Hetaryl Bromides Bearing the SO2F Group – Versatile Substrates for Palladium-Catalyzed C–C Coupling Reactions

Article abstract of DOI:10.1002/ejoc.201801270

Synthesis of novel five- and six-membered heteroaromatic sulfonyl fluorides bearing bromine atom at various positions of the heterocyclic ring is described. The synthetic utility of these compounds is demonstrated by the Suzuki, Stille, and Negishi cross-

Full text of DOI:10.1002/ejoc.201801270

A Journal of
Accepted Article
Title: Hetaryl Bromides Bearing SO2F Group – Versatile Substrates for
Palladium-Catalyzed C–C Coupling Reactions
Authors: Artem Yu. Cherepakha, Kateryna O. Stepannikova, Bohdan
V. Vashchenko, Marian V. Gorichko, Andrey A. Tolmachev,
and Oleksandr O Grygorenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801270
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10.1002/ejoc.201801270
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Hetaryl Bromides Bearing SO2F Group – Versatile Substrates for
Palladium-Catalyzed C–C Coupling Reactions
Artem Yu. Cherepakha,[a,b] Kateryna O. Stepannikova,[a,b] Bohdan V. Vashchenko,[a,b] Dr. Marian V.
Gorichko,[b] Prof. Dr. Andrey A. Tolmachev,[a,b] Dr. Oleksandr O. Grygorenko*[a,b]
Abstract: Synthesis of novel five- and six-membered heteroaromatic
sulfonyl fluorides bearing bromine atom at various positions of the
heterocyclic ring is described. Synthetic utility of these compounds is
demonstrated by the Suzuki, Stille and Negishi cross-coupling
reactions, which proceeded chemoselectively at the aryl bromide
moiety with 69–98% yields. Tolerance of the SO2F group towards
the coupling reaction conditions was confirmed in most of
experiments. The proposed method was efficient for either sp2–sp2
or sp2–sp3 C–C couplings. The developed procedure provides rapid
access to various substituted heterocyclic sulfonyl fluorides.
molecular pharmacology since they demonstrate appropriate
balance of biocompatibility (including aqueous stability) and
protein reactivity as the warheads.[11] Sulfonyl fluorides are
primarily used as covalent inhibitors; in particular, (2-amino-
ethyl)benzenesulfonyl fluoride (AEBSF, 2) is a non-toxic, specific
and irreversible inhibitor of serine proteases.[11–13] Compound 3
(DAS1) was developed as a specific reagent for labeling tyrosine
residues in peptides.[14] Sulfonyl fluorides are also used for the
protein fluorescent labeling: for example, 5-dimethylamino-
naphthalene-1-sulfofluoride (Dansyl fluoride, 4) was found to be
more selective analogue of the corresponding sulfonyl chloride
due to its lower reactivity and hence specificity towards serine
residues.[15] SF-p1-yne (5) was designed as a clickable covalent
probe targeting a tyrosine residue in the binding site of the
decapping scavenger enzyme DcpS.[16] 5'-Fluorosulfonylbenzoyl
5'-adenosine (FSBA, 6), an ATP-binding protein inhibitor, have
been used as a covalent probe targeting lysine residues.[11,17–21]
Sulfonyl fluorides 7 were found to be potent covalent kinetic
stabilizers of transthyretin (TTR), a transport protein involved
into pathologies related to amyloid diseases.[22]
Introduction
Sulfonyl fluorides have received significant attention in recent
years due to their unique chemical and biological properties.[1]
They are typically considered as close analogs of sulfonyl
chlorides – commonly used sulfur(VI) electrophiles. Due to the
high energy of the S–F bond, sulfonyl fluorides are stable toward
hydrolysis, metal catalysis, or reductive reaction conditions as
compared to other sulfonyl halides.[2] On the other hand, they
undergo selective nucleophilic substitution at the sulfur(VI)
electrophilic center under controllable reaction conditions. It is
not surprising therefore that sulfur(VI) fluoride exchange
(SuFEx) was considered as a new click reaction, with potential
extensive applications in organic synthesis and medicinal
chemistry.[1,3]
Heteroaromatic sulfonyl fluorides are known as deoxyfluorination
agents;[4,5] in particular, commercially available 2-pyridinesulfonyl
fluoride (PyFluorTM, 1) (Figure 1) is more stable and less prone
to the elimination side reaction as compared to other popular
deoxyfluorination agents (Deoxo-Fluor[6], XtalFluor[7], Fluolead[8]
or DAST[9]). Moreover, an analog of 1 bearing a 18F nuclei at the
sulfonyl fluoride moiety can be used for the preparation of 18F-
labeled compounds.[5,10]
In the field of medicinal chemistry, sulfonyl fluorides have found
significant utility as reactive probes in chemical biology and
[a]
[b]
A. Yu. Cherepakha, K. O. Stepannikova, B. V. Vashchenko, A. A.
Tolmachev, O. O. Grygorenko
Enamine Ltd. (www.enamine.net)
Chervonotkatska Street 78, Kyiv 02094, Ukraine
A. Yu. Cherepakha, K. O. Stepannikova, B. V. Vashchenko, A. A.
Tolmachev, O. O. Grygorenko
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua
Figure 1. Examples of practically significant sulfonyl fluorides
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. General methods for the synthesis of heteroaromatic sulfonyl fluorides (DABSO – DABCO-bis(sulfur dioxide); AmPhos – (di-tert-butyl(4-dimethyl-
aminophenyl)phosphine; NFSI – N-fluorobenzenesulfonimide)
Known methods for the synthesis of (hetero)aromatic sulfonyl
fluorides fall into one of the following categories (Scheme 1):


electrophilic substitution using fluorosulfonic acid;[23,24]
reaction of sulfonyl chlorides with fluorine anion source
(KHF2,[5] KF,[25] TBAF,[26] NH4F,[27,28] or [18F]KF – 2.2.2-
cryptand,[5,26]);


oxidative chlorination of thiols,[29–34] sulfides[35,36] (Cl2,
NaClO, NCS), followed by in situ nucleophilic
+
substitution by fluorine anion (KHF2 or BnNMe3 F-);
electrophilic fluorination of sulfinates or sulfonyl
hydrazides.[37] A recently developed modification of this
approach relies on in situ generation of sulfinate via
palladium-catalyzed reaction of the corresponding aryl
halides with DABSO, followed by oxidation with
Selectfluor or NFSI;[38,39]
Scheme 2. Literature examples of metal-catalyzed C–C coupling reactions
with aryl halides having SO2F group
In this work, we report synthesis of six novel hetaryl bromides
10–15 – derivatives of pyridine, furan and thiophene – bearing
sulfonyl fluoride group (Figure 2). In addition to that, utility of
these building blocks for the Suzuki, Stille and Negishi C–C
coupling reactions is also demonstrated, which provides rapid
access to various substituted heterocyclic sulfonyl fluorides.

cycloaddition and heterocyclization reactions.[40–42]
It should be noted that to the best of our knowledge,
heteroaromatic sulfonyl fluorides bearing a bromine or
iodine atom suitable for metal-catalyzed C–C coupling
reactions were not described in the literature to date
(although some representatives of SO2F-substituted hetaryl
chlorides were known, see Scheme 1). A few examples of
metal-catalyzed C–C couplings involving the substrates
with SO2F group were reported. In particular, aryl halides 8
were introduced into the Ullmann reaction as early as in
1930 (Scheme 2).[43] Nevertheless, first examples of the
palladium-catalyzed cross-coupling (i.e. the Suzuki
reaction) of bromo/iodo derivatives of benzenesulfonyl
fluorides 9 were reported only in 2016.[23]
Figure 2. Target molecules of this work
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Results and Discussion
In the first part of this work, we have aimed at the preparation of
5-bromopyridine-3-sulfonyl fluoride (10). Since pyridine deriva-
tives with SO2Cl group at the  position are stable compounds,
we anticipated reaction of the known sulfonyl chloride 16[44] with
KF as a possible approach to the synthesis of 10. To obtain 16,
we have developed an original method including reaction of 3-
bromo-5-fluoropyridine (17) and benzyl thiol in the presence of
K2CO3 (87% yield), followed by oxidative chlorination of the
corresponding sulfide 18 (79% yield). Reaction of 18 with KF
proceeded smoothly in refluxing dioxane and gave the target
sulfonyl fluoride in 91% yield (Scheme 3).
