Cobalt(III)-porphyrin complex (CoTCPP) as an efficient and recyclable homogeneous catalyst for the synthesis of tryptanthrin in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2015.12.052

The water soluble cobalt(III) porphyrin complex (CoTCPP) was employed as an efficient catalyst for the synthesis of the biologically active natural product tryptanthrin. The reaction proceeded under mild conditions in aqueous media at room temperature from various isatoic anhydride and isatin derivatives. The advantages of these reactions were excellent yields, short reaction times and a recoverable catalyst.

Full text of DOI:10.1016/j.tetlet.2015.12.052

Accepted Manuscript
Cobalt (III)-porphyrin Complex (CoTCPP) as an efficient and recyclable ho-
mogeneous catalyst for the synthesis of tryptanthrin in aqueous media
Mahmoud Abd El Aleem Ali Ali El-Remaily, O.M. Elhady
PII:
S0040-4039(15)30467-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.052
TETL 47099
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 June 2015
23 November 2015
9 December 2015
Please cite this article as: El-Remaily, M.A.E., Elhady, O.M., Cobalt (III)-porphyrin Complex (CoTCPP) as an
efficient and recyclable homogeneous catalyst for the synthesis of tryptanthrin in aqueous media, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.052
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Cobalt (III)-porphyrin Complex (CoTCPP) as an efficient and
recyclable homogeneous catalyst for the synthesis of tryptanthrin in
aqueous media.
Mahmoud Abd El Aleem Ali Ali El-Remaily* and O. M. Elhady
Department of Chemistry, Faculty of Science, Sohag University- 82524, Sohag, Egypt.
* Author: maeaali@kth.se, msremaily@yahoo.com, Tel:+201143627127, Fax: +2093601159,
Graphical Abstract:
Cobalt (III)-porphyrin Complex (CoTCPP) as an efficient and
recyclable homogeneous catalyst for the synthesis of tryptanthrin in
aqueous media.
Abstract:
The water soluble cobalt (III) porphyrin complex (CoTCPP) was employed as an
efficient catalyst for the synthesis of the biologically active natural product
tryptanthrin. The reaction proceeded under mild conditions in aqueous media at room
temperature from various isatoic anhydride and isatin derivatives. The advantages of
these reactions were excellent yields, short reaction times and a recoverable catalyst.
Keywords: CoTCPP, tryptanthrin, efficient catalyst, aqueous medium, recoverable
catalyst.
Introduction
Catalytic reactions performed using 5,10,15,20-tetrakis-(4-carboxlatophenyl)-
porphyrin-cobalt(III) chloride (CoTCPP) fulfill the prerequisite criteria of green
chemistry such as water-solubility,1 low toxicity, and high stability of the complexes.
Porphyrins, are typical examples of functional molecular materials and have attracted
great interest in the materials field because of their large conjugated electronic
molecular structures. They have also been extensively investigated in diverse areas,
such as physics, chemistry, medicine, and biology.2 The search for broadly applicable
metal catalysts that operate in aqueous solvent is currently a subject of high interest.3
1

