First and second generation of trifluoromethanesulfenamide reagent: A trifluoromethylthiolating comparison

Article abstract of DOI:10.1016/j.jfluchem.2015.06.007

Trifluoromethylthiolation of molecules is a more and more studied reaction. In particular, the direct electrophilic trifluoromethylthiolation plays an important role in this chemistry. Among the various developed reagents, trifluoromethanesulfenamides constitute an efficient family of reagents. However, no systematic comparison of these two generations has been realized. In this paper, the difference of reactivity of these reagents is studied towards various nucleophiles.

Full text of DOI:10.1016/j.jfluchem.2015.06.007

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Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
First and second generation of trifluoromethanesulfenamide reagent:
A trifluoromethylthiolating comparison§
Quentin Glenadel a,1, Sebastien Alazet a,1, Thierry Billard a,b,
*
´
a
´
´
Institute of Chemistry and Biochemistry (ICBMS, UMR CNRS 5246), Universite de Lyon, Universite Lyon 1, CNRS, 43 Bd du 11 novembre 1918, 69622 Lyon,
France
b CERMEP—In vivo imaging, Groupement Hospitalier Est, 59 Bd Pinel, 69003 Lyon, France
A R T I C L E I N F O
A B S T R A C T
Article history:
Trifluoromethylthiolation of molecules is a more and more studied reaction. In particular, the direct
electrophilic trifluoromethylthiolation plays an important role in this chemistry. Among the various
developed reagents, trifluoromethanesulfenamides constitute an efficient family of reagents. However,
no systematic comparison of these two generations has been realized. In this paper, the difference of
reactivity of these reagents is studied towards various nucleophiles.
Received 16 April 2015
Received in revised form 4 June 2015
Accepted 6 June 2015
Available online xxx
ß 2015 Elsevier B.V. All rights reserved.
Keywords:
Trifluoromethylthiolation
Trifluoromethanesulfenamide
Aromatic
Alkynes
Ketones
1. Introduction
methods of trifluoromethylthiolation which are more elegant and
practical in a synthetic point of view [19,20,22,23].
With the fluorine discovery [1], Moissan has open the way to a
fascinating chemistry which led to the design of new compounds
with specific and particular properties for a large panel of various
applications [2–5]. In particular, fluorinated molecules have found
a crucial place in life sciences due to their original physico-
chemical properties [6–12]. In this specific field of applications, the
trifluoromethylthio group appeared to be very contributive.
Indeed, this substituent is one of the most lipophilic fluoroalkyl
Such recent strategies have required the development of new
shelf-stable reagents. More specifically, new electrophilic trifluor-
omethylthiolating reagents [24–30] were highly required to
replace CF3SCl, the only reagent available until recently, but very
toxic [31].
2. Results and discussion
groups, with a Hansch parameter
pR = 1.44 [13]. Such important
One of the first developed reagents was the 1st generation of
trifluoromethanesulfenamide 1 [25,32–36]. Recently, the 2nd
generation of trifluoromethanesulfenamide 2 has been introduced
to realize more difficult reactions [29,37,38] (Fig. 1). A reactivity
comparison between these reagents could be interesting to well
rationalize the choice of the better trifluoromethanesulfenamide
reagent.
The first reaction described was the electrophilic addition onto
alkenes (Table 1) [32]. With Brønsted acids, the reagent 1a gave the
best results compared to 1b (entries 1–2, 4–5). This is particularly
clear with TFA since no addition product was observed (entries 4–
5). This could be explained by the bigger counter ion of
trifluoroacetate (N-Me anilinium) which strongly contribute to
decrease its already weak nucleophilicity. With 2, no reaction was
physico-chemical property greatly contributes to enhancing
molecules biodisponibility by favoring the transmembrane per-
meation [6,7,14–18].
This growing interest for the CF3S group has largely contributed
to the recent developments of new methodologies and new
reagents to introduce this moiety onto organic molecules [19–21].
More specifically, a particular focus was recently laid on direct
§
In honor of Ve´ronique Gouverneur, with congratulations.
*
Corresponding author. Tel.: +33 472448129.