Scheme 6. Products of sulfination of 2,6-dibromopyridine (24)
Next, benzyl sulfide 27 was synthesized from 2-bromo-6-
fluoropyridine (23) in 92% yield. To our surprise, oxidative
chlorination of 27 was not accompanied by cleavage of benzyl
group, so that sulfone 28 was obtained as white precipitate
formed upon reaction conditions (83% yield, 53% after
recrystallization). Therefore, we prepared tert-butyl sulfide 29
(71% yield from 23). In this case, oxidative chlorination in the
presence of KHF2 was successful and gave the target sulfonyl
fluoride 12 in 87% yield (Scheme 7).
Scheme 3. Synthesis of 5-bromopyridine-3-sulfonyl fluoride (10)
Synthesis of 5-bromopyridine-2-sulfonyl fluoride (11) commen-
ced from the readily available 5-bromopyridin-2(1H)-one (19).
Reaction of 19 with Lawesson's reagent gave thione 20 (68%
yield). Subsequent oxidative chlorination of 20 in the presence of
KHF2 gave the target compound 11 in 63% yield (Scheme 4).
Scheme 7. Synthesis of the target 6-bromopyridine-2-sulfonyl fluoride (12)
4-Bromopyridine-2-sulfonyl fluoride (13) was prepared from 4-
bromo-2-chloropyridine (30) using the similar reaction sequence.
In this case, the nucleophilic substitution step required heating to
50 C since the substrate 30 appeared to be less reactive as
compared to 23. The sulfide 31 (69% yield) was subjected to
oxidative fluorination conditions described above, which gave
the target product 13 in 69% yield (Scheme 8).
Scheme 4. Preparation of 5-bromopyridine-2-sulfonyl fluoride (11)
For the synthesis of isomeric 6-bromopyridine-2-sulfonyl fluoride
(12), we have envisaged analogous strategy. Unfortunately, all
attempts to prepare thione 21, namely, thionation of pyridone 22
with Lawesson's reagent or P4S10, as well as reaction of 2,6-di-
halopyridines 23 or 24 with NaSH in DMF, or with methyl 3-mer-
captopropanoate 25, followed by retro-Michael fragmentation,
were not fruitful (Scheme 5).
Scheme 8. Synthesis of 4-bromopyridine-2-sulfonyl fluoride (13)
5-Bromofuran- and -thiophene-2-sulfonyl fluorides (14 and 15)
were obtained from the corresponding suflonyl chlorides 32 and
33 by reaction with with KF in refluxing dioxane (88% and 90%
yield, respectively) (Scheme 9). In turn, the compounds 32 and
33 were obtained from 2,5-dibromofuran (34) and 2,5-
dibromothiophene (35), respectively, using the method
described in the literature for the thiophene derivative, namely,
Scheme 5. Attempted synthesis of 6-bromopyridine-2(1H)-thione (21)
Furthermore, lithiation of 2,6-dibromopyridine (24) with n-BuLi,
followed by subsequent treatment of the corresponding
organolithium intermediates with sulfur (IV) oxide and Selectfluor,
was not regioselective and gave ca. 1:2 mixture sulfonyl
fluorides 12 and 26 (Scheme 6). Several attempts to optimize
the metallation step of this reaction sequence by using i-PrMgBr,
i-PrMgBr – n-BuLi, or t-BuLi were also unsuccessful.
Scheme 9. Synthesis of 5-bromofuran-2-sulfonyl fluoride (14) and 5-
bromothiophene-2-sulfonyl fluoride (15)
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metallation and subsequent reaction with sulfur (IV) oxide and
Pd(dppf)2Cl2 as a catalyst and Na3PO4 as a base allows for the
preparation of the target cyclopropyl derivatives 37d–42d (Table
2, Entries 4, 8, 12, 16, 20, 24).
then – sulfuryl chloride (72% and 75% yield, respectively).[45]
Table 1. Optimization of the Suzuki reaction conditions
Furthermore, reaction of the bromo derivative 11 and vinyl
pinacolate 36e under the conditions described above for the
cyclopropylboronic acid (36d) proceeded smoothly for 2 weeks
and gave the target product 38e in 79% yield (Scheme 11).
Entry
Pd-catalyst
Base
Yield,%
98
1
2
3
4
5
6
7
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(dppf)2Cl2
Pd(PPh3)4
K2CO3
Et3N
87
DIPEA
DBU
91
Scheme 11. Reaction of hetaryl bromide 11 and pinacolate 36e
0
In the next part of this work, 4-, 5- and 6-bromopyridine-2-
sulfonyl fluorides (11–13) were introduced into the Negishi
cross-coupling reaction with diethylzinc. The best results of this
sp2–sp3 coupling were obtained using Pd(dppf)2Cl2 as a catalyst
in refluxing THF (Scheme 12). The corresponding products 45–
47 were isolated in 78–94% yield.
DIPEA
DIPEA
Et3N
92
70
Pd(OAc)2
30
All the bromo derivatives of hetaryl sulfonyl fluorides 10–15 were
introduced in the Suzuki-Miyaura cross-coupling reaction. First
of all, optimization of the Suzuki reaction conditions was
performed using 5-bromopyridine-3-sulfonyl fluoride (10) and
phenylboronic acid (36a) as the model compounds (Table 1). It
was found that the best results were obtained when the reaction
was performed in the presence of Pd(PPh3)2Cl2 and K2CO3 in
refluxing dioxane. Under these optimized conditions, phenyl
(37a–42a), furan-2-yl (37b–42b) and thiophene-2-yl (37c–42c)
derivatives of hetaryl sulfonyl fluorides 10–15 were obtained
using corresponding aryl boronic acids 36a–c (Table 2, Entries
1–3, 5–7, 9–11, 13–15, 17–19, 21–23).
Scheme 12. The Negishi reaction of 4-, 5- and 6-bromopyridine-2-sulfonyl
fluorides (11–13)
In addition to that, 5-bromopyridine-3-sulfonyl fluoride (10) was
subjected to the reaction with trimethylaluminium (Me3Al) under
analogous conditions. This transformation resulted in the
formation of known compound 48[39] in 87% yield (Scheme 13).
It should be noted that all our attempts to prepare thienyl
derivatives 38c and 40c from the corresponding aryl bromides
11 and 13 were unfruitful. In this case, the products of double
substitution 43 (39% yield) and 44 (46% yield) were formed
under the standard conditions (Scheme 10). Formation of these
products might be rationalized via oxidative addition of a Pd(0)
complex at the C–S bond of the starting sulfonyl fluoride – a
transformation which has been described for sulfonyl
chlorides.[46–48]
Scheme 13. Preparation of 5-methylpyridine-3-sulfonyl fluoride (44)
Finally, the Stille reaction of hetaryl bromide 10 and 4-
(tributylstannyl)pyridine (49) was studied (Scheme 14); this
transformation gave bipyridyl sulfonyl fluoride 50 upon
Pd(PPh3)4 catalysis in refluxing dioxane media (61% yield).
Scheme 10. Reaction of hetaryl bromides 11 and 13 with boronic acid 36c
Scheme 14. The Stille reaction of 4-bromopyridine-2-sulfonyl fluoride (10)
Unfortunately, reaction of hetaryl bromides 10–15 with
cyclopropylboronic acid (36d) under the conditions described
above was not successful; only starting compounds were
recovered. Further optimization of the reaction conditions
showed that switching to less-coordinating THF, as well as using
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Table 2. Synthesis of bi(het)aryl sulfonyl fluorides using the Suzuki reaction
Entry No.
