Mild, selective, and high-yield oxidation of hantzsch 1,4-dihydropyridines with lead(IV) acetate

Article abstract of DOI:10.3987/COM-04-10194

Aromatization of 1,4-dihydropyridines with lead(IV) acetate under mild reaction conditions is described. The method is very selective, mild and versatile in the synthesis of different substituted pyridines.

Full text of DOI:10.3987/COM-04-10194

HETEROCYCLES, Vol. 65, No. 1, 2005
23
HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 23 - 35
Received, 30th July, 2004, Accepted, 26th November, 2004, Published online, 29th November, 2004
MILD, SELECTIVE, AND HIGH-YIELD OXIDATION OF HANTZSCH
1,4-DIHYDROPYRIDINES WITH LEAD(IV) ACETATE
Mladen Litvić,a,* Ivica Cepanec,a Mirela Filipan,a Karmen Kos,a Anamarija
Bartolinčić,a Vinka Drušković,a Mohamed Majed Tibi,a and Vladimir
Vinkovićb
aR&D, Belupo Pharmaceuticals & Cosmetics Inc., Radnicka c. 224, 10000
b
Zagreb, Croatia; Rudjer Boskovic Institute, Bijenicka c. 54, 10002 Zagreb,
Croatia; e-mail: mladen.litvic@belupo.hr
Abstract – Aromatization of 1,4-dihydropyridines with lead(IV) acetate under
mild reaction conditions is described. The method is very selective, mild and
versatile in the synthesis of different substituted pyridines.
INTRODUCTION
1,4-Dihydropyridines (1,4-DHPs) are very important class of compounds because of their pharmacological
activity as a calcium antagonist or agonist.1 The 1,4-DHP compounds cause vasorelaxation by blocking
voltage-operated calcium channel in smooth muscle cells and also by increasing NO release from the intact
endothelium.2 Some representatives like nifedipine, nicardipine or amlodipine are widely used for
treatment of hypertension.
NO
2
Cl
NO
2
CH OOC
COOC H
CH OOC
COO
CH
Ph
CH OOC
COOCH
3
2
5
3
3
3
3
N
O
CH
N
H
NH
2
CH
N
H
CH
CH
N
H
CH
3
3
3
3
3
nifedipine
nicardipine
amlodipine
1,4-DHPs have also been extensively utilised as the analogs of NAD(P)H coenzymes to study the
mechanism and synthetic methods to obtain various NAD and NADH analogues. During the redox
processes3 and in the course of drug metabolism4 1,4-DHP systems are oxidatively transformed into the
corresponding 4-arylpyridine derivatives, which are found to be of use in the treatment of arteriosclerosis.5
Similarly, 1,4-DHPs are slowly oxidised with air oxygen during storage. Therefore, oxidised 1,4-DHPs are

24
HETEROCYCLES, Vol. 65, No. 1, 2005
important either for pharmacological studies or as analytical standards in analysis of pharmacologically
active 1,4-DHPs. Consequently, oxidation of 1,4-DHPs has been the subject in a large number of studies
and a plethora of reagents are used for this purpose. The oldest and the most used reagents for aromatization
of 1,4-DHPs is nitric acid of different concentrations, 20% HNO3,6,7 50% HNO3,8,9 2M HNO3,10 5M
HNO311 and 6M HNO3.12 Nitrous acid is also used in situ prepared from sodium nitrite and different acids;
17
NaNO2/HOAc,12-14 NaNO2/HCl,15 NaNO2/NaHSO4,16 NaNO2/Mg(HSO4)2 or NaNO2/oxalic acid
dihydrate.18 Gaseous nitrogen monoxide is also employed for that purpose.19,20 Metal nitrates such as
Bi(NO3)3·5H2O,21 Fe(NO3)3/SiO2,22 (NH4)2[Ce(NO3)6]; (CAN),23 and recently Zr(NO3)424 are described as
mild aromatization reagents. Additionally, the aromatization of 1,4-DHPs has been efficiently conducted
25
with chromium compounds such as CrO3, CrO2,26 H2CrO4,27 pyridinium dichromate,28 nicotinium
dichromate,29 pyridinium chlorochromate30 and Zn(ClCrO3)2·9H2O,31 as well as other metal salts such as
Mn(OAc)3,32 BaMnO4,33 FeCl3·6H2O,34 K3[Fe(CN)6],35 RuCl3/O2(g),36 KMnO437 Hg(OAc)238 and SnCl4.39
Other non-metallic reagents which are able to oxidise 1,4-DHPs include DDQ,40 chloranil,41
tert-butylhydroperoxide,42 dibenzoyl peroxide,43 and molecular iodine.44 Microwave promoted
aromatization of 1,4-DHPs is also described.45 The main drawback for the most of these methods is
prolonged heating needed to complete the conversion that cause lowering of the yield. Only few reagents
are able to complete the reaction at room temperature. On the other hand, almost all reagents are tested only
for model 1,4-DHPs that lack of the presence of functional groups sensitive to oxidation. The main problem
when metal nitrates or nitrites are used as oxidants is possible formation of carcinogenic N-nitroso
side-products. Therefore, it is still necessary to find milder and especially selective oxidant for the Hantzsch
1,4-DHPs. In this course we attempt to find strong and selective oxidant to complete oxidation under mild
conditions (room or lower temperature) but also to be tolerant to a variety of functionalities present in some
commercial 1,4-DHPs.
