Diversification of Trifluoromethylthiolation of Aromatic Molecules with Derivatives of Trifluoromethanesulfenamide

Article abstract of DOI:10.1002/ejoc.201800551

Trifluoromethylthiolation of aromatic compounds with different electrophilic reagents of the type ArNHSCF₃ was studied in the presence of triflic acid as an activator. The effect of the reagent structure on the reactivity was studied with three different reagents: PhNHSCF₃ (H/SCF₃, 1a), 4-ClC₆H₄NHSCF₃ (Cl/SCF₃, 1b) and C₆F₅NHSCF₃ (F₅/SCF₃, 1c). p-Chloro substituted reagent 1b was more stable than the unsubstituted 1a and was the most effective because it could not react by trifluoromethylthiolation of itself. This reaction was the most important side reaction of 1a. The pentafluoro derivative 1c was less reactive. Solvent played an important role in the transformation and, depending on the substrate, dichloromethane, hexane or trifluoroacetic acid gave the best yield of various trifluoromethylthiolated aromatic molecules (63–98 %).

Full text of DOI:10.1002/ejoc.201800551

A Journal of
Accepted Article
Title: Diversification of Trifluoromethylthiolation of Aromatic Molecules
with Derivatives of Trifluoromethanesulfenamide
Authors: Monika Horvat, Marjan Jereb, and Jernej Iskra
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10.1002/ejoc.201800551
European Journal of Organic Chemistry
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Diversification of Trifluoromethylthiolation of Aromatic
Molecules with Derivatives of Trifluoromethanesulfenamide
Monika Horvat, Marjan Jereb, Jernej Iskra*
Abstract: Trifluoromethylthiolation of aromatic compounds with
different electrophilic reagents of ArNHSCF3 type was studied in the
presence of triflic acid as an activator. The effect of the reagent
structure on the reactivity was studied with three different reagents -
PhNHSCF3 (H/SCF3, 1a), 4-ClC6H4NHSCF3 (Cl/SCF3, 1b) and
C6F5NHSCF3 (F5/SCF3, 1c). p-Chloro substituted reagent 1b was
more stable than the unsubstituted one 1a and the most effective, as
it could not react by trifluoromethylthiolation of itself. The later reaction
was the most important side reaction in reactions with 1a. The
pentafluoro derivative 1c was less reactive. Solvent played important
role in the transformation and depending on the substrate, DCM,
hexane or trifluoroacetic acid gave the best yield of various
trifluoromethylthiolated aromatic molecules (63-98%).
less studied and used due to toxic and gaseous radical reagents
(CF3SH, CF3SSCF3 and CF3SCl). Recently, this approach
become more interesting due to development of new methods,
e.g. photochemistry.[4e, 5s, 7]
Electrophilic
reagents
for
introduction
of
the
trifluoromethylsulfanyl group into the aromatic ring can be
classified into three groups: RSO2CF3, N-SCF3 and O-SCF3
reagents.[4e, 5a, 5b, 8] Among them, N-SCF3 reagents are interesting
with main reagents based on succinimide, phthalimide and
saccharin scaffold.[5c, 5i, 9] Interest in N-SCF3 reagents increased
when
Billard
and
co-workers
prepared
trifluoromethanesulfenamide reagent (PhNHSCF3, 1a) and later
PhN(CH3)SCF3, while PhSO2N(CH3)SCF3 was the second
generation.[10]
trifluoromethylthiolation
These
reagents
of alkynes,
are
useful
alkenes,
for
indoles,
the
organometallic substrates, tryptamines, allyl silanes, thiols and
Introduction
4e, 5b, 11]
.
amines.[4d,
A strong Lewis (Me3SiCl, BF3 Et2O, acetyl
chloride) or Brønsted (triflic acid, p-TsOH) acid is needed for the
activation of the reaction.
In recent years the development of new methods for the
introduction of the trifluoromethylsulfanyl group (SCF3) into
organic molecules is highly sought after. Organofluorine
compounds have high potential in pharmaceutical industry,
agrochemistry, fluoropolymers, material science and in medical
chemistry.[1] There are several marketed fluorinated
agrochemicals and pharmaceuticals, which possess enhanced
stability and biological activity. The trifluoromethylsulfanyl group
is of particular interest due to its remarkably high lipophilic
parameter (Hansch constant 1.44).[2] The trifluoromethylsulfanyl
group is found in several bioactive compounds, such as triflorex,
toltrazuril, methionine analogue, adenosine analogue, losartan
analogue, cefazaflur.[3]
Derivatives of trifluoromethanesulfenamide reagent were used for
direct electrophilic trifluoromethylthiolation of activated aromatic
and heteroaromatic molecules[10d, 10e, 12] and recently the second
generation of reagent was used for the trifluoromethylthiolation of
anilines in super acid media (SbF5).[13] We were interested in the
possibility of selective introduction of the trifluoromethylsulfanyl
group on various aromatic compounds. We studied how the
structure of the reagent and the solvent could affect the reactivity.
The effect of the reagent structure on its activity was studied
through modification of phenyl ring and three reagents were
prepared - PhNHSCF3 (H/SCF3, 1a), 4-ClC6H4NHSCF3 (Cl/SCF3,
1b) and C6F5NHSCF3 (F5/SCF3, 1c).