Sulfonyl fluoride
Boronic acid (R)
phenyl- (36a)
Pd-catalyst / base / solvent
Product
Yield,%
98
92
79
83
93
94
0[a]
79
91
90
81
71
81
84
0[a]
69
97
83
91
85
90
89
85
81
1
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(dppf)2Cl2 / Na3PO4 / THF
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(dppf)2Cl2 / Na3PO4 / THF
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(dppf)2Cl2 / Na3PO4 / THF
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(dppf)2Cl2 / Na3PO4 / THF
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(dppf)2Cl2 / Na3PO4 / THF
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(PPh3)2Cl2 / K2CO3 / dioxane
Pd(dppf)2Cl2 / Na3PO4 / THF
37a
37b
37c
37d
38a
38b
38c
38d
39a
39b
39c
39d
40a
40b
40c
40d
41b
41c
41a
41d
42a
42b
42c
42d
2
furan-2-yl- (36b)
thiophen-2-yl- (36c)
cyclopropyl- (36d)
phenyl- (36a)
3
4
5
6
furan-2-yl- (36b)
thiophen-2-yl- (36c)
cyclopropyl- (36d)
phenyl- (36a)
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
furan-2-yl- (36b)
thiophen-2-yl- (36c)
cyclopropyl- (36d)
phenyl- (36a)
furan-2-yl- (36b)
thiophen-2-yl- (36c)
cyclopropyl- (36d)
furan-2-yl- (36b)
thiophen-2-yl- (36c)
phenyl- (36a)
cyclopropyl- (36d)
phenyl- (36a)
furan-2-yl- (36b)
thiophen-2-yl- (36c)
cyclopropyl- (36d)
[a]The product 43 or 44 was isolated instead the expected sulfonyl fluoride, see Scheme 11
using the procedures developed in this work. They are efficient
substrates for the palladium-catalyzed sp2–sp2 and sp2–sp3 C–C
coupling, i.e. the Suzuki–Miyaura, Stille and Negishi reactions.
In 28 of the 30 cases studied, the reaction proceeded in a
regioselective manner at the hetaryl bromide moiety, so that the
sulfonyl fluoride function remained intact under basic reaction
conditions and/or upon heating. Since nearly all the Pd-
Conclusions
Isomeric bromopyridinesulfonyl fluorides, as well as the
corresponding furan and thiophene derivatives are stable
compounds which can be prepared on at least ca. 30 g scale
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reagent (46.9 g, 0.116 mol) was added in portions to the stirred solution
at rt. The reaction mixture was refluxed for 2 h, then cooled to rt. The
formed precipitate was filtered and washed with cold toluene (330 mL).
Yield 30.0 g (68%); yellowish solid; mp 197–199 °C. 1H NMR (500 MHz,
DMSO-d6) δ 13.76 (br s, 1H), 7.86 (s, 1H), 7.50 (dd, J = 9.3, 2.5 Hz, 1H),
7.18 (d, J = 9.2 Hz, 1H). 13C NMR (125 MHz, DMSO-d6) δ 177.6, 140.0,
138.7, 135.0, 105.8. MS (CI): m/z = 190/192 [M+H]+. Anal. calcd. for
C5H4BrNS: C, 31.60; H, 2.12; N, 7.37; S, 16.87; Br, 42.04. Found: C,
31.58; H, 1.82; N, 7.54; S, 16.80; Br, 41.72.
catalyzed couplings mentioned above were successful, we
believe that the methods developed in this work might be of a
general application. Therefore, the title bifunctional building
blocks, as well the products of their C–C coupling are promising
reagents for the SuFEx click chemistry; they also have great
potential as the starting points and synthetic intermediates for
early drug discovery.
2-(Benzylsulfonyl)-6-bromopyridine (28). KHF2 (27.9 g, 0.357 mol)
was added to a stirred suspension of benzyl sulfide 27 (20.0 g, 71.4
mmol) in MeOH – H2O (1:1 v/v, 400 mL) and the reaction mixture was
cooled to 0 °C. Then, gaseous Cl2 was bubbled through stirred reaction
mixture at 0 °C for 1 h (NOTE: the temperature shouldn’t exceed 5 °C).
The corresponding sulfone 28 was formed as white precipitate upon
reaction conditions. The crude sulfone was filtered and recrystallized
from MeOH (ca. 250 mL). Yield 11.8 g (53%); white solid; mp 121–
123 °C. 1H NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 6.2, 2.3 Hz, 1H), 7.68
(d, J = 6.5 Hz, 2H), 7.32 – 7.25 (m, 4H), 7.25 (s, 1H), 4.67 (s, 2H). 13C
NMR (125 MHz, CDCl3) δ 156.9, 142.3, 139.9, 132.2, 131.1, 128.9,
128.7, 127.0, 121.7, 58.1. MS (CI): m/z = 312/314 [M+H]+. Anal. calcd.
for C12H10BrNO2S: C, 46.17; H, 3.23; N, 4.49; S, 10.27; Br, 25.60. Found:
C, 46.17; H, 3.04; N, 4.61; S, 10.44; Br, 25.69.
Experimental Section
Compound 33 was prepared according to the literature method.[45] All
other reagents were available from Enamine Ltd. The solvents were
purified according to standard procedures.[49] When organic solutions
were concentrated under reduced pressure, a 35–40 °C bath was used.
Column chromatography was performed on silica gel 60 (230–400 mesh)
as the stationary phase. 1H, 13C, 19F NMR spectra were recorded at 400
and 500 MHz (for 1H NMR), 100 and 125 MHz (for 13C NMR), 376 and
470 MHz (for 19F NMR). NMR chemical shifts are reported in ppm (δ
scale) and are referenced using residual NMR solvent peaks at 7.26 and
77.16 ppm for 1H and 13C in CDCl3, 2.50 and 39.52 ppm for 1H and 13C in
DMSO-d6. Coupling constants (J) are shown in Hz. Spectra are reported
as follows: chemical shift (δ, ppm), multiplicity, integration, coupling
constants (Hz). LC-MS data were acquired on Agilent 1200 HPLC
system equipped with DAD/ELSD/LCMS-6120 diode matrix and mass-
selective detector, Poroshell 120 SBC18, 4.630 mm column. Eluent:
gradient MeCN–H2O (99 : 1) with 0.1% TFA to H2O with 0.1% TFA.
2-Bromo-6-(tert-butylthio)pyridine (29). t-BuSH (37.8 g, 0.419 mol)
was added dropwise to a stirred suspension of NaH (60%, 11.2 g, 0.281
mol) in THF (350 mL) at
0 °C; the reaction mixture was stirred
additionally at °C for 1 h. Then, the solution of corresponding
0
halopyridine 23 or 30 (0.281 mol) in THF (225 mL) was added dropwise
to stirred reaction mixture at 0 °C; the solution was warmed up to rt (for
23) or to 50 °C (for 30). The completion of the reaction was controlled by
TLC. The reaction mixture was washed with brine (3100 mL), the
organic phase was separated, dried over Na2SO4 and evaporated in
vacuo. The product was purified by distillation in vacuo (bp 83–85 °C /
0.2 mmHg). Yield 49.1 g (71%); yellowish liquid; bp 83–85 °C / 0.2
mmHg. 1H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 8.2 Hz, 1H), 7.14 (t, J =
8.2 Hz, 2H), 1.52 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 160.4, 140.9,
137.8, 123.9, 123.9, 48.3, 30.7. MS (EI): m/z = 245/247 [M]+. Anal. calcd.
for C9H12BrNS: C, 43.91; H, 4.91; N, 5.69; S, 13.02; Br, 32.46. Found: C,
43.57; H, 4.98; N, 5.32; S, 13.20; Br, 32.54.
5-Bromopyridine-3-sulfonyl chloride (16).[44] Sulfide 18 (35.1 g, 0.125
mol) was dissolved in CH2Cl2 – H2O (1:1 v/v, 700 mL); then, gaseous Cl2
was bubbled through the stirred reaction mixture for 75 min at rt. The
organic phase was separated and washed with H2O (375 mL) and brine
H2O (275 mL). The organic layer was separated, dried over Na2SO4 and
evaporated in vacuo to dryness. Yield 25.3 g (79%); white solid; mp 61–
63 °C. 1H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 2.1 Hz, 1H), 8.99 (d, J =
2.1 Hz, 1H), 8.42 (t, J = 2.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 156.7,
145.4, 141.5, 136.8, 121.2. MS (CI): m/z = 156/158 [M+H−SO2F]+. Anal.
calcd. for C5H3BrClNO2S: C, 23.41; H, 1.18; N, 5.46; S, 12.50; Cl, 13.82;
Br, 31.15. Found: C, 23.06; H, 0.97; N, 5.24; S, 12.14; Cl, 13.73; Br,
31.15.
