Microwave-accelerated Pd-catalyzed desulfitative direct C2-arylation of free (NH)-indoles with arylsulfinic acids

Article abstract of DOI:10.1002/asia.201300913

The rapid and efficient direct C2-arylation of free (NH)-indoles with arylsulfinic acids proceeded through a microwave-accelerated palladium-catalyzed desulfitation reaction. By using PdCl₂ as a catalyst, silver acetate as an oxidant, and H₂SO₄ as an additive, arylsulfinic acids with both electron-donating and electron-withdrawing groups underwent desulfitative coupling with an array of free (NH)-indoles, thereby selectively providing C2-arylindoles in good yields. From C2 shining sea: The direct C2-arylation of free (NH)-indoles with arylsulfinic acids proceeded through a Pd-catalyzed desulfitation reaction. In the presence of an oxidant and an additive, 2-arylindoles were selectively afforded in good yields. Copyright

Full text of DOI:10.1002/asia.201300913

FULL PAPER
DOI: 10.1002/asia.201300913
Microwave-Accelerated Pd-Catalyzed Desulfitative Direct C2-Arylation of
Free (NH)-Indoles with Arylsulfinic Acids
Tao Miao,[a] Pinhua Li,[a] Guan-Wu Wang,[b] and Lei Wang*[a, c]
Abstract: The rapid and efficient direct C2-arylation of free (NH)-indoles with ar-
ylsulfinic acids proceeded through a microwave-accelerated palladium-catalyzed
desulfitation reaction. By using PdCl2 as a catalyst, silver acetate as an oxidant,
and H2SO4 as an additive, arylsulfinic acids with both electron-donating and elec-
tron-withdrawing groups underwent desulfitative coupling with an array of free
(NH)-indoles, thereby selectively providing C2-arylindoles in good yields.
Keywords: arylation · desulfitation ·
indoles microwave chemistry
palladium
·
·
Introduction
arylindoles through the direct C2-H or C3-H functionaliza-
tion of free (NH)-indole derivatives.[4–8] Among these meth-
ods, Sames and co-workers made a significant contribution
with the direct C2-arylation of free (NH)-indole with aryl
The indole skeleton is frequently found in bioactive synthet-
ic and natural products and is a privileged structure in many
pharmaceuticals.[1] Thus, great efforts have been devoted to
the transition-metal-catalyzed chemical modification of
indole derivatives, in particular through direct C2-H or C3-
H arylation reactions. The direct arylation of indole deriva-
tives is an attractive alternative to conventional cross-cou-
pling methods, which require the prefunctionalization of in-
halides, catalyzed by [{Rh
ACHTUGNTREN(NUNG coe)2Cl2}2] (coe=cyclooctene) or
[Pd
AHCTUNGTRENNUNG
dure for the synthesis of 2-arylindoles, based on the Pd-cata-
lyzed arylation of free (NH)-indoles with diaryliodonium
tetrafluoroborates.[6] Subsequently, Shi and co-workers re-
ported that aryl boronic acids were good coupling partners
for the direct C-arylation of free (NH)-indoles in the pres-
ence of a palladium catalyst under an oxygen atmosphere.[7]
doles (i.e., halogenation or stoichiometric metalation reac-
tions) prior to the C C coupling step. Over the past few
[2]
À
decades, regioselective direct C-arylation reactions at either
the C2 or C3 positions of indole have been successfully ach-
ieved by using palladium, rhodium, and copper catalysis
with a variety of coupling species.[3] However, the C-aryla-
tion of free (NH)-indole derivatives is particularly challeng-
ing, because it eliminates the need for protecting groups and
reactive functionalities and requires the selective targeting
Zhang and co-workers reported the PdACTHNGUTRENU(NG OAc)2-catalyzed se-
lective C2-arylation of free (NH)-indoles with potassium ar-
yltrifluoroarylborates under mild conditions.[8] Although
these reactions are often synthetically useful, they suffer
from several notable disadvantages, including moderate
scope and functional-group tolerance and the requirement
of long reaction times.
À
À
of C H bonds in the presence of a reactive N H functional-
ity. In some cases, free (NH)-indoles have been reported to
be less reactive than their N-substituted analogues.[3a,q,8,11d]
To date, only a few procedures have been used to synthesize
Arylsulfinic acids (or salts) are relatively stable and easy
to handle and, hence, offer great potential as aryl sources
À
for C C bond-forming reactions through the release of SO2,
although they are generally used as sulfonylating reagents.
À
These desulfitative C C bond-formation reactions include
Heck-type reactions,[9] the synthesis of aryl ketones,[10] the
[a] T. Miao, P. Li, Prof. L. Wang
Department of Chemistry
[11]
À
direct C H arylation of heteroaromatic compounds, and
cross-coupling with aryl triflates and halides.[12] Notably,
Deng and co-workers recently reported a method for the
synthesis of 2-arylindoles by using sodium sulfinates with N-
substituted indoles in the presence of palladium; however,
no desired product was observed when free (NH)-indole
was used as a substrate.[11d] Herein, we report the micro-
wave-accelerated highly efficient palladium-catalyzed desul-
fitative C2-arylation of a wide range of free (NH)-indoles
with arylsulfinic acids to enrich these synthetic methods
(Scheme 1).
