One-pot synthesis of polyfunctionalized 4H-pyran derivatives bearing fluorochloro pyridyl moiety

Article abstract of DOI:10.1016/j.tetlet.2010.07.065

Polyfunctionalized 4H-pyran derivatives bearing fluorochloro pyridyl moiety were readily prepared in high yields via one-pot multicomponent reaction catalyzed by piperidine. This present protocol provides an efficient synthetic route to the target compoun

Full text of DOI:10.1016/j.tetlet.2010.07.065

Tetrahedron Letters 51 (2010) 4991–4994
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of polyfunctionalized 4H-pyran derivatives bearing
fluorochloro pyridyl moiety
*
Zhenjun Ye, Renbo Xu, Xusheng Shao, Xiaoyong Xu, Zhong Li
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Polyfunctionalized 4H-pyran derivatives bearing fluorochloro pyridyl moiety were readily prepared in
high yields via one-pot multicomponent reaction catalyzed by piperidine. This present protocol provides
an efficient synthetic route to the target compounds with the characteristics of short reaction time, high
yield, and easy separation of the products.
Received 19 May 2010
Revised 10 July 2010
Accepted 13 July 2010
Available online 17 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
4H-Pyran derivatives
Fluorochloro pyridyl
Multicomponent reactions (MCRs)
4H-Pyran is an important and common structural unit both in
natural compounds and synthetic heterocyclic molecules.1,2 In
recent years, polyfunctionalized 4H-pyran and its derivatives are
of great synthetic interest and have been widely recognized as
versatile scaffolds with diverse biological activities.3,4 These com-
pounds showed wide pharmacological activities and some of them
emerged as anti-coagulants, anti-anaphylactics, and anticancer
agents.5–7 In addition, they present a potential activity on the treat-
ment of neurodegenerative diseases such as Alzheimer’s disease
and Parkinson’s disease.8
O
O
N
F
F
N
H
O
N
CF3
Cl
N
Cl
Cl
N
Cl
1
2
Figure 1. Structure with insecticidal activity bearing 2,6-dichloro-5-fluoro pyridine
moiety.
As part of our ongoing drug discovery program, in this Letter we
introduced fluorochloro pyridyl moiety into a series of polyfunc-
tionalized 4H-pyran derivatives. Use as a key starting material to
synthesize quinolone antibiotics like enoxacin and tosufloxacin,9,10
2,6,-dichloro-5-fluoro pyridine has also attracted great attention in
pesticide research. Some compounds showed good activity against
armyworm and culexmosquito 1 and the structure with this multi-
halogen-containing pyridine fragment also presented pleased
inhibitory activity against sphaerotheca fuliginea 2 (Fig. 1).11,12
Employing this unique heterocyclic ring we hope would help to ex-
tend the activity profiles and improve the physicochemical proper-
ties of 4H-pyrans (Fig. 2).
The target-oriented synthetic method, retrosynthetic analysis,
is an important approach to breakdown the aim compound into
simple precursors.13 By disconnecting the C–O bond in the de-
signed molecule, synthon A was departed from fragment B which
could easily be obtained from synthon C and synthon D (Fig. 3).
Several issues proved our retrosynthetic plan,14–19and explorations
were also conducted in combining the synthetic steps into one-pot
synthesis.20–23 Meanwhile, auxiliary techniques such as micro-
wave, ultrasonic irradiation, and specific catalysts like ionic liquid
and strong metal bases also were applied to shorten reaction time
and increase yield.5,8,24–27 Till now, very few literature had
presented 4H-pyrans bearing heterocyclic rings like pyridine at
position 6 and introduce the unique heterocycle, that is 2,6-
dichloro-5-fluoro pyridine, might confer special physical and
chemical properties to the compounds. In this Letter, while con-
structing the target structure from unit A, C, and D, we bring a
protocol with the advantage of mild reaction condition, rapid
conversion rate, high yield, and easy work up.
The catalyst played an important role in the formation of fully
substituted 4H-pyrans. Initially, benzaldehyde 3, malononitrile 4,
and ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate
5 were selected as representative substrates to investigate the
reaction conditions. Without the catalyst, the reaction was con-
ducted with a long reaction time. Then, we focused our attention
on using various catalysts, which might help to reduce the reaction
time and improve the yields of the target compounds. Lewis acid
* Corresponding author. Tel.: +86 21 64253540; fax: +86 21 64252603.
E-mail address: lizhong@ecust.edu.cn (Z. Li).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.065

