S-(Diethyl phosphonodifluoromethyl)Benzenesulfonothioate: A New Reagent for the Synthesis of SCF2PO(OEt)2-containing Molecules

Article abstract of DOI:10.1002/adsc.201901454

In this manuscript, the synthesis of an original SCF₂PO(OEt)₂-containing reagent was depicted. Thanks to the unique properties of this newly-designed source, an unprecedented transformation with aldehydes was conducted under radical

Full text of DOI:10.1002/adsc.201901454

Title: S-(Diethyl phosphonodifluoromethyl)Benzenesulfonothioate: A
New Reagent for the Synthesis of SCF2PO(OEt)2-containing
Molecules.
Authors: Fabien Petit-Cancelier, Benjamin François, Xavier
Pannecoucke, samuel couve-bonnaire, and Tatiana Besset
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901454
Link to VoR: http://dx.doi.org/10.1002/adsc.201901454

Advanced Synthesis & Catalysis
10.1002/adsc.201901454
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
S-(Diethyl phosphonodifluoromethyl)Benzenesulfonothioate: A
New Reagent for the Synthesis of SCF PO(OEt) -containing
2
2
Molecules
a
a
a
Fabien Petit-Cancelier, Benjamin François, Xavier Pannecoucke, Samuel Couve-
a
a
Bonnaire and Tatiana Besset *
a
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France.
0
033235522403, E-mail: tatiana.besset@insa-rouen.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. In this manuscript, the synthesis of an original other classes of molecules with this fluorinated
SCF
the unique properties of this newly-designed source, an expertise,
unprecedented transformation with aldehydes was ArSSCF PO(OEt) derivatives as the SCF PO(OEt)
2 2
PO(OEt)
-containing reagent was depicted. Thanks to building block. Taking benefit from our in-home
[5,7]
we envisioned at first to use
2
2
2
2
conducted under radical conditions, offering an access to radical source. Unfortunately, all attempts with
value-added fluoroalkylthio compounds. Preliminary
mechanistic studies were conducted and supported a radical
reaction mechanism. Remarkably, thiol and disulfide
derivatives turned out to be suitable coupling partners in a
transition-metal-free transformation towards the synthesis
of difficult-to-synthesize unsymmetrical disulfides.
Finally, the difunctionalization of 4-phenyl-butene was
investigated using this reagent.
different classes of compounds only led to the
preferential incorporation of the ArS moiety instead
of the desired fluorinated group. We reasoned that to
reach the targeted goal, one solution relied on the
“
dessymetrization” of the S-S bond from the reagent
in order to favor the incorporation of the
SCF PO(OEt) moiety. In the course of our
investigations and inspired by the key advances made
2
2
[4b]
by several research groups, we anticipated that the
reactivity of a ArSO SCF PO(OEt) reagent would be
tailor-made as it should favor the targeted transfer of
the SCF PO(OEt) over the ArSO group. In this
Keywords: Fluorine; sulfur; diethyl
phosphonodifluoromethylthiolation reagent, radical
pathway; synthetic methodologies
2
2
2
2
2
2
context, the design and the synthesis of the reagent II
was achieved by mixing our in-home reagent I and
sodium para-toluenesulfinate in acetic acid for 16 h
at room temperature. Pleasingly, under these reaction
conditions, the reagent II was obtained in 81% yield
and its synthesis was easily scaled up to about 1g
with a similar yield (3.25 mmol, 89%). Note that
under acidic conditions, the reagent II is quite stable
while its decomposition was observed in the presence
The synthesis of organofluorine molecules is still
nowadays a compelling challenge due to the
[1]
importance of the fluorinated compounds
in
[2]
pharmaceutical and agrochemical industries.
Thanks to the properties of the fluorine atom and the
fluorinated groups,[ features of the fluorine-
containing molecules might be tuned at will. In
particular, to further meet the demand of original
fluorinated groups for academia and industrial
applications, several research groups investigated the
3]
[8]
of various bases in dichloromethane as a solvent.
design and the incorporation of SCF
H, F, FG, FG = functional group) onto molecules.
In particular, a strong interest was shown towards the
SCF PO(OEt) residue (Hansch-Leo parameter of =
Key reports generally dealt with the
2
R moieties (R =
[4]
2
2
[5]
0
.76).
2 2
Scheme 1. Synthesis of the new SCF PO(OEt) reagent II.
