A facile synthesis of substituted 1,8-naphthyridines based on the aza-Wittig/electrocyclic ring closure strategy

Article abstract of DOI:10.3987/COM-05-10629

Several new 1,8-naphthyridine derivatives (7) and (8) has been synthesized via an aza-Wittig reaction. Iminophosphoranes, 2-ethoxy-3-cyano-5-(2-ethoxycarbonyl)-4-phenyl-6-[(triphenylphosphoranilidene)aminolpyiridine (4) and 2-ethoxy-3-cyano-5-(2-cyanoviny

Full text of DOI:10.3987/COM-05-10629

HETEROCYCLES, Vol. 68, No. 2, 2006
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HETEROCYCLES, Vol. 68, No. 2, 2006, pp. 295 - 306. © The Japan Institute of Heterocyclic Chemistry
Received, 18th November 2005, Accepted, 11th January, 2006, Published online, 17th Januray, 2006. COM-05-10629
A FACILE SYNTHESIS OF SUBSTITUTED 1,8-NAPHTHYRIDINES
BASED ON THE AZA-WITTIG/ELECTROCYCLIC RING CLOSURE
STRATEGY
Carmen Veiga, José Mª Quintela,* Carlos Peinador,* Marcos Chas, and
Antonio Fernández
Department of Fundamental Chemistry, Faculty of Sciences, University of A
Coruña, Campus A Zapateira, E-15071, A Coruña, Spain. e-mail: jqqoqf@udc.es
Abstract – Several new 1,8-naphthyridine derivatives (7) and (8) has been
synthesized via an aza-Wittig reaction. Iminophosphoranes, 2-ethoxy-3-cyano-5-
(2-ethoxycarbonyl)-4-phenyl-6-[(triphenylphosphoranilidene)amino]pyiridine (4)
and 2-ethoxy-3-cyano-5-(2-cyanovinyl)-4-phenyl-6[(triphenylphosphoranilidene)-
amino]pyridine (5), easily obtained from the 2-chloro-5-cyano-6-ethoxy-4-
phenylpyridine-3-carboxaldehyde (1), react with heterocumumulenes such as
aromatic isocyanates to give directly the title compounds in an aza-
Wittig/electrocyclic ring closure process. The yields were from 60% to 97%.
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 There
is an enormous interest in the synthesis of new heterocyclic rings stimulated by recent reports that showed
antitumor activity in a wide range of heterocyclic compounds isolated from marine organisms.2
The naphthyridines and their derivatives exhibit various types of biological activity, and the organic
chemistry has been frequently reviewed.3 1,8-Naphthyridine are important scaffolds in many compounds
with pharmacological applications,4 and their anti-allergy, antibacterial, antihypertensive and anti-
inflammatory properties have been reported.5 Since the discovery of the first therapeutically useful
antibacterial quinolone, nalidixic acid, numerous derivatives have been prepared in search of improved
antibacterial activities.6 The resurgence of interest in quinolones, naphthyridones and related compounds
has resulted in an enormous account of research on new structural modifications to improve the overall
spectrum of antibacterial activity, bioavailability and safety. Detailed structure-activity relationships have
been reviewed.7 Different series of naphthyridine derivatives which possessed excellent broad-spectrum

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HETEROCYCLES, Vol. 68, No. 2, 2006
activity against Gram-positive and Gram-negative bacteria as well as good pharmacokinetic properties
have been prepared and are used clinically.8 Nevertheless a number of these compounds have quite often
exhibited other properties which caused toxicity and preclude their clinical use.9
On the other hand, 1,8-napthyridines are also known to be good bidentate ligands in organometallic
complexes. 1,8-Napthyridine (napy) and its simplest 2-substituted and 2,7-disubstituted derivatives may
act as monodentate and bidentate ligands, resembling the behavior of the carboxylate ligands.10 Special
interest was focused on the photochemistry and redox properties of mononuclear ruthenium complexes.11
Moreover, novel multidendate dinucleating ligands based on the 1,8-napthyridine skeleton have been
prepared with the aim of mimicking the coordination environment of dinuclear metalloenzymes and
diiron-containing, redox-active proteins.12 Finally, dinuclear ruthenium complexes with the 1,8-
naphthyridine ligand are stable and active catalysts for the oxidation of alcohols and the epoxidation of
alkenes.13
Recently, in the course of a study aimed at the discovery of new compounds to combat scuticociliatosis,
our results demonstrate that substituted naphthyridines are new antiprotozoals active against Philasterides
dicentrarchi, the causative agent of scuticiciliatosis in farmed turbot and Black Sea bass-bream.14
Consequently, the establishment of a facile and regioselective construction of these fundamental
heterocyclic skeletons is important.
