The synthesis of three new heterocycles: the pyrido[4,3 or 3,4 or 2,3-c]-1,5-naphthyridines

Article abstract of DOI:10.1016/j.tet.2006.10.046

Pyrido[4,3 or 3,4 or 2,3-c]-1,5-naphthyridines were obtained with good yields after chlorodehydroxylation and dehalogenation reactions starting from the parent pyridonaphthyridinones. These pyridonaphthyridinones were synthesized in a two-step procedure using a Suzuki cross-coupling reaction between 2-chloro-3-fluoropyridine and orthocyanopyridylboronic esters followed by a KOH-mediated anionic ring closure.

Full text of DOI:10.1016/j.tet.2006.10.046

Tetrahedron 63 (2007) 71–76
The synthesis of three new heterocycles: the
pyrido[4,3 or 3,4 or 2,3-c]-1,5-naphthyridines
a
Thomas Cailly, Frederic Fabis, Remi Legay, Hassan Oulyadi and Sylvain Rault
a
a
b
a,
*
ꢀ ꢀ
ꢀ
a
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie, U.F.R. des Sciences Pharmaceutiques,
´
Universite de Caen Basse-Normandie, 14032 Caen, France
´
Laboratoire de RMN, IRCOF, UMR 6014 CNRS, Universite de Rouen, 76821 Mont Saint Aignan, France
b
Received 19 September 2006; revised 18 October 2006; accepted 19 October 2006
Available online 13 November 2006
Abstract—Pyrido[4,3 or 3,4 or 2,3-c]-1,5-naphthyridines were obtained with good yields after chlorodehydroxylation and dehalogenation
reactions starting from the parent pyridonaphthyridinones. These pyridonaphthyridinones were synthesized in a two-step procedure using
a Suzuki cross-coupling reaction between 2-chloro-3-fluoropyridine and orthocyanopyridylboronic esters followed by a KOH-mediated
anionic ring closure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In this article we took into account our experience in the syn-
thesis of pyridylboronic acids6 and their use in the Suzuki
cross-coupling reaction to give oligopyridines,7 and more-
over, our results demonstrated that ortho-2-fluorophenylcya-
nopyridines could undergo intramolecular KOH anionic ring
closure to give benzonaphthyridinones.8 The enlargement of
these methodologies (Scheme 1) for the obtention of bipyri-
dinic systems 2 and their use in an intramolecular reaction,
allows us to describe for the first time an original route to
obtainpyridonaphthyridinones 3, which permitafter a chloro-
dehydroxylation and a dehalogenation process, an efficient
synthesis of pyridonaphthyridines 5 such as pyrido[4,3-c]-
1,5-naphthyridine 5a, pyrido[3,4-c]-1,5-naphthyridine 5b
and pyrido[2,3-c]-1,5-naphthyridine 5c.
The pyridonaphthyridines, which result from the fusion of
three pyridines without bridged nitrogen are of a difficult
chemical access and among all the 16 possible isomers
only a few publications describe the synthesis of five isomers.
Case1 and Hamada2 described the synthesis of the pyr-
ido[3,2-c]-1,5-naphthyridine by the use of a Skraup reaction
starting from aminonaphthyridines. Czuba3 also used this
strategy for the synthesis of the pyrido[2,3-c]-1,5-naphthyri-
dine. But none of these papers described a clear protocol.
Nutaitis4 used a multistep synthesis starting from 2- or
3-aminopyridine and 5-bromopyridine-3-carboxaldehyde
to obtain, with respectively 11 and 13% overall yield, the
pyrido[3,4-c]-1,7-naphthyridine and the pyrido[3,4-c]-1,8-
naphthyridine. Williams5 used a thermal reaction of bisacyl-
azido-3,30-bipyridine to obtain the pyrido[3,2-c]-1,8-naph-
thyridine via a double Curtius rearrangement. None of
these methods appear to be useable to produce pyridonaph-
thyridines as valuable scaffolds in medicinal chemistry.
2. Results and discussion
The required bipyridines 2 were synthesized by a Suzuki
cross-coupling reaction from the commercially available
KOH-mediated
N
N
N
chlorodehydroxylation
dehalogenation
anionic ring closure
N
N
N
5
CN
2
N
H
O
F
N
3
Scheme 1. Our strategy for the synthesis of some pyridonaphthyridines.
* Corresponding author. Tel.: +33 2 31 93 41 59; fax: +33 2 31 93 11 59; e-mail: sylvain.rault@unicaen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.046

72
T. Cailly et al. / Tetrahedron 63 (2007) 71–76
2-chloro-3-fluoropyridine and an orthocyanopyridylboronic
pinacol ester 1, we had recently described the synthesis.9
Unfortunately, these esters revealed an unstable profile in the
standard Suzuki cross-coupling conditions since they were
proned to protodeboronation. Begtrup’s group showed that
the use of the CuI/CsF couple as co-catalyst and base in di-
oxane at 60 ꢀC for 5 h with pyridylboronic neopentylglycol
esters favoured the cross-coupling instead of the protode-
boronation reaction (60–80% yield).10 However, when we
applied these conditions to our pinacol esters, we only recov-
ered after 5 h the unchanged starting materials. Recent re-
sults from our laboratory and others in microwave assisted
Suzuki cross-coupling11 reactions prompted us to use this
now commonly accepted routine methodology. As dioxane
is a poor microwave solvent because of its low polarity, we
used DMF to perform the reaction. The total conversion of
2-chloro-3-fluoropyridine was observed after heating for
30 min at 150 ꢀC under microwave irradiation, provided
that 2 equiv of orthocyanopyridylboronic pinacol esters
1a–c was used (Table 1).
