Palladium-catalyzed regioselective arylation of arene C-H bond assisted by the removable 2-pyridylsulfinyl group

Article abstract of DOI:10.1055/s-0031-1290320

A palladium-catalyzed arylation of arene C-H bond assisted by a removable 2-pyridylsulfinyl group is described. The reaction employs aryltrifluoroborates as the arylation reagent, leading to the corresponding products in moderate to good yield with broad substrate scope. The directing group can be removed or converted to other useful functionalities, which showcases the potential synthetic application of the methodology. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290320

LETTER
463
Palladium-Catalyzed Regioselective Arylation of Arene C–H Bond Assisted by
the Removable 2-Pyridylsulfinyl Group
D
irec
t
C–H Arylat
u
ion of
A
rene
n
s
bin Zhang,a Ming Yu,a Jinzhong Yao,a Yuhong Zhang*a,b
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953244; E-mail: yhzhang@zju.edu.cn
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received 26 October 2011
tion of 2-(arylsulfinyl)pyridines with a variety of
organotrifluoroborate substrates as coupling partner.
Abstract: A palladium-catalyzed arylation of arene C–H bond as-
sisted by a removable 2-pyridylsulfinyl group is described. The re-
action employs aryltrifluoroborates as the arylation reagent, leading
to the corresponding products in moderate to good yield with broad
substrate scope. The directing group can be removed or converted
to other useful functionalities, which showcases the potential syn-
thetic application of the methodology.
Organotrifluoroborate is frequently employed as an alter-
native in cross-coupling reactions due to its advantages
such as the stability to air and moisture, easy handling,
and the avoidance of byproducts from homocoupling.12 In
consideration of the advantages of organotrifluoroborate,
we initiated our investigation with the coupling between
2-(phenylsulfinyl)pyridine (1a) and potassium phenyltri-
fluoroborate (2a). When the substrates stirred with 10
mol% of Pd(OAc)2 and two equivalents of Ag2CO3 in
DCE at 130 °C, the desired product was isolated in 47%
yield (Table 1, entry 1). The addition of 1,4-benzoquinone
(BQ, Table 1, entry 2) led to the rapid increase of the iso-
lated yield, which was supposed to promote the reductive
elimination step.13 The use of PdCl2 (Table 1, entry 3) and
Pd(MeCN)2Cl2 (Table 1, entry 4) showed relatively lower
efficiency, while Pd(PPh3)2Cl2 (Table 1, entry 5) and
Pd(PPh3)4 (Table 1, entry 6) were completely ineffective.
Screening of the oxidants revealed that Ag2CO3 was the
most effective oxidant for this reaction (Table 1, entries
7–12). For the choices of the reaction solvents, DCE af-
forded the highest yield (Table 1, entries 13–18). Lower
temperature resulted in the lower yield (Table 1, entry
19). When phenylboronic acid was employed instead of
potassium phenyltrifluoroborate, no desired arylation
product was detected. The use of less Ag2CO3 and
Pd(OAc)2 led to the decrease of the yields (Table 1, entry
20).
Key words: C–H bond activation, arylation, aryltrifluoroborate,
sulfoxide, palladium catalysis
Biaryls are important structural motifs frequently found in
bioactive compounds and functional materials. During the
past few decades, extensive efforts have been devoted to
the development of constructing biaryl motifs.1 Compared
with the traditional cross-coupling methods (such as Su-
zuki coupling, Stille coupling, Negishi coupling, and Ku-
mada coupling) employing aryl halides or organometallic
derivatives, direct C–H bond arylation provides new op-
portunities in the synthesis of biaryl compounds.2 Cur-
rently, auxiliary-assisted C–H bond activation has
emerged as a powerful tool in organic synthesis.3 In the
majority of arene C–H bond functionalization examples, a
directing group has been used as a means of tuning the re-
gioselectivity. Under this speculation, a 2-pyridyl unit,4
imines,5 oxymes,6 carboxylic acids,7 and N-acetyl8 or N-
carbamoyl anilines9 have been successfully applied to
achieve arene C–H bond functionalization. However, in
some cases, the directing groups are not easily removed,
hence compromising the practicality of the reaction.
Therefore, the discovery of efficient removable directing
groups is highly desirable. Gevorgyan and co-workers re-
ported arene C–H bond transformations directed by py-
ridyldiisopropylsilyl (PyDipSi) that could be removed
easily from the products.10 Pyridylsulfinyl (PySO) was re-
ported as a removable directing group by the Carretero
group11a and the Mancheño Group,11b respectively. We
previously reported a Pd-catalyzed alkenylation and ary-
lation of arenes by the use of 2-pyridyl sulfoxide as direct-
ing group.11c However, for the arylation, we only got the
low regioselectivity and poor activities for limited sub-
strates. Herein, we report an efficient Pd-catalyzed aryla-
With the optimal reaction conditions in hand, we exam-
ined the substrate scope of aryltrifluoroborates as summa-
rized in Table 2. Among the aryltrifluoroborates, it was
found that various kinds of methyl, methoxy, fluoro, cy-
ano, and chloro substituents (Table 2, entries 1–10) were
tolerated under the reaction conditions, giving the corre-
sponding products in moderate to good yields. Aryltriflu-
oroborates with electron-deficient substituents (Table 2,
entries 9–10) gave lower yields compared to their elec-
tron-rich counterparts. ortho-Substituted aryltrifluorobo-
rates (Table 2, entry 11) delivers relatively lower yield
compared with its meta and para analogues due to the
steric hindrance.
The substrate scope of 2-(arylsulfinyl)pyridine was eval-
uated with potassium phenyltrifluoroborate (2a) as pre-
sented in Table 3. Both electron-rich and electron-
deficient 2-(arylsulfinyl)pyridines were accommodated
with good efficiency (Table 3, entries 1–3). The ortho
SYNLETT 2012, 23, 463–467
Advanced online publication: 25.01.2012
DOI: 10.1055/s-0031-1290320; Art ID: W59811ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