R3
N
R3
N
R3
N
R3
N
O
R4
R5
R2
R4
R5
R2
R4
R5
R2
R4
R5
H
PPh3
N
NHR1
N C NR1
N
Cl
Figure 1. General retrosynthetic pathway for synthesis of the substituted 1,8-naphthyridines
In this context, the aza-Wittig reaction of iminophosphoranes with heterocumulenes, e.g. carbon dioxide,
carbon disulfide, and isocyanates, or isothiocyanates is a very useful reaction in synthetic heterocyclic
chemistry. The aza-Wittig reaction has become one of the most important synthetic methods for
constructing novel C=N, N=N, and S=N double bonds containing compounds, especially in modern
nitrogen heterocyclic synthesis. In recent years, there has been a significant interest in the preparation and
reactivity of N-heteroaryliminophosphoranes because of their promising potential as building blocks for
the construction of nitrogen-containing heterocycles compounds, and many interesting heterocyclization
reactions involved functionalized iminophosphoranes have been reviewed.15 Consequently, improvements
that increase the efficiency or enlarge its applicability are desirable, and the discovery of novel
functionalized iminophosphoranes bearing a moiety able to react with the aza-Wittig product is important
in this respect.16

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297
Recently, in the course of our studies directed toward the synthesis of fused heterocycles, we have
reported the synthesis of fused pyrimidines based on the tandem aza-Wittig heterocumulene-mediated
annulation strategy.17 Work in our laboratories has been recently concerned with the synthesis of 1,8-
naphthyridines, pyridothienopyrimidines and pyridothienotriazines, with the aim of evaluating their
antiprotozoal activity.14 As a continuation of our search for new biologically active heterocycles, we now
report a new and facile approach to the synthesis of properly substituted 1,8-naphthyridine derivatives,
centered on the aza-Wittig reaction of iminophosphoranes with heterocumulenes. Our general approach to
the synthesis of poly-functionalized 1,8-naphthyridine derivatives (Figure 1) is centered on the aza-Wittig
reaction of iminophosphoranes with heterocumulenes to give a 1,3,5-hexatriene moiety containing a
carbon atom at one end and cumulated double bond at the other, which subsequently undergoes the
stepwise formation of the pyridine ring following the aza-Wittig/electrocyclic ring closure strategy.
Ph
O
Ph
Ph
i) 2a
ii) 2b
NC
NC
NC
H
iii
R2
R2
EtO
N
Cl
EtO
N
Cl
EtO
N
N3
1
2a: R2 = CO2Et (E/Z = 10:0)
2b: R2 = CN ( E/Z = 5:1)
3a: R2 = CO2Et (97%)
3b: R2 = CN (80%)
iv
Ph
Ph
Ph
NC
NC
EtO
v
NC
R2
NHR1
R2
N PPh3
R2
EtO
N
N
N C NR1
EtO
N
N
7,8
6
4: R2 = CO2Et (82%)
5: R2 = CN (94%)
Reagents and reactions conditions:
i)Ph3P=CHCO2Et, DMS, rt, 24 h, 75%; ii) Ph3PCH2CN Cl, HN(CH2)5, THF, rt, 15 h, 77%;
iii) NaN3, DMSO, rt, 1-4 h; iv) Ph3P, CH2Cl2, rt, 76 h; v) R1-NCO, dry toluene, reflux, 3-8 h.
Scheme 1. Synthesis and structure of substituted 1,8-naphthyridines (7) and (8).
The starting iminophosphoranes (4 and 5) for the intermolecular aza-Wittig reaction followed by
electrocyclization sequence were conveniently prepared from 2-chloro-5-cyano-6-ethoxy-4-
phenylpyridine-3-carboxaldehyde (1) (Scheme 1). This compound can be directly and efficiently obtained
by substitutive deamination [tert-butyl nitrite and anhydrous copper(II) chloride in dry acetonitrile] of 2-
amino-3-formylpyridine derivative.18 Carboxaldehyde (1) reacted with an equimolecular quantity of
(carboxymethylene)triphenyl phosphorane to give good yield of 2-chloro-3-vinylpyridine (2a). Only E-
isomer was obtained: the 1H NMR spectrum of 2a includes two characteristic doublets (δ = 5.84 and 7.43

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ppm, with J = 16.1 Hz) from a trans-configuration of the double bond, in addition to the set of signals due
13
to the phenyl and ethoxy groups. While, the C NMR spectrum showed signals at δ = 126.3 and 136.9
ppm to the vinyl carbons. The attempted Wittig reaction with (cyanomethyl)triphenylphosphorane to
yield 2b resulted in non-selectivity to give a mixture of E and Z isomers (E:Z = 5:1 according to its NMR
spectrum) in 75%.
Compounds (2) react with sodium azide in dimethyl sulfoxide at room temperature to give the 2-azido-3-
vinylpyrimidines (3a) and (3b) in 98% and 83% yield, respectively. The preparation of the desired key
iminophosphoranes (4) and (5) was accomplished very easily through the classical Staudinger reaction19
of 2-azidopyrimidines (3a) and (3b) with triphenylphosphine in dry methylene chloride at room
temperature in good yields.