Huaibei Normal University
Huaibei, Anhui 235000 (P. R. China)
Fax : (+86)561-3090518
E-mail: leiwang@chnu.edu.cn
[b] Prof. G.-W. Wang
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P. R. China)
[c] Prof. L. Wang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300913.
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Lei Wang et al.
(Table 1, entries 5 and 6). Much
to our pleasure, 82% yield was
achieved when a mixture of
DMF and MeCN (1:1 v/v) was
used as the solvent (Table 1,
entry 7). Various acids were
chosen to examine the effect of
the additive on the product
yield. Whereas HNO3 and TFA
were not beneficial for the cata-
Scheme 1. C2-arylation of free (NH)-indoles with arylsulfinic acids.
Results and Discussion
lytic reaction (Table 1, entries 9 and 13), H3PO4, HCl, and
AcOH showed very poor performance (Table 1, entries 10–
12). Further screening of oxidants revealed that AgOAc was
the optimal oxidant. Other inorganic oxidants Ag2CO3,
In our initial study, we investigated the direct C2-arylation
of indole (1a) with benzenesulfinic acid (2a) in the presence
of a palladium catalyst (5.0 mol%) under microwave (MW)
irradiation at 1008C; a maximum power of 100 W was em-
ployed to optimize the reaction conditions with different
solvents, additives, and oxidants. Promisingly, when DMF
was used as the solvent with AgOAc as the oxidant and
H2SO4 as an additive, the reaction of compound 1a with
compound 2a gave 2-arylindole 3a in 51% yield (Table 1,
entry 1). However, other solvents, including EtOH, DCE,
and toluene, prohibited the reaction (Table 1, entries 2–4).
MeCN and 1,4-dioxane were also ineffective and only gave
the desired product in 22% and 10% yield, respectively
Ag2O, and CuACHTUNRGTNEUNG(OAc)2 gave inferior results and generated
compound 3a in 25–64% yields (Table 1, entries 14–16).
K2S2O8 did not afford any product in the model reaction
(Table 1, entry 17). Under these reaction conditions, organic
oxidants BQ and TBHP were also found to be harmful to
this transformation (Table 1, entries 18 and 19). Moreover,
conventional heating at 1008C produced 2-arylindole 3a in
61% yield, but a longer reaction time (24 h) was required
compared to that with MW irradiation (40 min) under the
same reaction conditions (Table 1, entry 8 versus entry 7).
With the optimized reaction conditions in hand (PdCl2
(5.0 mol%), AgOAc (2 equiv), concentrated H2SO4
(2 equiv), DMF/MeCN (2.0 mL, 1:1 v/v), MW irradiation at
1008C, 40 min), this Pd-catalyzed desulfitative direct C2-ary-
lation reaction of indoles was extended to various free
(NH)-indoles and a wide range of arylsulfinic acids to ex-
plore the scope and limitations of this reaction (Table 2).
Electron-rich indoles showed higher reactivity and products
3b, 3c, and 3d were furnished in 70%, 80% and 75% yield,
respectively. Moreover, this reaction was also tolerant of
fluoro, chloro, and bromo substituents on the aromatic ring
of the (NH)-indole: 6-Fluoro-, 5-chloro-, and 5-bromoin-
doles reacted with benzenesulfinic acid to generate arylated
indoles 3e, 3 f, and 3g, respectively, in 66–83% yield. Elec-
tron-deficient indoles participated in the reaction to give
products 3h and 3i, but they were less active and the prod-
ucts were only formed in moderate yields.
To further expand the scope of this reaction, we examined
the reactions of several other arylsulfinic acids. A series of
functional groups, including methyl, tert-butyl, methoxy,
fluoro, chloro, and bromo groups, were tolerated under the
optimal reaction conditions and the desired products (3i–
3q) were obtained in moderate-to-good yields. However, ar-
ylsulfinic acids with an ortho-substituent delivered their cor-
responding arylated indoles (3l and 3q) in lower yields, thus
illustrating that steric hindrance played a role in the reac-
tion. 1- and 2-Naphthylsulfinic acids also efficiently reacted
with indole and the products (3s and 3t) were formed in
60% and 62% yield. Furthermore, 1-methylindole was
a good substrate for this arylation reaction, as shown in the
synthesis of compound 3u under these reaction conditions.
