Room-Temperature Palladium(II)-Catalyzed Direct 2-Arylation of Indoles with Tetraarylstannanes

Article abstract of DOI:10.1055/s-0040-1707196

A palladium(II)-catalyzed direct 2-arylation of indoles by tetraarylstannanes with oxygen (balloon) as the oxidant at room temperature has been developed. Various tetraarylstannanes can be employed as aryl sources for 2-arylation of indoles in up to 89% yield, providing a practical and efficient catalytic protocol for accessing 2-arylindoles.

Full text of DOI:10.1055/s-0040-1707196

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
Y. Liu et al.
Letter
Synlett
Room-Temperature Palladium(II)-Catalyzed Direct 2-Arylation of
Indoles with Tetraarylstannanes
Yuxia Liu*a
R3
Chao Wangb
Linjuan Huanga
Dong Xue*b
R3
R3
(MeCN)2Pd(OTs)2
2 (balloon)
HOAc, 25 °C
R2
R2
+
Sn
O
R3
N
R1
N
R1
a Shaanxi Natural Carbohydrate Resource Engineering Research
Center, College of Food Science and Technology, Northwest
University, Xi’an, 710069, P. R. of China
R1 = H, Me, Bn
R2, R3 = EDG, EWG
R3
yuxialiu@nwu.edu.cn
b Key Laboratory of Applied Surface and Colloid Chemistry, Ministry
of Education and School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an 710062, P. R. of China
xuedong_welcome@snnu.edu.cn
Received: 04.05.2020
Accepted after revision: 14.06.2020
Published online: 05.08.2020
with readily available and simple aryl sources is still highly
desirable.
Tetraarylstannanes20 are important organometallic re-
agents and are widely used in organic synthesis, because of
their stability, high reactivity, and ready availability.21 More
significantly, up to four aryl groups can be transferred from
an organostannane reactant. Tetraarylstannanes have the
potential to serve as ideal aryl sources for C–C bond form-
ing reactions under relatively mild conditions. Unfortunate-
ly, there are only a few reports of reactions in which
tetraarylstannanes were used for C–C bond formation. For
example, Wang and co-workers reported a palladium-cata-
lyzed atom-efficient Stille cross-coupling reaction of tetra-
phenylstannane with aryl bromides.22 Subsequently, our
group developed a palladium-catalyzed Stille cross-cou-
pling reaction of arylureas with tetraarylstannanes through
C–H bond activation.23 Zhang and co-workers reported a
transition-metal-free LiCl-promoted coupling reaction of
aryl halides with tetraarylstannanes to give biaryls.24
Therefore, the development of new methods for conver-
sions of aryl groups should provide significant opportuni-
ties for the facile construction of complex molecules. Here,
we wish to report a new and practical method for the syn-
thesis of 2-arylindoles through palladium-catalyzed 2-ary-
lation of indoles with tetraarylstannanes at room tempera-
ture with oxygen as the oxidant (balloon pressure), provid-
ing the desired arylindole-type products in good to
excellent yields (Scheme 1). To the best of our knowledge,
this is the first example of a direct 2-arylation of indoles
with tetraarylstannanes through C–H bond activation.
To begin our study, we selected N-methylindole (1a)
and tetraphenylstannane (2a) as model reactants for opti-
mization of the reaction conditions (Table 1). After screen-
ing a wide range of conditions [see Supporting Information
(SI), Table S1], we were delighted to find that by using
(MeCN)2Pd(OTs)2 as the catalyst, the corresponding 2-ary-
DOI: 10.1055/s-0040-1707196; Art ID: st-2020-l0267-l
Abstract A palladium(II)-catalyzed direct 2-arylation of indoles by
tetraarylstannanes with oxygen (balloon) as the oxidant at room tem-
perature has been developed. Various tetraarylstannanes can be em-
ployed as aryl sources for 2-arylation of indoles in up to 89% yield, pro-
viding a practical and efficient catalytic protocol for accessing 2-
arylindoles.
