Cu-Catalyzed Deoxygenative C2-Sulfonylation Reaction of Quinoline N-Oxides with Sodium Sulfinate

Article abstract of DOI:10.1021/acs.orglett.6b02289

An unexpected Cu-catalyzed deoxygenative C2-sulfonylation reaction of quinoline N-oxides in the presence of radical initiator K₂S₂O₈ was developed that used sodium sulfinate as a sulfonyl coupling partner. The mechanism studies indicate that the reaction proceeds via Minisci-like radical coupling step to give sulfonylated quinoline with good chemical yields.

Full text of DOI:10.1021/acs.orglett.6b02289

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Deoxygenative C2-Sulfonylation Reaction of Quinoline
N‑Oxides with Sodium Sulfinate
Bingnan Du, Ping Qian, Yang Wang, Haibo Mei, Jianlin Han,* and Yi Pan*
School of Chemistry and Chemical Engineering, State Key laboratory of Coordination Chemistry, Nanjing University, Nanjing
210093, China
S
* Supporting Information
ABSTRACT: An unexpected Cu-catalyzed deoxygenative
C2-sulfonylation reaction of quinoline N-oxides in the presence
of radical initiator K2S2O8 was developed that used sodium
sulfinate as a sulfonyl coupling partner. The mechanism studies
indicate that the reaction proceeds via Minisci-like radical cou-
pling step to give sulfonylated quinoline with good chemical yields.
n the past decade, transition-metal-catalyzed C−H function-
Scheme 1. Synthesis of 2-Sulfonyl Quinoline N-Oxide and
Quinoline
I
alization has received extensive attention in organic
synthesis,1 as it has been demonstrated to be a powerful and
versatile tool for directly introducing new functionalities via
C−H bond transformation with high atom economy. In the
past few years, significant achievements have been made in the
area of C−H bond functionalization of quinoline N-oxides with
C2 or C82 position regioselectivities under transition-metal
catalysis or metal-free conditions.3 Among these reactions, most
were catalytic reactions of quinoline N-oxides with C−H bond
transformation resulting in substituted quinoline N-oxides.4
The others were the deoxygenative functionalization reactions
using reductants or additives, affording substituted quinolines
as products.5 On the other hand, in the presence of oxidants,
the substituted quinoline N-oxides were found as products
without the cleavage of N−O bonds.6 To the best of our
knowledge, the coupling reaction with the deoxygenation of
quinoline N-oxides in the presence of oxidant has rarely been
explored.7
Heterocyclic aromatic sulfone is recognized as a crucial class
of scaffold in natural products, pharmaceuticals, and biologically
active compounds.8 In particular, quinoline sulfone compounds
exhibited biological antibacterial activities and antiproliferative
activity.9 The previous report on the synthesis of these com-
pounds was nucleophilic substitution reaction of halide with
thiol, followed by the oxidation of thioether to the corresponding
sulfone.10 In 2013, the Wu group reported an efficient and
concise protocol to synthesize sulfonylated quinoline N-oxides
via copper-catalyzed C−H bond activation with aryl sulfonyl
chlorides as the sulfonylation reagents (Scheme 1a).11
Recently, Li also developed an attractive method for the
synthesis of sulfonylated quinoline from quinoline N-oxides and
sulfonyl chlorides (Scheme 1b).12 However, a stoichiometric
amount of toxic H-phosphonate is required for the reduction of
N-oxides. Very recently, the He group reported an approach for
direct C2 sulfonylation of heteroaromatic N-oxides with
sulfonyl hydrazides affording 2-sulfonyl quinolines/pyridines
using NaI and TBHP as activators.13 Based on our continued
pursuit of Cu-catalyzed reactions and C−H bond activation,14
herein we report a new strategy to access quinoline sulfone
compounds via CuBr2- and K2S2O8-promoted reaction between
sodium sulfinates and quinoline N-oxides (Scheme 1c). Notably,
the reaction promoted by K2S2O8 afforded the unexpected
deoxygenative C2-sulfonylation15 product instead of the
envisioned sulfonylated quinoline N-oxide.
Based on the previous reports,4,5 we initiated the reaction
with quinoline N-oxide 1a and sodium p-toluenesulfinate 2a.
