A new synthesis of N-alkyl 3-acetyl-4-methoxycarbonylmethyl-2-methyl-1,4- dihydropyridines utilizing sec-aminodienyl esters with acetylacetone

Article abstract of DOI:10.1248/cpb.50.484

The reactions of sec-aminodienyl esters 3 with acetylacetone (4) afforded N-alkyl 3-acetyl-4-methoxycarbonylmethyl-2-methyl-1,4-dihydropyridines 5 and enamines 6, providing a new azaelectrocyclization reaction.

Full text of DOI:10.1248/cpb.50.484

484
Chem. Pharm. Bull. 50(4) 484—488 (2002)
Vol. 50, No. 4
A New Synthesis of N-Alkyl 3-Acetyl-4-methoxycarbonylmethyl-2-methyl-
1,4-dihydropyridines Utilizing sec-Aminodienyl Esters with Acetylacetone
Takeshi KOIKE* and Naoki TAKEUCHI
Showa Pharmaceutical University, 3–3165 Higashitamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received October 31, 2001; accepted December 26, 2001
The reactions of sec-aminodienyl esters 3 with acetylacetone (4) afforded N-alkyl 3-acetyl-4-methoxycar-
bonylmethyl-2-methyl-1,4-dihydropyridines 5 and enamines 6, providing a new azaelectrocyclization reaction.
Key words aminodienyl ester; acetylacetone; 1,4-dihydropyridine; azaelectrocyclization reaction
We are interested in the reactivities of the sec-aminodienyl lacetone (4) afforded N-alkyl 3-acetyl-4-methoxycarbonyl-
esters 3. The enaminic, dienic, and electronic “push pull” methyl-2-methyl-1,4-dihydropyridines 5 and enamines 6,
character of these molecules can lead to interesting cycload- [(Z)-4-(alkylamino)-3-penten-2-one], providing a new aza-
dition and azaelectrocyclization reactions, as well as nitrodi- electrocyclization reaction.
enamines and aminoacrylates synthons.1—4) Previously,1) we
The methyl 5-(N-alkylamino)-2,4-pentadienoate deriva-
reported the cycloaddition reactions of methyl 5-(N,N-di- tives listed in Table 1, sec-aminodienyl esters 3a—f, were se-
methylamino)-2,4-pentadienoate (tert-aminodienyl ester 1) lected for investigation (Chart 1). The sec-aminodienyl esters
with a,b-unsaturated carbonyl compounds and quinones to 3 were prepared by the reaction of the tert-aminodienyl ester
give aromatic compounds.1a) We also determined that the re- 1 with the corresponding primary amines, namely, 3,4,5-
actions of methyl 5-(N-alkylamino)-2,4-pentadienoates (sec- trimethoxybenzylamine (2a), 2-(2-methoxyphenyl)ethylamine
aminodienyl esters 3) with acetaldehyde provided 2,3-dihy- (2b), 4-methoxybenzylamine (2c), 3,4-dimethoxybenzylamine
dro-6H-1,3-oxazines1b) and the reactions of 3 in the presence (2d), 2-(2,5-dimethoxyphenyl)ethylamine (2e), and 1-naph-
of propargylaldehyde diethylacetal afforded N-alkyl 3-[2- thalenemethylamine (2f), respectively, under reflux in tetra-
(methoxycarbonyl)ethenyl]-4-methoxycarbonylmethyl-1,4- hydrofuran (THF) (Table 1).
