One-pot facile synthesis of polysubstituted pyridines via tandem reaction of the Blaise reaction intermediates and 3-formylchromones

Article abstract of DOI:10.1016/j.tetlet.2017.02.006

A novel tandem one-pot method for the synthesis of polysubstituted pyridine derivatives has been developed via Knoevenagel-type reaction and subsequent 6π electrocyclization of the Blaise reaction intermediates and 3-formylchromones. Short reaction time,

Full text of DOI:10.1016/j.tetlet.2017.02.006

Accepted Manuscript
One-pot facile synthesis of polysubstituted pyridines via tandem reaction of the
Blaise reaction intermediates and 3-formylchromones
Zhiwei Chen, Zhaoran Dai, Zhangxia Zhu, XiaoFeng Yang
PII:
S0040-4039(17)30170-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.006
TETL 48617
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 December 2016
23 January 2017
3 February 2017
Please cite this article as: Chen, Z., Dai, Z., Zhu, Z., Yang, X., One-pot facile synthesis of polysubstituted pyridines
via tandem reaction of the Blaise reaction intermediates and 3-formylchromones, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.02.006
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Tetrahedron Letters
One-pot facile synthesis of polysubstituted pyridines via tandem reaction of the Blaise
reaction intermediates and 3-formylchromones

Zhiwei Chena , Zhaoran Daia , Zhangxia Zhua and XiaoFeng Yanga
a Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, P. R. China;
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel tandem one-pot method for the synthesis of polysubstituted pyridine derivatives has
been developed via Knoevenagel-type reaction and subsequent 6π electrocyclization of the
Blaise reaction intermediates and 3-formylchromones. Short reaction time, moderate to good
yields and excellent functional group tolerance have been accomplished in this protocol.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Blaise reaction
Chromone
Tandem reaction
Pyridine derivatives
Of the N-heterocycles, pyridines are among the most prevalent
scaffolds which are not only present in natural products, but are
also widely used in functional materials, pharmaceuticals and
synthetic intermediates1. Due to their importance, a large amount
of synthetic methods have been developed for the preparation of
pyridines and its derivatives. Classical methods for the synthesis
of polysubstituted pyridines includes Hantzsch reaction2,
Krohnke reaction3, Aza-Diels-Alder reaction4. In addition to
those divergent strategies, modification of pre-existing pyridine
frameworks via metal-catalyzed cross-coupling reaction to afford
polysubstituted target products is also well developed5. Although
pyridines could be generated efficiently under the above reaction
conditions, difficulties arised from the preparation of starting
materials, long reaction time or expensive catalysts can preclude
their extensive application. Therefore, novel complementary
approaches to densely substituted pyridines still remains as a hot
research topic.
The classic reaction of zinc-mediated transformation of nitriles
and ethyl bromoacetate, known as the Blaise reaction6, has long
been prepared corresponding β-ketoesters and β-enaminoesters7.
In recent years, the Blaise reaction intermediates have been
trapped with suitable building blocks in a tandem manner, which
provided facile access to a great number of heterocyclic
compounds8. In this regard, Lee and co-workers have developed
an efficient protocol for the synthesis of polysubstituted pyridines
through a tandem one-pot reaction using the Blaise reaction
intermediates and 1,3-enynes9 (Scheme 1a). In order to overcame
the limitation of their previous procedure, an update of this
method has been reported recently allowing diverse substitutes to
be installed at the 4-position of the pyridine rings10 (Scheme 1b).
It is well known that 3-formylchromone possessing a very
reactive electrophilic center at C-2, a conjugated second carbonyl
group at C-3 and an unsaturated keto function11, have been used
as an important synthetic building blocks to prepare heterocyclic
compounds.
Previous work by Lee and co-works
This work
Scheme 1. Synthesis of polysubstituted pyridines via tandem reaction.
———
 Corresponding author. Tel. (fax): +86 571 88871087; e-mail: chenzhiwei@zjut.edu.cn

