until the color changed from dark red to yellow and poured into ice (600 g), and extracted with tert-buthylmethyl ether (MTBE) (5 × 50 mL). The extract was washed with brine (5 × 50 mL) and dried with MgSO4. The solvent was removed at atmospheric pressure and the residue distilled in vacuum.

3.1.1. Methyl ([(methylsulfanyl)carbonothioyl]oxy)acetate 1a

Yield 15.5 g (86%). Yellow oil: bp 129–130 °C (20 Torr). n class="Chemical">1H-NMR (400 MHz, CDCl3): δ 2.60 (s, 3H, SCH3), 3.77 (s, 3H, OCH3), 5.15 (s, 2H, CH2). 13C-NMR (100 MHz, CDCl3): δ 19.5 (s, SCH3), 52.4 (s, OCH3), 67.6 (s, CH2), 167.1 (s, C=O), 215.8 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 180 (69) [M]+. Anal. calcd for C5H8O3S2: C, 33.32; H, 4.47; S, 35.58; found: C, 33.14; H, 4.51; S, 35.51.

3.1.2. Methyl 3-([(methylsulfanyl)carbonothioyl]oxy)propanoate 1b

Yield 17.8 g (92%). Yellow oil: bp 94–95 °C (0.5 Torr). n class="Chemical">1H-NMR (400 MHz, CDCl3): δ 2.52 (s, 3H, SCH3), 2.80 (t, 3J = 6.4 Hz, 2H, CH2), 3.70 (s, 3H, OCH3), 5.15 (t, 3J = 6.4 Hz, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 18.7 (s, SCH3), 32.9 (s, CH2), 51.6 (s, OCH3), 68.2 (s, CH2), 170.2 (s, C=O), 215.2 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 194 (62) [M]+. Anal. calcd for C6H10O3S2: C, 37.09; H, 5.19; S, 33.01; found: C, 37.17; H, 5.29; S, 32.94.

3.1.3. O-(2-Cyanoethyl)-S-methyl-dithiocarbonate 1c

Yield 14.3 g (89%). Yellow oil: bp 94–95 °C (0.3 Torr). n class="Chemical">1H-NMR (300 MHz, CDCl3): δ 2.53 (s, 3H, SCH3), 2.82 (t, 3J = 6.3 Hz, 2H, CH2), 4.73 (t, 3J = 6.3 Hz, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 17.3 (s, CH2), 18.9 (s, SCH3), 66.2 (s, CH2), 116.1 (s, C≡N), 214.9 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 161 (67) [M]+. Anal. calcd for C5H7NOS2: C, 37.24; H, 4.38; S, 39.77; found: C, 37.30; H, 5.44; S, 39.70.

3.2. Synthesis of Xanthates : General Procedure

To the stirred solution of hydroxyderivatives (0.1 mol) in anhydrous n class="Chemical">DMF (50 mL) sodium hydride (60% in mineral oil) (4.4 g, 0.11 mol) was added with mechanistic stirring between −5 and 0 °C. After addition, stirring was continued for 2 h at room temperature. Carbon disulfide (9 mL, 0.15 mol) was added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. The color of the one was gradually changed to dark red. The reaction mixture was cooled to 0 °C and methyl iodide (7.8 mL, 0.12 mol) was added dropwise. The mixture was warmed to room temperature, stirred for 3 h until the color changed from dark red to yellow and poured into ice (100 g), extracted with CH2Cl2 (3 × 50 mL). The extract was washed with water (3 × 50 mL) and dried with MgSO4. After removal of the solvent the product was washed with hexane and dried in vacuum.

3.2.1. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl] S-Methyl Dithiocarbonate 1d

Yield 27.8 g (99%). Yellow powder: mp 105–106 °C. 1H-NMR (400 MHz, n class="Chemical">CDCl3): δ 2.49 (s, 3H, SCH3), 4.10 (t, 3J = 5.6 Hz, 2H, CH2), 4.82 (t, 3J = 5.6 Hz, 2H, CH2), 7.71–7.73 (m, 2H, arom H), 7.83–7.86 (m, 2H, arom H). 13C-NMR (125 MHz, DMSO-d6): δ 18.4 (s, SCH3), 36.3 (s, CH2), 70.6 (s, CH2), 123.2 (s, arom. C), 131.6 (s, arom. C), 134.6 (s, arom. C), 167.7 (s, C=O), 215.2 (s, C=S). LC-MS, m/z: 282 [M + H]+. Anal. calcd for C12H11NO3S2: C, 51.23; H, 3.94; N, 4.98; S, 22.79; found: C, 51.30; H, 4.00; N, 4.98; S, 22.70.