464
X. Zhang et al.
LETTER
Table 1 Optimization of Reaction Conditionsa,b
Table 2 Reaction of 2-(Phenylsulfinyl)pyridine with Different
Organotrifluoroboratesa,b
O
S
O
S
R
N
catalyst (10 mol%)
N
Pd(OAc)2 (10 mol%)
1a
oxidant (2.0 equiv)
O
S
1a
Ag2CO3 (2.0 equiv)
O
S
+
+
BQ (1.0 equiv)
solvent, 130 °C, 12 h
BQ (1.0 equiv)
DCE, 130 °C,12 h
BF3K
N
BF3K
N
R
2a
3a
2
3
Entry Catalyst
Oxidant
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
Ag2O
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Yield (%)
47c
83
Entry
2
Product 3
Yield (%)
1
2
Pd(OAc)2
Pd(OAc)2
PdCl2
O
3
34
BF3K
1
2
3
4
5
83
S
4
Pd(MeCN)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
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(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
19
2a
N
5
n.d.
n.d.
69
3a
MeO
6
7
MeO
BF3K
O
S
72
86
71
74
8
78
2b
9
AgNO3
Cu(OAc)2
PhI(OAc)2
K2S2O8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
36
N
10
11
12
13
14
15
16
17
18
19
20
27
3b
MeO
38
MeO
45
O
S
BF3K
1,4-dioxane 46
N
DMF
34
2c
3c
DMSO
toluene
xylene
anisole
DCE
n.d.
76
41
BF3K
O
S
35
2d
74d
54e
N
3d
DCE
a Reaction conditions: 2-(phenylsulfinyl)pyridine (0.2 mmol), potas-
sium phenyltrifluoroborate (0.4 mmol), palladium catalyst (0.02
mmol), BQ (0.2 mmol), oxidant (0.4 mmol) stirred in solvent (1.5
mL) at 130 °C for 12 h.
O
S
BF3K
b Isolated yield of 3a.
N
c In the absence of BQ.
2e
d The reaction was conducted at 120 °C.
3e
e Conditions: 1 equiv of Ag2CO3 and 5 mol% Pd(OAc)2 were used.
F
substituent gave the arylation product in 82% yield
(Table 3, entry 4). Notably, meta-substituted substrate
(Table 3, entry 5) reacted regioselectively at the sterically
less hindered C–H site. The arylation product was ob-
tained as a mixture of regioisomers when 2-(naphthalen-
2-ylsulfinyl)pyridine (Table 3, entry 6) was used as a sub-
strate, which illustrated that proper steric hindrance is cru-
cial for high regioselectivity.
F
BF3K
6
O
S
68
2f
N
3f
Synlett 2012, 23, 463–467
© Thieme Stuttgart · New York

