The controllable C2 arylation and C3 diazenylation of indoles with aryltriazenes under ambient conditions

Article abstract of DOI:10.1039/c9nj01728c

An efficient and regio-divergent method for both the C2 arylation and C3 diazenylation of C2,C3-unsubstituted indoles with aryltriazenes was developed. At room temperature, both reactions were carried out with HPF₆/ionic liquids (ILs) as the promoter. The C2 arylation and C3 diazenylation activated by HPF₆/ILs show remarkable reactivity, which results in corresponding products with yields of up to 99%. Notably, the practicality of the protocol was further demonstrated via gram-scale operations, late-stage modification and the reusability of the ILs.

Full text of DOI:10.1039/c9nj01728c

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

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DOI: 10.1039/C9NJ01728C
ARTICLE
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Controllable C2 arylation and C3 diazenylation of indoles with
arytriazenes under ambient conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Yonghong Liua, Xia Maa, Gengxin Wua, Ziran Liua, Xiang Yanga, Bin Wangb, Chenjiang Liua*,
Yonghong Zhanga* and Yan Huanga*
DOI: 10.1039/x0xx00000x
An efficient and regio-divergent method for both C2 arylation and C3 diazenylation of C2,C3-unsubstituted indoles with
arytriazenes was developed. At room temperature, both reactions were carried out with HPF6/ionic liquids (ILs) as the
promoter. The C2 arylation and C3 diazenylation activated by HPF6/ILs show a remarkable reactivity, which results in
corresponding products with yields up to 99%. Notably, the practicability of the protocol was further demonstrated via
gram-scale operations, late-stage modification and the reusability of ILs.
indoles. Few investigations have been done on intermolecular
Introduction
selective C2 arylation and C3 diazenylation of indoles with the same
9c]
coupling partners in high regio-selectivity.[9a,
Consequently,
Indoles and their derivatives widely exist in pharmaceuticals, natural
products and bioactive molecules, and exhibit a wide range of
significant biological activities.[1] Up to now, various of well-
established classical methods for functionalized indoles are
available.[2] Among all the successful strategies,[3] the direct C−H
activation of indole for generating carbon-carbon bond or carbon-
heteroatom bond seems to be the most straightforward pathway.[4-6]
The direct site-selective arylation of indoles at the C3 and C2
achieving C2 arylation and C3 diazenylation of C2, C3-unsubstituted
indoles with the same reagent presents some challenges, especially
with good chemo- and regio-selectivities.
Reagents are key factors for indole functionalization. Compared
with most of arylated reagents,[4b, 5b, 6e, 10] aryltriazenes are one of the
most powerful and versatile candidates because of their superior
reactivity, good stability, and diverse transformations.[9a, 11] Recently,
our lab established a direct C3/C2 diazenylation of C2/C3 subsituted
indoles with aryltriazenes using Brønsted ionic liquid (IL) as a
promoter at room temperature (Scheme 1a).[9a] To the best of our
knowledge, aryltriazenes simultaneously participated in arylation
and diazenylation of indoles under controllable reaction conditions
have rarely been reported. Enlightened by these reactions and our
interests in triazene chemistry,[9a, 11c, 11e, 11g] we supposed that the
positions via ligand, directing group and reagent controlled methods
6, 7]
have also been reported.[4,
However, most of protocols often
suffer from harsh reaction conditions including high reaction
temperatures, anaerobic and anhydrous conditions, long reaction
time, poor substrate scope and functional group tolerance.[4c, 6d, 6e, 8]
Wang group developed a palladium-catalyzed method for C2
arylation of N-substituted indoles with 1-aryltriazenes in the
presence of BF3·OEt2, however, the reaction was carried out at
higher temperature (80 oC), longer reaction time (12 h), and with
stoichiometric Lewis acid.[8d] Furthermore, compared with arylation
reaction, direct diazenylation of C2, C3-unsubstituted indoles at the
C3 or C2 positions is less studied.[9] Despite that Tu and co-
workers[9b] implemented the selective sulfonylation and diazotization
of indoles with arylsulfonyl hydrazide through TBHP/TBAI-
mediated oxidative coupling reaction, they mainly got the non-
regioselective 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles when C2,
C3-unsubstituted indoles was used as substrates, and the 2-
sulfonyldiazenyl-1H-indoles were obtained only by using C3-methyl
Scheme 1. C–C/C–N bond formation with arytriazenes.