4-Bromo-2-(tert-butylthio)pyridine (31). The compound 31 was
prepared from 30 using the procedure described above for 29. The
product was purified by column chromatography on silica gel using
hexanes – EtOAc (9:1) as eluent. Yield 47.7 g (71%); white crystals; bp
91–93 °C / 0.2 mmHg. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.5 Hz,
1H), 7.44 (s, 1H), 7.18 (d, J = 4.5 Hz, 1H), 1.52 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 160.9, 149.8, 132.1, 128.7, 123.6, 48.3, 30.9. MS (EI):
m/z = 246 [M]+. Anal. calcd. for C9H12BrNS: C, 43.91; H, 4.91; N, 5.69; S,
13.02; Br, 32.46. Found: C, 44.18; H, 4.84; N, 6.01; S, 12.97; Br, 32.37.
3-(Benzylthio)-5-bromopyridine (18). 3-Bromo-5-fluoropyridine (17)
(45.0 g, 0.256 mol), K2CO3 (42.4 g, 0.307 mol) and BnSH (31.8 g, 0.256
mol) were dissolved in DMF (400 mL); the reaction mixture was stirred at
80 °C overnight. Then, the solution was poured into H2O (900 mL) and
extracted with EtOAc (3500 mL). The organic phase was separated and
additionally washed with H2O (3150 mL) and brine (100 mL). The
organic layer was separated, dried over Na2SO4 and evaporated in vacuo
to dryness to give compound 18. Yield 62.4 g (87%); white powder; mp
40–42 °C. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.39 (s, 1H), 7.67
(s, 1H), 7.32 – 7.30 (m, 1H), 7.29 – 7.25 (m, 4H), 4.11 (s, 2H). 13C NMR
(125 MHz, CDCl3) δ 148.6, 148.4, 139.5, 136.1, 134.9, 128.9, 128.7,
127.7, 120.5, 38.9. MS (CI): m/z = 280/282 [M+H]+. Anal. calcd. for
C12H10BrNS: C, 51.44; H, 3.60; N, 5.00; S, 11.44; Br, 28.52. Found: C,
51.59; H, 3.65; N, 4.63; S, 11.29; Br, 28.90.
5-Bromofuran-2-sulfonyl chloride (32). 2,5-Dibromofuran (34) (23.8 g,
0.105 mol) was dissolved in THF (250 mL), and i-PrMgCl (2 M in THF,
52.5 mL, 0.105 mol) was added dropwise to the stirred solution at –78 °C
under argon atmosphere. The resulting mixture was stirred at –78 °C for
1 h; then, an ice-cold solution of SO2 (13.5 g, 0.210 mol) in THF (200 mL)
was added, and the reaction mixture was stirred for additional 15 min.
SO2Cl2 (10.2 mL, 17.0 g, 0.126 mol) was added dropwise, and the
solution was stirred for 15 min; then H2O (250 mL) was added, and the
resulting mixture was extracted with EtOAc (3250 mL). The combined
organic phases were dried over Na2SO4 and evaporated in vacuo. Yield
18.6 g (72%). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 1.7 Hz, 1H), 6.60
(d, J = 3.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 150.7, 130.9, 121.1,
2-(Benzylthio)-6-bromopyridine (27). The compound 27 was prepared
from 23 using the procedure described above for 18. Yield 66.0 g (92%).
For spectral and physical data, see ref.[50,51]
5-Bromopyridine-2(1H)-thione (20). 5-Bromopyridin-2(1H)-one (19)
(40.4 g, 0.232 mol) was dissolved in toluene (400 mL), and Lawesson’s
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801270
European Journal of Organic Chemistry
FULL PAPER
114.3. MS (EI): m/z = 244/246 [M]+. Anal. calcd. for C4H2BrClO3S: C,
19.57; H, 0.82; S, 13.06; Cl, 14.44; Br, 32.55. Found: C, 19.89; H, 1.07; S,
13.40; Cl, 14.28; Br, 32.16.
C5H3BrFNO2S: C, 25.02; H, 1.26; N, 5.84; S, 13.36; Br, 33.29. Found: C,
24.94; H, 1.41; N, 5.80; S, 13.69; Br, 33.13.
4-Bromopyridine-2-sulfonyl fluoride (13). The compound was purified
by trituration with cold MeOH (375 mL). Yield 26.2 g (69%); white
crystals; mp 87–89 °C. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 5.2 Hz,
1H), 8.25 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 5.2, 1.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 152.0 (d, J = 31.6 Hz), 151.5, 135.2, 132.5, 127.5 (d,
J = 2.2 Hz). 19F NMR (376 MHz, CDCl3) δ 55.7. MS (EI): m/z = 239/241
[M]+. Anal. calcd. for C5H3BrFNO2S: C, 25.02; H, 1.26; N, 5.84; S, 13.36;
Br, 33.29. Found: C, 24.73; H, 1.00; N, 6.20; S, 13.74; Br, 33.15.
General procedure for the preparation of 10, 14, and 15
The corresponding sulfonyl chloride 16, 32 or 33 (58.5 mmol) and KF
(17.0 g, 0.292 mol) were dissolved in dioxane (150 mL), and the reaction
mixture was refluxed until the reaction was complete (monitored by 1H
NMR). Then, most of dioxane was evaporated in vacuo and the residue
was dissolved in EtOAc (250 mL) and washed with H2O (375 mL). The
organic layer was separated, dried over Na2SO4 and evaporated in vacuo.
5-Bromopyridine-3-sulfonyl fluoride (10). The product was purified by
trituration with cold MeOH (330 mL). Yield 12.8 g (91%); white crystals;
mp 71–73 °C. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 9.03 (s, 1H),
8.40 (d, J = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.3, 146.8,
138.2, 131.0 (d, J = 26.5 Hz), 121.2. 19F NMR (376 MHz, CDCl3) δ 68.0.
MS (EI): m/z = 239/241 [M]+. Anal. calcd. for C5H3BrFNO2S: C, 25.02; H,
1.26; N, 5.84; S, 13.36; Br, 33.29. Found: C, 25.01; H, 1.15; N, 5.84; S,
13.38; Br, 33.30.
General procedure for the preparation of 37a–42c
The corresponding aryl bromide 10–15 (4.20 mmol) was dissolved in
dioxane (15 mL). Arylboronic acid 36a–36c (8.40 mmol), Pd(PPh3)2Cl2
(295 mg, 0.42 mmol), and DIPEA (1.63 g, 2.20 mL, 12.6 mmol) were
added under argon atmosphere; the resulting mixture was refluxed until
the reaction was complete (monitored by TLC). Then, EtOAc (40 mL)
was added and the resulting solution was washed with H2O (315 mL)
and brine H2O (310 mL). The organic layer was separated, dried over
Na2SO4 and evaporated in vacuo.
5-Bromofuran-2-sulfonyl fluoride (14). The product was purified by
distillation in vacuo (bp 87–89 °C / 0.2 mmHg). Yield 11.8 g (88%);
colorless liquid; bp 87–89 °C / 0.2 mmHg. 1H NMR (500 MHz, CDCl3) δ
7.37 (dd, J = 3.3, 1.3 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ 142.0 (d, J = 38.4 Hz), 131.7 (d, J = 3.0 Hz), 124.1 (d, J =
3.2 Hz), 114.4. 19F NMR (376 MHz, CDCl3) δ 63.8. MS (EI): m/z =
228/230 [M]+. Anal. calcd. for C4H2BrFO3S: C, 20.98; H, 0.88; S, 14.00;
Br, 34.89. Found: C, 20.58; H, 0.89; S, 13.70; Br, 34.66.
