1,6- And 1,7-naphthyridines. IV. Synthesis of hydroxycarboxamide derivatives

Article abstract of DOI:10.1002/jhet.5570420404

A series of 8-hydroxy-1,6-naphthyridin-5(6H)-one-7-carboxamides 1 and the isomeric 5-hydroxy-1,7-naphthyridin-8(7H)-one-6-carboxamides 2 were synthesized. N-Lactam unsubstituted compounds 1a-c and 2a,b were obtained by alkoxide-induced rearrangement of the corresponding quinolinimidoacetamides 3. Compounds 1e,f and 2e,f were synthesized by heterocyclization of the corresponding quinolinamic esters 6 and 7. Spectroscopic properties (uv, ir, ¹H and ¹³C nmr and ms) were analyzed and the proposed structures confirmed.

Full text of DOI:10.1002/jhet.5570420404

May-Jun 2005
493
1,6- and 1,7-Naphthyridines. IV. Synthesis of
Hydroxycarboxamide Derivatives
M. Mercedes Blanco, Celia B. Schapira, Gustavo Levin and Isabel A. Perillo*
Department of Organic Chemistry, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Junín
956 (1113), Buenos Aires, Argentina, e-mail: iperillo@ffyb.uba.ar
Received August 20, 2004
Dedicated to the memory of Dr. Samuel Lamdan
A series of 8-hydroxy-1,6-naphthyridin-5(6H)-one-7-carboxamides 1 and the isomeric 5-hydroxy-1,7-
naphthyridin-8(7H)-one-6-carboxamides 2 were synthesized. N-Lactam unsubstituted compounds 1a-c and
2a,b were obtained by alkoxide-induced rearrangement of the corresponding quinolinimidoacetamides 3.
Compounds 1e,f and 2e,f were synthesized by heterocyclization of the corresponding quinolinamic esters 6
1
13
and 7. Spectroscopic properties (uv, ir, H and C nmr and ms) were analyzed and the proposed structures
confirmed.
J. Heterocyclic Chem., 42, 493 (2005).
Introduction.
Scheme 1
In previous papers we have reported our findings on the
synthesis and spectroscopic properties of 8-hydroxy-1,6-
naphthyridin-5(6H)-one-7-carboxylic acid alkyl esters and
the isomeric 5-hydroxy-1,7-naphthyridin-8(7H)-one-6-car-
boxylic acid alkyl esters [1-3]. Due to our interest in this
type of compounds [4], we have now extended our studies
in order to obtain the corresponding carboxamides 1 and 2.
These amides belong to a type of compounds (hydroxypyri-
donecarboxamides containing an aromatic or heteroaro-
matic fused ring) which display interesting biological prop-
erties including antiinflammatory [6], herbicide [7], gastric
antisecretory [8-10] and antiallergic activity [10].
Initially, aminolysis of the corresponding esters seemed
to be the most direct route for the synthesis of these amides.
However, under diverse conditions, the reaction fails to
occur or a complex mixture of unidentified products was
obtained.
These results led us to outline a strategy that involved
similar methods to that used in the synthesis of the related
naphthyridine esters [1,2] which allowed naphthyridine-
carboxamides 1 and 2 to be obtained.
Results and Discussion.
Comp.
R
R
2
1
N-Lactam unsubstituted naphthyridines (1a-c and 2a,b)
were obtained by alkoxide induced rearrangement of the
corresponding 5H-pyrrolo[3,4-b]-pyridine-5,7-(6H)-
dione-6-acetamides 3 (quinolinimidoacetamides) which
were synthesized from quinolinimidoacetic acid via acyl
chloride and further aminolysis (Scheme I). Thus, the reac-
tion of imides 3a,b with sodium isopropoxide in anhy-
drous 2-propanol gave a mixture of two products with pre-
dominance of the one having the lower Rf value (tlc, 9:1
chloroform-methanol). Both gave positive reaction with
ferric chloride and were isolated by chromatographic
methods. The low Rf compounds proved to be the 1,6-
naphthyridines 1a,b (30–35% yield) and those of high Rf
the 1,7-naphthyridines 2a,b (16–25% yield).
1a, 2a
1b, 2b
1c, 2c
CH
C H
2
H
C H
6
C H
2
C H
6
3
5
5
5
5
In the case of N-monosubstituted quinolinimidoacetamides
results were hardly satisfactory. Reactions took place leading
to considerable amounts of low Rf by-products that showed
acidic features [11]. Thus, the reaction of N-phenylquinolin-
imidoacetamide (3c) with sodium isopropoxide gave 19% of
1c and only traces of a product that seems to be 2c by tlc.
Instead, reaction of N-isopropylquinolinimidoacetamide (3d)
gave N-(isopropylcarbamoylmethyl)-3-pyridinecarboxamide
(4), which could have originated from alfa-decarboxylation
of one of the reaction by-products [14] (Scheme II).

494
M. M. Blanco, C. B. Schapira, G. Levin, and I. A. Perillo
Vol. 42
Scheme II
N-Lactam substituted naphthyridines (1e,f and 2e,f) were
1
H Nmr spectra of compounds 1 and 2 showed broad
synthesized by two different routes which involved the syn-
thesis and ring closure of quinolinamic acid alkyl esters.
Route a starts from the stable hemiester 5 and leads to inter-
mediate esters 6 which were cyclized to the 1,6-naph-
thyridines 1e,f with sodium isopropoxide (Scheme III).
signals between 11.42-8.94 ppm assigned to NH and OH
hydrogens, and between 7.52–9.03 ppm those correspond-
ing to the three pyridine hydrogen atoms.
13
C Nmr spectra showed nine signals besides those
Scheme III
Comp.
R
R
R
3
1
2
1e
1f
CH
CH
CH
C H
6
C H
2
3
3
5
5
C H
3
2
5
Scheme IV
Route b involves the preparation of the intermediate
quinolinamic acid alkyl esters 6 and 7 by aminolysis of
quinolinic anhydride with the corresponding aminoac-
etamide and further esterification with diazomethane.
Treatment of the reaction mixture with sodium isopropoxide
led to a mixture of 1,7-naphthyridines 2e,f as the major and
1,6-naphthyridines 1e,f as the minor product (Scheme IV).
