Metal-free, C-H arylation of indole and its derivatives with aryl diazonium salts by visible-light photoredox catalysis

Article abstract of DOI:10.1016/j.tetlet.2016.04.051

In this Letter, we present the Rhodamine B catalyzed direct C-H arylation of indole with aryl diazonium salts. This method only requires green light and room temperature.

Full text of DOI:10.1016/j.tetlet.2016.04.051

Tetrahedron Letters 57 (2016) 2298–2302
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free, C–H arylation of indole and its derivatives with
aryl diazonium salts by visible-light photoredox catalysis
⇑
⇑
Ying-Peng Zhang , Xiao-Long Feng, Yun-Shang Yang , Bi-Xia Cao
School of Petrochemical Engineering, Lanzhou University of Technology, Lanzhou 730050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 February 2016
Revised 9 April 2016
Accepted 14 April 2016
Available online 25 April 2016
In this Letter, we present the Rhodamine B catalyzed direct C–H arylation of indole with aryl diazonium
salts. This method only requires green light and room temperature.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
C-arylated indoles
Metal-free
Aryl diazonium salts
Visible light
Free radical
Introduction
a.previous work:metal catalyzed direct C-H arylation of indole analogue
R1
X
H
N
transition metal
catalyzed
H
N
Indole and its derivatives are often found in functional materi-
als, pesticides, drugs, and natural products.1–4 C-arylindole shows
better medicinal value, especially in the aspect of cancer is more
outstanding. Since it was found in 1860s, scientists had been
committed to seek different synthesis methods for further func-
tionalization.5–7 The most efficient synthesis of arylindole is the
direct arylation of indole by C–H bond activation. Recently, much
focus has been devoted to transition-metal-catalyzed processes
such as direct arylation of indoles with activated arenes. The
method avoids the need for prefunctionalization of indole deriva-
tives and thus can potentially provide a promising synthetic
route.8–17 Under such conditions, aromatic halohydrocarbon is
one of the most commonly used coupling partners for the direct
arylation of indole derivatives. In addition, different aromatic
coupling partners as arylation agents have been successfully
applied18–26 (Scheme 1a).
+
R1
R2
R2
X=halogen,NH2NH2,B(OH)2,OTf,etc
b.this work:Rhodamine B catalyzed direct C-H arylation of indole analogue
R1
N2BF4
H
N
H
N
Rhodamine B (1mol%)
visible light,DMSO,RT
+
R1
R2
R2
Scheme 1. Metal catalyzed and photocatalytic approaches for direct C–H arylation
of indole analogue. (a) Previous work: metal catalyzed direct C–H arylation of
indole analogue. (b) This work Rhodamine B catalyzed direct C–H arylation of
indole analogue.
However, the above mentioned reaction process suffers from
several drawbacks, such as the need for a large catalyst, high cost,
ligands and restriction to aqueous reaction media. More recently
reports had appeared showing the direct arylation of furans and
thiophenes using EsoinY as catalyst.27 This method avoids the
high temperature, ligands, and the use of transition-metal. Thus,
photocatalyst is likely the most promising approach for direct
C-arylation of the diazonium salt and indole.
In the past ten years, the free radical reaction has played an
important role in organic synthesis for formation of C–C bonds.
Aryl diazonium salt was selected as a good free radical source
due to its high reduction potential.4,28 Aryl diazonium salts are
⇑
Corresponding authors.
E-mail addresses: yingpengzhang@126.com (Y.-P. Zhang), yangguang@lut.cn
(Y.-S. Yang).
http://dx.doi.org/10.1016/j.tetlet.2016.04.051
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

