Competitive formation of condensed azines and dihydropyridines in the reaction of ethyl 3,3-diaminoacrylate with o-halo carbaldehydes

Article abstract of DOI:10.1007/s10593-008-0061-1

The reaction of ethyl 3,3-diaminoacrylate with quinoline-3-carbaldehydes and 3-nitrobenzaldehydes to give a dihydropyridine and condensed azine has been studied with respect to the number and reactivity of the halogen atoms in an ortho position to the formyl groups. For the series of quinoline-3-carbaldehydes it was found that the reaction course is determined by the number of chlorine atoms. 2-and 4-Chloroquinoline-3-carbaldehydes give dihydropyridines and a benzo[c][2,7-]naphthyridine is formed in the reaction with 2,4- dichloroquinoline-3-carbaldehyde. The main products in the case of nitrobenzaldehydes are dihydropyridines which points the deciding influence of the low electrophilicity of aromatic ring.

Full text of DOI:10.1007/s10593-008-0061-1

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
COMPETITIVE FORMATION
OF CONDENSED AZINES AND
DIHYDROPYRIDINES IN THE
REACTION OF ETHYL 3,3-DIAMINO-
ACRYLATE WITH o-HALO CARB-
ALDEHYDES
I. I. Eliseev, Jr., D. V. Dar'in, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin*
The reaction of ethyl 3,3-diaminoacrylate with quinoline-3-carbaldehydes and 3-nitrobenzaldehydes to
give a dihydropyridine and condensed azine has been studied with respect to the number and reactivity
of the halogen atoms in an ortho position to the formyl groups. For the series of quinoline-
3-carbaldehydes it was found that the reaction course is determined by the number of chlorine atoms. 2-
and 4-Chloroquinoline-3-carbaldehydes give dihydropyridines and a benzo[c][2,7-]naphthyridine is
formed in the reaction with 2,4-dichloroquinoline-3-carbaldehyde. The main products in the case of
nitrobenzaldehydes are dihydropyridines which points the deciding influence of the low electrophilicity
of aromatic ring.
Keywords: benzonaphthyridine, dihydropyridine, ethyl 3,3-diaminoacrylate, Hantzsch reaction,
cyclocondensation.
In our recent study of the reaction of α-acylacetamidines (which exist in solution in the tautomeric
enediamine form) with 2-fluoro-5-nitrobenzaldehyde (1) and 4,6-dichloro-2-methylsulfanylpyrimidine-
5-carbaldehyde (2) the main reaction products are isoquinolines and pyrido[4,3-d]pyrimidines respectively
[1, 2]. α-Acylacetamidines react as C,N-dinucleophiles. The reaction occurs with a uniform chemo-selectivity:
the amidine α-carbon substitutes the halogen atom in the aromatic ring and the amino group binds to the formyl
carbon atom. However, in the case of the reaction of ethyl 3,3-diaminoacrylate (3) with the aldehyde 1 the
cyclocondensation is accompanied by a concurrent Hantzsch type reaction to form the dihydropyridine 6. This
reaction occurs using two molecules of the enediamine and one molecule of the aldehyde. Moreover, only the
carbonyl group in the aldehyde reacts, the halogen atom at the aromatic ring being unaffected. In addition, a
marked amount of the quinoline 5 is observed in the reaction which, as the dihydropyridine 6, is formed as a
result of an attack by the carbon nucleophilic center of the enediamine at the formyl group. At the same time, the
reaction of enediamine 3 with compound 2 gives only the corresponding pyrido[4,3-d]pyrimidine in virtually
quantitative yield.
_______
* Deceased.
_________________________________________________________________________________________
St. Petersburg State University, St. Petersburg 198504, Russia; e-mail: pslob@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 567-577, April, 2008. Original article submitted October
16, 2007.
442
0009-3122/08/4404-0442©2008 Springer Science+Business Media, Inc.

CO2Et
NH2
O2N
CHO
F
+
H2N
3
1
O2N
F
O2N
O2N
CO2Et
NH2
EtO2C
H2N
CO2Et
N
+
+
NH2
N
N
NH2
H
CO2Et
5
6
4
We propose that the different direction of the reaction of enediamine 3 with the aldehydes 1 and 2
occurs for two reasons. The first is a marked increase in the electrophilicity of the carbon atom bound with the
halogen atom (increased halogen ''activity'') relative to the formyl group on changing from the benzaldehyde 1 to
the pyrimidinecarbaldehyde 2. The second is the presence of two ortho substituents in the carbaldehyde 2 which
hinder the approach of the carbon nucleophilic center to the formyl group. In order to evaluate the effects of
these factors on the reaction course we have studied the behavior of enediamine 3 in reactions with some
π-deficient aldehydes differing in the number and reactivity of the halogen atoms in an ortho position to the
formyl group.
