Synthesis of novel pyrido[1,2-b][2,4]benzodiazepine derivatives

Article abstract of DOI:10.3184/174751912X13343956275474

A new method based on the reaction of [2-(bromomethyl)phenyl](4- chlorophenyl)methanone with pyridine-2-amines has been used for the synthesis of 6-(4-chlorophenyl)-11H-pyrido[1,2-b][2,4]benzodiazepin-12-ium salts. The quaternary pyridinium salts, which were formed on the first stage, gave the pyrido[1,2-b][2,4]benzodiazepine system upon heating with acids.

Full text of DOI:10.3184/174751912X13343956275474

312 RESEARCH PAPER
MAY, 312–314
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis of novel pyrido[1,2-b][2,4]benzodiazepine derivatives
Volodymyr O. Kovtunenkoa, Lyudmila M. Potikhaa*, Volodymyr V. Sypchenkoa,
Roman I. Zubatyukb and Oleg V. Shishkinb.c
aDepartment of Chemistry, Kiev NationalTaras Shevchenko University, Kiev, Ukraine
bSSI “Institute of Single Crystals” National Academy of Science of Ukraine, Kharkiv, Ukraine
cDepartment of Inorganic Chemistry, V.N.Karazin Kharkiv National University, Kharkiv, Ukraine
A new method based on the reaction of [2-(bromomethyl)phenyl](4-chlorophenyl)methanone with pyridine-2-amines
has been used for the synthesis of 6-(4-chlorophenyl)-11H-pyrido[1,2-b][2,4]benzodiazepin-12-ium salts. The quater-
nary pyridinium salts, which were formed on the first stage, gave the pyrido[1,2-b][2,4]benzodiazepine system upon
heating with acids.
Keywords: annelation, o-bromomethylbenzophenone, pyrido[1,2-b][2,4]benzodiazepine, pyridine-2-amine
Pyrido[1,2-b][2,4]benzodiazepine derivatives are poorly
studied compounds. At present, less than 40 representatives
of the above system have been described, the majority of which
are partially hydrogenated derivatives. The first report of the
synthesis of pyrido[1,2-b][2,4]benzodiazepine derivatives
appeared in 1971,1 when the cyclisation of 2-amino-1-(2-
carboxybenzyl)pyridinium salts was described, which leads
to 6-oxo-6,11-dihydro-derivatives of this heterocyclic system.
A few methods for the synthesis of these compounds are
known today. One is based on a pyridine ring closure forming
the diazepine.2 In another example, the diazepine ring was
added to a pyridine by using 2-bromomethylbenzoic acid
derivatives.1,3–5
We now describe a new method for the synthesis of pyrido
[1,2-b][2,4]benzodiazepines which is based on the reaction of
[2-(bromomethyl)phenyl](phenyl) methanone (о-bromometh-
ylbenzophenone, 1) derivatives with 2-aminopyridines (2).
Substances of type 1 are α-bromoacetophenone7 viniloges,6
which suggests the possibility of a cyclisation that is similar
to the Chichibabin synthesis. о-Bromomethylbenzophenone
derivatives have been known for a long time, but have not been
used extensively in heterocyclisations due to their relative
inaccessibility and instability. The [2-(bromomethyl)phenyl]
(4-chlorophenyl)methanone (1a), which is commonly avail-
able, was chosen as a model to study the reaction with 2-
aminopyridines.8
The yield of salts 3 depended on the nature of the substituent
in the pyridinium ring – it decreased with increasing of p-type
properties of the substituent R. The purity of alkylation
products was usually more than 95%. That allowed them to be
used in further transformations without additional purification,
except for the production of pyridine 2d (R=Cl) reaction.