4992
Z. Ye et al. / Tetrahedron Letters 51 (2010) 4991–4994
O
Ar
O
CN
Ar
Incorporate with
O
N
4
R
CN
fluorochloro pyridyl moiety
3
5
F
NH2
6
O
2 HN2
Cl
Cl
2-Amino-3-cyano4H-pyrans
4H-pyran scaffold
Unique pyridine heterocycle
Figure 2. Design strategy of novel polyfunctionalized 4H-pyran derivatives.
O
O
Ar
O
CN
Ar
O
N
O
N
CN
CN
F
+
F
NH2
O
Fragment B
Cl
Cl
Cl
Cl
Synthon A
Target molecule
H
CN
+
Ar
O
CN
Synthon D
Synthon C
Figure 3. Retrosynthetic analysis of the target compounds.
Table 1
One-pot reaction of benzaldehyde, malononitrile and 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate using different catalystsa
Entry
Catalystb
Time (h)
Yieldc (%)
1
2
3
4
5
6
ZnCl2
24
24
10
1.5
0.6
0.5
52
Trace
71
84
82
SnCl2Á2H2O
None
TEA
Morphline
Piperidine
85
a
b
c
Molar ratio of 3:4:5 = 1.2:1.2:1
The amount of 10 mol % catalyst was used.
Yields refer to isolated products.
ZnCl2 and SnCl2Á2H2O were employed28 and the results demon-
strated that they gave negative effects to the reaction, slowing
down the rate and decreasing the yields (Table 1, entries 1 and
2). Subsequently, the organic bases were introduced into the reac-
tion system. When morphline was applied to the reaction system,
the reaction time was shortened and the yield was increased (Table
1, entry 5). Encouraged by this result, we tried different organic
bases as listed in Table 1. Finally, piperidine showed a favorable
catalytic activity to the reaction in terms of the reaction time as
well as the yields.
to the reaction system and the following Michael addition finished
extremely rapid under reflux in ethanol in one to two minutes. The
reaction accomplished complete conversion and the pure target
compounds were obtained in considerably high yields without fur-
ther purification.29–31
Various component molar ratios were applied to the reaction
for optimization (Table 2). The results showed that the target com-
pound was obtained in a relatively high yield with the ratio of
3:4:5 = 1.2:1.2:1 (Table 2, entry 2). Further increasing the ratio of
benzaldehyde 3 and malononitrile 4 did not lead to an improve-
ment of the yield (Table 2, entry 3), while the lowest yield was ob-
served when the ratio of 3:4:5 = 1.1:1.1:1 (Table 2, entry 1).
Moreover, the impact of the catalyst amount on the reaction rate
and the conversion was also investigated. In the absence of the cat-
alyst the reaction proceeded for a relatively long time in low yield.
The mechanism of this reaction was shown in Scheme 1.5
Firstly, aryl aldehydes reacted with malononitrile and resulted in
the formation of arylidenemalononitriles through Knoevenagel
condensation in the presence of the catalyst at 35 °C. Secondly,
3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate was added

Z. Ye et al. / Tetrahedron Letters 51 (2010) 4991–4994
4993
R
CN
+
CN
CHO
R
Catalyst
R
O
O
O
CN
one-pot
CN 1-2 minutes
CN
F
O
N
+
O
F
O
R
NH2
Cl
N
Cl
Cl
Cl
R
R
O
O
O
CN
NH
CN
N
CN
O
N
O
N
O
N
F
F
F
CN
O
O-
O
Cl
Cl
Cl
Cl
Cl
Cl
Scheme 1. The reaction mechanism of the one-pot three components reaction.
Table 2
Optimization of the components ratio and amount of catalyst
After optimization, it was found that 10 mol % piperidine was the
appropriate amount to carry out the reaction smoothly. Further
increasing of the catalyst amount did not help to improve the reac-
tion time and the yield apparently, while decreasing the amount
led to a lower yield and a longer reaction time. The optimized con-
ditions and the results were illustrated in Table 2.
The optimal conditions for obtaining the target compounds in-
volved the use of 10 mol % piperidine as the catalyst. To explore the
overview of the one-pot transformation described above, different
Entry
Catalyst amount
(mol %)
Components molar
ratio (3:4:5)
Time (h)
Yielda (%)
1
2
3
4
5
6
0
0
0
5
10
15
1.1:1.1:1
1.2:1.2:1
1.3:1.3:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
10
10
10
1.5
0.5
0.5
65
71
71
77
85
86
a
Yields refer to isolated products (based on component 5).
Table 3
One-pot synthesis of different 4H-pyran derivatives containing fluorochloro pyridyl moiety catalyzed by piperidinea
Entry
R
Product
Time (min)
Yieldb (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3-CN
4-NO2
H
2-Cl-4-Br
2,3-F2
2-F-4-Me
4-Cl
3-NO2
4-Me
4-Cl-2-CF3
2,4-Cl2
4-CN
3-Br
4-F
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
20
50
30
30
20
80
65
40
300
110
25
45
30
92
82
85
79
87
85
82
86
83
83
90
81
85
86
203.1–204.1
129.8–131.4
152.1–152.9
200.5–201.5
181.8–182.9
190.4–191.1
178.3–180.1
192.2–193.4
183.8–185.2
205.1–206.2
185.4–186.9
148.9–150.6
155.7–157.0
129.6–131.1
85
a
All reactions were performed with substituted aldehyde (1.2 equiv), malononitrile (1.2 equiv), and 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate (1.0 equiv)
catalyzed by piperidine (0.10 equiv).
b
Yields refer to isolated products (based on compound 5).

