Strategic studies in the syntheses of novel 6,7-substituted quinolones and 7- or 6-substituted 1,6- and 1,7-naphthyridones

Article abstract of DOI:10.1016/j.tet.2008.01.055

This paper describes the different strategies devised and applied to overcome the selectivity issues in the syntheses of 6,7-disubstituted-1H-quinolin-4-one, 7-substituted-1H-1,6-naphthyridin-4-one and 6-substituted-1H-1,7-naphthyridin-4-one derivatives. They allowed us to improve the overall yields and the scaling-up feasibility. Several examples illustrate these strategies with their advantages and drawbacks.

Full text of DOI:10.1016/j.tet.2008.01.055

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2772e2782
www.elsevier.com/locate/tet
Strategic studies in the syntheses of novel 6,7-substituted quinolones
and 7- or 6-substituted 1,6- and 1,7-naphthyridones
*
*
´
Remy Morgentin , Georges Pasquet , Pascal Boutron, Frederic Jung,
´ ´
´
Maryannick Lamorlette, Mickael Maudet, Patrick Ple
¨
AstraZeneca, Centre de Recherches, Parc industriel Pompelle B.P.1050, 51689 Reims Cedex 2, France
Received 26 November 2007; received in revised form 10 January 2008; accepted 11 January 2008
Available online 16 January 2008
Abstract
This paper describes the different strategies devised and applied to overcome the selectivity issues in the syntheses of 6,7-disubstituted-1H-
quinolin-4-one, 7-substituted-1H-1,6-naphthyridin-4-one and 6-substituted-1H-1,7-naphthyridin-4-one derivatives. They allowed us to improve
the overall yields and the scaling-up feasibility. Several examples illustrate these strategies with their advantages and drawbacks.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Quinolone; Naphthyridone; Strategy; Regioselectivity
1. Introduction
O
thermal
condensation
N
H
OR
OR
NH2
cyclisation
As part of our continuing interest in 4-phenoxyquinolines
and naphthyridines as inhibitors of kinases involved in angio-
genesis, we required an efficient access to 7-substituted-1H-qui-
nolin-4-ones and 1H-1-naphthyridin-4-ones. Different methods
are known in the literature to build quinolin-4-one scaffolds.1
Probably the most useful preparative method for symmetri-
cal substituted anilines consists of preparing the enamine
derivative by reaction with an alkyl methoxymethylidene
propanedioate followed by a thermal cyclisation. The 1H-qui-
nolin-4-one core is thus obtained after a saponificationedecarb-
oxylation sequence (Scheme 1). Since the cyclisation can in
theory occur at either of the ortho positions of unsymmetrical
anilines, it could become tedious to prepare selectively
7-substituted-1H-quinolin-4-ones as the regioselectivity of
the cyclisation will depend on electronic and steric effects.
To address these issues, we decided to investigate new
strategies for the syntheses of 6,7-disubstituted-1H-quinolin-
O
O
O
O
O
O
OH
OR
thermal
decarboxyaltion
N
H
N
H
N
H
Scheme 1. 4-Step synthesis of 1H-quinolin-4-one using an alkyl methoxy-
methylidene propanedioate.
4-one (1, 2 and 3), 6-substituted-1H-1,7-naphthyridin-4-one
(4 and 5) and 7-substituted-1H-1,6-naphthyridin-4-one
(6 and 7) derivatives (Fig. 1).
O
O
O
R
R
N
N
R'
R
N
H
N
H
N
H
1 R=H, R'=OMe
2 R=H, R'=CO2Me
3 R=OMe, R'=CO2Me
4 R=H
5 R=OMe
6 R=OMe
7 R=Cl
* Corresponding authors. Tel.: þ33 (0) 3 26 61 68 68; fax: þ33 (0) 3 26 61
68 42.
E-mail addresses: remy.morgentin@astrazeneca.com (R. Morgentin),
georges.pasquet@astrazeneca.com (G. Pasquet).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.055

R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
2773
2. Results and discussion
R2
O
O
R1
+
R1
R1
R2
Dowtherm A
reflux
2.1. Synthesis of enamine precursors
R2
N
H
N
H
NH
Meld
The key enamine precursors were obtained by condensa-
tion of the anilines with Meldrum’s acid derivative 8.2 The
use of 8 instead of a standard dialkyl 2-(methoxymethyl-
idene)-propanedioate as shown in Scheme 1, allowed us to
carry out the thermal cyclisation and the subsequent decar-
boxylation in one pot.3 Their syntheses are summarised in
Table 1.
9
R1=H
R2=OMe
11 R1=H
R2=CO2Me
1 R1=H
R2=OMe
10 R1=H
R2=OMe
2 R1=H
12 R1=H
R2=CO2Me
3 R1=OMe
R2=CO2Me
16 R1=OMe
R2=CO2Me
15 R1=OMe
R2=CO2Me
R2=CO2Me
Ratio: 1:10=80:20, 2:12=60:40, 3:16=65:35
Scheme 2. Cyclisation reaction.
O
O
Meld =
O
O
R
O
O
O
1N HCl
+
HCl
N
H
R
R
N
H
N
H
Table 1
Synthesis of enamine precursors
1 R=OMe
1 R=OMe
2 R=CO2Me
10 R=OMe
12 R=CO2Me
2 R=CO2Me
O
O
O
Ar
Ratio : 1:10=80:20, 2:12=60:40
O
O
IPA
Ar
+
N
H
O
Scheme 3. Selective precipitation of hydrochloride salt.
O
O
NH2
O
8
2.2.2. Synthesis of methyl 4-oxo-1H-quinoline-7-
carboxylate (2)
Entry Substrate
Product Yield (%)
1
3-Methoxyaniline
Methyl 3-aminobenzoate
Methyl 5-amino-2-methoxybenzoate 14
9
96
92
92
84
92
88
100
71
79
93
71
92
The same route was applied for the synthesis of methyl 4-oxo-
1H-quinoline-7-carboxylate 2. Although methyl 3-aminobenz-
oate is commercially available, it was synthesised efficiently by
treating inexpensive 3-aminobenzoic acid with thionyl chlo-
ride and methanol in quantitative yield.6 Methyl 3-aminobenz-
oate was subsequently treated with Meldrum’s acid derivative
8 to give the corresponding enamine 11 in 92% yield (Table
1dentry 2), which after thermal cyclisationedecarboxylation
gave a 60:40 mixture of 7-substituted-quinolin-4-one 2 and
5-substituted-quinolin-4-one 12 in 60% yield (Scheme 2). This
lower regioselectivity has already been reported:5 Effectively,
in practice, a strong electron-withdrawing meta substituent,
such as an ester group, preferentially favours cyclisation in its or-
tho position. As previously seen, the two regioisomers 2 and 12
were difficult to separate by chromatography but treatment
with 1 N hydrochloric acid led to a selective precipitation of
the desired isomer 2 as its hydrochloride salt in 47% yield
(Scheme 3). On the other hand, saponification of the mixture of
regioisomers with LiOH in MeOH occurred exclusively with
the regioisomer 2, giving 13 in 53% yield while the regioisomer
12 remained unchanged under these conditions (Scheme 4).
2
11
15
3
4
3-Amino pyridine N-oxide hydrochloride 18 19
5
Methyl 3-amino-2-chlorobenzoate 22
2-Chloropyridin-3-amine
6-Methoxypyridin-3-amine
23
25
27
29
32
35
43
44
6
7
8
2-Chloro-6-methoxy-pyridin-3-amine
2-Methoxypyridin-4-amine 31
3-Bromo-2-methoxypyridin-4-amine 34
2-Chloropyridin-4-amine
9
10
11
12
2,6-Dichloropyridin-4-amine
2.2. Thermal ring closure strategy and regioisomers
separation
2.2.1. Synthesis of 7-methoxy-1H-quinolin-4-one (1)
The synthesis of 7-methoxy-1H-quinolin-4-one 14 has
previously been described in two steps using Meldrum’s acid
and 3-methoxyaniline via the corresponding enamine 9. The
electron-donating effects of the meta methoxy group favours
the cyclisation in its para position,5 giving the desired quino-
lin-4-one 1 in an 80:20 mixture contaminated with 5-methoxy-
1H-quinolin-4-one 10 (Scheme 2).4
O
O
O
O
O
Unfortunately, the two regioisomers could not be easily
separated by silica gel chromatography and selective recrystal-
lisation in boiling methanol led to poor recovery.4 However,
in boiling 1 N HCl the desired quinolin-4-one 1 precipitated
as a hydrochloride salt in 69% overall yield whereas the salt
of 5-methoxy-1H-quinolin-4-one 10 remained in solution,
allowing an easy separation of the two compounds
(Scheme 3).