RESULTS AND DISCUSSION
It is known from the literature46 that lead(IV) acetate, Pb(OAc)4, is a very strong oxidant used specially in
sugar chemistry for the cleavage of carbon-carbon bond or decarboxylation, and for rearrangement of
aliphatic or cyclic ethers. Lead(IV) acetate is also used as a mild and selective oxidant in dihydroacridine
chemistry.47,48 To our knowledge this reagent has not yet been used for aromatization of 1,4-DHPs. We
wish to report here that lead(IV) acetate readily and selectively oxidises substituted 1,4-DHPs in high
yields.49 Study of this reaction is performed on model compound but also on commercial 1,4-DHPs, such as
amlodipine (11), with protected (compound (10)) and free amino group. The selectivity obtained from the
reaction with Pb(OAc)4 increased the importance of this oxidant because it was reported that only CAN23
has a similar selectivity for the aromatization of 1,4-DHPs. Many oxidants published in the literature cause

HETEROCYCLES, Vol. 65, No. 1, 2005
25
polymerisation of starting material without a trace of the product. We have also noticed that Pb(OAc)4
dealkylates 4-alkyl-1,4-DHPs similarly to other metal oxidants. The results of oxidation presented by
Scheme 1 are summarised in Table 1.
Scheme 1
R'
R
COOR1
CH2R2
Pb(OAc)4, CH2Cl2/HOAc (9:1)
room temperature
CH3OOC
CH3
COOR1
CH2R2
CH3OOC
CH3
N
N
H
16-28
1-15
Table 1. The oxidation of 1,4-DHPs with lead(IV) acetate, Scheme 1
Yield/
time/
1,4-
R
R1
R2
Producta
R'
b
DHP
min
%
1
2
H
CH3
H
“
“
“
“
“
“
“
“
16
16
16
17
18
19
20
21
22
23
H
120
60
90
93
71
90
76
75
89
96
76
97
CH(CH3)2
CH2Ph
“
“
3
“
“
15
4
Ph
“
Ph
15
5
m-Cl-C6H4
p-Cl-C6H4
o-NO2-C6H4
m-NO2-C6H4
“
“
m-Cl-C6H4
p-Cl-C6H4
o-NO2-C6H4
m-NO2-C6H4
o-NO2-C6H4
o-Cl-C6H4
20
6
20
7
“
60
8
C2H5
60
9
o-NO2-C6H4 CH2CH(CH3)2
45
10
o-Cl-C6H4
C2H5
“
OCH2CH2Phtc
OCH2CH2NH2
OCH2CH2NBz2
OCH2CH2NHAcf
OCH2CH2Xg
H
1140
11
“
24
“
30
92d
95
91
86
e
12
13
14
15
“
“
“
“
“
“
25
26
27
28
“
15
1200
720
5
“
“
m-NO2-C6H4 (CH2)2NCH3Bze
m-NO2-C6H4
-
h
a
Pyridine derivatives (16-27) were fully characterised (EXPERIMENTAL) since the data present in the literature are not
complete.
b
g
c
d
e
f
Yield after purification in isopropyl ether. Pht = phthalimido group. Isolated as acetate salt. Bz = CH2Ph. Ac = CH3CO.
h
X = 3,4,5,6-tetrachlorophthalimido group. Decomposition of starting material.

26
HETEROCYCLES, Vol. 65, No. 1, 2005
The best solvent for oxidation of 1,4-DHPs using Pb(OAc)4 is proved to be a mixture of dichloromethane
and acetic acid (9:1, v/v). Usually, the common reaction medium used for oxidation of 1,4-DHPs with
metal salts is acetic acid,12-14,21,24,32 but such conditions required the complete neutralisation during the
work-up procedure. The employed mixture of solvents allows the precipitation of lead(II) acetate during the
reaction and almost quantitative removal of lead salts by filtration in the work-up procedure. This minimise
the toxic water waste usually present when other metal salts are used, such as chromium compounds,25-31
CAN,23 Mn(OAc)3,32 Bi(NO3)3,21 Zr(NO3)4,24 SnCl439 etc.
The oxidation is accomplished within 15-120 min except in the cases of imido derivatives (10 and 14)
and N-acetyl derivative (13). Although, the conversion of about 50% in all three N-acyl derivatives is
reached in approximatelly 30 min, the complete consumption of starting material is observed only after
prolonged stirring. It is also important to note that during oxidation of this three compounds (10), (13)
and (14) lead(II) acetate does not precipitate from the reaction mixture, suggesting that it remains
complexed with a product. On the contrary, free amino or dibenzylamino group present in compounds
(11) and (12) increases oxidation power of lead(IV) and does not complex lead(II). The presence of
N-acyl group in molecule seems to be crucial for decreasing of reaction speed probably via complexation
of lead(IV) by the product formed as the reaction proceeds. The conversion of starting material in all
cases is quantitative. Only compound (15) was not succesfully oxidised probably due to oxidative
dealkylation of an activated ester group present in molecule. The compound (24) is prepared
independently in the form of a free base starting from compound (23) by deprotection of phthalimido
group in reaction with hydrazine hydrate, according to Scheme 2.
