Synthesis of benzo[4,5]imidazo[2,1-a]phthalazines

Full text of DOI:10.1007/s11178-005-0085-2

Russian Journal of Organic Chemistry, Vol. 40, No. 11, 2004, pp. 1702-1704. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 11,
2004, pp. 1746-1748.
Original Russian Text Copyright Ó 2004 by Kuznetsov, Shubin, Petrov.
SHORT
COMMUNICATIONS
Synthesis of Benzo[4,5]imidazo[2,1-a]phthalazines
V.A. Kuznetsov, K.M. Shubin, and M.L. Petrov
St. Petersburg State Technological Institute, St. Petersburg, 190013 Russia
e-mail: mlpetrov@tu.spb.ru
Received March 2, 2004
We developed a new method of synthesis for
benzo[4,5]-imidazo[2,1-a]phthalazines involving building
up in succession of phthalazine and the benzimidazole
structure. The synthesis of phthalazinones III was
performed by cyclization of 2-acylbenzoic acid I with o
nitrophenylhydrazines II. One of the most common ways
of benzimidazole synthesis involves the use of o-aryl-
enediamines with one amino group acylated. The reaction
is successful in case the cyclization of the initial compound
affords a product of aromatic structure [3]. To prepare
such substrate we subjected phthalazinones III to
catalytic hydrogenetion with gaseous hydrogen aiming at
synthesizing aminophthalazinones IV. The heating of
compounds IV in polyphosphoric acid (PPA) afforded
benzo[4,5]imidazo-[2,1-a]phthalazines (V) due to
Benzo[4,5]imidazo[2,1-a]phthalazines constitute a
poorly studied class of angular polycyclic aromatic
heterocycles that can be regarded as isoelectronic
nitrogen-containing analogs of chrysene. Only twice
appeared publications describing preparation and
properties of these compounds. First benzo[4,5]imidazo-
[2,1-a]phthalazines were obtained by cyclization of
phthalazinones at heating in sealed tubes [1]. Phthalazi-
nones in their turn were synthesized from o-nitroaryl-
hydrazones of 2-carboxybenzaldehyde and 2-carboxy-
acetophenone. In 1992 an alternative procedure was
advanced for preparation of benzo[4,5]imidazo[2,1-
a]phthalazines from o-aminophenols [2].At the same time
the biological activity of this class compounds was
discovered.
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I, R = CH3 (a), C6H5 (b); II, R' = H (a), 4-NO2 (b), 5-Cl (c); III, R = CH3: R' = H (a), 4-NO2 (b), 5-Cl (c); R = C6H5, R' = 5-Cl (d); IV,
R = CH3, R' = 5-Cl (a), R = C6H5, R' = 5-Cl (b); V, R = CH3: R' = H (a), 10-NH2 (b), 9-Cl (c); R = C6H5, R' = 9-Cl (d).
1070-4280/04/4011-1702Ó2004 MAIK “Nauka/Interperiodica”

SYNTHESIS OF BENZO[4,5]IMIDAZO[2,1-a]PHTHALAZINES
1703
2.63 s (CH3), 7.52 d (H4'), 7.75 s (H6'), 7.78–7.99 m (H5,
H6, H7), 8.02 d (H3'), 8.44 d (H8). Found, %: C 56.96,
57.18; H 3.29, 3.41; N 13.17, 13.42. C15H10ClN3O3.
Calculated, %: C 57.07; H 3.19; N 13.31.
intramolecular dehydration (procedure a) where the
phthalazine fragment acted as a cyclic amide. We
simplified the synthesis by developing a direct procedure
of converting compound III into tetracyclic system V.
This method consists in reduction of nitro compounds III
with metallic iron in PPAat heating, and the arising amine
IV is converted into benzoimidazophthalazine (V) by
increasing the reaction mixture temperature to 130–140°C
(procedure b). By this method we succeeded in prepara-
tion of compounds Va, b unpossible to obtain by method
a because of low solubility of nitro compounds IIIa, b
and the corresponding amines. Compounds Vc, d were
synthesized by procedure b in higher yields.
