I2/NaH/DMF as oxidant trio for the synthesis of tryptanthrin from indigo or isatin

Article abstract of DOI:10.1016/j.dyepig.2019.107935

Tryptanthrin, a product present in several natural sources used as colorants and very relevant in the field of Medicinal Chemistry, was synthesized from indigo and isatin under mild conditions using microwave irradiation. A plausible mechanism for the synthesis of tryptanthrin using the oxidant system formed by iodine, sodium hydride and DMF, the latter acting with dual activity as solvent and as the oxygen source, is proposed.

Full text of DOI:10.1016/j.dyepig.2019.107935

Dyes and Pigments 173 (2020) 107935
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Dyes and Pigments
journal homepage: http://www.elsevier.com/locate/dyepig
I2/NaH/DMF as oxidant trio for the synthesis of tryptanthrin from indigo
or isatin
Pedro Brand a~ oa,b, Daniela Pinheiro , J. S �e rgio Seixas de Melo , Marta Pineiro
a
a
a,*
a
CQC and Department of Chemistry, University of Coimbra, Rua Larga, 3004-535, Coimbra, Portugal
b
�
�
�
Centro de Química de Evora, Institute for Research and Advanced Studies, University of Evora, Rua Rom a~ o Ramalho, 7000, Evora, Portugal
A R T I C L E I N F O
A B S T R A C T
Keywords:
Tryptanthrin
DMF
Tryptanthrin, a product present in several natural sources used as colorants and very relevant in the field of
Medicinal Chemistry, was synthesized from indigo and isatin under mild conditions using microwave irradiation.
A plausible mechanism for the synthesis of tryptanthrin using the oxidant system formed by iodine, sodium
hydride and DMF, the latter acting with dual activity as solvent and as the oxygen source, is proposed.
Oxidation
Isatin
Indigo
1
. Introduction
Tryptanthrin (indolo[2.1-b]quinazoline-6,12-dione) is an indolo-
2. Results and discussion
0
With the initial aim of synthesizing cis-N,N -alkylindigo derivatives,
we promoted the reaction between indigo and a diiodoalkane in the
presence of a base in DMF, under microwave irradiation. When
attempting the reaction using diiodomethane (Entry 1- Table 1), some
trans-N-monoalkylindigo was found, as well as a pale yellow compound.
When promoting the reaction using 1,3-diiodopropane (Entry 2), under
the same conditions, many side-products were obtained, including the
same yellow compound. By using 1,2-diiodoethane as the dihaloalkane
(Entry 3), the yellow product was achieved as the major product. After
isolation and characterization, and when compared with data reported
in the literature [8], the yellow product revealed to be tryptanthrin.
Indeed, the gas-chromatography-mass spectrometry (GC-MS) analysis of
quinazoline alkaloid isolated from several natural sources. The interest
in the synthesis of this alkaloid and its derivatives has been driven by the
various applications in the field of Medicinal Chemistry, and in photo-
electronic materials [1].
Several procedures have been reported and recently reviewed for the
synthesis of tryptanthrin [2]. The most common approach is the
condensation of anthranilic acid derivatives, in particular isatoic acid,
with oxindole or isatin derivatives (Scheme 1).
Since 1892, when O’Neill described the first synthesis of tryptanthrin
through the oxidation of indigo with KMnO [3], only a few oxidative
4
methods for the synthesis of tryptanthrin have been reported. These
include the oxidation of indigo using ozone with low yields [4] and the
�
the reaction media after 15 min of microwave irradiation (50 C) shows
oxidation of isatin with strong oxidants such as KMnO
4
or POCl
3
[5]. N,
the presence of isatin, isatoic anhydride, tryptanthrin and unreacted
indigo, (Figs. S1 and SI).
0
N -dimethylformamide (DMF) is a commonly used polar aprotic solvent
with a high boiling point but it has also the capability to serve as
building block for various units namely carbonyl, methyl or dimethyl-
amine groups [6]. Less common is the capability of DMF to act as oxygen
source in oxidation reactions, for example the synthesis of ethers from
allylic and benzylic bromides by treatment with NaH and DMF [7].
Herein we describe the synthesis of tryptanthrin from indigo or isatin
Intrigued by these findings, we decided to further explore this re-
�
action. Conducting it under conventional heating (15 min, 50 C),
tryptanthrin was also obtained in very low yield (5%). Therefore, we
assessed the viability of the formation of tryptanthrin under microwave
irradiation, using different conditions.
To verify the influence of the diiodoalkane, we attempted the reac-
tion without the use of this reactant (Entry 4). Under these experimental
conditions, only indigo was detected, indicating the absence of reac-
tivity in these circumstances.
trough oxidation using I
source.
2
/NaH/DMF as oxidant trio and DMF as oxygen
*
Corresponding author.
E-mail address: mpineiro@qui.uc.pt (M. Pineiro).
https://doi.org/10.1016/j.dyepig.2019.107935
Received 28 August 2019; Received in revised form 27 September 2019; Accepted 27 September 2019
Available online 30 September 2019
0
143-7208/© 2019 Elsevier Ltd. All rights reserved.