a Key Laboratory of Oil and Gas Fine Chemicals, Ministry of Education & Xinjiang
Uygur Autonomous Region, College of Chemistry and chemical Engineering,
Xinjiang University, Urumqi 830046, P. R. China. E-mail: pxylcj@126.com;
zhzhzyh@126.com; xjuchem_2012@163.com
reaction of indoles with triazenes would form 2-arylindole
derivatives at mild reaction condition by synergistic effect of
palladium and suitable acids. As a result, it was something of
satisfaction to find that aryl triazenes not only play the dual roles as
both aryl precursors and aryl azo donors, but also participate in
arylation and diazotization of indole with good regioselectivity.
b Physics and Chemistry Detecting Center, Xinjiang University, Urumqi, 830046,
China
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/x0xx00000x
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78c
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7e
Pd(OAc)2 HPF6
Pd(OAc)2 HPF6
DMF
DMF
DMF
DMF
DMF
ND
Herein, we report a highly efficient and divergent method for both
C2 arylation and C3 diazenylation of indoles with arytriazenes under
ambient condition (Scheme 1b).
View Article Online
8e,f
82c
84c
62
DOI: 10.1039/C9NJN01D728C
9e,f,g Pd(OAc)2 HPF6
ND
ND
ND
ND
41
10d
11e
Pd(OAc)2
IL3
IL3
Pd(OAc)2
55
Results and discussion
12d,h,i Pd(OAc)2
IL3
DMF/H2O 83(83c)
At the outset of our investigation, 1-methylindole 1a and (E)-1-
phenyl-2-(pyrrolidin-1-yl)diazene 2aa were selected as the model
substrate to optimize the C2 arylation (Table 1). Among a series of
screened additives (Table 1, entries 1-5), HPF6 was eventually
identified as the optimal promoter and the reaction could be
completed in 30 minutes when 1.0 equiv. of HPF6 was used (Table 1,
entry 5). Considering the solvent effect for arylation, it was revealed
that DMF was more effective than the other solvents (Table S1 and
S2, ESI†). Upon further examination, we found that 0.6 equiv. of
HPF6 as additive was sufficient for the transformation (Table 1,
entries 6, 7). When the volume of solvent was 1 mL and the molar
ratio of indole to aryltriazene was 1:1.3, compound 3a could reach
84% isolated yield (entries 8, 9). Due to the fascinating features of
ILs, such as good stability, nonvolatility and recyclability, the IL3
loading and the solvents were further screened (Table 1, entries 10-
12), we found that by the time an aqueous solution of IL3 was added
to the reaction system by dropwise, the yield of product 3a improved
dramatically (83% isolated yield). When 0.8 equiv. of IL3 was used
as promoter, DMF aqueous solution (VDMF: Vwater = 1:1) proved to
be the optimum choice for arylation (Table 1, entry 12). Gratifyingly,
in the absence of palladium, it was more advantageous to the
formation of C3 diazenylation products in moderate to excellent
yield (Table 1, entries 13-17). After a brief screening of additives,
IL4 was by far the best (Table 1, 16). Solvent effects have also been
examined (Table S1 and S2, ESI†), and TFE was shown as the ideal
solvent for C3 diazenylation. Decreasing the IL4 loading from 1.0
equiv. to 0.6 equiv., 4a could also be obtained in excellent yields
(entry 18). It is worth noting that by using HPF6 as the promoter, 4a
could reach 94% isolated yield (Table 1, entry 19), which matches
with the case of IL4 as additive (Table 1, entry 18).
13j
14j
-
-
-
-
-
-
-
IL1
TFE
TFE
TFE
TFE
TFE
TFE
TFE
ND
ND
ND
ND
ND
ND
ND
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IL2
90
15j
IL3
92
16j
IL4
96
93c
95(95c)
94c
17j
HPF6
IL4
18e,j
19e,j
HPF6
a
Reaction conditions: 1a (0.2 mmol), 2aa (0.24 mmol), additives (1 equiv),
solvent (2 mL), Pd(OAc)2 (5 mol%), HPF6 or IL aqueous solution was added
slowly over 30 min, the reaction time was determined by TLC detection. For C3
d
diazenylation b GC yield (benzophenone as internal standard). c Isolated yield.
Additive (0.8 equiv). e Additive (0.6 equiv). DMF (1 mL) g 2aa (0.26 mmol).h
f
V=2 mL (VDMF:Vwater = 1:1). i The IL3 was added slowly. j Free of Pd(OAc)2. TFE
= 2,2,2-Trifluoroethanol. ND = No detection.