dihydropyridines1d) (self-condensation products) as an unex-
Previous syntheses of 1,4-dihydropyridines have been re-
pected reaction, and the reactions of 3 with crotonaldehyde ported,6,7) but synthetic methods using the related aminodi-
yielded N-alkyl 3-[2-(methoxycarbonyl)ethenyl]-4-methyl- enyl esters have hardly been studied. On the basis of our ear-
1,4-dihydropyridines as the expected reaction.1f) Although lier report on the formation of the product N-alkyl 3-[2-
several reactions using related aminodienyl esters have been (methoxycarbonyl)ethenyl]-4-methyl-1,4-dihydropyridines
reported, their utility and basic reactivity have not been well by the reaction of sec-aminodienyl esters with crotonalde-
documented.5)
hyde,1f) we attempted to prepare the condensation product
Dihydropyridine derivatives are important for developing 3-acetyl-1-(3,4,5-trimethoxybenzyl)-4-methoxycarbonyl-
drugs and are relatively difficult to be synthesized. At this methyl-2-methyl-1,4-dihydropyridine (5a) by azaelectrocy-
time, we synthesized designed 1,4-dihydropyridine deriva- clization reaction of the sec-aminodienyl ester 3a with acetyl-
tives utilizing sec-aminodienyl esters 3 with acetylacetone acetone (4). As expected, the product 5a and the severed
(4) compound containing a 1,3-diketone moiety, which pro- enamine, (Z)-4-(3,4,5-trimethoxybenzylamino)-3-penten-2-one
duced the expected reaction. This reaction is a new synthetic (6a) were obtained by refluxing in xylene sec-aminodienyl
method for obtaining 1,4-dihydropyridine derivatives, which ester 3a with acetylacetone (4) in 37 and 36% yields, respec-
is interesting in terms of organic chemistry research and also tively.
regarding the biological activity of drugs (hypotensive, anti-
The structure of 5a was proposed on the basis of the fol-
inflammatory and mutagenic effects).6) The sec-aminodienyl lowing spectroscopic analyses. The molecular formula of 5a
esters 3 were prepared by reactions1b) of the tert-aminodienyl was found to be C21H27NO6. The H-NMR spectrum of 5a
1
ester 1 with primary amines 2. The reactions of 3 with acety- showed the presence of aromatic protons at d 6.36 (2H, s),
Chart 1
To whom correspondence should be addressed. e-mail: koike@ac.shoyaku.ac.jp
© 2002 Pharmaceutical Society of Japan

April 2002
485
Table 1. The Reactions of tert-Aminodienyl Ester 1 with Primary Amines 2a)
Starting
amine
Reaction Reaction Yield
time (h) product (%) [solvent, mp (°C)]
Appearance
R
1H-NMR, d (ppm)
IR (cmϪ1
)
2a
2b
2c
90
3a
3b
3c
62 Light yellow oil
30 Light yellow oil
3.70 (3H, s, -Me), 3.84 (3H, s, -Me), 3.85 (3H, s,
3370, 1730,
-Me), 3.86 (3H, s, -Me), 4.17 (2H, d, Jϭ5.0 Hz, meth- 1700, 1695,
ylene H), 5.37 (1H, dd, Jϭ13.1, 11.2 Hz, olefinic H),
5.50 (1H, d, Jϭ14.9 Hz, olefinic H), 6.50 (2H, s, aro-
matic H), 6.80 (1H, dd, Jϭ13.1, 7.5 Hz, olefinic H),
7.34 (1H, dd, Jϭ14.9, 11.2 Hz, olefinic H), [CDCl3]
2.88 (2H, t, Jϭ6.7 Hz, methylene H), 3.29 (2H, q,
1680, 1640,
(neat)
129
129
3350, 1730,
Jϭ6.7 Hz, methylene H), 3.69 (3H, s, -Me), 3.85 (3H, 1700, 1695,
s, -Me), 5.31 (1H, dd, Jϭ13.1, 8.6 Hz, olefinic H),
5.46 (1H, d, Jϭ14.7 Hz, olefinic H), 6.69 (1H, dd,
