An efficient three-component domino synthesis of difluoromethyl-containing 1,4-dihydropyridines under solvent and catalyst free conditions

Article abstract of DOI:10.1007/s11426-010-4005-0

The difluoromethyl-containing Hantzsch 1,4-dihydropyridines were synthesized in good yields by a one-pot cyclocondensation of ethyl difluoroacetoacetate (EDFAA), a variety of aromatic aldehydes and ammonium acetate under solvent and catalyst free conditions. The comparison of reaction conditions and products was made among the different 1,3-carbonyl substrates (ethyl acetoacetate, ethyl difluoroacetoacetate and ethyl trifluoroacetoacetate) for the Hantzsch reaction.

Full text of DOI:10.1007/s11426-010-4005-0

SCIENCE CHINA
Chemistry
July 2010 Vol.53 No.7: 1509–1513
doi: 10.1007/s11426-010-4005-0
• ARTICLES •
An efficient three-component domino synthesis of
difluoromethyl-containing 1,4-dihydropyridines under
solvent and catalyst free conditions
LI Hui, YU JinLong, CAO Song*, SHEN Li, WU MingXi,
CHENG JianHang & QIAN XuHong*
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy,
East China University of Science and Technology, Shanghai 200237, China
Received March 15, 2010; accepted May 8, 2010
The difluoromethyl-containing Hantzsch 1,4-dihydropyridines were synthesized in good yields by a one-pot cyclocondensation
of ethyl difluoroacetoacetate (EDFAA), a variety of aromatic aldehydes and ammonium acetate under solvent and catalyst free
conditions. The comparison of reaction conditions and products was made among the different 1,3-carbonyl substrates (ethyl
acetoacetate, ethyl difluoroacetoacetate and ethyl trifluoroacetoacetate) for the Hantzsch reaction.
three-component, difluoromethyl, 1,4-dihydropyridines, ethyl difluoroacetoacetate
difluoroacetoacetate [11]. Herein, we report a novel and
1 Introduction
efficient synthesis of the difluoromethyl-containing 1,4-
dihydropyridines under solvent and catalyst free conditions
without additional dehydrating agent (Scheme 1).
Recently, difluoromethyl-containing compounds have been
increasingly applied in pharmaceuticals, agrochemicals and
other fields as the incorporation of the difluoromethyl group
into biologically active compounds often gives rise to unique
physiological activities [1–6]. Therefore, much effort has
been made to develop novel and efficient methods to intro-
duce the difluoromethyl group into molecules [7, 8]. The
ethyl difluoroacetoacetate is a commercially available di-
fluorinated building block, which can undergo several reac-
tions to form difluoromethyl-containing compounds [8–10].
However, little is known about the reactivity, properties and
products of this useful difluoro-containing building block
when it is used as a component in the multicomponent reac-
tions which is a powerful tool for the construction of diverse
and complex molecules. There are only a few scattered re-
ports concerning three-component reactions based on ethyl
2 Results and discussion
At the initiation of the modified Hantzsch reaction, the
condensation of ethyl difluoroacetoacetate (EDFAA) with
benzaldehyde and ammonium acetate has been selected as a
model reaction to investigate the reaction conditions
(Scheme 2). Generally, the catalyst plays a key role in de-
termining the speed of the conventional Hantzsch reaction
[12, 13]. However, our preliminary experiments showed
that the reaction could proceed efficiently in the absence of
the catalyst and the reaction time was not significantly
shortened in the presence of catalysts such as piperidine.
The next step in our study was to focus on the search for the
optimum reaction conditions.
*Corresponding author (email: scao@ecust.edu.cn; xhqian@ecust.edu.cn)
Recently, much of our effort has involved the development
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
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LI Hui, et al. Sci China Chem July (2010) Vol.53 No.7
Scheme 1 Synthesis of difluoromethyl containing 1,4-dihydropyridines 3a–k under solvent and catalyst free conditions.
Scheme 2 Model reaction for the synthesis of 3a under solvent and catalyst free conditions.
of the multicomponent reactions such as Hantzsch reaction
under solvent-free conditions [14–17]. Thus, the first ex-
periments were conducted at different temperatures under
solvent-free conditions. Table 1 shows the yields of prod-
ucts were strongly dependent on the temperature. The
higher yield was obtained at 100 °C, whereas a further in-
crease in temperature showed no improvement in the yield.
