Journal of Fluorine Chemistry 246 (2021) 109799

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Journal of Fluorine Chemistry

journal homepage: www.elsevier.com/locate/fluor

Short Communication

Synthesis and reactions of ω-CF3O-substituted aliphatic sulfonyl chlorides

Ivan G. Logvinenko a, b, Ivan S. Kondratov a, b, *, Alexey V. Dobrydnev a, c, Andriy V. Kozytskiy a, d,
Oleksandr O. Grygorenko a, c, *
a
Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
b
V.P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Murmanska Street 1, Kyiv 02660, Ukraine
c
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
d
L. V. Pisarzhevskii Institute of Physical Chemistry of National Academy of Sciences of Ukraine, Nauky Avenue 31, Kyiv 03028, Ukraine

A R T I C L E I N F O A B S T R A C T

Keywords: A two-step approach to the synthesis of ω-CF3O-substituted aliphatic sulfonyl chlorides is reported. The method is
Aliphatic compounds based on the reaction of alkylating agents bearing a ω-CF3O substituent with thiourea and subsequent oxidative
Building blocks chlorination of the obtained isothiuronium salt. In this way, β-(trifluoromethoxy)ethane and γ-(tri­
Elimination
fluoromethoxy)propane sulfonyl chlorides were obtained and assessed as the reagents in the sulfonylation re­
Oxidative chlorination
Sulfonyl chlorides
action with amines. The former one participated the reaction affording the corresponding vinylsulfonamides
Trifluoromethoxy group because of β-elimination of trifluoromethanol, while the latter one allowed for the preparation of desired
γ-(trifluoromethoxy)propane sulfonamides.

1. Introduction
Modern pharmaceutical industry has been in incessant need of novel
small drug-like molecules possessing improved physicochemical prop­
erties and biological activities [1–4]. Among the numerous structural
motifs that endow the molecules with unique characteristics, the
fluorine-containing units are of special demand [5–7]. More than two
hundred and sixty fluorine-containing drugs have been approved and
used over the world [8], and half of the blockbuster drugs contain
fluorine atoms [9–13] (although there are some concerns on an enor­
mous increase of emission of fluorine-containing compounds into the
biosphere [14]).
Unlike the compounds bearing fluorinated substituents attached to their
framework via the C–C linkage, the fluoroalkoxy derivatives possessing
O–CXFY unit remained exotic for a long period of time. However, owing to
beneficial features of the fluoroalkoxy functionality [15,16], it has attracted
significant interest in recent years and has been increasingly used in phar­
maceutical industry, agrochemistry, and materials science. At the same
time, the scope of the marketed CF3O-containing derivatives is limited to
aromatic derivatives and demonstrated by approved drugs Delamanid (1)
[17] and Pretomanid (2) [18,19] (for treatment of tuberculosis), Riluzole
(3) [20] (addressing anti-amyotrophic lateral sclerosis), as well as fungicide
Thrifluzamide (4) [21], insecticide Triflumuron (5) [22], and plant growth
regulator Flurprimidol (6) [23] (Figure 1).
Previously, we [24] and others [25,26] have described the synthesis
of a series of simple aliphatic ω-CF3O-containing building blocks 7–18
(Figure 2), demonstrated their utility for the parallel synthesis, and
studied the physico-chemical properties (lipophilicity, kinetic solubility,
and microsomal stability) of obtained derivatives. Taking into account
the importance of sulfonamides in drug discovery [27–31], as well as in
line with our ongoing efforts towards synthesis of sulfonyl halide
building blocks [32–38], we have turned our attention to ω-CF3O
substituted aliphatic sulfonyl chlorides. Surprisingly, this compound
class appeared to be hitherto unknown, and their reactions have not
been elucidated in the literature.
The present work is aimed at developing an efficient and robust
method of obtaining ω-CF3O-substitiuted ethane- and propanesulfonyl
chlorides 19, 20 (Figure 2) as well as assessment of their synthetic utility
in the sulfonamidation reactions.
