Arylsulfonyl fluoride boronic acids: Preparation and coupling reactivity

Article abstract of DOI:10.1016/j.tet.2019.130782

We report the efficient and practical syntheses of ortho-, meta, and para-sulfonyl fluoride substituted benzene boronic acids. The syntheses of the para- and meta-isomers commence with the appropriate bromo-substituted benzenesulfonyl chlorides, and the o

Full text of DOI:10.1016/j.tet.2019.130782

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Arylsulfonyl fluoride boronic acids: Preparation and coupling reactivity
Terry Shing-Bong Lou, Michael C. Willis
PII:
S0040-4020(19)31178-0
https://doi.org/10.1016/j.tet.2019.130782
TET 130782
DOI:
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To appear in: Tetrahedron
Received Date: 21 September 2019
Revised Date: 2 November 2019
Accepted Date: 8 November 2019
Please cite this article as: Lou TS-B, Willis MC, Arylsulfonyl fluoride boronic acids: Preparation and
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Arylsulfonyl fluoride boronic acids:
Preparation and coupling reactivity
Leave this area blank for abstract info.
Terry Shing-Bong Lou, and Michael C. Willis
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK

1
Tetrahedron
journal homepage: www.elsevier.com
Arylsulfonyl fluoride boronic acids: Preparation and coupling reactivity
*
Terry Shing-Bong Lou, and Michael C. Willis
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
This paper is dedicated to Professor Steve Davies in recognition of his contributions to organic chemistry
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report the efficient and practical syntheses of ortho-, meta, and para-sulfonyl fluoride
substituted benzene boronic acids. The syntheses of the para- and meta-isomers commence with
the appropriate bromo-substituted benzenesulfonyl chlorides, and the ortho-isomer is prepared
from benzenesulfonyl fluoride. The para- and meta-substituted boronic acids undergo efficient
Sukuki-Miyaura coupling reactions with a range of aryl halides. We also report an efficient
Rh(I)-catalyzed conjugate addition reaction using the para-substituted boronic acid.
Available online
Keywords:
Boronic acid
Sulfonyl fluoride
Palladium
Rhodium
2
019 Elsevier Ltd. All rights reserved.
1
. Introduction
6. In addition, sulfonyl chlorides can often show limited stability,
7
and can be challenging to prepare and purify. Sulfonates, and
The balance of reactivity and stability available in sulfony1l
8
various sulfonate-derivatives such as sulfonylhydrazides, can
fluorides has made them popular motifs in medicinal chemistry
and chemical biology. Their stability to physiological
hydrolysis, their utility in SuFEx click chemistry, and the ability
to act as fluorinating reagents, has resulted in a variety of
applications. Scheme 1 illustrates this with examples of serine
also be transformed into sulfonyl flourides, although these
approaches can be limited by the availability of the required
substrates. Aryl halides and alkenyl triflates have been exploited
as sulfonyl fluoride precursors via palladium-catalyzed
2
3
9
sulfination chemistry, using sulfur dioxide surrogates, followed
4
10
protease inhibitors (AEBSF, Pefabloc and PMSF), the probe
reagent FBSA, and Doyle’s PyFluor fluorinating reagent.
by electrophilic fluorination. Sulfonyl fluoride synthesis by the
5
6
1
1
electrochemical oxidation of thiols has recently been reported.
O
O
F
O
O
F
The chemical stability present in sulfonyl flourides has allowed
alternative approaches to these motifs based on the
functionalization of molecules containing a pre-existing sulfonyl
fluoride functional group. A useful example of this is the use of
ethenesulfonyl fluoride (ESF) in a variety of conjugate addition-
S
S
O
O
F
Ph
S
H N
2
H2N
•HCl
Pefabloc
AEBSF
O
PMSF
12
N
type processes. The stability of sulfonyl fluorides has also been
exploited in a number of transition metal-catalyzed reactions, and
this chemistry has recently been reviewed by Chinthakindi and
N
NH
2
O
O
O
F
N
N
S
13
O
Arvidsson. Reaction 1 of Scheme 2 is illustrative, and shows
N
ESF being employed as the alkene component in a Heck coupling
HO
OH
O
14
with an aryl halide. Related Heck-type reactions using aryl
S
O
FSBA
PyFluor
15
16
F
boronic acids, and also aryl diazonium salts, both in
combination with ESF and palladium catalysts have also been
reported. Aryl halides substituted with sulfonyl fluorides have
been used as cross-coupling partners in Suzuki-Miyaura reactions
Scheme 1. Sulfonyl fluorides in medicinal chemistry, as chemical
probes, and as fluorinating reagents.
1
7
(
(
reaction 2, Scheme 2), in Sonogashira coupling reactions
The most common method to prepare sulfonyl fluorides is by
chloride to fluoride exchange using the corresponding sulfonyl
chlorides. These reactions typically use toxic potassium
bifluoride, or potassium fluoride in combination with 18-crown-
2a 2d
reaction 3, Scheme 2), in Stille coupling, and in a Negishi
17b
cross-coupling reaction with diethylzinc. In addition to these
palladium-catalyzed processes, sulfonyl fluorides have also been

2
2aTetrahedron
18
shown to be tolerant to certain copper-, iridium-, and
lithiation of benzenesulfonyl fluoride was achieved using LDA,
19
rhodium-catalyzed reactions.
and in situ quenching with isopropyl borate then provided the
22
corresponding boronic ester, which was treated directly with
aqueous HCl to provide ortho-benzenesulfonyl fluoride boronic
acid (3c) in 59% yield for this one-pot operation (Scheme 4c).
O
O
Pd(OAc)2
AgTFA
Me
Br
Br
Me
Br
S
O
O
F
(1)
(2)
F
S
acetone, 60 °C
99%
a)
Me
Me
Me
Me
O
O
O
O
B
B
O
O
F
O
O
Me
Me
Me
Me
Pd(OAc)
Et
O, rt, 97%
2
S
B(OH)
2
S
F
O
O
3
N
O
O
F
Pd(dppf)Cl2 (3 mol%)
S
S
H
2
Cl KHF2 (2.3 equiv)
KOAc (3 equiv)
Br
dioxane
80 °C , 2 h
CH
3
2
CN/H O (2:1)
rt, 6 h
Br
Br
1a, 98%
O
O
I
S
2
3
Me Si
PdCl
CuI, NEt3
2
(PPh
3
)
O
O
F
(3)
O
O
F
O
O
Me Si
S
3
F
S
NH OAc (5 equiv)
NaIO4 (4 equiv)
S
4
F
THF, rt
95%
Br
HO
O
B
OH 3a, 64%
acetone/H
2
O (1:1)
B
Me
Me
Me
Br
rt, 24 h
O
2a, 88%
Scheme 2. Sulfonyl fluorides containing molecules in palladium-
catalyzed reactions.
Me
b)
c)
OH
B
O
O
F
Although sulfonyl fluoride-substituted aryl halides have been
used in Suzuki-Miyaura cross-coupling reactions (reaction 1,
Scheme 2), the corresponding sulfonyl fluoride-substituted aryl
boronic acids have not been reported, although one example of a
O
O
S
as above
Br
S
HO
Cl
(
99%, 73%, 80%)
3
b
2a
boronic ester is known. Given the tolerance of sulfonyl
fluorides to a variety of palladium-catalyzed reactions, as well as
other metal-mediated processes, together with the widespread use
of Suzuki-Miyaura reactions in synthetic chemistry, we reasoned
that such boronic acids would be useful reagents, and would add
to the repertoire of methods available for the introduction of a
sulfonyl fluoride group. Introducing sulfonyl fluorides by way of
an aryl boronic acid reagent would also allow combination with
the vast number of commercially available aryl halides. In this
paper we report the efficient preparation of ortho-, meta-, and
para-benzenesulfonyl fluoride boronic acids, together with their
reactivity in coupling reactions (Scheme 3).
