3-Aminoindole Synthesis from 2-Nitrochalcones and Ammonia or Primary Amines

Article abstract of DOI:10.1002/adsc.201900551

A step-economic strategy for 3-aminoindoles synthesis with ammonia or primary amines as “N” source under transition-metal-free conditions was achieved. A series of 3-aminoindoles was obtained with abundant “N” source featuring high efficiency, mild condit

Full text of DOI:10.1002/adsc.201900551

Title: 3-Aminoindole Synthesis from 2-Nitrochalcones and Ammonia or
Primary Amines
Authors: Guan Zhang, Lu Lin, Kai Yang, Shihui Wang, Qiang Feng,
Jun Zhu, and Qiuling Song
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10.1002/adsc.201900551
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
3-Aminoindole Synthesis from 2-Nitrochalcones and Ammonia
or Primary Amines
Guan Zhang,a Lu Lin,b Kai Yang,c Shihui Wang,a Qiang Feng,a Jun Zhu*b and Qiuling
Song* a, c
a
Institute of Next Generation Matter Transformation, College of Material Sciences Engineering at Huaqiao University,
668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China.
Email: qsong@hqu.edu.cn.
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China
b
Email: jun.zhu@xmu.edu.cn.
College of Chemistry, Fuzhou University, Fuzhou 350116, P. R. China
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
construction of CAr-N bond with them. We present
Abstract：A step-economic strategy for 3-aminoindoles
synthesis with ammonia or primary amines as “ N ” herein a step-economic strategy for 3-aminoindoles
source under transition-metal-free conditions was achieved.
A series of 3-aminoindoles was obtained with abundant
“N” source featuring high efficiency, mild conditions,
environmental friendliness and scalability. Efficient
syntheses of the intermediates of COX-2 inhibitor and
tubulin polymerization inhibitor were successfully
accomplished with this newly developed strategy.
synthesis in one-step reaction with ammonia or
primary amines as “N” source (Figure 1C).
Keywords: 3-aminoindole; 2-nitrochalcone; ammonia;
primary amines; metal-free
3-Aminoindole frameworks are prevalent structural
motifs in myriad synthetic intermediates[1] and
biologically active molecules[2] (Figure 1A). Owing to
the significance of 3-aminoindoles, the development
of efficient synthetic approaches to access 3-
aminoindoles has gained great attention. A few
versatile and concise methods have been established
in which “N” source on C3 position of 3-
aminoindoles was mainly derived from cyano, [3] O-
benzoyl
hydroxylamines,[4]
amide,[5]
N-
pivaloyloxylamides,[6] isonitrile[7] and so on. Despite
the great advance, however, these known methods
cannot avoid the transition-metal catalysts, multi-step
syntheses are always required either in order to
access the starting materials or to construct the key
scaffold, and limited substrate ranges severely
hamper the broad application of these methods in
modern synthetic chemistry (Figure 1B). Therefore
the development of mild and pragmatic method to
access 3-aminoindoles is highly desirable. As one of
the most abundant and inexpensive N-containing
compounds, ammonia is indisputable the most
accessible N source;[8] meanwhile, primary amines as
one of the most valuable building blocks in organic
synthesis,[9] they are abundant and readily available
as well. Surprisingly, “N” source of C3 position from
the above two abundant N-containing compounds for
the construction of 3-aminoindoles has yet to be
reported, probably due to the difficulty of
Figure 1. Motivation and 3-Aminoindoles Synthesis.
Recently, Lee reported carbazoles or 3-
naphthylindoles synthesis through condensation of an
enolate to a nitro group intramolecularly.[10] In terms
of 3-aminoindoles, we envision that a process
involving Michael addition between ammonia or
primary amines as “ N ” source and 2-
nitrochalcones[11] would occur first to render the
enolate intermediate with a new C-N bond formed at
β-position, later intramolecular cyclization between
the enolate and nitro group will eventually deliver 3-
1
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10.1002/adsc.201900551
Advanced Synthesis & Catalysis
aminoindole derivatives. There are several
advantages on this method: 1) “N” sources for this
strategy are abundant and the starting materials are
readily available, which makes the method easily
operational and pragmatic; 2) a tandem reaction is
generated in one-step synthesis with high efficiency
and two C-N bonds formed along with the
construction of indole rings; 3) this reaction proceeds
under transition-metal free conditions, which features
mildness, environmental benignness, scalability, good
functional group tolerability as well as broad
substrate scopes.
