An efficient catalyst-free synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot four-component domino protocol in water

Article abstract of DOI:10.1016/j.tetlet.2014.10.067

A catalyst-free multicomponent reaction (MCR) capable of affording a wide range of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot two-step domino protocol, in water is reported. Catalyst-free conditions along with green solvent system

Full text of DOI:10.1016/j.tetlet.2014.10.067

Accepted Manuscript
An efficient catalyst-free synthesis of novel benzo[a][1,3]oxazino[6,5-c]phe-
nazine derivatives via one pot four-component domino protocol in water
Garima Khanna, Ankita Chaudhary, Jitender M. Khurana
PII:
S0040-4039(14)01750-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.067
TETL 45296
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 August 2014
11 October 2014
11 October 2014
Please cite this article as: Khanna, G., Chaudhary, A., Khurana, J.M., An efficient catalyst-free synthesis of novel
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot four-component domino protocol in water,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.067
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Graphical Abstract
An efficient catalyst-free synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine
derivatives via one pot four-component domino protocol in water
Garima Khanna, Ankita Chaudhary, Jitender M. Khurana*
R
O
O
N
NH2
NH2
N
N
OH
R NH ,
HCHO
H2O, 50 °C
2
N
N
O
+
OH
H2O, 50 °C
1

An efficient catalyst-free synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine
derivatives via one pot four-component domino protocol in water
Garima Khanna, Ankita Chaudhary, Jitender M. Khurana*
Department of Chemistry, University of Delhi, Delhi-110007, India
*Corresponding author. Tel.: +91 11 2766772; fax: +91 1 27667624
E-mail addresses: jmkhurana1@yahoo.co.in, jmkhurana@chemistry.du.ac.in
Abstract
A catalyst-free multicomponent reaction (MCR) capable of affording a wide range of novel
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot two-step domino protocol, in
water is reported. Catalyst-free conditions along with green solvent system make the process
ecofriendly as well as economical. Simple reaction conditions, easy work-up isolation and
purification of products are the significant advantages of the present protocol.
Keywords
Oxazines, phenazines, catalyst-free, water
In view of the environmental aspects, designing of novel, catalyst-free methods in aqueous
medium to synthesize a variety of pharmacological agents has acquired immense importance in
recent years.1 The rich and efficient chemistry that stems from multicomponent reactions
(MCRs) provide a convenient approach to pursue these ambitions.2 One pot MCRs often shorten
reaction periods and give comparatively higher overall chemical yields compared to multiple-
step syntheses, and thus reduce the use of energy and manpower.3 Replacement of hazardous
solvents with environmentally benign solvents4 is one of the major focus areas of green
chemistry. As a reaction medium, water complies with all the current stringent requirements on
sustainable chemistry. Water often enhances the rate of reaction due to its strong hydrogen
bonding ability, hydrophobic effects and high polarity.5 Reactions carried out in aqueous
medium also have the advantage of easy isolation of products. Also, catalyst-free synthetic
2

methods not only for laboratory synthesis but also in the chemical industry have acquired
immense interest because of reduced pollution, lower cost, mild conditions, and ease of
purification.6
1,3-Oxazine ring system is a core structure present in a number of biodynamic heterocycles. The
compounds containing dihydro-1,3-oxazine ring system exhibit a wide spectrum of
pharmacological activities such as anti-tumor7, anti-bacterial8, anti-HIV9 and antimalarial.10
Particular attention has been paid to this class of compounds since the discovery of the non-
nucleoside reverse transcriptase inhibitor trifluoromethyl-1,3-oxazine-2-one, which shows high
activity against a variety of HIV-1 mutant strains.11 This 1,3-oxazine ring system also find its
applicability in photo induced ring opening and thermal ring closing.12
Also, the phenazine based compounds have been demonstrated to possess a myriad of biological
functions viz. antimicrobial13, antimycobacterial14, antifungal15 and antitumour.16 Some of the
benzophenazines act as dual inhibitors of topoisomerase I and II, the two key enzymes that
affect the topology of DNA at different points in a cell cycle.17 Phenazine derivatives also
demonstrate the efficacy in the field of photodynamic therapy (PDT).18
Mannich reaction is one of the most useful carbon–carbon bond formation reactions in organic
synthesis. Most of the current Mannich reactions involve the condensation of enolizable ketones
with formaldehyde and amines. There are reports of a few examples of Mannich reaction
involving phenols and naphthols.19 It has been found that incorporation of two or more different
heterocyclic moieties in a single molecule leads to enhancement of biological activity.20
In the course of our ongoing research toward the synthesis of heterocycles via MCRs,21 we
envisaged that it would be of interest to combine the aforementioned heterocycles in a molecular
hybrid framework consisting of both phenazine and oxazine moieties. We decided to focus on
the development of catalyst free synthesis preferably in aqueous medium.
This is the first report on the catalyst-free synthesis of a novel series of 2,3-dihydro-1H-
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot, two-step domino protocol from 2-
hydroxy-1,4-naphthoquinone, 1,2-diaminobenzene, aromatic/aliphatic amines and formaldehyde
in aqueous medium at 50°C. The reaction conditions were optimized by attempting reactions of
2-hydroxy-1,4-naphthoquinone (1.0 mmol), 1,2-diaminobenzene (1.0 mmol), 4-methylaniline
3

