Synthesis of N-aryl-3-(arylimino)-3H-indol-2-amines via hypervalent iodine promoted oxidative diamination of indoles

Article abstract of DOI:10.1016/j.tetlet.2018.03.015

A direct and fast oxidative diamination of substituted indoles with anilines was realized by using 1-fluoro-1,2-benziodoxol-3(1H)-one under mild conditions. This protocol could provide a wide range of synthetically valuable N-aryl-3-(arylimino)-3H-indol-2-amine derivatives under peroxide-free conditions within 30 min in up to 91% yields.

Full text of DOI:10.1016/j.tetlet.2018.03.015

Accepted Manuscript
Synthesis of N-aryl-3-(arylimino)-3H-indol-2-amines via Hypervalent Iodine
Promoted Oxidative Diamination of Indoles
Xinpeng Jiang, Guizhou Li, Chuanming Yu
PII:
S0040-4039(18)30312-5
https://doi.org/10.1016/j.tetlet.2018.03.015
TETL 49784
DOI:
Reference:
Tetrahedron Letters
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2 March 2018
6 March 2018
Please cite this article as: Jiang, X., Li, G., Yu, C., Synthesis of N-aryl-3-(arylimino)-3H-indol-2-amines via
Hypervalent Iodine Promoted Oxidative Diamination of Indoles, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.03.015
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Tetrahedron Letters
Synthesis of N-aryl-3-(arylimino)-3H-indol-2-amines via Hypervalent Iodine
Promoted Oxidative Diamination of Indoles
Xinpeng Jiang, [a] Guizhou Li, [b] and Chuanming Yu*[a,b]
a
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P.R. China
b Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A direct and fast oxidative diamination of substituted indoles with anilines was realized by using
1-fluoro-1,2-benziodoxol-3(1H)-one under mild conditions. This protocol could provide a wide
range of synthetically valuable N-aryl-3-(arylimino)-3H-indol-2-amine derivatives under
peroxide-free conditions within 30min in up to 91% yields.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Hypervalent iodine
Indoles
Amination
Oxidation
Introduction
Hypervalent iodine compounds have been widely applied in
organic synthesis as mild and environmentally benign oxidants21.
Functionalized indoles1-4 are important synthetic building
blocks used in many pharmaceuticals5, pesticides6, and natural
products7, 8. They also serve as useful structural components in
Enlightened by PhI(OAc)2 promoted C-2,3 diacetoxylation of N-
substituted indoles22 and applications of Togni’s reagents23-25, we
expected that cyclic hypervalent iodine(III) could be used to
synthesize N-aryl-3-(arylimino)-3H-indol-2-amines via oxidative
diamination at the C2 and C3 positions of indoles (Scheme 1, eq
4).
medicinal chemistry due to their high receptor binding affinity9, 10
Among them, N-aryl-3-(arylimino)-3H-indol-2-amine derivatives
have recently attracted much attention owing to their application
in the synthesis of bioactive polymeric indole alkaloids11 and
nitric oxide synthase inhibitors12. A few procedures have been
established for their synthesis, but most of them involve multi-
.
step
transformation,
noble
transition-metal
catalyzed
functionalization, or potential dangerous peroxides8-12
.
Grimshaw reported a two-step synthesis that starting from
chlorination of indole-2,3-diones, the product then reacted with
excess aniline to afford N-aryl-3-(arylimino)-3H-indol-2-amines
(Scheme 1, eq 1)13. Tedious operation and environmentally
unfriendly reagent are main limitation of this reaction. In 2015,
Jiang revealed a palladium catalyzed isocyanides insertion-
cyclization strategy. However, the requirement of expensive
catalysts, highly toxic isocyanides14 and harsh reaction conditions
restricted its application (Scheme 1, eq 2)15. Although direct
diamination of indoles is an atom-economic approach to
synthesize N-aryl-3-(arylimino)-3H-indol-2-amines, efficient
methodologies for oxidative diamination at C2 and C3 position
of indoles remain rare16-19. As far as we know, the pioneering
direct diamination was realized by using iodine and excess
peroxides, nevertheless the reaction gave low yields with
halogen-substituted anilines (Scheme 1, eq 3)20. Therefore,
developing versatile and mild methods to synthesize N-aryl-3-
(arylimino)-3H-indol-2-amines directly from commercially
available indoles are highly valuable.
Scheme 1: Design of synthesis of N-aryl-3-(arylimino)-3H-indol-
2-amines