2. Results and discussion
We initiated our study with the reaction of S-nucleophiles with the
commercially available alkylating agents bearing ω-CF3O substituent in
order to estimate the utilization of interim sulfides as the possible pre­
cursors and find the most convenient pathway to the target sulfonyl
chlorides.
Firstly, we attempted the preparation of the corresponding sodium

* Corresponding authors. Tel.: +38-044-239-33-15; fax: +38-044-537-32-53

E-mail addresses: kondratov@mail.enamine.net (I.S. Kondratov), gregor@univ.kiev.ua (O.O. Grygorenko).

https://doi.org/10.1016/j.jfluchem.2021.109799
Received 8 April 2021; Received in revised form 19 April 2021; Accepted 21 April 2021
Available online 28 April 2021
0022-1139/© 2021 Elsevier B.V. All rights reserved.
I.G. Logvinenko et al.
ω-trifluorometoxy alkanesulfinates adopting the known methods
[39–41]. In this way, 2-mercaptopyrimidine was treated with triflate 21
to give sulfide 22, which was oxidized with MCPBA into the corre­
sponding sulfone 23. However, when the latter compound was subjected
to the action of sodium methoxide in methanolic media, β-elimination
took place; thus the conversion into corresponding vinylsulfone 24
occurred instead of sulfinate 25 formation (Scheme 1). This confirms our
previous finding that the CF3O group can be considered as a
pseudo-halogen acting as a leaving group not only in the substitution,
but also in β-elimination reactions (although so far, we observed this
only for the β-CF3O-substituted derivatives) [24].
VAt the same time, γ-(trifluoromethoxy)propane bromide 26 partici­
pated the above reaction sequence without any complications, eventually
Figure 1. Marketed representatives of F3CO-containing derivatives
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Journal of Fluorine Chemistry 246 (2021) 109799
affording sulfinate 29 in overall 28% yield for three steps (Scheme 2).
Since the above method turned out to be inappropriate for obtaining
β-(trifluoromethoxy)ethane sulfonyl chloride (19), we paid our atten­
tion to other approaches where the use of strong bases was avoided.
Thereby we envisioned the installation of the sulfonyl chloride func­
tionality via the nucleophilic substitution of the triflate group by the
thioacetate anion followed by oxidative chlorination [34,35,42–47].
In this way, potassium thioacetate was treated with β-(tri­
fluoromethoxy)ethyl triflate (21) in refluxing acetonitrile (Scheme 3).
Notably, the use of triflate as the leaving group was essential at this step;
in our previous study, we have shown that the analogous bromide un­
dergoes nucleophilic substitution at the OCF3 moiety [24]. The desired
β-(trifluoromethoxy)ethyl thioacetate (30) was obtained in 63% yield.
I.G. Logvinenko et al.
Figure 2. ω-CF3O-Substituted aliphatic building blocks
Scheme 1. The unsuccessful synthesis of sulfinate 25
Obviously, the yield was decreased due to the product volatility and
losses during work-up procedure. The further oxidative chlorination of
30 with KClO3 and 36% aqueous HCl in a two-phase medium (CH2Cl2)
afforded expected sulfonyl chloride 19 in 63% yield. It should be noted
that to the best of our knowledge, the aforementioned oxidative chlo­
rination conditions were not used in the synthesis of sulfonyl chlorides
previously.
Despite this method allowed for the preparation of the target sulfonyl
chloride, we aimed at developing another improved and general
method. Specifically, we needed S-nucleophile that would be converted
into non-volatile intermediate upon reaction with triflate 21. It is well-
known that alkylation of thiourea gives isothiuronium salts that meet
this requirement and can be elaboration into sulfonyl chlorides [48–55].
Thereby, triflate 21 reacted with thiourea in refluxing dioxane that
provided the corresponding isothiuronium triflate 31 in almost quanti­
tative yield. This salt turned out to be stable, easy-to-handle solid, which
can be stored for months; its subsequent oxidative chlorination under
the typical conditions provided the target sulfonyl chloride 19 in satis­
factory yield (53%) (Scheme 3).