Although the desired product was also obtained in boiling
ethanol, long reaction time has been required and the yield
was unsatisfactory.
In addition, effects of the molar ratio of benzaldehyde to
EDFAA to ammonium acetate on this reaction were also
investigated. It was found that when the molar ratio was
1:2.4:1, the reaction was finished within 5 h to give satis-
factory yield (83%) at 100 °C under solvent-free condition.
An increase in the amount of EDFAA or ammonium acetate
could not enhance the yield of the product.
aliphatic and aromatic aldehydes could give good yields of
1,4-dihydropyridines. Furthermore, the presence of electron-
withdrawing or electron-donating substituents on the aro-
matic ring did not make any difference in the yield of the
product.
For comparison, the reaction conditions and products of
different types of 1,3-dicarbonyl substrates (ethyl acetoace-
tate, ethyl difluoroacetoacetate and ethyl trifluoroacetoace-
tate) for the Hantzsch reaction are summarized in Scheme 3.
When ethyl acetoacetate served as the substrate, cyclization
reaction took place with low selectivity and low yield at
80 °C under solvent-free condition and gave mixtures of
1,4- and 1,2-dihydropyridine [17]. The classical 1,4-dihy-
dropyridine (III) was the major product when the reaction
was conducted in the presence of the catalysts under stan-
dard Hantzsch conditions. In the case of ethyl trifluoroace-
toacetate, the corresponding 2,6-bis(trifluoromethyl)-2,6-
dihydroxy-4-phenyl-3,5-pip-eridinedicarboxylate (II) was
obtained in refluxing ethanol for several hours. This inter-
mediate could be further dehydrated to 1,4-dihydropyridine
(IV) by using suitable dehydration agents such as sulfuric
acid, toluenesulfonic acid and trifluoroacetic anhydride [18,
19]. As to our work in this paper, no matter what the reac-
tion conditions were, under reflux conditions or solvent free
conditions, the reaction of ethyl difluoroacetoacetate with
aldehyde and ammonium acetate yielded the 1,4-DHP
product in good yield in the absence of catalysts. The unde-
sired products such as undehydrated products and the iso-
mers of 1,4-dihydropyridine were not observed. Scheme 3
shows the number of fluorine atoms on methyl group in
ethyl acetoacetate has a significant impact on the process of
Hantzsch reaction and the formation of products.
Under the optimized reaction condition, a variety of al-
dehydes were used to react with EDFAA and ammonium
acetate to synthesize the desired 1,4-dihydropyridines. Both
Table 1 Yields for the synthesis of 3a under the solvent-free condition at
different temperatures
Temperature (°C)
Solvent
ethanol
neat
Time (h)
>24
>48
>48
>48
12
Yield (%) a,b)
reflux
rt
72
15
30
47
68
80
81
40
neat
60
neat
80
neat
100
120
neat
5
In conclusion, we report an efficient and practical ap-
proach to the synthesis of difluoromethyl-containing 1,4-
dihydropyridines through a solvent and catalyst free one-pot
neat
5
a) Yields were based on GC analysis; b) the molar ratio of benzaldehyde
to EDFAA to ammonium acetate is 1:2:1.

LI Hui, et al. Sci China Chem July (2010) Vol.53 No.7
1511
Scheme 3 The comparison of reaction conditions and products among the different 1,3-carbonyl substrates for the Hantzsch reaction.
three-component condensation of ethyl difluoroacetoacetate,
aldehydes and ammonium acetate without additional dehy-
drating agent.
The mixture was stirred at 100 °C for 4–5 h until the reac-
tion was completed (monitored by TLC). Then, the reaction
mixture was treated with brine solution (10 mL), extracted
with dichloromethane (3 × 10 mL) and dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to
leave the crude product which was purified by chromatog-
raphy over silica gel.
3 Experimental
3.1 Materials and instruments
Diethyl 2,6-bis(difluoromethyl)-4-phenyl-1,4-dihydro pyri-
dine-3,5-dicarboxylate (3a)
All reagents were of analytic grade and obtained from
commercial suppliers and used without further purification.
Melting points were measured in an open capillary using
Büchi melting point B-540 apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded on a Bruker
AM-400 spectrometer (400 MHz and 100 MHz, respec-
tively) using TMS as the internal standard. The 19F NMR
was obtained using a Bruker AM-400 spectrometer (376
MHz) and measured with external CF3CO2H as the standard.
