Practical synthesis of 8-acyl-7-alkyl-1,6-naphthyridin-5(6H)-ones

Article abstract of DOI:10.1016/S0040-4020(02)01028-1

Reaction of a set of enaminones with 2-chloronicotinoyl chloride or 2,6-dichloro-5-fluoronicotinoyl chloride mainly leads to N-acylation products which cyclize directly or reacting with sodium hydride to give 8-acyl-7-alkyl-1,6-naphthyridin-5(6H)-ones. Due to their easy availability these compounds are attractive precursors for synthesis of polycondensed heterocycles like naphtho[2,3-h][1,6]naphthyridin-5-ones and pyrido[3,2-c][1,6]naphthyridin-6-ones.

Full text of DOI:10.1016/S0040-4020(02)01028-1

Tetrahedron 58 (2002) 8543–8551
Practical synthesis of 8-acyl-7-alkyl-1,6-naphthyridin-5(6H)-ones
*
Magali Vales, Vladimir Lokshin, Gerard Pepe, Robert Guglielmetti and Andre Samat
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Faculte des Sciences de Luminy, Universite de la Mediterranee, UMR 6114 CNRS, Case 901, 13288 Marseille Cedex 9, France
Received 3 June 2002; revised 24 July 2002; accepted 13 August 2002
Abstract—Reaction of a set of enaminones with 2-chloronicotinoyl chloride or 2,6-dichloro-5-fluoronicotinoyl chloride mainly leads to
N-acylation products which cyclize directly or reacting with sodium hydride to give 8-acyl-7-alkyl-1,6-naphthyridin-5(6H)-ones. Due to
their easy availability these compounds are attractive precursors for synthesis of polycondensed heterocycles like naphtho[2,3-
h][1,6]naphthyridin-5-ones and pyrido[3,2-c][1,6]naphthyridin-6-ones. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
8-acyl-7-alkyl-1,6-naphthyridin-5-ones (4) and N-acylated
enaminones (5) (Scheme 1).
1,6-Naphthyridin-5(6H)-ones are an important class of
azaheterocycles regarding their various biological
activity.1–4 On the other hand, these compounds can be
used as synthons for the building of enlarged heterocyclic
systems when they are conveniently substituted.5,6
Nevertheless, it can be noticed that the formation of whole
these compounds during a single reaction is not observed as
shown in Table 1. In half of the cases, a single product is
isolated (entries 1–3, 6, 9 and 10); in the others cases, a
mixture of two compounds, easily separated, is obtained
(entries 4, 5, 8, 9, 11, 12). Total yield in the different
products depends on the substitution of the nicotinoyl
chloride: it is low with 1b, but moderate to good with 1a.
The structure of compounds 3–5 have been established by
1H and 13C NMR and elemental analysis. Moreover, X-ray
crystallography data have confirmed the structure of 4bg
(Fig. 1).
The preparation of 1,6-naphthyridin-5(6H)-ones is rela-
tively well documented1,2,7–9 but few methods allow
the functionalisation with keto groups like acetyl or
benzoyl.10,11
We published recently12 a synthetic approach of benzoyl
substituted quinolin-4-ones and isoquinolin-4-ones based on
the acylation reaction of enaminones. In the present work
are reported results showing the possible application of this
method to the preparation of 8-acyl-7-alkyl-1,6-naphthy-
ridin-5(6H)-ones.
Data reported in Table 1 need some comments. Contrary to
enaminoesters which led exclusively to an a C-acylation,13,
14
enaminones 2 used in this work give mainly N-acylated
compounds (5). The cyclisation reaction of these ones in the
experimental conditions chosen depends on the structure of
the acid chloride. Compared to our previous results,
changing aromatic acid chlorides (i.e. 2,4,5-trifluoro-
benzoylchloride and 2-chloro-5-nitrobenzoylchloride)12 by
pyridinic acid chlorides 1a or 1b undergoes a complete
modification of the ratio between the three products of the
reaction. N-acylated enaminones 5 become the main
product here, while they were observed only once in the
previous work.
2. Results and discussion
2.1. Synthesis of 8-acyl-7-alkyl-1,6-naphthyridin-5(6H)-
ones
The reaction of 2-chloronicotinoyl chloride 1a or 2,6-
dichloro-5-fluoronicotinoyl chloride 1b with a series of
enaminones 2 was investigated according to the experimen-
tal procedure described previously.12
The experimental procedure has been tentatively modified
for experiments leading exclusively to compounds 5 (entries
1–3, 9, 10, Table 1). Indeed, one can reasonably assume that
the lack of cyclisation did not justify the use of two kinds of
bases. Curiously, when only one base (triethylamine or
DBU) was used, the yield in compound 5 was lower. On the
other hand, the classical acylation reaction in pyridine led to
the expected compounds like 5 only when primary
Using these conditions, three kinds of compounds were
isolated: 3-acyl-2-alkyl-1,8-naphthyridin-4-ones (3),
Keywords: acylation; enamines; naphthyridines; cyclisation.
*
Corresponding author. Tel: þ33-4-91-82-94-08; fax: þ33-4-91-82-93-
01; e-mail: lokshin@luminy.univ-mrs.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01028-1

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M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8544
Scheme 1.
All the enaminones (5) can be cyclised into naphthyridi-
nones 4 in presence of NaH in THF as solvent (Scheme 3)
(yield: 30–80%). Lower yield is observed for compounds
for which R5¼H despite an excess of sodium hydride.
Taking into account this result, the best efficient way for
preparing this kind of compound would consist in a
deprotection of the N-6 nitrogen atom. The preparation of
4aj (Scheme 4) confirms the feasibility of this approach.
Table 1. Yield for products obtained from the reaction of 1 with 2
Entry
Precursors
Products (yield, %)a
b
1
2
3
4
5
6
7
8
1a
2a
2b
2c
2d
2e
2f
2h
2i
2c
2d
2g
2h
–
–
–
–
–
–
–
5aa (48)
5ab (59)
5ac (84)
5ad (78)
5ae (71)
–
–
–
5bc (42)
5bd (37)
–
–
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
3ad (7)
3ae (26)
–
3ah (10)
3ai (13)
–
–
4af (52)
4ah (39)
4ai (47)
–
In summary, the methods proposed in this work allow
the preparation of 8-acyl-7-alkylnaphthyridin-5(6H)-ones 4
in one or two steps from simple precursors. The easy
obtention of precursors and the simplicity of the experi-
mental procedure compensate for the relatively low yield
observed.
9
10
11
12
–
–
3bg (11)
3bh (22)
4bg (14)
4bh (27)
a
Yield for isolated products.
Not observed.
b
2.2. Reaction of 8-acyl-7-alkyl-1,6-naphthyridin-5(6H)-
ones (4)
The various substitutions of the prepared naphthyridinones
4 allow different chemical transformations. Few examples
are given below (Schemes 5–8).
Then the chlorine atom of the compounds prepared from the
acid chlorides 1b (compound 4bh is taken as example) can
be easily substituted by different nucleophiles (Scheme 5).
This kind of reaction is often used in the chemistry of
antibacterial quinolones.15,16 Moreover, a classical method
based on the application of a mixture of phosphorus
oxychloride and phosphorus pentachloride5 allows the
conversion (in moderate yield) of 1,6-naphthyridin-5-ones
(R5¼H) to 1,6-naphthyridines (Scheme 6).
All the naphthyridinones 4 obtained bear acyl and alkyl
substituents placed in o-position (this is specific of the
proposed synthetic method). Then, different cyclisation
reactions implying these groups can occur. Two examples
of this kind of transformations (based on known
methods)17–19 are given in Schemes 7 and 8. The polycyclic
systems built, especially naphtho[2,3-h][1,6]naphthyridin-
5-ones (9 and 10) and pyrido[2,3-c][1,6]naphthyridin-6-
ones (13 and 14) are to the best of our knowledge not
described in the literature.
Figure 1. The ORTEP diagram of 4bg.
enaminones (2a, 2b, 2j) are used and in low yield (Scheme
2). Nevertheless, this latest approach could be interesting to
prepare 5aj which cannot be obtained using the general
method.

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M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8545
Scheme 2.
Scheme 3.
The biological activity of these compounds is now under
investigation.
3. Experimental
3.1. Materials and methods
1H and 13C NMR spectra were recorded on a Bruker BM
250 spectrometer (250 and 62.5 MHz, respectively, for H
and 13C) using tetramethylsilane as internal standard.
Scheme 4.
1
Scheme 5.
