Palladium-Catalyzed Highly Regioselective ortho -Halogenation of 2-Pyridyl Sulfoxides

Article abstract of DOI:10.1055/s-0036-1588756

A palladium-catalyzed regioselective ortho -halogenation of 2-pyridyl sulfoxides via a C-H activation pathway has been reported. Under the conditions established, this reaction proceeded smoothly and could tolerate a variety of functional groups under mild conditions.

Full text of DOI:10.1055/s-0036-1588756

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© Georg Thieme Verlag Stuttgart · New York
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A
J.-L. Zhao et al.
Letter
Synlett
Palladium-Catalyzed Highly Regioselective ortho-Halogenation of
2-Pyridyl Sulfoxides
Jun-Long Zhao◊
Xiang-Xiang Chen◊
O
S
O
S
Pd source (10 mol%)
NXS (1.1 equiv)
additive (0.5 equiv)
solvent
Hu Xie
N
N
H
X
Jiang-Tao Ren
Xiao-Feng Gou
Meng Sun*
Regioselective
C–H bond cleavage
X = Cl, Br, I
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry
& Materials Science, Northwest University,
Xi’an 710127, P. R. of China
sunmeng@nwu.edu.cn
◊ These two authors contributed equally to this work
Received: 23.02.2017
Accepted after revision: 26.02.2017
Published online: 16.03.2017
tors.11,12 Although their importance has attracted consider-
able attention for the preparation, the exploration of new
methodologies for C–H bond functionalization of S-con-
taining compounds is still an extremely attractive,13,14 but
challenging issue (the strong coordination generated by
poisoning of transition-metal catalysts15 and undesirable
redox processes). In continuation of our previous work on
C–H bond functionalization–halogenation research,16 here-
in we report a novel and direct palladium-catalyzed haloge-
nation reaction of 2-pyridyl sulfoxides with commercially
available electrophilic halogenating reagents – particularly
N-bromo-, N-chloro-, and N-iodosuccinimide (Scheme 1).
DOI: 10.1055/s-0036-1588756; Art ID: st-2017-w1852-l
Abstract A palladium-catalyzed regioselective ortho-halogenation of
2-pyridyl sulfoxides via a C–H activation pathway has been reported.
Under the conditions established, this reaction proceeded smoothly
and could tolerate a variety of functional groups under mild conditions.
Key words palladium-catalyzed, regioselectivity, halogenation, C–H
activation, sulfoxides
Aryl halides have been proved to be important starting
materials for constructing complex skeletons in synthetic
elaboration, which are able to serve as precursors for the
synthesis of organometallic reagents,1 nucleophilic aromat-
ic substitution,2 and cross-coupling reactions.3 Convention-
al methods of incorporating the halogen group into aromat-
ic rings include electrophilic aromatic substitution4 and
ortho-lithiation followed by a halogen quench,5 which,
however, suffer from several notable disadvantages.6 In re-
cent years, considerable attention has been focused on C–H
bond halogenation,7 which is an atom-economic strategy
for rapid building of carbon–halogen atom bonds. For ex-
ample, in 2004, Sanford8 reported a palladium-catalyzed
halogenation of benzo[h]quinolone. Subsequently, the
groups of Shi, Yu, Bedford, and Xu illustrated the major im-
portance of these halogenation reactions with the assis-
tance of diverse directing groups.9 However, although a
number of methods have been achieved, application of this
strategy to create carbon–halogen bonds for more diverse
structures is still highly desirable for expanding the realm
of selective C–H functionalization.
O
S
O
S
Pd catalysis
NXS (1.1 equiv)
ortho-selective
C–H halogenation
N
N
H
X
Scheme 1 Palladium-catalyzed ortho-halogenation of 2-pyridyl sulfox-
ides
We commenced our exploration by investigating the re-
action of 2-pyridyl sulfoxides17 (1a, 1.0 equiv) with NIS (1.1
equiv) in the presence of 10 mol% Pd(OAc)2 in DCE at 100 °C
for 20 hours (Table 1, entry 1). Encouraged by this result,
different solvents were screened, and chlorobenzene was
proved to be best in this transformation (36% yield). It is
noteworthy that Brønsted acids are conducive to this trans-
formation, which promoted the electrophilicity of the pal-
ladium(II) catalyst18 and rendering NIS a more effective
source of I+.19 For example, higher yield could be obtained
when TFA was added, while AcOH can also give a compara-
ble yield. Further catalyst screening demonstrated that
Pd(OAc)2 was superior to other catalysts and no product
was detected in the absence of catalyst. It was found that a
noticeable (15%) increase in yield was observed when low-
ering the temperature, while other parameter changes sup-
Organosulfur compounds have become widely used in
natural products, pharmaceuticals, and materials science.10
Moreover, they also take a privileged position in the fields
of reagents, ligands, catalysts, and organic semiconduc-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
J.-L. Zhao et al.
