Aluminium chloride-catalyzed synthesis of 4-benzyl cinnolines from aryl hydrazones

Article abstract of DOI:10.1080/00397911.2013.853799

An efficient synthesis of 4-benzyl cinnolines from aryl phenylallylidene hydrazone is described. In this report aluminium chloride as a Lewis acid catalyst and toluene as a solvent are used for the synthesis. This method is expected to more advantageous t

Full text of DOI:10.1080/00397911.2013.853799

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Aluminium Chloride–Catalyzed Synthesis
of 4-Benzyl Cinnolines from Aryl
Hydrazones
Prasanta Gogoi a , Sandhya Rani Gogoi b , Namita Devi a & Pranjit
Barman a
a Department of Chemistry , National Institute of Technology ,
Silchar , Assam , India
b Department of Chemical Science , Tezpur University , Tezpur ,
Assam , India
Accepted author version posted online: 08 Nov 2013.Published
online: 19 Mar 2014.
To cite this article: Prasanta Gogoi , Sandhya Rani Gogoi , Namita Devi & Pranjit Barman (2014)
Aluminium Chloride–Catalyzed Synthesis of 4-Benzyl Cinnolines from Aryl Hydrazones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:8, 1142-1148, DOI: 10.1080/00397911.2013.853799
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Synthetic Communications®, 44: 1142–1148, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.853799
ALUMINIUM CHLORIDE–CATALYZED SYNTHESIS
OF 4-BENZYL CINNOLINES FROM ARYL HYDRAZONES
Prasanta Gogoi,1 Sandhya Rani Gogoi,2 Namita Devi,1
and Pranjit Barman1
1Department of Chemistry, National Institute of Technology,
Silchar, Assam, India
2Department of Chemical Science, Tezpur University, Tezpur, Assam, India
GRAPHICAL ABSTRACT
Abstract An efficient synthesis of 4-benzyl cinnolines from aryl phenylallylidene hydrazone
is described. In this report aluminium chloride as a Lewis acid catalyst and toluene as a
solvent are used for the synthesis. This method is expected to more advantageous than the
other reported methods of synthesis of the cinnoline rings because of its low cost, better
yield, and benign reaction conditions.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aluminium chloride; aryl hydrazones; 4-benzyl cinnolines
Received August 9, 2013.
Address correspondence to Prasanta Gogoi, Department of Chemistry, National Institute of
Technology, Silchar 788010, Assam, India. E-mail: prasantanits.11@gmail.com
1142

SYNTHESIS OF 4-BENZYL CINNOLINES
1143
INTRODUCTION
Cinnolines have received considerable interest because of their wide range of
pharmacological profiles.[1] Many of these compounds have attracted considerable
attention in recent years for their roles in biological processes. These compounds pos-
sess antibacterial,[2] antitumor,[3] anti-inflammatory,[4] antifungal,[5] anticancer,[6] and
phosphodiesterase inhibitorys[7] properties. Some cinnolines have antileukemic[8] and
antipsychotic[9] properties. Some of these compounds show electrochemical proper-
ties,[10–12] in addition to their use as agrochemicals.[13] The chemistry of cinnolines has
received much attention and many methods of synthesis of these compounds have
been developed. Most syntheses of cinnolines involve arenediazonium salts,[14,15]
intramolecular arylation,[16] arylhydrazones,[17–19] arylhydrazines,[20] and nitriles[21] as
the starting materials. Recently, a Cu-catalyzed dehydrogenative cyclization of phenyl
hydrazones to cinnoline has been reported.[22] However, the requirement of strong basic
media is a limitation of the reported cyclization of phenylhydrazones into cinnolines.
Table 1. Synthesis of hydrazone derivatives (2)
Entry
Substrate
Product (2)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
20
15
12
10
12
15
14
15
13
14
16
12
10
10
65
60
85
65
75
65
60
67
55
59
54
85
95
90
aIsolated yield of 2.

1144
P. GOGOI ET AL.
In this article we present a general method for the formation of 4-benzyl cin-
nolines, adhering to our objective of developing a protocol that can fulfil the necessity
for a benign, less expensive, and safe synthetic method, by using a catalytic amount of
aluminium chloride in toluene as the solvent.
RESULTS AND DISCUSSION
Initially a series of hydrazones of cinnamaldehyde prepared as per the reported[23]
method are presented in Table 1 (2a–n). In the next step, the hydrazones are subjected to
an AlCl3-aided cyclization to the respective 4-benzylcinnolines (3a–n) and their charac-
terizations are presented in Table 2. A probable mechanism of the cyclization reaction
is presented in if Scheme 1. It is an intramolecular electrophilic aromatic substitution
leading to dihydrocinnoline and its dehydrogenation gives the final product.
The cyclization is initiated by AlCl3-aided tautomerization of the imino
azomethine group of the hydrazone (A) into the azo group of the azo tautomers (B).
The cinnoline hetero ring closure then takes place with the AlCl3-activated benzene
ring. The stabilized final products (3a–n) are then formed by rearomatization of the
para-benzoquinoid form due to reorganization of the π electrons. In our screening of
a few Lewis acid catalysts in this cyclization reaction we have found the best result
with AlCl3 Table 3.
Our solvent of choice is toluene because it has been found that this reaction gives
the best result in toluene as the solvent in comparison with other solvents Table 4.
Table 2. Formation of 4-benzyl cinnolines from cinnamaldehyde-derived phenyl hydrazones
Entry
Substrate (2)
Product (3)
Time (h)
Yield (%)a
1
2
3
4
5
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
7
9
5
10
8
5
74
90
65
80
48
6
70
7
8
9
2g
2h
2i
3g
3h
3i
6
8
6
65
67
71
10
11
12
13
14
2j
2k
2l
2m
2n
3j
3k
3l
3m
3n
7
4
11
15
12
65
82
Trace
Trace
Trace
aIsolated yield of 3.

