Palladium-catalyzed direct arylation of indoles with arylsulfonyl hydrazides

Article abstract of DOI:10.1039/c5ob02569a

A novel method to synthesise 2-arylindoles is demonstrated via direct arylation of indoles with arylsulfonyl hydrazides. Under the optimized reaction conditions, the reaction well tolerates a wide variety of functional groups to afford structurally diverse 2-arylindoles in good to excellent yields at 70 °C.

Full text of DOI:10.1039/c5ob02569a

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Palladium-catalyzed direct arylation of indoles
with arylsulfonyl hydrazides†
Cite this: DOI: 10.1039/c5ob02569a
Congrong Liu,*a Lianghui Ding,a Guang Guo,a Weiwei Liub and Fu-Lai Yangc
Received 15th December 2015,
Accepted 4th February 2016
DOI: 10.1039/c5ob02569a
www.rsc.org/obc
A novel method to synthesise 2-arylindoles is demonstrated via have versatile applications in organic chemistry.12 Moreover,
direct arylation of indoles with arylsulfonyl hydrazides. Under the sulfonyl hydrazides can be utilized as sulfonyl sources and sul-
optimized reaction conditions, the reaction well tolerates a wide fenyl sources through the cleavage of their sulfur–nitrogen
variety of functional groups to afford structurally diverse 2-aryl- bonds.13 In contrast, the reports that sulfonyl hydrazides are
indoles in good to excellent yields at 70 °C.
utilized as aryl sources are very few.14 To our knowledge, there
are no examples describing the direct arylation of indoles
using sulfonyl hydrazides as aryl sources. Herein we report an
efficient and facile synthesis of indole derivatives via direct ary-
lations of indoles with arylsulfonyl hydrazides [eqn (1)].
The indole moiety is an important unit because of its presence
in many relevant bioactive molecules, such as colchicines,
indolyl-3-glyoxamide D-24851 and 2-aryl-3-arylcarbonyl
indole.1 Developing efficient synthetic approaches to construct
differently substituted indole derivatives is one of the most
exciting topics in organic synthesis.2 Among them, the direct
carbon–hydrogen bond functionalization is a more convenient
method for the formation of carbon–carbon and carbon–
heteroatom bonds on indole rings.3 In this regard, direct aryla-
tions of indoles have emerged in recent years as attractive
alternatives to the classical transition-metal-catalyzed cross-
coupling reactions.4 Various aryl sources such as aryl sulfo-
nates,5 aryl halides,6 aryldiazonium salts,7 aryl boronic acid,8
arylcarboxylic acid derivatives,9 diaryliodonium salt10 or aryl-
sulfonyl chlorides11 were smoothly coupled with indoles.
These direct arylations of indoles significantly expand the
scope for structurally diverse indole derivative synthesis, but
each has its own limitations, such as harsh reaction con-
ditions, moderate scope and functional group tolerance. To
address such issues, it is highly desirable to explore new aryl
sources and reaction conditions for the direct arylations of
indoles.
ð1Þ
To test the aforementioned hypothesis, we treated indole
(1a) with p-toluenesulfonyl hydrazide (2a, 1.2 eq.) and 5 mol%
Pd(OAc)2 in nitromethane under an oxygen atmosphere at
70 °C and found that 2-arylindole 3a was formed in 26% yield
(Table 1, entry 1). Subsequently, a number of common solvents
were examined to improve the reaction efficiency (Table 1,
entries 2–7). Among the above solvents examined, dimethyl
sulfoxide was found to be the optimal reaction medium to give
product 3a in 65% yield (Table 1, entry 4). Replacing Pd (OAc)2
with a few other palladium catalysts led to much lower yields
or even no desired product at all (Table 1, entries 8–11). The
addition of a base did not improve this reaction efficiency
(Table 1, entry 12). To our delight, the catalytic ability of Pd
(OAc)2 was dramatically enhanced by Brønsted acids and the
addition of 1.2 equivalents of trifluoromethanesulfonic acid
improved the yield to 84% (Table 1, entry 14). Control experi-
ments indicated that the oxidant is essential for the desired
reaction, a lower yield (60%) was obtained from the reaction
under an air atmosphere, and no desired product was observed
under a nitrogen atmosphere (Table 1, entries 17 and 18).