2-(2-Nitro-5-chlorophenyl)-4-phenyl-1,2-di-
hydro-1-phthalazinone (IIId). From 13.6 g of 2-benzo-
yl-benzoic acid (Ib) and 10.7 g of 2-nitro-5-chloro-
phenylhydrazine (IIc) after recrystallization from a
mixture chloroform –ethanol we obtained 13.7 g (64%)
1
phthalazinone IIId, mp 137–139°C. H NMR spectrum
(DMSO), d, ppm: 7.52–7.86 m (H4', H6', 4-phenyl), 7.87–
8.01 m (H5, H6, H7), 8.19 d (H3'), 8.41 t (H8). Found, %:
C 63.47, 63.68; H 3.15, 3.44; N 11.03, 11.37.
C20H12ClN3O3. Calculated, %: C 63.59; H 3.20; N 11.12.
The synthetic procedures we developed are a lot
simpler than the previous one [2] and also make it possible
to synthesize a wide range of benzoimidazophthalazine
derivatives in a good yield.
2-(2-Amino-5-chlorophenyl)-4-methyl-1,2-
dihydro-1-phthalazinone (IVa). A solution of 1.9 g
(0.006 mol) of 2-(2-nitro-5-chlorophenyl)-4-methyl-1,2-
dihydro-1-phthalazinone (IIIc) in 20 ml of THF was
subjected to hydrogenation by gaseous hydrogen at
atmospheric pressure with constant stirring in the presence
of 0.16 g of a catalyst (5% Pd on carbon). After
consumption of 370 ml of hydrogen within 6 h the reaction
mixture was filtered from the catalyst and evaporated to
a volume of 10 ml. Then the residue was diluted with
petroleum ether (fraction of bp 40–70°C) to 100 ml. The
precipitated reaction product was chromatographically
pure and was used without additional purification. We
obtained 0.7 g (54%) of aminophthalazinone IVa, mp 182–
4-Methyl-2-(2-nitrophenyl)-1,2-dihydro-1-
phthalazinone (IIIa). Asolution of 9.8 g (0.060 mol) of
2-acetylbenzoic acid (Ia) and 8.8 g (0.057 mol) of
o-nitrophenylhydrazine (IIa) in a mixture of 80 ml of
ethanol and 40 ml of concn. sulfuric acid was boiled for
1.5 h, then it was poured on 300 g of crushed ice, and the
separated precipitate was filtered off. On recrystallization
from a mixture chloroform–ethanol we obtained 9.6 g
(60%) of phthalazinone IIIa, mp 195–197°C. 1H NMR
spectrum (DMSO), d, ppm: 2.61 s (CH3), 7.61–7.78 m
(H4', H5'), 7.82–8.01 m (H5, H6, H7, H6'),* 8.08 d (H3'),
8.37 d (H8). Found, %: C 63.93, 64.21; H 4.02, 4.13;
N 14.76, 15.01. C15H11N3O3. Calculated, %: C 64.05;
H 3.94; N 14.94.
1
184°C. H (DMSO), d, ppm: 2.59 s (CH3), 5.04 s (NH2),
6.81 d (H3'), 7.07–7.15 m (H4', H6'), 7.80–7.98 m (H5,
H6, H7), 8.37 d (H8). Found, %: C 62.87, 62.99; H 4.24,
4.41; N 14.56, 14.74. C15H12ClN3O.Calculated,%:C 63.05;
H 4.23; N 14.71.
2-(2,4-Dinitrophenyl)-4-methyl-1,2-dihydro-1-
phthalazinone (IIIb). Likewise from 9.9 g of compound
Ia and 11.4 g of 2,4-dinitrophenylhydrazine IIb after
recrystallization from DMF we obtained 9.9 g (54%) of
phthalazinone IIIb, mp 244–246°C. 1H NMR spectrum
(DMSO), d, ppm: 2.64 s (CH3), 7.83–8.18 m (H5, H6,
H7, H6'), 8.37 d (H8), 8.70 d (H5'), 8.80 s (H3'). Found, %:
C 55.13, 55.31; H 3.04, 3.29; N 17.19, 17.41. C15H10N4O5.