Several methods were reported for the introduction of the
trifluoromethylsulfanyl group into an aromatic ring (Ar-SCF3)
3-4]
through radical, electrophilic and nucleophilic pathways.[2a,
Reactions can be divided into a direct introduction of the
trifluoromethylsulfanyl group on an unsubstituted position, the
replacement of -B(OH)2, -N2+ or a halogen substituent and also by
catalytic reactions (metals, organocatalysts, photocatalysis).[5]
Initially used Hg(SCF3)2, that is very toxic and corrosive,[4d] was
substituted by other nucleophilic reagents AgSCF3, CuSCF3,
[(CF3S)2(TDAE)][5g, 6] that are of limited reactivity because of their
instability. Radical trifluoromethylthiolation reactions have been
M. Horvat, M. Jereb, J. Iskra,
Faculty of Chemistry and Chemical Technology,
University of Ljubljana,
Večna pot 113,
SI-1000 Ljubljana, Slovenia
E-mail: jernej.iskra@fkkt.uni-lj.si
Scheme 1
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10.1002/ejoc.201800551
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Results and Discussion
product is formed as
trifluoromethylthiolation. This side process was observed to a
much greater degree in the reaction carried out in polar solvents.
a
side product in aromatic
Anisole 2a was chosen as the model substrate for initial study of
the reaction conditions for the selective introduction of the
trifluoromethylsulfanyl group on the aromatic ring with the basic
reagent 1a (Table 1). A solution of anisole 2a, reagent H/SCF3 1a
and activator TfOH was stirred at room temperature for 20 h. After
the work-up procedure, conversion based on the starting material
1
2a was determined by H NMR on the crude reaction product.
Amongst the various tested solvents, the highest conversion was
observed in non-polar ones with DCM giving the best results
(Table 1, entry 5). Interestingly, reaction did not proceed in polar
solvents MeCN and HFIP, although the latter is being known for
facilitating the electrophilic processes.[14] Only TFA gave similar
yield of 3a as non-polar solvents. Increasing the amount of TfOH
increased the yield. When using 1.3 equiv. of 1a and TfOH the
product 3a was formed in 93% yield, while further increase of the
amount of triflic acid had only small effect on the yield.
Scheme 2
The result indicates that for less reactive substrates this side
reaction will be even more competitive. Hence, we thought of
preparing on alternative reagent with less reactive aniline ring and
with even higher reactivity. Li and coworkers found linear
correlation between the trifluoromethylsulfanyl radical donor
ability (Tt.DA) of electrophilic SCF3 reagents and Brown constant
Table 1. Optimization of the reaction conditions for trifluoromethylthiolation
of anisole 2a with 1aa
+
σp of the substituent on the aromatic ring of the reagent.[15]
According to the data from this theoretical study we chose to study
4-chloro derivative (Cl/SCF3, 1b) which had somewhat lower
Tt.DA value in DCM (59.9 kcal mol-1) than H/SCF3 1a (60.3 kcal
mol-1) and hence more reactive, while it has deactivated aromatic
ring for electrophilic substitution. As a comparison, we prepared
pentafluoroaniline derivative (F5/SCF3, 1c) that should have more
electrophilic character at the sulfur atom due to the electron-
withdrawing effect of fluorine atoms.
Entry
2:1a:TfOH
Solvent
Conv.b [%]
We have prepared all three reagents under the reported reaction
conditions. Pure reagents were analyzed by TGA for their stability.
Both substituted reagents Cl/SCF3 1b and F5/SCF3 1c were found
to be more stable than H/SCF3 1a and started to decompose
above 50 °C. The classical unsubstituted one 1a started to
decompose already at 40 °C with higher rate of decomposition
than 1b and 1c.
1
2
3
4
5
6
7
1:1.0:1.0
1:1.0:2.0
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:2.6
1:1.5:3.0
DCM
DCM
TFA
76
84
81
88
93
94
95
hexane
DCM
DCM
DCM
aReaction conditions: anisole 2a (0.1 mmol), reagent H/SCF3 1a (0.1 – 0.15
mmol), TfOH (0.1 – 0.30 mmol), solvent (1 mL), 20h, rt. bConversion to
product was determined by 1H NMR.
Since we needed 30% excess of the reagent to get the best yield
of trifluoromethylthiolation of anisole, we wondered if some side
reaction occurs. We stirred only the reagent 1a together with
TfOH in DCM. Reaction mixture was washed with basic aqueous
solution and organic phase was evaporated (Scheme 2). We
analyzed the reaction mixture to find that the sink of the reagent
was trifluoromethylthiolation of the reagent itself leading to
formation of 4-((trifluoromethyl)thio)aniline (4a) in 31% yield.
Next, we analysed the crude reaction mixture after the reaction of
trifluoromethylthiolation (Table 1, entry 5) and found that the same
Figure 1. Thermogravimetric analysis of stability of reagents 1
The effect of the substituent on the reactivity of the reagents 1
was studied in the case of anisole 2a and two substituted phenols,
4-tert-butyl 2b and 4-bromo 2c substituted ones. The best
reaction conditions from the Table
1
were taken for
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trifluoromethylthiolation of anisole 2a and results confirmed our
anticipation that reagent 1b is more effective than the classical
one (Table 2, entry 2). By slow addition of the reagent,
quantitative conversion to 4-trifluoromethylthioanisole 3a was
achieved. Surprisingly, F5/SCF3 1c was less reactive and only
44% of the product was formed under the same reaction
conditions. Even using twice the amount of acid, the conversion
was only 66%. Since the aromatic ring of the reagent is not active,
low reactivity could only arise from the reagent structure. The
same trend was even more obvious with activated phenol 2b.