Key words indoles, arylation, palladium catalysis, tetraarylstannanes,
C–H activation
2-Arylindoles represent a class of privileged and power-
ful building blocks for organic synthesis1 that are widely
present in natural products and pharmaceuticals, such as
antibiotics and anticancer drugs.2 Conventional approaches
for the synthesis of these compounds involve cross-cou-
pling between a C(2)-prefunctionalized indole and a func-
tionalized arene derivative; such approaches are not cost-
effective because of the requirement for prior functional-
ization of the substrate.3 Transition-metal-catalyzed C–H
functionalization has emerged as a powerful tool for the
late-stage modification of biologically relevant structures
such as indoles.4 Significant achievements have been ac-
complished in Pd-catalyzed direct 2-arylations of indoles
with various coupling partners, such as aryl halides,5 hy-
pervalent iodine arylating agents,6 organoboranes,7 orga-
nosilanes,8 sodium sulfinates,9 arylsulfonyl hydrazides,10
aryltriazenes,11 arenes,12 and arylhydrazines.13 Apart from
Pd, other transition metals such as Ru,14 Rh,15 Cu,16 Ag,17
and Ni18 have also been used for the direct 2-arylation of in-
doles with various arylation reagents. Furthermore, a tran-
sition-metal-free protocol for 2-arylation of indoles has re-
cently been developed.19 Despite this progress, the develop-
ment of mild and green methods for 2-arylation of indoles
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Liu et al.
Letter
Synlett
stantially less effective as catalysts (entries 3–7). The choice
of solvent was also critical; most of the solvents surveyed
gave moderate to low yields (entries 8–12). The addition of
HOAc was found to improve the yield of 3a,25 and the use of
HOAc as the solvent affording the highest isolated yield of
86%. This might be partly due to the lower solubility of 2a
in HOAc, which inhibits the homocoupling of 2a, a side re-
action that was often observed in cases when the product
yields were low. Investigation of the effects of various oxi-
R3
R3
R3
Sn
R2
R2
+
R3
(MeCN)2Pd(OTs)2
N
R1
N
R1
O
2 (balloon)
HOAc, 25 °C
R3
R1 = H, Me, Bn
R2, R3 = EDG, EWG
Scheme 1 Direct 2-arylation of indoles with tetraarylstannanes
Table 2 Direct 2-Arylation of N-Methylindole (1a) with Various
Tetraarylstannanes (2)a,b
lated product N-methyl-2-phenyl-1H-indole (3a) was ob-
tained in 86% isolated yield after 12 hours of reaction in
HOAc at 25 °C. Notably, the catalyst and dioxygen are both
essential for the reaction. In the absence of either of these
components, none of the product was detected, and the
starting materials remained unreacted (Table 1, entries 1
and 2). Other palladium species such as PdCl2, Pd(OAc)2,
(PPh3)2PdCl2, (PhCN)2PdCl2, and (MeCN)2PdCl2 were sub-
R
(MeCN)2Pd(OTs)2
R
R
(10 mol%)
Sn
H +
HOAc, 25 °C
R
N
N
O2 (balloon)
R
1a
2
3
Entry
1
Product
Yieldb (%)
86
Table 1 Optimization of Conditions for 2-Arylation of N-Methylindole
(1a) with Tetraphenylstannane (2a)a,b
N
N
3a
3b
Pd, oxidant
H +
Sn
solvent, 25 °C, 12 h
N
N
2
3
80
79
3a
1a
2a
Entry
Reaction conditions
Yieldb (%)
N
1
2
No catalyst, no O2, CHCl3
(MeCN)2Pd(OTs)2, no O2, CHCl3
PdCl2, O2, CHCl3
–
3c
–
3
26
35
–
4
66
4
Pd(OAc)2, O2, CHCl3
N
N
N
5
(PPh3)2PdCl2, O2, CHCl3
3d
3e
3f
6
(PhCN)2PdCl2, O2, CHCl3
trace
41
45
35
trace
26
29
86
33
21
32
18
–
Cl
F
7
(MeCN)2PdCl2, O2, CHCl3
5
6
67
68
8
(MeCN)2Pd(OTs)2, O2, CHCl3
(MeCN)2Pd(OTs)2, O2, DCE
(MeCN)2Pd(OTs)2, O2, MeCN
(MeCN)2Pd(OTs)2, O2, THF
(MeCN)2Pd(OTs)2, O2, EtOH
(MeCN)2Pd(OTs)2, O2, HOAc
(MeCN)2Pd(OTs)2, AgF, HOAc
(MeCN)2Pd(OTs)2, Ag2O, HOAc
(MeCN)2Pd(OTs)2, Ag2CO3, HOAc
(MeCN)2Pd(OTs)2, Cu(OAc)2, HOAc
(MeCN)2Pd(OTs)2, BQ, HOAc
(MeCN)2Pd(OTs)2, air, HOAc
9
10
11
12
13
14
15
16
17
18
19
F
7
8
56
62
N
3g
F
F
N
3h
38
a Reaction conditions: 1a (0.5 mmol), 2 (0.19 mmol), (MeCN)2Pd(OTs)2 (10
mol%, 0.05 mmol), HOAc (5 mL), O2 (balloon), 25 °C, 12 h.