Chemical shifts are given in ppm and coupling constants
in Hz. Melting points (8C), measured in capillary tubes on a
Buchi 510 apparatus, are uncorrected. Column chromato-
graphy was performed on silica gel Merck (70–230 mesh).
Elemental analysis was performed by the Microanalytical
Center of the University of Aix-Marseille III. The
identification of previously reported compounds were
made by 1H NMR and melting points comparison with
literature data.
Scheme 6.
3.2. Starting materials
Acid chloride 1a (Avocado), 1b (Aldrich), enaminone 2a
(Lancaster) and tert-butoxy-bis(dimethylamino)methane
(Bredereck’s reagent) (Aldrich) are commercially available.
Enaminones 2h–2j were prepared from corresponding 1,3-
diketones and primary amines according to a standard
procedure.20 Compounds 2b,21 2c,22 2d,23 2e,24 2f12 and
2g25 were synthesised by the described methods.
Scheme 7.

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8546
Scheme 8.
3.2.1. 3-Benzylamino-1,4-diphenylbut-2-en-1-one (2h).
White solid (79%). Mp 988C. 1H NMR (CDCl3): 3.69
(2H, s, CH2), 4.41 (2H, s, NCH2), 5.80 (1H, s, CH), 7.18–
7.31 (10H, m, H arom), 7.43 (3H, m, H arom), 7.83 (2H, m,
H arom), 11.70 (1H, s, NH).
152.1 (d), 157.2 (s), 165.3 (s), 192.4 (s). Anal. calcd for
C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31; found C, 63.92;
H, 4.34; N, 9.30.
3.3.3. 4-[N-Propyl-N-(2-chloronicotinoyl)amino]-pent-3-
en-2-one (5ac). Rf¼0.48 (cyclohexane/EtOAc 8:2), 84%
yield, yellow oil. 1H NMR (CDCl3): 0.91 (3H, t, J¼7.5 Hz,
CH2CH2CH3), 1.50 (2H, m, CH2CH2CH3), 2.00 (3H, s,
CH3), 2.21 (3H, s, COCH3), 3.52 (2H, m, CH2CH2CH3),
6.93 (1H, s, CH), 7.12 (1H, m, H-50), 7.61 (1H, dd, J¼7.8,
1.8 Hz, H-40), 8.27 (1H, dd, J¼4.5, 1.8 Hz, H-60). 13C NMR
(CDCl3): 11.2 (q), 18.5 (q), 21.2 (t), 31.7 (q), 47.6 (t), 122.5
(d), 125.3 (d), 133.1 (s), 136.8 (d), 147.2 (s), 150.0 (d),
151.2 (s), 165.2 (s), 196.2 (s). Anal. calcd for
C14H17ClN2O2: C, 59.89; H, 6.10; N, 9.98; found C,
59.90; H, 6.11; N, 9.96.
3.2.2. 1,4-Diphenyl-3-(4-methoxybenzyl)aminobut-2-en-
1one (2i). Yellow solid (96%). Mp 1118C. 1H NMR
(CDCl3): 3.70 (2H, s, CH2), 3.82 (3H, s, OCH3), 4.31
(2H, s, NCH2), 5.69 (1H, s, CH), 6.79 (2H, d, J¼8.7 Hz, H
arom), 7.12 (2H, d, J¼8.7 Hz, H arom), 7.22–7.43 (8H, m,
H arom), 7.84 (2H, m, H arom), 11.71 (1H, s, NH).
3.2.3. 3-Amino-1,4-diphenylbut-2-en-1-one (2j). Yellow
oil (96%). 1H NMR (CDCl3): 3.69 (2H, s, CH2), 6.10 (1H, s,
CH), 7.28–7.49 (8H, m, H arom), 7.79 (2H, m, H arom),
10.21 (2H, s, NH2).
3.3.4. 4-[N-Phenyl-N-(2-chloronicotinoyl)amino]-pent-3-
en-2-one (5ad). Rf¼0.43 (cyclohexane/EtOAc 8:2), 78%
yield, yellow oil. 1H NMR (CDCl3): 1.68 (3H, s, CH3), 1.98
(3H, s, COCH3) 5.7 (1H, s, CH), 6.72–6.85 (5H, m, H
arom), 7.24 (1H, m, H-50), 7.39 (1H, dd, J¼7.9, 1.7 Hz,
H-40), 7.78 (1H, dd, J¼4.4, 1.7 Hz, H-60). 13C NMR
(CDCl3): 18.7 (q), 31.8 (q), 121.8 (d), 122.1 (d), 123.4 (s),
127.7 (d), 128.2 (d), 129.3 (d), 137.8 (d), 139.4 (s), 146.5
(s), 150.0 (d), 152.9 (s), 165.8 (s), 197.2 (s). Anal. calcd for
C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90; found: C, 64.85;
H, 4.82; N, 8.93.
3.3. General method for the synthesis of compounds 3–5
A solution of acid chloride 1 (5 mmol) in dry toluene (8 ml)
was added to a mixture of enaminone 2 (3.2 mmol) and dry
Et3N (10 mmol) in dry toluene (7 ml). The resulting mixture
was refluxed for 3 h, then DBU (10 mmol) was added and
refluxing was maintained for 3 h more. The solvent was
evaporated to dryness and the residue was dissolved in
25 ml CH2Cl2. The organic phase was washed with a
saturated solution of NH4Cl and then with brine, dried
(MgSO4) and evaporated. The crude product was purified by
column chromatography on silica gel.
3.3.5. 3-Acetyl-2-methyl-1-phenyl-1,8-naphthyridin-
4(1H)-one (3ad). Rf¼0.27 (cyclohexane/EtOAc 8:2), 7%
yield, white solid, mp 142–1438C (from methanol). 1H
NMR (CDCl3): 2.11 (3H, s, CH3), 2.72 (3H, s, COCH3),
7.21 (2H, m, H arom), 7.34 (1H, m, H-6), 7.67 (3H, m, H
arom), 8.51 (1H, dd, J¼4.5, 1.9 Hz, H-7), 8.72 (1H, dd,
J¼7.8, 1.9 Hz, H-5). 13C NMR (CDCl3): 20.3 (q), 32.5 (q),
120.6 (d), 121.1 (s), 125.0 (s), 129.1 (d), 129.6 (d), 130.2
(d), 136.7 (d), 138.9 (s), 151.8 (s), 152.7 (s), 152.9 (d), 176.3
(s), 203.7 (s). Anal. calcd for C17H14N2O2: C, 73.37; H,
5.07; N, 10.07; found C, 73.26; H, 5.01; N, 10.04.
3.3.1. 4-(2-Chloronicotinoyl)aminopent-2-en-1-one
(5aa). Rf¼0.38 (cyclohexane/EtOAc 7:3), 48% yield,
white solid, mp 86–878C (from methanol). 1H NMR
(CDCl3): 1.90 (3H, s, CH3), 2.24 (3H, s, COCH3), 5.24
(1H, s, CH), 7.10 (1H, dd, J¼7.5, 4.8 Hz, H-50), 7.67 (1H,
dd, J¼7.5, 1.8 Hz, H-40), 8.24 (1H, dd, J¼4.8, 1.8 Hz, H-60),
12.59 (1H, s, NH). 13C NMR (CDCl3): 22.6 (q), 31.3 (q),
107.9 (d), 123.3 (d), 132.5 (s), 139.0 (d), 148.7 (s), 152.1
(d), 154.9 (s), 165.1 (s), 200.8 (s). Anal. calcd for
C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74; found: C,
55.33; H, 4.61; N, 11.76.
3.3.6. 4-[N-Propyl-N-(2-chloronicotinoyl)amino]-1-
phenylbut-2-en-1-one (5ae). Rf¼0.44 (cyclohexane/EtOAc
8:2), 71% yield, white solid, mp 80–818C (from methanol).
1H NMR (CDCl3): 1.02 (3H, t, J¼7.5 Hz, CH2CH2CH3),
1.71 (2H, m, CH2CH2CH3), 2.34 (3H, s, CH3), 3.76 (2H,
m, CH2CH2CH3), 6.61 (1H, s, CH), 7.32 (1H, m, H-50),
7.41 (2H, m, H arom), 7.52 (1H, m, H arom), 07.61 (2H, m,
H arom), 7.69 (1H, dd, J¼7.6, 1.7 Hz, H-6 ), 8.34 (1H,
m, H-40). 13C NMR (CDCl3): 11.4 (q), 19.3 (q), 21.7
(t), 47.6 (t), 122.6 (d), 123.4 (s), 128.7 (d), 128.8 (d), 133.2
(d), 133.3 (d), 136.5 (d), 138.1 (s), 147.8 (s), 150.2 (d),
3.3.2. 3-(2-Chloronicotinoyl)amino-1-phenylbut-2-en-1-
one (5ab). Rf¼0.62 (cyclohexane/EtOAc 7:3), 59% yield,
white solid, mp 128–1298C (from methanol). 1H NMR
(CDCl3): 2.44 (3H, s, CH3), 6.00 (1H, s, CH), 7.16 (1H, dd,
J¼7.5, 4.8 Hz, H-50), 7.22 (2H, m, H arom), 7.33 (1H, m, H
arom), 7.69 (2H, m, H arom), 7.78 (1H, dd, J¼7.5, 1.8 Hz,
H-40), 8.31 (1H, dd, J¼4.8, 1.8 Hz, H-60), 13.12 (1H, s, NH).