[
6]
construction of this fluorinated group or its direct
introduction using an electrophilic reagent on various
classes of compounds.[ Nevertheless, despite these
major advances, some synthetic limitations remain.
To overcome them and since no radical
[
a]
[b]
Reaction performed on 1.13 mmol scale.
performed on 3.25 mmol scale. Mes = mesityl
Reaction
5,7]
The reactivity of the reagent II was evaluated for the
synthesis of diethyl phosphonodifluoromethylated
thioesters (Scheme 2). Indeed, the direct introduction
SCF
2
PO(OEt) -source existed, we thought that the
2
design of a new reagent would be relevant, offering
new chemical spaces for the functionalization of
1
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901454
of the SCF
when combining NaN
EtOAc) at room temperature. A series of aromatic
aldehydes (1a-1u) were engaged in our standard
2
PO(OEt)
2
moiety was smoothly achieved
3
conditions. It turned out that electron rich substrates
(1b-1g) were efficiently functionalized and the
reaction was scaled up to 1 mmol scale in case of 1b
leading to the corresponding product in a slightly
lower yield (65% vs 79%). The transformation was
tolerant to various functional groups such as alcohol
and PIFA in a green solvent
(
(
2c), halogens (2i-2k and 2o) and nitrile (2q). In case
of electron poor aromatic aldehydes (compounds 1h,
l, 1p-1q), a slight modification of the reaction
conditions was necessary to ensure the synthesis of
1
the
corresponding
diethyl
in
phosphonodifluoromethylated
thioesters
satisfactory yields (up to 61% yield). The substitution
pattern on the aromatic ring did not have a strong
impact on the outcome of the reaction as meta and
ortho substituted aromatic aldehydes with electron
rich and poor substituents (1m-1s) were converted
into the expected products (2m-2s) in moderate to
high yields. This allowed us to functionalize
compounds of interest such as the Bn-protected
vanillin (1t) and syringaldehyde (1u), offering an
access
phosphonodifluoromethylated thioesters in 66% and
8% yields, respectively. Heteroaromatic aldehydes
such as pyrrole-2-carboxaldehyde 1v, 2-
thiophenecarboxaldehyde 1w and benzo[b]thiophene-
-carboxaldehyde 1x were also smoothly converted
to
the
corresponding
diethyl
6
2
into the corresponding fluorinated products 2v-2x in
low to moderate yields. When an aliphatic aldehyde
was engaged, 2y was obtained in 40% yield due to
purification issues. Finally, due to the importance of
[2a]
fluoroalkylthio moieties in bioactive molecules, the
synthetic value of the methodology was further
proven by the late-stage functionalization of a
complex molecule namely the cholesterol derivative
1z.
Control experiments were conducted to get more
insights into the reaction mechanism. The addition of
2
2
,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or
,6-di-tert-butyl-4-methylphenol (BHT) as radical
inhibitors completely inhibited the reaction, whatever
[8]
the added quantity. In case of 2 equivalents of
TEMPO, the corresponding TEMPO adduct was
detected by GC-HRMS. Note that when PIFA and
TEMPO were mixed, no degradation of the PIFA was
observed. Therefore, based on these observations and
literature data, the following tentative mechanism
was proposed (Scheme 3): after generation of the
radical azide from sodium azide in the presence of
PIFA, the corresponding acyl radical was obtained.
The latter reacted with the reagent II to afford the
expected product 2.
[9]
Scheme
2.
Synthesis
of
diethyl
phosphonodifluoromethylated thioesters from aldehydes
using the reagent II. Reaction performed on 0.2 mmol
scale: aldehyde 1 (0.2 mmol), reagent II (0.3 mmol), NaN
2 equiv.), PIFA (2 equiv.) in EtOAc at 22 °C for 3 h under
3
(
[
a]
argon. Isolated yields were given. Reaction on 1 mmol
scale. [ 6 h instead of 3 h. The reaction was carried out
b]
[c]
using 0.4 mmol of aldehyde 1, 0.2 mmol of reagent II,
NaN
3 2 2
(2 equiv.), PIFA (2 equiv.) in CH Cl at 22 °C for 16
[
d]
h under argon. The product was isolated in the presence
of an inseparable impurity. Reaction carried out at 27 °C.
[
e]
Scheme 3. Plausible mechanism.