Salt 3d proved to be impure and contained dehydrobromina-
tion reaction products from the initial benzophenone 1a; the
typical transformation of 2-bromomethylbenzophenones in
the presences of base.9 The position of the substituent on the
pyridine ring of 2 did not influence the reaction products,
with the exception of interaction of benzophenone 1a with
6-methylpyridine-2-amine. This reaction led to a complex
mixture of products which did not depend on the reaction
conditions. The major component of the mixture was 6-
1
methylpyridin-2-amine hydrobromide (according to H NMR
spectra data). [2-(Bromomethyl)-5-nitrophenyl](phenyl)meth-
anone 1b is inaccessible in a pure state,10 but we succeeded in
obtaining 2-aminopyridine 3e alkylation product with satisfactory
yield (58 %).
The salts 3 were stable upon heating in the presence of
Et3N, but under the action of MeONa they lost HBr and gave
(4-chlorophenyl){2-[(2-iminopyridin-1(2H)-yl)methyl]phenyl}
1
methanones (4a,b). All the proton signals of imines 4 in H
NMR spectra are shifted to higher field, with the exception of
4-chlorophenyl substituent. Salts 3a and 3b display symmetric
and asymmetric NH2 bands in the IR at 3250, 3193 and 3224,
3183 cm−1 respectively, whereas imines 4a and 4b displayed
a single NH band at 3310 and 3338 cm−1 respectively. The
quaternary pyridinium salts 3 were formed upon the interac-
tion of substances 4 with HBr in AcOH. Subsequent heating
Results and discussion
The moderate heating (45–55 °C) of a benzophenone 1a with
2-aminopyridines (2a–d) in anhydrous acetonitrile gave the
2-amino-1-(2-benzoylbenzyl)pyridinium bromides (3a–d).
Product
R
R’
R”
3a
3b
3c
3d
3e
4a
4b
5a
5b
5c
5d
5e
H
3-Me
4-Me
5-Cl
H
Cl
Cl
Cl
Cl
H
H
H
H
H
NO2
–
H
–
3-Me
H
4-Me
3-Me
2-Cl
H
–
–
Cl
Cl
Cl
Cl
H
H
H
H
H
NO2
Scheme 1
* Correspondent. E-mail: potikha_l@mail.ru

JOURNAL OF CHEMICAL RESEARCH 2012 313
Table 1 Crystallographic data for 5a
of the salts 3a–e in AcOH leads to intramolecular reaction
products; 6-aryl-11H-pyrido[1,2-b][2,4]benzodiazepin-12-ium
bromides (5a–e).
Chemical formula
Formula weight
C19H18BrClN2O2
421.71
The structures of the substances 5 were assigned based on
mass spectrometry, IR and NMR spectral data. The absence
of bands νC=O and νNH in IR spectra of salts 5 indicated the
formation of intramolecular condensation reaction products.
Crystal system
space group
Monoclinic
P21/c
a/Å
b/Å
7.83173(19)
15.8149(4)
1
The characteristic property of their H NMR spectra was the
c/Å
α/deg
15.0792(4)
90
presence of a proton signal for a methylene group C(11)H2 as
2
β/deg
94.902(2)
90
1860.84(8)
an AB-system with J = 13.5–15.0 Hz, that was correlated
γ/deg
with the formation of a sufficiently inflexible cyclic structure
in which conformational transformations are fixed. The assign-
ment of the proton signals in 1H NMR spectra and carbon sig-
nals in 13C NMR spectra was completed on the base of COSY,
NOESY, HMQC and HMBC experiments for compound 5a.
The final confirmation of the structure of the pyrido[1,2-b]
[2,4]benzodiazepine derivatives was based on X-ray data for
5a (Fig. 1). In the crystal compound 5a exists as the dihydrate
of the bromine salt of the organic cation (Table 1). The diaze-
pine ring adopts a boat conformation with a deviation of the
C6, N2 and C9 atoms from the mean plane of the remaining
ring atoms by –0.663(3) Å, –0.684(3) Å and –0.717(2) Å, respec-
tively. The parachlorphenyl substituent is slightly rotated with
respect to the plane of the N2–C6 double bond [the N2–C6–
C14–C19 torsion angle is 37.4(2)°]. The positive charge of
the cation is most probably localised on the pyridine ring.
