Synthesis of multisubstituted 2-aminopyrroles/pyridines via chemoselective michael addition/intramolecular cyclization reaction

Article abstract of DOI:10.1021/ol5018855

A facile and efficient synthetic strategy to construct polysubstituted 2-aminopyrroles/pyridines was developed via chemoselective Michael addition/intramolecular cyclization reaction under very mild conditions. It suggested that the chemoselectivity of the process could be controlled by the leaving ability of the halides.

Full text of DOI:10.1021/ol5018855

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Letter
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Synthesis of Multisubstituted 2‑Aminopyrroles/pyridines via
Chemoselective Michael Addition/Intramolecular Cyclization
Reaction
Xueyu Qi, Haoyue Xiang, Qian He, and Chunhao Yang*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai, 201203, China
S
* Supporting Information
ABSTRACT: A facile and efficient synthetic strategy to construct polysubstituted 2-aminopyrroles/pyridines was developed via
chemoselective Michael addition/intramolecular cyclization reaction under very mild conditions. It suggested that the
chemoselectivity of the process could be controlled by the leaving ability of the halides.
ultisubstituted pyrroles and pyridines are important
scaffolds in medicinal chemistry and organic chemistry
on Chichibabin reaction,18 but with a narrow scope,
unsatisfactory yields, and poor functional group tolerance for
the strong bases employed in this reaction. Recently, metal-
catalyzed aminations of 2-halopyridines and pyridine-N-oxides
have emerged as an alternative strategy to synthesize 2-
aminopyridines.19 However, these methods are established
upon the modification of the preformed pyridine nucleus and
need expensive transition metals, which are unsatisfactory from
an economical and ecological point of view. Thus, it is still
challenging and highly desirable to design facile, practical, and
streamlined synthetic methods for 2-aminopyrroles and 2-
aminopyridines under mild conditions, especially for those with
flexible substitution groups. Toward this end, the multi-
component reaction has recently been used as a powerful
tool to assemble multisubstituted 2-aminopyrroles17c and 2-
aminopyridines20 directly. Even so, there are still no simple and
straightforward methods for the synthesis of substituted 2-
aminopyrrole/pyridines simultaneously under the same reac-
tion conditions using readily available and simple starting
materials such as 3-halogenated chromones.
Chromones are greatly useful building blocks for construct-
ing various heterocycles.21 Recently, our group concentrates on
developing novel strategies for the synthesis of heterocyclic
scaffolds. Inspired by the success of the studies that reported 3-
halogenated chromones can react with N,N-bis-nucleophiles,
acetamidine hydrochloride,21c,e we used C,N-bis-nucleophiles,
ethyl 2-amidinoacetate hydrochloride 2a instead of the N,N-bis-
nucleophiles to react with 3-halogenated chromones. As we
expected, the 3-halogenated chromone 1 was first attacked by
the carbon ion, but not the nitrogen atom with lone pair
M
due to their prevalence in numerous natural products and
synthetic compounds. In particular, 2-aminopyrrole and its
derivatives, recognized as core structures in medicinal
chemistry, have shown a diverse range of bioactivities such as
MEK inhibitory1 and cytotoxicities.2 Furthermore, amino-
pyrroles have been used as precursors for the synthesis of
purine analogues including pyrrolopyrimidines, pyrrolo-
triazines, and pyrrolopyridines. These pyrrole-derived hetero-
cycles exhibit remarkable biological activities such as anti-
folates,3 anti-inflammatories,4 microtubule inhibitors,5 JAK3
kinase inhibitors,6 glycogen synthase kinase-3β inhibitors,7 and
NAMPT inhibitors.8 Additionally, as an important subset of
pyridines, 2-aminopyridines are not only extremely useful
building blocks for the construction of various significant
nitrogen-containing heterocycles9 but also highly attractive
compounds themselves since they are key structural cores of
natural products and medicinally important compounds that
are identified as promising leads along with a variety of
pharmacological and biological activity including antimalarial
agents,10 β-secretase (BACE1) inhibitors,11 nitric oxide
synthase (NOS) inhibitors,12 and CHK2 inhibitors.13
Over recent decades, considerable efforts have been devoted
to the synthesis of various substituted pyrroles and pyridines.14
Nevertheless, there are a limited number of methods that have
been developed for the preparation of 2-aminopyrroles that are
not readily available through general pyrrole ring-formation
methods. Most of these synthetic approaches to 2-amino-
pyrroles need a prolonged reaction time,15 expensive transition
metal additives,16 or require multistep elaboration from
commercially available materials.17 At the same time, many
methods have been developed for the synthesis of 2-
aminopyridines. Classical access to 2-aminopyridines has relied
Received: June 30, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5018855 | Org. Lett. XXXX, XXX, XXX−XXX