R
O
R
R
O
LiOH
+
O
MeOH
HO
N
H
N
H
N
H
2 R=H
3 R=OMe
12 R=H
16 R=OMe
13 R=H
17 R=OMe
Ratio: 2:12=60:40, 3:16=65:35
Scheme 4. Selective saponification.

2774
R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
Table 2
Cyclisation results depending on the concentration medium
A possible explanation for this difference in reactivity
could be that the methyl ester group at the C5 position of
the derivative 12 is twisted due to peri-interactions with the
C4 carbonyl group, thus hampering the access of the hydrox-
ide anion to this ester function. The overall yields for 2 and
13 are 28% and 32%, respectively, starting from methyl
3-aminobenzoate.
Entry
Concentration
Products ratio (20/21)
Crude yield (%)
1
2
a
[0.06 M]
[0.4 M]
85/15
33/67
41a
93b
Presence of other impurities by 1H NMR.
Unexploitable mixture.
b
2.2.3. Synthesis of methyl 6-methoxy-4-oxo-1H-quinoline-7-
carboxylate (3)
intra-molecular cyclisationedecarboxylation reaction of 19,
obtained from 18 by treatment with Meldrum’s acid derivative
8 (Table 1dentry 4), was not clean and depended on the
concentration. When the ring closure reaction was performed
under high dilution (i.e., 0.06 mol/L), as reported by Phuan
et al.,7 cyclisation mainly led to 7-oxido-1H-1,7-naphthy-
ridin-4-one 20, containing 17 mol % of its 5-regioisomer 21
along with other impurities (Table 2dentry 1).
The above route was applied to the synthesis of methyl 6-
methoxy-4-oxo-1H-quinoline-7-carboxylate 3. 2-Hydroxy-5-
nitro-benzoic acid was methylated with dimethylsulfate and
potassium carbonate in boiling acetone, to give methyl 2-me-
thoxy-5-nitro-benzoate in 92% yield, which was quantitatively
transformed into aniline 14 by catalytic reduction over palla-
dium on charcoal (Scheme 5).
Reduction of the crude naphthyridine N-oxide 20 was per-
formed in 46% yield using a method developed by Chandrase-
khar et al.10 with polymethylhydrosiloxane (PMHS) in the
presence of palladium on charcoal, giving the desired naph-
thyridone 4 (Scheme 6). In order to prepare a large amount
of this material, the cyclisation was carried out at a higher con-
centration (i.e., 0.4 mol/L) but under these conditions, an in-
separable 33:67 mixture of 20 and 21 was unfortunately
obtained (Table 2dentry 2).
O
i) Me2SO4 , K2CO3
acetone, 92%
HO
HO
O
O
NH2
ii) H2, Pd/C
EtOAc, quant.
N
O
O
O
14
Scheme 5. Preparation of aniline 14.
The methyl 5-amino-2-methoxy-benzoate 14 was then
treated with Meldrum’s acid derivative 8 to give the correspond-
ing enamine 15 in 92% yield (Table 1dentry 3). Thermal cycli-
sationedecarboxylation sequence gave a 65:35 mixture of
6,7-disubstituted-quinolin-4-one 3 and 5,6-disubstituted-quino-
lin-4-one 16 in 53% yield (Scheme 2). Again, the two re-
gioisomers were not easily separated by chromatography. In
this case, treatment of the mixture in a 1 N HCl aqueous solution
did not allow the separation of the two regioisomers, buta sapon-
ification performed with LiOH in MeOH was selective for the
isomer 17. The two products 16 and 17 were thus easily sepa-
rated and quantitatively recovered (Scheme 4).
2.3. Strategy involving blocking of one of the two a positions
2.3.1. Improvement for the synthesis of methyl 4-oxo-1H-
quinoline-7-carboxylate (2)
In order to improve the efficiency of the synthesis of 2, we de-
cided to investigate a route based on blocking one of the two
a positions to avoid the regioselectivity issue of the cyclisation
step. This strategy was first reported by Breslow et al.11 in an un-
ambiguous synthesis of 3,5-dimethyl-1H-quinolin-4-one. The
synthesis of the desired aniline 2212 has previously been
described in two steps from the commercially available
2-chloro-3-nitro benzoic acid. Aniline 22 was reacted with 8
to give the corresponding enamine 23 in 92% yield (Table
1dentry 5), which led to the 8-chloro-quinoline-4-one 24 in
96% yield after the thermal cyclisationedecarboxylation
sequence. The dehalogenation reaction was performed by re-
duction of 24 under hydrogen in the presence of palladium
on charcoal, to give the desired quinoline-4-one 2 in 96%
(Scheme 7). The overall yield with this five-step route (80%)
compares thus favourably with the yield obtained with the
shorter but non-selective approach described in Section
2.2.2 (28%).
2.2.4. Synthesis of 1H-1,7-naphthyridin-4-one (4)
The synthesis of 1H-1,7-naphthyridin-4-one 4 has previ-
ously been described in five steps7 in 34% yield from 3-amino
pyridine N-oxide 18, which seemed to favour cyclisation at the
C4 position. The pyridine N-oxide 18 can be obtained either
from nicotinic amide N-oxide via the Hoffmann reaction8 or
from 3-bromo-pyridine N-oxide via displacement of the bro-
mine atom with ammonia.9 We also found that it could be
obtained efficiently in 84% yield from pyridine-3-carboxylic
acid N-oxide via a Curtius rearrangement, followed by
a Boc deprotection without any purification (Scheme 6). The
-
N+
O
O
O
O
PHMS
i) DPPA, tBuOH
Pd/C10%
Dowtherm A
reflux
8
-
dioxane
ii) HCl, dioxane -O
84%
+
N+
Cl
NH+3
N
N+
N+
O
N+
Meld
EtOH
46%
-O
-O
DIPEA
IPA
N
H
-O
N
H
N
H
N
H
OH
18
19
20
4
21
Scheme 6. Note: N-oxide reduction step from the crude 20 of Table 2eentry 1.

R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
2775
O
Dowtherm A
[0.06 M]
8
O
O
H2, Pd/C
O
O
Meld
NH2
5
N
H
IPA
Dowtherm A
reflux
96%
TEA
EtOH
56%
N
reflux
9%
O
Cl
N
O
Cl
23
Meld
N
H
N
H
22
Cl
Cl
29
30
O
Scheme 10.
H2, Pd/C
O
2 ,HCl
N
H
EtOAc
EtOH
96%
When the a-blocked position strategy was applied to 29,
which was prepared by reduction of the nitro group of the com-
mercially available 2-chloro-6-methoxy-3-nitro-pyridine, fol-
lowed by reaction with 8 (Table 1dentry 8), ring closure
occurred only in very low yield, even under high dilution condi-
tions. Dehalogenation of the intermediate 30 gave the desired
product 5 in 56% (Scheme 10). A more efficient synthesis was
therefore necessary and will be discussed in Section 2.4.2.
O
Cl
24
Scheme 7.
2.3.2. Improvement for the synthesis of 1H-1,7-
naphthyridin-4-one (4)
Although the classical route was usable enough to access to
4 in 13% yield, we decided to apply the above strategy to this
closely related target. When a high concentration of 25 (Table
1dentry 6) was heated in Dowtherm A at 220 ꢀC, the thermal
cyclisation failed. High dilution was required and furnished 26
in 72% yield. The following dehalogenation step was also car-
ried out by palladium-catalysed hydrogenolysis in 71% yield.