Table 1. Physicochemical data for 1,8-naphthyridines (7a-d) and (8a-d)
Ph
NC
R2
EtO
N
N
NHR1
Compounda
Molecular formulab
R1
R2
mp (ºC)
Yield (%)
7a
7b
7c
7d
8a
8b
8c
8d
C6H5
CO2Et
CO2Et
CO2Et
CO2Et
CN
259-261
250-252
299-301
203-205
302-304
280-282
276-278
218-220
83c
93c
80c
87c
60d
63d
85d
60d
C26H22N4O3
C27H24N4O3
C26H21ClN4O3
C27H24N4O4
C24H16N5O
4-Me-C6H4
4-Cl- C6H4
4-MeO- C6H4
C6H5
4-Me- C6H4
4-Cl- C6H4
4-MeO- C6H4
CN
C25H19N5O
CN
C24H16ClN5O
C25H19N5O2
CN
a
b
c
d
All spectra data were consistent with the assigned structures.
All compounds analyzed for C, H, N; analytical results are within 0.4% of theoretical values.
Purified by flash chromatography using dichloromethane as eluent.
Recrystallized from ethanol/CH2Cl2
The reaction of the iminophosphoranes 2-ethoxy-3-cyano-5-(2-ethoxycarbonyl)-4-phenyl-6-
[(triphenylphosphoranilidene)amino]pyridine (4) and 2-ethoxy-3-cyano-5-(2-cyanovinyl)-4-phenyl-6-
[(triphenylphosphoranilidene)amino]pyrimidine (5) with aromatic isocyanates, in dry toluene at reflux
temperature, gave triphenylphosphine oxide and the corresponding functionalized 1,8-naphthyridines (7a-
d) and (8a-d), respectively.

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299
Presumably, the mechanisms of these conversions involve initial aza-Wittig reaction between the
iminophosphorane and the isocyanate to give a carbodiimide (6) as highly reactive intermediate, which
easily undergoes electrocyclic ring closure followed by [1,3-H] shift to afford the final substituted 1,8-
naphthyrines (7) and (8) in good yields (60-93%). This assumption is supported by the isolation of the
intermediate carbodiimides in aza-Wittig/electrocyclic-ring closure process.17, 20
The structure of compounds (7) and (8), shown in Table 1, was consistent with their elemental analyses
and spectral data. The mass spectra showed the expected molecular ion peak and the NH group of all 1,8-
naphthyiridine derivatives showed a strong absorption band at υ = 3200-3300 cm-1 in the IR spectra.
Moreover, IR spectra of compounds (7a-d) showed one strong absorption band at υ = 1690-1700 cm-1
1
due to the carbonyl group. In the H NMR spectra, the characteristic chemical shifts of the amino group
13
are found at δ = 7.65-10.70 ppm and those of H-5 at δ = 8.03-8.48 ppm as singlets, while the C NMR
13
spectra showed a signal at δ = 141.8-143.6 ppm due to the C-5 carbon. On the other hand, C NMR
spectra of compounds (7a-d) showed a signal at δ = 114.5-115 ppm and compounds (8a-d) two signals at
δ = 114.2−115.4 due to the one or two cyano groups, respectively. Complete information about the NMR,
IR and MS spectra is presented in the EXPERIMENTAL.
The above method demonstrate that the tandem aza-Wittig/electrocyclization strategy provides a new
entry to a variety of substituted 1,8-naphthyridines. Advantages of the present method are: easy
availability of starting materials, good yields in the iminophosphorane preparation as well as in the
cyclization step, and experimental simplicity of the synthetic procedure. Due to the easily accessible and
versatile starting materials, this method has the potential in the synthesis of many biologically and
pharmaceutically active naphthyridine derivatives, because dinucleating ligands based on 2,7-
disubstituted 1,8-naphthyridines are the nitrogen analogues of the carboxylate ligands, which bridge the
catalytic centres in metallohydrolases that perform the hydrolysis of biologically important substrates as
DNA, RNA, and peptides by the cooperation between two metal centers.21
EXPERIMENTAL
All reagents used were commercial grade chemicals from freshly opened containers. Melting points were
determined on a Büchi 510 apparatus and are uncorrected. IR spectra were recorded as potassium
1
13
bromide disks on a Perkin-Elmer 783 spectrophotometer. H and C NMR spectra were obtained on a
Brucker AC 200F instrument at room temperature. MS spectra were obtained on a VG QUATTRO
spectrometer. The silica gel 60 HF254+366 used for analytical thin layer chromatography and the silica gel
60 (230-400 mesh) employed for flash chromatography were purchased from Merck. Microanalyses for,
C, H, and N were performed by the elemental analyses general service of the University of A Coruña.
