An effcient synthesis of 1,4-dihydro-6-trifluoromethylpyridines: A facile and useful method for dehydration of α-trifluoromethyl alcohols by use of phosphorous oxychloride/pyridine adsorbed on silica gel

Article abstract of DOI:10.3987/COM-06-10827

The treatment of α-alkoxycarbonyl-α,β-unsaturated trifluoromethyl ketones (1) with β-aminocrotonates (2) affords 2-hydroxy-6-methyl-2-trifluoromethyl-1,2,3,4-tetrahydropyridines (3), which undergo facile dehydration by use of phosphorus oxychloride / pyri

Full text of DOI:10.3987/COM-06-10827

HETEROCYCLES, Vol. 68, No. 10, 2006
2087
HETEROCYCLES, Vol. 68, No. 10, 2006, pp. 2087 - 2096. © The Japan Institute of Heterocyclic Chemistry
Received, 27th June, 2006, Accepted, 28th August, 2006, Published online, 29th August, 2006. COM-06-10827
AN
EFFCIENT
SYNTHESIS
OF
1,4-DIHYDRO-6-
TRIFLUOROMETHYLPYRIDINES: A FACILE AND USEFUL METHOD
FOR DEHYDRATION OF α-TRIFLUOROMETHYL ALCOHOLS BY USE
OF PHOSPHOROUS OXYCHLORIDE / PYRIDINE ADSORBED ON
SILICA GEL
Isamu Katsuyama,* Kazumasa Funabiki, Masaki Matsui, Hiroshige
Muramatsu, and Katsuyoshi Shibata
Department of Chemistry, Faculty of Engineering, Gifu University, 1-1 Yanagido,
Gifu 501-1193, Japan
*
Present address: Hitec Co., Ltd, OAP 25F, 1-8-30 Temmabashi, Kita-ku,
Osaka-shi, Osaka 530-6025, Japan E-mail: katsuyama_i@ybb.ne.jp
Abstract – The treatment of α-alkoxycarbonyl-α,β-unsaturated trifluoromethyl
ketones (1) with β-aminocrotonates (2) affords 2-hydroxy-6-methyl-2-
trifluoromethyl-1,2,3,4-tetrahydropyridines (3), which undergo facile dehydration
by use of phosphorus oxychloride / pyridine adsorbed on silica gel, giving good
to high yields of 1,4-dihydro-2-methyl-6-trifluoromethylpyridines (4).
INTRODUCTION
Since the discovery of nifedipine®, which is a clinically important antihypertensive and antiangina drug,
much interest has been led to the synthesis of substituted 1,4-dihydropyridines and their ability as
1
therapeutic agents for cardiovascular ailments. This class of compounds is known to indicate its
biological effects by the inhibition of calcium ion influx across the cell membrane through slow calcium
2
channels. On the other hand, the introduction of a trifluoromethyl group into a biomolecule has
3
sometimes resulted in an improvement in its biological activity. Therefore, trifluoromethyl-substituted
1
,4-dihydropyridines have been worthy of remark for their potential biological properties.
Furthermore, they can be utilized as intermediates for the synthesis of trifluoromethyl-substituted
4
pyridines.

2088
HETEROCYCLES, Vol. 68, No. 10, 2006
NO2
MeO C
CO Me
2
2
H C
3
N
H
CH3
Nifedipine
This paper describes an efficient synthesis of trifluoromethyl-substituted derivatives (4) for
1
,4-dihydropyridine-3,5-dicarboxylates of the nifedipine® type.
1
R
2
3
R O C
CO R
2
2
F3C
N
CH3
H
4
RESULTS AND DISCUSSION
No efficient methods have been reported for the synthesis of unsymmetrical fluorine-containing
dihydropyridines such as 4. The previous methods such as Hantzsch conditions have the following three
disadvantages: (i) unsymmetrical dihydropyridines are often more difficult to prepare than their
symmetrical counterparts due to the formation of all the possible isomeric Hantzsch condensation
5
6
products. (ii) the intermediate hydroxytetrahydropyridines (3) seem to be very stable, and accordingly
7
difficult to dehydrate under the standard Hantzsch conditions. (iii) the intermediates (3) and desired
products (4) appear to be unstable for strong agents due to the presence of esters. (Scheme 1). In order
to improve the disadvantage (i), α-alkoxycarbonyl-α,β-unsaturated trifluoromethyl ketones (1) were
chosen as a starting material for the synthesis of 4: the ketones 1 were prepared by the reaction of
aldehydes with 4,4,4-trifluoroacetoacetates or by that of the Schiff bases for the aldehydes with the
8
acetoacetates.
1
1
1
R
R
R
O
2
3
2
3
3
2
R O C
CO R Hantzsch conditions R O C
CO R
CO R
2
2
2
2
R O C
2
2
HO
+
F3C
N
H
CH3
F3C
N
H
4
CH3
H N
2
CH3
F3C
1
2
3
strong agents
4
several by-products
Scheme 1

