Palladium-catalyzed desulfitative C-H arylation of heteroarenes with sodium sulfinates

Article abstract of DOI:10.1002/chem.201102644

Desulfitative C-H arylation: Palladium-catalyzed desulfitative C-H arylation of heteroarenes with sodium sulfinates has been disclosed to construct aryl-heteroaryl bonds without the need for any extra ligands (see scheme). Copyright

Full text of DOI:10.1002/chem.201102644

COMMUNICATION
DOI: 10.1002/chem.201102644
À
Palladium-Catalyzed Desulfitative C H Arylation of Heteroarenes with
Sodium Sulfinates
Bo Liu, Qiang Guo, Yangyang Cheng, Jingbo Lan, and Jingsong You*[a]
À
The structural motif with aryl–heteroaryl bonds is a pre-
dominant substructure of many biologically active com-
pounds, natural products, pharmaceuticals, and functional
efficient desulfitative C H arylation of a wide range of het-
eroarenes with arenesulfinic acid sodium salts to enrich the
current synthetic methodologies. However, we may face a
series of hindrances: 1) In comparison with alkenes, it is
well known that N-heteroarenes themselves are susceptible
to oxidative homocoupling and decomposition with transi-
tion-metal-catalyzed oxidative conditions; and 2) aromatic
sulfinic acid sodium salts were observed to easily encounter
desulfitative self-coupling in the presence of a PdII species
and an oxidant (Scheme 1). Thus, to achieve the heterocou-
À
materials. Transition-metal-catalyzed direct C H arylation
of heteroaromatics has recently received a great deal of at-
tention as an efficient approach for the straightforward syn-
thesis of aryl–heteroaryl units.[1] Over the past several years,
the scope of the arylating reagents has been extended from
aryl halides[2] to various surrogates such as arenesulfonates,[3]
arylsilanes,[4] aryl boronic acids,[5] aryltrifluoroborates,[6]
diaryl iodonium salts,[7] and aromatic carboxylic acids.[8] De-
spite remarkable advances in these types of transformations,
the search for new reliable alternative arylating reagents is
still critically important from both scientific and practical
standpoints.
Arylsulfonyl chlorides (ArSO2Cl) have been widely used
Scheme 1. Palladium-catalyzed desulfitative homocoupling of sodium
À
À
À
as sulfonylating agents for formation of S O, S N and S C
benzenesulfinate. Reaction conditions: PdACTHNUGTRENNUG(OAc)2 (5 mol%), CuACHTUNGTRENNUNG(OAc)2
bonds,[9] and have recently been demonstrated as electro-
(2.0 equiv), TBAB (20 mol%), and sodium benzenesulfinate (0.5 mmol)
in a 0.5m dioxane/DMSO (9:1) solution at 1108C for 24 h under N2.
TBAB=tetra-n-butylammonium bromide.
À
philic partners in transition-metal-catalyzed desulfitative C
C cross-coupling reactions.[10] Despite readily availability, in-
expensiveness, and high versatility, the active arylsulfonyl
chlorides generally suffer from moisture sensitivity with the
release of the acidic HCl gas. Thus, the air stable and easy
to handle arylsulfinic acids (or salts) would serve as the
pling process, both of the unwanted homocouplings of sub-
strates must be suppressed to some extent. In this work, we
describe the discovery, development, and solution of reac-
tions that meet these challenges.
Xanthines (for example, caffeine, theophylline, theobro-
mine, etc.) are important biologically active alkaloids with
an imidazole skeleton. 8- (Hetero)aryl-substituted xanthines
are highly potent and selective antagonists at human A2B ad-
enosine receptors.[15] Following our continuing interest in the
direct C-arylation of xanthines,[16] we initially focused on the
heterocoupling of caffeine 1 with sodium benzenesulfinate
2a (Scheme 2). The initial reaction screening led to disap-
À
ideal arylating reagent for the C C bond-forming reactions
through the liberation of sulphur dioxide gas. Nevertheless,
to date, sulfinic acids (or salts) are rarely used as the aryl
source in transition-metal-catalyzed desulfinative reac-
tions,[11] whereas current research is mainly focused on sulfo-
nylation reagents.[12] The presently known desulfitative C C
À
bond formation reactions include Heck-type coupling,[13]
and coupling between aldehydes or nitriles and arenesulfinic
acid salts to aryl ketones;[14] however, the extension of the
À
reaction to the direct C H arylation of heteroaromatics re-
mains unresolved. In line with our continuous efforts to
forge aryl–heteroaryl bonds, we herein wish to develop an
[a] B. Liu, Q. Guo, Y. Cheng, Prof. Dr. J. Lan, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology
of Ministry of Education, College of Chemistry
and State Key Laboratory of Biotherapy
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P.R. China)
Fax : (+86)28-85412203
À
Scheme 2. Direct C H arylation of caffeine with sodium benzenesulfi-
nate.
pointing results in the absence of an oxidant or a PdII salt
(Table 1, entries 1–2). In this model reaction, we screened
several parameters (for example, oxidant, solvent, additive,
and palladium source, etc.) shown in Table 1. Among the ox-
E-mail: jsyou@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102644.
Chem. Eur. J. 2011, 17, 13415 – 13419
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13415