2
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901454
The reagent II was not only efficient for the
functionalization of aldehyde derivatives, and other
classes of compounds were evaluated. Indeed, when
thiol 3 or disulfide 4 derivatives were engaged with
the reagent II in the presence of LiBr,[ the synthesis
of difficult-to-synthesize unsymmetrical disulfides
was successfully achieved (12 examples, up to 91%
yields, Scheme 4). This transition metal-free
approach was efficient offering a panel of para
Nevertheless, the transformation was highly atom-
economical and regioselective as 7 was obtained as a
[8]
single regioisomer.
10]
substituted
aromatic
diethyl
Scheme 5. Difunctionalization of the 4-phenyl-butene.
phosphonodifluoromethylthiolated
compounds
bearing electron-donating groups (5b and 5c, in 72%
and 52% yields, respectively) as well as halogens (5d
In summary, the synthesis of an original
and 5e) and a CF moiety (5f), the reaction being
3
SCF
2
PO(OEt)
2
reagent was achieved and its
more efficient for electron rich systems. The
substitution pattern on the aromatic ring did have a
strong effect on the outcome of the reaction as
demonstrated when comparing 5c, 5g and 5h. Note
that a thiophene derivative was a reluctant substrate
under these reaction conditions providing the
expected compounds in only 22% yield. Pleasingly,
the functionalization of aliphatic thiol derivatives was
achieved not only with the benzylic derivative 5j but
also with unactivated aliphatic derivatives (5k and 5l).
This showcased the added-value of this approach
reactivity was investigated. Indeed, the direct diethyl
phosphonodifluoromethylthiolation of aldehydes
provided an access to unprecedented thioester
derivatives. Preliminary mechanistic studies indicated
a radical pathway. Moreover, the access to
unsymmetrical
hetero)aromatic, benzylic and non-activated aliphatic
disulfides was achieved. With the reagent II, the
portfolio of SCF PO(OEt) -containing compounds
was significantly extended, opening further the
2
SCF PO(OEt)
2
-containing
(
2
2
[7]
chemical space of SCF FG-containing molecules and
2
compared to the existing methods,
demonstrated further its synthetic utility.
and
offering new possibilities for potential applications.
Experimental Section
General procedure for the synthesis of compounds 2.
Procedure A: The aldehyde 1 (0.2 mmol, 1 equiv.) was
charged in an oven-dried 10 mL tube equipped with a
stirring bar and filled under argon followed by the reagent
II (112.3 mg, 0.3 mmol, 1.5 equiv.), PIFA (172.0 mg, 0.4
mmol, 2 equiv.) and freshly distilled ethyl acetate (0.8 mL).
3
Then, NaN (26.8 mg, 0.4 mmol, 2 equiv.) was finally
introduced. The reaction mixture was stirred at 22 °C for 3
h before removing the solvent under reduced pressure. The
crude mixture was directly purified by flash column
chromatography on silica gel to afford the desired product
2
.
Note that in some cases, the same protocol was used but a
different treatment was necessary (procedure B).
Procedure B: The aldehyde 1 (0.2 mmol, 1 equiv.) was
charged in an oven-dried 10 mL tube equipped with a
stirring bar and filled under argon followed by the reagent
II (112.3 mg, 0.3 mmol, 1.5 equiv.), PIFA (172.0 mg, 0.4
mmol, 2 equiv.) and freshly distilled ethyl acetate (0.8 mL).
Scheme 4. Synthesis of unsymmetrical fluorinated
disulfides 5. Reaction conditions: RSH 3 (0.20 mmol),
reagent II (0.2 mmol), LiBr (1 equiv.) in HFIP at 40 °C for
3
Then, NaN (26.8 mg, 0.4 mmol, 2 equiv.) was finally
introduced. The reaction mixture was stirred at 22 °C for 3
h. After dilution in ethyl acetate (40 mL) and brine (20
[
a]
3
mL), an aqueous saturated solution of NaHCO (40 mL)
6
h under argon. Isolated yields were given.
Reaction
was added until pH = 8. The combined organic layers were
[
b]
performed using (ArS)
2
4 instead of 3. The product was
2 4
washed with water (3 × 20 mL), dried over Na SO ,
isolated in the presence of an inseparable impurity.
filtered and the solvents were carefully removed under
pressure. The residue was purified by flash column
chromatography on silica gel to afford the desired product
2
.