3.2.2. O-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl] S-Methyl Dithiocarbonate 1e

Yield 29.5 g (100%). Yellow powder: mp 101–102 °C. 1H-NMR (300 MHz, n class="Chemical">DMSO-d6): δ 2.08–2.12 (m, 2H, CH2), 3.34 (s, 3H, SCH3), 3.71 (t, 3J = 6.3 Hz, 2H, CH2), 4.58 (t, 3J = 6.0 Hz, 2H, CH2), 7.83–7.85 (m, 4H, arom H). 13C-NMR (100 MHz, DMSO-d6): δ 18.8 (s, SCH3), 27.3 (s, CH2), 35.0 (s, CH2), 72.4 (s, CH2), 123.4 (s, arom. C), 132.1 (s, arom. C), 134.7 (s, arom. C), 168.3 (s, C=O), 215.6 (s, C=S). LC-MS, m/z: 296 [M + H]+. Anal. calcd for C13H13NO3S2: C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.92; H, 4.52; N, 4.68; S, 21.70.

3.2.3. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpropyl] S-Methyl Dithiocarbonate 1f

Yield 27.5 g (89%). Yellow powder: mp 85–86 °C. 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 1.77 (s, 6H, 2CH2), 2.47 (s, 3H, SCH3), 4.98 (s, 2H, CH2), 7.70–7.73 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 18.5 (s, SCH3), 26.2 (s, 2CH3), 58.7 (s, C), 77.1 (s, CH2), 122.5 (s, arom. C), 131.4 (s, arom. C), 133.6 (s, arom. C), 168.8 (s, C=O), 214.7 (s, C=S). LC-MS, m/z: 310 [M + H]+. Anal. calcd for C14H15NO3S2: C, 54.35; H, 4.89; N, 4.53; S, 20.73; found: C, 54.42; H, 4.96; N, 4.50; S, 20.75.

3.2.4. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-methylethyl] S-Methyl Dithiocarbonate 1g

Yield 28.9 g (98%). Yellow powder: mp 85–86 °C. 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 1.43 (d, 3J = 6.4 Hz, 3H, CH3), 2.48 (s, 3H, SCH3), 3.89 (dd, 2J = 14.4 Hz, 3J = 3.2 Hz, 1H, CH2), 4.04 (dd, 2J = 14.4 Hz, 3J = 7.6 Hz, 1H, CH2), 6.00–7.10 (m, 1H, CH), 7.70–7.72 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 17.5 (s, CH3), 18.9 (s, SCH3), 43.7 (s, CH2), 77.6 (s, C), 123.5 (s, arom. C), 132.0 (s, arom. C), 134.2 (s, arom. C), 168.1 (s, C=O), 215.3 (s, C=S). LC-MS, m/z: 296 [M + H]+. Anal. calcd for C13H13NO3S2: C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.88; H, 4.86; N, 4.69; S, 21.76.

3.3. Synthesis of Trichloroderivatives : General Procedure

Chlorine was bubbled through the solution of n class="Chemical">xanthate 1a–g (50 mmol) in carbon tetrachloride (50 mL) at 0 °C for 1 h. The reaction mixture was warmed to 20 °C and chlorine was bubbled for further 1 h. Methylene chloride (10 mL) was added to the reaction mixture and chlorine was bubbled for further 1 h. Excess of chlorine was removed with stream of nitrogen. After removal of the solvent, product was distilled in vacuum or washed with hexane and dried in vacuum.