13C NMR (CDCl3): 23.4 (q), 104.2 (d), 123.4 (d), 128.6 (d),
129.4 (d), 132.6 (s), 133.6 (d), 139.0 (s), 139.1 (d), 148.9 (s),

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M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8547
152.4 (s), 165.3 (s), 190.1 (s). Anal. calcd for
C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17; found C,
66.55; H, 5.60; N, 8.19.
methanol). 1H NMR (CDCl3): 3.84 (3H, s, OCH3), 3.92 (2H,
s, CH2), 5.19 (2H, s, NCH2), 6.91 (2H, dd, J¼8.7, 1.5 Hz, H
arom), 7.09 (2H, dd, J¼8.7, 1.5 Hz, H arom), 7.21–7.39
(8H, m, H arom and H-3), 7.49 (1H, m, H arom), 7.88 (2H,
m, H arom), 8.74 (1H, dd, J¼8.1, 1.8 Hz, H-4), 8.80 (1H,
dd, J¼4.6, 1.8 Hz, H-2). 13C NMR (CDCl3): 36.7 (t), 46.3
(t), 55.3 (q), 114.4 (d), 120.1 (s), 120.7 (s), 122.1 (d), 126.8
(d), 127.3 (d), 127.8 (d), 129.1 (d), 129.7 (d), 133.7 (d),
135.7 (s), 135.8 (s), 136.6 (d), 137.6 (s), 142.8 (s), 152.0 (s),
154.8 (d), 159.0 (s), 163.2 (s), 195.7 (s). Anal. calcd for
C30H24N2O3: C, 78.24; H, 5.25; N, 6.08; found C, 78.19; H,
5.20; N, 6.02.
3.3.7. 3-Benzoyl-2-methyl-1-propyl-1,8-naphthyridin-
4(1H)-one (3ae). Rf¼0.32 (cyclohexane/EtOAc 8:2), 26%
yield, white solid, mp 177–1788C (from methanol). 1H
NMR (CDCl3): 1.02 (3H, t, J¼7.3 Hz, CH2CH2CH3), 1.81
(2H, m, CH2CH2CH3), 2.44 (3H, s, CH3), 4.50 (2H, t,
J¼7.2 Hz, CH2CH2CH3), 7.21 (1H, dd, J¼7.4, 4.5 Hz,
H-6), 7.41 (2H, m, H arom), 7.54 (1H, m, H arom), 7.92
(2H, m, H arom), 8.62 (1H, dd, J¼7.4, 1.7 Hz, H-5), 8.75
(1H, dd, J¼4.4, 1.8 Hz, H-7). 13C NMR (CDCl3): 11.4 (q),
18.4 (q), 22.8 (t), 47.0 (t), 120.1 (d), 121.2 (s), 123.6 (s),
128.8 (d), 129.5 (d), 133.6 (d), 135.9 (d), 137.7 (s), 150.3
(s), 150.4 (s), 152.6 (d), 175.6 (s), 197.0 (s). Anal. calcd for
C19H18N2O2: C, 74.49; H, 5.92; N, 9.14; found C, 74.40; H,
5.89; N, 9.09.
3.3.12. 3-Benzoyl-2-benzyl-1-(4-methoxybenzyl)-1,8-
naphthyridin-4(1H)-one (3ai). Rf¼0.12 (cyclohexane/
EtOAc 8:2), 13% yield, white solid, mp 98–998C (from
methanol). 1H NMR (CDCl3): 3.81 (5H, s, OCH3 and CH2),
4.01 (2H, s, NCH2), 6.81 (2H, dd, J¼8.7, 2.1 Hz, H arom),
6.92 (2H, dd, J¼8.7, 2.1 Hz, H arom), 7.19–7.49 (9H, m, H
arom and H-6), 7.88 (2H, m, H arom), 8.70 (2H, m, H-5 and
H-7). 13C NMR (CDCl3): 37.0 (t), 47.1 (t), 55.4 (q), 114.6
(d), 120.6 (d), 121.1 (s), 125.5 (s), 126.9 (d), 127.4 (d),
128.1 (d), 128.8 (d), 129.2 (d), 129.5 (d), 133.5 (d), 135.6
(s), 135.7 (s), 136.2 (d), 137.5 (s), 151.0 (s), 152.0 (s), 153.0
(d), 159.2 (s), 176.2 (s), 196.0 (s). Anal. calcd for
C30H24N2O3: C, 78.24; H, 5.25; N, 6.08; found C, 78.18;
H, 5.19; N, 5.99.
3.3.8. 8-Benzoyl-7-benzyl-6-propyl-1,6-naphthyridin-
5(6H)-one (4af). Rf¼0.35 (cyclohexane/EtOAc 8:2), 52%
yield, white solid, mp 167–1688C (from methanol). 1H
NMR (CDCl3): 0.92 (3H, t, J¼7.4 Hz, CH2CH2CH3), 1.61
(2H, m, CH2CH2CH3), 3.88 (2H, t, J¼7.8 Hz, CH2CH2-
CH3), 4.01 (2H, s, CH2), 7.25 (5H, m, H arom), 7.40 (3H, m,
H arom and H-3), 7.54 (1H, m, H arom), 7.89 (2H, m, H
arom), 8.68 (1H, dd, J¼8.0, 1.5 Hz, H-4), 8.77 (1H, dd,
J¼3.8, 1.5 Hz, H-2). 13C NMR (CDCl3): 11.3 (q), 22.0 (t),
37.0 (t), 46.4 (t), 120.1 (s), 120.2 (s), 121.9 (d), 127.2 (d),
128.0 (d), 128.7 (d), 129.0 (d), 129.7 (d), 133.7 (d), 135.9
(s), 136.2 (d), 137.7 (s), 142.4 (s), 151.8 (s), 154.6 (d), 162.7
(s), 196.1 (s). Anal. calcd for C25H22N2O2: C, 78.51; H,
5.80; N, 7.32; found C, 78.42; H, 5.71; N, 7.38.
3.3.13. 4-[N-Propyl-N-(2,5-dichloro-4-fluoronicotin-
oyl)amino]-pent-3-en-2-one (5bc). Rf¼0.50 (cyclo-
hexane/EtOAc 7:3), 42% yield, yellow oil. 1H NMR
(CDCl3): 0.87 (3H, t, J¼7.3 Hz, CH2CH2CH3), 1.57 (2H,
m, CH2CH2CH3), 1.99 (3H, s, CH3), 2.18 (3H, s, COCH3),
3.52 (2H, t, J¼7.1 Hz, CH2CH2CH3), 5.99 (1H, s, CH), 7.43
(1H, d, JHF¼6.9 Hz, H-40). 13C NMR (CDCl3): 10.9 (q),
18.2 (t), 20.9 (t), 31.6 (q), 47.6 (t), 125.0 (d, 2JCF¼24.8 Hz),
3.3.9. 8-Benzoyl-6,7-dibenzyl-1,6-naphthyridin-5(6H)-
one (4ah). Rf¼0.53 (cyclohexane/EtOAc 8:2), 39% yield,
white solid, mp 134–1358C (from methanol). 1H NMR
(CDCl3): 3.81 (2H, s, CH2), 5.22 (2H, s, NCH2), 7.09–7.44
(13H, m, H arom and H-3), 7.52 (1H, m, H arom), 7.89 (2H,
m, H arom), 8.74 (1H, dd, J¼8.0, 1.8 Hz, H-4), 8.79 (1H,
dd, J¼4.5, 1.8 Hz, H-2). 13C NMR (CDCl3): 37.0 (t), 47.0
(t), 120.3 (s), 120.9 (s), 122.3 (d), 126.0 (d), 127.5 (d), 127.7
(d), 128.0 (d), 129.2 (d), 129.3 (d), 129.9 (d), 133.9 (d),
135.7 (s), 135.9 (s), 136.8 (d), 137.8 (s), 142.9 (s), 152.2 (s),
155.1 (d), 163.3 (s), 195.7 (s). Anal. calcd for C29H22N2O2:
C, 80.91; H, 5.15; N, 6.51; found C, 80.82; H, 5.09; N, 6.43.