Jϭ13.1, 7.9 Hz, olefinic H), 7.35—6.83 (5H, m, aro-
matic and olefinic H), [CDCl3]
1685, 1630,
(neat)
36 Light yellow plates 3.69 (3H, s, -Me), 3.80 (3H, s, -Me), 4.16 (2H, d,
3320, 1730,
1690, 1615,
1595, 1510,
(KBr)
(ether–hexane,
92—93)
Jϭ5.5 Hz, methylene H), 5.35 (1H, dd, Jϭ13.1,
11.6 Hz, olefinic H), 5.48 (1H, d, Jϭ15.0 Hz, olefinic
H), 6.78 (1H, dd, Jϭ13.1, 7.9 Hz, olefinic H), 6.88
(2H, d, Jϭ8.9 Hz, aromatic H), 7.20 (2H, d,
Jϭ8.5 Hz, aromatic H), 7.33 (1H, dd, Jϭ15.0,
11.6 Hz, olefinic H), [CDCl3]
2d
2e
120
120
3d
3e
57 Light yellow prisms 3.68 (3H, s, -Me), 3.87 (6H, s, -Me), 4.16 (2H, d,
3390, 1700,
1620, 1595,
1515, 1500,
(KBr)
(ether–hexane,
111—113)
Jϭ5.3 Hz, methylene H), 5.36 (1H, t, Jϭ14.3 Hz,
olefinic H), 5.53 (1H, d, Jϭ14.7 Hz, olefinic H),
6.91—6.68 (4H, m, olefinic and aromatic H), 7.34
(1H, dd, Jϭ14.7, 11.0 Hz, olefinic H), [CDCl3]
2.84 (2H, t, Jϭ6.4 Hz, methylene H), 3.27 (2H, q,
35 Light yellow oil
68 Light yellow oil
3380, 1740,
Jϭ6.4 Hz, methylene H), 3.68 (3H, s, -Me), 3.75 (3H, 1700, 1695,
s, -Me), 3.80 (3H, s, -Me), 5.30 (1H, dd, Jϭ13.0,
11.4 Hz, olefinic H), 5.45 (1H, d, Jϭ14.7 Hz, olefinic
H), 6.88—6.57 (4H, m, olefinic and aromatic H), 7.32
(1H, dd, Jϭ14.7, 11.4 Hz, olefinic H), [CDCl3]
3.66 (3H, s, -Me), 4.55 (2H, d, Jϭ4.9 Hz, methylene
H), 5.39 (1H, dd, Jϭ13.1, 11.6 Hz, olefinic H), 5.49
1685, 1640,
(neat)
2f
98
3f
3355, 1730,
1700, 1695,
(1H, d, Jϭ15.0 Hz, olefinic H), 6.76 (1H, dd, Jϭ13.1, 1685, 1640,
7.3 Hz, olefinic H), 7.52—7.32 (5H, m, olefinic H and (neat)
aromatic H), 7.87—7.77 (3H, m, aromatic H),
[CDCl3]
a) All reactions were run in refluxing THF.
methylene protons at d 4.45 (1H, d, Jϭ16.8 Hz) and 4.68 the reactions of nitrodienamines with acetaldehyde to give
(1H, d, Jϭ16.8 Hz), and three methoxy protons at d 3.84 1,2-dihydropyridine derivatives,4d,f) and the reactions of amino-
(3H, s) and 3.85 (6H, s) due to a 3,4,5-trimethoxybenzyl dienyl esters with aminodienyl ester,1d) crotonaldehyde,1f) and
group, methoxy protons at d 3.67 (3H, s), methylene protons acetylacetone to afford 1,4-dihydropyridine derivatives.
at d 2.31 (2H, d, Jϭ8.2 Hz) due to a (methoxycarbonyl)- These results have shown that these azaelectrocyclization re-
methyl group, acetyl protons at d 2.29 (3H, s), methyl pro- actions depend on the nature of the electron-withdrawing
tons at d 2.31 (3H, s), a methine proton at d 3.84—3.81 (1H, group (a nitro or a methoxycarbonyl group) at the terminal
m), and two olefinic protons at d 5.12 (1H, t, Jϭ7.3 Hz) and position of the sec-dienylamines resulting in changes in the
6.04 (1H, d, Jϭ7.3 Hz) due to a 1,4-dihydropyridine ring. reactive carbon site in the transition state and the nature of
The IR spectrum of 5a indicated absorption bands at 1730, the acyl reagent. Their behavior suggests that we could make
1670 cmϪ1 (two carbonyl groups), and at 1640, 1595 cmϪ1 either 1,2- or 1,4-dihydropyridine derivatives as reaction
(two olefinic groups). The nuclear Overhauser effect correla- products depending on the choice of sec-dienylamines.
tion spectroscopy (NOESY) of 5a revealed the presence of a
1,4-Dihydropyridine derivatives are found in certain drugs.
