Synthesis of aryl 2,2,2-trifluoroethyl sulfides

Article abstract of DOI:10.1016/j.jfluchem.2020.109464

Aryl 2,2,2-trifluoroethyl sulfides were synthesized by copper(I)-catalyzed nucleophilic aromatic substitution reaction (Goldberg-Ullmann coupling). The method requires aryl iodides and 2,2,2-trifluoroethyl thioacetate as starting materials, benzylamine as solvent and base, and copper(I) bromide as a catalyst. The reaction mixture was stirred at 110 °C for 6 h under inert atmosphere to afford the targeted aryl 2,2,2-trifluoroethyl sulfides in moderate to good yield.

Full text of DOI:10.1016/j.jfluchem.2020.109464

Journal Pre-proof
Synthesis of aryl 2,2,2-trifluoroethyl sulfides
B a´ lint Menczinger, Anik o´ Nemes, D e´ nes Szab o´ , Gitta Schlosser,
Tam a´ s Jernei, Antal Cs a´ mpai, J o´ zsef R a´ bai
PII:
S0022-1139(20)30015-4
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109464
FLUOR 109464
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
31 October 2019
11 January 2020
12 January 2020
Please cite this article as: Menczinger B, Nemes A, Szab o´ D, Schlosser G, Jernei T, Cs a´ mpai
A, R a´ bai J, Synthesis of aryl 2,2,2-trifluoroethyl sulfides, Journal of Fluorine Chemistry
(2020), doi: https://doi.org/10.1016/j.jfluchem.2020.109464
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Synthesis of aryl 2,2,2-trifluoroethyl sulfides
Bálint Menczinger, Anikó Nemes, Dénes Szabó, Gitta Schlosser, Tamás Jernei, Antal Csámpai and
József Rábai
Institute of Chemistry, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest,
Hungary
1

Graphical abstract
This paper is dedicated to Professor Norio Shibata on the occasion of receiving the 2019 year ACS
Award for Creative Work in Fluorine Chemistry
Highlights



2,2,2-Trifluoroethyl thioacetate introduced as an easy to handle substitute for
the highly volatily and air sensitive 2,2,2-trifluoroethane thiol
Effective syntheses of aryl 2,2,2-trifuoroethyl sulfides from aryl iodides and in
situ generated 2,2,2-trifluoroethane thiol are disclosed
Selective S-arylation of CF
3
CH
2
SH by aryl iodides occurs in benzylamine
which plays the role of solvent, base and as a ligand for the CuBr catalyst
Abstract
Aryl 2,2,2-trifluoroethyl sulfides were synthesized by copper(I)-catalyzed nucleophilic aromatic
substitution reaction (Ullmann coupling). The method requires aryl iodides and 2,2,2-trifluoroethyl
thioacetate as starting materials, benzylamine as solvent and base, and a copper(I) bromide as a
catalyst. The reaction mixture was stirred at 110 °C for 6 h under inert atmosphere to afford the
targeted aryl 2,2,2-trifluoroethyl sulfides in moderate to good yield.
Keywords: S-Arylation; Aryl iodides; Copper catalyst; Substitution; Fluorine; Trifluoroethylthiolation
2

1
.
Introduction
The unique properties of fluorine [1] have been exploited for the development of novel and effective
biochemical tools and therapeutic agents, including active pharmaceutical ingredients (API’s) as well.
In the past three decades the extraordinary potential of fluorine-containing biologically relevant
molecules has been explored in medicinal chemistry [2], chemical biology, pharmacology, drug
discovery and development [3], as well as in diagnostic and therapeutic applications. In particular, the
fact that a large number of fluorine-containing agents have been approved by the US Food and Drug
Administration (FDA) for medical use clearly demonstrates the importance of fluorine in drug
discovery and development [4].
Consequently, fluorine is recognized as the second favorite heteroatom in current drug design, after
nitrogen. Following this paradigm, e.g. the replacement of a C-H or C=O bond with a C-F bond in
biologically active compounds frequently introduce beneficial properties such as higher metabolic
stability, increased binding affinity to target proteins, and increased membrane permeability [5]. In
practice, for making such fluorinated target molecules either fluorine containing building-blocks are
used [6], or selective fluorinating or fluoroalkylation reagents − allowing late formation of fluorinated
functional groups − can be applied in their synthesis strategy [7]. Recently, special attention is called
on the potential of the development of sulfur-fluorine overlap pharmaceuticals, where polarity tuning
of the target molecule is enabled by the changing the valences of the sulfur fragments (e.g. S, SO,
SO
Indeed, fluoroalkylthio groups, such as the trifluoromethylthio (CF
trifluoroethylthio (CF CH S-) groups [11], are often present in molecules of biologically active
2
) in the fluoro-organosulfur compounds [8].
3
S-) [9, 10], and the 2,2,2-
3
2
ingredients at the development or approved stage of drugs 1 [12], 2 [13], 3 [14], 4 [15] and
agrochemicals 5 [16], 6 [17] , 7 [18], 8 [19] (Figure 1).
3

