Metal-free-catalyzed oxidative trimerization of indoles using NaNO 2 to construct quaternary carbon centers: Synthesis of 2-(1H-Indol-3-yl)-2,3′-biindolin-3-ones

Article abstract of DOI:10.1080/00397911.2014.891743

A simple, convenient, and efficient synthesis of 2-(1H-indol-3-yl)-2, 3′-biindolin-3-one derivatives via a transition-metal-free-catalyzed oxidative trimeric reaction of indoles has been developed. This transformation may have occurred through a tandem oxidative homocoupling reaction by using NaNO₂ in pyridine as oxidant. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C2 position of indoles. Copyright

Full text of DOI:10.1080/00397911.2014.891743

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Metal-Free–Catalyzed Oxidative
Trimerization of Indoles Using NaNO2 to
Construct Quaternary Carbon Centers:
Synthesis of 2-(1H-Indol-3-yl)-2,3′-
biindolin-3-ones
Jun Xue a , Yunhong Bao a , Wenbing Qin a , Jiayi Zhu a , Yubo Kong a
, Hongen Qu a , Zhengwang Chen a & Liangxian Liu a
a Department of Chemistry and Chemical Engineering , Gannan
Normal University , Ganzhou , Jiangxi , China
Accepted author version posted online: 03 Apr 2014.Published
online: 06 Jun 2014.
To cite this article: Jun Xue , Yunhong Bao , Wenbing Qin , Jiayi Zhu , Yubo Kong , Hongen Qu ,
Zhengwang Chen & Liangxian Liu (2014) Metal-Free–Catalyzed Oxidative Trimerization of Indoles Using
NaNO2 to Construct Quaternary Carbon Centers: Synthesis of 2-(1H-Indol-3-yl)-2,3′-biindolin-3-ones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:15, 2215-2221, DOI: 10.1080/00397911.2014.891743
To link to this article: http://dx.doi.org/10.1080/00397911.2014.891743
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Synthetic Communications1, 44: 2215–2221, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.891743
METAL-FREE–CATALYZED OXIDATIVE
TRIMERIZATION OF INDOLES USING NaNO2 TO
CONSTRUCT QUATERNARY CARBON CENTERS:
SYNTHESIS OF 2-(1H-INDOL-3-YL)-2,3’-BIINDOLIN-
3-ONES
Jun Xue, Yunhong Bao, Wenbing Qin, Jiayi Zhu, Yubo Kong,
Hongen Qu, Zhengwang Chen, and Liangxian Liu
Department of Chemistry and Chemical Engineering, Gannan Normal
University, Ganzhou, Jiangxi, China
GRAPHICAL ABSTRACT
Abstract A simple, convenient, and efficient synthesis of 2-(1H-indol-3-yl)-2,30-biindolin-
3-one derivatives via a transition-metal-free-catalyzed oxidative trimeric reaction of indoles
has been developed. This transformation may have occurred through a tandem oxidative
homocoupling reaction by using NaNO2 in pyridine as oxidant. This methodology provides
an alternative approach for the direct generation of all-carbon quaternary centers at the C2
position of indoles.
Keywords Indole; quaternary carbon; trimerization
INTRODUCTION
Indolin-3-ones with a chiral center at the 2-position are encountered in a large
variety of natural products and can be used in the total synthesis of biologically active
alkaloids.[1–3] For example, 2-(1H-indol-3-yl)-2,30-biindolin-3-one 1 (Figure 1) was
isolated as the product of indole oxidation by a strain of Claviceps purpurea.[3a] This
compound has also been characterized from natural (bacterial) sources such as Vibrio
Received September 15, 2013.
Address correspondence to Liangxian Liu, Department of Chemistry and Chemical Engineering,
Gannan Normal University, Ganzhou, Jiangxi 341000, China. E-mail: lxliu@xmu.edu.cn
2215