E-mail address: thierry.billard@univ-lyon1.fr (T. Billard).
These two authors have contributed equally.
1
http://dx.doi.org/10.1016/j.jfluchem.2015.06.007
0022-1139/ß 2015 Elsevier B.V. All rights reserved.
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In the case of indole (5b), same results than with 5a were
observed when TsOH was used as the catalyst (entries 14–16).
Nevertheless, because of the nitrogen atom of 5b, no reaction was
observed with TfOH (entry 17). By using ClSiMe3, in acetonitrile,
good yields were observed with 2 (entry 19), contrary to the case of
cyclohexene (Table 1, entry 16). This confirms the necessity to
consider both activator and nucleophilicity to analyze results.
Catalytic amount of ClSiMe3 could be used both with 1b and 2 to
trifluoromethylthiolate indole (5b) (entries 20–21), which is more
nucleophile than 5a.
Fig. 1. 1st and 2nd generation of trifluoromethanesulfenamide.
observed with TsOH or TFA (entries 3, 6) because of the lower
basicity of the nitrogen atom which could not be easily protonated
by these too weak acids. This protonation step being crucial to
activate the reagents, no reactions can occur in these conditions.
With TfOH, all the reagents are reactive, even if the more basic
reagents 1 stays more efficient (entries 7–9). It should be noticed
that an increased temperature gave lower yields (entries 10–11),
the degradation of activated reagents being more rapid than the
electrophilic attack onto cyclohexene. With Lewis acid activation,
same observations have been made. Strong Lewis acid such as
BF3ÁEt2O succeeded to activate all the reagents (entries 12–14), but
more efficiently 1, whereas weak Lewis acid ClSiMe3 seemed able
to activate only 1b (entries 15–16).
When less electron-rich aromatic compounds were considered,
no reactions where observed with 1b or 1a, only 2 with TfOH (or
ClSiMe3 if the aromatic compound contents a nitrogen atom) was
able to perform aromatic trifluoromethylthiolation [38].
Trifluoromethylthiolation of Grignard reagent constitutes also a
convenient way to obtain various trifluoromethylthioethers
(Table 3) [34].
With Grignard compounds, 2 was systematically the better
trifluoromethylthiolating reagent. More particularly, in the case of
benzyl Grignard (7b), a degradation of the resulting product 8b
was observed in the reacting medium by using 1b whereas 8b
seemed stable when obtained from 2. This lets suggest that the
released amide during the reaction contribute to the degradation
Friedel-Crafts reactions have been then studied (Table 2)
[33,38]. With dimethoxybenzene (5a), reactions were observed
with all the reagents with TsOH as activator, with a better yield
obtained with 1a (entries 1–3). The product formation by using
2 proves that TsOH, contrary to the previous observation with
cyclohexene (Table 1, entry 3), could activate this one.
Consequently, the reagent activation seems to be not the lone
determining parameter, and the nucleophilicity of the nucleo-
phile appears also to be important. Hence, the couple activator/
nucleophilicity must be taken in consideration. Triflic acid could
also promote this reaction, even at room temperature, with
better results by using 2 (entries 4–7). Catalytic reaction was
also possible with TfOH but only with the more reactive
reagent 2, subject to heat at 80 8C (entries 8–10). As with
cyclohexene, BF3ÁEt2O was a better activator with 1b than with 2
(entries 11–13).
of 8b (because of the acidic benzylic hydrogens in a position of
SCF3). Therefore, if the N-methylanilide arising from 1b is basic
enough, the sulfonamide coming from 2 is a too weak base to
contribute to this degradation.
In the same strategy, terminal alkynes have been also
trifluoromethylthiolated in presence of lithium base (Table 4).
When the alkynes were previously deprotonated with 1 eq. of
BuLi, similar results than for Grignard reagents were obtained
(entries 1–4). With non base-sensitive trifluoromethylthiolated
alkyne (10a), both reagents gave similar yields (entries 1–2)
whereas with more sensitive product (10b), in situ degradation
was observed with 1b and not with 2 (entries 3–4). However, this
trifluoromethylthiolation could also work with catalytic amount of
BuLi but only by using 1b. With 2 the generated sulfonamide anion
is not basic enough to deprotonate the terminal alkynes and, thus,
to catalyze the reaction.