However, some bond length alternation is still observed within
this ring: the C1-C2 bond (1.347(3) Å) is considerably shorter
than the C2–C3, C3–C4 and C4–C5 bonds [1.383(3) Å,
1.372(3) Å, 1.383(2) Å, respectively].
In the crystal cations, 5a form channels along the (1 0 0)
crystallographic axis where the bromine anions and water
molecules are bound by a set of intermolecular hydrogen
bonds: O1w–H1w…Br1 (H…Br 2.43, O–H…Br 177°), O1w–
H2w…Br1i [i: 1–x, –y, –z] (H…Br 2.44, O–H…Br 167),
O2w–H3w…O1wii [ii: 2–x, –y –z] (H…O 2.02, O–H…O
160o), O2w–H4w…Br1 (H…Br 2.73, O–H…Br 170°).
Pyrido[1,2-b][2,4]benzodiazepine bromides 5 are stable
on heating with Ac2O, PhNO2, in the presence of benzaldehydes
(in Ac2O or AcOH) and amines (Et3N, morpholine). However,
when they are heated with MeONa cleavage of the benzodiaz-
epine ring occurs leading to the imines 4a,b.
V/Å3
Z
λ/Å
4
0.71073
2.367
856
Absorption coefficient /mm−1
F(000)
T/K
298(2)
2.91–30.00
1.505
Xcalibur–3 equipped with a
graphite monochromator
–10<=h<=11
–21<=k<=22
–21<=l<=21
31300
θ ranges for data collection
Density (Calcd) /g cm−1
The diffractometer that
was used
Index ranges
Diffraction reflection number
The number of independent
reflections
5417
Cell measurement reflections
used
3413
The programmes that were used SHELX–97
Final R1, wR2 (Obs. data)
Final R1, wR2 (All data)
0.0363, 0.0828
0.0712, 0.0889
0.988
0.365, –0.598
CCDC 854216
Goodness of fit on F2 (S)
Largest diff peak and hole /e Å3
Details of where the data has
been deposited and the
accession number.
determined by Schoniger’s method.10 [2-(Bromomethyl)phenyl](4-
chlorophenyl)methanone (1a) was prepared by the known procedure,9
[2-(bromomethyl)-5-nitrophenyl](phenyl)methanone (1b) was pre-
pared as a mixture with a content of 1b about 70%, by the known
procedure.11
Synthesis of 2-amino-1-(2-benzoylbenzyl)pyridinium bromides (3a–e);
general procedure
Experimental
The mixture of benzophenone 1a,b (3 mmol) and 2-aminopyridine
2a–d (3.3 mmol) in MeCN (10 mL) was heated for 3 h at 45–55 °C,
and then allowed to stand for 24 h at room temperature. The precipi-
tate was filtered off, washed with acetone, dried and crystallised from
nitromethane. The following compounds were obtained:
1H NMR spectra were recorded on a Bruker AVANCE DRX 500
(500 MHz), 2D experiments were carried out on a Varian-400 instru-
ment at 400 MHz (1H NMR) and 100 Hz (13C NMR) with SiMe4 as
the internal standard in DMSO-d6. Chemical shifts are reported in
ppm. IR spectra were recorded in KBr disks on a Perkin Elmer Spec-
trum BX spectrometer. Melting points were obtained on a Boetius
apparatus and are uncorrected. Elemental analyses were performed on
a Vario MIKRO Cube CHNS-elemental analyser, halogens were
3a:Yield, 0.76 g (63%); white crystals; m.p. 218–219 °C (MeNO2).
