Evaluation of efficient and practical methods for the preparation of functionalized aliphatic trifluoromethyl ethers

Article abstract of DOI:10.3390/molecules22050804

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.

Full text of DOI:10.3390/molecules22050804

molecules
Article
Evaluation of Efficient and Practical Methods
for the Preparation of Functionalized Aliphatic
Trifluoromethyl Ethers
1
1,†
2
1,‡
Taras M. Sokolenko , Maya I. Dronkina , Emmanuel Magnier , Lev M. Yagupolskii
and Yurii L. Yagupolskii 1
,3,
*
1
Institute of Organic Chemistry, NAS of Ukraine, Murmans’ka St. 5, Kiev 02660, Ukraine; taras_sk@ukr.net
Bâtiment Lavoisier, Université de Versailles-Saint-Quentin, 45 Avenue des Etats-Unis,
Versailles 78035, France; emmanuel.magnier@uvsq.fr
Enamine Ltd, A. Matrosova str. 23, Kiev 01103, Ukraine
Correspondence: Yagupolskii@ioch.kiev.ua; Tel.: +380-44-559-03-49
Retired.
2
3
*
†
‡
Passed away.
Academic Editor: Thierry Billard
Received: 28 April 2017; Accepted: 11 May 2017; Published: 14 May 2017
Abstract: 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.
Keywords: fluorination; chlorination; oxidative desulfurization-fluorination; antimony trifluoride;
hydrogen fluoride; trifluoromethyl ethers
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 [ ]. Nevertheless, growing interest in
emergent fluorinated substituents, like -fluorinated ethers, has been observed within recent years [ ].
While aromatic trifluoromethyl ethers, since their first publication [ ] in 1955, have been extensively
studied and widely used as pharmaceuticals and crop protection agents, as well as critical components
for liquid crystals design [ 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 SF leads to aliphatic trifluoromethyl ethers. For instance, methyl(trifluoromethoxy) acetate was
1–4
α
5–8
9
3–6,
4
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 NEt -HF are commonly used as
3
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].
Molecules 2017, 22, 804; doi:10.3390/molecules22050804
www.mdpi.com/journal/molecules

Molecules 2017, 22, 804
2 of 10
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 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).
NaH, CS2
then MeI
SMe
O
R OH
R
S
1a-g
Me
O
O
O
O
N
S
O
Me
O
O
1
c S
1
a
S
S
1b
S
S
O
O
O
O
Me
S
N
N
S
N
N
S
Me
O
O
S
O
O
S
S
O Me
O
S
O
O
1f
1g
1d
1e
S
Scheme 1. Synthesis and structures of methylxanthates.
Chlorination of xanthates 1a–g readily occurred with elemental chlorine to produce
trichloromethylethers 2a , which were isolated with almost quantitative yields (Scheme 2).
–
g
Chloroderivatives 2a–g can be stored in a fridge and they are extremely sensitive to moisture.
Method A: SbF with SbCl (cat.)
3
5
Cl2
SMe
Method B: HF with SbCl (cat.)
5
O
OCCl3
OCF3
R
R
R
S
1a-g
2a-g
3a-g
Method C: Py / HF70 %, DBH
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).

Molecules 2017, 22, 804
3 of 10
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
1
a
(Table 1, Entry 1). On the contrary, fluorination of trichloromethoxypropanecarboxylic acids
derivatives 2b and xanthates 1b was successfully performed by all three methods (Table 1, entry
,3). In the case of nitrile 2c reaction with SbF (method A) lead to low yield of trifluoromethylether 3c
–c
–c
2
3
(
Table 1, Entry 4). Thus, the presence of electron-withdrawing carboxylic group close to the reaction
center prevented successful fluorination processes.
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 SbF or HF (Table 1, entry 6).
3
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.
Table 1. Structures and yields of chlorinated and fluorinated products.