Scheme 2
Cl
Cl
N2H4·H2O, i-C3H7OH
CH3OOC
CH3
COOC2H5
CH3OOC
CH3
COOC2H5
O
reflux
O
O
N
N
N
NH2
O
24
23
The mechanism (Scheme 3, described on the model compound (4)) of lead(IV)-promoted oxidation
probably includes the formation of radical cation (29), which subsequently loses proton to generate the
radical (30) that is further oxidised to protonated derivative (31), similarly to manganese(III)-promoted
oxidation.32 Finally, deprotonation leads to pyridine derivative (17). It is also possible to predict the direct
oxidation of 1,4-DHP (4) to pyridinium salt (31) due to the fact that reduction of lead(IV) to lead(II)
requires two electron transfers from 1,4-DHP.

HETEROCYCLES, Vol. 65, No. 1, 2005
27
Scheme 3
-1 electron
+2 electrons
CH3OOC
H Ph
Ph
H Ph
COOCH3
CH3
CH3OOC
CH3
COOCH3
CH3
CH3OOC
CH3
COOCH3
CH3
-H+
Pb(IV)
+
-Pb(II)
CH3
N
N
H
N
H
4
H
30
29
+2 electrons
Pb(IV)
-Pb(II)
+2 electrons
-1 electron
Pb(IV)
-Pb(II); -H+
Ph
N
-2 electrons
CH3OOC
CH3
COOCH3
CH3
+
H
-H+
Ph
31
CH3OOC
CH3
COOCH3
CH3
N
13
In summary, new aromatization method of 1,4-DHPs using lead(IV) acetate allows fast, simple, practical
and efficient way of preparation of a wide variety of substituted pyridine derivatives. The highest
advantage of this method is the tolerance to various functional groups, such as free and substituted amino
group that allows one-step synthesis of valuable amlodipine oxidation product.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer Spectrum One spectrophotometer, and 1H-NMR and 13C-NMR
spectra on a Bruker 600 for CDCl3 solution, shifts are given in ppm downfield from TMS as an internal
standard. All the mass spectra were obtained on FTMS Finigen 2001 DD spectrometer. TLC analyses were
performed on Merck’s (Darmstadt, Germany) DC-alufolien with Kieselgel 60254. Elemental analyses were
done in Central Analytical Service (CAS) at Ruđer Bošković Institute. 1,4-DHPs (4-7), (12) and (13) are
prepared according to literature method.50-52 Amlodipine (11) as a free base is prepared from appropriate
besylate salt by acid-base extraction. Nitrendipine (8) was donated from Shijiazhuang Pharm., China, while
nisoldipine (9) from Triquimsat Co., Argentina.
General procedure for the oxidation of 1,4-DHP with Pb(OAc)4. To a solution of 1,4-DHP (2.0 mmol)
in CH2Cl2/HOAc (9:1, 6 mL) at rt Pb(OAc)4 (0.89 g, 2.0 mmol) was added in small portions during 15 min.
The reaction mixture was stirred for the time indicated in the Table 1. The precipitated solid was removed

28
HETEROCYCLES, Vol. 65, No. 1, 2005
by filtration, dichloromethane (20 mL) was added, and then reaction mixture was neutralised with 5%
aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The crude product was
additionally purified by recrystallisation from isopropyl ether.
2,6-Dimethyl-3,5-dimethoxycarbonylpyridine (16). Colorless plates; mp 103.0-104.0°C (lit.,53 100°C);
yields: Entry 1 (0.41 g, 90%), Entry 2 (0.41 g, 93%), Entry 3 (0.32 g, 71%). Rf (10% C2H5OAc/CH2Cl2)
0.38; IR ν (KBr) 1722, 1435, 1363, 1285, 1107, 772 cm-1. 1H-NMR (CDCl3) δ: 2.86 (6H, s, CH3), 3.93 (6H,
s, OCH3), 8.71 (1H, s, CH). 13C-NMR (CDCl3) δ: 24.65, 52.16, 122.61, 141.01, 162.42, 166.03. MS
(m/z, %) 224 (M,+ 100), 192 (5), 183 (5), 179 (6), 170 (21). Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87;