To our surprise, an unexpected deoxygenative product
2-(toluene-4-sulfonyl)quinoline 3aa was found with CuBr2 as
catalyst (entry 1, Table 1). Although only 11% chemical yield
was obtained, this unusual result still inspired us to optimize
this reaction by using other copper catalysts. Several copper
salts (entries 2−6) were screened; however, no improvement
was found. The results showed CuBr2 was the best choice for
this transformation. Further optimization was carried out with
Received: August 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02289
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope with Variation of Sodium
a,b
Sulfinate
b
entry
catalyst
CuBr2
additive
solvent
DMF
yield (%)
1
11
<5
9
2
CuI
DMF
3
CuBr
DMF
4
CuCl
DMF
6
5
Cu(OAc)2
Cu(OTf)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
DMF
<5
<5
13
33
17
<5
37
<5
11
51
70
68
62
41
45
75
14
6
DMF
7
DMA
8
DCE
9
dioxane
10
11
12
13
14
15
16
17
18
19
toluene
CH3NO2
DMSO
CH3CN
c
CH3NO2/DCE
CH3NO2/DCE
CH3NO2/DCE
CH3NO2/DCE
CH3NO2/DCE
CH3NO2/DCE
CH3NO2/DCE
CH3NO2/DCE
K2S2O8
Na2S2O8
I2
d
BQ
O2
e
20
K2S2O8
K2S2O8
e
21
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), catalyst (20 mol %),
solvent (4 mL) in a flask under argon balloon for 15 h at 40 °C.
a
Reaction conditions: 1a (0.25 mmol), 2 (0.5 mmol), CuBr2 (20 mol %),
b
c
d
Isolated yield based on 1a. Volume ratio = 3:1. Benzoquinone.
K2S2O8 (50 mol %), DCE (1 mL), CH3NO2 (3 mL), and H2O
e
b
0.1 mL of H2O was added.
(0.1 mL) under argon balloon at 40 °C for 15 h. Isolated yield based
on 1a.
the use of various solvents (entries 7−13), and it was found
that DCE (33% yield, entry 8) and CH3NO2 (37% yield,
entry 11) gave observable improvements. Surprisingly, the yield
was increased to 51% when a combination of CH3NO2 and
DCE with a volume ratio of 3:1 was employed as cosolvent
(entry 14). Encouraged by the positive result and based on the
observed conversion of sulfinate into a sulfonyl group in this
process, additional oxidants were investigated to improve the
efficiency. We were pleased to find that the yield was increased
to 70% with the addition of K2S2O8 (entry 15). Other oxidants
(entries 16−19), including Na2S2O8, iodide, BQ, and oxygen,
were also examined, and the results disclosed that K2S2O8 was
the best choice. We were glad to find that an addition of 0.1 mL
of H2O gave a slight promotion of yield to 75% (entry 20),
which is mainly because the addition of water could increase
the solubility of the catalyst and K2S2O8. It is essential for the
use of copper catalyst, as the reaction gave a very poor yield in
the absence of copper catalyst (entry 21). Thus, the optimized
reaction conditions were identified as 20 mol % of CuBr2,
0.5 equiv of K2S2O8, a 3:1 mixture of CH3NO2 and DCE as
the cosolvent, and 0.1 mL of H2O at 40 °C under argon
atmosphere for 15 h.
chemical yields. Generally, sulfinates containing electron-donating
groups performed better than substrates with electron-withdrawing
groups (3aa, 3an vs 3ad, 3am). Halogen groups on the
aromatic ring of sodium benzenesulfinates also could be well
tolerated in the Cu-catalyzed reaction, giving the desired
product in moderate to good yields (3ad−ai). Fortunately, the
reaction with iodo-substituted sodium benzenesulfinates also
proceeded smoothly, resulting in the desired product with 43%
yield (3ag). We can also find that o-substituted sodium benzene-
sulfinates gave lower yields (3ae vs 3ai), mainly because of the
steric hindrance. Moreover, alkyl sodium sulfinates could also be
suitable substrates and gave a moderate to good yield (3aj−al).
It is noteworthy that sodium sulfinate with an easily transferred
group showed good reactivity (cyclopropyl 3al and ester 3ap)
and afforded the desired product with 71% and 48% yield,
respectively. Finally, a heterocyclic sulfinate, sodium thiophene-
2-sulfinate 2r, has been used in this reaction and was converted
into the corresponding product 3ar in 41% yield. The chemical
structure of the obtained product has been confirmed by X-ray
analysis of 3aa (see the SI), which confirms that the N−O bond
cleavage occurs during the reaction.
