Synthesis of novel benzo[h][1,6]naphthyridines via a rearrangement of hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepines

Article abstract of DOI:10.1002/jhet.5570400209

Heating of hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-2,5,11-trione in boiling phosphoryl chloride led to a rearranged product like 3,5-dichlorobenzo[h][1,6]naphthyridine. This structure was established from x-ray diffraction analysis.

Full text of DOI:10.1002/jhet.5570400209

Mar-Apr 2003
255
Synthesis of Novel Benzo[h][1,6]naphthyridines via a Rearrangement
of Hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepines
Antoine Hinschberger, Frédéric Fabis, Jana Sopkova-de Oliveira Santos and Sylvain Rault*
Centre d’Etudes et de Recherche sur le Médicament de Normandie,
U.F.R. des Sciences Pharmaceutiques. 5, rue Vaubénard, F-14032 Caen (France)
Received October 7, 2002
Heating of hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-2,5,11-trione in boiling phosphoryl chloride
led to a rearranged product like 3,5-dichlorobenzo[h][1,6]naphthyridine. This structure was established from
X-ray diffraction analysis.
J. Heterocyclic Chem., 40, 255 (2003).
Carrying on with the study of rearrangement and aroma-
with conviction benzo[h][1,6]naphthyridines 5 and 6 and
not cyclopenta[b][1,4]benzodiazepines as we first claimed
[4] (Scheme 2). In contrary of 1a-b, the rearrangement of
compounds 3 and 4 in the same conditions is not complete
since we could observe the formation of pyrrolobenzo-
diazepine structures 7 (mixture with 5) and 8 (mixture
with 6) in a 40/60 ratio at the end of the reaction.
This rearrangement was performed in boiling phos-
phoryl oxychloride in the presence of pyridine under
microwave heating conditions. Conversion of starting
material was obtained in 90 min versus 8 h under thermal
conditions but no difference in yields or selectivity of the
reaction was observed.
tization reactions in the benzodiazepine series [1-4], we
wish to report here the reinvestigation of rearrangement of
2-substituted pyrrolo[2,1-c][1,4]benzodiazepines. We
have established that hexahydro-5H-pyrrolo[2,1-c][1,4]-
benzodiazepine-5,11-dione 1a and octahydropyrido-
[2,1-c][1,4]benzodiazepine-6,12-dione 1b rearranged
respectively into 5-chlorotetrahydrobenzo[h][1,6]naphthy-
ridine 2a and 6-chlorotetrahydro-1H-azepino[3,2-c]-
quinoline 2b, and not into cyclopenta[b][1,4]benzodi-
azepine as described in a preliminary note [1] (Scheme 1).
The structures were elucidated from X-ray diffraction
analysis [5].
Taking account of the originality and the potentiality of
these new structures in medicinal chemistry, we interested
herein in the investigation of further tricyclic derivatives.
We applied this rearrangement in pyrrolo[2,1-c]-
[1,4]benzodiazepine-2,5,11-trione 3 and 2-hydrox-
ypyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione 4.
The structure of compound 8 was undoubtedly con-
firmed by unequivocal synthesis from 4 following a previ-
ously reported procedure [2].
Even if it appeared that the rearrangement occurred with
aromatization of the tricycle leading to benzo[h][1,6]naph-
thyridine, the structure of compounds 5 and 6 had to be
confirmed. Compound 5 was separated from 7 by aqueous
sodium hydroxide treatment in acetone of the mixture. In
1
13
Analytical data (IR, H, C NMR, MS and elemental
analysis) and X-ray diffraction studies led us to ascertain

256
A. Hinschberger, F. Fabis, J. S.-de Oliveira Santos and S. Rault
Vol. 40
these conditions, the pyrrolobenzodiazepine 7 opened in
anthranilic derivative 9 which could have been easily iso-
lated in the form of its soluble sodium salt in the solvent
(Scheme 3). The same treatment applied to the mixture of
6 and 8 led to an open-derivative 10 separated from 6. We
have not isolated the compounds 7 and 8.