The reactions were carried out in DMF at room temperature. The structure of the compounds prepared
was confirmed from their 1H and 13C NMR spectra.
R1
CHO
3
R
N
7a-c
NH2
NH
NH2
NH2
NH2
EtO2C
R1
EtO2C
CO2Et
N
N
N
+
+
CO2Et
R
N
Cl
N
Cl
9b,c
8a
10b
8a R = R1 = Cl (77%); 9b R = Cl, R1 = H (42%), c R = H, R1 = Cl (72%);
10b R = Cl, R1 = H (25%)
The reaction of aldehyde 7a with enediamine 3 gave the benzo[c][2,7]naphthyridine 8a in 77% yield. Its
NOESY correlation spectrum showed strong cross peaks between the signal for the methylene in the carbethoxy
fragment and the H-10 proton doublet (7.97 ppm).
Treatment of the enediamine 3 with aldehyde 7b gave the dihydropyridine 9b as the main product.
1H NMR of the reaction mixture of the dihydropyridine 9b showed it to exist as the two tautomeric 1,4- and 3,4-
dihydro forms in the ratio 10:7. However, on recrystallization from chloroform the 1,4-dihydropyridine 9b is
1
converted to the 3,4-dihydro form 9b' which was separated and characterized. In the H NMR spectrum of
443

the 3,4-dihydropyridine 9b' the signals for the protons in positions 3 and 4 of the dihydropyridine ring appear as
singlets. For proof of structure the COSY spectrum of the 3,4-dihydropyridine 9b' was recorded and showed
cross peaks due to weak spin-spin interaction between these protons. In addition weak cross peaks between the
proton in position 4 of the dihydropyridine ring and the proton at position 4 of the quinoline ring were observed.
Prolonged holding (~ 1 month) of the 3,4-dihydropyridine 9b' in DMSO-d6 solution caused complete
conversion to the 1,4-dihydro form 9b.
NH2
NH
NH2
NH2
EtO2C
EtO2C
N
CHCl3, reflux
NH2
CO2Et
CO2Et
N
Cl
DMSO, room
temp.
N
Cl
9b
9b'
Besides the main product in this reaction the benzo[h][1,6]naphthyridine 10b was unexpectedly formed
1
(25% yield). Its structure was identified by H, 13C, and NOESY spectra. Cross peaks were observed in the
NOESY correlation spectrum due to NOE between the proton in position 4 and the ethoxycarbonyl group
protons.
Related reactions have been described before [4]. The authors carried out a direct, noncatalyzed
amination of a 5-azacinnoline using different amines. It was found that the oxidant in these reactions is
atmospheric oxygen.
The reaction of the enediamine 3 with aldehyde 7b was also carried out in alternative conditions, in fact
at 50ºC and with stepwise addition of a solution of the enediamine 3 to a solution of the aldehyde in DMF. The
yield of benzo[h][1,6]naphthyridine 10b was 33%. When carrying out the reaction of aldehyde 7b with the
hydrochloride of the enediamine 3 in DMF in the presence of potassium carbonate at room temperature
(conditions reported in [1]) only a 2:1 mixture of the 1,4-dihydropyridine 9b and 3,4-dihydropyridine 9b' was
obtained and did not contain the benzonaphthyridine 10b.
Reaction of aldehyde 7c with the enediamine 3 also gives only the dihydropyridine 9c as a mixture of
tautomeric the 1,4- and 3,4-dihydroforms (ratio ~ 6:1) and containing a small amount of admixture. Pure
1,4-dihydropyridine 9c was obtained in 86% yield by carrying out the reaction of aldehyde 7c with the
hydrochloride of the enediamine 3 in DMF at room temperature in the presence of potassium carbonate. The
tautomeric 3,4-dihydropyridine is not observed when carrying out the reaction under these conditions. Despite
the position 4 of the quinoline ring being more active towards nucleophilic attack than the position 2 we also did
not observe the formation of benzonaphthyridines (products of substitution of the chlorine atom) in this case.
Aldehyde 11 reacts with the enediamine 3 by the same route as its analog – 4,6-dichloro-2-methyl-
sulfanylpyrimidine-5-carbaldehyde (2) [2]. Only the single pyrido[4,3-d]pyrimidine product 12 was separated.