cross-peak between the 2-methyl protons at d 2.31 (3H) and Compounds containing methoxy groups such as natural
the methylene protons of a trimethoxybenzyl group at d 4.45 products have often been known to show good biological ac-
(1H) and 4.68 (1H), and a cross-peak between 2-methyl pro- tivity. Therefore, we synthesized 1,4-dihydropyridine deriva-
tons at d 2.31 (3H) and aromatic protons at d 6.36 (2H). tives having methoxy groups. In a similar manner, several
Therefore, it may be deduced that 5a is a 3-acetyl-2-methyl- other substituted 3-acetyl-4-methoxycarbonylmethyl-2-methyl-
1,4-dihydropyridine.
1,4-dihydropyridines 5b—f and enamines 6b—f listed in
Concerning sec-dienylamine chemistry, we have studied Table 2, were prepared from the corresponding 3b—f (Chart

486
Vol. 50, No. 4
Table 2. The Reactions of sec-Aminodienyl Esters 3 with Acetylacetone (4)a)
Formula,
HR-MS m/z
Calcd (Found)
Starting
amine
Reaction
time (h)
Reaction Yield
1H-NMR, d (ppm)
IR (cmϪ1
)
R
product
(%)
3a
4
5a
37
2.29 (3H, s, -Me), 2.31 (3H, s, -Me), 2.31 (2H, d, Jϭ8.2 Hz, methylene
H), 3.67 (3H, s, -Me), 3.84—3.81 (1H, m, methine H), 3.84 (3H, s,
-Me), 3.85 (6H, s, -Me), 4.45 (1H, d, Jϭ16.8 Hz, methylene H), 4.68
(1H, d, Jϭ16.8 Hz, methylene H), 5.12 (1H, t, Jϭ7.3 Hz, olefinic H),
6.04 (1H, d, Jϭ7.3 Hz, olefinic H), 6.36 (2H, s, aromatic H), [CDCl3]
1.93 (3H, s, -Me), 2.03 (3H, s, -Me), 3.83 (3H, s, -Me), 3.85 (6H, s,
-Me), 4.39 (2H, d, Jϭ6.4 Hz, methylene H), 5.05 (1H, s, olefinic H),
6.47 (2H, s, aromatic H), 11.08 (1H, br s, -NH), [CDCl3]
2.20 (1H, d, Jϭ8.9 Hz, methylene H), 2.22 (1H, d, Jϭ8.9 Hz, methylene
H), 2.26 (3H, s, -Me), 2.37 (3H, s, -Me), 2.89—2.83 (2H, m, methylene
H), 3.48—3.41 (2H, m, methylene H), 3.69 (3H, s, -Me), 3.77—3.67
(1H, m, methine H), 3.84 (3H, s, -Me), 5.08 (1H, dd, Jϭ7.0, 6.4 Hz,
olefinic H), 5.99 (1H, d, Jϭ7.3 Hz, olefinic H), 6.92—6.85 (2H, m, aro-
matic H), 7.10 (1H, dd, Jϭ7.3, 1.8 Hz, aromatic H), 7.25—7.20 (1H, m,
aromatic H), [CDCl3]
1730, 1670,
1640, 1595,
1540, (neat)
C21H27NO6
389.1839
(389.1860)
6a
5b
36
23
3420, 1610,
1590, 1570,
1550, (KBr)
1730, 1670,
1640, 1615,
1580, (neat)
C15H21NO
279.1471
(279.1471)
C20H25NO4
343.1784
3b
4
(343.1814)
6b
5c
69
27
1.84 (3H, s, -Me), 1.99 (3H, s, -Me), 2.87 (2H, t, Jϭ7.9 Hz, methylene
H), 3.44 (2H, dd, Jϭ14.7, 7.9 Hz, methylene H), 3.83 (3H, s, -Me), 4.92