2
125.4 (d), 133.1 (s), 137.7 (s, JCF¼21.4 Hz), 140.3 (s,
1
3JCF¼3.7 Hz), 150.7 (s), 153.5 (s, JCF¼263.4 Hz), 162.7
(s), 196.5 (s). Anal. calcd for C14H15Cl2FN2O2: C, 50.47; H,
4.54; N, 8.41; found C, 50.49; H, 4.55; N, 8.44.
3.3.14. 4-[N-Phenyl-N-(2,5-dichloro-4-fluoronicotin-
oyl)amino]-pent-3-en-2-one (5bd). Rf¼0.51 (cyclo-
hexane/EtOAc 7:3), 37% yield, yellow oil. 1H NMR
(CDCl3): 2.04 (3H, s, CH3), 2.31 (3H, s, COCH3), 6.11
(1H, s, CH), 7.12–7.26 (5H, m, H arom), 7.50 (1H, d,
JHF¼7.0 Hz, H-40). 13C NMR (CDCl3): 19.0 (q), 32.3 (q),
2
3.3.10. 3-Benzoyl-1,2-dibenzyl-1,8-naphthyridin-4(1H)-
one (3ah). Rf¼0.35 (cyclohexane/EtOAc 8:2), 10% yield,
white solid, mp 154–1558C (from methanol). 1H NMR
(CDCl3): 3.96 (2H, s, CH2), 5.70 (2H, s, NCH2), 7.00 (2H,
m, H arom), 7.21–7.49 (13H, m, H arom, H-6 and H-7),
7.91 (2H, m, H arom), 8.70 (1H, dd, J¼8.1, 1.7 Hz, H-5).
13C NMR (CDCl3): 37.1 (t), 47.5 (t), 120.6 (d), 121.1 (s),
125.5 (s), 127.4 (d), 127.7 (d), 128.1 (d), 128.7 (d), 129.2
(d), 129.5 (d), 133.6 (d), 135.5 (s), 136.3 (d), 136.9 (s),
137.5 (s), 151.0 (s), 151.9 (s), 153.0 (d), 176.2 (s), 195.9 (s).
Anal. calcd for C29H22N2O2: C, 80.91; H, 5.15; N, 6.51;
found C, 80.83; H, 5.10; N, 6.49.
126.5 (d, JCF¼22.3 Hz), 127.3 (d), 128.0 (d), 129.0 (d),
2
129.9 (d), 133.1 (s), 138.7 (s, JCF¼16.0 Hz), 139.4 (s),
140.4 (s, 3JCF¼3.8 Hz), 153.2 (s), 153.6 (s, 1JCF¼264.1 Hz),
163.8 (s), 197.5 (s). Anal. calcd for C17H13Cl2FN2O2:
C, 55.60; H, 3.57; N, 7.63; found C, 55.62; H, 3.59; N,
7.60.
3.3.15. 8-Benzoyl-7-benzyl-2-chloro-3-fluoro-6-phenyl-
1,6-naphthyridin-5(6H)-one (4bg). Rf¼0.75 (CH2Cl2/
pentane 9:1), 14% yield, white solid, mp 157–1588C
1
(from methanol). H NMR (CDCl3): 3.70 (2H, s, CH2),
6.69 (2H, m, H arom), 6.82 (2H, m, H arom), 7.00 (3H, m, H
arom), 7.29 (3H, m, H arom), 7.42 (2H, m, H arom), 7.59
(1H, m, H arom), 7.91 (2H, m, H arom), 8.29 (1H, d,
JHF¼7.6 Hz, H-4). 13C NMR (CDCl3): 37.6 (t), 118.8 (s),
121.0 (s, 3JCF¼3.3 Hz), 122.7 (d, 2JCF¼20.5 Hz), 126.9 (d),
3.3.11. 8-Benzoyl-7-benzyl-6-(4-methoxybenzyl)-1,6-
naphthyridin-5(6H)-one (4ai). Rf¼0.27 (cyclohexane/
EtOAc 8:2), 47% yield, white solid, mp 105–1068C (from

`
M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8548
128.3 (d), 128.4 (d), 128.8 (d), 129.1 (d), 129.3 (d), 129.8
(d), 134.0 (d), 135.5 (s), 136.8 (s), 137.6 (s), 144.4 (s,
4JCF¼2.1 Hz), 145.4 (s, 2JCF¼20.9 Hz), 148.1 (s), 153.1 (s,
1JCF¼263.1 Hz), 161.9 (s), 194.6 (s). Anal. calcd for
C28H18ClFN2O2: C, 71.72; H, 3.87; N, 5.97; found C,
71.69; H, 3.84; N, 5.93.
C, 72.12; H, 4.17; N, 5.80; found C, 72.07; H, 4.11; N,
5.79.
3.4. General method for primary enaminones acylation
in pyridine
A mixture of 1a (880 mg, 5 mmol) and 2 (2a, 2b, 2j)
(2.5 mmol) in dry pyridine (5 ml) was stirred at room
temperature for 5 h. The resulting solution was poured into
cold water (10 ml). The aqueous phase was acidified with
10% HCl to pH 5–6 and extracted with CH2Cl2 (2£20 ml).
The organic phase was washed with water (2£20 ml) and
brine (2£20 ml), dried (MgSO4) and evaporated. The crude
product was purified by column chromatography on silica
gel (cyclohexane/EtOAc 8:2).
Crystal data for 4bg. (C28H18ClFN2O2) Mr¼468.89,
˚
˚
orthorhombic,
a¼9.485(2) A,
b¼19.397(4) A,
3
˚
˚
c¼25.298(5) A, V¼4654.3(17) A , space group Pcab,
Z¼8, Dc¼1.338 mg m23, F(000)¼1936, m¼0.201 mm21
,
T¼293 K, umax¼26.978, 0,h,12, 0,k,24, 0,l,32,
reflections collected 3806, independent reflection 3806
(full-matrix least-squares on F 2). Atomic coordinates,
thermal parameters and bond lengths and angles have
been deposited at the Cambridge Crystallographic Data
Center as supplementary publication number CCDC
186741.
3.4.1. Compound 5aa. 32% yield. The obtained compound
has the same characteristics as those obtained by the method
discussed in Section 3.3 (cf. Section 3.3.1).
3.3.16. 3-Benzoyl-2-benzyl-7-chloro-6-fluoro-1-phenyl-
1,8-naphthyridin-4(1H)-one (3bg). Rf¼0.50 (CH2Cl2/
pentane 9:1), 11% yield, white solid, mp 132–1338C
3.4.2. Compound 5ab. 40% yield. The obtained compound
has the same characteristics as those obtained by the method
discussed in Section 3.3 (cf. Section 3.3.2).
1
(from methanol). H NMR (CDCl3): 3.81 (2H, s, CH2),
6.72 (2H, m, H arom), 6.89 (2H, m, H arom), 7.03 (3H, m, H
arom), 7.29 (2H, m, H arom), 7.44 (3H, m, H arom), 7.52
(1H, m, H arom), 7.89 (2H, m, H arom), 8.40 (1H, d,
JHF¼7.1 Hz, H-5). 13C NMR (CDCl3): 37.8 (t), 120.8 (s,
3.4.3. 3-(2-Chloronicotinoyl)amino-1,4-diphenylbut-3-
en-2-one (5aj). Rf¼0.43 (cyclohexane/EtOAc 8:2), 26%
yield, yellow oil. 1H NMR (CDCl3): 4.14 (2H, s, CH2), 6.16
(1H, s, CH), 6.99–7.37 (8H, m, H arom and H-50), 7.41 (1H,
m, H arom), 7.90 (1H, m, H arom), 8.09 (1H, dd, J¼7.7,
1.9 Hz, H-40), 8.39 (1H, dd, J¼4.8, 1.9 Hz, H-60), 13.20 (1H,
s, NH). 13C NMR (CDCl3): 44.0 (t), 121.6 (d), 122.6 (d),
125.9 (s), 128.1 (d), 128.9 (d), 129.0 (d), 129.1 (d), 129.8
(d), 133.5 (s), 133.9 (d), 136.4 (s), 141.0 (d), 142.8 (s), 150.6
(s), 152.7 (d), 162.0 (s), 195.6 (s). Anal. calcd for
C22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43; found: C,
70.10; H, 4.58; N, 7.45.
