Microwave-assisted synthesis of 7-azaindoles via iron-catalyzed cyclization of an o -haloaromatic amine with terminal alkynes

Article abstract of DOI:10.1039/c9ra08742g

An efficient and practical procedure was developed to prepare 7-azaindole, starting from an o-haloaromatic amine and corresponding terminal alkynes under microwave irradiation and the scope was demonstrated with a number of examples. The valuable features

Full text of DOI:10.1039/c9ra08742g

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Microwave-assisted synthesis of 7-azaindoles via
iron-catalyzed cyclization of an o-haloaromatic
amine with terminal alkynes†
bc
Cite this: RSC Adv., 2019, 9, 39684
Yi Le,abc Zhisong Yang,b Yumei Chen,b Dongmei Chen,b Longjia Yan,
*
Zhenchao Wangbc and Guiping Ouyang
abc
*
An efficient and practical procedure was developed to prepare 7-azaindole, starting from an o-
haloaromatic amine and corresponding terminal alkynes under microwave irradiation and the scope was
demonstrated with a number of examples. The valuable features of this procedure included the iron-
catalyzed cyclization, short reaction times and convenient operation. Furthermore, iron catalysis is an
interesting alternative to homogeneous catalysis for the synthesis of heterocycles.
Received 24th October 2019
Accepted 26th November 2019
DOI: 10.1039/c9ra08742g
rsc.li/rsc-advances
Our group has been focused on metal-catalyzed cross-
coupling reactions for the preparation of bioactive heterocy-
cles.10 Based on the broad activities of 7-azaindole, we are
Introduction
In the recent years, microwave (MW) irradiation in synthetic
organic chemistry has attracted considerable practical and
theoretical attention as a very effective and non-polluting
method of activation.1 Microwave irradiation oen helps to
reduce reaction times, minimize side products, increase yields
and improve reproducibility. Therefore, the technique of
microwave-assisted organic synthesis has been widely and
successfully employed in dipolar cycloadditions,2 transition
metal-catalyzed cross-coupling reactions3 and polymer
formation.4
1H-Pyrrolo[2,3-b]pyridines, oen referred to as 7-azaindoles,
are bioisosteres of the indole scaffold have been used in diverse
areas such as materials and medicinal chemistry due to their
physicochemical and pharmacological properties.5 For
example, the natural product Variolin B5 in Fig. 1 isolated from
an extremely rare antarctic sponge is a promising anti-cancer
agent. PLX5622 in Fig. 1,6 a brain pentrant CSF1R inhibitor
has been used in Alzheimer's disease (AD). Recently, the 7-
azaindole derivatives were also shown potential anti-cancer
activity, including AZD6738 a potent and selective ATR kinase
inhibitor7 and GSK1070916 an aurora kinase inhibitor.8 Thus,
development of synthetic methods to access these 7-azaindoles
is of great importance to the drug discovery community.9
interested in developing new strategies to prepare this novel
heterocyclic scaffold. In the literature, the common synthetic
methods to prepare azaindoles usually start from commercial
aminopyridines, followed by Sonogashira alkynylation by
subsequent base-mediated cyclization with various base for
building up the pyrrole ring.11 As shown in Fig. 2, these methods
were always used Pd-catalysts, such as Pd(PPh3)2Cl2,12a Pd2(-
dba)3,12b and Pd–NaY,12c and also have some disadvantages such
as the high price of palladium and problem of pollution.
Recently, the establishment of new catalytic methods using iron
is attractive owing to the low cost, abundance, ready availability,
and very low toxicity of iron.13 Furthermore, due to the avail-
ability of several catalytic cycles, iron catalysis offers a potential
for orthogonal selectivity when compared to other metals,
aState Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, State-Local Joint Laboratory for Comprehensive Utilization of
Biomass, Center for Research and Development of Fine Chemicals, Guizhou
University, Guiyang 550025, China
bSchool of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China.
E-mail: ylj1089@163.com; oygp710@163.com
cGuizhou Engineering Laboratory for Synthetic Drugs, Guiyang 550025, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra08742g
Fig. 1 Bioactive skeletons containing 7-azaindole framework.
39684 | RSC Adv., 2019, 9, 39684–39688
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the microwave-assisted synthesis of indole,16 we wish to report
the iron-catalyzed cyclization of o-haloaromatic amine with
terminal alkynes under the microwave irradiation.
Results and discussion
Initially, we chose the commercially available 3-iodo-pyridin-2-
ylamine 1a and ethynyl-benzene 2a as model starting mate-
rials. We examined the reaction conditions using 10%
Pd(PPh3)2Cl2, 10% CuI, 1.5 equiv. of K3PO4 in DMF under
microwave irradiation of 100 ꢀC, the reaction proceeded for
30 min and product 3a was obtained in 12%, which was puried
the intermediate 3aa for 35% yield (Table 1, entry 1). We
subsequently investigated the effect of various catalysts
including palladium, silver and iron (Table 1, entries 2–6).