However, owing to the high dilution required, another route
was devised and will be discussed in Section 2.4.1 (Scheme 8).
2.3.4. Synthesis of 7-methoxy-1H-1,6-naphthyridin-
4-one (6)
The standard approach for the synthesis of 7-methoxy-1H-
1,6-naphthyridin-4-one 6 was first attempted starting from
3114 (readily obtained as shown in Scheme 11) but the sole
product formed when 32 (Table 1dentry 9) was heated in
Dowtherm A at 220 ꢀC was the regioisomer 33 in 64% yield.
This result showed that the C-3 position is the most nucleo-
philic of 32 (Scheme 11).
Therefore, we decided to take advantage of the nucleophilic
reactivity of this position and block it by introduction of a halo-
gen atom. Indeed, the bromination was completely selective
for the C-3 position when 31 was treated with NBS in aceto-
nitrile, giving the intermediate 34. The enamine pyridine 35
(Table 1dentry 10) was cleanly converted into the 8-bromo-
7-methoxy-1,6-naphthyridin-4(1H)-one 36, which was subse-
quently debrominated with palladium on charcoal to give the
desired product 6 (Scheme 12).
O
Dowtherm A
[0.06 M]
H2, Pd/C
4
N
Meld
N
H
N
AcONa
EtOH
71%
reflux
72%
N
H
Cl
Cl
25
26
Scheme 8.
2.3.3. Synthesis of 6-methoxy-1H-1,7-naphthyridin-
4-one (5)
It is known that the most nucleophilic position in com-
pounds such as 27 is the a position of the pyridine ring.13
Therefore, we attempted the synthesis of 6-methoxy-1H-1,7-
naphthyridin-4-one 5 under high dilution conditions (i.e.,
0.06 mol/L), which should favour the obtention of the desired
regioisomer 5 and minimise side reactions. However, when 27
(Table 1dentry 7) was heated in Dowtherm A at 220 ꢀC the
sole product formed was the regioisomer 28 in 77% yield
(Scheme 9).
2.4. The modified LeimgrubereBatcho approach
2.4.1. Revisited synthesis of 1H-1,7-naphthyridin-4-one (4)
Koskinen et al.15 reported a modified Leimgrubere
Batcho16 procedure to form the 1H-quinolin-4-one core. We
MeOH
MeONa
8
N
N
Cu, 150°C
56%
IPA
Cl
NH2
N
O
NH2
31
O
O
O
X
X
N
O
N
H
N
H
Dowtherm A
[0.06 M]
N
6
Dowtherm A
reflux
O
5
Meld
O
N
H
O
reflux
O
O
N
N
Meld
N
H
N
O
32
27
77%
64%
N
H
N
H
28
33
Scheme 9.
Scheme 11.

2776
R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
O
N
N
NBS
8
i) BuLi, TMEDA
O
O
O
O
NH2
MeCN
98%
NH2
IPA
Et2O, -70 °C
N
Br
N
NHBoc
NHBoc ii)
N
31
34
O
O
40
41
DMFDEA
toluene
80 °C
37%
O
Pd/C
Dowtherm A
reflux
80%
O
NH4+HCOO-
N
N
TFA, DCM
6
O
N
MeOH, refl.
95%
79%
or
Meld
93%
O
N
H
N
H
O
5
N
Br
NHBoc
Br
EtONa, EtOH
36
35
42
Scheme 14.
Scheme 12.
decided to apply this methodology to the 1H-1,7-naphthyridin-
4-one series. Katritzky et al.17 have described a straightforward
route to 1-(3-nitropyridin-4-yl)ethanone 37 in 83% yield by ni-
tration of the 1-pyridin-4-ylethanone with the unstable dinitro-
gen pentoxide,18 generated in situ from TFAA and nitric
acid.19 Treatment of 37 with N-(diethoxymethyl)-N-methyl-
methanamine (DMFDEA) gave the enaminone 38 in 88%
yield. Reduction of the nitro function in 38 gave the interme-
diate 39, which underwent ring closure on reflux to give 4 in
76% yield (Scheme 13). We believe this strategy could be
seen as an efficient alternative route to the one described in
Section 2.2.4.
2.5. Synthesis of 7-chloro-1H-1,6-naphthyridin-4-one (7)
The thermal cyclisationedecarboxylation approach for the
synthesis of 7-chloro-1H-1,6-naphthyridin-4-one 7 was first
attempted with 43 (Table 1dentry 11), but a 1/1 mixture of
inseparable isomers was obtained in poor yield (Scheme 15).
Cl
O
O
N
N
N
Dowtherm A
reflux
+
Meld
Cl
N
H
N
H
N
H
Cl
20%
1/1
43
7
Scheme 15.
O
O
O
Dehalogenation selectivity issues of 8-halo-7-chloro-1H-
1,6-naphthyridin-4-one derivatives could be anticipated in
the a-blocked position strategy. We therefore focused on
devising a new route starting from the symmetrical enamine
pyridine 44. In precedent investigations, we found that the
C-5 position was more reactive than the C-7 in the quinazoline
series21 and this observation proved useful in the selective de-
halogenation of 45. The key intermediate 44 (Table 1dentry
12) was cyclised to give the naphthyridone 45 in good yield
when heated in Dowtherm A at reflux.
TFAA
DMFDEA
N
N
N
HNO3
83%
toluene
80 °C
88%
N
NO2
NO2
37
38
O
H2, Pd/C
EtOH
EtOH
reflux
76%
N
4
NH2
39
Scheme 13.
When treated with zinc and acetic acid, 45 underwent a
selective dehalogenation of the C-5 chlorine to furnish the
desired compound 7 in 73% yield (Scheme 16).
2.4.2. Synthesis of 6-methoxy-1H-1,7-naphthyridin-
4-one (5)
O
Cl
Cl
Zn, AcOH
N
N
Dowtherm A
reflux
It is known that lithiation of tert-butyl N-(6-methoxypyridin-
3-yl)carbamate 4020 with n-butyllithiumeTMEDA in diethyl
ether generates a carbanion at the 4 position of the pyridine
ring and minimises any nucleophilic addition of n-butyllithium
at C-4. Using this knowledge, we managed to quench the dianion
with Weinreb’s amide, N-methoxy-N-methyl-acetamide, to ob-
tain the acetyl pyridine 41 in 37% yield. Treatment of 41 by
DMFDEA gave the enaminone 42 in 90% yield and surprisingly,
ring closure and Boc deprotection readily occurred in one pot
using either TFA in dichloromethane or sodium ethoxide in
EtOH, to yield the desired 6-methoxy-1H-1,7-naphthyridin-
4-one 5 (Scheme 14).
7
Meld
MeOH
73%
N
H
Cl
N
H
Cl
91%
44
45
Scheme 16.
3. Conclusion
In this work,22 we have developed various strategies for the
syntheses of 6,7-disubstituted-1H-quinolin-4-one, substituted
1,6- and 1,7-naphthyridin-4-one derivatives to overcome

R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
2777
Table 3
Table summarising global yields from available starting materials according to the different strategies
Entry
Starting material
Strategy
Number of steps
Desired product
Overall yield (%)
O
1
3-Methoxyaniline
Classicale
3
66
O
N
H
1
O
2
3
3-Aminobenzoic acid
Classicale
4
5
28a
80
O
N
H
2-Chloro-3-nitro benzoic acid
a-Blocked position
2
O
O
O
4
2-Hydroxy-5-nitro-benzoic acid
Classicale
5
53b
HO
N
H
17
O
5
6
7
1-Oxidopyridine-3-carboxylic acid
2-Chloropyridin-3-amine
Classicale
5
3
4
13c
45c
55
O
a-Blocked position
Enaminonef
N
N
H
4
1-Pyridin-4-ylethanone
8
6-Methoxypyridin-3-amine
Classicale
2
4
4
0d
3c
O
O
9
2-Chloro-6-methoxy-3-nitro-pyridine
6-Methoxypyridin-3-amine
a-Blocked position
Enaminonef
N
N
H
5
10
30
O
11
12
Classicale
3
5
0d
N
2-Chloropyridin-4-amine
O
N
H
a-Blocked position
43
6
O
Starting from
symetrical aniline
N
13
2,6-Dichloropyridin-4-amine
3
61
Cl
N
H
7
a
The corresponding acid 13 was isolated in 32% overall yield with selective saponification.