4994
Z. Ye et al. / Tetrahedron Letters 51 (2010) 4991–4994
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donating ones were used as substrates. As shown in Table 3, under
optimized reaction conditions, the target compounds were ob-
tained in high yields. Notably, the electron-donating group and
the electron-withdrawing group on the aryl ring had some impact
on the reaction rates. Aryl aldehydes with electron-withdrawing
groups took less time to complete the reactions. In conclusion,
we introduced multihalogen-containing pyridine ring into a series
of polyfunctionalized 4H-pyran derivatives under mild conditions.
The reaction was completed in high yield via piperidine-catalyzed
one-pot three components reaction of aryl aldehyde, malononitrile,
and 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate. Our
presented process represents the feasibility and diversity of incor-
porating various moieties with potential bioactivity into polyfunc-
tionalized 4H-pyran derivatives, which would be a significant
practice for the further synthesis of biologically active molecules.
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Acknowledgments
22. Heber, D.; Stoyanov, E. V. Synthesis 2003, 227.
23. Shestopalov, A. A.; Rodinovskaya, L. A.; Shestopalov, A. M.; Litvinov, V. P. Russ.
Chem. Bull. 2004, 53, 2342.
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This work was financial supported by National Basic Research
Program of China (973 Program, 2010CB126106), National High
Technology Research and Development Program of China (863 Pro-
gram, 2010AA10A204), National Science Foundation China Pro-
gram Grant (20872034) and Program for New Century Excellent
Talents in University (NCET070284). This work was also partly sup-
ported by Shanghai Foundation of Science and Technology
(073919107, 09XD1401300, 09391911800). We thank Dr. Yucheng
Gu of Syngenta at Jealott’s Hill International Research Centre in the
UK for proofreading of the manuscript.
25. Zhou, J.; Tu, S.; Gao, Y.; Ji, M. Chin. J. Org. Chem. 2001, 21, 742.
26. El-Rahman, N. M. A.; El-Kateb, A. A.; Mady, M. F. Synth. Commun. 2007, 3961.
27. Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Gorbunov, S. V.; Nasybullin, R.
F.; Miloserdov, F. M.; Nikishin, G. I. Eur. J. Org. Chem. 2006, 4335.
28. Jayashree, P.; Shanthi, G.; Perumal, P. T. Synlett 2009, 917.
29. Experimental: All melting points (mp) were obtained with a Büchi Melting
Point B540 and are uncorrected. 1H and 13C NMR spectra were recorded on a
Brucker AM-400 (400 MHz) spectrometer with CDCl3 as the solvent and TMS as
the internal standard. Chemical shifts are reported in d (parts per million)
values. Coupling constants nJ are reported in Hz. High-resolution electron mass
spectra were recorded under electron impact (70 eV) condition using
a
MicroMass GCT CA 055 instrument. Analytical thin-layer chromatography
(TLC) was carried out on precoated plates (Silica Gel 60 F254), and spots were
visualized with ultraviolet (UV) light. All chemicals or reagents were purchased
from standard commercial supplies.
Supplementary data
30. General procedure for one-pot syntheses of 6a–n: To a solution of the appropriate
aldehyde (1.2 mmol) in ethanol (15 mL), malononitrile (1.2 mmol) and
piperidine (0.12 mmol) were added. The mixture was stirred for 0.5–1.5 h at
35 °C. After Knoevenagel condensation was finished, (monitored by TLC), 3-
(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate was added into the
reaction mixture, and warmed to reflux for 1–2 min. The solvent was
removed under reduced pressure. Then, the rude product was precipitated
by adding 5 mL mixture solvent (PE/EA = 3:1). After filtration and drying, the
pure compound was obtained.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.065.
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31. Typical data for
a
representative compound. Ethyl 6-amino-5-cyano-2-(2,6-
(6i): This
dichloro-5-fluoropyridin-3-yl)-4-p-tolyl-4H-pyran-3-carboxylate
compound was obtained as white solid following the above method, yield 83%,
mp 183.8–185.2 °C; 1H NMR (400 MHz, CDCl3): d 7.55 (1H, d, J = 7.2 Hz, Py-H),
7.21 (2H, d, J = 8.0 Hz, Ph-H), 7.15 (2H, d, J = 8.0 Hz, Ph-H), 4.74 (2H, s, NH2), 4.57
(1H, s, CH-Ph), 3.85–3.98 (2H, m, CH2CH3), 2.33 (3H, s, Ph-Me), 0.95 (3H, t,
J = 7.2 Hz, CH2CH3). 13C NMR (100 MHz, CDCl3): d 163.75, 159.88, 157.75, 154.92,
152.31, 149.12, 139.55, 138.66, 137.43, 130.932, 130.36, 129.55, 127.61, 118.34,
62.19, 61.37, 38.75, 21.01, 13.55. HRMS (EI+): calcd for C21H16N3O3F35Cl2 (M+),
447.0553; found, 447.0553; calcd for C21H16N3O3F35Cl37Cl (M+), 449.0523;
found, 449.0540; calcd for C21H16N3O3F37Cl2 (M+), 451.0494; found, 451.0518.
7. Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-Grundy, C.; Xu,
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