O
O
F
O
O
LDA (1.2 equiv)
Oi-Pr THF, -78 °C, 30 min
S
B
S
i-PrO
B
F
then
OH
Oi-Pr
aq. HCl, rt, 30 min
OH
c, 59%
3
Scheme 4. Preparation of benzenesulfonyl fluoride boronic acids
a-c.
3
The routes presented in Scheme 4 employ readily available
starting materials and allowed gram-scale quantities of the
targeted sulfonyl fluoride boronic acids to be obtained. However,
we also wanted to explore a route based on the catalytic
sulfination of a substrate featuring an intact boron-substituent.
Accordingly, para-bromo-substituted aryl pinocolate boronic
R
O
B(OH)
2
Pd cat.
O
S
R
O
S
O
F
Br
F
ester
conditions,
4 was subjected to palladium-catalyzed sulfination
10
followed by trapping with the electrophilic
Scheme 3. This work: Benzenesulfonyl fluoride boronic acids
and their coupling chemistry.
fluorinating reagent NFSI, to provide boronic ester substituted
sulfonyl fluoride 2a in 67% yield. This complementary route to
boronic ester 2a provides an alternative entry to these sulfonyl
fluorides, and could find application when late-stage introduction
of the sulfur functional group is needed.
2
. Results and discussion
The synthesis of the para-benzenesulfonyl fluoride boronic
acid starts from para-bromobenzenesulfonyl chloride, selected
for its ready availability and low-cost. Conversion of the sulfonyl
chloride group into the corresponding sulfonyl fluoride was
O
2
S N
N SO
2
PdCl (AmPhos) (5 mol%)
O
O
F
achieved by treatment with KHF in aqueous acetonitrile at room
Br
2
2
2
S
3a
Et N
3
i-PrOH, 75°C, 24 h
temperature, and provided sulfonyl fluoride 1a in 98% yield
Scheme 4a). Miyaura borylation using B pin with Pd(dppf)Cl
O
Me
Me
B
O
(
2
2
2
then
B
Me
Me
Me
20
O
as catalyst delivered boronic ester 2a in 88% yield. Hydrolysis
of the boronic ester to liberate the target boronic acid (3a) was
achieved using ammonium acetate and sodium periodate in 64%
NFSI, rt, 3 h
O
4
2a, 67%
Me
Me
Me
Me
2
N
PCy
2
21
yield.
para-Benzenesulfonyl fluoride boronic acid 3a was
AmPhos
purified by trituration with a hexane/dichloromethane mixture.
An identical sequence was completed starting from the meta-
sulfonyl chloride, ultimately providing meta-benzenesulfonyl
fluoride boronic acid 3b (Scheme 4b). The ortho-isomer required
an alternative route, and the developed synthesis started with
commercially available benzenesulfonyl fluoride. Ortho-
Scheme 5. Sulfonyl fluoride synthesis starting from pinocolate
boronic ester 5.

3
With the three key sulfonyl fluoride substituted boronic acids
available, we next explored their use in Suzuki-Miyaura coupling
reactions. We optimized reaction conditions using the coupling
between para-substituted boronic acid 3a, and 6-bromoquinoline
The optimized reaction conditions were then applied to a
range of aryl halide coupling partners, initially using para-
substituted boronic acid 3a as the fixed component (Table 2). As
can be seen, in addition to 6-bromoquinoline (5a), a range of
alternative heterocycles could also be successfully employed,
including 3-bromoquinoline (5b), a 3-bromopyridine (5c), a 3-
bromothiophene (5d), and a 4-bromopyrazole (5e). Electron-rich
and sterically demanding aryl bromides (5f and 5g) could be
employed, as could a 4-sulfonamide-substituted example (5h).
We then employed several more complex aryl halide coupling
partners of established worth in medicinal chemistry. For
example, the aryl fragments in products 5i, 5j and 5k (a 3-
bromopyridine) are present in Sildenafil, Celecoxib, and
Omipalisib, respectively. Meta-sulfonyl fluoride substituted
boronic acid 3b could be used in coupling reactions under
identical reaction conditions, and products 5l and 5m were
obtained in good yields in this way. Product 5m was obtained
using the aryl chloride as the coupling partner, demonstrating that
these less reactive aryl halides can be employed providing that an
activating substituent, such as trifluoromethyl in this case, is
present. The final example in Table 2 shows that the ortho-
substituted boronic acid (3c) was significantly more challenging
to engage in coupling chemistry than the corresponding para-
and meta-isomers. Using the conditions that were successful for
the para- and meta-isomers resulted in rapid decomposition of
the ortho-sulfonyl fluoride substituted boronic acid. However, the
use of KF as base in THF as solvent at room temperature (initial
(
Table 1). We evaluated a range of phosphine ligands, using
Pd(OAc) as the palladium source, and K PO as base, using
2
3
4
dioxane as solvent, initially at 60 °C. Yields were recorded after
hours, and 22 hours, with the latter being used to gauge any
2
decomposition of the product under the reaction conditions.
Entries 1-7 show that XPhos, SPhos, RuPhos and AmPhos (in
this case used as a preformed complex) all performed well under
these conditions. XPhos and AmPhos were then evaluated at
lower temperatures, with both performing well at 40 °C (entries 8
and 9). At 25 °C only XPhos was effective, with the AmPhos
system delivering only a low conversion (entries 10 and 11). All
entries to this point had used 2.0 equivalents of boronic acid;
entry 12 shows that using 1.5 equivalents of boronic acid can
achieve good conversion after 4 hours reaction at 40 °C, with
minimal decomposition being observed after 22 hours. This final
entry represents the conditions that were taken forward.
23
Table 1. Optimization of the coupling between boronic acid 3a
a
and 6-Br-quinoline.
O
O
F
Br
[
Pd] (5 mol%)
L (10 mol%)
S
N
O
O
F
+
K PO (2 equiv)
3 4
temperature
dioxane, 2 h
S
24
addition at 40 °C), along with an increased amount of palladium
catalyst, did restore some reactivity; after 12 hours reaction with
N
(
2
HO) B
3
a
5a
6
-bromoquinoline, coupled product 5n was obtained in 43%
yield.
Para-substituted sulfonyl fluoride boronic ester 2a could also
be used as a reaction partner in Suzuki-Miyaura coupling
processes, although reduced reactivity, relative to the boronic
acid was observed. For example, using the standard conditions, a
reaction time of 20 hours was needed to achieve an 80% yield of
biaryl 5a. In contrast, boronic acid 3a delivered coupled product
b
b
Entry
[Pd]
L
Temp. Yield
2 h)
Yield
(
(22 h)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
-
60 °C
XPhos 60 °C
SPhos 60 °C
RuPhos 60 °C
40%
92%
95%
96%
69%
29%
99%
99%
99%
38%
85%
85%
75%
60%
53%
92%
98%
93%
99%
-
5
a in 91% yield after 4 hours reaction.
PCy3
60 °C
60 °C
60 °C
40 °C
40 °C
25 °C
25 °C
40 °C
-
PdCl (AmPhos)
-
XPhos
-
2
2
2
2
Pd(OAc)2
PdCl (AmPhos)
2
c
1
1
1
0
1
2
Pd(OAc)2
XPhos
-
81%
PdCl (AmPhos)
10%
2
d
Pd(OAc)2
XPhos
94%
93%
a. Reaction conditions: Aryl halide (0.075 mmol, 1.0 equiv), boronic acid
2.0 equiv), [Pd] (5 mol%), L (10 mol%), K PO (1 M aq) (2.0 equiv),
(
3
4
dioxane [0.25 M], at given temperature. b. Yield determined by HPLC against
internal standard. c. 24 hours reaction. d. 4 hours reaction, using 1.5 equiv of
boronic acid.