6-ones 3 were isolated in 78–81% yield.12 They were then
submitted to a chlorodehydroxylation reaction using phos-
phorus oxychloride at 100 ꢀC for 12 h. The 6-chloropyri-
do[c]-1,5-naphthyridines 4 were easily obtained in good
yields.
In order to access to the parent pyrido[c]-1,5-naphthyridines,
the 6-chloropyrido[c]-1,5-naphthyridines 4 were submitted
to a dehalogenation reaction. Among the numerous dehalo-
genation methods, we decided to use a catalytic transfer hy-
drogenation reaction recently described by Schlosser et al.13
on chloropyridines using ammonium formate and palladium
on charcoal in alcoholic solvent. First, we tried this method-
ology with the 6-chloropyrido[4,3-c]-1,5-naphthyridine 4c.
After 12 h of stirring in MeOH with 4 equiv of ammonium
formate, the LC/MS monitoring of the reaction showed a to-
tal conversion of 4c and the formation of two products: the
expected pyrido[4,3-c]-1,5-naphthyridine 5c and a hydroge-
nated product, which could be 5,6-dihydropyrido[4,3-c]-1,5-
naphthyridine 6 (MW¼183 g molꢁ1 given by LC/MS). Our
attempts to separate this two products remained inefficient.
Compound 6 seemed to slowly oxidize into pyrido[4,3-c]-
1,5-naphthyridine 5c on silica gel or under an air oxygen.
This result prompted us to add DDQ14 to the crude mixture.
The LC/MS showed a total conversion into pyrido[4,3-c]-
1,5-naphthyridine 5c, which was isolated in a 87% yield
(Scheme 2).
The bipyridines 2 were then submitted to a KOH-mediated
anionic ring closure, which was realized under microwave
heating conditions. For 2a and 2c, the reaction required
a 10 min reaction time, whereas 30 min was needed for 2b
(Table 2). The three expected pyrido[c]-1,5-naphthyridin-
Table 1. Microwave Suzuki cross-coupling of 2-chloro-3-fluoropyridine
and orthocyanopyridylboronic pinacol ester
N
N
N
N
N
N
a
N
N
NC
b
c
CN
iv
O
B
v
N
+
N
Cl
F
N
Cl
N
N
a
O
N
N
H
i
N
c
+
b
4c
5c
6
5c 87%
F
1
2
Scheme 2. Dehalogenation of 6-chloropyrido[4,3-c]-1,5-naphthyridine 4c
into pyrido[4,3-c]-1,5-naphthyridine 5c (isolated yield). Reagents and con-
ditions: (iv) HCO2NH4 4 equiv, 10 mol % of Pd/C, MeOH, rt, 12 h and (v)
DDQ 1 equiv, DCM, rt, 1 h.
Starting materials
Products
Yields (%)
1a
1b
1c
2a
2b
2c
60a
72a
88a
Starting from 6-chloropyrido[2,3-c]-1,5-naphthyridine 4a
and using the same conditions as for 4c (Table 3, entry 1)
only unchanged starting material was recovered. By heating
the reaction mixture to reflux, the dehalogenation occurred
and the LC/MS this time showed after 3 h a total conversion
of the 6-chloropyrido[2,3-c]-1,5-naphthyridine 4a and the
a
Isolated yields. Reagents and conditions: (i) 1 equiv of aromatic halide,
2 equiv of boronic ester, 5 mol % of Pd(PPh3)4, 10 mol % of CuI, 2.5 equiv
of CsF, DMF, 150 ꢀC, sealed tube, microwave heating, 30 min.
Table 2. KOH anionic ring closure followed by chlorodehydroxylation
c
a
c
Table 3. Dehalogenation of 6-chloropyrido[2,3-c]-1,5-naphthyridine 4a
into pyrido[2,3-c]-1,5-naphthyridine 5a
NC
b
b
a
b
c
N
N
N
N
a
N
N
ii
iii
N
N
N
N
N
N
H
O
N
H
vi
Cl
N
F
+
3
2
4
N
Cl
N
N
KOH anionic ring closure
Chlorodehydroxylation
4a
5a
7
Starting materials Products Yields (%) Products
Yields (%)
Entry
Temperature
HCO2NH4
(equiv)
Time
(h)
5a Yields
(%)
7 Yields
(%)
2a
2b
2c
3a
3b
3c
81a
4a
4b
4c
76a
73a
72a
78a,b
80a
1
2
3
rt
4
4
1
12
3
24
0
0
46a
0
Reflux
Reflux
24a
81a
a
Isolated yields.
b
Reaction time increased to 30 min. Reagents and conditions: (ii) KOH
5 equiv, MeOH, 150 ꢀC, sealed tube, microwave heating, 10 min and
(iii) POCl3, 100 ꢀC, 12 h.
a
Isolated yields. Reagents and conditions: (vi) HCO2NH4, 10 mol % of
Pd/C, MeOH.

