Syntheses and spectral properties of unsymmetrically 3,5-disubstituted 2,6-dimethyl-1,4-dihydropyridines

Article abstract of DOI:10.1135/cccc19961233

Unsymmetrically 3,5-disubstituted 4-(5-X-2-furyl)-2,6-dimethyl-1,4-dihydropyridines (where X = H, Br, NO₂) have been synthesized and characterized by spectral methods (IR, UV, ¹H NMR and MS). The modified Hantzsch method made it possible to prepare the title compounds as well as their N-alkylated derivatives. The paper also describes the N-alkylation of sodium salts of substituted 1,4-dihydropyridines using the phase-transfer catalysis.

Full text of DOI:10.1135/cccc19961233

1,4-Dihydropyridines Alkylation
1233
SYNTHESES AND SPECTRAL PROPERTIES OF UNSYMMETRICALLY
3,5-DISUBSTITUTED 2,6-DIMETHYL-1,4-DIHYDROPYRIDINES
1
†Dusan ILAVSKY and Viktor MILATA
Department of Organic Chemistry, Slovak Technical University, 812 37 Bratislava, Slovak Republic;
e-mail: 1 vmilata@cvt.stuba.sk or vmilata@chelin.chtf.stuba.sk
Received January 31, 1996
Accepted April 9, 1996
Unsymmetrically 3,5-disubstituted 4-(5-X-2-furyl)-2,6-dimethyl-1,4-dihydropyridines (where X = H,
Br, NO2) have been synthesized and characterized by spectral methods (IR, UV, 1H NMR and MS).
The modified Hantzsch method made it possible to prepare the title compounds as well as their
N-alkylated derivatives. The paper also describes the N-alkylation of sodium salts of substituted 1,4-
dihydropyridines using the phase-transfer catalysis.
Key words: 1,4-Dihydropyridines, alkylation; Hantzsch synthesis.
1,4-Dihydropyridines form a well-known group of chemotherapeutics – calcium anta-
gonists, i.e. compounds with antihypertensive activity1–8. The original Hantzsch syn-
thesis9 is a suitable method for syntheses of symmetrically 3,5-disubstituted
2,6-dimethyl-1,4-dihydropyridines with various substituents at 4-position depending on
the aldehyde used. Starting from the mechanism suggested for this reaction1 we can
devise possible syntheses of unsymmetrically 3,5-disubstituted 1,4-dihydropyridines:
the molecule of 1,3-dicarbonyl compound reacting with the aldehyde can differ from
that reacting with the amine, i.e. an α,β-unsaturated ketone and an enamine prepared
separately from different 1,3-dicarbonyl compounds can give the expected unsymmetri-
cally disubstituted product when reacting with each other. This possibility, which is
particularly advantageous in the context of preparation of activated esters with different
substituents at 3,5-positions before their subsequent partial hydrolysis6, has been dealt
with in a relatively small number of papers so far7,8,10,11. The aim of the present com-
munication was to prepare 1,4-dihydropyridines carrying a 5-X-2-furyl substituent (X =
H, Br, NO2) at 4-position and different substituents at 3- and 5-positions (acetyl,
alkoxycarbonyl) using the modified Hantzsch reaction, as well as to introduce an alkyl
into the 1,4-dihydropyridine skeleton using N-alkylated enamines or alkylation of so-
dium salts of 1,4-dihydropyridines (Scheme 1).
In a four-component reaction involving different 1,3-dicarbonyl compounds (differ-
ing distinctly in their reactivities) one can expect a reaction mixture with one of the
products predominating. We prepared such a model mixture from equal molar amounts
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1234
Ilavsky, Milata:
of ethyl 3-oxobutanoate, 2,4-pentanedione, 5-furancarboxaldehyde and ammonia in ethanol,
and its reaction gave the following products (determined by gas chromatography): only
41% unsymmetrically 3,5-disubstituted compound 2,6-dimethyl-3-acetyl-5-ethoxycar-
bonyl-4-(2-furyl)-1,4-dihydropyridine (1a) beside the symmetrically disubstituted com-
pounds, viz. 3,5-diethoxycarbonyl derivative (36%) and diacetyl derivative (23%).
