Synthesis of derivatives of 8-cyano-6-ethoxycarbonyl-3-hydroxy-5- methylimidazo[1,2-a]pyridine and 9-alkoxycarbonyl- (or 9-carboxy)-3- ethoxycarbonyl-2-methyl-10H-benzo[b]-1,8-naphthyridine-5-one from the reaction of 2-chloro-5-ethoxycarbonyl-6-methylnicotinonitrile with amino acids

Article abstract of DOI:10.1023/B:COHC.0000033548.10379.02

2-Substituted 8-cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a] pyridine was formed from the interaction of 2-chloro-5-ethoxycarbonyl-6- methylnicotinonitrile with α-amino acids in DMF. The same nitrile on boiling with anthranilic acid or its esters in butanol gave, respectively, 2-(2-carboxyanilino)- or 2-(2-alkoxycarbonylanilino)-5-ethoxycarbonyl-6- methylnicotinonitriles which cyclized on heating in PPA to give 9-alkoxycarbonyl(or 9-carboxy)-3-ethoxycarbonyl-2-methyl-10H-benzo[b]-1,8- naphthyridin-5-ones.

Full text of DOI:10.1023/B:COHC.0000033548.10379.02

Chemistry of Heterocyclic Compounds, Vol. 40, No. 4, 2004
SYNTHESIS OF DERIVATIVES OF 8-CYANO-
6-ETHOXYCARBONYL-3-HYDROXY-5-METHYL-
IMIDAZO[1,2-a]PYRIDINE AND 9-ALKOXYCARBONYL-
(OR 9-CARBOXY)-3-ETHOXYCARBONYL-2-METHYL-
10H-BENZO[b]-1,8-NAPHTHYRIDINE-5-ONE FROM
THE REACTION OF 2-CHLORO-5-ETHOXYCARBONYL-
6-METHYLNICOTINONITRILE WITH AMINO ACIDS
A. B. Deyanov and M. E. Konshin
2-Substituted 8-cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridine was formed from
the interaction of 2-chloro-5-ethoxycarbonyl-6-methylnicotinonitrile with α-amino acids in DMF. The
same nitrile on boiling with anthranilic acid or its esters in butanol gave, respectively,
2-(2-carboxyanilino)- or (2-(2-alkoxycarbonylanilino)-5-ethoxycarbonyl-6-methylnicotinonitriles which
cyclized on heating in PPA to give 9-alkoxycarbonyl(or 9-carboxy)-3-ethoxycarbonyl-2-methyl-10H-
benzo[b]-1,8-naphthyridin-5-ones.
Keywords: 10H-benzo[b]-1,8-naphthyridin-5-ones, imidazo[1,2-a]pyridines, 2-(2carboxyanilino)-
nicotinonitriles.
We have shown previously that the reaction of 2-chloro-5-ethoxycarbonyl-6-methylnicotinonitrile (1)
with arylamines can be used to prepare biologically active derivatives of nicotinic acid [1] and also intermediates
for the synthesis of pyrido[2,3-d]pyrimidines (Scheme 1) [2, 3].
In this work, with the objective of extending these studies and elucidating the possibility of using nitrile
1 in the synthesis of functionally substituted imidazo[1,2-a]pyridines, pyrido[2,1-b]quinazolines and benzo[b]-
1,8-naphthyridines, we have studied the reactions of compound 1 with α-amino acids, anthranilic acid and its
esters.
As a result of the investigations it was found that the reaction of nitrile 1 with α-amino acids did not
result in substitution of chlorine atom by the amino acid residue, instead an intramolecular cyclization of the
intermediate N-(2-pyridyl) derivative of the amino acid occurred to give 2-substituted 8-cyano-6-
ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridines 2a-d (Table 1). This was indicated by the failure of
compounds 2a,b to dissolve in aqueous sodium hydrogencarbonate, and the absence of the characteristic signals
of the carboxy group protons in their 1H NMR spectra (Table 2).
__________________________________________________________________________________________
Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: pfa@degacom.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 608-613, April, 2004. Original article submitted June 22, 2001;
revision submitted March 20, 2002.
510
0009-3122/04/4004-0510©2004 Plenum Publishing Corporation

