K2CO3-assisted one-pot sequential synthesis of 2-trifluoromethyl-6-difluoromethylpyridine-3,5-dicarboxylates under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2010.07.041

A novel synthesis of 2-trifluoromethyl-6-difluoromethylpyridine-3,5- dicarboxylates by three-component reaction of ethyl trifluoroacetoacetate, aldehydes, and ammonium acetate in the presence of K₂CO₃ under solvent-free conditions via sequential Hantzsch reaction/dehydration/ dehydrofluorination in a one-pot process was described.

Full text of DOI:10.1016/j.tetlet.2010.07.041

Tetrahedron Letters 51 (2010) 4866–4869
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Tetrahedron Letters
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K2CO3-assisted one-pot sequential synthesis of
2-trifluoromethyl-6-difluoromethylpyridine-3,5-dicarboxylates
under solvent-free conditions
*
*
Li Shen, Song Cao , Jingjing Wu, Hui Li, Jian Zhang, Mingxi Wu, Xuhong Qian
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, 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:
A novel synthesis of 2-trifluoromethyl-6-difluoromethylpyridine-3,5-dicarboxylates by three-component
reaction of ethyl trifluoroacetoacetate, aldehydes, and ammonium acetate in the presence of K2CO3 under
solvent-free conditions via sequential Hantzsch reaction/dehydration/dehydrofluorination in a one-pot
process was described.
Received 28 April 2010
Revised 2 July 2010
Accepted 9 July 2010
Available online 13 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Trifluoromethylated pyridines have been widely used in medici-
nal and agricultural chemistry.1 For example, Enpiroline, a tri-
fluoromethyl-containing 4-pyridinemethanol phosphate, has been
discovered as a promising antimalarial compound.2 Fluazinam, an
N-phenylpyridinamine compound, is a highly active fungicide with
broad spectrum.3 In recent years, the introduction of difluoromethyl
group (–CF2H) into biologically active compounds has attracted
much interest due to its unique physiological properties.4 Compared
to the trifluoromethylated compounds, most difluoromethylated
derivatives can serve as hydrogen bond donors and provide further
opportunity for interaction with biological molecules.5 Thiazopyr,
a pyridine derivative with both trifluoromethyl and difluoromethyl
groups, has been registered as a new pre-emergence selective herbi-
cide for the control of various annual grasses and broadleaf weeds.6
The most straightforward method to introduce difluoromethyl
group into molecules involves the reaction of the corresponding
carbonyl compounds with fluorinating reagents such as diethylami-
reasons. Furthermore, solvent-free reactions not only represent a
clean, simple, efficient, and safe procedure with noticeable in-
creases in reactivity and selectivity but also sometimes lead to a
significant change in the course of a reaction and afford totally dif-
ferent products.11,12
Herein, we would like to describe an unexpected K2CO3-cata-
lyzed sequential cyclization/dehydration/dehydrofluorination/
aromatization for the synthesis of 2-trifluoromethyl-6-difluorom-
ethylpyridine-3,5-dicarboxylate via a one-pot three-component
condensations of aldehydes, ethyl trifluoroacetoacetate, and ammo-
nium acetate under solvent-free conditions (Scheme 1).
According to the literature, trifluoromethyl-substituted 1,4-
dihydropyridines can be prepared by the dehydration of the diethyl
2,6-dihydroxy-2,6-bis(trifluoromethyl)piperidine-3,5-dicarboxyl-
ates (III, Scheme 3), which are obtained by the Hantzsch reaction of
ethyl trifluoroacetoacetate.13 Up till now, several dehydration
agents such as phosphorus oxychloride-pyridine, sulfuric acid, and
phosphorus oxychloride-pyridine adsorbed on silica gel have been
developed and used for their dehydration.14–16 Recently, we plan-
ned to synthesize a series of trifluoromethyl-substituted 1,4-dihy-
dropyridines for the purpose of screening the bioactive compounds.
