Research on heterocyclic compounds. XLIII. Synthetic studies on 1,4-dihydropyridine derivatives

Article abstract of DOI:10.1002/jhet.5570390601

In order to obtain N-benzyl-3,5-dicarbethoxy-2,6-dimethyl-4-phenyl-1,4-dihydropyridine 1 as a lead compound of pharmacological interest, the classical Hantzsch synthetic method and the modified Collie procedure were used. However, only a very low yield of

Full text of DOI:10.1002/jhet.5570390601

Nov-Dec 2002
Research on Heterocyclic Compounds. XLIII. Synthetic Studies on
1,4-Dihydropyridine Derivatives
1117
1
1
1
1
Maria Grazia Rimoli *, Lucia Avallone , Serena Zanarone , Enrico Abignente ,
2
Alfonso Mangoni
1
Dipartimento di Chimica Farmaceutica e Tossicologica,
2
Dipartimento di Chimica delle Sostanze Naturali,
Facoltà di Farmacia, Università di Napoli Federico II,
Via Domenico Montesano 49, 80131 Napoli, Italy
Received September 21, 2000
Received Revised May 29, 2002
In order to obtain N-benzyl-3,5-dicarbethoxy-2,6-dimethyl-4-phenyl-1,4-dihydropyridine 1 as a lead
compound of pharmacological interest, the classical Hantzsch synthetic method and the modified Collie pro-
cedure were used. However, only a very low yield of 1 was obtained in a mixture with larger amounts of
some by-products (2, 3, 4). Compound 1 was then synthesized in satisfactory yield via a different method,
together with another by-product (9). The structures of all by-products were elucidated and possible mech-
anisms leading to the formation of such compounds are described.
J. Heterocyclic Chem., 39, 1117(2002).
Scheme I
Introduction.
As part of a research program directed towards the
design and synthesis of lead compounds potentially inter-
esting as drugs, we have taken into consideration com-
pound 1 (Figure 1) as a possible starting point to obtain
new substances with pharmacological activity in the car-
diovascular field.
Figure 1
Compound 1, namely N-benzyl-3,5-dicarbethoxy-2,6-
dimethyl-4-phenyl-1,4-dihydropyridine, was prepared by
Sausinset al. [1] together with a series of analogues and later
by Vanden Eynde et al. [2] using different synthetic methods.
Sausins et al. employed the classical cyclocondensation pro-
cedure first described by Hantzsch [3], which involved the
one-pot reaction of an aldehyde, an acetoacetic ester and
ammonium hydroxide, without isolation of intermediates. In
order to obtain 1, the starting compounds must be benzalde-
hyde, ethyl acetoacetate and benzylamine (in place of ammo-
nium hydroxide), respectively. We have adopted this
method, starting from a 1:2:1 mixture of the above com-
pounds (Scheme I) which was stirred at reflux for 24 hours.
In our hands this procedure gave disappointing results:
after the work-up and column chromatography of the
crude reaction product, only a small amount of the
required compound 1 was isolated, together with larger
quantities of three other products (2, 3, 4; Scheme I). The
first product eluted was N-benzyl-2,4-dicarbethoxy-5-
methyl-3-phenylaniline 2 (5% yield), followed by com-
pound 1 (1% yield) and then by 3,5-dicarbethoxy-2,6-
dimethyl-4-phenyl-1,4-dihydropyridine 4 (3%) and 2,4-
dicarbethoxy-5-hydroxy-5-methyl-3-phenylcyclohexa-
none 3 (48%). The structures of these four compounds
were elucidated by H- and C-nmr spectra and mass
spectra. Two-dimensional nmr experiments (HMQC and
HMBC) were also acquired for compounds 2 and 3.
1
13

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M. G. Rimoli, L. Avallone, S. Zanarone, E. Abignente, A. Mangoni
Vol. 39
It should be noted that compound 4 is well known and
adduct of ethyl acetoacetate to benzaldehyde (5) may
undergo an intramolecular aldol reaction yielding the
cyclohexanone 3. This side-reaction of the Hantzsch syn-
thesis has already been described for similar compounds
[16]. Compound 3 could in turn react with benzylamine to
give an imine, that after dehydration, tautomerism and oxi-
cited in a number of literature references, starting from the
ancient papers published by Hantzsch [3], Schiff [4] and
Knoevenagel [5] up to recent reports [6-8]. Also cyclo-
hexanone 3 is already known [9-15]. The only compound
unknown is 2.