N
N
N
CHO
Cl
N
N
N
3
+
MeS
MeS
N
NH2
CO2Et
11
12
444

Its structure was confirmed from 1H and 13C NMR data. The value of the direct 1JC5-H spin-spin coupling
of 179 Hz points to a positioning of the CH fragment directly next to the pyridine nitrogen atom thus allowing a
choice between the two isomeric pyridopyrimidines. Cross peaks are seen in the NOESY correlation spectrum
due to NOE between the methylsulfanyl group protons and those of the ethoxycarbonyl group which points to
their relative close proximity and is only realized in the pyrido[4,3-d]pyrimidine structure 12. As we expected
the aldehyde 11 proved markedly less active than the aldehyde 2, its reaction occurring at room temperature
over 3.5 month while that with aldehyde 2 occurred over several minutes.
The reaction of enediamine 3 with aldehyde 13a (as with aldehyde 1 [1]) gives a mixture of the
dihydropyridine 14a and, presumably, the quinoline 15a and isoquinoline 16a in the ratio 5:2:2. When the
reaction was carried out using the enediamine hydrochloride in the presence of potassium carbonate the pure
1,4-dihydropyridine 14a was obtained in 89% yield. Compounds 15a and 16a could not be separated and
conclusions about their structure are only made on the basis of the 1H NMR spectrum of the reaction mixture.
Cl
O2N
CHO
F
3
13a
H
N
H2N
NH2
Cl
Cl
O2N
CO2Et
NH2
O2N
N
EtO2C
Cl
CO2Et
F
+
+
NH2
N
CO2Et
O2N
15a
16a
14a
The aldehyde 13b proved to be much less active than aldehyde 13a and its reaction significantly slower.
A 2:1 mixture of the dihydropyridine 14b and quinoline 17 was obtained. The dihydropyridine 14b exists as a
2:1 mixture of two rotamers as shown by the double set of signals in the 1H NMR spectrum.
NH2
EtO2C
NH
Cl
Cl
Cl
O2N
O2N
CHO
Cl
CO2Et
NH2
NH2
3
+
CO2Et
Cl
N
NO2
13b
14b
17
The quinoline structure is, in fact, indicated for compound 17 by the value of the direct 1JC4-H spin-spin
1
1
coupling of 166.3 Hz (for C-1 in isoquinoline JC1-H = 178 Hz and for C-4 in quinoline JC4-H = 162 Hz [3],
depending little on the nature of the ring substituent). The fact that the chlorine atom is actually situated in an
ortho position to the nitro group can be deduced since the 1H NMR spectrum of quinoline 17 does not coincide
with the spectrum of quinoline 15a formed by the reaction of enediamine 3 with aldehyde 13a.
The results of the reactions in the quinolinecarbaldehyde series convincingly prove a decisive role for
the presence of two chloro atoms in ortho positions to the formyl group for determining the reaction route.
While in the reactions with aldehydes 7b and 7c the halogen atoms are not affected but the dihydropyridines 9b
445

and 9c are formed the aldehyde 7a gives only the benzonaphthyridine 8a. The reaction occurs at the more active
4 position. The formation of the benzonaphthyridine 10b in the reaction of aldehyde 7b with enediamine 3 is
somewhat unexpected. However, it also agrees with our proposal that it is the product of oxidation of the
secondary intermediate, most likely formed after addition of one molecule of the enediamine carbon
nucleophilic center to the formyl group and cyclization by addition of the amino group to position 4.
CHO
3
–H2O
N
Cl
7b
NH2
NH2
NH
EtO2C
CO2Et
HN
N
OH
–H2O
N
Cl
Cl
O2
3
NH2
NH2
CO2Et
EtO2C
N
NH
NH2
CO2Et
N
Cl
N
Cl
10b
9b
The aldehyde 11 reacts with the same chemoselectivity as the chloropyrimidinecarbaldehyde 2 [2] and,
in fact, the carbon nucleophilic center takes part in the stage of aromatic nucleophilic substitution of the halogen
and the nitrogen atom of the enediamine forms a bond with the formyl group. This result confirms the proposal
that the effect of the two ortho substituents is to hinder the approach to the formyl group and this determines the
reaction course despite the lowered activity of the ring.
The result of the reaction of enediamine 3 with aldehyde 13a is overall similar to the result with
aldehyde 1. A marked effect was not observed for the additional chlorine atom in the ortho position. However
some increase was seen in the fraction of cyclocondensation products involving the fluorine atom. In fact, the
ratio of dihydropyridine 14a, quinoline 15a, and isoquinoline 16a is 5:2:2 in the separated mixture while it is
10:3:3 for the analogous products in the reaction with aldehyde 2.