3.3.1. Methyl (trichloromethoxy)acetate 2a

Yield 9.0 g (87%). Colorless liquid: bp 87–88 °C (10 Torr). 1H-NMR (400 MHz, n class="Chemical">CDCl3): δ 3.83 (s, 3H, OCH3), 4.64 (s, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 52.7 (s, OCH3), 66.7 (s, CH2), 112.6 (s, CCl3), 166.2 (s, C=O). Anal. calcd for C4H5Cl3O3: C, 23.16; H, 2.43; Cl, 51.27; found: C, 33.12; H, 2.40; Cl, 52.35.

3.3.2. Methyl 3-(trichloromethoxy)propanoate 2b

Yield 9.8 g (89%). Colorless liquid: bp 64–65 °C (0.5 Torr). 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 2.76 (t, 3J = 6.4 Hz, 2H, CH2), 3.71 (s, 3H, OCH3), 5.35 (t, 3J = 6.4 Hz, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 32.9 (s, CH2), 51.7 (s, OCH3), 66.4 (s, CH2), 111.9 (s, CCl3), 169.7 (s, C=O). Anal. calcd for C5H7Cl3O3: C, 27.12; H, 3.19; Cl, 48.02; found: C, 27.07; H, 3.12; Cl, 48.09.

3.3.3. 3-(Trichloromethoxy)propanenitrile 2c

Yield 8.7 g (92%). Colorless liquid: bp 77–78 °C (0.3 Torr). 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 2.83 (t, 3J = 6.6 Hz, 2H, CH2), 4.29 (t, 3J = 6.6 Hz, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 17.6 (s, CH2), 64.8 (s, CH2), 111.9 (s, CCl3), 115.5 (s, C≡N). Anal. calcd for C4H4Cl3NO: C, 25.50; H, 2.14; Cl, 56.44; N, 7.43; found: C, 25.55; H, 2.14; Cl, 56.50; N, 7.40.

3.3.4. 2-[2-(Trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2d

Yield 14.8 g (96%). Colorless powder: mp 93–94 °C. 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 4.06 (t, 3J = 5.3 Hz, 2H, CH2), 4.34 (t, 3J = 5.3 Hz, 2H, CH2), 7.74–7.76 (m, 2H, arom H), 7.83–7.86 (m, 2H, arom H). 13C-NMR (100 MHz, CDCl3): δ 36.4 (s, CH2), 68.1 (s, CH2), 112.5 (s, CCl3), 123.5 (s, arom. C), 131.8 (s, arom. C), 134.2 (s, arom. C), 167.8 (s, C=O). Anal. calcd for C11H8Cl3NO3: C, 42.82; H, 2.61; Cl, 34.47; N, 4.54; found: C, 42.90; H, 2.52; Cl, 34.50; N, 4.44.

3.3.5. 2-[3-(Trichloromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 2e

Yield 15.3 g (95%). Colorless powder: mp 102–103 °C. 1H-NMR (400 MHz, n class="Chemical">CDCl3): δ 2.12–2.19 (m, 2H, CH2), 3.83 (t, 3J = 6.8 Hz, 2H, CH2), 4.16 (t, 3J = 6.0 Hz, 2H, CH2), 7.60–7.70 (m, 2H, arom H), 7.80–7.90 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 27.3 (s, CH2), 35.1 (s, CH2), 69.6 (s, CH2), 112.4 (s, CCl3), 123.3 (s, arom. C), 132.0 (s, arom. C), 134.0 (s, arom. C), 168.2 (s, C=O). Anal. calcd for C12H10Cl3NO3: C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75; H, 3.10; Cl, 33.00; N, 4.40.

3.3.6. 2-[1,1-Dimethyl-2-(trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2f

Yield 13.8 g (82%). Colorless powder: mp 93–94 °C. 1H-NMR (500 MHz, n class="Chemical">CDCl3): δ 1.79 (s, 6H, 2CH3), 4.53 (s, 2H, CH2), 7.68–7.71 (m, 2H, arom H), 7.75–7.80 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 24.7 (s, 2CH3), 58.8 (s, C), 75.6 (s, CH2), 112.6 (s, CCl3), 123.1 (s, arom. C), 131.9 (s, arom. C), 134.1 (s, arom. C), 169.4 (s, C=O). Anal. calcd for C13H12Cl3NO3: C, 46.39; H, 3.59; Cl, 31.60; N, 4.16; found: C, 46.45; H, 3.50; Cl, 31.68; N, 4.05.