PCy
2
PCy
OMe
2
PCy
Oi-Pr
2
i-Pr
i-Pr
MeO
i-PrO
i-Pr
XPhos
SPhos
RuPhos

4
Tetrahedron
a
Table 2. Suzuki-Miyaura couplings of boronic acids 3a-c.
Pd(OAc)2 (5 mol%)
XPhos (10 mol%)
K3PO4 (2 equiv)
Br
SO2F
SO2F
R
+
dioxane/H O (2:1)
R
(HO)2B
2
X
4
0 °C , 4-6 h
X
(
1 equiv)
(1.5 equiv)
5
SO2F
SO2F
SO2F
SO2F
N
N
S
Me
N
N
N
O
Boc
5
a, 91%
5b, 80%
5c, 80%
SO2F
5d, 87%
SO2F
(80% using Bpin ester)
SO2F
SO2F
Me
O
O
N
N
Me
H N
2
Me
S
O O
5g, 67%
5e, 43%
5f, 93%
5h, 73%
(
17% from ArCl)
Me
SO2F
F
F
O
N
Me
SO2F
O
O
N
SO2F
NH
S
N
HN
N
N
n-Pr
EtO
i, 62%
MeO
N
F3C
5
5j, 95%
5k, 42%b
SO2F
N
3
F C
SO2F
SO2F
N
5l, 91%
5m, 64%c
5n, 43%d
a. Reaction conditions: Aryl halide (1.0 equiv), boronic acid (1.5 equiv), Pd(OAc)
h. Isolated yields. b. 24 hours. c. Using aryl chloride substrate. d. Aryl halide (1.0 equiv), boronic acid (1.5 equiv), Pd(OAc)
3.3 equiv), THF, 40 °C, 0.5 h, then
2
(5 mol%), XPhos (10 mol%), K
3
PO
4
(1 M aq) (2.0 equiv), dioxane, 40 °C, 4-6
(20 mol%), XPhos (40 mol%), KF
25 °C, 12 h.
2
(
The rhodium(I)-catalyzed conjugate addition of aryl boronic
acids to electron-poor alkenes represents a further useful C-C
acids. These boronic acids undergo efficient Sukuki-Miyaura
coupling reactions, and we have also achieved an efficient Rh(I)-
catalyzed conjugate addition reaction. These syntheses and
reactions provide new methods for the installation of arylsulfonyl
fluoride groups and should find applications in medicinal
chemistry and chemical biology.
25
bond-forming reaction that employs boronic acids,
and
accordingly, we were interested in whether sulfonyl fluoride
substituted examples would engage in these types of reactions.
Scheme 6 shows that para-substituted boronic acid 3a was a
competent nucleophile in the addition to cyclohexenone using a
simple Rh(I) catalyst, providing the β-substituted ketone 6 in
4. Experimental
7
4% yield.
4
.1. General information
O
[
Rh(COD)(CH
5 mol%)
CO (1 equiv)
3
CN)
2
]BF
4
1
11
13
19
SO
2
F
H, B, C, and F NMR spectra were obtained on a Brüker
(
O
AVIII400 (400 MHz) or AVII (500 MHz) spectrometer. Proton-
decoupled spectra are denoted as { H}. Chemical shifts (δ) were
K
2
3
1
+
dioxane/H O (9:1)
2
5
5 °C , 2 h
reported in parts per million (ppm) using the residual solvent
SO2F
B(OH)
2
signal as an internal standard (CDCl : δ = 7.26 ppm, δ = 77.16
3
H
C
(
1 equiv)
3a (2 equiv)
6, 74%
ppm). All coupling constants (J values) were reported in Hertz
(Hz). Multiplicities were reported as follows: s, singlet; d,
doublet; t, triplet; q, quartet; quin., quintet; m, multiplet. High-
resolution mass spectrometry (HRMS) measurements were
recorded on a Bruker Daltronics microTOF (ESI) spectrometer.
Infrared spectra were recorded as thin films on a Bruker Tensor
Scheme 6. Rhodium(I)-catalyzed addition of boronic acid 3a to
cyclohexenone.
3
. Conclusions
2
7 FT-IR spectrometer. Flash chromatography was carried out
We have reported efficient and practical syntheses of ortho-,
meta, and para-sulfonyl fluoride substituted benzene boronic
using matrix 60 silica.

5
4
.2. Synthesis of bromobenzenesulfonyl fluorides
.2.1. General procedure
To a solution of KHF (2.3 equiv) in deionized water (2
Pd(dppf)Cl ·CH Cl (0.49 g, 0.60 mmol, 3 mol%), KOAc
(
2 2 2
5.88 g, 60.0 mmol, 3.0 equiv) and 1,4-dioxane (60 mL). The
4
crude product was purified by flash column chromatography (10–
30% EtOAc in petrol) to afford the corresponding sulfonyl
fluoride 2a as a white solid (5.06 g), 88% yield. mp 129–130 °C
(Et O); R 0.23 (10% EtOAc in hexane) [KMnO /UV]; H NMR
400 MHz, CDCl ) δ 8.05–8.02 (m, 2H), 8.00–7.96 (m, 2H), 1.36
M)
2
was added a solution of bromobenzenesulfonyl chloride (1 equiv)
in CH CN (1 ). The reaction was stirred at ambient temperature
for 24 h. The two phases were separated and the aqueous layer
was extracted with EtOAc three times. The combined organic
1
M
3
2
f
4
(
3
11
1
(
s, 12H);
B { H} NMR (128 MHz, CDCl3) δ 2 30.3;
1
3
1
extracts were washed with brine, dried with anhydrous MgSO4,
C { H} NMR (101 MHz, CDCl ) δ 135.8, 135.2 (d, JCF
3.9 Hz), 127.4, 84.9, 25.0 (1C missing);
=
3
19
1
filtered and concentrated in vacuo. The crude product was further
purified by flash column chromatography if required to afford the
corresponding bromobenzenesulfonyl fluoride.
2
(
F { H} NMR
-
1
377 MHz, CDCl ) δ 65.7; IR ν (neat)/cm 2976, 1396, 1357,
3 max
1
213, 1140, 1080, 853, 768; HRMS (ESI/APCI/EI) not found.
4
.2.2. 4-Bromobenzenesulfonyl fluoride (1a)
4
.3.3. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
Prepared according to general procedure, using 4-
yl)benzenesulfonyl fluoride (2b)
bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol, 1.0 equiv),
KHF (7.0 g, 90 mmol, 2.3 equiv), deionized water (20 mL) and
Prepared according to general procedure using 3-
bromobenzenesulfonyl fluoride (1.67 g, 7.0 mmol, 1.0 equiv),
B (pin)2 (1.96 g, 7.7 mmol, 1.1 equiv), Pd(dppf)Cl ·CH Cl
(172 mg, 0.21 mmol, 3 mol%), KOAc (2.06 g, 21 mmol,
3.0 equiv) and 1,4-dioxane (25 mL). The crude product was
purified by flash column chromatography (5–20% EtOAc in
petrol) to afford the corresponding sulfonyl fluoride 2b as a white
2
CH CN (40 mL) to afford the corresponding sulfonyl fluoride 1a
3
2
2
2
2
as a white solid (9.16 g), 98% yield. mp 66–67 °C (EtOAc); Rf
1
0
.46 (10% EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl )
3
δ 7.88 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H);
1
3
1
C { H} NMR (101 MHz, CDCl ) δ 133.3, 132.1 (d, J =
3
19
1
2
6
7
5.6 Hz), 131.5, 130.0; F { H} NMR (377 MHz, CDCl ) δ
3
-1
solid (1.47 g), 73% yield. mp 83–85 °C (pentane); R 0.21 (10%
f
1
6.4; IR νmax (neat)/cm 3097, 1574, 1406, 1393, 1211, 825, 779,
EtOAc in hexane) [KMnO /UV]; H NMR (400 MHz, CDCl ) δ
4
3
+ 79 + +
36; HRMS (EI ) m/z calc. for C H BrFO S [M] 237.9094,
8.44 (t, J = 1.4 Hz, 1H), 8.17 (d, J = 7.4 Hz, 1H), 8.07 (dt, J =
6
4
2
found 237.9092.