T. Cailly et al. / Tetrahedron 63 (2007) 71–76
73
formation of two products, the expected pyrido[2,3-c]-1,5-
naphthyridine 5a, and a product of molecular weight
185 g molꢁ1. After purification, classical NMR experiments
revealed that our unknown product was 7,8,9,10-tetrahydro-
pyrido[2,3-c]-1,5-naphthyridine 7 or 1,2,3,4-tetrahydropyr-
ido[2,3-c]-1,5-naphthyridine 8. HMBC NMR experiment
showed two common proton–carbon (2J–3J) correlations
between two quaternary carbons and protons H6 and H10 or
H4. Only one quaternary carbon can present this correlation
for compound 8 (Scheme 3). Our unknown structure was
7,8,9,10-tetrahydropyrido[2,3-c]-1,5-naphthyridine 7 (Table
3, entry 2).
4a–c could be interesting building blocks for the obtention
of new 6-substituted pyrido[c]-1,5-naphthyridines with great
potential interest in medicinal chemistry. Our studies also
revealed noticeable differences in the reactivity among the
three structures. In the future, our methodology should be ap-
plied to the synthesis of new isomers of pyridonaphthyridines
and we plan to extend this method to other heterocyclic
systems.
4. Experimental section
4.1. General
H10
H10
Melting points were determined on a Kofler melting point ap-
paratus. IR spectrum was recorded with a Perkin Elmer BX
FT-IR. 1H and 13C NMR spectra were recorded, respectively,
at 400 and 100 MHz with a Jeol Lambda 400 NMR spectro-
meter except for 5a, 5b and 5c for which the spectrometers
are mentioned in the Section 4.8. The microwave reactions
were performed using a Biotage Initiator microwave oven.
Temperature was measured with an IR-sensor and reaction
is given as hold times.
H
N
NH
H6
N
N
N
N
H6
H4
H4
7
8
Scheme 3. Comparison of possible common proton–carbon (2J–3J) correla-
tions for H6 and H9 or H4.
In order to avoid the formation of 7,8,9,10-tetrahydropyr-
ido[2,3-c]-1,5-naphthyridine 7, we postulated that the for-
mation of this compound was more difficult regarding to
the dehalogenation reaction. So, we decided to exploit this
difference by reacting 6-chloropyrido[2,3-c]-1,5-naphthyr-
idine 4a with 1 equiv of ammonium formate (Table 3, entry
3). The LC/MS monitoring showed after 24 h the total
conversion of 4a into 5a and the absence of 7. Pyrido[2,3-
c]-1,5-naphthyridine 5a was isolated with a 81% yield.
4.2. General procedure for Suzuki cross-coupling
In a microwave vial was introduced a magnetic stir bar, CsF
(2.0 g, 12.9 mmol), the chosen orthocyanopyridylboronic
ester(2.4 g, 10.5 mmol), CuI (0.1 g, 0.5 mmol)andPd(PPh3)4
(0.3 g, 0.25 mmol). The vial was sealed and purged with
argon through the septum inlet. A solution of 2-chloro-3-
fluoropyridine (0.68 g, 5.2 mmol) was degassed with argon
and added with a syringe through the vial’s septum. The sus-
pension was then heated at 150 ꢀC for 30 min. The resulting
mixture was poured into 75 mL of water and extracted three
times with 100 mL of EtOAc. The combined organic layers
were washed three times with 50 mL of brine, dried with
MgSO4, filtered and evaporated. The crude product was
then purified by silica gel chromatography.
Finally, 6-chloropyrido[3,4-c]-1,5-naphthyridine 4b was
submitted to these latter conditions. The reaction this time
was achieved in 3 h and afforded the pyrido[3,4-c]-1,5-naph-
thyridine 5b in a high 86% yield (Scheme 4). The use of these
conditions with the 6-chloropyrido[4,3-c]-1,5-naphthyridine
4c did not permit to obtain the expected pyrido[4,3-c]-1,5-
naphthyridine 5c without the formation of the hydrogenated
compound 6. The best conditions for 4c remains the use of
4 equiv of ammonium formate (Scheme 2) allowing the total
conversion of the starting material and to isolate the
pyrido[4,3-c]-1,5-naphthyridine 5c with a good yield.
