A synthetic route to pyridazino[4,5-b]-1,8-naphthyridines, a new tetraazaheterocyclic system

Article abstract of DOI:10.3987/COM-04-10265

A synthesis of the substituted pyridazino[4,5-b]-1,8-naphthyridin-6(7H)-ones (6) based on the reaction of ethyl 2-(dibromomethyl)-6-cyano-7-ethoxy-5-phenyl-1,8-naphthyridine-3-carboxyl ate (3) with hydrazone or substituted hydrazones is described.

Full text of DOI:10.3987/COM-04-10265

HETEROCYCLES, Vol. 65, No. 2, 2005
329
HETEROCYCLES, Vol. 65, No. 2, 2005, pp. 329 - 336
Received, 27th October, 2004, Accepted, 16th December, 2004, Published online, 17th December, 2004
A
SYNTHETIC
ROUTE
TO
PYRIDAZINO[4,5-b]-1,8-
NAPHTHYRIDINES, A NEW TETRAAZAHETEROCYCLIC SYSTEM
Juan Vilar, Carlos Peinador, and José Mª Quintela*
Department of Fundamental Chemistry. Faculty of Sciences. University of
A Coruna. Campus A Zapateira. E-15071. A Coruna. Spain
e-mail: jqqoqf@udc.es.
Abstract
–
A
synthesis
of
the
substituted
pyridazino[4,5-b]-1,8-naphthyridin-6(7H)-ones (6) based on the reaction of ethyl
2-(dibromomethyl)-6-cyano-7-ethoxy-5-phenyl-1,8-naphthyridine-3-carboxylate
(3) with hydrazone or substituted hydrazones is described.
The structural diversity and biological importance of nitrogen-containing heterocycles have made them
attractive targets for synthesis over many years. Nitrogen-containing heterocycles are of broad
pharmaceutical interest and this justifies continuing efforts in the development of structure-activity
relationship in this series and of new synthetic strategies.1 The recent discovery that showed antitumor
activity in a wide range of polyheterocyclic compounds isolated from marine organisms,2 promoted the
interest in the synthesis of new heterocyclic rings and in the study of their interaction with biomolecules.
In the search for new effective antitumor agents, polycondensed nitrogen heterocycles having a planar
structure are effective moieties for drugs endowed with antineoplastic activities. Their mechanism of
action is correlated with the capacity to intercalate with the macromolecule of DNA, and to interfere with
the activity of Topoisomerases I and II, two enzymes capable of modifying the topological state of DNA.3
In many cases, biochemical studies have to rely on synthetic materials because the isolation of
aza-polynuclear aromatic compounds from natural/environmental sources is sometimes very difficult. In
the course of our studies directed toward the discovery and development of synthesis of new heterocyclic
systems, we have previously reported on the synthesis of novel tri- and tetracyclic nitrogen-containing
ring systems with anti-inflammatory and antihistaminic activity.4
Unlike linear carbocyclic “acene” homologous series, very little information on their analogues
compounds, containing the pyridine ring as building unit is available.5 As part of our research programs
on the synthesis of new azaheterocyclic systems,6 we reported the first example of the formation of the
1,7,10-anthyridine system. A literature scan revealed no mention to the synthesis of
8-aza-1,7,10-anthyridine ring. We report here the first preparation and isolation of a series of hitherto

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HETEROCYCLES, Vol. 65, No. 2, 2005
unknown pyridazino[4,5-b]-1,8- naphthyridine system. The substituted annelated triheterocyclic poliaza
compounds (5a,e), (6a-d) and (7) were conveniently obtained as outlined in Scheme 1. Ethyl
3-cyano-2-ethoxy-7-methyl-4-phenyl-1,8-naphthyridine-6-carboxylate (1), readily obtained by
condensation of a suitably substituted 2-aminonicotinaldehyde with ethyl acetoacetate in ethanol using
piperidine as catalyst,7 is a versatile starting material for tetraazaanthracene derivatives.