5-Phenylpyridine-3-sulfonyl fluoride (37a). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.75. Yield 977 mg (98%); white solid; mp = 93–95 °C. 1H
NMR (400 MHz, CDCl3) δ 9.17 (d, J = 8.9 Hz, 2H), 8.42 (s, 1H), 7.61 (d,
J = 6.8 Hz, 2H), 7.58 – 7.46 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 154.3,
147.1, 137.8, 134.9, 133.8, 130.3 (d, J = 25.3 Hz), 129.7, 129.6, 127.3.
19F NMR (376 MHz, CDCl3) δ 67.7. MS (EI): m/z = 237 [M]+. Anal. calcd.
for C11H8FNO2S: C, 55.69; H, 3.40; N, 5.90; S, 13.51. Found: C, 55.92; H,
3.24; N, 6.13; S, 13.57.
5-Bromothiophene-2-sulfonyl fluoride (15). The product was purified
by distillation in vacuo (bp 89–91 °C / 0.2 mmHg). Yield 12.9 g (90%);
colorless liquid; bp 89–91 °C / 0.2 mmHg. 1H NMR (400 MHz, CDCl3) δ
7.66 (dd, J = 4.2, 1.2 Hz, 1H), 7.20 (dd, J = 4.2, 0.7 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 137.2 (d, J = 1.3 Hz), 131.9 (d, J = 31.6 Hz), 131.2,
125.3 (d, J = 2.5 Hz). 19F NMR (376 MHz, CDCl3) δ 70.9. MS (EI): m/z =
244/246 [M]+. Anal. calcd. for C4H2BrFO2S2: C, 19.60; H, 0.82; S, 26.16;
Br, 32.60. Found: C, 19.52; H, 0.74; S, 26.24; Br, 32.77.
5-Phenylpyridine-2-sulfonyl fluoride (38a). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (4:1) as
1
eluent. Rf = 0.75. Yield 927 mg (93%); white solid; mp = 118–120 °C. H
NMR (500 MHz, DMSO) δ 9.04 (s, 1H), 8.20 (s, 2H), 7.71 – 7.62 (m, 2H),
7.62 – 7.49 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 149.5 (d, J = 30.4 Hz),
149.4, 142.4, 136.3, 135.2, 129.9, 129.6, 127.6, 124.3. 19F NMR (376
MHz, CDCl3)
δ 56.2. MS (EI): m/z =
237 [M]+. Anal. calcd. for
C11H8FNO2S: C, 55.69; H, 3.40; N, 5.90; S, 13.51. Found: C, 55.84; H,
3.15; N, 6.16; S, 13.24.
General procedure for the preparation of 11–13
KHF2 (85.9 g, 1.10 mol) was added to a stirred suspension of the
corresponding compound 20, 29 or 31 (0.158 mol) in MeOH – H2O (8:3
v/v, 550 mL), and the reaction mixture was cooled to 0 °C. Then,
gaseous Cl2 was bubbled through the stirred reaction mixture for 3 h at
0 °C (NOTE: the temperature shouldn’t exceed 5 °C). Subsequently, the
reaction mixture was extracted with CH2Cl2 (3300 mL). The combined
organic phases were dried over Na2SO4 and evaporated in vacuo.
6-Phenylpyridine-2-sulfonyl fluoride (39a). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (4:1) as
eluent. Rf = 0.70. Yield 907 mg (91%); white solid; mp = 73–75 °C. 1H
NMR (500 MHz, CDCl3) δ 8.19 – 8.04 (m, 4H), 8.01 (dd, J = 7.3, 0.7 Hz,
1H), 7.61 – 7.44 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 159.1, 151.2 (d,
J = 29.8 Hz), 139.3, 136.3, 130.7, 129.1, 127.3, 125.4, 121.9 (d, J = 1.9
Hz). 19F NMR (376 MHz, CDCl3) δ 54.1. MS (EI): m/z = 237 [M]+. Anal.
calcd. for C11H8FNO2S: C, 55.69; H, 3.40; N, 5.90; S, 13.51. Found: C,
55.41; H, 3.74; N, 6.00; S, 13.78.
5-Bromopyridine-2-sulfonyl fluoride (11). The compound was purified
by washing with cold MeOH (375 mL). Yield 23.9 g (63%); white
crystals; mp 92–94 °C. 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.17 (d,
J = 8.6 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
152.3 (d, J = 1.2 Hz), 149.5 (d, J = 31.9 Hz), 141.2, 127.6, 125.2 (d, J =
2.2 Hz). 19F NMR (376 MHz, CDCl3) δ 56.2. . MS (EI): m/z = 239/241 [M]+.
Anal. calcd. for C5H3BrFNO2S: C, 25.02; H, 1.26; N, 5.84; S, 13.36; Br,
33.29. Found: C, 24.66; H, 1.39; N, 6.11; S, 13.40; Br, 33.65.
4-Phenylpyridine-2-sulfonyl fluoride (40a). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (7:3) as
eluent. Rf = 0.80. Yield 807 mg (81%); white solid; mp = 72–74 °C. 1H
NMR (500 MHz, CDCl3) δ 8.87 (d, J = 4.9 Hz, 1H), 8.34 (s, 1H), 7.92 –
7.87 (m, 1H), 7.75 – 7.67 (m, 2H), 7.61 – 7.55 (m, 3H). 13C NMR (125
MHz, CDCl3) δ 152.0 (d, J = 30.1 Hz), 151.7, 151.4, 135.6, 130.6, 129.7,
127.2, 126.6, 121.9 (d, J = 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ 55.4.
MS (EI): m/z = 237 [M]+. Anal. calcd. for C11H8FNO2S: C, 55.69; H, 3.40;
N, 5.90; S, 13.51. Found: C, 56.03; H, 3.12; N, 6.27; S, 13.68.
6-Bromopyridine-2-sulfonyl fluoride (12). The compound was purified
by trituration with cold MeOH (375 mL). Yield 33.0 g (87%); white
crystals; mp 91–93 °C. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 6.7 Hz,
1H), 7.93 – 7.86 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 151.1 (d, J =
31.9 Hz), 143.3, 140.4, 134.3, 123.0 (d, J = 2.3 Hz). 19F NMR (376 MHz,
CDCl3)
δ 55.3. MS (EI): m/z =
239/241 [M]+. Anal. calcd. for
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801270
European Journal of Organic Chemistry
FULL PAPER
5-Phenylfuran-2-sulfonyl fluoride (41a). The product was purified by
column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.75. Yield 845 mg (91%); white solid; mp = 41–43 °C. 1H
NMR (500 MHz, CDCl3) δ 7.83 – 7.76 (m, 2H), 7.51 – 7.43 (m, 4H), 6.85
(d, J = 3.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 160.9, 130.3, 129.1,
128.0, 125.3, 124.0, 123.9, 106.5. 19F NMR (470 MHz, CDCl3) δ 64.6.
MS (EI): m/z = 226 [M]+. Anal. calcd. for C10H7FO3S: C, 53.09; H, 3.12; S,
14.17. Found: C, 52.97; H, 3.07; S, 14.25.
[2,2'-Bifuran]-5-sulfonyl fluoride (41b). The product was purified by
column chromatography on silica gel using hexanes – EtOAc (2:3) as
eluent. Rf = 0.55. Yield 881 mg (97%); white solid; mp = 51–53 °C. 1H
NMR (400 MHz, CDCl3) δ 7.52 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 3.8, 1.8
Hz, 1H), 6.88 (d, J = 3.5 Hz, 1H), 6.72 – 6.67 (m, 1H), 6.53 (dd, J = 3.6,
1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 152.7, 144.4, 143.7, 138.8 (d,
J = 37.0 Hz), 124.0 (d, J = 3.3 Hz), 112.1, 110.3, 106.1. 19F NMR (376
MHz, CDCl3) δ 64.3. MS (EI): m/z = 216 [M]+. Anal. calcd. for C8H5FO4S:
C, 44.45; H, 2.33; S, 14.83. Found: C, 44.53; H, 2.62; S, 14.87.