4.2.1. 3-Fluoro-2,30-bipyridine-20-carbonitrile 2a. Start-
ing from 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
pyridine-2-carbonitrile 1a, following the general procedure
and using DCM and DCM/EtOAc (8/2) as eluents for the col-
umn chromatography, the product was obtained as a yellow
powder (0.90 g, 88%). Mp 91 ꢀC; IR (KBr) 3079, 2925,
2239 (CN), 1637, 1594, 1581, 1466, 1450, 1431, 1413, 1407,
1263, 1250, 1195, 1174, 1096, 1069, 1019, 812, 771, 685,
N
N
N
N
1
581, 555 cmꢁ1; H NMR (400 MHz, CDCl3) d¼7.46–7.50
vii
86%
(m, 1H), 7.61–7.66 (m, 2H), 8.09 (dt, J¼8.1 Hz, 1.3 Hz,
N
4b
Cl
N
5b
3
1H), 8.63 (dt, J¼4.6 Hz, 1.4 Hz, 1H), 8.75 (dd, J¼8.8 Hz,
4J¼1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d¼116.3,
124.5 (d, J¼19 Hz), 126.1 (d, J¼4 Hz), 126.3, 133.3 (d,
J¼2 Hz), 135.7 (d, J¼5 Hz), 138.8 (d, J¼3 Hz), 141.7 (d, J¼
Scheme 4. Dehalogenation of 6-chloropyrido[3,4-c]-1,5-naphthyridine 4b
into pyrido[3,4-c]-1,5-naphthyridine 5b (isolated yield). Reagents and con-
ditions: (vii) HCO2NH4 1 equiv, 10 mol % of Pd/C, MeOH, reflux, 3 h.
1
12 Hz), 146.1 (d, J¼5 Hz), 150.7, 157.4 (d, J¼260 Hz);
HRMS/EI (g molꢁ1) calcd for C11H6FN3 199.0546, found
199.0554.
3. Conclusion
In conclusion, we have established that KOH-mediated ring
closure allows the generation of new pyridine based hetero-
tricyclic structures such as the parent pyridonaphthyridines.
To our knowledge, all the synthesized intermediates are
new. Moreover, the 6-chloropyrido[c]-1,5-naphthyridines
4.2.2. 3-Fluoro-2,40-bipyridine-30-carbonitrile 2b. Start-
ing from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
nicotinonitrile 1b, following the general procedure and
using DCM and DCM/EtOAc (9/1) as eluents for the column
chromatography, the product was obtained as a yellow

74
T. Cailly et al. / Tetrahedron 63 (2007) 71–76
powder (0.52 g, 72%). Mp 102 ꢀC; IR (KBr) 3072, 2225
(CN), 1584, 1544, 1432, 1403, 1249, 1183, 1099, 1064,
3014, 2953, 2885, 1687 (CO), 1678, 1604, 1593, 1502,
1480, 1462, 1415, 1355, 1280, 1121, 1031, 910, 845, 810,
1
842, 801, 733, 702, 624, 587, 552, 508, 557 cmꢁ1
;
1H
672, 643 cmꢁ1; H NMR (400 MHz, DMSO) d¼7.64 (dd,
NMR (400 MHz, CDCl3) d¼7.48–7.53 (m, 1H), 7.61–7.66
3J¼8.3 Hz, 3J¼4.4 Hz, 1H), 7.75 (dd, 3J¼8.3 Hz, 4J¼
0.9 Hz, 1H), 8.52 (d, 3J¼5.3 Hz, 1H), 8.60 (dd, 3J¼4.4 Hz,
4J¼0.9 Hz, 1H), 8.98 (d, 3J¼5.3 Hz, 1H), 9.44 (s, 1H),
11.99 (br s, 1H); 13C NMR (100 MHz, DMSO) d¼115.8,
121.5, 123.7, 126.0, 133.1, 134.5, 140.9, 144.3, 149.7,
151.9, 159.6; HRMS/EI (g molꢁ1) calcd for C11H7N3O
197.0589, found 197.0592.
(m, 1H), 7.72 (d, 3J¼5.1 Hz, 1H), 8.64 (dt, J¼4.6 Hz,
3
1.5 Hz, 1H), 8.91 (d, J¼5.1 Hz, 1H), 9.04 (s, 1H); 13C
NMR (100 MHz, CDCl3) d¼109.4, 115.9, 124.2 (d,
J¼5 Hz), 124.8 (d, J¼19 Hz), 126.6 (d, J¼4 Hz), 141.3 (d,
J¼12 Hz), 145.5 (d, J¼5 Hz), 146.6 (d, J¼5 Hz), 152.7,
153.9, 157.3 (d, 1J¼261 Hz); HRMS/EI (g molꢁ1) calcd for
C11H6FN3 199.0546, found 199.0532.
4.3.3. Pyrido[4,3-c]-1,5-naphthyridin-6(5H)-one 3c.
Starting from 2c and following the general procedure the
product was obtained as a white powder (0.4 g, 80%). Mp
>260 ꢀC; IR (KBr) 3018, 2924, 2860, 1669 (CO), 1553,
1474, 1359, 1303, 1275, 1186, 1110, 1014, 910, 848, 808,
4.2.3. 3-Fluoro-2,30-bipyridine-40-carbonitrile 2c. Start-
ing from 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
isonicotinonitrile 1c, following the general procedure and
using DCM and DCM/EtOAc (9/1) as eluents for the column
chromatography, the product was obtained as a yellow pow-
der (0.62 g, 60%). Mp 92 ꢀC; IR (KBr) 3073, 2233 (CN),
1593, 1583, 1493, 1434, 1407, 1253, 1217, 1184, 1077,
754, 693, 681, 638, 578 cmꢁ1 1H NMR (400 MHz,
;
DMSO) d¼7.55 (dd, 3J¼8.3 Hz, 3J¼4.4 Hz, 1H), 7.74 (dd,
4
3
3J¼8.3 Hz, J¼1.4 Hz, 1H), 8.10 (d, J¼5.1 Hz, 1H), 8.57
1
3
4
3
845, 816, 803, 773, 740, 637, 590, 557 cmꢁ1; H NMR
(dd, J¼4.4 Hz, J¼1.4 Hz, 1H), 8.90 (d, J¼5.1 Hz, 1H),
9.97 (s, 1H), 12.08 (br s, 1H); 13C NMR (100 MHz,
DMSO) d¼119.4, 123.7, 125.0, 128.7, 132.4, 133.2, 133.8,
144.4, 146.5, 149.3, 159.3; HRMS/EI (g molꢁ1) calcd for
C11H7N3O 197.0589, found 197.0585.