3.3.7. 2-[2-(Trichloromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 2g

Yield 13.7 g (85%). Colorless powder: mp 96–97 °C. 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 1.55 (d, 3J = 6.3 Hz, 3H, CH3), 3.79 (dd, 2J = 14.1 Hz, 3J = 3.6 Hz, 1H, CH2), 4.06 (dd, 2J = 14.1 Hz, 3J = 8.1 Hz, 1H, CH2), 4.80–4.95 (m, 1H, CH), 7.70–7.80 (m, 2H, arom H), 7.85–7.95 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 18.4 (s, CH3), 42.1 (s, CH2), 78.2 (s, C), 123.5 (s, arom. C), 132.5 (s, arom. C), 134.2 (s, arom. C), 167.9 (s, C=O). Anal. calcd for C12H10Cl3NO3: C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75; H, 3.20; Cl, 33.00; N, 4.35.

3.4. Fluorination of Trichloromethoxy Derivatives with Antimony Trifluoride (Method A)

3.4.1. Fluorination of Esters 2a–b and Nitrile 2c: General Procedure

The mixture of pounded antimony trifluoride (17.9 g, 100 mmol) and antimonium pentachloride (1.5 g, 5 mmol) was carefully heated to 30−35 °C with mechanistic stirring to a homogenous pasty mass formation. The mixture was cooled to 0 °C and trichloromethoxy derivative 2a–c (50 mmol) was added at once. The reaction mixture was heated at 90 °C for 10 min. Then the mixture was heated to 120−135 °C with simultaneous vacuum (150 Torr) distillation of the product in the trap cooled with crushed ice. The pure product was obtained after redistillation.

3.4.2. Fluorination of Protected Amines 2d–g: General Procedure

The mixture of pounded antimony trifluoride (17.9 g, 100 mmol) and antimonium pentacloride (1.5 g, 5 mmol) was carefully heated to 30−35 °C with mechanistic stirring to a homogenous pasty mass formation. The mixture was cooled to 0 °C and trichloromethoxy derivative 2d–g (50 mmol) was added at once. The reaction mixture was gradually heated firstly at 25 °C for 30 min, then at 45 °C for 30 min, and finally at 95 °C for 20 min. After cooling to room temperature the reaction mixture was washed with CH2Cl2 (5 × 50 mL), combined organic extracts were washed with 10% aqueous HCl solution (10 × 20 mL) then with water (5 × 20 mL) and dried with MgSO4. The solution was filtered through SiO2 and evaporated to dryness. The pure product was obtained after crystallization from hexane.

3.5. Fluorination of Trichloromethoxy Derivatives with Hydrogenfluoride (Method B): General Procedure

Trichloromethoxy derivative 2a–g (50 mmol) was placed into n class="Chemical">stainless steel autoclave (100 mL volume) and cooled to −40 °C. Anhydrous HF (50 mL) and SbCl5 (0.75 g, 2.5 mmol) were added at the same temperature. Autoclave was sealed and the reaction mixture was heated at 45 °C for 0.5 h, then at 95 °C for 2.5 h, and cooled to room temperature. Excess of hydrogen fluoride and hydrogen chloride formed in the reaction were distilled in a polyethylene trap cooled to −15 °C. The residue was dissolved in CH2Cl2 (100 mL) washed with saturated aqueous K2CO3 solution (4 × 20 mL), then with water (3 × 20 mL), dried with MgSO4, and filtered through SiO2. After removal of the solvent, the product was distilled in vacuum or crystallized from hexane and dried in vacuum.

3.6. Fluorination of Xanthate with Pyridine-Hydrogenfluoride and 1,3-Dibromo-5,5-Dimethylhydantoin (DBH) (Method C): General Procedure

Reactions were performed in a polyethylene flask (500 mL) equipped with an additional n class="Chemical">polyethylene funnel, magnetic stirrer, and BOLA PTFE coated temperature probe.