A possible reaction mechanism leading to the formation
of compounds 1-4 is depicted in Scheme II. The bis-
dation (presumably by atmospheric O ) would lead to the
aniline 2. Alternatively, the addition of benzylamine (giv-
2
Scheme II

Nov-Dec 2002
Research on Heterocyclic Compounds. XLIII
1119
ing the intermediate 6) could precede the intramolecular
aldol reaction. The origin of the dihydropyridine 4 is more
difficult to explain. The most probable hypothesis
involves the nucleophilic attack of any of the nucleophiles
present in the reaction mixture on the benzylic methylene,
with subsequent loss of the resonance-stabilized anion of
compound 4 as the leaving group.
These results showed that the Hantzsch reaction was
inadequate to reach the objective of our research: conse-
quently, we attempted a variation of the Hantzsch proce-
dure, developed by Collie [17]. This method involves pre-
liminary preparation of two intermediate compounds
(Scheme III), namely ethyl 2-benzylideneacetoacetate 7
and ethyl 3-benzylaminocrotonate 8: both products were
obtained by reaction of ethyl acetoacetate either with ben-
zaldehyde in pyridine or with benzylamine in ethanol,
respectively. The cyclocondensation of 7 and 8 was per-
formed in pyridine at room temperature. The required
product 1 was obtained together with compound 2 as the
only by-product, but this result was not yet satisfactory,
because the yield of compound 1 was still very low.
(Scheme IV), namely the reaction of a mixture of ethyl
acetoacetate, benzaldehyde and ammonium hydroxide,
which gave 4 in quantitative yield in absence of by-prod-
ucts. The N-benzylation of 4 was then performed (Scheme
V) by reaction with benzyl bromide and sodium hydride in
anhydrous dimethylformamide, giving the target com-
pound 1 in reasonable yield (40%) together with small
amounts of unreacted 4, which was not recovered, and of a
by-product. This one was identified as N,3-dibenzyl-3,5-
dicarbethoxy-6-methyl-2-methylene-4-phenyl-1,2,3,4-
tetrahydropyridine 9, on the basis of its H- and C-nmr,
DEPT and HMQC spectra. The formation of this com-
pound can be reasonably explained by deprotonation of
one of the methyl groups in compound 1 using sodium
hydride to form the resonance-stabilized anion 10, which
can then react with benzyl bromide at C-3 to give the
dibenzyl derivative 9 (Scheme VI). As a consequence,
even though the transformation of the starting compound 4
is incomplete, this side-reaction prevents the possibility to
increase the reaction yield by forcing the reaction condi-
tions. For example, when we tried to use excess sodium
hydride and benzyl bromide, we only obtained increased
amounts of the by-product 9.
1
13
Scheme III
Scheme IV
Scheme V
Consequently, we shifted to a different synthetic strat-
egy, involving preparation of 3,5-dicarbethoxy-2,6-
dimethyl-4-phenyl-1,4-dihydropyridine 4 and its subse-
quent N-benzylation to give 1. The best method to prepare
4 turned out to be the classical Hantzsch procedure

1120
M. G. Rimoli, L. Avallone, S. Zanarone, E. Abignente, A. Mangoni
Vol. 39
Scheme VI
methylsilane as internal standard (d scale). Mass spectra were
recorded at 70 eV on a VG Prospec-Autospec (Fisons) mass
spectrometer. Elemental analyses were within ±0.4% of the theo-
retical values.
In spite of the relatively low yield of the last step, the
synthetic procedure described appears reasonably satisfac-
tory for further use of 1 as lead compound of pharmaco-
logical interest. However, such N-benzyl-1,4-dihydropyri-
dine could undergo N-debenzylation in vivo: in this case,
it would be inadequate for pharmacological purposes.
