Synthesis and spectroscopic properties of novel polyfunctionally substituted 2,6- and 2,7-naphthyridines

Article abstract of DOI:10.1016/j.molstruc.2009.01.012

Series of 5,6-dihydro-8-hydroxy-5-oxo-2,6-naphthyridine-7-carboxylic acid derivatives (2,4) and the isomeric 7,8-dihydro-5-hydroxy-8-oxo-2,7-naphthyridine-6-carboxylic acid derivatives (3,5) having potential pharmacological activity were synthesized from

Full text of DOI:10.1016/j.molstruc.2009.01.012

Journal of Molecular Structure 921 (2009) 307–313
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and spectroscopic properties of novel polyfunctionally substituted
2,6- and 2,7-naphthyridines
*
Isabel Amalia Perillo, Lautaro Diego Kremenchuzky, María Mercedes Blanco
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (1113), Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Series of 5,6-dihydro-8-hydroxy-5-oxo-2,6-naphthyridine-7-carboxylic acid derivatives (2,4) and the iso-
meric 7,8-dihydro-5-hydroxy-8-oxo-2,7-naphthyridine-6-carboxylic acid derivatives (3,5) having poten-
tial pharmacological activity were synthesized from 3,4-pyridinedicarboxylic acid derivatives.
Spectroscopic data (IR, 1H- and 13C-NMR, MS) are analyzed and support the enol–lactam structure of
compounds 2–5 in solution, solid state and gas phase. Results in the different series (2,6- vs 2,7- naph-
thyridines and N-unsubstituted lactam vs N-methyl derivatives) are compared, and common and differ-
ential features amongst them are indicated.
Received 25 November 2008
Received in revised form 7 January 2009
Accepted 8 January 2009
Available online 17 January 2009
Keywords:
Naphthyridinones
Lactam
Ó 2009 Elsevier B.V. All rights reserved.
Enol
Rearrangement
Spectroscopic properties
1. Introduction
4-pyridinedicarboximides 1 (N-substituted 1H-pyrrolo[3,4-c]pyri-
dine-1,3(2H)-diones), were treated with hot alkoxides affording
Hydroxypyridonecarboxylic acid derivatives containing an aro-
matic or heteroaromatic fused ring represent a type of polyfunc-
tional compounds which attracted researchers’ interest, either by
their value as synthetic intermediates [1,2] or to the variety of bio-
logical activities they have shown. 2-Quinolinones having immu-
nomodulating and antiangiogenic activity [3], isoquinolinones
with antiinflammatory and analgesic activity [2], and different
types of naphthyridinones have been described among others. Spe-
cially, 1,8-naphthyridine derivatives were the most studied ones,
some of which possess interesting biological properties such as
antiallergic, gastric antisecretory and herbicide [4]. On the other
hand, our group has synthesized a series of hydroxy-1,6- and
1,7-naphthyridinonecarboxylic acid [5,6] derivatives from 2,3-pyr-
idinedicarboxylic acid, under biological evaluation process at
present.
Opposite to compounds mentioned above, hydroxy derivatives
of 2,6- and 2,7-naphthyridinones have almost not been explored.
Gabriel Colman studied the rearrangement of 3,4-pyridinedicarb-
oximidoacetic acid ethyl ester (1a) with sodium methoxide and
only obtained one of the two possible products which was identi-
fied as the 2,7-diazaderivative 3 (X = CH3) (Scheme 1) [7]. Bearing
in mind the absence of further studies and the potential importance
of the expected compounds, we were interested in making deeper
research about them. Accordingly, a series of N-substituted 3,
the expected hydroxy derivatives of 2,6- and 2,7-naphthyridinones
(2 and 3, Scheme 1). Synthesis of N-lactam substituted naphthyrid-
inones 4 and 5 employing two synthetic approaches is also
presented (Scheme 2).
2. Experimental
2.1. General data
Melting points were taken on a Büchi capillary apparatus and
are uncorrected. The 1H and 13C NMR spectra were recorded on a
Bruker MSL 300 MHz spectrometer. Deuteriochloroform or
DMSO-d6 were used as the solvent, and the standard concentration
of the samples for 1H-NMR was 10 and 25 mg/mL for 13C-NMR.
Chemical shifts are reported in ppm (d) relative to TMS as an inter-
nal standard. Deuterium oxide was employed to confirm
exchangeable protons (ex). Splitting multiplicities are reported as
singlet (s), broad signal (br s), doublet (d), triplet (t), quartet (q),
and multiplet (m). Two-dimensional spectra (HMQC, HMBC and
ROESY) were recorded with a Bruker AVANCE DRX 300 spectrom-
eter. Electron impact MS were recorded with a GC-MS Shimadzu
QP-1000 spectrometer operating at 70 eV. The IR spectra were
recorded on a Perkin Elmer Spectrum One FT-IR spectrometer.
TLC analyses were carried out on Silica gel 60 F254 using chloro-
form–methanol (9:1) as solvent. Preparative thin layer separations
(PLC) were carried out by centrifugally accelerated, radial chroma-
tography using Chromatotron model 7924T. The rotors were
* Corresponding author. Tel./fax: +5411 49648250.
E-mail address: mblanco@ffyb.uba.ar (M.M. Blanco).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.01.012

308
I.A. Perillo et al. / Journal of Molecular Structure 921 (2009) 307–313
O
CONH-CH2-COX
RO-
NH
NH
O
N
N
N
N
ROH
CO2R
COX
COX
RO-
ROH
OH
OH
2a-d
3a-d
N-CH2-COX
N
O
1a-d
CO2R
RO-
ROH
CONH-CH2-COX
1,2,3
X
O
a
b
c
d
OC2H5
N(C2H5)2
N(CH3)C6H5
C6H5
Scheme 1. Synthesis of N-lactam unsubstituted naphthyridinones 2 and 3.
O
CH3
CON
NCH3
CH2-COX
RO-
O
N
N
N
N
Route a
1- CH3NHCH2-COX / TEA
ROH
COX
CO2CH3
O
N
OH
OH
4a,c
5a,c
6a,c
2- CH2N2
O
Route b
CH3OH
CO2CH3
COX
CO2CH3
CO2H
RO-
ROH
1- (ClCO)2
2- CH3NHCH2-COX / TEA
CH3
NCH3
N
CON
CH2-COX
O
8
7a,c
4,5
a
c
X
OC2H5
N(CH3)C6H5
Scheme 2. Synthesis of N-lactam substituted naphthyridinones 4 and 5.
coated with Silica Gel 60 PF254 and the layer thickness was 2 mm.
Chloroform and increasing percentages of methanol were used as
eluent. Reagents, solvents and starting materials were purchased
from standard sources and purified according to literature
procedures.