2
Tetrahedron Letter
Results and discussion
Table 1. Optimization of the reaction conditions a
Entry
1c
2
2a (eq)
solvent
CH3CN
CH3CN
CH3CN
EtOH
x (eq)
-
additive (eq)
yield (%)b
trace
60
3
3
Cl (3.5)
F (3.5)
F (3.5)
F (3.5)
F (3.5)
F (4)
3
3
-
85
4
3
-
37
5
3
DMF
-
47
6
3
CH3NO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
-
45
7
3
-
83
8
3
F (3)
-
-
75
9
2.5
3
F (3.5)
F (3.5)
F (3.5)
F (3.5)
F (3.5)
66
10
11
12
13
K2CO3 (1)
NaHCO3 (1)
Et3N (1)
50
3
42
3
19
3
p-TsOH·H2O (1)
57
[a] Reaction conditions: 1a (0.25 mmol), 2a and 1-halo-1,2-benziodoxol-3-(1H)-one (3.5 eq) in solvent (4 mL) at
room temperature for 30 min. [b] Isolated yields. [c] PhI(OAc)2 (3.5 eq) was used.
Since the 4-halogen substituted aniline gave low yields in I2/TBHP system20, our initial effort commenced with the reaction of
1H-indole 1a and 4-chloroaniline 2a under air conditions (Table 1). When PhI(OAc)2 was used, only trace amount of desired
product was detected (Table 1, entry 1). To our delight, the use of 1-chloro-1,2-benziodoxol-3-(1H)-one gave the desired product
(E)-N-(4-chlorophenyl)-3-((4-chloromophenyl)imino)-3H-indol-2-amine 3a in 60% yield (Table 1, entry 2). However, further
improvement of the yield turned out to be very difficult due to the formation of 3-chloro-1H-indole. We reasoned that it might be
caused by the chlorine’s strong nucleophilicity, which could be solved by replacing chlorine to fluorine. To our delight, the use of 1-
fluoro-1,2-benziodoxol-3-(1H)-one gave 3a in 85% yield, without incorporating any fluorine into the final products (Table 1, entry
3). Subsequently, solvent effect was also explored, ethanol, N,N-dimethylformamide, and nitro methane were evaluated under
identical conditions, but led to lower yields (Table 1, entries 4-6). Then we investigated the dosage of hypervalent iodine and 2a,
either increasing or reducing the amount of 1-fluoro-1,2-benziodoxol-3-(1H)-one gives inferior result (Table 1, entries 7-9). To
further improve the yield of this reaction, extra additives such as K2CO3, NaHCO3, Et3N, or p-TsOH·H2O were added to the reaction
system, but gave product 3a in lower yields (Table 1, entries 10-13). Thus, our optimal reaction conditions were determined as
indoles and substituted anilines (2 eq) were reacted with 1-fluoro-1,2-benziodoxol-3-(1H)-one (3.5 eq) in CH3CN under air
conditions at room temperature for 30 min.
With optimized reaction conditions in hand, we next investigated the substrate scope of this reaction. As summarized in Table 2,
a variety of anilines bearing different substituent were reacted with indole 1a to give N-phenyl-3-(phenylimino)-3H-indol-2-amines
in good yields. The reaction with aniline proceeded smoothly to give the corresponding product 3b in 66% yield. Halogen
substituent such as Br- was tolerated under the current conditions, which allowed further elaborations of product 3c. For precursors
with electron withdrawing substituent, such as –F and –CN group, the reaction proceeded smoothly gave 3d and 3e in excellent
yields. Aniline with electron donating methyl group gave 3f in 67% yield. Compared to meta-Cl anilne 2g, reaction of ortho-Cl
aniline 2h require higher temperature and longer time owing to deactivated amino group caused by intramolecular hydrogen bond
with ortho-Cl. Furthermore, alkyl amines, such as cyclohexanamine and octan-1-amine were also tested, but did not afford desired
products under standard conditions.
Table 2. Different substituted anilinesa,b