2216
J. XUE ET AL.
Figure 1. Representative natural products with a 2,20-disubstituent indolin-3-one structural unit.
parahaemolyticus[2a] and Haemophilus influenzae.[3b] In addition, isatisine A 2, an
oxindole system having indole 2-substituents, is present in the roots and leaves of
Isatis indigotica Fort. (Cruciferae). This biennial herbaceous plant is widely cultivated
in China and eastern Asia for the prevention and treatment of viral diseases such
as influenza, viral pneumonia, mumps, and hepatitis.[4] Therefore, developing
convenient methods for the construction of 2,2-disubstituted indolin-3-ones are
of considerable interest.[2d,4b,5] In 2008, Ganachaud and coworkers reported the
biocatalytic synthesis of 1 by trimerization of indole.[6a] However, the chemical
synthesis of 2-(1H-indol-3-yl)-2,30-biindolin-3-one 1 and its derivatives from indoles
has been rarely reported.[6b,c]
Recently, we have developed a biomimetic synthetic method for the trimeriza-
tion of indoles using 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) in air as oxidant
with excellent regioselectivity under mild conditions.[7] However, extensive study in
this group revealed several drawbacks: First, substrates with a strong electron-
withdrawing group, such as NO2 and CN, could not be applied. Second, the high
loading of TEMPO is required (0.7 equiv). Third, a long reaction time of 3 days is
needed. Thus, the development of new strategy for the oxidative trimerization of
indoles continues to be of considerable interest.
It is well known that NaNO2 has been recently used as a transition-metal-free
catalyst for aerobic transformations of organic compounds.[8] Inspired by these reports,
we envisioned that NaNO2 could be applied to the oxidative trimeric reaction of
indoles. We report herein on the construction of all-carbon quaternary centers at the
C2 position of indoles using sodium nitrite as the oxidant at room temperature.
RESULTS AND DISCUSSION
As a substrate for optimization studies we chose indole 5a. Preliminary
screening of Lewis acids and solvents allowed us to identify benzoic acid in CH3CN
as promising conditions for the trimeric reaction of indole at room temperature.
However, dimer 6 was observed as major side product in the reaction mixture
(Table 1, entry 1).[9] Changing benzoic acid to TsOH or carrying out the reaction
in other solvents was also not encouraging (Table 1, entries 2–8). To our delight,
when we treated 5a with NaNO2 and TsOH in the presence of pyridine at rt, a signi-
ficant improvement was realized, because 7a was the main product under the
reaction conditions (Table 1, entry 9).
Based on these promising initial results we decided to optimize the reaction
conditions further to increase the reaction yield, and the results are summarized in

OXIDATIVE TRIMERIZATION OF INDOLES
2217
Table 1. Optimization of the reaction conditionsa
Entry
Acid (mmol)
Solvent
CH3CN
CH3CN
Yield (%)b 7a/6
1
2
Benzoic acid (0.5)
TsOH (0.5)
TsOH (0.5)
Trace=48
25=40
21=42
Trace=29
17=36
Trace=25
30=36
32=31
65=10
16=45
13=42
36=34
35=27
29=46
55=30
63=23
65=27
78=trace
72=trace
80=0
3
THF
Xylene
4
TsOH (0.5)
TsOH (0.5)
5
1,4-Dioxane
CHCl3
DMF
6
TsOH (0.5)
TsOH (0.5)
7
8
TsOH (0.5)
TsOH (0.5)
DMSO
Pyridine
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
TsOH (0.5)
TsOH (0.5)
Trimethylamine
Diisopropylamine
Aniline
TsOH (0.5)
TsOH (0.5)
TsOH (0.5)
N,N-Dimethyl aniline
Imidazole
Pyridine
Oxalic acid (0.5)
CF3CO2H (0.5)
HBF4 (0.5)
Pyridine
Pyridine
CH3SO3H (0.5)
CH3SO3H (0.3)
CH3SO3H (0.7)
CH3SO3H (0.9)
CH3SO3H (1.0)
CH3SO3H (1.1)
Pyridine
Pyridine
Pyridine
Pyridine
84=0
87=0
Pyridine
Pyridine
82=0
aReaction conditions: indole (0.5 mmol), NaNO2 (0.5 mmol), and solvent (0.6 mL) at rt for overnight.
bIsolated yield.
Table 1. The study revealed that the amine as solvent was crucial for this transform-
ation. Pyridine gave the best outcome and other amines, such as trimethylamine,
diisopropylamine, aniline, N,N-dimethyl aniline, and imidazole, resulted in poor
yields (Table 1, entries 9–14). In addition, acid additive was critical to the trimeric
reaction. Thus, different acid additives were screened to improve the yield. CH3SO3H
was proven to be the best for the transformation of 5a, because 7a was obtained in
78% yield under the reaction conditions (Table 1, entry 18), whereas other acid addi-
tives such as oxalic acid, CF3CO2H, or HBF4 under the similar reaction conditions
resulted in the formation of 6 (Table 1, entries 15–17). With regards to the amount
of CH3SO3H used, it was also established that 2 equivalents of CH3SO3H was indeed
the preferred amount with more or less loading giving poor yields (Table 1, entries
19–23). Our best conditions for the oxidative trimeric reaction of indole were, there-
fore, 100 mol% NaNO2 and 200 mol% CH3SO3H in pyridine at rt (Table 1, entry 22).