However, when the Hantzsch reaction of ethyl trifluoroacetoace-
tate, benzaldehyde, and ammonium acetate was carried out
without a solvent, an unprecedented dehydration product was ob-
tained with the loss of one mole of water, diethyl 2-hydroxy-2,
nosulfur trifluoride (DAST), Deoxofluor™, and N,N-diethyl-a,a-di-
fluoro-(m-methylbenzyl) amine (DFMBA).7–9 However, there has
been little research on the nucleophilic fluorination reaction of
pyridine aldehydes or ketones. Although the dehydrofluorination
of trifluoromethyl-substituted dihydropyridines has been reported
as an alternate route for the synthesis of difluoromethyl-substituted
pyridines, the procedures were associated with several shortcom-
ings, includingtheadditionofdehydratingagentsandstrongorganic
bases, the use of toxic organic solvents, the long reaction time, and
the tedious work-up procedures.10 Therefore, it is highly desirable
to develop a practical and mild method for the synthesis of
difluoromethyl-containing pyridines.
O
R
O
RCHO
NH4OAc
K2CO3 , 100 C
Solvent-free
1a-o
+
EtO
HF2C
OEt
CF3
O
O
O
Nowadays, much attention has been given to the reactions
under solvent-free conditions for economic and environmental
N
F3C
2a-o
* Corresponding authors. Fax: +86 21 64252603 (S. Cao).
E-mail addresses: scao@ecust.edu.cn (S. Cao), xhqian@ecust.edu.cn (X. Qian).
Scheme 1. Synthesis of 2-trifluoromethyl-6-difluoromethylpyridine-3,5-dicarbox-
ylates 2a–o.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.041

L. Shen et al. / Tetrahedron Letters 51 (2010) 4866–4869
4867
O
Ph
O
O
Ph
O
PhCHO
NH4OAc
100 C
OEt
EtO
OEt
+
EtO
F3C
OH
CF3
HO
F3C
OH
CF3
O
O
solvent-free
N
H
N
H
F3C
OEt
3a
dehydration product
O
EtO
Ph
O
O
Ph
O
excessive NH4OAc
further dehydration
dehydrofluorination / aromatization
OEt
EtO
F2HC
OEt
CF3
F3C
N
H
CF3
N
2a
Scheme 2. Model reaction for the synthesis of 2a.
O
O
CHO + NH4OAc
+
R
OEt
R = CH3
Reflux
R = CF2H
Reflux
R = CF2H
R = CH3
R = CF3
Reflux
R = CF3
100 C
Solvent-free
C
C
100
Solvent-free
80
Solvent-free
Solvent
Mixture
EtO2C
H3C
CO2Et
CH3
EtO2C
HF2C
CO2Et
CF2H
EtO2C
F3C
CO2Et
EtO2C
F3C
CO2Et
CF3
CF3
OH
N
H
N
H
N
H
N
H
HO
HO
3a
I
II
III
Dehydration
Base
Oxidant
EtO2C
F3C
CO2Et
CF3
EtO2C
F2HC
CO2Et
CF3
EtO2C
H3C
CO2Et
CH3
N
H
N
2a
N
V
IV
This work
Scheme 3. The comparison of reaction conditions and products among the different 1,3-dicarbonyl substrates for the Hantzsch reaction.
Table 1
6-bis(trifluoromethyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxyl-
ate 3a was isolated as the main product. Furthermore, an increase in
the amount of NH4OAc resulted in the loss of another one mole of
water, and then the dehydrofluorination took place to generate
the aromatic product, diethyl 2-difluoromethyl-4-phenyl-6-tri-
fluoromethylpyridine-3,5-dicarboxylate 2a (Scheme 2). It was
unusual that both dehydration and dehydrofluorination proceeded
smoothly under such a mild condition to give trifluoromethyl- and
difluoromethyl-substituted pyridine in a one-pot process. Encour-
aged by this result, benzaldehyde, ethyl trifluoroacetoacetate, and
ammonium acetate were selected as representative reactants for
further optimization of the reaction conditions.