Scheme 1. Selected bioactive molecules featuring fluoroalkylthio groups with their approved and/or
potential application fields (cf. Refs [12-19]).
Although fluorine and sulfur substitution could expand the potential for drug discovery, the novel aryl
and/or hetaryl trifluoroethyl sulfides (e.g. ArSCH
2
CF ) are most frequently prepared by classical
3
sulfide synthesis methods, i.e. including the S-trifluoroethylation of the corresponding aryl
mercaptanes (ArSH), or by the base-assisted S-arylation of trifluoroethane thiolates with an activated
halide (ArX); while in the case of unactivated halides the addition of a transition metal catalyst (nickel
2
[
20] or palladium [21]) could result in useful S-C(sp ) coupling procedures (Scheme 2).
4

Scheme 2. Retrosynthetic analysis of aryl 2,2,2-trifluoroethyl sulfides.
The simplest way to synthesize such thioethers (disconnection type-i/Scheme 2) is the nucleophilic
substitution reaction between the thiophenols and 2,2,2-trifluoroethyl iodide [22], chloride [23],
sulfonates [24], or 2,2,2-trifluoro-1-diazoalkanes [25]. It is worthy to note, that CF
3
CH
CH
2 reactions. The disadvantage of
2
I reacts by
either ionic or radical mechanism. In case of S-trifluoroethylation reactions with CF
3
2
I the UV light
induced radical substitution (SRN1) afforded better yields than the S
N
3
such S-C(sp ) bond forming alkylation reactions is that the starting thiophenols have low tolerance of
numerous reaction conditions, thus the 2,2,2-trifluoroethylthio group should be introduced early in the
sequence of the synthesis of compounds having various functional groups [17, 18].
Recently some electrophilic coupling methods were implemented for the synthesis of aryl
trifluoroethyl sulfides (disconnection type-ii/Scheme 2). These processes applied
trifluoroalkanesulfonyl chloride (CF
3
CH
2
SO
2
Cl) [26], or sodium trifluoroalkanesulfinate
CH S moiety into an aromatic
(
CF CH SO Na) [11] along with a reducing agent to introduce the CF
3
2
2
3
2
system. However, the latter electrophilic substitution reactions have the disadvantage of the formation
of minor amount of positional isomers, and in the case of substrates with multiple aromatic rings the
method is not selective enough for the formation of a single product.
However, the title CF
based on the direct use of the highly volatile and malodorous 2,2,2-trifluoroethyl mercaptane
disconnection type-iii/Scheme 2) and their reaction with activated aryl (hetaryl) halides as reported in
3
2
CH SAr sulfides are often made by robust methods at pilot or industrial scale,
(
the literature [14, 15, 27] or disclosed in patents [16, 19, 28].
5

Liao and Cheng developed the first nucleophilic coupling method for the synthesis of such aryl
trifluoroethyl sulfides that is not based on the direct use of aryl and/or trifluoroethyl mercaptanes as
the precursor reagents [29]. They have reacted aryl iodides or bromides with trifluoroethyl iodide and
elemental sulfur, in the presence of copper(I) iodide with ligands and NaBH acting as catalyst and
4
reducing agents, respectively. This strategy is advantageous in the terms of good selectivity (usually
not providing positional isomers), and the large tolerance of the starting aryl towards functional groups
and reaction conditions. Thus, their method can also be applied for late-stage fluorination reactions
resulting in good to excellent yields based on the aryl halides used at 0.5-10 mmol scales.
Furthermore, the in situ formation of copper(I) trifluoroethylthiolate and/or copper(I) arenethiolates as
key intermediates in the reaction mechanism comprising major and minor pathways, respectively, was
experimentally supported.
It is noteworthy to state that the copper-catalyzed coupling of CF
3
CH SH with aryl halides has not
2
been attempted yet although the efficiency of using copper catalysts for S-arylation of appropriate
thiols with aryl halides is well known since the pioneering work of Irma Goldberg [30], which has
been developed further and later generalized by Buchwald.
In this paper, we present a copper-catalyzed aromatic nucleophilic substitution method (Ullmann
coupling) for the synthesis of aryl 2,2,2-trifluoroethyl sulfides at multigram scale using simple
reaction conditions (disconnection type-iii/Scheme 2).
2
.
Results and discussion
o
In our new synthesis, the requisite 2,2,2-trifluoroethane thiol (CF
3
CH
2
SH, bp = 36.5 C [31]) is
o
o
generated in situ from trifluoroethyl thioacetate (bp = 115 C [32]; 108-110 C [33]) and reacted with
aryl iodides in presence of copper catalyst (CuBr) and benzylamine as a base and solvent (Scheme 3).
6