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a
electrons. Afterward, 2-aminopyrrole/pyridines could be
chemoselectively obtained respectively, which was controlled
by using different halides with different leaving abilities
(Scheme 1).
Table 1. Optimization of the Reaction Conditions
Scheme 1. Outline of the New Strategy for the Synthesis of
2-Aminopyrroles/pyridines Starting with Halogenated
Chromones
b
entry
solvent
base
DBU
tem
yield (%)
1
NMP
100
100
100
100
100
100
100
80
36
2
DMSO
DMF
DBU
40
3
DBU
20
4
dioxane
toluene
MeCN
EtOH
DBU
16
5
DBU
16
6
DBU
12
7
DBU
trace
42
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DBU
9
DBU
60
52
10
11
DBU
40
45
DBU
rt
28
c
12
d
DBU
60
52
13
DBU
60
38
14
15
16
17
K2CO3
Et3N
60
76
60
trace
71
Cs2CO3
Na2CO3
K2CO3
60
60
72
It is worth noting that ortho-amino and carboxylate groups
can be introduced to pyrrole/pyridine rings simultaneously in
one step for this new strategy, and the desired products can be
further exploited to construct a pyrrolo[2,3-d]pyrimidine and
benzofuro[3,2-b]pyridine ring respectively which are found in
natural products and medicinal compounds, such as folate
antimetabolite Pemetrexed,22 Akt inhibitor CCT128930,23
marine alkaloids rigidins A−E,24 topoisomerase inhibitors,25
and endothelin receptor antagonist26 (Figure 1). Moreover,
d
18
60
73
a
Reaction conditions: 1a (0.5 mmol 1.0 equiv), 2a (5.5 mmol 1.1
equiv), base (2.4 equiv), solvent (2.0 mL); all reagents were mixed and
stirred under air at rt for 5 min and then were heated at 60 °C for 3 h.
Isolated yields. 1.5 equiv of 2a was used. 3.0 equiv of base was used.
b
c
d
2a in the presence of DBU (2.4 equiv) in NMP at 100 °C for 3
h. To our delight, the desired product 3a was obtained in a 36%
yield (Table 1, entry1). Afterward, the solvent was shown to
have a great influence on the yields, with DMSO providing the
best result (Table 1, entries 1−7). The investigation of reaction
temperature indicated that the optimal temperature was 60 °C
(Table 1, entries 2, 8−11). Further studies showed that
increasing the amount of ethyl 2-amidinoacetate hydrochloride
(1.5 equiv) had no obvious effect on the yield (Table 1, entry 9
vs 12), while increasing the amount of base resulted in a
reduced yield (Table 1, entry 9 vs 13, 14 vs 18). Finally, the
effect of base was investigated. We found that the inorganic
bases compared organic bases greatly improved the yield
(Table 1, entries 9, 14−17). Thus, the optimal reaction
conditions were determined to include K2CO3 (2.4 equiv),
amidine (1.1 equiv) in DMSO (2.0 mL) at 60 °C for 3 h. The
structure of 3a was unambiguously confirmed by X-ray
crystallographic analysis (Figure 2).
With the optimal reaction conditions in hand, the scope of
substrates for this new reaction was investigated (Scheme 2). It
was found that the chromone rings with electron-donating
groups gave the corresponding products in better yields than
those with electron-withdrawing groups (Scheme 2, 3b, 3c, 3f
vs 3d, 3e, 3g−3o). Whereas methoxy groups anywhere on the
chromones provided lower yields than other electron-donating
groups (Scheme 2, 3i vs 3h, 3m vs 3k). The steric factor also
greatly influences the yield (Scheme 2, 3a vs 3j). The results of
probing the effect of the different amidine reactants showed
that the amidine containing the ethoxycarbonyl group has a
higher yield than those with a carbamoyl group (Scheme 2,
3q−3v).
Figure 1. Structures of bioactive compounds with the pyrrolo[2,3-
d]pyrimidine and benzofuro[3,2-b]pyridine ring system.
compared to many reported methods, the reaction for the
synthesis of 2-amino-pyrroles/pyridines can be carried out
under mild conditions without any metal catalysts, which was
advantageous from the viewpoint of green chemistry and
sustainability. Therefore, a very practical synthetic strategy to
obtain polysubstituted 2-aminopyrroles/pyridines was devel-
oped here for their biological and chemical significance.
Initially, we screened parameters to find the optimal
conditions (Table 1). We started our studies by treating 3-
iodochromone 1a with ethyl 2-amidinoacetate hydrochloride
After successfully synthesizing 2-aminopyrroles from 3-
iodochromone, we turned our attention to 3-chlorochromone
B
dx.doi.org/10.1021/ol5018855 | Org. Lett. XXXX, XXX, XXX−XXX