(400 MHz, CDCl3) d¼7.47–7.51 (m, 1H), 7.62–7.67 (m,
3
1H), 7.71 (d, J¼4.6 Hz, 1H), 8.65 (dt, J¼4.6 Hz, 1.4 Hz,
1
1H), 8.86 (br s, 1H), 9.09 (br s, 1H); H NMR (400 MHz,
DMSO) d¼7.66–7.71 (m, 1H), 7.98–8.03 (m, 1H), 8.06 (d,
3J¼5.1 Hz, 1H), 8.65 (dt, J¼4.4 Hz, 1.4 Hz, 1H), 8.93
(d, 3J¼5.1 Hz, 1H), 9.06 (s, 1H); 13C NMR (100 MHz,
DMSO) d¼115.7, 119.2, 124.9 (d, J¼20 Hz), 126.8, 126.83,
126.88, 131.6 (d, J¼5 Hz), 140.5 (d, J¼13 Hz), 146.3 (d,
J¼5 Hz), 150.9 (d, J¼4 Hz), 156.9 (d, 1J¼258 Hz);
HRMS/EI (g molꢁ1) calcd for C11H6FN3 199.0546, found
199.0543.
4.4. General procedure for chlorodehydroxylation
The chosen pyridonaphthyridinone 3 (0.40 g, 2 mmol) was
heated at 100 ꢀC in POCl3 (10 mL), for 12 h (TLC monitor-
ing). The resulting mixture was poured carefully drop by
drop into cold water and the pH was adjusted to 10 using a
28% aqueous ammonia solution. The resulting solution was
extracted three times with EtOAc, dried with MgSO4, fil-
tered and evaporated. The crude product was then purified by
silica gel chromatography.
4.3. General procedure for KOH anionic ring closure
The chosen bipyridine 2 (0.5 g, 2.5 mmol) and KOH (0.7 g,
12.5 mmol) were solubilized in MeOH (5 mL) in microwave
vial. The suspension was then heated at 150 ꢀC for 10 min.
The resulting mixture was poured into 20 mL of water and
extracted three times with EtOAc. The combined organic
layers were dried with MgSO4, filtered and evaporated.
The crude product was then washed with acetonitrile and
filtered to give analytically pure product 3.
4.4.1. 6-Chloropyrido[3,4-c]-1,5-naphthyridine 4a. Start-
ing from 3a, following the general procedure and using
DCM/EtOAc (1/1) as eluent for the column chromatography,
the product was obtained as a white powder (0.32 g, 73%).
Mp 194 ꢀC; IR (KBr) 3054, 2924, 1607, 1558, 1561, 1500,
1446, 1422, 1399, 1337, 1321, 1282, 1259, 1177, 1107, 1031,
971, 957, 852, 801, 736, 621, 529 cmꢁ1; 1H NMR (400 MHz,
3
3
4.3.1. Pyrido[2,3-c]-1,5-naphthyridin-6(5H)-one 3a.
Starting from 2a and following the general procedure the
product was obtained as a white powder. Mp >260 ꢀC; IR
(KBr) 3043, 2978, 2841, 1717 (CO), 1667, 1589, 1559, 1451,
1413, 1350, 1299, 1259, 1202, 1147, 1100, 1064, 1020, 869,
803, 757, 713, 675, 639, 619, 583 cmꢁ1; 1H NMR (400 MHz,
DMSO) d¼7.56 (dd, 3J¼8.2 Hz, 3J¼4.4 Hz, 1H), 7.74 (dd,
3J¼8.2 Hz, 4J¼1.2 Hz, 1H), 7.89 (dd, 3J¼8.1 Hz, 3J¼
CDCl3) d¼7.80 (dd, J¼8.3 Hz, J¼4.4 Hz, 1H), 8.42 (dd,
4
3
3J¼8.3 Hz, J¼1.7 Hz, 1H), 8.94 (d, J¼5.5 Hz, 1H), 9.03
3
4
3
(dd, J¼4.4 Hz, J¼1.7 Hz, 1H), 9.12 (d, J¼5.5 Hz, 1H),
9.81 (s, 1H); 13C NMR (100 MHz, CDCl3) d¼116.3, 121.7,
126.2, 136.6, 139.37, 139.39, 140.1, 140.3, 150.43, 150.45,
150.7; HRMS/EI (g molꢁ1) calcd for C11H6ClN3 215.0250,
found 215.0245.