8
.0, 1.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 1.36 (s, 12H);
1
1
1
13
1
B { H} NMR (128 MHz, CDCl ) δ 30.2; C { H} NMR
3
(
101 MHz, CDCl ) δ 141.7, 134.6, 132.9 (d, J = 23.9 Hz), 130.7,
3
19
1
4
.2.3. 3-Bromobenzenesulfonyl fluoride (1b)
Prepared according to general procedure, using 3-
129.1, 84.9, 25.0 (1C missing);; F { H} NMR (377 MHz,
CDCl ) δ 65.8; IR νmax (neat)/cm 2980, 1600, 1406, 1353, 1208,
3
1142; HRMS (ESI) not found.
-1
bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol, 1.0 equiv),
KHF (1.4 g, 18 mmol, 2.3 equiv), deionized water (4 mL) and
2
CH CN (8 mL) to afford the corresponding sulfonyl fluoride 1b
3
as a pale yellow oil (1.78 g), 99% yield. R 0.38 (10% EtOAc in
4.4. Pd-catalyzed synthesis of benzenesulfonyl fluoride
boronic ester 2a from bromophenylboronic acid pinacol
ester, DABSO and NFSI
f
1
hexane) [UV]; H NMR (400 MHz, CDCl ) δ 8.15 (t, J = 1.9 Hz,
3
1
1
H), 7.98–7.94 (m, 1H), 7.93–7.89 (m, 1H), 7.53 (td, J = 8.0,
13 1
.1 Hz, 1H); C { H} NMR (101 MHz, CDCl ) δ 138.8, 134.8
3
19
1
A reaction tube was charged with 4-bromophenylboronic acid
pinacol ester (85 mg, 0.30 mmol, 1.0 equiv), DABSO (72 mg,
(d, J = 25.8 Hz), 131.4, 131.3, 127.1, 123.7; F { H} NMR
-1
(
8
2
377 MHz, CDCl ) δ 66.3; IR ν (neat)/cm 3091, 1410, 1209,
3 max
+ 79 + +
0.30 mmol, 1.0 equiv) and PdCl (AmPhos)2 (10.6 mg,
2
01, 786, 747; HRMS (EI ) m/z calc. for C H BrFO S [M]
6 4 2
37.9094, found 237.9077.
0
.015 mmol, 5.0 mol%), sealed with a rubber septum, evacuated
and back-filled with N2 three times. Anhydrous degassed
isopropanol (1.2 mL) and anhydrous triethylamine (0.13 mL,
0
.90 mmol, 3.0 equiv) were added subsequently, and the reaction
4
.3. Synthesis of benzenesulfonyl fluoride boronic acid
mixture was stirred under positive pressure of N in a preheated
2
pinacol esters from bromobenzenesulfonyl fluorides
aluminium heating block at 75 °C for 24 h. After cooling to
ambient temperature, NFSI (104 mg, 0.33 mmol, 1.1 equiv) was
added. The reaction mixture was stirred at ambient temperature
for 3 h until completion. The reaction mixture was then diluted
with EtOAc, filtered through a plug of Celite® and concentrated
in vacuo to yield the crude product which was then purified by
flash column chromatography (10–30% EtOAc in petrol),
affording the sulfonyl fluoride 2a as a white solid (57 mg), 67%
yield.
4
.3.1. General procedure
A
round bottom flask was charged with 4-
bromobenzenesulfonyl fluoride 1a (1 equiv), B (pin) (1.1 equiv),
Pd(dppf)Cl ·CH Cl (3 mol%) and KOAc (3 equiv), evacuated
and back-filled with N three times. Degassed anhydrous 1,4-
dioxane (0.33 M) was added and the reaction was stirred at 80 °C
for 16 h, then cooled to ambient temperature and concentrated in
vacuo. The mixture was diluted with EtOAc, washed sequentially
2
2
2
2
2
2
with water and brine, dried with anhydrous MgSO , filtered and
4
concentrated in vacuo. The crude product was purified by flash
column chromatography rapidly to afford the corresponding
benzenesulfonyl fluoride boronic acid pinacol ester.
4
.5. Synthesis of arylsulfonyl fluoride boronic acids from the
corresponding pinacolate boronic esters
4
.5.1. General procedure
4
-(Fluorosulfonyl)phenylboronic acid pinacol ester (1 equiv)
4
.3.2. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
was dissolved in acetone (0.2 ). A solution of NH OAc
5 equiv) in water (0.2
4 equiv). The mixture was stirred rigorously at ambient
temperature for 24 h, volatiles were then removed in vacuo and
M
4
yl)benzenesulfonyl fluoride (2a)
(
(
M) was then added, followed by NaIO4
Prepared according to general procedure, using 4-
bromobenzenesulfonyl fluoride 1a (4.78 g, 20.0 mmol,
1
.0 equiv),
B (pin)2
2
(5.59 g,
22.0 mmol,
1.1 equiv),

6
Tetrahedron
the residue was extracted with EtOAc. The organic layer was
temperature, 10% (v/v) aq. HCl (9 mL) was added and the
reaction was stirred at ambient temperature for 30 min. The
mixture was then diluted with EtOAc and the two phases were
separated. The aqueous extract was further extracted with EtOAc
three times and the combined organic extracts were dried over
anhydrous Na SO , filtered and concentrated in vacuo. The crude
washed with brine, and the combined aqueous extracts were
further extracted with EtOAc three times. The combined organic
extracts were dried over anhydrous Na SO , filtered and
concentrated in vacuo. The resultant solid was then triturated
with a mixture of hexane/CH Cl , followed by pentane to afford
2
4
2
2
2
4
the corresponding arylsulfonyl fluoride boronic acid.
product was purified by flash column chromatography (30–50%
EtOAc in petrol). The resultant oil was added with hexane and
sonicated to induce precipitation, which was then subsequently
4
.5.2. 4-(Fluorosulfonyl)phenylboronic acid (3a)
triturated with hexane, hexane/CH
Cl (5:1) and pentane to afford
2 2
the boronic acid 3c as a white solid (599 mg), 59% yield. mp 70–
Prepared according to general procedure, using 4-
fluorosulfonyl)phenylboronic acid pinacol ester 2a (1.2 g,
1
7
8
7
2 °C (CH Cl ); H NMR (400 MHz, CDCl ) δ 8.10 (d, J =
2 2 3
(
4
.1 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H),
.2 mmol, 1.0 equiv), NH OAc (1.64 g, 21 mmol, 5.0 equiv),
4
11
1
.67 (t, J = 7.4 Hz, 1H), 5.58 (br. s, 2H); B { H} NMR
NaIO (3.64 g, 17 mmol, 4.0 equiv), acetone (20 mL) and water
4
13
1
(128 MHz, CDCl ) δ 28.7; C { H} NMR (101 MHz, CDCl ) δ
(
(
20 mL). The crude product was triturated with hexane/CH Cl
3
3
2
2
1
36.2, 135.9 (d, J = 21.6 Hz), 135.0, 131.2 (br.), 130.8, 129.4;
1 -1
2:1), followed by pentane to afford the boronic acid 3a as a
19
F { H} NMR (377 MHz, CDCl ) δ 63.8; IR ν (neat)/cm
max
white solid (0.55 g), 64% yield. mp 240 °C (decomp.) (CH Cl );
3
2
2
−
1
3
387, 1394, 1332, 1207, 790, 763, 749; HRMS (ESI ) m/z calc.