Cl/SCF3 1b was the most active reagent with quantitative
conversion to 4-(tert-butyl)-2-((trifluoromethyl)thio)phenol 3b
under the slow addition of the reagent. The F5/SCF3 1c was not
active enough and the conversion of 37% was observed using 3.9
equiv. of TfOH. The deactivated 4-bromophenol 2c was not
included also less reactive substrates 4-tert-butyltoluene 2d and
4-bromoanisole 2e (Table 3). Reactions were performed on a 0.1
mmol scale and when the reaction was complete, the reaction
mixture was washed with saturated solution of NaHCO3 and
water; organic phase was evaporated and the crude reaction
mixture analyzed by 1H NMR spectroscopy. This work-up
procedure kept the reagent’s product 4b in the organic phase so
that we could determine the amount of SCF3 group that was
incorporated into the aromatic ring of the reagent. Anisole 2a was
trifluoromethylthiolated by 1b in all three solvents (DCM, Hex,
TFA) and no formation of 4b occurred (Table 3).
Trifluoromethylthiolation in DCM was quantitative with o-/p- ratio
of 3a 6/94. Reaction in hexane and TFA was less effective (71%
and 60% conversion, respectively) and slightly higher amount of
ortho product was formed in TFA (o-/p- ratio of 3a 9/91). Reaction
of 4-bromophenol 2c showed similar trend and reaction occurred
in all three solvents with conversion in TFA being the lowest. We
also observed the reaction on the reagent leading to the formation
of 4b in small amount. On contrary, 4-tert-butyltoluene 2d and 4-
bromoanisole 2e showed the best conversion in TFA and besides
3d and 3e, 4b was also formed.
converted
completely
to
the
4-bromo-2-
((trifluoromethyl)thio)phenol 3c and the highest conversion was
achieved by using Cl/SCF3 1b (50% conversion).
Table 2. The effect of reagent structure on the reactivitya
Table 3. The effect of solvent on the reaction of Cl/SCF3 1b with less
reactive arenesa
Entry
1
2
1
2:1:TfOH
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:2.6
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:2.6
1:1.3:3.9
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
Conv.b [%]
anisole 2a
1a
1b
1bc
1c
1c
1a
1b
1bc
1c
1c
1c
1a
1b
1c
93
95
100
44
61
75
96
100
0
2
anisole 2a
3
anisole 2a
4
anisole 2a
5
anisole 2a
Entry
1
2
Solvent
DCM
2
3b
4bc
0
6
4-tert-butylphenol 2b
4-tert-butylphenol 2b
4-tert-butylphenol 2b
4-tert-butylphenol 2b
4-tert-butylphenol 2b
4-tert-butylphenol 2b
4-bromophenol 2c
4-bromophenol 2c
4-bromophenol 2c
anisole 2a
5
95
71
60
45
52
15
63
89
91
0
7
2
anisole 2a
hexane
TFA
29
40
55
48
85
37
11
9
0
8
3
anisole 2a
0
9
4
4-bromophenol 2c
4-bromophenol 2c
4-bromophenol 2c
4-tert-butyltoluene 2d
4-tert-butyltoluene 2d
4-tert-butyltoluene 2d
4-bromoanisole 2e
4-bromoanisole 2e
4-bromoanisole 2e
DCM
10
11
13
41
16
17
0
10
11
12
13
14
5
5
hexane
TFA
37
35
50
0
6
7
DCM
8
hexane
TFA
9
aReaction conditions: reactant 2 (0.5 mmol), reagent 1 (0.65 mmol), TfOH
(0.65 mmol), DCM (5 mL), 20h, rt. bConversion to product 3 was determined
by 1H NMR. cStepwise addition of reagent 1.
10
11
12
DCM
100
87
59
hexane
TFA
13
41
19
28
aReaction conditions substrate 2 (0.1 mmol), reagent 1b (0.13 mmol),
TfOH (0.13 mmol), solvent (1 mL), 20h, rt. bFormation of 3 determined
relative to the initial amount of starting compound (2+3 = 100%). cThe
amount of 4b relative to the initial amount of starting compound.
We studied the effect of the solvent on the trifluoromethylthiolation
with Cl/SCF3 1b to improve its reactivity. We tested this approach
on wider substrate scope and besides 4-bromophenol 2c we
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Finally, the most activating reaction conditions were sought for
conversion of less reactive arenes. We used 4-bromophenol 1c
as the model compound, hexane as solvent and changed the
amount of reagent 1b and TfOH. By using 2 equiv. of 1b and 3
equiv. of TfOH in hexane and with slow addition of reagents,
complete conversion of 2c was observed. (Table 4, entry 5).
Table
4.
Optimization
of
the
reaction
conditions
for
trifluoromethylthiolation of 4-bromophenol 2c with 1ba
Entry
1b (eq.)
1.3
1.3
1.5
2
TfOH (eq.)
Conv.b [%]
1
2
3
4
5
1.3
2.6
2.6
3
52
83
87
88
100
2c
3c
aReaction conditions: 4-bromophenol 2c (0.5 mmol), reagent 1b (0.65 –
1.0 mmol), TfOH (0.13 – 1.5 mmol), hexane (5 mL), 20h, rt. bConversion
to product was determined by 1H NMR. cStepwise addition of reagent 1
and TfOH.
Scheme 3. Isolated yields of the trifluoromethylated products 3 (Method A:
2:1b:TfOH =1:1.3:1.3; Method B: 2:1b:TfOH =1:1.3:1.3, stepwise addition of 1b;
Method C: 2:1b:TfOH =1:2:3, stepwise addition of 1b and TFOH).