Spectroscopic Features of 1,6- and 1,7-Naphthyridines (1
and 2).
On the basis of literature data, the positive ferric chlo-
1
ride test [15], the presence in the H nmr spectra of signals
attributed to the enol protons, the presence of bands in the
1640-1665 range in the ir spectra and the absence of sig-
13
nals over 165 ppm in the C nmr spectra support the enol-
lactam structure for compounds 1 and 2.
Spectral assignments of H nmr (Tables I and II) and
1
13
C
nmr spectra (Table III) [16] were made on the basis of sig-
nal multiplicity, coupling constant values, attached proton
test (APT) in certain cases, and by comparison with data of
related compounds [1-3].
Comp.
R
R
R
3
1
2
1e, 2e CH
1f, 2f CH
CH C H
3 6
3
3
5
5
C H C H
2
5
2
belonging to the substituents. Two of them, which
appeared between 157.9 and 164.5 ppm, were assigned to
carbonyl carbons Ci(i') and Ch(h'). APT spectra displayed

May-Jun 2005
1,6- and 1,7-Naphthyridines. IV. Synthesis of Hydroxycarboxamide Derivatives
495
Table I
8-Hydroxy-1,6-naphthyridin-5(6H)-one-7-carboxamides 1a-c,e,f
1
Compd. Mp Yield Formula
Analyses IR
(Calcd./Found)
%C %H %Ν
UV
H-NMR [a]
Nº
(ºC) (%)
ν
0.1N HCl methanol 0.1N ΝaΟΗ δ (ppm)
Multiplicity
Assignment
-1
(cm )
λ
.(nm)
λ
(nm)
λ
(nm)
max
max.
max.
1a
230 35
[b]
C
H
N O
65.08 4.44 14.23 3465
65.13 4.48 14.19 3080
328
256
213
355
252
214
366
262
223
11.21
8.94
8.91
8.43
7.54
7.35
7.28
7.17
3.35
11.39
9.02
8.99
8.53
7.62
3.32
1.12
bs
bs
OH/NH [c]
OH/NH [c]
Ha
16 13
3
3
2980
1680
1650
1600
1550
1450
d [d]
d [d]
dd [d]
d [d]
t [d]
t [d]
s
Hc
Hb
C H , ortho H
6
5
C H , meta H
6
5
C H , para H
6
5
NCH
3
1b
194 30
[b]
C
C
H
N O
3 3
59.76 5.79 16.08 3340
59.79 5.83 16.12 3016
327
260
221
350
249
220
358
262
229
bs
bs
OH/NH [c]
OH/NH [c]
Ha
13 15
2980
1665
1652
1605
1550
1450
dd [e]
dd [e]
dd [e]
q [e]
t [e]
Hc
Hb
NCH
2
CH
3
1c
[f]
272 19
[b]
H
N O
3 3
64.05 3.94 14.94 3450
63.99 3.98 14.87 2990
326
255
216
356
252
214
360
260
224
10.54
9.03
8.57
7.85
7.74
7.40
7.17
8.77
8.59
7.52
7.44-7.15
3.63
3.54
9.24
9.01
8.58
7.63
bs
d [g]
d [g]
dd [g]
d [g]
t [g]
t [g]
dd [j]
dd [j]
dd [j]
m
s
s
bs
dd [m]
dd [m]
dd [m]
m
s
m
OH/NH [c]
15 11
Ha
Hc
Hb
1660
1650
1600
1560
C H , ortho H
6 5
C H , meta H
6 5
C H , para H
6 5
1e
[h]
49
[i]
C
C
H
N O
66.01 4.89 13.58 3390
66.07 4.93 13.53 1673
328
257
222
215
359
253
228
216
361
263
226
224
Ha
Hc
Hb
17 15
3
3
1650
1628
1590
C H
6 5
NCH
NCH
3
3
1f
[k]
91
[b]
33
[i]
H
N O
61.08 6.22 15.26 3411
61.15 6.27 15.20 1662
325
256
220
214
350
256
225
215
359
260
222
219
OH [l]
Ha
Hc
14 17
3
3
1654
1623
1584
1473
Hb
3.58 and 3.41
3.34
3.30 and 3.26
1.17
NCH
NCH
NCH
2
3
2
t [m]
t [m]
CH
CH
3
1.09
3
[a] Spectra of compounds 1a-c,f were performed in DMSO-d ; spectra of compound 1e was performed in CCl D; [b] Recrystallized from 2-propanol;
6
3
3
3
3
3
3
[c] Exchangeable, the assignment could not be confirmed; [d] J
: 4.2 Hz, J
: 7.6 Hz, J
: 7.5 Hz, J
: 7.5 Hz. [e] J
: 4.6 Hz,
Ha-Hb
Hb-Hc
Ho-Hm
Hm-Hp
Ha-Hb
4
3
3
J
: 1.6 Hz, J
: 8.0 Hz, J
: 6.9 Hz; [f] Two dastereomers were observed in the nmr spectra, signals of the major product are indicated;
Ha-Hc
Hb-Hc
CH2-CH3
3
3
3
3
[g] J
(route a); [j]
: 4.4 Hz, J
: 7.8 Hz, J
: 7.9 Hz, J
: 7.9 Hz; [h] The compound was isolated as an oil; [i] Yield starting from the hemiester 5
Hm-Hp
: 8.1 Hz; [k] Assignments in the nmr spectra were confirmed by HMQC and HMBC;
Ha-Hb
Hb-Hc
Ho-Hm
3
4
3
J
: 4.6 Hz,
J
: 1.8 Hz,
J
Ha-Hb
Ha-Hc
Hb-Hc
3
4
3
3
3
[l] Exchangeable; [m] J
: 4.6 Hz, J
: 1.8 Hz, J
: 8.1 Hz, J
: 6.9 Hz, J
: 7.2 Hz.
CH3-CH2
Ha-Hb
Ha-Hc
Hb-Hc
CH3-CH2
three signals of the highest intensity with the same phase,
that were assigned to pyridine carbons Ca(a')
(153.6–149.3), Cb(b') (122.7–126.6 ppm) and Cc(c')
(129.9–137.3 ppm). The four remaining carbons could be
identified on the basis of the full-coupled spectra of com-
pounds 1e and 2e. Such spectra showed two singlets at ca.