(1H, s, olefinic H), 6.85 (1H, d, Jϭ8.2 Hz, aromatic H), 6.90 (1H, td,
Jϭ7.6, 1.8 Hz, aromatic H), 7.14 (1H, dd, Jϭ7.6, 1.8 Hz, aromatic H),
7.22 (1H, td, Jϭ8.2, 1.5 Hz, aromatic H), 10.87 (1H, br s, -NH), [CDCl3]
2.28 (2H, dd, Jϭ8.9, 5.2 Hz, methylene H), 2.28 (3H, s, -Me), 2.30 (3H,
s, -Me), 3.67 (3H, s, -Me), 3.80 (3H, s, -Me), 3.84—3.81 (1H, m, me-
thine H), 4.50 (1H, d, Jϭ16.8 Hz, methylene H), 4.63 (1H, d,
Jϭ16.8 Hz, methylene H), 5.10 (1H, d, Jϭ7.3, 6.4 Hz, olefinic H), 6.02
(1H, d, Jϭ7.3 Hz, olefinic H), 6.89 (2H, d, Jϭ8.9 Hz, aromatic H), 7.07
(2H, d, Jϭ8.9 Hz, aromatic H), [CDCl3]
3430, 1615,
1580, 1515,
1495, (neat)
C14H19NO2
233.1416
(233.1417)
3c
4
1730, 1670,
1640, 1615,
1590, (neat)
C19H23NO4
329.1628
(329.1640)
6c
56
30
1.92 (3H, s, -Me), 2.02 (3H, s, -Me), 3.79 (3H, s, -Me), 4.39 (2H, d,
Jϭ6.1 Hz, methylene H), 5.02 (1H, s, olefinic H), 6.87 (2H, d,
Jϭ8.9 Hz, aromatic H), 7.17 (2H, d, Jϭ8.5 Hz, aromatic H), 11.10 (1H,
br s, -NH), [CDCl3]
2.28 (3H, s, -Me), 2.28 (1H, d, Jϭ5.5 Hz, methylene H), 2.29 (1H, d,
Jϭ5.5 Hz, methylene H), 2.31 (3H, s, -Me), 3.67 (3H, s, -Me), 3.85—
3.80 (1H, m, methine H), 3.87 (6H, s, -Me), 4.48 (1H, d, Jϭ16.5 Hz,
methylene H), 4.66 (1H, d, Jϭ16.5 Hz, methylene H), 5.11 (1H, t,
Jϭ7.3 Hz, olefinic H), 6.04 (1H, d, Jϭ7.3 Hz, olefinic H), 6.66 (1H, d,
Jϭ1.8 Hz, aromatic H), 6.69 (1H, dd, Jϭ8.2, 1.8 Hz, aromatic H), 6.84
(1H, d, Jϭ8.2 Hz, aromatic H), [CDCl3]
3440, 1610,
1580, 1510,
1460, (neat)
C13H17NO2
219.1259
(219.1285)
3d
5
5d
1730, 1670,
1640, 1610,
1595, (neat)
C20H25NO5
359.1733
(359.1735)
6d
5e
40
25
1.93 (3H, s, -Me), 2.03 (3H, s, -Me), 3.87 (3H, s, -Me), 3.87 (3H, s,
-Me), 4.39 (2H, d, Jϭ6.1 Hz, methylene H), 5.04 (1H, s, olefinic H),
6.76 (1H, d, Jϭ1.8 Hz, aromatic H), 6.84—6.79 (2H, m, aromatic H),
11.10 (1H, br s, -NH), [CDCl3]
2.21 (1H, d, Jϭ8.5 Hz, methylene H), 2.22 (1H, d, Jϭ8.5 Hz, methylene
H), 2.26 (3H, s, -Me), 2.37 (3H, s, -Me), 2.84—2.80 (2H, m, methylene
H), 3.50—3.42 (2H, m, methylene H), 3.66 (3H, s, -Me), 3.75—3.68
(1H, m, methine H), 3.75 (3H, s, -Me), 3.80 (3H, s, -Me), 5.08 (1H, dd,
Jϭ7.3, 6.4 Hz, olefinic H), 5.99 (1H, d, Jϭ7.3 Hz, olefinic H), 6.79—
6.68 (3H, m, aromatic H), [CDCl3]
3420, 1615,
1580, 1560,
1520, (neat)
C14H19NO3
249.1365
(249.1375)
3e
5
1730, 1670,
1640, 1595,
1545, (neat)