With all the knowledge about the trifluoromethylthiolation of
arenes that we obtained, we studied the trifluoromethylthiolation
of various aromatic and heteroaromatic molecules. In all cases
quantitative transformation to 3 was observed with complete
selectivity for the mono-substitution and the isolated yields are
presented in Scheme 3. Only in the case of 2a and 2g a small
amount of the ortho isomer was formed as was determined by
GC-MS. Depending on the reactivity of arene three reaction
conditions were used. Typical reaction conditions (method A)
were 2:1b:TfOH =1:1.3:1.3 and DCM was used as solvent (rt,
20 °C). For less reactive substrates reagent 1b was added
stepwise to the reaction mixture (method B) to achieve complete
conversion of 2. The most activated conditions were used for even
less reactive substrates, where higher amount of TfOH (3 equiv.)
and 1b (2 equiv.) had to be used and added slowly to the reaction
mixture, while solvent had to be hexane or TFA. Toluene 2o
reacted with the TsNMeSCF3 in only 8% conversion.[10d] With the
reagent Cl/SCF3 1b toluene was completely transformed into a
mixture of ortho and para substituted products 3o in ratio 45/55
as determined from the 1H NMR spectra. TFA had to be used as
a solvent. Benzothiophene 2p and indole 2r were more reactive
and complete conversion was obtained in DCM.
Conclusions
We have studied the effect of the structure of the
trifluoromethanesulfenamide reagent and reaction conditions on
trifluoromethyllthiolation of arenes and found that by introducing a
chlorine atom to the aniline ring of the reagent, a more reactive
and stable reagent 1b was obtained relative to classical one 1a.
On the other hand, pentafluoro substituted derivative 1c was less
reactive. The reagent 1b is able to quantitatively
trifluoromethylthylthiolate a wide range of aromatic compounds
under mild conditions with no formation of disubstituted products.
The reaction is limited by the reactivity of the 4-chloroanilinium
cation as the reagent decomposes through formation of
trifluoromethylthiolated aniline 4. Reactivity of 1 depends and the
amount of reagent and activator (triflic acid), while the solvent
plays a crucial role and DCM, hexane or TFA are the solvents of
choice depending on the reactivity of the arene.
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10.1002/ejoc.201800551
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found 227.9860. GC-MS: 227 (M, 91%), 188 (10%), 158 (100%), 114
(36%), 95 (10%), 69 (15%).
Experimental Section
General information
The effect of solvent on the trifluoromethylation of 2c-e and
determination of the amount of side products 4
TLC was performed on Merck-60-F254 plates using mixtures of petroleum
ether:dichloromethane (10:1) or dichloromethane. The crude products
were purified by column chromatography on silica gel (63-200 µm, 70-230
mesh ASTM; Fluka). The melting points were determined on OptiMelt
MPA100. Products were characterized using 1H, 13C and 19F NMR spectra,
HRMS, elemental CHN analysis and melting points of solids. 1H spectra
were recorded on Bruker Avance 300 DPX, 1H, 13C and 19F NMR spectra
were recorded on Bruker Avance III 500 instruments, C, H, N analysis were
recorded on Analizator Perkin-Elmer 2400 II, LC MS analysis were
recorded on system Shimadzu LCMS-IT-TOF. Dynamic thermogravimetric
To a solution of aromatic compound 2 (0.1 mmol) in 1 mL of solvent was
added reagent Cl/SCF3 1b (0.13 mmol) and TfOH (0.13 mmol). The
reaction mixture was stirred at room temperature for 20 h. Conversion was
followed by GC-MS. After reaction was complete, the reaction mixture was
washed first with water (1 × 3 mL) and with aqueous NaHCO3 (1 × 3 mL).
The organic layer was dried over anhydrous Na2SO4 and evaporated in
vacuo. The isolated reaction mixture was analysed by NMR spectroscopy
and GC-MS. Results are presented in the Table 3.
measurements were performed on
a Mettler Toledo TGA/DSC 1
Instrument in temperature range from 25 to 400 °C under a dynamic argon
flow (100 mLmin-1). Heating rate was 5 Kmin-1. Initial masses of the
samples were from 6,0 to 8,7 mg; 150 µL platinum crucibles were used. A
baseline was subtracted in all measurements. GC-MS was recorded on
GC/MS Hewlett Packard 6890 (HP-1 MS column, initial temperature -
80 °C, 20 °C/min, final temperature - 270 °C; except for 1c, 5a and 5b,
where initial temperature was 130 °C).
General procedure
To a solution of aromatic compound 2 (0.5 mmol) in 5 mL of solvent was
added reagent Cl/SCF3 1b (0.65-1.0 mmol, 1.3-2 equiv.) and TfOH (0.65
– 1.5 mmol, 1.3 – 3 equiv.). The reagent and TfOH were added in one
portion or slowly in 6 portions every 1 h. The reaction mixture was stirred
at room temperature for 2-20 h. Conversion was followed by GC-MS. After
reaction was complete, the reaction mixture was washed first with water (1
× 5 mL), then with aqueous HCl (1 × 5 mL), with water (1 × 5 mL) and with
aqueous NaHCO3 (1 × 5 mL). The organic layer was dried over anhydrous
Na2SO4 and evaporated in vacuo. The crude product was analyzed by
NMR spectroscopy and the product purified by column chromatography on
silica gel. Structure was determined by spectroscopic data and
comparison with literature data. The structure of 3d was determined after
its oxidation to the corresponding sulfoxide 3d’ with MCPBA by the
literature method.[18] Structure of ortho isomers of 3a and 3g was
confirmed by the GC-MS analysis of the by-product and comparison of
literature data.[19] Results are presented in the Tables 1, 2 and 4 and the
Scheme 3.
