Validation of Arylphosphorothiolates as Convergent Substrates for Ar-SF 4Cl and Ar-SF 5Synthesis

Article abstract of DOI:10.1055/s-0040-1706039

In this manuscript we describe the oxidative fluorination of aryl phosphorothiolates to access Ar-SF₄Cl compounds. These compounds serve as precursors for the highly coveted Ar-SF5 compounds. The use of phosphorothiolates as starting materials permits access to Ar-SF₄Cl from a wide variety of available starting materials, namely boronic acids, diazonium salts, aryl iodides, thiophenols, or simple arenes. The protocol has been demonstrated for 10 examples and showed good tolerance to various functional groups. Finally, we demonstrated that AgBF4 can be used as a fluorinating agent, affording good yields of an Ar-SF5.

Full text of DOI:10.1055/s-0040-1706039

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–E
special topic
A
Special Issue dedicated to Prof. Sarah Reis-
L. Wang et al.
Special Topic
Synthesis
Validation of Arylphosphorothiolates as Convergent Substrates
for Ar-SF4Cl and Ar-SF5 Synthesis
I
Lin Wang
Shengyang Ni
Josep Cornella*
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aryl iodides
H
Department of Organometallic Chemistry, Max-Planck-Institut
für Kohlenforschung, Kaiser-Wilhelm-Platz, 1, 45470, Mülheim
an der Ruhr, Germany
SEAr methods
O
S
P
F
S
F
cat. TFA
TCICA
KF
F
S
F
F
OEt
F
F
Cl
EtO
cornella@kofo.mpg.de
AgBF4
N2
F
F
aryl
X
Published as part of the
MeCN, rt
phosphorothiolates
Special Issue dedicated to Prof. Sarah Reisman, recipient of the
2019 Dr. Margaret Faul Women in Chemistry Award
[modular starting materials]
[facile access]
[convergent strategy]
Ar-SF4Cl
Ar-SF5
aryldiazonium
eJDoMespeapaiClrCotcmrorreennseptloloanf@dOkirnoggfaonA.moumtphgeo.tdraellic Chemistry, Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz, 1, 45470, Mülheim an der Ruhr, Germany
B(OH)2
SH
boronic acids
thiophenols
Received: 16.04.2021
Accepted: 19.04.2021
Published online: 20.05.2021
DOI: 10.1055/s-0040-1706039; Art ID: ss-2021-t0216-st
analog, the SF5 group is more hydrophobic and is robust
when confronted to harsh acidic or basic conditions (for
Ph-SF5).12
t
With the volume comparable to a Bu group and the
Abstract In this manuscript we describe the oxidative fluorination of
aryl phosphorothiolates to access Ar-SF4Cl compounds. These com-
pounds serve as precursors for the highly coveted Ar-SF5 compounds.
The use of phosphorothiolates as starting materials permits access to
Ar-SF4Cl from a wide variety of available starting materials, namely bo-
ronic acids, diazonium salts, aryl iodides, thiophenols, or simple arenes.
The protocol has been demonstrated for >10 examples and showed
good tolerance to various functional groups. Finally, we demonstrated
that AgBF4 can be used as a fluorinating agent, affording good yields of
an Ar-SF5.