2.2.2. N,N-Diethyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione-2-
acetamide (1b)
Yield 65%, mp 106–108 °C (2-propanol). 1H NMR (CDCl3):
3
d = 9.19 (s, 1H, H-4), 9.09 (d, JH6-H7 = 4.6 Hz, 1H, H-6), 7.84
3
(d, JH6-H7 = 4.6 Hz, 1H, H-7), 4.52 (s, 2H, NCH2), 3.39 (br q, 4H,
3
NCH2), 1.33 (t, JCH2-CH3 = 7.1 Hz, 3H, CH3) and 1.13 (t,
2.2. 1H-Pyrrolo[3,4-c]pyridine-1,3(2H)-dione-2-acetic acid derivatives
(3,4-Pyridinedicarboximidoacetic acid derivatives) (1a–d): General
procedure
3JCH2-CH3 = 7.1 Hz, 3H, CH3). 13C NMR (CDCl3): d = 166.8, 166.5 and
163.8 (3 CO), 155.5 (C-6), 144.8 (C-4), 139.7 (C-7a), 126.1 (C-3a),
117.0 (C-7), 41.3 (NCH2), 40.9 (NCH2), 39.3 (NCH2), 14.1 (CH3)
and 12.8 (CH3). IR (KBr): 3442, 2933, 1782, 1721, 1654,
1396 cmꢀ1. MS (EI): m/z 261 (M+Å, 16%), 161 (29%), 105 (9%), 100
(86%), 72 (100%), 58 (19%), 50 (26%), 44 (50%). Analyses
(%C,%H,%N) calcd for C13H15N3O3: 59.77, 5.75, 16.09; found:
59.68, 5.80, 16.02.
A mixture of 3,4-pyridinedicarboximide [8] (1 g, 0.007 mol),
triethylamine (1.10 g, 0.008 mol), the corresponding halogen
derivative (0.008 mol) and dimethylformamide (5 mL) was heated
for 2–3 h in an oil bath (80–90 °C) and monitored by TLC. When the
reaction was completed, the reaction mixture was poured into ice-
water and the resulting solid filtered, washed with water and
recrystallized.
2.2.3. N-Methyl-N-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione-
2-acetamide (1c)
Yield 77%, mp 116–118 °C (2-propanol). 1H NMR (CDCl3):
3
2.2.1. 1H-Pyrrolo[3,4-c]pyridine-1,3(2H)-dione-2-acetic acid ethyl
ester (1a)
d = 9.15 (s, 1H, H-4), 9.05 (d, JH6-H7 = 4.7 Hz, 1H, H-6), 7.75 (d,
3
3JH6-H7 = 4.7 Hz, 1H, H-7), 7.50 (t, JHm-Hp = 3JHm-Ho = 6.7 Hz, 2H,
Yield 74%, mp 82–84 °C (2-propanol) (lit. [7] 101 °C). 1H NMR
Hm-C6H5), 7.42 (t, JHm-Hp = 6.7 Hz, 1H, Hp-C6H5), 7.37 (d,
3
3
(CDCl3): d = 9.20 (s, 1H, H-4), 9.11 (d, JH6-H7 = 4.5 Hz, 1H, H-6),
3JHo-Hm = 6.7 Hz, 2H, Ho-C6H5), 4.19 (s, 2H, NCH2) and 3.29 (s,
3H, NCH3). 13C NMR (CDCl3): d = 166.7, 166.3 and 165.0 (3 CO),
155.6 (C-6), 144.8 (C-4), 142.0 (Cipso-C6H5), 139.7 (C-7a), 130.3
(Cm-C6H5), 128.7 (Cp-C6H5), 127.4 (Co-C6H5), 126.0 (C-3a),
116.9 (C-7), 40.0 (NCH2) and 37.7 (NCH3). IR (KBr): 2923, 1722,
1674, 1596, 702 cmꢀ1. MS (EI): m/z 295 (M+Å, 63%), 161 (60%),
147 (4%), 134 (100%), 120 (12%), 107 (62%), 106 (64%), 105
(15%), 78 (33%), 77 (63%), 51 (28%), 50 (20%). Analyses
(%C,%H,%N) calcd for C16H13N3O3: 65.08, 4.41, 14.24; found:
64.95, 4.46, 14.18.
3
7.82 (d, JH6-H7 = 4.5 Hz, 1H, H-7), 4.46 (s, 2H, NCH2), 4.24 (q,
3
3JCH2-CH3 = 7.2 Hz, 2H, OCH2) and 1.29 (t, JCH2-CH3 = 7.2 Hz, 3H,
CH3). 13C NMR (CDCl3): d = 166.7, 166.2 and 165.9 (3 CO), 155.8
(C-6), 145.0 (C-4), 139.4 (C-7a), 125.8 (C-3a), 117.1 (C-7), 62.1
(OCH2), 39.1 (NCH3) and 14.0 (CH3). IR (KBr): 3417, 2985, 1783,
1720, 1613 cmꢀ1. MS (EI): m/z 234 (M+Å, 8%), 189 (3%), 162 (44%),
161 (100%), 134 (7%), 133 (4%), 106 (7%), 105 (16%), 78 (26%), 77
(15%), 51 (17%), 50 (43%). Analyses (%C,%H,%N) calcd for
C11H10N2O4: 56.41, 4.27, 11.97; found: 56.30, 4.30, 11.92.

I.A. Perillo et al. / Journal of Molecular Structure 921 (2009) 307–313
309
3
2.2.4. 1H-Pyrrolo[3,4-c]pyridine-1,3(2H)-dione-2-acetophenone (1d)
Yield 57%, mp 155–158 °C (2-propanol). 1H NMR (CDCl3):
3JHm-Hp = 3JHm-Ho = 6.9 Hz, 2H, Hm-C6H5), 7.17 (t, JHm-Hp = 6.9 Hz,
1H, Hp-C6H5) and 3.34 (s, 3H, NCH3). 13C NMR (DMSO-d6):
d = 162.7 (COX), 158.4 (C-5), 147.3 (C-3), 146.5 (C-1), 143.1 (Cip-
so-C6H5), 130.9 (C-4a), 129.9 (C-8), 129.2 (Cm-C6H5), 128.1
(C-8a), 127.6 (Cp-C6H5), 126.6 (Co-C6H5), 122.1 (C-7), 119.6 (C-4)
and 37.3 (NCH3). IR (KBr): 2923, 1722, 1674, 1596, 702 cmꢀ1. MS
(EI): m/z 295 (M+Å, 100%), 278 (1%), 189 (3%), 161 (8%), 134 (9%),
107 (76%), 106 (35%), 78 (23%), 77 (51%), 65 (7%), 51 (24%). Analy-
ses (%C,%H,%N) calcd for C16H13N3O3: 65.08, 4.41, 14.24; found:
65.20, 4.46, 14.17.