Applications have been reported in preparative organic synthesis, and also in the
degradation of bio renewables (e.g., lignin) as an important sources of chemical
feedstocks. However, most metal-based catalytic applications have been reported in
organic solvents, due to the sensitivity of these complexes to moisture. Accordingly,
the number of metal complexes suitable for catalysis in an aqueous environmental
remains limited and the need for such catalysts has resulted in detailed studies.4,5
Tryptanthrin can be isolated from Candida lipolytica in the presence of tryptophan.6
Its structure is slightly twisted with aromatic character according to single crystal
X-ray analysis.7 Tryptanthrin and its derivatives are indoloquinazoline alkaloids
which are found in many plants.8 For example, eight indoloquinazolines were isolated
from the methanol extract of Phaius mishmensis. Among these compounds,
tryptanthrin was shown to have excellent cytotoxicity against human breast carcinoma
(MCF-7)9a, lung carcinoma (NCI-H460), and central nervous system carcinoma (SF-
268) cell lines.9b Several tryptanthrin derivatives were also found to exhibit
remarkable antileishmanial activity and are potential succedaneums of sodium
stibogluconate (Pentostam) and meglumine antimonate (Glucantime), which are
current treatments for leishmaniases that unfortunately show hazardous side effects
and alarming cardiotoxicity.10 More recently, it was also discovered that tryptanthrins
are potential antitubercular agents.11
Previous method for the synthesis of tryptanthrin focus on its construction from isatin.
For example, cathodic reduction of isatin afforded tryptanthrin in moderate yield.12
Treatment of isatin with POCl3,9b,13 KMnO414a NiCl2·6H2O/NaBH414b or Cu-catalyzed
reactions15 also led to the formation of tryptanthrin. However, the structural diversity
of tryptanthrins is confined by these methods due to the use of a single starting
material. Structured diversity could be achieved by the condensation reaction between
isatins and isatoic anhydrides in the presence of triethylamine16 or in an aqueous
17
solution of β-cyclodextrin. An alternative condensation uses the reaction of isatin
and ortho-aminobenzoic acid in the presence of SOCl2.18 The lithiation of
orthobromophenyl isocyanide, followed by addition of electrophilic methyl 2-
isocyanatobenzoate, is an unusual method which has also been utilised.19
One of our aims in the last years have been the development of new tools and
methodologies for synthesizing bioactive compounds.20-22
2

In this communication, CoTCPP was found to be an efficient catalyst for the
synthesis of tryptanthrin derivatives in aqueous medium from isatoic anhydrides and
isatins at room temperature using an environmentally benign protocol.
Results and discussion:
The preparation of the CoTCPP catalyst was performed according to reported
literature procedures.23-26 Firstly, metal free 5,10,15,20-tetra(4-carboxyphenyl)-
porphyrin was prepared by the reaction of pyrrole and 4-carboxy benzaldehyde in
propanoic acid. Coordination of cobalt into the porphyrin core was carried out by the
reaction of CoCl2 with the metal-free porphyrin at reflux, giving 5,10,15,20-tetrakis-
(4-carboxlatophenyl)-porphyrin-cobalt(III) chloride in 83% yield (Figure 1).
Fig. 1 Structure of the CoTCPP catalyst.
CoTCPP was then examined as an efficient and recoverable catalyst for the synthesis
of tryptanthrin derivatives 3a-p (Scheme 1). Due to the low solubility of some starting
materials in water, a mixed solvent of water and ethanol (5:1) was used.
Scheme 1: Synthesis of tryptanthrin derivatives 3a-p.
The role of CoTCPP as a catalyst was confirmed when the model reaction between
isatoic anhydride 1a and isatin 2a was carried out in the absence of any catalyst; no
product was obtained even with a long reaction time (Table 1, entry 1). We examined
the influence of a variety of different Lewis acids, using the selected reaction
conditions (Table 1, entries 2-11). It is noteworthy that the CoTCPP catalyst
performed much better in comparison with all of the other water-soluble Lewis acids
3