C21H27NO5
373.1887
(373.1877)
6e
5f
44
20
1.84 (3H, s, -Me), 1.99 (3H, s, -Me), 2.84 (2H, t, Jϭ7.3 Hz, methylene
H), 3.43 (2H, q, Jϭ7.3 Hz, methylene H), 3.76 (3H, s, -Me), 3.78 (3H, s,
-Me), 4.92 (1H, s, olefinic H), 6.81—6.72 (3H, m, aromatic H), 10.88
(1H, br s, -NH), [CDCl3]
2.31 (3H, s, -Me), 2.32 (3H, s, -Me), 2.34—2.30 (2H, m, methylene H),
3.68 (3H, s, -Me), 3.93—3.89 (1H, m, methine H), 5.05 (1H, d,
Jϭ17.1 Hz, methylene H), 5.12 (1H, d, Jϭ17.1 Hz, methylene H), 5.14
(1H, dd, Jϭ7.3, 6.4 Hz, olefinic H), 6.03 (1H, d, Jϭ7.3 Hz, olefinic H),
7.19 (1H, dd, Jϭ7.3, 0.9 Hz, aromatic H), 7.46 (1H, t, Jϭ7.3 Hz, aro-
matic H), 7.59—7.53 (2H, m, aromatic H), 7.92—7.80 (3H, m, aromatic
H), [CDCl3]
3390, 1615,
1580, 1565,
1505, (neat)
C15H21NO3
263.1522
(263.1537)
3f
4
1730, 1670,
1635, 1615,
1600, (neat)
C22H23NO3
349.1678
(349.1686)
6f
53
1.97 (3H, s, -Me), 2.05 (3H, s, -Me), 4.91 (2H, d, Jϭ6.4 Hz, methylene
H), 5.10 (1H, s, olefinic H), 7.45—7.39 (2H, m, aromatic H), 7.80—
7.50 (2H, m, aromatic H), 7.89 (1H, dd, Jϭ7.9, 0.6 Hz, aromatic H),
7.93 (1H, d, Jϭ8.6 Hz, aromatic H), 11.26 (1H, br s, -NH), [CDCl3]
3420, 1610,
1580, 1520,
1450, (KBr)
C16H17NO
239.1273
(239.1290)
a) All reactions were run in refluxing xylene.

April 2002
487
Chart 2
N, 5.05. Found: C, 64.91; H, 6.93; N, 5.07.
1, Table 2). On the other hand, treatment of 3,4,5-trimethoxy-
benzylamine (2a) (primary amine) with acetylacetone (4) in
xylene gave (Z)-4-(3,4,5-trimethoxybenzylamino)-3-penten-
2-one (6a) in 67% yield.
Methyl 5-[2-(2,5-Dimethoxyphenyl)ethylamino]-2,4-pentadienoate (3e):
Amine 2e: 91 mg. Solvent for chromatography: 40% ethyl acetate in hexane.
Product 3e: 51 mg. High-resolution EI-MS m/z: Calcd for C16H21NO4 (Mϩ):
291.1468. Found: 291.1443.
The 6p-azaelectrocyclization reactions of sec-aminodienyl
esters 3 with acetylacetone (4) may be explained as follows.
Initially, the condensation reaction of 3 with acetylacetone
(4) may generate the intermediate 7, followed by dehydra-
tion, which could lead to 3-acetyl-2-methyl-1,4-dihydropy-
ridines 5, as shown in Chart 2.
These results provide a new method of synthesizing N-
alkyl 3-acetyl-4-methoxycarbonylmethyl-2-methyl-1,4-dihy-
dropyridines 5 and enamines 6, [(Z)-4-(alkylamino)-3-pen-
ten-2-one], utilizing sec-aminodienyl esters 3 with acetylace-
tone (4).