2
Tetrahedron Letters
Based on the previous works as well as our continuous
Under the optimized reaction conditions, we next explored the
scope and limitation of the reaction. As shown in Table 2, the
examined substrates provided moderate to good yields. In early
experiments, for the substituted R2, ter-butyl in place of methyl
or ethyl resulted in a slight increasement of yields (entries 1-3,
Table 2). This results indicating that the steric bulk of the
bromoacetic ester was favorable in the process which may
decrease the side product formed from the attack of Reformatsky
to the -COOR2 group. For the substituted R1, readily available
aryl nitriles substituted with electron-withdrawing groups such
as 2-Cl, 4-Cl, 4-F and 4-CF3 offered high yields of tandem
products (entries 6-9 Table 2). On the other hand, reactions
involving aryl nitriles with electron rich substituents produced
desired pyridines in slight lower yields (entries 4-5, Table 2). In
addition, due to the steric hindrance of the substitutes on the aryl
groups, the aryl nitriles bearing ortho-substituted group gave rise
to products in lower yield than para-substituted nitriles.
Especially, 2-(4-methylphenyl)benzonitrile with large steric bulk
participated in the tandem raction to afford a few desired
pyridine (entry 11, Table 2). To our delight, the Blaise
intermediates, prepared form aliphatic nitriles (entries 12-16,
Table 2), reacted smoothly under the optimized conditions to
give the corresponding tandem products. However, acetonitrile,
pentanenitrile and cyclopropanecarbonitrile were carried out in
the poor performance towards the generation of the
corresponding products. For the substituted R3, 3-
formylchromone substituted with 6-CH3 and 6-Br also showed
good reactivity(entry 17-18, Table 2).
interests on the development of multicomponent heterocyclic
chemistry12, we envisioned the one-pot method for the feasible
synthesis of polysubstituted pyridine derivatives via tandem
reaction of the Blaise reaction intermediates and 3-
formylchromones.
Table 1
Optimization of the reaction conditionsa
Entry
1
Catalysts
-
Loading (mol%)
Solvents
THF
Yield(%)
70
-
2
-
-
DCE
60
3
-
-
1,4-dioxane
THF
67
4
Cu(OTf)2
Cu(OTf)2
Yb(OTf)3
Zn(OTf)2
ZnCl2
CuCl2
AlCl3
20
50
20
20
20
20
20
20
20
20
70
5
THF
68
6
THF
65
7
THF
62
8
THF
69
9
THF
68
10
11
12
13
THF
58
THF
63
BF3∙ Et2O
MeSO3H
PTSA
THF
59
THF
55
Moreover, these initial findings encouraged us to extend this
methodology to other substrates. As shown in Table 3, the
tandem reaction of the Blaise intermediates and
3-cyanochromones were carried out under the standard reaction
conditions to afford more complex and diverse products, which
could introduce a amino group at the 4-position of the pyridine
ring in a convenient manner. Overall, the combination of the
Blaise intermediates and 3-cyanochromones afforded the
corresponding polysubstituted pyridine derivatives in 75-86%
a
All reactions were carried out with benzonitrile (1 mmol), zinc (2 mmol)
and ethyl bromoacetate (1.5 mmol) in THF at reflux for 1 h, 3-
formylchromone (1.5 mmol) was then added at r.t..
b Isolated yields based on benzonitrile.
To check our hypothesis, we initially performed a model
reaction between 3-formylchromone (2.0 equiv) and the Blaise
reaction intermediate which was formed from the reaction
between benzonitrile and a Reformatsky reagent generated in
situ from ethyl bromoacetate (1.5 equiv) and zinc powder (2.0
equiv) in THF. To our delight, the expected product ethyl 5-(2-
hydroxybenzoyl)-2-phenylnicotinate 5a was obtained in 70%
yield (Table 1, entry 1). Then, screening of the solvents in this
reaction revealed that THF was better than DCE and 1,4-dioxane
in regards of yield. Thus, THF was the most suitable solvent due
to the stablization of THF imposed on zinc complex13. With the
optimal solvent in hand, diverse Lewis acids and protic acids
were investigated for the tandem reaction in THF. Among them,
Cu(OTf)2, Yb(OTf)3, Zn(OTf)2, ZnCl2, CuCl2, AlCl3, BF3∙Et2O,
MeSO3H and PTSA showed moderate reactivity and there was
no effect to promote the reaction. Consequently, the second step
yields.
Table 3
Synthesis of 4-NH2 substituted pyridine derivatives.
of the tandem reaction was perfomed without any additive.
Table 2
Synthesis of various substituted pyridine derivatives a
Entry
R1
R2
R3
H
H
H
H
H
H
H
H
H
Product
5a
Yield(%)b
Entry
10
R1
2-MeC6H4
2-(p-tolyl)C6H4
C6H5CH2
4-ClC6H4CH2
CH3
R2
R3
H
Product
5j
Yield(%)b
1
2
3
4
5
6
7
8
9
C6H5
Et
70
68
73
69
66
79
75
77
67
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
71
53
65
63
59
55
60
69
72
C6H5
Me
5b
11
H
5k
C6H5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
5c
12
H
5l
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-ClC6H4
4-FC6H4
2-ClC6H4
5d
13
H
5m
5n
5e
14
H
5f
15
CH3(CH2)3
Cyclopropyl
C6H5
H
5o
5g
16
H
5p
5h
17
Me
5q
5i
18
C6H5
Br
5r
a All reactions were carried out with nitrile 1 (1 mmol), zinc (2 mmol) and bromoacetic ester 2 (1.5 mmol) in THF at reflux for 1 h, 3-formylchromone 3 (1.5
mmol) was then added at r.t.. b Isolated yields based on nitrile 1.