Scheme 3. New synthesis of aryl 2,2,2-trifluoroethyl sulfides by Ullmann reaction.
Recently, we have reported the synthesis of (fluoroalkyl)methane thiols (C 2n+1CH SH, n = 1-3) from
n
F
2
commercially available (fluoroalkyl)methanols via the corresponding thioacetates [34]. In the present
work, we use 2,2,2-trifluoroethyl thioacetate (9) as the thiol source that allows the synthesis of aryl
o
2,2,2-trifluoroethyl sulfides by copper catalyzed reaction. Compound 9 (d = 1.278, n
D
= 1.3940, 25 C)
was prepared in good yield reacting trifluoroethyl benzenesulfonate with an excess of thiolacetic acid
in the presence of K CO . Using vacuum distillation of the crude mixture product isolation was
2
3
improved relative to that reported in [33]. On cooling the colorless distillate separated into two liquid
phases, the lower one enriched in trifluoroethyl thioacetate 9, while the upper one in DMSO (cf.
Experimental).
Our aim was to develop a 2,2,2-trifluoroethylthiolation method for aromatic compounds with broad
functional group tolerance and substrate scope. Thus thiolester 9 was tested as a thiol precursor in a
copper-catalyzed nucleophilic aromatic substitution reaction of unactivated aryl halides, such as
iodobenzene (10a). During the optimization process we used iodobenzene 10a as substrate, and tested
the effect of the copper source, ligand, solvent, temperature and reaction time on the isolated yield of
phenyl trifluoroethyl sulfide (11a). First copper(I) iodide, -bromide and -oxide were selected as the
copper source.
The test reaction of 10a with 9 was carried out in DMSO at 110 °C, employing 2 equivalents of
imidazole acting as a nucleophile for cleavage of 9 [cf. 32] and as a base to remove the formed
hydrogen iodide. The best yield of 11a was achieved by using stoichiometric amount of copper (I)
oxide or catalytic amount of copper(I) halides and adding 2 mol of tetramethylethylenediamine
(TMEDA) for 1 mol of copper catalyst to the mixture (Table 1). Thus, we choose CuBr as a copper
source for further reactions.
Table 1. The role of copper source in the DMSO-imidazole system.
Entry Catalyst
mol% Cu
Yield (%)*
7

1
2
3
4
5
Cu
CuI
CuBr
CuBr
none
2
O
100
20
20
20
0
88
27
29
61**
0
*
10a (1 mmol), 9 (1 mmol), imidazole (2 mmol) and catalyst, 110 °C, 4h
*
*10a (1 mmol), 9 (1 mmol), imidazole (2 mmol), catalyst, and 60 μl TMEDA, 110 °C, 4h
In the second optimization stage we used amine type solvents, which can also react as ligand
enhancing the efficiency of the substitution reactions. Amines and nitrogen-containing heteroaromatic
compounds are good ligands for solubilizing copper(I) species. Although these molecules can also act
as nucleophiles, in our case the thiol/thiolate soft S-species present in the reaction mixture are much
stronger nucleophiles than these amines with relatively hard nucleophilic character [30f], thus the
reaction proceeds via the formation of the expected sulfide (11a). Here we tested benzylamine,
dibenzylamine, pyridine and 2-aminoethanol serving as both solvents and bases. Although pyridine is
often used as solvent and ligand for Ullmann-type coupling reactions, the reaction of 9 with 10a did
not take place in pyridine, thus the starting materials were recovered (Table 2, Entry 8). This latter
observation is in accord with the proposed reaction pathway, where the thiolation reagent is the in situ
o
o
formed CF
3
CH SH (Scheme 4). All solvents except pyridine in Table 2 provide the requisite 1 or 2
2
amines for the aminolysis reaction of trifluoroethyl thioacetate (9). This view is in line with the
successful transformations effected by imidazole dissolved in DMSO (cf. [32]) as demonstrated by the
yields listed in Table 1 (Scheme 4).
Scheme 4. Generation of hydrogen bonded mercaptane-amine complexes.
Table 2. Effect of solvent and temperature on sulfide 11a formation
8

Temperature
Time
(h)
4
4
4
6
6
6
Yield
(%)*
87
86
21
90
69
75
68
Entry Solvent
o
(
C)
1
2
3
4
5
6
7
8
benzylamine
dibenzylamine
110
110
2-aminoethanol 110
benzylamine 110
2-aminoethanol 110
benzylamine 130
2-aminoethanol 130
pyridine 110
6
4
0
*
10a (5 mmol), 9 (6 mmol), CuBr (0.25 mmol), solvent (15 mmol).
Yields (Table 2, Entries 1, 2 and 4) show that the best results were achieved by the procedures
employing benzylamine and dibenzylamine that simultaneously serve as solvent and ligand. Although
2
-aminoethanol, also capable of coordinating to metal center through hydroxyl group, gave smaller
yield. This figure (Table 2, Entry 3) seems to correlate with the preference of the latter solvent to form
intramolecular hydrogen bonding thus it might have a decreased ability to assist thiol deprotonation
step via intermolecular hydrogen bonding opposed to the benzyl amines.
To further optimize the reaction conditions temperature and the reaction time were also varied in the
experiments performed in amine type solvents (Table 2). In all cases longer reaction times improved
the yield at 110 °C. On heating the reaction mixture up to 130 °C slight decrease in the yield was
observed. Based on the above results the optimal conditions are selected as follows: starting materials
were stirred with CuBr catalyst in benzylamine solvent for 6 h at 110 °C. Unfortunately these reaction
conditions were not successful when bromobenzene was used as substrate (Table 3, Entry 2).
Table 3. Effect of Cu/CuBr catalyst and of substrate halogen (C
6
5
H I/C
6
5
H Br)
Entry Ar halide, X Catalyst
Equiv. 9
Yield *
1
2
3
I
Br
I
Cu
CuBr
CuBr
1.2
1.2
2
83
0
86
9