2-Chloro-5-cyano-6-ethoxy-3-(2-ethoxycarbonyl)-4-phenylpyridine (2a):

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HETEROCYCLES, Vol. 68, No. 2, 2006
A mixture of 1 (0.30 g, 1.05 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (0.41 g, 1.17
mmol) in DMF (6 mL) was stirred at rt for 14 h. Water (10 mL) was added and the aqueous phase was
extracted with ether (3x50 mL) and the organic layer was dried over anhydrous sodium sulfate and
filtered. Concentration to dryness yielded a crude material which was purified by flash chromatography
using CH2Cl2/hexane (2:1, v/v) as eluent to yield 2a (0.28 g, 75%): mp 104-106 ºC (EtOH). IR (KBr, cm-
1) ν = 3000, 2220 (CN), 1705 (CO), 1650, 1590, 1560. MS (EI, m/z %) = 358 (M+ + 2, 6), 356 (M+, 15),
321 (33), 311 (17), 293 (58), 283 (82), 265 (92), 255 (100), 191 (86), 164 (84). 1H NMR (CDCl3) δ = 1.23
(t, 3H, J = 7.2 Hz, CH3); 1.49 (t, 3H, J = 7.0 Hz, CH3); 4.15 (q, 2H, J = 7.2 Hz, OCH2); 4.57 (q, 2H, J =
7.0 Hz, OCH2); 5.84 (d, 1H, J = 16.1 Hz, H-2’); 7.43 (d, 1H, J = 16.1 Hz, H-1’); 7.24-7.52 (m, 5H, C6H5).
13C NMR (CDCl3): δ = 14.1 (CH3); 14.2 (CH3); 60.7 (CH2);64.8 (CH2); 97 (C-CN); 112.8 (CN); 121.9
(C-3); 126.3 (C-2’); 128.6, 129.0, 130,1, 134.2 (C6H5), 136.9 (C-1’); , 158.2 (C-Cl), 162.6, 165.8 (CO).
Anal. Calcd for C19H17N2O3Cl: C, 63.96; H, 4.80; Cl, 9.94; N, 7.85. Found: C, 63.75; H, 4.86; Cl, 10.14;
N, 7.74.
2-Chloro-5-cyano-3-(2-cyanovinyl)-6-ethoxy-4-phenylpyridine (2b):
To a mixture of 1 (0.30 g, 1.05 mmol) and (cyanomethyl)triphenylphosphonium chloride (0.42 g, 1.25
mmol) in dry THF (20 mL) triethylamine (0.17 mL, 1.26 mmol) was added, and the mixture was stirred at
rt for 20 h. The solvent was evaporated and the resulting solid was purified by flash chromatography
using CH2Cl2/hexane/AcOEt (5:20:1,) as eluent to give an E and Z mixture (5:1) of 2b (0.25 g, 77%): mp
120-122 ºC (EtOH). IR (KBr, cm-1) ν = 3000, 2220 (CN), 2210 (CN), 1620, 1550, 1540, 1450, 1420. MS
(EI, m/z %) = 311 (M+ + 2, 7), 309 (M+, 51), 282 (42), 280 (100), 254 (37), 246 (39), 217 (45) 191 (60),
180 (60), 164 (73). 1H NMR (CDCl3): E isomer: δ = 1.49 (t, 3H, J = 7.1 Hz, CH3); 4.69 (q, 2H, J = 7.1 Hz,
OCH2); 5.33 (d, 1H, J = 17.1 Hz, H-2’), 7.20 (d, 1H, J = 16.1 Hz, H-1’); 7.23-7.58 (m, 5H, C6H5); Z
isomer: 5.56 (d, 1H, J = 11.2 Hz, H-2’); 6.97 (d, 1H, J = 11.2 Hz, H-1’). Anal. Calcd for C17H12N3OCl: C,
65.92; H, 3.90; Cl, 11.45; N, 13.57. Found: C, 65.75; H, 3.86; Cl, 11.69; N, 13.44.
2-Azido-5-cyano-6-ethoxy-3-(2-ethoxycarbonyl)-4-phenylpyridine (3a):
To a well-stirred solution of sodium azide (0.05 g, 0.76 mmol) in DMSO/AcOH(20:1, v/v)(2 mL) was
added the 2-chloro-4-cyano-5-ethoxy-3-(2-ethoxycarbonyl)-4-phenylpyridine (2a) (0.18 g, 0.50 mmol)
and the reaction mixture was stirred at rt for 4 h. The precipitate obtained was filtered off and
recrystallized from acetone to yield 3a (0.18 g, 98%): mp 158-160 ºC (EtOH). IR (KBr, cm-1) ν = 3000,
2220 (CN), 2190, 2175 (N3), 1710 (CO), 1640, 1550, 1500. MS (EI, m/z %) = 363 (M+ + 2, 2), 335 (M+ -
N2, 43), 307 (26), 311 (17), 288 (11), 261 (66), 248 (17), 235 (100), 234 (59), 206 (52). 1H NMR (CDCl3)
δ = 1.24 (t, 3H, J = 7.1 Hz, CH3); 1.49 (t, 3H, J = 7.1 Hz, CH3); 4.15 (q, 2H, J = 7.1 Hz, OCH2); 4.59 (q,
2H, J = 7.1 Hz, OCH2); 6.44 (d, 1H, J = 16.6 Hz, H-2’); 7.24 (d, 1H, J = 16.6 Hz, H-1’); 7.23-7.52 (m,
5H, C6H5). Anal. Calcd for C19H17N5O3: C, 62.80; H, 4.72; N, 19.27. Found: C, 62.93; H, 4.57; N, 19.18.