The aldehyde 13b proved to be markedly less reactive. The outcome of its reaction with enediamine 3
does not agree with the initial proposal for the effect on the reaction course of the two halogen atoms in the
ortho position to the formyl group. Both main separated products, dihydropyridine 14b and quinoline 17 are
formed via attack of the carbon nucleophilic center of the enediamine at the formyl group. It may be linked to
the very low reactivity of the ring (chlorine atom ''activity'') in aldehyde 13b. Becides that the chlorine is
strongly less active than the fluorine, the presence of the chlorine atom ortho to the nitro group possible
decreases its electron acceptor influence on the ring. Hence it can be proposed that the aromatic nucleophilic
substitution reaction takes place so slowly in this case that the addition at the formyl group predominates despite
the steric hindrance. Moreover, for the intermediate formed after addition of one molecule of enediamine, there
are two possible routes for continuing the reaction. The first is addition of a second molecule
446

to form the dihydropyridine and the second is cyclization with substitution of a chlorine atom to form the
quinoline 17. This is a very similar result to that achieved in the reaction of enediamine 3 with 2-chloro-
quinoline-3-carbaldehyde (7b) where, in addition to the dihydropyridine 9b formed by the Hantzsch reaction,
some amount of the product of initial attack of the α-carbon at the formyl group is formed and this is
subsequently cyclized to an aromatic ring. In this case, even in the absence of a leaving group, cyclization
occurs at the more active 4 position via oxidative substitution of a hydrogen atom. For the 2,6-dichloro-3-nitro-
benzaldehyde (13b) the chlorine atom situated ortho to the nitro group is more active.
It was noted that only in the case of the single enediamine (diaminoacrylate 3 [1]) does the reaction of
enediamines with aldehyde 1 form a dihydropyridine. Thus the reaction of aldehyde 1 with the enediamine 18
forms only the isoquinoline 19 in high yield.
O
O2N
N
O2N
CHO
F
N
+
NH2
H2N
NH2
18
N
O
1
19
Furthermore, even in reaction with 2-chloro-5-nitrobenzaldehyde in which the halogen atom is markedly
less active, the enediamine 18 gives only the isoquinoline 19 although in low yield (30%). Characteristic signals
for a dihydropyridine of type 6 were completely absent in the 1H NMR spectrum of the reaction mixture.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker DPX 300 (300 and 75 MHz) using DMSO-d6
(compounds 8a, 9b',c, 10b, 12, 13a, 14a, 17, 19) or CDCl3 (compound 11) solvent with the signals of the
1
solvent at 2.50 and 7.26 ppm for the H nucleus and 39.7 and 77.7 ppm for the 13C nucleus respectively. The
1
spin-spin couplings in the H NMR spectra were measured to a first order approximation. Mass spectra were
taken on a Finnigan MAT Incos 50 instrument. Elemental analysis was carried out on a Hewlett Packard HP-
185B CHN analyzer. The purity of the materials and extent of the reaction course were monitored by TLC on
Silufol UV-254 plates. Aldehydes 13a and 13b were prepared by nitration of commercially available 6-chloro-
2-fluoro- and 2,6-dichlorobenzaldehydes under the conditions reported for 2-fluoro-5-nitrobenzaldehyde (1) [5].
Reaction of Diaminoacrylate 3 with 2,4-Dichloroquinoline-3-carbaldehyde (7a) [6]. Enediamine 3
(1.17 g, 9.0 mmol) was added to a solution of aldehyde 7a (0.97 g, 4.3 mmol) in dry DMF (5 ml). The solution
was left overnight at 4ºC. The precipitate was filtered, washed with water, and dried to give ethyl 2-amino-
5-chlorobenzo[c][2,7]naphthyridine-1-carboxylate (8a) (1.0 g, 77%); mp 225-227ºC. A sample purified for
1
analysis was prepared by crystallization from acetonitrile. H NMR spectrum, δ, ppm (J, Hz): 1.27 (3H, t,
J = 7.3, CH3); 4.48 (2H, q, J = 7.3, CH2); 7.24 (2H, s, NH2); 7.66 (1H, t, J = 7.8, H-9); 7.82 (1H, t, J = 7.8, H-8);
13
7.89 (1H, d, J = 7.8, H-10); 7.97 (1H, d, J = 7.8, H-7); 9.23 (1H, d, H-3). C NMR spectrum, δ, ppm (J, Hz):
14.4 (CH3); 63.0 (CH2); 102.3 (C-1); 112.5 (C-10a); 121.5 (C-4a); 126.5 (C-9); 127.8 (C-10); 129.9 (C-8); 132.4
(C-7); 139.1 (C-10b); 146.0 (C-6a); 150.8 (C-2); 153.5 (C-4; 1JC-H = 183); 158.9 (C-5); 169.4 (CO). Found, %:
C 59.90; H 4.00; N 13.78. C15H12ClN3O2. Calculated, %: C 59.71; H 4.01; N 13.93.