electronegativity resembling a NO2 group, the introduction
of SF5 into lead compounds has captivated the interest of
medicinal chemists. For example, analogues of mefloquine
(antimalarial) or bosentan (pulmonary arterial hyperten-
sion) bearing an SF5 group have shown to be more potent
than its CF3 analog, highlighting some of the potential ap-
plications of the pentafluorosulfanyl group (Scheme 1A).13
Despite the interesting chemical properties of this group,
its synthesis and strategies for its straightforward introduc-
tion are still somewhat limited. Although early examples
using Cl2, F2, or XeF2 are known, limitations in functional
group tolerance, scope, and practicality have prevented
their adoption by organic chemists.14 In groundbreaking
work, Pitts, Santschi, Togni, and co-workers reported a
practical variation of the Umemoto process,14d which en-
abled the synthesis of a wide variety of Ar-SF5 compounds
in a simple and straightforward manner.15 The strategy con-
sists of the oxidation of aryl disulfides (from thiols) with
TCICA (tetrachloroisocyanuric acid) in the presence of an
excess of KF, to forge the key intermediate Ar-SF4Cl (Scheme
1B). Simple Cl-F exchange then leads to Ar-SF5. It is import-
ant to mention that such a strategy has also been used in
the oxidation of other chalcogens and even organophos-
phorus compounds.16 Our group has recently contributed to
this area reporting the possibility to use aryl sulfenylph-
thalimides as precursors, which can be obtained from the
parent Ar-ZnX compounds (Scheme 1B).17 Despite these ad-
vances, the current methodologies are still restricted to
thiophenols and organozinc reagents as precursors. With
Key words fluorine, phosphorus, sulfur, pentafluorosulfanylation,
isosteres
Nearly a quarter of the pharmaceuticals in the market
contain at least one fluorine atom in their structure.1 The
impact of fluorine in drug discovery campaigns has been
remarkable and methods to create X-F bonds in organic
molecules are highly coveted.2 In this context, chemists
have identified groups of fluorinated functionalities which
have had a dramatic impact on the ADME (i.e. Absorption,
Distribution, Metabolism and Excretion) properties of cer-
tain biologically active compounds.3 For example, CF3,4
OCF3,5 SCF3,6 CF2H,7 CFH2,8 and trifluorocyclopropyl9 have
all been studied as bioisosteres of CH3, OCH3, and tBu
groups. In recent years, a related fluorinated functionality
t
has also been identified as a bioisostere of the CF3 and Bu
groups: the pentafluorosulfanyl group (SF5).10 This hyper-
valent sulfur moiety is characterized by an octahedral ar-
rangement of the F atoms around the S(VI) atom, resulting
in high electronegativity11 (Scheme 1A). Compared to its CF3
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
L. Wang et al.
Special Topic
Synthesis
possibility to access these compounds from a myriad of di-
verse starting materials further supports the consideration
of Ar-S-P(O)(OR)2 as convergent linchpin reagents. In this
work, we demonstrate that oxidation of Ar-S-P(O)(OR)2
with TCICA in the presence of KF delivers Ar-SF4Cl in good
yields with a variety of substitution patterns at the aryl
moiety (Scheme 1C). Additionally, we also demonstrate that
Ar-SF4Cl can be converted into the corresponding Ar-SF5 via
the use of AgBF4.
A. Ar-SF5: functional group overview
F
F
F
F
F
SF5
S
NH
HO
R
O
N
OMe
CF3
octahedral
O
HO
N
[volume: 49.2 cm3 mol–1
]
N
N
NH
S
[Hammett constant (σp): 0.68
(4-SF5-C6H4-CO2H)]
N
O
O
[electronegativity: 3.65]
SF5
[dipole moment (μ): 2.60 D (PhSF5)]
SF5
bosentan analogue
(pulmonary artery
hypertension)
mefloquine analogue
(antimalarial)
[stability: H2SO4 and NaOH]
Optimization of the oxidative fluorination started by the
testing of various phenyl phosphorothiolates. As shown in
Scheme 2, when a mixture of TCICA and KF is used in MeCN
at room temperature, phenyl phosphorothiolates bearing
OMe (1) or OEt (2) led to good yields of 6a (entries 1 and 2).