With the optimal reaction conditions in hand, we turned our
attention to the substrates scope for this transformation. Several
sodium sulfinates were evaluated in the reaction with quinoline
N-oxide 1a (Scheme 2). As shown in Scheme 2, a wide range of
sodium sulfinates, bearing aryl, alkyl, and cycloalkyl groups,
could work well in this reaction, affording the corresponding
reduction product 2-sulfonyl quinoline 3aa with up to 77%
Then, several quinoline N-oxides were explored as substrates
by reaction with sodium p-toluenesulfinate 2a (Scheme 3).
o-, m- and p-methyl-substituted quinoline N-oxides could all
work well in the reaction, giving the desired product in good
yields (3ba−da). The reactions of halogen group substituted
quinoline N-oxide also proceeded well to give slightly lower
yields (3ea−ga). Finally, isoquinoline N-oxide 1i was used as
B
DOI: 10.1021/acs.orglett.6b02289
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Organic Letters
Letter
into the reaction mixture of 1a and 2a. The formation of
product 3aa was suppressed, and the DPE coupling product 4
was obtained with 43% yield. This result further indicates the
current system is a radical process (Scheme 4c). To clarify
which species participates in the reduction of product, a
reaction of 2-(toluene-4-sulfonyl)quinoline N-oxide with
sodium p-toluenesulfinate was carried out under the standard
conditions (Scheme 4d). Almost no desired product was found,
which indicates the reaction does not undergo a sequence of
sulfonylation and deoxygenation. We then added excess sodium
p-toluenesulfinate in the reaction system in the absence of
CuBr2 and K2S2O8 to examine whether sodium p-toluenesulfinate
is the reducing agent (Scheme 4e). However, the experimental
evidence indicates that sodium p-toluenesulfinate cannot reduce
the quinoline N-oxide 1a to quinoline. Finally, we used sodium
p-toluenesulfonate instead of sodium p-toluenesulfinate as the
sulfonyl precursor (Scheme 4f). However, no desired product
was obtained, which implies that p-toluenesulfinate rather
than p-toluenesulfonate acts as reactive species in this trans-
formation.
Scheme 3. Substrate Scope with Variation of Quinoline N-
Oxide
a,b
a
Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), CuBr2 (20 mol %),
K2S2O8 (50 mol %), DCE (1 mL), CH3NO2 (3 mL) and H2O (0.1 mL)
On the basis of the results obtained above and the previous
literature,4,5 a plausible mechanism via Minisci-like radical
coupling step for this deoxygenative sulfonation reaction was
proposed in Scheme 5. In the initial step, sodium sulfinate 2b is
b
under argon balloon at 40 °C for 15 h. Isolated yield based on 1.
the reactant to investigate the regioselectivity. The results
disclose that the reaction showed no evident regioselectivity,
and both two positions adjacent to N−O group were sul-
fonylated with the ratio of 1:1.1 (3ia). Fortunately, these two
isomers 3ia can be relatively easy obtained by using routine
column chromatography.
Scheme 5. Proposed Mechanism
To clarify the reaction mechanism, some control experi-
ments were carried out (Scheme 4). When quinoline, instead of
Scheme 4. Control Experiments
oxidized by Cu(II) or K2S2O8 to form a sulfinate radical A via
SET.16 Then, the intermediate A reacts with quinoline N-oxide
1a through a Minisci-like reaction to generate intermediate B.17
Radical B is rapidly seized by Cu(I) to give hydroxylamine
intermediate C, which is converted into the final product 3ab
through elimination of water and regenerates Cu(II) for the
next cycle.
To conclude, an unexpected Cu-catalyzed deoxygenative
C2-sulfonylation reaction of quinoline N-oxides in the presence
of K2S2O8 was developed. This reaction was carried out under
mild conditions, which provides an easy pathway for the prepa-
ration of bioactive 2-sulfonyl quinolines with soldium sulfinate
as a sulfonyl precursor. The mechanism studies indicate that the
reaction proceeds via a Minisci-like radical-coupling step.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02289.
■
quinoline N-oxide, was used as the reactant under the standard
conditions, no desired 2-sulfonyl quinoline was found, which
indicates that the N-O group plays an important role in the
transformation (Scheme 4a). Moreover, addition of a radical
scavenger 2,2,6,6-tetramethylpiperidyl-1-oxyl (TEMPO) to
the reaction mixture will suppress this reaction (Scheme 4b),
suggesting the possibility of a radical nature of this process.
Then, 1,1-diphenylethylene (DPE) (DPE:1a = 1:1) was added
S
Experimental procedures, full spectroscopic data for
1
compounds 3 and 4, X-ray analysis of 3aa, and H and
13C NMR spectra (PDF)
X-ray data for 3aa (CIF)
C
DOI: 10.1021/acs.orglett.6b02289
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hanjl@nju.edu.cn.
*E-mail: yipan@nju.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21472082).
■
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