Studies on pyrrolidinones. Synthesis of fused 1,5-naphthyridines

Article abstract of DOI:10.1016/j.tet.2012.04.056

The synthesis of new condensed indolizinediones derived from pyroglutamic acid is described. The Semmler-Wolff transposition of the oxime of these ketones leads to fused dihydro-1,5-naphthyridinones. Easy introduction of side amino chains indicates that p

Full text of DOI:10.1016/j.tet.2012.04.056

Tetrahedron 68 (2012) 5644e5654
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Studies on pyrrolidinones. synthesis of fused 1,5-naphthyridines
a
,
,
c
a
a,
b,
d
Rufine Akue-Gedu b, Daniel Couturier a , Jean-Pierre Henichart , Benoît Rigo
, Gerard Sanz ,
*
ꢀ
ꢀ
ꢀ
Luc Van Hijfte d, Anne Bourry a
,
b
a Univ Lille Nord de France, 59000 Lille, France
b UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, 59046 Lille, France
c
ꢀ
ꢀ
ꢀ
ꢀ
Laboratoire d’Ingenierie Moleculaire, Universite des Sciences et Technologies de Lille I, 59655 Lille, France
d Janssen Research and Development, 2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of new condensed indolizinediones derived from pyroglutamic acid is described.
The SemmlereWolff transposition of the oxime of these ketones leads to fused dihydro-1,5-
naphthyridinones. Easy introduction of side amino chains indicates that potential DNA-intercalating
heterocyclic systems fused on 1,5-naphthyridine nucleus could be obtained in these series.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 February 2012
Received in revised form 10 April 2012
Accepted 13 April 2012
Available online 21 April 2012
This article is dedicated to the memory of
ꢀ
ꢀ
co-author Dr. Rufine Akue-Gedu, a dear
colleague who contributed much to the
chemistry of pyroglutamic derivatives, and
who sadly passed away in December 2011,
at 43 years
Keywords:
Pyroglutamic acid
Fused indolizinediones
Fused 1,5-naphthyridines
SemmlereWolf rearrangement
N-Acyliminium
1. Introduction
pyroglutamic acids.1a,1f,1i,1l,1m,6 Now, N-methylindoles derivatives
14 and 15 were obtained by reacting 12 and 13 with dimethylsulfate
The benzo[f]indolizinedione skeleton1 of compounds 1 is a very
rich scaffold obtained from pyroglutamic acid.2 We have previously
described that treatment of 1 in acidic3,4 or basic4,5 media can lead
to allylic dehydration, retro-pinacol, pinacol-like rearrangements,
and enamide reactions, which provide a variety of new isoquino-
lines 2e7 or succinimides 8 (Fig. 1). In order to obtain compounds
with potential biological properties, we studied the synthesis then
the reactivity of new oximes in these series, focusing toward
products issued from their SemmlereWolff rearrangement.
in the presence of potassium carbonate. Interestingly, ketone 12
needed only 4 h to deliver 90% of product 14 while ketone 13,
substituted by an electro-donating methoxy group required 24 h to
yield the same amount of ketone 15. Oxime 16 was already de-
scribed by Martin,1c and in analogous series, the OH group of the
oxime was generally placed in anti position from the aromatic
group.1c,7 We have utilized the conditions described1c (hydroxyl-
amine hydrochloride in an EtOH/H2O/AcONa mixture) to prepare
products 16e22. It can be observed in Table 1 that even a little steric
hindrance, or the introduction of the methoxy group in 13 and 15,
increased the reaction time (compare entries 4 to 6, 5 to 7, 4 to 5
and 6e7).
While checking reactivity of ketone 23 with the withdrawing
N-tosyl protecting group,1m we found that the main product
obtained was the known acid 251m (85%) accompanied by a low
amount of a compound assigned as oxime 24 on the basis of his NMR
spectrum (Scheme 2). We have previously described that oxidation
of amidoketones, with the same scaffold as compounds 9e13
2. Results and discussion
2.1. Synthesis of oximes
The starting ketones 9e13 have previously been synthesized
from FriedeleCrafts cyclization of the corresponding N-substituted
* Corresponding author. E-mail address: benoit.rigo@hei.fr (B. Rigo).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.056

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5645
the same ways as when it was oxidized in MeONa/MeOH sol-
utions,1m bubbling nitrogen in the reaction mixture did not avoid
oxidation of the starting ketone. It is to be noted that hydrolysis of
the tosyl group probably initiated by hydroxylamine, occurred
somewhere during this process8a (Scheme 2).
In order to increase the chemical diversity for biological testing,
oximes ether 29 and 30 were also synthesized. When stirring oxime
16 and benzyl chloride in refluxing acetone, in the presence of
potassium carbonate for 30 h, only low yields of desired products
were observed along with many by-products. However, by using
benzyl bromide in the biphasic water/dichloromethane solvent,
tetrabutylammonium hydrogensulfate as a phase transfer agent
and sodium hydroxide as the base,9a 62% of pure oxime ether 29
was obtained (Scheme 3).
HO2C
N
Ar
Ar
N
N
O
O
O
N
N
Ar
Ar
Ar
CO2H
2
3
4
O
OH
O
CO2H
O
O
N
H
N
N
Ar
Ar
5
Pyroglutamic acid
1
2.2. SemmlereWolff rearrangement
In the series of fused indolizinediones, treatment of oximes 30
with PPA can led to a Beckman rearrangement (Scheme 4, e.g.,
lactam 31),1e,7,8b to the formation of a nitrile (e.g., pyrrolinone
32)1c,9b or to a SemmlereWolff transposition (e.g., tetrahydropyr-
idones 33).1c,1e,8b Noteworthy, the mechanism leading to 32 or 33
involves the formation of a stabilized N-acyliminium salt,10 and in
the case of products 33, is quiet similar to the one leading to
compound 28 (Scheme 2).
CO2H
CO2H
OH
O
N
N
N
O
Ar
Ar
Ar
HO2C
6
7
Fig. 1. Some compounds issued from pyroglutamic acid.
8
The synthesis of compound 34 described by Martin with
52e63% yields1c was repeated in their conditions (PPA, 100 ꢀC).1c In
our hands, this reaction was irreproducible, with yields ranging
from 50% to 75%, and thus we investigate other acidic media. A
catalytic amount of triflic acid in trifluoroacetic acid, or Eaton re-
agent11,12 led to a reproducible 71e75% yield but the best result was
obtained using methanesulfonic acid, neat at 100 ꢀC for 1 h (Table 2,
entries 1e4). However, no general conditions were found for the
other oximes of the set (Scheme 5), and it proved necessary to
adjust the media depending on the substituents present on the
aromatic group. For instance, Eaton reagent and oxime 19 gave an
irreproducible 85% yield of lactam 37, while a catalytic amount of
triflic acid in methanesulfonic acid led to a reproducible 76% yield
of heterocycle 37 (Table 2, entries 7 and 8). Another interest in
using mixtures of triflic acid in trifluoroacetic or methanesulfonic
acid is the easy quenching of the reaction media when large
quantities of oximes were employed. Also, traces of dienes 413,13
(Scheme 5) were sometimes observed in the crude. Finally, ther-
mal transposition of oxime 20 was also checked without interesting
results; in one instance only, at a temperature superior to 160 ꢀC,
a very few amount of indolodiazepine 42 was observed and char-
acterized by NMR, but we were unable to reproduce this formation.
Table 1
Synthesis of oximes 16e22
NOH
R4
NOH
O
O
N
N
R
N
R3
R2
16-18
R1
19-22
Entry Oxime
R
R1
R2, R3
R4
Time (hours) Yield (%)
1
2
3
4
5
6
7
16
17
18
19
21
20
22
H, H
OCH2O
OCH3, OCH3 OH 18
H
H
5
5
95
92
82
75
78
60
65
H
H
H
OCH3
H
5
24
24
48
CH3
CH3 OCH3
(Scheme 1), in MeOH/MeONa was very fast, ultimately leading to
acids 7 (Fig. 1).1m,5 We thus thought that ketone 23 underwent an
oxidation reaction from the oxygen dissolved in EtOH/H2O.
Hydroxyketone 26 thus formed was not isolated. Formation of an
N-acyliminium salt 27 occurred followed by the opening of the
lactam ring to provide iminoketone 28 then hydroxyquinoline 25. In
2.3. Synthesis of fused naphthyridones
Many fused naphthyridones have already been described,14 and
for some of them with interesting biological properties. We were
now interested in aromatizing the previous compounds 34e40 in
X
N
X
X
X
X
N
O
O
O
O
O
N
N
N
N
N
OH
R
R
OMe
O
O
OMe
MeO
9 X = O
16 X = NOH
10 X = O
17 X = NOH
11 X = O
18 X = NOH
12 R = H X = O
14 R = Me X = O
19 R = H X = NOH
20 R = Me X = NOH
13 R = H X = O
15 R = Me X = O
21 R = H X = NOH
22 R = Me X = NOH
(i)
(ii)
(i)
(ii)
Scheme 1. Reaction conditions: (i) Me2SO4/K2CO3/acetone, reflux, 90%; (ii) H2NOH, HCl/AcONa/EtOH/H2O, reflux; exact conditions and yields are given in Table 1.

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5646
CO2H
OH
O
N
NOH
Tos
O
O
N
N
N
(i)
+
Tos
H
N
N
O2
AcONa
EtOH/H2O
MeO
MeO
MeO
23
24
25 85%
CO2H
O
OH
O
+
H2O
O
N
O
O
O
O
N
N
N
N
+
R
N
R
R
N
R
N
H
MeO
MeO
MeO
28
MeO
26
27
Scheme 2. Reaction conditions: (i) H2NOH, HCl/AcONa/EtOH/H2O, reflux 5 h.
yielded a small quantity of heterocycle 49 (Scheme 6). This naph-
thyridone 49 was not obtained by refluxing compound 37 with
DDQ18 in acetic acid or with Pd/C19 in naphthalene at 175 ꢀC.
However, dehydrogenation of dihydropyridones 37e40 to fused
naphthyridones 49e52 proceeded with good yields by refluxing
them with selenium oxide20 in acetic acid for 15e36 h (Scheme 6).
O
N
NOH
(i)
O
O
N
N
+
CH2Br
16
29 62%
2.4. Synthesis of fused naphthyridines
Scheme 3. Reaction conditions: (i) 1 M NaOH, nBu4NþSO4Hꢁ, CH2Cl2, reflux 12 h.
The next step was the synthesis of products substituted by a 2-
amino or a 2-methoxy group. They were obtained from precursors
prepared by chlorination of the previous naphthyridones 49e52.