The structure of isothiuronium triflate 31 was confirmed by X-ray
diffraction studies (Figure 3). The noteworthy structural feature of 31 is
a bisecting conformation adopted by the α,β-disubstituted ethane unit.
3
Journal of Fluorine Chemistry 246 (2021) 109799
Scheme 2. The synthesis of sulfinate 29
Scheme 3. The synthesis of β-(trifluoromethoxy)ethanesulfonyl chloride 19
This arises from hyperconjugative interactions between electron-
donating σC–H orbitals and σ*C–O as well as electron-accepting σ*C–S
orbitals, known as the gauche effect of fluorine [56–60].
Being inspired by these results, we have applied the same strategy for
the synthesis of homologous sulfonyl chloride 20. In this way, thiourea
was treated with bromide 26, and the resulting isothiuronium bromide
32 was subjected to the oxidative chlorination procedure to give the
target sulfonyl chloride 20 in 23% yield over two steps (Scheme 4).
With compounds 19 and 20 in hands, we undertook the sulfonylation
of a model amine, aniline, under the typical reaction conditions (pyri­
dine, CH2Cl2, 0 ◦ C). Despite our expectations, the reaction with β-(tri­
fluoromethoxy)ethane sulfonyl chloride (19) resulted in complex
mixture of products, presumably due to the competing elimination. At
the same time, the use of γ-(trifluoromethoxy)propane sulfonyl chloride
(20) afforded the desired product 33 in 80% yield (Scheme 5).
In order to investigate the reason for the failure in the reaction of 19
with aniline and to find the appropriate conditions for sulfonylation of
amines with this reagent, a series of additional experiments was per­
formed. Thus, sulfonyl chloride 19 was involved in the reaction with
ammonia under varied conditions. Specifically, 25% aqueous NH3 in
THF at 0 ◦ C, saturated solution of NH3 in CH2Cl2 at –40 ◦ C, and liquid
ammonia (–33 ◦ C) were tested. However, all the experiments accom­
plished with the elimination of trifluoromethanol and formation of
vinylsulfonamide 34 (Scheme 6).
These results are in line with our previous data on the ability of the
I.G. Logvinenko et al.
Figure 3. Molecular structure of compound 31 according to X-ray diffrac­
tion study
Scheme 4. The synthesis of γ-(trifluoromethoxy)propanesulfonyl chloride 20
Scheme 5. The reaction of ω-(trifluoromethoxy) sulfonyl chlorides 19 and 20
with aniline
aliphatic OCF3 group to act as a nucleofuge [24], as well as the chemical
reactivity of other sulfonyl chlorides bearing a leaving group at the
β-position of alkyl chain (such as 2-chloroethane sulfonyl chloride) that
are prone to E1cB elimination [61–68].
In turn, γ-(trifluoromethoxy)propane sulfonyl chloride (20) reacted
with aqueous ammonia in THF media, possibly via the intermediate
sulfene formation [69–72], to give the expected γ-CF3O-substituted
sulfonamide 35 in 73% yield (Scheme 7).
4
Journal of Fluorine Chemistry 246 (2021) 109799
Scheme 6. The reaction of β-(trifluoromethoxy)ethanesulfonyl chloride 19
with ammonia
3. Conclusions
In this work, we disclose the efficient and robust synthesis of ω-CF3O-
substitiuted aliphatic sulfonyl chlorides. The first representatives of this
compound class, namely β-(trifluoromethoxy)ethane sulfonyl chloride
(19) and γ-(trifluoromethoxy)propane sulfonyl chloride (20) were ob­
tained via the corresponding isothiuronium salts starting from the
readily available alkylating agents bearing a ω-CF3O substituent.