HETEROCYCLES, Vol. 68, No. 10, 2006
2089
The reaction of the trifluoromethyl ketone (1a) with β-aminocrotonate (2a) gave a quantitative yield of
the intermediate hydroxytetrahydropyridine (3a), which did not undergo dehydration in the absence of
catalysts in boiling alcohol (standard Hantzsch conditions) (Table 1, Entry 1). Here, it was confirmed
9
that a dehydration reagent is essential for the synthesis of 4. The dehydration of 3a using several agents
1
0
was then attempted for the synthesis of 4a. The use of usual catalysts resulted in both a moderate
consumption of 3a and formation of 4a in a low yield (Table 1, Entries 2-4). The reaction using other
1
1
reagents led to the satisfactory consumption of 3a. These conditions, however, gave only a low to
moderate yield of 4a (Table 1, Entries 5-6). In addition, most of the above methods require hazardous
reagents and aqueous workup procedure that are detrimental to the environment. Therefore, another
procedure was investigated for this reaction.
Ph
CO Et
EtO C
2
2
Solvent
H N
2
CH3
F3C
Ph
O
1a
2a
Ph
EtO C
CO Et
EtO C
CO Et
2
2
2
2
reagent
Solvent
HO
F3C
N
H
CH3
F3C
N
H
CH3
3a
4a
Table 1 Synthesis of CF -Dihydropyridine under Various Conditions
3
Timea
b
Yield / %
Entry
Reagent
Solvent
Temperature
/h
3a
4a
1
2
3
4
5
6
7
8
EtOH
MeOH
EtOH
reflux
reflux
reflux
5-10°C
reflux
rt
6
2
3
1
3
3
3
3
98
50
trace
14
8
conc.HCl
H PO
3
4
50
conc.H SO
CH Cl
2
2
54
14
31
57
39
91
2
4
p-TsOH
EtOH
trace
trace
trace
trace
(CF CO) O
(CH Cl)
2
2
2
2
3
2
POCl /C H N
(CH Cl)
2
reflux
reflux
3
5 5
POCl /C H N-SiO
2
(CH Cl)
2
3
5
5
a
Dehydration time. b Isolated yields referred to 1a.
Phosphorus oxychloride or thionyl chloride/ pyridine is known to be a good dehydration system and
1
2
therefore is often used for the dehydration of alcohols.
However, this system usually require large
excess amount of phosphorus oxychloride or thionyl chloride and pyridine; this is inconvenient to
manipulate and may cause severe bodily harm because of quite strong corrosion. Thus, the dehydration