131 and 120 ppm and another two signals with long-range
3
3
correlations (139.9–147.4 ppm, dd, J
5 Hz and 120.4–128.9 ppm, d, J
~ 12 Hz, J
~
C-H
CH
3
~ 6 Hz). Singlets were
C-H
assigned to Cf(f') and Cg(g') in agreement with literature

496
M. M. Blanco, C. B. Schapira, G. Levin, and I. A. Perillo
Vol. 42
Table II
5-Hydroxy-1,7-naphthyridin-8(7H)-one-6-carboxamides 2a,b,e,f
1
Compd. Mp Yield Formula
Analyses IR
(Calcd./Found)
%C %H %Ν
UV
H-NMR [a]
Nº
(ºC) (%)
ν
0.1N HCl methanol 0.1N ΝaΟΗ δ (ppm)
Multiplicity
Assignment
-1
(cm )
λ
.(nm)
λ
(nm)
λ
(nm)
max
max.
max.
2a
180 25
[b]
C
H
N O
65.08 4.44 14.23 3447
65.01 4.49 14.17 3030
333
260
225
325
252
229
367
261
227
11.32
9.04
8.72
8.14
7.65
7.34
7.25
7.13
3.28
bs
bs
OH/NH [c]
OH/NH [c]
Ha'
16 13
3
3
2944
1652
1634
1601
1547
d [d]
d [d]
dd [d]
d [d]
t [d]
t [d]
s
Hc'
Hb'
C H , ortho H
6 5
C H , meta H
6 5
C H , para H
6
5
NCH
3
2b
2e
189 16
[b]
C
C
H
N O
3 3
59.76 5.79 16.08 3400
59.83 5.84 16.02 3064
322
257
223
321
270
252
225
358
263
225
11.42
9.01
8.82
8.30
7.76
3.35
1.12
9.21
8.75
8.17
7.68
7.35
7.24
7.15
3.51
bs
bs
OH/NH [c]
OH/NH [c]
Ha'
13 15
2930
1658
1608
1590
d [e]
d [e]
dd [e]
q [e]
t [e]
bs
dd [i]
dd [i]
dd [i]
d [i]
t [i]
t [i]
s
Hc'
Hb'
NCH
2
CH
3
OH [j]
Ha'
Hc'
Hb'
104 32
H
N O
3 3
66.01 4.89 13.58 3470
66.09 4.93 13.51 2962
331
256
220
213
326
250
226
219
362
258
218
17 15
[f] [g] [b]
[h]
1640
1633
1580
1323
C H , ortho H
6 5
C H , meta H
6 5
C H , para H
6
5
NCH
3
3.35
s
NCH
3
2f
[k]
32
[h]
C
H
N O
61.08 6.22 15.26 3470
61.14 6.26 15.22 2962
331
256
220
213
326
250
226
219
362
258
226
218
8.94
8.83
7.86
7.63
3.75-3.55
3.48
bs
OH [j]
Ha'
Hc'
14 17
3
3
bs [l]
bs [l]
bs [l]
m
1640
1633
1580
1323
Hb'
NCH
NCH
2
s
3
1.45-1.01
m
CH
3
[a] Spectra of compounds 2a,b,e were performed in DMSO-d spectra compound 2f was performed in CCl D; [b] Recrystallized from 2-propanol; [c]
6;
3
3
3
3
3
3
3
Exchangeable, the assignment could not be confirmed; [d] J
: 4.6 Hz, J
: 8.2 Hz, J
: 7.7 Hz, J
: 7.7 Hz. [e] J
: 4.3 Hz,
J
:
Ha-Hb
Hb-Hc
Ho-Hm
Hm-Hp
Ha-Hb
Hb-Hc
3
8.2 Hz, J
: 7.1 Hz; [f] Two diastereomers were observed in the nmr spectra; signals of the major product are indicated; [g] Assignments in the nmr
CH2-CH3
3
4
3
spectra were confirmed by HMQC and HMBC; [h] Total yield starting from quinolinic anhydride (Route b); [i] J
: 4.1 Hz, J
: 1.5 Hz, J
:
Ha-Hb
Ha-Hc
Hb-Hc
3
3
8.2 Hz, J
: 7.3 Hz, J
: 7.3 Hz; [j] Exchangeable; [k] The compound was isolated as an oil; [l] Broad multiplets typical of coalescent signals.
Ho-Hm
Hm-Hp
data in related benzothiazines and isoquinolones [17]. The
three-bond correlation Cf'– Hc' confirms the 1,7-naph-
thyridine structure of compound 2e.
In N,N-disubstituted carboxamides the partial double
bond character of amide CO-N bond, which arises from
the contribution of a polar resonance structure along with
the normal covalent one, would lead to the nonequivalence
13
1
double doublet, which displayed a large J C- H charac-
13
1
teristic of the C- H three bond coupling through nitrogen
[18], was assigned to Ce(e') and the doublet to Cd(d').
Previous assignments were unequivocally confirmed by
two dimensional heteronuclear correlation spectra (HMQC
and HMBC) of compounds 1f and 2e. The observed one
(or more) bond correlations are indicated in Tables IV and
V. The three-bond correlation for Ch-Hc supports the
1,6–naphthyridine structure of compound 1f, while the
of the two substituents when R R as well as to the pres-
1=
2
ence of diastereomeric amides when R ≠ R [19] (A).