Aiming at demonstrating further the synthetic
Procedure C: The aldehyde 1 (0.4 mmol, 2 equiv.) was
charged in an oven-dried 10 mL tube equipped with a
stirring bar and filled under argon followed by the reagent
II (74.9 mg, 0.2 mmol, 1 equiv.), PIFA (172.0 mg, 0.4
mmol, 2 equiv.) and freshly distilled dichloromethane (2.4
potential of the reagent II, the difunctionalization of
[11]
unactivated alkenes was studied.
After intensive
investigations, the diethyl phosphonodifluoro-
methylthiolation sulfonylation of 6 was achieved
leading to the corresponding product 7, although in a
low yield (21%) despite all our efforts (Scheme 5).
mL). Then, NaN
3
(26.8 mg, 0.4 mmol, 2 equiv.) was
finally introduced. The reaction mixture was stirred at
2
2 °C for 16 h before removing the solvent under reduced
pressure. The crude was directly purified by flash column
3
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901454
chromatography on silica gel to afford the desired product
H. Liu, Chem. Rev. 2014, 114, 2432-2506; b) S. Purser,
P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320-330; c) E. P. Gillis, K. J. Eastman,
M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med.
Chem. 2015, 58, 8315-8359; d) E. A. Ilardi, E. Vitaku,
J. T. Njardarson, J. Med. Chem. 2014, 57, 2832-2842;
e) Fluorine in Life Sciences: Pharmaceuticals,
Medicinal Diagnostics, and Agrochemicals, 1st ed.,
Progress in Fluorine Science Series, (Eds.: G. Haufe, F.
R. Leroux), Elsevier, Academic Press, 2018.
2
.
General procedure for the synthesis of compounds 5.
An oven-dried 10 mL tube equipped with a stirring bar was
charged with II (75 mg, 0.2 mmol, 1 equiv.), and
anhydrous lithium bromide (17 mg, 0.2 mmol, 1 equiv.).
The tube was evacuated and backfilled with argon three
times, then the derivative 3 or 4 (0.2 mmol, 1 equiv.) and
HFIP (1 mL) were introduced. The tube was sealed and the
resulting suspension was stirred at 40 °C for 6 hours. Once
cooled down at room temperature, the reaction mixture
was diluted with water (10 mL) and extracted with CH
2
Cl
2
[3] D. O'Hagan, Chem. Soc. Rev. 2008, 37, 308-319.
(
3 × 15 mL). The combined organic layers were washed
with brine (10 mL), dried over sodium sulfate and
concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to
afford the desired product 5.
[4] a) H.-Y. Xiong, X. Pannecoucke, T. Besset, Chem. Eur.
J. 2016, 22, 16734-16749; b) X. Pannecoucke, T.
Besset, Org. Biomol. Chem. 2019, 17, 1683-1693 and
references therein.
Procedure for the synthesis of the compound 7.
[
5] J. Wang, H.-Y. Xiong, E. Petit, L. Bailly, X.
Pannecoucke, T. Poisson, T. Besset, Chem. Commun.
In a glovebox, in an oven-dried 10 mL tube equipped with
2
019, 55, 8784-8787.
6] a) A. Konno, T. Fuchigami, J. Org. Chem. 1997, 62,
579-8581; b) T. Lequeux, F. Lebouc, C. Lopin, H.
Yang, G. Gouhier, S. R. Piettre, Org. Lett. 2001, 3,
85-188; c) A. Henry-dit-Quesnel, L. Toupet, J.-C.
3
a stirring bar was added AgNO (17 mg, 0.1 mmol, 0.5
equiv.). Then II (75 mg, 0.2 mmol, 1 equiv.), Na
2
S
2
O
8
(48
[
mg, 0.2 mmol, 1 equiv.), 4-phenyl-butene (30 μL, 0.2
8
mmol, 1 equiv.) and a mixture of DMSO:H
2
O (8:1, 0.9
mL) were introduced under argon. The tube was sealed and
the resulting suspension was stirred at 22 °C for 15 hours.
The reaction mixture was diluted with water (10 mL) and
1
Pommelet, T. Lequeux, Org. Biomol. Chem. 2003, 1,
2486-2491; d) L. Aliouane, S. Chao, L. Brizuela, E.