Despite β-(trifluoromethoxy)ethane sulfonyl chloride (19) turned
out to be inappropriate for the sulfonylation reaction because of
β-elimination of the trifluoroalkoxy group, its counterpart 20 worked
well in the sulfonamide synthesis. Thus, aliphatic sulfonyl chlorides
bearing a ω-CF3O-substituent placed at least three carbon atoms far from
the main functional group can be promising sp3-enriched building blocks
for early drug discovery and agrochemical programs [73–75].
4. Experimental
4.1. General
The solvents were purified according to the standard procedures [76].
All the starting materials were obtained from Enamine Ltd. and UORSY.
Melting points were measured on MPA100 OptiMelt automated melting
point system. Analytical TLC was performed using Polychrom SI F254
plates. 1H, 13C{1H}, and 19F{1H} NMR spectra were recorded on a Agilent
ProPulse 600 spectrometer (at 600 MHz for 1H NMR and 151 MHz for 13C
NMR), a Bruker 170 Avance 500 spectrometer (at 500 MHz for 1H, 126 MHz
for 13C, and 470 MHz for 19F), or a Varian Unity Plus 400 spectrometer (at
400 MHz for 1H, 101 MHz for 13C, and 376 MHz for 19F). Chemical shifts are
reported in ppm downfield from TMS as an internal standard. Elemental
analyses were performed on a CHNOS elementary Vario MICRO Cube
analyzer. Mass spectra were recorded on an Agilent 1100 LCMSD SL in­
strument (chemical ionization (APCI)) and Agilent 5890 Series II 5972
GCMS instrument (electron impact ionization (EI)). Deposition Number
2075424 (for 31) contains the supplementary crystallographic data for this
paper. These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Ac­
cess Structures service www.ccdc.cam.ac.uk/structures.
Scheme 7. The reaction of β-(trifluoromethoxy)ethanesulfonyl chloride (20)
with ammonia
I.G. Logvinenko et al.
4.2. General procedure for the preparation of 2-((ω-(trifluoromethoxy)
alkyl)thio)pyrimidines 22 and 27
K2CO3 (1.8 g, 13 mmol) was added to the stirred solution of
pyrimidine-2-thiol (1.23 g, 11 mmol) in DMF (20 mL) and the resulting
suspension was cooled to 10 ◦ C followed by dropwise addition of triflate
21 or bromide 26 (10 mmol) maintaining the internal temperature
below 15 ◦ C. The reaction mixture was allowed to equilibrate to r.t. and
left to react with stirring overnight. Then it was poured into ice-cold
water (100 mL) and extracted with EtOAc (3 × 40 mL). The combined
organic layer was sequentially washed with water (3 × 40 mL) and brine
(3 × 40 mL), dried (Na2SO4) and evaporated at reduced pressure to give
the title product 22 or 27.
4.2.1. 2-{[2-(Trifluoromethoxy)ethyl]thio}pyrimidine (22)
From triflate 21 (2.62 g, 10 mmol), pyrimidine-2-thiol (1.23 g, 11
mmol), and K2CO3 (1.8 g, 13 mmol). Yield 1.85 g (83%); yellow liquid.
1
H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.9 Hz, 2H), 6.99 (t, J = 4.9 Hz,
1H), 4.22 (t, J = 7.1 Hz, 2H), 3.42 (t, J = 7.1 Hz, 2H). 13C NMR (126
MHz, CDCl3) δ 170.9, 157.4, 121.5 (q, J = 255.1 Hz), 116.9, 65.6 (t, J =
3.2 Hz), 29.1. 19F NMR (376 MHz, CDCl3) δ –61.0. LC/MS (CI): m/z =
225 [M+H]+. Anal. calcd. for C7H7F3N2OS: C 37.50; H 3.15; N 12.50; S
14.30. Found: C 37.49; H 3.08; N 12.65; S 14.40.
4.2.2. 2-{[3-(Trifluoromethoxy)propyl]thio}pyrimidine (27)
From bromide 26 (1.04 g, 5 mmol), pyrimidine-2-thiol (0.61 g,
5.5 mmol), and K 2CO3 (1.8 g, 13 mmol). Yield 0.86 g (80%); yellow
liquid. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (d, J = 4.8 Hz, 2H), 7.86
(t, J = 4.8 Hz, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.75–3.66 (m, 2H), 2.12
(p, J = 6.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 165.1, 159.7,
125.3, 121.6 (q, J = 256.4 Hz), 66.7, 47.4, 22.3. 19F NMR (376 MHz,
DMSO-d6) δ –59.4. LC/MS (CI): m/z = 239 [M+H]+. Anal. calcd. for
C8H9F3N2OS: C 40.33; H 3.81; N 11.76; S 13.46. Found: C 40.71; H
3.64; N 11.72; S 13.55.