IR (KBr): ν 3250 (NH2), 3193 (NH2), 3047, 3008, 1678 (C=O), 1639,
1580, 1309, 1270, 929, 747 cm–1. 1H NMR (DMSO-d6): δ 8.53 (br. s,
3
3
2H, NH2), 8.07 (d, 1H, J = 7.0 Hz, H-6), 7.96 (t, 1H, J = 8.0 Hz,
H-4), 7.78 (d, 2H, 3J = 9.0 Hz, H-2″, H-6″), 7.67 (d, 2H, 3J = 9.0 Hz,
H-3″, H-5″), 7.64 (t, 1H, 3J = 8.0 Hz, H-4’), 7.61 (d, 1H, 3J = 8.0 Hz,
3
3
H-6′), 7.54 (t, 1H, J = 8.0 Hz, H-5′), 7.14 (d, 1H, J = 8.5 Hz, H-3),
6.97 (t, 1H, 3J = 7.0 Hz, H-5), 6.89 (d, 1H, 3J = 7.5 Hz, H-3′), 5.65 (s,
2H, CH2). Anal. Calcd for C19H16BrClN2O: C, 56.53; H, 3.99; Br,
19.79; Cl, 8.78; N, 6.94. Found: C, 56.61; H, 4.03; Br, 19.82; Cl, 8.75;
N, 6.96%.
3b:Yield, 0.70 g (56%); white crystals; m.p. 228–229 °C (MeNO2).
IR (KBr): ν 3224 (NH2), 3183(NH2), 3076, 1672 (C=O), 1637, 1589,
1533, 1299, 1269, 1087, 927, 842, 791, 749 cm–1. 1H NMR (DMSO-
3
d6): δ 8.18 (br. s, 2H, NH2), 8.00 (d, 1H, J = 7.0 Hz, H-6), 7.85 (t,
1H, 3J = 8.0 Hz, H-4), 7.77 (d, 2H, 3J = 9.0 Hz, H-2″, H-6″), 7.67 (d,
3
2H, J = 9.0 Hz, H-3″, H-5″), 7.60 (m, 2H, H-4′, H-6′), 7.52 (t, 1H,
3
3
3J = 8.0 Hz, H-5′), 6.93 (t, 1H, J = 7.0 Hz, H-5), 6.83 (d, 1H, J =
7.5 Hz, H-3′), 5.72 (s, 2H, CH2), 2.24 (s, 3H, CH3). Anal. Calcd for
C20H18BrClN2O: C, 57.51; H, 4.34; Br, 19.13; Cl, 8.49; N, 6.71. Found:
C, 57.64; H, 4.30; Br, 19.19; Cl, 8.51; N, 6.70%.
3c:Yield, 0.68 g (54%); white crystals; m.p. 226–227 °C (MeNO2).
IR (KBr): ν 3206 (br., NH2), 3052, 3008, 1675 (C=O), 1665, 1637,
1584, 1267, 1087, 925, 747 cm–1. 1H NMR (DMSO-d6): δ 8.41 (br. s,
Fig. 1 Molecular structure of the salt 5a. Thermal ellipsoids of
non-hydrogen atoms are shown at 50% probability level.

314 JOURNAL OF CHEMICAL RESEARCH 2012
2H, NH2), 7.97 (d, 1H, 3J = 7.0 Hz, H-6), 7.76 (d, 2H, 3J = 9.0 Hz, H-
5b:Yield, 0.88 g (73%); white crystals; m.p. 270–272 °C (decomp.,
MeCN). IR (KBr): ν 3025, 2960, 1632, 1584, 1545, 1505, 1316, 1276,
3
2″, H-6″), 7.66 (d, 2H, J = 9.0 Hz, H-3″, H-5″), 7.59 (m, 2H, H-4′,
H-6′), 7.52 (t, 1H, 3J = 8.0 Hz, H-5′), 6.92 (s, 1H, H-3), 6.87 (d, 1H,
1
1084, 957, 851, 733, 666 cm-1. H NMR (DMSO-d6): δ 9.00 (d, 1H,
3
3J = 7.0 Hz, H-5), 6.84 (d, 1H, J = 7.5 Hz, H-3′), 5.60 (s, 2H, CH2),
3
3
3J = 5.5 Hz, H-1), 8.40 (d, 1H, J = 7.5 Hz, H-3), 7.93 (d, 2H, J =
2.34 (s, 3H, CH3). Anal. Calcd for C20H18BrClN2O: C, 57.51; H, 4.34;
Br, 19.13; Cl, 8.49; N, 6.71. Found: C, 57.39; H, 4.37; Br, 19.18; Cl,
8.45; N, 6.74%.