N, 6.27. Found: C, 59.1; H, 5.7; N, 6.1.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-phenylpyridine (17). Pale yellow plates; mp 128.0-132.0°C
(from isopropyl ether); yield 0.54 g (90%). Rf (10% C2H5OAc/CH2Cl2) 0.26; IR ν (KBr): 2956, 1733, 1563,
1439, 1288, 1243, 702 cm-1. 1H-NMR (CDCl3) δ: 2.69 (6H; s, CH3), 3.55 (6H, s, OCH3), 7.22-7.26 (2H, m,
13
Ph), 7.41-7.43 (3H, m, Ph). C-NMR (CDCl3) δ: 21.38, 52.36, 127.86, 127.35, 128.27, 128.95, 135.42,
154.58, 166.98. MS (m/z, %) 300 (MH,+ 100), 268 (47), 236 (23), 224 (34), 194 (19), 170 (20). Anal. Calcd
for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.1; H, 5.8; N, 4.6.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(m-chlorophenyl)pyridine (18). Colorless prisms; mp
112.5-114.0°C (from isopropyl ether); yield 0.51 g (76%). Rf (10% C2H5OAc/CH2Cl2) 0.30; IR ν (KBr):
2961, 1732, 1559, 1423, 1238, 1210, 1108, 1033 cm-1. 1H-NMR (CDCl3) δ: 2.61 (6H, s, CH3), 3.59 (6H, s,
OCH3), 7.14 (1H, d, J = 7.5 Hz, Ph), 7.26 (1H, t, J = 1.8 Hz, Ph), 7.30–7.38 (2H, m, Ph). 13C-NMR (CDCl3)
δ: 22.75, 52.06, 125.98, 126.36, 127.76, 128.55, 129.31, 134.03, 137.94, 144.52, 155.65, 167.76. MS
(m/z, %) 334 (MH,+ 100), 301 (16), 270 (39). Anal. Calcd for C17H16NO4Cl: C, 61.18; H, 4.83; N, 4.20; Cl,
10.62. Found: C, 61.2; H, 4.7; N, 4.1; Cl, 10.4.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(p-chlorophenyl)pyridine (19). Colorless needles; mp
140.0-143.0°C (from isopropyl ether) (lit.,53 137-139°C); yield 0.50 g (75%). Rf (10% C2H5OAc/CH2Cl2)
0.28; IR ν (KBr): 2953, 1733, 1557, 1492, 1435, 1241, 1039, 1020, 857 cm-1. 1H-NMR (CDCl3) δ: 2.60 (6H,
s, CH3) 3.58 (6H, s, OCH3 ), 7.19 (2H, d, J = 2.0 Hz, Ph), 7.36 (2H, d, J = 2.0 Hz, Ph). 13C-NMR (CDCl3) δ:
32.45, 51.79, 126.13, 128.00, 128.77, 134.29, 144.48, 155.23, 167.60. MS (m/z, %) 334 (MH,+ 100), 302
(65), 270 (18), 179 (17), 170 (20), 123 (21). Anal. Calcd for C17H16NO4Cl: C, 61.18; H, 4.83; N, 4.20; Cl,
10.62. Found: C, 61.1; H, 4.7; N, 4.1; Cl, 10.5.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-nitrophenyl)pyridine
(20).
Yellow
powder;
mp
103.0-105.0°C (from isopropyl ether); yield 0.61 g (89%). Rf (10% C2H5OAc/CH2Cl2) 0.31; IR ν (KBr)
2954, 1727, 1615, 1562, 1531, 1437, 1355, 1253, 1114, 1039, 968, 870, 842, 811, 794, 755, 703 cm-1.
1H-NMR (CDCl3) δ: 2.66 (s, 6H, CH3), 3.51 (s, 6H, OCH3), 7.19–7.22 (1H, m, Ph), 7.55–7.67 (2H, m, Ph),
8.21 (1H, d, J = 8.0 Hz, Ph). 13C-NMR (CDCl3) δ: 23.61, 52.18, 124.32, 124.78, 129.59, 130.59, 131.94,

HETEROCYCLES, Vol. 65, No. 1, 2005
29
132.94, 145.20, 147.56, 157.02, 167.18. Anal. Calcd for C17H16N2O6: C, 59.30; H, 4.68; N, 8.14. Found: C,
59.1; H, 4.5; N, 8.0.
2,6-Dimethyl-3-methoxycarbonyl-4-(m-nitrophenyl)-5-ethoxycarbonylpyridine (21). Yellow oil; yield
0.69 g (96%). Rf (10% C2H5OAc/CH2Cl2) 0.36; IR ν (liquid film): 2983, 1721, 1560, 1438, 1373, 1293,
1214, 1108 cm-1. 1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz, CH3), 2.63 (3H, s, CH3), 2.64 (3H, s, CH3),
3.59 (3H, s, OCH3), 4.07 (2H, q, J = 14.3 Hz, CH2), 7.57–7.63 (2H, m, Ph), 8.17–8.18 (1H, m, Ph),
13
8.23–8.30 (1H, m, Ph). C-NMR (CDCl3) δ: 13.55, 22.94, 22.98, 52.25, 61.54, 123.03, 123.29, 129.12,
134.06, 137.90, 143.45, 147.70, 155.97, 156.09, 167.00, 167.55. MS (m/z, %) 359 (MH,+ 100), 341 (19),
327 (9), 313 (10). Anal. Calcd for C18H18N2O6: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.2; H, 5.0; N, 7.7.