Although the mechanism of this reaction is not clear at
present, on the basis of our data and previous reports,[9a,10a–-
Table 1. Palladium-catalyzed desulfitative direct C2-arylation of free
(NH)-indole with benzenesulfinic acid under various conditions.[a]
Entry
Oxidant
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
Ag2O
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
HNO3
H3PO4
HCl
DMF
EtOH
DCE
toluene
MeCN
1,4-dioxane
51[c]
trace[d]
0[d]
0
22[d]
10
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
82
61[e]
40[f]
15[g]
13[h]
11
9
10
11
12
13
14
15
16
17
18
19
AcOH
TFA
35
38
64
25
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
Cu
(OAc)2
K2S2O8
BQ
TBHP
0
trace
0
[a] Reaction conditions: Compound 1a (0.35 mmol), compound 2a
(0.25 mmol), PdCl2 (5 mol%), solvent (2.0 mL), MW irradiation, 40 min.
[b] Yield of isolated product. [c] 98% H2SO4 was used. [d] Heated at
reflux. [e] Heated at 1008C for 24 h. [f] 65% HNO3 was used. [g] 85%
H3PO4 was used. [h] 37% HCl was used. DCE=1,2-dichoroethane,
TFA=trifluoroacetic acid, BQ=p-benzoquinone, TBHP=tert-butyl hy-
droperoxide.
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Lei Wang et al.
Table 2. Palladium-catalyzed direct desulfitative C2-arylation of free (NH)-indoles with arylsulfinic acids.[a]
tive functionalization of the
indole at the C2 position under
acidic conditions.
Conclusions
In summary, we have developed
a microwave-accelerated palla-
dium-catalyzed
desulfitative
3a
3d
82%
75%
3b
3e
70%
83%
3c
3 f
80%
71%
system for the direct C2-aryla-
tion of free (NH)-indoles with
arylsulfinic acids, with silver
acetate as an oxidant and
H2SO4 as an additive. This
simple catalytic system will
enable rapid and effective
access to a variety of 2-arylated
(NH)-indole products, thereby
broadening the scope of Pd-cat-
alyzed desulfitative coupling re-
actions. The investigation of ar-
ylsulfinic acids as the aryl
source in other coupling reac-
tions is underway.
3g
66%
3h
50%
3i
41%
3j
81%
74%
3k
3n
77%
3l
60%
70%
3m
63%[c]
3o
Experimental Section
General
1H and 13C NMR spectra were record-
3p
80%
3q
56%
3r
72%
ed on
a 400 MHz Bruker FT-NMR
spectrometer (400 and 100 MHz, re-
spectively). Chemical shifts (d) are
given in ppm and are referenced to
tetramethylsilane (TMS) as an internal
standard. Peak multiplicities are indi-
cated as follows: s singlet, d doublet,
t triplet, m multiplet, q quartet. Cou-
pling constants (J) are reported in
Hertz (Hz). Chemicals and solvents
were purchased from commercial sup-
3s
60%
3t
62%
3u
83%
[a] Reaction conditions: Compound 1 (0.35 mmol), compound 2 (0.25 mmol), PdCl2 (5 mol%), AgOAc
(0.50 mmol), H2SO4 (0.50 mmol), DMF/MeCN (2.0 mL, 1:1 v/v), MW irradiation, 1008C, 40 min. [b] Yield of
isolated product. [c] 10 mol% PdCl2 was used.
c,11a,13]
which provided strong evidence for the C2 and C3 se-
lectivity of indole with Pd,[13] we propose a possible pathway
as shown in Scheme 2. The first step is the reaction of PdII
with arylsulfinic acid to provide palladium salt A. Elimina-
tion of SO2 from complex A generates an ArPdII species,
which reacts with indole 1 at the C2-position to give inter-
mediate B. Reductive elimination from intermediate B fur-
nishes the final coupling product (3) and a Pd0 species. Oxi-
dation of Pd0 by AgOAc regenerates the PdII catalyst. How-
ever, we cannot rule out another pathway, which involves in-
itial palladation on the indole, followed by reaction with ar-
ylsulfinic acid to form intermediate B through the release of
SO2 and reductive elimination. Moreover, although the role
of H2SO4 is not clear at this stage, on the basis of previous
reports,[3b,d,r,6–8,14] we reasoned that H2SO4 may minimize the
decomposition of indole and facilitate the highly regioselec-
Scheme 2. Proposed reaction mechanism.
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Lei Wang et al.
pliers (Aldrich, USA, or Shanghai Chemical Company, China). The sol-
vents were dried and freshly distilled prior to use. The products were pu-
rified by flash chromatography on silica gel (100–200 mesh). All MW re-
actions were carried out in a Discover SP (CEM) microwave reactor.