With the aim of avoiding the chromatographic separation of compounds of similar
type, we tried to synthesize the unsymmetrically substituted 1,4-dihydropyridines making
use of the well-known mechanism of the Hantzsch reaction. Ethyl and methyl 3-oxo-
butanoates react with 5-X-2-furancarboxaldehydes at the conditions of the Knoevenagel
reaction to give the respective esters of 2-(5-X-2-furylidene)-3-oxobutanoic acid which
are directly converted into dihydropyridines (as the only products) in the Michael reac-
tion with equimolar amount of 2-amino-2-penten-3-one (Procedures A, C).
Starting from the mechanism of the Hantzsch reaction and from the finding that the
formation of dihydropyridine 1 necessitates the presence of at least one acetyl group at
the double bond in β-position with respect to 5-X-2-furyl residue, we carried out the
syntheses of dihydropyridines of type 1 also by the second possible way, viz. by the
reaction of ethyl 3-amino-2-butenoate with the 3-(5-X-2-furylidene)-2,4-pentanediones
obtained by the Knoevenagel reactions of the corresponding 5-X-2-furancarboxalde-
hydes with 2,4-pentanedione (Method B). The yields of dihydropyridines 1 are approxi-
mately equal in the two synthetic methods (Table I).
The N-substituted 4-(5-X-2-furyl)-3-acetyl-5-ethoxycarbonyl-2,6-dimethyl-1,4-di-
hydropyridines 3a, 3b, 4a were obtained by benzylation or methylation of the sodium
salts of dihydropyridines 1a and 1b according to ref.12 (Method E, Scheme 2). The
alkylation of sodium salt of dihydropyridine 1c was impossible at the reaction condi-
X
O
A, B, C
O
H
Me
X
Ac
+
Z
Ac
COOR
Me
Y
NH
2
Me
N
H
A : Y =COOEt; Z = Ac
B : Y =Ac; Z = COOEt
R = Et
1,
2,
Y =COOMe; Z = Ac
R = Me
C :
X
1, 2
H
a
b
c
Br
NO
2
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1,4-Dihydropyridines Alkylation
1235
TABLE I
Physico-chemical properties of 4-(5-X-2-furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydro-
pyridines 1–4
Calculated/Founda
Formula
M.w.
M.p., °C
Method
Yield, %
Compound
RF
% C
% H
% N
1a
1b
1cc
2a
2b
2c
3a
3b
4a
4b
4c
C16H19NO4
289.3
118–120
0.53b
A, B
66.42
66.28
6.62
6.54
4.84
4.65
85, 91
C16H18BrNO4
368.3
138–240
0.56b
A, B
52.19
51.99
4.93
4.89
3.80
3.68
80, 72
C16H18N2O6
334.3
149–153
0.50b
A, B
57.48
57.32
5.43
5.21
8.38
8.12
53, 49
C15H17NO4
275.3
164–165
0.53b
C
65.44
65.22
6.22
6.07
5.09
4.96
63
C15H16BrNO4
354.2
162–164
0.55b
C
50.87
50.68
4.55
4.32
3.95
3.78
68
C15H16N2O6
320.3
182–184
0.50b
C
56.25
56.04
5.03
4.87
8.75
8.56
62
C
23H25NO4
379.5
150–151
0.38d
D, F1
24, 5e
72.80
72.65
6.64
6.46
3.69
3.43
C23H24BrNO4
458.4
134–136
0.42d
F1, F2
8e, 6e
60.27
60.09
5.28
5.13
3.06
2.86
C17H21NO4
303.4
52–53
0.64d
E, F1, F2
38, 9e, 7e
67.31
67.13
6.98
6.76
4.62
4.45
C17H20BrNO4
382.3
72–73
0.70d
F2
10e
53.42
53.21
5.27
5.08
3.66
3.48
C17H20N2O6
348.4
96–100
0.62d
F1
8e
58.61
58.49
5.79
5.76
8.04
8.12
a % Br (calculated/found): for 1b: 21.70/21.89; 2b: 22.56/22.34; 3b: 17.43/17.24; 4b: 20.90/20.69.
b Chloroform–ethanol 10 : 1. c Ref.7 gives m.p. 149–150 °C. d Chloroform–ethanol 20 : 1. e Yields of
chromatography.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1236
Ilavsky, Milata:
tions mentioned because the reaction mixture turned black immediately upon formation of
the respective sodium salt (due to the presence of the nitro group in the furan nucleus).
