Interrupted reduction of CF3SO2Cl using tricyclohexylphosphine allows for electrophilic trifluoromethylsulfinylation

Article abstract of DOI:10.1016/j.jfluchem.2016.11.020

The monoreduction of trifluoromethanesulfonyl chloride by an appropriate phosphine, preferentially tricyclohexylphosphine, generates the reactive trifluoromethanesulfinyl chloride CF₃SOCl as donor of CF₃S(O)⁺ cation. The direct trifluoromethylsulfinylation of indoles, pyrroles, other azaarenes, amines, and phenols was successfully achieved in moderate to high yields.

Full text of DOI:10.1016/j.jfluchem.2016.11.020

Accepted Manuscript
Title: Interrupted Reduction of CF SO Cl Using
3
2
Tricyclohexylphosphine Allows for Electrophilic
Trifluoromethylsulfinylation
Author: H e´ l e` ne Chachignon Dominique Cahard
PII:
S0022-1139(16)30297-4
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.11.020
FLUOR 8907
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
3-10-2016
29-11-2016
29-11-2016
Please cite this article as: H e´ l e` ne Chachignon, Dominique Cahard,
Interrupted Reduction of CF3SO2Cl Using Tricyclohexylphosphine Allows
for Electrophilic Trifluoromethylsulfinylation, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.11.020
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Interrupted Reduction of CF
3
SO Cl Using Tricyclohexylphosphine Allows for
2
Electrophilic Trifluoromethylsulfinylation
a
a,
Hélène Chachignon, Dominique Cahard *
a) UMR 6014 COBRA, CNRS, Université de Rouen et INSA de Rouen, 1 Rue Tesnière, F-
7
6821 Mont-Saint-Aignan Cedex, France
*
Corresponding author
E-mail address: dominique.cahard@univ-rouen.fr

Graphical abstract
Highlights
A new use of trifluoromethanesulfonyl chloride CF
•
3
SO Cl is described for the transfer of
2
+
CF S(O) cation.
3
•
•
A new method is presented for direct electrophilic trifluoromethylsulfinylation.
We performed the trifluoromethylsulfinylation of indoles, pyrroles, other azaarenes, amines,
and phenols.
The reaction mechanism involves a reductive monodeoxygenation of CF
tricyclohexylphosphine initiated by halogen bonding.
•
3
SO Cl by means of
2
Abstract: The monoreduction of trifluoromethanesulfonyl chloride by an appropriate
phosphine, preferentially tricyclohexylphosphine, generates the reactive
trifluoromethanesulfinyl chloride CF SOCl as donor of CF S(O) cation. The direct
+
3
3
trifluoromethylsulfinylation of indoles, pyrroles, other azaarenes, amines, and phenols was
successfully achieved in moderate to high yields.
Keywords: Sulfur; Fluorine; Phosphine; Indole; Halogen bond
1
. Introduction
A substantial number of molecules bearing the CF
applications in the pharmaceutical and agrochemical fields. The introduction of the CF
3
S(O) group have been synthesized for
S(O)
3
motif into organic molecules modifies and often enhances their biological properties. For
example, the broadly used insecticide Fipronil and several analogues feature a
trifluoromethanesulfinyl moiety that is responsible for increased lipid solubility favouring the
transport of the molecule across lipid membranes [1,2]. The CF
3
S(O) group stands between
, respectively, in terms of
its lower and higher oxidation state congeners CF S and CF SO
3
3
2
Hammett substituent constants [3] and Taft’s σ* parameters [4]. The synthesis of
trifluoromethanesulfoxides was achieved mainly by two approaches: (i) the monooxidation of
the corresponding trifluoromethyl sulfides by means of a wide variety of oxidants (ii) the
nucleophilic trifluoromethylation of sulfinyl halides or sulfinic esters with TMSCF
direct introduction of the CF S(O) group using trifluoromethanesulfinyl halides CF
CF S(O)Cl has seldom been reported because of the toxicity, the volatility and the poor
stability of these reagents [6]. Alternatively, few direct trifluoromethylsulfinylation methods
were described on (het)arenes with the aid of sodium or potassium triflinates CF SO M (M =
Na, K) in the presence of triflic acid [7] or phosphoryl chloride [8], or with N-SOCF
3
[5]. The
3
3
S(O)F or
3
3
2
3