17 is the corresponding acid of the target 3.
High dilution conditions were required for cyclisation.
b
c
d
e
f
The undesired regioisomer was obtained.
Strategy using thermal ring closure and separation of the two regioisomers if necessary.
Strategy using the modified LeimgrubereBatcho approach.
selectivity issues when unsymmetrical substituted anilines are
(500 MHz) spectrometer. Chemical shifts are expressed in
d (ppm) units, and peak multiplicities are expressed as follows:
s, singlet; d, doublet; dd, doublet of doublets; t, triplet; br s,
broad singlet; m, multiplet. Mass spectrometry was carried
out on an analytical Waters LC/MS system with positive and
negative ion data collected automatically. NMR and mass
spectra were run on isolated products and were consistent
with the proposed structures and compounds described in
the literature. The following abbreviations have been used:
Boc, tert-butoxycarbonyl; DCM, dichloromethane; DIPEA,
N,N-diisopropylethylamine; DMFDEA, N-(diethoxymethyl)-
N-methyl-methanamine (N,N-dimethylformamide diethyl ace-
tal); DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl
used in high temperature cyclisation reactions. Results and
yields showing the efficacy of the various approaches are sum-
marised in Table 3.
4. Experimental section
4.1. General
All experiments were carried out under an inert atmosphere
and at room temperature unless otherwise stated. Flash chro-
matography was carried out on Merck Kieselgel 50 (Art.
9385). NMR spectra were obtained on a Bruker Avance 500

2778
R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
azide; IPA, propan-2-ol; NBS, 1-bromopyrrolidine-2,5-
dione (N-bromosuccinimide); PHMS, polymethylhydrosilox-
ane; TEA, N,N,N-triethylamine; TFA, trifluoroacetic acid;
TFAA, (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (trifluoro-
acetic anhydride); TMEDA, N,N,N0,N0-tetramethylethane-1,2-
diamine. DowthermÒ A is a eutectic mixture of two very
stable compounds: 26.5% of diphenyl (C12H10) and 73.5%
of diphenyl oxide (C12H10O). DowthermÒ A is commonly
used as a heat transfer agent.
J¼13.5 Hz, 1H), 8.12 (d, J¼7.5 Hz, 1H), 7.67 (d, J¼7.5 Hz,
1H), 7.56 (t, J¼7.5 Hz, 1H), 3.88 (s, 3H), 1.69 (s, 6H). MS
(ESI) m/z 338 and 340 (MꢁH)ꢁ.
4.2.1.6. 5-[[(2-Chloropyridin-3-yl)amino]methylidene]-2,2-di-
methyl-1,3-dioxane-4,6-dione (25). Yield: 88%. 1H NMR
(500 MHz, CDCl3): d 11.63 (d, J¼13.6 Hz, 1H), 8.62 (d,
J¼13.6 Hz, 1H), 8.31 (dd, J¼4.8 Hz, 1.5 Hz, 1H), 7.75 (dd,
J¼8.1 Hz, 1.5 Hz, 1H), 7.39 (dd, J¼8.1 Hz, 4.8 Hz, 1H),
1.78 (s, 6H). MS (ESI) m/z 225 and 227 (MHꢁ(CH3)2C]O)þ.
4.2. General procedures
4.2.1.7. 5-[[(6-Methoxypyridin-3-yl)amino]methylidene]-2,2-
1
4.2.1. Synthesis of enamine derivatives 9, 11, 15, 19, 23, 25,
27, 29, 32, 35, 43 and 44
dimethyl-1,3-dioxane-4,6-dione (27). Yield: 100%. H NMR
(500 MHz, CDCl3): d 11.18 (d, J¼13.9 Hz, 1H), 8.49 (d,
J¼13.9 Hz, 1H), 8.12 (d, J¼2.8 Hz, 1H), 7.52 (dd,
J¼9.0 Hz, 2.8 Hz, 1H), 6.83 (d, J¼9.0 Hz, 1H), 3.96 (s, 3H),
1.76 (s, 6H). MS (ESI) m/z 221 (MHꢁ(CH3)2C]O)þ.
To a suspension of Meldrum’s acid derivative 8 (1 equiv) in
propan-2-ol (2 mL per mmol of substrate) was portionwise
added the appropriate aniline (1 equiv) at room temperature
(1 equiv of DIPEA was added when aniline hydrochloride
was used). A precipitate slowly formed. The mixture was
heated to reflux for 5 min and then cooled down to room tem-
perature. The precipitate was collected by filtration, washed
with propan-2-ol and diethyl ether, giving the expected
product.
4.2.1.8. 5-[[(2-Chloro-6-methoxy-pyridin-3-yl)amino]methyl-
idene]-2,2-dimethyl-1,3-dioxane-4,6-dione (29). Yield: 71%.
1H NMR (500 MHz, CDCl3): d 11.52 (d, J¼13.8 Hz, 1H),
8.50 (d, J¼13.8 Hz, 1H), 7.65 (d, J¼8.7 Hz, 1H), 6.81 (d,
J¼8.7 Hz, 1H), 3.97 (s, 3H), 1.76 (s, 6H). MS (ESI) m/z 255
and 257 (MHꢁ(CH3)2C]O)þ.
4.2.1.1. 5-[[(3-Methoxyphenyl)amino]methylidene]-2,2-dimethyl-
1,3-dioxane-4,6-dione (9). Yield: 96%. 1H NMR (500 MHz,
CDCl3): d 11.21 (d, J¼14.0 Hz, 1H), 8.63 (d, J¼14.0 Hz,
1H), 7.33 (t, J¼8.1 Hz, 1H), 6.82 (m, 2H), 6.76 (t, J¼
2.2 Hz, 1H), 3.85 (s, 3H), 1.76 (s, 6H). MS (ESI) m/z 220
(MHꢁ(CH3)2C]O)þ.
4.2.1.9. 5-[[(2-Methoxypyridin-4-yl)amino]methylidene]-2,2-
dimethyl-1,3-dioxane-4,6-dione (32). Yield: 79%. 1H NMR
(500 MHz, DMSO-d6): d 11.13 (s, 1H), 8.67 (s, 1H), 8.14
(d, J¼5.7 Hz, 1H), 7.25 (dd, J¼5.7 Hz, 2.0 Hz, 1H), 7.06 (d,
J¼2.0 Hz, 1H), 3.86 (s, 3H), 1.69 (s, 6H). MS (ESI) m/z 279
(MH)þ.
4.2.1.2. Methyl 3-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylide-
ne)methylamino]benzoate (11). Yield: 92%. 1H NMR
(500 MHz, CDCl3): d 11.32 (d, J¼13.9 Hz, 1H), 8.70 (d,
J¼13.9 Hz, 1H), 7.95 (m, 2H), 7.53 (t, J¼8.3 Hz, 1H), 7.43
(dd, J¼7.3 Hz, 1.6 Hz, 1H), 3.97 (s, 3H), 1.77 (s, 6H). MS
(ESI) m/z 248 (MHꢁ(CH3)2C]O)þ.
4.2.1.10. 5-[[(3-Bromo-2-methoxy-pyridin-4-yl)amino]methyl-
idene]-2,2-dimethyl-1,3-dioxane-4,6-dione (35). Yield: 93%.
1H NMR (500 MHz, DMSO-d6): d 11.58 (d, J¼13.6 Hz,
1H), 8.87 (d, J¼13.6 Hz, 1H), 8.15 (d, J¼5.8 Hz, 1H), 7.57
(d, J¼5.8 Hz, 1H), 3.96 (s, 3H), 1.71 (s, 6H). MS (ESI) m/z
299 and 301 (MHꢁ(CH3)2C]O)þ.