For this reason we tried to synthesize the N-benzyl derivative 3a by a method using
2-benzylamino-2-penten-4-one instead of 2-amino-2-penten-4-one (which gives com-
pound 3a directly in the cyclocondensation reaction – Method D) but the dihydro-
pyridines 3b, 3c could not be prepared in this way either.
The benzylation was also carried out by the method of phase transfer catalysis
(Method F) using triethylbenzylammonium chloride (TEBA) (F1) and dimethylbenzyl-
dodecylammonium bromide (F2) as the catalysts. Both the methods give approximately
equal yields which, however, do not reach those of the cyclocondensation reaction. The
yields of compound 4a are higher in the methylation of sodium salt than in the phase-
transfer catalysis method, which is probably connected with the fact that compound 4a
separates almost quantitatively from aqueous medium as a precipitate which merely
needs to be recrystallized, whereas the reaction mixture obtained from the phase-transfer
method has to be separated by chromatography. The yields of compounds 3b and 4b
are about the same in the individual methods of preparation. In the case of methylation
of compound 1c by the phase-transfer catalysis method the reaction mixture turned
black but, nevertheless, it was possible to isolate compound 4c from it. Dihydro-
pyridine 3c could not be obtained by this method either. In all the cases, the alkylation
agent was used in 50% excess.
The UV spectra of these compounds (Table II) represent a superposition of absorp-
tion bands of two chromophores: 1,4-dihydropyridine and furan. The bands were
1
X
5’
E, F
4’
O
2’
3’
H
3
4
Ac
COOEt
5
D
2
Me
6
N 1 Me
R
O
Me
X
Ac
+
Ac
COOEt
NH CH2Ph
R = CH2Ph
R = Me
3,
4,
X
3, 4
H
a
b
c
Br
NO2
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1,4-Dihydropyridines Alkylation
1237
denoted as it is usual in literature. In all the cases the absorption bands represent a
typical π–π* transition of 1,4-dihydropyridine skeleton (band III) and furan or benzyl
substituent (bands I and II). The interpretation of UV spectra of compounds 1–4 could
start from the comparison of the UV spectra of these compounds with those of their
analogues, i.e. 3,5-diacetyl- (λmax = 404 nm), 3,5-diethoxycarbonyl- (λmax = 369 nm,
log ε = 2.88), 3,5-diacetyl-4-(2-furyl)- (λmax = 376 nm, log ε = 2.96), and 3,5-diethoxy-
carbonyl-4-(2-furyl)-2,6-dimethyl-1,4-dihydropyridines (λmax = 347, log ε = 2.96).
The introduction of a bulky substituent (furan nucleus) into 4-position causes a
hypsochromic shift and intensity increase of the longest-wave band (III). This phe-
nomenon agrees with available findings: an introduction of 4-substituent generally
causes a hypsochromic shift of this band which represents the π–π* transition of 1,4-di-
hydropyridine chromophore. The comparison of synthesized and model compounds
shows that the position of the longest-wave band is closest to that of 4-furyl-3,5-diacetyl
derivative. The bromo derivatives 1b and 2b show slight hypsochromic shift of band III,
whereas this shift is considerable (about 35 nm) in nitro derivatives 1c and 2c with
concomitant intensity increase of this band as compared with unsubstituted derivatives
1a and 2a.
TABLE II
UV spectra of 4-(5-X-2-furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines 1–4
Band I
Band II
Band III
Compound
λmax
log ε
λmax
log ε
λmax
log ε
1a
1b
1c
2a
2b
2c
3a
3b
4a
4b
4c
223
–
3.45
–
245
241
242
245
238
241
225
245
250
248
253
3.26
3.32
3.40
3.36
3.44
3.40
3.04
3.39
3.11
3.23
3.32
366
364
331
363
363
328
329
365
364
359
327
3.00
2.97
3.30
3.05
3.00
3.29
3.21
3.07
2.88
2.88
3.30
–
–
222
–
3.29
–
–
–
212
228
219
228
208
3.28
3.41
3.10
3.19
3.10
a λmax in nm, ε in m2 mol–1.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1238
Ilavsky, Milata:
The intensities of band II vary in the limits of 1 820–2 760 m2 mol–1 and those of the
less intensive band III in the limits of 930–2 000 m2 mol–1. The values of molar absorp-
tion coefficient of band III are about the same as those of the model symmetrical com-
pounds; for band II these values are in the middle between the values of the
above-mentioned model substances.