+
succinimide as CF S(O) donor source [9, 10]. The electrophilic O-trifluoromethylthiolation
3
of allylic alcohols followed by a [2,3]-sigmatropic rearrangement is also a route to prepare
allylic trifluoromethyl sulfoxides [11]. As part of our ongoing research on the synthesis of
SCF
CF SO
reducing agent. The complete reduction of CF
that reacts in situ with various nucleophiles [12]. We now report that tuning the nature of the
phosphine and the ratio substrate / CF SO Cl / phosphine allows for the controlled
monoreduction of CF SO Cl into CF S(O)Cl for the direct C-trifluoromethylsulfinylation of
3
compounds, we recently reported a novel use of trifluoromethanesulfonyl chloride,
Cl, as a new source of electrophilic SCF in the presence of a phosphine as the
SO Cl generates the highly reactive CF SCl
3
2
3
3
2
3
3
2
3
2
3
indoles, pyrroles, other azaarenes and phenols as well as the N-trifluoromethylsulfinylation of
amines.
2
. Results and discussion
As mentioned earlier in the text, we recently developed an innovative methodology allowing
the C-trifluoromethylthiolation of a variety of nucleophiles by reacting them with the in situ
generated CF
3
SCl from a combination of CF
3
SO Cl / trimethylphosphine in a ratio 1:2 in
2
THF at –78°C to room temperature [12]. During the experiments carried out as part of this
work with indole as substrate, an interesting side product was invariably observed: the
trifluoromethylsulfinylated derivative featuring the CF S(O) group, which resulted from the
3
reaction between said substrate and monodeoxygenated sulfonyl chloride. The formation of
this a priori undesired side product was however greatly disfavoured compared to the
trifluoromethylthiolated analogue, and it was consequently isolated in very poor yields (Table
1
, entries 1, 2). Yet, interestingly enough, it was obtained in particularly higher proportions
(62% NMR yield) when using tricyclohexylphosphine as the reducing agent, instead of
trimethylphosphine or triphenylphosphine (Table 1, entry 3). This phenomenon can be
explained by a subtle variation of the nucleophilicity of phosphines, making the sulfinyl
chloride reduction process slower than its reaction with indole [13]. Steric hindrance appeared
to be less influential, considering the important difference between the yields reached using
PPh
3
and PCy
3
. Trimethyl phosphite, P(OMe)
3
, failed to generate CF S(O)Cl under our
3
reaction conditions [14].
To further exploit this unique property of tricyclohexylphosphine, we conducted a series of
experiments on indole aimed at maximizing the yield of the trifluoromethylsulfinylation
reaction. To this end, we first screened different solvents (Table 1, entries 3–6). However, it
was soon found out that their influence on the yield of the reaction was quite negligible.
Indeed, the use of DCM only allowed to slightly increase the yield from 62 to 67%. On the
other hand, the ratio CF
intuitively, decreasing it to 1:1 lead to the formation of fewer SCF
consequently to an improved yield of 79% (Table 1, entries 7, 8). The yield was ultimately
increased to 89% when reducing the equivalents of CF SO Cl and PCy from 1.8 to 1.5
Table 1, entries 9, 10), which was an appreciable result in a perspective of reagent economy.
3
SO
2
Cl / PCy
3
proved to be a much more significant parameter: quite
3
by-product, and
3
2
3
(
Any attempt to perform the reaction at higher temperatures resulted in lower yields, especially
above –20°C (Table 1, entries 11–14). Similarly, diluting or concentrating any further the
reaction medium appeared to be detrimental to the formation of the desired product (Table 1,
entries 15, 16). It is noteworthy to report that when raising the concentration to 0.9 M,
tricyclohexylphosphine was no more properly soluble in DCM at –78°C, which caused the
freezing of the reaction mixture, making its stirring impossible until the temperature had
increased enough to reverse the phenomenon.

A
variety of indole derivatives were then submitted to the optimized
trifluoromethylsulfinylation reaction conditions. The reaction proceeded smoothly with most
of them, regardless of the carried functional groups or their positions. Indeed, electron-
withdrawing and electron-donating substituents in positions 2, 4, 5, 6 and 7 were equally well
tolerated, even though it was necessary to increase the quantities of CF
3
SO
2
Cl and PCy to
3
1
.8 equivalents for the less reactive brominated indoles in order to achieve full conversion of
the starting material (Table 2, entries 2, 3). N-Methylated indoles appeared to be compatible
as well with the selected reaction conditions (Table 1, entries 8, 9). 7-Azaindole showed the
least satisfying results (Table 1, entry 10), which was however predictable considering the
deactivating effect of its electron-deficient pyridine moiety.
Considering the encouraging results obtained with indole derivatives, we decided to submit
other azaarenes to our reaction conditions. We first examined pyrrole derivatives, which
afforded their trifluoromethylsulfinylated analogues in moderate to good yields (Table 3,
entries 1–5). Pyrrole itself provided product 3a in 52% yield, as the starting material was
involved in side polymerisation reactions (Table 3, entry 1). Despite their very similar
structures, 2,4-dimethylpyrrole gave access to a lower yield than 2,5-dimethylpyrrole (Table
3
, entries 2, 3). This is due to partial consumption of product 3b by bis-functionalisation,
whereas product 3c remained untouched, its available C3 position being more hindered. As
1
9
for N-methylpyrrole, formation of product 3e was observed in good yield by F NMR, but it
however appeared to be unstable and could not be isolated in a pure form. The CF S(O) group
3
was also successfully introduced in moderate yields on methyl indolizine-1-carboxylate and
pyrazolone after slight adjustment of the reaction conditions (Table 3, entries 6, 7); on the
other hand the CF S(O)-substituted imidazo[1,2-a]pyridine 6 could only be obtained with a
3
disappointing 9% yield, mostly due to steric hindrance issues (Table 3, entry 8).
Moreover, azaarenes were not the only substrates worth considering: a variety of aryl and
aliphatic amines were also readily converted to the corresponding sulfinamides using our
CF
3
SO
2
Cl / PCy
3
system via regioselective N-trifluoromethylsulfinylation. Aniline
derivatives in particular showed a great reactivity toward our reagent; however, degradation
of the obtained products occurred invariably in the reaction medium, which lead to moderate
yields despite the full consumption of the starting materials and the absence of
trifluoromethylthiolated side product (Table 4, entries 1–5). It is noteworthy to specify that
the isolated products were stable yet, except for the N-methylsulfonamide 7d that could not be
isolated in a pure form. Benzylamine and isopropyl amine were more difficultly consumed,
and consequently afforded products 7f and 7g in lower yields. Sulfinamide 7g was also
unstable and underwent degradation during its purification.
The reaction was finally performed on two phenol derivatives, 1-naphthol and resorcinol,
which gave access to the corresponding C-trifluoromethylsulfinylated products albeit in poor
yields (Table 5). An interesting phenomenon was nonetheless observed during the reaction
19
realised on 1-naphthol: formation of a species with a F NMR chemical shift of –79.5 ppm,
which could corresponds to the O-trifluoromethylsulfinylated product. This product was then
consumed, as the quantity of the C-trifluoromethylsulfinylated product (δ = –74.1 ppm)
increased. This could suggest that the reaction mechanism involves a Thia-Fries
rearrangement. Even if this kind of process usually requires a Lewis acid [15] or a strong base