3
d = 9.22 (s, 1H, H-4), 9.12 (d, JH6-H7 = 4.9 Hz, 1H, H-6), 8.01 (d,
3
3JHo-Hm = 7.2 Hz, 2H, Ho-C6H5), 7.82 (d, JH6-H7 = 4.9 Hz, 1H, H-7),
3
3
7.65 (t, JHm-Hp = 7.2 Hz, 1H, Hp-C6H5), 7.54 (t, JHm-Hp = 3JHm-Ho
=
7.2 Hz, 2H, Hm-C6H5) and 5.17 (s, 2H, NCH2). 13C NMR (CDCl3):
d = 190.2, 166.7 and 166.3 (3 CO), 155.8 (C-6), 145.0 (C-4), 139.5
(C-7a), 134.3 (Cp-C6H5), 134.1 (Cipso-C6H5), 129.0 (Co-C6H5),
128.2 (Cm-C6H5), 126.0 (C-3a), 117.0 (C-7) and 44.4 (NCH2). IR
(KBr): 1779, 1722, 1596, 1219, 772 cmꢀ1. MS (EI): m/z 266 (M+Å,
3%), 161 (6%), 106 (13%), 105 (100%), 78 (12%), 77 (56%), 51
(26%), 50 (20%). Analyses (%C,%H,%N) calcd for C15H10N2O3: 67.67,
3.76, 10.53; found: 67.74, 3.80, 10.48.
2.3.4. 7-Benzoyl-5,6-dihydro-8-hydroxy-5-oxo-2,6-naphthyridine
(2d)
Yield 28%, mp 228–230 °C (dec) (2-propanol). 1H NMR (DMSO-
d6): d = 12.20 and 11.13 (br s, ex, 2H, OH and NH) 9.39 (s, 1H, H-1),
8.86 (d, 3JH3-H4 = 5.0 Hz, 1H, H-3), 8.09 (d, 3JH3-H4 = 5.0 Hz, 1H, H-4),
2.3. Reaction of compounds 1a–d with sodium alkoxides: General
procedure
7.89 (d,3JHo-Hm = 7.1 Hz, 2H, Ho-C6H5), 7.67 (t, JHm-Hp = 7.1 Hz, 1H,
3
3
To a solution of sodium alkoxide prepared from sodium (0.23 g,
0.01 mol) in the corresponding anhydrous alcohol (5 mL, ethanol
for compound 1a, 2-propanol for compounds 1b–d) heated in an
oil bath (90–100 °C), 3,4-pyridinedicarboximides 1 (0.0025 mole)
were added all at once as the powder. After 30 min the reaction
mixture was poured into ice-acetic acid and extracted with chloro-
form (3 ꢁ 10 mL). The organic layers were pooled, washed with
water, dried and evaporated in vacuo. The crude products obtained
showed two spots by TLC. Separation of the two compounds was
achived by centrifugal PLC. The first band eluted gave the 2,6-
naphthyridine derivatives 2a-d. The slower moving band afforded
the 2,7-naphthyridine derivatives 3a-d.
Hp-C6H5) and 7.55 (t, JHm-Hp = 3JHm-Ho = 7.1 Hz, 2H, Hm-C6H5). 13C
NMR (DMSO-d6): d = 190.8 (COX), 155.9 (C-5), 150.6 (C-3), 149.1
(C-1), 144.0 (C-8), 136.7 (Cipso-C6H5), 133.3 (Cp-C6H5), 131.2 (C-
4a), 129.7 (Co-C6H5), 128.9 (Cm-C6H5), 126.8 (C-8a), 121.1 (C-7)
and 120.7 (C-4). IR (KBr): 1660, 1626, 1600, 1312, 694 cmꢀ1. MS
(EI): m/z 266 (M+Å, 83%), 248 (4%), 188 (9%), 160 (14%), 133 (13%),
105 (35%), 103 (19%), 78 (23%), 77 (100%), 51 (28%). Analyses
(%C,%H,%N) calcd for C15H10N2O3: 67.67, 3.76, 10.53; found:
67.79, 3.83, 10.46.
2.3.5. 7,8-Dihydro-5-hydroxy-8-oxo-2,7-naphthyridine-6-carboxylic
acid ethyl ester (3a)
Yield 54%, mp 170–171 °C (dec) (methanol). 1H NMR (CDCl3):
3
2.3.1. 5,6-Dihydro-8-hydroxy-5-oxo-2,6-naphthyridine-7-carboxylic
acid ethyl ester (2a)
d = 10.34 (br s, ex, 1H, NH), 9.67 (s, 1H, H-1), 8.97 (d, JH3-H4
=
3
5.6 Hz, 1H, H-3), 8.87 (br s, ex, 1H, OH), 7.97 (d, JH3-H4 = 5.6 Hz,
Yield 35%, mp 204–205 °C (dec) (methanol). 1H NMR (CDCl3):
d = 10.49 (br s, ex, 1H, NH), 9.55 (s, 1H, H-1), 9.10 (br s, ex, 1H,
1H, H-4), 4.51 (q, JCH2-CH3 = 7.0 Hz, 2H, OCH2) and 1.48 (t, JCH2-
CH3 = 7.0 Hz, 3H, CH3). 13C NMR (CDCl3): d = 164.2 (COX), 158.2 (C-
8), 152.3 (C-3), 151.2 (C-1), 145.1 (C-5), 137.2 (C-4a), 125.5 (C-8a),
116.1 (C-4), 110.2 (C-6), 63.3 (OCH2) and 14.2 (CH3). IR (KBr):
3394, 1648, 1586, 1271 cmꢀ1. MS (EI): m/z 234 (M+Å, 75%), 206
(37%), 188 (100%), 160 (65%), 133 (51%), 105 (15%), 78 (33%), 77
(33%), 51 (55%), 50 (68%). Analyses (%C,%H,%N) calcd for
C11H10N2O4: 56.41, 4.27, 11.97; found: 56.54, 4.31, 11.90.
3
3
3
3
OH), 8.94 (d, JH3-H4 = 5.2 Hz, 1H, H-3), 8.20 (d, JH3-H4 = 5.2 Hz,
3
3
1H, H-4), 4.51 (q, JCH2-CH3 = 7.3 Hz, 2H, OCH2) and 1.48 (t, JCH2-
CH3 = 7.3 Hz, 3H, CH3). 13C NMR (CDCl3): d = 164.3 (COX), 157.7
(C-5), 154.2 (C-3), 150.4 (C-1), 147.5 (C-8), 134.4 (C-4a), 125.4
(C-8a), 120.0 (C-4), 108.1 (C-7), 63.0 (OCH2) and 14.2 (CH3). IR
(KBr): 3390, 1650, 1624, 1585, 1286 cmꢀ1. MS (EI): m/z 234 (M+Å,
100%), 206 (38%), 188 (92%), 160 (33%), 133 (83%), 105 (56%),
103 (43%), 78 (39%), 77 (36%), 51 (28%), 50 (33%). Analyses
(%C,%H,%N) calcd for C11H10N2O4: 56.41, 4.27, 11.97; found:
56.32, 4.35, 12.06.