The N-methylation causes a bathochromic shift in band II (by 5–11 nm), whereas
band III is shifted hypsochromically (by 2–5 nm). The intensities of these bands are not
substantially changed as compared with those of the nonalkylated derivatives. The
1-benzylation changes the shape of the whole absorption spectrum which becomes a
superposition of absorption bands of three chromophores. A mild increase is observed
in the intensity of band III (e.g. ∆ log ε = 0.21 for compound 3a).
The infrared spectra of 4-substituted 1,4-dihydropyridines (Table III) show absorption
bands due to γ(C–H) vibrations in the regions of 852–885 and 925–965 cm–1. The
bands of symmetrical and asymmetrical vibrations ν(C–O–C) of furan nucleus are
found in the regions of 993–1 013 and 1 207–1 235 cm–1. This statement agrees with
the results by Gross13: all 2-substituted and 5-nitro-2-substituted furan derivatives show
two strong absorption bands in these regions which correspond to the above-mentioned
vibrations.
TABLE III
Infrared spectra of 4-(5-X-2-furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines 1–4
ν(C–O–C)
sym. asym.
ν(C=O)
Compound
ν(C–H)
δ(Me)s
ν(C=C)skel.
COMe COOR
1a
1b
1ca
2a
2b
2c
880 w 940 m 1 008 m 1 225 m 1 380 m 1 465 s 1 580 m 1 635 w 1 665 s 1 685 s
875 w 945 m 1 010 s 1 235 s 1 375 m 1 460 m 1 580 m 1 635 w 1 665 s 1 685 s
875 w 940 m 1 008 s 1 235 s 1 350 m 1 480 s 1 575 w 1 635 w 1 665 s 1 690 s
885 w 935 m 1 004 s 1 220 s 1 375 s 1 460 s 1 580 s 1 635 w 1 665 s 1 685 s
875 w 950 m 1 008 m 1 220 m 1 375 m 1 460 s 1 580 m 1 633 w 1 665 s 1 690 s
875 w 960 w 1 013 s 1 235 s 1 375 m 1 480 s 1 575 m 1 633 w 1 670 s 1 695 s
b
3a
3b
4a
4b
4c
852 w
–
1 000 s 1 220 s 1 365 s 1 440 s 1 550 s 1 590 s
1 695 sa
860 w 935 s 1 000 s 1 213 s 1 367 s 1 450 s 1 575 s 1 625 s 1 655 s 1 675 s
880 m 940 s 1 000 s 1 215 s 1 365 s 1 460 m 1 535 s 1 610 s 1 645 s 1 675 s
860 w 965 s 1 000 s 1 215 s 1 368 s 1 460 m 1 535 s 1 608 s 1 645 s 1 675 s
885 w 925 s
993 s 1 207 s 1 390 s 1 390 w 1 458 s 1 585 sc 1 630 s 1 660 s
a Ref.7: 3 375 (NH); 1 720, 1 690 (CO); 1 640–1 650 (C=C, NH); 1 495, 1 385 (NO2). b Three bands
with low intensity, not assigned. c Not resolved.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1,4-Dihydropyridines Alkylation
1239
The peaks of deformation vibrations δ(CH3) of methyl group are found in the region
of 1 350–1 390 cm–1. The bands of skeletal vibrations ν(C=C) of furan and dihydro-
pyridine nuclei are found in the region of 1 450–1 635 cm–1. Strong absorption bands
of carbonyl groups ν(C=O) are found in the region of 1 630–1 695 cm–1 and are usually
split (especially so for compounds 2 and 4), which corresponds to vibrations of two
different carbonyl groups (acetyl and ester). Starting from analogous wavenumbers of
the model compounds, 4-furyl-3,5-diacetyl- and -diethoxycarbonyl analogues (ν(C=O)
1 670 and 1 705 cm–1), we can assign the higher-energy band to carbonyl group of
alkoxycarbonyl and the lower-energy one to that of acetyl.