3
4
4.4 Hz, 1H), 8.55 (dd, J¼4.4 Hz, J¼1.2 Hz, 1H), 8.99
4.4.2. 6-Chloropyrido[2,3-c]-1,5-naphthyridine 4b. Start-
ing from 3b, following the general procedure and using
DCM/EtOAc (1/1) as eluent for the column chromatography,
the product was obtained as a white powder (0.33 g, 76%).
Mp 196 ꢀC; IR (KBr) 3427, 3050, 1732, 1561, 1451, 1421,
1317, 1291, 1252, 1173, 987, 791, 755, 634 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d¼7.76 (dd, 3J¼8.4 Hz, 3J¼4.4 Hz, 1H),
7.93 (dd, 3J¼8.2 Hz, 3J¼4.4 Hz, 1H), 7.74 (dd, 3J¼8.4 Hz,
4J¼1.7 Hz, 1H), 9.04 (dd, 3J¼4.4 Hz, 4J¼1.7 Hz, 1H),
9.26 (dd, 3J¼4.4 Hz, 4J¼1.7 Hz, 1H), 9.51 (dd, 3J¼8.2 Hz,
4J¼1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) d¼124.8,
126.4, 130.8, 132.4, 136.3, 138.2, 139.9, 140.6, 150.1, 152.4,
3
4
3
4
(dd, J¼4.4 Hz, J¼1.5 Hz, 1H), 9.09 (dd, J¼8.1 Hz, J¼
1.5 Hz, 1H), 11.87 (br s, 1H); 13C NMR (100 MHz, DMSO)
d¼124.2, 125.8, 128.1, 132.6, 133.8, 135.1, 143.9, 145.0,
152.3, 160.0 (a quaternary carbon’s signal wasn’t observed);
HRMS/EI (g molꢁ1) calcd for C11H7N3O 197.0589, found
197.0587.
4.3.2. Pyrido[3,4-c]-1,5-naphthyridin-6(5H)-one 3b.
Starting from 2b and following the general procedure but
the reaction time has to be extended to 30 min the product
was obtained as a white powder. Mp >260 ꢀC; IR (KBr)

T. Cailly et al. / Tetrahedron 63 (2007) 71–76
75
153.2; HRMS/EI (g molꢁ1) calcd for C11H6ClN3 215.0250,
found 215.0253.
then purified by silica gel chromatography using DCM/
EtOAc (1/1)+3% MeOH eluent to give pyrido[2,3-c]-1,5-
naphthyridine 5a as white powder (0.68 g, 81%).
4.4.3. 6-Chloropyrido[4,3-c]-1,5-naphthyridine 4c. Start-
ing from 3c, following the general procedure and using
DCM/EtOAc (2/1) as eluent for the column chromatography,
the product was obtained as a white powder (0.31 g, 72%).
Mp 191 ꢀC; IR (KBr) 3049, 1603, 1570, 1457, 1393, 1316,
1281, 1209, 1167, 106, 982, 802, 767, 746, 724, 639, 605,
4.6.3. Pyrido[2,3-c]-1,5-naphthyridine 5a. Mp 123 ꢀC; IR
(KBr) 3260, 2924, 2854, 1591, 1570, 1455, 1378, 1324,
1219, 1129, 1187, 1129, 1096, 1056, 937, 836, 778, 739,
1
3
614 cmꢁ1; H NMR (400 MHz, CDCl3) d¼7.77 (dd, J¼
3
3
3
8.3 Hz, J¼4.4 Hz, 1H), 7.87 (dd, J¼8.3 Hz, J¼4.4 Hz,
1
3
3
4
3
575 cmꢁ1; H NMR (400 MHz, CDCl3) d¼7.76 (dd, J¼
1H), 8.54 (dd, J¼8.3 Hz, J¼1.7 Hz, 1H), 9.05 (dd, J¼
3
3
4
4
3
4
8.3 Hz, J¼4.4 Hz, 1H), 8.20 (dd, J¼5.7 Hz, J¼0.6 Hz,
4.4 Hz, J¼1.7 Hz, 1H), 9.17 (dd, J¼4.4 Hz, J¼1.7 Hz,
1H), 9.46 (ddd, 3J¼8.3 Hz, 4J¼1.7 Hz, 4J¼0.8 Hz, 1H),
9.62 (s, 1H); 13C NMR (100 MHz, CDCl3) d¼124.8, 126.3,
129.7, 132.2, 137.9, 139.7, 140.6, 144.1, 150.5, 152.9,
156.1; HRMS/EI (g molꢁ1) calcd for C11H7N3 181.0640,
found 181.0644.
3
4
1H), 8.42 (dd, J¼8.3 Hz, J¼1.7 Hz, 1H), 9.08–9.10 (m,
2H), 10.56 (s, 1H); 13C NMR (100 MHz, CDCl3) d¼118.8,
125.1, 128.4, 130.6, 136.5, 139.2, 139.7, 148.9, 148.9,
150.7, 150.9; HRMS/EI (g molꢁ1) calcd for C11H6ClN3
215.0250, found 215.0259.