*
Aryl halide (5 mmol), catalyst (0.25 mmol) in BnNH (1.64 ml = 15 mmol) at 110 °C, 6 h.
2
With these optimized conditions we examined the scope of the reaction. As starting materials, a
variety of aryl/hetaryl iodides were chosen (Figure 1). Iodobenzene derivatives with methyl-(10d,
1
0f), methoxy-(10b, 10c), trifluoromethyl-(10e), and chloro- (10g) substituents gave high isolated
yields, while the reaction of nitro-derivatives (10h, 10i) resulted in lower yields because of losses
during their chromatographic purification. However, under same conditions 2-iodothiophene (10k)
and 2-iodopyridine (10j) gave medium to good isolated yield.
Finally, the reaction of a sterically hindered and electron-rich aryl iodide (10l) was tested. Pleasingly,
slight modification of the experimental conditions applied to the 5 mmol scale experiments allowed
the safe preparation of the corresponding 2,6-dimethyl-6-tert-butyl-phenyl trifluoroethyl sulfide (11l)
at 15 times larger – multigram – scale in 78% yield (Figure 1).
1
0

Figure 1. Substrate scope of the reaction of 9 with aryl/hetaryl iodides
In addition, the work-up of the latter reaction mixture resulted in the isolation of N-benzyl acetamide
(92%) as the co-product of 11l and the recovery of inorganic iodides in the form of copper (I) iodide in
about 80% yields. In the double blank experiment, conducted without CuBr and aryl iodide, the
mixing of trifluoroethyl thioacetate 9 and benzyl amine initiated an exothermic reaction, leading to the
o
isolation of CF
3
CH
2
SH formed as a colorless liquid in 58% yield with bp = 38 C (cf. Experimental).
A preliminary mechanistic consideration of the reaction pathway can be drawn based on the analysis
of the above larger scale reaction (10l 11l) and the relevant literature data [29, 30]. The
experimental fact, that the isolation of trifluoroethane thiol by atmospheric distillation from the
benzylamine media was possible, indicates that no thiolate salt formation occurred there, thus this
solvent acts only as a hydrogen-bond base [35] assisting CF
Ullmann-coupling) sequence, which involves oxidative addition of aryl iodides to the amine solvent
coordinated copper(I) trifluoroethyl thiolate species. In addition, the high efficiency (Table 1, Entry 1)
of using one equivalent of Cu O in the DMSO-imidazole system can probably be attributed to the high
initial concentration of a solvent coordinated CuSCH CF complex in the course of its stoichiometric
3
CH
2
SH in the copper (I) catalyzed
(
2
2
3
coupling reaction with iodobenzene. At this point we do not have sufficient data to prove all details of
the suggested reaction pathway presented in Scheme 5.
1
1

Scheme 5. Proposed pathway of sulfide formation via copper-catalyzed S-arylation reaction.
3
.
Conclusion
A method was developed for the introduction of trifluoroethylthio group into aromatic compounds by
a copper catalyzed aromatic nucleophilic substitution reaction. A systematic optimization of the
reaction conditions regarding the choice of the copper source, the applied ligand and solvent, along
with the temperature and the reaction time led to the identification of an efficient protocol prescribing
the reaction of aryl iodides with 1.2 equivalent of thioacetate 9 in presence of copper(I) bromide
catalyst in benzylamine at 110°C for 6 h. Since benzylamine acted as a solvent, ligand, and base
without other additives, the product isolation and purification was simple and efficient. This
trifluoroethylthiolation method could easily be adopted for the introduction of trifluoroethylthio group
into target molecules of pharmaceutical or agrochemical relevance in discovery laboratories at
multigram scale.
4
.
Experimental Section
4.1. General description of methods and materials.
The precursor iodides 10a-k and benzyl amine were purchased from Fluorochem, while the other
reagents and the solvents from Sigma-Aldrich. Sterically hindered aryl iodide 10l was prepared as
1
2

1
13
19
reported [36]. H NMR, C NMR and F NMR spectra were recorded on Bruker Avance 250 and
1
13 31 19
1
13 15
DRX500 spectrometers using 5 mm inverse H/ C/ P/ F and H/ C/ N probeheads at room
temperature, respectively. Data were expressed as chemical shifts in ppm relative to residual
1
13
19
chloroform ( H δ = 7.27), CDCl
3
( C δ = 77.0) or an external standard for F (CFCl , δ = 0) on the δ
3
scale. Exact mass measurements were performed on a high resolution QExactive Focus hybrid
quadrupole-orbitrap mass spectrometer (Thermo Scientific, Bremen, Germany), equipped with heated
electrospray ionization (HESI) source. Samples were dissolved in methanol-water solvent mixture
(1:1, V/V) containing 0.1% formic acid. Mass spectra were recorded in positive ionization mode using
direct sample infusion with a syringe pump (10 μL/min flow rate). Resolution was set to 70.000.
4.2 Synthesis of 2,2,2-trilfuoroethyl thioacetate 9
To the stirred suspension of 2,2,2-trifluoroethyl benzenesulfonate (150 g; 0.625 mol) and K
2
CO (128
3
g; 0.925 mol) in DMSO (750 ml) thiolacetic acid (133 ml, 1.875 mol) was added dropwise during 1.5
h. Then the volatile components were distilled out from mixture at water pump vacuum using and
o
heating it with a 150 – 160 C temperature oil bath. On cooling the colorless distillate was separated
into two liquid phases, of which the lower one is enriched in trifluoroethyl thioacetate, while the upper
one in DMSO. Ice (100 g) and CH
separated and dried (Na SO ). The solvent was removed by distillation at ambient pressure. Then the
crude product was purified by distillation. Yield: 67.0 g (68%) colorless liquid, bp 107–110 °C; d =
2
Cl
2
(100 ml) were added and the lower organic phase was
2
4
o
o
1
.278 (25 C), n
D
= 1.3940 (25 C).
At smaller scale using 0.25 mol of trifluoroethyl benzenesulfonate 64% yield of 9 was obtained.
1
3
13
H NMR (250 MHz, CDCl
NMR (75 MHz, CDCl
Hz, CF CH S), 29.8 (s, C(O)CH
ν = 1711, 1309, 1271, 1241, 1121, 1082, 957, 847 cm .
3
): δ 3.58 (q, JHF = 9.9 Hz, 2H, CF
3
CH
2
S), 2.42 (s, 3H, SC(O)CH ); C
3
1
2
3
): δ 191.6 (s, C(O)CH
3
), 124.7 (q, JCF = 276 Hz, CF
3
CH S), 30.6 (q, JCF = 34
2
1
9
3
3
2
3
); F NMR (235 MHz, CDCl
3
): δ −67.05 (t, JHF = 9.9 Hz). IR (neat):
−
1
4.3.
General procedure (GP) for the synthesis of aryl 2,2,2-trifluoroethyl sulfides
1
3