Complex HF70%-n class="Chemical">pyridine was added dropwise at −78 °C to a suspension of DBH (42.9 g, 0.15 mol) in CH2Cl2 (130 mL). The mixture was stirred for 10 min and the solution of corresponding xanthate 1a–g (0.05 mol) in CH2Cl2 (70 mL) was added at the same temperature. The reaction mixture was stirred at −78 °C for 1 h, warmed to room temperature, stirred for 5 h and poured into ice (100 g). As saturated aqueous solution of Na2SO3 was added to the mixture until the red color of the mixture changed to light yellow. Then the mixture was neutralized with aqueous K2CO3 solution. The organic layer was separated and the aqueous solution was extracted with CH2Cl2 (3 × 50 mL). Combined organic extracts were washed with water (3 × 500 mL) and dried with MgSO4. After removal of the solvent, the product was distilled or crystallized from hexane and dried in vacuum.

3.6.1. Methyl (trifluoromethoxy)acetate 3a

Yield 2.84 g (36% method C). Colorless liquid: bp 102–104 °C (lit. 110 °C [11]). 1H-NMR (400 MHz, n class="Chemical">CDCl3): δ 3.81 (s, 3H, OCH3), 4.48 (s, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 52.5 (s, OCH3), 62.9 (q, 3JCF = 2.5 Hz, CH2), 121.4 (q, JCF = 256.4 Hz, CF3), 166.5 (s, C=O). 19F-NMR (376.5 MHz, CDCl3): δ −62.12 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 158 (46) [M]+. Anal. calcd for C4H5F3O3: C, 30.39; H, 3.19; found: C, 30.12; H, 3.04.

3.6.2. Methyl 3-(trifluoromethoxy)propanoate 3b

Yield 4.55 g (53% method A). Yield 5.9 g (69% method B). Yield 5.4 g (63% method B). Colorless liquid: bp 124–125 °C. 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 2.64 (t, 3J = 5.4 Hz, 2H, CH2), 3.66 (s, 3H, OCH3), 4.17 (t, 3J = 5.4 Hz, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 33.2 (s, CH2), 51.3 (s, OCH3), 62.2 (q, 3JCF = 3.3 Hz, CH2), 121.0 (q, JCF = 253.3 Hz, CF3), 169.8 (s, C=O). 19F-NMR (188 MHz, CDCl3): δ −61.88 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 172 (52) [M]+. Anal. calcd for C5H7F3O3: C, 34.89; H, 4.10; found: C, 34.55; H, 4.02.

3.6.3. 3-(Trifluoromethoxy)propanenitrile 3c

Yield 1.5 g (22% method A). Yield 4.6 g (66% method B). Yield 4.6 g (66% method B). Colorless liquid: bp 100–102 °C (120 Torr). 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 2.70 (t, 3J = 6.3 Hz, 2H, CH2), 4.11 (t, 3J = 6.3 Hz, 2H, CH2). 13C-NMR (125 MHz, CDCl3): δ 18.0 (s, CH2), 61.2 (q, 3JCF = 3.4 Hz, CH2), 115.3 (s, C≡N), 120.8 (q, JCF = 255.1 Hz, CF3). 19F-NMR (188 MHz, CDCl3): δ −62.10 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 139 (66) [M]+. Anal. calcd for C4H4F3NO: C, 34.54; H, 2.90; N, 10.07; found: C, 34.40; H, 2.84; N, 9.90.

3.6.4. 2-[2-(Trifluoromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 3d

Yield 11.65 g (90% method A). Yield 12.0 g (93% method B). Yield 12.4 g (96% method B). Colorless powder: mp 73–74 °C (lit. 77 °C [16]), bp 100–102 °C (0.2 Torr). 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 3.93 (t, 3J = 5.3 Hz, 2H, CH2), 4.20 (t, 3J = 5.3 Hz, 2H, CH2), 7.70–7.77 (m, 2H, arom H), 7.80–7.90 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 36.7 (s, CH2), 63.9 (s, CH2), 121.7 (q, JCF = 255.2 Hz, CF3), 123.5 (s, arom. C), 131.8 (s, arom. C), 134.2 (s, arom. C), 167.8 (s, C=O). 19F-NMR (188 MHz, CDCl3): δ −61.55 (s, CF3). LC-MS, m/z: 260 [M + H]+. Anal. calcd for C11H8F3NO3: C, 50.98; H, 3.11; N, 5.40; found: C, 50.90; H, 3.23; N, 5.44.