9.9 Hz), 109.0 (d, J=24.3 Hz), 99.9 (d, J=1.0 Hz), 97.3 ppm (d, J=
26.0 Hz).
5-Chloro-2-phenyl-1H-indole (3 f)[7]
White solid (40.3 mg, 71% yield); 1H NMR (400 MHz, CDCl3): d=8.33
(br s, 1H), 7.63 (d, J=7.5 Hz, 2H), 7.58 (s, 1H), 7.44 (t, J=7.5 Hz, 2H),
7.34 (t, J=7.5 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.13 (dd, J=8.6, 1.5 Hz,
1H), 6.75 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=139.3, 135.1,
131.9, 130.3, 129.1, 128.1, 125.9, 125.2, 122.6, 120.0, 111.9, 99.6 ppm.
Typical Procedure for the Synthesis Arylsulfinic Acids[15]
Benzenesulfinic acid and p-methyl benzenesulfinic acid were obtained by
the acidification of commercially available sodium benzenesulfinate and
p-methyl benzenesulfinate, respectively, followed by recrystallization
from water. Other arylsulfinic acids were prepared according to the fol-
lowing procedure: Arylsulfonyl chloride (2.0 mmol) and anhydrous
sodium sulfite (6.0 mmol) were dissolved in water (8.0 mL) and the reac-
tion mixture was heated at 70–808C for 5 h. After the reaction was com-
plete, the aqueous solution was washed with CHCl3, acidified with a con-
centrated aqueous solution of HCl, cooled to RT, and filtered. The as-
formed white precipitate was recrystallized from water, thus yielding the
corresponding arylsulfinic acid.
5-Bromo-2-phenyl-1H-indole (3g)[17]
White solid (44.7 mg, 66% yield); 1H NMR (400 MHz, CDCl3): d=8.37
(br s, 1H), 7.74 (s, 1H), 7.64 (d, J=7.5 Hz, 2H), 7.44 (t, J=7.5 Hz, 2H),
7.34 (t, J=7.5 Hz, 1H), 7.26 (s, 2H), 6.74 ppm (d, J=1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=139.1, 135.4, 131.8, 131.0, 129.1, 128.1,
125.2, 125.1, 123.1, 113.4, 112.3, 99.4 ppm.
2-Phenyl-1H-indole-5-carbonitrile (3h)[8]
Typical Procedure for the Direct C2-Arylation of Free (NH)-Indoles with
Arylsulfinic Acids
White solid: (27.3 mg, 50% yield); 1H NMR (400 MHz, CDCl3): d=8.78
(br s, 1H), 7.96 (s, 1H), 7.68 (d, J=7.3 Hz, 2H), 7.48–7.38 (m, 5H),
6.87 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=140.3, 138.4, 131.3,
129.2, 129.0, 128.6, 126.0, 125.4, 125.2, 120.7, 111.7, 103.4, 100.2 ppm.
In a 10 mL sealable reaction tube that with fitted a Teflon-coated cap
and equipped with a magnetic stirrer bar was added an indole (1,
0.35 mmol), an arylsulfinic acid (2, 0.25 mmol), PdCl2 (0.0125 mmol),
AgOAc (0.50 mmol), and DMF/MeCN (2.0 mL, 1:1 v/v) and the desired
amount of 98% H2SO4 (0.50 mmol) was added by syringe. The reaction
vessel was placed in a Discover SP (CEM) microwave reactor and the re-
action mixture was irradiated at 100 W and 1008C for 40 min. Then, the
mixture was cooled to RT and extracted twice with EtOAc. The organic
layers were combined, dried over MgSO4, and concentrated under re-
duced pressure to yield the crude product, which was further purified by
flash chromatography on silica gel (n-hexane/EtOAc) to give the desired
2-arylindole (3).
Methyl 2-phenyl-1H-indole-4-carboxylate (3i)[8]
White solid (25.7 mg, 41% yield); 1H NMR (400 MHz, CDCl3): d=8.60
(br s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 2H), 7.60 (d, J=
7.8 Hz, 1H), 7.49 (s, 1H), 7.47 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H),
7.23 (t, J=7.8 Hz, 1H), 4.01 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=168.1, 140.0, 137.6, 131.9, 129.1, 128.9, 128.3, 125.5, 123.8, 121.4, 115.6,
101.3, 51.8 ppm.
2-(p-Tolyl)-1H-indole (3j)[7]
2-Phenyl-1H-indole (3a)[7]
White solid (41.9 mg, 81% yield); 1H NMR (400 MHz, CDCl3): d=8.28
(br s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.38 (d, J=
7.5 Hz, 1H), 7.24 (d, J=7.9 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H), 7.11 (t, J=
7.5 Hz, 1H), 6.78 (s, 1H), 2.39 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=138.1, 137.6, 136.7, 129.7, 129.6, 129.4, 125.1, 122.1, 120.5,
120.2, 110.8, 99.4, 21.2 ppm.
White solid (39.6 mg, 82% yield); 1H NMR (400 MHz, CDCl3): d=8.29
(br s, 1H), 7.65–7.62 (m, 3H), 7.43 (t, J=7.5 Hz, 2H), 7.38 (d, J=7.5 Hz,
1H), 7.31 (t, J=7.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz,
1H), 6.82 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=137.9, 136.8,
132.4, 129.3, 129.0, 127.7, 125.1, 122.3, 120.7, 120.3, 110.9, 100.0 ppm.