2
3JCF¼2.9 Hz), 121.9 (d, JCF¼20.5 Hz), 124.8 (s), 127.0
(d), 128.5 (d), 128.6 (d), 128.8 (d), 129.4 (d), 129.5 (d),
129.6 (d), 133.8 (d), 135.5 (s), 137.0 (s), 137.2 (s), 142.6 (s,
2JCF¼20.1 Hz), 147.2 (s, 4JCF¼2.6 Hz), 152.8 (s), 156.1 (s,
1JCF¼261.1 Hz), 175.3 (s), 195.4 (s). Anal. calcd for
C28H18ClFN2O2: C, 71.72; H, 3.87; N, 5.97; found C,
71.69; H, 3.81; N, 5.93.
3.3.17. 8-Benzoyl-2-chloro-6,7-dibenzyl-3-fluoro-1,6-
naphthyridin-5(6H)-one (4bh). Rf¼0.41 (cyclohexane/
EtOAc 8:2), 27% yield, white solid, mp 160–1618C (from
methanol). 1H NMR (CDCl3): 3.81 (2H, s, CH2), 5.21 (2H,
s, NCH2), 7.09–7.41 (12H, m, H arom), 7.49 (1H, m, H
arom), 7.82 (2H, m, H arom), 8.40 (1H, d, JHF¼7.6 Hz,
H-4). 13C NMR (CDCl3): 36.9 (t), 47.2 (t), 119.5 (s), 120.5
(s, 3JCF¼3.3 Hz), 122.9 (d, 2JCF¼20.4 Hz), 126.0 (d), 127.6
(d), 127.9 (d), 128.0 (d), 128.8 (d), 129.3 (d), 129.4 (d),
129.7 (d), 134.0 (d), 135.5 (s), 136.3 (s), 137.6 (s), 143.7 (s),
3.5. General method for cyclisation of 5 in 4
To a stirred suspension of NaH (3 mmol, 9 mmol for 5aa,
5ab and 5aj) in dry THF (5 ml) a solution of compound 5
(3 mmol) in dry THF (5 ml) was slowly added. The mixture
was refluxed for 4 h and the solvent was evaporated in
vacuo. The resulting oil was dissolved in cooled water. The
aqueous phase was acidified with 10% HCl to pH 5–6 and
extracted with CH2Cl2 (2£20 ml). The combined organic
phases were washed with water (30 ml) and brine
(2£30 ml), dried (MgSO4) and evaporated. The crude
product was purified by column chromatography on silica
gel.
2
4
145.5 (s, JCF¼20.9 Hz), 147.8 (s, JCF¼4.4 Hz), 153.1 (s,
1JCF¼263.2 Hz), 162.0 (s), 194.4 (s). Anal. calcd for
C29H20ClFN2O2: C, 72.12; H, 4.17; N, 5.80; found C,
72.13; H, 4.15; N, 5.82.
3.3.18. 3-Benzoyl-7-chloro-1,2-dibenzyl-6-fluoro-1,8-
naphthyridin-4(1H)-one (3bh). Rf¼0.37 (cyclohexane/
EtOAc 8:2), 22% yield, white solid, mp 153–1548C
3.5.1. 8-Acetyl-7-methyl-1,6-naphthyridin-5(6H)-one
(4aa). Rf¼0.32 (EtOAc/cyclohexane 8:2), 30% yield,
1
1
(from methanol). H NMR (CDCl3): 3.95 (2H, s, CH2),
white solid, mp .2508C. H NMR (DMSO-d6): 2.04 (3H,
5.60 (2H, s, NCH2), 7.01 (2H, m, H arom), 7.09–7.42 (10H,
m, H arom), 7.51 (1H, m, H arom), 7.75 (2H, m, H
arom), 8.10 (1H, d, JHF¼6.0 Hz, H-5). 13C NMR (CDCl3):
2JCF¼20.1 Hz), 125.6 (s), 127.8 (d), 128.0 (d), 128.1 (d),
128.2 (d), 129.0 (d), 129.5 (d), 129.6 (d), 129.7 (d), 134.0
(d), 135.0 (s), 136.0 (s), 136.9 (s), 142.7 (s, 2JCF¼22.3 Hz),
146.0 (s, 4JCF¼4.0 Hz), 152.1 (s), 152.2 (s, 1JCF¼260.5 Hz),
174.7 (s), 195.3 (s). Anal. calcd for C29H20ClFN2O2:
s, CH3), 2.37 (3H, s, COCH3), 7.29 (1H, dd, J¼8.1, 4.8 Hz,
H-3), 8.28 (1H, dd, J¼8.1, 1.8 Hz, H-4), 8.71 (1H, dd,
J¼4.8, 1.8 Hz, H-2), 11.57 (1H, s, NH). 13C NMR (DMSO-
d6): 18.3 (q), 30.1 (q), 119.3 (s), 120.6 (s), 122.6 (d), 136.5
(d), 143.6 (s), 153.4 (s), 155.5 (d), 163.0 (s), 203.2 (s). Anal.
calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85; found C,
65.30; H, 4.95; N, 13.82.
3
37.0 (t), 48.5 (t), 121.1 (s, JCF¼6.0 Hz), 122.1 (d,
3.5.2. 8-Benzoyl-7-methyl-1,6-naphthyridin-5(6H)-one

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M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8549
(4ab). Rf¼0.38 (EtOAc/cyclohexane 8:2), 35% yield, white
solid, mp .2508C. 1H NMR (DMSO-d6): 1.93 (3H, s, CH3),
7.21 (1H, dd, J¼8.1, 4.5 Hz, H-3), 7.29 (2H, m, H arom),
7.41 (1H, m, H arom), 7.59 (2H, m, H arom), 8.30 (1H, dd,
J¼8.1, 1.8 Hz, H-4), 8.48 (1H, dd, J¼4.5, 1.8 Hz, H-2),
11.68 (1H, s, NH). 13C NMR (DMSO-d6): 18.1 (q), 116.9
(s), 120.7 (s), 122.6 (d), 130.0 (d), 130.4 (d), 134.7 (d),
136.4 (d), 139.1 (s), 142.7 (s), 154.3 (s), 155.5 (d), 163.3 (s),
196.8 (s). Anal. calcd for C16H12N2O2: C, 72.72; H, 4.58; N,
10.60; found C, 72.69; H, 4.59; N, 10.62.
naphthyridin-5(6H)-one (4bc). Rf¼0.43 (cyclohexane/
1
EtOAc 7:3), 41% yield, white solid, mp 110–1128C. H
NMR (CDCl3): 0.94 (3H, t, J¼6.3 Hz, CH2CH2CH3), 1.62
(2H, m, CH2CH2CH3), 2.37 (3H, s, CH3), 2.56 (3H, s,
COCH3), 3.97 (2H, t, J¼7.6 Hz, CH2CH2CH3), 8.18 (1H, d,
JHF¼7.8 Hz, H-4). 13C NMR (CDCl3): 11.2 (q), 17.1 (q),
3
21.9 (t), 33.1 (q), 46.3 (t), 119.7 (s, J¼3.4 Hz), 119.8 (s),
2
2
122.5 (d, JCF¼20.1 Hz), 142.4 (s), 144.4 (s, JCF
¼
¼
2
1
20.6 Hz), 146.6 (s, JCF¼4.8 Hz), 152.3 (s, JCF
267.2 Hz), 160.8 (s), 202.6 (s). Anal. calcd for C14H14-
ClFN2O2: C, 56.67; H, 4.76; Cl, 11.95; F, 6.40; N, 9.44;
found C, 56.65; H, 4.77; Cl, 11.92; F, 6.39; N, 9.45.
3.5.3. 8-Acetyl-7-methyl-6-propyl-1,6-naphthyridin-
5(6H)-one (4ac). Rf¼0.22 (cyclohexane/EtOAc 8:2), 51%
1
yield, white solid, mp 59–618C. H NMR (CDCl3): 0.92
3.5.8. 8-Acetyl-2-chloro-3-fluoro-7-methyl-6-phenyl-1,6-
naphthyridin-5(6H)-one (4bd). Rf¼0.46 (cyclohexane/
(3H, t, J¼7.4 Hz, CH2CH2CH3), 1.61 (2H, m, CH2CH2-
CH3), 2.31 (3H, s, CH3), 2.54 (3H, s, COCH3), 3.91 (2H, t,
J¼8.0 Hz, CH2CH2CH3), 7.25 (1H, dd, J¼8.1, 4.5 Hz,
H-3), 8.52 (1H, dd, J¼8.1, 2.1 Hz, H-4), 8.74 (1H, dd,
J¼4.5, 2.2 Hz, H-2). 13C NMR (CDCl3): 11.1 (q), 16.9 (q),
21.8 (t), 33.1 (q), 45.8 (t), 119.3 (s), 121.0 (s), 121.2 (d),
135.9 (d), 140.7 (s), 150.7 (s), 153.9 (d), 161.8 (s), 203.9 (s).