SYNTHESIS OF 4-BENZYL CINNOLINES
1145
Scheme 1. A plausible mechanism for the formation of 4-benzyl cinnolines.
Table 3. Screening of Lewis acid catalysts for cyclization reaction
Entry
Lewis acid
Time (h)
Yield (%)a
1
2
3
4
5
TiCl4
AlCl3
FeCl3
InCl3
9
7
8
12
9.5
34
74
23
Trace
44
SnCl2.2H2O
aIsolated yield of 3a.
Table 4. Optimization of reaction conditions for the preparation of 4-benzylcinoline
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
6
7
CH3CN
THF
6
5
7
4
7
8
7
20
48
74
44
50
40
35
Toluene
DCM
DMF
DMSO
CCl4
aIsolated yield of 3a.

1146
P. GOGOI ET AL.
It is more likely that AlCl3 activates the azo group as an electrophile, and
therefore arene is the nucleophile. This may be the reason why the presence of
inductively activating alkyl group(s) in the aryl ring favor the cyclization step, whereas
the presence of strong resonatingly deactivating nitro group(s) in the ring disfavor the
cyclization reaction.
CONCLUSION
In conclusion, we have been able to develop a benign, safe, and quite efficient
method for the synthesis of 4-benzyl cinnolines from easily preparable aryl hydra-
zones of cinnamaldehyde in the presence of Lewis acid catalyst aluminium chloride.
Good yields of cinnolines, a very simple workup procedure, and easy and safe method
of preparation are the advantages.
EXPERIMENTAL
All solvents and chemicals were purchased commercially and used without
further purification. Melting points were determined by open glass capillary method
and are uncorrected. NMR spectra were recorded on a FT-NMR Bruker Avance II
400-MHz instrument (400 MHz for 1H NMR, 100 MHz for 13C NMR) using CDCl3
as solvent and tetramethylsilene (TMS) as an internal reference. Infrared (TR) spectra
were recorded on a Nicolet Impact 410 FT-IR spectrometer. Solid samples were exam-
ined as a thin film between KBr salt plates. Mass spectra were recorded on a LC-MS
Waters ZQ-4000 instrument. Elemental analyses were carried out in a Perkin-Elmer
model 240 analyzer.
Typical Procedure for the Synthesis of 4-Benzyl Cinnoline (3a)
Anhydrous AlCl3 (10mol%) and toluene (4.0mL) were added to a round-
bottomed flask equipped with a reflux condenser with 1-(phenyl)-2-(3-phenyl-
allylidene) hydrazine (1.1g, 0.5mmol). The flask was placed in a hot oil bath and
stirred at 110°C for 7h. Upon completion of the reaction the mixture was filtered
and diluted with water. The precipitated product was collected and purified by col-
umn chromatography on silica gel using ethyl acetate / hexane (10–25%) to give
4-benzylcinnoline (3a).
Selected Data
Yellowish solid; mp: 103°C (lit.[24] 104.5°C); IR υ/(KBr) cm−1: 3089cm−1 (Ar-
H), 2846cm−1 (C-H), 1592cm−1 (N=N), 1280cm−1 (-C-N=N), 1195cm−1 (-N=N-C). 1H
NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.81 (d, J=7.5Hz,
1H), 7.67 (t, J=7.8Hz, 1H), 7.44–7.38 (m, 5H), 7.26 (s, 1H) 4.62 (s, 1H); [13]C NMR
(100MHz, CDCl3) δ 152.2, 148.1, 138.6, 137.3, 135.5, 132.8, 131.2, 129.1, 128.7,
126.3, 125.2, 120.2, 54.4; Mass: m/z 221.1 [M+H]+. Anal. calcd. for C15H12N2 (220):
C, 81.79; H, 5.49; N, 12.72. Found: C, 81.43; H, 5.55; N, 12.75.

SYNTHESIS OF 4-BENZYL CINNOLINES
1147
SUPPORTING INFORMATION
Full experimental and spectral details can be found via the Supplementary
Content section of this article’s Web page.
ACKNOWLEDGMENTS
The authors are grateful to K. Mohan Rao, head of the Sophisticated Analytical
Instrument Facility (SAIF), Northeastern Hill University (NEHU), Shillong, for
NMR and mass spectroscopy support of this research and CIF of Tezpur University.
We thank S. K. Bhattacharjee, Department of Chemistry, Gauhati University,
Guwahati, Assam, India, for valuable suggestions.
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