2-(m-Tolyl)-1H-indole (3k)[7]
5-Methyl-2-phenyl-1H-indole (3b)[8]
White solid (39.9 mg, 77% yield); 1H NMR (400 MHz, CDCl3): d=8.32
(br s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.48 (s, 1H), 7.46 (d, J=7.8 Hz, 1H),
7.39 (d, J=7.7 Hz, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H),
7.15–7.09 (m, 2H), 6.81 (d, J=1.1 Hz, 1H), 2.42 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=138.7, 138.0, 136.8, 132.3, 129.3, 128.9, 128.5,
125.9, 122.3, 122.2, 120.6, 120.2, 110.8, 99.9, 21.5 ppm.
White solid (36.3 mg, 70% yield); 1H NMR (400 MHz, CDCl3): d=8.25
(br s, 1H), 7.67 (d, J=7.4 Hz, 2H), 7.48–7.44 (m, 2H), 7.36–7.30 (m, 2H),
7.05 (d, J=8.0 Hz, 1H), 6.78 (d, J=1.3 Hz, 1H), 2.49 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=137.9, 135.2, 132.5, 129.5, 129.4, 128.9,
127.5, 125.0, 124.0, 120.3, 110.5, 99.5, 21.4 ppm.
7-Methyl-2-phenyl-1H-indole (3c)[8]
2-(o-Tolyl)-1H-indole (3l)[7]
White solid (41.4 mg, 80% yield); 1H NMR (400 MHz, CDCl3): d=8.16
(br s, 1H), 7.67 (d, J=7.4 Hz, 2H), 7.47 (d, J=7.1 Hz, 1H), 7.43 (t, J=
7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.04–6.98 (m, 2H), 6.82 (s, 1H),
2.52 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=137.6, 136.4, 132.6,
129.0, 128.8, 127.6, 125.2, 122.9, 120.5, 120.0, 118.4, 110.6, 16.7 ppm.
White solid (31.1 mg, 60% yield); 1H NMR (400 MHz, CDCl3): d=8.11
(br s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.47–7.45 (m, 1H), 7.31 (d, J=7.6 Hz,
1H), 7.31–7.26 (m, 3H), 7.20 (t, J=7.6 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H),
6.61ACHTNUGRTNEUNG
(s, 1H), 2.50 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=137.4,
136.1, 132.6, 131.1, 129.0, 128.9, 128.0, 126.1, 122.0, 120.5, 120.0, 110.7,
103.0, 21.1 ppm.
5-Methoxy-2-phenyl-1H-indole (3d)[7]
White solid (41.8 mg, 75% yield); 1H NMR (400 MHz, CDCl3): d=8.22
(br s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.32–7.25 (m,
2H), 7.08 (d, J=1.9 Hz, 1H), 6.85 (dd, J=8.7, 2.3 Hz, 1H), 6.75 (d, J=
1.1 Hz, 1H), 3.86 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=138.6,
132.5, 132.1, 129.8, 129.0, 127.6, 125.1, 112.6, 111.6, 102.4, 99.9, 55.9 ppm.
2-(4-(tert-Butyl)phenyl)-1H-indole (3m)[18]
White solid (46.1 mg, 74% yield); 1H NMR (400 MHz, CDCl3): d=8.30
(br s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.46 (d, J=
8.4 Hz, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.11 (t, J=
7.8 Hz, 1H), 6.80 (s, 1H), 1.36 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=150.9, 138.0, 136.7, 129.6, 129.3, 126.0, 124.9, 122.1, 120.5,
120.2, 110.8, 99.5, 34.7, 31.3 ppm.
6-Fluoro-2-phenyl-1H-indole (3e)[16]
White solid (43.8 mg, 83% yield); 1H NMR (400 MHz, CDCl3): d=8.31
(br s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.54–7.50 (m, 1H), 7.43 (t, J=7.6 Hz,
2H), 7.32 (t, J=7.6 Hz, 1H), 7.07 (dd, J=9.5, 1.7 Hz, 1H), 6.88 (dt, J=
9.2, 1.7 Hz, 1H), 6.78 ppm (d, J=1.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=160.1 (d, J=236.7 Hz), 138.4 (d, J=3.8 Hz), 136.8 (d, J=
12.4 Hz), 132.1, 129.1, 127.7, 125.8 (d, J=8.7 Hz), 125.0, 121.3 (d, J=
2-(4-Methoxyphenyl)-1H-indole (3n)[7]
White solid (35.1 mg, 63% yield); 1H NMR (400 MHz, CDCl3): d=8.24
(br s, 1H), 7.60–7.58 (m, 3H), 7.38 (d, J=7.4 Hz, 1H), 7.17 (t, J=7.4 Hz,
1H), 7.11 (t, J=7.4 Hz, 1H), 6.99 (d, J=8.2 Hz, 2H), 6.72 (s, 1H),
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3.86 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.4, 138.0, 136.7,
129.5, 126.5, 125.3, 121.9, 120.4, 120.2, 114.5, 110.7, 98.9, 55.4 ppm.