Chlorinated
Product
Fluorinated
Product
Yield %
Entry
Yield%
Method A Method B Method C
Me
O
Me
O
O
O
1
87
traces
traces
36
O CCl3
O CF3
2a
3a
O
O
2
3
89
92
53
22
69
66
63
66
Me O
O CCl3
Me O
O CF3
2
b
3b
O CF3
O CCl3
N
N
2
c
3c
O
O
N
N
4
5
96
95
90
88
93
90
96
95
O CCl3
O CF3
O
O
2d
3d
O
O
N
N
O
O CF3
O
O
CF3
2e
3e
O
O
Me
Me
N
Me
O
N
Me
O
6
7
82
85
60
23
62
34
85
99
O CF3
O CF3
2f
3f
O
O
N
N
O CCl3
O CF3
O Me
O Me
2g
3g
Note: Method A: SbF3 with SbCl5 (cat.), method B: HF with SbCl5 (cat.), method C: Py / HF70 %, DBH.

Molecules 2017, 22, 804
4 of 10
It must be added that fluorination with pyridine-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).
1
3
C-NMR-spectra (proton decoupled) were recorded on a Bruker AVANCE DRX 500 instrument at
19
1
1
25 MHz, or at 100 MHz with Varian UNITY-Plus 400 spectrometer. F-NMR spectra were recorded at
88 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 Me Si and CCl F,
4
3
1
13
19
respectively, as internal or external standards. H-, C-, and F-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 SOCl . HF70%/pyridine was prepared
2
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 1a–c: General Procedure
◦
30 C to the suspension of sodium
hydride (60% in mineral oil) (4.4 g, 0.11 mol) in anhydrous dimethylformamide (DMF) (200 mL).
Carbon disulfide (18.1 mL, 0.3 mol) was added dropwise at
−
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
◦
1
Yield 15.5 g (86%). Yellow oil: bp 129–130 C (20 Torr). H-NMR (400 MHz, CDCl ):
δ
2.60 (s, 3H,
3
13
SCH ), 3.77 (s, 3H, OCH ), 5.15 (s, 2H, CH ). C-NMR (100 MHz, CDCl3):
δ 19.5 (s, SCH ), 52.4
3
3
2
3

Molecules 2017, 22, 804
5 of 10
+
(
s, OCH ), 67.6 (s, CH ), 167.1 (s, C=O), 215.8 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 180 (69) [M] .
3
2
Anal. calcd for C H O S : C, 33.32; H, 4.47; S, 35.58; found: C, 33.14; H, 4.51; S, 35.51.
5
8
3 2
3
.1.2. Methyl 3-([(methylsulfanyl)carbonothioyl]oxy)propanoate 1b
◦
1
Yield 17.8 g (92%). Yellow oil: bp 94–95 C (0.5 Torr). H-NMR (400 MHz, CDCl ):
2
δ
13
2.52 (s, 3H, SCH3),
3
3
3
.80 (t, J = 6.4 Hz, 2H, CH ), 3.70 (s, 3H, OCH ), 5.15 (t, J = 6.4 Hz, 2H, CH ). C-NMR (125 MHz,
2 3 2
CDCl3):
δ 18.7 (s, SCH ), 32.9 (s, CH ), 51.6 (s, OCH ), 68.2 (s, CH ), 170.2 (s, C=O), 215.2 (s, C=S).
3 2 3 2
+
GC-MS, 70 eV, m/z (rel. int.): 194 (62) [M] . Anal. calcd for C H O S : C, 37.09; H, 5.19; S, 33.01;
6
10
3 2
found: C, 37.17; H, 5.29; S, 32.94.
3
.1.3. O-(2-Cyanoethyl)-S-methyl-dithiocarbonate 1c
◦
1
Yield 14.3 g (89%). Yellow oil: bp 94–95 C (0.3 Torr). H-NMR (300 MHz, CDCl ):
δ
2.53 (s, 3H, SCH3),
.82 (t, J = 6.3 Hz, 2H, CH ), 4.73 (t, J = 6.3 Hz, 2H, CH ). C-NMR (125 MHz, CDCl3): 17.3 (s,
N), 214.9 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 161 (67)
M] . Anal. calcd for C H NOS : C, 37.24; H, 4.38; S, 39.77; found: C, 37.30; H, 5.44; S, 39.70.