Y.-P. Zhang et al. / Tetrahedron Letters 57 (2016) 2298–2302
2299
Table 1
well-known oxidative quenchers in photoredox chemistry. It
was first applied by Cano-Yelo and Deronzier to synthesize
phenanthrene derivatives using Ru(bpy)23+ as a photoredox cata-
lyst.29–31 In this Letter, we present the Rhodamine B catalyzed
direct C–H arylation of indole with aryl diazonium salts. This
method only requires green light and room temperature.
Optimization of reaction conditionsa
H
N
N2BF4
H
N
1mol% Rhodamine B
+
DMSO ,light,RT,1h
Results and discussion
2a
1a
3a
Initially, we examined the direct arylation using indole (1a)
and aryl diazonium salts (2a) as the model. The reaction was car-
ried out under 25 W white light-emitting diode (LED) irradiation
with 1 mol % Rhodamine in N,N-dimethylformamide (DMF). The
desired product 3a was obtained in 69% yield after 1 h (Table 1,
entry1). Inspired by this result, we screened other parameters.
Firstly, the reaction of organic solvents such as THF, EtOH,CH3-
CN,MeOH, DMSO, and CH2Cl2 was investigated. Different yields
were obtained in such cases (Table 1, entries 2–7). The results
show that dimethyl sulfoxide (DMSO) is a more suitable solvent
for the photoreaction (Table 1, entry 7). Aromatic product was
obtained in better yields using a bit more indole 1a (Table 1,
entries 8 and 9). Yield of the control reactions was significantly
reduced in the absence of photocatalyst or light (Table 1, entries
10 and 11). The reaction can also be performed in the presence of
water (Table 1, entry 15).
Entry
Conditions
Yield (%)
1
2
3
4
5
6
7
Rhodamine B, DMF
Rhodamine B, EtOH
Rhodamine B, MeOH
Rhodamine B, CH3CN
Rhodamine B,THF
Rhodamine B, CH2Cl2
Rhodamine B, DMSO
Rhodamine B, DMSO
Rhodamine B, DMSO
Without light, DMSO
Without catalyst, DMSO
EsoinY, DMSO
69
26
23
54
19
21
79
81
b8
c9
10
11
12
13
14
15
81
Trace
Trace
66
Rose Bengal, DMSO
Rhodamine 6G, DMSO
Rhodamine B, DMSO/H2O (4:1)
69
73
47
a
b
c
Yields were determined by column chromatography.
1.5 equiv of indole was used.
2 equiv indole was used.
Table 2
Scope of aryl diazonium salts and indolea
R1
H
N
N2BF4
H
N
1mol% Rhodamine B
DMSO ,light,RT,1h
+
R1
R2
R2
1
2
3
Entry
Substrate 1
Substrate 2
N2BF4
Product
Yieldb (%)
H
N
H
N
2a
1
81
1a
3a
H
H
N
N2BF4
N
H3CO
H3CO
2
3
71
2b
2c
1b
3b
H
N
H
N
N2BF4
H3CO
H3CO
72
1c
3c
(continued on next page)

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Y.-P. Zhang et al. / Tetrahedron Letters 57 (2016) 2298–2302
Table 2 (continued)
Entry
Substrate 1
Substrate 2
Product
Yieldb (%)
H
N
H
N
N2BF4
4
73
1d
2d
3d
3e
N2BF4
N
N
5
70
2e
1e
H
N
NO2
H
N
N2BF4
6
7
54
53
NO2
1f
2f
3f
H
N
H
N
N2BF4
Br
Br
2g
1g
3g
H
N
H
N2BF4
N
Cl
8
66
47
57
1h
2h
3h
Cl
H
N
Br
H
N
N2BF4
Br
Br
9
Br
1i
3i
2i
H
N
H
N
N2BF4
O2N
1j
10
2j
3j
NO2
H
H
N
N2BF4
2k
N
Cl
Cl
11
12
22
25
1k
3k
3l
H
N
H
N
N2BF4
2l
O2N
O2N
1l

