2
Tetrahedron Letters
1. Introduction
and tricyclic heterocyclic compounds through N-acylated
benzotriazoles. The reaction gives excellent yields and runs either
under microwave or conventional heating. The best results are
achieved under microwave irradiation.
Nitrogen-containing bi- and tricyclic heterocycles bearing
diazepine, diazocine, and benzimidazole moieties are of current
research interest because of their pharmacological properties.1–3
They are also found in many potential pharmaceutical
compounds (Figure 1).
2. Results and Discussion
2.1. Preparation of N-acylbisbenzotriazoles 2a–g
N-acylbisbenzotriazoles 2a–f were prepared in 78–94% yields
using our standard procedure by the reaction of the corresponding
dicarboxylic acids 1a–g with 8 equiv of 1H-benzotriazole and 2.2
equiv of SOCl2 in DCM at 20 C for 4 h (Scheme 1).28
Figure 1. Some potential bicyclic and tricyclic compounds
Several synthetic methodologies were utilized/developed for
the synthesis of various bicyclic and tricyclic compounds because
of their unique biological properties.4-8 Benzodiazepines are one
of the bicylic heterocyclic class of compounds and are known for
various pharmaceutical applications. They are widely used as
anticonvulsant, antianxiety, analgesic, sedative, antidepressant,
hypnotic, and anti-inflammatory agents.9-11 1,5-Benzodiazepines
are valuable synthons for the preparation of other fused ring
compounds
such
as
triazolobenzodiazepines,12
oxadiazolobenzodiazepines,13 oxazinobenzodiazepines,14 or
furanobenzodiazepines.15 Benzodiazocines and benzimidazoles
are known for various biological properties such as amoebicidal,
anti-inflammatory, antitumor, anti-inflammatory, antimicrobial,
antiviral, antidiabetic, antiparasitic, anthelmintic, anti-HIV,
anticonvulsant, antihypertensive, and proton pump inhibitor
activities.16-20 Bicyclic and tricyclic cores are also common in a
large number of natural products and pharmacologically active
compounds. Research in this field is still very active and is
directed towards the synthesis of compounds with enhanced
pharmacological activity. Generally, these compounds are
synthesized by the condensation of ortho-phenylenediamine with
α, β-unsaturated carbonyl compounds, β-haloketones, or
ketones.16 Diverse reagents such as BF3-etherate, NaBH4,
polyphosphoric acid, SiO2, MgO/POCl3, Al2O3/P2O5, and AcOH
under microwave conditions and in ionic liquids have been
utilized for the condensation reactions.21 Most recently, this
condensation reaction has also been reported to proceed in the
presence of bromodimethylsulfonium bromide, organic acids,
and AgNO3.22 However, all these methods have disadvantages
such as drastic reaction conditions, several side reactions and
tedious purification process. 1,6-Benzodiazocine has been
synthesized by the condensation of ortho-phenylenediamine with
diethyl succinate for 16 h in 26% yield.23 1,6-Benzodiazocine has
also been synthesized in three steps by (i) the condensation of
anilinic acids with PPA/AcOH, affording 3,4-dihydro-1-
benzazepine-2,5(1H)diones, (ii) treatment with hydroxylamine
hydrochloride, giving the corresponding oxime derivative, and
(iii) Beckmann rearrangement of the oxime, furnishing 1,6-
benzodiazocine in 76% yield.24 Nitrogen-containing tricyclic
heterocycles bearing a benzimidazole moiety such as 3,4-
dihydro-pyrido[1,2-a]benzimidazol-1(2H)-one has been prepared
by the condensation of glutaric anhydride with ortho-
phenylenediamine catalyzed by dibromotriphenylphosphorane.25
Scheme 1. Synthesis of N-acylbisbenzotriazoles 2a-g.
2.2. Preparation of bi- and tricyclic compounds 4a-g
The nucleophilic attack of ortho-phenylenediamine 3 (1
equiv) with N-acylbisbenzotriazoles 2a-g (1.2 equiv) in the
presence of K2CO3 (1.5 equiv) in DMF under microwave
irradiation at 70 °C for 1 h afforded bicyclic and tricyclic
compounds 4a-g in excellent yields. The nucleophilic attack of
ortho-phenylenediamine 3 (1 equiv) with compound 2a-c (1.2
equiv) resulted in the formation of bicyclic compounds 4a-c
however compound 2d-g leads to tricyclic compounds 4d-g
under same reaction condition in excellent yields. All the
synthesized compounds were fully characterized with NMR and
mass spectroscopy. The structure of the compounds were also
confirmed by 2D NMR studies.
Most of the compounds are synthesized earlier by different
methods which are more tedious and less efficient. Compound 4a
and 4b were synthesized form ortho-phenylenediamine in two
step synthesis with moderate yields.29,30 Compound 4c was
prepared from ortho-phenylenediamine and diethyl ester of
phthalic acid in presence of NaH in THF with less yield.31
Compound 4d was synthesized in various methods with multistep
synthesis and less yield. The synthesis of compound 4d was
reported in 39% yield.25 Compound 4e-g are new to the literature.
Optimization of reaction conditions (Table 1) revealed the
best results for the preparation of both bicyclic and tricyclic
compounds was under microwave heating at 70 °C for 1 h in
DMF. However the formation of bicyclic compounds with some
impurities was also observed in THF. In conventional heating
method in DMF we have observed the formation of both the
products as well with some other byproducts which needs
column chromatography for purification.
To the best of our knowledge, all the current methods for the
synthesis of bi- and tricyclic heterocycles which are biologically
important class of compounds involve multiple steps synthesis,
column chromatography or tedious purification process and
moderate to high yields. Therefore, alternative an efficient and
high-yielding methods for these class compounds are in demand.
Benzotriazole chemistry has been practiced extensively in our
group in various types of reactions like acylation, aroylation,
heteroaroylation, cyclization, alkylation etc. and has often been
found to be superior to conventional routes.26,27 In this
communication we report an efficient synthetic route to bicyclic
Elagawany, Mohamed
