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

Article abstract of DOI:10.1016/j.tetlet.2003.12.070

5,9-Disubstituted benzo[4,5]imidazo[2,1-a]phthalazines are synthesized efficiently from acylbenzoic acids and 2-nitro-5-chlorophenylhydrazine. Nucleophilic substitution in phthalazinones gave a variety of the title compounds after reduction and cyclizatio

Full text of DOI:10.1016/j.tetlet.2003.12.070

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1407–1408
Synthesis of benzo[4,5]imidazo[2,1-a]phthalazines
Kirill M. Shubin,* Viktor A. Kuznetsov and Vladimir A. Galishev
Saint-Petersburg State Institute of Technology (Technical University), Moskovsky pr. 26, Saint-Petersburg 190013, Russia
Received 11 October 2003; revised 30 November 2003; accepted 11 December 2003
Abstract—5,9-Disubstituted benzo[4,5]imidazo[2,1-a]phthalazines are synthesized efficiently from acylbenzoic acids and 2-nitro-5-
chlorophenylhydrazine. Nucleophilic substitution in phthalazinones gave a variety of the title compounds after reduction and
cyclization.
Ó 2003 Elsevier Ltd. All rights reserved.
3
An analysis of the reactivity of substituted 2-(2-amino-
benzene)-phthalazine-1-ones has shown, that highly
UV-luminescent products are formed, which have
been identified as benzo[4,5]imidazo[2,1-a]phthalazines
(Fig. 1).
Razvi and Ramalingam have synthesized several ana-
logues of the title structure, but the most interesting
point of their work is their more rational approach to
the synthesis of substituted benzimidazophthalazines.
Also they reported for the first time their biological
activity, namely antihypertensive and antiinflammatory
activity.
This heterocyclic system has been investigated rather
1–3
1
sporadically.
The first publication on the synthesis
of benzimidazophthalazines lacks analytical data not
only on the title compounds, but also on intermediates.
Moreover, only a few members of this class were
described. In addition, the scope of the synthetic meth-
odology to include other substituents was not discussed.
Other research2 mentions a single example of the title
compound which, however, has a specific charge distri-
bution, which distinguishes it from the uncharged
structure. This property rendered it impossible to char-
acterize by NMR or MS.
A synthesis of benzimidazophthalazines using aryl
hydrazines substituted in the benzene ring to introduce
the N–N group has been developed. Cyclization of such
hydrazines with o-acylbenzoic acids (Scheme 1) leads to
the generation of the phthalazine ring. This makes it
easier to change substituents in position 4 of the
phthalazinone. Thus, the employment of different o-acyl
substituted benzoic acids gave a set of C-5 substituted
benzimidazophthalazines. In the present work o-acetyl-
benzoic, o-benzoylbenzoic, and 2-(4-toluoyl)benzoic
acids (1a–c) were used.
The reactions were carried out in a boiling ethanolic
solution of concentrated sulfuric acid. Cyclization of 2-
nitro-5-chlorophenylhydrazine 2 with acylbenzoic acids
yielded 2-(2-nitro-5-chlorobenzene)-4-substituted phth-
alazin-1-ones 3a–c (see Table 1 for yields). A chlorine
atom in the p-position relative to the nitro group of the
benzene ring is sufficiently activated for nucleophilic
aromatic substitution, and was easily exchanged by ali-
phatic amines. Applying this reaction phthalazinones
4a–f were prepared.
R 1
5
4
6
3
2
N
N
7
8
1
R 2
13N
9
12
10
11
Figure 1. 5-R1-9-R2-Benzo[4,5]imidazo[2,1-a]phthalazine.
Nitrocompounds 3a–c and 4a–f were reduced to the
corresponding anilines 5a–i by hydrogenation with
hydrogen at room temperature and at normal pressure.
This process was carried out in a THF solution because
of the solubility of the reagents and products. When a
Keywords: Heterocycles; Cyclodehydration; Phthalazine; Benzoimi-
dazole.
* Corresponding author. Tel./fax: +7-812-316-3377; e-mail: kir101@
orgchem.spb.ru
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.070