In order to prepare the key intermediate (3), when the naphthyridinecarboxylate (1) and pyridinium
tribromide8 in dichloromethane were stirred at room temperature for 20 h a one to one mixture of two
brominated compounds were obtained in 84% yield, which were readily separated by silica gel column
chromatography affording the bromo (2) and dibromo (3) derivatives, respectively. However, when 1 and
pyridinium tribromide in dichloromethane were stirred at room temperature for 12 h and then refluxed for
4 h only the dibrominated naphthyridine (3) was obtained in 84% yield. The structures (2) and (3) are
derivable from MS, IR and NMR spectral data. For example, the 1H NMR spectrum of
2-bromomethyl-1,8-napthyridine (2) showed a methylene proton signal at δ = 5.18 (s, 2H) and the
methine proton signal of dibromomethyl derivative (3) appears as a singlet at δ = 8.01 ppm. The MS
spectra of 2 and 3 showed molecule ion peaks at m/z = 441 and 439 for 2, and m/z = 519, 518 and 517 for
3. Also, the 1H and 13C NMR spectra showed characteristic signals due to the ethoxy groups.
When ethyl 2-dibromomethyl-6-cyano-7-ethoxy-5-phenyl-1,8-naphthyridine-3-carboxylate (3) was
allowed to reflux with hydrazine hydrate in ethanol, pyridazino[4,5-b][1,8]naphthyridin-6(7H)-one (6a)
was afforded in 70% yield. The reaction of 3 with 2-hydrazinopyridine in reflux ethanol yielded directly
the compound (5e). As shown in Scheme 1, the intermediate hydrazone compounds (4) could be isolated
by treatment of 3 with substituted hydrazines in reflux ethanol. Only one isomer, Z-configuration
(chelated via an intramolecular hydrogen-bond between the 8-nitrogen of the 1,8-naphthyridine ring and
the hydrogen of the NH hydrazone) of these hydrazones was observed. This Z-configuration is consistent
1
with H NMR spectral evidence as the NH proton (15.32-16.14 ppm). Ring closure of the hydrazone
derivative (4a) with sodium ethoxide in ethanol at room temperature yielded the annelated
pyridazinonaphthyridone (5a). Several attempts to ring closure of 4b were uniformly unsuccessful under
a variety of conditions by the instability of the furan moiety. On the other hand, the reaction of 6a with
electrophilic reagents such as methyl iodide, chloroacetonitrile, and 2-bromoacetophenone in THF or
toluene and sodium hydride afforded the 7-substituted pyridazinonaphthyridones (6b-d) in moderate
yields.
The molecular structure of tetraazaheterocyclic compounds (6a-d) was supported by the general data (IR,
1H NMR, 13C NMR, and MS) and elemental analysis. In particular, the MS spectrum showed the
expected molecular ion peak and the IR spectra showed strong absorptions at ν = 1660-1670 cm-1, while
in the 1 H NMR spectra, the H-5 and H-9 protons appear at δ = 8.03-8.78 and δ = 9.07-9.14, respectively.
The most salient features of the 1H NMR and 13C NMR spectra are summarized in EXPERIMENTAL.

HETEROCYCLES, Vol. 65, No. 2, 2005
331
Finally, when ethyl 2-bromomethyl-6-cyano-7-ethoxy-5-phenyl-1,8-naphthyridine- 3-carboxylate (2)
reacts with hydrazine hydrate in ethanol, ethoxy-6,7,8,9-tetrahydro- 6-oxo-4-phenylpyridazino[4,5-b]-
1,8-naphthyridine-3-carbonitrile (7) is obtained in 77% yield. The structure of 6,7,8,9-
tetrahydropyridazino[4,5-b][1,8]naphthyridine (7) was confirmed by their elemental analysis and
spectroscopic data. The MS spectrum showed strong molecule ion peak at m/z = 345 with 100%
abundance. The IR spectrum showed strong absorptions at ν = 3245 and 3200 cm-1 attributed to the NH
1
group and ν = 1680 cm-1 due to the CO group. In the H NMR spectrum, the CH2N and NHCO protons
appear at δ = 4.21 ppm and δ = 9.58 ppm (exchangeable with D2O), respectively, in addition to the set of
signals due to the ethoxy group and aromatic protons. Also, the 13C NMR spectrum showed signals at δ =
14.2 and 64.0 ppm due to ethoxy group.