Fortunately, we found that Fe(acac)3 was given the best result
(Table 1, entry 6). We also tested the amount of CuI, it was no
product without CuI and the similar yield using 20% CuI (Table
1, entries 7 and 8). Another blank test was performed only with
CuI and shown that 3aa was obtained in 8% yield (Table 1, entry
9). It was no reaction at the absence of Fe(acac)3 and CuI (Table
1, entry 10). Replacement of K3PO4 by KOAc, or K2CO3 led to
lower yields and KOtBu gave a satisfactory yield (Table 1, entries
11–13). Next, we screened different organic solvents and
Fig. 2 Different strategies for synthesis of 7-azaindoles.
which allows for streamlined construction of complex mole-
cules by modern cross-coupling chemistry.14 Encouraged by the
development of iron-catalytic Sonogashira alkynylation15 and
Table 1 Optimization of the metal-catalyzed cyclization 3aa
Entry
Catalyst
CuI (%)
Base
Solvent
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2
Pd(dppf)Cl2
AgNO3
AgOAc
FeCl3
Fe(acac)3
Fe(acac)3
Fe(acac)3
—
10
10
10
10
10
10
—
20
10
—
10
10
10
10
10
10
10
10
10
10
10
10
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOAc
K2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
Dioxane
NMP
NMP
NMP
NMP
NMP
NMP
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
110
120
130
140
130
130
12
21
Trace
Trace
11
32
0
31
c
9
—
10
11
12
13
14
15
16
17
18
19
20
21
22
—
0
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Pd(PPh3)2Cl2
Pd(dppf)Cl2
28
25
38
36
42
22
58
61
62
58
44
48
a
Reagents and conditions: 1a (1 mmol), 2a (2 mmol), catalyst (0.1 mmol), CuI (0.1 mmol), base (1.5 mmol), solvent (2 mL), 30 min MW, 100 ꢀC.
Isolated yields. c Only 3aa was obtained with 8% yield.
b
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identied NMP as the most effective solvent (Table 1, entry 15), bioactivity and metabolic stability.17 In this paper, we also show
while dioxane resulted in a poor yield (Table 1, entry 16). The such examples of the CF3 substituted 7-azaindoles (Table 3,
yield could be further improved by increasing the temperature entries 9–16). We found that the reaction conditions were
to a maximum of 130 ꢀC (Table 1, entry 19), whereas higher adaptable with phenyl (3i) and electron-donating substituents
temperatures led to partial decomposition (Table 1, entry 20). at the aryl alkynes, such as methoxy group (3k). In addition to
Interestingly, when we used Pd(PPh3)2Cl2 reported by Mueller12a electron-donating substituent, halogens such as F and Cl were
or Pd(dppf)Cl2 under the optimized condition, the yield was also tolerated (3j, 3m and 3n). However, aryl groups with an
44% and 48%, respectively (Table 1, entries 21 and 22).
electron decient substituent led to a lower yield (3l). Addi-
In order to optimize the reaction conditions, we speculated tionally, aliphatic groups afforded the corresponding products
that the equivalent of alkyne and microwave time might also be with reduced yields (3o and 3p).
efficient in promoting the microwave-assisted cyclized reaction.
Finally, this procedure was applied to the preparation of 1,2-
Aer exploring several reaction conditions (Table 2), 3a was disubstituted 7-azaindoles 5. As shown in Table 4, the Sonoga-
obtained in 72% yield by heating 3 equiv. 2a, 0.1 equiv. shira and consequently cyclization could be used for prepara-
Fe(acac)3, 0.1 equiv. CuI, 1.5 equiv. KOtBu in NMP for 60 min at tion the N-arylation of azaindoles. The electron-donating
130 ꢀC (Table 2, entry 4). We also tried the reaction under groups on the phenyl acetylene, such as OCH3 (5c and 5m) were
conventional thermal heating condition and the yield of the obtained the much higher yield of 78% than the electron-
desired product was 33% (Table 2, entry 7).