5-Phenylthiophene-2-sulfonyl fluoride (42a). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.75. Yield 916 mg (90%); white solid; mp = 58–60 °C. 1H
NMR (400 MHz, CDCl3) δ 7.85 (d, J = 4.0 Hz, 1H), 7.63 – 7.58 (m, 2H),
7.45 (d, J = 4.4 Hz, 3H), 7.33 (d, J = 4.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 156.2, 137.8, 131.7, 130.2, 129.5, 128.9 (d, J = 30.5 Hz), 126.6,
123.6. 19F NMR (376 MHz, CDCl3) δ 71.3. MS (EI): m/z = 242 [M]+. Anal.
calcd. for C10H7FO2S2: C, 49.57; H, 2.91; S, 26.47. Found: C, 49.40; H,
3.02; S, 26.36.
5-(Furan-2-yl)thiophene-2-sulfonyl fluoride (42b). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(2:3) as eluent. Rf = 0.5. Yield 868 mg (89%); white solid; mp = 37–39 °C.
1H NMR (500 MHz, CDCl3) δ 7.84 – 7.81 (m, 1H), 7.53 (d, J = 2.0 Hz,
1H), 7.39 – 7.16 (m, 2H), 6.79 (d, J = 3.2 Hz, 1H), 6.55 (d, J = 1.8 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 146.3, 144.0, 143.6, 137.1, 127.5,
121.5, 112.0, 109.0. 19F NMR (470 MHz, CDCl3) δ 72.1. MS (EI): m/z =
232 [M]+. Anal. calcd. for C8H5FO3S2: C, 41.37; H, 2.17; S, 27.61. Found:
C, 41.04; H, 1.77; S, 27.44.
5-(Furan-2-yl)pyridine-3-sulfonyl fluoride (37b). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(3:2) as eluent. Rf = 0.55. Yield 878 mg (92%); white solid; mp = 73–
75 °C. 1H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H), 9.05 (s, 1H), 8.48 (d, J
= 2.2 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.96 (t, J = 2.9 Hz, 1H), 6.60 (d, J
= 2.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 150.8, 148.2, 146.2, 144.7,
130.4 (d, J = 25.8 Hz), 129.9, 127.7, 112.5, 109.4. 19F NMR (376 MHz,
CDCl3) δ 67.3. MS (EI): m/z = 227 [M]+. Anal. calcd. for C9H6FNO3S: C,
47.58; H, 2.66; N, 6.16; S, 14.11. Found: C, 47.79; H, 3.02; N, 6.33; S,
14.06.
5-(Thiophen-2-yl)pyridine-3-sulfonyl fluoride (37c). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(2:3) as eluent. Rf = 0.55. Yield 807 mg (79%); white solid; mp = 90–
92 °C. 1H NMR (400 MHz, CDCl3) δ 9.18 (d, J = 2.2 Hz, 1H), 9.05 (s,
1H), 8.37 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 3.8 Hz, 2H), 7.20 – 7.16 (m,
1H). 13C NMR (125 MHz, CDCl3) δ 152.6 (d, J = 1.0 Hz), 146.6, 137.0,
132.0, 131.6, 130.4 (d, J = 25.6 Hz), 128.9, 128.3, 126.4.19F NMR (376
MHz, CDCl3) δ 67.6. MS (EI): m/z = 243 [M]+. Anal. calcd. for
C9H6FNO2S2: C, 44.44; H, 2.49; N, 5.76; S, 26.36. Found: C, 44.23; H,
2.13; N, 5.94; S, 26.06.
5-(Furan-2-yl)pyridine-2-sulfonyl fluoride (38b). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.65. Yield 897 mg (94%); white solid; mp = 111–
113 °C. 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.21 (d, J = 8.2 Hz,
1H), 8.13 (d, J = 8.3 Hz, 1H), 7.66 (s, 1H), 7.03 (d, J = 3.3 Hz, 1H), 6.62
(dd, J = 3.4, 1.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 148.7, 148.3 (d, J
= 31.1 Hz), 146.01 (s), 145.3, 131.8, 131.7, 124.5 (d, J = 2.0 Hz), 112.7,
110.8. 19F NMR (376 MHz, CDCl3) δ 56.3. MS (EI): m/z = 227 [M]+. Anal.
calcd. for C9H6FNO3S: C, 47.58; H, 2.66; N, 6.16; S, 14.11. Found: C,
47.70; H, 3.01; N, 6.50; S, 13.82.
6-(Thiophen-2-yl)pyridine-2-sulfonyl fluoride (39c). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(3:2) as eluent. Rf = 0.55. Yield 828 mg (81%); white solid; mp = 104–
106 °C. 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 7.3 Hz, 1H), 7.97 –
7.87 (m, 2H), 7.82 – 7.73 (m, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.23 – 7.11
(m, 1H). 13C NMR (100 MHz, CDCl3) δ 154.4, 151.0 (d, J = 30.0 Hz),
141.5, 139.0, 130.1, 128.5, 127.4, 124.0, 121.3. 19F NMR (376 MHz,
CDCl3) δ 53.9. MS (EI): m/z = 243 [M]+. Anal. calcd. for C9H6FNO2S2: C,
44.44; H, 2.49; N, 5.76; S, 26.36. Found: C, 44.47; H, 2.29; N, 6.16; S,
26.13.
6-(Furan-2-yl)pyridine-2-sulfonyl fluoride (39b). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.6. Yield 859 mg (90%); white solid; mp = 81–83 °C.
1H NMR (400 MHz, CDCl3) δ 8.04 – 7.94 (m, 2H), 7.92 – 7.83 (m, 1H),
7.56 (d, J = 0.8 Hz, 1H), 7.25 (d, J = 3.9 Hz, 1H), 6.56 (dd, J = 3.4, 1.7
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 151.3, 151.2, 150.9 (d, J = 14.9
Hz), 144.9, 139.1, 123.4, 121.2 (d, J = 2.2 Hz), 112.7, 112.2. 19F NMR
(376 MHz, CDCl3) δ 54.0. MS (EI): m/z = 227 [M]+. Anal. calcd. for
C9H6FNO3S: C, 47.58; H, 2.66; N, 6.16; S, 14.11. Found: C, 47.81; H,
2.73; N, 6.17; S, 14.10.
5-(Thiophen-2-yl)furan-2-sulfonyl fluoride (41c). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.60. Yield 810 mg (83%); white solid; mp = 46–
48 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 3.4 Hz, 1H), 7.42 (t, J =
4.5 Hz, 2H), 7.10 (t, J = 4.3 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 155.8 (d, J = 2.5 Hz), 138.1 (d, J = 36.9 Hz), 129.5,
127.7 (d, J = 7.6 Hz), 126.5, 123.8, 123.7, 105.7. 19F NMR (470 MHz,
CDCl3) δ 72.1. MS (EI): m/z = 232 [M]+. Anal. calcd. for C8H5FO3S2: C,
41.37; H, 2.17; S, 27.61. Found: C, 41.29; H, 2.22; S, 27.81.
4-(Furan-2-yl)pyridine-2-sulfonyl fluoride (40b). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(3:2) as eluent. Rf = 0.5. Yield 802 mg (84%); white solid; mp = 71–73 °C.
1H NMR (400 MHz, CDCl3) δ 8.74 – 8.63 (m, 1H), 8.20 (s, 1H), 7.78 (d, J
= 5.0 Hz, 1H), 7.58 (s, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.63 – 6.49 (m, 1H).
13C NMR (100 MHz, CDCl3) δ 151.8 (d, J = 30.2 Hz), 151.3, 148.9, 145.6,
140.2, 122.2, 117.9 (d, J = 2.2 Hz), 112.9, 111.9. 19F NMR (376 MHz,
CDCl3) δ 54.9. MS (EI): m/z = 227 [M]+. Anal. calcd. for C9H6FNO3S: C,
47.58; H, 2.66; N, 6.16; S, 14.11. Found: C, 47.44; H, 2.99; N, 6.43; S,
13.79.