Aryl iodide (5.00 mmol) was dissolved in benzylamine (1.64 ml) and CuBr (0.036 g, 0.25 mmol) was
added to the mixture. After purging with argon 2,2,2-trifluoroethylthioacetate (9, 0.948 g, 6 mmol)
was added to the suspension and the vial was sealed under argon. The mixture was stirred at 110 °C
bath temperature for 6 h. After cooling to room temperature, hexane (15 ml) was added to the mixture
and the resulted suspension was stirred for 2 min then filtered through a Celite pad. The filtrate was
washed with 1 M HCl (2 × 10 ml) and water (10 ml), then dried over Na
2
SO . The solvent was
4
removed under reduced pressure and the crude product was purified by flash chromatography (silica
gel/hexane).
4.3.1 Phenyl 2,2,2-trifluoroethyl sulfide (11a)
Iodobenzene 10a (1.02 g, 5.00 mmol) was reacted according to GP to afford 0.96 g (87%) of 11a as a
1
colorless liquid. H NMR (500 MHz, CDCl
3
) δ 7.52 – 7.45 (m, 2H, Ar), 7.36 – 7.27 (m, 3H, Ar), 3.44
3
13
(
(
(
q, JHF = 9.7 Hz, 2H, CH
2
); C NMR (126 MHz, CDCl
3
) δ 137.5 (Ar), 131.8 (Ar), 129.3 (Ar), 128.0
1
2
19
Ar), 125.4 (q, JCF = 276 Hz, CF
3
), 38.2 (q, JCF = 33 Hz, CH
2
); F NMR (235 MHz, CDCl
3
) δ -66.81
3
t, JHF = 9.7 Hz). HRMS (ESI) m/z calcd. for C
8
H
7
3
F S: 192.02206, found 192.02196. Mass error: -0.5
ppm. Characterization data matched that reported in the literature [22, 23, 24a, 25b, 37].
4
3
.3.2 3-Methoxyphenyl 2,2,2-trifluoroethyl sulfide (11b)
-Methoxy-iodobenzene 10b (1.17 g, 5.00 mmol) was reacted according to GP to afford 0.90 g (81%)
1
3
of 11b as a colorless liquid. H NMR (500 MHz, CDCl ) δ 7.22 (t, JHH = 8.0 Hz, 1H, Ar), 7.07 – 7.01
3
3
3
3
(
m, 1H, Ar), 7.01 – 6.98 (m, 1H, Ar), 6.81 (ddd, JHH = 8.3, JHH = 2.5, JHH = 0.8 Hz, 1H, Ar), 3.78 (s,
3
13
3
1
H, CH
3
), 3.43 (q, JHF = 9.7 Hz, 2H, CH
2
); C NMR (126 MHz, CDCl ) δ 160.0 (Ar), 134.9 (Ar),
3
1
2
30.1 (Ar), 125.3 (q, JCF = 277 Hz, CF
3
), 123.6 (Ar), 116.9 (Ar), 113.8 (Ar), 55.3 (CH ), 37.9 (q, JCF
3
19
3
=
33 Hz, CH
2
); F NMR (235 MHz, CDCl
3
) δ -66.77 (t, JHF = 9.7 Hz). HRMS (ESI) m/z calcd. for
C
9
H
9
3
F OS: 222.03262, found 222.03216. Mass error: -2.0 ppm. Characterization data matched that
reported in the literature [29].
4.3.3 4-Methoxyphenyl 2,2,2-trifluoroethyl sulfide (11c)
1
4