H NMR (400 MHz, DMSO-d ) δ 8.58 (s, 2H), 8.14–8.07 (m,
6
− −
11
1
for C H BFO S [M−H] 202.9991, found 202.9991.
4
H); 1
B { H} NMR (126 MHz, DMSO-d6)
δ
27.7;
6
5
4
13
C { H} NMR (101 MHz, DMSO-d ) δ 143.9 (br.), 135.5, 132.6
6
19
1
(
6
1
d, J = 22.7 Hz), 127.0; F { H} NMR (377 MHz, DMSO-d ) δ
6
-1
4
.7. Suzuki-Miyaura Coupling (SMC) reactions
6.1; IR νmax (neat)/cm 2160, 1405, 1349, 1304, 1209, 1108,
−
−
075, 1015, 803, 785, 741; LRMS (ESI ) m/z 203.0 ([M−H] );
HRMS (ESI ) m/z calc. for C H BFO S [M−H] 202.9991,
−
−
−
4.7.1. General procedure
6
5
4
A reaction tube was charged with benzenesulfonyl fluoride
found 202.9990.
boronic acid 3 (61 mg, 0.30 mmol, 1.5 equiv), Pd(OAc) (2.3 mg,
2
0
1
.010 mmol, 5.0 mol%) and XPhos (9.5 mg, 0.020 mmol,
0 mol%), sealed with a rubber septum, evacuated and back-
4
.5.3. 3-(Fluorosulfonyl)phenylboronic acid (3b)
Prepared according to general procedure, using 3-
filled with N2 three times. Degassed 1,4-dioxane (0.8 mL),
degassed 1.0 M aq. K PO4 solution (0.4 mL, 0.40 mmol,
2
subsequently, and the reaction mixture stirred under positive
pressure of N in a preheated aluminium heating block at 40 °C
for 4 h (5a, b, f, g, h, l), 6 h (5c, d, e, i, j, m) or 24 h (5k). After
cooling to ambient temperature, the reaction mixture was diluted
3
(fluorosulfonyl)phenylboronic acid pinacol ester 2b (1.45 g,
.0 equiv) and aryl halide* (0.20 mmol, 1.0 equiv) were added
5
.1 mmol, 1.0 equiv), NH OAc (1.93 g, 25 mmol, 5.0 equiv),
4
NaIO (4.28 g, 20 mmol, 4.0 equiv), acetone (25 mL) and water
4
2
(25 mL). The crude product was triturate with hexane/CH Cl
2 2
(4:1), followed by pentane to afford the boronic acid 3b as a
1
white solid (0.83 g, 80%); mp 240 °C (decomp.) (CH Cl ); H
NMR (400 MHz, DMSO-d ) 8.58 (s, 2H), 8.46 (app. s, 1H), 8.29
2
2
with EtOAc, dried with anhydrous MgSO , filtered over Celite®
4
6
and concentrated in vacuo. The crude product was purified by
flash column chromatography to afford the biarylsulfonyl
fluoride.
(d, J = 7.5 Hz, 1H), 8.15 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.76 (t, J
11
1
=
7.7 Hz, 1H); B { H} NMR (128 MHz, DMSO-d ) δ 27.0;
6
13
1
C { H} NMR (126 MHz, DMSO-d ) δ 142.0, 137.0 (d, J =
6
2
0.8 Hz), 133.3, 131.1 (d, J = 22.3 Hz), 129.72, 129.70;
*In the case where aryl halide is a solid, it was added to the
vessel before evacuating and back-filling.
1
9
1
-1
F { H} NMR (377 MHz, DMSO-d ) δ 66.4; IR ν (neat)/cm
6
max
1
598, 1568, 1401, 1344, 1203, 1091, 841, 762, 721; HRMS
− − −
(ESI ) m/z calc. for C H BFO S [M−H] 202.9991, found
6 5 4
2
02.9988.
4.7.2. 4-(Quinolin-6-yl)benzenesulfonyl fluoride (5a)
White solid, 91% yield. mp 135–136 °C (CH Cl ); R 0.26
2
2
f
1
(
30% EtOAc in hexane) [KMnO /UV]; H NMR (400 MHz,
4
4
.6. Synthesis of 2-(fluorosulfonyl)phenylboronic acid (3c)
CDCl ) δ 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.28–8.23 (m, 2H),
3
through ortho-lithiation/borylation of benzenesulfonyl
fluoride
8
7
.15–8.12 (m, 2H), 8.07 (d, J = 2.1 Hz, 1H), 7.99–7.93 (m, 3H),
13 1
.49 (dd, J = 8.3, 4.2 Hz, 1H); C { H} NMR (101 MHz, CDCl )
3
δ 151.6, 148.4, 147.9, 136.7, 136.6, 132.1 (d, J = 24.9 Hz), 130.9,
Preparation of LDA solution
19
1
1
29.3, 128.7, 128.6, 128.5, 126.9, 122.2;
F { H} NMR
-
1
Diisopropylamine (0.92 mL, 6.6 mmol, 1.32 equiv) was
dissolved in anhydrous THF (6 mL) under N atmosphere and the
solution was cooled to 0 °C. A solution of n-BuLi (2.4
(377 MHz, CDCl ) δ 66.5; IR ν (neat)/cm 3071, 1591, 1406,
1212, 1193, 1097; LRMS (ESI ) m/z 288.0 ([M+H] ); HRMS
+ + +
3
max
+
+
2
M
in
(ESI ) m/z calc. for C H FNO S [M+H] 288.0489, found
15 11 2
hexane) (2.5 mL, 6.0 mmol, 1.2 equiv) was then added dropwise
and the mixture was stirred at 0 °C for 15 min.
288.0490.
Using boronic ester 2a: The general procedure was followed
with benzenesulfonyl fluoride boronic ester 2a (86 mg,
Ortho-lithiation/borylation
0
.30 mmol, 1.5 equiv) used in place of boronic acid 3a, and the
reaction mixture was stirred at 40 °C for 20 h. Upon purification,
biarylsulfonyl fluoride 5a was afforded as white solid
Under N2 atmosphere, benzenesulfonyl fluoride (0.60 mL,
5
.0 mmol, 1.0 equiv) was dissolved in anhydrous THF (5 mL)
and the solution was cooled to -78 °C. Triisopropyl borate
2.8 mL, 12 mmol, 2.4 equiv) was added to the solution, followed
a
(45.7 mg), 80% yield. Data as above.
(
by the slow addition of LDA solution prepared as described
above over 10 min and the reaction was stirred at -78 °C for
4
.7.3. 4-(Quinolin-3-yl)benzenesulfonyl fluoride (5b)
3
0 min. The reaction mixture was then warmed to ambient

7
White solid, 80% yield. mp 161–163 °C (CH Cl ); R 0.42
3079, 2922, 1594, 1505, 1477, 1442, 1405, 1223, 1209, 1186,
1100, 1033; HRMS (ESI) not found.