Table 1
Electrophilic addition onto alkenes
.
Entry
Reagent
Conditions
T (8C)
4 (%)a
1
1a
1b
2
TsOH (2.5 eq.)
50
50
50
50
50
50
RT
RT
RT
50
50
50
RT
RT
RT
RT
4a: X = OTs (80)
4a: X = OTs (70)
4a: X = OTs (0)
2
TsOH (2.5 eq.)
3
TsOH (2.5 eq.)
4
1a
1b
2
TFA (2.5 eq.)
4b: X = O2CCF3 (75)
4b: X = O2CCF3 (0)
4b: X = O2CCF3 (0)
4c: X = O2CPh (69)
4c: X = O2CPh (71)
4c: X = O2CPh (54)
4c: X = O2CPh (50)
4c: X = O2CPh (35)
4a: X = OTs (85)
4a: X = OTs (90)
4a: X = OTs (0)
5
TFA (2.5 eq.)
6
TFA (2.5 eq.)
7
1a
1b
2
TfOH (2.0 eq.)/PhCO2H (1.5 eq.)
TfOH (2.0 eq.)/PhCO2H (1.5 eq.)
TfOH (2.0 eq.)/PhCO2H (1.5 eq.)
TfOH (2.0 eq.)/PhCO2H (1.5 eq.)
TfOH (2.0 eq.)/PhCO2H (1.5 eq.)
BF3ÁEt2O (5.0 eq.)/TsONa (1.5 eq.)
BF3ÁEt2O (5.0 eq.)/TsONa (1.5 eq.)
BF3ÁEt2O (5.0 eq.)/TsONa (1.5 eq.)
ClSiMe3 (5.0 eq.)
8
9
10
11
12
13
14
15
16
1b
2
1a
1b
2
1b
2
4d: X = Cl (84)
ClSiMe3 (5.0 eq.)
4d: X = Cl (0)
a
Crude yield determine by 19F NMR using PhOCF3 as an internal standard. All the compounds were isolated with yields in accordance with titration.
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Table 2
Aromatic electrophilic substitution
.
Entry
Reagent
Aromatic
Conditions
Solvent
T(8C)
6 (%)a
1
1a
1b
2
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
TsOH (2.5 eq.)
TsOH (2.5 eq.)
TsOH (2.5 eq.)
TfOH (1 eq.)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
50
50
50
50
50
RT
RT
50
80
80
RT
RT
50
50
50
50
50
50
80
80
80
6a (94)
6a (45)
6a (36)
6a (65)
6a (92)
6a (66)
6a (88)
6a (40)
6a (90)
6a (<5)
6a (69)
6a (0)
2
3
4
1b
2
5
TfOH (1 eq.)
6
1b
2
TfOH (1 eq.)
7
TfOH (1 eq.)
8
2
TfOH (0.2 eq.)
TfOH (0.2 eq.)
TfOH (0.2 eq.)
BF3ÁEt2O (5 eq.)
BF3ÁEt2O (5 eq.)
BF3ÁEt2O (5 eq.)
TsOH (2.5 eq.)
TsOH (2.5 eq.)
TsOH (2.5 eq.)
TfOH (1 eq.)
9
2
10
11
12
13
14
15
16
17
18
19
20
21
1b
1b
2
2
6a (16)
6b (100)
6b (80)
6b (0)
1a
1b
2
2
6b (0)
2
ClSiMe3 (1 eq.)
ClSiMe3 (1 eq.)
ClSiMe3 (0.2 eq.)
ClSiMe3 (0.2 eq.)
6b (0)
2
6b (95)
6b (95)
6b (95)
2
1b
a
Crude yield determine by 19F NMR using PhOCF3 as an internal standard. All the compounds were isolated with yields in accordance with titration.
Table 3
Trifluoromethylthiolation of Grignard reagents
.