3
3
3
13
2
δ
2
2
CH ), 18.9 (s, SCH ), 66.2 (s, CH ), 116.1 (s, C
≡
2
+
3
2
[
5
7
2
3
.2. Synthesis of Xanthates 1d–g: General Procedure
To the stirred solution of hydroxyderivatives (0.1 mol) in anhydrous DMF (50 mL) sodium
hydride (60% in mineral oil) (4.4 g, 0.11 mol) was added with mechanistic stirring between
−
5 and
◦
0
0
C. After addition, stirring was continued for 2 h at room temperature. Carbon disulfide (9 mL,
.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 CH Cl (3
×
50 mL). The extract was washed with water (3
×
50 mL) and dried
2
2
with MgSO . After removal of the solvent the product was washed with hexane and dried in vacuum.
4
3
.2.1. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl] S-Methyl Dithiocarbonate 1d
◦
1
Yield 27.8 g (99%). Yellow powder: mp 105–106 C. H-NMR (400 MHz, CDCl ):
δ
2.49 (s, 3H, SCH3),
3
3
3
4
.10 (t, J = 5.6 Hz, 2H, CH ), 4.82 (t, J = 5.6 Hz, 2H, CH ), 7.71–7.73 (m, 2H, arom H), 7.83–7.86 (m, 2H,
2
2
13
arom H). C-NMR (125 MHz, DMSO-d6):
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 C H NO S : C, 51.23; H, 3.94; N, 4.98; S, 22.79; found: C, 51.30; H, 4.00; N, 4.98; S,
δ 18.4 (s, SCH ), 36.3 (s, CH ), 70.6 (s, CH ), 123.2 (s, arom.
3 2 2
+
12
11
3 2
2
2.70.
3
.2.2. O-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl] S-Methyl Dithiocarbonate 1e
◦
1
Yield 29.5 g (100%). Yellow powder: mp 101–102 C. H-NMR (300 MHz, DMSO-d ):
δ
2.08–2.12
6
3
3
(
(
(
m, 2H, CH ), 3.34 (s, 3H, SCH ), 3.71 (t, J = 6.3 Hz, 2H, CH ), 4.58 (t, J = 6.0 Hz, 2H, CH ), 7.83–7.85
δ 18.8 (s, SCH ), 27.3 (s, CH ), 35.0 (s, CH ), 72.4
3 2 2
s, CH ), 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,
2
3
2
2
1
3
m, 4H, arom H). C-NMR (100 MHz, DMSO-d6):
2
+
m/z: 296 [M + H] . Anal. calcd for C H NO S : C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.92;
13
13
3 2
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
◦
1
Yield 27.5 g (89%). Yellow powder: mp 85–86 C. H-NMR (300 MHz, CDCl ):
2
δ 1.77 (s, 6H, 2CH ),
2
3
13
.47 (s, 3H, SCH ), 4.98 (s, 2H, CH ), 7.70–7.73 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H). C-NMR
3 2
(
125 MHz, CDCl3):
δ 18.5 (s, SCH ), 26.2 (s, 2CH ), 58.7 (s, C), 77.1 (s, CH ), 122.5 (s, arom. C), 131.4
3 3 2
+
(
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 C H NO S : 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.
14
15
3 2

Molecules 2017, 22, 804
6 of 10
3
.2.4. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-methylethyl] S-Methyl Dithiocarbonate 1g
◦
1
3
Yield 28.9 g (98%). Yellow powder: mp 85–86 C. H-NMR (300 MHz, CDCl ):
δ
1.43 (d, J = 6.4 Hz,
3
2
3
2
3
H, CH ), 2.48 (s, 3H, SCH ), 3.89 (dd, J = 14.4 Hz, J = 3.2 Hz, 1H, CH ), 4.04 (dd, J = 14.4 Hz,
J = 7.6 Hz, 1H, CH ), 6.00–7.10 (m, 1H, CH), 7.70–7.72 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H).
δ 17.5 (s, CH ), 18.9 (s, SCH ), 43.7 (s, CH ), 77.6 (s, C), 123.5 (s, arom. C),
3 3 2
32.0 (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.
3
3
2
3
2
13
C-NMR (125 MHz, CDCl3):
+
1
calcd for C H NO S : 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.