withdrawing group F (5b and 5i), Cl (5d, 5k and 5l) and CF3
Having determined the optimal reaction conditions (Table 2, (5e and 5j). 3,3,-Dimethyl-but-1-yne led to 2-tert-butyl-1-(3,4,5-
entry 4), the scope of the reaction was explored with different trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 5f (42%), the
substituted 3-iodo-pyridin-2-ylamine 1 (Table 3), which were decrease in yield may be due to decomposition of compound 2
prepared by the reaction of pyridin-2-ylamines with Ag2SO4 and under the MW conditions. Interestingly, the ethyl ester
I2, to afford various 7-azaindoles 3. As illustrated in Table 3, substituted group 5g was also separated with 33% yield under
a variety of substituted 7-azaindoles was readily prepared in our MW protocol. In addition to substituted aryl group of R3,
good yield through this protocol, and assigned by spectroscopic the alkyl-substituted compound 4 were also compatible with
methods (1H NMR and 13C NMR) and HRMS. Both electron- this process, furnishing the desired product 5n and 5o in 34%
donating group –CH3 (Table 3, entries 3 and 4) and electron- and 38% yield.
withdrawing group –CN (Table 3, entries 5–8) of R1 are toler-
To investigate the mechanism of this transformation,
ated at a variety of positions on the aromatic ring. Alkynes experiments were carried out. The desired product 3a was
bearing benzene ring such as 4-OCH3 and 4-F were also toler-
ated under reaction conditions as 3b and 3d were afforded in
73% and 68% yields, respectively. Additionally, aliphatic groups
Table 3 Preparation of 7-azaindoles 3a–pa
afforded the corresponding products with decreased yields (3h).
This result was consistent with the observation by Mueller et al.
when Pd(PPh3)2Cl2/(1-Ad)2PBn was used as catalyst.12a The
introduction of triuoromethyl group into organic compounds
frequently renders remarkable changes in their special size,
Table 2 Optimization of the iron-catalyzed cyclization 3aa
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
72
73
73
68
65
61
66
43
62
56
79
45
58
32
33
48
4-OCH3-Ph
Ph
4-F-Ph
Ph
4-F-Ph
4-OCH3-Ph
Me
Me
Me
CN
CN
CN
CN
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Entry
2a (equiv.)
Time (min)
Yieldb (%)
9
Ph
1
2
3
4
5
6
7
2
3
4
3
3
3
3
30
30
30
60
90
120
120
62
68
66
72
71
58
33c
10
11
12
13
14
15
16
4-F-Ph
4-OCH3-Ph
4-CF3-Ph
4-Cl-Ph
2-Cl-Ph
Me
t-Butyl
a
a
Reagents and conditions: 1a (1 mmol), 2a, Fe(acac)3 (0.1 mmol), CuI
Reagents and conditions: 1 (1 mmol), 2 (3 mmol), Fe(acac)3 (0.1
mmol), CuI (0.1 mmol), KOtBu (1.5 mmol), NMP (2 mL), 60 min MW,
130 ꢀC. b Isolated yields.
(0.1 mmol), KOtBu (1.5 mmol), NMP (2 mL), MW, 130 ꢀC. Isolated
b
yields. c Under conventional thermal heating condition.
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obtained in 70% yield under standardized reaction conditions
(Scheme 1). We also tested the absence of Fe(acac)3 and CuI, it
was 22% yield when 3aa and KOtBu were used in NMP under
MW conditions for 60 min. Base on the observed experimental
results and pioneering reports,15,18 we have described a plau-
sible mechanistic pathway in Scheme 2. Oxidation addition of
Fe(acac)3 by the amine and pyridine functional units resulting
in an organoiron complex A. At this stage, trans-metalation by
copper complex B provides an intermediate Fe-species C,
which could then undergo reductive elimination to forge the
new carbon–carbon triple bond, thus yielding the compound
3aa. Aer furnished the typical Sonogashira coupling, the
Scheme 1 Complementary experiments.
Table 4 Preparation of 1,2-disubstituted 7-azaindoles 5a–ma
Scheme 2 Proposed mechanism.
desired 7-azaindole was generated under the microwave
condition.
Conclusions
In summary, we have described the synthesis of biologically
relevant 7-azaindole ring systems using an iron-catalyzed cyclic
reaction under microwave irradiation. This approach provides
a rapid and economical access to a diverse range of 7-azain-
doles. The method employs readily available reagents and
possesses broad scope and good tolerance of functional group,
iron catalysis could be an interesting. Further efforts to utilize
these compounds as versatile building blocks for assembling
interesting heterocyclic molecules which can be applied in
medicinal chemistry research are currently underway in our
laboratories.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This project is supported by the National Natural Science
Foundation of China (21867004), State Key Laboratory of
Functions and Applications of Medicinal Plants (No.
FAMP201707K) and (No. FAMP201801K).
a
Reagents and conditions: 4 (1 mmol), 2 (3 mmol), Fe(acac)3 (0.1
mmol), CuI (0.1 mmol), KOtBu (1.5 mmol), NMP (2 mL), 60 min MW,
130 ꢀC.
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