Encouraged by our preliminary findings, we investigated
the substrate scope for the direct arylation of indole (1a) with
arylsulfonyl hydrazides (2). Under the optimized reaction con-
ditions, a range of arylsulfonyl hydrazides smoothly reacted
with indole 1a to give the corresponding 2-arylindoles in good
to excellent yields (Table 2, entries 1–11). It is noteworthy that
Sulfonyl hydrazides are readily accessible and they have
been employed to form heterocycles and hydrazones which
aSchool of Environment Engineering, Nanjing Institute of Technology,
1 Hongjingdadao, Nanjing, Jiangsu 211167, China. E-mail: congrong@njit.edu.cn;
Fax: +86-025-86118974
bSchool of Communication Engineering, Nanjing Institute of Technology,
1 Hongjingdadao, Nanjing, Jiangsu 211167, China
cDepartment of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob02569a
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Table 1 Optimization of reaction conditionsa
This direct arylation allowed the synthesis of 2-vinylindole
from the corresponding vinylsulfonyl hydrazide, but its reactiv-
ity was much lower than that of arylsulfonyl hydrazides
(Table 2, entry 13). By contrast, no reactivity was observed with
alkylsulfonyl hydrazides such as 1-octanesulfonyl hydrazide
(Table 2, entry 14).
The influence of the substituents on the indole moiety was
also evaluated and the results are presented in Table 3. In
general, the arylation took place at the C2 position of the
indole ring (Table 3, entries 1, 4–15). However, the C3 position
of the indole ring was the reaction site of choice when the C2
position was occupied by a substituent (Table 3, entries 2
and 3). Under the optimized reaction conditions, a number of
indoles bearing either electron-withdrawing groups (Cl, Br and
CO2Me) or electron-donating groups (Me and OMe) on the N-1,
C-2, C-3, C-4, C-5, C-6 or C-7 positions of the indole rings were
transformed into their corresponding 2-arylindoles or 3-aryl-
indoles in moderate to excellent yields. Indoles with electron-
donating groups showed good reactivity with phenylsulfonyl
hydrazides, and the corresponding products 3 were obtained
in good yield. Nevertheless, lower yields were obtained when
electron-withdrawing groups, like halogen groups or a carbo-
methoxy group, were present at the indole rings.
Entry
Catalyst
Solvent
Additive
Yieldb
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
MeNO2
MeCN
AcOH
DMSO
DMF
None
None
None
None
None
None
None
None
None
None
None
PPh3
TsOH
TfOH
AcOH
CuI
26
33
Trace
65
33
25
14
EtOH
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Trace
0
9
10
11
12
13
14
15
16
17c
18d
20
12
29
73
84
63
55
60
TfOH
TfOH
0
a Reaction conditions: indole 1a (0.20 mmol), benzenesulfonyl
hydrazide 2a (0.24 mmol), catalyst (5 mol%), additive (if any,
1.2 equiv.), O2 (1 atm.), solvent (1.0 mL), 70 °C (oil bath), 20 h.
b Isolated yield based on 1a. c Under air. d Under N2.
When
a stoichiometric amount of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy, a well known radical-capturing
species) was added to this reaction mixture, the arylation
proceeded smoothly to give the corresponding product 3aa in
86% yield (Scheme 1).15 Therefore, the reaction mechanism
may not be a radical pathway.
both electron-withdrawing and electron-donating groups were
introduced into the arylation products by employing arylsulfo-
nyl hydrazides bearing such groups on the aromatic rings.
Heteroarylsulfonyl hydrazides were also found to be suitable
substrates for this direct arylation (Table 2, entry 12).