Refluxing compound 49 in POCl3 for 10 h led to 56% of fused
chloropyridine 53. However, in the same conditions N-methyl
heterocycle 50 yielded only 5% of 54 after 48 h of reflux. Exchanging
phenylphosphonic dichloride21 for phosphorus oxychloride at
150 ꢀC for 36 h raised the yield to 80%, and working at 180 ꢀC for
15 h in a closed TeflonÒ bottle allowed the obtention of 85% of
heterocycle 54. These optimized conditions were utilized to obtain
products 55 and 56 in good yields (Scheme 7). It is to be noted that
the use of PhPOCl2 at 180 ꢀC led to cleaner products than using
POCl3 at 110 ꢀC.
order to have access to new 2-subtituted compounds with potential
DNA-intercallating properties. Many methods are described for the
aromatization of dihydropyridones.15 Bromine in AcONa/AcOH16a
led only, in an irreproducible manner, to very few amounts of
pyridones 43e45 from lactams 34e36 (Scheme 6), and in the case
of indole derivative 37, its aromatization yielded mixtures of many
brominated products. However, when lactam 34 was refluxed with
1.2 equiv of bromine in bromobenzene for 12 h,16b 56% of pyridone
43, accompanied by 31% of a monobrominated compounds 46
(position of the bromine atom was not determined) were obtained;
alternatively,17 by heating 34 with thionyl chloride for 9 h, it fur-
nished a mixture of 21% of pyridone 47 containing a chlorine and
a sulfur atom (position of substituents was not determined), and of
34% of chloronaphthyridine 48. In the same conditions, lactam 37
Now, naphthyridine 53 was reacted with N,N-diethy-
lethylenediamine. In refluxing methanol or ethanol, the yield of 57
H
.
N
H
+
N
.
N
O
O
O
(i)
H2O
O
H
N
N
N
+
O
Ar
30a
S
S
31
.
N
N
H
+
+
.
(i)
(i)
O
O
O
O
O
O
O
O
H
N
N
CN
CN
CN
N
N
N
N
Cl
Cl
Cl
Ar
30b
32
O
H
.
.
+
H
+
NH
NH
NH2
NH
O
O
H
N
N
N
+
+
Ar
Ar
Ar
Ar
33
Ar
30c
Scheme 4. Rearrangements of oximes in acidic conditions. Reaction conditions: (i) PPA, 100e120 ꢀC.

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5647
Table 2
Synthesis of fused dihydropyridones
O
O
NH
NH
N
N
R4
R3
R
N
R2
R1
37-40
34-36
Entry
Dihydropyridone
R
R1
R2, R3
R4
Conditions
Temperature (hours)
Yield (%)
1
2
3
4
5
6
7
8
34
34
34
34
35
36
37
37
38
39
40
H, H
H, H
H, H
H, H
OCH2O
OCH3, OCH3
H
H
H
H
H
OH
PPA
100 (0.15)
100 (0.15)
72 ꢀC (4)
100 (1)
72 (4)
521c
71
75
84
81
70
85
76
68
86
78
MeSO3H/P2O5
CF3CO2H/CF3SO3H
MeSO3H
CF3CO2H/CF3SO3H
CF3CO2H/CF3SO3H
MeSO3H/P2O5
MeSO3H/CF3SO3H
CF3CO2H/CF3SO3H
MeSO3H/CF3SO3H
CF3CO2H/CF3SO3H
72 (6)
H
H
H
CH3
CH3
H
H
OCH3
H
OCH3
100 (1)
120 (36)
72 (24)
120 (4)
72 (4)
9
10
11
O
indicates that potential DNA-intercalating heterocyclic systems
fused on 1,5-naphthyridine nucleus could be obtained in these
series.
NOH
+
H
NH
O
O
N
N
N
R3
R3
R3
R2
R2
R2
R2
4. Experimental section
4.1. General
R2
16 R2, R3 = H
17 R2 = OCH2O, R3 = H
18 R2 = OCH3, R3 = OH
R2
34
41
35
36
Melting points were determined using an Electrothermal ap-
paratus and are uncorrected. 1H and 13C NMR spectra were
obtained on a Varian Gemini 2000 at 200 and 50 MHz, re-
spectively; noteworthy, NMR spectra of most of the compounds
described are strongly dependent on concentration and solvent
utilized. IR spectra were obtained in ATR mode on a FTIR Bruker
Tensor 27. Thin layer chromatographies were performed on pre-
coated Kieselgel 60F254 plates. MS were obtained by LC-MS on
O
H
N
NOH
+
NH
O
O
N
H
N
N
O
R
R
N
N
NH
MeO
R1
R1
19 R, R1 = H
20 R = H, R1 = OCH3
21 R = CH3, R1 = H
37
38
42
a
HPLC combined with a Surveyor MSQ (Thermo Electron)
39
40
equipped with an APCI-source. Microanalyses were performed by
22 R = CH3, R1 = OCH3
ꢀ
the "Service de Microanalyses" of LSEO, Universite de Bourgogne,
Dijon, France.
Scheme 5. Synthesis of fused dihydropyridones. Reaction conditions: See Table 2.
4.2. 10-Methyl-5,10-dihydro-1H-indolizino[7,6-b]indole-
3,11(2H,11aH)-dione (14)
was only 5%, which rose up to 80% when boiling in neat amine (Bp
146 ꢀC) for 24 h. However, in the same conditions compound 54 led
only to 45% of product 58 after 72 h. In the same way as for the
chlorination, working in a closed TeflonÒ bottle allow to obtain
a better yield (150 ꢀC, 15 h, 85%) of product 58, and these conditions
were utilized to prepare 59 and 60 in good yields (Scheme 7). On
the other hand, refluxing chloropyridine 53 in a MeONa/MeOH
mixture led quantitatively to fused methoxynaphthyridine 61
(Scheme 7).
A stirred mixture of ketone 12 (55.6 g, 0.22 mol), potassium
carbonate (30.8 g, 0.22 mol) and dimethylsulfate (56.2 g, 0.45 mol)
in acetone (300 mL) was refluxed for 4 h. The solid obtained upon
evaporation was stirred in dichloromethane. After washing three
times with water, the organic phase was dried (Na2SO4). The solid
obtained was recrystallized from acetone to give 90% of ketone 14
as light brown powder; mp (acetone) 186e188ꢀC; Rf (EtOAc) 0.6; IR
n
(cmꢁ1): 1647, 1610, 1505, 1475; 1H NMR (CDCl3)
d (ppm):
2.37e2.66 (m, 4H), 4.10 (s, 3H), 4.35e4.45 (m, 1H), 4.41 (d,
J¼17.7 Hz, 1H), 5.53 (d, J¼17.7 Hz, 1H), 7.20 (td, J¼7.0, 1.3 Hz, 1H),
7.40 (dt, J¼7.0, 1.0 Hz, 1H), 7.47 (td, J¼8.2, 1.3 Hz, 1H), 7.64 (dt, J¼8.2,
3. Conclusion
In this paper, we described the synthesis of new condensed
indolizinediones derived from pyroglutamic acid, and the Semm-
lereWolff transposition of the oxime of these ketones, which
furnished novel heterocyclic scaffolds in the fused naphthyridine
series. Noteworthy, the easy introduction of side amino chains
1.0 Hz, 1H); 13C NMR (CDCl3)
d (ppm): 20.8 (CH2), 30.2 (CH2), 31.6
(CH3), 37.2 (CH2), 62.7 (CH), 110.5 (CH), 121.0 (CH), 121.2 (CH), 122.7
(CH, C), 125.1 (C), 127.6 (C), 140.3 (C), 174.0 (C), 188.1 (C). Anal. Calcd
for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.58; H, 5.87;
N, 10.77.

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
O
NH
N
R1
43 R1, R2 = H
44 R1 = H, R2 = OCH2O
45 R1 = OH, R2 = OCH3
R2
R3
(i)
very poor yields
SH
N
Br
Cl
O
O
Cl
O
NH
R1
NH
N
NH
N
N
N
N
N
(iii)
(ii)
+
+
R2
R3
34 R1, R2, R3 = H
35 R1 = H; R2R3 = OCH2O
36 R1 = OH; R2, R3 = OCH3
46 31%
43 56%
47 21%
48 34%
O
O
O
NH
NH
NH
N
N
N
(ii)
(iv)
R
R
N
N
NH
R1
R1
very poor yields
49
37
R, R1 = H
49 15h, 76%
50 15h, 86%
51 24h, 60%
39
38
40
R = CH3, R1 = H
R = H, R1 = OCH3
R = CH3, R1 = OCH3
52 24h, 83%
Scheme 6. Reaction conditions: (i) Br2, AcONa, AcOH, 20 ꢀC, 12 h; (ii) SOCl2, reflux, 12 h; (iii) Br2, PhBr, reflux, 12 h; (iv) SeO2, AcOH, reflux.
4.3. 7-Methoxy-10-methyl-5,10-dihydro-1H-indolizino[7,6-b]
indole-3,11(2H,11aH)-dione (15)
4.4. 1,10a-Dihydropyrrolo[1,2-b]isoquinoline-3,10(2H,5H)-
dione 10-oxime (16)
A stirred mixture of ketone 13 (11.6 g, 43 mmol), potassium car-
bonate (5.9 g, 43 mmol), and dimethylsulfate (10.8 g, 90 mmol) in
acetone (200 mL) was refluxed for 4 h. The solid obtained upon
evaporation was stirred in dichloromethane. After washing three
times with water, the organic phase was dried (Na2SO4). The solid
obtained was recrystallized from acetone to give 90% of ketone 15 as
a white powder; mp (acetone) 188e190 ꢀC; Rf (EtOAc/MeOH 95/5)
A stirred mixture of ketone 9 (20.4 g, 101 mmol), sodium ac-
etate trihydrate (28.9 g, 213 mmol), and hydroxylamine hydro-
chloride (14.1 g, 203 mmol) in ethanol (160 mL) and water
(160 mL) was refluxed for 5 h. The solid obtained upon cooling at
room temperature was filtered and the filtrate was partly evap-
orated to give a solid. The combined solids were washed with
cold (4 ꢀC) water, then recrystallized from ethanol to give 95%
of oxime 16 as a white powder; mp (ethanol) 215e217 ꢀC
0.66; IR n d (ppm):
(cmꢁ1): 1677, 1658, 1505, 1446; 1H NMR (CDCl3)
2.34e2.65 (m, 4H), 3.87 (s, 3H), 4.07 (s, 3H), 4.37 (d. J¼17.0 Hz, 1H),
4.37e4.48 (m,1H), 5.48 (d, J¼17.0 Hz,1H), 6.97 (d, J¼2.4 Hz,1H), 7.13
(dd, J¼9.1, 2.4 Hz, 1H), 7.29 (d, J¼9.1, Hz, 1H); 13C NMR (CDCl3)
(lit.213.5e2161c); IR
n
(cmꢁ1): 3139, 1648, 1505, 1466; 1H NMR
(CDCl3) (ppm): 1.84e2.22 (m, 1H), 2.29e2.72 (m, 2H), 2.86e3.11
d
(m, 1H), 4.00 (d, J¼15.0 Hz, 1H), 4.98 (t, J¼8.4 Hz, 1H), 5.13
d
(ppm): 20.9 (CH2), 30.3 (CH2), 31.8(CH3), 37.3 (CH2), 55.7 (CH3), 62.8
(d, J¼15.0 Hz, 1H), 7.28 (m, 3H), 7.86 (d, J¼6.8 Hz, 1H);13C NMR
(CH), 100.4 (CH),111.7 (CH),120.0 (CH), 122.8 (C), 124.2 (C), 128.4 (C),
136.1 (C), 154.9 (C), 174.1 (C), 188.0 (C). Anal. Calcd for C16H16N2O3:
C, 67.59; H, 5.67; N, 9.85. Found: C, 67.62; H, 5.90; N, 9.69.