(1.0 mmol) and formaldehyde (2.0 mmol) as model substrates in water at different temperatures
(Scheme 1). When this four-component condensation was attempted in water at room
temperature, the reaction was found to be incomplete by TLC (eluent: ethyl acetate-petroleum
ether, 30:70, v/v) and showed a number of spots on TLC. (Table 1, entry 1). After further
manipulation of reaction conditions, we observed that if the reaction was performed by initial
condensation of 2-hydroxy-1,4-naphthoquinone (1.0 mmol) and 1,2-diaminobenzene (1.0 mmol)
in water at room temperature to form the intermediate benzo[a]phenazin-5-ol in an appropriate
time as monitored by TLC, followed by the addition of 4-methylaniline (1.0 mmol) and
formaldehyde (1.0 mmol) in the same pot, the reaction was found to be completed in 4 h and
afforded 75% of 2-(4-methylphenyl)-2,3-dihydro-1H-benzo[a][1,3]oxazino[6,5-c]phenazine
(Table 1, entry 2). The same reaction when performed in water at 50°C in sequential manner was
found to proceed to completion in 60 min yielding 90% of the desired product 2a after separation
(Table 1, entry 3). Reaction attempted in water at higher temperature in an analogous manner did
not show any significant difference in the time and yield of reaction (Table 1, entry 4). The same
reaction when performed using paraformaldehyde instead of formaldehyde, required longer
reaction time and gave inferior yield of 2a (Table 1, entry 5). Also, the reaction when performed
in ethanol at 50°C was found to be completed in 1h 15 min yielding only 82% of the product 2a
(Table 1, entry 6).
Me
NH2
N
O
N
N
OH
NH2
NH2
, HCHO
N
O
Me
+
OH
N
O
2a
Scheme 1
<Table 1>
Therefore, a one pot sequential catalyst-free reaction of 2-hydroxy-1,4-naphthoquinone (1.0
mmol) and 1,2-diaminobenzene (1.0 mmol) in water followed by the addition of 4-methylaniline
(1.0 mmol) and formaldehyde (2.0 mmol) at 50°C proved to be the optimum condition.
Subsequently, this protocol was extended to other aromatic amines. All the reactions proceeded
satisfactorily and were completed in 60-90 min. The desired 2,3-dihydro-1H-
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives were obtained in high yields by a simple work
4

up (entries 1-10, Table 2).22 The reactions were then attempted with aliphatic amines and
benzylamine as well. The reactions proceeded smoothly with n-butyl, n-hexyl, n-octyl,
cyclohexyl amines and benzylamine to give corresponding 2,3-dihydro-1H-
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives in high yields (entries 11-15, Table 2)
(Scheme 2). The same reaction did not proceed with heterocyclic amines viz 2-
aminobenzothiazole, 5-amino-3-methylpyrazole, 1,3-dimethyl-5-aminouracil etc. The structures
of all the above synthesized benzo[a][1,3]oxazino[6,5-c]phenazine derivatives were fully
characterized by 1H NMR and 13C NMR and IR and mass spectra.
R
N
O
R NH2 , HCHO
N
N
OH
NH2
NH2
H2O, 50 °C
N
N
O
(1)
+
OH
H2O, 50 °C
O
2
Scheme 2
<Table 2>
A proposed mechanistic route for the formation of the products is exhibited in Scheme 3. At first,
amination reaction occurs between the formaldehyde and amine (RNH2) followed by H2O
elimination providing imine intermediate ‘A’. ‘A’ is then attacked by benzo[a]phenazin-5-ol (B)
to form ‘C’ which further reacts with formaldehyde and eliminates H2O, further cyclization
occurs to form the final product (2).
O
H
H
H
N
R NH2
NH2
H
-H2O
(A)
R
R
N
H
O
O
O
N
N
N
OH
-H2O
+
NH2
N
OH
(C)
(B)
R
N
R
N
H
O
H
H
H
H
N
N
O
N
N
O
-H2O
(2)
Scheme 3. A probable mechanistic pathway for the synthesis of benzo[a][1,3]oxazino[6,5-
c]phenazine derivatives (2).
5