Nevertheless, some reports showed that several similar
compounds proved to be stable in vivo and to have inter-
esting pharmacological activity. For example, Ohsumi et
al. [18] synthesized a series of N-arylalkyl-4-aryl-3,5-
dicarbomethoxy-2,6-dimethyl-1,4-dihydropyridines
(including the N-benzyl derivative) which showed high
antitumor activity in vitro and in vivo in combination with
vincristine and were more potent than verapamil in poten-
tiating the cytoxicity of vincristine. Donkor et al. [19]
described a series of analogous N-adamantyl substituted
compounds with radioprotective activity, whereas another
series of N-substituted (also with benzyl moiety) 1,4-dihy-
dropyrines were described by Lusis and Duburs [20].
Hantzsch Procedure for Preparation of Compound 1.
A mixture of 20 ml (0.2 mol) of benzaldehyde, 50 ml (0.4
mol) of ethyl acetoacetate and 22 ml (0.2 mol) of benzylamine
was stirred at reflux for 24 hours. The crude reaction product
was partitioned between diethyl ether and water. The ethereal
phase was dried over anhydrous sodium sulfate, evaporated and
purified by column chromatography on silica gel, using chloro-
form as eluent. The first product eluted was the fluorescent com-
pound 2 (5% yield), followed by the required compound 1 (1%
yield) and then by the dihydropyridine 4 (3% yield) and the
phenylcyclohexanone 3 (48% yield).
N-Benzyl-3,5-dicarbethoxy-2,6-dimethyl-4-phenyl-1,4-dihy-
dropyridine (1).
This compound was obtained as a white powder, mp 157-158°
(n-hexane); 1H nmr (deuteriochloroform): d 7.20-7.10 (several
overlapping signals, 10H, phenyl protons), 5.12 (s, 1H, 4-H),
4.79 (s, 2H, NCH2), 4.05 (q, J = 7 Hz, 4H, 3,5-COOCH2CH3),
2.04 (s, 6H, 2,6-CH3), 1.20 (t, J = 7 Hz, 6H, 3,5-COOCH2CH3);
13C nmr (deuteriochloroform): d 167.9 (two CO), 148.4 (2,6-C),
146.2 (phenyl 1-C), 137.5 (benzyl 1-C), 128.5-125.7 (10 benzyl
and phenyl CH), 106.7 (3,5-C), 59.7 (two ethyl CH2), 49.3
(NCH2), 38.0 (4-CH), 16.5 (2,6-CH3), 14.0 (two ethyl CH3).
Anal. Calcd. for C26H29NO4: C, 74.44; H, 6.97; N, 3.34.
Found: C, 74.24; H, 6.79; N, 3.15.
EXPERIMENTAL
Analytical thin layer chromatography (tlc) was carried out on
precoated (0.25 mm) Merck silica gel 60 F254 plates; detection
of compounds was made by uv light and/or treatment with iodine
vapours. Preparative chromatography was performed using
columns packed with Farmitalia Carlo Erba silica gel RS (0.05-
0.20 mm). Melting points were determined by a Kofler hot-stage
microscope and are uncorrected. 1H- and 13C-nmr spectra were
recorded on a Bruker AMX-500 spectrometer equipped with a
Bruker X-32 computer, using deuterated solvents and tetra-
N-Benzyl-2,4-dicarbethoxy-5-methyl-3-phenylaniline (2).
This compound was obtained as a white powder, mp 86-87° (n-
hexane); 1H nmr (deuteriochloroform): d 7.40-7.15 (several over-

Nov-Dec 2002
Research on Heterocyclic Compounds. XLIII
1121
lapping signals, 10H, 3-phenyl and benzyl aromatic protons), 6.90
(br, 1H, NH), 6.40 (s, 1H, 6-H), 4.39 (br, 2H, NCH2), 3.79, 3.70
(2q, each, 2H, ethyl CH2, J = 7 Hz), 2.21 (s, 3H, 5-CH3), 0.79, 0.58
(2t, each, 3H, ethyl CH3, J = 7 Hz); 13C nmr (deuteriochloroform):
d 168.0 (two CO), 148.0 (5-C), 142.9 (3-C), 140.2 (phenyl 1-C),
139.0 (benzyl 1-C), 138.0 (1-C), 129.0-126.0 (10 benzyl and
phenyl CH), 122.9 (2-C), 111.8 (4-C), 111.0 (6-CH), 60.0, 60.1
(two ethyl CH2), 46.5 (NCH2), 20.0 (5-CH3), 12.8, 12.2 (two ethyl
CH3); eims: m/z 417 (100), 370 (78), 342 (71), 314 (35), 91 (72).