& Son, Glasgow, 1985; c) I. J. Ninomiya, Nat. Prod. 1992, 55, 541–
564; d) R. J. Sundberg, Indoles, Academic Press, San Diego, CA,
1996; e) N. K. Garg, R. Sarpong, B. M. Stolz, J. Am. Chem. Soc.
2002, 124, 13179–13184; f) J. Roncali, Chem. Rev. 1992, 92, 711–
738; g) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–2920;
h) M. Somei, F. Yamada, Nat. Prod. Rep. 2005, 22, 73–103.
[2] a) S. S. Labadie, E. Teng, J. Org. Chem. 1994, 59, 4250–4254; b) B.
Chauder, A. Larkin, V. Snieckus, Org. Lett. 2002, 4, 815–817; c) X.
Cai, V. Snieckus, Org. Lett. 2004, 6, 2293–2295; d) I. Bennacef, C. N.
Haile, A. Schmidt, A. O. Koren, J. P. Seibyl, J. K. Staley, F. Bois,
R. M. Baldwin, G. Tamagnan, Bioorg. Med. Chem. 2006, 14, 7582–
7591; e) R. Dandu, M. Tao, K. A. Josef, E. R. Bacon, R. L. Hudkins,
J. Heterocycl. Chem. 2007, 44, 437–440; f) C. A. Merlic, Y. You,
D. M. McInnes, A. L. Zechman, M. M. Miller, Q. Deng, Tetrahedron
2001, 57, 5199–5212; g) C. G. Hartung, A. Fecher, B. Chapell, V.
Snieckus, Org. Lett. 2003, 5, 1899–1902.
2-(4-Fluorophenyl)-1H-indole (3o)[7]
White solid (36.9 mg, 70% yield); 1H NMR (400 MHz, CDCl3): d=8.24
(br s, 1H), 7.63–7.58 (m, 3H), 7.38 (d, J=7.7 Hz, 1H), 7.19 (t, J=7.7 Hz,
1H), 7.15–7.10 (m, 3H), 6.74 ppm (s, 1H); 13C NMR (100 MHz, CDCl3):
d=162.4 (d, J=245.1 Hz), 136.9 (d, J=18.7 Hz), 129.2, 128.7 (d, J=
3.3 Hz), 126.9 (d, J=18.0 Hz), 122.4, 120.5 (d, J=25.0 Hz), 116.0 (d, J=
20.7 Hz), 110.9, 99.9 ppm (d, J=1.2 Hz).
2-(4-Chlorophenyl)-1H-indole (3p)[7]
White solid (55.4 mg, 80% yield); 1H NMR (400 MHz, CDCl3): d=8.24
(br s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.39 (d, J=
8.3 Hz, 2H), 7.38 (d, J=7.5 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.12 (t, J=
7.5 Hz, 1H), 6.80 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=136.9,
136.7, 133.4, 130.9, 129.2, 126.3, 122.7, 120.8, 120.5, 110.9, 100.5 ppm.
[3] For the direct C2-arylation of indoles, see: a) Y. Akita, Y. Itagaki, S.
Takizawa, A. Ohta, Chem. Pharm. Bull. 1989, 37, 1477–1480; b) N.
Lebrasseur, I. Larrosa, J. Am. Chem. Soc. 2008, 130, 2926–2927;
c) E. T. Nadres, A. Lazareva, O. Daugulis, J. Org. Chem. 2011, 76,
471–483; d) Z. J. Liang, B. B. Yao, Y. H. Zhang, Org. Lett. 2010, 12,
3185–3187; e) B. S. Lane, D. Sames, Org. Lett. 2004, 6, 2897–2900;
f) A. Garcꢁa-Rubia, B. Urones, R. Gꢂmez Arrayꢃs, J. C. Carretero,
Chem. Eur. J. 2010, 16, 9676–9685; g) S. Kirchberg, R. Frçhlich,
A. S. Studer, Angew. Chem. 2009, 121, 4299–4302; Angew. Chem.
Int. Ed. 2009, 48, 4235–4238; h) F. Bellina, C. Calandri, S. Cauteruc-
cio, R. Rossi, Tetrahedron 2007, 63, 1970–1980; i) S. Potavathri,
A. S. Dumas, T. A. Dwight, G. R. Naumiec, J. M. Hammann, B.
DeBoef, Tetrahedron Lett. 2008, 49, 4050–4053; j) C. Bressy, D. Al-
berico, M. Lautens, J. Am. Chem. Soc. 2005, 127, 13148–13149; k) S.
Potavathri, K. C. Pereira, S. I. Gorelsky, A. Pike, A. P. LeBris, B.
