Metal free Lewis acid promoted one-pot synthesis of 14-aryl-14H dibenzo [a,j] xanthenes and their simple biological evolution

Article abstract of DOI:10.1016/j.tetlet.2017.07.037

A green, competent one-pot synthesis of 14-aryl 14H-dibenzo [a,j] xanthene and its bio-computational studies are reported. Target compounds are prepared by the condensation of 2-naphthol with benzaldehyde and its substituents using metal free benzyltrimet

Full text of DOI:10.1016/j.tetlet.2017.07.037

Accepted Manuscript
Metal free Lewis acid promoted one-pot synthesis of 14-aryl -14H dibenzo [a,j]
xanthenes and their simple biological evolution
Uppalaiah Kusampally, Ramakanth Pagadala, Kamatala Chinna Rajanna
PII:
S0040-4039(17)30883-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.037
TETL 49119
Reference:
Tetrahedron Letters
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3 July 2017
10 July 2017
Please cite this article as: Kusampally, U., Pagadala, R., Rajanna, K.C., Metal free Lewis acid promoted one-pot
synthesis of 14-aryl -14H dibenzo [a,j] xanthenes and their simple biological evolution, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.037
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Tetrahedron Letters
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Metal free Lewis acid promoted one-pot synthesis of 14-aryl -14H dibenzo [a,j]
xanthenes and their simple biological evolution
Uppalaiah Kusampallya, Ramakanth Pagadalab, Kamatala Chinna Rajannaa, ∗
a
Department of Chemistry, Osmania University, Hyderabad – 500 007, Telangana, India
b
Department of Chemistry, Institute of Aeronautical Engineering, Dundigal, Hyderabad – 500 043, Telangana, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A green, competent one-pot synthesis of 14-aryl 14H-dibenzo [a, j] xanthene and its bio-
computational studies are reported. Target compounds are prepared by the condensation of 2-
naphthol with benzaldehyde and its substituents using metal free benzyltrimethylammonium
tribromide (BTMA-Br3) catalyst under solvent free thermal and microwave conditions. . This
technique has more advantages such as high yield, a clean procedure, low reaction time, simple
workup and mild Lewis organo acid catalyst.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Dibenzo [a,j] xanthenes
Solvent-free & Microwave condensation
BTMA-Br3
Metal free mild catalyst
few years ago, Chaudhuri et al., reported,24 the
1. Introduction
A
The chemical sciences play an imperative role in the process
of drug discovery and synthetic routes to develop in order to
deliver more clinically effective remedies.1 The benzo-fused
xanthene functionality is a key structural element of many
biologically active compound. Particularly 14-aryl-14H-dibenzo
[a,j] xanthene has attracted considerable attention by chemists
because of their biological and pharmaceutical properties such as
anti-inflammatory2 antiviral3 and antibacterial activities and
antagonists for the paralyzing acting of zoxazolamine.4 Besides,
these compounds can also be used as dyes,5 pH-sensitive
fluorescent materials for visualization of bio-molecules6 and
utilized in laser technologies7. In view of these striking
applications, the synthesis of xanthenes derivatives has received
up surging interest. The chemical synthesis of 14-aryl-14H-di
benzo [a. j] xanthenes and related compounds have been prepared
by the reaction of 2-naphthol with Formamide, 2-naphthol-1-
methanol and carbon monoxide.8 On the other hand, a number of
methods have been documented by condensation of 2-naphthol
and aldehydes in the presence of strontium sulfamic acid,9
Amberlyst-15,10 K5CoW12O40.3H2O,11 FeCl3,12 WO3/ZrO2,13
PS/AlCl3,14 Alum,15 In(OTF)3,16 PVPP-BF3,17 Mg(HSO4)2,18 ionic
liquid [H-NMP][HSO4],19 Poly(4-vinylpyridinium)hydrogen
environmentally benign synthesis of various organic ammonium
tribromide and their application in bromination reactions since,
Heterogenization of homogeneous catalysts has been an
interesting area of research from an industrial point of view; this
combines the advantages of homogeneous catalysts such as high
activity, selectivity, etc.
In this significance that
Benzyltrimethylammonium tribromide (BTMA-Br3) is a non-
toxic, stable, mild and solid and economically cheap and efficient
metal free organic Lewis acid. This catalyst contains a benzyl
ring with quaternary ammonium tribromide salt. It has been used
for bromination and oxidation of aromatic compounds such as
phenols, aromatic amines, acetanilide, alcohols, ethers, and
thiols, N-bromination of amides, Hofmann degradation of
amides25 etc. In this part of the work, we have taken an
opportunity to further explore the catalytic activity of BTMA-Br3
towards the formation of C-C and C–X bond (X=N, O & S) by
condensation reaction with 2-naphthol and benzaldehydes under
solvent free and micro wave irradiation by employing BTMA-Br3
as a novel organic Lewis acid catalyst (Scheme-1). The reaction
afforded 14-aryl-14H-di benzo [a, j] xanthenes in excellent
yields.
Initially we conducted a model reaction using 2-naphthol (2
mmol) and 4-NO2 benzaldehyde (1 mmol) in ethanol (EtOH) as
the solvent in the absence of catalyst at room temperature for
180 min. The reaction did not proceed even after 180 minutes
(Table 1, entries 1 and 2) under reflux. Then the reaction is
conducted using 4.8 mol% of BTMA-Br3 catalyst in the presence
of various solvents at reflux conditions. The reaction was
sluggish even under these conditions and afforded very low
product yields (Table 1, entries 7 - 11). But very good results
(Table 1, entry 5) were obtained with the composite BTMA-Br3
(4.8 mol%), at 110oC in the absence of solvent. Encouraged by
sulfate20,
mesoporous
SBA-15,21
sulfonated
starch
nanoparticles,22 and various methods.23 However, all these
methods have some drawbacks such as poor yields, prolonged
reaction times, toxic organic solvents, excess reagents; Metal
based catalysts and harsh reaction conditions. Therefore, in
recent years, a significant attention has been focused on
designing environmentally benign synthetic strategies processes
have received much more attention.
———
∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: kcrajannaou@yahoo.com