447

Reaction of Diaminoacrylate 3 with 2-Chloroquinoline-3-carbaldehyde (7b). A. Enediamine 3
(1.02 g, 7.8 mmol) was added to a solution of compound 7b [7] (0.72 g, 3.7 mmol) in dry DMF (10 ml) and left
for 4 days at room temperature. Solvent was evaporated at 40ºC at reduced pressure. The residue was treated
with water (40 ml) and left for 2 h at 4ºC. The precipitate was filtered off, washed with water, and dried to give a
mixture (1.3 g) of dihydropyridine 9b, dihydropyridine 9b', and the benzonaphthyridine 10b. Signals for the
1
1,4-dihydropyridine 9b were seen in the H NMR spectrum of the mixture at 0.95 (6H, t, J = 8.0, CH3); 3.84
(4H, q, J = 8.0, CH2); 5.06 (1H, s, H-4); 7.17 (4H, s, NH2), and 8.71 ppm (1H, s, NH). The crystals obtained
were mixed with chloroform (35 ml) and heated to reflux and the precipitate formed in the solution was filtered
off, washed with water, and dried to give diethyl 2,6-diamino-4-(2-chloro-3-quinolyl)-3,4-dihydropyridine-
3,5-dicarboxylate (9b') (0.65 g, 42%); mp 253-255ºC. A sample purified for analysis was prepared by
1
crystallization from acetonitrile. H NMR spectrum, δ, ppm: 0.93 (3H, t, J = 7.4, CH3); 1.18 (3H, t, J = 7.3,
CH3); 3.63 (1H, s, H-3); 3.78 (1H, m, CH2); 3.91 (1H, m, CH2); 4.16 (2H, m, CH2); 4.90 (1H, s, H-4); 6.72 (1H,
s, 2-NH2); 7.30 (1H, s, 3-NH2); 7.53 (1H, s, 3-NH2); 7.60 (1H, t, J = 8.0, Hquin-7); 7.77 (1H, s, Hquin-4); 7.78 (1H,
t, J = 8.0, Hquin-6); 7.95 (2H, d, Hquin-5,8); 8.09 (1H, s, 2-NH2). 13C NMR spectrum, δ, ppm: 14.4 (CH3); 15.0
(CH3); 37.1 (C-4); 48.5 (C-3); 57.9 (CH2); 61.5 (CH2); 72.6 (C-5); 127.4 (Cquin-3); 127.9 (Cquin-6); 128.18
(Cquin-8); 128.22 (Cquin-5); 130.9 (Cquin-7); 134.8 (Cquin-4a); 137.2 (Cquin-4); 146.6 (C-2); 150.7 (Cquin-8a); 162.3
(Cquin-2); 168.3 (CO); 168.7 (CO). Found, %: C 57.49; H 5.11; N 13.44. C20H21ClN4O4. Calculated, %: C 57.63;
H 5.08. N 13.44.
Benzonaphthyridine 10b contained in the filtrate was purified chromatographically eluting with
chloroform containing 2% methanol. Recrystallization from ethanol gave ethyl 2-amino-5-chloro-
benzo[h][1,6]naphthyridine-3-carboxylate (10b) (0.27 g, 25%); mp 181-183ºC. 1H NMR spectrum, δ, ppm (J,
Hz): 1.39 (3H, t, J = 7.3, CH3); 4.40 (2H, q, J = 7.3, CH2); 7.71 (1H, t, J = 8, H-9); 7.85 (1H, t, J = 8, H-8); 7.90
(1H, d, J = 8, H-10); 7.99 (1H, s, NH2); 8.23 (1H, s, NH2); 8.74 (1H, d, J = 8, H-7); 8.86 (1H, s, H-4). 13C NMR
spectrum, δ, ppm: 14.9 (CH3); 62.4 (CH2); 109.9 (C-3); 112.9 (C-4a); 124.2 (C-10a); 125.1 (C-9); 127.9 (C-10);
128.9 (C-8); 132.7 (C-7); 140.6 (C-4); 146.8 (C-6a); 150.4 (C-10b); 153.4 (C-2); 160.4 (C-5); 166.1 (CO). Mass
spectrum, (EI, 70 eV), m/z (Irel, %): 418 (12), 416 (34), 343 (100), 297 (26), 235 (23), 136 (21). Found, %:
C 59.65; H 4.37; N 13.55. C15H12ClN3O2. Calculated, %: C 59.71; H 4.01; N 13.93.
