A new synthesis of N-alkyl 4-methyl-1,4-dihydropyridines utilizing sec-aminodienyl esters with crotonaldehyde

Article abstract of DOI:10.1248/cpb.49.558

The reactions of sec-aminodienyl esters 3 with crotonaldehyde (4) afforded N-alkyl 3-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-dihydropyridines 5, providing a new azaelectrocyclization reaction.

Full text of DOI:10.1248/cpb.49.558

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Chem. Pharm. Bull. 49(5) 558—562 (2001)
Vol. 49, No. 5
A New Synthesis of N-Alkyl 4-Methyl-1,4-dihydropyridines Utilizing
sec-Aminodienyl Esters with Crotonaldehyde
Takeshi KOIKE*
Showa Pharmaceutical University, Higashitamagawagakuen 3–3165, Machida, Tokyo 194–8543, Japan.
Received October 27, 2000; accepted January 9, 2001
The reactions of sec-aminodienyl esters 3 with crotonaldehyde (4) afforded N-alkyl 3-[2-(methoxy-
carbonyl)ethenyl]-4-methyl-1,4-dihydropyridines 5, providing a new azaelectrocyclization reaction.
Key words aminodienyl ester; primary amine; crotonaldehyde; 1,4-dihydropyridine; azaelectrocyclization reaction
We are interested in the reactivities of the sec-aminodienyl 1 with the corresponding primary amines, namely, 3,4,5-
esters 3. The enaminic, dienic, and electronic “push pull” trimethoxybenzylamine (2a), 4-chlorobenzylamine (2b), 2-
character of these molecules can lead to interesting cycload- (4-chlorophenyl)ethylamine (2c), 2-(2-chlorophenyl)ethyl-
dition and azaelectrocyclization reactions, as well as nitrodi- amine (2d), 2-(4-bromophenyl)ethylamine (2e), and 2,4-di-
1
—4)
1)
enamines and aminoacrylates synthons.
reported the cycloaddition reactions of methyl 5-(N,N-di- drofuran (THF) (Table 1).
methylamino)-2,4-pentadienoate (tert-aminodienyl ester 1) Previous syntheses of 1,4-dihydropyridines have been re-
Previously, we fluorobenzylamine (2f), respectively, under reflux in tetrahy-
6
,7)
with a,b-unsaturated carbonyl compounds and quinones ported, but synthetic methods using the related aminodi-
gave aromatic compounds. We also determined that the re- enyl esters have barely been studied. On the basis of our ear-
1
a)
actions of methyl 5-(N-alkylamino)-2,4-pentadienoates (sec- lier report on the formation of the product 2,3-dihydro-6H-
1
b)
aminodienyl esters 3) with acetaldehyde provided 2,3-dihy- 1,3-oxazines by the reaction of sec-aminodienyl esters with
dro-6H-1,3-oxazines, and the reactions of 3 in the presence acetaldehyde, we attempted to prepare the product 1-(3,4,5-
of propargylaldehyde diethylacetal afforded self-condensa- trimethoxybenzyl)-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-
tion products, 1,4-dihydropyridines, as an unexpected reac- 1,4-dihydropyridine (5a) by azaelectrocyclization reaction of
1
b,d)
tion.
Although several reactions using related aminodi- the sec-aminodienyl ester 3a with crotonaldehyde (4). As ex-
enyl esters have been reported, their utility and basic reactiv- pected, the product 5a was obtained in 53% yield by reflux-
5
)
ity have not been well documented.
Dihydropyridine derivatives are important for developing
ing 3a with crotonaldehyde (4) in xylene.
The structure of 5a was proposed on the basis of the fol-
drugs and are relatively difficult to be synthesized. At this lowing spectroscopic analyses. The molecular formula of 5a
1
time, we firstly synthesized designed 1,4-dihydropyridine de- was found to be C H NO . The H-NMR spectrum of 5a
2
0
25
5
rivatives utilizing sec-aminodienyl esters 3 with crotonalde- showed the presence of aromatic protons at d 6.40 (2H, s),
hyde (4), which produced the expected reaction. This reac- methylene protons at d 4.29 (2H, s), and three methoxy pro-
tion is a new synthetic method for obtaining 1,4-dihydropyri- tons at d 3.84 (3H, s) and 3.85 (6H, s) due to a 3,4,5-
dine derivatives, which is interesting in terms of organic trimethoxybenzyl group, methoxy protons at d 3.72 (3H, s),
chemistry research and also regarding the biological activity two olefinic protons at d 5.62 (1H, d, Jϭ15.3 Hz) and 7.25
of drugs (hypotensive, anti-inflammatory and mutagenic ef- (1H, d, Jϭ15.3 Hz) due to (methoxycarbonyl)ethenyl group,
6
)
fects). The sec-aminodienyl esters 3 were prepared by reac- methyl protons at d 1.13 (3H, d, Jϭ6.4 Hz), a methine proton
tions of the tert-aminodienyl ester 1 with primary amines 2. at d 3.40 (1H, q, Jϭ6.4 Hz), and three olefinic protons at d
The reactions of 3 with crotonaldehyde (4) afforded N-alkyl 4.84 (1H, dd, Jϭ7.9, 4.9 Hz), 5.83 (1H, dd, Jϭ7.9, 1.5 Hz)
3
-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-dihydropy- and at 6.35 (1H, d, Jϭ0.9 Hz) due to a 1,4-dihydropyridine
ridines 5, providing a new azaelectrocyclization reaction. ring. The IR spectrum of 5a indicated absorption bands at
Ϫ1
The methyl 5-(N-alkylamino)-2,4-pentadienoate deriva- 1720 cm (methoxycarbonyl group), and at 1690, 1680,
Ϫ1
tives listed in Table 1, sec-aminodienyl esters 3a—f, were se- 1670 cm (three olefinic groups). The nuclear Overhauser
lected for investigation (Chart 1). The sec-aminodienyl esters effect correlation spectroscopy (NOESY) of 5a revealed the
3
were prepared by the reaction of the tert-aminodienyl ester presence of a cross-peak between the 4-methyl protons at d
Chart 1
∗
To whom correspondence should be addressed. e-mail: koike@ac.shoyaku.ac.jp
© 2001 Pharmaceutical Society of Japan