2.3.6. N,N-Diethyl-7,8-dihydro-5-hydroxy-8-oxo-2,7-naphthyridine-
6-carboxamide (3b)
Yield 50%, mp 215–217 °C (2-propanol). 1H NMR (DMSO-d6):
d = 11.51 (br s, ex, 2H, NH and OH), 9.28 (s, 1H, H-1), 8.79 (d,
3
2.3.2. N,N-Diethyl-5,6-dihydro-8-hydroxy-5-oxo-2,6-naphthyridine-
7-carboxamide (2b)
3JH3-H4 = 5.5 Hz, 1H, H-3), 7.72 (d, JH3-H4 = 5.5 Hz, 1H, H-4), 3.40
3
3
(q, JCH2-CH3 = 7.2 Hz, 4H, NCH2) and 1.10 (t, JCH2-CH3 = 7.2 Hz, 6H,
CH3). 13C NMR (DMSO-d6): d = 162.1 (COX), 153.9 (C-8), 151.2 (C-
3), 150.6 (C-1), 137.3 (C-5), 136.9 (C-4a), 123.4 (C-8a), 120.1 (C-
6), 117.2 (C-4), 42.2 (NCH2) and 13.9 (CH3). IR (KBr): 2970, 1655,
1594, 1479, 1456 cmꢀ1. MS (EI): m/z 262 (36%), 261 (M+Å, 54%),
244 (2%), 189 (11%), 188 (14%), 162 (33%), 161 (18%), 134 (11%),
105 (7%), 74 (39%), 73 (18%), 72 (100%), 58 (77%), 44 (26%). Analy-
ses (%C,%H,%N) calcd for C13H15N3O3: 59.77, 5.75, 16.09; found:
59.85, 5.80, 16.01.
Yield 31%, mp 222–224 °C (2-propanol). 1H NMR (DMSO-d6):
d = 11.56 (br s, ex, 2H, NH and OH), 9.23 (s, 1H, H-1), 8.70 (d,
3
3JH3-H4 = 5.2 Hz, 1H, H-3), 7.97 (d, JH3-H4 = 5.2 Hz, 1H, H-4), 3.40
3
3
(q, JCH2-CH3 = 7.0 Hz, 4H, NCH2) and 1.10 (t, JCH2-CH3 = 7.0 Hz, 6H,
CH3). 13C NMR (DMSO-d6): d = 161.9 (COX), 158.7 (C-5), 146.7 (C-
3), 146.1 (C-1), 130.5 (C-4a), 129.9 (C-8), 128.3 (C-8a), 122.9 (C-
7), 119.2 (C-4), 40.1 (NCH2) and 13.4 (CH3). IR (KBr): 2965, 1661,
1602, 1545, 1457 cmꢀ1. MS (EI): m/z 262 (35%), 261 (M+Å, 67%),
244 (3%), 189 (7%), 162 (19%), 161 (18%), 134 (11%), 133 (12%),
74 (39%), 73 (22%), 72 (100%), 58 (76%), 44 (28%). Analyses
(%C,%H,%N) calcd for C13H15N3O3: 59.77, 5.75, 16.09; found:
59.65, 5.73, 16.02.
2.3.7. 7,8-Dihydro-5-hydroxy-N-methyl-8-oxo-N-phenyl-2,7-
naphthyridine-6-carboxamide (3c)
Yield 58%, mp 236-238 °C (2-propanol). 1H NMR (DMSO-d6):
d = 11.40 (br s, ex, 1H, NH), 9.19 (s, 1H, H-1), 9.11 (br s, ex, 1H,
3
3
2.3.3. 5,6-Dihydro-8-hydroxy-N-methyl-5-oxo-N-phenyl-2,6-
naphthyridine-7-carboxamide (2c)
OH), 8.71 (d, JH3-H4 = 5.3 Hz, 1H, H-3), 7.61 (d, JH3-H4 = 5.3 Hz,
3
1H, H-4), 7.35 (d, JHo-Hm = 7.1 Hz, 2H, Ho-C6H5), 7.29 (t,
3
Yield 36%, mp 249-251 °C (2-propanol). 1H NMR (DMSO-d6):
d = 11.50 (br s, ex, 1H, NH), 9.19 (br s, ex, 1H, OH), 9.10 (s, 1H, H-
3JHm-Hp = 3JHm-Ho = 7.1 Hz, 2H, Hm-C6H5), 7.17 (t, JHm-Hp = 7.1 Hz,
1H, Hp-C6H5) and 3.34 (s, 3H, NCH3). 13C NMR (DMSO-d6):
d = 162.4 (COX), 151.5 (C-8), 151.3 (C-3), 150.3 (C-1), 143.8
(Cipso-C6H5), 139.0 (C-4a), 131.2 (C-5), 129.3 (Cm-C6H5), 127.8
3
3
1), 8.64 (d, JH3-H4 = 5.0 Hz, 1H, H-3), 7.88 (d, JH3-H4 = 5.0 Hz,
3
1H, H-4), 7.35 (d, JHo-Hm = 6.9 Hz, 2H, Ho-C6H5), 7.29 (t,

310
I.A. Perillo et al. / Journal of Molecular Structure 921 (2009) 307–313
(Cp-C6H5), 126.6 (Co-C6H5), 125.4 (C-6), 120.5 (C-8a), 115.7 (C-4)
and 39.4 (NCH3). 13C NMR (CDCl3): d = 165.2 (COX), 156.2 (C-8),
151.9 (C-3), 150.7 (C-1), 142.2 (C-5), 141.5 (Cipso-C6H5), 137.9
(C-4a), 131.1 (Cm-C6H5), 129.7 (Cp-C6H5), 126.2 (Co-C6H5), 125.1
(C-8a), 121.5 (C-4), 112.2 (C-6) and 40.0 (NCH3). IR (KBr): 3419,
1652, 1593, 1495, 699 cmꢀ1. MS (EI): m/z 295 (M+Å, 100%), 189
(2%), 161 (9%), 134 (12%), 107 (86%), 106 (41%), 105 (39%), 78
(31%), 77 (79%), 65 (12%), 51 (40%). Analyses (%C,%H,%N) calcd for
C16H13N3O3: 65.08, 4.41, 14.24; found: 65.10, 4.43, 14.30.
Compounds 7a,c (1.1 g) obtained as above were treated with
the corresponding sodium alkoxide as was described for route a
affording compounds 5a,c.