(DMSO-d6) d (ppm): 24.5 (CH2), 30.0 (CH2), 40.3 (CH2), 55.0 (CH),
126.4 (CH), 126.9 (CH), 129.7 (C, CH), 134.2 (CH), 135.2 (C), 152.9
(C), 172.4 (C).
Scheme 7. Synthesis and reaction of chloronaphthyridines.

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5649
4.5. 9,9a-Dihydro[1,3]dioxolo[4,5-g]pyrrolo[1,2-b]
isoquinoline-7,10(5H,8H)-dione 10-oxime (17)
ethanol to give 60% of oxime 20 as a grayewhite powder; mp
(ethanol) 243e245 ꢀC; Rf (EtOAc) 0.52; IR (cmꢁ1): 3166, 1653,
1594, 1461; 1H NMR (CDCl3)
(ppm): 1.97e2.20 (m, 1H), 2.28e2.65
n
d
A stirred mixture of ketone 10 (10.0 g, 41 mmol), sodium acetate
trihydrate (11.7 g, 86 mmol), and hydroxylamine hydrochloride
(5.7 g, 82 mmol) in ethanol (90 mL) and water (90 mL) was refluxed
for 5 h. The solid obtained upon cooling at room temperature was
filtered, washed with cold (4 ꢀC) water and then recrystallized from
ethanol to give 92% of a 80/20 mixture of the two isomers of oxime
(m, 2H), 3.02e3.21 (m, 1H), 4.01(s, 3H), 4.04 (d, J¼16.1 Hz, 1H), 4.92
(dd, J¼7.2, 7.0 Hz, 1H), 5.38 (d, J¼16.1 Hz, 1H), 7.11 (tdd, J¼8.1, 5.6,
2.5 Hz, 1H), 7.27 (td, J¼7.4 Hz, 1H), 7.32 (dd, J¼8.1, 0.9 Hz, 1H), 7.53
(dt, J¼7.4, 1.0 Hz, 1H), 10.97 (s, 1H, deuterium oxide exchangeable);
13C NMR (DMSO-d6)
d (ppm): 25.3 (CH2), 29.9 (CH2), 32.5 (CH3),
35.3 (CH2), 55.7 (CH), 110.0 (CH), 114.0 (C), 119.0 (CH), 119.6 (CH),
123.3 (CH), 123.7 (C), 127.6 (C), 138.7 (C), 149.5 (C), 172.5 (C). Anal.
Calcd for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 67.01; H,
5.77; N, 15.38.
17 as a white powder; mp (ethanol) 205e229 ꢀC; IR
n
(cmꢁ1): 3260,
1710, 1480, 1230; 1H NMR (CDCl3)
d
(ppm): 1.83e2.11 (m, 1H),
2.27e2.65 (m, 2H), 2.86e3.10 (m, 1H), 3.88 (d, J¼15.8 Hz, 1H), 4.89
(t, J¼8.2 Hz, 1H), 5.01 (d, J¼15.8 Hz, 1H), 5.99 and 6.04 (2s, 80/20,
2H), 6.66 and 6.71 (2s, 80/20, 1H), 7.31 and 7.50 (2s, 80/20, 1H); 13C
4.9. 7-Methoxy-5,10-dihydro-1H-indolizino[7,6-b]indole-
3,11(2H,11aH)-dione 11-oxime (21)
NMR (DMSO-d6)
d (ppm): 25.6 (CH2), 30.8 (CH2), 41.1 (CH2), 55.7
(CH), 102.3 (CH2), 104.5 (CH), 107.1 (CH), 123.9 (C), 131.1 (C), 147.7
(C), 149.2 (C), 153.6 (C), 173.1 (C). Anal. Calcd for C13H12N2O4: C,
60.00; H, 4.65; N, 10.76. Found: C, 59.77; H, 4.58; N, 10.75.
A stirred mixture of ketone 13 (12.0 g, 44 mmol), sodium acetate
trihydrate (12.1 g, 90 mmol), and hydroxylamine hydrochloride
(6.2 g, 90 mmol) in ethanol (100 mL) and water (50 mL) was
refluxed for 24 h. The solid obtained upon evaporation was washed
with cold (4 ꢀC) water then recrystallized from EtOAc/MeOH to give
4.6. 9-Hydroxy-7,8-dimethoxy-1,10a-dihydropyrrolo[1,2-b]
isoquinoline-3,10(2H,5H)-dione 10-oxime (18)
78% of oxime 21 as
232e234 ꢀC; Rf (EtOAc/MeOH 95/5) 0.58; IR
1677, 1642, 1500, 1482; 1H NMR (CDCl3)
4H), 3.85 (s, 3H), 4.26 (d, J¼16.7 Hz, 1H), 4.54e4.66 (m, 1H), 5.25 (d,
J¼16.7 Hz, 1H), 6.94 (dd, J¼9.5, 2.5 Hz, 1H), 6.94 (d, J¼2.5 Hz, 1H),
7.35 (d, J¼9.5 Hz, 1H), 10.13 (s, 1H, deuterium oxide exchangeable),
11.34 (s, 1H, deuterium oxide exchangeable); 13C NMR (CDCl3)
a
white powder; mp (EtOAc/MeOH)
(cmꢁ1): 3400, 3300,
(ppm): 2.43e2.62 (m,
A stirred mixture of ketone 11 (10.0 g, 36 mmol), sodium acetate
trihydrate (10.3 g, 76 mmol), and hydroxylamine hydrochloride
(5.0 g, 72 mmol) in ethanol (80 mL) and water (80 mL) was refluxed
for 18 h. The solid obtained upon cooling at room temperature was
filtered, washed with cold (4 ꢀC) water then recrystallized from
methanol to give 82% of oxime 18 as white powder; mp (methanol)
n
d
140e142 ꢀC; IR
(CDCl3/CF3CO2H)
n
(cmꢁ1): 3220, 1660, 1550, 1440, 1110; 1H NMR
(ppm): 2.20e2.46 (m, 1H), 2.55e2.90 (m, 2H),
d (ppm): 22.0 (CH2), 30.1 (CH2), 37.1 (CH2), 55.8 (CH3), 57.4 (CH),
d
100.8 (CH), 111.7 (CH), 112.1 (CH), 114, 5 (C), 119.9 (C), 126.0 (C),
129.9 (C), 135.5 (C), 154.6 (C), 173.6 (C). Anal. Calcd for C15H15N3O3,
MeOH: C, 61.78; H, 5.69; N, 13.95. Found: C, 62.11; H, 5.34; N, 13.59.
3.20e3.42 (m, 1H), 3.92 (s, 3H), 4.00 (s, 3H), 4.11 (d, J¼16.4 Hz, 1H),
5.16 (t, J¼8.3 Hz, 1H), 5.16 (d, J¼16.4 Hz, 1H), 6.57 (s, 1H). 13C NMR
(DMSO-d6)
d (ppm): 25.7 (CH2), 30.6 (CH2), 41.1 (CH2), 55.4 (CH),
56.8 (CH3), 60.7 (CH3), 102.4 (CH), 108.2 (CH), 132.1 (C), 136.0 (C),
152.6 (C), 154.8 (C), 157.8 (C), 173.1 (C). Anal. Calcd for C14H16N2O5:
C, 57.53; H, 5.52; N, 9.58. Found: C, 57.55; H, 5.51; N, 9.56.
4.10. 7-Methoxy-10-methyl-5,10-dihydro-1H-indolizino[7,6-b]
indole-3,11(2H,11aH)-dione 11-oxime (22)
A stirred mixture of ketone 15 (10.4 g, 36 mmol), sodium acetate
trihydrate (19.8 g, 150 mmol), and hydroxylamine hydrochloride
(10.1 g, 150 mmol) in ethanol (150 mL) and water (50 mL) was
refluxed for 48 h. The solid obtained upon evaporation was washed
with cold (4 ꢀC) water then recrystallized from EtOAc to give 65% of
oxime 22 as a white powder; mp (EtOAc) >250 ꢀC; Rf (EtOAc/MeOH
4.7. 5,10-Dihydro-1H-indolizino[7,6-b]indole-3,11(2H,11aH)-
dione 11-oxime (19)
A stirred mixture of ketone 12 (36.3 g, 150 mmol), sodium ac-
etate trihydrate (46.6 g, 320 mmol), and hydroxylamine hydro-
chloride (21.8 g, 310 mmol) in ethanol (200 mL) and water (200 mL)
was refluxed for 5 h. The solid obtained upon evaporation was
washed with cold (4 ꢀC) water, then recrystallized from ethanol to
give 75% of a 70/30 mixture of two isomers of oxime 19 as a white
powder; mp (ethanol) 212e214 ꢀC; Rf (EtOAc/MeOH 90/10) 0.83; IR
95/5 0.7) 0.83; IR
(CDCl3) (ppm): 2.05e2.25 (m, 1H), 2.32e2.70 (m, 2H), 2.97e3.22
n
(cmꢁ1): 3128, 1652, 1628, 1550; 1495; 1H NMR
d
(m, 1H), 3.85 (s, 3H), 3.93 (s, 3H), 4.05 (d, J¼16.0 Hz, 1H), 4.87e4.98
(dd, J¼7.2, 7.0 Hz, 1H), 5.41 (d, J¼16.0 Hz, 1H), 6.95 (s, 1H), 6.98 (dd,
J¼8.8, 2.5 Hz, 1H), 7.21 (dd, J¼8.8, 2.0 Hz, 1H); 13C NMR (CDCl3)
n
(cmꢁ1): 3280, 1680; 1H NMR (CDCl3/CF3CO2H)
d
(ppm): 2.22e2.53
d (ppm): 21.2 (CH2), 30.1 (CH2), 31.2 (CH3), 37.8 (CH2), 55.8 (CH3),
(m, 1H), 2.65e2.86 (m, 2H), 3.11e3.36 (m, 1H), 4.28 and 4.45 (2d,
30/70, J¼16.9 and 17.5 Hz, 1H), 4.86 and 5.09 (2t, 70/30, J¼6.8 and
8.6 Hz, 1H), 5.45 and 5.58 (2d, 70/30, J¼17.5 and 16.9 Hz, 1H),
7.18e7.30 (m, 1H), 7.40e7.55 (m, 2H), 7.57e7.67 (m, 1H). 13C NMR
61.8 (CH), 102.6 (CH), 109.8 (C), 110.2 (CH), 113.4 (CH), 123.1 (C),
125.1 (C), 126.8 (C), 130.4 (C), 154.7 (C), 173.6 (C). Anal. Calcd for
C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C, 63.87; H, 6.05; N,
13.84.