4.2.1.3. Methyl 5-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylide-
ne)methylamino]-2-methoxy-benzoate (15). Yield: 92%. 1H
NMR (500 MHz, CDCl3): d 11.24 (d, J¼14.4 Hz, 1H), 8.56
(d, J¼14.4 Hz, 1H), 7.74 (d, J¼3.0 Hz, 1H), 7.36 (dd,
J¼8.9 Hz, 3.0 Hz, 1H), 7.05 (d, J¼8.9 Hz, 1H), 3.94 (s, 3H),
3.93 (s, 3H), 1.76 (s, 6H). MS (ESI) m/z 278
(MHꢁ(CH3)2C]O)þ.
4.2.1.11. 5-[[(2-Chloropyridin-4-yl)amino]methylidene]-2,2-
dimethyl-1,3-dioxane-4,6-dione (43). Yield: 71%. 1H NMR
(500 MHz, DMSO-d6): d 11.21 (br s, 1H), 8.73 (s, 1H), 8.37
(d, J¼5.5 Hz, 1H), 7.86 (d, J¼1.8 Hz, 1H), 7.66 (dd,
J¼5.5 Hz, 1.8 Hz, 1H), 1.69 (s, 6H). MS (ESI) m/z 225 and
227 (MHꢁ(CH3)2C]O)þ.
4.2.1.4. 2,2-Dimethyl-5-[[(1-oxidopyridin-3-yl)amino]methyl-
idene]-1,3-dioxane-4,6-dione (19). Yield: 84%. 1H NMR
(500 MHz, DMSO-d6): d 11.16 (d, J¼13.4 Hz, 1H), 8.66 (t,
J¼1.2 Hz, 1H), 8.53 (d, J¼13.4 Hz, 1H), 8.06 (dd,
J¼6.5 Hz, 1.2 Hz, 1H), 7.61 (dd, J¼8.5 Hz, 1.2 Hz, 1H),
7.44 (dd, J¼8.5 Hz, 6.5 Hz, 1H), 1.69 (s, 6H). MS (ESI) m/z
263 (MꢁH)ꢁ.
4.2.1.12. 5-[[(2,6-Dichloropyridin-4-yl)amino]methylidene]-2,2-
dimethyl-1,3-dioxane-4,6-dione (44). Yield: 92%. 1H NMR
(500 MHz, DMSO-d6): d 11.21 (br s, 1H), 8.73 (s, 1H), 7.92
(s, 2H), 1.69 (s, 6H). MS (ESI) m/z 315, 317 and 319 (MꢁH)ꢁ.
4.2.2. Ring closure reaction. Synthesis of compounds
1e3, 10, 12, 16, 20, 21, 24, 26, 28, 30, 33, 36 and 45
To Dowtherm A (appropriate dilutiondsee Sections
4.2.2.1 and 4.2.2.2) at 220 ꢀC was added portionwise the en-
amine derivative. After bubbling stopped, the mixture was
heated for an additional 10 min, and then allowed to cool to
4.2.1.5. Methyl2-chloro-3-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-
1
5-ylidene)methylamino] benzoate (23). Yield: 92%. H NMR
(500 MHz, DMSO-d6): d 11.71 (d, J¼13.5 Hz, 1H), 8.79 (d,

R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
2779
room temperature. The mixture was diluted with petroleum
ether, the solid was collected by filtration and washed with
petroleum ether. Depending on the synthesised compound,
one of the work-ups described in the main text was carried
out.
TFA-d) d: 7.93 (d, J¼7.5 Hz, 5.0 Hz, 1H), 7.51 (s, 1H),
6.19 (d, J¼7.5 Hz, 1H). MS (ESI) m/z 215, 217 and 219
(MH)þ.
4.2.3. Selective precipitation. Synthesis of compounds 1
and 2
4.2.2.1. High dilution conditions. A dilution of 60 mL of
Dowtherm A per gram of substrate was used for the syntheses
of 20, 21, 26, 28 and 30. Substrates 25, 27, 29, respectively,
gave 26, 28, 30 whereas substrate 19 led to a mixture of 20
and 21.
4.2.2.1.1. 7-Oxido-1H-1,7-naphthyridin-4-one (20). Crude
yield: 41%. Extrapolated 1H NMR (500 MHz, DMSO-d6):
d 8.48 (s, 1H), 8.02 (dd, J¼6.8 Hz, 1.3 Hz, 1H), 7.97 (d,
J¼7.5 Hz, 1H), 7.89 (d, J¼6.8 Hz, 1H), 6.07 (d, J¼7.5 Hz,
1H). MS (ESI) m/z 163 (MH)þ.
A mixture of regioisomers was stirred at the appropriate
temperature in a 1 N HCl solution for the appropriate time.
The solid was collected by filtration, washed with water and
dried overnight under vacuum at 50 ꢀC over phosphorous
pentoxide. The dry solid was washed with ethyl acetate and
diethyl ether, to give the pure desired regioisomer as the
hydrochloride salt.
This procedure was applied to an 80/20 mixture of 1 and 10
and a 60/40 mixture of 2 and 12 to prepare, respectively, 1 and
2. 10 and 12 were not isolated.
4.2.2.1.2. 8-Chloro-1H-1,7-naphthyridin-4-one (26). Yield:
72%. 1H NMR (500 MHz, DMSO-d6): d 11.98 (br s, 1H), 8.25
(d, J¼5.3 Hz, 1H), 7.94 (m, 2H), 7.25 (br s, 1H). MS (ESI) m/z
181 and 183 (MH)þ.
4.2.3.1. 7-Methoxy-1H-quinolin-4-one hydrochloride (1).
Precipitation reaction conditions. 100 ꢀC, 5 min. Yield: 69%.
1H NMR (500 MHz, DMSO-d6): d 8.46 (br s, 1H), 8.16 (d,
J¼9.7 Hz, 1H), 7.26 (m, 2H), 6.74 (br s, 1H), 3.94 (s, 3H).
MS (ESI) m/z 176 (MH)þ.
4.2.2.1.3. 6-Methoxy-1H-1,5-naphthyridin-4-one(28). Yield:
1
77%. H NMR (500 MHz, CDCl3): d 8.57 (d, J¼5.3 Hz, 1H),
8.23 (d, J¼9.0 Hz, 1H), 7.16 (d, J¼9.0 Hz, 1H), 7.05 (d,
J¼5.3 Hz, 1H), 4.09 (s, 3H). MS (ESI) m/z 177 (MH)þ.
4.2.2.1.4. 8-Chloro-6-methoxy-1H-1,7-naphthyridin-4-one
4.2.3.2. Methyl 4-oxo-1H-quinoline-7-carboxylate hydro-
chloride (2)
1
(30). Yield: 9%. H NMR (500 MHz, DMSO-d6): d 7.92 (br
s, 1H), 7.27 (s, 1H), 6.12 (br s, 1H), 3.91 (s, 3H). MS (ESI)
4.2.3.2.1. Classical strategy. Precipitation reaction condi-
1
tions: 25 ꢀC, 15 h. Yield: 47%. H NMR (500 MHz, DMSO-
m/z 211 and 213 (MH)þ.
d6): d 12.9 (br s, 1H), 8.28 (s, 1H), 8.23 (d, J¼8.4 Hz, 1H),
8.17 (d, J¼7.3 Hz, 1H), 7.87 (dd, J¼8.4 Hz, 1.2 Hz, 1H),
6.30 (d, J¼7.3 Hz, 1H), 3.93 (s, 3H). MS (ESI) m/z 204
(MH)þ.
4.2.3.2.2. a-Blocked position strategy. A mixture of 24
(3.3 g, 13.9 mmol), palladium on charcoal 5% (50% H2O,
2.5 g) in a mixture of ethanol (125 mL) and ethyl acetate
(10 mL) was stirred at room temperature under a hydrogen
atmosphere (3 bar) for 8 h. The catalyst was removed by filtra-
tion over a pad of CeliteÒ, washed with methanol and the
filtrate was concentrated to dryness, giving 2.7 g (99%) of
methyl 4-oxo-1H-quinoline-7-carboxylate hydrochloride 2 as
a solid.