Synthesis of reagent 1
Reagents (1a, 1b, 1c) were prepared using the literature procedure of
Billard and coworkers using aniline, 4-chloroaniline and 2,3,4,5,6-
pentafluoroaniline, respectively.[16] The yield of reagents were: 1a 61 %;
1b 58 % and 1c 49 %. Structure of reagents 1a and 1b was determined by
comparison of literature data. Reagent 1c was determined by 1H and 19
F
NMR spectra and GC-MS, where only one signal was obtained, while there
was no ionization in LCMS.
N-(perfluorophenyl)-S-(trifluoromethyl)thiohydroxylamine (F5/SCF3,
1c). 69 mg (49%). Yellow-brown liquid. 19F NMR (471 MHz, CDCl3, 25°C):
δ –53.1 (t, J = 3 Hz, 3F), –153.5 (d, J = 22 Hz, 2F), –161.6 (t, J = 22 Hz,
1F), –162.7 (m, 2F). GC-MS: 283 (M, 100%), 214 (50%), 182 (82%), 155
(80%), 69 (33%).
(4-methoxyphenyl)(trifluoromethyl)sulfane (3a).[5s] Orange, viscous
liquid. 102 mg (98%). H NMR (500 MHz, CDCl3, 25°C): δ = 7.57 (d, J =
1
8.8 Hz, 2 H, ArH), 6.93 (d, J = 8.9 Hz, 2 H, ArH), 3.91 (s, 0.2 Hortho, CH3),
3.83 (s, 3 H, CH3) ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 161.9,
138.3, 129.6 (q, J = 308 Hz), 121.2, 115.0, 55.4 ppm. 19F NMR (471 MHz,
CDCl3, 25°C): δ = –42.9 (s, 0.18 Fortho), –44.5 (s, 3 F) ppm. GC-MS
(t=6.44): 208 (M, 100%), 139 (18%), 111 (36%), 95 (16%), 69 (21%), 45
(18%). GC-MS (t=6.38): 208 (M, 67%), 139 (100%), 124 (12%), 96 (14%),
69 (17%).
Decomposition of reagent 1
To a solution of 1.0 mmol of reagent 1 in dichloromethane (5 mL) was the
TfOH (140 µL, 1.5 mmol) added. The mixture was stirred at room
temperature for 20 h. After the reaction was complete, the reaction mixture
was washed first with aqueous NaHCO3 (5 mL) and then with water (5 mL).
The organic layer was dried over anhydrous Na2SO4 and evaporated in
vacuo. The crude reaction was subjected to column chromatography
(SiO2, CH2Cl2). Solvent was evaporated in vacuo to provide the product 4.
4-(tert-butyl)-2-((trifluoromethyl)thio)phenol (3b).[12] Yellow, viscous
liquid. 118 mg (94%). H NMR (500 MHz, CDCl3, 25°C): δ = 7.54 (d, J =
1
2.5 Hz, 1 H, ArH), 7.46 (dd, J = 8.6, 2.5 Hz, 1 H, ArH), 7.00 (d, J = 8.6 Hz,
1 H, ArH), 6.18 (s, 1 H, OH), 1.30 (s, 9 H, C(CH3)3) ppm. 13C NMR (126
MHz, CDCl3, 25°C): δ = 155.8, 144.5, 134.8, 131.6, 128.8 (q, J = 310 Hz),
115.7, 107.6, 34.2, 31.3 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –42.9
(s, 3 F) ppm. ESI-HRMS: m/z calcd for C11H13F3OS (M – H)– 249.0557,
found 249.0560. GC-MS: 250 (M, 27%), 235 (100%), 215 (28%), 187
(44%).
4-((trifluoromethyl)thio)aniline (4a).[17] Yellow viscous liquid. 41 mg
(43%). 1H NMR (500 MHz, CDCl3, 25°C): δ = 7.41 (d, J = 8.5 Hz, 1H, ArH),
6.65 (d, J = 8.6 Hz, 1H, ArH) ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ
= 149.1, 138.3, 129.8 (q, J = 308 Hz), 115.4, 111.2 ppm. 19F NMR (471
MHz, CDCl3, 25°C): δ = –44.9 (s, 3 F) ppm. GC-MS: 193 (M, 76%), 124
(100%), 80 (31%).
4-bromo-2-((trifluoromethyl)thio)phenol (3c).[10d] Orange liquid. 127 mg
(93%). 1H NMR (500 MHz, CDCl3, 25°C): δ = 7.71 (d, J = 2.4 Hz, 1 H, ArH),
7.54 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 6.98 (d, J = 8.8 Hz, 1 H, ArH), 6.29
(brs, 1 H, OH) ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 157.3, 139.9,
137.3, 128.5 (q, J = 311 Hz), 118.0, 112.6, 110.1 ppm. 19F NMR (471
MHz, CDCl3, 25°C): δ = –43.0 (s, 3 F) ppm. ESI-HRMS: m/z calcd for
C7H3BrF3OS (M – H)– 270.9046, found 270.9044. GC-MS: 274 (M+2,
4-chloro-2-((trifluoromethyl)thio)aniline (4b). Orange viscous liquid. 44
mg (39%). 1H NMR (500 MHz, CDCl3, 25°C): δ = 7.48 (s, 1 H, ArH), 7.25
(d, J = 8.7 Hz, 1 H, ArH), 6.73 (d, J = 8.7 Hz, 1 H, ArH), 4.48 (s, 2 H, NH2)
ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 148.9, 137.9, 133.2, 129.3 (d,
J = 310 Hz), 129.2, 122.5, 116.6 ppm. 19F NMR (471 MHz, CDCl3, 25°C):
δ = –43.0 ppm. ESI-HRMS: m/z calcd for C7H5ClF3NS (M+H)+ 227.9856,
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64%), 272 (M, 64%), 254 (100%), 205 (21%), 188 (57%), 175 (33%), 124
(12%), 96 (53%), 69 (41%), 45 (17%).