In conclusion, the present study clearly shows the usefulness of suitably ortho-substituted naphthyridines
for the synthesis to tetracyclic pyridazine compounds (5a,e, 6a-d and 7) bearing various substituents on
the pyridine and pyridazine rings. Because the starting materials are quite affordable and the experimental
procedure is simple, the proposed synthetic approach provides a new, general entry to a variety of
substituted derivatives of the pyridazino[4,5-b]-1,8-naphthyridine system. Tetraazaheterocyclic
compounds (5a,e, 6a-d and 7) can be useful compounds in medicinal chemistry since polycondensed
nitrogen heterocycles are effective moieties for drugs and have been widely used as pharmaceuticals.
Ph
Ph
Ph
N
NC
CO2Et
N
NC
CO2Et
X
NC
CO2Et
Me
f
a
EtO
N
N
H
EtO
N
N
EtO
N
N
R
Br
1
2 X = H
3 X = Br
4a R = C6H5
4b R =
O
O
h
b
g
N
NHNH2
Ph
O
Ph
O
Ph
N
O
NC
R
NC
EtO
NC
R
N
N
NH
NH
N
N
EtO
N
N
N
N
EtO
N
5a R = C6H5
7
6a R = H
6b R = Me
6c R = CH2CN
6d R = CH2COC6H5
c
d
N
5e R =
e
Scheme 1
Reaction Conditions: a: pyridinium tribromide, CH2Cl2. b: NH2NH2, EtOH. c: MeI, NaH, THF. d:
ClCH2CN, NaH, THF. e: BrCH2COC6H5, NaH, toluene. f: RNHNH2, EtOH, reflux. g: NaOEt/EtOH,
reflux. h: NH2NH2, EtOH, reflux.

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HETEROCYCLES, Vol. 65, No. 2, 2005
EXPERIMENTAL
All reagents used were comercial grade chemicals from freshly opened containers. Mps were
determinated on a Bibby SMP3 apparatus and are uncorrected. IR spectra were recorded as potassium
1
13
bromide disks on a Bruker vector 22 FT-IR. H and C NMR spectra were obtained on a Bruker AC
200F instrument at room temperature. MS spectra were obtained on a VG-QUATTRO spectrometer. The
silica gel 60F-254 used for analytical thin layer chromatography was purchased from Merck.
Microanalyses for C, H, N, and S were performed by the elemental analyses general services of the
University of La Coruña.
Ethyl 2-bromomethyl-6-cyano-7-ethoxy-5-phenyl-1,8-naphthyridine-3-carboxylate (2)
Pyridinium tribromide (2.22 g, 6.94 mmol) was added, in small portions, to a solution of 1 (1.0 g, 2.77
mmol) in dichloromethane (70 mL) at -25 °C. The reaction mixture was stirred for 5 h and then warmed
to rt, stirring was continued for 20 h. The solvent was evaporated and the residue was purified by flash
chromatography (99.5/0.5 dichloromethane/ethanol) to yield 2 (0.49 g, 40%) and 3 (0.59 g 41%).
Compound (2). mp: 192-193 °C (hexane). IR (KBr, cm-1): 2980, 2225 (CN), 1720 (CO), 1590, 1575,
1
1445, 1390, 1255, 1025, 815. H NMR (CDCl3): 1.38 (3H, t, J = 7.1 Hz, CH3), 1.56 (3H, t, J = 7.1 Hz,
CH3), 4.40 (2H, q, J = 7.1 Hz, OCH2), 4.71 (2H, q, J = 7.0 Hz, OCH2), 5.18 (2H, s, CH2Br), 7.47-7.66
13
(5H, m, C6H5), 8.58 (1H, s, H-4). C NMR(CDCl3): 14.0, 14.3, 32.6, 62.2, 64.9, 100.6, 113.7, 116.6,
123.1, 129.2, 129.3, 130.7, 132.1, 141.3, 155.9, 159.0, 162.3, 163.9, 164.6. MS (EI, m/z, %): 441 (M+, 9),
439 (M+, 8), 413 (10), 411 (10), 361 (27), 360 (97), 304 (100). Anal. Calcd for C21H18N3O3Br: C, 57.29;
H, 4.12; N, 9.54. Found C, 57.34; H, 4.14; N, 9.46.