Entry
Reagent
Grignard 7
8 (%)a
1
2
3
4
5
6
1b
2
7a
7a
7b
7b
7c
7c
8a (86)
8a (94)
8b (10)
8b (63)
8c (67)
8c (72)
1b
2
1b
2
a
Crude yield determine by 19F NMR using PhOCF3 as an internal standard. All the compounds were isolated with yields in accordance with titration.
Ketones could be also trifluoromethylthiolated with trifluor-
omethanesulfenamide (Table 5) [29].
enol or enolate forms before side reactions, such as auto-aldol
reactions, can occur.
In basic conditions, only reagent 2 was able to react with
ketones, no reaction being observed with 1b. Nevertheless, by
using 2 in these conditions, only bis-trifluoromethylthiolation
(12b) was observed (entries 1–2). By analogy with halogenation of
ketones, acidic conditions have been also tested [39]. Again, only 2
was enough reactive to give the expected mono-trifluoro-
methylthiolated product (12a) with good yields. These results
suggest that a very reactive reagent should be used to quickly trap
Finally, trans-amination reactions to access to other trifluor-
omethanesulfenamides (14) have been envisaged (Scheme 1)
[36].
Both reagents gave same results (14a), but with more hindered
amine, the highest reactivity of 2 allowed to achieve better yield
(14b). With very weak nucleophilic amine, 1b appeared to be not
enough electrophilic to react whereas 2 succeeded to perform N-
trifluoromethylthiolation with a good yield (14c).
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Table 4
Trifluoromethylthiolation of terminal alkynes
.
Entry
Reagent
9
BuLi (eq.)
T (8C)
10 (%)a
1
2
3
4
5
6
1b
2
9a
9a
9b
9b
9a
9a
1
À78
À78
À78
À78
0
10a (73)
10a (72)
10b (19)
10b (90)
10a (88)
10a (0)
1
1b
2
1
1
1b
2
0.1
0.1
0
a
Crude yield determine by 19F NMR using PhOCF3 as an internal standard. All the compounds were isolated with yields in accordance with titration.
Table 5
Trifluoromethylthiolation of ketones
.
Entry
Reagent
Conditions
T (8C)
12 (%)a
1
2
3
4
1b
2
LDA (1.2 eq.) in THF
À78
À78
90
0
LDA (1.2 eq.) in THF
12b (56)
0
1b
2
TMSCl (0.3 eq.) in CH3CN
TMSCl (0.3 eq.) in CH3CN
90
12a (92)
a
Crude yield determine by 19F NMR using PhOCF3 as an internal standard. All the compounds were isolated with yields in accordance with titration.
resume, the electrophilicity of the reagent, the nature of the
released amide, the choice of the used activator and the
nucleophilicity of the substrate must be carefully analyzed to
select the better trifluoromethylthiolating reagent.
To conclude, these two generations of trifluoromethanesulfe-
namide are fully complementary and, even if the 2nd generation
seems more reactive, for certain reactions the 1st generation
conserves some specificities and cannot be advantageously
substituted by the 2nd generation.
4. Experimental
4.1. General information
Scheme 1. Trans-amination reaction with amines. (Crude yield determine by 19F
NMR using PhOCF3 as an internal standard. All the compounds were isolated with
yields in accordance with titration).
Dry solvents were purchased from Sigma Aldrich. Commercial
reagents were used as supplied. NMR spectra were recorded on a
Bruker AV 400 spectrometer at 400 MHz (1H NMR), 100 MHz (13
C
NMR), 376 MHz (19F NMR). All coupling constants were reported in
Hz.
3. Conclusion
In this paper, the comparison of reactivity between both
generations of trifluoromethanesulfenamide reagents has been
realized. These results confirmed clearly that the 2nd generation
(2) is more electrophilic than the 1st one (1). Nevertheless, it is
noteworthy that to determine which reagent used, the reaction
conditions could also play a crucial role in this selection. To
4.2. Electrophilic addition onto alkenes (Brønsted acid)
To a solution of 1 or 2 (0.30 mmol, 1.0 equiv.) in dry DCM (1 mL)
were added cyclohexene (3) (0.30 mmol, 1.0 equiv.) and the
Bronsted acid (0.75 mmol, 2.5 equiv.). The reaction mixture was
stirred at the indicated temperature for 18 h. The organic phase
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was washed with water, dried over Na2SO4 and filtered. After
removing solvent in vacuo, the crude was purified by flash
chromatography to afford the desired product.