[
16, 17] to proceed, which doesn’t match our conditions, some examples of similar
photocatalyzed reactions were also reported [18, 19], making our hypothesis conceivable.
Additionnally, the direct transfer of the difluoromethylsulfinyl motif S(O)CF R in which R is
2
a functional group would be of great interest allowing rapid generation of molecular
complexity. In this context, we performed the reductive selective monodeoxygenation of
methyl 2-(chlorosulfonyl)-2,2-difluoroacetate MeO
2
CCF
2
SO Cl [20]. The reaction proceeded
2
smoothly and the reaction with indole provided the expected product 9, which was isolated in
a good yield of 65% (Scheme 1).
The mechanism of the reductive monodeoxygenation consists in the heterolytic cleavage of
the covalent S−Cl bond triggered by the halogen bond that forms between the positive
electrostatic potential on the outer side of the chlorine atom in RCF
of phosphorus atom in PCy . The chlorophosphonium sulfinate is then converted into the O-
sulfinatophosphonium chloride, which undergo Arbuzov collapse to sulfinyl chloride
2
SO Cl and the lone pair
2
3
3
1
RCF
2
S(O)Cl and tricyclohexylphosphine oxide, as confirmed by P NMR spectroscopy.
S(O)Cl reacts with indole or other nucleophiles with release of
Then, the electrophilic RCF
2
HCl (Scheme 2). The addition of an inorganic or an organic base to the reaction mixture
lowered the reaction yield and favored the trifluoromethanesulfonylation at the nitrogen atom
of indole.
3
. Conclusion
During our investigation of the reductive deoxygenation–trifluoromethylthiolation reaction,
we discovered that tuning the nature of the phosphine and the ratio substrate / CF SO Cl /
phosphine allows for the controlled monoreduction of CF SO Cl into CF S(O)Cl as donor of
S(O) cation. A number of reactions were carried out that include the direct C-
3
2
3
2
3
+
CF
3
trifluoromethylsulfinylation of indoles, pyrroles, other azaarenes and phenols as well as the N-
trifluoromethylsulfinylation of aryl- and alkylamines. Moreover, methyl 2-(chlorosulfonyl)-
2
,2-difluoroacetate was also selectively monodeoxygenated allowing the direct transfer of the
electrophilic difluoromethylsulfinyl motif MeO CCF S(O).
2
2
4
. Experimental
4
.1. General remarks
The reactions were monitored by thin-layer chromatography (TLC) performed with 0.20 mm
silica gel 60 with fluorescent indicator UV254. The TLC plates were visualized with UV light
(
254 nm). Column chromatography was performed on a column packed with silica gel 60M
1
13
19
spherical neutral size 40-63 μm. H (300 MHz), C (75.5 MHz) and F (282 MHz) NMR
spectra for solution in CDCl or DMSO-d were recorded on Bruker Avance 300. Chemical
shifts (δ) for H and C NMRs are expressed in ppm downfield from tetramethylsilane using
the residual protonated solvent as an internal standard (CDCl
ppm; DMSO-d
internal standard ( F 0.00 ppm). The following abbreviations were used to show the
multiplicities: s: singlet, d: doublet, t: triplet, q: quadruplet, dd: doublet of doublets, td: triplet
of doublets, dt: doublet of triplets, m: multiplet, b: broad. High resolution mass spectrometry
3
6
1
13
1
13
3
, H 7.26 ppm and C 77.16
1
13
19
6
H 2.50 ppm and C 39.52 ppm) or, for F NMR, upfield from CFCl as the
3
1
9
(HRMS) was carried out on an electrospray ionization mass spectrometer with a micro-TOF
analyzer. Unless otherwise noted, all reagents were purchased from commercial sources and