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a
,b
Scheme 3. Synthesis of 2-Aminopyridine
Figure 2. X-ray crystal structure of 3a.
a
,b
Scheme 2. Synthesis of 2-Aminopyrroles
a
Reagents and reaction conditions: 3-chlorochromone derivatives 1
(0.5 mmol), ethyl 2-amidinoacetate hydrochloride 5a (0.55 mmol),
and K2CO3 (1.2 mmol) in DMSO (2 mL), heated to 60 °C for 3 h. b
Isolated yield.
electrophilicity of the carbonyl group. The amidine containing
the carbamoyl group delivered the corresponding products in
diminished yield (Scheme 3, 4i−4l).
To demonstrate the synthetic utility of the reaction’s
products, 2-aminopyrrole-3-carboxamide 3s was smoothly
converted to pyrrolo[2,3-d]pyrimidine 5 in 88% yield under
microwave irradiation at 120 °C for 10 min and compound 6
was obtained in 99% yield catalyzed by CuBr (Scheme 4).
Scheme 4. Synthetic Utility of 2-Aminopyrrole/pyridine
In conclusion, our investigation has successfully provided a
direct and facile synthesis of 2-aminopyrrole/pyridines through
a chemoselective Michael addition/intramolecular cyclization
sequence. The synthetic ultility of the resulting 2-amino-
pyrroles/pyridines was demonstrated by converting com-
pounds 3s and 4d to the corresponding pyrrolo[2,3-d]-
pyrimidine 5 and benzofuro[3,2-b]pyridine 6 respectively.
Although the utility of the final products is somewhat limited
by the presence of a phenolic hydroxyl group in these
structures, we believe that these products could be widely
applied in constructing natural products and medicinal
derivatives with the pyrrolo[2,3-d]pyrimidine or benzofuro-
[3,2-b]pyridine ring system.
a
Reagents and reaction conditions: 3-iodochromone derivatives 1 (0.5
mmol), amidine 5 (0.55 mmol), and K2CO3 (1.2 mmol) in DMSO (2
mL), heated to 60 °C for 3 h. Isolated yield.
b
to obtain 2-aminopyridines. Because of the weak leaving ability
of the chlorine atom, the yield of 2-aminopyridines 4a was 84%
under previous optimized conditions. We next examined the
scope of substrates by using a variety of substituted 3-
chlorochromones (Scheme 3). As we expected, the chromone
rings bearing electron-withdrawing groups afforded better
yields of the corresponding products than those with
electron-donating groups (Scheme 3, 4c, 4d vs 4b, 4e, 4f,
4h), because electron-withdrawing groups can strengthen the
C
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ASSOCIATED CONTENT
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CCDC-1009838 contains the supplementary crystallographic
data for compound 3a. Copies of these data can be obtained
free of charge via www.ccdc.cam.ac.uk. General experimental
information and copies of 1H and 13C NMR of new compounds
are also provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chyang@simm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Ministry of Science
and Technology of China (“Key New Drug Creation and
Manufacturing Program”, 2012ZX09301001-001), the National
Natural Science Foundation of China (81321092), and
SKLDR/SIMM (SIMM1403ZZ-01).
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