5-(tert-butyl)-3-((trifluoromethyl)thio)benzene-1,2-diol (3i). Brown,
viscous liquid. 128 mg (96%). 1H NMR (500 MHz, CDCl3, 25°C): δ = 7.19
(s, 1 H, ArH), 7.04 (s, 1 H, ArH), 1.45 (s, 9 H, C(CH3)3) ppm. 13C NMR (126
MHz, CDCl3, 25°C): δ = 148.2, 145.3, 140.9, 129.5 (q, J = 309 Hz), 126.2,
117.2, 115.1, 36.2, 31.4 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –42.9
(s, 3 F) ppm. ESI-HRMS: m/z calcd for C11H12F3O2S (M – H)– 256.0516,
found 256.0516. GC-MS: 266 (M, 53%), 251 (44%), 182 (100%), 167
(33%), 57 (10%).
(5-(tert-butyl)-2-methylphenyl)(trifluoromethyl)sulfane (3d). Yellow,
viscous liquid. 108 mg (87 %). 1H NMR (500 MHz, CDCl3, 25°C): δ = 7.66
(d, J = 1.8 Hz, 1 H, ArH), 7.40 (dd, J = 8.0, 2.1 Hz, 1 H, ArH), 7.24 (s, 1 H,
ArH), 2.50 (s, 3 H, CH3), 1.31 (s, 9 H, C(CH3)3) ppm. 13C NMR (126 MHz,
CDCl3, 25°C): δ = 150.1, 140.9, 135.4, 130.7, 130.0 (q, J = 308 Hz), 128.5,
123.3, 34.4, 31.2, 20.6 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –43.0
(s, 3 F) ppm. GC-MS: 248 (M, 29%), 233 (100%), 205 (15%).
Mesityl(trifluoromethyl)sulfane (3j).[21] Colorless liquid. 102 mg (93%).
1H NMR (500 MHz, CDCl3, 25°C): δ = 6.99 (s, 2 H, ArH), 2.52 (s, 6 H, CH3),
2.29 (s, 3 H, CH3) ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 145.3,
141.4, 130.2 (q, J = 309 Hz), 129.6, 120.1, 22.1, 21.2 ppm. 19F (500 MHZ,
CDCl3, 25°C): δ = –42.5 (s, 3 F) ppm. GC-MS: 220 (M, 85%), 151 (100%),
107 (25%), 91 (15%), 45 (16%).
4-(tert-butyl)-1-methyl-2-((trifluoromethyl)sulfinyl)benzene
(3d’).[20]
1
Colorless liquid. 54 % (14.2 mg). H NMR (500 MHz, CDCl3, 25°C): δ =
8.02 (d, J = 1.3 Hz, 1 H, ArH), 7.54 (dd, J = 8.0, 2.1 Hz, 1 H, ArH), 7.24 (d,
J = 8.0 Hz, 1 H, ArH), 2.43 (s, 3 H, CH3), 1.35 (s, 9 H, C(CH3)3) ppm. 13
C
NMR (126 MHz, CDCl3, 25°C): δ = 150.8, 134.9, 133.4, 131.1, 130.4,
125.3 (q, J = 335 Hz), 122.5, 35.0, 31.1, 17.7 ppm. 19F NMR (471 MHz,
CDCl3, 25°C): δ = –74.1 (s, 3 F) ppm. ESI-HRMS: m/z calcd for
C12H15F3OS (M+H)+ 265.0868, found 265.0869. GC-MS: 264 (M, 10%),
195 (100%), 180 (38%), 165 (14%), 115 (15%), 91 (16%), 69 (15%), 57
(54%).
1-((trifluoromethyl)thio)naphthalen-2-ol (3k).[9f] Orange liquid. 99 mg
(81%). 1H NMR (500 MHz, CDCl3, 25°C): δ = 8.33 (d, J = 8.5 Hz, 1 H, ArH),
7.95 (d, J = 9.0 Hz, 1 H, ArH), 7.81 (d, J = 8.1 Hz, 1 H, ArH), 7.63 (m, 1 H,
ArH), 7.43 (m, 1 H, ArH), 7.30 (d, J = 9.0 Hz, 1 H, ArH), 6.92 (s, 1 H, OH)
ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 158.4, 135.8, 134.9, 129.4,
128.8 (d, J = 313 Hz), 128.6, 128.4, 124.4, 124.3, 117.1, 100.8 ppm. 19F
NMR (471 MHz, CDCl3, 25°C): δ = –42.3 (s) ppm. ESI-HRMS: m/z calcd
for C11H6F3OS (M – H)– 243.0097, found 243.0098. GC-MS: 244 (M, 73%),
224 (19%), 175 (66%), 158 (10%), 147 (100%), 102 (11%), 69 (20%).