The presence of the two chlorine atoms in the napthyri-
dine 5 made us to consider its reactivity towards nucle-
ophilic substitutions. Thus, by warming the compound 5
with one equivalent N-benzylpiperazine in refluxing
dimethylformamide in the presence of triethylamine for 2
hours, we obtained the 3-chloro-5-N-benzylpiperazi-
nobenzo[h][1,6]naphthyridine 11.
Reaction of 5 with an excess of N,N-dimethyl-
aminoethylamine in ethanol in a sealed tube under
microwave heating conditions (160 °C, 4 bars, 300 W)
gave more rapidly with a global better yield the monosub-
stituted derivative 12 without trace of a possible disubsti-
tuted one (Scheme 4). This compound was crystallised
from diethyl ether to give good single crystals that permit
us to confirm its structure from X-ray analysis (Figure 1),
and the structure of 5 as 3,5-dichloro benzo[h][1,6]naph-
thyridine. The compound 6 would be by analogy 5-
chlorobenzo[h][1,6]naphthyridine.
The substitutions with N-alkylpiperidine methyl alco-
hols required preliminary formation of alcoholate anions
that react in refluxing toluene for 4 h [6,7].
The hypothetical mechanism of this rearrangement
could be transposed with a related process that we previ-
ously described [1]. We supposed a chlorodehydroxylation
of the starting compound 3 (steps 1-2) leading to a
chloroalkene that is then rearranged (steps 3-8) to give
after a final thermal aromatization (step 9) the expected
dichlorobenzonaphthyridine 5 (Scheme 5). This mecha-
nism applied to the hydroxylated compound 4 would give
a dehydrated intermediate before the reaction of rearrange-
ment (Scheme 6).
In conclusion, this rearrangement was a new method to
synthesise aromatic benzo[h][1,6]naphthyridines [8-13]
and these new tricyclic structures appeared as promising
scaffolds in medicinal chemistry with potential anti-tumor
Figure 1. Ortep diagram of crystal structure of 12. Displacement ellip-
soids are shown at 50% probability levels and H atoms are drawn as
small circles of arbitrary radii.

Mar-Apr 2003
Synthesis of Novel Benzo[h][1,6]naphthyridines
257
effect particularly for the amidine 11. Recent biological
results (binding with leucemic cells : L-1210) showed a
micromolar affinity (IC = 4.1µM) for this amidine. In the
50
light of this encouraging result, and taking into account an
hypothetical intercalating property for these new aromatic
systems, a pharmacomodulation of the aromatic ring will
be further developed.
EXPERIMENTAL
Melting points were determined on a Köfler melting point
apparatus and are uncorrected. The infrared spectra were taken
1
with a Genesis Series FT-IR spectrometer. H nmr (400 MHz)
13
and C nmr (100 MHz) were recorded on a JEOL Lambda 400
spectrometer. Chemical shifts were expressed in parts per million
downfield from TMS as the internal standard. Mass spectra (MS)
were obtained on a JEOL JMS GCMate spectrometer at an ioniz-
ing potential of 70eV. Elemental analyses were performed at the
“Institut de Recherche en Chimie Organique Fine” (Rouen).
Reaction times were monitored by TLC until no starting material
remained. Thin-layer chromatography (TLC) were performed on
0.2-mm precoated plates of silica gel 60F-264 (Merck).
Visualization was made with ultraviolet light. All solvents and
reagents were purchased from Acros and Aldrich Chimie and
used without further purification.
General Procedure for the Reaction of Rearrangement of
Benzodiazepinones (3,4).
Method A.
A solution of hexahydro-5H-pyrrolo[2,1-c][1,4]benzo-
diazepine-2,5,11-trione 3 (9 g, 39 mmol) in POCl (80 ml) and
3
pyridine (2 ml) was heated with stirring under microwave
irradiation (500 W) for 90 min. in a Normatron apparatus.