2
Tetrahedron Letters
the results with BTMA-Br3, and based on literature reports27 we
have used BTMA-Br3 as calyst under solvent free conditions for
rest of the one-pot reactions.
Also the reaction with respect to variety of aromatic aldehydes
bearing substitutions at ortho-, meta-, and para-positions
participated well in this reaction (Table-2). Mechanistically, we
assume that the reaction proceeds via the formation of
orthoquninonemethide from 2-naphthol and aldehyde.
Subsequent Michael addition of 2-napthol followed by
cyclodehydration would give the desired 14-aryl-14H-di benzo
[a, j] xanthenes in the presence of BTMA-Br3 catalyst by the
highlighting role of this catalyst as a promoter for the
condensation reaction by elimination of water or ammonia
molecules (Mechanism-1).
To establish the optimal amount of catalyst, the title reaction
was run with different initial amounts of the BTMA-Br3 (1.7, 3.3
and 6.4 mol%) and the product yields were 40, 70 and 92%
respectively (Table 1, entries 3, 4 and 6). The results suggest that
for chosen reaction conditions 4.8 mol% of BTMA-Br3 catalyst
was adequate to carry out the reaction efficiently. The reactions
afforded good results at 110oC (Scheme 1).
We next investigated the scope of microwave (MW)
irradiation by using optimal condition, affording the desired
product in good yields, with undiminishing efficiency. To
ascertain the effect of microwave on these reactions, the same
reactions were carried out without microwave under otherwise
similar conditions;28 which afforded lower yields and took longer
reaction times (Table 2).
Antimicrobial activity
The 14-aryl-14H-dibenzo [a, j] Xanthenes derivatives are very
good cytotoxic agents26 which have shown fairly good
antimicrobial activity compared to Amplicine and Miconazole as
standard compounds (Table-3 entries R1 & R2). The functional
groups containing nitrogen, oxygen, and alkyl substituent
compounds (3-d, h, i, l, m & p) indicated moderately to good anti
bacterial activity against Gram-Ve bacteria such as Escherichia
Coli & Pseudomonas Aeruginosa. But halogen and oxygen
containing (3-b, c & e) xanthenes directly bound to phenyl ring
derivatives have shown slightly too moderate antifungal activity
against fungal microorganisms such as Aspergills Niger and
Fusarium Moniliforme.
Scheme 1. The synthesis of 14-aryl-14H-di benzo [a. j] xanthenes
Table 1. Catalyst Optimization in various reaction conditions
Entry Solvent Catalyst Temp. Time Yield
Table 3. Antimicrobial inhibition zones (mm) of 14-aryl-14H-di
benzo [a, j] xanthenes
(0C)
(min)
(%)
Bacterial inhibition
Fungal inhibition
zone (mm)
Pseudomonas Aspergillus Fusarium
(mol%)
zone (mm)
1
2
EtOH
None
None
None
None
None
EtOH
DCE
0
0
180
0
Escherichia
Coli
Entry
1
Product
Aeruginosa
Niger
++
++
++
+
Moniliforme
0
0
180
30
0
3a
+
+
+
++
++
++
+
3
1.7
3.3
4.8
6.4
4.8
4.8
4.8
4.8
4.8
110
40
70
94
92
50
30
25
50
30
2
3b
+
4
110
30
3
3c
+
+
5
110
25
4
3d
++
+
++
6
110
35
5
3e
+
++
++
+
+
7
Reflux
Reflux
Reflux
Reflux
Reflux
180
180
180
180
180
6
3f
+
+
++
+
8
7
3g
+
++
9
ACN
MeOH
CHCl3
8
3h
+++
++
+
++
++
++
++
+
+
10
11
9
3i
+++
++
+
Table 2. The synthesis of 14-aryl-14H-di benzo [a. j] xanthene
derivative by BTMA-Br3
10
11
12
13
14
15
16
R1
R2
3j
+
3k
++
++
+++
+++
+++
+++
++++
-
++
+
Time (min)
SF/MW
20/5
Yield(%)
3l
++
-
+
Entry
R
H
Product
3a
SF MW
1
2
87
89
90
92
3m
3n
+++
+++
+++
+++
+++++
-
+
++
+
4-F-
3b
20/4
++
++
++
-
24/6
3
4
3-Br-
4-OH-
3c
3d
3e
3f
90
91
92
91
89
90
90
90
92
92
93
91
91
94
91
92
93
92
93
90
93
93
94
96
92
92
93
96
23/5
22/4
24/6
22/5
21/5
25/6
20/5
22/6
21/5
23/6
25/6
25/5
25/6
3o
+
5
4-Cl-
3p
++
-
6
2-Cl-
7
4-Me-
3g
3h
3i
Ampicillin
Miconazole
8
4-(CH3)2N-
4-OH, 3-MeO-
4-MeO-
3-MeO-
3-NO2-
9
++++
++++
10
11
12
13
14
15
16
3j
Inhibition Zones (mm): Inactive (-); slightly active (+); moderately active
3k
3l
(++); good active (+++); very good active (++++).
2-NO2-
3m
3n
3o
3p
In summary, we have developed one pot synthesis of
pharmacologically potent 14-aryl-14H-di benzo [a, j] xanthenes
using a catalytic amount of metal-free BTMA-Br3 under solvent-
free conditions. The reactions were also conducted under
microwave irradiation. Both the methods have multiple
3, 4-Meo
3, 4, 5-Meo-
4-NO2-
Note: All Solvent free (SF) reactions are carried out at 110oC