With the optimized reaction conditions in hand, we examined the
nature of the terminal tertiary amine substituent of phenyldiazenes
with ionic liquid or HPF6 as additive separately (Table 2). Except for
dibutylamino group, the other tested linear and cyclic substituents
could effectively promote the formation of 3a or 4a (Table 2, entries
1-5). Although phenyldiazene with dimethylamino group performed
unsatisfactorily for HPF6 as the promoter, it could be made up by
using ionic liquid IL4 as additive (Table 2, entry 3). For C2
arylation, phenyldiazene with diethylamino group was selected as
the optimum substrate, which produced 3a in 91% (Con. A) and 89%
(Con. B) isolated yields (Table 2, entry 2). For C3 diazenylation,
phenyldiazene with pyrrolidine substituent was proved to be efficient
partners, affording product 4a in 95% (Con. C) and 94% (Con. D)
isolated yields (Table 2, entry 1).
Table 2. Substrate Scope of N-substituted 1-Aryltriazenes
Table 1. Optimization of C2 arylation and C3 diazenylation of
indole a
Yield 3a
Yield 4a
Entry
R
2
con. A con. B con. C con. D
1
2
83%
91%
84%
89%
95%
82%
94%
91%
2aa
2ba
–NEt2
3
–NMe2
86%
65%
80%
58%
2ca
Yield (%)b
4
5
–NBu2
79%
81%
74%
81%
47%
91%
79%
85%
2da
2ea
Entrya Catalyst Additives
Solvent
3a
32
4a
ND
ND
ND
ND
Trace
ND
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
IL1
IL2
IL3
IL4
DMF
DMF
DMF
DMF
DMF
DMF
Con. A: 1a (0.20 mmol), 2 (0.24 mmol), Pd(OAc)2 (5.0 mol%), IL3 (0.8 equiv),
DMF (1 mL), H2O (1 mL), rt, 5 h, isolated yields. Con. B: 1a (0.2 mmol), 2 (0.26
mmol), HPF6 (0.6 equiv) was added slowly over 30 min, DMF (1 mL), Pd(OAc)2
(5.0 mol%), rt, 4 h, isolated yields. Con. C: 1a (0.20 mmol), 2 (0.24 mmol), IL4
(0.6 equiv), TFE (2 mL), rt, 2 h, isolated yields. Con. D: 1a (0.2 mmol), 2 (0.24
mmol), HPF6 (0.6 equiv) was added slowly over 30 min, CF3CH2OH (2 mL), rt, 1
h, isolated yields.
54
3
57
4
Trace
67
5
6d
Pd(OAc)2 HPF6
Pd(OAc)2 HPF6
77c
2 | J. Name., 2012, 00, 1-3
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Next, the applicability of substrates was studied in more detail. accordingly in high yields (4l-4o). 4-methyl indoleVaienwdArt2ic-lpehOennlinyel
Once 2-arylindole library was firstly established, a series of indole could also form the target moleculeDsO(I4:p10.a1n0d394/Cq9)N, Ja0n1d72t8hCe
aryltriazenes and indoles were then selected to realize the structural compound 4q could be gained almost in quantitative yield.
diversities of 2-arylindole (Table 3). Aryltriazene with electron-
neutral or electron-rich substituent on aryl groups gave the
corresponding 2-arylindole smoothly (3a-3m). Interestingly, the
Table 4. Substrate scope of C3 diazenylation of indole
sterically hindered 2-arylindoles, such as 2-methoxylphenyl (3b), 2-
methylphenyl (3c), 2,6-dimethoxylphenyl (3j), 3,5-dimethylphenyl
(3k), and 3,4,5-trimethoxylphenyl (3m) groups, were still
successfully obtained in good to excellent isolated yield. In light of
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60
Yield (%)a
the important role of fluorine compounds in medicinal chemistry,
Entry
R1
R2
Ar
4
fluorine atom was introduced into 2-aryl indole skeleton under the
promotion of IL3, in which 2-(3-fluorophenyl)-1-methyl-1H-indole
(3e) could be afforded in 67% isolated yield by reaction at 60 °C for
5 h. N- and C-substituted indoles also gave the corresponding
products in good yield (3n-o, 3p-3q). The bromo substituent in
compound 3q could be further used in cross coupling reactions.