Ethyl 2-dibromomethyl-6-cyano-7-ethoxy-5-phenyl-1,8-naphthyridine-3-carboxylate (3)
Pyridinium tribromide (0.56 g, 1.75 mmol) was added, in small portions, to a solution of 1 (0.25 g, 0.69
mmol) in dichloromethane (20 mL) at -25 °C. The reaction mixture was stirred for 5 h and then warmed
to rt, stirring was continued for 20 h. The solution was refluxed for 4 h. The solvent was evaporated and
the residue purified by flash chromatography (99.5/0.5 dichloromethane/ethanol) to yield 3 (0.30 g, 84%).
mp: 150-151 °C (hexane). IR (KBr, cm-1): 3060, 2980, 2225 (CN), 1720 (CO), 1585, 1330, 1260, 1020,
925, 815. 1H NMR(CDCl3): 1.33 (3H, t, J = 7.1 Hz, CH3), 1.49 (3H, t, J = 7.0 Hz, CH3), 4.37 (2H, q, J =
7.1 Hz, OCH2), 4.74 (2H, q, J = 7.0 Hz, OCH2), 7.44-7.65 (5H, m, C6H5), 8.01 (1H, s, CHBr2), 8.35 (1H,
13
s, H-4). C NMR(CDCl3): 14.0, 14.3, 39.3, 62.5, 65.2, 101.0, 113.6, 117.3, 119.1, 129.2, 129.3, 130.8,
132.1, 141.5, 156.5, 158.8, 161.3, 164.1. MS (EI, m/z, %): 521 (M++4, 6), 519 (M+, 11), 518 (M+, 19),
517 (M+, 5), 441 (24), 440 (99), 438 (100). Anal. Calcd for C21H17N3O3Br2: C, 48.58; H, 3.30; N, 8.09.
Found C, 48.42; H, 3.36; N, 8.12.
General procedure for the synthesis of hydrazones (4a,b).

HETEROCYCLES, Vol. 65, No. 2, 2005
333
A solution of dibromide (3) (0.1 g, 0.19 mmol) and the appropriate hydrazine (0.28 mmol) in ethanol (6
mL) was refluxed for 2 h. After cooling, the precipitate was filtered off and the solid recrystallized from
ethanol.
Ethyl 6-cyano-7-ethoxy-5-phenyl-2-phenylhydrazonomethyl-1,8-naphthyridine-3- carboxylate (4a) yield:
1
78%. mp: 199-200 °C. IR (KBr, cm-1): 3975, 2225 (CN), 1710 (CO), 1355, 1230, 1065, 850, 810. H
NMR(CDCl3): 1.37 (3H, t, J = 7.0 Hz, CH3), 1.63 (3H, t, J = 7.1 Hz, CH3), 4.39 (2H, q, J = 7.0 Hz,
OCH2), 4.82 (2H, q, J = 7.0 Hz, OCH2), 7.02-7.06 (2H, m, C6H5), 7.38-7.66 (8H, m, C6H5), 8.16 (1H, s,
13
CH), 8.48 (1H, s, H-4), 15.32 (1H, s, NH). C NMR(CDCl3): 14.1, 14.3, 62.1, 64.5, 98.9, 113.5, 114.2,
114.3, 114.6, 122.5, 122.7, 123.6, 129.4, 130.6, 132.3, 140.1, 143.7, 154.9, 155.1, 158.3, 164.1, 165.1.