Anal. calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47;
found C, 68.79; H, 6.62; N, 11.41.
1
EtOAc 7:3), 54% yield, white solid, mp 119–1208C. H
NMR (CDCl3): 1.95 (3H, s, CH3), 2.63 (3H, s, COCH3),
7.16 (2H, m, H arom), 7.40 (3H, m, H arom), 8.22 (1H, d,
JHF¼7.7 Hz, H-4). 13C NMR (CDCl3): 19.1 (q), 33.1 (q),
119.7 (s), 120.3 (s, 3JCF¼3.4 Hz), 122.8 (d, 2JCF¼20.2 Hz),
128.1 (d), 129.5 (d), 130.1 (d), 137.7 (s), 143.3 (s), 144.9 (s,
4
1
2JCF¼25.8 Hz), 147.6 (s, JCF¼4.3 Hz), 153.0 (s, JCF
¼
258.5 Hz), 161.1 (s), 202.2 (s). Anal. calcd for C17H12-
ClFN2O2: C, 61.73; H, 3.66; N, 8.47; found C, 61.72; H,
3.63; N, 8.49.
3.5.4. 8-Acetyl-7-methyl-6-phenyl-1,6-naphthyridin-
5(6H)-one (4ad). Rf¼0.45 (cyclohexane/EtOAc 8:2), 46%
1
yield, white solid, mp 91–928C. H NMR (CDCl3): 1.70
3.6. 8-Benzoyl-7-benzyl-1,6-naphthyridin-5(6H)-one
(4aj) (by deprotection reaction)
(3H, s, CH3), 2.40 (3H, s, COCH3), 6.93 (2H, m, H arom),
7.00 (1H, dd, J¼8.0, 4.6 Hz, H-3), 7.19 (3H, m, H arom),
8.22 (1H, dd, J¼8.0, 1.7 Hz, H-4), 8.62 (1H, dd, J¼4.5,
1.7 Hz, H-2). 13C NMR (CDCl3): 18.8 (q), 33.2 (q), 119.8
(s), 120.9 (s), 121.7 (d), 128.2 (d), 129.0 (d), 129.8 (d),
136.2 (d), 137.9 (s), 141.5 (s), 151.3 (s), 154.4 (d), 162.5 (s),
203.7 (s). Anal. calcd for C17H14N2O2: C, 73.37; H, 5.07; N,
10.07; found C, 73.32; H, 5.05; N, 10.04.
A solution of 4ai (120 mg, 0.26 mmol) in methanesulfonic
acid (4 ml) was stirred at room temperature for 4 h. The
resulting mixture was poured into cold water. The aqueous
phase was basified with a concentrated NaOH solution. The
precipitate formed was filtered, washed with water, dried
and purified by column chromatography on silica gel
(cyclohexane/EtOAc 1:1, Rf¼0.57 (cyclohexane/EtOAc
2:8)) to afford compound 4aj (70 mg, 78%) as a white
solid.
3.5.5. 8-Benzoyl-7-methyl-6-propyl-1,6-naphthyridin-
5(6H)-one (4ae). Rf¼0.32 (cyclohexane/EtOAc 6:4), 80%
yield, white solid, mp 156–1578C. 1H NMR (CDCl3): 1.00
(3H, t, J¼7.3 Hz, CH2CH2CH3), 1.79 (2H, m, CH2CH2-
CH3), 2.40 (3H, s, CH3), 4.14 (2H, t, J¼7.3 Hz, CH2CH2-
CH3), 7.32 (1H, m, H3), 7.39 (2H, m, H arom), 7.52 (1H, m,
H arom), 7.95 (2H, m, H arom), 8.65 (1H, dd, J¼7.9,
1.6 Hz, H-4), 8.69 (1H, dd, J¼4.6, 1.6 Hz, H-2). 13C NMR
(CDCl3): 11.4 (q), 17.8 (q), 22.1 (t), 46.0 (t), 118.5 (s), 119.6
(s), 121.5 (d), 128.8 (d), 129.7 (d), 133.7 (d), 136.2 (d),
137.8 (s), 141.8 (s), 151.8 (s), 154.5 (d), 162.4 (s), 196.6 (s).
Anal. calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14;
found C, 74.46; H, 5.90; N, 9.11.
The obtained compound has the same characteristics as
those obtained by the method discussed in Section 3.5. (cf.
Section 3.5.6).
3.6.1. 8-Benzoyl-6,7-dibenzyl-3-fluoro-2-piperidino-1,6-
naphthyridin-5(6H)-one (6). A solution of 4bf (120 mg,
0.25 mmol) and piperidine (85 mg, 1 mmol) in acetonitrile
(30 ml) was refluxed for 7 h and the solvent was evaporated.
The resulting oil was dissolved in CH2Cl2 (20 ml), washed
with water (2£30 ml), brine (2£30 ml), dried (MgSO4) and
evaporated. The crude product was purified by column
chromatography on silica gel (CH2Cl2/pentane 9:1,
Rf¼0.48) to afford compound 6 (100 mg, 75%) as a white
solid.
3.5.6. 8-Benzoyl-7-benzyl-1,6-naphthyridin-5(6H)-one
(4aj). 42% yield, white solid, mp .2508C. 1H NMR
(DMSO-d6): 4.22 (2H, s, CH2), 7.18–7.26 (5H, m, H arom),
7.31 (3H, m, H arom and H-3), 7.45 (1H, m, H arom), 7.75
(2H, m, H arom), 8.50 (1H, dd, J¼7.8, 1.8 Hz, H-4), 8.55
(1H, dd, J¼4.4, 1.8 Hz, H-2), 10.60 (1H, s, NH). 13C NMR
(DMSO-d6): 43.3 (t), 118.5 (s), 122.3 (d), 126.7 (s), 128.4
(d), 128.6 (d), 128.8 (d), 128.9 (d), 130.1 (d), 132.0 (s),
134.0 (d), 136.0 (s), 137.2 (d), 153.3 (d), 160.5 (s), 160.9 (s),
177.5 (s), 193.7 (s). Anal. calcd for C22H16N2O2: C, 77.63;
H, 4.74; N, 8.23; found C, 77.64; H, 4.70; N, 8.19.
1
Mp 100–1018C. H NMR (CDCl3): 1.21 (6H, m, CH2 of
piperido), 3.19 (4H, m, CH2 of piperido), 3.84 (2H, s, CH2),
5.20 (2H, s, NCH2), 7.02–7.29 (12H, m, H arom), 7.41 (1H,
m, H arom), 7.72 (2H, m, H arom), 7.91 (1H, d,
JHF¼14.2 Hz, H-4). 13C NMR (CDCl3): 24.9 (t), 25.9 (t),
36.7 (t), 48.4 (t), 53.7 (t), 112.7 (s, 3JCF¼3.6 Hz), 120.0 (s),
2
120.8 (d, JCF¼21.4 Hz), 126.1 (d), 127.4 (d), 127.6 (d),
128.2 (d), 128.6 (d), 129.2 (d), 129.3 (d), 129.5 (d), 133.1
(d), 136.7 (s), 137.4 (s), 139.0 (s), 143.2 (s), 148.2 (s), 148.4
3.5.7. 8-Acetyl-2-chloro-3-fluoro-7-methyl-6-propyl-1,6-

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M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8550
(s, 1JCF¼257.8 Hz), 151.3 (s, 2JCF¼7.3 Hz), 162.5 (s), 196.7
(s). Anal. calcd for C34H30FN3O2: C, 76.82; H, 5.69; N,
7.90; found C, 76.85; H, 5.65; N, 7.92.
column chromatography (silica gel, CH2Cl2, Rf¼0.8) to
afford compound 9 as a white solid (170 mg, 63%).
Mp 1598C. 1H NMR (CDCl3): 1.10 (3H, t, J¼7.5 Hz,
CH2CH2CH3), 1.93 (2H, m, CH2CH2CH3), 4.39 (2H, t,
J¼7.7 Hz, CH2CH2CH3), 7.15 (3H, m, H arom), 7.25 (1H,
m, H arom), 7.41–7.52 (5H, m, H arom), 7.80 (1H, m, H
arom), 7.94 (1H, m, H arom), 8.32 (1H, dd, J¼4.4, 1.9 Hz,
H-2), 8.61 (1H, dd, J¼7.9, 1.9 Hz, H4). 13C NMR (CDCl3):
11.6 (q), 20.5 (t), 44.8 (t), 111.4 (d), 118.5 (s), 121.9 (s),
122.1 (d), 124.9 (d), 126.2 (d), 127.3 (d), 127.5 (d), 127.8
(d), 127.9 (d), 129.4 (d), 130.1 (s), 133.9 (s), 136.0 (d),
136.1 (s), 140.9 (s), 142.3 (s), 150.9 (s), 151.6 (d), 161.3 (s).