4.2.2.2. Low dilution conditions. A dilution of 10 mL per
gram of substrate was used for the syntheses of 1, 2, 3, 10,
12, 16, 21, 24, 33, 36 and 45. Substrates 19, 23, 32, 35, 44, re-
spectively, gave 21, 24, 33, 36, 45 whereas substrates 9, 11, 15,
respectively, led to mixtures of 1 and 10, 2 and 12, 3 and 16.
4.2.2.2.1. 5-Oxido-1H-1,5-naphthyridin-4-one (21). Crude
yield: 93%. 1H NMR (500 MHz, DMSO-d6): d 8.80 (d,
J¼6.1 Hz, 1H), 8.78 (d, J¼5.9 Hz, 1H), 8.28 (d, J¼9.0 Hz,
1H), 7.91 (dd, J¼9.0 Hz, 6.1 Hz, 1H), 7.10 (d, J¼5.9 Hz,
1H). MS (ESI) m/z 163 (MH)þ.
4.2.2.2.2. Methyl 8-chloro-4-oxo-1H-quinoline-7-carboxy-
late (24). Yield: 96%. 1H NMR (500 MHz, DMSO-d6):
d 8.06 (d, J¼8.4 Hz, 1H), 7.86 (d, J¼6.6 Hz, 1H), 7.56 (d,
J¼8.4 Hz, 1H), 6.12 (d, J¼6.6 Hz, 1H), 3.85 (s, 3H). MS
(ESI) m/z 238 and 240 (MH)þ.
4.2.4. Selective saponification. Synthesis of compounds
13, 16 and 17
A mixture of regioisomers (1 equiv) and LiOH$H2O
(4 equiv) in MeOH (10 mL per gram of mixture) was stirred
overnight at room temperature. The solution was concentrated
and water (10 mL per gram of mixture) was added. The pH
was adjusted to 7 by addition of a 6 N HCl solution, the aque-
ous phase was extracted with DCM, the organic phase was
dried over magnesium sulfate, filtered and concentrated to
give the unreacted regioisomer. The aqueous phase’s pH was
adjusted to 2 by addition of a 2 N HCl solution. The precipi-
tate was collected by filtration, washed with water, ethyl
acetate and ether, to afford the desired acid.
4.2.2.2.3. 5-Methoxy-1H-1,6-naphthyridin-4-one (33). Yield:
1
64%. H NMR (500 MHz, DMSO-d6): d 8.05 (d, J¼5.9 Hz,
1H), 7.75 (d, J¼7.6 Hz, 1H), 6.94 (d, J¼5.9 Hz, 1H), 6.02 (d,
J¼7.6 Hz, 1H), 3.89 (s, 3H). MS (ESI) m/z 177 (MH)þ.
4.2.2.2.4. 8-Bromo-7-methoxy-1H-1,6-naphthyridin-4-one
(36). Yield: 93%. 1H NMR (500 MHz, DMSO-d6): d 11.18 (br
s, 1H), 8.85 (s, 1H), 7.80 (d, J¼7.8 Hz, 1H), 6.09 (d,
J¼7.8 Hz, 1H), 4.03 (s, 3H). MS (ESI) m/z 255 and 257
(MH)þ.
4.2.2.2.5. 5,7-Dichloro-1H-1,6-naphthyridin-4-one (45).
Yield: 91%. 1H NMR (500 MHz, DMSO-d6): d 12.0
(br s, 1H), 7.92 (dd, J¼7.8 Hz, 5.0 Hz, 1H), 7.47 (s, 1H),
6.17 (d, J¼7.8 Hz, 1H). 1H NMR (500 MHz, DMSO-d6/
This procedure was applied to a 60/40 mixture of 2 and
12 and a 65/35 mixture of 3 and 16 to prepare, respectively,
13, 16 and 17. 12 was not isolated.

2780
R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
4.2.4.1. 4-Oxo-1H-quinoline-7-carboxylic acid (13). Yield:
53%. H NMR (500 MHz, DMSO-d6): d 13.4 (br s, COOH),
12.0 (br s, 1H), 8.15 (m, 2H), 7.99 (dd, J¼7.3 Hz, 4.8 Hz,
1H), 7.79 (dd, J¼8.5 Hz, 1.4 Hz, 1H), 6.09 (d, J¼7.3 Hz,
1H). MS (ESI) m/z 190 (MH)þ.
1H), 7.91 (d, J¼5.2 Hz, 1H), 7.78 (d, J¼12.2 Hz, 1H), 7.37
(d, J¼5.2 Hz, 1H), 5.78 (br s, 2H), 5.65 (d, J¼12.2 Hz, 1H),
3.18 (br s, 3H), 2.94 (br s, 3H). MS (ESI) m/z 192 (MH)þ.
The filtrate containing the intermediate 39 was heated to reflux
for 10 h. The solution was concentrated down and the crude
was purified by flash chromatography on silica gel eluting
with 0e15% of methanol in DCM, giving 1.4 g (76%) of
1H-1,7-naphthyridin-4-one 4 as a solid.
1
4.2.4.2. Methyl 6-methoxy-4-oxo-1H-quinoline-5-carboxylate
(16). Yield: 31%. 1H NMR (500 MHz, DMSO-d6): d 11.8
(br s, 1H), 7.87 (d, J¼7.3 Hz, 1H), 7.63 (d, J¼9.1 Hz, 1H),
7.55 (d, J¼9.1 Hz, 1H), 5.91 (d, J¼7.3 Hz, 1H), 3.82 (s,
3H), 3.75 (s, 3H). MS (ESI) m/z 234 (MH)þ.
4.3.1.2. 6-Methoxy-1H-1,7-naphthyridin-4-one (5)
4.3.1.2.1. a-Blocked position strategy. A mixture of 30
(270 mg, 1.28 mmol), TEA (178 mL, 1.28 mmol) and palla-
dium on charcoal 5% (50% H2O, 60 mg) in ethanol (27 mL)
was stirred at room temperature under hydrogen atmosphere
(3 bar) overnight. The catalyst was removed by filtration
over a pad of CeliteÒ and the filtrate was concentrated
down. The crude was purified by flash chromatography on
silica gel eluting with 0e10% methanol in a 1/1 mixture of
ethyl acetate and DCM, giving 126 mg (56%) of 6-methoxy-
4.2.4.3. 6-Methoxy-4-oxo-1H-quinoline-7-carboxylic acid (17).
1
Yield: 69%. H NMR (500 MHz, DMSO-d6): d 13.15 (br s,
1H), 11.8 (br s, 1H), 7.94 (m, 1H), 7.83 (s, 1H), 7.59 (s,
1H), 6.05 (d, J¼7.4 Hz, 1H), 3.88 (s, 3H). MS (ESI) m/z
220 (MH)þ.
4.3. Specific procedures
1
1H-1,7-naphthyridin-4-one 5 as a solid. H NMR (500 MHz,
4.3.1. Synthesis of compounds 4e8, 14, 18, 31, 34, 38,
41, 42
DMSO-d6): d 12.0 (br s, 1H), 8.71 (s, 1H), 7.97 (d,
J¼7.2 Hz, 1H), 7.24 (s, 1H), 6.02 (d, J¼7.2 Hz, 1H), 3.91
(s, 3H). MS (ESI) m/z 177 (MH)þ.