8.5 Hz, H-2′, H-6′), 7.88–7.80 (m, 3H, H-2, H-9, H-10), 7.74 (d, 2H,
3
3J = 8.5 Hz, H-3′, H-5′), 7.68 (t, 1H, J = 8.0 Hz, H-8), 7.52 (d, 1H,
2
3J = 8.0 Hz, H-7), 5.93 (d, 1H, J = 15.0 Hz, HA-11), 5.52 (d, 1H,
2J = 15.0 Hz, HB-11), 2.60 (s, 3H, CH3). 13C NMR (DMSO-d6): δ
173.7 (C-6), 151.3 (C-4a), 146.7 (C-3), 140.6 (C-1), 139.3 (C-4′),
139.2 (C-10a), 136.8 (C-1′), 135.0 (C-9), 134.5 (C-4), 133.7 (2C,
C-2′, C-6′), 133.0 (C-6a), 131.5 (C-7), 130.6 (C-8), 129.8 (2C, C-3′,
C-5′), 129.5 (C-10), 124.2 (C-2), 57.7 (C-11), 18.2 (CH3). Anal.
Calcd for C20H16BrClN2: C, 60.10; H, 4.03; Br, 19.99; Cl, 8.87; N,
7.01. Found: C, 60.28; H, 4.07; Br, 20.06; Cl, 8.85; N, 7.05%.
3d:Yield, 0.28 g (21%); white crystals; m.p. 219–221 °C (MeNO2).
IR (KBr): ν 3266 (NH2), 3190 (NH2), 3076, 1669 (C=O), 1655, 1577,
1519, 1304, 1270, 1168, 1087, 930, 842, 735 cm–1. 1H NMR (DMSO-
d6): δ 8.89 (br. s, 2H, NH2), 8.46 (s, 1H, H-6), 8.03 (d, 1H, 3J = 8.0 Hz,
H-4), 7.77 (d, 2H, 3J = 9.0 Hz, H-2″, H-6″), 7.66 (d, 2H, 3J = 9.0 Hz,
H-3″, H-5″), 7.60 (m, 2H, H-4′, H-6′), 7.52 (t, 1H, 3J = 8.0 Hz, H-5′),
3
3
7.16 (d, 1H, J = 8.5 Hz, H-3), 6.92 (d, 1H, J = 7.5 Hz, H-3′), 5.64
(2H, c, CH2). Anal. Calcd for C19H15BrCl2N2O: C, 52.08; H, 3.45; Br,
18.24; Cl, 16.18; N, 6.39. Found: C, 52.11; H, 3.48; Br, 18.19; Cl,
16.16; N, 6.40%.
5c:Yield, 0.90 g (75%); white crystals; m.p. 284–286 °C (decomp.,
MeCN). IR (KBr): ν 2992, 2965, 1588, 1542, 1489, 1315, 1080, 955,
793, 722 cm–1. 1H NMR (DMSO-d6): δ 8.98 (d, 1H, 3J = 5.5 Hz, H-1),
7.91 (m, 3H, H-10, H-2′, H-6′), 7.84 (m, 2H, H-2, H-9), 7.73 (d, 2H,
3e:Yield, 0.72 g (58%); white crystals; m.p. 168–169 °C (MeNO2).