Reaction conditions: a) 2-nitrochalcone 1a (0.2 mmol)
under N2 atomosphere unless otherwise specified; b)
isolated yield; c) Hantzsch ester as additive (0.6 equiv); d)
Hantzsch ester as additive (0.5 equiv)
With the optimized conditions available, the
substrate scope of 2-nitrochalcones in this tandem
transformation was investigated (Scheme 1). First, we
demonstrated that our reaction could be scalable
without significant reduction in yield. To probe the
universality of the current reaction, a variety of halo-,
alkyl-, alkoxy-, and heteroaryl-substituted 2-
nitrochalcones 1 were tested as electrophile partners
under standard reaction conditions with aqueous
ammonia. In comparison with 2-nitrochalcone,
similar yields were obtained with halogenated
substituents on aromatic rings (Cl and F) (3ba-3da,
3ia). Different substituents on Ar1 rings, such as
trifluoromethyl, methyl, alkoxy as well as other ether
did not impede under the standard conditions (3ea-
3ga). When Ar2 rings were replaced by naphthalene,
benzofuran, benzothiophene, thiophene, furan and
pyridine, the corresponding products 3ja–3oa were
obtained in moderate to good yields (51-85%). The
structure of 3na was unambiguously confirmed by X-
To validate our hypothesis, 2-nitrochalcone (1a)
and ammonia (2a) in EtOH were chosen as the test
substrates for the optimization study because of their
ready availability (Table 1). To our delight, exposure
of 1a to NH3-EtOH and Na2CO3 triggered both C-N
bond construction as well as indole formation to
afford product 3aa in 51% yield (entry 1). Further
base screening suggested that K2CO3 was the best one
among Na2CO3, CsF and K3PO4 (entries 1−4). Next,
reaction temperature was surveyed (entries 5–6).
Interestingly, the temperature decreasing from 100 °C
to 90 °C improved the yield of 3aa (entry 5).
Shortening the reaction time from 4 hours to 1 hour
did not affect the efficiency of the reaction, and the
desired product was obtained in 65% isolated yield
(entry 8). A slightly lower yield was observed when
the time was reduced to 0.5 hour (entry 9). The yield
of 3aa was further increased when the loading of
K2CO3 was reduced to 0.5 equivalent (entry 10).
Gratifyingly, changing the ammonia in EtOH to
aqueous ammonia improved the 3-aminoindole
product 3aa to 75% (entry 11). There may be oxidant
in the system that was detrimental to the 3-
aminoindole product, so we used Hantzsch ester
ray
crystallographic
analysis.[12]
2-
Nitrodibenzylideneacetone was a good substrate for
this transformation as well with high regioselectivity,
the corresponding 3-aminoindole product was
obtained with moderate yield (3pa). Aza-indole and
1H-benzo[g]indole were important structural units of
biologically active molecules, this method also can be
applied for the preparation of 3-amino- aza-indole
(3qa) and 3-amino-1H-benzo[g]indole (3ra) with
moderate yields. Unfortunately, 2-acyl-3-amino
indole (3sa) and 2-sulfonyl-3-amino indole (3ta)
cannot be obtained under standard conditions.
(diethyl
1,4-dihydro-2,6-dimethyl-3,5-
pyridinedicarboxylate) as an additive and the yield
has indeed increased to 85% (entries 11-12).
Table 1. Development of optimized conditions for 3-
amioindole formationa.
Time
(h)
4
Yield b
(%)
51
Entry
Base (equiv)
Temp (oC)
Ammonia /Solvent (mL)
1
2
Na2CO3 (2)
CsF (2)
100
100
100
100
90
NH3-EtOH (2)
NH3-EtOH (2)
4
48
3
K3PO4 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
NH3-EtOH (2)
4
38
4
NH3-EtOH (2)
4
55
5
NH3-EtOH (2)
4
65
6
80
NH3-EtOH (2)
4
63
7
90
NH3-EtOH (2)
2
64
8
90
NH3-EtOH (2)
1
65
9
90
NH3-EtOH (2)
0.5
1
60
10
11
12c
13d
90
NH3-EtOH (2)
70
90
NH3-H2O(0.2)/EtOH (0.8)
NH3-H2O(0.2)/EtOH (0.8)
NH3-H2O(0.2)/EtOH (0.8)
1
75
90
1
84
90
1
85
2
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10.1002/adsc.201900551
Advanced Synthesis & Catalysis
Scheme 1. Substrate scope of 2-Nitrochalcones.a Reaction
conditions: a) 2-nitrochalcone 1 (0.2 mmol), NH3-H2O (0.2
mL), K2CO3 (0.1 mmol), Hantzsch ester (0.1 mmol), EtOH
(0.8 mL), 90 C, 1 h; b) Reaction performed on a 10 mmol
scale.
synthesis of 3-aminoindole derivatives, we decided to
demonstrate the applicability towards the syntheses
of some biologically active compounds. Compound 4,
a COX-2 inhibitor,[2b] was efficiently synthesized by
using 2-nitro-4-methoxychalcone (1u) and ammonia
under the standard conditions (Scheme 3a). Upon the
treatment of 3’,4’,5’-trimethoxy-2-nitro-4-methoxy
chalcone (1v) and ammonia under the standard
condition, 3-aminoindole product 3va, which is the
intermediate of tubulin polymerization inhibitor 5,[2h]
was obtained in 46% yield (Scheme 3b).
o
Then we explored the scope of amines, both
primary aromatic and alkyl amines worked well with
2-nitrochalcone (1a) under the standard conditions to
afford the desired products 3ab-3aq (Scheme 2). A
range of aromatic amines were efficiently
transformed into the corresponding 3-aminoindoles
(3ab-3al), including those possessing free phenol
(3ae), halide (3af), ester (3ag, 3al), fluorene (3ai),
fluorenone (3aj) and aromatic heterocyclic amines
(3ak, 3al). Notably, transformations with alkyl-
substituted amines were equally efficient (3am).