B. A solution of the enediamine 3 (0.534 g, 4.1 mmol) in dry DMF (3 ml) was added dropwise with
stirring to a solution of aldehyde 7b (0.358 g, 1.9 mmol) in dry DMF (4 ml) over 9 h and left at room
temperature overnight. The precipitate was filtered off, washed with water, and dried to give the
benzonaphthyridine 10b (0.185 g, 33%); mp 183-185ºC. Water (40 ml) was added dropwise to the filtrate and
left for 2 h at 4ºC. The precipitate was filtered off, washed with water, and dried to give a mixture (195 mg) of
dihydropyridine 9b and dihydropyridine 9b' in the ratio 10:7.
C. Potassium carbonate (0.9 g, 6.6 mmol) was added to a solution of the aldehyde 7b (0.6 g, 3.1 mmol)
and the enediamine hydrochloride 3 (1.1 g, 6.6 mmol) in dry DMF (10 ml), stirred for 4 h at room temperature,
and left overnight. The reaction mixture was then poured into water (40 ml) and the precipitate formed was
filtered off, washed with water, and dried to give a mixture (1.16 g, 89%) of the dihydropyridine 9b and
dihydropyridine 9b' in the ratio 2:1.
Reaction of Diaminoacrylate 3 with 4-Chloroquinoline-3-carbaldehyde (7c). A. The enediamine 3
(0.6 g, 4.6 mmol) was added to a solution of the aldehyde 7c [8] (0.42 g, 2.2 mmol) in dry DMF (5 ml) and then
left overnight at room temperature. Solvent was evaporated off at 40ºC under reduced pressure. Water (20 ml)
was added to the residue and left for 2 h at 4ºC. The precipitate was filtered off, washed with water, and dried to
give a mixture (0.77 g, 72%) of the 1,4-dihydropyridine 9c and 3,4-dihydropyridine 9c' in the ratio ~ 6:1.
B. K2CO3 (0.705 g, 5.1 mmol) was added to a solution of the aldehyde 7c (0.465 g, 2.4 mmol) and
enediamine hydrochloride 3 (0.85 g, 5.1 mmol) in dry DMF (10 ml) and stirred for 4 h at room temperature. The
reaction mixture was left overnight and poured into water (40 ml). The precipitate formed was filtered off,
washed with water, and dried to give diethyl 2,6-diamino-4-(4-chloro-3-quinolyl)-1,4-dihydropyridine-
448

3,5-dicarboxylate (9c); mp 220-225ºC (decomp.). A sample purified for analysis was prepared by
1
recrystallization from methylene chloride. H NMR spectrum, δ, ppm (J, Hz): 0.96 (6H, t, J = 7.4, CH3); 3.83
(4H, m, CH2); 5.20 (1H, s, H-4); 7.16 (4H, s, NH2); 7.68 (1H, t, J = 8.0, Hquin-7); 7.73 (1H, t, J = 8.0, Hquin-6);
7.95 (1H, d, J = 8.0, Hquin-5); 8.22 (1H, d, J = 8.0, Hquin-8); 8.68 (1H, d, Hquin-2); 8.71 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 15.2 (CH3); 35.0 (C-4); 58.8 (CH2); 76.9 (C-3); 124.6 (Cquin-3); 126.6 (Cquin-6); 128.4
(Cquin-5); 129.78, 129.82 (Cquin-4a,7); 137.8 (Cquin-8); 140.7 (Cquin-4); 147.1 (C-2); 152.8 (Cquin-8a); 154.8
(Cquin-2); 169.1 (CO). Found, %: C 57.19; H 5.28; N 13.64. C20H21ClN4O4. Calculated, %: C 57.63; H 5.08;
N 13.44.