[2,2'-Bithiophene]-5-sulfonyl fluoride (42c). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (1:1) as
eluent. Rf = 0.65. Yield 887 mg (85%); white solid; mp = 58–60 °C. 1H
NMR (400 MHz, CDCl3) δ 7.80 – 7.75 (m, 1H), 7.40 (d, J = 4.0 Hz, 1H),
7.33 (s, 1H), 7.21 – 7.17 (m, 1H), 7.10 – 7.06 (m, 1H). 13C NMR (125
MHz, CDCl3) δ 148.5, 137.2, 133.6, 128.3, 128.1, 127.5, 126.4, 123.1.
19F NMR (376 MHz, CDCl3) δ 71.4. MS (EI): m/z = 248 [M]+. Anal. calcd.
for C8H5FO2S3: C, 38.70; H, 2.03; S, 38.74. Found: C, 38.89; H, 2.23; S,
38.37.
General procedure for the preparation of 37d–42d, 43 and 44
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801270
European Journal of Organic Chemistry
FULL PAPER
The corresponding aryl bromide 10–15 (4.20 mmol) was dissolved in
THF (15 mL), and cyclopropylboronic acid (36d) (0.72 g, 8.40 mmol),
Pd(dppf)2Cl2 (307 mg, 0.42 mmol), Na3PO4 (2.06 g, 12.6 mmol) were
added under argon atmosphere; the resulting mixture was refluxed and
the completion of reaction was controlled by TLC. Then, EtOAc (40 mL)
was added and the resulting solution was washed with H2O (315 mL)
and brine H2O (310 mL). The organic layer was separated, dried over
Na2SO4 and evaporated in vacuo.
(4:1) as eluent. Rf = 0.4. Yield 702 mg (81%); yellowish liquid; bp = 93–
95 °C / 1 mmHg. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 4.1 Hz, 1H),
6.82 (d, J = 4.1 Hz, 1H), 2.16 (tt, J = 8.7, 5.0 Hz, 1H), 1.24 – 1.15 (m,
2H), 0.90 – 0.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 162.5, 137.3,
126.0 (d, J = 29.8 Hz), 123.5, 12.0, 11.7. 19F NMR (376 MHz, CDCl3) δ
71.0. MS (EI): m/z = 206 [M]+. Anal. calcd. for C7H7FO2S2: C, 40.76; H,
3.42; S, 31.09. Found: C, 40.99; H, 3.58; S, 30.74.
2,5-Di(thiophen-2-yl)pyridine (43). 1H NMR (500 MHz, CDCl3) δ 8.88 –
8.83 (m, 1H), 7.88 (dd, J = 8.2, 2.2 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.61
(d, J = 3.5 Hz, 1H), 7.42 (d, J = 5.0 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.14 (t,
J = 4.8, 3.8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 151.3, 146.6, 144.5,
140.4, 133.6, 128.6, 128.3, 128.1, 127.7, 125.8, 124.6, 123.9, 118.7. MS
(EI): m/z = 243 [M]+. Anal. calcd. for C13H9NS2: C, 64.17; H, 3.73; N, 5.76;
S, 26.35. Found: C, 63.85; H, 3.68; N, 6.12; S, 26.65.
5-Cyclopropylpyridine-3-sulfonyl fluoride (37d). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.7. Yield 701 mg (83%); white solid; mp = 66–68 °C.
1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.81
(d, J = 2.3 Hz, 1H), 2.02 (tt, J = 8.4, 5.0 Hz, 1H), 1.21 – 1.15 (m, 2H),
0.87 – 0.81 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 154.5, 145.6, 141.4,
132.0, 127.7, 13.1, 10.2. 19F NMR (376 MHz, CDCl3) δ 67.4. MS (EI): m/z
= 201 [M]+. Anal. calcd. for C8H8FNO2S: C, 47.75; H, 4.01; N, 6.96; S,
15.93. Found: C, 47.45; H, 3.92; N, 6.93; S, 15.55.
2,4-Di(thiophen-2-yl)pyridine (44). 1H NMR (500 MHz, CDCl3) δ 8.56 (d,
J = 5.3 Hz, 1H), 7.84 (s, 1H), 7.67 (dd, J = 3.7, 1.1 Hz, 1H), 7.56 (dd, J =
3.7, 1.2 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.36 (dd, J = 5.2, 1.8 Hz, 1H), 7.22
– 7.11 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 153.2, 150.1, 144.6, 142.2,
141.2, 128.4, 128.0, 127.8, 127.2, 125.4, 124.7, 118.3, 115.0. MS (EI):
m/z = 243 [M]+. Anal. calcd. for C13H9NS2: C, 64.17; H, 3.73; N, 5.76; S,
26.35. Found: C, 64.36; H, 3.66; N, 5.82; S, 26.32.
5-Cyclopropylpyridine-2-sulfonyl fluoride (38d). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(4:1) as eluent. Rf = 0.4. Yield 668 mg (79%); white solid; mp = 78–80 °C.
1H NMR (500 MHz, CDCl3) δ 8.61 – 8.53 (m, 1H), 7.98 (d, J = 7.9 Hz,
1H), 7.55 (d, J = 7.3 Hz, 1H), 2.04 (s, 1H), 1.25 (d, J = 5.2 Hz, 2H), 0.89
(d, J = 4.7 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 148.7, 146.8, 133.4,
128.7, 123.4, 13.1, 10.8. 19F NMR (376 MHz, CDCl3) δ 56.2. MS (EI): m/z
= 201 [M]+. Anal. calcd. for C8H8FNO2S: C, 47.75; H, 4.01; N, 6.96; S,
15.93. Found: C, 47.40; H, 4.37; N, 6.89; S, 16.01.
tert-Butyl
6-(fluorosulfonyl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-
carboxylate (38e). 5-Bromopyridine-2-sulfonyl fluoride (11) (1.01 g, 4.20
mmol) was dissolved in THF (15 mL), and pinacolate 36e (2.60 g, 8.40
mmol), Pd(dppf)2Cl2 (307 mg, 0.42 mmol), Na3PO4 (2.06 g, 12.6 mmol)
were added under argon atmosphere. The resulting mixture was refluxed
until the reaction was complete (monitored by TLC, ca. 2 weeks). Then,
EtOAc (40 mL) was added and the resulting solution was washed with
H2O (315 mL) and brine (310 mL). The organic layer was separated,
dried over Na2SO4 and evaporated in vacuo. The product was purified by
column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.7. Yield 1.13 g (79%); white solid; mp = 96–98 °C. 1H NMR
(400 MHz, CDCl3) δ 8.81 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H),
7.90 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 4.14 (d, J = 4.1 Hz, 2H), 3.67 (t, J =
5.6 Hz, 2H), 2.53 (s, 2H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
154.6, 149.1 (d, J = 30.4 Hz), 147.7, 141.6, 133.9, 124.0 (d, J = 2.2 Hz),
80.5, 80.2, 41.2, 28.4 (d, J = 6.8 Hz), 26.9. 19F NMR (376 MHz, CDCl3) δ
56.1. MS (EI): m/z = 342 [M]+. Anal. calcd. for C15H19FN2O4S: C, 52.62; H,
5.59; N, 8.18; S, 9.36. Found: C, 52.29; H, 5.92; N, 8.45; S, 9.28.
6-Cyclopropylpyridine-2-sulfonyl fluoride (39d). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(3:2) as eluent. Rf = 0.55. Yield 600 mg (71%); white solid; mp = 81–
83 °C. 1H NMR (500 MHz, CDCl3) δ 7.92 – 7.74 (m, 2H), 7.59 – 7.43 (m,
1H), 2.25 – 2.09 (m, 1H), 1.16 (d, J = 13.8 Hz, 4H). 13C NMR (125 MHz,
CDCl3) δ 166.2, 150.9 (d, J = 29.1 Hz), 137.8, 126.9, 120.3 (d, J = 2.2
Hz), 17.2, 11.6. 19F NMR (376 MHz, CDCl3) δ 53.3. MS (EI): m/z = 201
[M]+. Anal. calcd. for C8H8FNO2S: C, 47.75; H, 4.01; N, 6.96; S, 15.93.
Found: C, 47.79; H, 4.30; N, 7.34; S, 15.70.