Letter
Synlett
pressed the efficiency. Finally, the optimized reaction con-
ditions for the ortho-C–H halogenation of 2-pyridyl sulfox-
ides were determined to be NIS (1.1 equiv) with 10 mol%
Pd(OAc)2 as the catalyst, of TFA (0.5 equiv) as additive, and
PhCl as solvent, at 80 °C under air for 20 hours.
With the optimized reaction conditions in hand, the
scope of the transformation was investigated.20 The results,
summarized in Scheme 2, revealed that the substrates bear-
ing either electron-donating or electron-withdrawing sub-
stituents on the 2-pyridyl sulfoxides were smoothly trans-
formed into the corresponding products in acceptable to
good yields for most case. For example, good yields were
obtained when substrates with a methyl group at the ortho,
meta, or para position of the aromatic rings of sulfoxides
were involved. Moreover, halogenated substrates (e.g., F, Cl,
and Br) executed this chemistry well, producing the desired
products in acceptable yields with the possibility of further
transformation into other important skeletons. In addition,
the strategy was also applicable to 2-(naphthalen-2-yl-
sulfinyl)pyridine, which highly selectively afforded the cor-
responding 2-[(3-iodonaphthalen-2-yl)sulfinyl]pyridine in
moderate yield.
O
S
O
S
NIS (1.2 equiv)
Pd(OAc)2 (10 mol%)
R
R
TFA (0.5 equiv)
PhCl, 80 °C
N
N
I
1
2
O
S
O
S
O
S
Table 1 Optimization of the Reaction Conditionsa,b
N
N
I
N
I
I
O
S
O
S
NIS (1.2 equiv)
Pd source (10 mol%)
2a, 85%
2b, 85%
2c, 82%
O
S
O
S
O
S
additive (0.5 equiv)
solvent
N
N
I
1a
2a
N
N
I
N
I
F
Cl
I
2d, 87%
2e, 56%
2f, 54%
Entry
Catalyst
Additive
Solvent
Yield (%)
O
S
O
S
O
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
DCE
20
trace
23
5
S
MeCN
DME
toluene
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
N
N
I
N
Br
I
MeO
I
3
2ha
2g, 48%
2i, 55%
4
Scheme 2 Scope of sulfoxide compounds in ortho-iodination reac-
tions. All the reactions were carried out in the presence of 0.2 mmol of
1, 0.22 mmol of NIS and 0.1 mmol of TFA in 1.0 mL PhCl at 80 °C under
air conditions. Isolated yields are given. a The product could not be iso-
lated in pure form.
5
36
56
60
15
27
23
59
46
38
47
75
62
33
69
6
AcOH
TFA
7
8
TfOH
MeSO3H
TsOH
TFA
9
However, there is a notable exception when a methoxy
group was included on the aromatic ring, and some uniden-
tified compounds were observed in this process.
10
11
12
13
14
15c
16d
17e
18f
TFA
Further exploration of this strategy demonstrated that
the coupling partner is not restricted to NIS, variation of
different halides, such as NBS and NCS, was also found to be
compatible with this protocol with a subtle change of reac-
tion parameters (Scheme 3). Reactions of 2-pyridyl sulfox-
ides bearing electron-donating substituents (ortho-, meta-,
and para-methyl) afforded the desired products in good
yields, respectively. When the electron-deficient substrates
were exposed to the reaction conditions, the corresponding
2-bromo- and 2-chloro-substituted sulfoxides were isolat-
ed in moderate yields, which are consistent with iodination
procedure.
PdCl2(MeCN)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TFA
TFA
TFA
TFA
TFA
TFA
a All the reactions were carried out in the presence of 0.2 mmol of 1a, 0.22
mmol of NBS, and 0.1 mmol of acid (if any) in 1.0 mL of solvents at 100 °C
under air condition.
b Isolated yield.
c At 80 °C.
d At 60 °C.
e 0.5 mL of PhCl was used.
f 2.0 mL of PhCl was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
J.-L. Zhao et al.
Letter
Synlett
Although the exact mechanism of this reaction is not
clear, a proposed pathway is depicted in Scheme 5.16 Firstly,
the Pd(II) catalyst reacted with 2-pyridyl sulfoxide to form a
five-membered palladacycle intermediate I with the assis-
tance of N atom, which is generally considered to be a bet-
ter coordinating atom than O. Then, the palladacycle inter-
mediate I was oxidized to Pd(IV) complex II21 with NXS. Fi-
nally, reductive elimination from intermediate II generated
the ortho-halogenated sulfoxides and released active Pd(II)
to continue the catalytic cycle.