Methyl 5-(1-Naphthalenemethylamino)-2,4-pentadienoate (3f): Amine 2f:
79 mg. Solvent for chromatography: 30% ethyl acetate in hexane. Product
3f: 91 mg. High-resolution EI-MS m/z: Calcd for C17H17NO2 (Mϩ):
267.1259. Found: 267.1294.
General Procedure for Reactions of sec-Aminodienyl Esters 3 with
Acetylacetone (4) A solution of sec-aminodienyl ester 3 (0.3 mmol) and
acetylacetone (10.0 mg, 0.1 mmol) in xylene (1.5 ml) was refluxed for an ap-
propriate period. The reaction mixture was subjected to silica gel column
chromatography with appropriate solvents. The reaction conditions and
properties of the prepared compounds 5 and 6 are shown in Table 2.
3-Acetyl-1-(3,4,5-trimethoxybenzyl)-4-methoxycarbonylmethyl-2-meth-
yl-1,4-dihydropyridine (5a) and (Z)-4-(3,4,5-Trimethoxybenzylamino)-3-
penten-2-one (6a): Substrate 3a: 92 mg. Solvent for chromatography: 60%
ethyl acetate in hexane. Product 5a: 14 mg. Light yellow oil. 13C-NMR
(125 MHz, CDCl3) d: 16.6, 29.6, 31.4, 43.4, 51.5, 53.9, 56.1, 56.1, 60.9,
102.9, 102.9, 106.0, 108.8, 131.5, 133.4, 137.3, 148.8, 153.8, 153.8, 171.9,
198.9. Product 6a: 10 mg. Colorless plates (ether–hexane). mp 78—80 °C.
13C-NMR (125 MHz, CDCl3) d: 19.0, 29.0, 47.0, 56.2, 56.2, 60.9, 76.8,
77.1, 77.3, 96.0, 103.8, 103.8, 133.7, 137.3, 153.6, 153.6, 163.0, 195.5. Sig-
nificant NOESY correlations: C-5 Me H-3, C-1 Me H-3, C-1Ј CH2 C-
5 Me, NH C-5 Me. Anal. Calcd for C15H21NO4: C, 64.49; H, 7.58; N, 5.01.
Found: C, 64.42; H, 7.62; N, 5.06.
3-Acetyl-4-methoxycarbonylmethyl-1-[2-(2-methoxyphenyl)ethyl]-2-
methyl-1,4-dihydropyridine (5b) and (Z)-4-[2-(2-Methoxyphenyl)ethyl-
amino]-3-penten-2-one (6b): Substrate 3b: 78 mg. Solvent for chromatogra-
phy: 40% ethyl acetate in hexane. Product 5b: 8 mg. Light yellow oil. Prod-
uct 6b: 16 mg. Light yellow oil.
3-Acetyl-1-(4-methoxybenzyl)-4-methoxycarbonylmethyl-2-methyl-1,4-
dihydropyridine (5c) and (Z)-4-(4-Methoxybenzylamino)-3-penten-2-one
(6c): Substrate 3c: 74 mg. Solvent for chromatography: 50% ethyl acetate in
hexane. Product 5c: 9 mg. Light yellow oil. Product 6c: 12 mg. Light yellow
oil.
3-Acetyl-1-(3,4-dimethoxybenzyl)-4-methoxycarbonylmethyl-2-methyl-
1,4-dihydropyridine (5d) and (Z)-4-(3,4-Dimethoxybenzylamino)-3-penten-
2-one (6d): Substrate 3d: 83 mg. Solvent for chromatography: 60% ethyl ac-
etate in hexane. Product 5d: 11 mg. Light yellow oil. Product 6d: 10 mg.
Colorless oil.
3-Acetyl-4-methoxycarbonylmethyl-1-[2-(2,5-dimethoxyphenyl)ethyl]-2-
methyl-1,4-dihydropyridine (5e) and (Z)-4-[2-(2,5-Dimethoxyphenyl)ethyl-
amino]-3-penten-2-one (6e): Substrate 3e: 87 mg. Solvent for chromatogra-
phy: 40% ethyl acetate in hexane. Product 5e: 9 mg. Light yellow oil. Prod-
uct 6e: 12 mg. Light yellow oil.