4
-Methoxy-iodobenzene 10c (1.17 g, 5.00 mmol) was reacted according to GP to afford 0.95 g (85%)
1
3
3
of 11c as colorless liquid. H NMR (500 MHz, CDCl
3
) δ 7.45 (d, JHH = 8.8 Hz, 2H, Ar), 6.84 (d, JHH
3
13
=
8.8 Hz, 2H, Ar), 3.78 (s, 3H, CH
3
), 3.29 (q, JHF = 9.8 Hz, 2H, CH
2
); C NMR (126 MHz, CDCl
3
) δ
1
1
60.2 (Ar), 1345.4 (Ar), 125.5 (q, JCF = 277 Hz, CF
3
), 124.0 (Ar), 114.8 (Ar), 55.3 (CH ), 39.6 (q,
3
2
19
3
J
CF = 32 Hz, CH
2
); F NMR (235 MHz, CDCl
3
) δ -66.77 (t, JHF = 9.7 Hz). HRMS (ESI) m/z calcd.
for C
9
H
9
3
F OS: 222.03262, found 222.03229. Mass error: -1.5 ppm. Characterization data matched that
reported in the literature [29].
4
2
1
.3.4 2-Methylphenyl 2,2,2-trifluoroethyl sulfide (11d)
-Methyl-iodobenzene 10d (1.09 g 5.00 mmol) was reacted according to GP to afford 0.98 g (95%) of
1
3
1d as a colorless liquid. H NMR (500 MHz, CDCl
3
) δ 7.45 (t, JHH = 7.2 Hz, 1H, Ar), 7.25 – 7.13
3
13
(
m, 3H, Ar), 3.37 (q, JHF = 9.7 Hz, 2H, CH
2
), 2.45 (s, 3H, CH
3
); C NMR (126 MHz, CDCl
3
) δ 140.1
1
(
Ar),132.8 (Ar), 132.4 (Ar), 130.6 (Ar), 128.3 (Ar), 126.8 (Ar), 125.4 (q, JCF = 277 Hz, CF
3
), 37.9 (q,
2
19
3
J
CF = 33 Hz, CH
2
), 20.6 (CH
S = 206.03771, found 206.03739. Mass error: -0.3 ppm. For an alternative
preparation and H NMR spectrum, cf. [38].
3
); F NMR (235 MHz, CDCl ) δ -66.77 (t, JHF = 9.7 Hz). HRMS (ESI)
3
m/z calcd. for C
9
H
F
9 3
1
4
3
.3.5 2,2,2-Trifluoroethyl 3-(trifluoromethyl)phenyl sulfide (11e; n. c.)
-Trifluoromethyl-iodobenzene 10e (1.36 g, 5.00 mmol) was reacted according to GP to afford 1.08 g
1
3
(
83%) of 11e as a colorless liquid. H NMR (500 MHz, CDCl
3
) δ 7.71 (s, 1H, Ar), 7.64 (d, JHH = 7.9
3
3
3
Hz, 1H, Ar), 7.53 (d, JHH = 7.8 Hz, 1H, Ar), 7.44 (t, JHH = 7.8 Hz, 1H, Ar), 3.45 (q, JHF = 9.5 Hz,
13
2
2H, CH
2
); C NMR (126 MHz, CDCl ) δ 135.1 (Ar), 134.6 (Ar), 131.8 (q, JCF = 33 Hz, Ar), 129.7
3
3
1
2
(
Ar), 128.1 (q, JCF = 4 Hz, Ar), 125.1 (q, JCF = 275 Hz, CF
3
), 124.8 (q, JCF = 33 Hz, Ar), 123.5 (q,
); F NMR (235 MHz, CDCl ) δ -63.43 (s, 3F, CF Ar),
). HRMS (ESI) m/z calcd. for C S=260.00944, found
1
2
19
J
CF = 273 Hz, CF
3
), 37.7 (q, JCF = 33 Hz, CH
2
3
3
3
-
66.84 (t, JHF = 9.5 Hz, 3F, CH
2
CF
3
9
H
F
6 6
2
60.00911. Mass error: -1.3 ppm.
4.3.6 4-Methylphenyl 2,2,2-trifluoroethyl sulfide (11f)
1
5

4
1
8
1
3
-Methyl-iodobenzene 10f (1.09 g, 5.00 mmol) was reacted according to GP to afford 0.85 g (82%) of
1
3
3
1f as a colorless liquid. H NMR (500 MHz, CDCl
3
) δ 7.38 (d, JHH = 8.2 Hz, 2H, Ar), 7.12 (d, JHH =
3
13
.2 Hz, 2H, Ar), 3.36 (q, JHF = 9.7 Hz, 2H, CH
2
), 2.32 (s, 3H, CH
3
); C NMR (126 MHz, CDCl
3
) δ
1
2
38.44 (Ar), 132.52 (Ar), 131.20 (Ar), 130.03 (Ar), 125.45 (q, JCF = 276 Hz, CF
3
), 38.72 (q, JCF
=
1
9
3
2.5 Hz, CH
2
), 21.10 (CH
S=206.03771, found 206.03732. Mas error: -0.4 ppm. Characterization data matched
that reported in the literature [20, 23, 29].
3
); F NMR (235 MHz, CDCl ) δ -66.84 (t, JHF = 9.7 Hz). HRMS (ESI) m/z
3
calcd. for C
9
H
F
9 3
4
2
1
.3.7 2-Chlorophenyl 2,2,2-trifluoroethyl sulfide (11g; n. c.)
-Chloro-iodobenzene 10g (1.19 g, 5.00 mmol) was reacted according to GP to afford 0.83 g (73%)
1
1g as colorless liquid. H NMR (500 MHz, CDCl
3
) δ 7.58 – 7.49 (m, 1H, Ar), 7.45 – 7.37 (m, 1H,
3
13
Ar), 7.28 – 7.17 (m, 2H, Ar), 3.46 (q, JHF = 9.6 Hz, 2H, CH
2
); C NMR (126 MHz, CDCl
3
) δ 136.5
), 36.4
1
(
(
Ar), 133.5 (Ar), 132.1 (Ar), 130.21 (Ar), 129.5 (Ar), 127.4 (Ar), 125.3 (q, JCF = 277 Hz, CF
3
2
19
3
q, JCF = 33 Hz, CH
2
); F NMR (235 MHz, CDCl ) δ -66.37 (t, JHF = 9.6 Hz). HRMS (ESI) m/z
3
calcd. for C
8
H
6
ClF S = 225.98308, found 225.98265. Mass error: -1.9 ppm.
3
4
3
.3.8 3-Nitrophenyl 2,2,2-trifluoroethyl sulfide (11h)
-Nitro-iodobenzene 10h (1.25 g, 5.00 mmol) was reacted according to GP to afford 0.43 g (36%) 11h
1
3
19
as yellow oil. H NMR (250 MHz, CDCl ) δ 8.32 – 7.53 (m, 4H), 3.54 (q, JHF = 9.7 Hz, 2H); F
3
3
NMR (235 MHz, CDCl
literature [29].
3
) δ -66.63 (t, JHF = 9.7 Hz). Characterization data matched that reported in the
4
4
.3.9 4-Nitrophenyl 2,2,2-trifluoroethyl sulfide (11i)
-Nitro-iodobenzene 10i (1.25 g, 5.00 mmol) was reacted according to GP to afford 0.48g (40%) 11i
1
3
3
as pale yellow oil. H NMR (500 MHz, CDCl
3
) δ 8.15 (d, JHH = 8.9 Hz, 2H, Ar), 7.49 (d, JHH = 8.9
3
13
Hz, 2H, Ar), 3.57 (q, JHF = 9.4 Hz, 2H, CH
2
); C NMR (126 MHz, CDCl
3
) δ 146.6 (Ar), 143.1 (Ar),
1
2
19
1
28.9 (Ar), 124.9 (q, JCF = 276 Hz, CF
3
), 124.2 (Ar), 35.9 (q, JCF = 34 Hz, CH
2
); F NMR (235
1
6