13
13
3 2
3
.3. Synthesis of Trichloroderivatives 2a–g: General Procedure
Chlorine was bubbled through the solution of xanthate 1a
50 mL) at 0 C for 1 h. The reaction mixture was warmed to 20 C and chlorine was bubbled for
–
g
(50 mmol) in carbon tetrachloride
◦
◦
(
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
◦
1
Yield 9.0 g (87%). Colorless liquid: bp 87–88 C (10 Torr). H-NMR (400 MHz, CDCl ):
δ
3.83 (s, 3H,
3
13
OCH ), 4.64 (s, 2H, CH ). C-NMR (125 MHz, CDCl3):
δ 52.7 (s, OCH ), 66.7 (s, CH ), 112.6 (s, CCl ),
3
2
3
2
3
1
66.2 (s, C=O). Anal. calcd for C H Cl O : C, 23.16; H, 2.43; Cl, 51.27; found: C, 33.12; H, 2.40; Cl, 52.35.
4 5 3 3
3
.3.2. Methyl 3-(trichloromethoxy)propanoate 2b
◦
1
Yield 9.8 g (89%). Colorless liquid: bp 64–65 C (0.5 Torr). H-NMR (300 MHz, CDCl ):
(
δ 2.76
3
3
3
13
t, J = 6.4 Hz, 2H, CH ), 3.71 (s, 3H, OCH ), 5.35 (t, J = 6.4 Hz, 2H, CH ). C-NMR (125 MHz, CDCl3):
2 3 2
δ
32.9 (s, CH ), 51.7 (s, OCH ), 66.4 (s, CH ), 111.9 (s, CCl ), 169.7 (s, C=O). Anal. calcd for C H Cl O :
2 3 2 3 5 7 3 3
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, CDCl3):
◦
δ
2.83
17.6 (s, CH2),
N). Anal. calcd for C H Cl NO: C, 25.50; H, 2.14; Cl, 56.44; N,
3
3
13
(
t, J = 6.6 Hz, 2H, CH ), 4.29 (t, J = 6.6 Hz, 2H, CH ). C-NMR (125 MHz, CDCl3):
δ
2
2
6
7
4.8 (s, CH ), 111.9 (s, CCl ), 115.5 (s, C
.43; found: C, 25.55; H, 2.14; Cl, 56.50; N, 7.40.
≡
2
3
4
4
3
3
.3.4. 2-[2-(Trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2d
◦
1
3
Yield 14.8 g (96%). Colorless powder: mp 93–94 C. H-NMR (300 MHz, CDCl ):
δ
4.06 (t, J = 5.3 Hz,
3
3
13
2
H, CH ), 4.34 (t, J = 5.3 Hz, 2H, CH ), 7.74–7.76 (m, 2H, arom H), 7.83–7.86 (m, 2H, arom H). C-NMR
2
2
(
100 MHz, CDCl3):
δ 36.4 (s, CH ), 68.1 (s, CH ), 112.5 (s, CCl ), 123.5 (s, arom. C), 131.8 (s, arom. C),
2 2 3
1
34.2 (s, arom. C), 167.8 (s, C=O). Anal. calcd for C H Cl NO : C, 42.82; H, 2.61; Cl, 34.47; N, 4.54;
11
8
3
3
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
◦
1
Yield 15.3 g (95%). Colorless powder: mp 102–103 C. H-NMR (400 MHz, CDCl ):
δ
2.12–2.19 (m,
3
3
3
2
7
H, CH ), 3.83 (t, J = 6.8 Hz, 2H, CH ), 4.16 (t, J = 6.0 Hz, 2H, CH ), 7.60–7.70 (m, 2H, arom H),
.80–7.90 (m, 2H, arom H). C-NMR (125 MHz, CDCl3):
2
2
2
13
δ 27.3 (s, CH ), 35.1 (s, CH ), 69.6 (s, CH ),
2 2 2
1
12.4 (s, CCl ), 123.3 (s, arom. C), 132.0 (s, arom. C), 134.0 (s, arom. C), 168.2 (s, C=O). Anal. calcd for
3
C H Cl NO : 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.