2218
J. XUE ET AL.
After the establishment of optimized reaction conditions, we extended this
new protocol to substituted indoles. A variety of representative indole derivatives
were subjected to the optimized conditions, as depicted in Table 2. Thus, a trimeric
reaction of substituted indoles proceeded smoothly to provide corresponding
2-(1H-indol-3-yl)-2,30-biindolin-3-one derivatives in moderate to excellent yields.
The reaction can tolerate a variety of functional groups at the 1, 4, 5, 6, and 7 positions
of indoles, such as F, Cl, Br, CH3, CH2CH3, CH3O, BnO, NHAc, CO2CH3, and NO2,
providing opportunities for further synthetic elaboration.
It was found that the electronic nature of the substituents on the indole ring did
not play a key role. Both electron-donating and electron-withdrawing indoles were
readily converted to the corresponding products in moderate to excellent yields.
We were delighted to note that the substrates with a strongly electron-withdrawing
group, such as NO2, smoothly underwent the reaction to afford corresponding
Table 2. Trimeric reaction of indoles by using NaNO2 in air as oxidanta
Entry
R1
R2
Product
Yield (%)b
1
2
H
5-Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
87
80
73
77
63
66
91
78
56
49
61
78
71
63
68
43
67
60
51
3
5-F
4
5-CH3
5-OCH3
5-OBn
5-NHAc
5-CO2CH3
5-NO2
5-CN
5
6
7
7g
7h
7i
8
9
10
11
12
13
14
15
16
17
18
19
7j
6-CI
6-F
7k
71
7m
7n
7o
7p
7q
7r
7s
6-CO2CH3
7-CH3
7-OCH3
7-NO2
4-OCH3
H
CH3
CH2CH3
H
aReaction conditions: indole (0.5 mmol), NaNO2 (0.5 mmol), CH3SO3H (1.0 mmol),
pyridine (0.6 mL), rt.
bIsolated yield.

OXIDATIVE TRIMERIZATION OF INDOLES
2219
Scheme 1. Plausible pathway for the formation of 7a.
products in moderate yields. For example, 5-nitro-1H-indole was transformed into
trimer 7i in 56% yield (Table 2, entry 9). In our previous work on oxidative trimeric
reaction of indoles,[7] the efficiency of this transformation is highly dependent upon
the electronic properties of R1 groups. Electron-rich groups showed better results
than electron-withdrawing groups in this trimerization. In contrast, the strongly
electron-withdrawing group, NO2, totally inhibited the process.
Based on these preliminary results and previous study,[10] a tentative pathway
for the formation of 7a is proposed in Scheme 1. The first step is indolenine tautomer
13 reacts with ꢀ NO2 generated from HNO2, leading to the formation of radical inter-
mediate 14. A coupling reaction between 14 and nitrogen dioxide (through its oxygen
atom) would lead to indol-3-one 16. Subsequently, the highly reactive species 16 is
trapped by second indole molecule to give dimer 17, which is further oxidized (likely
by NaNO2) to result in the formation of dimer 18. Finally, a CH3SO3H-catalyzed
nucleophilic addition of third indole molecule to dimer 18 affords compound 7a.
CONCLUSIONS
In summary, we have developed an operationally simple and efficient method
to construct all-carbon quaternary centers at the C2 position of indoles via a
transition-metal-free-catalyzed oxidative trimeric reaction of indoles. It is note-
worthy that the substrates with strongly electron-withdrawing group, such as
NO2, smoothly underwent the reaction to afford corresponding products in moder-
ate yields. Moreover, it is highly regioselective (2,30-linkage). Importantly, the broad
group tolerance made this method useful to construct such unique scaffolds from
commercially available indole and its derivatives.
EXPERIMENTAL
General Procedure for the Preparation of 2-(1H-Indol-3-yl)-2,30-
biindolin-3-ones
CH3SO3H (1.0 mmol) was added to a solution of indole (0.5 mmol) and NaNO2
(0.5 mmol) in pyridine (0.6 mL) in air and the mixture was stirred at rt overnight. The

2220
J. XUE ET AL.
reaction mixture was concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: EtOAc=PE ¼ 1:2) to yield the corre-
sponding product.
FUNDING
The authors are grateful to the National Science Foundation of China (Nos.
21162001 and 21202023), the National Key Technology Research and Development
Program of China (No. 2009BAI78B01), Jiangxi Province Key Support Program
(No. 2009BNB06200), Natural Science Foundation of Jiangxi Province (No.
20132BAB203007), and Jiangxi Province Office of Education Support Program
(No. GJJ13666) for financial support.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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