SO2F2-mediated deoxygenative C2-sulfonylation of quinoline N-oxides with sodium sulfinates

Article abstract of DOI:10.1016/j.tetlet.2020.152586

A mild and efficient method for deoxygenative C2-sulfonylation of quinoline N-Oxides in the presence of a base has been developed employing extremely inexpensive SO₂F₂ as an activator and sodium sulfinate as nucleophilic sulfonylation source. It is noteworthy that the reaction proceeded well under metal- and oxidant-free conditions to give a variety of 2-sulfonylquinolines in medium to good yields.

Full text of DOI:10.1016/j.tetlet.2020.152586

Journal Pre-proofs
SO F -Mediated Deoxygenative C2-Sulfonylation of Quinoline N-Oxides
2
2
with Sodium Sulfinates
Chengmei Ai, Xudong Liao, Yi Zhou, Zhaohua Yan, Sen Lin
PII:
S0040-4039(20)31085-6
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152586
TETL 152586
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 August 2020
10 October 2020
18 October 2020
Please cite this article as: Ai, C., Liao, X., Zhou, Y., Yan, Z., Lin, S., SO F -Mediated Deoxygenative C2-
2
2
Sulfonylation of Quinoline N-Oxides with Sodium Sulfinates, Tetrahedron Letters (2020), doi: https://doi.org/
0.1016/j.tetlet.2020.152586
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Tetrahedron Letters
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SO F -Mediated Deoxygenative C2-Sulfonylation of Quinoline N-Oxides with
2
2
Sodium Sulfinates
Chengmei Ai, Xudong Liao, Yi Zhou, Zhaohua Yan,* Sen Lin*
College of Chemistry, Nanchang University, Nanchang 330031, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A mild and efficient method for deoxygenative C2-sulfonylation of quinoline N-Oxides in the
presence of a base has been developed employing extremely inexpensive SO as an activator
and sodium sulfinate as nucleophilic sulfonylation source. It is noteworthy that the reaction
2 2
F
proceeded well under metal- and oxidant-free conditions to give
sulfonylquinolines in medium to good yields.
a variety of 2-
Received in revised form
Accepted
2020 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Sulfuryl fluoride
Metal-free
Oxidant-free
2
-sulfonylquinolines
Introduction
NH2
In the past decades, C-H functionalization has become a highly
attractive strategy for organic chemists, as it has been proved to
be a powerful and versatile tool for installation of a series of
functional groups through C-H bond activation.1 By this
approach the derivatization of quinolines at C2 or C8 position
O
S
O
N
N
S
O
HN OH
O
O
Antibacterial agents
Antitumor agents
Fig 1. Examlpes of bioactive 2-sulfonylquinoline derivative molecules
2
regioselectively can be realized in a relatively simple way. N-
heteroaromatic compounds with a sulfur moiety at side chain
exhibit a broad range of physical, chemical and biological
activities, and play important roles in agricultural, industrial and
N-heteroaromatic compounds are commonly synthesized by
oxidation of corresponding sulfides or by alkylation of sulfinate
3
pharmaceutical chemistry (Fig. 1). Traditionally, 2-sulfonyl
4
salts. Both methods suffer the following flaws: that the basic raw
materials are often 2-halopyridines, and that most of which have
a terrible odor.
In the past few years, significant achievements have been
made for preparation of 2-sulfonylquinolines under transition-
5
metal catalysis or metal-free conditions. For instance, in 2015,
Zhao and Chen developed a powerful strategy for the synthesis of
sulfonylated quinolines from quinoline N-oxides and sulfonyl