3.6.5. 2-[3-(Trifluoromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 3e

Yield 12.0 g (88% method A). Yield 12.3 g (90% method B). Yield 13.0 g (96% method B). Colorless powder: mp 77–78 °C. 1H-NMR (400 MHz, n class="Chemical">CDCl3): δ 2.04–2.12 (m, 2H, CH2), 3.70–3.82 (m, 2H, CH2), 4.00–4.12 (m, 2H, CH2), 7.68–7.72 (m, 2H, arom H), 7.80–7.88 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 28.0 (s, CH2), 34.8 (s, CH2), 65.1 (s, CH2), 121.6 (q, JCF = 254.0 Hz, CF3), 123.4 (s, arom. C), 132.1 (s, arom. C), 134.2 (s, arom. C), 168.3 (s, C=O). 19F-NMR (376.5 MHz, CDCl3): δ −61.49 (s, CF3). LC-MS, m/z: 274 [M + H]+. Anal. calcd for C12H10F3NO3: C, 52.75; H, 3.69; N, 5.13; found: C, 52.77; H, 3.70; N, 5.22.

3.6.6. 2-[1,1-Dimethyl-2-(trifluoromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 3f

Yield 8.6 g (60% method A). Yield 8.9 g (62% method B). Yield 12.2 g (85% method B). Colorless powder: mp 73–74 °C. 1H-NMR (300 MHz, n class="Chemical">CDCl3): δ 1.69 (s, 6H, 2CH3), 4.35 (s, 2H, CH2), 7.60–7.67 (m, 2H, arom H), 7.70–7.77 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 24.8 (s, 2CH3), 58.3 (s, C), 70.7 (s, CH2), 120.2 (q, JCF = 253.3 Hz, CF3), 122.5 (s, arom. C), 131.3 (s, arom. C), 133.6 (s, arom. C), 168.9 (s, C=O). 19F-NMR (376.5 MHz, CDCl3): δ −61.11 (s, CF3). LC-MS, m/z: 288 [M + H]+. Anal. calcd for C13H12F3NO3: C, 54.36; H, 4.21; N, 4.88; found: C, 54.47; H, 4.47; N, 4.85.

3.6.7. 2-[2-(Trifluoromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 3g

Yield 3.1 g (23% method A). Yield 4.6 g (34% method B). Yield 13.5 g (99% method B). Colorless powder: mp 71–72 °C. 1H-NMR (500 MHz, n class="Chemical">CDCl3): δ 1.40–1.43 (m, 3H, CH3), 3.79 (dd, 2J = 14.0 Hz, 3J = 2.0 Hz, 1H, CH2), 3.94–4.00 (m, 1H, CH2), 4.80–4.95 (m, 1H, CH), 7.74 (s, 2H, arom H), 7.87 (s, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 18.6 (s, CH3), 42.3 (s, CH2), 72.9 (s, C), 121.5 (q, JCF = 255.1 Hz, CF3), 123.5 (s, arom. C), 131.7 (s, arom. C), 134.2 (s, arom. C), 168.0 (s, C=O). 19F-NMR (376.5 MHz, CDCl3): δ −59.19 (s, CF3). LC-MS, m/z: 274 [M + H]+. Anal. calcd for C12H10F3NO3: C, 52.75; H, 3.69; N, 5.13; found: C, 52.70; H, 3.44; N, 4.12.

4. Conclusions

The “chlorination/fluorination” technique for aromatic trifluoromethyl ether syntheses, since 1955, has been a powerful driver of research in organofluorine chemistry. More than 30,000 substances [4] with such a group were prepared in the last half century. It was shown that this method, as well as oxidative desulfurization-fluorination, can be successfully applied for a wide range of aliphatic substrates with various functional groups. It requires cheap reagents and it is promising in industrial applications.