LETTER
Direct C–H Arylation of Arenes
465
Table 2 Reaction of 2-(Phenylsulfinyl)pyridine with Different
curs under the aid of the pyridine group at the ortho site of
the substrates, and the subsequent deprotonation leads to
the formation of the intermediate A. Transmetalation be-
tween aryltrifluoroborates and the intermediate A affords
the intermediate B,12f,14 which undergoes reductive elimi-
nation by librating the arylation product and Pd(0), with
the acceleration of BQ.13 Oxidation of Pd(0) by Ag2CO3
regenerates Pd(II) for the next catalytic cycle.
Organotrifluoroboratesa,b (continued)
O
S
R
N
Pd(OAc)2 (10 mol%)
Ag2CO3 (2.0 equiv)
1a
O
S
+
BQ (1.0 equiv)
DCE, 130 °C,12 h
BF3K
N
Table 3 Reaction of 2-(Arylsulfinyl)pyridine with Different Phe-
R
nyltrifluoroboratesa,b
2
3
O
S
Entry
2
Product 3
Yield (%)
R
F
N
Pd(OAc)2 (10 mol%)
Ag2CO3 (2.0 equiv)
F
1
O
S
O
S
+
7
8
61
BF3K
BQ (1.0 equiv)
DCE, 130 °C, 12 h
R
BF3K
N
N
2g
2a
3
3g
NC
Entry 1
Product 3
Yield (%)
NC
O
78
O
S
BF3K
S
O
S
1
91
N
2h
N
3h
N
1b
Cl
3l
O
S
Cl
BF3K
9
43
O
S
O
S
2
3
4
68
62
82
2i
N
N
MeO
N
MeO
1c
3i
3m
Cl
Cl
O
O
S
O
S
10
11
48
BF3K
S
N
Cl
N
N
2j
Cl
1d
3j
3n
O
S
O
S
44c
O
BF3K
S
N
N
2k
N
N
1e
3k
3o
a Reaction conditions: 2-(phenylsulfinyl)pyridine (0.2 mmol), orga-
notrifluoroborate (0.4 mmol), Pd(OAc)2 (0.02 mmol), BQ (0.2 mmol),
Ag2CO3 (0.4 mmol) stirred in DCE (1.5 mL) at 130 °C for 12 h.
b Isolated yield.
O
MeO
S
MeO
S
c Obtained as a 1:1 mixture of diastereoisomers.
5
70
O
N
On the basis of previous studies11 and our experimental re-
sults, a plausible mechanism of the reaction is proposed as
shown in Scheme 1. The electrophilic palladation first oc-
1f
3p
© Thieme Stuttgart · New York
Synlett 2012, 23, 463–467

466
X. Zhang et al.
LETTER
Table 3 Reaction of 2-(Arylsulfinyl)pyridine with Different Phe-
nyltrifluoroboratesa,b (continued)
1) n-BuLi (4 equiv)
THF, –78 °C
O
S
O
S
2) NH4Cl (aq)
R
N
N
N
N
N
Pd(OAc)2 (10 mol%)
3l
4l 62%
1
Ag2CO3 (2.0 equiv)
O
S
+
BQ (1.0 equiv)
DCE, 130 °C, 12 h
R
BF3K
N
O
S
Mg
SH
2a
3
MeOH, 0 °C, 2 h
Entry 1
Product 3
Yield (%)
3l
5l 75%
N
O
S
O
S
O
S
MCPBA
S
6
61c
O
CH2Cl2, 0 °C, 1 h
O
N
N
3l
6l 81%
1g
3q
a Reaction conditions: 2-(arylsulfinyl)pyridine (0.2 mmol), potassium
phenyltrifluoroborate (0.4 mmol), Pd(OAc)2 (0.02 mmol), BQ (0.2
mmol), Ag2CO3 (0.4 mmol) stirred in DCE (1.5 mL) at 130 °C for
12 h.
O
S
Na–Hg
S
S
MeOH, r.t., 1 h
b Isolated yield.
3l
c Obtained as a 42:58 mixture of regioisomers by GC–MS.
7l 65%
Scheme 2 Transformations and removal of the directing group
In order to demonstrate the potential synthetic application
of the methodology, we explored further transformations
of the arylation product (Scheme 2). Firstly, the (2-py-
ridyl)sulfinyl group could be easily removed by the treat-
ment of the corresponding arylation product with n-BuLi
in 62% yield.11,15 Treatment of the product with Mg af-
fords the thiol 5l in 75% yield.11a The sulfoxide can be ox-
idized to afford the sulfone product 6l in 81% yield. In the
presence of sodium amalgam, disulfide 7l can be obtained
in 65% yield.11c
O
S
HX
N
ArBF3K
O
S
Pd
X
A
N
KBF3X
O
S
[PdX2]
N
Pd
Ar
B
Ag
Ar
O
S
Pd(0)
N
Ag2CO3
Scheme 1 Plausible mechanism
Synlett 2012, 23, 463–467
© Thieme Stuttgart · New York

LETTER
Direct C–H Arylation of Arenes
467
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In summary, we have successfully developed an efficient
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pyridyl sulfoxide as a removable directing group. This
protocol expands the scope of the arylation reactions by
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group has been removed or converted to other useful func-
tionalities to prove the potential synthetic usefulness of
the methodology.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
Funding from National Basic Research Program of China (No.
2011CB936003) and NSFC (No. 20872126, No. 21072169) is ac-
knowledged.
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