were used without further purification. 2-Phenylpyrrole [21], 2-phenylimidazo[1,2-a]pyridine
[
[
22], methyl indolizine-1-carboxylate [23] and methyl 2-(chlorosulfonyl)-2,2-difluoroacetate
20] were prepared referring to previously reported procedures.
4
.2. Representative procedure for the trifluoromethylsulfinylation
To a solution of substrate (0.85 mmol) and tricyclohexylphosphine (Procedure A: 1.5 equiv or
Procedure B: 1.8 equiv) in DCM (5 mL) was added trifluoromethanesulfonyl chloride
(Procedure A: 1.5 equiv or Procedure B: 1.8 equiv) at –78 °C. The reaction mixture was
stirred until the full consumption of the starting material (TLC monitored), as the temperature
was let to increase to room temperature. The reaction mixture was quenched with water. The
aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried
over magnesium sulfate, and concentrated under vacuum. The crude product was purified by
flash chromatography (cyclohexane/ethyl acetate).
3
-((Trifluoromethyl)sulfinyl)-1H-indole (2a) [12]. CAS [1909315-34-9]. Procedure A. White
1
solid. 176 mg, 88% yield. H NMR (CDCl
J = 2.6 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.35 (qt, J = 7.7 Hz, 2H) ppm; C NMR (CDCl
1
1
1
2
3
): δ 9.64 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.84 (d,
1
3
3
): δ
36.8, 130.79, 125.6 (q, J = 334.5 Hz), 124.5, 124.1, 122.8, 120.2 (q, J = 1.7 Hz), 112.5,
19
-1
08.4 (q, J = 2.2 Hz) ppm; F NMR (CDCl ): δ –73.6 (s, 3F) ppm. ATR-FTIR (cm ): 3103,
3
+
502, 1415, 1176, 1127, 1038, 748. HRMS (ESI): Calculated for C
51.0461; Found: 251.0466.
9
H
10
N
2
OF
3
S [M+NH ] :
4
4
8
-Bromo-3-((trifluoromethyl)sulfinyl)-1H-indole (2b). Procedure B. White solid. 212 mg,
1
0%. H NMR (CDCl
3
): δ 9.58 (s, 1H), 8.07 (s, 1H), 7.48 (t, J = 8.5 Hz, 2H), 7.21 (t, J = 7.9
): δ 137.9, 132.3, 125.5, 125.1 (q, J = 337.8 Hz), 124.7,
1
3
Hz, 1H) ppm; C NMR (DMSO-d
24.3, 112.8, 111.0, 107.8 (q, J = 2.2 Hz) ppm; F NMR (CDCl
6
1
9
1
3
): δ –75.6 (s, 3F) ppm. ATR-
-1
FTIR (cm ): 3132, 1735, 1631, 1171, 1123, 1038, 775, 732, 607. HRMS (ESI): Calculated
for C
+
9
H
6
NOF
3
SBr [M+H] : 311.9304; Found: 311.9306.
5
9
-Bromo-3-((trifluoromethyl)sulfinyl)-1H-indole (2c). Procedure B. White solid. 241 mg,
1
1%. H NMR (CDCl ): δ 9.69 (s, 1H), 8.11 (s, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.7
3
1
3
Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H) ppm; C NMR (CDCl ): δ 135.4, 131.3, 127.8, 125.7,
1
NMR (CDCl ): δ –73.8 (s, 3F) ppm. ATR-FTIR (cm ): 3208, 2931, 1450, 1411, 1295, 1178,
1
3
1
9
25.5 (q, J = 334.5 Hz), 122.9 (q, J = 2.2 Hz), 116.2, 113.9, 108.4 (q, J = 2.2 Hz) ppm; F
-
1
3
+
128, 1039, 802, 611. HRMS (ESI): Calculated for C
9
H
9
N
2
OF
3
SBr [M+NH ] : 328.9565;
4
Found: 328.9571.
5
8
2
1
-Methoxy-3-((trifluoromethyl)sulfinyl)-1H-indole (2d). Procedure B. White solid. 192 mg,
1
5% yield. H NMR (CDCl
H), 7.00 (d, J = 8.9 Hz, 1H), 3.87 (s, 3H) ppm; C NMR (CDCl
25.7 (q, J = 334.5 Hz), 125.0, 115. 3, 113.3, 107.9, 101.5 (q, J = 1.7 Hz), 55.7 ppm; F
3
): δ 8.92 (s, 1H), 7.75 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 9.1 Hz,
1
3
3
): δ 156.1, 131.5, 130.7,
1
9
-1
NMR (CDCl ): δ –73.6 (s, 3F) ppm. ATR-FTIR (cm ): 3117, 3000, 2958, 1588, 1488, 1293,
1
3
+
213, 1178, 1030, 811. HRMS (ESI): Calculated for C10
H
12
N
2
O
2
F
3
S [M+NH ] : 281.0569;
4
Found: 281.0572.
6
8
-Fluoro-3-((trifluoromethyl)sulfinyl)-1H-indole (2e). Procedure A. White solid. 184 mg,
1
6% yield. H NMR (CDCl ): δ 9.76 (s, 1H), 7.89 (dd, J = 8.5, 5.3 Hz, 1H), 7.76 (d, J = 2.8
3
13
Hz, 1H), 7.14 (dd, J = 8.9, 1.7 Hz, 1H), 7.06 (td, J = 9.1, 1.9 Hz, 1H) ppm; C NMR
CDCl ): δ 160.8 (d, J = 242.6 Hz), 137.1 (d, J = 12.7 Hz), 131.2, 125.5 (q, J = 334.5 Hz),
21.4 (dq, J = 10.5, 2.2 Hz), 120.4, 111.8 (d, J = 24.8 Hz), 108.7 (q, J = 2.2 Hz), 99.0 (d, J =
(
1
3