Table 1. Optimization of the coupling of caffeine with sodium benzenesulfinate.[a]
matic sulfinic acid sodium salts highly selectively
À
underwent the desulfitative C H arylation, which
may be subject to further synthetic transformations
(Scheme 3, 3j).
Entry Palladium
source
Oxidant
Additive Solvent
Solvent Yield
ratio
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane
dioxane/DMSO 1:1
DMSO
DMF
NMP
[%][b]
1
–
Cu
–
N
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
n.r.
n.r.
trace
n.r.
n.r.
trace
trace
68
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
ACHTUNGTRENNUNG
We subsequently applied this protocol to other
xanthines (for example, benzylic theobromine, ben-
zylic theophylline, and n-butyl theophylline, etc.) to
synthesize 8-arylated xanthines in good to excellent
yields (Scheme 4, 4a–c). Our methodology could
also be suitable for the synthesis of various 8-arylat-
ed purines (Scheme 4, 4d–f). In addition to these
important alkaloids, we next determined that a
wide range of azoles were amenable to the coupling
reactions at the C2 site. However, azoles (for exam-
ple, benzoxazoles, benzothiazoles, 1,3,4-oxadiazoles,
imidazoles, thiazoles, and oxazoles, etc.) sluggishly
carried out the arylation under the standard condi-
tions. To our delight, as shown in Scheme 4, the re-
A
O2
BQ
K2S2O8
Ag2CO3
AgOAc
N
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
9[c]
10[d]
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
N
A
44
25
G
N
N
R
–
55
N
E
trace
trace
28
18
28
R
E
–
–
–
–
–
N
ACHTUNGTRENNUNG
G
G
E
E
DMA
toluene
N
G
trace
72
G
E
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
dioxane/DMSO 9:1
U
E
35
77
82
90
84
93
72
placement of PdACTHUNTRGENN(UG PhCN)2Cl2 with PdACHTUTGNREN(NGUN OAc)2 in com-
T
N
bination with tetra-n-butylammonium bromide
(TBAB, 20 mol%) could significantly advance the
catalytic efficiency (Scheme 4, 4h–q). Worthy of
note was that the 2,5-unsubstituted azoles would
usually go through the arylation at both the C2 and
C5 positions with various arylating reagents. In this
current catalytic system, the 2,4,5-unsubstituted
azoles selectively underwent the C2 arylation, and
the C5-substituted azoles were not observed at all
(Scheme 4, 4k and 4m). Besides the abovemen-
tioned azoles, quinoxaline N-oxide also smoothly
furnished the desired product 4q in 72% yield
(Scheme 4, 4q).
E
G
G
–
–
–
–
Pd
Pd
Pd
2A
A
H
G
E
T
[a] Reactions were carried out using
a
palladium source (5 mol%), CuACTHNGUETRNNU(G OAc)2
(2.0 equiv), additive (20 mol%), caffeine (0.25 mmol), and sodium benzenesulfinate
(0.5 mmol) in 0.25m solution at 1108C for 24 h. [b] Isolated product yields.
[c] 1.5 equiv of Cu(OAc)2 was used. [d] 1.0 equiv of Cu(OAc)2 was used. DMSO=di-
a
N
ACHTUNGTRENNUNG
methyl sulfoxide, DMF=N,N-dimethylformamide, NMP=N-methyl-2-pyrrolidone,
DMA=N,N-dimethyl acetamide, n.r.=no reaction, BQ=benzoquinone, dba=diben-
zylideneacetone, dppf=1,1’-bis(diphenylphosphino)ferrocene, PivOH=pivalic acid,
NMP=N-methyl-2-pyrrolidone, DMA=dimethylacetamide.
It is well known that CuI salts have been used as
À
idants investigated, Cu
(Table 1, entries 3–8). An attempt to lower the amount of
Cu(OAc)2 to one equivalent resulted in a low consumption
A
catalyst or activator in direct C H functionalization of N-
heteroarenes.[17] As demonstrated in Table 1, other oxidants
including inorganic oxidants, organic oxidants, and dioxygen
ACHTUNGTRENNUNG
of caffeine (Table 1, entries 8–10). After examining a variety
of solvents (e.g., dioxane, DMSO, DMF, NMP, DMA, and
toluene, etc.), dioxane/DMSO (9:1) was clearly the best sol-
vent system (Table 1, entries 8 and 11–17). Remarkably, the
use of PdACHTUNGTRENNUNG(PhCN)2Cl2 as the palladium source significantly
improved the catalytic efficiency (Table 1, entries 8, 22–25).
Thus, the best results were obtained in the presence of Pd-
except Cu
catalytic cycle, suggesting that an (even catalytic) amount of
copper(I) formed from Cu(OAc)2 might promote the gener-
ACHTUNGRTEN(NUNG OAc)2 were completely incapable of fulfilling the
AHCTUNGTRENNUNG
ation of the azole–copper species IM2, which could take
part in the catalytic cycle.[18] In addition, an addition of
extra CuBr (20 mol%) could result in an improvement of
the yield of the heterocoupling product, hinting that the
copper(I) salt played an important role (Table 1, entries 8
and 20). Although the mechanism was not well understood
at this stage, on the basis of the above observations, we pro-
posed that a plausible catalytic route could consist of 1) de-
sulfitation of sodium sulfinate to form the arylpalladium
species IM1, and 2) subsequent transmetalation with the
azole–copper species IM2 to give the key heterocoupling in-
termediate IM3, followed by reductive elimination to pro-
duce the desired product. Pd0 could be reoxidized by Cu-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1108C for 24 h.
With the optimized conditions in hand, we explored the
scope of this process with respect to sodium sulfinate struc-
tures summarized in Scheme 3. It was gratifying to find that
À
our catalyst system accelerated the C H arylation of caf-
feine with a variety of sodium sulfinates. Whether sodium
sulfinates were electron rich, electron poor, or having sub-
stituents at a different position on the aromatic ring, all of
them afforded good to excellent yields (Scheme 3, 3a–n). It
AHCTUNGTRENNUNG
À
is known that aryl bromides can go through the direct C H
arylation with N-heteroarenes in the presence of palladium
catalyst. It is important to stress that bromo-substituted aro-
expensive and easily available, air stable and easy to handle
sodium sulfinates can be used as the coupling partners in
À
the transition-metal-catalyzed C H arylation of a wide
13416
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13415 – 13419