(CDCl3/DMSO-d6)
d (ppm) (major isomer): 21.8 (CH2), 30.1 (CH2),
37.1 (CH2), 56.6 (CH),113.0 (CH),113.5 (C),119.1 (CH),119.7 (C),122.9
(CH), 124.0 (C), 124.1 (CH), 137.2 (C), 144.4 (C), 173.6 (C). Anal. Calcd
for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found: C, 65.83; H, 5.17;
N, 16.41.
4.11. 3-(4-Hydroxy-8-methoxy-5H-pyrido[4,3-b]indol-3-yl)
propionic acid (25)
Ketone 23 (13 mg) was reacted with hydroxylamine in the same
conditions as for ketone 12. Known acid 251m (85%) was identified
by NMR spectrum of the crude reaction mixture.
4.8. 10-Methyl-5,10-dihydro-1H-indolizino[7,6-b]indole-
3,11(2H,11aH)-dione 11-oxime (20)
Acid 25: 1H NMR (CDCl3/DMSO-d6)
d
(ppm): 2.58 (t, J¼6.8 Hz,
2H), 3.07 (t, J¼6.8 Hz, 2H), 7.04 (dd, J¼9.0, 2.3 Hz, 1H), 7.43 (d,
J¼9.0 Hz, 1H), 7.69 (d, J¼2.3. Hz, 1H), 8.75 (s, 1H), 8.30 (bs, 1H, OH),
11.50 (bs, 1H, deuterium oxide exchangeable). It contains also
a compound with the following H NMR spectrum: 1H NMR (CDCl3/
A stirred mixture of ketone 14 (56.0 g, 220 mmol), sodium ac-
etate trihydrate (60.0 g, 440 mmol), and hydroxylamine hydro-
chloride (30.6 g, 440 mmol) in ethanol (600 mL) and water
(200 mL) was refluxed for 24 h. The solid obtained upon evapora-
tion was washed with cold (4 ꢀC) water then recrystallized from
DMSO-d6)
d (ppm): 1.83e2.10 (m, 1H), 2.33 (s, 3H), 2.36e2.69 (m,
2H), 2.96e3.15 (m, 1H), 3.83 (s, 3H), 3.85 (d, J¼16.8 Hz, 1H), 5.01 (t,

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5650
J¼7.0 Hz,1H), 5.21 (d, J¼16.8 Hz,1H), 6.80 (d, J¼2.5 Hz,1H), 7.03 (dd,
J¼9.2, 2.5 Hz, 1H), 7.12 (d, J¼8.2 Hz, 2H), 8.47 (d, J¼8.2 Hz, 2H), 8.10
(d, J¼9.2 Hz, 1H).
The solid obtained upon evaporation was recrystallized from
methanol to give 81% of dihydronaphthyridone 35; IR
n
(cmꢁ1):
(ppm):
3535, 1705, 1630, 1500e1470, 1195; 1H NMR (DMSO-d6)
d
2.78 (t, J¼7.7 Hz, 2H), 3.34 (t, J¼7.7 Hz, 2H), 6.40 (s, 2H), 7.74 (s, 1H),
4.12. 1,10a-Dihydropyrrolo[1,2-b]isoquinoline-3,10(2H,5H)-
dione 10-(O-benzyloxime) (29)
7.96 (s, 1H), 9.09 (s, 1H), 10.82 (bs, 1H, deuterium oxide exchange-
able). 13C NMR (DMSO-d6)
d (ppm): 22.8 (CH2), 28.9 (CH2), 97.6
(CH), 103.8 (CH2), 104.4 (CH), 124.6 (C), 126.1 (C), 127.8 (C), 131.5 (C),
135.4 (CH),150.1 (C),155.2 (C),169.9 (C). Anal. Calcd for C13H10N2O3:
C, 64.46; H, 4.16; N, 11.56. Found: C, 64.31; H, 4.48; N, 11.10.
A stirred mixture of oxime 16 (0.30 g,1.38 mmol), benzyl bromide
(0.24 g, 1.38 mmol), and tetrabutylammonium hydrogensulfate
(0.067 g, 0.2 mmol)in 1 M sodium hydroxide aqueous solution(3 mL)
and dichloromethane (3 mL) was refluxed for 12 h. The residue
obtained uponevaporationwascrystallizedfromEtOActogive62% of
oxime benzyl ether 29, which was only characterized by NMR; 1H
4.16. 10-Hydroxy-8,9-dimethoxy-3,4-dihydrobenzo[c]-1,5-
naphthyridin-2(1H)-one (36)
NMR (CDCl3)
d
(ppm): 1.75e2.08 (m, 1H), 2.25e2.60 (m, 2H),
Oxime 18 (20 g, 68.5 mmol) was added to trifluoroacetic acid
(60 mL). Triflic acid (0.8 mL, 9 mmol) was added and the mixture
was refluxed for 6 h under nitrogen. The residue obtained upon
evaporation was poured in water (80 mL) and the aqueous phase
was extracted with dichloromethane then dried (Na2SO4). The solid
obtained upon evaporation was recrystallized from methanol to
give 70% of dihydronaphthyridone 36. Mp (methanol) 240e242 ꢀC;
2.80e3.00 (m,1H), 3.96 (d, J¼16.2 Hz,1H), 4.89 (dd, J¼6.0, 7.5 Hz,1H),
5.08 (d, J¼16.2 Hz,1H), 5.19 (d, J¼11.7 Hz,1H), 5.22 (d, J¼11.7 Hz,1H),
7.19 (dd, J¼1.8, 7.3 Hz, 1H), 7.29 (m, 2H), 7.33e7.43 (m, 5H), 7.92 (dd,
J¼7.3, 1.8 Hz, 1H); 13C NMR (CDCl3)
d (ppm): 25.1 (CH2), 30.4 (CH2),
40.8 (CH2), 55.7 (CH), 77.1 (CH2), 124.9 (CH), 126.0 (CH), 127.5 (2 CH),
127.9 (CH), 128.2 (2 CH), 129.6 (2 CH), 134.3 (C), 134.8 (CH), 137.0 (C),
153.4 (C), 173.0 (C).
IR
(CDCl3)
6H), 6.86 (s, 1H), 8.67 (s, 1H); 13C NMR (DMSO-d6)
n
(cmꢁ1): 3110, 3200, 1700, 1600, 1480, 1430, 1200; 1H NMR
(ppm): 2.83 (t, J¼7.8 Hz, 2H), 3.32 (t, J¼7.8 Hz, 2H), 4.01 (s,
(ppm): 23.5
d
4.13. 9,9a-Dihydro[1,3]dioxolo[4,5-g]pyrrolo[1,2-b]
d
isoquinoline-7,10(5H,8H)-dione 10-(O-benzyloxime) (30)
(CH2), 28.3 (CH2), 56.2 (CH3), 60.9 (CH3), 100.4 (CH), 113.5 (C), 125.0
(C), 126.4 (C), 131.3 (C), 137.6 (C), 140.6 (CH), 145.0 (C), 154.5 (C),
168.9 (C). Anal. Calcd for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21.
Found: C, 60.93; H, 5.56; N, 9.96.
A stirred mixture of oxime 17 (0.30 g, 1.15 mmol), benzyl bro-
mide (0.20 g, 1.15 mmol), and tetrabutylammonium hydro-
gensulfate (0.067 g, 0.2 mmol) in 1 M sodium hydroxide aqueous
solution (3 mL) and dichloromethane (3 mL) was refluxed for 12 h.
The residue obtained upon evaporation crystallized from EtOAc to
4.17. 1,3,4,11-Tetrahydro-2H-indolo[3,2-c]-1,5-naphthyridin-2-
one (37)
give 67% of oxime benzyl ether 30; mp (EtOAc) 149e150 ꢀC; IR
(cmꢁ1): 1681, 1495, 1478, 1456; 1H NMR (CDCl3)
(ppm): 1.76e2.02
n
d
Oxime 19 (97.2 g, 380 mmol) was added to methanesulfonic acid
(500 mL). Triflic acid (3.35 mL, 40 mmol) was added and the mix-
ture was heated at 120 ꢀC for 36 h under nitrogen. After cooling at
room temperature, it was poured on ice and then 10 M sodium
hydroxide aqueous solution was added to pH 2e3. The solid
obtained was washed with water to give 76% of dihydronaphthyr-
idone 37; yellow powder; mp (MeOH) >250 ꢀC; Rf (MeOH) 0.73; IR
(m, 1H), 2.25e2.58 (m, 2H), 2.78e2.96 (m, 1H), 3.85 (d, J¼16.4 Hz,
1H), 4.80 (dd, J¼14.0, 7.3 Hz, 1H), 5.08 (d, J¼16.4 Hz, 1H), 5.16
(d, J¼11.9 Hz, 1H), 5.23 (d, J¼11.9 Hz, 1H), 5.96 (d, J¼15.6 Hz, 1H),
5.97 (d, J¼15.6 Hz, 1H), 6.63 (s, 1H), 7.30e7.36 (m, 5H), 7.37 (s, 1H).