Anal. calcd for C25H20N2O: C, 82.39; H, 5.53; N, 7.69;
found C, 82.42; H, 5.50; N, 7.67.
3.6.2. 8-Benzoyl-6,7-dibenzyl-3-fluoro-2-methoxy-1,6-
naphthyridin-5(6H)-one (7). To a stirred solution of 4bf
(120 mg, 0.25 mmol) in dry DME (10 ml) was added slowly
a 1.0 M solution of MeONa (2.5 ml, 2.5 mmol). The
mixture was stirred at room temperature for 16 h and
poured into cold water. The aqueous phase was acidified
with 10% HCl to pH 6–7 and extracted with CH2Cl2
(2£20 ml). The organic phase was washed with water
(1£20 ml), brine (2£20 ml), dried (MgSO4) and evaporated.
The crude product was purified by column chromatography
on silica gel (CH2Cl2) to afford compound 7 (110 mg, 89%)
as a white solid.
3.6.5. 6-Benzyl-12-phenylnaphto[2,3-h][1,6]naphthyri-
din-5(6H)-one (10).
1
Rf¼0.70 (CH2Cl2/pentane 8:2), mp 163–1648C. H NMR
A
solution of 4ah (108 mg,
(CDCl3): 3.40 (3H, s, OCH3), 3.81 (2H, s, CH2), 5.24 (2H, s,
NCH2), 7.02–7.32 (12H, m, H arom), 7.39 (1H, m, H arom),
7.72 (2H, m, H arom), 8.1 (1H, d, JHF¼9.9 Hz, H-4). 13C
NMR (CDCl3): 36.4 (t), 46.8 (t), 54.2 (q), 115.4 (s,
0.25 mmol) in aqueous HBr (2 ml) was heated at 1008C
for 4 h. The resulting mixture was poured into water with
ice. The aqueous phase was basified with a concentrated
NaOH solution. The precipitate formed is filtered, washed
with water, dried and purified by column chromatography
on silica gel (CH2Cl2, Rf¼0.75) to provide compound 10
(70 mg, 68%) as a white solid.
3JCF¼3.1 Hz), 119.4 (s), 120.9 (d, JCF¼17.2 Hz), 125.8
2
(d), 127.2 (d), 127.5 (d), 127.8 (d), 128.4 (d), 129.0 (d),
129.1 (d), 129.2 (d), 133.1 (d), 135.9 (s), 136.5 (s), 138.4 (s),
143.6 (s), 146.3 (s, 4JCF¼5.0 Hz), 146.6 (s, 1JCF¼261.3 Hz),
156.2 (s, 2JCF¼14.5 Hz), 162.1 (s), 195.4 (s). Anal. calcd for
C30H23FN2O3: C, 75.30; H, 4.84; N, 5.85; found C, 75.28;
H, 4.82; N, 5.89.
Mp 180–1818C. 1H NMR (CDCl3): 5.70 (2H, s, CH2),
7.09–7.43 (14H, m, H arom), 7.62 (2H, m, H arom), 8.32
(1H, dd, J¼4.4, 1.9 Hz, H-2), 8.65 (1H, dd, J¼8.0, 1.9 Hz,
H-4). 13C NMR (CDCl3): 47.4 (t), 112.8 (d), 118.6 (s), 121.9
(s), 122.4 (d), 125.2 (d), 126.4 (d), 126.7 (d), 127.5 (d),
127.55 (d), 127.6 (d), 127.9 (d), 128.1 (d), 129.2 (d), 129.5
(d), 130.4 (s), 133.9 (s), 136.4 (s), 136.5 (d), 136.6 (s), 141.0
(s), 142.4 (s), 151.4 (s), 152.1 (d), 162.1 (s). Anal. calcd for
C29H20N2O: C, 84.44; H, 4.89; N, 6.79; found C, 84.40; H,
4.86; N, 6.75.
3.6.3. 8-Benzoyl-7-benzyl-5-chloro-1,6-naphthyridine
(8). A mixture of 4aj (125 mg, 0.33 mmol) and PCl5
(100 mg, 0.47 mmol) in POCl3 (1 ml) was refluxed for one
day and the solvent was evaporated. The resulting oil was
dissolved in cold water. The aqueous phase was basified
with a saturated Na2CO3 solution to pH 7–8 and extracted
with CH2Cl2 (3£10 ml). The organic phase was washed
with water (1£20 ml), brine (2£20 ml), dried (MgSO4) and
evaporated. The crude product was purified by column
chromatography on silica gel (cyclohexane/EtOAc 8:2,
Rf¼0.41) to afford compound 8 (48 mg, 41%) as a white
solid.
3.7. Reaction of compounds 4 with Bredereck’s reagent.
General procedure
To a stirred solution of compound 4ac or 4ae (0.5 mmol) in
1,4-dioxane (5 ml), Bredereck’s reagent (0.55 mmol) was
added. The resulting mixture was heated under reflux for
5 h. After cooling to ambient temperature, the solution was
poured into water (5 ml). The red precipitate was filtered,
washed with water, dried and purified by column chroma-
tography on silica gel to provide compound 11 or 12.
Mp 158–1598C. 1H NMR (CDCl3): 4.10 (2H, s, CH2),
7.00–7.24 (5H, m, H arom), 7.32 (2H, m, H arom), 7.45
(2H, m, H arom and H-3), 7.69 (2H, m, H arom), 8.49 (1H,
dd, J¼8.5, 1.7 Hz, H-4), 8.80 (1H, dd, J¼4.4, 1.8 Hz, H-2).
13C NMR (CDCl3): 41.6 (t), 120.7 (s), 123.3 (d), 126.5 (d),
128.3 (d), 128.6 (d), 129.3 (d), 129.7 (d), 130.9 (s), 133.9
(d), 134.5 (d), 137.3 (s), 137.7 (s), 150.9 (s), 151.1 (s), 153.6
(s), 155.4 (d), 196.3 (s). Anal. calcd for C22H15ClN2O: C,
73.64; H, 4.21; N, 7.81; found C, 73.67; H, 4.18; N, 7.80.
3.7.1. 8-Acetyl-7-(2-dimethylaminovinyl)-6-propyl-1,6-
naphthyridin-5(6H)-one (11). 54% yield, red solid, mp
1298C. 1H NMR (CDCl3): 0.78 (3H, t, J¼7.2 Hz, CH2CH2-
CH3), 1.52 (2H, m, CH2CH2CH3), 2.22 (3H, s, CH3), 2.66
(6H, s, N(CH3)2), 3.88 (2H, t, J¼7.2 Hz, CH2CH2CH3),
4.57 (1H, d, J¼12.6 Hz, CHN(CH3)2), 6.37 (1H, d,
J¼12.6 Hz, CH), 7.02 (1H, dd, J¼8.1, 4.5 Hz, H-3), 8.35
(1H, dd, J¼8.1, 1.8 Hz, H-4), 8.60 (1H, dd, J¼4.5, 1.8 Hz,
H-2). 13C NMR (CDCl3): 11.5 (q), 21.1 (t), 33.1 (COCH3),
41.1 (q), 46.5 (t), 87.8 (d), 114.2 (s), 118.8 (s), 121.5 (C3),
136.9 (C4), 146.1 (s), 149.0 (d), 154.5 (s), 163.2 (s), 196.1
(s). Anal. calcd for C17H21N3O2: C, 68.20; H, 7.07; N,
14.04; found C, 68.24; H, 7.05; N, 14.01.