After elimination of phosphoryl chloride under reduced
pressure, the residue was taken up in water, basified (pH 11)
with 28% aqueous ammonia solution and extracted with
diethyl ether. The organic layer was evaporated to give a
mixture of 5 and 7. This mixture was dissolved in acetone and
treated with a saturated aqueous sodium hydroxide solution
for ten minutes at 50 °C (approx.) in order to separate the two
compounds (see Scheme 3). After filtration, 1.2 g of a beige
solid 5 (12%) crystallized from methanol was isolated,
whereas the filtrate was acidified (pH 1) with 37% aqueous
hydrochloric acid solution. The resulting brown precipitate
was washed with water then extracted with ethyl acetate. The
organic layer was dried over magnesium sulfate, treated with
charcoal and evaporated to dryness to give 0.6 g of a yellow
powder 9 (6%) crystallized from diethyl ether.
Method B.
The reaction was carried out under conventional heating for 8 h.
3,5-Dichlorobenzo[h][1,6]naphthyridine (5).
This compound was obtained as a beige solid (methanol), mp
174 °C; ir (potassium bromide): CN 1600, 1575, 1510, 1450,
-1
1
1390, 1330, 1290, 1180, 1115, 990, 780 cm
. H nmr
(DMSO-d ): δ 9.30 (s, 1H, 2-H), 8.95 (d, 1H, 10-H, J= 8.1 Hz),
6
8.79 (s, 1H, 4-H), 8.08 (d, 1H, 7-H, J= 7.8 Hz), 7.96 (t, 1H, 8-H,
13
J= 6.9 Hz), 7.86 (t, 1H, 9-H, J= 6.9 Hz). C nmr (DMSO-d ): δ
6

258
A. Hinschberger, F. Fabis, J. S.-de Oliveira Santos and S. Rault
Vol. 40
153.4, 148.3, 147.1, 144.4, 133.6, 131.6, 130.7, 128.6, 128.3,
124.0, 123.6, 120.3; ms: m/z 252 (M , +4), 250 (M , +2), 249
(100), 213 (85), 179 (26).
0.66 mmol), the mixture was warmed under reflux for 3 min, then
cooled to furnish a yellow powder 11, which was crystallized
from isopropanol to yield 0.06 g (25%), mp 228 °C; ir (potassium
+
+
Anal. Calcd. for C H N Cl : C, 57.86; H, 2.43; N, 11.25.
Found: C, 57.66; H, 2.25; N, 11.45.
bromide): CO fumarate 1707, 1571, 1453, 1424, 1376, 1299,
12
6
2
2
-1 1
1151 cm . H nmr (DMSO-d ): δ 9.16 (s, 1H, 2-H), 8.82 (d, 1H,
6
10-H J= 8.4 Hz), 8.45 (s, 1H, 4-H), 7.83 (d, 1H, 7-H, J= 8.4 Hz),
7.76 (t, 1H, 8-H, J= 8.2 Hz), 7.58 (t, 1H, 9-H, J= 7.1 Hz), 7.37-
7.28 (m, 5H, phenyl), 6.62 (s, 2H, 2CH fumarate), 3.62 (s, 2H,
2-[(Chloro-1H-pyrrole-2-carbonyl)-amino]benzoic Acid (9).
This compound was obtained as a yellow powder (ether), mp >
260 °C; ir (potassium bromide): OH 3259, CO 1677, CO 1630,
CH benzyl), 3.45 (m, 4H, 2CH ), 2.70 (m, 4H, 2CH ); ms: m/z
2
2
2
-1 1
1601, 1535, 1449, 1415, 1240 cm . H nmr (DMSO-d ): δ 12.25
389 (M+, 16), 242 (100), 213 (42), 159 (70), 146 (66), 91 (50).
Anal. Calcd. for C N O Cl: C, 64.22; H, 4.99; N, 11.1.
6
(s, 1H, NH pyrrole), 11.88 (s, 1H, NH lactam), 8.59 (d, 1H,
phenyl, J= 8.2 Hz), 8.03 (d, 1H, phenyl, J= 7.8 Hz), 7.63 (t, 1H,
phenyl, J= 7.5 Hz), 7.16 (m, 2H, H phenyl and H pyrrole), 6.72
H
27 25
4 4
Found: C, 64.44; H, 5.02; N, 11.32.