2,6-Dimethyl-3-isobutyloxycarbonyl-4-(o-nitrophenyl)-5-methoxycarbonylpyridine (22). Yellow oil;
yield 0.59 g (76%). Rf (10% C2H5OAc/CH2Cl2) 0.37; IR ν (liquid film): 2962, 1729, 1559, 1532, 1349,
1236, 1110, 1042 cm-1. 1H-NMR (CDCl3) δ: 0.67 (6H, d, J = 6.9 Hz, (CH3)2CH), 1.52–1.59 (1H, m, CH),
2.56 (3H, s, CH3), 2.58 (3H, s, CH3), 3.41 (3H, s, OCH3), 3.52–3.55 (1H, m, CH2CH), 3.69–3.72 (1H, m,
CH2CH), 7.13–7.15 (1H, m, Ph), 7.47–7.50 (1H, m, Ph), 7.54–7.57 (1H, m, Ph), 8.11–8.13 (1H, dd, J1 = 8.1
Hz, J2 = 1.2 Hz, Ph). 13C-NMR (CDCl3) δ: 18.71, 18.76, 23.42, 23.52, 27.27, 51.93, 71.56, 124.20, 124.49,
125.04, 129.36, 130.06, 131.87, 132.73, 144.62, 147.42, 156.56, 156.70, 166.82, 167.08. Anal. Calcd for
C20H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.0; H, 5.6; N, 7.1.
2-[2-(N-Phthalimido)ethoxymethyl]-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-6-
methylpyridine (23). Pale yellow plates; mp 121.0-123.0°C (from izopropyl ether); yield 1.04 g (97%). Rf
1
(10% C2H5OAc/CH2Cl2) 0.25; IR ν (KBr): 1772, 1717, 1563, 1392, 1231, 1114, 717 cm-1. H-NMR
(CDCl3) δ: 0.91 (3H, t, J = 7.1 Hz, CH2CH3), 2.61 (3H, s, CH3), 3.53 (3H, s, OCH3), 3.72 (2H, t, J = 5.8 Hz,
CH2), 3.88 (2H, t, J = 5.8 Hz, CH2), 4.01 (2H, q, J = 13.9 Hz, CH2), 4.82–4.90 (2H, m, CH2), 7.14 (1H, dt,
J1 = 7.3 Hz, J2 = 1.6 Hz, Ph), 7.23–7.33 (2H, m, Ph), 7.39 (1H, d, J = 7.4, Ph), 7.70 (2H, dd, J1 = 3.0 Hz, J2
= 5.4 Hz, Ph), 7.83 (2H, dd, J1 = 3.0 Hz, J2 = 5.4 Hz, Ph). 13C-NMR (CDCl3) δ: 13.45, 23.18, 37.33, 52.17,
61.36, 67.60, 72.84, 123.19, 126.05, 126.42, 128.20, 129.05, 129.77, 130.29, 132.17, 132.89, 133.83,
134.97, 144.93, 156.09, 166.29, 167.35, 168.13. MS (m/z, %) 537 (MH,+ 100), 407 (16), 347 (12), 345 (16),
268 (16), 260 (17), 174 (10). Anal. Calcd for C28H25N2O7Cl: C, 62.63; H, 4.69; N, 5.22; Cl, 6.60. Found: C,
62.5; H, 4.6; N, 5.1; Cl, 6.5.
2-(2-Aminoethoxy)methyl-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-6-methyl-
pyridine as acetate salt (24). Pale yellow powder; mp 100.0-103.0°C (from isopropyl ether); yield 0.86 g
(92%). Rf (3% NH3(aq)/17% CH3OH/40% CH3CN/40% dioxane) 0.54; IR ν (KBr): 2988, 2952, 1727,
1555, 1434, 1415, 1236 cm-1. 1H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7.1 Hz, CH2CH3), 1.92 (3H, s, CH3),
2.65 (3H, s, CH3CO), 3.08 (2H, t, J = 4.8 Hz, CH2), 3.54 (3H, s, OCH3), 3.72 (2H, t, J = 4.9 Hz, CH2), 4.00
(2H, q, J = 7.1 Hz, CH2CH3), 4.81 (1H, d, J = 13.4 Hz, CH2O), 4.84 (1H, d, J = 13.4 Hz, CH2O), 7.17 (1H,

30
HETEROCYCLES, Vol. 65, No. 1, 2005
dd, J1 = 7.2 Hz, J2 = 1.6 Hz, Ph), 7.28 (1H, dt, J1 = 7.3 Hz, J2 = 1.1 Hz, Ph), 7.33 (1H, dt, J1 = 7.7 Hz, J2 =
1.6 Hz, Ph), 7.41 (1H, dd, J1 = 7.8 Hz, J2 = 0.9 Hz, Ph), 7.65 (3H, br s, D2O exchangeable, NH3). 13C-NMR
(CDCl3) δ: 13.23, 22.76, 22.92, 39.69, 52.01, 61.46, 68.74, 72.29, 125.99, 128.06, 128.95, 129.73, 130.07,
132.68, 134.75, 145.01, 155.54, 156.37, 166.36, 166.93, 176.97. Anal. Calcd for C22H27N2O7Cl: C, 56.59;
H, 5.83; N, 6.00; Cl, 7.59. Found: C, 56.5; H, 5.7; N, 5.9.