b Isolated yield.
a Reaction conditions: 1a (0.5 mmol), 2a (0.19 mmol), Pd catalyst (10
mol%, 0.05 mmol), solvent (5 mL), 25 °C, 12 h.
b Isolated yield.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
Y. Liu et al.
Letter
Synlett
Table 3 (continued)
Entry
dants revealed that O2 is the best oxidant for the reaction;
other oxidants such as AgF, Ag2O, Ag2CO3, Cu(OAc)2, or 1,4-
benzoquinone (BQ) gave poorer results (entries 14–18).
When the reaction was performed under air, the yield of 3a
was reduced to 38% (entry 19). Moreover, the reaction tem-
perature plays an important role; increasing the tempera-
ture did not improve the yield of the reaction (SI, Table S1,
entries 26–28).
Having established the optimal reaction conditions, we
next investigated the substrate scope of the reaction. First,
we examined the reactions of N-methylindole (1a) with
various tetraarylstannanes bearing electron-donating or
electron-withdrawing substituents. Like 2a, tetraarylstan-
nanes with substituents in the para- or meta-positions of
the phenyl rings reacted well with 1a and afforded good to
excellent yields of the desired products (Table 2). To our de-
light, tetraarylstannanes carrying halogen substituents,
such as Cl or F groups, were successfully coupled with 1a to
give the corresponding 2-arylated products 3e–g in yields
of 56–79%. Moreover, tetraarylstannanes with disubstituted
phenyl rings were also found to be viable reactants (3d,
66%; 3h, 62%).
Product
Yieldb (%)
N
6
7
71
89
F
Bn
5f
N
Bn
5g
8
81
N
Bn
5h
5i
O
Cl
F
9c
10
11
60
70
76
N
Bn
N
Bn
5j
Table 3 Direct 2-Arylation of N-Benzylindoles (4) with Various Tetraar-
ylstannanes (2)a,b
N
Bn
5k
R
F
F
(MeCN)2Pd(OTs)2
R
R
(10 mol%)
12
13
66
75
R'
H
+
R'
N
Sn
N
Bn
N
Bn
HOAc, 25 °C
O2 (balloon)
R
Bn
5l
R
4
2
5
Cl
N
Bn
Entry
1
Product
Yieldb (%)
5m
a Reaction conditions: 1a (0.5 mmol), 2 (0.19 mmol), (MeCN)2Pd(OTs)2 (10
mol%, 0.05 mmol), HOAc (5 mL), O2 (balloon), 25 °C, 12 h.
N
84
71
b Isolated yield.
c 48 h.
Bn
5a
To extend the versatility of this protocol, we examined
the Pd(II)-catalyzed 2-arylation of a variety of N-benzylin-
doles 4 with various tetraarylstannanes under the opti-
mized reaction conditions (Table 3). In most cases, good
yields of the desired products 5a–k were obtained from the
reactions of 4 with a wide range of tetraarylstannanes.
When N-benzylindole (4a) was used instead of N-methylin-
dole (1a) to react with 2a under the optimized conditions,
product 5a was obtained in a high isolated yield of 84% (Ta-
ble 3, entry 1).