However, side products were also observed, which were
identified to be mainly the S(IV) product Ph-SF3 and the
partially hydrolyzed S(VI) product Ph-SOF3 (shown together
as 7). When the alkoxy groups in the phosphorus ester are
replaced by phenoxy (3), the yields dramatically decreased,
resulting in only 25% overall yield with almost no selectivi-
ty for Ar-SF4Cl (entry 3). When the P(O)(OR)2 group is re-
placed by P(O)Ph2 (4), good yields were also obtained in
high selectivity (entry 4). Finally, the replacement of P=O by
P=S reduced the yield of the desired product 6a, presumably
through the undesired oxidation of the terminal sulfide
group (entry 5). Although slightly better yields were ob-
tained for compound 4, we selected compound 2 as our
phosphorothiolate of choice, because of the wider availabil-
ity of methods to access this particular moiety. Although
several protocols can lead to Ar-S-P(O)(OEt)2, we utilized
the methods reported by Gooen and Zhao to access our
starting materials 2b–m.20
B. Current synthetically viable strategies to access Ar-SF5: via Ar-SF4Cl
F
F
S
Cl
SF5
F–
FG
F
R
R
R
R
F
O
TCICA
KF
cat. TFA
S
R
N
S
R
S
O
MeCN, rt
[1–3 steps]
SH
F
F
S
Cl
ZnX
R
F
R
R
F
Ar-SF4Cl
thiophenols
arylzinc reagents
C. This work: Arylphosphorothiolates as unified entry points for oxidation
SF5
H
N2
I
R
X
R
R
R
R
SEAr methods
Ar-SF5
aryldiazonium
aryl iodides
SH
[modular starting materials]
[facile access]
F
[convergent strategy]
thiophenols
B(OH)2
O
S
F
F
Cl
F
known
methods
P
S
F
R
OR
[ox]
RO
R
R
aryl
phosphorothiolates
boronic acids
Ar-SF4Cl
TFA (10 mol%)
TCICA (18 equiv)
KF (32 equiv)
F
S
F
Cl
F
F
X
SOxFy
S
Scheme 1 (A) Physical and chemical properties of Ar-SF5; (B) Current
strategies to access Ar-SF4Cl; (C) Use of aryl phosphorothiolates in oxi-
dative fluorination
P
+
R
MeCN, 25 °C
R
6a
7a
1–5
S
O
O
O
S
S
O
S
S
S
P
P
P
P
P
Ph
OPh
OPh
OMe
OMe
OEt
OEt
Ph
Ph
Ph
4
the aim of expanding the palette of opportunities in terms
of a wider spectrum of precursors, we focused our atten-
tion on the oxidative fluorination of aryl phosphorothio-
lates, en route to valuable Ar-SF4Cl (Scheme 1C).
1
2
3
5
yield (%)b (6a+7)
entry
starting Ar-S-PR3
ratiob (6a/7)
1
2
3
4
5
71:28
75:25
<5:24
82:18
43:43
1
2
3
4
5
>99
>99
25
>99
86
Indeed, aryl phosphorothiolates can be accessed
through a variety of different starting materials and their
synthesis has been widely explored. For example, Ar-S-
P(O)(OR)2 can be easily accessed in one step from thiophe-
nols by the simple reaction with H-P(O)(OR)2 or Cl-
P(O)(OR)2.18 Schoenebeck has recently shown that Ar-S-
P(O)(OR)2 can also be easily accessed via palladium catalysis
from the parent aryl iodides.19 Additionally, Gooen and
Tang have developed protocols which enable the synthesis
of aryl phosphorothiolates through SEAr from electron-rich
arenes or via Cu-catalyzed/mediated cross-coupling from
the corresponding diazonium salt or boronic acid.20 The
Scheme 2 Optimization of the reaction conditions. a Combined inte-
gration for Ph-SF3 and Ph-SOF3. b Yields determined by 19F NMR spec-
troscopy with ,,-trifluorotoluene as internal standard.
With this optimization in hand, we scrutinized the
scope of this transformation. As depicted in Scheme 3, the
method functioned well in the presence of halogens. For ex-
ample, aryl groups substituted with p-Br (6b), p-Cl (6c), p-F
(6d), or multiple halogens (6e) afforded good yields of the
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E

C
L. Wang et al.
Special Topic
Synthesis
corresponding Ar-SF4Cl 6. Product 6f with an alkyl groups
in the meta position of the ring was smoothly obtained in
51% yield. Aromatic substituents were also tolerated, as ex-
emplified by 6g (52%). The presence of other electron-with-
drawing substituents such as CF3 both in the meta (6h) and
para (6i) positions did not present any hurdles in the oxida-
tive fluorination. When CN or NO2 groups are attached to
the aryl ring, good yields of the desired Ar-SF4Cl products 6j
and 6k were also obtained. Interestingly, the presence of an
ester did not pose any hurdle, affording 6l in excellent yield.