investigated. Thus, CoTCPP was found to be the most effective catalyst and afforded
the desired product 3a in 96% yield (Table 1, entry 12). We screened different
solvents such as CH3OH, CHCl3, DMF, DMSO, THF, CH3CN and water with
CoTCPP as a catalyst and found promising results with water as a solvent due to
better solubility of CoTCPP (Table 1, entries 13-18).
Table 1. Use of different Lewis acids for the reaction to form 3ab
Entry
Cat (mol%)
Conditionsb
Yield (%)a
1
No catalyst
H2O, r.t, 3 d
H2O, r.t, 3 h
0
2
CoCl2•6H2O (3)
37
3
Co(NO2)2•6H2O (3)
H2O, r.t, 3 h
38
4
5
CoO (3)
FeCl2•6H2O (3)
FeCl3•6H2O (3)
AlCl3 (3)
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
H2O, r.t, 3 h
CH3OH, r.t, 3 h
CHCl3, r.t, 3 h
DMF, r.t, 3 h
THF, r.t, 3 h
DMSO, r.t, 3 h
CH3CN, r.t, 3 h
21
33
31
28
18
23
22
14
95
73
68
61
66
70
72
6
7
8
ZnBr2 (3)
9
MgCl2 (3)
10
11
12
13
14
15
16
17
18
CuCl2(3)
TiCl4 (3)
CoTCPP(3)
CoTCPP(3)
CoTCPP(3)
CoTCPP(3)
CoTCPP(3)
CoTCPP(3)
CoTCPP(3)
aIsolated yield based on 3a, bReaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst (3
mol%), water:ethanol (5:1), room temperature.
4

With the optimized reaction conditions in hand, we investigated the model reaction
further by varying the amount of the CoTCPP catalyst. It was observed that 3 mol%
gave the highest yield of 95% and further increases were not beneficial to the process.
Table 2: the amount of CoTCPP catalyst for the synthesis of tryptanthrin 3ab.
Entry
Cat. (mol%)
Yield %a
1
2
3
1
2
3
4
51
83
95
95
4
b
aIsolated yield based on 3a, Reaction conditions: 1a (1 mmol), 2a (1 mmol), CoTCPP (3 mol%),
water:ethanol (5:1), room temperature.
The substrate scope was explored under the optimized condition to give a series of
tryptanthrin derivatives 3a-p (Table 3).
Table 3: Synthesis of tryptanthrin derivativesa.
Entry
1
Compound
R1
H
R2
H
Time (h)
Yield (%)b
3a
3b
3c
3d
3e
3f
3
5
5
6
3
4
4
4
5
3
6
5
4
3
6
95
91
90
88
93
95
91
89
92
94
91
92
93
95
91
2
H
CH3
H
3
CH3
CH3
H
4
CH3
OCH3
OCH3
OCH3
CH3
Cl
5
6
OCH3
CH3
OCH3
H
7
3g
3h
3i
8
9
10
11
12
13
14
15
3j
Cl
Cl
3k
3l
Cl
CH3
Cl
CH3
H
3m
3n
3o
Br
Br
Br
Br
CH3
5

16
3p
CH3
Br
5
90
aReaction conditions: 1a-p (1 mmol), 2a-p (1 mmol), CoTCPP (3 mol%), water:ethanol (5:1),
b
room temperature. Isolated yields.
A possible mechanism for the formation of product 3a in the presence catalytic
CoTCPP involves CoTCPP activating the carbonyl carbon at position 4 of the isatoic
anhydride 1a for nucleophilic attack by isatin 2a, leading to cleavage of the anhydride
ring and formation of the intermediate. This then reacts at position 2 of isatin to form
the product 3a.
The catalyst reusability was studied in the model reaction to from 3a. Despite an
inevitable loss of catalyst in the recovery process, no significant loss in catalytic
activity was observed (Figure 2). The catalyst was used directly several times in other
reactions under similar conditions without a loss of efficiency.
95
95
95
94
95
94
93
92
91
90
1
2
3
4
Run
Fig 2: Recyclability of CoTCPP in the model reaction.
Conclusion:
In conclusion, we report CoTCPP as an efficient and environmentally benign catalyst
for the synthesis of the biologically active natural product tryptanthrin in aqueous
medium at room temperature. This method is has merits such as high yields and cost
effectiveness, using aqueous conditions, as well as being environmentally benign in
nature and using a recoverable catalyst. This represents the first example of using
CoTCPP as a catalyst in water for the synthesis of tryptanthrin derivatives.
Supporting Information:
General procedures spectra and data for all compounds is located in the supporting
information.
Acknowledgment:
6

The author is deeply grateful to Sohag University in Egypt for supporting and
facilitating this study.
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