DeBoef, J. Am. Chem. Soc. 2010, 132, 14676–14681; l) D. G. Pintori,
M. F. Greaney, J. Am. Chem. Soc. 2011, 133, 1209–1211; m) D. R.
Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
12072–12073; n) L. Wang, W.-B. Yi, C. Cai, Chem. Commun. 2011,
47, 806–808. For direct C3-arylation of indoles, see: o) D. R. Stuart,
K. Fagnou, Science 2007, 316, 1172–1175; p) R. J. Phipps, N. P.
Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 8172–8174;
q) J. Cornella, P. F. Lu, I. Larrosa, Org. Lett. 2009, 11, 5506–5509;
r) J. Zhou, P. Hu, M. Zhang, S. Huang, M. Wang, W. Su, Chem. Eur.
J. 2010, 16, 5876–5881.
[4] For the palladium-catalyzed C3-arylation of free (NH)-indoles, see:
a) F. Bellina, F. Benelli, R. Rossi, J. Org. Chem. 2008, 73, 5529–
5535; b) Z. Zhang, Z. Hu, Z. Yu, P. Lei, H. Chi, Y. Wang, R. He,
Tetrahedron Lett. 2007, 48, 2415–2419; c) G. Cusati, L. Djakovitch,
Tetrahedron Lett. 2008, 49, 2499–2502.
[5] a) X. Wang, B. S. Lane, D. Sames, J. Am. Chem. Soc. 2005, 127,
4996–4997; b) B. B. Tourꢄ, B. S. Lane, D. Sames, Org. Lett. 2006, 8,
1979–1982; c) X. Wang, D. V. Gribkov, D. Sames, J. Org. Chem.
2007, 72, 1476–1479; d) B. S. Lane, M. A. Brown, D. Sames, J. Am.
Chem. Soc. 2005, 127, 8050–8057.
[6] N. R. Deprez, D. Kalyani, A. Krause, M. S. Sanford, J. Am. Chem.
Soc. 2006, 128, 4972–4973.
[7] S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y. Li, Z.-J. Shi, Angew.
Chem. 2008, 120, 1495–1498; Angew. Chem. Int. Ed. 2008, 47, 1473–
1476.
2-(2-Chlorophenyl)-1H-indole (3q)[17]
White solid (31.8 mg, 56% yield); 1H NMR (400 MHz, CDCl3): d=8.76
(br s, 1H), 7.66 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.7 Hz, 1H), 7.42 (d, J=
7.7 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 7.29–7.20 (m, 2H), 7.14 (t, J=
7.7 Hz, 1H), 6.87 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=136.4,
135.1, 131.3, 131.2, 130.8, 130.7, 128.8, 128.2, 127.2, 122.7, 120.8, 120.2,
111.0, 103.6 ppm.
2-(4-Bromophenyl)-1H-indole (3r)[17]
White solid (48.6 mg, 72% yield); 1H NMR (400 MHz, CDCl3): d=8.24
(br s, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.49 (d, J=
8.2 Hz, 2H), 7.37 (d, J=7.4 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H), 7.12 (t, J=
7.4 Hz, 1H), 6.80 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=136.9,
136.6, 132.1, 131.3, 129.1, 126.6, 122.7, 121.5, 120.8, 120.5, 110.9,
100.5 ppm.
2-(Naphthalen-1-yl)-1H-indole (3s)[17]
White solid (36.5 mg, 60% yield); 1H NMR (400 MHz, CDCl3): d=8.29
(d, J=8.0 Hz, 1H), 8.23 (s, 1H), 7.91–7.85 (m, 2H), 7.70 (d, J=7.4 Hz,
1H), 7.59 (d, J=7.0 Hz, 1H), 7.52–7.46 (m, 3H), 7.40 (d, J=7.4 Hz, 1H),
7.23 (t, J=7.4 Hz, 1H), 7.17 (t, J=7.4 Hz, 1H), 6.78 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=136.7, 136.4, 133.9, 131.5, 131.1, 128.9,
128.6, 128.5, 127.2, 126.7, 126.1, 125.7, 125.3, 122.2, 120.6, 120.2, 110.8,
103.7 ppm.
2-(Naphthalen-2-yl)-1H-indole (3t)[8]
White solid (37.7 mg, 62%); 1H NMR (400 MHz, CDCl3): d=8.47 (s,
1H), 8.04 (s, 1H), 7.90–7.80 (m, 4H), 7.60 (d, J=7.7 Hz, 1H), 7.53–7.45
(m, 2H), 7.42 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.14 (t, J=
7.7 Hz, 1H), 6.95 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=137.8,
137.0, 133.6, 132.9, 129.7, 129.3, 128.8, 128.0, 127.8, 126.7, 126.1, 123.8,
123.0, 122.5, 120.7, 120.3, 110.9, 100.7 ppm.