Unfortunately, the methodology met its limitations when
alkyl aryl ketones are present, affording only traces of 6m.
This is probably due to side reactions on the -carbon. As
noticed in previous works, Ar-SF4Cl compounds are highly
reactive and their isolation is extremely challenging. There-
fore, the yields were calculated by 19F NMR spectroscopy by
using an internal standard.
quired.21 With these potential issues in mind, we developed
a proof-of-concept protocol for the Cl-F exchange using BF4
anions. To exemplify this possibility, compound 6b was
mixed with AgBF4 (2.0 equiv) in DCM at 100 °C; 8 was
smoothly formed in 49% yield from 2b, which is obtained
from (4-bromophenyl)boronic acid (Scheme 4). Although
this process resembles the silver-induced self-immolative
protocol using Ag2CO3, more information is required to pro-
vide a full mechanistic rationale by which this last Cl-F ex-
change occurs.22
F
as in
Scheme 3
AgBF4
(2.0 equiv)
Cl
F
F
SF5
O
S
S
F
P
OEt
DCM, 100 °C
48 h
EtO
Br
Br
Br
2b
1 step from boronic acid
6b
0.1 mmol
8
49%
Scheme 4 Cl-F exchange protocol based on AgBF4 to access Ar-SF5
TFA (10 mol%)
TCICA (18 equiv)
KF (32 equiv)
F
S
F
Cl
F
F
O
S
P
In conclusion, we have developed an oxidative fluorina-
tion protocol that converts Ar-S-P(O)(OR)2 to Ar-SF4Cl in a
practical manner. This new protocol broadens the palette of
starting materials to access Ar-SF5 compounds, whose prac-
tical synthesis is still highly coveted by practitioners in me-
dicinal and agrochemical sciences. Although these results
are still far from ideal, we believe that they provide a step
forward in the field and will be an incentive for the devel-
opment of even more practical methods, finally leading to
routine investigations of Ar-SF5 compounds in drug discov-
ery campaigns.
OEt
OEt
R
R
MeCN, 25 °C
2b–p
6b–m
F
F
F
F
S
F
Cl
Cl
F
F
Cl
F
F
S
S
F
F
F
F
Cl
Br
6b, 72% (51%)a
6d, 56%
6c, 68%
F
F
F
F
Cl
F
F
Cl
F
Cl
F
F
Cl
S
F
Ph
S
Me
S
F
F
F
6f, 51%
6g, 52%
6e, 71%
F
F
F
F
F
S
F
Cl
F
Cl
Cl
F
S
S
F3C
Unless stated otherwise, all manipulations were performed using
standard Schlenk techniques under anhydrous argon in flame-dried
glassware. Anhydrous solvents were distilled from appropriate drying
agents and were transferred under argon: MeCN (CaH2), DCM (CaH2),
hexane (Na/K), Et3N (MS). Unless stated otherwise, all chemicals were
purchased from Sigma-Aldrich, Alpha Aesar, and TCI and used with-
out prior drying or purification. Cu(OTf)2 (34946-82-2) and Cs2CO3
(534-17-8) were purchased from Sigma-Aldrich and stored under ar-
gon. Trichloroisocyanuric acid (TCICA, powder, 87-90-1) was pur-
chased from Alpha Aesar and transferred in an argon-filled glovebox
before usage. Potassium fluoride (KF, powder, 7789-23-3) was pur-
chased from Sigma-Aldrich, rigorously dried under high vacuum (10–6
mbar) at 120 °C for 24 h, and stored under argon. Flash chromatogra-
phy was performed on Merck silica gel 60 (40–63 m). GC-MS (FID)
was carried out on a GC-MS-QP2010 equipped instrument (Shimadzu
Europe Analytical Instruments). NMR spectra were recorded using a
Bruker Avance VIII-300 spectrometer. 1H NMR spectra (300.13 MHz)
were referenced to the residual protons of the deuterated solvent
used. All 19F NMR spectra were acquired on a 300 MHz spectrometer.