Anal. Calcd. for C26H27NO4: C, 74.80; H, 6.52; N, 3.35.
Found: C, 74.58; H, 6.35; N, 3.23.
Hantzsch Procedure for Preparation of Compound 4.
A mixture of 10 ml (0.08 mol) of ethyl acetoacetate, 4 ml (0.04
mol) of benzaldehyde and 4 ml of concentrated ammonia was
stirred and refluxed for 3 hours. The crude reaction product was
partitioned in dichloromethane/water mixture. The organic phase
was dried on anhydrous sodium sulfate and then evaporated to
give 13 g of compound 4 (100% yield).
Preparation of Compound 1 by N-Benzylation of Compound 4.
The reaction was carried out under a nitrogen atmosphere. A
solution of 1 g of 4 (3 mmol) in dry dimethylformamide was
stirred at room temperature and added dropwise with 100 mg of
sodium hydride (60% dispersion in mineral oil). After 30 min the
reaction mixture was cooled at 0° and 375 mg (1.5 mmol) of ben-
zyl bromide were added. After 30 min cooling was stopped and
the same amounts of sodium hydride and benzyl bromide were
added again. The reaction was run at 0° for 30 min and then at
room temperature for 60 min. The mixture was evaporated and
extracted with diethyl ether. The organic phase was washed with
water, dried over sodium sulfate, concentrated and purified by
column chromatography on silica gel, using dichloromethane as
eluent. The first product eluted in small amount was compound
9, followed by the required compound 1 (40% yield).
2,4-Dicarbethoxy-5-hydroxy-5-methyl-3-phenylcyclohexanone
(3).
This compound was obtained as an amorphous solid; mp 156-
157° (n-hexane); 1H nmr (deuteriochloroform): d 7.25-7.15 (some
overlapping signals, 5H, phenyl protons), 3.97 (q, 2H,
2-COOCH2CH3), 3.92 (m, 1H, 3-H), 3.78 (q, 2H,
4-COOCH2CH3), 3.69 (s, 1H, 5-OH), 3.64 (d, J = 10 Hz, 1H,
2-H), 2.99 (d, J = 10 Hz, 1H, 4-H), 2.66 (d, J = 12 Hz, 1H, 6-H),
2.47 (br d, J = 12 Hz, 1H, 6-H), 1.30 (s, 3H, 5-CH3), 0.98 (t, J = 7
Hz, 3H, 2-COOCH2CH3), 0.75 (t, J = 7 Hz, 3H, 4-COOCH2CH3);
13C nmr (deuteriochloroform): d 201.1 (1-CO), 173.6 (2-COOEt),
167.4 (4-COOEt), 137.8 (phenyl 1-C), 128.4-127.5 (five phenyl
CH), 72.8 (5-C), 62.2 (2-CH), 60.8 (two ethyl CH2), 56.7 (4-CH),
52.4 (6-CH2), 45.0 (3-CH), 28.4 (5-CH3), 13.6-13.2 (two ethyl
CH3); fabms (glycerol, positive ion mode): m/z 349 (100).
Anal. Calcd. for C19H24O6: C, 65.50; H, 6.94. Found: C,
65.22; H, 6.74.
N,3-Dibenzyl-3,5-dicarbethoxy-6-methyl-2-methylene-4-
phenyl-1,2,3,4-tetrahydropyridine (9).