Scheme 1
Me
CN
CO2R2
NH2
R1
NH2
OH
EtO2C
Me
CN
Cl
EtO2C
RCHCO2H
N
R
N
N
1
O
2a–d
R1
R1
EtO2C
Me
EtO2C
Me
CN
PPA
N
N
H
N
N
H
3a–c
CO2R 2
CO2R 2
5a–c
3a
POCl3
Me
O
EtO2C
N
N
CN
4
2 a R = H, b R = CH2OH, c R = CH2CO2H, d R = CH2CH2CO2H;
3, 5 a R1 = R2 = H, b R1 = H, R2 = Et, c R1 = R2 = Me
In the IR spectra of imidazopyridines 2a-d stretching bands of the 3-OH were observed at
1
3510-3580 cm-1, and signals of hydroxyl protons appeared at 3.67-3.82 ppm in their H NMR spectra. These
data, and also the absence of signals of the NH group protons permitted the conclusion that compounds 2a-d
evidently exist in the enol form, and not the carbonyl form which is in agreement with some results presented in
the review [4].
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
H
N
2a
2b
2c
2d
3a
3b
3c
4
C12H11N3O3
58.77
59.02
56.72
56.64
55.45
55.70
56.78
57.16
62.76
62.98
64.58
64.30
64.58
64.74
66.44
66.57
4.52
4.41
4.76
5.03
4.32
4.27
4.77
4.75
4.65
4.79
5.42
5.58
5.42
5.65
4.26
4.53
17.13
17.38
15.27
15.60
13.86
14.06
13.24
13.00
12.92
13.09
11.89
12.15
11.89
11.92
13.67
13.52
89-92
100-102
97-99
35
46
41
42
71
74
65
35
58
61
76
C13H13 N3O4
C14H13N3O5
C15H15N3O5
C17H15N3O4
C19H19N3O4
C19H19N3O4
C17H13N3O3
C17H15N2O5
C19H19N2O5
C19H19N2O5
93-96
236-237
208-209
168-169
135-137
242-244
224-226
216-217
5a
5b
5c
62.38
62.60
64.22
64.24
64.22
64.10
4.62
4.74
5.39
5.11
5.39
5.09
8.56
8.53
7.88
8.17
7.88
8.02
511

TABLE 2. Spectroscopic Characteristics of the Compounds Synthesized
1H NMR spectrum, δ, ppm
IR spectrum, ν, cm-1*
Com-
pound
СН3
(3H, s)
NН
(1Н, s)
СН2СН3
ОСН2СН3
(3Н, q)
Н arom., m H pyridine, s
other protons
C=O
C≡N
N–H
other
(3Н, t)
2а
2.58
2.58
—
—
8.25
8.18
1.30
1.25
4.22
4.18
3.28 (1Н, s, 2-Н),
3.67 (1Н, s, 3-ОН)
1720
1722
2234
2230
—
—
3580 (О–Н)
3565 (О–Н)
2b
3.22 (2Н, d, СН2ОН),
3.71 (1Н, s, 3-ОН),
2.45 (1Н, d, СН2ОН)
2c
2.48
2.48
—
—
8.12
8.18
1.28
1.32
4.18
4.20
3.28 (2Н, s, СН2СООН),
3.82 (1Н, s, 3-ОН)
1726
1726
2232
2228
—
—
3520 (О–Н)
3510 (О–Н)
2d
3.25 (4Н, m, СН2СООН),
3.76 (1Н, s, 3-ОН)
3a
3b
3c
2.68
2.81
2.70
8.68
11.68
11.43
7.02-8.15
7.42-8.26
7.23-8.18
8.28
8.42
8.39
1.25
1.38
1.35
4.32
4.35
4.21
11.65 (1H, s, COOH)
—
2.26 (3H, s, R),
3.97 (3H, s, R')
1720
1716
1710
2230
2228
2230
3330
1700 (С=О), 3550 (О–Н)
1692 (C=O)
1694 (C=O)
4
5a
5b
2.55
2.65
2.62
—
8.78
7.01-8.05
7.45-8.30
6.97-8.29
8.30
8.46
8.58
1.28
1.35
1.30
4.26
4.32
4.32
—
9.43 (1H, s, COOH)
—
1718
1718
1714
2234
—
3330
3336
1660 (C=O)
1696 (C=O), 1676 (C(5)=О)
1700 (C=O), 1652 (C(5)=О)
9.18,
11.92
5c
2.62
11.98
7.47-8.32
8.55
1.35
4.28
3.85 (3H, s, COOMe),
2.32 (3H, s, R)
1716
3412
1698 (C=O), 1652 (C(5)=O)
_______
* The IR spectra of compounds 3a and 5 were obtained in CCl4 (c = 0.05 mol/l), those of compounds 3b, 3c – in CHCl3
(c = 0.05 mol/l), the others as nujol mulls.