2
2
f
1
(
30% EtOAc in hexane) [KMnO /UV]; H NMR (400 MHz,
4
CDCl ) δ 9.19 (d, J = 2.4 Hz, 1H), 8.39 (dd, J = 2.4, 0.8 Hz, 1H),
3
8
.21–8.14 (m, 3H), 7.99–7.95 (m, 2H), 7.95–7.92 (m, 1H), 7.81
(
ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.65 (ddd, J = 8.2, 6.9, 1.2 Hz,
4.7.8. 2',6'-Dimethyl-[1,1'-biphenyl]-4-sulfonyl fluoride (5g)
13
1
1
1
1
H); C { H} NMR (101 MHz, CDCl ) δ 149.1, 148.3, 145.5,
3
White solid, 67% yield. mp 133–134 °C (CHCl ); R 0.56
3 f
1
34.6, 132.5 (d, J = 25.4 Hz), 131.4, 130.7, 129.6, 129.5, 128.6,
(
10% EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl ) δ
3
19
1
28.4, 127.8, 127.8; F { H} NMR (377 MHz, CDCl ) δ 66.5;
3
8.09 (dtd, J = 8.2, 2.0, 0.4 Hz, 2H), 7.44 (dtd, J = 8.6, 1.9,
0.9 Hz, 2H), 7.23 (dd, J = 8.4, 6.7 Hz, 1H), 7.16–7.13 (m, 2H),
-
1
+
IR νmax (neat)/cm 3606, 1595, 1403, 1216, 1097; LRMS (ESI )
m/z 288.0 ([M+H] ); HRMS (ESI ) m/z calc. for C H FNO S
[
+
+
+
13
1
15
11
2
2.01 (s, 6H); C { H} NMR (101 MHz, CDCl ) δ 149.6, 139.4,
3
+
M+H] 288.0489, found 288.0490.
1
35.4, 131.6 (d, J = 24.6 Hz), 130.8, 128.9, 128.3, 127.9, 20.9;
1
9
1
-1
F { H} NMR (377 MHz, CDCl ) δ 66.1; IR ν
(neat)/cm
3
max
3
088, 2966, 2923, 1590, 1464, 1403, 1208, 1179, 1163, 1092;
4
.7.4. tert-Butyl 4-(5-(4-(fluorosulfonyl)phenyl)pyridin-2-
HRMS (ESI) not found.
yl)piperazine-1-carboxylate (5c)
White solid, 80% yield. mp 198–200 °C (CHCl ); R 0.42
3
f
1
(
8
30% EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl ) δ
4.7.9. 4'-Sulfamoyl-[1,1'-biphenyl]-4-sulfonyl fluoride (5h)
3
.49 (dd, J = 2.6, 0.7 Hz, 1H), 8.04 (dt, J = 8.5, 2.1 Hz, 2H), 7.77
White solid, 73% yield. mp 181–183 °C (EtOAc); R 0.14
f
1
(dd, J = 8.1, 1.9 Hz, 1H), 7.75–7.72 (m, 2H), 6.74 (dd, J = 9.0,
(
30% EtOAc in hexane) [UV]; H NMR (400 MHz, DMSO-d ) δ
6
0
.8 Hz, 1H), 3.69–3.60 (m, 4H), 3.61–3.50 (m, 4H), 1.49 (s, 9H);
8
.25 (d, J = 8.6 Hz, 2H), 8.14 (d, J = 8.1 Hz, 2H), 8.02–7.95 (m,
13
1
13 1
C { H} NMR (101 MHz, CDCl ) δ 159.3, 154.9, 147.0, 145.9,
3
4H), 7.49 (s, 2H); C { H} NMR (101 MHz, CDCl ) δ 146.4,
3
1
4
36.3, 130.6 (d, J = 24.8 Hz), 129.3, 126.8, 123.4, 107.0, 80.3,
1
44.6, 140.7, 130.9 (d, J = 23.9 Hz), 129.2, 128.9, 128.1, 126.5;
19
1
19
1
-1
4.9, 43.3 (br.), 28.6; F { H} NMR (377 MHz, CDCl ) δ 66.6;
3
F { H} NMR (377 MHz, CDCl ) δ 66.6; IR ν
(neat)/cm
max
−
3
-
1
IR νmax (neat)/cm 2981, 2923, 1673, 1605, 1589, 1424, 1403,
1
HRMS (ESI ) m/z calc. for C H FN O S [M+H] 422.1544,
found 422.1548.
3367, 3263, 1594, 1404, 1329, 1215, 1153, 1097; LRMS (ESI )
m/z 313.9 ([M−H] ); HRMS (ESI ) m/z calc. for C H FNO S
4 2
[M−H] 313.9963, found 313.9961.
+
+
−
−
−
243, 1212, 1190, 1172; LRMS (ESI ) m/z 422.0 ([M+H] );
12
9
+
+
+
−
20
25
3
4
4
.7.10. 4'-Ethoxy-3'-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-
4
.7.5. 4-(2-Acetylthiophen-3-yl)benzenesulfonyl fluoride (5d)
Off-white solid, 87% yield. mp 127–129 °C (CHCl ); R 0.44
pyrazolo[4,3-d]pyrimidin-5-yl)-[1,1'-biphenyl]-4-sulfonyl
fluoride (5i)
3
f
1
(30% EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl ) δ
3
5-(5-Bromo-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-
H-pyrazolo[4,3-d]pyrimidin-7-one (39.1 mg, 0.10 mmol,
.0 equiv), 4-(fluorosulfonyl)phenylboronic acid 3a (31 mg,
8
7
.05 (dt, J = 8.5, 1.8 Hz, 2H), 7.66 (dtd, J = 8.8, 1.9, 0.8 Hz, 2H),
7
1
.61 (d, J = 5.1 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 2.39 (s, 3H);
13
1
C { H} NMR (101 MHz, CDCl ) δ 190.5, 144.3, 144.1, 138.9,
3
0.15 mmol, 1.5 equiv), Pd(OAc) (1.1 mg, 5.0 µmol, 5.0 mol%),
XPhos (4.8 mg, 10 µmol, 10 mol%), 1.0 M aq. K PO solution
(0.2 mL, 0.20 mmol, 2.0 equiv) and 1,4-dioxane (0.4 mL) were
used. Sulfonyl fluoride 5i was isolated as a white solid (29.0 mg),
62% yield. mp 176–178 °C (CHCl ); R 0.26 (50% EtOAc in
2
1
32.6 (d, J = 25.3 Hz), 131.9, 131.2, 130.7, 128.5, 29.9;
3
4
19
1
-1
F { H} NMR (377 MHz, CDCl ) δ 66.2; IR ν
(neat)/cm
+
3
max
3
2
105, 1672, 1402, 1274, 1209, 1186, 1095; LRMS (ESI ) m/z
85.0 ([M+H] ); HRMS (ESI ) m/z calc. for C H FO S
3 2
+
+
+
1
2
10
3
f
+
1
[
M+H] 285.0050, found 285.0051.