HETEROCYCLES, Vol. 68, No. 2, 2006
301
2-Azido-5-cyano-3-(2-cyanovinyl)-6-ethoxy-4-phenylpyridine (3b):
To a stirred solution of sodium azide (0.06 g, 0.97 mmol) in DMSO/AcOH(20:1, v/v) (2 mL) was added
the E and Z mixture (5:1) of 2-chloro-4-cyano-5-ethoxy-3-(2-cyanovinyl)-4-phenylpyridine 2b (0.20 g,
0.64 mmol) and the reaction mixture was stirred at rt for 1 h. The precipitate obtained was filtered off and
purified by flash chromatography using CH2Cl2/hexane/AcOEt (5:20:1) as eluent to give 3b (0.18 g,
84%): mp 156-158 ºC (EtOH). IR (KBr, cm-1) ν = 3000, 2220 (CN), 2210 (CN), 2150, 2140 (N3), 1610,
1
1550, 1400. MS (EI, m/z %) = 316 (M+, 28), 288 (M+ - N2, 37), 287 (52), 260 (100). H NMR (CDCl3):
δ = 1.50 (t, 3H, J = 7.1 Hz, CH3); 4.60 (q, 2H, J = 7.1 Hz, OCH2); 6.10 (d, 1H, J = 17.0 Hz, H-2’); 6.91 (d,
1H, J = 17.0 Hz, H-1’); 7.19-7.56 (m, 5H, C6H5). 13C NMR ): δ = 14.3 (CH3); 64.2 (CH2); 89.7 (C-CN);
94.1 (CN); 101.6 (C-2’); 111.6, 113.8 (CN); 118,1; 128.5, 129.3, 130.3, 133.7, 135.5 (C6H5); 141.3 (C-1’),
159.5, 163.1 ppm. Anal. Calcd for C17H12N6O: C, 64.55; H, 3.82; N, 26.57. Found: C, 64.75; H, 3.86; N,
26.44.
2-Ethoxy-3-cyano-5-(2-ethoxycarbonyl)-4-phenyl-6-[(triphenylphosphoranilidene)amino]pyridine (4)
A mixture of 3a (0.70 g, 1.93 mmol) and triphenylphosphine (0.56 g, 2.12 mmol) in CH2Cl2 (4 mL) was
stirred at rt for 6 h. Concentration to dryness yielded a crude material, which was recrystallized from
ethanol/acetone to yield 4 (0.94 g, 82%): mp 189-191 ºC. IR (KBr, cm-1) ν = 3000, 2220 (CN), 1700 (CO),
1
1640, 1560, 1540, 1500, 1450. MS (EI, m/z %) = 597 (M+, 10), 524 (100), 496 (9), 262 (25). H NMR
(CDCl3) δ = 0.95 (t, 3H, J = 7.1 Hz, CH3); 1.25 (t, 3H, J = 7.1 Hz, CH3); 3.48 (q, 2H, J = 7.1 Hz, OCH2);
4.13 (q, 2H, J = 7.1 Hz, OCH2); 7.21 (d, 1H, J = 15.6 Hz, H-2’); 7.25-7.79 (m, 21H, C6H5 + H-1’) ppm.
13C NMR (CDCl3) δ = 14.4 (CH3), 59.7 (CH2), 62.1 (CH2), 84.9 (C-CN); 113.4, 113.8, 117.0, 119.2 (C-
2’), 128.0, 128.5, 128.7, 128.9, 130.0, 132.3, 132.7, 132.9, 136.6, 140.4 (C-1’), 157.8, 162.4, 163.6, 163.7,
31
168.6 (CO) ppm. P NMR (CDCl3) δ = 18.56 ppm. Anal. Calcd for C37H32N3O3P: C, 74.86; H, 5.40; N,