4.3. General procedure for the preparation of 2-{[ω-(trifluoromethoxy)
alkyl]sulfonyl}pyrimidines 23 and 28
The solution of sulfide 22 or 27 (1 mmol) in CH2Cl2 (5 mL) was
cooled to 0 ◦ C followed by portionwise addition of MCPBA (345 mg, 2
mmol) at the above temperature. The reaction mixture was allowed to
equilibrate to r.t. and left to react with stirring overnight. Then it was
filtered and the filtrate was evaporated at reduced pressure to give crude
sulfone 23 or 28.
4.3.1. 2-{[2-(Trifluoromethoxy)ethyl]sulfonyl}pyrimidine (23)
From sulfide 22 (224 mg, 1 mmol) and MCPBA (345 mg, 2 mmol).
The crude product was used in subsequent step without further pu­
rification. Yield 200 mg (78%); yellowish liquid. 1H NMR (400 MHz,
DMSO-d6) δ 9.10 (d, J = 4.9 Hz, 2H), 7.54 (t, J = 4.9 Hz, 1H), 4.49 (t,
J = 5.5 Hz, 2H), 4.12 (t, J = 5.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ
165.4, 158.7, 124.0, 121.0 (q, J = 256.8 Hz), 60.7 (q, J = 3.7 Hz),
50.4. 19F NMR (376 MHz, CDCl3) δ –62.2. LC/MS (CI): m/z = 257
[M+H]+.
4.3.2. 2-{[3-(Trifluoromethoxy)propyl]sulfonyl}pyrimidine (28)
From sulfide 27 (480 mg, 2 mmol) and MCPBA (690 mg, 4 mmol).
The crude product was purified by column chromatography (EtOAc as
eluent). Yield 230 mg (43%); colorless liquid. 1H NMR (500 MHz,
DMSO-d6) δ 8.50 (d, J = 4.8 Hz, 2H), 6.96 (t, J = 4.8 Hz, 1H), 4.10 (t, J
= 6.5 Hz, 2H), 3.23 (t, J = 6.5 Hz, 2H), 2.14 (p, J = 6.5 Hz, 2H). 13C NMR
(151 MHz, CDCl3) δ 171.9, 157.3, 121.6 (q, J = 254.3 Hz), 116.6, 65.8
(q, J = 3.2 Hz), 28.5, 26.7. 19F NMR (376 MHz, CDCl3) δ –61.3. LC/MS
(CI): m/z = 271 [M+H]+. Anal. calcd. for C8H9F3N2O3S: C 35.56; H
3.36; N 10.37; S 11.86. Found: C 35.74; H 3.50; N 10.43; S 12.24.
5
Journal of Fluorine Chemistry 246 (2021) 109799
4.4. Sodium 3-(trifluoromethoxy)propane-1-sulfinate (29)
The solution of sulfone 23 (1.58 g, 5.8 mmol) in MeOH (10 mL) was
added to the stirred ice-cold solution of MeONa (prepared from Na (134
mg, 5.8 mmol) and MeOH (20 mL)). The reaction mixture was allowed
to equilibrate to r.t. and left to react with stirring overnight. Then it was
evaporated at reduced pressure, the residue was triturated with MTBE
(10 mL) and filtered to give the title sulfinate 29. Yield: 1.01 g (81 %);
white powder. 1H NMR (500 MHz, D2O) δ 4.08 (tt, J = 6.7, 3.6 Hz, 2H),
2.92 (td, J = 6.7, 3.6 Hz, 2H), 2.03 (p, J = 6.7 Hz, 2H). 13C NMR (126
MHz, DMSO-d6) δ 121.4 (q, J = 253.4 Hz), 66.2, 47.2, 23.9. 19F NMR
(376 MHz, DMSO-d6) δ –60.8. LC/MS (CI): m/z = 208 [M–H+NH3]–.