Owing to the extensive existence of primary amines
in drugs and nature products, the importance of the
tandem reaction can be further featured by modifying
these active molecules. Riluzole, Tyrosine,
Nimesulide and Linagliptin with 1a could be
smoothly converted into the corresponding 3-
amioindole products (3an-3aq) with excellent
functional group tolerance, partial racemization
occurred in 3ao.
Scheme 3. Synthetic applications.
On the basis of the above results and previous
[10, 13]
reports,
we proposed a mechanism for this
transformation (Scheme 4), which was supported by
density functional theory (DFT) calculations on a
thermodynamic examination (see the Supplementary
Information (SI) for details). 2-Nitrochalcone (1a)
and ammonia (2a) undergo Michael addition to
obtain the enolate intermediate INTB with -1.5
kcal/mol of exothermicity, then the nitro group in
INTB is attacked by the in situ newly formed enolate
to afford bicyclic intermediate INTC (-8.0 kcal/mol)
via an intramolecular cyclization. Intermediate INTC
undergoes protonation and rearrangement to give N-
hydroperoxide INTD (20.0 kcal/mol), which further
2-
eliminate H2O2 under the induction of base (CO3 ) to
render 3H-indole INTG with -18.5kcal/mol of
exothermicity.[10] Finally, tautomerization to the
desired 3-aminoindole product 3aa is highly
exothermic by -40.2 kcal/mol.
Scheme 2. Substrate scope of amines. Reaction conditions:
2-nitrochalcone 1a (0.2 mmol), amine (0.4 mmol), K2CO3
(0.1 mmol), Hantzsch ester (0.1 mmol), EtOH (2 mL), 90
oC, 1 h.
Scheme 4. Proposed mechanism.
In order to validate the mechanism of this reaction,
the following experiments were implemented
With the development of CAr-N bond construction
along with the indole formation reaction for the
3
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10.1002/adsc.201900551
Advanced Synthesis & Catalysis
with nitrogen for three cycles. Then, ethanol (2 mL) was
added at room temperature. The reaction was allowed to
stir at 90 °C for 1 h. Upon completion, the reaction was
cooled to room temperature and proper amount of silica gel
was added. After removal of the solvent, the crude reaction
mixture was purified on silica gel (petroleum ether: ethyl
acetate = 5:1-3:1) to afford the desired product.
(Scheme 5). 4-Methoxychalcone without 2-nitro was
subjected to the similar reaction conditions and the
Michael addition product was obtained in 13% yield,
thus showing first undergoing Michael addition of
this transformation (Scheme 5a). Hantzsch ester as
additive was converted into pyridine product 8 and 4-
phenylboronic acid (9) was oxidized to 4-
phenylphenol (10) in our system, which indicated that
an oxidant (H2O2)[14] was generated in our system
(Scheme 5b and 5c).
Acknowledgements
Financial support from the National Natural Science Foundation
(21772046) and the Natural Science Foundation of Fujian
Province (2016J01064) is gratefully acknowledged. We also
thank Instrumental Analysis Center of Huaqiao University for
analysis support. G. Zhang thanks the Subsidized Project for
Cultivating Postgraduates' Innovative Ability in Scientific
Research of Huaqiao University.
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Scheme 5. Control experiment.
We have developed a novel approach for 3-
aminoindoles synthesis with ammonia or primary
amines as “N” source under transition-metal-free
conditions. By using this method, the intermediates of
COX-2 inhibitor and tubulin polymerization inhibitor
were successfully accomplished with high efficiency.
Our future experiments are aimed at further
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Experimental Section
General procedure A for the preparation of 3-
aminoindole products from NH3-H2O and o-
nitrochalcones. In air, a 25 mL schlenk tube was charged
with o-Nitrochalcone (0.2 mmol, 0.0506 g, 1 equiv) ，
Hantzsch ester (0.1 mmol, 0.0253 g, 0.5 equiv) and
potassium carbonate (0.1 mmol, 0.0138 g, 0.5 equiv). The
tube was evacuated and filled with nitrogen for three
cycles. Then, NH3-H2O (0.20 mL) and Ethanol (0.8 mL) or
amines (0.4 mmol, 2 equiv) and Ethanol (2 mL) were
added to the tube at room temperature. The reaction was
allowed to stir at 90 °C for 1 h. Upon completion, the
reaction was cooled to room temperature and proper
amount of silica gel was added. After removal of the
solvent, the crude reaction mixture was purified on silica
gel (petroleum ether: ethyl acetate = 5:1-3:1) to afford the
desired product.
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0.0138 g, 0.5 equiv). The tube was evacuated and filled
4
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10.1002/adsc.201900551
Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
3-Aminoindole Synthesis from 2-Nitrochalcones
and Ammonia or Primary Amines
Adv. Synth. Catal. Year, Volume, Page – Page
Guan Zhang,a Lu Lin,b Kai Yang,c Shihui Wang,a
Qiang Feng,a Jun Zhu*b and Qiuling Song* a,
6
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