6-Chloro-2-methylsulfanyl-4-(1-piperidyl)pyrimidine-5-carbaldehyde (11). A solution of piperidine
(0.38 g, 4.5 mmol) and triethylamine (0.46 g, 4.5 mmol) in absolute acetonitrile (5 ml) was added dropwise with
stirring to a solution of the 2-methylsulfanyl-4,6-dichloropyrimidine-5-carbaldehyde (2) [9] (1 g, 4.5 mmol) in
absolute acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 3 h, left overnight,
poured into water, and the precipitated crystals were filtered off, dried and recrystallized from acetonitrile. Yield
of aldehyde 11 0.81 g (66%); mp 120-122ºC. 1H NMR spectrum, δ, ppm: 1.61 (6H, m, CH2CH2CH2); 2.46 (3H,
s, SCH3); 3.54 (4H, m, CH2NCH2); 10.01 (1H, s, CHO).
Reaction of Diaminoacrylate
3 with 6-Chloro-2-methylsulfanyl-4-(1-piperidyl)pyrimidine-
5-carbonitrile (11). Enediamine 3 (0.3 g, 2.3 mmol) was added to a solution of the aldehyde 11 (0.3 g,
1.1 mmol) in dry DMF (3 ml). It was left at room temperature for 4 months. The reaction mixture was poured
into water and left for 2 h at 4ºC. The precipitate was filtered off, carefully washed with water, and dried.
Recrystallization from acetonitrile gave ethyl 7-amino-2-methylsulfanyl-4-(1-piperidyl)pyrido[4,3-d]pyri-
1
midine-8-carboxylate (12) (230 mg, 60%); mp 149-151ºC. H NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, t,
J = 7.3, CH3); 1.65 (6H, s, CH2CH2CH2); 2.46 (3H, s, SCH3); 3.73 (4H, s, CH2NCH2); 4.29 (2H, q, J = 7.3,
CH2); 7.09 (2H, s, NH2); 8.72 (1H, s, H-5). 13C NMR spectrum, δ, ppm: 14.3 (OCH2CH3); 15.0 (SCH3); 24.8
(NCH2CH2CH2); 26.4 (NCH2CH2CH2); 50.8 (NCH2CH2CH2); 61.3 (OCH2CH3); 99.0 (C-8); 102.8 (C-4a); 153.1
1
(C-7); 156.3 (C-5, JC—H = 179); 160.0 (C-4); 162.3 (C-8a); 168.3 (CO); 171.5 (C-2). Found, %: C 55.37;
H 5.94; N 20.09. C16H21N5O2S. Calculated, %: C 55.31; H 6.09; N 20.16.
Reaction of Diaminoacrylate 3 with 2-Chlorobenzaldehyde-6-fluoro-3-nitro- (13a). A. The
enediamine 3 (0.805 g, 6.2 mmol) was added to a solution of compound 13a (0.6 g, 2.5 mmol) in dry DMF
(5 ml) and left overnight at room temperature. Solvent was evaporated off at 40°C under reduced pressure and
water (30 ml) was added to the residue. It was left for 2 h at 4°C and the precipitate formed was filtered off,
washed with water, and dried to give a mixture (1.15 g) of the dihydropyridine 14a, quinoline 15a, and
1
isoquinoline 16a in the ratio 5:2:2. H NMR signals were seen for the quinoline 15a (J, Hz) at 1.37 (3H, t,
J = 7.3, CH3); 4.40 (2H, q, J = 7.3, CH2); 7.53 (2H, s, NH2); 8.02 (1H, d, J = 9.8, H-8), 8.36 (1H, d, J = 9.8,
H-7), and 8.92 ppm (1H, s, H-4). Signals were seen in the mixture for the isoquinoline 16a at 1.37 (3H, t,
J = 7.3, CH3); 4.40 (2H, q, J = 7.3, CH2); 7.53 (2H, s, NH2); 8.15 (1H, d, J = 9.7, H-5); 8.45 (1H, d, J = 9.7,
H-6), and 9.48 ppm (1H, s, H-1).
B. K2CO3 (0.712 g, 5.16 mmol) was added with stirring to a solution of the aldehyde 13a (0.5 g,
2.46 mmol) and the enediamine hydrochloride 3 (0.86 g, 5.16 mmol) in dry DMF (10 ml) and stirred for 3 h at
room temperature. The reaction mixture was poured into water (40 ml) and the precipitate formed was filtered
off, washed with water, and dried to give the diethyl 2,6-diamino-4-(2-chlorophenyl-6-fluoro-3-nitro)-
1,4-dihydropyridine-3,5-dicarboxylate (14a) (0.94 g, 89%); mp 151-153ºC. A pure sample for analysis was
1
prepared by recrystallization from methylene chloride. H NMR spectrum, δ, ppm (J, Hz): 0.97 (6H, t, J = 7.4,
CH3); 3.84 (4H, m, CH2); 5.31 (1H, br. s, H-4); 7.0-7.3 (4H, s, NH2); 7.27 (1H, t, J = 9.4, Har-5); 7.78 (1H, dd,
J = 5, J = 8.7, Har-4); 8.67 (1H, s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 14.51 (CH3); 32.01 (C-4); 58.31
(CH2); 73.86 (C-3); 115.41 (Car-5); 122.91 (Car-4); 126.08 (Car-1); 136.65 (Car-2); 146.44 (Car-3); 152.89 (C-2);
163.00 (d, J = 24.2, Car-6); 168.62 (CO). Found, %: C 47.38; H 4.11; N 13.09. C17H18ClFN4O6. Calculated, %:
C 47.62; H 4.23; N 13.07.