13C NMR (CDCl3)
d (ppm): 25.1 (CH2), 30.4 (CH2), 40.8 (CH2), 55.7
(CH), 77.1 (CH2), 124.8 (CH), 126.0 (CH), 127.4 (2 CH), 127.8 (CH),
127.9 (CH), 128.2 (2 CH), 129.6 (2 CH), 134.7 (2C), 137.0 (C), 153.4 (C),
173.0 (C). This compound was not submitted for elemental analysis.
n
(cmꢁ1): 3440, 1675, 1645; 1H NMR (DMSO-d6)
d (ppm): 2.69 (t,
J¼7.3 Hz, 2H), 3.18 (t, J¼7.3 Hz, 2H), 7.25 (t, J¼7.6 Hz, 1H), 7.46 (t,
J¼7.6 Hz, 1H), 7.63 (d, J¼7.6 Hz, 1H), 8.18 (d, J¼7.6, 1H), 8.91 (s, 1H),
9.96 (bs, 2H, deuterium oxide exchangeable); 13C NMR (DMSO-d6)
4.14. 3,4-Dihydrobenzo[c]-1,5-naphthyridin-2(1H)-one (34)
d
(ppm): 27.7 (CH2), 30.6 (CH2), 111.4 (CH), 118.4 (CH), 119.6 (C),
Oxime 16 (20 g, 93 mmol) was added to hot (100 ꢀC) meth-
anesulfonic acid (200 mL). The mixture was stirred for 1 h under
nitrogen. After cooling at room temperature it was poured on ice,
and the aqueous phase was washed with dichloromethane and
then 10 M sodium hydroxide aqueous solution was added to pH
2e3. The solid obtained was washed with water to give 84% of
dihydronaphthyridone 34 with the same properties as described in
literature;1m mp (95% EtOH) 228e230 ꢀC (lit. 227e228 ꢀC1m); 1H
120.2 (CH), 121.0 (CH), 126.4 (CH), 132.1 (C), 135.5 (C), 137.6 (C),
139.4 (C), 143.4 (C), 170.0 (C). LC-MS (APCIþ) m/z 238.3 (MHþ). Anal.
Calcd for C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.59; H,
4.81; N, 17.98.
4.18. 8-Methoxy-1,3,4,11-tetrahydro-2H-indolo[3,2-c]-1,5-
naphthyridin-2-one (38)
NMR (CDCl3)
d
(ppm): 2.87 (t, J¼7.6 Hz, 2H), 3.35 (t, J¼7.6 Hz, 2H),
Oxime 21 (1.5 g, 5.5 mmol) was added to trifluoroacetic acid
(8.1 mL). Triflic acid (0.05 mL, 0.5 mmol) was added and the mix-
ture was refluxed for 24 h under nitrogen. After cooling at room
temperature, the solution was poured on ice and neutralized with
satd. K2CO3 solution. The solid obtained was washed with water
and then recrystallized from methanol to give 68% of dihy-
dronaphthyridone 36; yellow powder; mp (methanol) >250 ꢀC; Rf
7.62 (td, J¼6.9, 1.2 Hz, 1H), 7.81 (td, J¼6.9, 1.2 Hz, 1H), 7.96 (d,
J¼6.9 Hz, 1H), 8.15 (d, J¼6.9 Hz, 1H), 8.92 (s, 1H), 9.88 (bs, 1H,
deuterium oxide exchangeable); 13C NMR (CDCl3)
d (ppm): 27.9
(CH2), 30.7 (CH2), 119.0 (C), 125.0 (CH), 126.8 (2 CH), 127.5 (CH),
127.8 (C), 130.6 (C), 135.9 (C), 146.0 (CH), 171.9 (C).
4.15. 3,4-Dihydro[1,3]benzodioxolo[5,6-c]-1,5-naphthyridin-
2(1H)-one (35)
(EtOAc/MeOH 95/5) 0.7; IR
n
(cmꢁ1): 3142, 1652, 1633, 1500; 1470;
1H NMR (DMSO-d6)
2H), 3.86 (s, 3H), 7.05 (dd, J¼8.8, 2.5 Hz, 1H), 7.50 (d, J¼8.8 Hz, 1H),
7.72 (d, J¼2.5 Hz, 1H), 8.88 (s, 1H), 9.98 (bs, 1H, deuterium oxide
exchangeable), 11.01 (bs, 1H, deuterium oxide exchangeable); 13C
d
(ppm): 2.68 (t, J¼8.2 Hz, 2H), 3.17 (t, J¼8.2 Hz,
Oxime 17 (20 g, 77 mmol) was added to trifluoroacetic acid
(60 mL). Triflic acid (0.8 mL, 1.36 g, 9 mmol) was added and the
mixture was refluxed for 4 h under nitrogen. The residue obtained
upon evaporation was poured in water (80 mL) and the aqueous
phase was extracted with dichloromethane then dried (Na2SO4).
NMR (CDCl3/DMSO-d6)
d (ppm): 25.8 (CH2), 33.9 (CH2), 55.6 (CH3),
103.4 (CH), 112.7 (CH), 115.9 (CH), 119.0 (CH), 121.8 (C), 130.6 (2C),
134.8 (C), 137.0 (C), 138.6 (C), 154.0 (C), 174.9 (C). LC-MS (APCIþ) m/z

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5651
266.1 (MHþ). Anal. Calcd for C15H13N3O2: C, 67.41; H, 4.90; N, 15.72.
Found: C, 67.70; H, 4.98; N, 15.55.
J¼7.9 Hz, 1H), 8.09 (d. J¼7.9 Hz, 1H), 8.23 (d, J¼9.6 Hz, 1H) 8.93(d.
J¼8.4 Hz, 1H), 9.11 (s, 1H), 13.78 (bs, 1H, deuterium oxide ex-
changeable). 13C NMR (CDCl3)
d (ppm): 121.6 (CH), 123.1 (CH), 125.1
4.19. 11-Methyl-1,3,4,11-tetrahydro-2H-indolo[3,2-c]-1,5-
naphthyridin-2-one (39)
(C), 128.6 (CH), 128.7 (C), 129.4 (CH), 131.2 (C), 131.4 (C), 131.7 (CH),
143.7 (CH), 148.9 (CH), 164.5 (C). Anal. Calcd for C12H8N2O: C, 73.46;
H, 4.11; N, 14.28. Found: C, 73.17; H, 4.51; N, 13.97.
Oxime 20 (28.2 g,100 mmol) was added to methanesulfonic acid
(135 mL). Triflic acid (0.9 mL, 10 mmol) was added and the mixture
was heated at 120 ꢀC for 4 h under nitrogen. After cooling at room
temperature, it was poured on ice and then 10 M sodium hydroxide
aqueous solution was added to pH 2e3. The solid obtained was
washed with water to give 86% of dihydronaphthyridone 39; yellow
Bromopyridone 46: light brown solid, 31%; Rf 0.5 (CH2Cl2); 1H
NMR (CDCl3/CF3COOH)
d
(ppm): 8.22 (t. J¼7.9 Hz, 1H), 8.46
(t. J¼7.9 Hz, 1H), 8.60 (d. J¼7.9 Hz, 1H), 8.86 (d. J¼7.9 Hz, 1H), 8.97
(s, 1H), 9.81 (s, 1H). LC-MS (APCIþ) m/z 275.2 and 277.2 (MHþ). This
compound was not subjected to elemental analysis.
powder; mp (EtOH) >250 ꢀC; Rf (MeOH/Et3N 95/5) 0.7; IR
n
(cmꢁ1):
4.23. Heterocycle 47 and 2-chlorobenzo[c]-1,5-naphthyridine
(48)
3137, 1647, 1579, 1495; 1H NMR (DMSO-d6)
d
(ppm): 2.50
(t, J¼7.8 Hz, 2H), 2.65 (t, J¼7.8 Hz, 2H), 4.10 (s, 3H), 7.28 (t, J¼7.6 Hz,
1H), 7.52 (t, J¼8.3 Hz, 1H), 7.64 (d J¼8.3 Hz, 1H), 8.20 (d, J¼7.6, 1H),
8.95 (s, 1H), 9.90 (bs, 1H, deuterium oxide exchangeable); 13C NMR
A stirred mixture of dihydropyridone 34 (0.36 g, 0.13 mmol) in
thionyl chloride (11 mL) was refluxed for 9 h. The solid obtained
after cooling at room temperature and evaporation was stirred in
a satd solution of sodium hydrogen carbonate and dichloro-
methane. The organic phase was dried (Na2SO4), and the residue
obtained upon evaporation was stirred in ethyl acetate (15 mL) for
1 h. The solid obtained upon filtration was heterocycle 47, and the
solution contains the naphthyridine 48.
(DMSO-d6)
d (ppm): 28.4 (CH2), 30.7 (CH2), 31.6 (CH3), 109.8 (CH),
119.1 (C), 119.8 (C), 120.2 (CH), 120.4 (CH), 126.7 (CH), 136.1 (C, CH),
140.7 (C), 141.5 (C), 142.3 (C), 170.6 (C). LC-MS (APCIþ) m/z 250.2
(MHþ). Anal. Calcd for C15H13N3O, 1/4H2O: C, 70.43; H, 5.32; N,
16.43. Found: C, 70.18; H, 5.44; N, 16.27.
4.20. 8-Methoxy-11-methyl-1,3,4,11-tetrahydro-2H-indolo
[3,2-c]-1,5-naphthyridin-2-one (40)
Heterocycle 47: light brown solid, 21%; mp (EtOAc) 216e218 ꢀC;
IR
n
(cmꢁ1): 1663, 1573, 1491, 1443; 1H NMR (CDCl3/CF3CO2H)
d
(ppm): 8.06 (t, J¼8.0 Hz, 1H), 8.42 (t. J¼8.0 Hz, 1H), 8.50 (d.
Oxime 22 (0.50 g, 2 mmol) was added to trifluoroacetic acid
(1.3 mL). Triflic acid (0.01 mL, 0.1 mmol) was added and the mixture
was refluxed for 4 h under nitrogen. After cooling at room tem-
perature, the solution was poured on ice and neutralized with
a saturated K2CO3 aqueous solution. The solid obtained was washed
with water then recrystallized from methanol to give 78% of
dihydronaphthyridone 40; yellow powder; mp (MeOH) >250 ꢀC; Rf
J¼8.0 Hz, 1H), 8.90 (s, 1H), 9.35 (d, J¼8.0 Hz, 1H) 9.74 (s, 1H). Anal.
Calcd for C12H7ClN2S: C, 58.42; H, 2.86; N, 11.35. Found: C, 58.41; H,
2.54; N, 11.65.