4.9. Aromatic electrophilic substitution
A 10 mL sealed tube equipped with a magnetic stirrer was
charged with 5 (0.50 mmol, 1.0 equiv.) and 1 or 2 (1.2 equiv.) in dry
solvent. The reaction was stirred at room temperature for 1 min.
and acid was slowly added. The reaction mixture was stirred at the
indicated temperature for the indicated time. Conversion was
checked by 19F NMR with PhOCF3 as internal standard. After
completion, the reaction was cooled to room temperature, DCM
was added and the organic phase was washed three times with
distilled water and brine. The organic phase was dried over MgSO4,
filtered and concentrated to dryness. The residue was purified by
flash chromatography (100% pentane to 95/5 pentane/Et2O) to
afford the desired product.
4.3. Electrophilic addition onto alkenes (mixture of Brønsted acids)
To a solution of 1 or 2 (0.30 mmol, 1.0 equiv.) in dry DCM (1 mL)
were added cyclohexene (3) (0.30 mmol, 1.0 equiv.), benzoic acid
(0.45 mmol, 1.5 equiv.) and TfOH (0.60 mmol, 2.0 equiv.). The
reaction mixture was stirred at the indicated temperature for 18 h.
The organic phase was washed with water, dried over Na2SO4 and
filtered. After removing solvent in vacuo, the crude was purified by
flash chromatography to afford the desired product.
4.4. Electrophilic addition onto alkenes (Lewis acid)
4.10. Synthesis of 2,4-dimethoxy-1-
To a solution of 1 or 2 (0.30 mmol, 1.0 equiv.) in dry DCM (1 mL)
were added cyclohexene (3) (0.30 mmol, 1.0 equiv.) and sodium
tosylate (0.45 mmol, 1.5 equiv.). The resulting suspension was
vigorously stirred at room temperature. After stirring for 5 min, the
Lewis acid (1.5 mmol, 5.0 equiv.) was added dropwise. The
resulting mixture was stirred at the defined temperature for 4 h.
The reaction mixture was then partitioned between Et2O and H2O,
the organic phase was washed with aqueous HCl (2 M), dried over
Na2SO4 and filtered. After removing solvent in vacuo, the crude
was purified by flash chromatography to afford the desired product
[(trifluoromethyl)sulfanyl]benzene (6a)
1H NMR:
3.83 (s, 3H).
19F NMR:
d
= 7.53 (m, 1H), 6.54–6.50 (massif, 2H), 3.88 (s, 3H),
d
= À44.13 (s, 3F).
In accordance with literature [33].
4.11. Synthesis of 3-[(trifluoromethyl)sulfanyl]-1H-indole (6b)
1H NMR:
7.42 (m, 1H), 7.32–7.24 (massif, 2H).
19F NMR:
d = 8.56 (br, 1H), 7.80 (m, 1H), 7.53 (d, J = 2.6 Hz, 1H),
4.5. (1R*,2R*)-2-[(trifluoromethyl)sulfanyl]cyclohexyl 4-
d
= À45.36 (s, 3F).
methylbenzene-1-sulfonate (4a)
In accordance with literature [33].
Eluent for the flash chromatography: pentane/acetone: 70/1.
1H NMR:
d = 7.80 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.49
4.12. Trifluoromethylthiolation of Grignard reagents
(td, J = 6.6 Hz, 3.6 Hz, 1H), 3.29 (td, J = 6.9 Hz, 4.2 Hz, 1H), 2.44 (s,
3H), 2.22 (m, 1H), 2.03 (m, 1H), 1.69–1.65 (m, 3H), 1.48–1.44 (m,
3H).
A dry and nitrogen-flushed 10 mL flask equipped with a
magnetic stirrer and a septum was charged with 1 or 2 (1.2 equiv.).