IR (KBr): ν 3240 (NH2), 3065 (NH2), 1708 (C=O), 1667, 1659, 1587,
1525 (NO2), 1352 (NO2), 765, 724, 696 cm–1. 1H NMR (DMSO-d6): δ
3
3J = 8.5 Hz, H-3′, H-5′), 7.63 (t, 1H, J = 8.0 Hz, H-8), 7.49 (d, 1H,
2
3
4
3J = 8.0 Hz, H-7), 5.89 (d, 1H, J = 14.0 Hz, HA-11), 5.51 (d, 1H,
8.66 (br. s, 2H, NH2), 8.41 (dd, 1H, J = 9.0 Hz, J = 2.5 Hz, H-4′),
2J = 14.0 Hz, HB-11), 2.55 (s, 3H, CH3). 13C NMR (DMSO-d6): δ
174.6 (C-6), 159.9 (C-3), 152.1 (C-4a), 142.0 (C-1), 139.3 (C-4′),
139.2 (C-10a), 136.7 (C-1′), 135.0 (C-9), 133.7 (2C, C-2′, C-6′), 132.8
(C-6a), 131.4 (C-7), 130.5 (C-8), 129.7 (2C, C-3′, C-5′), 129.5 (C-10),
125.5 (C-4), 124.4 (C-2), 57.3 (C-11), 21.9 (CH3). Anal. Calcd for
C20H16BrClN2: C, 60.10; H, 4.03; Br, 19.99; Cl, 8.87; N, 7.01. Found:
C, 60.24; H, 4.05; Br, 20.03; Cl, 8.90; N, 7.00%.
4
3
8.31 (d, 1H, J = 2.5 Hz, H-6′), 8.16 (d, 1H, J = 7.0 Hz, H-6), 7.96
3
3
(t, 1H, J = 7.5 Hz, H-4), 7.86 (d, 2H, J = 8.0 Hz, H-2″, H-6″), 7.77
(t, 1H, 3J = 8.0 Hz, H-4″), 7.63 (t, 2H, 3J = 8.0 Hz, H-3″, H-5″), 7.21
(d, 1H, 3J = 9.0 Hz, H-3′), 7.10 (d, 1H, 3J = 8.0 Hz, H-3), 6.99 (t, 1H,
3J = 7.0 Hz, H-5), 5.83 (s, 2H, CH2). Anal. Calcd for C19H16BrN3O3:
C, 55.09; H, 3.89; Br, 19.29; N, 10.14. Found: C, 55.25; H, 3.91; Br,
19.30; N, 10.15%.
(4-Chlorophenyl){2-[(2-iminopyridin-1(2H)-yl)methyl]phenyl}meth-
anone (4a): The mixture of salt 5a 0.39 g (1.0 mmol) and 0.22 g
(4.0 mmol) of MeONa in MeOH (30 mL) was heated for 3 h, and the
solvent was evaporated under reduced pressure. The residue was
washed with water to give the oily product.Yield, 0.29 g (88%). IR
(KBr): ν 3310 (NH), 3064, 1650, 1640, 1569, 1535, 1264, 1088, 928,
5d:Yield, 0.82 g (65%); white crystals; m.p. 269–271 °C (decomp.,
MeCN). IR (KBr): ν 3048, 1602, 1559, 1563, 1542, 1491, 1323, 1267,
1
4
1087, 731 cm–1. H NMR (DMSO-d6): δ 9.49 (d, 1H, J = 2.0 Hz,
3
4
3
H-1), 8.67 (dd, 1H, J = 9.0 Hz, J = 2.0 Hz, H-3), 8.10 (d, 1H, J =
9.0 Hz, H-4), 7.95 (d, 2H, 3J = 8.5 Hz, H-2′, H-6′), 7.89–7.83 (m, 2H,
3
3
H-9, H-10), 7.74 (d, 2H, J = 8.5 Hz, H-3′, H-5′), 7.67 (t, 1H, J =
8.0 Hz, H-8), 7.52 (d, 1H, 3J = 8.0 Hz, H-7), 5.85 (d, 1H, 2J = 14.0 Hz,
1
3
745 cm–1. H NMR (DMSO-d6): δ 7.76 (d, 2H, J = 8.5 Hz, H-2″,
H-6″), 7.56 (d, 2H, 3J = 8.5 Hz, H-3″, H-5″), 7.50 (t, 1H, 3J = 8.0 Hz,
HA-11), 5.57 (d, 1H, J = 14.0 Hz, HB-11). 13C NMR (DMSO-d6): δ
2
3
H-4′), 7.37–7.24 (m, 4H, H-6, H-3′, H-5′, H-6′), 6.73 (t, 1H, J =
175.1 (C-6), 151.8 (C-4), 146.3 (C-3), 141.8 (C-1), 139.4 (C-10a),
138.8 (C-4′), 136.6 (C-1′), 135.2 (C-9), 134.0 (2C, C-2′, C-6′),
132.9 (C-2), 132.6 (C-6a), 131.6 (C-7), 130.3 (C-8), 129.9 (C-10),
129.7 (2C, C-3′, C-5′), 125.9 (C-4), 58.2 (C-11). Anal. Calcd for
C19H13BrCl2N2: C, 54.32; H, 3.12; Br, 19.02; Cl, 16.88; N, 6.67.