Y.-P. Zhang et al. / Tetrahedron Letters 57 (2016) 2298–2302
2301
Table 2 (continued)
Entry
Substrate 1
Substrate 2
Product
Yieldb (%)
H
N
Br
H
N
N2BF4
Cl
Cl
Br
13
14
Br
1m
2m
3m
H
H
N
N2BF4
N
Br
Cl
1n
14
31
2n
3n
Cl
N2BF4
N
N
Cl
15
62
2o
1o
3o
Cl
H
N
NO2
H
N
N2BF4
H3CO
H3CO
NO2
16
60
17
1p
2p
3p
H
N
HN
N2BF4
17
1q
2q
3q
a
The reaction was performed with 1 (0.5 mmol), 2a (1.5 equiv), and Rhodamine B (0.01 equiv) in 2.0 mL of DMSO.
Isolated yields after purification on SiO2.
b
H
N
O
R2
R2
NEt2
Et2
Cl
EsoinY:
O
OR1
R2
O
O
R1=R3=H,R2=Br;
Rose Bengal:
HCl
N
O
C
R2
R3
R3
CO2R1
O
R1=Na,R2=I,R3=Cl;
R3
Rhodamine 6G
Rhodamine B
R3
In addition, other organic dyes except Rhodamine B such as
In order to better understand the mechanism of this reaction,
eosin Y, Rose Bengal and its sodium salt, and Rhodamine 6G were
also successful in accelerating this indole arylation process, albeit
with somewhat lower efficiencies (Table 1, entries 12–14).
two kinds of control experiments were performed, and the results
are presented in Scheme 2. Preliminary studies have verified this
Based on the optimized conditions, we examined the scope and gen-
erality of the indole (1a) with diazonium salt (2a), various indole deriva-
tives and diazonium salt have been successfully applied in this reaction.
The results are listed in Table 2. Electron-donor indole and diazonium
salt (Table 2, entries 2–5), were found to be more effective in the forma-
tion of the product than electron-acceptor substituted (Table 2, entries
6–14). For N-substituted indoles, the corresponding 3-arylindole prod-
ucts were also obtained (Table 2, entries 5 and 15). Moreover, electron-
donor indole and electron-acceptor diazonium salt also gained a good
60% yield (Table 2, entry 16). Not surprisingly, for the indole with a
naphthylgroupdiazoniumsalt, 3-(naphthalen-2-yl)-1H-indole (Table2,
entry 17) was formed under identical conditions. In addition, nitro, bro-
mide and chloride were successfully introduced in the photochemical
reaction, which is useful for further synthesis elaboration.
N2BF4
H
N
1mol% Rhodamine B
DMSO, light,RT,0.5-1h
+
(a)
(b)
1r
2r
H
N
N2BF4
H
N
+
1mol% Rhodamine B TEMPO
DMSO ,light,RT,1h
2a
1a
3a,10%
Scheme 2. Control experiments.

2302
Y.-P. Zhang et al. / Tetrahedron Letters 57 (2016) 2298–2302
N2BF4
2a
dye*
visible
light
A
H
N
dye
1a
dye
H
N
R2
H
N
H
N
B
BF
4
C
D
3a
Scheme 3. Plausible reaction mechanism. Dye = Rhodamine B.
hypothesis. As expected, no desired product was obtained when 3-
methylindole was subjected to this reaction (Scheme 2a). Reaction
was conducted while a widely known radical-scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy(TEMPO) was added led to complete
inhibition of the intended reactivity, only a 10% yield of product
was obtained (Scheme 2b). Which shows that a radical intermedi-
ate involves in this reaction.
Based on the above observations and literature reports a plausi-
ble mechanism for this photoreaction is proposed (Scheme 2). Ini-
tially, aryl radical A is formed from the excited state of Rhodamine
B to aryldiazonium salt 2a. Addition of aryl radical A to indole 1a
gives radical intermediate B, which is transformed into a carboca-
tion intermediate C by a Possible route oxidation of the radical
intermediate B by the Rhodamine B radical cation to give C. Finally,
intermediate C is deprotonated, Regeneration systems of aromatic
results in the desired coupling product 3a (Scheme 3).
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This work was supported financially by grants from the Gansu
Province Natural Science Foundation of China (No. 2014GS03265).
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.
051.