2
Tetrahedron
chlorides via H-phosphonate-mediated C−H activation.
work on SuFEx-based click chemistry, sulfuryl fluoride has been
widely used in other chemical conversion.11 Very recently, Qin
6
[
Scheme 1, A, 1)]. In 2016, the Han group reported an efficient
and concise methodology to afford sulfonylated quinoline N-
oxides via copper-catalyzed C-H activation with sodium sulfinate
2 2
group reported a variety of SO F -mediated synthesis of chemical
functional groups, including arylnitriles, ethenesulfonyl fluorides,
arylcarboxylic acids, alkynes, and amides.12 Meanwhile, our
7
as the sulfonylation reagent [Scheme 1, A, 2)]. Meanwhile, the
He group disclosed the hypoiodite-mediated C-H activation of
quinoline N-oxides with sulfonyl hydrazides for direct synthesis
of 2-sulfonyl quinolines. All the above reported methods are
successful in conversion of quinoline N-oxides into the
group recently reported an efficient SO
of olefins with hydrogen peroxide (Scheme 1, C).13 However, to
the best of our knowledge, SO as an inexpensive reagent, has
2 2
F -mediated epoxidation
2 2
F
not yet been employed as an activator for deoxygenative C2
functionalization of quinoline N-oxides. Therefore, we
envisioned that sulfuryl fluoride can serve as an activator and
sodium sulfinate as a nucleophilic reagent to implement a one-
pot synthesis of 2-sulfonyl quinolines. Herein, we report a metal-
8
corresponding C2 sulfonylation products. However, they still
have disadvantages of using metal catalysis and oxidants, and
requiring strictly anhydrous reaction conditions. Therefore, it is
still a challenging task for chemists to develop mild, metal- and
oxidant-free, and water-insensitive approaches for C2
sulfonylation of quinoline N-oxides.
2 2
and oxidant-free, and mild SO F -mediated deoxygenative C2
sulfonylation of quinoline N-oxides.
Results and discussion
Scheme 1. 2-functionalization of N-Oxides via C-H Activation
A Current methods for 2-sulfonyl quinoline via C-H activation
Our study started with the reaction of quinoline N-oxide (1a)
and sodium benzenesulfinate (2a) under a SO atmosphere.
Much to our delight, in the presence of Et N as a base, at room
O
Cl
S
KOH
2 2
F
1
)
O
S
O
+
i
HP(O)( OPr)2
N
O
N
3
O
O
S
temperature for 16 h, the reaction smoothly proceeded to give the
desired sulfonylation product 3aa in a moderate yield (Table 1,
entry 1). Encouraged by this result, we screened other solvents
for the optimal conditions. DMF and dioxane showed negative
effects just providing 3aa in 36% and 30% yields, respectively
(Table 1, entries 2-3). It is noteworthy that just trace 4-
sulfonylquinoline was detected in these reactions. Further
CuBr2, K2S2O8
2
)
ONa
O
S
+
N
O
N
O
B
Common approach to 2-functionalization of N-oxides
Activating
Nucleophile
Agent
N
O
N
O
X
-
A-X
Nu
N
Nu
A
A-X=MSC, Ms2O, Ac2O, BzBr, PyBrop, Ts2O
optimization of various bases was carried out, including Et
3
N,
C
Our group previous work
SO2F2 (balloon)
O
DBU, DIPEA, K CO , Cs CO and base-free (Table 1, entries 4-
2
3
2
3
30% H2O2/4 N K2CO3
8
3
). Results showed that Et N as a base exhibited higher efficiency
This work: SO F -activated, metal-free, oxidant-free 2-sulfonylation of N-oxides
2
2
compared with the others. Meanwhile, the best outcome of the
reaction was observed when slightly elevating the reaction
SO2F2
Et3N
O
S
R1
+
R1
O
S
R2
o
R2
ONa
temperature to 40 C (Table 1, entry 9) with the formation of 3aa
N
DMSO
o
N
40
C
O
O
in 82% yield.
The development of C2 functionalization of N-oxide
regioselectively can be traced back to 1936, in which M. Henze
first achieved the target products with N-phenylbenzimidoyl
9
chlorides as activator (Scheme 1, B). On the other hand, sulfuryl
2 2
fluoride gas (SO F ) has been used as fumigant for a long time,
and its application in organic synthesis only recently came into
our eyes. In 2014, Sharpless revealed a new class of click
chemistry based on sulfur(VI) fluoride exchange (SuFEx), which
provides a fast and highly efficient way to effect chemical
functionalization.10 Sulfuryl fluoride is a cheap (0.1 US$ mol-1)
and stable reagent (currently, SO
2 2
F gas in a steel cylinder is
commercially available in China). Since Sharpless’ pioneering