Found: C, 54.46; H, 3.15; Br, 19.00; Cl, 16.90; N, 6.64%.
3
8.0 Hz, H-4), 6.23 (d, 1H, J = 8.5 Hz, H-3), 6.03 (br. s, 1H, NH),
3
5.66 (t, 1H, J = 7.0 Hz, H-5), 5.05 (s, 2H, CH2). Anal. Calcd for
C19H15ClN2O: C, 70.70; H, 4.68; Cl, 10.98; N, 8.68. Found: C, 70.91;
H, 4.67; Cl, 11.00; N, 8.69%.
(4-Chlorophenyl){2-[(2-imino-3-methylpyridin-1(2H)-yl)methyl]
phenyl}methanone (4b): MeONa 0.22 g (4.0 mmol) was added to the
solution of salt 3b 0.42 g (1.0 mmol) in methanol (20 mL). The mix-
ture was heated for 1 h and then the solvent was evaporated under
reduced pressure. The precipitate was filtered off, washed with water,
dried and crystallised from hexane. Yield, 0.28 g (82%); white crys-
tals; m.p. 119–121 °C (Hexane). IR (KBr): ν 3338 (NH), 3085, 3025,
5e:Yield, 0.53 g (45%); white crystals; m.p. 250–252 °C (decomp.,
MeCN). IR (KBr): ν 3007, 1620, 1605, 1553, 1520, 1349, 1326, 1259,
1
3
1155, 794, 734, 701 cm–1. H NMR (DMSO-d6): δ 9.24 (d, 1H, J =
3
4
3
6.0 Hz, H-1), 8.66 (dd, 1H, J = 9.0, J = 2.5, H-9), 8.56 (t, 1H, J =
7.5 Hz, H-3), 8.24 (d, 1H, 3J = 8.5 Hz, H-4), 8.16 (d, 1H, 4J = 2.5 Hz,
H-7), 8.08 (d, 1H, 3J = 8.5 Hz, H-10), 8.01 (d, 2H, 3J = 8.5 Hz, H-2′,
1
1651, 1641, 1569, 1548, 1261, 1220, 1088, 931, 758, 737 cm–1. H
3
3
3
H-6′), 7.93 (t, 1H, J = 8.0 Hz, H-2), 7.80 (t, 1H, J = 8.5 Hz, H-4′),
NMR (DMSO-d6): δ 7.75 (d, 2H, J = 8.5 Hz, H-2″, H-6″), 7.56 (d,
3
2
3
3
7.67 (t, 2H, J = 8.5 Hz, H-3′, H-5′), 6.23 (d, 1H, J = 13.0 Hz, HA-
11), 5.68 (d, 1H, 2J = 13.0 Hz, HB-11). Anal. Calcd for C19H14BrN3O2:
C, 57.59; H, 3.56; Br, 20.17; N, 10.60. Found: C, 57.55; H, 3.57; Br,
20.15; N, 10.61%.
2H, J = 8.5 Hz, H-3″, H-5″), 7.48 (t, 1H, J = 8.0 Hz, H-4′), 7.36–
3
7.23 (m, 4H, H-6, H-3′, H-5′, H-6′), 6.72 (d, 1H, J = 8.0 Hz, H-4),
5.64 (br. m, 2H, NH, H-5), 5.11 (s, 2H, CH2), 1.85 (s, 3H, CH3). Anal.
Calcd for C20H17ClN2O: C, 71.32; H, 5.09; Cl, 10.53; N, 8.32. Found:
C, 71.19; H, 5.11; Cl, 10.56; N, 8.30%.