Anal. calcd. for C4H6F3NaO3S: C 22.44; H 2.82; S 14.97. Found: C 22.53;
H 2.91; S 14.94.
4.5. S-[2-(Trifluoromethoxy)ethyl]ethanethioate (30)
Triflate 21 (13.0 g, 49 mmol) was added dropwise to the stirred
suspension of KSAc (7.94 g, 70 mmol) in MeCN (60 mL) maintaining the
internal temperature at 10–15 ◦ C. The reaction mixture was allowed to
equilibrate to r.t. and left to react with stirring overnight. Then it was
poured into ice-cold water (200 mL) and extracted with Et2O (4 × 50
mL). The combined organic layer was sequentially washed with water
(1 × 50 mL) and brine (1 × 50 mL), dried (Na2SO4) and evaporated at
atmospheric pressure and distilled to give the title product 30. Yield
5.92 g (63%); yellow liquid; b.p. 102–105 ◦ C. 1H NMR (500 MHz, CDCl3)
δ 4.03 (t, J = 6.5 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H), 2.35 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 194.6, 121.4 (q, J = 255.3 Hz), 65.6, 30.5, 27.7. 19F
NMR (376 MHz, CDCl3) δ –61.3. LC/MS (CI): m/z = 146
[M–CH3COH+H]+. Anal. calcd. for C5H7F3O2S: C 31.92; H 3.75; S
17.04. Found: C 32.24; H 3.87; S 16.97.
4.6. General procedure for the preparation of isothiuronium salts 31 and
32
Triflate 21 or bromide 26 (0.4 mol) was dissolved in dioxane (1L),
then thiourea (30.5 g, 0.4 mol) was added and the resulting mixture was
refluxed overnight. The volatiles were evaporated at reduced pressure,
the residue was dissolved in water (200 mL) and also evaporated at
reduced pressure. This procedure was repeated two times more in order
to remove the dioxane traces from the target product 31 or 32.
4.6.1. 2-[2-(Trifluoromethoxy)ethyl]isothiouronium
trifluoromethanesulfonate (31)
From triflate 21 (105 g, 0.4 mol) and thiourea (30.5 g, 0.4 mol). Yield
134 g (99%); yellowish crystals; m.p. 80–82 ◦ C. 1H NMR (400 MHz,
DMSO-d6) δ 9.15 (s, 2H), 8.97 (s, 2H), 4.29 (t, J = 5.7 Hz, 2H), 3.53 (t, J
= 5.7 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 169.0, 120.6 (q, J =
322.2 Hz), 121.1 (q, J = 254.3 Hz), 66.2 (q, J = 3.0 Hz), 29.2. 19F NMR
(376 MHz, DMSO-d6) δ –59.7, –78.3. LC/MS (CI): m/z = 189 [M+H]+.
Anal. calcd. for C5H8F6N2O4S2: C 17.76; H 2.38; N 8.28; S 18.96. Found:
C 17.94; H 2.54; N 8.07; S 18.75.
4.6.2. 2-[3-(Trifluoromethoxy)propyl]isothiouronium bromide (32)
From bromide 26 (41.4 g, 0.2 mol) and thiourea (16.0 g, 0.2 mol).