7.03. Found: C, 74.75; H, 5.56; N, 7.14.
2-Ethoxy-3-cyano-5-(2-cyanovinyl)-4-phenyl-6-[(triphenylphosphoranilidene)amino]pyridine (5)
A mixture of 3b (0.12 g, 0.38 mmol) and triphenylphosphine (0.12 g, 0.42 mmol) in CH2Cl2 (2 mL) was
stirred at rt for 7 h. Concentration to dryness yielded a crude material, which was purified by flash
chromatography using CH2Cl2/hexane/AcOEt (5:20:1, v/v) to yield 5 (0.19 g, 94%): mp 227-229 ºC
(EtOH). IR (KBr, cm-1) ν = 2210 (CN), 1600, 1550, 1540, 1530, 1490, 1440. MS (EI, m/z %) = 550 (M+,
1
26), 549 (37), 521 (17), 510 (9), 473 (9), 262 (47), 183 (100). H NMR (CDCl3) δ = 0.93 (t, 3H, J = 7.1
13
Hz, CH3); 3.45 (q, 2H, J = 7.1 Hz, OCH2); 7.12-7.72 (m, 22H, C6H5 + H-1’+ H-2’) ppm. C NMR
(CDCl3) δ = 14.2 (CH3), 62.4 (CH2), 85.7, 88.8 (C-CN), 96.0 (CN); 112.4 (C-1’), 112.8, 116.5 (CN),
31
120.8, 127.5, 128.7, 128.8, 129.1, 129.5, 132,5, 132,7, 136.0, 145.9 (C-2’), 153.0, 158.0, 162.2 ppm. P
NMR (CDCl3) δ = 20.95 ppm. Anal. Calcd for C35H27N4OP: C, 76.35; H, 4.94; N, 10.18. Found: C, 76.43;
H, 4.76; N, 10.44.

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3-Cyano-2-ethoxy-6-ethoxycarbonyl-4-methyl-1,8-naphthyridines (7a-d); General Procedure:
To a stirred solution of iminophosphorane (4) (0.1 g, 0.16 mmol) in dry toluene (6 mL) was added the
appropriate aromatic isocyanate (0.82 mmol) under argon. After the reaction mixture was refluxed for
2.5-6 h (TLC monitored), the solvent was removed off under reduced pressure and the resulting solid was
purified by flash chromatography using CH2Cl2 as eluent.
3-Cyano-2-ethoxy-6-ethoxycarbonyl-4-phenyl-7-N-phenylamino-1,8-naphthyridine (7a) (86%): mp 259-
261 ºC (EtOH). IR (KBr, cm-1) ν = 3200 (NH), 2210 (CN), 1690 (CO), 1610, 1600, 1580, 1550. MS (EI,
m/z %) = 438 (M+, 43), 437 (100), 391 (12), 363 (32), 335 (19). 1H NMR (CDCl3) δ = 1.31 (t, 3H, J = 7.1
Hz, CH3); 1.53 (t, 3H, J = 7.1 Hz, CH3); 4.34 (q, 2H, J = 7.1 Hz, OCH2); 4.75 (q, 2H, J = 7.1 Hz, OCH2);
13
7.15-7.95 (m, 10H, 2C6H5); 8.47 (s, 1H, H-5); 10.66 (br s, 1H, NH) ppm. C NMR (CDCl3) δ = 14.0
(CH3), 14.4 (CH3), 61.9 (CH2), 64.1 (CH2), 95.0 (C-CN), 109.3, 111.0, 114.5 (CN), 121.1, 124.0, 128.9,
129.0, 129.4, 130.2, 133.1, 138.7 (C6H5), 141.9 (C-5), 156.4, 158.4, 164.9, 166.5 (CO). Anal. Calcd for
C26H22N4O3: C, 71.22; H, 5.06; N, 12.78. Found: C, 71.15; H, 5.26; N, 12.74.
3-Cyano-2-ethoxy-6-ethoxycarbonyl-4-phenyl-7-N-(4-methylphenyl)amino-1,8-naphthyridine
(7b)
(93%): mp 250-252 ºC (EtOH). IR (KBr, cm-1) ν = 3300 (NH), 3000, 2220 (CN), 1700 (CO), 1610, 1600,
1
1580, 1550. MS (EI, m/z %) = 452 (M+, 50), 451 (100), 405 (10), 377 (20), 349 (19). H NMR (CDCl3)
δ = 1.31 (t, 3H, J = 7.1 Hz, CH3); 1.52 (t, 3H, J = 7.1 Hz, CH3); 2.37 (s, 3H, CH3); 4.34 (q, 2H, J = 7.1 Hz,
OCH2); 4.74 (q, 2H, J = 7.1 Hz, OCH2); 7.22, 7.78 (AA’XX’ system, 4H, J = 8.3 Hz, C6H4); 7.45-7.62 (m,
13
5H, C6H5); 8.45 (s, 1H, H-5); 10.57 (br s, 1H, NH) ppm. C NMR (CDCl3) δ = 14.0 (CH3), 14.4 (CH3),
20.9 (CH3), 61.8 (CH2), 64.0 (CH2), 94.6 (C-CN), 109.2, 110.8, 115.0 (CN), 121.3, 128.8, 129.4, 129.5,
130.1, 133.2, 133.6, 136.1 (C6H5 + C6H4), 141.8 (C-5), 156.5, 158.4, 164.9, 166.5 (CO). Anal. Calcd for
C27H24N4O3: C, 71.67; H, 5.35; N, 12.38. Found: C, 71.75; H, 5.46; N, 12.24.