2.4.1. 5,6-Dihydro-8-hydroxy-6-methyl-5-oxo-2,6-naphthyridine-7-
carboxylic acid ethyl ester (4a)
Yield 49%, mp 104–106 °C (2-propanol). 1H NMR (CDCl3): d =
3
11.21 (br s, ex, 1H, OH), 9.52 (s, 1H, H-1), 8.91 (d, JH3-H4 = 5.1 Hz,
3
3
1H, H-3), 8.22 (d, JH3-H4 = 5.1 Hz, 1H, H-4), 4.51 (q, JCH2-
3
CH3 = 7.4 Hz, 2H, OCH2) 3.70 (s, 3H, NCH3), and 1.46 (t, JCH2-
2.3.8. 6-Benzoyl-7,8-dihydro-5-hydroxy-8-oxo-2,7-naphthyridine
(3d)
CH3 = 7.4 Hz, 3H, CH3). 13C NMR (CDCl3): d = 166.2 (COX), 159.1
(C-5), 150.4 (C-3), 148.4 (C-8), 147.2 (C-1), 134.4 (C-4a), 124.9
(C-8a), 121.8 (C-7), 120.2 (C-4), 63.0 (OCH2), 36.6 (NCH3) and
14.1 (CH3). IR (KBr): 2985, 1719, 1680, 1577, 1319 cmꢀ1. MS (EI):
m/z 248 (M+Å, 67%), 220 (1%), 202 (57%), 191 (29%), 175 (34%),
174 (75%), 164 (19%), 150 (11%), 133 (78%), 118 (6%), 105 (79%),
78 (39%), 77 (39%), 50 (100%). Analyses (%C,%H,%N) calcd for
C12H12N2O4: 58.06, 4.84, 11.29; found: 58.22, 4.93, 11.19.
Yield 49%, mp 255–257 °C (dec) (2-propanol). 1H NMR (DMSO-
d6): d = 11.29 and 9.57 (br s, ex, 2H, OH and NH) 9.41 (s, 1H, H-1),
3
3
8.90 (d, JH3-H4 = 5.3 Hz, 1H, H-3), 7.90 (d, JHo-Hm = 7.0 Hz, 2H, Ho-
3
3
C6H5), 7.86 (d, JH3-H4 = 5.3 Hz, 1H, H-4), 7.70 (t, JHm-Hp = 7.0 Hz,
1H, Hp-C6H5) and 7.57 (t, JHm-Hp = 3JHm-Ho = 7.0 Hz, 2H, Hm-C6H5).
3
13C NMR (DMSO-d6): d = 201.5 (COX), 156.4 (C-8), 151.8 and
151.7 (C-3 and C-1), 139.6 (C-4a), 137.7 (C-5), 136.8 (Cipso-C6H5),
134.2 (Cp-C6H5), 130.1 (Co-C6H5), 129.1 (Cm-C6H5), 126.1 (C-8a),
122.5 (C-6) and 116.3 (C-4). IR (KBr): 2295, 1645, 1602, 1266,
693 cmꢀ1. MS (EI): m/z 266 (M+Å, 100%), 248 (2%), 188 (5%), 160
(10%), 133 (14%), 105 (29%), 77 (78%), 51 (34%). Analyses
(%C,%H,%N) calcd for C15H10N2O3: 67.67, 3.76, 10.53; found:
67.58, 3.80, 10.47.
2.4.2. 5,6-Dihydro-8-hydroxy-N,6-dimethyl-5-oxo-N-phenyl-2,6-
naphthyridine-7-carboxamide (4c)
Yield 47%, mp 176–179 °C (2-propanol). NMR spectra of the ma-
jor diastereomer is detailed. 1H NMR (DMSO-d6): 9.11 (br s, ex, 1H,
3
OH), 9.10 (s, 1H, H-1), 8.63 (d, JH3-H4 = 4.9 Hz, 1H, H-3), 7.89 (d,
3
3JH3-H4 = 4.9 Hz, 1H, H-4), 7.33 (d, JHo-Hm = 7.0 Hz, 2H, Ho-C6H5),
3
3
7.23 (t, JHm-Hp = 3JHm-Ho = 7.0 Hz, 2H, Hm-C6H5), 7.15 (t, JHm-Hp
=
2.4. Synthesis of naphthyridinones 4 and 5: General procedures
7.0 Hz, 1H, Hp-C6H5), 3.50 (s, 3H, NCH3) and 3.45 (s, 3H, NCH3).
13C NMR (DMSO-d6): d = 161.8 (COX), 158.3 (C-5), 146.6 (C-3),
145.3 (C-1), 141.6 (Cipso-C6H5), 129.2 (C-4a), 128.5 (Cm-C6H5),
128.3 (C-8), 127.3 (Cp-C6H5), 125.4 (C-8a), 125.2 (Co-C6H5), 125.0
(C-7), 118.8 (C-4) 36.1 (NCH3) and 32.7 (NCH3). IR (KBr): 3059,
1655, 1622, 1586, 1495, 696 cmꢀ1. MS (EI): m/z 309 (M+Å, 24%),
175 (5%), 134 (60%), 107 (100%), 79 (13%), 77 (59%), 65 (11%), 51
(5%), 50 (22%), 42 (39%). Analyses (%C,%H,%N) calcd for
C17H15N3O3: 66.02, 4.85, 13.59; found: 66.12, 4.79, 13.68.
Route a: to a solution of 3,4-pyridinedicarboxylic anhydride
[9] (0.007 mol) and the appropriate N-methylaminoacetic acid
derivative hydrochloride (0.008 mol) in chloroform (10 mL) at
room temperature, was added dropwise and with stirring trieth-
ylamine (0.008 mol) in chloroform (10 mL). After stirring for 1 h
the reaction mixture was cooled (ice bath), filtered, and the or-
ganic solution concentrated in vacuo. The oily residue was dis-
solved in anhydrous methanol (5 mL) (ice bath) and an
ethereal solution of diazomethane was added in small portions
until the solution acquired a pale yellow colour. After 2 h at
room temperature, the reaction mixture (containing compounds
6 and 7) was concentrated in vacuo and used in the next step
without purification.
A mixture of compounds 6 and 7 obtained as above (1.1 g) was
dissolved in the appropriate alcohol (5 mL, ethanol for compounds
6a,7a and 2-propanol for compounds 6c,7c) and 3 mL of the corre-
sponding 2 M sodium alkoxide was added and heated at reflux for
15 min. The brown–red suspension was poured into ice-acetic acid
and extracted three times with chloroform. The organic layers
were pooled, washed with water, dried and concentrated in vacuo.
The crude product showed two spots by TLC (in 9:1 chloroform–
methanol). Separation of the two products was accomplished by
centrifugal PLC. The first band eluted gave the major product
which was recrystallized affording compounds 4a,c. The slower
moving band afforded compounds 5a,c (35% and 32%,
respectively).
Route b: a suspensión of the stable hemiester 8 [9] (3.3 g,
0.018 mol) in dry benzene (7 mL) and oxalyl chloride (2.8 g,
0.022 mol) was heated at 40 °C for 3 h. The solvent and excess of
oxalyl chloride were removed in vacuo and the residual oil was dis-
solved in dry THF (7 mL). The solution was stirred and treated with
the appropriate N-methylaminoacetic acid derivative hydrochlo-
ride (0.018 mol) and then triethylamine (2.9 g, 0.029 mol) was
added dropwise. The reaction mixture was heated at reflux for
1 h, evaporated in vacuo and dry benzene (5 mL) was added twice
evaporating each time to dryness affording the corresponding
compound 7 as oil which was used in the next step without
purification.