Chloropyridone 48: light brown solid, 34%; purified by chro-
matography on SiO2 (EtOAc/Heptane 50/50); mp (EtOAc)
178e180 ꢀC; IR
n
(cmꢁ1): 1609, 1490, 1439; 1H NMR (CDCl3)
d
(ppm): 7.68 (d, J¼8.5 Hz, 1H), 7.82 (t, J¼7.5 Hz, 1H), 7.99
(EtOAc/MeOH 95/5) 0.65; IR
n
(cmꢁ1): 3150, 1655, 1620, 1500, 1475;
(t, J¼7.5 Hz, 1H), 8.09 (d, J¼7.5 Hz, 1H), 8.41 (d, J¼8.5 Hz, 1H), 9.11
1H NMR (DMSO-d6)
d
(ppm): 2.82 (t, J¼7.5 Hz, 2H), 3.33 (t, J¼7.5 Hz,
(d, J¼7.5 Hz, 1H), 9.34 (s, 1H); 13C NMR (CDCl3)
d (ppm): 124.2 (CH),
2H), 3.93 (s, 3H), 4.10 (s, 3H), 7.16 (dd, J¼9.0, 2.5 Hz, 1H), 7.30
(d, J¼9.0 Hz,1H), 7.55 (d J¼2.5 Hz,1H), 7.86 (bs,1H, deuterium oxide
125.8 (CH), 127.1 (CH), 128.4 (C), 131.8 (CH), 131.9 (CH), 133.2 (C),
134.8 (CH), 137.5 (C), 140.8 (C), 149.5 (CH), 153.8 (C). LC-MS (APCIþ)
m/z 215.2 and 217.4 (MHþ); 256.2 and 258.0 (MþþMeCN).
exchangeable), 8.88 (bs, 1H); 13C NMR (DMSO-d6)
d (ppm): 28.4
(CH2), 30.7 (CH2), 31.6 (CH3), 55.8 (CH3), 95.4 (CH), 104.6 (CH), 112.7
(C), 115.4 (CH), 120.0 (CH), 130.6 (C), 138.2 (C), 141.5 (C), 141.8 (C),
144.3 (C), 154.1 (C), 170.6 (C). Anal. Calcd for C16H15N3O2, 1/3H2O: C,
66.89; H, 5.50; N, 14.62. Found: C, 67.97; H, 5.69; N, 14.50.
4.24. 1,11-Dihydro-2H-indolo[3,2-c]-1,5-naphthyridin-2-one
(49)
A stirred mixture of dihydropyridone 37 (20.0 g, 85 mmol) and
selenium dioxide (9.5 g, 85 mmol) in acetic acid (300 mL) was
refluxed for 15 h. The solid obtained after cooling at room tem-
perature and evaporation was refluxed in water for 30 min. The
solid obtained after cooling at room temperature and filtration was
purified by chromatography on SiO2 (EtOAc/MeOH 70/30) to give
76% of naphthyridone 49; yellow powder; mp (MeOH) >250 ꢀC; Rf
4.21. 2-Methoxy-5,7,7a,8,9,12-hexahydropyrrolo[10,20:1,2][1,3]
diazepino[5,6-b]indole-6,10-dione (42)
This compound was observed by 1H NMR in an attempt to
transpose thermally oxime 20 at a temperature superior to 160 ꢀC.
1H NMR (CDCl3)
d (ppm): 2.30e2.80 (m, 4H), 3.86 (s, 3H), 4.62
(d, J¼17.9 Hz, 1H), 5.27e5.43 (m, 1H), 5.36 (d, J¼17.9 Hz, 1H), 6.35
(bs, 1H), 6.96 (d, J¼2.5 Hz, 1H), 7.05 (dd, J¼9.2, 2.5 Hz, 1H), 7.33
(d, J¼9.2 Hz, 1H), 9.05 (bs, 1H, deuterium oxide exchangeable).
(EtOAc/MeOH 70/30) 0.6; IR
n
(cmꢁ1): 3335, 3310, 1665, 1610, 1590,
1537, 1510; 1H NMR (DMSO-d6)
d
(ppm): 6.72 (d, J¼9.8 Hz, 1H), 7.35
(t, J¼7.6 Hz, 1H), 7.55 (t, J¼7.6 Hz, 1H), 7.78 (d, J¼8.3 Hz, 1H), 8.10 (d,
J¼9.8 Hz, 1H), 8.31 (d, J¼8.3 Hz, 1H), 9.28 (s, 1H), 11.66 (bs, 1H,
deuterium oxide exchangeable), 11.85 (bs, 1H, deuterium oxide
4.22. Benzo[c]-1,5-naphthyridin-2(1H)-one (43) and
monobrominated compound 46
exchangeable); 13C NMR (DMSO-d6)
d (ppm): 112.4 (CH), 119.4 (C),
121.1 (2 CH), 122.8 (C), 123.0 (CH), 127.1 (CH), 130.6 (C), 132.2 (C),
136.9 (C), 138.8 (CH), 139.4 (C), 142.6 (CH), 161.4 (C). Anal. Calcd for
C14H9N3O: C, 66.41; H, 4.38; N, 16.59. Found: C, 66.53; H, 4.03; N,
16.47.
A stirred mixture of dihydropyridone 34 (0.250 g, 1.3 mmol) and
bromine (0.08 mL, 1.6 mmol) in bromobenzene (5 mL) was refluxed
for 12 h. The solid obtained after cooling at room temperature and
partial evaporation was stirred in an aqueous saturated solution of
sodium hydrogen sulfite and then separated by chromatography on
SiO2 (CH2Cl2/MeOH 98/2) to give 56% of naphthyridone 43 and of
bromonaphthyridone 46.
4.25. 11-Methyl-1,11-dihydro-2H-indolo[3,2-c]-1,5-
naphthyridin-2-one (50)
Pyridone 43: light brown solid, 56%; mp (CH2Cl2) 200e202 ꢀC;
A stirred mixture of dihydropyridone 39 (22.0 g, 90 mmol) and
selenium dioxide (9.7 g, 90 mmol) in acetic acid (200 mL) was
refluxed for 36 h. The solid obtained after cooling at room
Rf (CH2Cl2) 0.3; IR
(ppm): 7.02 (d, J¼9.6 Hz, 1H), 7.82 (t. J¼7.5 Hz, 1H), 8.01 (t.
n
(cmꢁ1): 1650, 1629, 1581; 1H NMR (CDCl3)
d

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5652
temperature and evaporation was refluxed in water for 30 min. The
solid obtained after cooling at room temperature and filtration was
purified by chromatography on SiO2 (EtOAc/MeOH 95/5) to give
86% of naphthyridone 50; yellow powder; mp (MeOH) >250 ꢀC;
120.5 (2 CH), 120.6 (C), 121.5 (C), 123.9 (CH), 126.2 (CH), 134.0 (C),
139.3 (2C), 140.7 (CH), 145.8 (CH), 147.7 (C). A mixture of this in-
termediate 53 (1.0 g, 4 mmol) in N,N-diethylethylenediamine
(4.6 g, 39 mmol) was refluxed for 24 h. Upon cooling at room
temperature, the solution was washed with water, diethyl ether
was added and the organic phase was washed with water. The
solid obtained upon drying (Na2SO4) and evaporation was
recrystallized from EtOAc to give 80% of aminonaphthyridine 57;
slightly brown powder; mp (EtOAc) 150e152 ꢀC; Rf (MeOH/Et3N
Rf (EtOAc/MeOH 95/5) 0.76; IR
n
(cmꢁ1): 3132, 1658, 1633, 1550,
(ppm): 4.60 (s, 3H), 7.09
1500, 1446; 1H NMR (DMSO-d6/CDCl3)
d
(d, J¼9.2 Hz, 1H), 7.39 (t, J¼7.5 Hz, 1H), 7.60 (td, J¼7.7, 1.2 Hz, 1H),
7.76 (d, J¼8.3 Hz, 1H), 8.32 (d, J¼9.2 Hz, 1H), 8.35 (d, J¼8.1 Hz, 1H),
9.45 (s, 1H), 11.39 (bs, 1H, deuterium oxide exchangeable); 13C NMR
(DMSO-d6)
d
(ppm): 32.3 (CH3), 110.3 (CH), 113.8 (C), 117.4 (C), 120.2
95/5) 0.65; IR
(CDCl3)
n
(cmꢁ1): 3680, 3400, 1610, 1530, 1482; 1H NMR
(CH),120.7 (CH),120.8 (CH),126.1 (CH),131.2 (C),135.9 (C),137.4 (C),
140.7 (CH),141.0 (CH),141.2 (C),160.5 (C). Anal. Calcd for C15H11N3O,
½H2O: C, 66.76; H, 4.68; N, 16.27. Found: C, 66.90; H, 4.66; N, 16.24.
d
(ppm): 1.09 (t, J¼7.1 Hz, 6H), 2.66 (q, J¼7.1 Hz, 4H), 2.80
(t, J¼5.8 Hz, 2H), 3.68 (q, J¼5.8 Hz, 2H), 5.53 (t, J¼4.0 Hz, 1H,
deuterium oxide exchangeable), 6.88 (d, J¼8.9 Hz, 1H), 7.35 (td, 1H,
J¼7.3, 1.3 Hz, 1H), 7.49 (td, J¼7.3, 1.2 Hz, 1H), 7.61 (d, J¼8.2 Hz, 1H),
8.17 (d, J¼8.9 Hz, 1H), 8.20 (dt, J¼7.3, 1.0 Hz, 1H), 9.28 (s, 1H), 9.80
(bs, 1H, deuterium oxide exchangeable); 13C NMR (DMSO-d6)
4.26. 8-Methoxy-1,11-dihydro-2H-indolo[3,2-c]-1,5-
naphthyridin-2-one (51)
d
(ppm): 12.6 (2 CH3), 39.8 (CH3), 47.4 (2 CH2), 52.7 (CH2), 113.1
A stirred mixture of dihydropyridone 38 (0.9 g, 3.5 mmol) and
selenium dioxide (0.39 g, 3.5 mmol) in acetic acid (30 mL) was
refluxed for 24 h. The solid obtained after cooling at room tem-
perature and evaporation was refluxed in water for 30 min. The
solid obtained after cooling at room temperature and filtration was
purified by chromatography on SiO2 (EtOAc/MeOH 95/5) to give
60% of naphthyridone 51; yellow powder; mp (EtOH) >250 ꢀC;
(CH), 115.0 (CH), 118.4 (CH), 121.0 (CH), 121.2 (C), 126.5 (CH), 133.6
(C), 136.8 (C), 138.4 (CH), 139.1 (CH), 139.8 (C), 140.0 (C), 140.2 (CH),
157.3 (C). Anal. Calcd for C20H23N5: C, 72.04; H, 6.95; N, 21.00.
Found: C, 71.78; H, 7.30; N, 20.96.