Calculated, %: C 55.22; H 3.09; N 17.17.
2-(2-Amino-5-chlorophenyl)-4-phenyl-1,2-
dihydro-1-phthalazinone (IVb). Likewise from 2.3 g
of 2-(2-nitro-5-chlorophenyl)-4-phenyl-1,2-dihydro-1-
phthalazinone (IIId) we obtained 1.9 g (93%) of
1
aminophthalazinone IVa, mp 185–187°C. H NMR
spectrum (CDCl3), d, ppm: 3.99 s (NH2), 6.80 d (H3'),
7.17 d (H4'), 7.40 d (H6'), 7.45–7.58 m (H2, H4, H6
4-phenyl), 7.59–7.65 m (H3, H5 4-phenyl), 7.76–7.86 m
(H5, H6, H7), 8.61 t (H8). Found, %: C 69.13, 69.24;
H 3.98, 4.17; N 12.22, 12.37. C20H14ClN3O. Calculated,
%: C 69.07; H 4.06; N 12.08.
4-Methyl-2-(2-nitro-5-chlorophenyl)-1,2-
dihydro-1-phthalazinone (IIIc). From 9.8 g of com-
pound Ia and 10.7 g of 2-nitro-5-chlorophenyl-hydrazine
IIc after recrystallization from a mixture chloroform–
ethanol we obtained 13.5 g (75%) of phthalazinone IIIc,
5-Methylbenzo[4,5]imidazo[2,1-a]phthalazine
(Va). Procedure b. To a solution of 1.25 g (0.005 mol) of
4-methyl-2-(2-nitrophenyl)-1,2-dihydro-1-phthalazinone
(IIIa) in 20 g of PPA heated to 100°C was added by
portions at stirring 1.25 g of iron powder. After all iron
1
mp 168–170°C. H NMR spectrum (CDCl3), d, ppm:
* Here and hereinafter the protons of aryl substituent in position
2 are marked with a dash.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

KUZNETSOV et al.
1704
was added the reaction mixture was heated for 15 min to
140°C. On cooling the mixture was diluted with water to
a 10-fold volume, alkalinized with aqueous NaOH to
strongly alkaline reaction, and reaction products were
extracted into chloroform (5´50 ml). The combined
extracts were dried with Na2SO4, filtered, and evaporated.
On recrystallization from a mixture chloroform–ethanol
we obtained 0.76 g (65%) of compound Va, colorless
crystals, mp 159–161°C (publ.: 163°C [1]). 1H NMR
spectrum (DMSO), d, ppm: 2.75 s (CH3), 7.42 m (H8,
H9), 7.71–8.02 m (H2, H3, H4, H7, H10), 8.52 d (H5).
Mass spectrum, m/z (Irel, %): M+ 233 (100). Found, %:
C 77.24, 77.45; H 4.54, 4.63; N 18.13, 18.26. C15H11N3.
Calculated, %: C 77.23; H 4.75; N 18.01.
(b) From 1.6 g (0.005 mol) of 2-(2-nitro-5-chloro-
phenyl)-4-methyl-1,2-dihydro-1-phthalazinone (IIIc) and
1.6 g of iron powder we obtained 0.73 g(58%) of
compound Vc.
5-Phenyl-9-chloroObenzo[4,5]imidazo[2,1-a]-
phthalazine (Vd). Procedure (a) . In 15 g of PPA 1.5 g
(0.0043 mol) of 2-(2-amino-5-chlorophenyl)-4-phenyl-1,2-
dihydro-1-phthalazinone (IVb) was heated at 130°C. On
cooling the reaction mixture was diluted with water to a
10-fold volume, alkalinized with aqueous NaOH to
strongly alkaline reaction, and reaction products were
extracted into chloroform (3´30 ml). The combined
extracts were dried with Na2SO4, filtered, and evaporated.