12
10
3
3
3
.3.6. 2-[1,1-Dimethyl-2-(trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2f
◦
1
Yield 13.8 g (82%). Colorless powder: mp 93–94 C. H-NMR (500 MHz, CDCl ):
δ
1.79 (s, 6H, 2CH3),
3
13
4
.53 (s, 2H, CH ), 7.68–7.71 (m, 2H, arom H), 7.75–7.80 (m, 2H, arom H). C-NMR (125 MHz, CDCl3):
2

Molecules 2017, 22, 804
7 of 10
δ
24.7 (s, 2CH ), 58.8 (s, C), 75.6 (s, CH ), 112.6 (s, CCl ), 123.1 (s, arom. C), 131.9 (s, arom. C), 134.1
3 2 3
(
s, arom. C), 169.4 (s, C=O). Anal. calcd for C H Cl NO : C, 46.39; H, 3.59; Cl, 31.60; N, 4.16; found:
13 12 3 3
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
◦
1
3
Yield 13.7 g (85%). Colorless powder: mp 96–97 C. H-NMR (300 MHz, CDCl ):
δ
1.55 (d, J = 6.3 Hz,
3
2
3
2
3
3
4
H, CH ), 3.79 (dd, J = 14.1 Hz, J = 3.6 Hz, 1H, CH ), 4.06 (dd, J = 14.1 Hz, J = 8.1 Hz, 1H, CH ),
.80–4.95 (m, 1H, CH), 7.70–7.80 (m, 2H, arom H), 7.85–7.95 (m, 2H, arom H). C-NMR (125 MHz,
18.4 (s, CH ), 42.1 (s, CH ), 78.2 (s, C), 123.5 (s, arom. C), 132.5 (s, arom. C), 134.2 (s, arom.
3
2
2
13
CDCl3):
δ
3
2
C), 167.9 (s, C=O). Anal. calcd for C H Cl NO : C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75;
12
10
3
3
H, 3.20; Cl, 33.00; N, 4.35.
3
.4. Fluorination of Trichloromethoxy Derivatives 2a–g 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
added at once. The reaction mixture was heated at 90 C for 10 min. Then the mixture was heated to
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.
–
c
(50 mmol) was
◦
◦
1
20
−
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
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
–
g
(50 mmol) was
◦
◦
◦
was washed with CH Cl (5
×
50 mL), combined organic extracts were washed with 10% aqueous
2
2
HCl solution (10
×
20 mL) then with water (5 20 mL) and dried with MgSO . The solution was
×
4
filtered through SiO and evaporated to dryness. The pure product was obtained after crystallization
2
from hexane.
3.5. Fluorination of Trichloromethoxy Derivatives 2a–g with Hydrogenfluoride (Method B): General Procedure
Trichloromethoxy derivative 2a
–
g
(50 mmol) was placed into stainless steel autoclave (100 mL
◦
volume) and cooled to
−
40 C. Anhydrous HF (50 mL) and SbCl (0.75 g, 2.5 mmol) were added at
5
◦
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 CH Cl (100 mL) washed with saturated aqueous K CO solution (4
×
20 mL), then
2
2
2
3
with water (3
×
20 mL), dried with MgSO , and filtered through SiO . After removal of the solvent,
4
2
the product was distilled in vacuum or crystallized from hexane and dried in vacuum.
3
.6. Fluorination of Xanthate 1a–g 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
polyethylene funnel, magnetic stirrer, and BOLA PTFE coated temperature probe.
◦
Complex HF70%-pyridine was added dropwise at
−
78 C to a suspension of DBH (42.9 g, 0.15 mol)
in CH Cl (130 mL). The mixture was stirred for 10 min and the solution of corresponding xanthate
2
2
1
a–g (0.05 mol) in CH Cl (70 mL) was added at the same temperature. The reaction mixture was
2 2

Molecules 2017, 22, 804
8 of 10
◦
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 Na SO was added to the mixture until the red color of the mixture
2
3
changed to light yellow. Then the mixture was neutralized with aqueous K CO solution. The organic
2
3
layer was separated and the aqueous solution was extracted with CH Cl (3
×
50 mL). Combined
2
2
organic extracts were washed with water (3
×
500 mL) and dried with MgSO . After removal of the
4
solvent, the product was distilled or crystallized from hexane and dried in vacuum.