The wavenumber values of vibrations of substituents in the dihydropyridine nucleus
are lower than those in pyridine nucleus, which indicates a higher degree of conjuga-
tion of these substituents with dihydropyridine skeleton. N-Substitution of 1,4-dihydro-
pyridine skeleton causes no distinct changes in positions of absorption bands.
No ν(NH) vibrations were recorded since these are usually found above 3 200 cm–1
while the range covered by the apparatus used was 700–3 100 cm–1 only.
1
In the H NMR spectra (Table IV) of compounds 1 and 2 (except for 1b) it is im-
possible to differentiate between the proton signals of methyl groups at 2- and 6-posi-
tions and that of methyl group in acetyl. The signals of these protons are found at
TABLE IV
1H NMR spectra of 4-(5-X-2-furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines 1–4
Compound
H-4′
H-3′
H-5′
CH
CH3(CH2)O– CH3C= CH3CO–
NH, NR
1a
1b
1ca
2a
2b
2c
6.20 q
6.13 d
7.19 q
6.19 q
6.11 d
7.18 d
6.28 q
6.11 d
6.19 q
5.88 q
5.87 d
6.27 d
5.92 d
5.89 d
6.24 d
6.00 d
5.88 d
5.83 d
7.20 q
5.18 s
5.16 s
5.32 s
5.17 s
5.15 s
5.31 s
4.35 s
5.13 s
5.21 s
1.28 t, 4.21 q 2.30 s
1.29 t, 4.22 q 2.32 s
1.30 t, 4.22 q 2.36 s
2.30 s
2.30 s
2.36 s
2.31 s
2.31 s
2.35 s
1.88 s
2.28 s
2.38 s
7.11 s
–
6.68 s
–
7.20 q
–
6.99 s
3.74 s
3.75 s
3.76 s
2.31 s
2.31 s
2.35 s
6.89 s
6.46 s
–
7.35
3a
3b
4a
7.29 q
–
1.18 t, 4.18 q 1.25 s
1.28 t, 4.21 q 1.24 s
4.43 s, 7.30 m
4.20 s, 7.33 m
3.19 s
7.28 q
1.33 t, 4.28 q 2.45 s
2.48 s
4b
4c
6.06 d
7.12 d
5.79 d
6.13 d
–
5.14 s
5.25 s
1.28 t, 4.22 q 2.41 s
2.45 s
2.33 s
2.33 s
3.17 s
3.23 s
–
1.29 t, 4.22 q 2.43 s
2.48 s
a
Ref.7 (CDCl3, TMS): 2.34 s, 3 H (CH3); 1.21 t, 2 H (OCH2); 4.11 q, 3 H (CH3); 2 20 s, 3 H
(COCH3); 5.05 s, 1 H (CH); 6.20 d, 1 H (H-3′); 7.19 d, 1 H (H-4′).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1240
Ilavsky, Milata:
2.30–2.36 ppm. The proton signals of alkoxycarbonyl groups are found about 4.21 and
1.29 ppm and at 3.75 ppm, respectively. The position of NH signal does not change: it
is found at 6.47–7.04 ppm. The proton signals of furan nucleus are at 5.79–6.00 ppm
and 6.06–6.28 ppm, respectively; for the nitro derivatives, these are shifted downfield
3
by about 0.3 and 1.0 ppm, respectively. The JAB coupling constant values of furan
protons vary in the limits of 3.30–3.80 Hz. The 4-H proton signal (at an sp3 carbon of
compounds 1 and 2) shows the largest variability among all the measured chemical
shifts of 1,4-dihydropyridine skeleton of the substances studied. It is found in the re-
gion of 5.15–5.32 ppm, which also characterizes a different effect of the 5-substituted
furan on the carbon atom at 4-position.
The N-methyl signal is found in the region of 3.17–3.23 ppm. The derivatives having
an N-methyl group show two signals of methyl groups at 2- and 6-positions which, at
the same time, are different from the methyl signal of acetyl group. The signal of proton at
the sp3 carbon atom in 4-position is found at usual δ values (5.14–5.25) characteristic
of 1,4-dihydropyridine skeleton. The signal of proton at 4-position of compound 3a is
shifted upfield. Similarly, the signals of methyl groups at 2- and 6-positions are shifted
upfield, which is probably due to the presence of the phenyl nucleus in benzyl group.