May 2001
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d

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Vol. 49, No. 5
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Chart 2
1
.13 (3H) and the olefinic proton of a (methoxycarbonyl)- vents. The isolated yield of 3 is based on 2. The reaction conditions and
properties of the prepared compounds 3 are shown in Table 1.
ethenyl group at d 5.62 (1H), and a cross-peak between the
Methyl 5-(3,4,5-trimethoxybenzylamino)-2,4-pentadienoate (3a) was syn-
thesized by the previously reported method.
Methyl 5-(4-Chlorobenzylamino)-2,4-pentadienoate (3b): Amine 2b: 71
methylene protons of a trimethoxybenzyl group at d 4.29
1d)
(
2H) and the 6-olefinic proton at d 5.83 (1H). Therefore, it
may be deduced that 5a is a 4-methyl-1,4-dihydropyridine.
Regarding sec-dienylamine chemistry, we investigated the
reactions of nitrodienamines with acetaldehyde gave 1,2-di-
mg. Solvent for chromatography: 40% ethyl acetate in hexane. Product 3b:
ϩ
9
1 mg. High-resolution EI-MS m/z: Calcd for C H ClNO (M ): 251.0711.
13 14
2
Found: 251.0505. Anal. Calcd for C H ClNO : C, 62.03; H, 5.61; N, 5.57.
1
3
14
2
Found: C, 61.20; H, 5.44; N, 5.48.
Methyl 5-[2-(4-Chlorophenyl)ethylamino]-2,4-pentadienoate (3c): Amine
4
d)
hydropyridine derivatives, and the reactions of aminodienyl
esters with crotonaldehyde in affording 1,4-dihydropyridine
2
c: 78 mg. Solvent for chromatography: 40% ethyl acetate in hexane. Prod-
ϩ
derivatives. These results have shown that their azaelectrocy- uct 3c: 84 mg. High-resolution EI-MS m/z: Calcd for C H ClNO (M ):
clization reactions depend on the nature of the electron-with-
drawing group at the terminal position of the sec-dieny-
lamines, which result in changes in the reactive carbon site in
1
4
16
2
2
65.0867. Found: 265.0677.
Methyl 5-[2-(2-Chlorophenyl)ethylamino]-2,4-pentadienoate (3d): Amine
2
d: 78 mg. Solvent for chromatography: 40% ethyl acetate in hexane. Prod-
ϩ
uct 3d: 112 mg. High-resolution EI-MS m/z: Calcd for C H ClNO (M ):
1
4
16
2
the transition state. Their behavior suggests that we could 265.0867. Found: 265.0864.
make either 1,2- or 1,4-dihydropyridine derivatives as reac-
tion products depending on the choice of sec-dienylamines.
Namely, reagent treatment of sec-dienylamines which have a
nitro group would provide 1,2-dihydropyridines, and reagent
Methyl 5-[2-(4-Bromophenyl)ethylamino]-2,4-pentadienoate (3e): Amine
2
e: 100 mg. Solvent for chromatography: 40% ethyl acetate in hexane. Prod-
ϩ
uct 3e: 95 mg. High-resolution EI-MS m/z: Calcd for C H BrNO (M ):
1
4
16
2
3
09.0360. Found: 309.0357.
Methyl 5-(2,4-Difluorobenzylamino)-2,4-pentadienoate (3f): Amine 2f:
treatment of sec-dienylamines having a methoxycarbonyl 72 mg. Solvent for chromatography: 40% ethyl acetate in hexane. Product
ϩ
group would yield 1,4-dihydropyridines.
,4-Dihydropyridine compounds are a product of certain
drugs. Drug derivatives containing halogen atoms (ex. Br, Cl,
3f: 87 mg. High-resolution EI-MS m/z: Calcd for C13
H
13
F
2
NO
2
(M ):
2
5
53.0915. Found: 253.0942. Anal. Calcd for C H F NO : C, 61.65; H,
1
13 13
2
2
.17; N, 5.53. Found: C, 60.92; H, 5.06; N, 5.42.
General Procedure for Reactions of sec-Aminodienyl Esters 3 with
Crotonaldehyde (4) A solution of sec-aminodienyl esters 3 (0.6035