In conclusion, we have developed an eco-friendly catalyst-free water, mediated synthesis of
novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via the reaction of 2-hydroxy-1,4-
naphthoquinone, 1,2-diaminobenzene, aromatic/ aliphatic amines and formaldehyde at 50°C in
high to excellent yields. Our protocol achieves the highest level of green chemical process in
terms of economy, ecology, avoidance of catalyst as well as conventional volatile organic
solvents, operable under mild reaction conditions, no waste formation, easy separation and
purification of products.
Supplementary Material
1
Spectral data and copies of H NMR and 13C NMR spectra are available on the Journal’s
website.
Acknowledgments
G.K. and A.C. thank the Council of Scientific and Industrial Research, New Delhi, India for the
grant of junior and senior research fellowship, respectively.
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7

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22. General procedure for the synthesis of benzo[a][1,3]oxazino[6,5-c]phenazine derivatives: A
mixture of 2-hydroxy-1,4-naphthoquinone (1.0 mmol), 1,2-diaminobenzene (1.0 mmol) and
water (10 mL) was placed in a 50 mL round-bottomed flask mounted over a magnetic stirrer.
The contents were stirred magnetically in an oil-bath maintained at 50°C. After the formation of
an orange solid of benzo[a]phenazin-5-ol (~ 45 min), aromatic/aliphatic amine (1.0 mmol) and
formalin (37%, w/v, 2.0 mmol) were added to the above reaction mixture which was heated
further at same temperature for an appropriate time as shown in Table 2. The progress of the
reaction was monitored by TLC using ethyl acetate:petroleum ether (30:70, v/v) as eluent. After
completion of the reaction, the reaction mixture was allowed to cool at room temperature and the
precipitate formed was collected by filtration at pump. The crude product so obtained was
dissolved in chloroform:ethyl acetate (3:1 v/v) and filtered. The filtrate so obtained was
concentrated and petroleum ether was added dropwise to precipitate out the pure product. The
products were identified by spectral data. 13C NMR data of 2n and 2o could not be recorded due
to their low solubility.
8

Tables
Table 1: Optimization of reaction conditions for the synthesis of 2,3-dihydro-1H-
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives.
Entry
Solvent
Temp.
Time
Yield (%)
a,b
1.
H2O
r.t.
-
-
2.
H2O
r.t.
4h
75c
3.
H2O
50°C
Reflux
50°C
50°C
1h
90c
91c
75c,d
82 c
4.
H2O
1h
5.
H2O
2h
6.
Ethanol
1h 15min
a2-Hydroxy-1,4-naphthoquinone (1.0 mmol), 1,2-diaminobenzene (1.0 mmol), 4-methylaniline (1.0 mmol) and
formaldehyde (2.0 mmol) were added simultaneously.
bIncomplete reaction with number of spots on TLC.
c2-Hydroxy-1,4-naphthoquinone (1.0 mmol) and 1,2-diaminobenzene were first allowed to stir in solvent at
appropriate temp. and then 4-methylaniline (1.0 mmol) and formaldehyde (2.0 mmol) were added after 45 min.
dParaformaldehyde was used instead of formaldehyde.

Table 2: Synthesis of 2,3-dihydro-1H-benzo[a][1,3]oxazino[6,5-c]phenazine derivatives.
Entry
Compound
R
Time (min)
Yield (%)
1.
4-MeC6H4
C6H5
60
85
75
85
90
75
85
60
75
75
60
70
90
90
60
90
2a
2b
2c
2d
2e
2f
2.
82
3.
4-(OMe)C6H4
4-Br C6H4
4-Cl C6H4
4-F C6H4
3-Cl C6H4
2-(OMe) C6H4
2-Me
93
4.
87
5.
91
6.
85
7.
89
2g
2h
2i
8.
82
9.
93
10.
11.
12.
13.
14.
15.
3-F
85
2j
CH2CH2CH2CH3
CH2(CH2)4CH3
CH2(CH2)6CH3
CH2C6H5
C6H11
84
2k
2l
86
83
2m
2n
2o
80
80

Highlights:
 Novel phenazine-oxazine hybrids have been synthesized
 Catalyst free, green approach employed
 Characterized by spectroscopic data