2.4.3. 7,8-Dihydro-5-hydroxy-7-methyl-8-oxo-2,7-naphthyridine-6-
carboxylic acid ethyl ester (5a)
Yield 68%, mp 90–92 °C (2-propanol). 1H NMR (CDCl3): d = 10.90
(br s, ex, 1H, OH), 9.66 (s, 1H, H-1), 8.91 (d, 3JH3-H4 = 5.8 Hz, 1H, H-
3), 7.91 (d, 3JH3-H4 = 5.8 Hz, 1H, H-4), 4.50 (q, 3JCH2-CH3 = 7.0 Hz, 2H,
3
OCH2), 3.67 (s, 3H, NCH3) and 1.45 (t, JCH2-CH3 = 7.0 Hz, 3H, CH3).
13C NMR (CDCl3): d = 166.1 (COX), 159.6 (C-8), 151.6 and 151.3
(C-3 and C-1), 146.8 (C-5), 135.9 (C-4a), 122.0 (C-8a), 115.9 (C-4),
115.3 (C-6), 63.2 (OCH2), 36.1 (NCH3) and 14.0 (CH3). IR (KBr):
2984, 1728, 1682, 1590, 1318 cmꢀ1. MS (EI): m/z 248 (M+Å, 73%),
220 (1%), 202 (72%), 175 (33%), 174 (95%), 134 (23%), 133 (95%),
105 (94%), 78 (40%), 77 (42%), 51 (46%), 50 (64%), 42 (100%). Anal-
yses (%C,%H,%N) calcd for C12H12N2O4: 58.06, 4.84, 11.29; found:
58.08, 4.92, 11.20.
2.4.4. 7,8-Dihydro-5-hydroxy-N,7-dimethyl-8-oxo-N-phenyl-2,7-
naphthyridine-6-carboxamide (5c)
Yield 71%, mp 157–158 °C (2-propanol). NMR spectra of the ma-
jor diastereomer is detailed. 1H NMR (DMSO-d6): d = 10.05 (br s, ex,
1H, OH), 9.28 (s, 1H, H-1), 8.70 (d, 3JH3-H4 = 5.4 Hz, 1H, H-3), 7.60 (d,
3
3JH3-H4 = 5.4 Hz, 1H, H-4), 7.34 (d, JHo-Hm = 7.3 Hz, 2H, Ho-C6H5),
3
3
7.24 (t, JHm-Hp = 3JHm-Ho = 7.3 Hz, 2H, Hm-C6H5), 7.18 (t, JHm-Hp
=
7.1 Hz, 1H, Hp-C6H5), 3.52 (s, 3H, NCH3) and 3.41 (s, 3H, NCH3).
13C NMR (DMSO-d6): d = 161.5 (COX), 158.3 (C-8), 150.7 and
150.3 (C-3 and C-1), 141.2 (Cipso-C6H5), 137.5 (C-4a), 129.3 (C-5),
129.0 (Cm-C6H5), 128.5 (Cp-C6H5), 127.9 (Co-C6H5), 125.8 and
125.6 (C-6 and C-8a), 114.8 (C-4), 36.5 (NCH3) and 32.8 (NCH3).
IR (KBr): 3057, 1652, 1618, 1592, 1495, 702 cmꢀ1. MS (EI): m/z
309 (M+Å, 22%), 202 (1%), 175 (3%), 134 (40%), 107 (100%), 105
(23%), 77 (67%), 65 (11%), 51 (33%), 50 (29%), 42 (39%). Analyses

I.A. Perillo et al. / Journal of Molecular Structure 921 (2009) 307–313
311
(%C,%H,%N) calcd for C17H15N3O3: 66.02, 4.85, 13.59; found: 66.12,
4.83, 13.65.
H4
O
H4
H1
OH
O
O
H3
H3
NH
CH3
N
N
N
3. Results and discussion
N
NH
CH3
H1
OH
O
3.1. Synthesis
2c
3c
Reaction of compounds 1a–d with hot alkoxides under different
conditions led in all cases to two main compounds ferric chloride
positive. These compounds were isolated by chromatographic
methods, and were identified (see below) as the corresponding
5,6-dihydro-8-hydroxy-5-oxo-2,6-naphthyridine-7-carboxylic acid
derivatives (2a–d) and 7,8-dihydro-5-hydroxy-8-oxo-2,7-naph-
thyridine-6-carboxylic acid derivatives (3a–d) (Scheme 1). Such re-
sult is in agreement with the general accepted mechanism (a ring
opening-ring closing rearrangement) [10]. In all cases, 2,7-naph-
thyridine 3 was mainly obtained as the result of alkoxide attack
on the most reactive carbonyl group (4 respect to pyridine
nitrogen).
N-Methylnaphthyridinones 4 and 5 were obtained through syn-
thetic strategies employing 3,4-pyridinedicarboxylic anhydride as
starting material, and involved synthesis and ring closing of N,N-
disubstituted amide esters (6 and 7, respectively) (Scheme 2).
Route a involves 3,4-pyridinedicarboxylic anhydride aminolysis
with methylaminoacetic acid derivatives and further methylation
with diazomethane, leading to a mixture of the amide esters 6
and 7. Treatment of reaction products with hot alkoxides leads to
a mixture of naphthyridinones 4a,c (main products) and 5a,c. Such
result is in agreement with regioselective cleavage of the anhy-
dride leading preferably to esters 6. Route b employs the stable
hemiester 8 [9] as intermediate, which becomes compounds 7 by
amidation with methylaminoacetic acid derivatives vía acid halide.
Subsequent cyclization with alkoxides lead to naphthyridinones
5a,c.
Fig. 2. Main correlations observed in the ROESY spectra.
present greater chemical shifts for H-4 but lower chemical shifts
for H-1 and H-3, vs the corresponding protons in the 2,7-naph-
thyridines 3 and 5. These results may be a consequence of the pres-
ence of lactam carbonyl through the contribution of mesomeric
structures A (for 2,6-naphthyridines) and A0 and B0 (for 2,7-naph-
thyridines) (Fig. 3).
In the case of pyridine carbons, chemical shifts are also mainly
influenced by the presence of the heterocyclic nitrogen, C-1 and C-
3 appearing as the most deshielded, and C-4 and C-8a as the most
shielded. However, the influence of the lactam moiety on pyridine
nucleus allows us again to distinguish the 2,6- from 2,7-naphthyri-
dine series. Thus, the contribution of electronic effects through
structures A,B determines that in compounds 2,4 C-4 and C-8a ap-
pear more deshielded than in compounds 3,5. Likewise, contribu-
tion of electronic effects through structures A0–C0 determines the
greatest chemical shifts for C-1, C-3 and C-4a in the 2,7- vs 2,6-
series.