1
2
However, chemical equivalence of both ethyl groups in the
1
H nmr spectra of compounds 1b and 2b as well as the

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1,6- and 1,7-Naphthyridines. IV. Synthesis of Hydroxycarboxamide Derivatives
497

498
M. M. Blanco, C. B. Schapira, G. Levin, and I. A. Perillo
Vol. 42
Table IV
HMQC Single-bond and HMBC Long-range Proton-carbon Correlations of Compound 1f
Carbon
Proton single-bond coupling
Proton three bond coupling
Proton two bond coupling
δ(ppm)
δ(ppm)
δ(ppm)
δ(ppm)
Ci (161.6)
Ch (158.9)
Ca (153.6)
Ce (146.7)
Cc (136.2)
Cf (132.0)
Cg (124.5)
Cb (122.9)
Cd (120.4)
_
_
NCH (3.58, 3.41, 3.30 and 3.26)
_
_
2
NCH (3.34), Hc (8.58)
3
Ha (9.01)
Hc (8.58)
Ha (9.01), Hc (8.58)
Ha (9.01)
Hb (7.63)
_
_
_
_
Hc (8.58)
_
_
_
Hb (7.63)
_
NCH (3.34)
_
Ha (9.01)
_
3
_
Hb (7.63)
NCH (42.5)
CH (3.30 and 3.26)
_
_
_
_
_
CH CH (1.09)
CH CH (1.17)
2 3
2
2
2 3
NCH (38.6)
CH (3.58 and 3.41)
2
2
NCH (31.9)
NCH (3.34)
_
3
3
CH CH (13.8)
CH CH (1.09)
CH (3.30 and 3.26)
2
3
2
3
2
CH CH (12.4)
CH CH (1.17)
CH (3.58 and 3.41)
2
2
3
2
3
Table V
HMQC Single-bond and HMBC Long-range Proton-carbon Correlations of Compound 2e
Carbon
Proton single-bond coupling
Proton three bond coupling
Proton two bond coupling
δ(ppm)
δ(ppm)
δ(ppm)
δ(ppm)
Ci’ (161.9)
Ch’ (157.8)
Ca’ (149.7)
Cj’ (142.2)
Ce’ (139.9)
Cc’ (130.8)
Cl’ (128.9)
Cm’ (127.7)
Cf’ (126.9)
Cd’ (126.5)
Cb’ (125.9)
Ck’ (125.7)
Cg’ (125.0)
_
_
NCH (3.35)
_
_
3
NCH (3.51)
3
Ha’ (8.75)
Hc’ (8.17)
Hb’ (7.68)
_
_
NCH (3.35), Hl’ (7.24)
_
_
_
_
_
_
_
3
Ha’ (8.75), Hc’ (8.17)
Ha’ (8.75)
_
Hc’ (8.17)
Hl’ (7.24)
Hm’ (7.15)
_
Hk’ (7.35)
Hc’ (8.17)
Hb’ (7.68)
_
_
Hb’ (7.68)
Hk’ (7.35)
_
Ha’ (8.75)
Hm’ (7.15)
_
_
_
_
NCH (3.51)
3
NCH (36.5)
NCH (3.35)
_
_
3
3
NCH (32.2)
NCH (3.51)
3
3
absence of diastereomeric carboxamides 1a and 2a indi-
cate that the CO-N bond enjoy free rotation at room tem-
perature. These facts are in line with a resonance-assisted
hydrogen bonding effect (RAHB) [20] where the stabi-
lized keto-enol system involves the amide carbonyl lead-
ing to an important single-bond character of the amide
CO-N bond (B) [21]. With regard to the spectra of naph-
with the presence of two diastereomeric amides [22].
Stability of both species could be related to the strong
intermolecular association of N-monosubstituted amides,
in which rotation rate may involve breaking and making of
hydrogen bonds [19a].
Lactam N-substitution inhibits planarity of the keto-enol
system [23] leading to the existence of diastereomeric car-
boxamides in compound 2e and to the chemical nonequiv-
thyridine 1c (R =H, R =C H ), signals are in agreement
1
2
6 5

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499
alence of the ethyl groups in compounds 1f and 2f. Thus,
13
the C nmr spectrum of compound 1f exhibited two sig-
nals for methylene carbons (38.6 and 42.5 ppm) as well as
for methyl carbons (12.4 and 13.8 ppm), indicating the
partial double bond character of the amide CO-N bond.
1
Accordingly, in the H nmr spectra methyl groups are
anisochronous appearing as two triplets at 1.17 and 1.09
ppm. In addition, in the HMQC and HMBC spectra in
DMSO-d6, methylene hydrogens appeared as four signals
at 3.58 and 3.41 ppm, (those linked to the more shielded
carbon) and at 3.30 and 3.26 ppm (those linked to the more
deshielded carbon). Diastereotopicity of methylene hydro-
gens could be associated to the presence of a chiral axis
[24] arising from a restricted rotation around the naph-
thyridine-CONH bond, which lead to the presence of atro-
pisomers [25].
Table VI
Select Fragments in the EI Mass Spectra of Compounds 1 and 2
Ion
1a
1b
1c
1e
1f
2a
2b
2e
2f
R= H
R= H
R= H
R= CH
R= CH
R= H
R= H
R= CH
R= CH
3
3
3
3
R = CH
R = C H
R = C H
R = CH
R = C H
R = CH
R = C H
R = CH
R = C H
1 2
1
3
1
2
5
5
1
6
5
1
3
1
2
5
5
1
3
1
2
5
5
1
3
5
R = C H
R = C H
R = H
R = C H
R = C H
R = C H
R = C H
R = C H
R = C H
2
6
5
2
2
2
2
6
5
2
2
2
6
5
2
2
2
6
5
2 2
5
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
+ ·
M
295 (22.2)
296 (10.7)
134 (22.9)
106 (27.8)
107 (100.0)
189 (2.8)
261 (3.4)
262 (0.6)
100 (18.2)
72 (100.0)
73 (6.5)
189 (1.7)
161 (1.5)
133 (1.9)
244 (-)
162 (10.1)
78 (12.5)
58 [b] (16.9)
44 [c] (40.3)
281 (58.6)
282 (13.6)
120 (-)
309 (7.6)
310 (0.9)
134 (100.0)
106 (68.6)
275 (20.4)
276 (4.9)
100 (1.8)
72 (100.0)
73 (8.6)
203 (8.9)
175 (12.7)
147 (3.1)
258 (1.4)
176 (61.2)
58 [b] (25.9)
295 (6.2)
296 (1.5)
134 (10.5)
106 (61.0)
107 (100.0)
189 (2.2)
161 (4.8)
133 (4.9)
278 (6.6)
162 (15.6)
79 (23.9)
78 (33.7)
77 (40.3)
51 (35.6)
261 (4.6)
262 (3.3)
100 (34.1)
72 (100.0)
73 (7.0)
189 (2.9)
161 (5.5)
133 (3.7)
244 (-)
162 (18.4)
78 (20.6)
58 [b] (18.0)
51 (14.4)
44 [c] (59.5)
309 (5.9)
310 (2.3)
134 (72.3)
106 (60.4)
107 (100.0)
203 (1.3)
175 (2.9)
147 (1.3)
292 (2.8)
275 (17.2)
276 (11.9)
100 (17.2)
72 (100.0)
73 (5.6)
203 (2.9)
175 (4.4)
147 (3.0)
258 (-)
+
[M+1]
[CONR R ]
+
1
2
+
[NR R ]
92 (-)
1
2
+ ·
[HNR R ]
[M-NR R ]
[M-NR R -CO]
[M-NR R -2CO] 133 (2.3)
[M-OH)]
Others
[a]
93 (100.0) 107 (55.2)
1
2
+
189 (4.1)
161 (2.5)
133 (2.1)
264 (1.9)
203 (1.7)
175 (4.7)
147 (5.6)
292 (10.1)
1
2
+
161 (3.9)
1
2
+
1
2
+
278 (13.0)
162 (20.7)
149 (15.8)
176 (35.2)
58 [b] (20.9)
+
+
[a] Peaks greater than 10% are included. [b] Corresponds to [HNR R -CH ] . [c] Corresponds to [NR R -C H ] .
