Efficient three-step synthesis of benzo[e]imidazo[1,2-c][1,2,3]triazines

Article abstract of DOI:10.1080/00397911.2016.1152376

A novel three-step sequence toward benzo[e]imidazo[1,2-c][1,2,3]triazine derivatives is investigated. This pathway started from commercially available starting materials afforded 5a-h in good to excellent yields. In this method, we took the advantage of d

Full text of DOI:10.1080/00397911.2016.1152376

Synthetic Communications
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An Efficient Three-Step Synthesis of
Benzo[e]Imidazo[1,2-c][1,2,3]Triazines
Hedieh Pilali, Shirin Faraji Kamazani, Shahram Moradi, Setareh Moghimi,
Mohammad Mahdavi, Loghman Firoozpour, Abbas Shafiee & Alireza
Foroumadi
To cite this article: Hedieh Pilali, Shirin Faraji Kamazani, Shahram Moradi, Setareh Moghimi,
Mohammad Mahdavi, Loghman Firoozpour, Abbas Shafiee & Alireza Foroumadi (2016):
An Efficient Three-Step Synthesis of Benzo[e]Imidazo[1,2-c][1,2,3]Triazines, Synthetic
Communications, DOI: 10.1080/00397911.2016.1152376
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Date: 22 February 2016, At: 22:35

An Efficient Three-Step Synthesis of Benzo[e]Imidazo[1,2-c][1,2,3]Triazines
Hedieh Pilali1, Shirin Faraji Kamazani2, Shahram Moradi1, Setareh Moghimi2,
Mohammad Mahdavi2, Loghman Firoozpour3, Abbas Shafiee2, Alireza Foroumadi2,3
1Department of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran,
2Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran, Iran, 3Drug Design and
Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
Corresponding author. Alireza Foroumadi, Email: aforoumadi@yahoo.com
Abstract
A novel three step sequence towards benzo[e]imidazo[1,2-c][1,2,3]triazine derivatives is
investigated. This pathway started from commercially available starting materials
afforded 5a-h in good to excellent yields. In this method, we took the advantage of
diazonium chemistry which was followed by intramolecular N-N bond formation in the
construction of N-rich cycles.
Graphical Abstract:
1

KEYWORDS: Benzotriazine, Diazonim salt, Imidazole, N-N bond, Heterocyclization.
INTRODUCTION
The prevalence of heterocyclic-heterocyclic systems especially those containing simple
nitrogen-rich heterocycles in naturally occurring compounds clearly discloses the ever-
increasing interests towards the synthesis of these structural motifs. Imidazoles and
benzotriazines are both attractive enough in respect to synthetic and biological aspects.
Imidazole derivatives have been reported as anti-HIV,[1] anti-inflammatory,[2] anti-
bacterial,[3] anti-cancer,[4] antifungal [5] and anti-tubercular agents.[6] This nucleus is also
present in many drugs with diverse therapeutical properties. Moreover, benzotriazines are
intriguing core exhibited interesting biological responses such as antitumor,[7]
antibacterial [8] and inhibitor of vascular endothelial growth factor receptor-2.[9] Both of
these cores were studied extensively, but, there is still a need to construct novel
molecules containing both imidazoles and benzotriazines, which are differently fused.
This led to large libraries with potential applications in drug discovery sector, therefore,
synthesis of new ring structures is desired.
Aryl diazonium salts, an important staring material or intermediate in organic
synthesis,[10] are typically considered as an efficient electrophilic site for cyclization and
subsequent construction of N-heterocycles.[11] The addition of nucleophiles like
heteroatoms[12] and carbon[13] led to conjugated compounds serving as dyes and
pigments.[14] Moreover, this functional group is amenable for further transformation
involving substitution [15] and reduction,[16] highlighting the synthetic scope of this salt in
2

organic synthesis. Acting as aryl halide surrogate in metal-catalyzed approaches [17] were
increasingly reported in recent years, indicating the electrophilicity of this salt by losing
N2. In parallel with our studies in the synthesis of N-containing cycles,[18] herein, we
investigated the nucleophilic attack on diazonium moiety and intramolecular N-N bond
formation via simple and metal-free strategy.
RESULTS AND DISCUSSION
Initially, we carried out the reaction of benzil 1, with 2-nitrobenzaldehyde derivatives 2
and NH4OAc in acetic acid at reflux temperature to yield 3, represented in Scheme 1. In
the presence of 7 equiv. ammonium acetate, the desired imidazole derivatives were
obtained. 2-Nitrobenzaldehyde was chosen containing reducible nitro group at ortho
position to install diazonium moiety, coincided with the attack of nitrogen nucleophile in
one-pot manner. The reducible character of nitro group was also reported previously in
the synthesis of heterocycles with bridgehead nitrogen atom.[19] So, we attempted to
reduce nitro group by the assistance of cheap zinc powder in the mixture of MeOH/H2O.
This reaction was simply carried out in the presence of ammonium chloride at room
temperature, completed in 1-1.5 h. The final step includes the diazotation of amine
moiety and subsequent cyclization, proceeded in presence of equimolar amounts of
sodium nitrite in aqueous acidic solution. Due to crucial role of counter ion in the
stability of diazonium salt, HCl (10 %) was chosen, in which short distance between
anion and cation led to the more stable salt.[20] The cyclized product was successfully
separated upon completion, determined by thin layer chromatography (TLC). The solid
3