3-Chloro-5-(N,N-dimethylaminoethylamino)benzo[h][1,6]naph-
thyridine, (Fumarate Salt) (12).
+
(s, 1H, pyrrole); ms: m/z 264 (M , 22), 230 (25), 169 (22), 137
(62).
Anal. Calcd. for C H N ClO : C, 54.46; H, 3.43; N, 10.58.
Found: C, 54.62; H, 3.39; N, 10.29.
N,N-Dimethylaminoethylamine (4.4 ml, 40 mmol) was added
to a solution of 3,5-dichlorobenzo[h][1,6]naphthyridine 5 (0.5 g,
2 mmol) in ethanol (10 ml). The solution was stirred for 40 min-
utes under pressure (4 bars) at 160 °C in a sealed tube under
microwave heating conditions (300 W). The solvent and excess
of reactive were removed under reduced pressure and the result-
ing residue was taken up in water (50 ml). After stirring for 20
minutes (approx.), the precipitate was collected by filtration and
dried to give a beige powder. The resulting solid was dissolved in
isopropyl alcohol (6 ml), fumaric acid (0.23 g, 2 mmol) was
added and the mixture was warmed at reflux for 35 minutes.
After cooling, the precipitate was collected by filtration and dried
to afford a white powder 12 which was crystallized from iso-
propanol to yield 0.36 g (34%), mp 190 °C; ir (potassium bro-
12
9
2
3
5-Chlorobenzo[h][1,6]naphthyridine (6).
The same procedure as for 5 from the 2-hydroxypyrrolobenzodi-
azepine 4 (10 g, 43 mmol) gave a mixture of 6 and 8. This mixture
was dissolved in acetone and treated with a saturated aqueous
sodium hydroxide solution for ten minutes at 50 °C (approx.) in
order to separate the two compounds (see Scheme 3). After filtra-
tion, 1.0 g of a beige solid 6 (11%) crystallized from diethyl ether
was isolated, whereas the filtrate was acidified (pH 1) with 37%
aqueous hydrochloric acid solution. The resulting precipitate was
washed with water then extracted with ethyl acetate. The organic
layer was dried over magnesium sulfate, treated with charcoal and
evaporated to dryness to give 0.5 g of a white powder 10 (6%)
mide): NH 3407, CO fumarate 1693, 1584, 1536, 1360, 1256,
1
crystallized from diethyl ether. Compound 6: mp 100 °C; H nmr
-1 1
1208 cm . H nmr (DMSO-d ): δ 9.09 (s, 1H, 2-H), 8.92 (s, 1H,
6
(DMSO-d ): δ 9.30 (d, 1H, 2-H, J= 8.1 Hz), 9.02 (d, 1H, 3-H, J=
6
4-H), 8.69 (d, 1H, 10-H, J=7.8 Hz), 8.13 (s, 1H, NH), 7.62 (m,
2H, 7-H and 8-H), 7.36 (m, 1H, 9-H), 6.52 (s, 4H, 4CH
8.1 Hz), 8.77 (t, 1H, 2-H, J= 8.1 Hz), 8.08 (d, 1H, 10-H, J= 7.8 Hz),
13
7.96-7.85(m, 2H, 7-H, 8H), 7.85 (t, 1H, 9-H, J= 7.8 Hz). C nmr
fumarate), 3.86 (m, 2H, CH ), 3.13 (m, 2H, CH ), 2.64 (s, 6H,
2
2
(DMSO-d ): δ 154.6, 149.4, 148.8, 144.4, 135.1, 131.2, 128.2,
6
+
2CH ); ms: m/z 300 (M , 21), 254 (60), 242 (100), 230 (56), 213
3
+
128.1; 124.6, 124.3, 123.6, 119.7; ms: m/z 216 (M ,+2, 37), 214
(M , 100).
