Three-component bicyclization providing an expedient access to pyrano[2′,3′:5,6]pyrano[2,3- b ]pyridines and its derivatives

Article abstract of DOI:10.1021/co500100c

A new three-component bicyclization for the efficient synthesis of a fused pyrano[2,3-b]pyridine library has been developed. The syntheses were achieved by reacting diverse C,O-containing nucleophiles, aldehydes, and 2-aminoprop-1-ene-1,1,3-tricarbonitrile under microwave irradiation, providing 50 examples of chemically and biomedically significant pyrano[2,3-b]pyridine analogues with the concomitant formation of two new rings and four σ bonds. This procedure features short reaction times, low-cost, and easily available starting materials, reliable scalability and mild reaction conditions, as well as operational simplicity.

Full text of DOI:10.1021/co500100c

Research Article
pubs.acs.org/acscombsci
Three-Component Bicyclization Providing an Expedient Access to
Pyrano[2′,3′:5,6]pyrano[2,3‑b]pyridines and Its Derivatives
Xing-Jun Tu, Wei Fan, Wen-Juan Hao,* Bo Jiang, and Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu
Normal University, Xuzhou, 221116, P. R. China
S
* Supporting Information
ABSTRACT: A new three-component bicyclization for the
efficient synthesis of a fused pyrano[2,3-b]pyridine library has
been developed. The syntheses were achieved by reacting
diverse C,O-containing nucleophiles, aldehydes, and 2-amino-
prop-1-ene-1,1,3-tricarbonitrile under microwave irradiation,
providing 50 examples of chemically and biomedically
significant pyrano[2,3-b]pyridine analogues with the concomitant formation of two new rings and four σ bonds. This
procedure features short reaction times, low-cost, and easily available starting materials, reliable scalability and mild reaction
conditions, as well as operational simplicity.
KEYWORDS: three-component bicyclization, bis-pyrans, pyrano[2,3-b]pyridines, microwave irradiation
2), aldehydes (Figure 3), and 2-aminoprop-1-ene-1,1,3-
tricarbonitrile, allowing [3 + 2 + 1]-annulation and intra-
molecular cyclization for the efficient synthesis of functionalized
bis-pyrans.
INTRODUCTION
■
Over the past several years, great efforts have been devoted to
synthesize libraries of small heterocyclic molecules because of
their high degree of structural diversity and extensive utility as
therapeutic agents.1 Bis-pyrans are key structural components,
which are widespread in a myriad of natural products,2 such as
acanilol A,3 distemonanthin,4 and pulcherrimin5 (Figure 1).
They also occupy a pivotal place in the family of small
heterocyclic molecules because of their important biological
activities, including kinase and DYRK1A inhibition,3 toxicity
toward RAW and HT-29 cell lines,5 vasoconstriction,6 and
antimycobacterial activity.7 Therefore, we turned our attention
to synthesize this type of functional bis-pyrans having biological
significance. A survey of the literature revealed that there are
few reports on the construction of functional bis-pyran
skeleton.8 However, to the best of our knowledge, a one-step
expedient synthesis of fused pyrano[2′,3′:5,6]pyrano[2,3-b]-
pyridines derivatives via a three-component bicyclization of
kojic acid has not been reported so far.
Since the pioneering discovery of multicomponent reactions
(MCRs), they have become very useful reaction protocols for
the rapid and efficient construction of important molecules, as
they increase the efficiency by combining several operational
steps without the isolation of intermediates or changing the
reaction conditions.9 The diversity generating potential of
MCRs has been recognized, and their utility in preparing
libraries to screen functional molecules is well appreciated.10 As
a part of our ongoing interest in multicomponent reactions,11
herein, we would like to report a new three-component
bicyclization leading to the formation of tricyclic pyrano-
[2′,3′:5,6]pyrano[2,3-b]pyridines in a convergent manner
(Scheme 1). The present method would enable the
straightforward utilization of low-cost and readily available
starting materials, such as C,O-containing nucleophiles (Figure
RESULTS AND DISCUSSION
■
The reaction of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one
(kojic acid) 1{1} with 4-chlorobenzaldehyde 2{1}, and 2-
aminoprop-1-ene-1,1,3-tricarbonitrile 3 was initially investi-
gated by using various bases, such as K2CO3, Et3N, piperidine,
pyrrolidine, and N,N-dimethyl-4-aminopyridine (DMAP)
under microwave (MW) irradiation. Although 4{1,1} can be
generated in the presence of all these bases, only Et3N resulted
in higher chemical yield. The reaction media, amounts of Et3N,
and reaction temperature were then examined carefully and the
results were summarized in Table 1. A mixture of 1{1}, 2{1},
and 3 in dichloromethane (DCM) was heated under
microwave irradiation at 80 °C in the presence of Et3N (1.0
equiv) for 16 min, and the product 4{1,1} was produced in low
yield (45%) because of incomplete consumption of the
reactants (Table 1, entry 1). Our attention was then shifted
to investigate the effect of solvents on the product yields. DMF
resulted in a good outcome (Table 1, entry 2); however,
ethanol gave higher yields (Table 1, entry 3). Subsequently, the
amounts of Et3N were screened. Increasing or decreasing the
amount of Et3N gave unsatisfactory yields (Table 1, entries 4
and 5). When the reaction was carried out at 60 or 100 °C, no
improvement was observed (Table 1, entries 6−7). Accord-
ingly, the reaction of 1{1}, 2{1}, and 3 in EtOH was also
conducted under classical heating (CH) conditions at 80 °C for
Received: June 30, 2014
Revised: September 4, 2014
© XXXX American Chemical Society
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Figure 1. Several representative natural products.