Enol carbon appears in a variable range (128.3–148.4 ppm),
mainly depending on the nature of X group (being more deshielded
in esters and ketones than in amides) and on the nature of the sol-
vent (see below). Instead, it does not vary substantially with the
series (2,6- or 2,7-) and with N-methylation. Chemical shifts of
the other alkene carbon (C-7 for 2,6- series and C-6 for 2,7-series)
and the lactam carbonyl (d 108.1–125.6 and d 151.5–159.6 ppm,
respectively) were within the range of related compounds [6,11].
Chemical equivalence of both ethyl groups in the 1H and 13C-
NMR of compounds 2b and 3b, as well as the absence of diaste-
reomeric carboxamides for compounds 2c and 3c indicate that
the CO-N bond enjoy free rotation at room temperature. This
facts are in line with a resonance assisted hydrogen bonding
effect (RAHB) [6,12] where the stabilized keto–enol system in-
volves the extranuclear amide carbonyl leading to an important
3.2. Spectroscopic properties of hydroxynaphthyridinones 2–5
The polyfunctional features of the synthesized naphthyridines,
and the possibility of protrotopic equilibria derived from them
(lactam–lactim and keto–enol) determinate the possibility of
several structures for those compounds. However, positive ferric
chloride test, the presence of signals assigned to enol protons in
1H-NMR spectra, IR bands between 1640 and 1665 cmꢀ1 (assigned
to a lactam carbonyl), and the absence of signals over 170 ppm in
13C-NMR spectra account for the enol–lactam structure of
compounds 2–5. Structures and assignment of NMR spectra were
confirmed by bidimensional heteronuclear correlation spectra
(HMQC, HMBC) and ROESY for compounds 2c and 3c. The main
correlations observed which account for proposed structures are
shown in Figs. 1 and 2.
-
-
O
O
O
4
1
4a
8a
3
5
NR
+
NR
NR
6
N
N
N
7
N
2
COX
COX
+
8
COX
COX
COX
COX
OH
OH
OH
OH
OH
A
B
2,4
Chemical shifts in NMR spectra are strongly conditioned by
mesomeric effects. 1H-NMR spectra show the three pyridine pro-
tons sharply differentiated with their expected chemical shifts
and multiplicity, appearing H-1 at 9.50–9.67, H-3 at 8.63–8.97
and H-4 at 7.60–8.22 ppm. However, 2,6-naphthyridines 2 and 4
OH
5
4
1
4a
8a
3
6
+
N
N
NR
NR
8
+
NR
NR
7
2
-
-
O
O
A'
O
B'
3,5
H4
H1
O
OH
H4
OH
O
H3
COX
H3
NH
CH3
N
N
+
N
N
N
NH
CH3
-
OH
O
O
H1
O
C'
2c
3c
Fig. 3. Mesomeric structures of naphthyridinones 2–5 showing the influence of
Fig. 1. Main correlations observed in the HMBC spectra.
lactam carbonyl.

312
I.A. Perillo et al. / Journal of Molecular Structure 921 (2009) 307–313
δ+
Main fragmentation pathways begin with lateral chain degrada-
H
δ-
tion and support the enol structure of compounds 2–5 in gas phase
(Scheme 3). Thus in esters, the dominant route involves CO-OR
cleavage with enol hydrogen transfer to the OR group (ortho effect)
and subsequent heterolytic cleavage affording [M-ROH]+ꢂ ions
(Route a) and fragments derived from them. Instead, in amides
homolytic cleavage leads to odd electron ions [HNRR0]+Å (base ion
for compounds 4c and 5c) (Route b), thus reflecting the strong ten-
dency of carboxamide nitrogen to originate ions with charge reten-
tion. Although in N,N-diethyl amides 2b and 3b such odd electron
ion ([NHEt2]+Å) appears with low abundance, ions arising from their
further fragmentation are observed (m/z 58, [NHEt2-Me]+, >70%);
therefore this route cannot be discarded in such compounds.
δ-
O
O
O
OH
O
O
R1
δ+ R1(R2)
N
R2
N
N
N
NCH3 R2(R1)
NH
I
II
Fig. 4. Structures showing electron delocalization in naphthyridinecarboxamides.
single-bond character of the amide CO-N bond (Fig. 4, Structure
I). On the contrary, NMR spectra of compounds 4c and 5c show
the existence of diastereomeric carboxamides. This fact is ex-
plained as the result of lactam N-substitution steric effect which
inhibits the keto–enol system planarity [13] and hence the RAHB
effect, thus favoring delocalization typical of amides, and leading
to a partial double bond character of amide CO–N bond (Fig. 4,
Structure II).
Solvent influence was evaluated by comparison of spectra of
amide 3c in deuteriochloroform and in DMSO-d6. Substantial vari-
ation is only observed in carbons of the lactam moiety. A paramag-
netic shift for enol carbon (C-8) and a diamagnetic shift of the other
alkene carbon (C-7) is observed specially in deuteriocloroform.
Such behavior is similar to that observed in other enol compounds
with intramolecular hydrogen bond [11].
Infrared spectra of compounds 2–5 in solid state (potassium
bromide) show absorption bands which do not allow us to differ-
entiate series 2,6- from 2,7-naphthyridines. Importance of lactam
nitrogen N-methylation is observed in the ester carbonyl stretch-
ing. This band appears in compounds 2a and 3a at ca. 1650 cmꢀ1
compatible with a structure similar to I (Fig. 4), having an intramo-
lecular hydrogen bond. Instead, in N-methyl derivatives 4a and 5a
the ester carbonyl absorption occurs at ca. 1710 cmꢀ1, in the range
Other pathway (Route c) involves an a-cleavage leading to car-
boxamide ion [CONRR0]+Å Fragmentation continues with the loss of
CO originating [NRR0]+, base ion for compounds 2b and 3b.
Esters 2a and 3a present important peak at m/z 206 resulting
from McLafferty rearrangement of the molecular ion. Instead, the
corresponding peak (at m/z 220) appears with very low intensity
in the spectra of the N-methyl derivatives 4a and 5a.
Spectra of ketones 2d and 3d present, besides the expected ions
m/z 105 [COPh]+ and 77 [Ph]+ resulting from
a-cleavage, ions at m/
z 188, 160 and 133 which composition corresponds to fragments
originated by route a. This type of fragmentation, uncommon in
ketones, may be explained by an enol hydrogen transfer to C-phe-
nyl, followed by heterolytic cleavage and benzene liberation.
Opposite to the other compounds, ketones 2d and 3d present char-
acteristic low intensity peaks resulting from the loss of water.
Others less important fragmentation routes, which begin with
the loss of X, OH and R-NCO from the molecular ion, are observed
in some cases.
4. Conclusions
of the frequency of benzoic and a,b-unsaturated esters [14], prob-
ably as the result of N-lactam substitution which inhibits the pla-
narity of the keto–enol system as was indicated above.
The electron impact mass spectra of naphthyridines 2–5 show
molecular ions with variable abundance, being most intense in
N-lactam unsubstituted compounds (base ions for compounds
2a,c and 3c,d). Related to them, M+1 ions resulting from ion-mol-
ecule reactions are important, specially in N,N-diethylamides (2b
and 3b), with a relative abundance of 52% and 67% of the parent
ion, respectively.