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N. L.; Jacob, P. Chem. Res. Toxicol. 2015, 28, 1007.
Based on the above observations and previous reports9, 14, a
plausible pathway for the formation of ethyl 5-(2-
hydroxybenzoyl)-2-phenylnicotinate 5a is proposed in scheme 2.
Initially, a zinc-mediated Blaise reaction between benzonitrile 1
and ethyl bromoacetate 2 takes place to give an enamino ester
intermediate A. Secondly, intermediate B is afforded through
Knoevenagel-type reaction of the Blaise intermediate A and 3-
formylchromone 3, Then, intermediate B undergoes a subsequent
2.
(a) Kumar, A.; Maurya, R. A. Synlet 2008, 883; (b) Debache, A.;
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intramolecular
transformation
to
produce
N-zincated
intermediate C, which could facilitate a 6π electrocyclization to
afford intermediate D. Finally, the product 5a is given via C–O
bond cleavage and elimination of BrZnOH after workup.
Accordingly, 3-cyanochromone participates the tandem reaction
through a very similar pathway(scheme 3).
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7. (a) Rathke, M. W.; Weipert, P. in Comp. Org. Synth., ed. B. M. Trost,
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H.; Shin, H.; Lee, S.-G. Org. Biomol. Chem. 2011, 1317; (e) Chun, Y.
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J.; Zhao, W. X. Appl. Organometal. Chem. 2016, 30, 47.
Scheme 2. Proposed mechanism of the reaction of 3-formylchromone
9.
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L. M.; Sathicq, A. G.; Jios, J. L.; Baronetti, G. T.; Thomas, H.o J.;
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Scheme 3. Proposed mechanism of the reaction of 3-cyanochromone
In summary, we have described a novel divergent one-pot
method for the synthesis of polysubstituted pyridine derivatives
from easily accessible starting materials. This tandem reaction
proceeds through the regio- and chemoselective Knoevenagel-
type reaction between the Blaise reaction intermediates and 3-
formylchromones, followed by an intramolecular cyclization to
afford target products. Furthermore, We have extended the
applications of the present method using 3-cyanochromones as
substrates to introduce amino group at the pyridine core in a
feasible pathway.
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15. Typical procedure for the synthesis of polysubstituted pyridine derivative:
To a stirred suspension of commercial zinc dust (2.0 mmol) in
anhydrous THF (3.0 mL) was added a solution of MeSO3H in THF (1.0
M, 0.2 mL) at 80°C (oil bath). After stirring for 10 min, benzonitrile 1
(1.0 mmol) and ethyl bromoacetate 2 (1.5 mmol) was added over 1 h,
and then the reaction mixture was further stirred at reflux for 1 h. After
confirmed conversion of benzonitrile 1 (>95%) to the Blaise reaction
intermediate A by gas chromatography, the reaction mixture was cooled
to room temperature, and then 3-formylchromone 3 (1.5 mmol) was
added. Upon completion of the reaction, aqueous NH4Cl (10 mL) was
added and the excess zinc was filtered. The filtrate was concentrated and
water (5 mL) was added to the residue. The solution was extracted with
EtOAc (3 x 10 mL). The organic phases were combined, dried with
anhydrous Na2SO4 and then concentrated. The residue was purified by
column chromatography (EtOAc/hexane, 1:10 v/v) to afford product 5a.
Yield: (243 mg, 70%); Characteristic: pale yellow powder; Mp 89-91oC
(Lit.[11b]: 80-90oC). 1H NMR (400 MHz, CDCl3) δ 11.78 (s, 1H), 9.03 (d,
J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.65-7.53 (m, 4H), 7.51-7.41
(m, 3H), 7.11 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 4.20 (q, J =
7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
197.72, 166.95, 163.15, 160.95, 150.48, 139.08, 138.20, 136.89, 132.65,
131.28, 129.22, 128.63, 128.06, 127.12, 119.03, 118.92, 118.69, 61.85,
13.74. MS (ESI): m/z = 348 [M+H]+.
Acknowledgments
We are grateful for the National Natural Science Foundation of
China (Nos. 21276237 and 21676253 ) for financial support.
Cooperation from the colleagues analytical research and
development is highly appreciated.
References and notes
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Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337; (f) Roughley, S. D.; Jordan, A. M. J. Med. Chem.

Graphical Abstract
Graphical Abstract.
Leave this area blank for abstract info.
One-pot facile synthesis of polysubstituted pyridines
via tandem reaction of the Blaise reaction intermediates
and 3-formylchromones
Zhiwei Chen, Zhaoran Dai , Zhangxia Zhu and XiaoFeng Yang

Highlights
1． A tandem synthesis of 2,3,5-substituted pyridine derivatives has been
developed.
2． 3-cyanochromones have been used to extend the application.
3． Two similar mechanisms have been proposed, respectively.