2090
HETEROCYCLES, Vol. 68, No. 10, 2006
of 3a using small excess amount of the reagents was attempted for the synthesis of 4a. However, at rt
no reaction proceeded while at higher temperature 4a was obtained only in a low yield (Table 1, Entry 7).
During the further studies, phosphorus oxychloride / pyridine adsorbed on silica gel (POCl /C H N-SiO )
3
5
5
2
has been found to be an efficient reagent for the synthesis of 4a via the dehydration of 3a (Table 1, Entry
). The high yield was due to both a satisfactory consumption of 3a and a decrease in the amount of
8
by-products. Moreover, it was found that this reagent does not have severe stimulating smell in contrast
to POCl /C H N; this is convenient to manipulate.
3
5
5
1
1
R
R
3
2
3
2
CO R
R O C
CO R
R O C
2
2
2
2
1) (CH Cl) , reflux
2 2
+
H N
CH3
2) POCl /C H N-SiO
2
F3C
N
H
4
CH3
F3C
O
2
3
5
5
1
2
Table 2 One-pot Synthesis of 1,4-Dihydro-2-methyl-6-trifluoromethylpyridines (4)
R1
R2
R3
Timea/
h
Product
/%
Yieldb
4
4
4
4
4
a
b
c
d
e
91
77
76
73
77
80
78
91
80
88
Ph
Et
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Me
Et
Et
3
5
5
6
3
5
6
6
4
6
2
2
2
2
2
3
3
2
2
-ClC H
6
4
4
-ClC H
6
-CF C H
6 4
3
-NO C H
2
6
4
4
4
4
4f
4j
-NO C H
2
6
-NO C H
2
6
4h
4i
-NO C H
2
6
-Furyl
4j
-Thienyl
a
Dehydration time. b Isolated yields referred to 1.
Table
trifluoromethylpyridines (4) via the dehydration of the intermediate (3) by use of POCl /C H N-SiO
2
2
summarizes the results of the one-pot synthesis of 1,4-dihydro-2-methyl-6-
3
5
5
starting from 1. In every case, the desired dihydropyridines (4) were obtained in good to high yields.
It is worthy to notice that reactive functional groups such as esters are found to be stable under the
reaction conditions.
Scheme
2
shows
a
possible mechanism for the synthesis of 1,4-dihydro-2-methyl-6-
trifluoromethylpyridines (4) via the dehydration of 3 by use of POCl /C H N-SiO . In the present
3
5
5
2
conditions, most of 3 and POCl /C H N are presumably adsorbed on the silica surface although the latter
3
5
5
would present as the coordinated pyridine complex in a solution. The first step involves the
condensation of 3 in the liquid phase with POCl activated by the silanol group. The resulting
3

HETEROCYCLES, Vol. 68, No. 10, 2006
2091
intermediates (5) undergo the addition of the chlororide and the elimination of the phosphoric moiety,
yielding the chlorination derivatives (6) along with HPO Cl . The dehydrochlorination of 6 provides the
2
2
dihydropyridines (4). The adsorption of POCl and HPO Cl on SiO can prevent the formation of
3
2
2
2
by-products arising from the addition of these phosphoric compounds to 3, 4, 5, or 6.
1
R
Cl
Cl
Cl
N
H
CF3
NH
P
1
R
H
O
H
CF3
NH
2
O
R O C
1
2
H
H
3
R
2
OH
R O C
2
Cl
CF3
Cl
Cl
Cl
H
H
Cl
Cl
5
P
P
2
O
N
O
H
N
N
O
H
R O C
2
H
O
H
H
H
H
O H
O
O
H
O
O
O
SiO2
SiO2
1
R
H
H
CF3
2
NH
Cl
R O C
2
1
R
6
H
H
CF3
Cl
Cl
2
N
R O C
O P
H
2
H
Cl
H
O
O
H
N
H
O
O
H
O
SiO2
-
HCl
1
R
NH
H
2
R O C
CF3
2
4
1
R
N
H
H
ClH
H
2
N
R O C
CF3
2
H
O
H
O
O Cl PH
2
2
H
O
H
N
O
O
SiO2
Scheme 2