Remarkably, we also observed that N-substitution of indole has a
certain influence on the formation of 2-arylindole. Compared with
the other tested N-substituents, methyl group is more conducive to
the formation of 2-arylated products.
Con. C Con. D
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17
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
n-Pr
i-Pr
Bn
Me 4-Me
Me 2-Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
82
81
71b
85
87
90
92
81b
79b
64
95
98
89
88
83
99
94
72
79
73
80
82
81
79
86
76
66
92
91
84
69b
76b
99
2-OMeC6H4
3-MeC6H4
3-ClC6H4
4-MeC6H4
4-OMeC6H4
4-i-PrC6H4
4-t-BuC6H4
4-FC6H4
4-ClC6H4
3,5-(OMe)2C6H3 4k
4j
Table 3. Substrate scope of C2 arylation of indole
Ph
Ph
Ph
Ph
Ph
Ph
4l
4m
4n
4o
4p
4q
Yield (%)a
Con. A Con. B
Entry R1
R2
Ar
3
Reaction conditions C: 1 (0.20 mmol), 2b (0.24 mmol), IL4 (60 mol %), TFE (2
mL), rt, 2 h; Reaction conditions D: 1 (0.2 mmol), 2a (0.24 mmol), HPF6 (0.6
equiv), TFE (2 mL), rt, 1 h. a Isolated yields. b 4 h.
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
96
85
91
67b
91
93
92
94
71b
80
79
82
92
89
87
69b
89
93
82
89
Trace
88
2-MeOC6H4
2-MeC6H4
3-MeC6H4
3-FC6H4
4-MeC6H4
4-MeOC6H4
4-i-PrC6H4
4-t-BuC6H4
The recyclability of IL was investigated subsequently under the
optimized conditions (Figure 1). IL could be easily recovered from
the reaction mixture by extraction with water and reused for the next
cycle. For the diazenylation reaction, IL4 can be reused at least three
times without a significant loss of activity (Figure 1, right). However,
for the arylation reaction, the yield of product 3b gradually
decreased as the number of cycles increased (Figure 1, left).
90
89
90
10 Me
11 Me
12 Me
13 Me
14
15 n-Pr
2,6-(MeO)2C6H3 3j
3,5-Me2C6H3 3k
3,4-(MeO)2C6H3 3l
3,4,5-(MeO)3C6H2 3m
65c
82
Figure 1. ILs Recycling Experiment.
66
72
82
Et
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
3n
3o
3p
3q
71
16 Me 4-Me
17 Me 5-Br
83c
79c
Reaction conditions A: 1 (0.20 mmol), 2b (0.24 mmol), Pd(OAc)2 (5.0 mol %),
DMF (1 mL), IL3 (0.8 equiv.) was dissolved in H2O (1 mL) and then added to the
above solution by dropwise, rt, 5 h; Reaction conditions B: 1 (0.2 mmol), 2a (0.26
mmol), DMF (1 mL), HPF6 (0.6 equiv) was added slowly over 30 min, Pd(OAc)2
(5.0 mol%), rt, 4 h. a Isolated yields. b 60 oC, 5 h. c 60 oC, 10 h.
Moreover, 3-arylazoindole library was then investigated with the
established optimization method (Table 4). Firstly, aryltriazenes
bearing electron-rich, -neutral, and -deficient groups were studied.
All of them proceeded smoothly with 1-methylindole to afford the
corresponding 3-arylazoindoles prosperously (4a-4k). Secondly, the
scope of indole nucleus was carefully considered. Both N-alkyl and
N-benzyl indoles performed well, diazenylation products obtained
This journal is © The Royal Society of Chemistry 20xx
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
the 3-arylazoindole 4a was generated by IL/PF6 or R1R2NH
View Article Online
assisted deprotonation and rearomatizaDtiOonI: 10o.1f039/C9NJ01728C
E. For both
reactions mentioned above, IL and HPF6 were concurrently
released whereby another triazene substrate was activated.