3-Cyano-2-ethoxy-6-ethoxycarbonyl-4-phenyl-7-N-(4-chlorophenyl)amino-1,8-naphthyridine (7c) (80%):
mp 299-301 ºC (EtOH). IR (KBr, cm-1) ν = 3250 (NH), 2990, 2210 (CN), 1700 (CO), 1610, 1580, 1560.
MS (EI, m/z %) = 474 (M+ + 2, 24), 473 (M+ + 1, 46), 472 (M+, 68), 471 (100), 425 (11), 397 (24), 371
(16). 1H NMR (CDCl3) δ = 1.32 (t, 3H, J = 7.1 Hz, CH3); 1.54 (t, 3H, J = 7.1 Hz, CH3); 4.34 (q, 2H, J =
7.1 Hz, OCH2); 4.75 (q, 2H, J = 7.1 Hz, OCH2); 7.37, 7.89 (AA’XX’ system, 4H, J = 8.8 Hz, C6H4);
7.33-7.90 (m, 5H, C6H5); 8.48 (s, 1H, H-5); 10.70 (br s, 1H, NH) ppm. 13C NMR (CDCl3) δ = 14.0 (CH3),
14.4 (CH3), 62.0 (CH2), 64.2 (CH2), 95.2 (C-CN), 109.2, 111.1, 114.8 (CN), 122.2, 128.9, 129.4, 130.2,
133.0, 137.3 (C6H4 + C6H5), 141.9 (C-5), 156.2, 158.1, 158.5 (C-Cl), 165.0, 166.4 (CO). Anal. Calcd for
C26H21N4O3Cl: C, 66.03; H, 4.48; Cl, 7.50; N, 11.85. Found: C, 65.95; H, 4.59; Cl, 7.78; N, 11.64.
3-Cyano-2-ethoxy-6-ethoxycarbonyl-4-phenyl-7-N-(4-methoxyphenyl)amino-1,8-naphthyridine
(7d)
(87%): mp 203-205 ºC (EtOH). IR (KBr, cm-1) ν = 3250 (NH), 2990, 2210 (CN), 1700 (CO), 1600, 1580,
1550. MS (EI, m/z %) = 469 (M+ + 1, 30), 468 (M+, 100), 467 (82), 421 (12), 393 (13), 365 (15). 1H NMR

HETEROCYCLES, Vol. 68, No. 2, 2006
303
(CDCl3) δ = 1.31 (t, 3H, J = 7.1 Hz, CH3); 1.51 (t, 3H, J = 7.1, CH3); 3.84 (s, 3H, OCH3); 4.34 (q, 2H, J =
7.1 Hz, OCH2); 4.74 (q, 2H, J = 7.1 Hz, OCH2); 6.96, 7.80 (AA’XX’ system, 4H, J = 9.0 Hz, C6H4); 7.45-
7.64 (m, 5H, C6H5); 8.45 (s, 1H, H-5); 10.51 (br s, 1H, NH) ppm. 13C NMR (CDCl3) δ = 14.0 (CH3), 14.4
(CH3), 55.5 (OCH3), 61.8 (CH2), 64.0 (CH2), 109.2, 115.0 (CN), 114.2, 122.8, 128.8, 129.4, 129.5, 130.1,
133.2 (C6H5 + C6H4), 141.8 (C-5), 156.5, 158.5, 166.5 (CO). Anal. Calcd for C27H24N4O4: C, 69.22; H,
5.16; N, 11.96. Found: C, 69.05; H, 5.16; N, 12.04.
3,6-Dicyano-2-ethoxy-4-methyl-1,8-naphthyridines (8a-d); General Procedure:
To a stirred solution of iminophosphorane (5) (0.15 g, 0.27 mmol) in dry toluene (6 mL) was added the
appropriate aromatic isocyanate (1.36 mmol) under argon and the reaction mixture was heated at reflux
for 3-8 h (TLC monitored). After cooling, the precipitate obtained was filtered off and recrystallized from
ethanol/CH2Cl2.