449

Reaction of Diaminoacrylate 3 with 2,6-Dichloro-3-nitrobenzaldehyde (13b). Enediamine 3
(0.745 g, 5.73 mmol) was added to a solution of aldehyde 13b (0.6 g, 2.73 mmol) in dry DMF (5 ml) and left at
room temperature for 2 weeks. The reaction mixture was poured into water (40 ml) and the precipitate formed
was filtered off, washed with water, and dried to give a mixture (0.93 g) of the diethyl 2,6-diamino-4-(2,6-
dichloro-3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (14b) and ethyl 2-amino-5-chloro-
8-nitroquinoline-2-carboxylate (17) in the ratio 2:1. Signals for the dihydropyridine 14b were seen in the
1H NMR spectrum of the mixture (δ, ppm (J, Hz)): two rotamers 0.92 (6H, t, J = 7.4, CH3); 3.78, 3.86 (4H, m,
CH2); 5.51, 5.56 (1H, s, H-4); 7.0-7.3 (4H, s, NH2); 7.46 (1H, d, J = 8.7, Har-5); 7.68 (1H, d, J = 8.7, Har-4);
8.68, 8.72 (1H, s, NH). The mixture was separated on a chromatographic column using methylene chloride
containing 5% methanol as eluent. Recrystallization from ethanol gave 17 (0.16 g, 20%); mp 209-211ºC (with
decomp.). 1H NMR spectrum, δ, ppm (J, Hz): 1.39 (3H, t, J = 8.0, CH3); 4.40 (2H, q, J = 8.0, CH2); 7.47 (1H, d,
J = 8.7, H-6); 7.6-8.1 (2H, s, NH2); 8.13 (1H, d, J = 8.7, H-7); 8.86 (1H, s, H-4). 13C NMR spectrum, δ, ppm:
14.3 (CH3); 62.1 (CH2); 112.5 (C-3); 120.3 (C-4a); 121.0 (C-6); 126.6 (C-7); 135.2 (C-5); 138.2 (C-4); 142.1
(C-8a); 144.2 (C-8); 157.7 (C-2); 165.3 (CO). Found, %: C 48.53; H 3.46; N 14.16. C12H10ClN3O4. Calculated,
%: C 48.75; H 3.41; N 14.21.
3-Amino-7-nitro-4-pyrrolidinocarbonylisoquinoline (19). A solution of the aldehyde 1 (0.3 g,
1.8 mmol) and the enediamine 18 [2] (0.58 g, 3.7 mmol) in dry DMF (3 ml) was held at room temperature for 10
min. The mixture was poured into water (20 ml), potassium carbonate (0.1 g) was added, and the crystals formed
were filtered off and dried to give the isoquinoline 19 (0.39 g, 77%); mp 181-184ºC. A pure sample for analysis
1
was prepared by recrystallization from methanol. H NMR spectrum, δ, ppm (J, Hz): 1.70-2.00 (4H, d,
N(CH2CH2)2); 2.90-3.70 (4H, m, N(CH2CH2)2); 6.61 (2H, s, NH2); 7.47 (1H, d, J = 9.4, H-5); 8.20 (1H, dd, J =
3, J = 9.4, H-6); 8.93 (1H, d, J = 2, H-8); 9.19 (1H, s, H-1). 13C NMR spectrum, δ, ppm: 24.9, 26.2
(N(CH2CH2)2); 46.1, 47.2 (N(CH2CH2)2); 106.4 (C-4); 120.4 (C-8a); 123.9 (C-5); 125.1 (C-6); 127.2 (C-8);
137.7 (C-4a); 142.0 (C-7); 155.2 (C-3); 156.6 (C-1); 165.3 (CO). Found, %: C 58.38; H 4.81; N 19.50.
C14H14N4O3. Calculated, %: C 58.74; H 4.93; N 19.57.
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