3
MHz, CDCl ) δ -66.53 (t, JHF = 9.4 Hz). Characterization data matched that reported in the literature
3
[29].
4
2
.3.10 2-Pyridyl 2,2,2-trifluoroethyl sulfide (11j)
-Iodopyridine 10j (1.03 g, 5.00 mmol) was reacted according to GP to afford 0.68 g (70%) of 11j as
1
3
3
3
colorless liquid. H NMR (500 MHz, CDCl ) δ 8.42 (ddd, JHH = 4.9, JHH = 1.8, JHH = 0.9 Hz, 1H),
3
3
3
3
3
3
7
.50 (ddd, JHH = 8.0, JHH = 7.4, JHH = 1.9 Hz, 1H), 7.20 (dt, JHH = 8.1, JHH = 1.0 Hz, 1H), 7.02
3
3
3
3
13
(
ddd, JHH = 7.4, JHH = 4.9, JHH = 1.0 Hz, 1H), 4.02 (q, JHF = 10.0 Hz, 2H); C NMR (126 MHz,
1
CDCl
3
) δ 154.7 (Ar), 149.4 (Ar), 136.5 (Ar), 125.4 (q, JCF = 274 Hz), 122.4 (Ar), 120.5 (Ar), 31.0 (q,
2
19
3
J
CF = 34 Hz, CH
NS = 193.01730, found 193.01694. Mass error: -0.8 ppm. Characterization data matched
that reported in the literature [23, 39].
2
); F NMR (235 MHz, CDCl ) δ -66.71 (t, JHF = 9.7 Hz). HRMS (ESI) m/z calcd.
3
for C
7
H F
6 3
4
2
.3.11 2-Thienyl 2,2,2-trifluoroethyl sulfide (11k)
-Iodothiophene 10k (1.05 g, 5.00 mmol) was reacted according to GP to afford 0.48 g (48%) of 11k
1
3
3
as a colorless liquid. H NMR (500 MHz, CDCl ) δ 7.39 (dd, JHH = 5.4, JHH = 1.3 Hz, 1H), 7.25 (dd,
3
3
3
3
3
3
13
J
HH = 3.6, JHH = 1.2 Hz, 1H), 6.97 (dd, JHH = 5.4, JHH = 3.6 Hz, 1H), 3.29 (q, JHF = 9.7 Hz, 2H); C
1
NMR (126 MHz, CDCl
3
) δ 136.2 (Ar), 131.4 (Ar), 131.1 (Ar), 127.8 (Ar), 125.2 (q, JCF = 277 Hz,
2
19
3
CF
3
), 41.4 (q, JCF = 32 Hz, CH
2
); F NMR (235 MHz, CDCl
: 197.97848, found 197.97829. Mass error: -0.9 ppm. Characterization
data matched that reported in the literature [11].
3
) δ -66.71 (t, JHF = 9.7 Hz). HRMS
(
ESI) m/z calcd. for C
6
H
5
F S
3 2
4.3.12 2,6-Dimethyl-4-tert-butylphenyl 2,2,2-trifluoroethyl sulfide (11l; n. c.)
A glass ampule of 170 mm of length and 50 mm diameter was supplied with an egg-shaped magnetic
stirrer bar, charged with benzyl amine (24.6 ml, 24.1 g) and purged with argon. Next CuBr (0.54 g,
3.76 mmol), trifluoroethyl thioacetate (14.2 g, 90 mmol) and the aryl iodide 10l (21.6 g, 75 mmol) was
o
added. Then it was sealed, next immersed in 40 mm deep into an oil bath of 110 C temperature and
stirred for 18 h. The ampule was cooled, opened and the crude mixture was distilled with steam
1
7