Scheme 1. Domino Synthesis of Fused Pyrano[2,3-
Table 1. Optimization of Reaction Conditions under MW
b]pyridines 4
a
c
entry
solvent
t (°C)
Et3N (eqiv)
time (min)
yield (%)
1
2
3
4
5
6
7
8
DCM
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
80
80
1.0
1.0
1.0
1.5
0.5
1.0
1.0
16
16
16
16
16
16
16
45
76
82
80
70
63
38
75
80
80
80
60
Figure 2. Diversity of C,O-containing nucleophiles 1{1−4}.
100
80
b
1.0
50
a
b
50 min using 1.0 equiv of Et3N as a base promoter, providing
the desired product 4{1,1} in 75% chemical yield (Table 1,
entry 8). From the above investigations, ethanol with 1.0 equiv
of Et3N at 80 °C under microwave irradiation was established
as the optimized reaction conditions for this one-step synthesis.
With the optimized reaction conditions in hand, we next
explored the substrate diversity of this three-component
bicyclization of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one,
aldehydes, and 2-aminoprop-1-ene-1,1,3-tricarbonitrile under
the optimized reaction conditions. The results were summar-
ized in Table 2. At the beginning, the scope of aldehydes was
investigated, by using 5-hydroxy-2-(hydroxymethyl)-4H-pyran-
4-one 1{1} and 2-aminoprop-1-ene-1,1,3-tricarbonitrile 3 as
model substrates. Aromatic aldehydes bearing either electron-
withdrawing or electron-donating substituents were well
Microwave (MW) irradiation. Classical heating (CH) conditions.
c
Isolated yields.
tolerated under the optimized reaction conditions, providing
the heterocyclic product 4 in excellent yields (Table 2, entries
1−18). The effect of steric hindrance of aromatic aldehyde did
not reduce the reactivity. Also, the reactions worked well with
aldehydes bearing substituents in the ortho position and the
desired products were obtained. Alternatively, 4-(benzo[d]-
oxazol-2-yl)benzaldehyde was converted into the desired fused
pyrano[2,3-b]pyridines 4{1,22} in 82% yield (Table 2, entry
19). Heteroaromatic aldehydes also showed high reactivity to
afford the corresponding products in good yields (Table 2,
entries 20 and 21). Similarly, aliphatic aldehydes, such as
Figure 3. Diversity of aldehydes 2{1−28}.
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Table 2. Three-Component Bicyclization for Forming Fused
Table 3. Expanded Scope of Three-Component Bicyclization
Pyrano[2,3-b]pyridines 4
a
entry
product
time (min)
yield (%)
a
entry
product
time (min)
yield (%)
1
4{2,5}
4{2,9}
4{2,17}
4{2,23}
4{3,1}
4{3,2}
4{3,3}
4{3,5}
4{3,8}
4{3,9}
4{3,10}
4{3,15}
4{3,16}
4{3,17}
4{3,23}
4{4,1}
4{4,2}
4{4,3}
4{4,8}
4{4,9}
4{4,10}
4{4,11}
4{4,15}
4{4,16}
4{4,17}
4{4,23}
16
19
18
17
16
17
16
18
17
18
17
19
20
18
16
18
17
16
18
17
17
16
18
17
19
20
88
89
92
93
94
92
93
89
89
88
90
91
93
89
88
92
93
89
88
89
92
91
93
85
85
90
1
4{1,1}
16
17
16
18
16
19
18
17
17
18
17
19
16
17
16
18
16
19
18
17
17
18
17
19
82
80
81
79
77
76
81
82
74
79
80
81
84
82
83
79
78
79
82
83
79
78
80
81
2
2
4{1,3}
3
3
4{1,4}
4
4
4{1,6}
5
5
4{1,7}
6
6
4{1,9}
7
7
4{1,10}
4{1,11}
4{1,12}
4{1,13}
4{1,14}
4{1,15}
4{1,16}
4{1,17}
4{1,18}
4{1,19}
4{1,20}
4{1,21}
4{1,22}
4{1,24}
4{1,25}
4{1,26}
4{1,27}
4{1,28}
8
8
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
Isolated yields.
a
Isolated yields.