P. Brand a~ o et al.
Dyes and Pigments 173 (2020) 107935
Scheme 1. Previous approaches for the synthesis of tryptanthrin.
Table 1
a)
Microwave-assisted tryptanthrin synthesis using indigo as starting material.
Entry
a)
b)
NaH
Iodine source
Solvent
% Tryptanthrin
1
2
3
4
5
6
7
8
9
1
1
1
2 equiv.
2 equiv.
2 equiv.
2 equiv.
2 equiv.
2 equiv.
2 equiv.
2 equiv.
4 equiv.
–
CH
2
I
2
DMF (2 mL)
9
2
C
C
–
C
C
C
C
C
C
C
3
H
H
6
I
I
2
DMF (2 mL)
c
2
4
2
DMF (2 mL)
23 (22 )
DMF (2 mL)
0
2
H
2
H
2
H
2
H
2
H
2
H
2
H
4
4
4
4
4
4
4
I
2
I
2
I
2
I
2
I
2
I
2
I
2
DMF (2 mL)
24
Trace
2
Cyrene (1.8 mL) þ DMF (200
2-MeTHF (2 mL)
μ
L)
2-MeTHF (2 mL) þ DMF (58
thioDMF (2 mL)
DMF (2 mL)
μL)
7
0
0
1
2
0
4 equiv.
2 equiv.
DMF (2 mL)
83
c
I
2
DMF (2 mL)
69 (64 )
a
b
c
All reactions were performed using 100 mg (1 equiv.) of indigo and 2 equiv. of iodine source (except if specified otherwise).
Yields determined by GC-MS.
Isolated Yields.
The mechanism would therefore involve oxidation of indigo to isatin,
dimethylthioformamide – under the condition in which higher yield was
achieved (Entry 9). Using this solvent and keeping all the other variables
as previously described no tryptanthrin was detected, only indigo,
indicating that the reaction does not occur. Furthermore, this allows us
to infer that any dissolved oxygen, water traces or hydroxyl anions can’t
be considered responsible for the oxidative processes. When a mixture of
DMF and dimethylthioformamide (1:1) was used as solvent, tryptan-
thrin was detected showcasing again the importance of DMF as oxygen
source under the conditions described in this work.
followed by its oxidative cyclization. The evident oxidant in the reaction
media of our experiments would be atmospheric oxygen. Therefore, in
order to assess the role of oxygen, the reaction was performed under N
2
saturated atmosphere (Entry 5). We found that tryptanthrin is still
formed, thus showing that oxygen is not the oxidant in these conditions.
Knowing that DMF is not considered an environmentally friendly
option, we decided to evaluate its role as oxygen source using green
solvents. Cyrene usually described as a good alternative to DMF and 2-
methyltetrahydrofuran (2-MeTHF) was chosen. Knowing the decompo-
sition of cyrene in basic conditions we performed the reaction using a
To verify the relevance of NaH, two reactions were performed using
DMF as solvent, one without the presence of NaH (Entry 10) and other
with doubled equivalents (Entry 11). Under these reaction conditions,
the GC-MS profile showed only unreacted indigo in the first case and a
dramatic increase in the tryptanthrin formation in the second, show-
casing the relevance of NaH to the success of the reaction. This yield
improvement might be due to several reasons: (i) the involvement of
NaH in the decomposition of the dihaloalkane and production of reac-
tive oxidant species; (ii) the need to have deprotonated indigo to pro-
mote the reaction; (iii) to the existence of a secondary reaction that
might take place between NaH and DMF, as described in the literature
stoichiometric amount of NaH, in the presence of 200 L of DMF, and
μ
just after added the 1,2-diiodoethane in 1.8 mL of cyrene (Entry 6)
obtaining only traces of tryptanthrin. Using 2-MeTHF a small amount of
tryptanthrin, traces of isatin and a considerable quantity of 1,2-diiodo-
ethane were detected (Entry 7). By adding two equivalents (58 L) of
μ
DMF (Entry 8), a greater amount of isatin and tryptanthrin were ob-
tained, pointing out to the involvement of DMF in the indigo oxidation
to isatin and consecutive oxidative cyclization. To verify this hypothesis,
we decided to use a solvent with similar properties and structure –
2