We also examined the effects of substituents on the in-
dole moiety under the standard reaction conditions. N-Ben-
zylindoles containing a methyl, methoxy, or fluoro group
on the phenyl ring reacted smoothly with 2a to give the
corresponding 2-arylated N-benzylindoles 5b–f in yields of
2
N
Bn
5b
5c
N
3
4
5
61
68
76
Bn
N
Bn
5d
O
N
Bn
5e
Thieme. All rights reserved. Synlett 2020, 31, A–F

D
Y. Liu et al.
Letter
Synlett
Table 4 (continued)
Entry
61–76%. Pleasingly, tetraarylstannanes bearing either elec-
tron-rich (CH3) or electron-deficient groups (F or Cl) in the
para- or meta-positions on the phenyl rings were tolerated
in the reaction with 4a under the present reaction condi-
tions and gave the corresponding products 5g–l in good to
excellent yields of 60–89%.
Product
Yield b (%)
6
7
70
62
N
H
7f
Finally, N-unsubstituted indoles were found to be
slightly less reactive than N-protected indoles (Table 4). The
reaction of indole (6a) with 2a gave 2-phenyl-1H-indole
(7a) in 73% yield, compared with 86% for 3a and 84% for 5a.
It was also necessary to increase the reaction time to 24
hours to obtain favorable yields in the case of indoles bear-
ing substituents on their benzene rings. Indoles with a
methyl group in the C-5, C-6, or C-7 positions all coupled
smoothly with 2a to give the desired products 7b–d in
yields of 66, 65, and 55%, respectively. Notably, the methoxy
group on indole was well tolerated under these reaction
conditions, and the desired product 7e was obtained in 60%
yield. However, tetraarylstannanes bearing methoxy groups
showed a lower reactivity than electron-deficient ones
(e.g., 7h versus 7i, or 7j). In particular, 7h was obtained in a
low yield of 48%, even on prolonging the reaction time and
increasing the catalyst loading.
N
H
7g
7h
7i
O
Cl
F
8 d
48
65
62
N
H
9
N
H
10
N
H
7j
a Reaction conditions: 6 (0.5 mmol), 2 (0.19 mmol), (MeCN)2Pd(OTs)2 (10
mol%, 0.05 mmol), HOAc (5 mL), O2 (balloon), 25 °C, 12 h.
b Isolated yield.
c 24 h.
d (MeCN)2Pd(OTs)2 (20 mol%), 48 h.
Table 4 Direct 2-Arylation of Indoles 6 with Various Tetraarylstan-
nanes (2)a,b
Although the mechanism of this reaction has not been
clear until now, on the basis of reports in the litera-
ture5k,7b,8,23,26,27 and our own observations, we propose a
possible mechanism involving a Pd(0)/Pd(II) process,26b,28 as
shown in Scheme 2. Initially, the Pd(II) catalyst reacts with
Ph4Sn (2a) and a phenyl group is transferred from the tin in
2a to palladium to form a Ph–Pd(II)–XL2 complex (X = OAc,
OTs; L = MeCN) intermediate 8. Intermediate 8 then reacts
with a C–H group of N-methylindole (1a) to give intermedi-
ate 10, which undergoes an electrophilic palladation prefer-
entially at the C3-position of the indole. Subsequently, a C3-
to-C2 migration gives the cationic intermediate 11,26b,29 and
deprotonation leads to the formation of the arylpalladium
complex 12. Reductive elimination of the complex 12 then
affords the desired product 3a, together with the Pd(0) spe-
cies 13, which is oxidized to Pd(II) by O2 to close the catalyt-
ic cycle.
In summary, we have developed an efficient, high-
atom-economy, Pd(II)-catalyzed, direct 2-arylation of in-
doles with tetraarylstannanes.30 The reaction proceeds at
room temperature with (MeCN)2Pd(OTs)2 as catalyst and
molecular oxygen as the terminal oxidant in an acidic me-
dium. This is the first report of a C–H arylation of indoles
using tetraarylstannanes as aryl sources by means of a Pd-
catalyzed cross-coupling process. The operationally simple
procedure makes this an ideal catalytic system for the di-
R
(MeCN)2Pd(OTs)2
R
(10 mol%)
R
R'
H
+
R'
Sn
HOAc, 25 °C
O2 (balloon)
N
N
R
H
H
R
6
2
7
Entry
1
Product
Yield b (%)
73
N
H
7a
7b
7c
2 c
3 c
4 c
66
65
55
N
H
N
H
N
H
7d
O
5 c
60
N
H
7e
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E
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Synlett
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Catal. Sci. Technol. 2014, 4, 1979.