(5-bromo-2-methoxyphenyl)(trifluoromethyl)sulfane (3e). Yellow,
viscous oil. 131 mg (91 %).1H NMR (500 MHz, CDCl3, 25°C): δ = 7.73 (d,
J = 2.5 Hz, 1 H, ArH), 7.55 (dd, J = 8.8, 2.5 Hz, 1 H, ArH), 6.86 (d, J = 8.8
Hz, 1 H, ArH), 3.89 (s, 3 H, CH3) ppm. 13C NMR (126 MHz, CDCl3, 25°C):
δ = 159.7, 140.2, 135.5, 129.3 (q, J = 309 Hz), 114.5, 113.2, 112.6, 56.4
ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –42.6 (s, 3 F) ppm. ESI-
HRMS: m/z calcd for C8H6OSF3Br 285.9275, found: 285.9271. GC-MS:
288 (M+2, 100%), 286 (M, 100%), 138 (62%), 108 (25%), 95 (30%), 69
(23%).
Naphthalen-1-yl(trifluoromethyl)sulfane (3l).[6a] Brown, viscous oil. 99
mg (87%).1H NMR (500 MHz, CDCl3, 25°C): δ = 8.53 (d, J = 8.5 Hz, 1 H,
ArH), 7.98 (d, J = 8.5 Hz, 1 H, ArH), 7.95 (d, J = 7.2 Hz, 1 H, ArH), 7.87 (d,
J = 8.2 Hz, 1 H, ArH), 7.63 (m, 1 H, ArH), 7.55 (m, 1 H, ArH), 7.48 (dd, J =
8.2, 7.2 Hz, 1 H, ArH) ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 137.8,
135.4, 134.3, 132.4, 129.7 (q, J = 309.2 Hz), 128.6, 127.7, 126.8, 125.8,
125.6, 121.6 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –42.7 (s, 3 F).
GC-MS: 228 (M, 100%), 159 (88%), 115 (86%).
4-((trifluoromethyl)thio)benzene-1,2-diol (3f).[12] Brown, viscous liquid.
91 mg (87%).1H NMR (500 MHz, CDCl3, 25°C): δ = 7.17 (d, J = 2.0 Hz, 1
H, ArH), 7.14 (dd, J = 8.2, 2.0 Hz, 1 H, ArH), 6.90 (d, J = 8.2 Hz, 1 H, ArH)
ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 146.5, 143.7, 130.5, 129.6 (q,
J = 308 Hz), 123.3, 116.0, 115.0 ppm. 19F NMR (471 MHz, CDCl3, 25°C):
δ = –44.3 (s, 3 F) ppm. ESI-HRMS (m/z) calcd for C7H4F3O2S (M – H)–
208.9890, found 208.9889. GC-MS: 210 (M, 89%), 141 (100%), 123
(10%), 95 (11%), 69 (18%), 45 (10%).
Anthracen-9-yl(trifluoromethyl)sulfane (3m).[6b] Yellow solid. Mp 145.2-
147.7 °C. 121 mg (87%). 1H NMR (500 MHz, CDCl3, 25°C): δ = 8.86 (d, J
= 8.9 Hz, 2 H, ArH), 8.67 (s, 1 H, ArH), 8.05 (d, J = 8.4 Hz, 2 H, ArH), 7.71
– 7.65 (m, 2 H, ArH), 7.58 – 7.53 (m, 2 H, ArH) ppm. 13C NMR (126 MHz,
CDCl3, 25°C): δ = 136.1, 132.5, 131.8, 130.5 (q, J = 137 Hz), 128.9, 127.9,
126.5, 125.7, 117.1 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –41.8 (s,
3 F). Anal Calced for C15H9SF3: C, 64.74; H, 3.26, found: C, 64.47; H, 2.90.
GC-MS: 278 (M, 80%), 209 (100%), 165 (68%).
2-benzyl-4-((trifluoromethyl)thio)phenol (3g).[12] Brown, viscous liquid.
137 mg (96%).1H NMR (500 MHz, CDCl3, 25°C): δ = 7.43 – 7.39 (m, 2 H,
ArH), 7.31 – 7.29 (m, 2 H, ArH), 7.24 –7.20 (m, 3 H, ArH), 6.78 (d, 1 H,
ArH), 4.03 (s, 0.18 Hortho, CH2), 3.98 (s, 2 H, CH2) ppm. 13C NMR (126
MHz, CDCl3, 25°C): δ = 156.3, 139.4, 138.8, 136.6, 135.1, 129.7 (q, J =
296 Hz), 128.8, 128.6, 128.5, 128.4, 126.7, 116.8, 115.1, 36.2 ppm. 19F
Phenanthren-9-yl(trifluoromethyl)sulfane (3n).[6b] Yellow solid. Mp
1
96.6–98.2 °C (98.3–99.8 °C). 119 mg (86%). H NMR (500 MHz, CDCl3,
25°C): δ = 8.74–8.62 (m, 3 H, ArH), 8.32 (s, 1 H, ArH), 7.92 (d, J = 7.6 Hz,
1 H, ArH), 7.74–7.71 (m, 3 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H, ArH) ppm. 13
C
NMR (471 MHz, CDCl3, 25°C): δ = –43.2 (s, 3 F), –43.4 (s, 0.20 Fortho
)
ppm. ESI-HRMS: m/z calcd for C14H10F3OS (M – H)– 283.0410, found
283.0409. GC-MS (t=10.43): 284 (M, 100%), 263 (10%), 206 (64%), 181
(43%), 165 (30%), 152 (29%), 137 (18%), 109 (15%), 91 (18%), 77 (12%),
65 (11%), 51 (10%). GC-MS (t=11.29): 284 (M, 100%), 206 (63%), 183
(38%), 165 (19%), 152 (20%), 137 (22%), 109 (23%), 91 (16%), 69 (10%).