It might be expected that anthranilic acid and its esters would react with nitrile 1 to give substituted
pyrido[2,1-b]quinazolin-10-one since this was observed in the case of the reaction of 2-chloronicotinamides with
anthranilic acid [5]. However 2-(2-carboxyanilino)-3a or 2-(2-alkoxycarbonyl-4-R-anilino)-5-ethoxycarbonyl-6-
methylnicotinonitriles 3b,c were obtained as a result of this reaction.
Compound 3a has a free carboxyl group and dissolves in aqueous sodium hydrogencarbonate solution.
In the IR spectrum of compound 3a in carbon tetrachloride solution stretching vibrations were observed at 3550
1
(COOH) and 3300 cm-1(NH). The H NMR spectrum of this compound has signals at 8.68 (1H, NH) and
11.65 ppm (1H, COOH) which correspond to suggested structure. This reaction stops at the acid 3a which does
not cyclize to derivative of pyrido[2,1-b]quinazoline, which is probably connected with steric hindrance by the
methyl group at position 6. As a confirmation of this idea we carried out the reaction between 2-chloro-6-
methylnicotinonitrile and anthranilic acid to give 2-(2-carboxyanilino)-6-methylnicotinonitrile.
When acid 3a was boiled with an excess of phosphorus oxychloride for 1.5 h 4-cyanopyrido-2-
ethoxycarbonyl-1-methyl[2,1-b]quinazolin-10-one (4) was obtained in 35% yield. Attempts to cyclize acid 3a by
boiling for 12 h in ethylene glycol or glacial acetic acid were unsuccessful.
Compound 4 is a crystalline substance insoluble in aqueous sodium hydrogencarbonate solution, but
soluble in general organic solvents. In distinction from the spectrum of the starting acid 3a, the IR and 1H NMR
spectra of compound 4 do not contain signals for the secondary amino group or OH of a carboxyl group.
The IR and 1H NMR spectra of the esters 3b and 3c differ somewhat from the spectra of 2-arylamino-5-
ethoxycarbonylnicotinonitriles [1]. For example, in the IR spectra of compounds 3b,c in Nujol mulls or
chloroform the stretching frequency due to a secondary amino group is missing and the stretching vibration
1
band of one of the ester carbonyl groups is shifted to low frequency. In the NMR spectra a signal for one
proton is observed at 11.43 or 11.68 ppm, whereas the signal for the proton of NH group in
2-arylaminonicotinonitriles is usually observed at 9.21-9.55 ppm. The absence of stretching vibration bands in
the 3100-3600 cm-1 region of the IR spectra and the weak field shift of the signal of the NH proton in the
1H NMR spectra of esters 3b,c indicate that they exist in the form of chelates with an intramolecular hydrogen
bond between the NH groups and the neighbouring carbalkoxy group.
In the mass spectra of compounds 3b,c the molecular ions correspond to the molecular mass.
Decomposition of the molecular ions of these compounds evidently proceeds in two directions: either with
elimination of alcohol and intramolecular cyclization into the ion 307 (321)* [M - AlkOH]+ , having the
structure of pyrido[2,1-b]quinazolin-10-one, or by loss of alkoxycarbonyl radical with formation of the ion 280
(294) [M - COOAlk]+. The preference for the second route of decomposition is indicated by the 100% intensity
of the peaks of ions 280 (294), the stability of which is explained by redistribution of the positive charge onto
the heterocyclic system. Fragmentation of the ions 307 (321) is related to the loss of CO molecule or the
isocyanic acid radical with the formation of the ions 279 (293) and 265 (289) respectively. The ions 280 (294)
lose H and are also converted into ions 279 and 293. The latter either lose the nitrile radical or are converted by
ortho-splitting with loss of a molecule of ethanol. Further fragmentation is connected with breakdown of the
heterocyclic system.
Heating of 2-arylaminonicotinonitriles in concentrated acids led to cyclization into derivatives of
benzo[b]-1,8-naphthyridin-10-one [6]. Because under the electronic impact from the molecular ion of
compounds 3b,c ion was formed which had the structure of pyrido[2,1-b]quinazolin-10-one, and also that
possibility of cyclization of compound 3a was confirmed preparatively, it seemed of interest to discover which
route would follow the reactions on heating these compounds in PPA.
It was established that when compounds 3a-c were heated in PPA at 135-145°C for 2h they cyclized into
9-alkoxycarbonyl(carboxy)-3-ethoxycarbonyl-2-methyl-7H-(methyl)-10H-benzo[b]-1,8-naphthyridin-5-ones
_______
* Here and below we use the value m/z for ion peaks.
513