MS (EI, m/z, %): 465 (M+, 57), 437 (4), 436 (11), 364 (28). Anal. Calcd for C27H23N5O3: C, 69.66; H,
4.98; N, 15.04. Found C, 69.82; H, 4.91; N, 14.80.
Ethyl 6-cyano-7-ethoxy-5-phenyl-2-(2-furoylhydrazonomethyl)-1,8-naphthyridine-3- carboxylate (4b)
yield: 67%. mp: 288-289 °C. IR (KBr, cm-1): 2929, 2225 (CN), 1715 (CO), 1700 (CO), 1590, 1560, 1430,
1
1265, 1160, 1025, 775. H NMR(CDCl3): 1.38 (3H, t, J = 7.1 Hz, CH3), 1.66 (3H, t, J = 7.1 Hz, CH3),
4.42 (2H, q, J = 7.1 Hz, OCH2), 4.88 (2H, q, J = 7.1 Hz, OCH2), 6.61-6.62 (1H, m, C4H3O), 7.51-7.69
13
(7H, m, C6H5, C4H3O), 8.64-8.69 (2H, m, CH, H-5), 16.14 (1H, s, NH). C NMR(CDCl3): 14.1, 14.4,
62.7, 64.6, 101.1, 112.2, 113.6, 116.0, 116.3, 124.1, 129.4, 131.0, 131.7, 134.0, 141.8, 145.4, 147.2,
154.0, 154.4, 155.9, 158.8, 164.3. MS (FAB, m/z, %): 484 [(MH)+, 100)], 438 (5), 387 (11), 375 (15).
Anal. Calcd for C26H21N5O5: C, 64.59; H, 4.38; N, 14.48. Found C, 64.41; H, 4.49; N, 14.53.
2-Ethoxy-6,7-dihydro-6-oxo-4,7-diphenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile (5a)
A suspension of 4a (0.1 g, 0.21 mmol) and sodium ethoxide (0.05 g, 0.71 mmol) in ethanol (8 mL) was
refluxed for 0.5 h. After cooling, the precipitate was filtered off and the solid recrystallized from ethanol
to yield 5a (0.07 g, 81%). mp: > 300 °C. IR (KBr, cm-1): 3500, 2225 (CN), 1660 (CO), 1585, 1415, 1330,
1
1120, 760. H NMR(CDCl3): 1.61 (3H, t, J = 7.1 Hz, CH3), 4.89 (2H, q, J = 7.1 Hz, OCH2), 7.41-7.68
(10H, m, 2C6H5), 8.73 (1H, s, H-5), 9.14 (1H, s, H-9). 13C NMR (CDCl3): 14.3, 65.4, 102.1, 113.5, 120.0,
121.6, 125.3, 128.2, 128.9, 129.3, 129.5, 131.1, 131.9, 139.7, 141.1, 148.7, 157.9, 158.2, 160.0, 164.1.
MS (EI, m/z, %): 419 (M+, 82), 418 (63), 391 (43), 390 (45). Anal. Calcd for C25H17N5O2: C, 71.59; H,
4.08; N, 16.70. Found C, 71.63; H, 4.04, N; 16.75.
2-Ethoxy-6,7-dihydro-6-oxo-4-phenyl-7-(pyridin-2-yl)pyridazino[4,5-b][1,8]naphthyridine-3- carbonitrile
(5e).
A solution of dibromide (3) (0.1 g, 0.19 mmol) and 2-hydrazinopyridine (0.03 g, 0.28 mmol) in ethanol (6
mL) was refluxed for 3 h. After cooling, the precipitate was filtered off and the solid recrystallized from
ethanol/dichloromethane to yield 5e (0.07 g, 87%). mp: 266-267 °C. IR (KBr, cm-1): 2230 (CN), 1670

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HETEROCYCLES, Vol. 65, No. 2, 2005
(CO), 1590, 1470, 1305, 1125, 815. 1H NMR(CDCl3): 1.61 (3H, t, J = 7.1 Hz, CH3), 4.89 (2H, q, J = 7.1
Hz, OCH2), 7.37-7.74 (7H, m, C6H5, C5H4N), 7.87-7.95 (1H, m, C5H4N), 8.67-8.70 (1H, m, C5H4N),
8.78 (1H, s, H-5), 9.14 (1H, s, H-9). 13C NMR(CDCl3): 14.3, 65.4, 102.1, 113.4, 120.9, 121.6, 123.7,
129.4, 129.5, 131.1, 131.9, 138.1, 139.6, 140.3, 148.9, 149.4, 152.6, 158.0, 158.4, 158.6, 160.0, 164.2.