collecting ~1 liter of condensate. The steam volatile oil – mixture of title product and benzyl amine –
was extracted with dichloromethane (2 x 150 ml), then the separated organic layer was sequentially
washed with 1M HCl (2 x 100 ml) and water (2 x 30 ml) then dried over Na
2
SO . The solvent was
4
removed by evaporation (Rotavap) and the residue was distilled in vacuum. The main fraction was
o
collected at 142-143 C/16 mmHg as a colorless liquid. Yield: 16.12 g (77.8%).
1
3
H NMR (500 MHz, CDCl
3
) δ 7.17 (s, 2H, Ar), 3.20 (q, JHF = 9.9 Hz, 2H, CH ), 2.59 (s, 6H, Ar-
2
13
CH
3
), 1.33 (s, 9H, C(CH
3
)
3
); C NMR (126 MHz, CDCl
3
) δ 152.3 (Ar), 142.7 (Ar), 128.4 (Ar), 125.7
1
2
19
(
Ar), 125.6 (q, JCF = 277 Hz, CF
3
), 37.6 (q, JCF = 38 Hz, CH
2
), 34.4 (C(CH
3
)
3
), 31.2 (C(CH
3
)
3
); F
3
NMR (282 MHz, CDCl
3
) δ -66.36 (t, JHF = 10.0 Hz, 3F, CF
3
). HRMS (ESI) m/z calcd. for C14
H
19
3
F S:
276.11596, found 276.11587. Mass error: -0.3 ppm.
4.3.12.1
Gravimetric determination of the aryl iodide conversion
Using 1/3 amounts of reagents and same conditions as above but heating the reaction mixture only for
o
6
h at 110 C resulted in ~80% conversion of aryl iodide (30 mmol), the limiting reagent. This figure
was calculated by gravimetric analysis of the water soluble iodide ions in the form of CuI precipitate.
For this reason the steam distillation residue of the boiler flask was first extracted with ether to remove
the co-product N-benzyl acetamide and the residual free benzyl amine. Next the water layer was
filtered to remove the remains of the copper (I) catalyst (5 mol %) used. Note that CuBr was
transformed to CuI in the reaction due to its higher stability and lower solubility in the amine solvents
and water. The clear filtrate was treated with CuSO
4
×5H
2
O (35 mmol) and the liberated I was titrated
2
with NaHSO solution. The precipitated CuI was filtered, triturated with methanol, filtered again and
3
washed with 20% HCl and water, and dried to give 4.6 g (24 mmol) of CuI as cream-white powder.
Working up the steam distillate of this experiment as shown in subsection 4.3.12 gave 6.04 g (73%)
o
1
1l sulfide as a colorless oil of bp 142-143 C/16 mmHg, containing ~15 mol% unreacted 10l aryl
1
iodide as determined by H NMR analysis. This result suggests that the sulfide 11l and its precursor
iodide 10l should have similar boiling points, thus they are difficult to separate by distillation. Instead,
longer reaction time or the use of a larger excess of the CF
3
CH SH source could result in the complete
2
1
8

conversion of this sterically hindered aryl iodide and will allow simple isolation of the pure product by
distillation.
4.3.12.2
Isolation of the N-benzyl acetamide co-product
The ether extract of the experiment in subsection 4.3.12.1 was washed with 5% HCl and water, then
dried (Na
2
SO
4
). Evaporation of the solvent afforded slightly brown crystalline product, which was
1
13
identified by H and C NMR as CH
3
CONHCH
2
C
6
H
5
. Yield: 4.10 g (27.5 mmol, 92% referred to the
30 mmol of trifluoroethyl thioacetate 9 used).
1
3
H NMR (250 MHz, CDCl
3
) δ 7.40 – 7.15 (m, 5H, Ar), 6.28 (br s, 1H, NH), 4.38 (d, JHH = 5.7 Hz,
1
3
2
1
H, CH
2
), 1.97 (s, 3H, CH
3
); C NMR (63 MHz, CDCl
3
) δ 170.61 (CO), 138.61 (Ar), 129.06 (Ar),
28.19 (Ar), 127.86 (Ar), 44.08 (CH
3
), 23.54 (CH ).
2
4
.3.12.3
Double blank experiment – isolation of CF
3
CH SH
2
A 100 ml volume pearl shaped distillation flask was charged with trifluoroethyl thioacetate 9 (15.8 g,
100 mmol) and mixed with benzylamine (27 ml, 247 mmol). An exothermic reaction started and the
o
distillation of the title compound with bp 36 C was maintained by heating with an oil bath up to 150
o
C. Yield: 6.7 g (58%) colourless liquid. Characterization data matched that reported in the literature
[34].
Conflict of interest
All authors of this paper have no confilct of interest.
1
9

Acknowledgements.
The authors thank the National Research, Development and Innovation Office (K115764) for
supporting this work. GS was supported by the MTA Premium Post-Doctorate Research Program of
the Hungarian Academy of Sciences (HAS, MTA). Purchase of the UHRMS mass spectrometer was
supported by grant (VEKOP-2.3.3-15-2017-00020) from the European Union and the State of
Hungary, co-financed by the European Regional Development Fund.
2
0

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