On the basis of literature reports12,13 and our experiments, a
phenylacetaldehyde and pentanal, were suitable for this domino
bicyclization, affording the products 4 {1,26} and 4 {1,27} in
78% and 80% yields, respectively (Table 2, entries 22−23).
Notably, treatment of isophthalaldehyde with 5-hydroxy-2-
(hydroxymethyl)-4 H-pyran-4-one and 2-aminoprop-1-ene-
1,1,3-tricarbonitrile in a 1:2:2 molar ratio gave polycyclic
derivatives containing bis-pyrano[2,3- b]pyridine core (Table 2,
entry 24). Furthermore, this special domino bicyclization
provides a new route for constructing bis-pyran motif in an
economical fashion, which is a valuable synthetic strategy to
discover new bioactive compounds.
To further expand the scope of the current method, 4-
hydroxyquinolin-2(1H)-one 1{2}, 5,5-dimethylcyclohexane-
1,3-dione 1{3}, and cyclohexane-1,3-dione 1{4} were examined
as a replacement for the kojic acid 1{1}, the reactions
proceeded well and gave excellent yields. The substituent
effects of the aromatic aldehydes did not hamper reaction
progress. When thiophene-2-carbaldehyde was used, the
desired fused pyrano[2,3-b]pyridine products were also
produced in excellent yields (Table 3, entries 4, 15, and 26).
The results exhibit the scope and generality of the new three-
component bicyclization with respect to a wide range of C,O-
containing nucleophiles and aldehyde substrates. It is worth
mentioning that this protocol provides a direct access to
functional pyrano[2,3-b]pyridines, which are generally prepared
via multistep routes.12
plausible mechanism for this three-component bicyclization was
postulated in Scheme 2. First, Et3N promoted Knoevenagel
condensation between 2-aminoprop-1-ene-1,1,3-tricarbonitrile
3 and aldehydes 2 gives rise to intermediate A. Next, Michael
addition of kojic acid 1{1} to intermediate A occurs, followed
by tautomerization and subsequent intramolecular cyclization
twice, to afford final fused pyrano[2,3-b]pyridines 4.
In conclusion, we have developed a facile and reliable three-
component bicyclization for efficient synthesis of fused
pyrano[2,3-b]pyridine derivatives. By using different types of
commercially available C,O-containing nucleophiles with
diverse aldehydes and 2-aminoprop-1-ene-1,1,3-tricarbonitrile,
we could obtain novel libraries of pyrano[2,3-b]pyridine
derivatives. This methodology is simple, practical and provides
an alternative synthetic route to obtain good yields of bispyran
derivatives by microwave irradiation. The separation and
purification processes are very simple and convenient and the
pure products were isolated by simple recrystallization. Further
investigation of their biological activity is in progress.
EXPERIMENTAL PROCEDURES
■
General Information. Microwave irradiation was carried
out with initiator 2.5 microwave synthesizers from Biotage,
Uppsala, Sweden. Melting points were determined in open
capillaries and were uncorrected. IR spectra were taken on a
C
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Research Article
Scheme 2. Possible Mechanism for the Formation of 4
FT-IR-Tensor 27 spectrometer in KBr pellets and reported in
Jiangsu Higher Education Institutions, the Qing-Lan Project
(12QLG006).
1
cm−1. H NMR spectra were measured on a Bruker DPX 400
MHz spectrometer in DMSO-d6 with chemical shift (δ) given
in ppm relative to TMS as an internal standard. HRMS (ESI)
was determined by using microTOF-Q II HRMS/MS instru-
ment (BRUKER).
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̈
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ASSOCIATED CONTENT
* Supporting Information
Further details on the experimental procedures and results.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*Tel.: 0086-516-83500065. Fax: 0086-516-83500065. E-mail:
wjhao@jsnu.edu.cn.
*E-mail: laotu@jsnu.edu.cn.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We are grateful to financial support from the National Science
Foundation of China (No. 21232004 and 21102124), PAPD of
■
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