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OH
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Mechanisum 1. Plausible Mechanism for the Reaction
Acknowledgments
We greatly acknowledge Head of the Chemistry Department,
Osmania University Hyderabad for laboratory facilities and
Professor P.K. Saiprakash (former Dean, Science Faculty, O.U.)
for constant encouragement. We also thank the Department of
Chemistry, Institute of Aeronautical Engineering for technical
support with the manuscript.
28. Synthesis of 14-(4-Nitro Phenyl)-14H-dibenzo [a, j] xanthene:
The reaction mixture of 2-napthol (2 mmol), 4-nitro benzaldehyde
o
(1mmol) and BTMA-Br3 (60 mg) was heated at 110 C for about
25 minutes. After completion reaction the mixture was cooled to
room temperature and extracted in to ethyl acetate and washed
with 15% Na2CO3; the resultant mixture was purified by column
chromatography using silica gel (60-120 mesh size) and
recrystallized in aqueous EtOH (15%) to obtain pure product (3a-
3p). And also in Microwave irradiated technique, the above same
reaction mixture was placed in a laboratory microwave oven
(BPL, 800T model) on a silica gel solid support and heated at 300
W for the appropriate time 6 min. Further the product isolation
and purification methods are same as above mentioned.
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4
Tetrahedron Letters
Highlights of the manuscript
Metal free Lewis acid promoted one-pot
synthesis of 14-aryl -14H dibenzo [a,j] xanthenes
and their simple biological evolution
ꢀ
ꢀ
ꢀ
ꢀ
A green one-pot synthesis of 14-aryl 14H-dibenzo [a, j]
xanthenes is developed under solvent free conditions
Metal free benzyltrimethylammonium tribromide
worked as an efficient catalyst
Microwave assisted reactions reduced reaction times and
incresed product yields
Prepared xanthenes are very good cytotoxic agents with
fairly good antimicrobial activity

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Metal free Lewis acid promoted one-pot
synthesis of 14-aryl -14H dibenzo [a,j]
xanthenes and their simple biological
evolution
Uppalaiah Kusampallya, Ramakanth Pagadalab, Kamatala Chinna Rajannaa*
A green, competent one-pot synthesis of 14-aryl 14H-dibenzo [a, j] xanthene and its bio-computational studies are
reported. Target compounds are prepared by the condensation of 2-naphthol with benzaldehyde and its substituents using
metal free benzyltrimethylammonium tribromide (BTMA-Br3) catalyst under solvent free thermal and microwave
conditions.
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