3
Table 1. Optimization of the reaction conditionsa
Scheme 2. Substrate Scope with Variation of Sodium sulfinates
SO2F2 (balloon)
O
SO2F2 (balloon)
+
O
Et3N (5.0 equiv.)
O
S
S
base
R
+
O
S
N
O
R
ONa
N
S
DMSO
Ph
Ph
ONa
solvent, temp.
o
N
O
N
40
C
O
1a
2a-o
3aa-ao
O
1a
2a
3aa
H
3aa, 82%
3ab, 78%
3ac, 58%
3ad, 65%
3ae, 64%
3af, 72%
3ag, 73%
p-Me
o-Me
p- Bu
p-OMe
p-F
p-Cl
solvent
DMSO
DMF
base
Et3N
Et3N
temp.
RT
yieldb
60%
36%
30%
entry
t
1
2
RT
O
S
R1
R1=
N
3
4
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Et3N
RT
p-Br
p-CF3
p-NO2
3ah, 75%
3ai, 64%
3aj, 48%
O
RT
RT
RT
RT
RT
13%
54%
20%
5
6
7
DBU
m-NO2
3ak, 63%
DIPEA
O
S
O
S
2
Cs CO3
22%
25%
82%
N
S
N
8
K2CO3
O
3al, 80%
O
3am, 70%
40 o
C
9
Et N
3
O
S
O
S
aReaction conditions:1a (0.3 mmol), 2a (0.9 mmol),1.5 mmol of base, 2.5 mL
of solvent ,under SO2F2 atmosphere ( using a balloon combined with syringe
needle ), at room temperature for 16 h.
N
N
3an, 65%
O
3ao, 71%
O
a
General conditions: 1a (0.3 mmol), 2 (0.9 mmol),1.5 mmol of Et N, under
3
bisolated yield.
SO2F2 atmosphere ( using a balloon combined with syringe needle ), for 16 h at
0oC. bisolate yields
4
With the optimum conditions (Table 1, entry 9) in hand, we
subsequently explored the substrate scope. A set of sodium
sulfinates including aromatic and aliphatic sulfinates were
evaluated in the reactions with quinoline N-oxide (1a). Results
are shown in Scheme 2. Reactions of o-methyl, p-methyl, p-
methoxy, and p-tert-butyl benzenesulfinates proceeded well to
furnish corresponding products (3ab-3ae). That o-substituted
sulfinates gave a relatively low yield suggests steric factor has a
negative effect on the conversion of starting material. Halogen (-
F, -Br, -Cl) on the benzene ring of benzenesulfinates could be
tolerated well, all affording targeted products in over 70% yields
On the other hand, the compatibility of the functional groups
on the quinoline N-oxides were also tested in the reaction. As
shown in Scheme 3, using sodium benzenesulfinate (2a) as the
model substrate, a wide range of substituted quinoline N-oxides
were smoothly transformed to diverse sulfonyl-decorated
quinolines. 3-, 4-, 6-, 7-methyl-substituted quinoline N-oxides
worked well in the reactions, providing the desired products in
medium to good yields. Obviously, the lower yield of 3-methyl
quinoline N-oxide might be due to steric hindrance. Halogen-
substituted quinoline N-oxides were also tolerated to give the
corresponding products (3fa-3ga) in 46% and 77% yields,
respectively. Meanwhile, methoxy-substituted quinoline N-
oxides produced sulfonylated quinolines in medium yields (3ha-
(3af-3ah). Fortunately, benzenesulfinates containing electron-
withdrawing groups were also suitable substrates and produced
desired compounds (3ai-3ak) in acceptable yields ranging from
4
8%-64%. When sodium thiazole sulfonate used, a good yield
3
ia). Subsequently, isoquinoline N-oxide 1i was used as a
was received (3kl). In the end, besides the aromatic sulfinates,
several aliphatic sulfinates were smoothly converted to desired
products in 70%, 65%, and 71% yields, respectively (3am, 3an,
substrate to examine the regioselectivity, and the results
demonstrated that the reaction showed no obvious selectivity.
Finally, we tried the reaction of N,N-dialkylaniline N-oxide with
sodium benzenesulfinate, and a 35% yield of 3ka was obtained.
3
ao).