4.29. N,N-Diethyl-N0-(11-methyl-11H-indolo[3,2-c]-1,5-
naphthyridin-2-yl)ethane-1,2-diamine (58)
Rf (EtOAc/MeOH 95/5) 0.7; IR
n
(cmꢁ1): 3344, 1677, 1638, 1588,
(ppm): 3.88 (s, 3H), 6.67
1485; 1H NMR (DMSO-d6/CDCl3)
d
A TeflonÒ bottle was charged with a stirring bar, naphthyridone
50 (3.0 g, 12 mmol) and phenylphosphonic dichloride (8.5 mL,
60 mmol). The closed bottle was placed in a heating bath (180 ꢀC),
and the mixture was stirred for 15 h. Upon cooling at room tem-
perature, the reaction mixture was added to water (100 mL) and
then refluxed for 1 h. The solution obtained upon filtration was
basified then extracted with dichloromethane. The residue
obtained upon drying (Na2SO4) and evaporation was purified by
chromatography on SiO2 (EtOAc) to give 85% of intermediate 54;
light brown powder; mp (EtOH) 192e194 ꢀC; Rf (EtOAc/heptane/
(d, J¼9.3 Hz, 1H), 7.13 (dd, J¼8.8, 2.3 Hz, 1H), 7.63 (d, J¼8.8 Hz, 1H),
7.80 (d, J¼2.3 Hz, 1H), 8.04 (d, J¼9.3 Hz, 1H), 9.26 (s, 1H), 11.47
(bs, 1H, deuterium oxide exchangeable), 11.83 (bs, 1H, deuterium
oxide exchangeable). 13C NMR (DMSO-d6)
d (ppm): 65.1 (CH3),103.4
(CH), 113.6 (CH), 117.2 (CH), 119.8 (C), 121.9 (C), 123.0 (C), 123.2 (CH),
131.2 (C), 132.2 (C), 134.5 (CH), 139.4 (C), 143.1 (CH), 155.0 (C), 161.7
(C). Anal. Calcd for C15H11N3O2, H2O: C, 63.60; H, 4.63; N, 14.83.
Found: C, 63.50; H, 5.06; N, 14.45.
4.27. 8-Methoxy-11-methyl-1,11-dihydro-2H-indolo[3,2-c]-
1,5-naphthyridin-2-one (52)
Et3N (5 drops) 50/50) 0.5; IR
n
(cmꢁ1): 1632, 1620, 1500, 1485;
1H NMR (CDCl3)
d
(ppm): 4.65 (s, 3H), 7.45e7.55 (m, 1H), 7.65e7.75
(m, 3H), 8.28 (d, J¼7.5 Hz, 1H), 8.47 (d, J¼8.3 Hz, 1H), 9.57 (s, 1H).
A TeflonÒ bottle was charged with this intermediate 54 (0.5 g,
1.9 mmol), a stirring bar and N,N-diethylethylenediamine (0.25 g,
2.2 mmol). The closed bottle was placed in a heating bath (150 ꢀC)
and the mixture was stirred for 15 h. Upon cooling at room tem-
perature, the reaction mixture was added to water (30 mL), the
solid obtained was filtered, washed with water then recrystallized
from EtOAc to give 80% of aminonaphthyridine 58; slightly brown
A stirred mixture of dihydropyridone 40 (0.25 g, 0.9 mmol) and
selenium dioxide (0.1 g, 0.9 mmol) in acetic acid (30 mL) was
refluxed for 24 h. The solid obtained after cooling at room tem-
perature and evaporation was refluxed in water for 30 min. The
solid obtained after cooling at room temperature and filtration was
purified by chromatography on SiO2 (EtOAc/MeOH 95/5) to give
83% of naphthyridone 52; yellow powder; mp (MeOH) >250 ꢀC;
Rf (EtOAc/MeOH 95/5) 0.75; 1H NMR (CDCl3)
d
(ppm): 3.76 (s, 3H),
powder; mp (EtOAc) >250 ꢀC; Rf (MeOH/Et3N 95/5) 0.65; IR
n
3.95 (s, 3H), 6.99 (d, J¼9.1 Hz, 1H), 7.20 (dd, J¼8.7, 2.3 Hz, 1H), 7.54
(d, J¼8.7 Hz, 1H), 7.73 (d, J¼2.3 Hz, 1H), 8.25 (d, J¼9.1 Hz, 1H), 9.30
(s, 1H). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.04.
Found: C, 69.07; H, 5.04; N, 14.87.
(cmꢁ1): 3680, 3400, 1633, 1603, 1549, 1495; 1H NMR (CDCl3)
d
(ppm): 1.09 (t, J¼7.1 Hz, 6H), 2.66 (q, J¼7.1 Hz, 4H), 2.80
(t, J¼5.8 Hz, 2H), 3.68 (q, J¼5.8 Hz, 2H), 4.70 (s, 3H), 5.50 (bq,
J¼5.5 Hz,1H, deuterium oxide exchangeable), 6.84 (d, J¼8.9 Hz,1H),
7.40 (td, J¼7.4, 1.3 Hz, 1H), 7.63 (bd, J¼8.2 Hz, 2H), 8.20 (d, J¼8.9 Hz,
1H, ArH), 8.25 (dt, J¼7.4, 1.0 Hz, 1H), 9.29 (s, 1H); 13C NMR (DMSO-
4.28. N,N-Diethyl-N0-11H-indolo[3,2-c]-1,5-naphthyridin-2-
ylethane-1,2-diamine (57)
d6) d (ppm): 11.5 (2 CH3), 32.3 (CH3), 39.3 (CH2), 46.6 (2 CH2), 51.4
(CH2), 109.3 (CH), 112.7 (CH), 117.7 (C), 119.8 (CH), 120.4 (CH), 121.5
(C), 125.5 (CH),134.1 (CH), 137.1 (C), 137.4 (C), 138.3 (CH), 139.7 (CH),
140.8 (CH), 155.1 (C). Anal. Calcd for C21H25N5, ¼H2O: C, 71.66; H,
7.30; N, 19.90. Found: C, 71.91; H, 7.38; N, 19.67.
A stirred solution of dihydropyridone 49 (7.80 g, 33.4 mmol) in
phosphorus oxychloride (30 mL) was refluxed for 10 h. The residue
obtained upon evaporation was stirred with a saturated aqueous
potassium carbonate solution. The solid obtained was washed
with water and then recrystallized from EtOH to give 56% of
chloronaphthyridine 53; light brown powder; mp (EtOH) >250 ꢀC;
4.30. N,N-Diethyl-N0-(8-methoxy-11H-indolo[3,2-c]-1,5-
naphthyridin-2-yl)ethane-1,2-diamine (59)
Rf (EtOAc/heptane/Et3N (5 drops) 50/50) 0.65; IR
n
(cmꢁ1): 3400,
(ppm): 7.45 (td, J¼7.5, 1.3 Hz,
1630; 1600; 1505; 1H NMR (CDCl3)
d
A TeflonÒ bottle was charged with a stirring bar, naphthyridone
51 (1.0 g, 3.8 mmol) and phenylphosphonic dichloride (2.7 mL,
18.8 mmol). The closed bottle was placed in a heating bath
(180 ꢀC) and the mixture was stirred for 15 h. Upon cooling at
room temperature, the reaction mixture was added to water
1H), 7.59 (td, J¼7.6, 1.3 Hz, 1H), 7.64 (d, J¼8.8 Hz, 1H), 7.70
(ddd, J¼8.1, 1.2, 0.8 Hz, 1H), 8.27 (ddt, J¼7.9, 1.2, 0.8 Hz, 1H), 8.49
(d, J¼8.8 Hz, 1H), 9.60 (s, 1H), 9.84 (bs, 1H, deuterium oxide ex-
changeable). 13C NMR (DMSO-d6)
d (ppm): 112.9 (CH), 118.4 (C),

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5653
(30 mL) and then refluxed for 1 h. The solution obtained upon
filtration was basified with a saturated aqueous potassium car-
bonate solution then extracted with dichloromethane. The residue
obtained upon drying (Na2SO4) and evaporation was purified by
chromatography on SiO2 (EtOAc) to give 80% of intermediate 55;
slightly brown powder; mp (EtOH) >250 ꢀC; Rf (EtOAc) 0.5;
98% of methoxynaphthyridine 61; slightly brown powder; mp
(MeOH) >250 ꢀC; Rf (MeOH) 0.6; IR (cmꢁ1): 3400, 1613, 1515,
1490; 1H NMR 1H (CDCl3)
n
d
(ppm): 4.23 (s, 3H), 7.51 (d, J¼9.2 Hz,
1H), 7.54 (t, J¼7.5 Hz, 1H), 7.70 (t, J¼8.1 Hz, 1H), 7.90 (d, J¼8.1 Hz,
1H), 8.48 (d, J¼7.5 Hz, 1H), 8.59 (d, J¼9.2 Hz, 1H), 9.93 (s, 1H);
13C NMR (DMSO-d6)
d (ppm): 55.3 (CH3), 114.3 (CH), 117.7 (CH),
1H NMR (CDCl3)
d
(ppm): 3.99 (s, 3H), 7.21 (dd, J¼8.6, 2.5 Hz, 1H),
118.7 (C), 122.5 (C), 122.7 (CH), 123.7 (C), 134.1 (CH), 129.3 (C), 129.8
(CH),130.5 (CH),133.3 (C),137.0 (C),141.4 (CH),142.7 (CH),163.4 (C).
Anal. Calcd for C15H11N3O, H2O: C, 67.41; H, 4.90; N, 15.72. Found: C,
67.06; H, 4.96; N, 15.79.
7.58 (d, J¼8.6 Hz, 1H), 7.62 (dd, J¼8.6 Hz, 1H), 7.68 (d, J¼2.5 Hz, 1H),
8.48 (d, J¼8.6 Hz, 1H), 9.54 (s, 1H). A TeflonÒ bottle was charged
with a stirring bar, intermediate 55 (1.0 g, 3.5 mmol) and N,N-
diethylethylenediamine (4.1 g, 35.2 mmol). The closed bottle was
placed in a heating bath (150 ꢀC) and the mixture was stirred for
15 h. Upon cooling at room temperature, the reaction mixture
was added to water (40 mL), the solid obtained was filtered,
washed with water then recrystallized from EtOAc to give 77%
of aminonaphthyridine 59; slightly brown powder; mp (EtOAc)
Acknowledgements
The authors would like to thank the Norbert Segard Foundation
for R.A.-G. and A.B.’s scholarships.