Received 30 January 2012; accepted 27 February 2012
Paper 1201138 doi: 10.3184/174751912X13343956275474
Published online: 10 May 2012
Synthesis of 6-Aryl-11H-pyrido[1,2-b][2,4]benzodiazepin-12-ium
bromides (5a–e); general procedure
2-Amino-1-(2-benzoylbenzyl)pyridinium bromide 3a–e (3 mmol)
was dissolved in acetic acid (25 mL). The mixture was refluxed for
9 h. The solvent was evaporated under reduced pressure and acetone
(10 mL)was added to the residue. The precipitate was filtered off,
washed with acetone, dried and crystallised from acetonitrile. The
following compounds were obtained:
References
1
M. Davis, P. Knowles, B.W. Sharp, R.J.A. Walsh and K.R.H. Wooldridge,
J. Chem. Soc. C., 1971, 2449.
2
P. Knowles and K.R.H. Wooldridge, J. Chem. Soc. Perkin Trans. I, 1972,
975.
5a:Yield, 0.92 g (80%); white crystals; m.p. 265–267 °C (decomp.,
MeCN). IR (KBr): ν 3019, 2980, 1583, 1547, 1496, 1278, 1085, 945,
803 cm–1. 1H NMR (DMSO-d6): δ 9.14 (d, 1H, 3J = 5.5 Hz, H-1), 8.54
(t, 1H, 3J = 8.0 Hz, H-3), 8.08 (d, 1H, 3J = 8.0 Hz, H-4), 7.95 (m, 3H,
3
4
H. Moehrle and J. Lessel, Arch. Pharm., 1991, 324, 367.
V.A. Kovtunenko, O.T. Fal’kovskaya, A.K. Tyltin, A.V. Turov and
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H. Moehrle, J. Lessel, J. Kurz and P. Schmitt, Arch. Pharmazie., 1992, 325,
177.
3
3
5
H-10, H-2′, H-6′), 7.92 (t, 1H, J = 7.5 Hz, H-2), 7.86 (t, 1H, J =
3
3
8.0 Hz, H-9), 7.73 (d, 2H, J = 8.5 Hz, H-3′, H-5′), 7.66 (t, 1H, J =
7.5 Hz, H-8), 7.51 (d, 1H, 3J = 7.5 Hz, H-7), 5.96 (d, 1H, 2J = 13.5 Hz,
6
7
R.C. Fuson, Chem. Rev., 1935, 16, 1.
I.K. Moiseev, M.N. Zemtsova and N.V. Makarova, Chem. Heterocycl.
Compd., 1994, 30, 745.
HA-11), 5.56 (d, 1H, J = 13.5 Hz, HB-11). 13C NMR (DMSO-d6): δ
2
174.4 (C-6), 152.5 (C-4a), 146.4 (C-3), 142.8 (C-1), 139.0 (C-4′),
138.9 (C-10a), 136.4 (C-1′), 134.8 (C-9), 133.5 (2C, C-2′, C-6′), 132.6
(C-6a), 131.2 (C-7), 130.4 (C-8), 129.4 (2C, C-3′, C-5′), 129.3 (C-10),
124.7 (C-4), 124.3 (C-2), 57.9 (C-11). Anal. Calcd for C19H14BrClN2:
C, 59.17; H, 3.66; Br, 20.72; Cl, 9.19; N, 7.26. Found: C, 59.30; H,
3.65; Br, 20.75; Cl, 9.15; N, 7.27%.
8
9
D.H. Kim, A.A. Santilli, T.S. Sulkowski and S.J. Childress, J. Org. Chem.,
1967, 32, 3720.
R. Faragher and T.L. Gilchrist, J. Chem. Soc. Perkin Trans. I, 1976, 336.
10 W. Schöniger, Microchimica Acta, 1955, 43, 123.
11 S. Gobbi, A.Cavalli, M. Negri, K.E. Schewe, F. Belluti, L.Piazzi, R.W.
Hartmann, M. Recanatini, and A. Bisi, J. Med. Chem., 2007, 50, 3420.

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