On recrystallization from a mixture chloroform–ethanol
we obtained 0.9 g (64%) of compound Vd, colorless
5-Methyl-10-aminobenzo[4,5]imidazo[2,1-a]-
phthalazine (Vb). Likewise from 1.7 g of 2-(2,4-dinitro-
phenyl)-4-methyl-1,2-dihydro-1-phthalazinone (IIIb) and
1.7 g of iron powder after recrystallization from a mixture
chloroform–ethanol we obtained 0.73 g (58%) of
compound Vb, colorless crystals, mp >270°C (decomp.).
1H NMR spectrum (CDCl3), d, ppm: 2.84 s (CH3),
3.83 s (NH2), 6.85 d (H9), 7.21 s (H7), 7.64–7.96 m (H2,
H3, H4), 7.98 d (H10), 8.65 d (H5). Found, %: C 72.36,
72.59; H 4.54, 4.67; N 22.21, 22.43. C15H12N4.
Calculated, %: C 72.56; H 4.87; N 22.57.
1
crystals, mp 223–225°C. H NMR spectrum (DMSO),
d, ppm: 7.41 d (H8), 7.58–8.00 m (H2, H3, H4, H7, H10),
8.62 d (H5). Mass spectrum, m/z (Irel., %): M+ 329 (100).
Found, %: C 72.58, 72.81; H 3.39, 3.47; N 12.83, 12.91.
C20H12ClN3. Calculated, %: C 72.84; H 3.67; N 12.74.
(b) From 1.9 g of 2-(2-nitro-5-chlorophenyl)-4-phenyl-
1,2-dihydro-1-phthalazinone (IIIc) and 1.9 g of iron
powder we obtained 1.1 g (64%) of compound Vc.
..
Melting points were measured on a Boetius heating
block. 1H NMR spectra were registered on spectrom-
eter Bruker AMX-400 (400 MHz), as internal
references served signals of residual protons (1H) of
deuterated solvents. Mass spectra were recorded on
a mass spectrometer Kratos MS 890 at a direct
admission of a sample into the ion source, ionizing
electrons energy 70 eV, temperature in the ionization
chamber 200°C. The reaction progress was monitored
by TLC on Silufol UV-254 plates, spots were visualized
by UV irradiation. All solvents used in the study were
purified and dried by standard procedures.
5-Methyl-9-chloroObenzo[4,5]imidazo[2,1-a]-
phthalazine (Vc). (a) In 20 g of PPA 1.4 g (0.005 mol)
of 2-(2-amino-5-chlorophenyl)-4-methyl-1,2-dihydro-1-
phthalazinone (IVa) was heated at 140°C. On cooling
the reaction mixture was diluted with water to a 10-fold
volume, alkalinized with aqueous NaOH to strongly
alkaline reaction, and reaction products were extracted
into chloroform (3´30 ml). The combined extracts were
dried with Na2SO4, filtered, and evaporated. On
recrystallization from a mixture chloroform–ethanol we
obtained 0.9 g (71%) of compound Vc, colorless crystals,
mp 180–181°C. 1H NMR spectrum (DMSO), d, ppm:
2.68 s (CH3), 7.35 d (H8), 7.81–8.00 m (H2, H3, H4, H7,
H10), 8.41 d (H5). Mass spectrum, m/z (IOtn., %): M+ 267
(100). Found, %: C 67.43, 67.56; H 3.39, 3.63; N 15.53,
15.78. C15H10ClN3. Calculated, %: C 67.30; H 3.77;
N 15.70.
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J. Chem. Soc., 1937, p. 90.
2. Razvi M. and Ramalingam T., Indian. J. Chem. 1992, 31B,
p. 788.
3. Grimmett, M.R., Imidazole and Benzimidazole Synthesis,
Leningrad:Academic Press, 1997, 265 p.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004