6
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8
9
Conclusions
In summary, aryltriazenes were applied successfully to the synthesis
of 2-aryl and 3-aryldiazenyl indoles by the function of IL or HPF6
promoting effect under mild conditions. In which, aryl triazenes play
the dual roles as both aryl precursors and aryl azo donors in arylation
and diazotization of indole, the reactions selectively establish C-C
and C-N bonds through regio- and chemo-selective C2 arylation and
C3 diazenylation of the indole framework in controllable reaction
conditions, enabling a mild and practical access to functionalized
indoles with good to excellent selectivity and chemical yields. For
C3 diazenylation, the products could be easily achieved by simple
precipitation and recrystallization. Furthermore, complementary
effects of IL and HPF6 existed in the synthesis of special compounds,
IL3 favored the formation of fluorinated C2 aryl indole, and HPF6
contributed the late-stage diversification of sulfadiazine in C3
diazenylation of indole. The viability of late-stage and site-selective
diversification of sulfadiazine drug candidates will provide candidate
compounds for the discovery of new biologically active compounds.
Unfortunately, when free (NH)-indoles or N-substitution indole with
electron-withdrawing group were used, products were hardly
obtained for both C2 arylation and C3 diazenylation. The biological
activity of modified drugs and optical properties of the diazenylated
adducts are being studied in the laboratory.
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In order to further explore the efficiency and practicability of the
protocol, gram scale experiments and late-stage diversification were
carried out. As is shown in Scheme 2, 2-(2-methoxyphenyl)-1-
methyl-1H-indole 3b could be obtained in 74% (Con. A) and 81%
(Con. B) isolated yield. We then performed late-stage diversification
of sulfadiazine drug candidates with the developed method for C3
diazenylation of indole. The results showed that 3-sulfanilamido-
azoindoles (4r, 4s) could be successfully synthesized at the
preferable effect of HPF6. However, IL4 does not show feasibility
for this protocol.
Scheme 2. Gram-scale experiment and late-stage modification of
sulfadiazines
Scheme 3. The proposed reaction mechanism
9a, 11a, 12]
Based on the literature,[8d,
the possible reaction
mechanisms for the formation of 2-aryl and 3-aryldiazenyl indoles
are depicted in Scheme 3. In this process, aryltriazene 2 was
activated by IL or HPF6 to give ammonium salt A, then B and the
secondary amine (R1R2NH) emerged accordingly. For C2 arylation,
the diazonium salt B underwent oxidative addition of Pd(0), which
was in situ reduced from Pd(OAc)2 by DMF, the ensuing extrusion
of N2 led to the formation of arylpalladium species C. Afterwards, C
alternatively reacted with 1a via a Heck-type carbopalladation
Conflicts of interest
There are no conflicts to declare.

reaction,12 thus providing intermediate D. Finally, IL/PF6 or
R1R2NH promoted anti--deprotonation aromatization from D,
producing the coupling product 3a, in which Pd(0) was regenerated.
For C3 diazenylation, 1-methylindole 1a reacted with
Acknowledgements
This work was financially supported by the National Natural Science
Foundation of China (21462042, 21502162, 21262036, 21762041,
electrophile diazonium salt
B to get the intermediate E. Then,
4 | J. Name., 2012, 00, 1-3
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2005, 127, 4996-4997. (c) Lane, B. S.; Sames,VDiew. OArtricgl.e OLneltint.e,
DOI: 10.1039/C9NJ01728C
2004, 6, 2897-2900. (d) Liu, C.; Miao, T.; Zhang, L.; Li, P.;
and 21861036), China Postdoctoral Science Foundation (2017-015
and 2017M613256). The authors thank the Ministry Key Laboratory
of Oil and Gas Fine Chemicals for the assistance of GC-MS testing.
The authors also acknowledge facilities and staff at the Physics and
Chemistry Detecting Center of Xinjiang University.
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New Journal of Chemistry
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View Article Online
DOI: 10.1039/C9NJ01728C
Table of Contents
H
R2
H
Pd(OAc)2 (5.0 mol %)
HPF6 (0.6 equiv)
DMF, rt, 4 h
Ar
N N
HPF6 (0.6 equiv)
TFE, rt, 1 h
N
R1
R2
Ar
R2
+ R4
N
or
or
N
N
Pd(OAc)2 (5.0 mol %)
IL4
(0.6 equiv)
TFE, rt, 2 h
R1
R1
R3
IL3
(0.8 equiv)
VDMF: Vwater = 1:1
rt, 5 h
N
N
17 examples
up tp 96% yield
19 examples
Ar
up to 99% yield
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 Mild conditions
 Open Flask
 Gram scale
 C-C/C-N bond formation
 Chemo/regio-divergent
 ILs Recycle
 Highly efficient
 Simple post-treatment
Controllable C2 arylation and C3 diazenylation of indoles with arytriazenes under ambient
conditions