F) have often been known to show strong biological activity.
Therefore, we synthesized 1,4-dihydropyridine derivatives mmol) and crotonaldehyde (10.0 ml, 0.1207 mmol) in xylene (3 ml) was re-
fluxed for 20 h. The reaction mixture was subjected to NH silica gel column
chromatography with appropriate solvents. The properties of the prepared
compound 5 are shown in Table 2.
having halogenated groups. In a similar manner, several other
substituted 3-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-di-
hydropyridines, 5b—f, listed in Table 2, were prepared from
the corresponding 3b—f (Chart 1, Table 2).
1
-(3,4,5-Trimethoxybenzyl)-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-
1
,4-dihydropyridine (5a): Substrate 3a: 185 mg. Solvent for chromatogra-
1
3
The 6p-azaelectrocyclization reactions of sec-aminodienyl phy: 40% ethyl acetate in hexane. Product 5a: 23 mg. C-NMR (125 MHz,
CDCl ) d: 23.4, 27.3, 51.1, 56.1, 57.5, 57.5, 60.9, 103.7, 103.7, 107.3,
esters 3 with crotonaldehyde (4) may be explained as fol-
lows. Initially, the condensation reaction of 3 with croton-
aldehyde (4) may generate the intermediate 6, followed by
3
1
08.6, 112.6, 127.6, 133.0, 137.5, 138.9, 146.2, 153.6, 153.6, 168.8.
1
-(4-Chlorobenzyl)-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-dihy-
dropyridine (5b): Substrate 3b: 152 mg. Solvent for chromatography: 20%
intramolecular ring closure with dehydration, which could ethyl acetate in hexane. Product 5b: 20 mg.
lead to 4-methyl-1,4-dihydropyridines 5, as shown in Chart
1-[2-(4-Chlorophenyl)ethyl]-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-
,4-dihydropyridine (5c): Substrate 3c: 160 mg. Solvent for chromatography:
0% ethyl acetate in hexane. Product 5c: 15 mg.
1
2
2
.
These results provide a new method of synthesizing N-
alkyl 3-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-dihydro-
1
-[2-(2-Chlorophenyl)ethyl]-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-
1
,4-dihydropyridine (5d): Substrate 3d: 160 mg. Solvent for chromatogra-
pyridines 5 utilizing sec-aminodienyl esters 3 with croton- phy: 25% ethyl acetate in hexane. Product 5d: 16 mg.
aldehyde (4).
1-[2-(4-Bromophenyl)ethyl]-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-
,4-dihydropyridine (5e): Substrate 3e: 187 mg. Solvent for chromatogra-
1
Experimental
phy: 25% ethyl acetate in hexane. Product 5e: 18 mg.
1-(2,4-Difluorobenzyl)-3-[2-(methoxycarbonyl)ethenyl]-4-methyl-1,4-di-
ratus and are uncorrected. IR spectra were recorded with a JASCO FT/IR- hydropyridine (5f): Substrate 3f: 153 mg. Solvent for chromatography: 20%
00 spectrometer, and H- and C-NMR spectra with a JEOL JNM-EX 90 ethyl acetate in hexane. Product 5f: 18 mg.
All melting points were determined on a Yanagimoto melting point appa-
1
13
2
or JEOL JNM-a500 spectrometer, with tetramethylsilane as an internal stan-
dard. MS were recorded with a JEOL JMS-D 300 spectrometer. Elemental
Acknowledgements The author is grateful to Mr. T. Nakagomi, Y. Ya-
analyses were recorded on a Yanaco CHN-corder MT-3. NH-DM 1020 maura, and Miss R. Yanagisawa for assisting in part of this study.
basic 100 Å type silica gel, Fuji Silysia Chemical, Ltd.) was used for col-
umn chromatography and thin layer chromatography (TLC). All runs were References
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