2092
HETEROCYCLES, Vol. 68, No. 10, 2006
In conclusion, 1,4-dihydro-6-trifluoromethylpyridines have successfully been synthesized by use of
phosphorus oxychloride / pyridine adsorbed on silica gel (POCl /C H N-SiO ), which has been developed
3
5
5
2
as an efficient reagent for the dehydration of α-trifluoromethyl alcohols. The significant advantages
offered by this method are: (i) the reagent can be readily handled, (ii) the procedure does not require
aqueous workup and large excess amount of dehydration reagent, (iii) it is compatible with a sensitive
functional group. Thus, this method is expected to provide wide application in particular when the
dehydration of α-trifluoromethyl alcohols is required in complex molecules containing sensitive
functional groups.
EXPERIMENTAL
All the commercially available reagents were used without further purification. Melting points were
measured with a Yanagimoto MP-S2 micro melting point apparatus and are uncorrected. Infrared (IR)
1
spectra were measured with a Perkin Elmer FT-IR 1640 spectrometer. H NMR spectra were recorded
19
with a JEOL α-400 spectrometer using tetramethylsilane (TMS) as an internal standard.
F NMR
spectra were obtained on the same apparatus using trifluoroacetic acid (TFA) as an external standard.
Mass (MS) spectra (EI, 70 eV) were obtained on a Shimadzu QP-1000 spectrometer. Starting materials
8
(
1) were prepared by using the method described in our previous papers. Phosphorus oxychloride /
1
3
pyridine adsorbed on silica gel (POCl /C H N-SiO ) was prepared by the following our procedure.
3
5
5
2
General Procedure for the Preparation of POCl /C H N-SiO : To a solution of phosphorus
3
5
5
2
oxychloride (3mL) and pyridine (6mL) in CHCl (50mL) was slowly added silica gel (MerckArt.7734,20g)while
2
2
being cooled. The mixture was stirred for 1 h at rt. After removal of the solvent, the residue was dried
in a rotary evaporator over a period of several hours.
General Procedure for the Synthesis of 1,4-Dihydro-6-trifluoromethyl-pyridines (4): A solution of
α-alkoxycarbonyl-α,β-unsaturated trifluoromethyl ketones (1) (1 mmol) and β-aminocrotonates (2) (1
mmol) in dichloroethane (4 mL) was refluxed for 2-3 h. Phosphorus oxychloride / pyridine adsorbed on
silica gel (0.9 g; ca.1mmol based on POCl /C H N) was then added, and the mixture was further refluxed
3
5
5
while being stirred until 3 was consumed as monitored by GLC analysis. After removal of the solvent,
the residue was chromatographed on silica gel using CH Cl /CH CO Et (20 /1) as an eluent. Spectral
2
2
3
2
data of 4 are shown bellow.
Diethyl 1,4-Dihydro-2-methyl-4-phenyl-6-(trifluoromethyl)pyridine-3,5-dicarboxylate (4a): mp
-
1
1
1
2
11-112 °C (hexane/Et O); IR (Nujol)ν 3356, 1707 cm ; H NMR (CDCl ) δ 1.21 (t, J = 7.2 Hz, 6H),
2
3
19
.39 (s, 3H), 4.12 (m, 4H), 5.05 (s, 1H), 6.05 (br s, 1H), 7.18-7.26 (m, 5H); F NMR (CDCl ) δ 14.25 (s,
3