145e147 ꢀC; Rf (MeOH/Et3N 95/5) 0.7; 1H NMR (CDCl3)
d (ppm):
Supplementary data
1.09 (t, J¼7.1 Hz, 6H), 2.66 (q, J¼7.1 Hz, 4H), 2.80 (bt, J¼5.8 Hz, 2H),
3.62 (q, J¼5.8 Hz, 2H), 3.95 (s, 3H), 5.60 (bq, J¼5.5 Hz, 1H, deute-
rium oxide exchangeable), 6.87 (d, J¼9.1 Hz, 1H), 7.09 (dd, J¼8.8,
2.2 Hz, 1H), 7.43 (d, J¼8.8 Hz, 1H), 7.62 (d, J¼2.2 Hz, 1H), 8.16
(d, J¼8.9 Hz, 1H), 9.22 (s, 1H), 10.39 (bs, 1H, deuterium oxide ex-
changeable). Anal. Calcd for C21H25N5O: C, 69.40; H, 6.93; N, 19.27.
Found: C, 69.21; H, 7.09; N, 19.55.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.04.056. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
4.31. N,N-Diethyl-N0-(8-methoxy-11-methyl-11H-indolo[3,2-
c]-1,5-naphthyridin-2-yl)ethane-1,2-diamine (60)
1. (a) Rigo, B.; Kolocouris, N. J. Heterocycl. Chem. 1983, 20, 893; (b) Buckley, T. F., III;
Rapoport, H. J. Org. Chem. 1983, 48, 4222; (c) Martin, L. L.; Scott, S. J.; Agnew, M.
N.; Setescak, L. L. J. Organomet. Chem. 1986, 51, 3697; (d) Martin, L. L.; Scott, S. J.;
Setescak, L. L.; Van Engen, D. J. Heterocycl. Chem. 1987, 24, 1541; (e) Lee, G. S.;
Cho, Y. S.; Shim, S. C.; Khim, W. J.; Eibler, E.; Wiegrebe, W. Arch. Pharmacol. 1989,
322, 607; (f) Marchalin, S.; Decroix, B.; Morel, J. Acta Chem. Scand. 1993, 47, 287;
(g) Rigo, B.; Gautret, P.; Legrand, A.; El Ghammarti, S.; Couturier, D. Synth.
Commun. 1994, 24, 2609; (h) Mamouni, A.; Netchitaïlo, P.; Daïch, A.; Decroix, B.
Phosphorus, Sulfur Silicon Relat. Elem. 1996, 119, 169; (i) Daïch, A.; Decroix, B. J.
Heterocycl. Chem. 1996, 33, 873; (j) Al Akoum Ebrik, S.; Legrand, A.; Rigo, B.;
Couturier, D. J. Heterocycl. Chem. 1999, 36, 997; (k) Legrand, A.; Rigo, B.; Gautret,
A TeflonÒ bottle was charged with a stirring bar, naphthyridone
52 (1.0 g, 3.6 mmol) and phenylphosphonic dichloride (2.6 mL,
18 mmol). The closed bottle was placed in a heating bath (180 ꢀC)
and the mixture was stirred for 15 h. Upon cooling at room tem-
perature, the reaction mixture was added to water (30 mL) and
then refluxed for 1 h. The solution obtained upon filtration was
basified with a saturated aqueous potassium carbonate solution
then extracted with dichloromethane. The residue obtained upon
drying (Na2SO4) and evaporation was purified by chromatography
on SiO2 (EtOAc) to give 83% of chloronaphthyridine 56; slightly
brown powder; mp (EtOH) >250 ꢀC; Rf (EtOAc) 0.65; 1H NMR
ꢀ
P.; Henichart, J.-P.; Couturier, D. J. Heterocycl. Chem. 1999, 36, 1263; (l) Legrand,
ꢀ
A.; Rigo, B.; Henichart, J.-P.; Norberg, B.; Camus, F.; Durant, F.; Couturier, D.
ꢀ
ꢀ
J. Heterocycl. Chem. 2000, 37, 215; (m) Akue-Gedu, R.; Al Akoum Ebrik, S.;
Witczak-Legrand, A.; Fasseur, D.; El Ghammarti, S.; Couturier, D.; Decroix, B.;
ꢀ
ꢀ
Othman, M.; Debacker, M.; Rigo, B. Tetrahedron 2002, 58, 9239; (n) Akue-Gedu,
ꢀ
R.; Couturier, D.; Henichart, J.-P.; Rigo, B.; Sanz, G.; Van Hijfte, L.; Bourry, A.
Tetrahedron 2011, 68, 1117.
(CDCl3)
d
(ppm): 3.98 (s, 3H), 4.10 (s, 3H), 7.16 (dd, J¼8.6, 2.5 Hz,1H),
2. For complementary reviews covering the main aspects of pyroglutamic acid
chemistry, see: (a) Rigo, B.; Cauliez, P.; Fasseur, D.; Sauvage, F. X. Trends Het-
erocycl. Chem. 1991, 2, 155; (b) Smith, M. B. Alkaloids: Chem. Biol. Perspect. 1998,
12, 229; (c) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245.
7.52e7.69 (m, 3H), 8.42 (d, J¼8.6 Hz, 1H), 9.53 (s, 1H). A TeflonÒ
bottle was charged with a stirring bar, intermediate 56 (1.0 g,
3.4 mmol) and N,N-diethylethylenediamine (3.9 g, 33.5 mmol). The
closed bottle was placed in a heating bath (150 ꢀC) and the mixture
was stirred for 15 h. Upon cooling at room temperature, the re-
action mixture was added to water (40 mL), the solid obtained was
filtered, washed with water then recrystallized from EtOAc to give
76% of aminonaphthyridine 60; slightly brown powder; mp (EtOAc)
188e190 ꢀC; Rf (MeOH/Et3N 95/5) 0.75; 1H NMR 1H (CDCl3)
ꢀ
ꢀ
3. Akue-Gedu, R.; Bourry, A.; Camus, F.; Norberg, B.; Durant, F.; Couturier, D.;
Debacker, M.; Rigo, B. Heterocycles 2004, 63, 1855.
ꢀ
ꢀ
4. Rigo, B.; Akue-Gedu, R. Targets Heterocycl. Syst. 2006, 10, 359.
ꢀ
5. Bourry, A.; Couturier, D.; Sanz, G.; Van Hijfte, L.; Henichart, J.-P.; Rigo, B. Tet-
rahedron 2006, 62, 4400.
6. Bourry, A.; Akue-Gedu, R.; Henichart, J.-P.; Sanz, G.; Rigo, B. Tetrahedron Lett.
2004, 45, 2097.
ꢀ
ꢀ
ꢀ
7. Marchalin, S.; Decroix, B. J. Heterocycl. Chem. 1994, 31, 495.
8. (a) Thanks to a Referee who told us that in a rather similar reaction, 1-hydrox-
ybenzotriazole removes the tosyl group of N-tosylimidazole: Fuji, T.; Sakakibara, S.
Bull. Chem. Soc. Jpn.1974, 47, 3146; (b) Marchalin, S.; Decroix, B. J. Heterocycl. Chem.
1993, 30, 667.
d
(ppm): 1.10 (t, J¼7.1 Hz, 6H), 2.23 (q, J¼7.1 Hz, 4H), 2.80 (bt,
J¼5.9 Hz, 2H), 3.77 (bq, J¼5.9 Hz, 2H), 3.97 (s, 3H), 4.38 (s, 3H), 6.56
(bt, J¼5.6 Hz, 1H, deuterium oxide exchangeable), 6.90 (d, J¼8.9 Hz,
1H), 7.23 (dd, J¼8.8, 2.4 Hz, 1H); 7.53 (d, J¼8.8 Hz, 1H); 7.86
(d, J¼2.4 Hz, 1H); 8.15 (d, J¼8.9 Hz, 1H); 9.43 (s, 1H). Anal. Calcd for
C22H27N5O: C, 70.00; H, 7.21; N, 18.55. Found: C, 70.34; H, 7.29;
N, 18.17.
9. (a) Dang, Z.; Yang, Y.; Ji, R.; Zhang, S. Bioorg. Med. Chem. Lett. 2007, 17, 4523; (b)
ꢀ
€
For a rather similar reaction, see: Merour, J.-Y.; Piroelle, S.; Faure, R. J. Heterocycl.
Chem. 1994, 31, 141.
10. For some aspects on the reactivty of N-acyliminium salts in these series, see
ref. 4.
11. Eaton, P. F.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38, 4071.
12. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 3037.
13. Rigo, B.; Tullier, E.; Barbry, D.; Couturier, D.; Warin, V.; Lamiot, J.; Baert, F. J.
Heterocycl. Chem. 1990, 27, 1383.
4.32. 2-Methoxy-11H-indolo[3,2-c]-1,5-naphthyridine (61)
14. (a) Case, F. H.; Brennan, J. A. J. Am. Chem. Soc. 1959, 81, 6297; (b) Kessar, S. V.;
Joshi, G. S. Tetrahedron 1973, 29, 419; (c) Schaaf, R.; Perkampus, H.-H. Tetrahe-
Intermediate 53 was obtained in the same ways as for the
synthesis of 57; a mixture of this intermediate 53 (5.0 g, 19.7 mmol)
and 30% MeONa in MeOH (7.9 mL, 79 mmol) in MeOH (100 mL) was
refluxed for 48 h. Upon cooling at room temperature, the solution
was concentrated, the residue was dissolved in dichloromethane
and then washed with water. The solid obtained upon drying
(Na2SO4) and evaporation was recrystallized from MeOH to give
€
dron 1981, 37, 341; (d) Malm, J.; Hornfeld, A.-B.; Gronowitz, S. J. Heterocycl.
Chem. 1994, 31, 521; (e) Bisagni, E.; Landras, C.; Thirot, S.; Huel, C. Tetrahedron
1996, 52, 10427.
15. (a) Gisby, G. P.; Royall, S. E.; Sammes, P. G. J. Chem. Soc., Perkin Trans. I 1982, 169;
(b) Singh, B. Synthesis 1985, 305.
16. (a) Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.; Henderson, C. G.; Roberts,
D. A.; Ruddock, K. S.; Samuels, G. M. R.; Stefaniak, M. H. J. Med. Chem. 1988, 31,
2048; (b) Angibaud, P.; Bourdrez, X.; Devine, A.; End, D. W.; Freyne, E.; Ligny, Y.;

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 5644e5654
5654
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19. (a) Shono, T.; Matsumura, Y.; Kashimura, S. J. Org. Chem. 1981, 46, 3719; (b)
Chelucci, G.; Marchetti, M.; Soccolini, F.; Botteghi, C. J. Heterocycl. Chem. 1984,
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1984, 106, 6735.
17. However, we have not submitted compounds 34e36 to oxidation by selenium
oxide, which succeeds in case of 37e40.
20. (a) Busacca, C. A.; Eriksson, M. C.; Dong, Y. J. Org. Chem. 1999, 64, 4564; (b)
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