2-(2-Aminoethoxy)methyl-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-6-methyl-
pyridine as free base (24). To
a
suspension of 2-[2-(N-phthalimido)ethoxymethyl]-
3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-6-methylpyridine (23) in 10 mL of 96% ethanol
at rt hydrazine monohydrate (0.24 mL, 5.0 mmol) was added at once. The resulting solution was stirred for
20 h. The formed precipitate was filtered and washed with 5 mL of 96% ethanol. The organic solvent was
evaporated and the residue dissolved in 40 mL of dichloromethane. The resulting suspension was stirred for
15 min, filtered and obtained crystals washed with 15 mL of dichloromethane. Dichloromethane extracts
were evaporated and the residue was purified by chromatography on silica column with 10%
CH3OH/dichloromethane as eluent. After evaporation of selected fractions, Rf 0.14, compound (24) was
isolated as yellow oil; yield 0.40 g (98%). Rf (3% NH3(aq)/17% CH3OH/40% CH3CN/40% dioxane) 0.54;
IR ν (liquid film): 3376, 2951, 1731, 1595, 1436, 1232, 1109, 1043 cm-1. 1H-NMR (CDCl3) δ: 0.92 (3H, t,
J = 7.1 Hz, CH2CH3), 2.65 (3H, s, CH3), 2.75 (2H, br s, D2O exchangeable, NH2), 2.83 (2H, t, J = 4.9 Hz,
CH2), 3.49-3.54 (5H, m, CH2+CH3), 4.00 (2H, q, J = 14.22 Hz, CH2), 4.78 (1H, d, J = 12.7 Hz, CH2O), 4.84
(1H, d, J = 12.6 Hz, CH2O), 7.18 (1H, dd, J1 = 7.3 Hz, J2 = 1.7 Hz, Ph), 7.27-7.35 (2H, m, Ph), 7.42 (1H, d,
13
J = 7.3 Hz, Ph). C-NMR (CDCl3) δ: 13.37, 23.16, 41.69, 52.11, 61.24, 73.09, 73.31, 126.04, 128.10,
129.03, 129.75, 130.19, 132.81, 134.90, 156.02, 156.26, 166.54, 167.28. Anal. Calcd for C20H23N2O5Cl: C,
59.04; H, 5.70; N, 6.89; Cl, 8.71. Found: C, 59.0; H, 5.6; N, 6.8.
2-[2-(N,N-Dibenzylamino)ethoxymethyl]-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-
6-methylpyridine (25). Yellow oil; yield 0.56 g (95%). Rf (10% C2H5OAc/CH2Cl2) 0.50; IR ν (liquid
film): 3028, 2950, 1732, 1559, 1480, 1453, 1436, 1297, 1230, 1108, 1043, 750 cm-1. 1H NMR (CDCl3) δ:
0.83 (3H, t, J = 7.0 Hz, CH2CH3), 2.66 (3H, s, CH3), 3.56 (3H, s, OCH3), 3.59-3.61 (4H, m, CH2CH2), 3.64
(4H, s, 2xCH2Ph), 3.83-3.85 (2H, m, CH2CH3), 4.77 (1H, d, J = 12.5 Hz, CH2O), 4.80 (1H, d, J = 12.6 Hz,
CH2O), 7.18 (1H, d, J = 6.5 Hz, Ph), 7.24 (1H, d, J = 6.9 Hz, Ph), 7.29-7.32 (5H, m, Ph), 7.34-7.41 (6H, m,
13
Ph), 7.43 (1H, d, J = 7.9 Hz, Ph). C-NMR (CDCl3) δ: 13.44, 23.28, 52.17, 52.50, 58.89, 61.10, 69.70,
73.24, 126.09, 126.50, 128.17, 128.34, 128.76, 129.10, 129.77, 130.31, 132.95, 135.12, 139.64, 144.84,
156.02, 156.56, 166.41, 167.43. MS (m/z, %) 587 (MH,+ 100), 498 (26), 364 (21), 224 (61), 132 (33). Anal.
Calcd for C34H35N2O5Cl: C, 69.56; H, 6.01; N, 4.77; Cl, 6.04. Found: C, 69.7; H, 5.9; N, 4.9, Cl, 6.2.

HETEROCYCLES, Vol. 65, No. 1, 2005
31
2-[2-(N-Acetylamino)ethoxymethyl]-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-6-
methylpyridine (26). Yellow cubes; mp 66.0-68.0°C (from isopropyl ether); yield 0.40 g (91%). Rf (10%
1
CH3OH/CH2Cl2) 0.56; IR ν (KBr): 2949, 1732, 1657, 1559, 1430, 1286, 1227, 1042 cm-1. H NMR
(CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz, CH2CH3), 1.98 (3H, s, CH3), 2.68 (3H, s, CH3CO), 3.42 (2H, t, J = 4.8
Hz, CH2), 3.56 (3H, s, OCH3), 3.57-3.58 (2H, m, CH2), 4.06 (2H, q, J = 7.1, CH2CH3), 4.79 (1H, d, J = 12.7,
CH2O), 4.84 (1H, d, J = 12.8, CH2O), 6.40 (1H, br s, D2O exchangeable, NH), 7.17 (1H, dd, J1 = 7.5, J2 =
1.3, Ph), 7.29-7.32 (1H, m, Ph), 7.36 (1H, t, J = 7.5, Ph), 7.44 (1H, d, J = 7.9, Ph). 13C-NMR (CDCl3) δ:
13.50, 23.07, 23.20, 39.17, 52.24, 61.62, 69.96, 73.09, 126.18, 126.50, 128.43, 129.21, 130.02, 130.21,
132.89, 134.73, 145.19, 155.90, 156.28, 167.09, 167.15, 170.24. MS (m/z, %) 449 (MH,+ 100), 364 (16),
347 (14), 179 (26), 170 (70), 123 (41). Anal. Calcd for C22H25N2O6Cl: C, 58.86; H, 5.61; N, 6.24; Cl, 7.90.