To gain more insights into the reaction mechanism, we
carried out ESI-MS spectroscopic analysis of the 20 : 1 mixture
Table 3 The direct arylation of indoles 1 with sulfonyl hydrazides 2a
Table 2 The direct arylation of indole 1a with sulfonyl hydrazides 2a
Entry
1 (R1)
2
3 or 3′
Yieldb
Entry
2, R
3
Yieldb
1
2
3
4
5
6
7
8
1b (1-Me)
1c (2-Me)
1d (2-Ph)
1e (3-Me)
1f (4-Br)
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
2i
3bb
3cb′
3db′
3eb
3fb
3gb
3hb
3ib
3jb
3kb
3lb
3bc
3bi
3bk
3ic
84
70
62
66
61
70
63
80
57
58
60
85
81
71
73
1
2
3
4
5
6
7
8
2a, 4-MeC6H4
2b, Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
84
85
87
81
80
75
71
62
73
68
63
65
39
0
2c, 4-tBuC6H4
2d, 4-MeOC6H4
2e, 4-FC6H4
1g (5-Cl)
2f, 4-ClC6H4
2g, 4-IC6H4
2h, 4-F3CC6H4
2i, 2-FC6H4
2j, 1-Naphthyl
2k, 2-Naphthyl
2l, 2-Thienyl
2m, PhCHvCH
2n, Me(CH2)7
1h (5-Br)
1i (5-OMe)
1j (5-CO2Me)
1k (6-Cl)
9
9
10
11
12
13
14
15
10
11
12
13
14
1l (7-Cl)
1b (1-Me)
1b (1-Me)
1b (1-Me)
1i (5-OMe)
2k
2c
a Reaction conditions: 1a (0.20 mmol), 2 (0.24 mmol), Pd(OAc)2 (5 mol%), a Reaction conditions: 1 (0.20 mmol), 2a (0.24 mmol), Pd(OAc)2 (5 mol%),
TfOH (0.24 mmol) DMSO (1.0 mL), 70 °C, O2 (balloon), 20 h. b Isolated TfOH (0.24 mmol), DMSO (1.0 mL), 70 °C, O2 (balloon), 20 h. b Isolated
yields based on 1a.
yields based on 1.
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formation of arylpalladium 8. Complex 8 undergoes aromatic
C–H palladation to give complex 9 and meanwhile releases
HOAc. Complex 9 undergoes reductive elimination to give
product 3 and meanwhile releases Pd0, which is oxidized by
dioxygen to regenerate the Pd (OAc)2 catalyst (Scheme 2).
Scheme 1 Control experiment.
of p-toluenesulfonyl hydrazide (2a) and Pd(OAc)2 in DMSO at Conclusions
room temperature. Gratifyingly, three arylpalladium(II) species
In summary, we have developed an unprecedented direct aryla-
were successfully assigned, which suggests that the acetate
anion of the Pd(OAc)2 can be displaced by an arylsulfonyl
hydrazide and a carbon–palladium bond can be formed
through successive extrusion of nitrogen and sulfur dioxide
(Fig. 1).16
On the basis of our results and previous relevant mechanis-
tic studies,15–17 we proposed the reaction pathway depicted in
Scheme 2 for the palladium-catalyzed arylation of indoles with
arylsulfonyl hydrazides. Arylsulfonyl hydrazide 2 would be
electrophilically attacked by Pd(OAc)2, followed by elimination
of HOAc to give complex 4. Complex 4 undergoes β-hydride
elimination to give sulfonyl diazene 5 and meanwhile release
HPdOAc. Reductive elimination of HPdOAc followed by oxi-
dation with dioxygen regenerates the Pd(OAc)2 catalyst. Sulfo-
nyl diazene 5 is attacked by Pd(OAc)2, followed by elimination
of HOAc to give complex 6. Successive extrusion of nitrogen
and sulfur dioxide from complex 6 and 7 leads to the
tion of indoles with arylsulfonyl hydrazides through the clea-
vage of sulphur–nitrogen and sulphur–carbon bonds. In the
presence of 5 mol% of Pd(OAc)2, 1.2 equivalents of trifluoro-
methanesulfonic acid and dioxygen under normal pressure, a
broad range of indoles smoothly underwent direct arylation
with arylsulfonyl hydrazides to give structurally diverse 2-aryl-
indoles or 3-arylindoles in moderate to excellent yields. The
reaction well tolerates a wide variety of functional groups such
as alkoxy, halo, and ester. The current study paves the way for
the use of sulfonyl hydrazides as a unique aryl source in
chemical synthesis.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (no. 21202154), the
Natural Science Foundation of The Jiangsu Higher Education
Institutes of China (15KJB150007), Nanjing Institute of
Technology Scientific Research Foundation for Introducing
Talents (no. YKJ201329, YKJ201326, YKJ201318, YKJ201419),
Nanjing Institute of Technology.
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