4.5. Synthesis of pyrido[4,3-c]-1,5-naphthyridine 5c
4.6.4. 7,8,9,10-Tetrahydropyrido[2,3-c]-1,5-naphthyri-
dine 7. IR (KBr) 3306 (NH), 2940, 2857, 1713, 1671,
1588, 1576, 1523, 1483, 1343, 1298, 1219, 1100, 914, 815,
6-Chloropyrido[4,3-c]-1,5-naphthyridine
4c
(0.100 g,
1
0.45 mmol), ammonium formate (0.117 g, 1.85 mmol) and
Pd/C 10% (0.049 g, 0.045 mmol) were stirred for 12 h (LC/
MS monitoring) in methanol (20 mL). The solution was fil-
tered through paper, evaporated and solubilized with DCM
(20 mL) before addition of DDQ (0.105 g, 0.45 mmol).
The mixture was allowed to stir for 1 h, diluted with DCM
(30 mL), washed three times with 40 mL of a saturated aque-
ous NaHCO3 solution, dried with MgSO4, filtered and evap-
orated. The crude product was then purified by silica gel
chromatography using DCM/EtOAc (1/1)+3% MeOH as
eluent to give pyrido[4,3-c]-1,5-naphthyridine 5c as white
powder (0.073g, 87%). Mp 142 ꢀC; IR (KBr) 3050, 2963,
2927, 1729, 1586, 1562, 1484, 1452, 1415, 1380, 1280, 1241,
1154, 1096, 1038, 1013, 954, 790, 739, 724, 632, 620, 502,
801, 776, 757, 675, 638, 618 cmꢁ1; H NMR (400 MHz,
3
CDCl3) d¼2.08 (m, 2H), 3.25 (t, J¼6.3 Hz, 2H), 3.44 (t,
J¼4.3 Hz, 2H), 4.31 (br s, 1H), 7.32 (dd, 3J¼8.3 Hz,
3J¼4.4 Hz, 1H), 8.17 (dd, 3J¼8.3 Hz, 4J¼1.5 Hz, 1H), 8.34
3
4
(s, 1H), 8.81 (dd, J¼4.4 Hz, J¼1.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d¼21.0, 21.2, 41.5, 119.9, 121.2, 136.9,
137.4, 141.4, 143.5, 144.0, 150.4; HRMS/EI (g molꢁ1) calcd
for C11H11N3 185.0953, found 185.0948.
4.7. Synthesis of pyrido[3,4-c]-1,5-naphthyridine 5b
6-Chloropyrido[3,4-c]-1,5-naphthyridine 4b (0.100 g,
0.45 mmol), ammonium formate (0.030 g, 0.45 mmol) and
Pd/C 10% (0.049 g, 0.045 mmol) were stirred for 3 h (LC/
MS monitoring) in refluxing methanol (20 mL). The solution
was filtered through paper and evaporated. The crude product
was then purified by silica gel chromatography using DCM/
EtOAc (1/1)+3% MeOH as eluent to give pyrido[3,4-c]-1,5-
naphthyridine 5b as white powder (0.72 g, 86%). Mp 146 ꢀC;
IR (KBr) 2924, 1727, 1610, 1578, 1506, 1447, 1384, 1281,
1
3
457 cmꢁ1; H NMR (600 MHz, CDCl3) d¼7.80 (dd, J¼
8.3 Hz, 3J¼4.4 Hz, 1H), 7.94 (d, 3J¼5.4 Hz, 1H), 8.53 (dd,
4
3
3J¼8.3 Hz, J¼1.7 Hz, 1H), 9.07 (d, J¼5.4 Hz, 1H), 9.07
(dd, 3J¼4.4 Hz, 4J¼1.7 Hz, 1H), 9.44 (s, 1H), 10.55 (s, 1H);
13C NMR (150 MHz, CDCl3) d¼118.7, 124.0, 126.2, 130.2,
136.9, 139.2, 139.4, 147.3, 147.9, 150.2, 152.3; HRMS/EI
(g molꢁ1) calcd for C11H7N3 181.0640, found 181.0649.
1261, 1224, 1110, 1020, 898, 848, 799, 735, 620, 559 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d¼7.83 (dd, 3J¼8.3 Hz,
4.6. Synthesis of pyrido[2,3-c]-1,5-naphthyridine 5a and
7,8,9,10-tetrahydropyrido[2,3-c]-1,5-naphthyridine 7
3J¼4.3 Hz, 1H), 8.54 (dd, 3J¼8.3 Hz, 4J¼1.5 Hz, 1H),
3
3
8.94 (d, J¼5.6 Hz, 1H), 9.08 (d, J¼5.6 Hz, 1H), 9.10
(dd, 3J¼4.3 Hz, 4J¼1.5 Hz, 1H), 9.50 (s, 1H), 9.52 (s, 1H);
13C NMR (100 MHz, CDCl3) d¼116.7, 123.5, 126.1, 138.0,
138.5, 139.9, 141.5, 150.1, 150.7, 152.0, 153.4; HRMS/EI
(g molꢁ1) calcd for C11H7N3 181.0640, found 185.0635.
4.6.1. Using 4 equiv of ammonium formate. 6-Chloropyr-
ido[2,3-c]-1,5-naphthyridine 4a (0.100 g, 0.45 mmol), am-
monium formate (0.117 g, 1.85 mmol) and Pd/C 10%
(0.049 g, 0.045 mmol) were stirred for 3 h (LC/MS monitor-
ing) in refluxing methanol (20 mL). The solution was filtered
through paper and evaporated. The crude product was then
purified by silica gel chromatography using DCM/EtOAc
(1/1)+3% MeOH as eluent to give pyrido[2,3-c]-1,5-naph-
thyridine 5a as white powder (0.020 g, 24%) and 7,8,9,10-
tetrahydropyrido[2,3-c]-1,5-naphthyridine 7 (0.040 g, 46%)
as a yellow oil.