Pfund, O. Cuvillier, L. Jean, P.-Y. Renard, T. Lequeux,
Bioorg. Med. Chem. 2014, 22, 4955-4960; e) C. De
Schutter, E. Pfund, T. Lequeux, Tetrahedron 2013, 69,
2 2
extracted with CH Cl (3 × 15 mL). The combined organic
layers were washed with brine (2 × 10 mL), dried over
sodium sulfate and concentrated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel to afford the desired product 7.
5
920-5926; f) M. V. Ivanova, A. Bayle, T. Besset, X.
Pannecoucke, T. Poisson, Angew. Chem. Int. Ed. 2016,
5, 14141-14145; g) M. V. Ivanova, A. Bayle, X.
Pannecoucke, T. Besset, T. Poisson, Eur. J. Org. Chem.
017, 2475-2480; h) M. V. Ivanova, A. Bayle, T.
Acknowledgements
5
This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029),
Région Normandie (Crunch Network) and Innovation Chimie
Carnot (I2C). F. P.-C., B.F., T. B. thanks the European Research
Council (ERC) under the European Union’s Horizon 2020
research and innovation program (grant agreement no. 758710).
F. P.-C. thanks the Region Normandy for a doctoral fellowship.
2
Besset, X. Pannecoucke, T. Poisson, Chem. Eur. J.
2017, 23, 17318-17338; i) Y. Ou, L. J. Goossen, Asian
J. Org. Chem. 2019, 8, 650-653.
[
[
7] H.-Y. Xiong, A. Bayle, X. Pannecoucke, T. Besset,
Angew. Chem. Int. Ed. 2016, 55, 13490-13494.
References
8] For more details, see the supporting information.
[
1] a) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem.
Int. Ed. 2013, 52, 8214-8264; b) T. Besset, T. Poisson,
X. Pannecoucke, Chem. Eur. J. 2014, 20, 16830-16845;
c) C. Ni, J. Hu, Chem. Soc. Rev. 2016, 45, 5441-5454;
d) G. Landelle, A. Panossian, F. R. Leroux, Curr. Top.
Med. Chem. 2014, 14, 941-951; e) G. Landelle, A.
Panossian, S. Pazenok, J.-P. Vors, F. R. Leroux,
Beilstein J. Org. Chem. 2013, 9, 2476-2536; f) P. A.
Champagne, J. Desroches, J.-D. Hamel, M. Vandamme,
J.-F. Paquin, Chem. Rev. 2015, 115, 9073-9174; g) E.
Merino, C. Nevado, Chem. Soc. Rev. 2014, 43, 6598-
[9] B. Xu, D. Li, L. Lu, D. Wang, Y. Hu, Q. Shen, Org.
Chem. Front. 2018, 5, 2163-2166.
[
10] Note that in absence of LiBr, only traces of compound
were detected.
[
11] For related reactions for the introduction of the SCF
and SCH F groups, see: a) D. Zhu, X. Shao, X. Hong,
L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2016, 55,
5807-15811; b) Q. Zhao, L. Lu, Q. Shen, Angew.
2
H
2
1
Chem. Int. Ed. 2017, 56, 11575-11578; c) S.-H. Guo,
X.-L. Zhang, G.-F. Pan, X.-Q. Zhu, Y.-R. Gao, Y.-Q.
Wang Angew. Chem. Int. Ed. 2018, 57, 1663-1667.
6
608; h) H. Egami, M. Sodeoka, Angew. Chem. Int. Ed.
014, 53, 8294-8308; i) M.-C. Belhomme, T. Besset, T.
2
Poisson, X. Pannecoucke, Chem. Eur. J. 2015, 21,
2836-12865; j) T. Besset, P. Jubault, X. Pannecoucke,
1
T. Poisson, Org. Chem. Front. 2016, 3, 1004-1010; k)
H.-X. Song, Q.-Y. Han, C.-L. Zhao, C.-P. Zhang,
Green Chem. 2018, 20, 1662-1731.
[
2] a) J. Wang, M. Sánchez-Roselló, J. L. Aceňa, C. del
Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok,
4
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901454
COMMUNICATION
S-(Diethyl
phosphonodifluoromethyl)Benzene-
sulfonothioate: A New Reagent for the Synthesis of
2
SCF PO(OEt) -containing Molecules.
2
Adv. Synth. Catal. Year, Volume, Page – Page
Fabien Petit-Cancelier, Benjamin François, Xavier
Pannecoucke, Samuel Couve-Bonnaire and Tatiana
Besset*
5
This article is protected by copyright. All rights reserved.