For 19F NMR yield determination, ,,-trifluorotoluene was used as
internal standard (19F,  = –63.10 in CD3CN). 13C{1H} NMR spectra
(75.47 MHz) were referenced internally to the D-coupled 13C reso-
nances of the NMR solvent. The 12 mL PTFE vials were purchased
from AHF Analysentechnik in Tübingen, Germany.
F
F
F
F
NC
F3C
6i, 56%
6h, 75%
6j, 76%
F
F
F
F
S
F
F
F
Cl
F
F
Cl
F
S
S
O2N
F
F
F
Me
MeO
O
O
6m, 5%
6l, 70%
6k, 74%
Scheme 3 Scope of the reaction for aryl tetrafluorosulfanyl chlorides.
Reagents and conditions: Ar-S-P(O)(OEt)2 (0.2 mmol, 1.0 equiv), tri-
chloroisocyanuric acid (TCICA, 18 equiv), rigorously dried KF (32 equiv),
0.1 M TFA in MeCN (0.2 mL), MeCN (2 mL), in a PTFE vessel, 25 °C, un-
der argon, 24 h; yields calculated by 19F NMR using ,,-trifluorotolu-
ene as reference. a Reaction performed on 1.0 mmol scale.
Having shown the viability of aryl phosphorothiolates
as precursors to access Ar-SF4Cl, we decided to explore
whether the protocol was suited for the formation of Ar-
SF5. It is important to mention that the byproducts formed
during oxidative fluorination are P(V) fluoro compounds,
which could potentially affect the Cl-F exchange and gener-
ate side reactions through the additional fluorides re-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–E

D
L. Wang et al.
Special Topic
Synthesis
Ar-SF4Cl 6; General Procedure
Acknowledgment
In a glovebox under argon, the appropriate Ar-S-P(O)(OEt)2 precursor
2 (0.2 mmol, 1 equiv), TCICA (840 mg, 3.6 mmol, 18 equiv), and rigor-
ously dried KF (372 mg, 6.4 mmol, 32 equiv) were added to an oven-
dried 12 mL PTFE reaction vial equipped with a stir bar. Under vigor-
ous stirring, anhydrous and degassed MeCN (2.0 mL) was added to the
mixture, followed by the addition of a 0.1 M solution of TFA in MeCN
(0.2 mL). Then the vial was sealed with a septum-pad cap and the re-
action was stirred at rt in the glovebox for 24 h. After this time, the
atmosphere in the vial was vented carefully and the internal standard
,,-trifluorotoluene was added into the mixture. After 10 min of
stirring, an aliquot of the resulting solution was filtered under argon.
The NMR sample was prepared with the filtered aliquot (0.4 mL) and
CD3CN (0.1 mL) for 19F NMR yield determination. Please note that, al-
though Ar-SF4Cl is not too sensitive to moisture, the use of dry reac-
tion vials and anhydrous solvent, as well as carrying out the experi-
ment and workup under argon benefited the reaction. See Supporting
Information for NMR analysis.
We are thankful to all analytical services at the MPI Kohlenforschung
for help. In particular, we are grateful to Dr. M. Leutzsch and the NMR
Department for help in structure elucidation. We are thankful to Prof.
Dr. A. Fürstner for discussions and generous support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706039. Su
p
p
ortingI
n
formatio
n
S
u
p
p
ortingInformati
o
n
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1H NMR (298 K, 300 MHz, CDCl3):  = 7.55–7.48 (m, 4 H).
19F{1H} NMR (298 K, 282 MHz, CDCl3):  = 83.5 (m, 1 F), 63.0 (d, J =
150.3 Hz, 4 F).
13C NMR (298 K, 75 MHz, CDCl3):  = 152.6 (m), 131.9, 127.6 (quin, J =
4.7 Hz), 126.1.
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Conflict of Interest
The authors declare no conflict of interest.
Funding Information
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Pentafluorosulfanylation of Aromatics and Heteroaromatics, In
Financial support for this work was provided by the Max-Planck-Ge-
sellschaft, the Max-Planck-Institut für Kohlenforschung, and the
Fonds der Chemischen Industrie (VCI). This work was also supported
by an Exploration Grant of the Boehringer Ingelheim Foundation
(BIS).Max-Planck-Geselschaft()Verban
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L. Wang et al.
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