4.8. Pyridonaphthyridines 5a,b,c 1H and 13C NMR
assignments
For 5c, NMR experiments were achieved at 300 K on a
Bruker DMX 600 spectrometer equipped with a 5 mm triple
resonance {1H (600.13 MHz), 13C (150.90 MHz), 15N
(60.81 MHz)} Cryoprobe including shielded z-gradients. In-
ternal reference from CDCl3 (dH¼7.26, dC¼77.36). For 5a
and 5b, NMR experiments were achieved at 296 K on a
Bruker DRX 400 spectrometer equipped with a 5 mm quad-
ripolar nuclear probe {1H (400.13 MHz), 13C (100.62 MHz),
19F (376.50 MHz), 31P (161.98 MHz)} including shielded
z-gradients. Internal reference from CDCl3 (dH¼7.26 and
dC¼77.36) (Table 4).
4.6.2. Using 1 equiv of ammonium formate. 6-Chloro-
pyrido[2,3-c]-1,5-naphthyridine 4a (0.100 g, 0.45 mmol),
ammonium formate (0.030 g, 0.45 mmol) and Pd/C 10%
(0.049 g, 0.045 mmol) were stirred for 24 h (LC/MS moni-
toring) in refluxing methanol (20 mL). The solution was fil-
tered through paper and evaporated. The crude product was

76
T. Cailly et al. / Tetrahedron 63 (2007) 71–76
Table 4. Pyridonaphthyridines 5a,b,c 1H and 13C NMR chemical shifts
2. Hamada, Y.; Sato, M.; Takeuchi, I. Yakugaku Zasshi 1975, 95,
1492–1497.
3. Czuba, W. Rocz. Chem. 1967, 41, 289–297.
4. Nutaitis, C. F.; Brennan, M. Org. Prep. Proced. Int. 2004, 36,
367–370.
assignement by HMBC and HMQCa
9
10
8
1
N
10a
N
7
2
10b
4a
6a
3
5. Williams, R. L.; ElFayoumy, M. G. J. Heterocycl. Chem. 1972,
9, 1021–1025.
6
N
4
5
6. (a) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2002, 58, 2885–2890; (b) Bouillon, A.;
Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
2002, 58, 3323–3328; (c) Bouillon, A.; Lancelot, J. C.;
Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 4369–
4373.
7. Bouillon, A.; Voisin, A. S.; Robic, A.; Lancelot, J. C.;
Collot, V.; Rault, S. J. Org. Chem. 2003, 68, 10178–
10180.
No.
5c
5b
5a
1
2
3
4
4a
5
6
6a
7
8
N
N
N
150.2, 9.07
124.0, 7.80
136.9, 8.53
139.4
150.7, 9.10
126,1, 7.83
138.0, 8.54
141.5
150.5, 9.05
124,8, 7.77
137.9, 8.54
139.7
N
N
N
152.3, 9.44
130.2
118.7, 7.94
147.3, 9.07
N
147.9, 10.55
126.2
139.2
153.4, 9.50
123.5
152.0, 9.52
N
150.1, 9.08
116.7, 8.94
138.5
156.1, 9.62
144.1
N
152.9, 9.17
126.3, 7.87
132.2, 9.46
129.7
8. Cailly, T.; Fabis, F.; Rault, S. Tetrahedron 2006, 62, 5862–
5867.
9
ˆ
9. Cailly, T.; Fabis, F.; Lemaıtre, S.; Bouillon, A.; Sopkova, J.;
Rault, S. Synlett 2006, 53–56.
10
10a
10b
139.9
140.6
ꢀ
10. Hansen, H. M.; Lysen, M.; Begtrup, M.; Kristensen, J.
Tetrahedron 2005, 61, 9955–9960.
1H chemical shifts are in italic, 13C in regular and both are expressed in
parts per million.
a
11. For a general review, see: Kappe, C. O. Angew. Chem., Int. Ed.
2004, 43, 6250–6284; Suzuki cross-coupling: (a) Miao, G.; Ye,
P.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005, 76, 2332–2334;
(b) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 11, 2101–
2104.
Acknowledgements
ꢀ
We thank ‘Les Laboratoires Servier’, The ‘Conseil Regional
12. Two references describe the synthesis of compound 3a.
(a) Mannich, C.; Abdullah, S. M. Ber. 1935, 68B, 113–120;
(b) Brydowna, W. Rocz. Chem. 1934, 14, 304–325.
13. Bobbio, C.; Schlosser, M. J. Org. Chem. 2005, 70, 3039–
3045.
de Basse-Normandie’ and ‘Les Sapins de l’Espoir’ for their
financial support.
References and notes
14. Vanden eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke,
Y. Tetrahedron 1995, 51, 6511–6516.
1. Case, F. H.; Brennan, J. A. J. Am. Chem. Soc. 1959, 81, 6297–
6301.