1
9
): δ –73.4 (s, 3F), –117.1 (s, 1F) ppm. ATR-FTIR (cm-1):
2
3
6.4 Hz) ppm; F NMR (CDCl
125, 3002, 2920, 1616, 1511, 1419, 1242, 1187, 1132, 1040, 809. HRMS (ESI): Calculated
3
+
for C
9
H
9
N
2
OF
4
S [M+NH
4
] : 269.0372; Found: 269.0370.
7
6
7
3
-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (2f). Procedure B. Beige solid. 128 mg,
1
1% yield. H NMR (CDCl
.17 (t, J = 7.0 Hz, 1H), 2.53 (s, 3H) ppm; C NMR (CDCl
34.5 Hz), 125.0, 123.9, 122.9, 121.7, 117.9, 109.3 (q, J = 1.9 Hz), 16.5 ppm; F NMR
3
): δ 9.36 (s, 1H), 7.85–7.71 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H),
13
3
): δ 136.3, 130.0, 125.5 (q, J =
1
9
-1
(CDCl ): δ –73.7 (s, 3F) ppm. ATR-FTIR (cm ): 3207, 2929, 1435, 1167, 1134, 1042, 784,
3
+
7
36. HRMS (ESI): Calculated for C10
H
12
N
2
OF
3
S [M+NH
4
] : 265.0622; Found: 265.0619.
2
8
7
3
-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (2g). Procedure A. White solid. 183 mg,
1
7% yield. H NMR (CDCl
.32–7.20 (m, 2H), 2.60 (s, 3H) ppm; C NMR (DMSO-d
37.3 Hz), 124.9, 122.9, 121.6, 119.2 (q, J = 2.2 Hz), 112.1, 102.2 (q, J = 2.2 Hz), 11.8 ppm;
3
): δ 8.88 (s, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.41–7.34 (m, 1H),
13
6
): δ 144.8, 135.8, 126.2 (q, J =
1
9
-1
F NMR (CDCl
3
): δ –72.8 (s, 3F) ppm. ATR-FTIR (cm ): 3096, 1519, 1457, 1171, 1129,
+
1
050, 741. HRMS (ESI): Calculated for C10
H
9
NOF S [M+H] : 248.0357; Found: 248.0359.
3
1
-Methyl-3-((trifluoromethyl)sulfinyl)-1H-indole (2h). Procedure A. Pale yellow solid. 167
1
mg, 79% yield. H NMR (CDCl
3
): δ 7.96 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.48–7.29 (m,
H), 3.90 (s, 3H) ppm; C NMR (CDCl ): δ 137.7, 133.8, 125.6 (q, J = 335.0 Hz), 125.1,
24.1, 122.5, 120.5, 110.5, 107.2 (q, J = 2.2 Hz), 33.8 ppm; F NMR (CDCl
1
3
3
1
3
3
1
9
3
): δ –74.1 (s,
F) ppm. ATR-FTIR (cm ): 3097, 2922, 1519, 1457, 1174, 1128, 1061, 740. HRMS (ESI):
-1
+
Calculated for C10
H
9
NOF
3
S [M+H] : 248.0357; Found: 248.0357.
1
7
2
1
,2-Dimethyl-3-((trifluoromethyl)sulfinyl)-1H-indole (2i). Procedure A. Pink solid. 163 mg,
1
3% yield. H NMR (CDCl
3
): δ 8.01 (d, J = 7.6 Hz, 1H), 7.41–7.22 (m, 3H), 3.74 (s, 3H),
.61 (s, 3H) ppm; C NMR (CDCl ): δ 143.8, 137.3, 126.1 (q, J = 335.6 Hz), 124.9, 123.2,
22.4, 120.2, 109.7, 103.6 (q, J = 2.8 Hz), 30.0, 11.1 ppm; F NMR (CDCl
13
3
1
9
3
): δ –73.0 (s, 3F)
-1
ppm. ATR-FTIR (cm ): 1477, 1404, 1315, 1165, 1129, 1064, 749. HRMS (ESI): Calculated
for C11
+
H11NOF
3
S [M+H] : 262.0513; Found: 262.0517.
3
-((Trifluoromethyl)sulfinyl)-1H-pyrrolo[2,3-b]pyridine (2j). Procedure A. White solid. 70
1
mg, 35% yield. H NMR (CDCl ): δ 8.52 (d, J = 4.2 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.03
3
1
3
(s, 1H), 7.35 (dd, J = 7.9, 4.7 Hz, 1H) ppm; C NMR (DMSO-d ): δ 137.9, 132.3, 125.0 (q, J
6
1
9
=
7
7
337.3 Hz), 124.7, 124.4, 112.8, 111.0, 107.8 (q, J = 2.2 Hz) ppm; F NMR (CDCl ): δ –
3
-
1
3.9 (s, 3F) ppm. ATR-FTIR (cm ): 3123, 2928, 2855, 1581, 1410, 1281, 1159, 1131, 1067,
+
69. HRMS (ESI): Calculated for C
8
H
6
N
2
OF
3
S [M+H] : 235.0153; Found: 235.0145.
2
-((Trifluoromethyl)sulfinyl)-1H-pyrrole (3a) [24]. CAS [62665-45-6]. Procedure A.
1
Colourless oil. 81 mg, 52% yield. H NMR (CDCl
6
Hz), 119.0 (d, J = 1.7 Hz), 118.7 (d, J = 1.1 Hz), 110.4 ppm; F NMR (CDCl
3
3
): δ 10.88 (s, 1H), 7.23–7.17 (m, 1H),
1
3
.95–6.89 (m, 1H), 6.39–6.32 (m, 1H) ppm; C NMR (CDCl ): δ 127.3, 124.5 (q, J = 334.5
3
1
9
3
): δ –74.2 (s,
-1
F) ppm. ATR-FTIR (cm ): 3242, 2960, 1176, 1126, 1029, 743. HRMS (ESI): Calculated for
–
C
5
H
3
NOF
3
S [M-H] : 181.9887; Found: 181.9889.
3
,5-Dimethyl-2-((trifluoromethyl)sulfinyl)-1H-pyrrole (3b). Procedure A. Beige solid. 111
1
mg, 61% yield. H NMR (CDCl
3
): δ 9.52 (s, 1H), 5.89 (s, 1H), 2.30 (s, 3H), 2.20 (s, 3H) ppm;
1
3
C NMR (CDCl
3
): δ 137.9, 132.2, 124.9 (q, J = 335.1 Hz), 114.0 (q, J = 1.7 Hz), 111.0, 13.2,
1
9
-1
1
0.9 ppm; F NMR (CDCl ): δ –74.2 (s, 3F). ATR-FTIR (cm ): 3219, 3170, 1390, 1169,
3