1408
K. M. Shubin et al. / Tetrahedron Letters 45 (2004) 1407–1408
Table 1. Yields of benzoimidazophthalazines and intermediates
R1
Cl
Product
R1
R2
Yield (%)
O
O
3a
3b
3c
4a
4b
4c
4d
4e
4f
CH3
Ph
Cl
Cl
65
54
60
79
74
71
78
81
68
65
40
79
71
69
49
66
69
65
61
55
45
75
42
46
41
50
55
+
H2N
NH
2
NO2
p-CH3–C6H4
Cl
OH
1a-c
CH3
CH3
CH3
Ph
Pyrrolidyl
Piperidyl
Morpholyl
Pyrrolidyl
Piperidyl
Morpholyl
Cl
H2SO4, EtOH
Cl
R1
R1
O
R2
Ph
Ph
N
N
N
5a
5b
5c
5d
5e
5f
CH3
CH3
CH3
CH3
Ph
N
H , cat
2
Pyrrolidyl
Piperidyl
Morpholyl
Cl
O
O2N
H2N
5a-i
3a-c
HN
Ph
Ph
Pyrrolidyl
Piperidyl
Morpholyl
Cl
PPA
R1
5g
5h
5i
H , cat
2
Ph
p-CH3–C6H4
CH3
CH3
CH3
CH3
Ph
R1
6a
6b
6c
6d
6e
6f
Cl
N
N
N
Pyrrolidyl
Piperidyl
Morpholyl
Cl
N
N
R2
6a-i
N
O
O2N
4a-f
Ph
Ph
Pyrrolidyl
Piperidyl
Morpholyl
Cl
6g
6h
6i
N
N
N
N
O
=
(4a,d);
(4b,e);
(4c,f)
Ph
p-CH3–C6H4
Scheme 1.
Pd(0)-catalyst or fresh Raney nickel was used, only
selective nitro group reduction occurred. Other frag-
ments of the molecule remain unchanged (including
R2 ¼ Cl). Anilines were obtained which were pure by
TLC by crystallization from the reaction mixture (after
filtration of the catalyst) by dilution with petrol ether
(40–70 °C) in a 1:8 ratio.
added iron to the solution of the nitro compound in
PPA at 100 °C in small batches. At the end of the pro-
cess, the temperature was raised to 140 °C for a short
period of time. The reaction mixture was worked up as
in the case of the cyclodehydration of pure anilines 5a–i.
The yields of this process approximately equaled the
overall yields in the two stage experiment.
Heating the aminophthalazinones 5a–i in polyphos-
phoric acid (PPA) to 100–120 °C for a short time yielded
benzimidazophthalazines 6a–i by intramolecular cyclo-
dehydration. The PPA was diluted with water in a 1:10
ratio, basified to pH ¼ 8 and extracted with chloroform.
Extracts were dried with anhydrous Na2SO4, evaporated
under reduced pressure and the residue was recrystal-
lized from ethanol.
A simple and efficient method is proposed for the syn-
thesis of a practically unreported heterocyclic system––
benzo[4,5]imidazo[2,1-a]phthalazine. A variety of the
title compounds were synthesized employing different
o-acylbenzoic acids and dialkylamines. The structures of
all the compounds were established by NMR, MS, and
elementary analysis.
The hydrogenation of the pyrrolidine-substituted
nitrophthalazinone 4a (R1 ¼ Me) was difficult, because
the product of the reaction––2-(2-amino-5-pyrrolidine-
benzene)-4-methyl-phthalazin-1-one is poorly soluble in
THF and deactivates the catalyst. As an alternative we
carried out the reduction of this compound in PPA with
iron powder. In this way the reduction stage and the
cyclodehydration stage were a Ôone potÕ synthesis. We
References and notes
1. Rowe, F. M.; Adams, D. A. W.; Peters, A. T.; Gillam, A.
E. J. Chem. Soc. 1937, 90 .
2. King, F. D. J. Chem. Soc., Perkin Trans. 1 1988, 3381.
3. Razvi, M.; Ramalingam, T. Indian J. Chem. 1992, 31B,
788.