4.3.1.1. 1H-1,7-Naphthyridin-4-one (4)
4.3.1.2.2. Enaminone strategy (only acidic conditions are
described here). A solution of 42 (1.5 g, 4.66 mmol) and
TFA (4 mL) in DCM (15 mL) was stirred at room temperature
overnight. The solution was concentrated down and taken up
into ethyl acetate and stirred for 10 min. The solid was
collected by filtration, washed with ethyl acetate, diethyl ether
and dried, giving 1 g (79%) of the trifluoroacetate salt of
4.3.1.1.1. Classical strategy. To a mixture of crude 20
(15.6 g, 86.6 mmol) and PHMS (13 g, 216 mmol) in ethanol
(500 mL) was added palladium on charcoal 10% (2.5 g) under
argon. The reaction mixture was heated to reflux for 2 h. Fur-
ther palladium on charcoal 10% (2.5 g) was added and the
reaction mixture was heated for an additional 2 h. The hot
mixture was filtered and then allowed to cool down to room
temperature. The filtrate was concentrated and then taken up
into diethyl ether. The upper phase was removed and the lower
phase was stirred at room temperature over weekend. The
resulting precipitate was collected by filtration and purified
by flash chromatography on silica gel eluting with 10% of
methanol in DCM, giving the 1H-1,7-naphthyridin-4-one 4
as a solid (5.8 g, 46%). 1H NMR (500 MHz, DMSO-d6):
d 12.15 (br s, 1H), 9.00 (s, 1H), 8.45 (d, J¼5.3 Hz, 1H),
8.06 (d, J¼7.3 Hz, 1H), 7.09 (d, J¼5.3 Hz, 1H), 6.17 (d,
J¼7.3 Hz, 1H). MS (ESI) m/z 147 (MH)þ.
1
6-methoxy-1H-1,7-naphthyridin-4-one 5 as a solid. H NMR
(500 MHz, DMSO-d6): d 12.25 (br s, 1H), 8.74 (s, 1H), 8.03
(d, J¼7.4 Hz, 1H), 7.25 (s, 1H), 6.10 (d, J¼7.4 Hz, 1H),
3.92 (s, 3H). MS (ESI) m/z 177 (MH)þ.
4.3.1.3. 7-Methoxy-1H-1,6-naphthyridin-4-one (6). To a solu-
tion of 36 (9.18 g, 36 mmol) in methanol (180 mL) were added
ammonium formate (9 g, 144 mmol) and palladium on charcoal
5% (900 mg). Themixturewas heated to reflux for3.5 h. The hot
mixture was filtered, the solid was washed with methanol and
the filtrate was concentrated down. The crude was dissolved in
a 2/3 mixture of methanol and DCM and stirred overnight in
the presence of CaCO3 (9 g). The insoluble was removed by
filtration and the filtrate was concentrated down, giving 6 g
(95%) of 7-methoxy-1H-1,6-naphthyridin-4-one 6 as a solid.
1H NMR (500 MHz, DMSO-d6): d 11.16 (br s, 1H), 8.89 (s,
1H), 7.86 (d, J¼7.6 Hz, 1H), 6.67 (s, 1H), 5.97 (d, J¼7.6 Hz,
1H), 3.92 (s, 3H). MS (ESI) m/z 177 (MH)þ.
4.3.1.1.2. a-Blocked position strategy. A mixture of 26
(52 mg, 0.29 mmol), AcONa (94 mg, 1.15 mmol) and palla-
dium on charcoal 5% (50% H2O, 20 mg) in ethanol (5 mL)
was stirred at room temperature under hydrogen atmosphere
(1.1 bar) for 30 min. The catalyst was removed by filtration
through a pad of CeliteÒ and the filtrate was concentrated
down. Purification by flash chromatography on silica gel
eluting with 10% of methanol in DCM gave 30 mg (71%) of
1H-1,7-naphthyridin-4-one 4 as a solid.
4.3.1.4. 7-Chloro-1H-1,6-naphthyridin-4-one (7). To a suspen-
sion of 45 (215 mg, 1 mmol) in methanol (5 mL) were added
zinc powder (325 mg, 5 mmol) and acetic acid (572 mL,
10 mmol). The reaction mixture was heated to 60 ꢀC for
1.5 h and then the insoluble was removed by filtration. The
filtrate was concentrated down; the crude was taken up into
water and stirred for 15 min. The precipitate was collected
by filtration, washed with a 1/1 mixture of ethanol and diethyl
4.3.1.1.3. Enaminone strategy. A mixture of 38 (2.8 g,
12.7 mmol) and palladium on charcoal 5% (590 mg) in etha-
nol (140 mL) was stirred under hydrogen atmosphere
(1.3 bar) for 2 h. The catalyst was removed by filtration
through a pad of CeliteÒ. An aliquot was concentrated to dry-
ness, to afford 1-(3-aminopyridin-4-yl)-3-dimethylamino-
1
prop-2-en-1-one 39. H NMR (500 MHz, CDCl3): d 8.11 (s,

R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
2781
1
ether and dried, giving 132 mg (73%) of 7-chloro-1H-1,6-
naphthyridin-4-one 7. 1H NMR (500 MHz, DMSO-d6):
d 8.99 (s, 1H), 8.0 (d, J¼6.7 Hz, 1H), 7.50 (s, 1H), 6.17 (d,
J¼6.7 Hz, 1H). MS (ESI) m/z 181 and 183 (MH)þ.
solid. H NMR (500 MHz, DMSO-d6): d 8.15 (t, J¼2.1 Hz,
1H), 8.10 (dd, J¼6.2 Hz, 1.4 Hz, 1H), 7.60 (dd, J¼8.7 Hz,
6.2 Hz, 1H), 7.41 (dd, J¼8.7 Hz, 1.4 Hz, 1H).
4.3.1.8. 2-Methoxypyridin-4-amine (31).14 A mixture of 2-
chloropyridin-4-amine (15.4 g, 120 mmol), copper powder
(1.1 g, 18 mmol) and sodium methylate (16.2 g, 300 mmol)
in methanol (35 mL) was heated to 160 ꢀC in an autoclave
overnight. The insoluble was removed by filtration and the
filtrate was concentrated down. The residue was taken up
into water and extracted several times with diethyl ether.
The combined organic phases were washed with brine, dried
over magnesium sulfate and concentrated down, giving 8.3 g
(56%) of 2-methoxypyridin-4-amine 31 as an oil, which crys-
4.3.1.5. 5-(Methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-
dione (8).2 A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione
(Meldrum’s acid) (100 g, 0.7 mol) in trimethyl orthoformate
(360 mL) was heated to reflux overnight. The solution was
allowed to cool to room temperature and concentrated down.
The resulting brown solid was taken up into diethyl ether, col-
lected by filtration and washed with diethyl ether, giving
69.5 g (54%) of 8 as a white solid. 1H NMR (500 MHz,
CDCl3): d 8.15 (s, 1H), 4.28 (s, 3H), 1.73 (s, 6H).
1
tallised on standing. H NMR (500 MHz, DMSO-d6): d 7.61
4.3.1.6. Methyl 5-amino-2-methoxy-benzoate (14). A mixture
of 2-hydroxy-5-nitro-benzoic acid (2 g, 11 mmol) and potas-
sium carbonate (3.2 g, 23 mmol) in acetone (20 mL) was
stirred at 40 ꢀC for 10 min. Dimethylsulfate (2.2 mL,
23 mmol) was slowly added and the yellow reaction mixture
was heated to reflux for 6 h. The mixture was allowed to
cool to room temperature and diluted with water (200 mL).
The aqueous phase was extracted twice with diethyl ether
and the combined organic phases were dried over magnesium
sulfate, giving 2 g (88%) of methyl 2-methoxy-5-nitro-benzo-
(d, J¼5.7 Hz, 1H), 6.16 (dd, J¼5.7 Hz, 1.6 Hz, 1H), 5.9 (br
s, 2H), 5.80 (d, J¼1.6 Hz, 1H), 3.70 (s, 3H). MS (ESI) m/z
125 (MH)þ.
4.3.1.9. 3-Bromo-2-methoxy-pyridin-4-amine (34). To a solu-
tion of 31 (6.82 g, 55 mmol) in acetonitrile (40 mL) was added
at 10 ꢀC under argon a solution of NBS (9.8 g, 55 mmol) in
acetonitrile (80 mL) over a period of 15 min. The yellow solu-
tion was allowed to warm to room temperature, stirred 30 min
and concentrated down. The residue was taken up into diethyl
ether, washed with water, dried over magnesium sulfate and
concentrated down, giving 11 g (98%) of 3-bromo-2-me-
thoxy-pyridin-4-amine 34, which crystallised on standing. It
was used in the next step without further purification. 1H
NMR (500 MHz, DMSO-d6): d 7.60 (d, J¼5.5 Hz, 1H), 6.16
(d, J¼5.5 Hz, 1H), 6.21 (br s, 2H), 3.80 (s, 3H). MS (ESI)
m/z 203 and 205 (MH)þ.