+
1
2
123, 1036, 801. HRMS (ESI): Calculated for C
12.0354.
7
H
9
NOF S [M+H] : 212.0357; Found:
3
2
,5-Dimethyl-3-((trifluoromethyl)sulfinyl)-1H-pyrrole (3c). Procedure A. Beige solid. 149
1
mg, 83% yield. H NMR (CDCl
3
): δ 8.68 (s, 1H), 6.23 (s, 1H), 2.38 (s, 3H), 2.23 (s, 3H) ppm;
1
3
C NMR (CDCl
3
): δ 134.8, 129.6, 125.3 (q, J = 332.9 Hz), 112.1 (q, J = 2.2 Hz), 104.4, 12.7,
1
9
-1
1
1
2
1.3 ppm; F NMR (CDCl ): δ –74.6 (s, 3F) ppm. ATR-FTIR (cm ): 3253, 1404, 1167,
132, 1046, 807. HRMS (ESI): Calculated for C
12.0360.
3
+
7
H
9
NOF S [M+H] : 212.0357; Found:
3
2
6
2
-Phenyl-5-((trifluoromethyl)sulfinyl)-1H-pyrrole (3d). Procedure A. Purple solid. 136 mg,
1
2% yield. H NMR (CDCl
3
): δ 10.58 (s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.7 Hz,
H), 7.36 (t, J = 7.4 Hz, 1H), 6.96 (dd, J = 4.0, 2.7 Hz, 1H), 6.63 (dd, J = 3.8, 2.6 Hz, 1H)
13
ppm; C NMR (CDCl
3
): δ 141.2, 130.6, 129.0, 128.4, 125.3, 125.6 (q, J = 335.6 Hz), 120.0
19
(d, J = 1.1 Hz), 119.9 (q, J = 2.2 Hz), 107.9 ppm; F NMR (CDCl
3
): δ –73.8 (s, 3F) ppm.
-1
ATR-FTIR (cm ): 3240, 1459, 1179, 1132, 1034, 800, 763. HRMS (ESI): Calculated for
C
+
11
H
9
NOF
3
S [M+H] : 260.0357; Found: 260.0358.
Methyl 3-((trifluoromethyl)sulfinyl)indolizine-1-carboxylate (4). Procedure B. Yellow solid.
1
1
7
34 mg, 54% yield. H NMR (CDCl
.83 (s, 1H), 7.40 (t, J = 8.7 Hz, 1H), 7.00 (t, J = 6.8 Hz, 1H), 3.92 (s, 3H) ppm; C NMR
): δ 163.6, 140.8, 127.6 (q, J = 2.7 Hz), 127.0, 125.7 (q, J = 338.4 Hz), 125.5, 120.3,
3
): δ 8.93 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 9.1 Hz, 1H),
1
3
(CDCl
3
1
9
1
14.8, 111.4 (q, J = 2.2 Hz), 106.3, 51.4 ppm; F NMR (CDCl ): δ –70.7 (s, 3F) ppm. ATR-
FTIR (cm ): 3118, 1696, 1510, 1185, 1163, 1125, 1048, 775, 753. HRMS (ESI): Calculated
3
-1
+
for C11
H
9
NO
3
F
3
S [M+H] : 292.0255; Found: 292.0260.
3
-Methyl-1-phenyl-4-((trifluoromethyl)sulfinyl)-1H-pyrazol-5-ol (5). Procedure B. Yellow
1
solid. 115 mg, 46% yield. H NMR (CDCl ): δ 7.70 (d, J = 7.7 Hz, 2H), 7.23 (t, J = 7.0 Hz,
3
1
3
2
1
3
H), 7.08 (t, J = 7.2 Hz, 1H), 2.12 (s, 3H) ppm; C NMR (CDCl
3
): δ 162.6, 147.4, 139.1,
28.4, 125.4 (q, J = 335.6 Hz), 124.6, 120.6, 120.4, 13.0 ppm; F NMR (CDCl ): δ –74.3 (s,
F) ppm. ATR-FTIR (cm ): 2927, 2856, 1603, 1574, 1358, 1170, 1126, 1008, 757, 728.
1
9
3
-1
+
HRMS (ESI): Calculated for C11
H
10
N
2
O
2
F
3
S [M+H] : 291.0415; Found: 291.0419.
2
-Phenyl-3-((trifluoromethyl)sulfinyl)imidazo[1,2-a]pyridine (6). Procedure B. Dark brown
1
oil. 24 mg, 9% yield. H NMR (CDCl ): δ 8.98 (d, J = 6.8 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H),
3
1
3
7
1
1
.79–7.71 (m, 2H), 7.59–7.43 (m, 4H), 7.07 (t, J = 7.0 Hz, 1H) ppm; C NMR (CDCl
3
): δ
55.5, 149.1, 131.2, 130.2, 130.0 (q, J = 337.8 Hz), 129.6, 129.3, 128.9, 128.5 (q, J = 3.3 Hz),
19
18.2, 114.6, 108.6 (q, J = 2.8 Hz) ppm; F NMR (CDCl ): δ –68.7 (s, 3F) ppm. ATR-FTIR
3
-1
(cm ): 3041, 2921, 2851, 1461, 1440, 1350, 1172, 1122, 1066, 765, 689. HRMS (ESI):
+
Calculated for C14
H
10
N OF
2 3
S [M+H] : 311.0466; Found: 311.0461.
1
,1,1-Trifluoro-N-phenylmethanesulfinamide (7a) [8]. CAS [108530-14-9]. Procedure B.
1
Yellow solid. 124 mg, 70% yield. H NMR (CDCl ): δ 7.37 (t, J = 7.7 Hz, 2H), 7.20 (t, J =
7
1
3
13
.4 Hz, 1H), 7.12 (d, J = 7.7 Hz, 2H), 6.48 (bs, 1H) ppm; C NMR (CDCl
3
): δ 138.0, 129.9,
): δ –78.4 (s, 3F) ppm. ATR-
NOF
19
25.5, 123.6 (q, J = 333.4 Hz), 120.4 ppm; F NMR (CDCl
3
-1
FTIR (cm ): 3167, 1482, 1186, 1083, 906, 753. HRMS (ESI): Calculated for C
7
H
5
3
S
–
[
M-H] : 208.0040; Found: 208.0044.
1
,1,1-Trifluoro-N-(4-methoxyphenyl)methanesulfinamide (7b) [25]. CAS [868395-06-6].
1
Procedure A. Brown solid. 95 mg, 47%. H NMR (CDCl ): δ 7.11 (dt, J = 8.9, 2.1 Hz, 2H),
3