Found: C, 58.7; H, 5.8; N, 6.4, Cl, 7.8.
2-[2-N-(3,4,5,6-Tetrachlorophthalimido)ethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-
methoxycarbonyl-6-methyl-1,4-dihydropyridine (27). Yellow cubes; mp 131.0-133.0°C (from 20%
i-C3H7OH/isopropyl ether); yield 0.58 g (86%). Rf (10% C2H5OAc/CH2Cl2) 0.53; IR ν (KBr): 1721, 1559,
1423, 1396, 1234, 1103, 1044 cm-1.1H-NMR (CDCl3) δ: 0.98 (3H, t, J = 7.1 Hz, CH2CH3), 2.63 (3H, s,
CH3), 3.53 (3H, s, OCH3), 3.66-3.69 (2H, m, CH2), 3.85-3.93 (2H, m, CH2), 4.00 (2H, q, J = 14.1 Hz, CH2),
4.74 (1H, d, J = 13.1, CH2O), 4.89 (1H, d, J = 13.1, CH2O), 7.09 (1H, dd, J1 = 7.5 Hz, J2 = 1.5 Hz, Ph),
7.24–7.30 (2H, m, Ph), 7.36 (1H, d, J = 7.2, Ph). 13C-NMR (CDCl3) δ: 13.49, 22.87, 38.28, 52.16, 61.44,
66.99, 73.20, 125.95, 126.23, 128.01, 128.31, 128.99, 129.38, 129.73, 130.21, 132.80, 134.78, 139.60,
145,10, 156.02, 156.10, 163.46, 166.08, 167.29. MS (m/z, %) 672 (M,+ 20), 363 (18), 347 (100), 318 (39),
268 (96). Anal. Calcd for C28H25N2O7Cl5: C, 49.84; H, 3.14; N, 4.15; Cl, 26.27. Found: C, 49.8; H, 3.0; N,
4.2; Cl, 26.4.
Synthesis of model 1,4-DHPs by modified Hantzsch condensation
2,6-Dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine (1). To a solution of methyl acetoacetate
(116.12 g, 1 mol) and 37% formaldehyde solution (40 mL, 15.55 g, 0.52 mol), cooled to 3°C, 1 mL of
triethylamine was added. The reaction mixture was stirred for 44 h and then extracted with distilled water
(200 mL). Water layer (upper) was additionally extracted with three portions of ether (100 mL). Organic
layers were gathered, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue
was dissolved in absolute ethanol (80 mL). Gaseous ammonia was introduced to that solution, previously
cooled to 0°C, during 2 h by keeping the temperature between 0-5°C. Reaction mixture was stirred for 48 h
at rt. After that the crystals were removed by filtration and washed with 96% ethanol (3x20 mL). Crude
product was additionally purified in refluxing isopropyl ether (200 mL) during 1 h, cooled to 3°C and left at
that temperature for 20 h. Crystals were filtered and washed with cold isopropyl ether (3x50 mL). After

32
HETEROCYCLES, Vol. 65, No. 1, 2005
drying in vacuum, product (1) was isolated as pale yellow powder; mp 211-219°C (from isopropyl ether);
yield 38.33 g (34%). Rf (10% C2H5OAc/CH2Cl2) 0.33; IR ν (KBr): 3346, 1698, 1646, 1505, 1432, 1219,
1183 cm-1. 1H-NMR (CDCl3) δ: 2.25 (6H, s, CH3), 3.27 (2H, s, CH2), 3.71 (6H, s, OCH3), 5.20 (1H, s, NH),
13
ppm; C-NMR (CDCl3) δ: 19.00, 24.71, 50.88, 99.28, 144.95, 168.24. Anal. Calcd for C11H15NO4: C,
58.66; H, 6.71; N, 6.22. Found: C, 58.4; H, 6.6; N, 6.1.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-isopropyl-1,4-dihydropyridine (2). To a solution of methyl
acetoacetate (232.24 g, 2.0 mol) and ammonium acetate (385.41 g, 5.0 mol) in 96% ethanol (1300 mL),
isobutyraldehyde (72.11 g, 1.0 mol) was added during 30 min. Reaction mixture was stirred at rt for 140 h.
After that solvent was evaporated and to the residue dichloromethane (1000 mL) and water (800 mL) were
added. The mixture was stirred for 15 min and the layers were separated. Water layer was additionally
extracted with dichloromethane (200 mL). Organic layers were collected, dried over anhydrous sodium
sulfate, filtered and evaporated. Crude product was crystallised from hot isopropyl ether (600 mL). After
drying in vacuum, product (2) was isolated as a colorless needles; mp 168.0-169.5°C; yield 90.38 g (38%).