In the mass spectra (Table V) of compounds 1, 2 (except for 1a, 2a), the molecular
ion has the intensity below 20%, however, the (M+• – 1) and (M+• – 2) peaks formed
by splitting off of hydrogen atom and molecule, respectively, show even lower inten-
sities, which means that the fragmentation does not involve the splitting off of neutral
hydrogen molecule as the first step (as it is usual with symmetrical derivatives).
TABLE V
The most important peaks in mass spectra of 4-(5-X-2-furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-
1,4-dihydropyridines 1–4
Compound
Relative intensity
1a
1b
1c
2a
2b
2c
3a
4a
4b
289 (91), 260 (44), 246 (100), 216 (90), 206 (85)
369 (14), 367 (13), 288 (100), 246 (100), 216 (46), 214 (38)
334 (14), 206 (93), 71 (67), 57 (84), 43 (100)
275 (59), 232 (100), 216 (52), 208 (26)
355 (19), 353 (18), 312 (35), 310 (32), 274 (100), 232 (68)
320 (6), 277 (11), 261 (20), 230 (42), 208 (39), 192 (63)
379 (13), 336 (28), 306 (11), 91 (100)
303 (7), 288 (4), 274 (5), 260 (49), 216 (9), 188 (12)
383 (7), 340 (65), 338 (65), 308 (18), 302 (15), 230 (100), 56 (100), 43 (100)
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1,4-Dihydropyridines Alkylation
1241
In compounds 1a and 2a, the dominant process is splitting off of CH3CO fragment
(M+• – 43) and COOEt fragment (M+• – 73). Both these fragmentations are confirmed
by metastable peaks. The bromo derivatives split off a bromine atom (M+• – 79, M+• – 81),
whereas the nitro derivatives undergo the elimination of ammonia (M+• – 17) and sub-
sequent splitting off of the nitrofuran fragment (M+• – 111). The other fragmentations
are analogous to those in 1a and 2a. No differences were observed between the frag-
mentations of N-methyl derivatives and the corresponding N-unsubstituted analogues.
Again, the CH3CO and COOEt fragments are split off. In contrast to 3,5-dicyano sub-
stituted 1,4-dihydropyridines, no preference for splitting of N-methyl group is ob-
served. The (M+• – 15) peak has only negligible intensities (below 2%) in both the
spectra. Splitting off of a CH4N fragment seems much more likely because it was found
in both spectra. A similar fragmentation is also observed in compound 3a where an
additional splitting of alkyl–nitrogen bond takes place, which is proved by the presence
of the tropylium cation (91 – the most intense peak) formed by splitting off of benzyl.
EXPERIMENTAL
The melting points were determined with a Kofler apparatus and were not corrected. The reaction
course and purity of substances were monitored by means of TLC: Silufol 254 plates, detection in
UV light or in iodine vapours. The elemental analyses of newly synthesized substances were carried
out with a CHNO model 1102 (Carlo Erba, Milan, Italy). The reaction mixture from the four-compo-
nent reaction was analyzed by GC using a Hewlett–Packard 7620A apparatus with flame ionization
detector and a glass column (1.9 m length, 3 mm inner diameter) packed with 10% OU 101 on Chro-
mosorb WHP DMCS (80–100 mesh). The inlet temperature 240 °C. The temperature regime for separation
in column: 180 °C, 6 min, isothermal; 180–240 °C with the temperature increase of 10 °C min–1.
Carrier gas: nitrogen, 35 ml min–1 flow rate. Retention times: 3,5-diacetyl derivative – 13.14 min,
3-acetyl-5-ethoxycarbonyl derivative – 13.85 min, 3,5-diethoxycarbonyl derivative – 15.26 min. The
UV spectra were measured with a double-beam UV-VIS spectrophotometer (Zeiss, Jena) in the range
of 210–800 nm. The solutions measured were placed in 1 cm cells and their concentrations were in
the limits of 1 . 10–5–7 . 10–5 mol l–1. The accuracy of measurements was ±1 nm. The IR spectra
were measured with a double-beam spectrophotometer Perkin–Elmer 503 in the region of 700–3 100 cm–1
1
using 0.1 mm KBr cells. The accuracy of wavenumber readings was ±1 cm–1. The H NMR spectra
were measured with an 80 MHz spectrometer BS 487 C Tesla at 25 °C in deuteriochloroform using
tetramethylsilane as the internal standard. The mass spectra were measured with an MS 902 S apparatus
with direct inlet. Ionization energy 70 eV, electron current 100 or 500 µA, temperature of ion source
from 40 to 140 °C depending on the substance measured.