Yield 56.6 g (99%); yellowish crystals; m.p. 52–54 ◦ C. 1H NMR (400
MHz, DMSO-d6) δ 6.89 (s, 2H), 4.20 (t, J = 6.6 Hz, 2H), 3.13–3.00 (m,
2H), 2.07 (p, J = 6.6 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.0,
121.7 (q, J = 253.4 Hz), 66.9, 51.0, 23.9. 19F NMR (376 MHz, DMSO-d6)
δ –59.3. LC/MS (CI): m/z = 195/197 [M–CF3OH+Br]–. Anal. calcd. for
C5H10BrF3N2OS: C 21.21; H 3.56; N 9.90; S 11.32. Found: C 21.42; H
3.75; N 9.81; S 10.94.
4.7. Oxidative chlorination of thioacetate 30
Thioacetate 30 (4.92 g, 26 mmol) was dissolved in a stirred mixture
I.G. Logvinenko et al.
of CH2Cl2 (50 mL) and 36% aqueous HCl (50 mL) and cooled with an ice
water bath. Then KClO3 (3.84 g, 31 mmol) was added portionwise
maintaining the temperature below 5 ◦ C. Then the reaction mixture was
allowed to stir at 0 ◦ C for 2 h. The organic layer was set apart and the
water layer was extracted with CH2Cl2 (2 × 25 mL). The combined
organic layer was sequentially washed with water (1 × 25 mL) and brine
(1 × 25 mL), dried (Na2SO4) and evaporated at reduced pressure. Thus
obtained residue was distilled in vacuo to give sulfonyl chloride 19.
Yield 3.53 g (63%). Physical and spectral characteristics were identical
to those as described below.
4.8. General procedure for the oxidative chlorination of isothiuronium
salts 31 and 32
Isothiuronium salt 31 or 32 (0.2 mol) was dissolved in a stirred
mixture of CH2Cl2 (500 mL) and 36% aqueous HCl (500 mL) and cooled
with an ice-salt bath. Then KClO3 (29.4 g, 0.24 mol) was added por­
tionwise maintaining the temperature at –5 – +5 ◦ C. Then the reaction
mixture was allowed to stir at above temperature for 100 min. The
organic layer was set apart and the water layer was extracted with
CH2Cl2 (3 × 150 mL). The combined organic layer was sequentially
washed with water (1 × 200 mL), saturated aqueous NaHCO3 (1 × 200
mL), and brine (1 × 200 mL), dried (Na2SO4) and evaporated at reduced
pressure. Thus obtained residue was distilled in vacuo to give sulfonyl
chloride 19 or 20.
4.9. 2-(Trifluoromethoxy)ethane-1-sulfonyl chloride (19)
From isothiuronium triflate 31 (67.7 g, 0.2 mol). Yield 22.5 g (53%);
yellowish liquid; b.p. 62–65 ◦ C (6 mbar). 1H NMR (400 MHz, CDCl3) δ
4.51 (t, J = 6.1 Hz, 2H), 4.02 (t, J = 6.1 Hz, 2H). 13C NMR (126 MHz,
CDCl3) δ 121.2 (q, J = 257.4 Hz), 62.9, 60.3. 19F NMR (376 MHz, CDCl3)
δ –62.2. LC/MS (CI): m/z = 193 [M–H]– (for the corresponding acid).
Anal. calcd. for C3H4ClF3O3S: C 16.95; H 1.90; S 15.08. Found: C 17.19;
H 1.97; S 15.11.
4.10. 3-(Trifluoromethoxy)propane-1-sulfonyl chloride (20)
From isothiuronium bromide 32 (57 g, 0.2 mol). Yield 10.5 g (23%);
yellowish liquid; b.p. 58–60 ◦ C (1 mbar). 1H NMR (500 MHz, CDCl3) δ
4.17 (t, J = 5.8 Hz, 2H), 3.87 (t, J = 7.4 Hz, 2H), 2.41 (p, J = 6.3 Hz, 2H).
13
C NMR (151 MHz, CDCl3) δ 121.3 (q, J = 255.9 Hz), 65.3, 63.7 (q, J =
2.9 Hz), 24.4. 19F NMR (376 MHz, CDCl3) δ –61.6. LC/MS (CI): m/z =
207 [M–H]– (for the corresponding acid). Anal. calcd. for C4H6ClF3O3S:
C 21.20; H 2.67; S 14.15. Found: C 20.95; H 2.86; S 13.93.