1
2
3
1
2
2 4
Scheme V

500
M. M. Blanco, C. B. Schapira, G. Levin, and I. A. Perillo
Vol. 42
The organic layers were pooled, washed with 5% aqueous acetic
acid and water until neutral pH, dried (sodium sulfate) and evap-
orated in vacuo. The resulting oil was triturated with ice-ethanol
affording compounds 3a-d.
With regard to the uv spectra, in contrast with 1,7-naph-
thyridines 2, 1,6-naphthyridines 1 in methanol present a
predominance of the zwitterion structure C as shown by
the striking similarity with those spectra measured in basic
medium (enolate anion) and a significant difference with
spectra taken in acidic solution (Tables I and II).
N-Methyl-N-phenyl-5H-pyrrolo[3,4-b]-pyridine-5,7-(6H)-dione-
6-acetamide (3a).
Ms showed mainly fragments with charge retention on
This compound was obtained in 60% yield; mp 152 °C (2-
propanol); ir: 3061, 2943, 1741, 1734, 1674, 1593, 1384 cm ;
H nmr (deuteriochloroform): δ 8.96 (dd, 1H, H2, J = 4.9, 1.4
Hz), 8.16 (dd, 1H, H4, J = 7.6, 1.4 Hz), 7.60 (dd, 1H, H3, J =
-1
+
+
the nitrogen moiety: [CONR1R2] , [NR1R2] and
1
+
·
[HNR1R2] (Table VI, Scheme V). In particular, the pres-
ence of amine radical-ions resulting from intramolecular
hydrogen transfer to the amide nitrogen and further
homolytic cleavage, supports the enol structure in the gas
phase.
7.6, 4.9 Hz), 7.40-7.60 (m, 5H, C H ), 4.24 (s, 2H, CH CO),
6
5
2
13
3.35 (s, 3H, CH ); C nmr (deuteriochloroform): δ 165.9 and
3
165.8 (C5 and C7), 165.1 (CONR R ), 155.2 (C2), 151.8 (C7a),
1
2
142.1 (C H , ipso carbon), 131.3 (C4), 130.2 (C H , meta car-
6
5
6 5
bon), 128.7 (C H , para carbon), 127.5 (C H , ortho carbon),
6
5
6 5
EXPERIMENTAL
127.4 (C4a), 127.3 (C3), 40.0 (CH ), 37.7 (NCH ); ms: m/z 295
2
3
+.
(28.5 %) (M ).
Melting points were taken on a Büchi capillary apparatus and
Anal. Calcd. for C
H N O : C, 65.08; H, 4.44; N, 14.23.
16 13 3 3
1
13
are uncorrected. The H and C nmr spectra were recorded on a
Bruker MSL 300 MHz. Chemical shifts are quoted in parts per
million (δ) downfield from an internal TMS reference. The pres-
ence of exchangeable protons was confirmed by use of deuterium
oxide. Proton signals are quoted as: s (singlet), bs (broad signal),
d (doublet), dd (doublet of doublet), t (triplet), dt (doublet of
triplet), q (quartet) and m (multiplet). Two-dimensional spectra
(HMQC and HMBC) were recorded with a Bruker AVANCE
DRX 300 spectrometer.
Found: C, 65.14; H, 4.47; N, 14.17.
N,N-Diethyl-5H-pyrrolo[3,4-b]-pyridine-5,7-(6H)-dione-6-
acetamide (3b).
This compound was obtained in 52% yield; mp 142 °C (2-
propanol); lit. [14] mp 142 °C; ir: 3095, 2997, 1783, 1728, 1659,
-1 13
1593, 1471,1395 cm ; C nmr (deuteriochloroform): δ 166.0
and 165.9 (C5 and C7), 163.9 (CONR R ), 155.2 (C2), 151.8
1
2
(C7a), 131.3 (C4), 127.5 (C4a), 127.3 (C3), 39.2 (CH CO), 41.3
2
Ms (electron impact) were performed on a MS Shimadzu QP-
1000 instrument at 20 eV. The ir spectra were recorded on a
Perkin Elmer Spectrum One FT-IR spectrometer and samples
were run as potassium bromide pellets. The uv spectra were
recorded on a Jasco 7850 UV-VIS spectrophotometer. Analytical
tlc was carried out on aluminum sheets Silica Gel 60 F254.
Preparative thin layer separations (plc) were carried out by cen-
trifugally accelerated, radial chromatography using
Chromatotron model 7924T. The rotors were coated with Silica
+.
and 40.8 (CH CH ), 12.8 (CH ); ms: m/z 261 (9.5 %) (M ).
2
3
3
N-Phenyl-5H-pyrrolo[3,4-b]-pyridine-5,7-(6H)-dione-6-
acetamide (3c).