The flask was cooled to 0 8C, and Grignard reagent solution (7) (in
THF, 1.0 equiv.) was added dropwise. After 10 min of stirring, the
reaction temperature was increased to 20 8C. The reaction was
stirred for further 3 h (conversion was checked by 19F NMR with
PhOCF3 as internal standard) and was then quenched with aqueous
HCl (0.5 M). Pentane was added and the organic phase was washed
with aqueous HCl (12 M) and water, dried over Na2SO4 and
concentrated in vacuo. The crude residue was purified by flash
chromatography (pentane) to afford the desired product.
19F NMR:
d
= À40.06 (s, 3F).
In accordance with literature [32].
4.6. (1R*,2R*)-2-[(trifluoromethyl)sulfanyl]cyclohexyl 2,2,2-
trifluoroacetate (4b)
Eluent for the flash chromatography: pentane/acetone: 70/1.
1H NMR:
d
= 4.94 (td, J = 9.3 Hz, 4.2 Hz, 1H), 3.28 (m, 1H), 2.30
(m, 1H), 2.15 (m, 1H), 1.87–1.35 (m, 6H).
19F NMR:
d
= À39.82 (s, 3F), À75.68 (s, 3F).
4.13. Synthesis of [(trifluoromethyl)sulfanyl]benzene (8a)
In accordance with literature [32].
1H NMR:
19F NMR:
d
d
= 7.67 (d, J = 7.2 Hz, 2H), 7.45 (m, 3H).
= À43.26 (s, 3F).
4.7. (1R*,2R*)-2-[(trifluoromethyl)sulfanyl]cyclohexyl benzoate (4c)
In accordance with literature [34].
Colorless oil.
Eluent for the flash chromatography: pentane/acetone: 200/1.
4.14. Synthesis of {[(trifluoromethyl)sulfanyl]methyl}benzene (8b)
1H NMR:
d = 8.06 (m, 2H), 7.58 (m, 1H), 7.46 (m, 2H), 5.01 (td,
J = 9.0 Hz, 4.1 Hz, 1H), 3.40 (td, J = 9.6 Hz, 4.1 Hz, 1H), 2.34 (m, 1H),
2.20 (m, 1H), 1.84–1.42 (massif, 6H).
1H NMR:
19F NMR:
d
d
= 7.35 (m, 5H), 4.15 (s, 2H).
= À42.15 (s, 3F).
13C NMR:
d
= 166.0, 133.5, 133.3 (q, J = 307 Hz), 130.4, 130.1,
128.8, 74.1, 47.5 (q, J = 2 Hz), 33.2, 31.5, 25.2, 23.5.
19F NMR:
= À39.60 (s, 3F).
In accordance with literature [40].
d
4.15. Synthesis of 3-[(trifluoromethyl)sulfanyl]pyridine (8c)
4.8. (1R*,2R*)-1-chloro-2-[(trifluoromethyl)sulfanyl]cyclohexane
A dry and nitrogen-flushed 10 mL flask equipped with a
magnetic stirrer and a septum was charged with iPrMgClÁLiCl
solution (1.3 M in THF, 1.1 equiv.). The reaction mixture was
cooled to À15 8C, and a solution of 3-bromopyridine (1.0 equiv.) in
THF (0.5 mL) was added dropwise. After 1 h of stirring, the reaction
temperature was increased to 0 8C and a solution of 1 or 2
(1.2 equiv.) in dry THF (1 M) was added dropwise. After 10 min of
stirring, the reaction temperature was increased to 25 8C. The
(4d)
Eluent for the flash chromatography: pentane/acetone: 200/1.
1H NMR:
d
= 4.10 (m, 1H), 3.45 (m, 1H), 2.39 (m, 1H), 2.22 (m,
1H), 1.86–1.67 (m, 3H), 1.62–1.38 (m, 3H).
19F NMR:
= À39.95 (s, 3F).
In accordance with literature [32].
d
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Q. Glenadel et al. / Journal of Fluorine Chemistry xxx (2015) xxx–xxx
reaction was stirred for further 3 h (conversion was checked by 19
F
the solvent was removed under vacuum and the residue was
purified by flash chromatography to afford the desired product.
Eluent for flash chromatography: 100% pentane to pentane/
Et2O: 97/3.