Rf (10% C2H5OAc/CH2Cl2) 0.33; IR ν (KBr): 3338, 2954, 1706, 1651, 1490, 1218, 1077 cm-1. 1H-NMR
(CDCl3) δ: 0.73 (6H, d, J = 6.9, CH3), 1.52–1.61 (1H, m, CH), 2.31 (6H, s, CH3), 3.71 (6H, s, OCH3), 3.89
(1H, d, J = 5.4, CH), 6.09 (1H, br, NH). 13C-NMR (CDCl3) δ: 18.09, 19.05, 35.29, 38.61, 50.68, 101.16,
144.93, 169.07. Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C, 62.7; H, 7.9; N, 5.1.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-benzyl-1,4-dihydropyridine (3). To a solution of methyl
acetoacetate (58.06 g, 0.5 mol) and ammonium acetate (96.35 g, 1.25 mol) in 96% ethanol (300 mL), a
solution of phenylacetaldehyde (60.08 g of solution, 30.04 g of aldehyde, 0.25 mol) in diethyl phtalate
diluted with 96% ethanol (100 mL) was added during 30 min. Reaction mixture was stirred at rt for 140 h.
After that the solvent was evaporated to dryness and to the residue dichloromethane (500 mL) and water
(300 mL) were added. The layers were stirred for 15 min and separated. Water layer was additionally
extracted with dichloromethane (200 mL). Organic layers were collected, dried over anhydrous sodium
sulfate, filtered and evaporated. Crude product was crystallised from hot isopropyl ether (300 mL). After
drying in vacuum product (3) was isolated as a pale yellow powder; mp 156.0-159.0°C; yield 10.79 g
(13.7%). Rf (10% C2H5OAc/CH2Cl2) 0.45; IR ν (KBr): 3335, 1700, 1659, 1647, 1491, 1435, 1215 cm-1.
1H-NMR (CDCl3) δ: 2.19 (6H, s, CH3), 2.58 (2H, d, J = 5.5, CH2Ph), 3.60 (6H, s, OCH3), 4.19 (1H, t, J =
13
5.5, CH), 5.50 (1H, br, NH), 7.01-7.04 (2H, m, Ph), 7.11-7.22 (3H, m, Ph). C-NMR (CDCl3) δ: 19.01
35.28, 42.22, 50.74, 101.38, 125.50, 127.08, 129.97, 138.96, 145.62, 168.10. Anal. Calcd for C18H21NO4: C,
68.55; H, 6.71; N, 4.44. Found: C, 68.4; H, 6.6; N, 4.4.
2-[2-N-(3,4,5,6-Tetrachlorophthalimido)ethoxymethyl]-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-
met-hoxycarbonyl-6-methyl-1,4-dihydropyridine (14). To a solution of amlodipine (11, 2.05 g, 5
mmol) in glacial acetic acid (20 mL) 3,4,5,6-tetrachlorophtalanhydride (1.43 g, 5 mmol) was added. The

HETEROCYCLES, Vol. 65, No. 1, 2005
33
reaction mixture was heated at reflux temperature during 2 h. After cooling to rt reaction mixture was
poured in water (100 mL), neutralised with solid NaHCO3 and extracted with dichloromethane (3 x 50
mL). Combined organic layers were collected, dried over anhydrous sodium sulfate, filtered and
evaporated. Crude product was crystallised from hot methanol (50 mL). After drying in vacuum product
(14) was isolated as a yellow cubes; mp 185.0-187.0°C; yield 1.80 g (53%). Rf (10% C2H5OAc/CH2Cl2)
0.74; IR ν (KBr): 3360, 3061, 2982, 1775, 1720, 1693, 1641, 1614, 1482, 1429, 1395, 1365, 1309, 1281
1
cm-1. H-NMR (CDCl3) δ: 1.16 (3H, t, J = 7.18, CH2CH3), 2.45 (3H, s, CH3), 3.60 (3H, s, OCH3),
3.74–3.78 (2H, m, CH2CH3), 3.98–4.05 (4H, m, CH2CH2), 4.61 (1H, d, J = 15.64, CH2O), 4.73 (1H, d, J
= 15.64, CH2O), 5.29 (1H, s, CH), 5.35 (1H, s, NH), 6.99–7.12 (2H, m, Ph), 7.21 (1H, dd, J1 = 7.7 Hz, J2
= 1.3 Hz, Ph), 7.35 (1H, dd, J1 = 7.7 Hz, J2 = 1.7 Hz, Ph). 13C-NMR (CDCl3) δ: 13.96, 18.93, 36.70,
38.59, 50.53, 59.55, 68.03, 68.44, 100.83, 103.58, 126.72, 127.22, 127.43, 129.06, 129.80, 131.41, 132.20,
140.35, 144.58, 144.70, 145.85, 163.82, 167.12, 168.03. Anal. Calcd for C28H23N2O7Cl5: C, 49.69; H,
3.43; N, 4.14; Cl, 26.19. Found: C, 49.5; H, 3.3; N, 4.2; Cl, 26.3.
ACKNOWLEDGEMENTS
The authors wish to express their gratitude to the Belupo Pharmaceuticals & Cosmetics Inc. for financial
support of this research.
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