hexane) [KMnO /UV]; H NMR (400 MHz, CDCl ) δ 10.94 (s,
4
3
1
8
H), 8.67 (d, J = 2.5 Hz, 1H), 8.08–8.00 (m, 2H), 7.80 (dd, J =
.9, 0.8 Hz, 2H), 7.65 (dd, J = 8.6, 2.5 Hz, 1H), 7.11 (d, J =
4
.7.6. 4-(1-Methyl-1H-pyrazol-4-yl)benzenesulfonyl fluoride (5e)
White solid, 43% yield. mp 85–86 °C (CHCl ); R 0.29 (50%
8.7 Hz, 1H), 4.35–4.26 (m, 2H), 4.21 (s, 3H), 2.87 (dd, J = 8.0,
7.1 Hz, 2H), 1.80 (h, J = 7.4 Hz, 2H), 1.58 (t, J = 7.0 Hz, 3H),
0.96 (t, J = 7.4 Hz, 3H) (recorded as a mixture of tautomers at
3
f
1
EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl ) δ 7.98 (dt,
J = 8.5, 1.9 Hz, 2H), 7.85 (d, J = 0.9 Hz, 1H), 7.75 (d, J = 0.8 Hz,
3
13
1
ratio of 82:13:5); C { H} NMR (101 MHz, CDCl ) δ 157.3,
3
1
H), 7.67 (dtd, J = 8.8, 2.1, 1.0 Hz, 2H), 3.99 (s, 3H);
153.9, 147.8, 147.4, 146.9, 138.6, 132.2, 131.5 (d, J = 24.7 Hz),
13
1
C { H} NMR (101 MHz, CDCl ) δ 140.5, 137.5, 130.0 (d, J =
131.2, 130.3, 129.3, 128.0, 124.7, 121.2, 113.9, 65.9, 38.4, 27.9,
3
1
9
1
19
1
2
4.3 Hz), 129.4, 128.3, 126.0, 121.1, 39.5; F { H} NMR
22.5, 14.8, 14.2; F { H} NMR (377 MHz, CDCl
3
) δ 66.5; IR
-
1
-1
(377 MHz, CDCl ) δ 66.5; IR νmax (neat)/cm 3101, 2948, 1597,
νmax (neat)/cm 3310, 2959, 2932, 1697, 1593, 1566, 1486, 1473,
1406, 1213, 1159, 1031; LRMS (ESI ) m/z 471.2 ([M+H] );
HRMS (ESI ) m/z calc. for C23
3
+
+
+
1
564, 1402, 1206, 1192, 1097; LRMS (ESI ) m/z 241.0
+
+
+
+
+
+
+
([M+H] ); HRMS (ESI ) m/z calc. for C H FN O S [M+H]
H24FN
4
O
4
S [M+H] 471.1497,
10
10
2
2
2
41.0442, found 241.0443.
found 471.1496.
4
.7.7. 4-(Benzo[d][1,3]dioxol-5-yl)benzenesulfonyl fluoride (5f)
White solid, 93% yield. mp 104–105 °C (CHCl ); R 0.45
4.7.11. 4'-(5-(p-Tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-[1,1'-
biphenyl]-4-sulfonyl fluoride (5j)
3
f
1
(20% EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl ) δ
1-(4-Bromophenyl)-5-(p-tolyl)-3-(trifluoromethyl)-1H-
3
8
0
0
.03 (dtd, J = 8.8, 2.0, 0.5 Hz, 2H), 7.74 (dtd, J = 8.8, 2.1,
.9 Hz, 2H), 7.12 (dd, J = 8.0, 1.9 Hz, 1H), 7.09 (dd, J = 1.9,
pyrazole
4-(fluorosulfonyl)phenylboronic acid 3a (31 mg, 0.15 mmol,
1.5 equiv), Pd(OAc) (1.1 mg, 5.0 µmol, 5.0 mol%), XPhos
(4.8 mg, 10 µmol, 10 mol%), 1.0 M aq. K PO solution (0.2 mL,
(38.1 mg,
0.10 mmol,
1.0 equiv),
.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H);
2
13
1
C { H} NMR (101 MHz, CDCl ) δ 148.9, 148.8, 148.4, 132.8,
3
4
3
1
31.0 (d, J = 24.6 Hz), 129.1, 127.9, 121.7, 109.1, 107.8, 101.8;
0.20 mmol, 2.0 equiv) and 1,4-dioxane (0.4 mL) were used.
Sulfonyl fluoride 5j was isolated as an off-white solid (43.5 mg),
19
1
-1
F { H} NMR (377 MHz, CDCl ) δ 66.5; IR ν
(neat)/cm
3
max
9
5% yield. mp 121–123 °C (CHCl ); R 0.41 (10% EtOAc in
3 f

8
Tetrahedron
1
hexane) [UV]; H NMR (400 MHz, CDCl ) δ 8.09 (ddt, J =
4.7.15. 2-(Quinolin-6-yl)benzenesulfonyl fluoride (5n)
3
1
03.1, 8.5, 2.0 Hz, 2H), 7.82 (dtd, J = 8.9, 2.1, 0.8 Hz, 2H), 7.62
A reaction tube was charged with KF (48 mg, 0.83 mmol,
(
(
dt, J = 8.7, 2.5 Hz, 2H), 7.47 (dt, J = 8.8, 2.2 Hz, 2H), 7.19–7.15
m, 4H), 6.75 (s, 1H), 2.38 (s, 3H); C { H} NMR (101 MHz,
3
.3 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.20 equiv) and
13
1
XPhos (48 mg, 0.10 mmol, 0.40 equiv), sealed with a rubber
CDCl ) δ 147.3, 145.1, 143.8 (d, J = 38.9 Hz), 140.2, 139.6,
1
1
septum, evacuated and back-filled with N three times. Degassed
3
2
38.4, 132.1 (d, J = 24.7 Hz), 129.7, 129.2, 128.9, 128.3, 128.2,
anhydrous THF (0.25 mL) and 6-bromoquinoline (34 µL,
0.25 mmol, 1.0 equiv) were added subsequently, the mixture was
stirred at ambient temperature for 5 min, then warmed to 40 °C
and a solution of 2-(fluorosulfonyl)phenyl boronic acid 3c
(76 mg, 0.37 mmol, 1.5 equiv) in degassed THF (1 mL) was
added over a period of 30 min. The reaction mixture was stirred
at 40 °C for an additional 30 min, then stirred at ambient
temperature for 12 h. The reaction was then diluted with EtOAc,
filtered over Celite and concentrated in vacuo. The crude product
was purified by flash column chromatography (40–50% EtOAc
in petrol) to afford an off-white solid (30.5 mg), 43% yield. mp
19
26.3, 126.1, 121.4 (d, J = 269.5 Hz), 106.0, 21.5; F NMR
(
377 MHz, CDCl ) δ 66.5 (s, 1F), -62.3 (s, 3F); IR ν
3 max
-1
(neat)/cm 3061, 2925, 1595, 1472, 1408, 1376, 1236, 1213,
+
+
1
161, 1133, 1097; LRMS (ESI ) m/z 461.0 ([M+H] ); HRMS
+
+
+
(ESI ) m/z calc. for C H F N O S [M+H] 461.0941, found
21 17 4 2 2
4
61.0938.
4
.7.12. 4-(5-((2,4-Difluorophenyl)sulfonamido)-6-
methoxypyridin-3-yl)benzenesulfonyl fluoride (5k)
N-(5-Bromo-2-methoxypyridin-3-yl)-2,4-difluoro-
95–96 °C (CHCl
3
);
/UV]; H NMR (400 MHz, CDCl
3
R
f
0.31 (50% EtOAc in hexane)
1
benzenesulfonamide
(37.9 mg,
-(fluorosulfonyl)phenylboronic acid 3a (31 mg, 0.15 mmol,
.5 equiv), Pd(OAc)2 (1.1 mg, 5.0 µmol, 5.0 mol%), XPhos
0.10 mmol,
1.0 equiv),
[KMnO
4
) δ 8.99 (dd, J = 4.3,
4
1
(
1.7 Hz, 1H), 8.23 (dd, J = 8.1, 1.3 Hz, 3H), 8.21–8.17 (m, 2H),
7.86–7.84 (m, 1H), 7.81 (td, J = 7.6, 1.4 Hz, 1H), 7.72 (ddd, J =
8.7, 2.0, 0.9 Hz, 1H), 7.66 (ddt, J = 9.1, 7.7, 1.4 Hz, 1H), 7.55
(dd, J = 7.7, 1.3 Hz, 1H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H);
4.8 mg, 10 µmol, 10 mol%), 1.0 M aq. K PO solution (0.2 mL,
3 4
0
.20 mmol, 2.0 equiv) and 1,4-dioxane (0.4 mL) were used.