CDCl3 was used as NMR solvent for all cases. Gas chro-
matography-mass spectra (GC-MS) were recorded on HP
5973 MSD with 6890 GC. High resolution mass spectra
(HRMS) were recorded under electron impact conditions
using a MicroMass GCT CA 055 instrument and recorded
on a MicroMass LCTTM spectrometer. Column chroma-
tography was carried out with Merck 60 (230–400 mesh)
silica gel.
Yield 75% (isolated yield and the same below), white solid,
1
mp 88.1–88.3 °C. H NMR:  = 1.26 (t, J = 7.2 Hz, 6H),
4.13–4.21 (m, 4H), 5.10 (s, 1H), 7.07 (s, 1H), 7.21–7.29 (m,
5H), 7.44 (t, JHF = 54.4 Hz, 2H) ppm; 13C NMR:  = 14.0,
39.7, 61.2, 108.4 (t, 3JCF =5.6 Hz), 108.9 (t, 1JCF =239.4 Hz),
2
127.4, 128.1, 128.5, 137.4 (t, JCF = 22.1 Hz), 144.8, 165.0
ppm; 19F NMR:  = 121.5 (d, J = 54.4 Hz, 2F), 121.8 (d,
J = 54.4 Hz, 2F) ppm; HRMS (EI) for C19H19F4NO4, calcd:
401.1250, found: 401.1251.
Diethyl 2,6-bis(difluoromethyl)-4-(4-methylphenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (3b)
1
Yield 77%, white solid, mp 92.1–92.4 °C. H NMR:  =
1.27 (t, J = 7.1 Hz, 6H), 2.31 (s, 3H), 4.13–4.20 (m, 4H),
5.05 (s, 1H), 7.03 (s, 1H), 7.08–7.18 (m, 4H), 7.42 (t, JHF
=
54.2 Hz, 2H) ppm; 13C NMR:  = 14.0, 21.1, 39.2, 61.1,
3
1
108.4 (t, JCF = 5.7 Hz), 108.9 (t, JCF = 239.5 Hz), 128.0,
3.2 General procedure for the synthesis of 3a–k
2
129.2, 137.1, 137.2 (t, JCF = 22.0 Hz), 141.9, 165.1 ppm;
19F NMR:  = 121.5 (d, J = 54.2 Hz, 2F), 121.8 (d, J =
To a stirred ethyl difluoroacetoacetate (2.4 mmol), aldehyde
(1 mmol) and ammonium acetate (1.2 mmol) were added.
54.2 Hz, 2F) ppm; HRMS (EI) for C20H21F4NO4, calcd:

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LI Hui, et al. Sci China Chem July (2010) Vol.53 No.7
ppm; 13C NMR:  = 14.1, 37.1, 61.3, 107.7 (t, 3JCF =5.6 Hz),
415.1407, found: 415.1346.
108.7 (t, 1JCF = 241.3 Hz), 121.5, 130.7, 132.2, 132.6, 133.5,
2
137.9 (t, JCF = 22.2 Hz), 142.1, 164.8 ppm; 19F NMR:  =
Diethyl 2,6-bis(difluoromethyl)-4-(4-bromophenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (3c)
121.9 (s, 2F), 121.0 (s, 2F) ppm; HRMS (EI) for
C19H17BrClF4NO4, calcd: 514.6932, found: 514.9946.
1
Yield 70%, white solid, mp 85.9–86.8 °C. H NMR:  =
1.26 (t, J = 7.1 Hz, 6H), 4.13–4.22 (m, 4H), 5.06 (s, 1H),
7.05 (s, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.4 Hz,
2H), 7.42 (t, JHF = 54.2 Hz, 2H) ppm; 13C NMR:  = 14.0,
39.4, 61.3, 107.9 (t, 3JCF =5.7 Hz), 108.8 (t, 1JCF =239.7 Hz),
Diethyl 2,6-bis(difluoromethyl)-4-(2,3-difluorophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3h)
1
Yield 68%, white solid, mp 112.0–113.7 °C. H NMR:  =
2
121.4, 129.8, 131.6, 137.6 (t, JCF = 22.2 Hz), 143.7, 164.8
1.23 (t, J = 7.2 Hz, 6H), 4.13–4.16 (m, 4H), 5.42 (s, 1H),
ppm; 19F NMR:  = 121.6 (d, J = 54.2 Hz, 2F), 121.7 (d,
J = 54.2 Hz, 2F) ppm; HRMS (EI) for C19H18BrF4NO4,
calcd: 479.0355, found: 479.0357.