3
.6.1. Methyl (trifluoromethoxy)acetate 3a
◦
◦
1
Yield 2.84 g (36% method C). Colorless liquid: bp 102–104 C (lit. 110 C [11]). H-NMR (400 MHz,
13
CDCl ):
δ 3.81 (s, 3H, OCH ), 4.48 (s, 2H, CH ). C-NMR (125 MHz, CDCl ): δ 52.5 (s, OCH ), 62.9
3 2 3 3
3
3
19
(
q, J = 2.5 Hz, CH ), 121.4 (q, J = 256.4 Hz, CF ), 166.5 (s, C=O). F-NMR (376.5 MHz, CDCl3):
δ
CF
2
CF
3
+
−
62.12 (s, CF ). GC-MS, 70 eV, m/z (rel. int.): 158 (46) [M] . Anal. calcd for C H F O : C, 30.39; H,
3 4 5 3 3
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:
◦
1
3
bp 124–125 C. H-NMR (300 MHz, CDCl ):
δ 2.64 (t, J = 5.4 Hz, 2H, CH ), 3.66 (s, 3H, OCH ),
2 3
3
3
13
4
.17 (t, J = 5.4 Hz, 2H, CH ). C-NMR (125 MHz, CDCl3): δ 33.2 (s, CH ), 51.3 (s, OCH ), 62.2 (q,
JCF = 3.3 Hz, CH ), 121.0 (q, J = 253.3 Hz, CF ), 169.8 (s, C=O). F-NMR (188 MHz, CDCl3):
61.88 (s, CF ). GC-MS, 70 eV, m/z (rel. int.): 172 (52) [M] . Anal. calcd for C H F O : C, 34.89; H,
3 5 7 3 3
.10; found: C, 34.55; H, 4.02.
2
2
3
3
19
δ
2
CF
3
+
−
4
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
◦
1
3
3
1
2
1
00–102 C (120 Torr). H-NMR (300 MHz, CDCl ):
δ
2.70 (t, J = 6.3 Hz, 2H, CH ), 4.11 (t, J = 6.3 Hz,
3
2
H, CH2). 13C-NMR (125 MHz, CDCl ):
δ
18.0 (s, CH ), 61.2 (q, J = 3.4 Hz, CH ), 115.3 (s, C
3
≡
N),
3
2
CF
2
19
20.8 (q, JCF = 255.1 Hz, CF ). F-NMR (188 MHz, CDCl3): δ −62.10 (s, CF ). GC-MS, 70 eV, m/z (rel.
3
3
+
int.): 139 (66) [M] . Anal. calcd for C H F NO: C, 34.54; H, 2.90; N, 10.07; found: C, 34.40; H, 2.84;
4
4 3
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
◦
◦
3
◦
1
powder: mp 73–74 C (lit. 77 C [16]), bp 100–102 C (0.2 Torr). H-NMR (300 MHz, CDCl ):
δ 3.93 (t,
3
3
J = 5.3 Hz, 2H, CH ), 4.20 (t, J = 5.3 Hz, 2H, CH ), 7.70–7.77 (m, 2H, arom H), 7.80–7.90 (m, 2H, arom
2
2
13
H). C-NMR (125 MHz, CDCl3):
δ
36.7 (s, CH ), 63.9 (s, CH ), 121.7 (q, J = 255.2 Hz, CF ), 123.5 (s,
2
2
CF
3
1
9
arom. C), 131.8 (s, arom. C), 134.2 (s, arom. C), 167.8 (s, C=O). F-NMR (188 MHz, CDCl3): δ −61.55
+
(
s, CF ). LC-MS, m/z: 260 [M + H] . Anal. calcd for C H F NO : C, 50.98; H, 3.11; N, 5.40; found: C,
3
11
8
3
3
5
0.90; 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
◦
1
powder: mp 77–78 C. H-NMR (400 MHz, CDCl ):
δ 2.04–2.12 (m, 2H, CH ), 3.70–3.82 (m, 2H, CH ),
2 2
3
13
4
.00–4.12 (m, 2H, CH ), 7.68–7.72 (m, 2H, arom H), 7.80–7.88 (m, 2H, arom H). C-NMR (125 MHz,
2
CDCl3):
δ
28.0 (s, CH ), 34.8 (s, CH ), 65.1 (s, CH ), 121.6 (q, J = 254.0 Hz, CF ), 123.4 (s, arom. C),
2
2
2
CF
3
19
1
32.1 (s, arom. C), 134.2 (s, arom. C), 168.3 (s, C=O). F-NMR (376.5 MHz, CDCl3): δ −61.49 (s, CF3).