L2PdX2
O2
HX
2a
L2Pd0
Ph
II
Ph
X
N
L2Pd
13
3a
8
1a
reductive
elimination
L
L
H
II
Pd
II
Ph
Pd PhL2
N
N
9
12
electrophilic
substitution
II
Pd
PhL2
H
H
H
PdII PhL2
N
N
10
migration
11
Scheme 2 Proposed mechanism for the reaction
rect 2-arylation of indoles. The reaction mechanism and
further application of this new arylation method are being
actively explored in our group.
Funding Information
We are grateful for the financial support of the National Natural Sci-
ence Foundation of China (21902126), China Postdoctoral Science
Foundation (2019M663947XB), and the 111 Project (B14041).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707196.
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References and Notes
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Letter
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(30) 1-Methyl-2-Phenyl-1H-indole (3a); Typical Procedure
A Schlenk tube equipped with a magnetic stirrer bar was
charged with N-methylindole (1a; 0.5 mmol, 1.0 equiv), Ph4Sn
(2a; 0.19 mmol), and (MeCN)2Pd(OTs)2 (10 mol%, 0.05 mmol).
HOAc (5 mL) was then introduced by using a syringe. The tube
was degassed (×3) then charged with O2, and the O2 atmosphere
was maintained by using a balloon. The mixture was then
stirred at 25 °C for 12 h. The HOAc was removed by rotary evap-
oration, and the residue was dissolved in CH2Cl2 (50 mL) and the
solution was washed with aq NaHCO3 (2 × 30 mL). The organic
layers were combined, washed with brine, and dried (Na2SO4).
The solvent was removed by rotary evaporation, and the crude
product was purified by column chromatography (silica gel, PE–
CH2Cl2) to give a white solid; yield: 89 mg (86%); mp 67.5–
69.5 °C; Rf = 0.2 (PE–CH2Cl2, 10:1).
1H NMR (300 MHz, acetone-d6):  = 7.59–7.57 (m, 3 H), 7.50–
7.48 (m, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.20 (t, J = 7.2 Hz, 1 H),
7.18 (t, J = 7.2 Hz, 1 H), 6.55 (s, 1 H), 3.75 (s, 3 H).13C NMR (75
MHz, acetone-d6):  = 141.9, 139.2, 133.4, 129.7, 129.1, 128.7,
128.4, 122.0, 120.8, 120.1, 110.3, 101.9, 31.1. HRMS (ESI); m/z
[M + Na]+ calculated for C15H13NNa: 230.0946; found: 230.0948.
1-Methyl-2-(4-tolyl)-1H-indole (3b)
White solid; yield: 88 mg (80%); mp 97.5–100.5 ℃; Rf = 0.2 (PE–
CH2Cl2, 10:1). 1H NMR (300 MHz, acetone-d6):  = (m, 1 H),
7.48–7.40 (m, 3 H), 7.33–7.31 (m, 2 H), 7.18 (t, J = 7.2 Hz, 1 H),
7.07 (t, J = 7.2 Hz, 1 H), 6.50 (s, 1 H), 3.75 (s, 3 H), 2.40 (s, 3 H).
13C NMR (75 MHz, acetone-d6):  = 142.0, 139.1, 138.2, 130.5,
129.7, 129.3, 128.8, 120.6, 120.4, 120.1, 110.3, 101.5, 31.1, 20.9.
HRMS (ESI); m/z [M + Na]+ calculated for C16H15NNa: 244.1102;
found: 244.1104.
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J. Synlett 2012, 23, 1941.
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2016, 81, 9422.
(25) For details, see SI.
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Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; corri-
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Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148.
(d) Takeda, D.; Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M.
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11463.
(28) Jackson, A. H.; Lynch, P. P. J. Chem. Soc., Perkin Trans. 2 1987,
1215.
Characterization data for other products are reported in the SI.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F