needed simple recrystallization from petroleum ether/ethyl acetate, regarded as an
advantageous feature in the synthesis of benzo[e]imidazo[1,2-c][1,2,3]triazines.
To extend the scope of this method, different benzils and 2-nitro benzaldehyde
derivatives were examined and good to excellent yields were obtained in this cyclization
process (Table 1).
The structure of synthesized compounds 5a-h were confirmed by IR, 1H NMR, and 13C
NMR spectroscopic data. The 1H NMR spectrum of compound 5f showed two singlets at
δ 3.77 and 3.78 ppm, due to methoxy groups. Aromatic protons appeared in the region
between δ 6.91-8.44 ppm. Four doublets clearly confirmed the presence of eight para
substituted aromatic protons. Three protons of chlorine substituted ring appeared as dd (J
= 8.8, 2.0 Hz), d (J = 8.8 Hz) and d (J = 2.0 Hz) at δ 7.92, 8.39 and 8.44 ppm,
respectively. The 13C NMR spectrum exhibited two peaks at δ 55.0 and 55.2 ppm related
to methoxy groups along with 17 distinct signals for aromatic carbons.
CONCLUSION
In summary, we report a simple and efficient synthesis of benzo[e]imidazo[1,2-
c][1,2,3]triazines through sequential imidazole formation, reduction of nitro group
accompanied by diazonium formation and intramolecular N-N bond formation. Further
studies on biological properties of these compounds is under investigation in our lab.
4

EXPERIMENTAL
Melting points were taken on a Kofler hot-stage apparatus and are uncorrected. 1H and
13C NMR spectra were recorded on a Bruker FT-500, using tetramethylsilane (TMS) as
an internal standard. The infrared (IR) spectra were obtained on a Nicolet Magna FTIR
550 spectrophotometer (KBr disks). Mass spectra were recorded on an Agilent
Technology (HP) mass spectrometer operating at an ionization potential of 70eV.
Elemental analyses were carried out with a Perkin-Elmer model 240-C apparatus.
General Procedure For The Synthesis Of Compounds 5a-H
To the stirred solution of compound 4 (1 mmol), dissolved in minimum amount of
acetone HCl (10%, 2 mL) was added at 0 oC. Then, a solution of sodium nitrite (1 mmol,
minimum amount of water), over 10 minutes was slowly added at this temperature. The
reaction was continued at room temperature and after 2h, the reaction was poured into
ice-water. The resultant precipitate was collected and recrystallized from petroleum
ether/ethyl acetate to afford 5a-h.
9-Chloro-2,3-Bis(4-Methoxyphenyl)Benzo[E]Imidazo[1,2-C][1,2,3]Triazine (5f)
Yield: 0.35 g (85%); orange powder; mp 216-218oC. IR (KBr): 2836, 1609, 1517, 1487,
1379, 1249, 1174, 1023, 829, 741 cm-1. 1H NMR (500 MHz, DMSO-d6): δ = 3.77 (s, 3H),
3.87 (s, 3H), 6.92 (d, J = 9.0 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H),
7.62 (d, J = 8.5 Hz, 2H), 7.92 (dd, J = 8.8, 2.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.44 (d,
J = 2.0 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ = 55.0, 55.2, 113.9, 114.4, 117.4,
119.8, 120.1, 123.2, 125.2, 128.9, 130.3, 130.7, 131.5, 132.0, 136.2, 138.7, 139.9, 159.2,
5

159.8. Anal. calcd. for C23H17ClN4O2: C, 66.27; H, 4.11; N, 13.44. Found: C, 66.39; H,
4.00; N, 13.28.
SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra are available. This material can
be found via the supplementary content section of this article’s web page.
ACKNOWLEGEMENTS
This work was supported and funded by Research Council of Tehran University of
Medical Sciences (TUMS) (Grant no. 94-03-92-30269) and Iran National Science
Foundation (INSF).
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Table 1. Synthesis of benzo[e]imidazo[1,2-c][1,2,3]triazine derivatives.a
Entry Product
Yield (%)b
1
2
3
4
5
6
7
8
5a R1= H; R2= H; R3= H; R4= H
81
79
84
85
89
85
81
5b R1= H; R2= H; R3= H; R4= Cl
5c R1= H; R2= H; R3; R4= OCH2O
5d R1= H; R2= OMe; R3= H; R4= H
5e R1= OMe; R2= H; R3= H; R4= H
5f R1= OMe; R2= H; R3= H; R4= Cl
5g R1= OMe; R2= H; R3; R4= OCH2O
5h R1= OMe; R2= OMe; R3= H; R4= H 83
a Condition: 4 (1 equiv.), NaNO2 (1 equiv.), acetone, HCl (10%), 0 oC→r.t.
b Isolated yields.
10

Scheme 1. Reagents and conditions: a) NH4OAc, HOAc, reflux, 12 h; b) Zn, NH4Cl,
MeOH:H2O (7:1), r.t.; c) NaNO2/H2O, acetone, HCl (10%), 0 oC, then r.t., 2 h.
11