(52), 178 (46), 151 (48).
+
Anal. Calcd. for C
H N ClO : C, 54.09; H, 4.73; N, 10.51.
24 25 4 8
Anal. Calcd. for C H N Cl: C, 67.15; H, 3.29; N, 13.05.
12
7 2
Found: C, 54.24; H, 4.93; N, 10.92.
Found: C, 67.43; H, 3.28; N, 12.95.
X-ray.
2-[(1H-Pyrrole-2-carbonyl)-amino]benzoic Acid (10).
Suitable crystals of the title compound (12) were obtained by
slow evaporation from diethyl ether at room temperature.
Examined crystal reveals a monoclinic system (the space group
C2/c) with the following unit cell dimensions: a=23.216(5)Å,
b=9.060(7)Å, c=11.268(1)Å, β= 128.79(1)°.
1
This compound has Mp>260 °C; H nmr (DMSO-d ): δ 13.8
6
(s, 1H, COOH), 11.9 (s, 1H, NH), 8.69 (d, 1H, Hphenyl,
J=7.5Hz), 8.03 (d, 1H, Hphenyl, J=7.5Hz), 7.63 (t, 1H, Hphenyl,
J=7.5Hz), 7.14 (t, 1H, Hphenyl, J=7.5Hz), 7.03 (m, 1H,
Hpyrrole), 6.78 (m, 1H, Hpyrrole), 6.24 (m, 1H, Hpyrrole).
nmr (DMSO-d ): δ 170.1, 158.7, 141.7, 134.3, 131.3, 126.2,
123.5, 122.0, 119.2, 115.3, 110.3, 109.4; m/z 230 (M ,80).
13
C
Intensity data for compound 12 were collected on an Enraf-
6
+
Nonius - CAD4 diffractometer with Mo K radiation (λ=
α
0.71073 Å) at room temperature. The data treatment, polarisation
and decay corrections, was carried out with JANA98 programme
[14] The crystal structure was solved by direct methods using
SHELX97 package [15]. All non-hydrogen atoms were refined
anisotropically. The H atoms were determined via difference
Fourier maps and refined with isotropic atomic displacement
parameters.
The crystal packing in 12 consists of 3-chlorobenzo[h]-
[1,6]naphthyridine pairs made up through two symmetry-equiv-
alent stacking interactions of the aromatic rings that form across
inversion centre. The interplanar spacing of the parallel rings in
the pair is 3.5 Å. The base-pair dimers lies between them via a
water molecule, present in the crystal, through a network of four
Anal. Calcd. for C
Found: C, 62.54; H, 4.46; N, 12.19.
H N O : C, 62.60; H, 4.39; N, 12.17.
12 10 2 3
3-Chloro-5-N-benzylpiperazinobenzo[h][1,6]naphthyridine,
(Fumarate Salt) (11).
N-Benzylpiperazine (0.1 ml, 0.57 mmol) was added to a
solution of 3,5-dichlorobenzo[h][1,6]naphthyridine 5 (0.12 g,
0.48 mmol) and triethylamine (0.07 ml, 0.53 mmol), in N,N-
dimethylformamide (5 ml). After stirring for 2 hours under
reflux, the solvent was removed. The residue was crystallised in
water, filtered, and purified by chromatography on silicagel with
chloroform-methanol (99:1 v/v) as eluent to give a yellow solid.
After dissolution in isopropanol (3 ml) with fumaric acid (0.08 g,

Mar-Apr 2003
Synthesis of Novel Benzo[h][1,6]naphthyridines
259
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(1971).
hydrogen bonds, two from a molecule of one base-pair dimer
and two symmetry-equivalent from a molecule of another
base-pair dimer.
[9] Y. Hamada, I. Takeuchi and M. Hirota, Chem. Pharm. Bull.,
22, 485 (1974).
REFERENCES AND NOTES
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G. M. Sheldrick, 1997, SHELX97. Program for the Refinement of
Crystal Structures. University of Gottingen. Germany.
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