O
S
O
S
NXS (1.1 equiv)
Pd (10 mol%)
R
R
solvent
N
N
X
X = Br, Cl
3–4
1
O
S
O
S
O
S
N
X
N
X
N
X
3b, X = Br, 75%
4b, X = Cl, 86%
3c, X = Br, 76%
4c, X = Cl, 81%
3a, X = Br, 77%
4a, X = Cl, 81%
O
S
O
S
O
S
O
S
O
S
N
X
N
X
N
X
F
Cl
N
N
Pd(II)
X
3e, X = Br, 60%
4e, X = Cl, 65%
3f, X = Br, 56%
4f, X = Cl, 63%
3d, X = Br, 79%
4d, X = Cl, 77%
1a
2–4
O
S
O
S
O
S
cyclopalladation
N
N
X
N
X
MeO
X
3h,a X = Br
4h,a X = Cl
Br
reductive elimination
3i, X = Br, 47%
4i, X = Cl, 51%
3g, X = Br, 55%
4g, X = Cl, 55%
O
S
Scheme 3 Scope of sulfoxide compounds in ortho-bromination/chlori-
nation reactions. Bromination reactions were carried out in the pres-
ence of 0.2 mmol of 1, 0.22 mmol of NBS, and 10 mol% of Pd(acac)2 in
1.0 mL PhCl at 80 °C under air conditions. Chlorination reactions were
carried out in the presence of 0.2 mmol of 1, 0.22 mmol of NCS, and
0.1 mmol of PivOH in 1.0 mL DCE at 100 °C under air conditions. Isolat-
ed yields are given. a The products could not be isolated in pure form.
O
S
N
Pd
O
X
N
N
Pd
L
O
I
II
X
N
Aiming to further expand the scope of the reaction, we
examined this protocol on gram scale under the established
conditions, which is usually a key restraining factor in the
use of transition-metal-catalyzed C–H functionalization
O
O
NXS (X = Cl, Br, I)
Scheme 5 Proposed reaction mechanism
strategies
in
organic
synthesis.
2-[(2-Iodophe-
nyl)sulfinyl]pyridine was achieved in moderate yield (2.57
g, 78%) but good regioselectivity, which demonstrates the
possibility to use this transformation in general organic
synthesis (Scheme 4).
To demonstrate the synthetic usefulness of this method,
derivatization of 2aa has been carried out (Scheme 6). The
widely used m-CPBA can oxidize the sulfoxide to the corre-
sponding sulfone in good yield. In addition, treatment of
2aa with CuCN led to cyano-substituted sulfoxide and the
desired product was isolated in 43% yield.16b
In summary, we have realized the palladium-catalyzed
regioselective ortho-halogenation of 2-pyridyl sulfoxides
with various NXS. This protocol proceeded smoothly in
moderate to good yields, and the potential for gram-scale
functionalization has been demonstrated. Moreover, the es-
tablished efficient method can provide a useful strategy for
the synthesis of S-containing compounds, overcoming the
O
S
O
S
NIS (1.1 equiv)
Pd(OAc)2 (10 mol%)
TFA (0.5 equiv)
PhCl, 80 °C
N
N
I
1
2
10 mmol
2.57 g, 78%
Scheme 4 Scale-up of the iodination reaction
Br
Br
O
CN
O
S
O
O
m-CPBA
S
S
CuCN
DMF, 150 °C
43%
CH2Cl2
90%
N
N
N
5
2aa
6
Scheme 6 Representative transformations of the iodination sulfoxides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
J.-L. Zhao et al.
Letter
Synlett
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Acknowledgment
We are grateful to China Postdoctoral Science Foundation
(2016M590967), Shaanxi Provincial Science and Technology Develop-
ment Funds (2016JQ2022), National Found for Fostering Talents of
Basic Science (NFFTBS-J1103311, J1210057), and the National Natural
Science Foundation of China (21402071) for financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588756.
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under reduced pressure. The contents were subjected to flash
chromatography to give the corresponding product (60.0 mg,
85%) as pale yellow solid. The purified material was dried under
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2-[(2-Iodophenyl)sulfinyl]pyridine (2a)
1
Pale yellow solid. H NMR (400 MHz, CDCl3): δ = 8.58 (dd, J =
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0.8, 4.0 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.87 (dd, J = 2.0, 8.0 Hz,
1 H), 7.85–7.83 (m, 1 H), 7.80 (dd, J = 1.6, 8.0 Hz, 1 H), 7.52 (dt,
J = 1.2, 8.0 Hz, 1 H), 7.36–7.33 (m, 1 H), 7.17 (dt, J = 1.6, 8.0 Hz, 1
H). 13C NMR (100 MHz, CDCl3): δ = 164.81, 150.09, 147.09,
139.59, 137.95, 132.67, 129.21, 127.34, 125.14, 120.49, 94.66.
ESI-HRMS: m/z [M + Na]+ calcd for C11H8INOSNa+: 351.9296;
found: 351.9272.
A mixture of 2-pyridyl sulfoxides (40.6 mg, 0.2 mmol, 1.0
equiv), NIS (49.5 mg, 0.22 mmol, 1.1 equiv), TFA (11.4 mg, 0.1
mmol, 0.5 equiv), and Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol %)
in PhCl (1 mL) was stirred under air at 80 °C for 20 h. The reac-
(21) For a review on organopalladium(IV) chemistry, see: Xu, L.-M.;
Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E