NMR with PhOCF3 as internal standard) and was then quenched
with saturated aqueous NH4Cl solution (2 mL). Pentane was added
and the organic phase was washed with saturated aqueous NH4Cl
solution and water, dried over Na2SO4, and concentrated in vacuo.
The crude residue was purified by flash chromatography (pentane)
to afford the desired product.
1H NMR:
1H), 7.53 (t, J = 7.6 Hz, 2H), 4.51 (s, 2H).
19F NMR:
d = 7.96 (dd, J = 8.3 Hz, 1.3 Hz, 2H), 7.66 (t, J = 8.4 Hz,
d
= À41.91 (s, 3F).
1H NMR:
1H).
19F NMR:
d
= 8.84 (m, 1H), 8.72 (m, 1H), 7.98 (m, 1H), 7.38 (m,
In accordance with literature [41].
d
= À42.85 (s, 3F).
4.20. Synthesis of 1-phenyl-2,2-bis[(trifluoromethyl)sulfanyl]ethan-
In accordance with literature [34].
1-one (12b)
4.16. Trifluoromethylthiolation of terminal alkynes
A dry and nitrogen-flushed 10 mL tube equipped with a
magnetic stirrer and a septum was charged with acetophenone
(11) (0.50 mmol, 1.0 equiv.) and was evacuated and refilled with
nitrogen three times. Dry THF (0.5 mL) was added and the reaction
flask was again evacuated and refilled with nitrogen three times.
Under nitrogen atmosphere, the reaction mixture was cooled to
À78 8C, and LDA solution (1.6 M in THF, 0.375 mL, 0.60 mmol,
1.2 equiv.) was added dropwise via a syringe. After 1 h of stirring at
À78 8C, a solution of 1 or 2 (2.2 equiv.) in dry THF (1 mL) was added
dropwise. Conversion was checked by 19F NMR with PhOCF3 as
internal standard. After completion, the reaction was quenched
with distilled water. The reaction mixture was warmed to room
temperature and Et2O was added. The organic phase was washed
with aqueous HCl 0.5 M, saturated aqueous NaHCO3, brine, dried
Procedure A: A dry and nitrogen-flushed 10 mL flask equipped
with a magnetic stirrer and a septum was charged with alkyne (9)
(1.0 equiv.) and dry THF (0.5 M). The reaction mixture was cooled
to À78 8C, and nBuLi solution (1.6 M in THF, 1.1 equiv.) was added
dropwise. After 1 h of stirring, a solution of 1 or 2 (1.2 equiv.) in dry
THF (0.5 M) was added dropwise. The reaction was stirred for
further 3 h (conversion was checked by 19F NMR with PhOCF3 as
internal standard) and was then quenched with aqueous HCl.
Pentane was added and the organic phase was washed with
aqueous HCl and water, dried over Na2SO4 and concentrated in
vacuo. The crude residue was purified by flash chromatography
(pentane) to afford the desired product.
Procedure B: A dry and nitrogen-flushed 10 mL Schlenk tube
equipped with a magnetic stirrer and a septum was charged
with 1 or 2 (1.2 equiv.) and alkyne (9) (1.0 equiv.) and was
evacuated and refilled with nitrogen three times. Dry THF (2 M)
was added and the reaction flask was again evacuated and
refilled with nitrogen three times. The reaction mixture was
cooled to 0 8C, and nBuLi solution (1.6 M in THF, 10–20 mol%)
was added at 0 8C. After 1 min of stirring (conversion was
checked by 19F NMR with PhOCF3 as internal standard), the
reaction mixture was quenched with aqueous HCl. Pentane was
added and the organic phase was washed with aqueous HCl and
water, dried over Na2SO4 and concentrated in vacuo. The crude
residue was purified by flash chromatography (pentane) to
afford the desired product.
over MgSO4, filtered and concentrated to dryness under a
moderate vacuum of 400 mbar at 20 8C. The crude residue was
purified by flash chromatography to afford the desired product.
Eluent for flash chromatography: 100% pentane to pentane/
DCM: 9/1.