Effect of several bases on the synthesis of compound 2a
Entry
Base (equiv)
Time (h)
Yield of 2aa
b
1
2
3
4
5
6
7
None
24
5
24
2
2.5
2
17
—
CH3COONH4 (3.0)
Pyridine (1.0)
DBU (1.0)
DMAP (1.0)
K2CO3 (1.0)
NaOH
43
Tracec
75
76
77
37
a
b
c
Yields were based on GC analysis.
Compound 3a was obtained as the main product in 54% yield.
Compound 3a was obtained as the main product in 52% yield.
Initially, attempts to improve the yield of 2a by increasing the
amount of NH4OAc were unsuccessful. As NH4OAc might not be
the appropriate base for the HF elimination, we turned our atten-
tion to search for a more suitable base. Several bases were screened
and the results are shown in Table 1. The yield was significantly

4868
L. Shen et al. / Tetrahedron Letters 51 (2010) 4866–4869
Table 2
could be further oxidized to (V). The reaction proceeded in a differ-
ent way when it was conducted under solvent-free conditions and
a mixture of 1,4- and 1,2-dihydropyridine was observed.12a The
reaction of ethyl difluoroacetoacetate with benzaldehyde and
ammonium acetate yielded 1,4-DHP (II) products in good yield un-
der both refluxing and solvent-free conditions.20 When ethyl triflu-
oroacetoacetate served as the substrate, dehydration process was
promoted in the absence of dehydrating agents under solvent-free
conditions affording tetrahydropyridine 3a instead of product (III),
which was obtained as the main product in refluxing solvent. Com-
pound 3a could either be further dehydrated to 1,4-DHP (IV) by
using a dehydration agent such as sulfuric acid or aromatized to
product 2a in the presence of base under solvent-free conditions.
In conclusion, an efficient, solvent-free K2CO3-assisted method
has been developed for the synthesis of 2-trifluoromethyl-6-diflu-
oromethylpyridine-3,5-dicarboxylates. The fluorine-containing
pyridines were obtained by the reaction of trifluoromethyl aceto-
acetate with aldehydes, ammonium acetate via dehydration, dehy-
drofluorination, and aromatization under mild conditions without
additional dehydration reagent and oxidant.
Effect of temperature on the one-pot reaction under solvent-free conditions
Entry
Temperature (°C)
Time (h)
Yield of 2aa
1
2
3
90
100
120
18
2.5
1
59
77
69
a
Yields were based on GC analysis.
Table 3
Synthesis of 2-trifluoromethyl-6-difluoromethylpyridine-3,5-dicarboxylate 2a–o
under solvent-free conditions
Compd
R
Yielda
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
C6H5
77
58
67
74
93
72
53
92
73
75
66
78
86
29
25
4-CH3C6H4
4-OCF3C6H4
4-OCH3C6H4
4-CNC6H4
4-FC6H4
3-BrC6H4
3-(6-Cl-pyridinyl)
3-CH3-thienyl-2-
Thienyl-3-
4-ClC6H4
3-Pyridinyl
4-BrC6H4
Acknowledgments
We are grateful for the financial supports from the National Ba-
sic Research Program of China (973 Program, 2010CB126101), the
Shanghai Foundation of Science of Technology (09391911800), and
the Shanghai Leading Academic Discipline Project (B507).
Furan-2-
CH3CH2CH2
a
Yields were based on GC analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.041.
affected by the base. When the model reaction was performed in
the absence of base, no further dehydration and dehydrofluorina-
tion reactions occurred and 3a was obtained as the main product.
Among the various bases tested, 1,5-diazabicyclo[4.3.0]non-5-ene
(DBU), 4-dimethylaminopyridine (DMAP), and K2CO3 gave good
yield of 2a. Long reaction time was needed and only low yield
of 2a was obtained when NaOH was used as base. Considering
K2CO3 as an easily available, economical, and toxicologically harm-
less base, we selected it as base to perform this one-pot sequen-
tial synthesis of 2-difluoromethyl-6-trifluoromethylpyridine-3,
5-dicarboxylate.