1
ate. H NMR (500 MHz, CDCl3): d 8.71 (d, J¼2.7 Hz, 1H),
8.37 (dd, J¼9.4 Hz, 2.7 Hz, 1H), 7.08 (d, J¼9.4 Hz, 1H),
4.03 (s, 3H), 3.94 (s, 3H).
A solution of methyl 2-methoxy-5-nitro-benzoate (2 g,
94 mmol) in ethyl acetate (30 mL) was stirred under hydrogen
atmosphere (1.4 atm) in the presence of palladium on charcoal
5% (150 mg) for 5 h. The catalyst was removed by filtration
through pad of CeliteÒ and the filtrate was concentrated, giv-
ing 1.7 g (99%) of methyl 5-amino-2-methoxy-benzoate 14.
1H NMR (500 MHz, DMSO-d6): d 6.89 (d, J¼2.9 Hz, 1H),
6.85 (d, J¼8.7 Hz, 1H), 6.73 (dd, J¼8.7 Hz, 2.9 Hz, 1H),
4.87 (br s, 2H), 3.74 (s, 3H), 3.67 (s, 3H). MS (ESI) m/z
182 (MH)þ.
4.3.1.10. 3-Dimethylamino-1-(3-nitropyridin-4-yl)prop-2-en-1-
one (38). A solution of acetyl pyridine 3717 (2.4 g,
14.5 mmol) and DMFDEA (3.46 mL, 20.2 mmol) in toluene
(30 mL) was heated to 80 ꢀC for 4 h and then the solution
was concentrated down. The resulting dark oil was stirred in
diethyl ether (10 mL) for 10 min and the formed precipitate
was collected by filtration, giving 2.8 g (88%) of (E)-3-dime-
thylamino-1-(3-nitropyridin-4-yl)prop-2-en-1-one 38 as an
4.3.1.7. 1-Oxidopyridin-3-amine hydrochloride (18). A suspen-
sion of 1-oxidopyridine-3-carboxylic acid (60 g, 0.43 mol),
DIPEA (150 mL, 0.86 mol) and DPPA (98 mL, 0.45 mol) in
a mixture of dioxane (900 mL) and tert-butanol (300 mL) was
stirred at room temperature for 30 min under argon. The result-
ing solution was heated at reflux for 2 h. The solution was al-
lowed to cool to room temperature and concentrated down.
The crude was diluted with DCM, washed with a saturated
aqueous solution of NaHCO3, twice with a saturated aqueous
solution of ammonium chloride and then water. The organic
phase was dried over magnesium sulfate, giving 263 g of crude
Boc-intermediate, which was used in the next step without any
further purification.
1
yellow solid. H NMR (500 MHz, CDCl3): d 9.21 (br s, 1H),
8.83 (d, J¼4.7 Hz, 1H), 8.2e7.5 (br s, 1H), 7.41 (d,
J¼4.7 Hz, 1H), 5.22 (br s, 1H), 3.16 (br s, 3H), 2.90 (s, 3H).
MS (ESI) m/z 222 (MH)þ.
4.3.1.11. tert-Butyl N-(4-acetyl-6-methoxy-pyridin-3-yl)carba-
mate (41). A solution of tert-butyl N-(6-methoxypyridin-3-yl)-
carbamate 4020 (3.6 g, 16.1 mmol) and TMEDA (7.45 mL,
49.8 mmol) in ether (84 mL) was cooled down to ꢁ70 ꢀC under
Argonand treated slowly with a1.6 Msolution of n-BuLi in hex-
anes (30 mL, 48.2 mmol). The resulting solution was allowed to
warm to ꢁ10 ꢀC and kept under ꢁ10 ꢀC for 2 h. The milky
slurry was cooled down to ꢁ70 ꢀC and N-methoxy-N-methyl-
acetamide (Weinreb’s acetamide) (3.4 mL, 32.1 mmol) was
added dropwise and then the reaction mixture was allowed to
warm to 10 ꢀC. The solution was poured into a mixture of ice
A solution of the crude obtained above was stirred in a 4 N
solution of HCl in dioxane (1 L) at room temperature over-
night. The resulting precipitate was collected by filtration,
washed with dioxane, diethyl ether and dried, giving 53 g
(84%) of 1-oxidopyridin-3-amine hydrochloride 18 as a white

2782
R. Morgentin et al. / Tetrahedron 64 (2008) 2772e2782
3. (a) Briehl, H.; Lukosch, A.; Wentrup, C. J. Org. Chem. 1984, 49, 2772; (b)
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and solid ammonium chloride and then diluted with ethyl
acetate. The two phases were separated and the aqueous phase
was extracted twice with ethyl acetate. The combined organic
phases were washed with brine, dried over magnesium sulfate
and concentrated down. The crudewas purified by flash chroma-
tography on silica gel eluting with 2% of ethyl acetate in DCM,
giving 1.6 g (37%) of tert-butyl N-(4-acetyl-6-methoxy-pyri-
din-3-yl)carbamate 41 as a solid. 1H NMR (500 MHz,
CDCl3): d 9.59 (br s, 1H), 9.18 (s, 1H), 7.08 (s, 1H), 3.95 (s,
3H), 2.62 (s, 3H), 1.52 (s, 9H). MS (ESI) m/z 267 (MH)þ.
4. Wang, X.-D.; Sun, L.-Q.; Sit, S.-Y.; Sin, N.; Scola, P. M.; Hewawasam, P.;
Good, A. C.; Chen, Y.; Campbell, J. A. W.O. Patent 03099274, 2003.
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6. Bhaskar, D. H.; Rajesh, H. D. Tetrahedron Lett. 1996, 37, 6375.
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Stuttgart, 2004; Vol. 15, pp 959e964.
8. Greco, C. V.; Hunsberger, I. M. J. Heterocycl. Chem. 1970, 7, 761.
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Rao, J. Synlett 2002, 349.
4.3.1.12. tert-Butyl N-[4-[(E)-3-dimethylaminoprop-2-enoyl]-
6-methoxy-pyridin-3-yl]carbamate (42). A solution of 41
(1.45 g, 5.45 mmol) and DMFDEA (1.31 mL, 7.63 mmol) in
toluene (10 mL) was heated to 85 ꢀC for 1.5 h. The solution
was concentrated down. The crudewas purified byflash chroma-
tography on silica gel eluting with 0e2% methanol in DCM,
giving 1.4 g (80%) of tert-butyl N-[4-[(E)-3-dimethylamino-
prop-2-enoyl]-6-methoxy-pyridin-3-yl]carbamate 42. 1H NMR
(500 MHz, CDCl3): d 8.49 (br s, 1H), 8.99 (br s, 1H), 7.77 (d,
J¼12.3 Hz, 1H), 6.92 (s, 1H), 5.54 (d, J¼12.3 Hz, 1H), 3.94
(s, 3H), 3.19 (s, 3H), 2.94 (s, 3H), 1.50 (s, 9H). MS (ESI) m/z
322 (MH)þ.
11. Breslow, D. S.; Bloom, M. S.; Shivers, J. C.; Adams, J. T.; Weiss, M. J.;
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Denney, M. L.; Hite, G. A.; Kinnick, M. D.; Vasileff, R. T.; Morlin, J.
M., Jr.; Lin, H.-S.; Richett, M. E.; Harper, R. W.; McGill, J. M.; Anderson,
A.; Harn, N. K.; Loncharich, R. J.; Schevitz, R.W. U.S. Patent 6,177,440,
2001.
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Acknowledgements
18. Bakke, J. M. Pure Appl. Chem. 2003, 75, 1403.
We would like to acknowledge the excellent NMR exper-
tise of Christian Delvare.
19. CAUTION: Nitrated pyridines can be powerful explosives. Appropriate
safety and handling procedures should be employed. (a) Spitzner, D.
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