4-Cyclopropylpyridine-2-sulfonyl fluoride (40d). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
(2:3) as eluent. Rf = 0.5. Yield 583 mg (69%); white solid; mp = 50–52 °C.
1H NMR (500 MHz, CDCl3) δ 8.61 (d, J = 5.0 Hz, 1H), 7.73 (s, 1H), 7.31
(d, J = 4.9 Hz, 1H), 2.08 – 2.00 (m, 1H), 1.31 – 1.25 (m, 2H), 0.97 – 0.89
(m, 2H). 13C NMR (125 MHz, CDCl3) δ 157.7, 150.8 (d, J = 29.6 Hz),
149.9, 125.4, 120.4 (d, J = 1.9 Hz), 15.1, 11.5. 19F NMR (376 MHz,
CDCl3) δ 55.2. MS (EI): m/z = 201 [M]+. Anal. calcd. for C8H8FNO2S: C,
47.75; H, 4.01; N, 6.96; S, 15.93. Found: C, 47.55; H, 3.77; N, 7.00; S,
15.61.
General procedure for the preparation of 45–47
The corresponding sulfonyl fluoride 10–13 (101 mg, 4.20 mmol) was
dissolved in THF (15 mL), and Pd(dppf)2Cl2 (307 mg, 0.42 mmol) was
added under argon atmosphere. Et2Zn solution in hexanes (1M, 6.30 mL,
6.30 mmol) was added dropwise and resulting mixture was refluxed and
the completion of reaction was controlled by TLC. Then, EtOAc (40 mL)
was added to the reaction mixture and the resultion solution was washed
with H2O (315 mL) and brine H2O (310 mL). The organic layer was
separated, dried over Na2SO4 and evaporated in vacuo.
5-Cyclopropylfuran-2-sulfonyl fluoride (41d). The product was purified
by column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.55. Yield 727 mg (91%); yellowish liquid; bp = 69–71 °C / 1
mmHg. 1H NMR (500 MHz, CDCl3) δ 7.30 (dd, J = 3.6, 1.8 Hz, 1H), 6.20
(d, J = 3.6 Hz, 1H), 2.01 (tt, J = 8.4, 5.1 Hz, 1H), 1.11 – 1.06 (m, 2H),
1.01 – 0.94 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 165.8 (d, J = 2.4 Hz),
137.0 (d, J = 36.2 Hz), 123.3 (d, J = 3.2 Hz), 105.6, 9.0, 8.0. 19F NMR
(470 MHz, CDCl3) δ 64.2. MS (EI): m/z = 290 [M]+. Anal. calcd. for
C7H7FO3S: C, 44.21; H, 3.71; S, 16.86. Found: C, 43.89; H, 3.44; S,
16.47.
5-Ethylpyridine-2-sulfonyl fluoride (45). The product was purified by
column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.8. Yield 675 mg (85%); yellowish oil; bp = 66–68 °C / 0.2
mmHg. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 2.2 Hz, 1H), 8.01 (d, J =
8.0 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 2.80 (q, J = 7.6 Hz, 2H), 1.30 (t, J =
7.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 150.9, 148.6 (d, J = 30.5 Hz),
146.4, 137.5, 124.0 (d, J = 2.2 Hz), 26.2, 14.7. 19F NMR (376 MHz,
CDCl3) δ 55.9. MS (EI): m/z = 189 [M]+. Anal. calcd. for C7H8FNO2S: C,
44.44; H, 4.26; N, 7.40; S, 16.95. Found: C, 44.77; H, 4.03; N, 7.05; S,
17.13.
5-Cyclopropylthiophene-2-sulfonyl fluoride (42d). The product was
purified by column chromatography on silica gel using hexanes – EtOAc
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801270
European Journal of Organic Chemistry
FULL PAPER
6-Ethylpyridine-2-sulfonyl fluoride (46). The product was purified by
column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.75. Yield 747 mg (94%); white solid; mp = 55–57 °C. 1H
NMR (400 MHz, CDCl3) δ 7.97 – 7.82 (m, 2H), 7.53 (dd, J = 6.0, 2.8 Hz,
1H), 2.95 (q, J = 7.7 Hz, 2H), 1.34 (t, J = 7.7 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.2, 150.7 (d, J = 29.1 Hz), 138.6, 127.9, 121.3 (d, J = 2.2
Hz), 31.1, 13.4. 19F NMR (376 MHz, CDCl3) δ 54.3. MS (EI): m/z = 189
[M]+. Anal. calcd. for C7H8FNO2S: C, 44.44; H, 4.26; N, 7.40; S, 16.95.
Found: C, 44.82; H, 4.48; N, 7.26; S, 17.15.
J. Lin, L. C. Lo, Tetrahedron 2016, 72, 58–68.
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4-Ethylpyridine-2-sulfonyl fluoride (47). The product was purified by
column chromatography on silica gel using hexanes – EtOAc (3:2) as
eluent. Rf = 0.75. Yield 620 mg (78%); yellowish oil; bp = 75–77 °C / 0.2
mmHg. 1H NMR (500 MHz, СDCl3) δ 8.66 (d, J = 4.8 Hz, 1H), 7.93 (s,
1H), 7.51 (d, J = 4.8 Hz, 1H), 2.81 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz,
3H). 13C NMR (125 MHz, СDCl3) δ 156.8, 151.2 (d, J = 29.4 Hz), 150.8,
128.7, 123.7 (d, J = 2.1 Hz), 28.3, 13.9. 19F NMR (470 MHz, СDCl3) δ
55.7. MS (EI): m/z = 189 [M]+. Anal. calcd. for C7H8FNO2S: C, 44.44; H,
4.26; N, 7.40; S, 16.95. Found: C, 44.41; H, 4.48; N, 7.06; S, 17.07.
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Pd(PPh3)4 (482 mg, 0.417 mmol), Me3Al (2 M in hexanes, 2.09 mL, 4.17
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was refluxed and the completion of reaction was controlled by TLC. Then,
EtOAc (40 mL) was added to the reaction mixture and the resulting
solution was washed with H2O (315 mL) and brine H2O (310 mL). The
organic layer was separated, dried over Na2SO4 and evaporated in vacuo.
Purified by column chromatography on silica gel using hexanes – EtOAc
(3:2) as eluent. Rf = 0.5. Yield 610 mg (61%); white solid; mp = 172–
174 °C. 1H NMR (500 MHz, CDCl3) δ 9.28 (s, 1H), 9.25 (s, 1H), 8.83 (d, J
= 4.6 Hz, 2H), 8.50 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 4.3 Hz, 2H). 13C NMR
(125 MHz, CDCl3) δ 154.1, 151.0, 148.8, 142.4, 135.0, 134.1, 130.7 (d, J
= 26.2 Hz), 121.6. 19F NMR (470 MHz, CDCl3) δ 68.4. MS (EI): m/z = 238
[M]+. Anal. calcd. for C10H7FN2O2S: C, 50.42; H, 2.96; N, 11.76; S, 13.46.
Found: C, 50.81; H, 2.64; N, 11.85; S, 13.67.
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Acknowledgements
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The work was funded by Enamine Ltd.
Keywords: Heterocyclic, sulfonyl fluoride, Suzuki coupling,
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10.1002/ejoc.201801270
European Journal of Organic Chemistry
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Sulfonyl fluorides
Artem Yu. Cherepakha, Kateryna O.
Stepannikova, Bohdan V. Vashchenko,
Marian V. Gorichko, Andrey A.
Tolmachev, Oleksandr O. Grygorenko*
Page No. – Page No.
Synthesis of novel five- and six-membered heteroaromatic sulfonyl fluorides
bearing bromine atom at various positions of the heterocyclic ring is described.
Synthetic utility of these compounds is demonstrated by the chemoselective Suzuki,
Stille and Negishi sp2–sp2 or sp2–sp3 C–C cross-coupling reactions, which
proceeded at the aryl bromide moiety with 69–98% yields with expected tolerance
of the SO2F group towards the coupling reaction conditions.
Hetaryl Bromides Bearing SO2F
Group – Versatile Substrates for
Palladium-Catalyzed C–C Coupling
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