HETEROCYCLES, Vol. 68, No. 10, 2006
2093
+
3
5
F); MS m/z (%) 383 (M , 5), 306 (100), 278 (15), 183 (18). Anal. Calcd for C H NO F : C, 59.53; H,
19 20 4 3
.26; N, 3.65. Found: C, 59.28; H, 5.17; N, 3.70.
Diethyl
4-(2-Chlorophenyl)-1,4-dihydro-2-methyl-6-(trifluoromethyl)-pyridine-3,5-dicarboxylate
-
1 1
(
4b): mp 119-120 °C (hexane/Et O); IR (Nujol)ν 3311, 1708 cm ; H NMR (CDCl ) δ 1.15 (t, J = 7.1 Hz,
2 3
3
H), 1.18 (t, J = 7.1 Hz, 3H), 2.39 (s, 3H), 4.04 (m, 2H), 4.13 (m, 2H), 5.05 (s, 1H), 5.89 (br s, 1H), 7.12
(
td, J = 7.7, 1.6 Hz, 1H), 7.20 (td, J = 7.7, 1.6 Hz, 1H), 7.28 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 (dd, J = 7.7,
19
+
1
.6 Hz, 1H); F NMR (CDCl ) δ 13.28 (s, 3F); MS m/z (%) 417 (M , 3), 306 (100), 278 (16), 182 (19).
3
Anal. Calcd for C H NO ClF : C, 54.62; H, 4.58; N, 3.35. Found: C, 54.37; H, 4.51; N, 3.40.
1
9
19
4
3
3
-Ethyl
5-Methyl
4-(2-Chlorophenyl)-1,4-dihydro-2-methyl-6-(trifluoromethyl)pyridine-3,5-
-1
1
dicarboxylate (4c): mp 116-117 °C (hexane/Et O); IR (Nujol)ν 3381, 1703 cm ; H NMR (CDCl ) δ
2
3
1
.15 (t, J = 7.1 Hz, 3H), 2.40 (s, 3H), 3.67 (s, 3H), 4.05 (m, 2H), 5.49 (s, 1H), 5.91 (br s, 1H), 7.12 (td, J
7.7, 1.6 Hz, 1H), 7.20 (td, J = 7.7, 1.6 Hz, 1H), 7.29 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (dd, J = 7.7, 1.6 Hz,
=
1
9
+
1
H); F NMR (CDCl ) δ 13.28 (s, 3F); MS m/z (%) 403 (M , 7), 374 (23), 292 (100), 244 (22). Anal.
3
Calcd for C H NO ClF : C, 53.54; H, 4.24; N, 3.47. Found: C, 53.39; H, 4.14; N, 3.60.
18
17
4
3
Diethyl
1,4-Dihydro-2-methyl-6-(trifluoromethyl)-4-[(2-trifluoromethyl)-phenyl]pyridine-3,5-
-
1
1
dicarboxylate (4d): mp 95-96 °C (hexane/Et O); IR (Nujol)ν 3315, 1703 cm ; H NMR (CDCl ) δ
2
3
1
1
.08 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H), 2.42 (s, 3H), 3.96-4.13 (m, 4H), 5.41 (s, 1H), 5.78 (br s,
1
9
+
H), 7.32-7.57 (m, 4H); F NMR (CDCl ) δ 12.73 (s, 3F), 21.11 (s, 3F); MS m/z (%) 451 (M , 9), 306
3
(
100), 278 (20). Anal. Calcd for C H NO F : C, 53.22; H, 4.24; N, 3.10. Found: C, 52.85; H, 4.14; N,
20 19 4 6
3
.15.
Diethyl 1,4-Dihydro-2-methyl-4-(2-nitrophenyl)-6-(trifluoromethyl)-pyridine-3,5-dicarboxylate (4e):
-
1 1
mp 113-115 °C (hexane/Et O); IR (Nujol)ν 3359, 1707 cm ; H NMR (CDCl ) δ 1.09 (t, J = 7.1 Hz, 3H),
2
3
1
.20 (t, J = 7.1 Hz, 3H), 2.40 (s, 3H), 3.92-4.20 (m, 4H), 5.75 (s, 1H), 5.92 (br s, 1H), 7.32-7.78 (m, 4H);
1
9
+
F NMR (CDCl ) δ 12.87 (s, 3F); MS m/z (%) 428 (M , 6), 411 (100), 352 (35), 338 (70), 322 (28). Anal.
3
Calcd for C H N O F : C, 53.27; H, 4.47; N, 6.54. Found: C, 53.18; H, 4.37; N, 6.56.
19
19
2
6 3
5
-Ethyl
3-Methyl
1,4-Dihydro-2-methyl-4-(2-nitrophenyl)-6-(trifluoromethyl)pyridine-3,5-
-1
1
dicarboxylate (4f): mp 127-128 °C (hexane/i-Pr O); IR (Nujol)ν 3312, 1736 cm ; H NMR (CDCl ) δ
2
3
1
1
.20 (t, J = 7.2 Hz, 3H), 2.39 (s, 3H), 3.53 (s, 3H), 3.53 (s, 3H), 4.10-4.22 (m, 2H), 5.68 (s, 1H), 5.90 (br s,
1
9
+
H), 7.32-7.74 (m, 4H); F NMR (CDCl ) δ 13.03 (s, 3F); MS m/z (%) 414 (M , 5), 397 (100), 352
3
(
28), 338 (70), 324 (33), 322 (23). Anal. Calcd for C H N O F : C, 52.18; H, 4.14; N, 6.76. Found: C,
18 17 2 6 3
5
1.89; H, 4.03; N, 6.71.