3-Acetyl-4-methoxycarbonylmethyl-1-(1-naphthalenemethyl)-2-methyl-
1,4-dihydropyridine (5f) and (Z)-4-(1-Naphthalenemethylamino)-3-penten-
2-one (6f): Substrate 3f: 80 mg. Solvent for chromatography: 30% ethyl ac-
etate in hexane. Product 5f: 7 mg. Light orange oil. Product 6f: 13 mg. Light
yellow needles (ether–hexane). mp 76—77 °C. Anal. Calcd for C16H17NO:
C, 80.30; H, 7.16; N, 5.85. Found: C, 79.75; H, 7.23; N, 5.71.
Experimental
All melting points were determined on a Yanagimoto melting point appa-
ratus and are uncorrected. IR spectra were recorded with a JASCO FT/IR-
1
200 spectrometer, and H- and 13C-NMR spectra with a JEOL JNM-EX 90
or JEOL JNM-a500 spectrometer, with tetramethylsilane as an internal stan-
dard. MS were recorded with a JEOL JMS-D 300 spectrometer. Elemental
analyses were recorded on a Yanaco CHN-corder MT-3. Merck Kieselgel G
nach Stahl (silica gel) and NH-DM 1020 (basic 100 Å type silica gel, Fuji
Silysia Chemical, Ltd.) were used for column chromatography and thin layer
chromatography (TLC). All runs were carried out under an argon atmos-
phere.
General Procedure for Reactions of tert-Aminodienyl Ester 1 with
Primary Amines 2 A solution of the tert-aminodienyl ester 1 (233 mg,
1.5 mmol) and an amine 2 (0.5 mmol) in THF (4 ml) was refluxed for an ap-
propriate period until the disappearance of the amine (checked by TLC). The
reaction mixture was concentrated under vacuum, then the residue was sub-
jected to NH silica gel column chromatography with appropriate solvents.
The isolated yield of 3 is based on 2. The reaction conditions and properties
of the prepared compounds 3 are shown in Table 1.
Methyl 5-(3,4,5-trimethoxybenzylamino)-2,4-pentadienoate (3a) was syn-
thesized by the previously reported method.1d)
Methyl 5-[2-(2-Methoxyphenyl)ethylamino]-2,4-pentadienoate (3b): Amine
2b: 76 mg. Solvent for chromatography: 30% ethyl acetate in hexane. Prod-
uct 3b: 39 mg. High-resolution electron impact (EI)-MS m/z: Calcd for
C15H19NO3 (Mϩ): 261.1365. Found: 261.1397.
Methyl 5-(4-Methoxybenzylamino)-2,4-pentadienoate (3c): Amine 2c:
69 mg. Solvent for chromatography: 40% ethyl acetate in hexane. Product
3c: 45 mg. High-resolution EI-MS m/z: Calcd for C14H17NO3 (Mϩ):
247.1208. Found: 247.1208. Anal. Calcd for C14H17NO3: C, 67.99; H, 6.93;
N, 5.66. Found: C, 67.82; H, 6.96; N, 5.65.
Methyl 5-(3,4-Dimethoxybenzylamino)-2,4-pentadienoate (3d): Amine
2d: 84 mg. Solvent for chromatography: 50% ethyl acetate in hexane. Prod-
uct 3d: 79 mg. High-resolution EI-MS m/z: Calcd for C15H19NO4 (Mϩ):
277.1312. Found: 277.1304. Anal. Calcd for C15H19NO4: C, 64.96; H, 6.91;

488
Reaction of 3,4,5-Trimethoxybenzylamine (2a) with Acetylacetone (4)
A solution of 3,4,5-trimethoxybenzylamine (2a) (99 mg, 0.5 mmol) and
acetylacetone (50 mg, 0.5 mmol) in xylene (1.5 ml) was refluxed for 4 h. The
reaction mixture was subjected to silica gel column chromatography. (Z)-4-
(3,4,5-Trimethoxybenzylamino)-3-penten-2-one (6a): Solvent for chro-
matography: 50% ethyl acetate in hexane. Product 6a: 93 mg (67%). Color-
less plates (ether–hexane). mp 78—80 °C. This product was identical with
6a previously obtained.
Vol. 50, No. 4
T., Tobinaga S., Heterocycles, 38, 613—627 (1994); c) Koike T., Hagi-
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Acknowledgements The authors are grateful to Prof. S. Tobinaga,
Showa Pharmaceutical University, for helpful suggestions.
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