1H NMR:
1.2 Hz, 1H), 7.56 (tt, J = 8.2 Hz, 1.4 Hz, 2H), 6.11 (s, 1H).
19F NMR:
d = 7.97 (dq, J = 8.3 Hz, 1.2 Hz, 2H), 7.70 (tt, J = 7.5 Hz,
d
= À40.17 (s, 6F).
In accordance with literature [29].
4.21. Trans-amination reaction with amines
A dry and nitrogen-flushed 10 mL round bottom flask equipped
with a magnetic stirrer and a septum was charged with amine (13)
(0.50 mmol, 1.0 equiv.) and was evacuated and refilled with
nitrogen three times. Dry THF (0.5 mL) was added and the reaction
flask was again evacuated and refilled with nitrogen three times.
The reaction mixture was cooled to 0 8C, and nBuLi solution (1.6 M
in THF, 0.55 mmol, 1.1 equiv.) was added. After 5 min of stirring, 1
or 2 (0.55 mmol, 1.1 equiv.) was added at 0 8C and the reaction was
checked by 19F NMR with PhOCF3 as internal standard. Reaction
was quenched with saturated aqueous NaHCO3 and EtOAc was
added. The organic phase was washed with water, dried over
Na2SO4, and concentrated in vacuo. The crude residue was purified
by flash chromatography to afford the desired product.
4.17. Synthesis of {2-[(trifluoromethyl)sulfanyl]ethynyl}benzene
(10a)
1H NMR:
19F NMR:
d
d
= 7.51 (m, 2H), 7.48 (m, 3H).
= À44.10 (s, 3F).
In accordance with literature [34].
4.18. Synthesis of {4-[(trifluoromethyl)sulfanyl]but-3-yn-1-
yl}benzene (10b)
1H NMR:
2H).
19F NMR:
d = 7.26 (m, 5H), 2.87 (d, J = 7.3 Hz, 2H), 2.68 (d, J = 7.3,
4.22. 1-Phenyl-4-[(trifluoromethyl)sulfanyl]piperazine (14a)
d
= À44.70 (s, 3F).
In accordance with literature [35].
Eluent for flash chromatography: cyclohexane/EtOAc: 95/5.
1H NMR:
4H).
19F NMR:
d
= 7.24 (m, 2H), 6.84 (m, 3H), 3.38 (m, 4H), 3.19 (m,
4.19. Synthesis of 1-phenyl-2-[(trifluoromethyl)sulfanyl]ethan-1-one
(12a)
d
= À46.53 (s, 3F).
In accordance with literature [36].
A 10 mL sealed tube equipped with a magnetic stirrer was
charged with acetophenone (11) (0.50 mmol, 1.0 equiv.) in dry
ACN followed by 1 or 2 (0.60 mmol, 1.2 equiv.). The reaction
mixture was stirred at room temperature for 1 min., TMSCl was
added and the reaction was stirred at 90 8C for 18 h. The conversion
was checked by 19F NMR with PhOCF3 as internal standard. After
completion, the reaction mixture was cooled to room temperature,
4.23. Dibenzyl[(trifluoromethyl)sulfanyl]amine (14b)
Eluent for flash chromatography: cyclohexane/EtOAc: 99/1.
1H NMR:
19F NMR:
d
= 7.49–7.37 (m, 10H), 4.35 (s, 4H).
= À47.72 (s, 3F).
d
In accordance with literature [36].
Please cite this article in press as: Q. Glenadel, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.06.007

G Model
FLUOR-8580; No. of Pages 7
Q. Glenadel et al. / Journal of Fluorine Chemistry xxx (2015) xxx–xxx
7
[15] D.E. Clark, Drug Discovery Today 8 (2003) 927–933.
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4.24. Benzyl N-[(trifluoromethyl)sulfanyl]carbamate (14c)
Eluent for flash chromatography: cyclohexane/EtOAc: 80/20.
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1H NMR:
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d
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Folkers, Pharmacokinetics and Metabolism in Drug Design, Wiley, Weinheim,
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In accordance with literature [42].
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The CNRS and the French Ministry of Research are thanked for
their financial supports. The French Fluorine Network is also
thanked for its support.
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