4.11. N-Phenyl-3-(trifluoromethoxy)propane-1-sulfonamide (33)
A solution of sulfonyl chloride 20 (450 mg, 2 mmol) in CHCl3 (3 mL)
was added to the stirred ice-cold solution of aniline (186 mg, 2 mmol) in
pyridine (5 mL). The reaction mixture was allowed to equilibrate to r.t.
and left to react with stirring overnight. Then it was evaporated at
reduced pressure, acidified with 20% aqueous HCl to pH 1 and extracted
with EtOAc (3 × 15 mL). The combined organic layer was washed with
brine (15 mL), dried (Na2SO4) and evaporated at reduced pressure to
give the title product 33. Yield 450 mg (80%); orange liquid. 1H NMR
(500 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.20 (d, J
= 7.7 Hz, 2H), 7.09 (t, J = 7.7 Hz, 1H), 4.14 (t, J = 6.5 Hz, 2H),
3.20–3.13 (m, 2H), 2.04 (p, J = 6.5 Hz, 2H). 13C NMR (151 MHz, DMSO-
d6) δ 138.4, 129.8, 124.4, 121.6 (q, J = 253.5 Hz), 120.2, 66.5 (d, J =
3.0 Hz), 47.2, 23.4. 19F NMR (376 MHz, DMSO-d6) δ –59.4. LC/MS (CI):
m/z = 282 [M–H]–. Anal. calcd. for C10H12F3NO3S: C 42.40; H 4.27; N
4.94; S 11.32. Found: C 42.80; H 4.45; N 4.70; S 11.00.
6
Journal of Fluorine Chemistry 246 (2021) 109799
4.12. Ethenesulfonamide (34)
Sulfonyl chloride 19 (420 mg, 2 mmol) was added dropwise to liquid
ammonia (20 mL). Then the reaction mixture was allowed to evaporate
at atmospheric pressure followed by equilibrating to r.t. The residue was
diluted with EtOAc (50 mL), dried (Na2SO4), filtered and evaporated at
reduced pressure affording the title sulfonamide 34. Yield 150 mg
(70%); colorless liquid. For spectral data see [77].
4.13. 3-(Trifluoromethoxy)propane-1-sulfonamide (35)
A solution of sulfonyl chloride 20 (450 mg, 2 mmol) in THF (3 mL)
was added dropwise to the stirred ice-cold solution of 25% aqueous NH3
(2 mL) in THF (10 mL). The reaction mixture was allowed to equilibrate
to r.t. and left to react with stirring overnight. Then it was evaporated at
reduced pressure, diluted with EtOAc (25 mL), dried (Na2SO4), filtered,
and evaporated at reduced pressure. Thus obtained residue was tritu­
rated with hexane (4 mL) and filtered, affording the title sulfonamide
35. Yield 310 mg (73%); white powder; m.p. 50–52 ◦ C. 1H NMR (500
MHz, DMSO-d6) δ 6.88 (s, 2H), 4.18 (t, J = 6.5 Hz, 2H), 3.10–3.00 (m,
2H), 2.06 (p, J = 6.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 121.7 (q,
J = 253.3 Hz), 66.9, 51.0, 23.9. 19F NMR (376 MHz, DMSO-d6) δ –59.3.
LC/MS (CI): m/z = 122 [M–CF3OH+H]+. Anal. calcd. for C4H8F3NO3S:
C 23.19; H 3.89; N 6.76; S 15.48. Found: C 23.24; H 3.64; N 6.93; S
15.83.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The work was funded by Enamine Ldt. Additional funding from
Ministry of Education and Science of Ukraine, Grants No. 19BF037-03
(A.V.D. and O.O.G.) and 21BF037-01M (O.O.G.) is also acknowledged.
The authors thank Dr. Eduard Rusanov for X-Ray diffraction studies and
Prof. Andrey A. Tolmachev for his encouragement and support.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2021.109799.
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