3.6.4. 12-Phenyl-6-propylnaphto[2,3-h][1,6]naphthyri-
din-5(6H)-one (9). A 1.0 M solution of boron tribromide
in CH2Cl2 (3 ml, 3 mmol) was added slowly to a stirred
solution of 4af (289 mg, 0.75 mmol) in CH2Cl2 (20 ml) at
2788C under a dry argon atmosphere. The solution was
allowed to warm to ambient temperature and was stirred
overnight. The resulting solution was poured into water
(30 ml). The organic phase was washed with water (30 ml)
and then with brine (30 ml), dried over MgSO4 and
concentrated in vacuo. The crude product was purified by
3.7.2. 8-Benzoyl-7-(2-dimethylaminovinyl)-6-propyl-1,6-

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M. Vales et al. / Tetrahedron 58 (2002) 8543–8551
8551
naphthyridin-5(6H)-one (12). 46% yield, red solid,
References
mp1608C. 1H NMR (CDCl3): 0.90 (3H, t, J¼7.4 Hz,
CH2CH2CH3), 1.70 (2H, m, CH2CH2CH3), 2.50 (6H, s,
N(CH3)2), 4.00 (2H, t, J¼7.4 Hz, CH2CH2CH3), 4.40 (1H,
d, J¼12.9 Hz, CHN(CH3)2), 6.39 (1H, d, J¼12.9 Hz, CH),
7.10 (1H, dd, J¼8.0, 4.5 Hz, H-3), 7.26 (2H, m, H arom),
7.39 (1H, m, H arom), 7.72 (2H, m, H arom), 8.55 (1H, dd,
J¼8.0, 1.8 Hz, H-4), 8.68 (1H, dd, J¼4.5, 1.8 Hz, H-2). 13C
NMR (CDCl3): 11.5 (q), 22.1 (t), 40.3 (q), 46.1 (t), 87.6 (d),
115.7 (s), 118.9 (s), 120.5 (C3), 128.4 (d), 129.2 (d), 132.7
(d), 136.4 (C4), 139.3 (s), 146.0 (s), 148.6 (d), 152.5 (s),
154.6 (C2), 162.7 (s), 196.4 (s). Anal. calcd for
C22H23N3O2: C, 73.11; H, 6.41; N, 11.63; found C, 73.14;
H, 6.45; N, 11.62.
1. Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ. Chem.
Rev. 2001, 70(4), 299–320, and references therein.
2. Nishiwaki, N.; Komatsu, M.; Ohshiro, Y. Synthesis 1991,
41–42, and references therein.
3. Showalter, H. D. H. (Warner-Lambert Company). US Patent 5
391 554, 1992.
4. Dondela, B.; Sliwa, W. Chem. Heterocycl. Compd (Engl.
Transl.) 2000, 36(7), 830–836.
5. Sakamoto, T.; Miura, N.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1986, 34(5), 2018–2023.
6. Jung, M. E.; Dansereau, S. M. K. Heterocycles 1994, 39(2),
767–778.
7. Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ. Chem.
Rev. 2000, 69(3), 201–220, and references therein.
8. Blanco, M.; Perillo, I. A.; Schapira, C. B. J. Heterocycl. Chem.
1999, 36, 979–984.
3.8. Synthesis of pyrido[3,2-c][1,6]naphthyridin-6(5H)-
ones. General procedure
0.5 mmol of 11 or 12 in DMF (5 ml) was added to a stirred
solution of ammonium acetate (70 mg, 1 mmol) in DMF
(5 ml). The reaction mixture was heated at 95–1008C for
5 h. The resulting solution was allowed to cool to ambient
temperature and then was poured into water (5 ml). The
precipitate formed was filtered off, washed with water and
dried to provide compounds 13 and 14.
9. Heber, D.; Stoyanov, E. V. J. Heterocycl. Chem. 2000, 37,
871–874.
10. Jhalani, V. K.; Ghalsasi, L. P.; Acharya, S. P.; Usgaonkar,
R. N. Indian J. Chem. 1989, 28B, 173–174.
11. Ohta, T.; Fujisawa, H.; Kawazome, M.; Nakai, Y.; Furukawa,
I. J. Heterocycl. Chem. 2001, 38, 159–164.
` `
12. Vales, M.; Lokshin, V.; Pepe, G.; Samat, A.; Guglielmetti, R.
Synthesis 2001, 16, 2419–2426.
3.8.1. 1-Methyl-5-propylpyrido[3,2-c][1,6]naphthyridin-
6(5H)-one (13). 69% yield, yellow solid, mp 135–1368C.
1H NMR (CDCl3): 0.88 (3H, t, J¼7.2 Hz, CH2CH2CH3),
1.62 (2H, m, CH2CH2CH3), 3.13 (3H, s, CH3), 4.10 (2H, t,
J¼7.8 Hz, CH2CH2CH3), 6.95 (1H, d, J¼5.7 Hz, H-7), 7.31
(1H, dd, J¼8.1, 4.5 Hz, H-3), 8.34 (1H, d, J¼6.0 Hz, H-8),
8.58 (1H, dd, J¼8.1, 2.1 Hz, H-4), 8.86 (1H, dd, J¼4.5,
2.1 Hz, H-2). 13C NMR (CDCl3): 12.1 (q), 21.4 (t), 30.4 (t),
45.4 (t), 108.2 (d), 115.5 (s), 122.5 (s), 123.2 (d), 137.2 (d),
145.8 (s), 149.2 (d), 151.9 (s), 153.6 (d), 161.2 (s), 162.3 (s).
Anal. calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59;
found C, 71.11; H, 5.99; N, 16.56.
13. Grohe, K.; Heitzer, H. Liebigs Ann. Chem. 1987, 29–37.
14. Grohe, K.; Heitzer, H. Liebigs Ann. Chem. 1987, 871–879.
15. Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Pihuleac,
E.; Nordeen, C. W.; Maleczka, Jr. R. E.; Pernet, A. G. J. Med.
Chem. 1985, 28, 1558–1563.
16. Uno, T.; Takamatsu, M.; Inoue, Y.; Kawahaba, Y.; Iuchi, K.;
Tsukamoto, G. Pharmazie 1987, 30, 2163–2170.
17. Singh, B.; Bacon, E. R.; Lesher, G. Y.; Robinson, S.; Pennock,
P. O.; Bode, D. C.; Pagani, E. D.; Bentley, R. G.; Connell,
M. J.; Hamel, L. T.; Silver, P. J. J. Med. Chem. 1995, 38,
2546–2550.
18. Wrobel, J.; Sredy, J.; Moxham, C.; Dietrich, A.; Li, Z.;
Sawick, D. R.; Seestaller, L.; Wu, L.; Katz, A.; Sullivan, D.;
Tio, C.; Zhang, Z. J. Med. Chem. 1999, 42, 3199–3202.
19. Vingiello, F. A.; Stevens, R. K. J. Am. Chem. Soc. 1958, 80,
5256–5257.
3.8.2. 1-Phenyl-5-propylpyrido[3,2-c][1,6]naphthyridin-
6(5H)-one (14). 65% yield, white solid, mp 1818C. 1H NMR
(CDCl3): 1.10 (3H, t, J¼7.5 Hz, CH2CH2CH3), 1.90 (2H, m,
CH2CH2CH3), 4.41 (2H, t, J¼7.8 Hz, CH2CH2CH3), 7.21
(1H, d, J¼5.0 Hz, H-7), 7.32–7.43 (6H, m, H arom and
H-3), 8.50 (1H, dd, J¼4.4, 2.6 Hz, H-2), 8.67 (1H, dd,
J¼7.1, 1.9 Hz, H4), 8.71 (1H, d, J¼4.8 Hz, H-8). 13C NMR
(CDCl3): 11.5 (q), 20.8 (t), 44.7 (t), 107.8 (d), 114.4 (s),
121.6 (s), 123.1 (d), 127.6 (d), 127.8 (d), 128.6 (d), 136.1
(d), 143.9 (s), 145.5 (s), 148.7 (d), 149.7 (s), 152.4 (d), 160.5
(s), 161.6 (s). Anal. calcd for C20H17N3O: C, 76.17; H, 5.43;
N, 13.32; found C, 76.14; H, 5.40; N, 13.29.
20. Maroni, P.; Cazaux, L.; Tisnes, P.; Zambetti, M. Bull. Soc.
Chim. Fr. 1980, 2(3–4), 179–186.
21. Valduga, C. J.; Squizani, A.; Braibante, H. S.; Braibante, M. E.
F. Synthesis 1998, 1019–1022.
22. Dabrowski, J.; Kamienska-Trela, K. J. Am. Chem. Soc. 1976,
98, 2826–2834.
23. Braibante, M. E. F.; Braibante, H. S.; Missio, L.; Andricopulo,
A. Synthesis 1994, 898–900.
24. Nishio, T.; Omote, Y. Synthesis 1980, 390–392.
25. Bol’shedvorskaya, R. L.; Pavlova, G. A.; Gavrilov, L. D.;
Alekseeva, N. V.; Vereshchagin, L. I. Zh. Org. Chem. 1972,
8(9), 1879–1884.
Acknowledgements
´
Conseil Regional PACA is gratefully acknowledged for its
financial support.