7.00–7.11 (m, 4H), 7.43 (t, JHF = 54.4 Hz, 2H) ppm; 13C
3
NMR:  = 13.7, 33.9, 61.3, 106.9 (t, JCF =5.6 Hz), 108.6 (t,
1JCF = 239.7 Hz), 116.1 (d, J = 17.4 Hz), 124.1 (dd, J1 = 4.8
Hz, J2 = 6.6 Hz), 125.4, 134.8 (d, J=11.0 Hz), 138.2 (t, 2JCF
= 22.2 Hz), 149.1 (dd, J1 = 13.2 Hz, J2 =30.1 Hz), 151.7 (d,
J = 13.6 Hz), 164.7 ppm; 19F NMR:  = 122.1 (s, 2F),
122.3 (s, 2F), 138.9 (d, J = 18.7 Hz, 1F), 141.4 (d, J =
20.6 Hz, 1F) ppm; HRMS (EI) for C19H17F6NO4, calcd:
437.1062, found: 437.1063.
Diethyl 2,6-bis(difluoromethyl)-4-(4-methoxyphenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (3d)
1
Yield 73%, white solid, mp 81.8–82.1 °C. H NMR:  =
1.26 (t, J = 7.1 Hz, 6H), 3.78 (s, 3H), 4.12–4.21 (m, 4H),
5.07 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.02 (s, 1H), 7.19 (d,
J = 8.6 Hz, 2H), 7.42 (t, JHF = 54.3 Hz, 2H) ppm; 13C NMR:
3
 = 14.0, 38.8, 55.2, 61.1, 108.6 (t, JCF = 5.7 Hz), 109.0 (t,
Diethyl 2,6-bis(difluoromethyl)-4-(4-chloro-2-(trifluoromethyl)
2
1JCF = 240.8 Hz), 113.8, 129.2, 137.1 (t, JCF = 22.0 Hz),
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3i)
158.9, 165.1 ppm; 19F NMR: =121.5 (d, J=54.3 Hz, 2F),
121.7 (d, J = 54.3 Hz, 2F) ppm; HRMS (EI) for C20H21F4-
NO5, calcd: 431.1356, found: 431.1359.
1
Yield 76%, white solid, mp 88.6–89.4 °C. H NMR:  =
1.22 (t, J = 7.1 Hz, 6H), 4.05–4.28 (m, 4H), 5.71 (s, 1H),
7.10 (s, 1H), 7.24–7.56 (m, 5H) ppm; 13C NMR:  = 13.8,
35.3 (q, J=3.7 Hz), 61.4, 108.8 (t, 1JCF =241.2 Hz), 109.0 (t,
3JCF = 5.6 Hz), 122.6 (q, J = 275.3 Hz),127.1 (q, J=5.1 Hz),
Diethyl 2,6-bis(difluoromethyl)-4-(4-fluorophenyl)-1-dihy-
2
dropyridine-3,5-dicarboxylate (3e)
128.6 (q, J = 31.1 Hz), 132.7, 132.9, 133.8, 137.7 (t, JCF
=
1
22.3 Hz), 142.3, 164.8 ppm; 19F NMR:  = 56.1 (s, 3F),
121.7 (d, J=54.1 Hz, 2F), 121.9 (d, J=54.1 Hz, 2F) ppm;
HRMS (EI) for C20H17ClF7NO4, calcd: 503.0734, found:
503.0737.
Yield 65%, white solid, mp 81.5–82.0 °C. H NMR:  =
1.25 (t, J = 7.1 Hz, 6H), 4.13–4.22 (m, 4H), 5.07 (s, 1H),
7.02 (s, 1H), 6.94–7.26 (m, 4H), 7.42 (t, JHF = 54.4 Hz, 2H)
ppm; 13C NMR:  = 14.0, 39.0, 61.2, 108.2 (t, 3JCF =5.6 Hz),
108.9 (t, 1JCF = 239.6 Hz), 115.2 (d, J=21.3 Hz), 129.6 (d, J
2
Diethyl 2,6-bis(difluoromethyl)-4-propyl-1,4-dihydropyridine-
= 8.0 Hz), 137.4 (t, JCF = 22.1 Hz), 140.6, 160.8, 163.3,
164.8 ppm; 19F NMR:  = 114.9– 115.0 (m, 1F), 121.6
(d, J = 54.3 Hz, 2F), 121.7 (d, J=54.3 Hz, 2F) ppm; HRMS
(EI) for C19H18F5NO4, calcd: 419.1156, found: 419.1157.