À
Palladium-Catalyzed Desulfitative C H Arylation
COMMUNICATION
range of N-heteroarenes to con-
struct aryl–heteroaryl bonds
without the need for any extra
ligands. We believe that this
methodology would provide a
valuable complement to syn-
thetic and medicinal chemistry
both in industry and in academ-
ia. Additionally studies aimed
at extending sodium sulfinates
to other cross-coupling reac-
tions are underway.
Experimental Section
General
(2.8 mg,
Procedure:
0.0125 mmol)
Pd
or
ACHTUNGTRENNUNG
AHCTUNGTERG(NNUN PhCN)2Cl2 (4.8 mg, 0.0125 mmol), N-
heterocycle (0.25 mmol), aromatic sul-
finic acid sodium salt (0.5 mmol), Cu-
AHCTUNRTGEG(NNNU OAc)2 (0.5 mmol) and dioxane/
DMSO (9: 1) (1.0 mL) in presence or
absence of TBAB (20 mol%) was
added to a flame-dried Schlenk test
tube with
a magnetic stirring bar
Scheme 3. Catalytic C-arylation of caffeine with a variety of aromatic sulfinic acid sodium salts. Reactions
were carried out using PdACHTUNGRTENNUG(PhCN)2Cl2 (5 mol%), CuAHCTUNGTREN(NUGN OAc)2 (2.0 equiv), caffeine (0.25 mmol), and aromatic sul-
finic acid sodium salt (0.5 mmol) in a 0.25m dioxane/DMSO (9: 1) solution at 1108C for 24 h. The yields of the
isolated products are in parentheses.
under N2. A rubber septum was re-
placed with a glass stopper, and the
system was then evacuated twice and
back filled with N2. The reaction mix-
ture was stirred for 5 min at room
temperature, and then heated at
1108C for 24 h. The reaction mixture
was then cooled to ambient tempera-
ture, diluted with 20 mL of CH2Cl2, fil-
tered through
a Celite pad, and
washed with 10–20 mL of CH2Cl2. The
combined organic extracts were con-
centrated, and the resulting residue
was purified by column chromatogra-
phy on silica gel to provide the desired
product.
Acknowledgements
This work was supported by grants
from the National NSF of China (Nos
21025205, 20972102, 21021001, and
20872101), Doctoral Foundation of
Education
(20090181110045),
Ministry
of
China
(No
PCSIRT
IRT0846) and the National Basic Re-
search Program of China (973 Pro-
gram, 2011CB808600). We thank the
Centre of Testing & Analysis, Sichuan
University for NMR measurements.
Scheme 4. Catalytic C-arylation of heteroarenes with aromatic sulfinic acid sodium salts. Reactions were car-
ried out using Pd
acid sodium salt (0.5 mmol) in a 0.25m dioxane/DMSO (9: 1) solution at 1108C for 24 h. The yields of the iso-
lated products are in parentheses. [a] Pd(OAc)2 (5 mol%) in combination with TBAB (20 mol%). [b] Pd-
(OAc)2 (5 mol%), and free TBAB. [c] Reaction time=6 h.
ACHTUNGTRENNUNG(PhCN)2Cl2 (5 mol%), CuHCATUNGTREN(NGUN OAc)2 (2.0 equiv), heteroarene (0.25 mmol), and aromatic sulfinic
À
Keywords: C H activation
cross-coupling · heterocycles ·
palladium · sodium sulfinates
·
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Chem. Eur. J. 2011, 17, 13415 – 13419
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13417

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COMMUNICATION
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Received: August 25, 2011
Published online: November 3, 2011
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