1
3
6
1
.89 (dt, J = 8.9, 2.1 Hz, 2H), 6.25 (s, 1H), 3.81 (s, 3H) ppm; C NMR (CDCl
3
): δ 158.2,
19
30.2, 124.5, 123.6 (q, J = 333.9 Hz), 115.0, 55.5 ppm; F NMR (CDCl
ppm. ATR-FTIR (cm ): 3172, 2846, 1509, 1303, 1180, 1076, 1029, 903, 826. HRMS (ESI):
3
): δ –78.4 (s, 3F)
-1
–
Calculated for C
8
H
7
NO
2
F
3
S [M-H] : 238.0150; Found: 238.0147.
1
,1,1-Trifluoro-N-(m-tolyl)methanesulfinamide (7c). Procedure A. Brown solid. 65 mg, 34%
1
yield. H NMR (CDCl ): δ 7.23 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H),
3
1
3
6
1
3
.91 (d, J = 7.9 Hz, 1H), 6.63 (s, 1H), 2.35 (s, 3H) ppm; C NMR (CDCl
3
): δ 140.0, 138.0,
29.6, 126.2, 123.6 (q, J = 333.4 Hz), 120.9, 117.3, 21.3 ppm; F NMR (CDCl ): δ –78.4 (s,
F) ppm. ATR-FTIR (cm ): 3218, 2926, 1609, 1472, 1149, 1170, 1091, 773. HRMS (ESI):
1
9
3
-1
–
Calculated for C
8
H
7
NOF
3
S [M-H] : 222.0200; Found: 222.0204.
1
,1,1-Trifluoro-N-(naphthalen-1-yl)methanesulfinamide (7e). Procedure A. Beige solid. 138
1
mg, 62% yield. . H NMR (CDCl ): δ 8.04 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.82
3
13
(d, J = 6.2 Hz, 1H), 7.59 (qt, J = 3.8 Hz, 2H), 7.53–7.41 (m, 2H), 6.55 (s, 1H) ppm; C NMR
(
1
1
CDCl
3
): δ 134.4, 133.1, 128.9, 128.6, 128.2 (q, J = 334.0 Hz), 127.8, 127.2, 126.9, 125.5,
1
9
-1
21.8, 121.5 ppm; F NMR (CDCl
162, 1148, 1086, 784, 765. HRMS (ESI): Calculated for C10
3
): δ –78.3 (s, 3F) ppm. ATR-FTIR (cm ): 3236, 1403,
–
H
12
N
2
O
2
F
3
S [M-H] : 258.0194;
Found: 258.0200.
N-Benzyl-1,1,1-trifluoromethanesulfinamide (7f) [26]. CAS [868395-10-2]. Procedure A.
1
Colourless oil. 61 mg, 32% yield. H NMR (CDCl ): δ 7.45–7.29 (m, 5H), 4.77 (s, 1H), 4.48
3
1
3
(
1
dd, J = 14.0, 6.2 Hz, 1H), 4.32 (dd, J = 14.0, 5.3 Hz, 1H) ppm; C NMR (CDCl
28.9, 128.3, 128.1, 123.7 (q, J = 334.5 Hz), 46.4 ppm; F NMR (CDCl
3
): δ 136.5,
): δ –77.3 (s, 3F)
19
3
-1
ppm. ATR-FTIR (cm ): 3208, 1456, 1169, 1148, 1079, 1027, 741, 696. HRMS (ESI):
–
Calculated for C
8
H
7
NOF
3
S [M-H] : 222.0200; Found: 222.0192.
Naphthalen-1-yl trifluoromethanesulfinate (8a) [15]. CAS [655226-96-3]. Procedure B.
1
Brown solid. 37 mg, 16% yield. H NMR (DMSO-d
6
): δ 8.30 (d, J = 7.9 Hz, 1H), 8.20 (d, J =
8
1
.3 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.69 (td, J = 8.3, 1.1 Hz, 1H), 7.61 (td, J = 8.1, 0.9 Hz,
13
H), 7.17 (d, J = 8.1 Hz, 1H) ppm; C NMR (DMSO-d ): δ 159.2, 131.7, 128.7, 126.1, 125.5
6
1
9
(q, J = 337.8 Hz), 124.6, 123.2, 121.8, 118.7, 108.2 ppm; F NMR (CDCl
3
): δ –74.1 (s, 3F)
-1
ppm. ATR-FTIR (cm ): 3240, 2924, 1571, 1346, 1172, 1123, 1042, 826, 757. HRMS (ESI):
Calculated for C11
–
H
6
O
2
F
3
S [M-H] : 259.0041; Found: 259.0038.
4
-((Trifluoromethyl)sulfinyl)benzene-1,3-diol (8b). Procedure A. Colourless oil. 46 mg, 24%
1
yield. . H NMR (DMSO-d
=
1
6
): δ 7.49 (d, J = 8.9 Hz, 1H), 6.54 (dd, J = 8.7, 2.1, 1H), 6.44 (d, J
1
3
2.1 Hz, 1H) ppm; C NMR (DMSO-d ): δ 163.9, 158.6, 127.6, 125.3 (q, J = 337.8 Hz),
6
1
9
09.9 (q, J = 1.7 Hz), 108.9, 102.7 ppm; F NMR (DMSO-d
6
): δ –75.1 (s, 3F) ppm. HRMS
–
(ESI): Calculated for C
7
H
4
O F
3 3
S [M-H] : 224.9833; Found: 224.9830.
Methyl 2-((1H-indol-3-yl)sulfinyl)-2,2-difluoroacetate (9). Procedure A. Beige solid. 153 mg,
1
6
1
1
1
5% yield. H NMR (CDCl
H), 7.46 (d, J = 7.6 Hz, 1H), 7.36–7.21 (m, 2H), 3.72 (s, 3H) ppm; C NMR (CDCl
60.1 (t, J = 29.2 Hz), 136.5, 129.9, 124.7, 124.2, 122.4, 120.0, 118.6 (t, J = 301.5 Hz), 112.5,
3
): δ 9.72 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 3.0 Hz,
1
3
3
): δ
1
9
08.3 (t, J = 3.8 Hz), 54.1 ppm; F NMR (CDCl ): δ –109.9 (d, J = 225.8 Hz, 1F), –110.9 (d,
J = 225.8 Hz, 1F) ppm. ATR-FTIR (cm ): 3204, 2930, 1753, 1419, 1318, 1164, 1124,
048, 742, 701. HRMS (ESI): Calculated for C10
3
-1
+
1
H
12
N
2
O
2
F S [M+H] : 274.0349; Found:
3
2
74.0349.