The reaction was also conducted in various solvents, but all the
reactions were found to proceed slower, and the yields were much
lower, than the reactions performed under solvent-free conditions.
The effects of the temperature on the reaction were examined
under solvent-free conditions in the presence of K2CO3. As shown
in Table 2, the reaction proceeded smoothly at 100 °C, yielding
the expected product in 76% yield. However, increasing or decreas-
ing the temperature would lead to a decrease in yield.
Under these optimized reaction conditions, we investigated the
generality and scope of the one-pot three-component reaction (Ta-
ble 3). In all cases of substituted benzaldehydes, the reaction could
afford 2-trifluoromethyl-6-difluoromethylpyridine-3,5-dicarbox-
ylate 2a–o in good yields.17–19 The electron-withdrawing substitu-
ents on the aromatic ring seemed to be favorable for the reaction.
Heterocyclic aromatic aldehydes, except furan aldehyde, were
good substrates as well. Whereas, when aliphatic aldehydes were
used, the products were obtained in low yields.
As indicated above, quite different results of Hantzsch reaction
of ethyl trifluoroacetoacetate have been obtained under solvent-
free conditions. Therefore, it was of interest for us to compare
the reaction conditions and products of Hantzsch reaction of other
1,3-dicarbonyl substrates (Scheme 3). In the case of ethyl acetoac-
etate, the classic Hantzsch reaction proceeded efficiently in solvent
at reflux and the corresponding product, 1,4-dihydropyridine (I),
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solution was washed with satd aq NaCl solution and dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to leave the crude
product which was purified by chromatography over silica gel.
17. Experimental: All chemicals were purchased commercially and used without
further purification. Melting points were measured in open capillary using
Büchi melting point B540 apparatus and were uncorrected. 1H NMR and 13C
NMR spectra were recorded on a Bruker AM-400 spectrometer (400 MHz and
100 MHz, respectively) using TMS as internal standard. The 19F NMR was
measured with external CF3CO2H as the standard. Gas chromatography (GC)
was recorded on HP 6890 Plus GC instrument and high-resolution mass spectra
(HRMS) were recorded under electron impact conditions using a MicroMass
GCT CA 055 instrument.
18. General procedure for the synthesis of substituted pyridines 2a–o: The mixture of
aldehyde 1 (2 mmol), ethyl trifluoroacetoacetate (4 mmol), ammonium acetate
(2 mmol), and K2CO3 (2 mmol) was stirred at 100 °C until the reaction was
completed (monitored by TLC). Ethyl acetate (5 mL) was added and the
19. Typical data for representative compound: Diethyl 2-difluoromethyl-4-phenyl-
6-trifluoromethylpyridine-3,5-dicarboxylate (2a): Light yellow viscous oil; 1H
1
NMR (CDCl3, 400 MHz): d = 7.49–7.29 (5H, m, PhH), 6.84 (1H, t, JHF = 54.2 Hz,
CHF2), 4.09 (4H, q, J = 7.2 Hz, 2 Â CO2CH2CH3), 1.01 (3H, t, J = 7.6 Hz, CO2CH2
CH3), 0.98 (3H, t, J = 7.2 Hz, CO2CH2CH3) ppm; 13C NMR (CDCl3, 100 MHz):
2
2
d = 164.1, 163.8, 149.8, 148.9 (t, JCF = 26.0 Hz), 143.9 (q, JCF = 35.8 Hz), 133.2,
1
1
131.4, 130.7, 129.7, 128.4, 128.3, 120.5 (q, JCF = 274.3 Hz), 112.7 (t, JCF
=
242.5 Hz), 62.6, 62.5, 13.4 ppm; 19F NMR (CDCl3, 376 MHz): d = À64.9 (3F, s,
–CF3), À115.7 (2F, d, JHF = 54.3 Hz, –CHF2) ppm; HRMS: calcd for C19H16NO4F5
(M+): 417.0999, found: 417.0995.
20. Li, H.; Yu, J.; Cao, S.; Shen, L.; Wu, M.; Cheng, J.; Qian, X. Sci. China Chem. 2010,
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