NMR (126 MHz, CDCl3, 25°C): δ = 140.2, 132.5, 131.8, 131.2, 131.0,
129.7 (q, J = 309 Hz), 129.3, 128.9, 127.5, 127.4, 127.3, 126.8, 123.0,
122.8, 120.6 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ –42.6 (s, 3 F). GC-
MS: 278 (M, 75%), 209 (38%), 165 (100%).
p-tolyl(trifluoromethyl)sulfane and o-tolyl(trifluoromethyl)sulfane
(3o).[21,22] Colourless oil. 61 mg (63%, o/p 45/55). 1H NMR (300 MHz,
CDCl3, 25°C) δ = 7.66 (d, J = 7.7 Hz, 1H, o-ArH), 7.54 (d, J = 7.9 Hz, 2.H,
p-ArH), 7.42 – 7.31 (m, 3H, o-ArH), 7.23 (d, J = 7.7 Hz, 2H, p-ArH), 2.55
(s, 3H, o-CH3), 2.39 (s, 3H, p-CH3) ppm. 13C NMR (126 MHz, CDCl3,
25°C): δ = 144.1, 141.4, 138.3, 136.4, 131.4, 131.1, 130.3, 129.6 (q, J =
290 Hz), 129.8 (q, J = 288 Hz), 129.2, 126.9, 121.6, 21.4, 21.2 ppm. 19F
NMR (471 MHz, CDCl3, 25°C): δ = –42.9 (s, 3 F), –43.7 (s, 3 F) ppm. GC-
MS (t=4.730): 192 (100%), 123 (50%), 91 (13%), 77 (14%), 95 (31%). GC-
MS (t=4.818): 192 (M, 100%), 123 (60%), 91 (23%), 79 (15%), 45 (11%).
2,6-dimethoxy-3-((trifluoromethyl)thio)phenol (3h).[12] Brown solid. mp
46.4-48.6 °C (lit. 44.7-46.5 °C). 123 mg (97%). 1H NMR (500 MHz, CDCl3,
25°C): δ = 7.17 (d, J = 8.7 Hz, 1 H, ArH), 6.69 (d, J = 8.7 Hz, 1 H, ArH),
3.98 (s, 3 H, CH3), 3.94 (s, 3 H, CH3) ppm. 13C NMR (126 MHz, CDCl3,
25°C): δ = 150.5, 149.0, 139.2, 129.1, 129.4 (q, J = 309 Hz), 109.5 (d, J =
2.0 Hz), 106.7, 61.3, 56.3 ppm. 19F NMR (471 MHz, CDCl3, 25°C): δ = –
43.6 (s, 3 F) ppm. ESI-HRMS: m/z calcd for C9H10F3O3S (M + H)
255.0297, found 255.0297. GC-MS: 254 (M, 100%), 185 (11%), 139
(52%), 111 (10%), 69 (12%).
+
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10.1002/ejoc.201800551
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3-((trifluoromethyl)thio)benzo[b]thiophene (3p).[6a] Orange oil. 87 mg
(74%). 1H NMR (300 MHz, CDCl3, 25°C) δ = 8.07 (d, J = 8.0 Hz, 1H, ArH),
7.98 (s, 1H, CH), 7.91 (d, J = 8.0 Hz, 1H, ArH), 7.50 (dt, J = 21.3, 7.0 Hz,
2H, ArH) ppm. 1H NMR (300 MHz, CDCl3, 25°C) δ = 8.07 (d, J = 8.0 Hz,
1H, ArH), 7.98 (s, 1H, CH), 7.91 (d, J = 8.0 Hz, 1H, ArH), 7.50 (dt, J = 21.3,
7.0 Hz, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3, 25°C): δ = 139.4, 139.4,
137.9, 129.0 (q, J = 310 Hz), 125.4, 125.3, 122.9, 122.8, 115.2 ppm. 19F
NMR (471 MHz, CDCl3, 25°C): δ = –43.1 (s, 3 F) ppm. GC-MS: 234 (M,
75%), 165 (100%), 121 (46%), 69 (11%).
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ArH), 7.52 (d, J = 2.7 Hz, 1H, ArH), 7.46 – 7.37 (m, 1H, ArH), 7.33 – 7.30
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Acknowledgements
Financial support of the Slovenian Research Agency (P1-0134,
P1-0230) is greatly appreciated. The authors are grateful to Prof.
Dr. R. Cerc Korošec (TGA analysis), A. Kristl (LCMS) and the staff
of The Centre for Research Infrastructure at the Faculty of
Chemistry and Chemical Technology (IC UL FCCT).
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Keywords: fluorine chemistry • trifluoromethanesulfenamide •
trifluoromethylthiolation • arenes • reactivity
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10.1002/ejoc.201800551
European Journal of Organic Chemistry
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Trifluoromethylthiolation of aromatic
compounds with different electrophilic
reagents of ArNHSCF3 type was
studied in the presence of triflic acid
as activator. p-Chloro substituted
reagent 1b was more stable than the
unsubstituted one 1a and the most
effective for trifluoromethylthiolation of
arenes. Reactions in DCM, hexane or
trifluoroacetic acid gave various
trifluoromethylthiolated aromatic
molecules with isolated yields of 81-
98%.
Trifluoromethylthiolation of aromatic
molecules*
Monika Horvat, Marjan Jereb, Jernej
Iskra*
Page No. – Page No.
Diversification of
Trifluoromethylthiolation of Aromatic
Molecules with Different
Trifluoromethanesulfenamides
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.