This compound was obtained in 50% yield; mp 215 °C (2-
-1
propanol); ir: 3420, 1752, 1735, 1648, 1605, 1598, 1485 cm ;
1
H nmr (deuteriochloroform): δ 9.01 (dd, 1H, H2, J = 4.5, 1.4
Hz), 8.22 (dd, 1H, H4, J = 6.7, 1.4 Hz), 7.63 (dd, 1H, H3, J =
6.7, 4.5 Hz), 7.55 (bs, 1H, NH) 7.49 (d, 2H, C H , ortho
6
5
Gel 60 PF
and the layer thickness was 2 mm. Chloroform and
254
hydrogen, J = 7.8 Hz), 7.31 (dd, 2H, C H , meta hydrogen, J =
6
5
increasing percentages of methanol were used as eluent.
Reagents, solvents and starting materials were purchased from
standard sources and purified according to literature procedures.
Experiments performed with toxic or severely irritant substances
were carried out in an efficient fume cupboard.
7.8, 7.4 Hz), 7.13 (t, 1H, C H , para hydrogen, J = 7.4 Hz),
6
5
13
4.59 (s, 2H, CH CO); C nmr: δ (deuteriochloroform) 165.8
2
and 165.6 (C5 and C7), 163.1 (CONR R ), 155.5 (C2), 151.6
1
2
(C7a), 137.0 (C H , ipso carbon), 131.6 (C4), 129.1 (C H ,
6
5
6 5
meta carbon), 127.6 (C3), 127.4 (C4a), 124.8 (C H , para car-
6
5
5H-Pyrrolo[3,4-b]-pyridine-5,7-(6H)-dione-6-acetamides
(Quinolinimidoacetamides) (3).
bon), 119.9 (C H , ortho carbon), 41.6 (CH ); ms: m/z 281
6
5
2
+.
(29.7 %) (M ).
Anal. Calcd. for C H N O : C, 64.05; H, 3.94; N, 14.94.
General Procedure.
15 11
3 3
Found: C, 64.00; H, 3.98; N, 14.99.
A mixture of quinolinimidoacetic acid [29] (2.06 g, 10
mmoles) in dry benzene (10 mL) and oxalyl chloride (1.39 g, 11
mmoles) (caution) was heated at 40º for 5 hours. The reaction
mixture was concentrated in vacuo and the resulting oil washed
twice with dry benzene and concentrated, affording quinolinimi-
doacetyl chloride (85%) which was used in the next step without
purification.
To a mixture of methylene chloride (10 mL), 20% sodium
hydroxide (20 mL) and the appropriate amine (4.5 mmoles), a
solution of 1 g (4.5 mmoles) of quinolinimidoacetyl chloride in
methylene chloride (10 mL) was added dropwise, the tempera-
ture being maintained at –15º during the addition. The suspension
was stirred at room temperature for 1 hour and the aqueous layer
was separated and extracted with methylene chloride (2 x 5 mL).
N-Isopropyl-5H-pyrrolo[3,4-b]-pyridine-5,7-(6H)-dione-6-
acetamide (3d).
This compound was obtained in 49% yield; mp 209 °C (2-
propanol); ir: 3428, 3060, 1778, 1732, 1645, 1595, 1476, 1382
-1
1
cm ; H nmr (deuteriochloroform): δ 9.00 (dd, 1H, H2, J = 4.7,
1.3 Hz), 8.20 (dd, 1H, H4, J = 7.7, 1.3 Hz), 7.64 (dd, 1H, H3, J =
7.7, 4.7 Hz), 6.50 (bs, 1H, NH), 4.80 (m, 1H, CH, J = 6.7 Hz),
13
4.36 (s, 2H, CH CO), 1.18 (d, 6H, CH , J = 6.7 Hz); C nmr: δ
2
3
(deuteriochloroform) 165.9 and 165.6 (C5 and C7), 164.3
(CONR R ), 155.4 (C2), 151.7 (C7a), 131.5 (C4), 127.5 (C3),
1
2
127.4 (C4a), 42.2 (CH), 40.9 (CH ), 22.6 (CH ); ms: m/z 247
2
3
+.
(1.0 %) (M ).

May-Jun 2005
1,6- and 1,7-Naphthyridines. IV. Synthesis of Hydroxycarboxamide Derivatives
501
Anal. Calcd. for C
H
N O : C, 58.29; H, 5.30; N, 16.99.
8-hydroxy-1,6-naphthyridines 1e and 1f. Yields, melting points,
recrystallization solvents, analyses and spectroscopic data of the
compounds are given in Tables I, III, and VI.
12 13
3 3
Found: C, 58.23; H, 5.34; N, 17.05.
Reaction of Compounds 3 with Sodium Alkoxides.
General Procedure.
An analytical sample of 6 (X=N(CH )C H , R=CH ) was iso-
3
6
5
3
1
lated as an oil (81% yield) and purified by centrifugal plc; H nmr
(deuteriochloroform): δ 8.69 (dd, 1H, H-6), 7.89 (dd, 1H, H-4),
To a solution of sodium isopropoxide prepared from sodium
(0.23 g, 0.01 mol) in anhydrous 2-propanol (5 mL) heated in an
oil bath (90-100 ºC), quinolinimidoacetamides 3 (2.5 mmoles)
were added all at once in powder form. After 30 minutes the
reaction mixture was poured into ice-acetic acid and extracted
with chloroform (3 x 10 mL). The organic layers were pooled,
washed with water, dried and evaporated in vacuo. The crude
products obtained from 3a-c showed two spots by tlc.
Separation of the two compounds was achived by centrifugal
plc. The first eluted band gave the 1,7-naphthyridine derivatives
2a,b and only traces of compound 2c were detected. The slower
moving band afforded the 1,6-naphthyridine derivatives 1a-c.
Yields, recrystallization solvents, melting points, analyses and
spectroscopic data of the compounds are given in Tables I, II,
III and VI. When sodium methoxide in methanol or tert-butox-
ide in tert-butanol was used to promote the rearrangement
yields were lower in all cases.