In general, spectra of isomeric 2,6- and 2,7-naphthyridinones
are similar, not presenting features which allow us to distinguish
them by this method. Instead, fragmentation pattern shows differ-
ences according to the function derived from carboxyl group, and
in minor proportion to the presence of methyl group on the lactam
nitrogen.
Series of novel selectively substituted 2,6- and 2,7-naphthyrid-
inones were obtained employing different methods that involve
the synthesis of the lactam ring from pyridine derivatives. Thus,
5,6-dihydro-8-hydroxy-5-oxo-2,6-naphthyridine-7-carboxylic acid
derivatives (2) and the isomeric 7,8-dihydro-5-hydroxy-8-oxo-
2,7-naphthyridine-6-carboxylic acid derivatives (3) were obtained
by alkoxide induced rearrangement of 3,4-pyridinedicarboximido-
acetic acid derivatives (1). Analogous compounds substituted on
the lactam nitrogen (4 and 5) were obtained employing two
approaches that involve the synthesis and ring closing of N,N-
disubstituted amide esters 6 and 7 obtained from 3,4-pyridinedi-
carboxylic anhydride.
Spectroscopic properties (IR, 1H and 13C NMR and MS) of com-
pounds were analyzed and the proposed structures confirmed. 1H
and 13C chemical shifts are strongly conditionated by mesomeric
O
O
+
+
O
CO
CNR
C
+
C7H3NO2
m/z 133
N
N
XH
NR
NR
OH
O
+
O
O
+
XH
O
X
i
CO
O
O
C
C
Route a
O
M - XH - CO
M - XH
+
N
C6H3NO
m/z 105
N
r
H
NR
NR
Route b
XH
+
CO
M
2-5
+
O
O
+
X= OEt, NR1R2, Ph
C
C5H3N
m/z 77
Route c
N
NR
CO
C
O
X
+
X
O
+
Scheme 3. Mass spectra fragmentation pathways of naphthyridinones 2–5 under EI conditions.

I.A. Perillo et al. / Journal of Molecular Structure 921 (2009) 307–313
313
J.F. Blake, J.B. Fell, J.P. Fischer, R.T. Hendricks, S.R. Spencer, P.J. Stengel, Chem.
Abstr. 145 (2006) 489244;
J.F. Blake, J.B. Fell, J.P. Fischer, J.E. Robinson, S.R. Spencer, P.J. Stengel, R.T.
Hendricks, Chem. Abstr. 144 (2006) 254140.
effects and allow to distinguish the 2,6- from 2,7-series. Differ-
ences amongst N-lactam unsubstituted naphthyridines (2 and 3)
and the corresponding N-methyl derivatives (4 and 5) are also ob-
served. The first group show a resonance-assisted hydrogen bond-
ing effect (RAHB) where the stabilized keto–enol system involves
the extranuclear carbonyl (Structure I). Instead, the lactam N-sub-
stitution probably inhibits the keto–enol system planarity and the
RAHB effect, leading to a partial double bond character of amide
CO–N bond in amides 4c and 5c (Structure II), and a higher fre-
quency of the ester carbonyl stretching in the IR spectra of com-
pounds 4a and 5a. Main fragmentation pathways observed in the
mass spectra begin with lateral chain degradation and support
the enol structure of compounds 2–5 in gas phase.
[2] 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, G. Trummlitz, J.
Med. Chem. 40 (1997) 980.
[3] S. Jönsson, G. Andersson, T. Fex, T. Fristedt, G. Hedlund, K. Jansson, L. Abramo, I.
Fritzson, O. Pekarski, A. Runström, H. Sandin, I. Thuvesson, A. Björk, J. Med.
Chem. 47 (2004) 2075;
J. Shi, Z. Xiao, M.A. Ihnat, C. Kamat, B. Pandit, Z. Hu, P.-K. Li, Biorg. Med. Chem.
Lett. 13 (2003) 1187.
[4] C. Nuebling, W. Von Deyn, H. Theobald, K.-O. Westphalen, U. Kardorff, W.
Helmut, T. Kappe, M. Gerber, Chem. Abstr. 120 (1994) 323554;
A.C. Scotese, A.A. Santilli, Chem. Abstr. 96 (1982) 6706;
B.J. Armitage, B.W. Leslie, Chem. Abstr. 125 (1996) 114712.
[5] M.M. Blanco, I.A. Perillo, C.B. Schapira, J. Heterocycl. Chem. 36 (1999) 979;
M. Blanco, M.G. Lorenzo, I.A. Perillo, C.B. Schapira, J. Heterocycl. Chem. 33
(1996) 361.
The presented methods were appropriate for the obtention of
polyfunctional naphthyridinones 2–5, a practically unexplored
kind of compounds until the present.
[6] M.M. Blanco, C.B. Schapira, G. Levin, I.A. Perillo, J. Heterocycl. Chem. 42 (2005)
493.
[7] S. Gabriel, J. Colman, J. Ber. 35 (1902) 1358.
Acknowledgment
[8] J.D. Crum, C.H. Fuchsman, J. Heterocycl. Chem. 3 (1966) 252.
[9] I. Praly-Deprez, C. Rivalle, C. Huel, J. Belehradek, C. Paoletti, E. Bisagni, J. Chem.
Soc. Perkin Trans. 1 (1991) 3165.
[10] M.M. Blanco, M.S. Shmidt, I.A. Perillo, ARKIVOC xii (2005) 195.
[11] M.M. Blanco, G.Y. Buldain, C.B. Schapira, I.A. Perillo, J. Heterocycl. Chem. 39
(2002) 341.
[12] C.G. Pozzi, A.C. Fantoni, A.E. Goeta, C.C. Wilson, J.C. Autino, G. Punte, J. Mol.
Struct. 753 (2005) 173 (and references cited therein).
[13] L. Giacomelli, M. Santo, R. Cattana, J.J. Silber, M.M. Blanco, G. Levin, I.A. Perillo,
XIX SINAQO (FQO-44), Rosario, Argentina, 2003.
[14] E. Pretsch, P. Bühlmann, C. Affolter, A. Herrera, R. Martínez, Determinación
estructural de compuestos orgánicos, ed. Springer-Verlag Ibérica, Barcelona,
España, 2001.
This work was financially supported by the Universidad de Bue-
nos Aires.
References
[1] J. Alonso-Silva, M. Pardo, J.L. Soto, Heterocycles (Japan) 27 (1988) 357;
M. Toyama, H. Otomasu, Chem. Pharm. Bull. 33 (1985) 5543;
G.M. Coppola, J.D. Fraser, G.E. Hardtmann, M.J. Shapiro, J. Heterocycl. Chem. 22
(1985) 193;
Fujisawa Pharmaceutical Co., Chem. Abstr. 124 (1996) 117079;