MS (EI, m/z, %): 420 (M+, 53), 392 (39), 365 (31), 364 (28). Anal. Calcd for C24H16N6O2: C, 68.56; H,
3.84; N, 19.99. Found C, 68.32; H, 3.98; N, 19.77.
2-Ethoxy-6,7-dihydro-6-oxo-4-phenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile (6a)
A solution of 3 (0.12 g, 0.23 mmol) in ethanol (10 mL) and 80% hydrazine monohydrate (0.1 mL, 2.0
mmol) was refluxed for 24 h. After cooling, the precipitate was filtered off and recrystallized from
ethanol to yield 6a (0.055 g,70%). mp: > 300 °C. IR (KBr, cm-1): 3800, 2215 (CN), 1685 (CO), 1420,
1
1380, 1010, 815. H NMR(DMSO-d6): 1.49 (3H, t, J = 7.0 Hz, CH3), 4.71 (2H, q, J = 7.0 Hz, OCH2),
7.62-7.74 (5H, m, C6H5), 8.52 (1H, s, H-5), 8.60 (1H, s, H-9), 13.01 (1H, s, NHCO). 13C NMR
(DMSO-d6): 14.1, 64.5, 100.9, 114.0, 119.5, 120.9, 129.1, 129.5, 130.7, 132.4, 137.3, 139.1, 149.1, 157.0,
159.2, 159.6, 163.1. MS (EI, m/z, %): 343 (M+, 41), 342 (100), 316 (22), 315 (76). Anal. Calcd for
C19H13N5O2: C, 66.47; H, 3.82; N, 20.40. Found C, 66.63; H, 3.65; N, 20.44.
2-Ethoxy-6,7-dihydro-7-substituted6-oxo-4-phenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile
(6b-d). General procedure.
A suspension of naphthyridine (6a) (0.08 g, 0.23 mmol), sodium hydride (0.009 g, 0.40 mmol) and the
appropriate electrophile (0.31 mmol) in dry THF (6 mL) (toluene was used for 6d) was refluxed for 24 h.
The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography
(dichloromethane/ethanol 99:1) and recrystallized from dichloromethane/ethanol.
2-Ethoxy-6,7-dihydro-7-methyl-6-oxo-4-phenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile (6b)
1
yield: 72%. mp: 224-226 °C. IR (KBr, cm-1): 3040, 2220 (CN), 1665 (CO), 1590, 1260, 800. H NMR
(CDCl3): 1.45 (3H, t, J = 7.1 Hz, CH3), 3.85 (3H, s, CH3), 4.72 (2H, q, J = 7.1 Hz, OCH2), 7.43-7.69 (5H,
13
m, C6H5), 8.40 (1H, s, H-5), 8.74 (1H, s, H-9). C NMR(CDCl3): 12.9, 38.2, 39.6, 109.6, 113.7, 117.8,
119.4, 128.7, 129.3, 129.5, 131.1, 131.6, 137.9, 138.6, 147.4, 152.1, 157.4, 158.5. MS (EI, m/z, %): 357
(M+, 100), 356 (63), 342 (10), 329 (35), 314 (74), 301 (96). Anal. Calcd for C20H15N5O2: C, 67.22; H,
4.23; N, 19.60. Found C, 67.17; H, 4.06; N, 19.87.