Acknowledgments
This research was supported by the Centre National de la Recherche Scientifique CNRS,
University of Rouen, INSA Rouen, and Labex SynOrg (ANR-11-LABX-0029). H.C. thanks
the French “Ministère de la Recherche et de l’Enseignement Supꢀrieur” for a doctoral
fellowship.
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Scheme 1
Synthesis of methyl 2-((1H-indol-3-yl)sulfinyl)-2,2-difluoroacetate.
Scheme 2
Proposed monodeoxygenative sulfinylation mechanism.
Table 1
Optimization of reaction conditions
Ratio
Entry Phosphine
Solventa
Temp. (°C)
Yield (%)b
1
a/CF
3
SO Cl/phosphine
2
1
2
3
4
5
PMe
PPh
PCy
PCy
PCy
3
1:1.8:3.6
1:1.8:3.6
1:1.8:3.6
1:1.8:3.6
1:1.8:3.6
THF
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–78 to rt
11
5
3
THF
3
THF
62
66
67
3
toluene
DCM
3

6
7
8
9
1
PCy
PCy
PCy
PCy
PCy
PCy
PCy
PCy
PCy
PCy
PCy
3
1:1.8:3.6
1:1.8:2.7
1:1.8:1.8
1:1.5:1.5
1:1.1:1.1
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCMc
DCMd
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–78 to rt
–40 to rt
–20 to rt
0 to rt
65
73
79
89
85
85
84
61
59
77
53
3
3
3
0
3
11
3
1
1
1
1
2
3
4
5
6
3
3
3
rt
3
–78 to rt
–78 to rt
1
3
1:1.5:1.5
a
b
19
Concentration: 0.17 M. Yields were determined by F NMR using trifluorotoluene as an
c
d
internal standard. Concentration: 0.09 M. Concentration: 0.9 M.

Table 2
Scope of trifluoromethylsulfinylation of indole derivatives.
Entry
1
Substrate 1
Time (h)
6
Product 2
Yield (%)a
88
2b
18
80
3b
4
18
6
91
85
86
5
5
6b
7
61
7
8
9
6
6
6
87
79
73

1
0
24
35
a
Isolated yields. b 1.8 equivalents of trifluoromethanesulfonyl chloride and tricyclohexyl
phosphine were used.

Table 3
Scope of trifluoromethylsulfinylation of pyrrole derivatives and other azaarenes.
Entry
1
Substrate
Time (h)
2
Product
Yield (%)a
52
2
3
2
2
61
83
4
8
62
5b
24
73c
6b
8
54
7b
6
46
9
8b
24
a
Isolated yields. b 1.8 equivalents of trifluoromethanesulfonyl chloride and tricyclohexyl
c
19
phosphine were used. Yield was determined by F NMR using trifluorotoluene as an
internal standard.

Table 4
Scope of N-trifluoromethylsulfinylation of aryl- and alkylamines.
Entry
1
Substrate
Time (h)
6
Product
Yield (%)a
70
2
4
7
4
6
47
34
42c
62
3
4b
5
6
6
7
32
7
28c
a
Isolated yields. b 1.8 equivalents of trifluoromethanesulfonyl chloride and tricyclohexyl
c
19
phosphine were used. Yields were determined by F NMR using trifluorotoluene as an
internal standard.

Table 5
C-Trifluoromethylsulfinylation of phenol derivatives.
Entry
Substrate
Time (h)
24
Product
Yield (%)a
16c,d
1b
2
24
24c
a
Isolated yields. b 1.8 equivalents of trifluoromethanesulfonyl chloride and tricyclohexyl
phosphine were used The starting material was partly recovered. d The corresponding
trifluoromethylthiolated side-product was formed.
c