3
[a] Reaction were performed with 1a (0.25 mmol, 1 eq), 2 (0.75 mmol, 3 eq), 1-fluoro-1,2-benziodoxol-3-(1H)-one (0.89 mmol, 3.5
eq) in CH3CN (4.0 ml) was stirred at room temperature for 30 min. [b] Yields were given for the isolated products. [c] Reaction was
conducted under 35oC for 1h.
Encouraged by these results, we further explored the scope of this reaction by evaluating a range of substituted indoles under
standard conditions (Table 3). The substituent on indole rings showed significant influence to the yields. For example, when C5 or
C7 position of the indole ring was substituted by halogen, the corresponding products could be obtained in good yields (3j-k and
3n-o). Whereas indoles substituted with halogen at C4 or C6 position only gave diamination products in 60-81% yields (3l, 3m, and
3p). Indoles bearing methyl group at C4 and C5 position gave 3i and 3s in moderate yields, while 4- and 5-benzyloxyindole only
gave trace amount of corresponding products on account of strong electron donating property and steric hindrance of benzyl group.
Furthermore, N-methyl substituted indole could also react with aniline and gave 3t in 62% yield.
Table 3. Reactions with various indoles and anilines a,b
[a] Reaction were performed with 1 (0.25 mmol), 2 (0.75 mmol, 3 eq), and 1-fluoro-1,2-benziodoxol-3-(1H)-one (0.89 mmol, 3.5
eq) in CH3CN (4.0 ml) was stirred for 30 min at room temperature. [b] Yields were given for the isolated products.
To gain an insight of possible reaction mechanism, a control experiment was carried out. As shown in Scheme 3, when radical
scavenger TEMPO (2 eq) was added to the reaction mixture, its slightly lower yield ruled out the possibility of radical mechanism.
On the basis of our results, a plausible mechanism was outlined in Scheme 4. Initially, intermediate A, which was derived from
indole 1a and 1-fluoro-1,2-benziodoxol-3-(1H)-one, captured aniline via nucleophilic addition to access intermediate B. After
elimination of o-iodobenzoic acid, 2-amino indole C was formed. Next, nucleophilic attack of C to 1-fluoro-1,2-benziodoxol-3-
(1H)-one afforded intermediate D, which was then attacked by aniline to form 2,3-diamine indole E. Finally, nitrogen atom at C3

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Tetrahedron Letter
position of E underwent nucleophilic attack to 1-fluoro-1,2-benziodoxol-3-(1H)-one forming intermediate F, which would easily
afforded the final product 3 after subsequent elimination.
Scheme 3: Control experiment
Scheme 4: Proposed mechanism
In conclusion, we developed a practical synthesis of N-aryl-3-(arylimino)-3H-indol-2-amines via 1-fluoro-1,2-benziodoxol-
3(1H)-one promoted oxidative diamination of indoles. A wide range of products were synthesized in good to excellent yields under
mild reaction conditions. Other advantages of this methodology include the significantly reduced reaction time and wider substrate
scopes (high yields with halogen substituted anilines). In view of these advantages, the applications of this reaction to achieve the
facile synthesis of bioactive compounds are currently undergoing.
Acknowledgment
This work was supported by the National Science Foundation of China (grant number 21506191 and 21676252).
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Tetrahedron Letter
1. Direct oxidative diamination of substituted indoles with anilines realized under
peroxides-free conditions in excellent yields.
2. The new methodology has better functional group tolerance (high yields with
halogen-substituted anilines).
3. The reaction time significantly reduced from several hours to 30min.

7

8
Tetrahedron Letter

9
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Synthesis of N-aryl-3-(arylimino)-3H
-indol-2-amines via Hypervalent Iodine Promoted
Oxidative Diamination of Indoles
Leave this area blank for abstract info.
Xinpeng Jiang, Guizhou Li, and Chuanming Yu*
A direct and fast oxidative diamination of substituted indoles with anilines were realized by using hypervalent iodine under mild conditions. This
protocol could provide a wide range of synthetically valuable N-aryl-3-(arylimino)-3H-indol-2-amine derivatives under peroxide-free conditions
within 30min in up to 91% yields.