2-Ethoxy-6,7-dihydro-7-cyanomethyl-6-oxo-4-phenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile
(6c) yield: 72%. mp: 205-207. °C. IR (KBr, cm-1): 2920, 2840, 2220 (CN), 1675 (CO), 1600, 1450, 1260,
1105, 800. 1H NMR (CDCl3): 1.44 (3H, t, J = 7.1 Hz, CH3), 4.72 (2H, q, J = 7.1 Hz, OCH2), 5.08 (2H, s,
CH2), 7.43-7.68 (5H, m, C6H5), 8.46 (1H, s, H-5), 8.71 (1H, s, H-9). 13C NMR(CDCl3): 12.8, 38.3, 38.9,
113.4, 113.7, 118.1, 119.0, 128.6, 129.6, 129.8, 130.1, 130.6, 131.3, 136.0, 137.0, 138.6, 139.9, 140.2,

HETEROCYCLES, Vol. 65, No. 2, 2005
335
157.1, 157.7. MS (EI, m/z, %): 382 (M+, 88), 381 (54), 354 (17), 326 (54). Anal. Calcd for C21H14N6O2:
C, 65.96; H, 3.69; N, 21.98. Found C, 66.15; H, 3.76; N, 21.73.
2-Ethoxy-6,7-dihydro-6-oxo-7-phenacyl-4-phenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile (6d)
yield 40 %. mp: 234-236 °C. IR (KBr, cm-1): 3045, 2220 (CN), 1690 (CO), 1655 (CO), 1585, 1410, 1325,
1010, 810. 1H NMR(CDCl3): 1.60 (3H, t, J = 7.1 Hz, CH3), 4.88 (2H, q, J = 7.1 Hz, OCH2), 5.66 (2H, s,
CH2), 7.47-7.66 (8H, m, C6H5), 8.00-8.05 (2H, m, C6H5), 8.63 (1H, s, H-5), 9.07 (1H, s, H-9). 13C NMR
(CDCl3): 14.3, 57.6, 65.3, 102.0, 113.5, 119.8, 120.8, 128.1, 128.9, 129.3, 129.4, 131.0, 132.0, 134.1,
134.6, 139.2, 139.8, 149.2, 157.8, 158.9, 160.0, 164.0, 191.7. MS (EI, m/z, %): 461 (M+, 8). Anal. Calcd
for C27H19N5O3: C, 70.27; H, 4.15, N; 15.18. Found C, 70.20; H, 4.19; N, 15.33.
2-Ethoxy-6,7,8,9-tetrahydro-6-oxo-4-phenylpyridazino[4,5-b][1,8]naphthyridine-3-carbonitrile (7)
A solution of 2 (0.10 g, 0.23 mmol) in ethanol (10 mL) and hydrazine monohydrate 80% (0.1 mL, 2.0
mmol) was refluxed for 24 h. After cooling, the precipitate was filtered off and recrystallized from
ethanol to yield 7 (0.061 g, 77%). mp: > 300 °C. IR (KBr, cm-1): 3245, 3200, 2900, 2225 (CN), 1680
1
(CO), 1330, 1200, 1015, 910, 710. H NMR (DMSO-d6): 1.46 (3H, t, J = 7.0 Hz, CH3), 4.21 (2H, br s,
CH2N), 4.66 (2H, q, J = 7.0 Hz, OCH2), 5.90 (1H, br s, CH2NH) 7.55-7.92 (5H, m, C6H5), 8.20 (1H, s,
13
H-5), 9.58 (1H, br s, NHCO). C NMR (DMSO-d6): 14.2, 50.6, 64.0, 98.7, 114.2, 116.8, 121.9, 129.0,
129.3, 130.4, 132.8, 135.2, 155.7, 159.3, 162.5, 163.4, 165.2. MS (EI, m/z, %): 345 (M+, 100), 344 (76),
317 (25), 316 (77), 288 (21). Anal. Calcd for C19H15N5O2: C, 66.08; H, 4.38; N, 20.28. Found C, 66.23;
H, 4.19; N, 20.41.
ACKNOWLEDGEMENTS
Financial support from Xunta de Galicia CICYT (BQU 2003-00754) and XUGA
(PGIDT04PXIC10307PN) is gratefully acknowledged.
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