+
LC-MS, m/z: 274 [M + H] . Anal. calcd for C H F NO : C, 52.75; H, 3.69; N, 5.13; found: C, 52.77; H,
12
10
3
3
3
.70; N, 5.22.

Molecules 2017, 22, 804
9 of 10
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:
◦
1
mp 73–74 C. H-NMR (300 MHz, CDCl ):
δ
1.69 (s, 6H, 2CH ), 4.35 (s, 2H, CH ), 7.60–7.67 (m, 2H,
3
3
2
arom H), 7.70–7.77 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3):
δ
24.8 (s, 2CH ), 58.3 (s, C), 70.7 (s,
3
CH ), 120.2 (q, J = 253.3 Hz, CF ), 122.5 (s, arom. C), 131.3 (s, arom. C), 133.6 (s, arom. C), 168.9 (s,
2
CF
3
1
9
+
C=O). F-NMR (376.5 MHz, CDCl3): δ −61.11 (s, CF ). LC-MS, m/z: 288 [M + H] . Anal. calcd for
3
C H F NO : C, 54.36; H, 4.21; N, 4.88; found: C, 54.47; H, 4.47; N, 4.85.
13
12
3
3
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:
◦
1
2
3
mp 71–72 C. H-NMR (500 MHz, CDCl ):
δ 1.40–1.43 (m, 3H, CH ), 3.79 (dd, J = 14.0 Hz, J = 2.0 Hz,
3
3
1
H, CH ), 3.94–4.00 (m, 1H, CH ), 4.80–4.95 (m, 1H, CH), 7.74 (s, 2H, arom H), 7.87 (s, 2H, arom H).
2
2
13
C-NMR (125 MHz, CDCl3):
δ 18.6 (s, CH ), 42.3 (s, CH ), 72.9 (s, C), 121.5 (q, J = 255.1 Hz, CF3),
3 2 CF
19
123.5 (s, arom. C), 131.7 (s, arom. C), 134.2 (s, arom. C), 168.0 (s, C=O). F-NMR (376.5 MHz, CDCl3):
+
δ −59.19 (s, CF ). LC-MS, m/z: 274 [M + H] . Anal. calcd for C H F NO : C, 52.75; H, 3.69; N, 5.13;
3
12 10
3
3
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 [ ] with
4
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.
Supplementary Materials: 1H-, 13C-, and 19F-NMR spectra of products associated with this article are
available online.
Author Contributions: L.M.Y. conceived idea of the article; T.M.S., M.I.D., E.M., and Y.L.Y. conceived and
performed the experiments; and T.M.S. and Y.L.Y. wrote the paper. All authors except L.M.Y. read and approved
the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
6.
7.
8.
Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; John Wiley & Sons Ltd.: Chichester, UK, 2009.
CrossRef]
O’Hagan, D.J. Fluorine in health care: Organofluorine containing blockbuster drugs. J. Fluor. Chem. 2010
31, 1071–1081. [CrossRef]
Leroux, F.; Manteau, B.; Vors, J.-P.; Pazenok, S. Trifluoromethyl ethers—Synthesis and properties of
an unusual substituent. Beilstein J. Org. Chem. 2008, 4, 13. [CrossRef] [PubMed]
Leroux, F.; Jeschke, P.; Schlosser, M. α-Fluorinated Ethers, Thioethers, and Amines: Anomerically Biased
Species. Chem. Rev. 2005, 105, 827–856. [CrossRef] [PubMed]
Landelle, G.; Panossian, A.; Leroux, F.R. Trifluoromethyl Ethers and Thioethers as Tools for Medicinal
Chemistry and Drug Discovery. Curr. Top. Med. Chem. 2014, 14, 941–951. [CrossRef] [PubMed]
[
,
1
Besset, T.; Jubault, P.; Pannecoucke, X.; Poisson, T. New entries toward the synthesis of OCF -containing
3
molecules. Org. Chem. Front. 2016, 3, 1004–1010. [CrossRef]
Tlili, A.; Toulgoat, F.; Billard, T. Synthetic Approaches to Trifluoromethoxy-Substituted Compounds.