13
1
Sulfonyl fluoride 5k was isolated as an off-white solid (19.4 mg),
2% yield. mp 152–154 °C (CHCl ); R 0.52 (50% EtOAc in
C { H} NMR (101 MHz, CDCl
3
) δ 151.3, 147.9, 142.3, 136.6,
4
136.3, 135.0, 133.3, 132.6 (d, J = 22.4 Hz), 130.5, 130.3, 129.4,
128.7, 128.4, 127.7, 122.0; F { H} NMR (377 MHz, CDCl
3
f
1
19
1
hexane) [UV]; H NMR (500 MHz, CDCl ) δ 8.13 (d, J =
3
) δ
3
-
1
2
1
1
.3 Hz, 1H), 8.08 (dt, J = 8.6, 2.0 Hz, 2H), 7.99 (d, J = 2.3 Hz,
H), 7.91–7.86 (m, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.28 (br. s,
67.5; IR νmax (neat)/cm 3064, 1478, 1404, 1210, 763; LRMS
+
+
+
(ESI ) m/z 288.0 ([M+H] ); HRMS (ESI ) m/z calc. for
13
1
19
+
+
H), 6.98–6.93 (m, 2H), 3.98 (s, 3H); C { H, F} NMR
C H11FNO S [M+H] 288.0489, found 288.0488.
15 2
(
126 MHz, CDCl ) δ 166.4, 160.0, 155.0, 144.7, 140.9, 132.5,
3
1
29.4, 128.5, 127.9, 126.3, 123.5, 121.0, 112.2, 106.0, 54.6 (1C
19
missing); F NMR (377 MHz, CDCl ) δ 66.4 (s, 1F), -98.5 (m,
4.8. Rh(I)-catalyzed conjugate addition for the synthesis of 4-
(3-oxocyclohexyl)benzenesulfonyl fluoride (6)
3
-
1
1
1
4
F), -103.8 (m, 1F); IR νmax (neat)/cm 3285, 3103, 2929, 2856,
+
602, 1480, 1407, 1347, 1213, 1178, 1149; LRMS (ESI ) m/z
+
+
+
A
reaction tube was charged with 4-(fluorosulfonyl)-
phenylboronic acid 3a (61 mg, 0.30 mmol, 2.0 equiv),
Rh(COD)(CH CN) ]BF (2.9 mg, 7.5 µmol, 5.0 mol%) and
59.0 ([M+H] ); HRMS (ESI ) m/z calc. for C H F N O S
18
14
3
2
5 2
+
[
M+H] 459.0291, found 459.0291.
[
3
2
4
K CO3 (21 mg, 0.15 mmol, 1.0 equiv), sealed with a rubber
2
septum, evacuated and back-filled with N three times. Degassed
2
4
.7.13. 3-(Quinolin-6-yl)benzenesulfonyl fluoride (5l)
White solid, 91% yield. mp 111–113 °C (CHCl ); R 0.24
1
,4-dioxane (1.35 mL), degassed water (0.15 mL) and 2-
3
f
1
cyclohexen-1-one (14.5 µL, 0.15 mmol, 1.0 equiv) were added
sequentially, and the reaction mixture stirred under positive
(30% EtOAc in hexane) [UV]; H NMR (400 MHz, CDCl ) δ
3
8
.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.27–8.22
pressure of N in a preheated aluminium heating block at 55 °C
2
(m, 2H), 8.12–8.08 (m, 1H), 8.06–8.02 (m, 2H), 7.96 (dd, J = 8.8,
for 2 h. After cooling to ambient temperature, the reaction
mixture was diluted with EtOAc, washed with water and then
2
1
1
.2 Hz, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.3, 4.2 Hz,
13
1
H); C { H} NMR (101 MHz, CDCl ) δ 151.4, 148.2, 142.5,
3
brine, dried with anhydrous MgSO , filtered and concentrated in
4
36.5, 136.4, 134.4, 134.1 (d, J = 24.6 Hz), 130.8, 130.5, 128.5
19
1
vacuo. The crude product was purified by flash column
chromatography (20–40% EtOAc in petrol) to afford a white
(2C), 127.4, 127.2, 126.5, 122.1; F { H} NMR (377 MHz,
-1
CDCl ) δ 66.1; IR ν (neat)/cm 3067, 1593, 1480, 1404, 1208;
LRMS (ESI ) m/z 288.0 ([M+H] ); HRMS (ESI ) m/z calc. for
C H FNO S [M+H] 288.0489, found 288.0489.
3
max
+
+
+
solid (28.5 mg), 74% yield. mp 61–62 °C (CH
2
Cl
/UV]; H NMR (400 MHz, CDCl
.98 (dt, J = 8.4, 2.0 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 3.15 (tt, J
2
); R
f
0.38 (30%
1
+
+
EtOAc in hexane) [KMnO
4
3
) δ
15
11
2
7
=
11.6, 4.0 Hz, 1H), 2.62 (ddt, J = 14.0, 4.2, 1.9 Hz, 1H), 2.59–
2
.45 (m, 2H), 2.47–2.34 (m, 1H), 2.25–2.13 (m, 1H), 2.16–2.09
4
(
.7.14. 4'-(Trifluoromethyl)-[1,1'-biphenyl]-3-sulfonyl fluoride
5m)
Off-white solid, 64% yield. mp 50–51 °C (CHCl ); R 0.70
13 1
(m, 1H), 1.97–1.74 (m, 2H); C { H} NMR (101 MHz, CDCl ) δ
3
2
09.4, 152.8, 131.5 (d, J = 24.7 Hz), 129.1, 128.1, 48.2, 44.7,
19 1
3
f
41.1, 32.4, 25.4; F { H} NMR (377 MHz, CDCl ) δ 66.1; IR
3
-1
1
(30% EtOAc in hexane) [UV/KMnO ]; H NMR (500 MHz,
4
νmax (neat)/cm 2980, 2884, 1712, 1597, 1404, 1211, 1186, 804,
+ + +
CDCl ) δ 8.22 (t, J = 1.9 Hz, 1H), 8.06 (dt, J = 7.9, 1.5 Hz, 1H),
8
3
771; HRMS (APCI ) m/z calc. for C H FO S [M+H]
12 14 3
13
1
.00 (dt, J = 7.8, 1.4 Hz, 1H), 7.78–7.71 (m, 5H); C { H} NMR
2
57.0642, found 257.0641.
(101 MHz, CDCl ) δ 141.9, 141.9, 134.3, 134.2 (d, J = 24.6 Hz),
3
1
31.1 (app. d, J = 32.7 Hz), 130.6, 127.9, 127.8, 127.2, 126.4 (q,
Acknowledgements
19
J = 3.7 Hz), 124.1 (app. d, J = 272.5 Hz); F NMR (377 MHz,
CDCl ) δ 66.1 (s, 1F), -62.7 (s, 3F); IR ν
1
3
-
1
(neat)/cm 3076,
3
max
We thank the Croucher Foundation (to T.S.-B.L.) for financial
support for this research.
−
619, 1409, 1325, 1210, 1167, 1125, 1071; LRMS (ESI ) m/z
−
+
+
39.1 ([M+Cl] ); HRMS (ESI ) m/z calc. for C H F O SNa
13
8
4
2
+
[
M+Na] 327.0073, found 327.0080.

9
Appendix A. Supplementary data
19. Wang, S.-M.; Li, C.; Leng, J.; Bukhari, S. N. A.; Qin, H.-L.,
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Tetrahedron Lett. 1994, 35, 5109-5112.
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Sulfonyl fluoride substituted aryl boronic acids synthesized for the first time
Used in efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reactions
Used in rhodium-catalyzed conjugate addition reactions to enones

We have no competing interests to declare.