This compound was obtained as an amorphous solid. 1H nmr
(deuteriochloroform): d 7.40-7.15 (several overlapping signals,
15H, aromatic protons), 5.19 (d, J = 12 Hz, 1H, N-CH2Ph), 4.82
(br s, 1H, 2-CH2), 4.65 (d, J = 12 Hz, 1H, N-CH2Ph), 4.58 (br s,
1H, 2-CH2), 4.28 (s, 1H, 4-H), 4.02 (q, J = 7 Hz, 2H,
5-COOCH2CH3), 3.84 (q, J = 7 Hz, 2H, 3-COOCH2CH3), 3.50
(d, J = 11 Hz, 1H, 3-CH2Ph), 3.08 (d, J = 11 Hz, 1H, 3-CH2Ph),
2.63 (s, 3H, 6-CH3), 1.15 (t, J = 7 Hz, 3H, 5-COOCH2CH3), 1.03
(t, J = 7 Hz, 3H, 3-COOCH2CH3); 13C nmr (deuteriochloro-
form): d 171.1 (3-CO), 168.2 (5-CO), 149.0 (6-C), 142.5 (2-C),
138.2 (phenyl 1-C), 137.2 (3-benzyl 1-C), 130.2-125.6 (15 ben-
zyl and phenyl CH), 101.5 (5-C), 99.2 (exocyclic =CH2), 60.4
(3-COOCH2CH3), 59.5 (5-COOCH2CH3), 55.4 (3-C), 53.6 (N-
benzyl CH2), 48.7 (4-CH), 43.4 (3-benzyl CH2), 17.2 (6-CH3),
14.2 (3-COOCH2CH3), 13.7 (5-COOCH2CH3).
3,5-Dicarbethoxy-2,6-dimethyl-4-phenyl-1,4-dihydropyridine
(4).
This compound was obtained as a white powder, mp 156-157°
(n-hexane);1H nmr (deuteriochloroform): d 7.30-7.10 (some over-
lapping signals, 5H, phenyl protons), 6.10 (s, 1H, NH), 5.02 (s, 1H,
4-H), 4.10 (q, J = 7 Hz, 4H, 3,5-COOCH2CH3), 2.30 (s, 6H, 2,6-
CH3), 1.25 (t, J = 7 Hz, 6H, 3,5-COOCH2CH3); 13C nmr (deuteri-
ochloroform): d 167.5 (two CO), 147.5 (2,6-C), 144.0 (phenyl
1-C), 128.5-126.1 (five phenyl CH), 104.1 (3,5-C), 60.0 (two ethyl
CH2), 40.0 (4-CH), 19.8 (2,6-CH3), 14.0 (two ethyl CH3).
Anal. Calcd. for C19H23NO4: C, 69.28; H, 7.04; N, 4,25.
Found: C, 69.04; H, 6.84; N, 4.16.
Anal. Calcd. for C33H35NO4: C, 77.77; H, 6.92; N, 2.75.
Found: C, 77.65; H, 6.78; N, 2.55.
Collie Procedure for Preparation of Compound 1.
Acknowledgements.
To a solution of 2 ml (0.02 mol) of benzaldehyde in pyridine,
cooled at 0°, 2.5 ml (0.02 mol) of ethyl acetoacetate and some
drops of diethylamine were added. The solution was stirred at
room temperature for 10 hours and then evaporated obtaining the
first intermediate product, namely ethyl 2-benzylideneacetoac-
etate 7. At the same time, a mixture of 2.7 ml (0.02 mol) of ben-
zylamine and 2.5 ml (0.02 mol) of ethyl acetoacetate in ethanol
was stirred and refluxed for 10 hours. The solution was then
evaporated in order to obtain the second intermediate product,
namely ethyl 3-benzylaminocrotonate 8, which was dissolved in
pyridine and added to the first compound 7. The mixture was
stirred at room temperature for 24 hours, then evaporated and
extracted with chloroform. The extract was washed with water,
dried over sodium sulfate, concentrated and purified by column
chromatography on silica gel, using ethyl acetate/n-hexane as
eluent. The first product eluted was 2, followed by the required
compound 1 (2% yield).
The NMR spectra were performed at "Centro di Ricerca
Interdipartimentale di Analisi Strumentale", Università di Napoli
Federico II. The assistance of the staff is gratefully appreciated.
REFERENCES AND NOTES
*
Corresponding author; E-mail: rimoli@unina.it;
Telephone: 01139-081-678612; Telefax: 01139-081-678609.
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Vol. 39
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