Angew. Chem. Int. Ed. 2016, 55, 11726–11735. [CrossRef] [PubMed]
Guo, S.; Cong, F.; Guo, R.; Wang, L.; Tang, P. Asymmetric silver-catalysed intermolecular
bromotrifluoromethoxylation of alkenes with a new trifluoromethoxylation reagent. Nat. Chem. 2017
CrossRef]
Yagupolskii, L.M. Synthesis of derivatives of phenyl trifluoromethyl ethers. Dokl. Acad. Nauk SSSR 1955, 105,
00–102, Chem. Abstr. 1956, 50, 11270b.
.
[
9
.
1

Molecules 2017, 22, 804
10 of 10
1
1
1
1
0. Yarovenko, N.N.; Vasileva, V.S. A new method of introduction of trihalomethyl group into organic
compounds. J. Gen. Chem. USSR 1958, 28, 2539.
1. Yagupolskii, L.M.; Alekseenko, A.N.; Ilchenko, A.Y. Perfluoroalcoxyacetic acids and they derivatives.
Sov. Prog. Chem. (Engl. Transl.), 1978, 44, 52–55.
2. Farnham, W.B.; Middleton, W.J. Tris(disubstituted amino)sulfonium perfluoroalkoxides and
perfluoroalkylmercaptides and process for their preparation. US Patent 4628094, 9 December 1986.
3. Kanie, K.; Tanaka, Y.; Shimizu, M.; Kuroboshi, M.; Hiyama, T. Oxidative desulfurization-fluorination of
alkanol xanthates. Control of the reaction pathway to fluorination or trifluoromethoxylation. Chem. Commun.
1
997, 3, 309–310.
1
1
4. Thibaudeau, C.; Nishizono, N.; Sumita, Y.; Matsuda, A.; Chattopadhyaya, J. Determination of the Group
1
Electronegativity of CF3 Group in 3’-O-CF Thymidine by H-NMR. Nucleosides Nucleotides 1999, 18,
3
1
035–1053. [CrossRef]
5. Kuroboshi, M.; Suzuki, K.; Hiyama, T. Oxidative desulfurization-fluorination of xanthates. A convenient
synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers. Tetrahedron Lett. 1992, 33,
4
173–4176. [CrossRef]
1
1
1
1
2
6. Blazejewski, J.-C.; Anselmi, E.; Wakselman, C. 2-Trifluoromethoxyethyl Triflate: A Versatile Trifluoromethoxyethyl
Carrier. J. Org. Chem. 2001, 66, 1061–1063. [CrossRef] [PubMed]
7. Inoue, T.; Fuse, C.; Hara, S. Synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers by the
reaction of dithiocarbonates with IF -pyridine-HF. J. Fluor. Chem. 2015, 179, 48–52. [CrossRef]
5
8. Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. A novel synthesis of trifluoromethyl ethers via xanthates
utilizing BrF . J. Fluor. Chem. 1999, 97, 75–78. [CrossRef]
3
9. Umemoto, T.; Singh, R.P. Arylsulfur chlorotetrafluorides as useful fluorinating agents: Deoxo- and
dethioxo-fluorinations. J. Fluor. Chem. 2012, 140, 17–27. [CrossRef]
0. Manteau, B.; Genix, P.; Brelot, L.; Vors, J.-P.; Pazenok, S.; Giornal, F.; Leuenberger, C.; Leroux, F.R. A General
Approach to (Trifluoromethoxy)pyridines: First X-ray Structure Determinations and Quantum Chemistry
Studies. Eur. J. Org. Chem. 2010, 2010, 6043–6066. [CrossRef]
2
1. Speers, L.; Szur, A.J.; Terrell, R.C.; Treadwell, J.; Ucciardi, T.U. General anesthetics. 2. Halogenated methyl
isopropyl ethers. J. Med. Chem. 1971, 14, 593–595. [CrossRef] [PubMed]
2
2. Olah, G.A.; Nojima, M.; Kerekes, I. Synthetic Methods and Reactions II. Hydrofluorination of Alkenes,
Cyclopropane and Alkynes with Poly-Hydrogen Fluoride/Pyridine (Trialkylamine)Reagents. Synthesis 1973
,
1
973, 779–780. [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(