3,5-dicarboxylate (3j)
1
Yield 70%, oil. H NMR:  = 0.87 (t, J = 7.1 Hz, 3H),
1.22–1.40 (m, 10H), 4.05 (t, J = 5.7 Hz, 1H), 4.21–4.31 (m,
4H), 7.03 (s, 1H), 7.36 (t, JHF =54.3 Hz, 2H) ppm; 13C NMR:
 = 13.9, 14.1, 17.6, 33.1, 38.0, 61.0, 107.9 (t, 3JCF =5.7 Hz),
Diethyl 2,6-bis(difluoromethyl)-4-(3-cyanophenyl)-1,4-dihy-
1
2
dropyridine-3,5-dicarboxylate (3f)
108.8 (t, JCF = 240.2 Hz), 138.5 (t, JCF = 22.0 Hz), 165.4
ppm; 19F NMR:  = 121.3 (d, J = 54.3 Hz, 2F), 121.4 (d,
J = 54.3 Hz, 2F) ppm; HRMS (EI) for C16H21F4NO4, calcd:
367.1407, found: 367.1408.
1
Yield 75%, white solid, mp 141.3–142.7 °C. H NMR:  =
1.25 (t, J = 7.0 Hz, 6H), 4.13–4.21 (m, 4H), 5.13 (s, 1H),
7.15 (s, 1H), 7.38–7.56 (m, 6H) ppm; 13C NMR:  = 14.0,
39.7, 61.5, 107.4 (t, 3JCF =5.6 Hz), 108.7 (t, 1JCF =241.5 Hz),
2
Diethyl 2,6-bis(difluoromethyl)-4-ethyl-1,4-dihydropyridine-
3,5-dicarboxylate (3k)
112.5, 118.7, 129.5, 131.1, 131.8, 132.6, 138.1 (t, JCF
=
22.3 Hz), 146.1, 164.5 ppm; 19F NMR:  = 121.6 (s, 2F),
121.7 (s, 2F) ppm; HRMS (EI) for C20H18F4N2O4, calcd:
426.1203, found: 426.1205.
Yield 70%, oil. 1H NMR: =0.84 (t, J=7.5 Hz, 3H), 1.35 (t,
J = 7.1 Hz, 6H), 1.44–1.51 (m, 2H), 4.04 (t, J=5.4 Hz, 1H),
4.21–4.36 (m, 4H), 7.01 (s, 1H), 7.40 (t, JHF = 54.3 Hz, 2H)
ppm; 13C NMR:  = 8.7, 14.1, 28.4, 34.4, 61.0, 107.3 (t, 3JCF
Diethyl 2,6-bis(difluoromethyl)-4-(4-bromo-2-chlorophenyl)-
1
2
1,4-dihydropyridine-3,5-dicarboxylate (3g)
= 5.6 Hz), 108.8 (t, JCF = 240.2 Hz), 138.6 (t, JCF = 22.0
Hz), 165.4 ppm; 19F NMR:  = 121.2 (d, J = 54.3 Hz, 2F),
121.3 (d, J = 54.3 Hz, 2F) ppm; HRMS (EI) for
C15H19F4NO4, calcd: 353.1250, found: 353.1261.
1
Yield 65%, white solid, mp 88.7–89.0 °C. H NMR:  =
1.24 (t, J = 7.2 Hz, 6H), 4.12–4.20 (m, 4H), 5.51 (s, 1H),
7.10 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.34–7.54 (m, 4H)

LI Hui, et al. Sci China Chem July (2010) Vol.53 No.7
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This work was supported by the National Basic Research Program of
China (2010CB126101), Shanghai Foundation of Science and Technology
(09391911800), the National High Technology Research and Development
Program of China (2006AA10A201), and the Shanghai Leading Academic
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