5-Bromo-2-furancarboxaldehyde was prepared by bromination of 2-furancarboxaldehyde in
dichloroethane; 5-nitro-2-furancarboxaldehyde was prepared by hydrolysis of the 5-nitro-2-furyl-
methylene diacetate prepared by treating 2-furancarboxaldehyde with nitric acid in acetanhydride.
Ethyl 3-amino-2-butenoate, 2-amino-2-penten-3-one, and 2-benzylamino-2-penten-3-one were pre-
pared according to ref.14; the other starting materials used were commercial products.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1242
Ilavsky, Milata:
Preparation of 4-(2-Furyl)-3-acetyl-5-ethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (1a)
by Hantzsch Reaction
A mixture of 2,4-pentanedione (1.0 g, 10 mmol), ethyl 3-oxobutanoate (1.3 g, 10 mmol), 2-furan-
carboxaldehyde (0.96 g, 10 mmol) in dry ethanol saturated with ammonia (30 ml) was refluxed on
water bath 6 h, whereupon the reaction mixture was cooled and evaporated in vacuum until dry. The
product was analyzed by means of TLC and GC, and the identification of substances in the mixture
was verified by comparing with the authentic standards synthesized by the Hantzsch reaction. The
mixture contained: 41% 4-(2-furyl)-3-acetyl-5-ethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (1a),
36% 4-(2-furyl)-3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, and 23% 4-(2-furyl)-3,5-
diacetyl-2,6-dimethyl-1,4-dihydropyridine.
4-(5-X-2-Furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines 1, 2 (Methods A–C)
5-X-2-Furylidene-1,3-dicarbonyl compound (10 mmol) was dissolved with enamine (2-amino-2-pen-
ten-4-one or ethyl 3-amino-2-butenoate; 10 mmol) in dry ethanol (30 ml) and the mixture was re-
fluxed on water bath 6 h, cooled, and a part of the solvent was evaporated in vacuum. After some
time, the product began to crystallize from the reaction mixture, which could be speeded up by
undercooling or addition of water. The separated crystals were collected by suction and washed with
cold dry ethanol. The recrystallization was carried out (by boiling with charcoal) from ethanol with
water until constant melting point. The product forms yellow crystalline solid showing blue fluores-
cence in UV light. The yields and physical characteristics of the substances synthesized are presented
in Table I.
1-Benzyl-4-(5-X-2-furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines 3 (Method D)
Ethyl 2-(5-X-2-furylmethylidene)-3-oxobutanoate (10 mmol) was dissolved together with 2-benzyl-
amino-2-penten-4-one (10 mmol) in dry ethanol (30 ml), and 5 drops of 10% sodium ethoxide was
added. The reaction mixture was heated on a water bath 10 h. The reaction course and formation of
product were monitored by TLC. When the reaction was finished, the mixture was cooled and a part
of the solvent was evaporated in vacuum. After standing overnight, a voluminous crystalline precipi-
tate (compound 3a) was formed which was collected by suction and washed with cold methanol. The
product was recrystallized from methanol (boiling with charcoal) until constant melting point. The
obtained white fibrillar solid showed fluorescence in UV light. If the compound did not separate on
standing overnight, the products were separated by chromatography (silica gel; benzene–chloroform
1 : 1) and recrystallized from methanol.
Alkylation of Sodium Salts of 4-(5-X-2-Furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydro-
pyridines 1 (Method E)
The sodium salt of nonalkylated dihydropyridine 1 was prepared in analogy to the method by Ku-
than12. A solution of the respective dihydropyridine (20 mmol) in dry dimethylformamide (15 ml)
was treated with sodium hydride (0.58 g, 25 mmol) added with continuous stirring and cooling with
ice during 20 min in nitrogen atmosphere, whereupon the reaction mixture was heated at 35–40 °C 3 h.