7.50 (dd, 1H, H-5),7.39 (m, 5H, C H ), 3.96 (s, 3H, OCH ), 3.52
6
5
3
(s, 2H, NCH ), 3.26 (s, 3H, NCH ) and 3.20 (s, 3H, NCH ); ms:
2
3
3
+.
m/z 341 (27.0%) (M ), 105 (100%).
Anal. Calcd. for C N O : C, 63.33; H, 5.61; N, 12.31.
H
18 19
3 4
Found: C, 63.25; H, 5.66; N, 12.26.
Route b.
To a mixture of quinolinic anhydride (5 mmoles), the appropri-
ate aminoacetamide hydrochloride (6 mmoles) and dry tetrahy-
drofuran (10 mL) in an ice bath, triethylamine (0.81 g, 8 mmoles)
in tetrahydrofuran (10 mL) was added dropwise and with stirring.
After stirring for 1 hour at room temperature, the reaction mix-
ture was cooled (ice bath) filtered and the organic solution con-
centrated in vacuo. The pasty solid was dissolved in anhydrous
methanol (5 mL) and an ethereal solution of diazomethane (cau-
tion) was added in small portions until the solution acquires a
pale yellow colour. After 24 hours at room temperature, the reac-
tion mixture was concentrated in vacuo affording a mixture of
compounds 6 and 3-methoxycarbonyl-N-(carbamoylmethyl)-N-
methyl-2-pyridinecarboxamides 7 which was used in the next
step without purification.
A crude mixture of esters 6 and 7 obtained as above was
treated with sodium isopropoxide as was described for route a
affording a mixture of 6,7-disustituted 5-hydroxy-1,7-naph-
thyridines 2e,f as the major product together with little amounts
of the corresponding 6,7-disubstituted 8-hydroxy-1,6-naph-
thyridines 1e,f. Yields, melting points, recrystallization solvents,
analyses and spectroscopic data of the compounds are given in
Tables I, II, III and VI.
The crude product obtained from reaction of compound 3d
with alkoxides showed only one spot by tlc which was isolated
and identified as N-(N-isopropylcarbamoylmethyl)-3-
pyridinecarboxamide (60% yield; ); mp 179-182 °C (ethanol-
1
water); H nmr (deuteriochloroform): δ 9.05 (d, 1H, H-2),
8.73 (dd, 1H, H-6), 8.15 (dd, 1H, H-4), 7.38 (dd, 1H, H-5),
7.30 (bs, 1H, NH), 5.95 (d, 1H, NH), 4.35-4.17 (m, 1H, CH),
4.13 (d, 2H, NCH ) and 1.24 (d, 6H, CH ); ms: m/z 222
2
3
+
(MH ) (100%).
Anal. Calcd. for C H N O : C, 59.71; H, 6.83; N, 18.99.
11 15
3 2
Found: C, 59.75; H, 6.88; N, 18.92.
Synthesis and Cyclization of Quinolinamic Acid Methyl Esters 6
and 7.
An analytical sample of compound 7 (X=N(CH )C H ,
3
6
5
R=CH ) was obtained from the reaction of quinolinic anhydride
3
General Procedures.
with N-methyl-N-phenyl-2-(methylamino)acetamide and further
reaction with diazomethane. The crude reaction product showed
two spots by tlc. Separation was accomplished by centrifugal plc.
Route a.
A suspension of 2,3-pyridinedicarboxylic acid 2-methyl ester 5
(0.85 g, 5 mmoles), prepared following Kenyon and Thaker´s pro-
cedure [30], in dry benzene (5 mL) and oxalyl chloride (0.75 g, 6
mmoles) was stirred at 40º for 3 hours. The solvent and excess of
oxalyl chloride were removed in vacuo. The residual oil was dis-
solved in dry chloroform (5 mL). Solution was stirred and treated
with the appropriate aminoacetamide hydrochloride (5 mmoles)
and then a solution of triethylamine (0.81 g, 8 mmoles) in dry chlo-
roform (10 mL) was added dropwise. The reaction mixture was
refluxed for 1 hour, cooled and filtered. Solution was concentrated
in vacuo and dry benzene (5 mL) added twice evaporating each
time to dryness affording the corresponding 2-methoxycarbonyl-
N-(carbamoylmethyl)-N-methyl-3-pyridinecarboxamide 6 as an
oil that was used in the next step without purification.
Cyclization of quinolinamic acid methyl esters 6 was per-
formed by treating crude products (1.1 g) dissolved in boiling
2-propanol (3 mL) with 2 M sodium isopropoxide (3 mL) and
refluxed for 30 minutes. The red-yellow syrup was poured into
ice-acetic acid and extracted with chloroform (4 x 5 mL). After
washing with water the organic layer was dried, concentrated in
vacuo and purified by centrifugal plc affording 6,7-disubstituted
The first band eluted afforded compound 7 (X=N(CH )C H ,
3
6 5
1
R=CH ) (70%) as an oil; H nmr (deuteriochloroform): δ 8.78 (dd,
3
1H, H-6), 8.29 (dd, 1H, H-4), 7.45 (dd, 1H, H-5),7.43 (m, 5H,
C H ), 3.84 (s, 3H, OCH ), 3.55 (s, 2H, CH ), 3.25 (s, 3H, NCH )
6
5
3
2
3
+.
y 3.19 (s, 3H, NCH ); ms: m/z 341 (35.78%) (M ), 77 (100%).
3
Anal. Calcd. for C
H N O : C, 63.33; H, 5.61; N, 12.31.
18 19 3 4
Found: C, 63.39; H, 5.56; N, 12.36.
The second band eluted (20% yield) was identified as com-
pound 6 (X=N(CH )C H , R=CH ).
3
6
5
3
Acknowledgements.
This work was financially supported by the Universidad de
Buenos Aires and CONICET (Consejo Nacional de
Investigaciones Científicas y Técnicas).
REFERENCES AND NOTES
[1] M. M. Blanco, M. G. Lorenzo, I. A. Perillo and C. B.
Schapira, J. Heterocyclic Chem., 33, 361 (1996).
[2] M. M. Blanco, I. A. Perillo and C. B. Schapira, J. Heterocyclic

502
M. M. Blanco, C. B. Schapira, G. Levin, and I. A. Perillo
Vol. 42
Chem., 36, 979 (1999).