4
Tetrahedron
Scheme 3. Substrate Scope with Variation of N-Oxides
Scheme 5. Control Experiments
O
S
SO2F2 (balloon)
Et3N (5.0 equiv.)
R
R
O
S
O
S
+
(a)
(b)
standard conditions
Ph
ONa
Ph
N
O
DMSO
N
+
O
S
Ph
Ph
Ph
o
N
Ph
ONa 3.0 equiv. TEMPO
1
b-j
2a
40
C
3ba-ja
O
N
O
O
1
a, 0.3 mmol
2a, 0.9 mmol
3aa, 78%
O
S
O
S
O
S
O
S
O
S
Ph
Ph
Ph
Ph
Ph
Ph
Et3N (1.5 equiv.)
N
N
N
N
+
O
S
Ph
ONa
DMSO
3
ba, 52%
O
3ca, 88%
O
3da, 79%
3ea, 80%
O
N
O
o
N
O
40
C
Br
O
MeO
Ph
1a, 0.3 mmol
2a, 0.9 mmol
3aa, n.p.
O
S
O
S
O
S
O
S
O
S
SO2F2
Ph
N
N
N
(c)
(d)
+
O
S
N
Ph
ONa
DMSO
F
O
O
OMe
O
N
O
N
O
o
40 C
3
fa, 77%
3ga,46%
3ha, 70%
3ia, 60%
O
1
a, 0.3 mmol
2a, 0.9 mmol
3aa,
35%
Ph
O
S
N
O
O
S
standard conditions
O
+
only trace of 4-isomer
was detected
N
N
Ph
N
O
Ph
ONa
S
O
S
Ph
O
1
k, 0.3 mmol
2a, 0.9 mmol
O
3
ja-1:3ja-2=1.8:1, 56%
3ka, 35%
a
General conditions: 1 (0.3 mmol), 2a (0.9 mmol),1.5 mmol of Et3N, 2.5 mL of DMSO,
under SO2F2 atmosphere ( using a balloon combined with syringe needle ), for 16 h at
0oC. bisolated yields
On the basis of the mechanism investigation in previous
literature14 and the above experiment observations, a plausible
mechanism was proposed as shown in Scheme 6. At first,
tautomerization of sulfinate anion I exists in equilibrium S-
4
In order to demonstrate the practicality of this method, a gram-
scale reaction was performed under standard conditions. As
2 2
centered anion II. Meanwhile, SO F as an activator was attacked
shown in Scheme 4, 1.25 g of quinoline N-oxide (1a) afforded
by the oxygen atom of quinoline N-oxide to form intermediate
III. Then the C2 of the intermediate III was nucleophilically
attacked by sulfonyl anion II and gives an intermediate IV,
which subsequently suffer rearomatized to form 2-
sulfonylquinoline 3.
2
.02 g of 2-sulfonyl quinoline (3aa) in 87% yield, which proved
that this method can be applicable in organic synthesis.
Scheme 4. Gram-Scale synthesis of 2-sulfonylquinoline
SO2F2 (balloon)
O
+
Et N (5.0 equiv.)
3
O
S
S
N
O
Ph
ONa
Ph
DMSO
40 oC
N
O
1
1
a
2a
3aa
2.02 g, 87%
.25 g
Scheme 6. Plausible Mechanism
O
S
O
S
O
S
To explore the reaction mechanism, some control experiments
were carried out (Scheme 5). First, a radical trapping reagent
RSO Na
Ph
2
Ph
O
Ph
O
N
2
I
II
3
O
Et3N
(
TEMPO) had little influence on the reaction efficiency, proving
that the reaction is not involved in free radical intermediate
Scheme 5, (a)]. Subsequently, no sulfonylation occurred
between quinoline N-oxide (1a) and sodium benzenesulfinate (2a)
without SO indicating SO plays a key role in the reaction
Scheme 5, (b)]. When the reaction was performed in the absence
SO2F2
H
N
N
N
SO2Ph
[
O
1
III
OSO2F
IV
OSO2F
2
F
2
2 2
F
[
Conclusions
of a base, a low yield was obtained [Scheme 5, (c)]. It confirmed
that base greatly promoted the transformation. Finally, treatment
of 2-methylquinoline N-oxide under standard reaction conditions
could not afford the 2-sulfonylation product and only trace of 4-
sulfonylation product can be detected, which proved the
sulfonylation of quinoline N-oxide regioselectively occurred at
C2 position [Scheme, (d)].
In conclusion, we have reported the SO
2
F
2
-mediated
deoxygenative sulfonylation of quinoline N-oxides under metal-
and oxidant-free conditions with sodium sulfinates via C-H bond
2 2
activation. SO F was used as an activator to promote the
synthesis of a variety of substituted 2-sulfonylquinolines. One
distinct advantage of this method is that by-products derived
2
-
-
2 2 4
from the use of SO F is water-soluble anions SO and F which
can be easily removed by aqueous work-up operation.
Acknowledgements

5
We thank the National Natural Science Foundation of China (No.
1362022) and The Natural Science Foundation of Jiangxi
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6
Tetrahedron
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4
. Metal- and Oxidant-free conditions are the other
two advantages.
High lights
Graphical Abstract
1
. SO F was used as an efficient activator for C-2
2 2
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instructions in the template box below.
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sulfonylation of quinoline N-oxides.
2
. Low-cost (around 1 US dollar/kg) and
environmentally benign SO F was used.
2
2
3
. The method possesses broad substrate scope.
High lights
5
. SO F was used as an efficient activator for C-2
2
2
Leave this area blank for abstract
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SO F -Mediated Deoxygenative C2-Sulfonylation of Quinoline N-Oxides with Sodium Sulfinates
2
2
Chengmei Ai, Xudong Liao, Yi Zhou, Zhaohua Yan*, Sen Lin*
SO F inexpensive and aboundant reagent
2
2
SO2F2
Et N
3
mild conditions
metal-free
O
S
R1
R1
+
O
S
R2
R2
ONa
N
DMSO
oxidant-free
gram-scale reaction
N
o
4
0 C
sulfonylation of quinoline N-oxides.
. Low-cost (around 1 US dollar/kg) and
environmentally benign SO F was used.
6
2
2
7
8
. The method possesses broad substrate scope.
. Metal- and Oxidant-free conditions are the other
two advantages.