P. Brand a~ o et al.
Dyes and Pigments 173 (2020) 107935
Table 2
a)
Microwave-assisted tryptanthrin synthesis using isatin as starting material.
Entry
b)
NaH
Iodine source
Solvent
% Tryptanthrin
13
14
15
16
17
18
1 equiv.
1 equiv.
1.5 equiv.
4 equiv.
–
C
2
H
4
I
2
(2 equiv.)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
2-MeTHF (2 mL)
56
0
–
I
2
(0.2 equiv.)
(2 equiv.)
0
I
2
39
0
C
C
2
H
H
4
I
I
2
(2 equiv.)
(2 equiv.)
1 equiv.
2
4
2
0
a
b
All reactions were performed using 100 mg (1 equiv.) of isatin.
Yields determined by GC-MS.
[
9]; (iv) it might be involved in an acid-base reaction with isatin
intermediates/side-products and a considerable increase on the tryp-
tanthrin yield (68.8%), with only 17.8% of indigo left unreacted. This
data clearly shows that the formation of tryptanthrin from indigo is
promoted when iodine (molecular iodine or organic iodine)/DMF/NaH
are simultaneously present.
increasing its nucleophilicity; and (v) the use of excess of the hydride
might promote this secondary reaction that facilitates the formation of
tryptanthrin.
Since we observed the formation of a gas immediately after the
addition of the 1,2-diiodoethane, we conducted a headspace GC-MS
analysis in the closed microwave reactor. The result showed the pres-
ence of ethylene, indicating the decomposition of this diiodoalkane in
basic conditions, resulting in the formation of iodine or iodide radicals.
Iodine is a universal oxidizing agent and a mild and nontoxic Lewis acid
catalyst, widely applied in the synthesis of heterocyclic compounds. For
these reasons, we pointed it as the oxidant agent in our reaction.
With this information in mind, we decided to conduct the same re-
Since isatin and isatoic anhydride have been observed in many
reactional conditions, we wanted to understand if the reactant trio was
required only to promote the oxidation of indigo to isatin/isatoic an-
hydride, or if it was also relevant to promote the second step of the
oxidative cyclization. To assess such information, we performed some
reactions, replacing indigo by isatin (Table 2). First, we promoted the
reaction between isatin, NaH and 1,2-diiodoethane in 2 mL of DMF.
Tryptanthrin was formed in considerable yield (Entry 13) under such
conditions, in opposition to what happens when no iodine source is
placed in the reactor vessel (Entry 14), where no tryptanthrin was
action using molecular iodine I
2
(Entry 12). In this case, we could detect
both isatin and isatoic anhydride, confirming the existence of these two
Scheme 2. Proposed mechanism for the decomposition of indigo to isatin and oxidation to isatoic anhydride.
3

P. Brand a~ o et al.
Dyes and Pigments 173 (2020) 107935
formed. This indicates that iodine is crucial not only to react with indigo
to originate isatin, but also to promote the oxidative cyclization to afford
tryptanthrin. We also tested if using a catalytic amount of molecular
iodine (0.2 eq.) the reaction would occur, but no tryptanthrin was
Notes
The authors declare no competing financial interest.
Acknowledgements
2
detected in 15 min of reaction (Entry 15). By using 2 equivalents of I ,
tryptanthrin was formed in considerable amount (Entry 16). Overall, the
best reaction conditions are achieved when the starting material (indigo
or isatin) is deprotonated with an excess of NaH and allowed to react
P. Brand a~ o and D. Pinheiro acknowledge FCT for the PhD grants PD/
BD/128490/2017 - CATSUS FCT-PhD Program and SFRH/BD/74351/
2 2 4 2
with iodine (as I or C H I ) under the described microwave irradiation
2
010, respectively. The Coimbra Chemistry Centre is supported by the
conditions (see Supplementary Data). By removing NaH, (Entry 17) or
DMF (by substitution with 2-MeTHF) (Entry 18) no tryptanthrin was
observed after 15 min under MW irradiation, showcasing the relevance
FCT, Portuguese Agency for Scientific Research, through the Project
PEst-OE/QUI/UI0313/2014. This work was supported by Project
“
Hylight” (no. 031625) 02/SAICT/2017 which is funded by the Portu-
2
of the I /NaH/DMF trio for the tryptanthrin formation.
guese Science Foundation and Compete Centro 2020 and project “Sun-
Storage - Harvesting and storage of solar energy” for financial support,
reference POCI-01-0145-FEDER-016387, funded by European Regional
Development Fund (ERDF), through COMPETE 2020- Operational Pro-
gramme for Competitiveness and Internationalization (OPCI), and by
national funds, through FCT. We acknowledge funding by Fundo
Europeu de Desenvolvimento Regional (FEDER) through Programa
Operacional Factores de Competitividade (COMPETE).
After collecting all this information, and based on the previous re-
ports on the tryptanthrin synthesis and the ability of DMF to act as ox-
ygen donor, we hypothesize the mechanism for the decomposition of
indigo to isatin presented in Scheme 2. Iodine addition to indigo double
bond (I) followed by the addition of DMF as proposed by Sudalai and co-
workers [10], led to the formation of intermediate II. Iodine atom could
be further substituted by DMF forming intermediate III, as proposed by
Liu et al. [11]. Then, addition-elimination processes where hydride acts
as the nucleophile [7] led to the formation of isatin precursors (IV-VII).
From there, isatin could be oxidize to isatoic anhydride through DMF
addition, intramolecular cyclization (similar to the proposed for the
oxidation with peroxide by Wu and Co-workers [12]) and hydride
addition-elimination. The condensation of isatin and isatoic acid could
form tryptanthrin trough a well stablished mechanism [2a,13].
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.dyepig.2019.107935.
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