3,6-Dicyano-2-ethoxy-4-phenyl-7-N-phenylamino-1,8-naphthyridine (8a) (60%): mp 302-304 ºC. IR
(KBr, cm-1) ν = 3280 (NH), 2220 (CN), 1610, 1600, 1580, 1550. MS (EI, m/z %) = 391 (M+, 62), 390 (96),
362 (100), 189 (10), 182 (18). 1H NMR (CDCl3) δ = 1.53 (t, 3H, J = 7.1 Hz, CH3); 4.76 (q, 2H, J = 7.1 Hz,
OCH2); 7.12-7.83 (m, 11H, NH + 2C6H5); 8.06 (s, 1H, H-5) ppm. 13C NMR (CDCl3) δ = 14.3 (CH3), 64.5
(CH2), 95.2 (C-CN), 96.3 (C-CN), 111.2, 114.3 (CN), 115.4 (CN), 121.3, 125.2, 129.1, 129.3, 130.6,
132.4, 137.4 (C6H5), 143.6 (C-5), 155.8, 157.8, 165.1. Anal. Calcd for C24H16N5O: C, 73.64; H, 4.38; N,
17.89. Found: C, 73.75; H, 4.56; N, 17.62.
3,6-Dicyano-2-ethoxy-4-phenyl-7-N-(4-methylphenyl)amino-1,8-naphthyridine (8b) (63%): mp 280-282
ºC. IR (KBr, cm-1) ν = 3330 (NH), 2210 (CN), 1640, 1600, 1580, 1560. MS (EI, m/z %) = 405 (M+, 85),
1
376 (100), 253 (16), 239 (19), 189 (34), 173 (14). H NMR (CDCl3) δ = 1.52 (t, 3H, J = 7.1 Hz, CH3);
2.38 (s, 3H, CH3); 4.73 (q, 2H, J = 7.1 Hz, OCH2); 7.14-7.68 (m, 10H, NH + C6H5 + C6H4); 8.03 (s, 1H,
13
H-5) ppm. C NMR (CDCl3) δ = 14.3 (CH3), 21.0 (CH3), 64.5 (CH2), 95.1 (C-CN), 96.1 (C-CN), 111.1,
114.3 (CN), 115.4 (CN), 121.6, 129.1, 129,2, 129.8, 130.5, 132.0, 132.5, 134.8, 135.1, 135.4 (C6H5),
143.6 (C-5), 155.6, 157.8, 165.0. Anal. Calcd for C25H19N5O: C, 74.06; H, 4.72; N, 17.27. Found: C,
73.85; H, 4.86; N, 17.44.
3,6-Dicyano-2-ethoxy-4-phenyl-7-N-(4-chlorophenyl)amino-1,8-naphthyridine (8c) (85%): mp 276-278
ºC. IR (KBr, cm-1) ν = 3330 (NH), 2220 (CN), 1630, 1580, 1550, 1490. MS (EI, m/z %) = 427 (M+ + 2,
29), 426 (M+ + 1, 45), 425 (M+, 87), 424 (88), 398 (35), 396 (100). 1H NMR (CDCl3) δ = 1.54 (t, 3H, J =
7.1 Hz, CH3); 2.38 (s, 3H, CH3); 4.75 (q, 2H, J = 7.1 Hz, OCH2); 7.37-7.80 (m, 10H, NH + C6H5 + C6H4);
8.07 (s, 1H, H-5) ppm. 13C NMR (CDCl3) δ = 14.3 (CH3), 64.6 (CH2), 95.1 (C-CN), 96.1 (C-CN), 111.4,
114.2 (CN), 115.3 (CN), 122.5, 129.1, 129,3, 130.2, 130.6, 132.3, 136.0 (C6H5), 143.6 (C-5), 155.2, 157.5,
158.0 C-Cl). Anal. Calcd for C24H16N5OCl: C, 67.69; H, 3.79; Cl, 8.32; N, 16.44. Found: C, 67.85; H,
3.86; Cl, 8,10; N, 16.27.

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3,6-Dicyano-2-ethoxy-4-phenyl-7-N-(4-methoxyphenyl)amino-1,8-naphthyridine (8d) (60%): mp 218-
220 ºC. IR (KBr, cm-1) ν = 3300 (NH), 2210 (CN), 1600, 1580, 1550. MS (FAB, m/z %) = 422 [(MH+,
47)], 394 (26), 367 (13), 291 (100), 288 (11). 1H NMR (CDCl3) δ = 1.51 (t, 3H, J = 7.1 Hz, CH3); 3.85 (s,
3H, OCH3); 4.73 (q, 2H, J = 7.1 Hz, OCH2); 6.98, 7.64 (AA’XX’ system, 4H, J = 9.3 Hz, C6H4); 7.40-
7.64 (m, 6H, NH + C6H5); 8.03 (s, 1H, H-5) ppm. Anal. Calcd for C25H19N5O2: C, 71.25; H, 4.54; N, 16.62.
Found: C, 71.55; H, 4.86; N, 16.24.
ACKNOWLEDGEMENTS
Financial support from Ministerio de Educación y Cultura and Xunta de Galicia (BQU2003-00754 and
PGIDIT04PXIC10307PN) is gratefully acknowledged
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