5a-c in yields of 58-76%. Compound 5b was also obtained by prolonged standing of compound 3b at room
temperature in concentrated sulfuric acid.
Compounds 5a-c are yellow crystalline compounds, soluble in DMF and concentrated acetic acid. In
their IR spectra, in contrast with the spectra of starting materials 3a-c the nitrile stretching frequency has
disappeared and there is one more carbonyl group band at 1652-1676 cm-1. These data, and also the presence of
1
the signal of one proton at 11.70 (11.93) ppm and a weak signal at 9.18 ppm in the H NMR spectra of
naphthyridones 5b,c indicate the existence of compounds 5b,c in both the chelate and non-chelate forms.
EXPERIMENTAL
IR spectra were recorded on UR-20 spectrometer. 1H NMR spectra were recorded on a PC-60 (60 MHz)
spectrometer for solutions of compounds 2b, 2d, 5a-c in CDCl3, the rest in DMSO-d6 with HMDS as internal
standard. Mass spectra were recorded on MX-1303 apparatus with direct inlet of the sample into the ion source,
ionizing voltage 70 eV, standard for comparison 200Hg.
2-Substituted
8-Cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridines
(2a-d).
Compound 1 (2.25 g, 0.01 mol) was dissolved in DMF (10 ml), the corresponding α-amino acid (0.015 mol) was
added and the mixture was heated to complete solution of the latter and then for a further 1 h. The cooled
solution was poured into water (100 ml). The precipitate was filtered off and crystallized from 2-propanol–water
mixture.
2-(2-Carboxyanilino)- (3a) or 2-(2-Alkoxycarbonyl-4-R-anilino)-5-ethoxycarbonyl-6-methyl-
nicotinonitriles (3b,c). Solution of compound 1 (2.25 g, 0.01mol) and anthranilic acid or its ester (0.015 mol) in
butanol (25 ml) was boiled for 6 h. The precipitate formed on cooling was filtered off and crystallized
(compound 3a from a DMF water mixture, 3b,c – from 2-propanol). Mass spectra, m/z (Irel, %): 3b 353 [M]+
(47), 307 (15), 280 (100), 279 (60), 265 (10), 253 (25), 234 (10), 233 (12), 207 (12), 179 (9); 3c 353 [M]+ (77),
321 (23), 294 (100), 293 (87), 279 (10), 267 (24), 247 (16), 221 (10), 193 (3).
2-(2-Carboxyanilino)-6-methylnicotinonitrile (3a). Solution of nitrile 1 (1.53 g, 0.01 mol) and
anthranilic acid (2.06 g, 0.015 mol) in 50% acetic acid (15 ml) was boiled for 4 h. The precipitate was filtered
1
off, dried, and crystallized from 1:1 benzene–hexane. M.p. 140°C. Yield 1.81 g (71%). H NMR spectrum,
δ, ppm: 10.27 (1H, s, COOH); 8.63 (1H, s, NH); 7.25 (6H, m, arom. prot.); 2.19 (3H, s, CH3). Found, %: C 66.6;
H 4.3; N 16.4. C14H11N3O2. Calculated, %: C 66.4; H 4.4; N 16.6.
4-Cyanopyrido-2-ethoxycarbonyl-1-methyl[2,1-b]quinazolin-10-one (4). Solution of compound 3a
(3.25 g, 0.01 mol) in phosphorus oxychloride (25 ml, 0.28 mol) was boiled for 1.5 h. The mixture was cooled
and poured into water (100 ml) and carefully alkalized with ammonia solution to pH 8. The precipitate was
filtered off, dried, and crystallized from 85% acetic acid. M.p. 135-137°C, yield 1.07 g (35%).
9-Alkoxycarbonyl(carboxy)-3-ethoxycarbonyl-2-methyl-7H-(methyl)-10H-benzo[b]-1,8-naphthyridin-
5-ones (5a-c). Solution of the corresponding compound 3a-c (0.01 mol) in PPA was heated for 2 h at
135-145°C. The mixture was poured into water (100 ml), the precipitate was filtered off and crystallized from
aqueous acetic acid.
3,9-Di(ethoxycarbonyl)-2-methyl-10H-benzo[b]-1,8-naphthyridin-5-one (5b). Compound 3b (3.53 g,
0.01 mol) was dissolved in concentrated H2SO4 (25 ml) and kept at 18-22°C for 240 h. The solution was poured
into water (100 ml) and carefully neutralized with ammonia solution. The precipitate was filtered off, dried and
crystallized. Yield 3.02 g (89%). Melting point of mixed sample with compound 5b, prepared in the previous
experiment, gave no depression.
514

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