N-Methylation of Sodium Salts of 4-(5-X-2-Furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihy-
dropyridines 1
The sodium salt of dihydropyridine (20 mmol) prepared in the previous experiment was cooled with
ice with continuous stirring and treated with methyl iodide (3.6 g, 25 mmol). Then the reaction mix-
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

1,4-Dihydropyridines Alkylation
1243
ture was refluxed 10 h. After the reaction was finished, the mixture (in the case of compound 1a)
was concentrated in vacuum to one half of the original volume and ice water was added thereto. The
obtained precipitate was recrystallized from methanol (boiling with charcoal). In the case of com-
pound 1b, the reaction mixture was evaporated in vacuum until dry and separated by chromatography
(silica gel; benzene–chloroform 1 : 1). The product was recrystallized from methanol.
N-Benzylation of Sodium Salts of 4-(5-X-2-Furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-di-
hydropyridines 1
Benzyl chloride (3.2 g, 25 mmol) was added to sodium salt of dihydropyridine (20 mmol) with stir-
ring and cooling with ice. The reaction mixture was heated at 35–40 °C 10 h. After concentrating to
one half of the original volume in vacuum, 40 ml ice water was added, and the product was extracted
with 3 × 50 ml benzene. The extract was dried with anhydrous sodium sulfate, evaporated until dry,
and purified by chromatography (silica gel; benzene–hexane 2 : 1).
Alkylation of 4-(5-X-2-Furyl)-3-acetyl-5-alkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines 1
by Phase-Transfer Catalysis Method (Method F)
A mixture of dihydropyridine 1 (20 mmol), alkylating agent (methyl iodide or benzyl chloride, 30 mmol),
catalyst (TEBA or dimethylbenzyldodecylammonium bromide, 10 mmol), 50% aqueous sodium
hydroxide (5 ml), and benzene (40 ml) was heated with continuous stirring at 40–45 °C 10 h. Then
the benzene layer was separated, washed with saturated sodium chloride solution, and dried over an-
hydrous sodium sulfate. The solvent was evaporated in vacuum and the residue was separated by
chromatography (silica gel; benzene–hexane 1 : 1 for N-benzyl derivatives, benzene–chloroform 1 : 1 for
N-methyl derivatives) and the product was recrystallized from methanol. The obtained white or yellow
substances showed fluorescence in UV light (methyl derivatives showed fluorescence quenching).
The authors wish to thank Mrs M. Hrobonova for measurement of UV spectra, Mrs S. Markusova for
measurement of IR spectra, and Mrs M. Ondrejkovicova for performing the elemental analyses.
REFERENCES
1. Eisner U., Kuthan J.: Chem. Rev. 72, 1 (1972).
2. Bossert F., Meyer H., Wehinger E.: Angew. Chem., Int. Ed. 20, 762 (1981).
3. Kuthan J., Kurfurst A.: Ind. Eng. Chem., Prod. Res. Dev. 21, 191 (1982).
4. Stout D. M., Meyers A. I.: Chem. Rev. 82, 223 (1982).
5. Sausins A., Duburs G.: Heterocycles 27, 269, 291 (1988).
6. Goldman S., Stoltefuss J.: Angew. Chem., Int. Ed. Engl. 30, 1559 (1991).
7. Balicky R., Nantka-Namirski P.: Pol. J. Pharmacol. Pharm. 26, 647 (1974).
8. Marchalin S., Kuthan J.: Collect. Czech. Chem. Commun. 48, 3123 (1983).
9. Hantzsch A.: Justus Liebigs Ann. Chem. 215, 1 (1882).
10. Bossert F., Vater W.: Med. Res. Rev. 9, 291 (1989).
11. Loev B., Goodman M. M., Snader K. M., Tedeschi R., Macko E.: J. Med. Chem. 17, 956 (1974).
12. Palecek J., Kuthan J.: Collect. Czech. Chem. Commun. 39, 3711 (1974).
13. Gross A. H. J., Stevens G. E., Watta T. H. E.: J. Appl. Chem. (London) 7, 562 (1957).
14. Becker H., et al.: Organicka synteza – Organikum. Academia, Praha 1965.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)