1-Methyl-2-phenyl-1H-indole (3u)[7]
White solid (43.0 mg, 83% yield); 1H NMR (400 MHz, CDCl3): d=7.64
(d, J=7.5 Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.46 (t, J=7.4 Hz, 2H), 7.41–
7.35 (m, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 6.56 (s,
1H), 3.74 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=141.5, 138.3,
132.9, 129.4, 128.5, 127.9, 127.8, 121.6, 120.5, 119.8, 109.6, 101.6, 31.1 ppm.
[8] J.-L. Zhao, Y.-H. Zhang, K. Cheng, J. Org. Chem. 2008, 73, 7428–
7431.
[9] a) G.-W. Wang, T. Miao, Chem. Eur. J. 2011, 17, 5787–5790; b) X.-Y.
Zhou, J.-Y. Luo, J. Liu, S.-M. Peng, G.-J. Deng, Org. Lett. 2011, 13,
1432–1435; c) K. Garves, J. Org. Chem. 1970, 35, 3273–3275; d) R.
Selke, W. Thiele, J. Prakt. Chem. 1971, 313, 875; e) E. Wenkert,
T. W. Ferreira, E. L. Michelotti, J. Chem. Soc. Chem. Commun.
1979, 637; f) H. Wang, Y. Li, R. Zhang, K. Jin, D. Zhao, C. Duan, J.
Org. Chem. 2012, 77, 4849–4853.
Acknowledgements
This work was financially supported by the National Science Foundation
of China (21172092).
[10] a) T. Miao, G.-W. Wang, Chem. Commun. 2011, 47, 9501–9503; b) J.
Liu, X.-Y. Zhou, H.-H. Rao, F.-H. Xiao, C.-J. Li, G.-J. Deng, Chem.
Eur. J. 2011, 17, 7996–7999; c) M. Behrends, J. Sçrmarker, P. Sjç-
[1] a) K. G. B. Torssell, Natural Product Chemistry, Wiley, Chichester,
1983; b) R. H. Thomson, The Chemistry of Natural Products, Blackie
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Lei Wang et al.
berg, M. Larhed, ACS Catal. 2011, 1, 1455–1459; d) H. Rao, L.
Yang, Q. Shuai, C.-J. Li, Adv. Synth. Catal. 2011, 353, 1701–1706.
[11] a) B. Liu, Q. Guo, Y. Cheng, J. Lan, J. You, Chem. Eur. J. 2011, 17,
13415–13419; b) R. Chen, S. Liu, X. Liu, L. Yang, G.-J. Deng, Org.
Biomol. Chem. 2011, 9, 7675–7679; c) M. Wang, D. Li, W. Zhou, L.
Wang, Tetrahedron 2012, 68, 1926–1930; d) M. Wu, J. Luo, F. Xiao,
S. Zhang, G.-J. Deng, H.-A. Luo, Adv. Synth. Catal. 2012, 354, 335–
340.
[13] Y. Li, W.-H. Wang, K.-H. He, Z.-J. Shi, Organometallics 2012, 31,
4397–4400.
[14] E. M. Ferreira, B. M. Stoltz, J. Am. Chem. Soc. 2003, 125, 9578–
9579.
[15] S. Oae, H. Togo, Bull. Chem. Soc. Jpn. 1983, 56, 3802–3812.
[16] Y.-Q. Fang, M. Lautens, J. Org. Chem. 2008, 73, 538–549.
[17] L. Joucla, N. Batail, L. Djakovitcha, Adv. Synth. Catal. 2010, 352,
2929–2936.
[12] a) C. Zhou, Q. Liu, Y. Li, R. Zhang, X. Fu, C. Duan, J. Org. Chem.
2012, 77, 10468–10472; b) K. Sato, T. Okoshi, US Patent 5,159,082,
1992; c) W. Chen, P. Li, T. Miao, L. Meng, L. Wang, Org. Biomol.
Chem. 2013, 11, 420–424; d) S. Sꢄvigny, P. Forgione, Chem. Eur. J.
2013, 19, 2256–2260.
[18] A. Prakash, M. Dibakar, K. Selvakumar, K. Ruckmani, M. Sivaku-
mar, Tetrahedron Lett. 2011, 52, 5625–5628.
Received: July 10, 2013
Published online: && &&, 0000
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ÝÝ These are not the final page numbers!

FULL PAPER
Microwave Chemistry
Tao Miao, Pinhua Li, Guan-Wu Wang,
Lei Wang*
&&&& — &&&&
Microwave-Accelerated Pd-Catalyzed
Desulfitative Direct C2-Arylation of
Free (NH)-Indoles with Arylsulfinic
Acids
From C2 shining sea: The direct C2-
arylation of free (NH)-indoles with
arylsulfinic acids proceeded through
a Pd-catalyzed desulfitation reaction.
In the presence of an oxidant and an
additive, 2-arylindoles were selectively
afforded in good yields.
7
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