2094
HETEROCYCLES, Vol. 68, No. 10, 2006
Diethyl
1,4-Dihydro-2-methyl-4-(3-nitrophenyl)-6-(trifluoromethyl)-pyridine-3,5-dicarboxylate
-1
1
(
4g): mp 103-104 °C (hexane/Et O); IR (Nujol)ν 3341, 1709 cm ; H NMR (CDCl ) δ 1.23 (t, J = 7.2
2 3
Hz, 6H), 2.44 (s, 3H), 4.07-4.20 (m, 4H), 5.17 (s, 1H), 6.23 (br s, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.63 (d, J
1
9
+
=
7.9 Hz, 1H), 8.06-8.13 (m, 2H); F NMR (CDCl ) δ 14.30 (s, 3F); MS m/z (%) 428 (M , 4), 306
3
(
100), 278 (21). Anal. Calcd for C H N O F : C, 53.27; H, 4.47; N, 6.54. Found: C, 53.07; H, 4.36; N,
19 19 2 6 3
6
.54.
5
-Ethyl
3-Methyl
1,4-Dihydro-2-methyl-4-(3-nitrophenyl)-6-(trifluoromethyl)-pyridine-3,5-
-1
1
dicarboxylate (4h): mp 105-107 °C (hexane/Et O); IR (Nujol)ν 3365, 1709 cm ; H NMR (CDCl ) δ
2
3
1
.24 (t, J = 7.1 Hz, 3H), 2.45 (s, 3H), 3.67 (s, 3H), 4.13-4.22 (m, 2H), 5.17 (s, 1H), 6.23 (br s, 1H), 7.45 (t,
19
J = 7.9 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 8.06-8.12 (m, 2H); F NMR (CDCl ) δ 14.35 (s, 3F); MS m/z
3
+
(
%) 414 (M , 4), 292 (100), 264 (17), 196 (19). Anal. Calcd for C H N O F : C, 52.18; H, 4.14; N,
1
8
17
2
6 3
6
.76. Found: C, 51.92; H, 4.01; N, 6.80.
Diethyl 1,4-Dihydro-2-methyl-4-(2-furyl)-6-(trifluoromethyl)pyridine-3,5-dicarboxylate (4i): mp
-
1 1
6
8-70 °C (hexane/Et O); IR (Nujol)ν 3339, 1703 cm ; H NMR (CDCl ) δ 1.26 (t, J = 7.1 Hz, 3H), 1.27
2 3
(
t, J = 7.1 Hz, 3H), 2.39 (s, 3H), 4.12-4.25 (m, 4H), 5.23 (s, 1H), 6.03 (d, J = 2.8 Hz, 1H), 6.25 (br s, 1H),
1
9
+
6
.25 (s, 1H), 7.26 (d, J = 2.8 Hz, 1H); F NMR (CDCl ) δ 14.34 (s, 3F); MS m/z (%) 373 (M , 21), 344
3
(
20), 328 (22), 300 (100), 272 (20). Anal. Calcd for C H NO F : C, 54.69; H, 4.86; N, 3.75. Found: C,
17 18 5 3
5
4.44; H, 4.83; N, 3.76.
Diethyl 1,4-Dihydro-2-methyl-4-(2-thienyl)-6-(trifluoromethyl)pyridine-3,5-dicarboxylate (4j): mp
-
1
1
8
1
6
1-82 °C (hexane/Et O); IR (Nujol)ν 3344, 1690 cm ; H NMR (CDCl ) δ 1.28 (t, J = 7.1 Hz, 3H),
2 3
.29 (t, J = 7.1 Hz, 3H), 2.40 (s, 3H), 4.14-4.26 (m, 4H), 5.38 (s, 1H), 6.27 (br s, 1H), 6.83-6.84 (m, 1H),
1
9
.88 (dd, J = 5.1, 3.7 Hz, 1H), 7.12 (dd, J = 5.1, 1.2 Hz, 1H); F NMR (CDCl ) δ 14.38 (s, 3F); MS
3
+
m/z (%) 389 (M , 21), 360 (60), 343 (31), 320 (30), 316 (100), 306 (34), 288 (30), 204 (51), 111 (35).
Anal. Calcd for C H NO F S: C, 52.44; H, 4.66; N, 3.60. Found: C, 52.29; H, 4.61; N, 3.66.
1
7
18
4 3
ACKNOWLEDGEMENTS
We are grateful to Osaka University for elemental analyses.
REFERENCES AND NOTES
1
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