[3] M. M. Blanco, G. Y. Buldain, C. B. Schapira and I. A. Perillo,
J. Heterocyclic Chem., 39, 341 (2002).
[4] A recent communication highlights the importance of some 7-
substituted 8-hydroxy-1,6 naphthyridines which display anti HIV activity
[5]. These compounds are structurally related with the 1,6-naphthyridines
described in this paper.
[17a] J. Geckle, D. Rescek and E. Whipple, Magn. Reson. Chem.,
27, 150 (1989); [b] J. Bordner, P. Hammen and E. Whipple, J. Am. Chem.
Soc., 111, 6572 (1989); [c] J. Frigola, J. Chem. Soc. Perkin Trans., II, 241
(1988); [d] C. Schapira and I. Perillo, J. Heterocyclic Chem., 30, 1051
(1993).
[18] V. M. S.Gil and W. von Philipsborn, Magn. Res. Chem., 27,
409 (1989).
[5] L. Zhuang, J. S. Wai, M. W. Embrey, T. E. Fisher, M. S.
Egbertson, L. S. Payne, J. P. Ware, Jr., J. P. Vacca, D. J. Hazuda, P. J.
Felock, A. L. Wolfe, K. A. Stillmock, M. V. Witmer, G. Moyer, W. A.
Schleif, L. J. Gabryelski, Y. M. Leonard, J. J. Lynch, Jr., S. R. Michelson
and S. D. Young, J. Med. Chem., 46, 453 (2003).
[6] E. Lazer, C. K. Miao, C. L. Cywin, R. Sorcek, H-C. Wong, Z.
Meng, I. Potocki, M. Hoermann, R. J. Snow, M. A. Tschantz, T. A. Kelly, D.
W. McNeil, S. J. Coutts, L. Churchill, A. G. Graham, E. David, P. M. Grob,
W. Engel, H. Meier and G. Trummlitz, J. Med. Chem., 40, 980 (1997).
[7] C. Nuebling, W. Von Deyn, H. Theobald, K.-O. Westphalen,
U. Kardorff, W. Helmut, T. Kappe and M. Gerber, Ger. Offen. DE
4,227,747 (1993); Chem. Abstr., 120, 323554z (1994).
[19a] W. E. Stewart and T. H. Siddall, Chem. Rev., 70, 517 (1970);
[b] H. Kessler, Angew. Chem., Int. Ed., 9, 219 (1970).
[20] G. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford
University Press, Oxford, NY, 1982.
[21] Similar results were observed in related isoquinolones [12]
and 1,2-benzothiazine-1,1-dioxides [17d].
[22] Hydrogens of the benzo ring showed similar features to those
observed in anilides where chemical shifts are attributable to the high
positive charge on the nitrogen, indicating a considerable contribution of
the polar resonance structure to the ground state of the amide.
[23] L. Giacomelli, M. Santo, R. Cattana, J. J. Silber, M. M.
Blanco, G. Levin and I. A. Perillo, Competition between inter and
intramolecular hydrogen bonds in naphthyridines and isoquinolones
(FQO-44), XIV SINAQO, Rosario, Argentina, 2003.
[8] A. C. Scotese and A. A. Santilli, S. African ZA 80 00,631
(1981); Chem. Abstr., 96, 6706p (1982).
[9] A. C. Scotese, R. L. Morris and A. A. Santilli, US Patent
4,301,281 (1981); Chem. Abstr., 97, 23815m (1982).
[10] R. L. Morris, A. A. Santilli and A. A. Scotese, US Patent
4,215,216 (1980); Chem. Abstr., 94, 65719b (1981).
[11] By-products with acid features were also observed in the
alkoxide-induced rearrangement of phtalimidoacetamides [12] and sac-
charin-2-acetamides [13]. The acidic character of amide hydrogen could
allow its deprotonation in basic medium; this fact would result in a less
probable formation of the carbanion necessary for rearrangement.
[12] C. B. Schapira, M. I. Abasolo and I. A. Perillo, J. Heterocyclic
Chem., 22, 577 (1985).
[24] J. Clayden, Angew. Chem. Int. Ed., 36, 949 (1997).
[25] Axial chirality in amides have been studied in hindered aro-
matic amides specially in benzamides [26], naphtamides [26a,27] and in a
series of N-benzyl-N,7-dimethyl-5-phenyl-1,7-naphthyridine-6-carbox-
amides [28], closely related with compounds 1 and 2.
[26a] J. Clayden and L. W. Lai, Tetrahedron Lett., 42, 3163 (2001)
and references cited therein; [b] J. Clayden, L. W. Lai and M. Helliwell,
Tetrahedron: Asymmetry, 12, 695 (2001); [c] J. Claiden, P. Johnson, J. H.
Pink and M. Helliwell, J.Org. Chem., 65, 7033 (2000).
[27] W.-M. Dai, K. K. Y. Yeung, C. W. Chow and I. D. Williams,
Tetrahedron: Asymmetry, 12, 1603 (2001) and references cited therein;
[b] S. Thayumanavan, P. Beak and D. P. Curran, Tetrahedron Lett., 37,
2899 (1996).
[13] I. A. Perillo, C. B. Schapira and S. Lamdan, J. Heterocyclic
Chem., 20, 155 (1983).
[14] M. M. Blanco, G. J. Levín, C. B. Schapira and I. A. Perillo,
Heterocycles, 57, 1881 (2002).
[15] Compounds 1 give a green coloration with ferric chloride and
compounds 2 give brown coloration.
[16] We are using the same letter to identify the chemically similar
carbons in both series in order to have a better comprehension.
[28a] Y. Ikeura, Y. Ishichi, T. Tanaka, A. Fujishima, M.
Murabayashi, M. Kawada, T. Ishimaru, I. Kamo, T. Doi and H. Natsugari,
J. Med. Chem., 41, 4232 (1998).
[29] F. C. Lee and L. R. Caswell, J. Heterocyclic Chem., 8, 831
(1971).
[30] J. Kenyon and K. Thaker, J. Chem. Soc., 2531 (1957).