Microwave-induced bismuth(III)-catalyzed synthesis of linear indoloquinolines

Article abstract of DOI:10.1016/j.tetlet.2017.06.040

Microwave-induced Bi(NO₃)₃-catalyzed one-pot synthesis of a series of linear indoloquinolines is accomplished under mild reaction conditions. While majority of these examples were carried out under solvent-free conditions, in a few cases, minimal quantity of THF is used as solvent. The methodology involves several unique reaction pathways, providing different linear indolo[2,3-b]quinolines in good yields from readily available starting materials and using environmentally benign Bi(NO₃)₃·5H₂O as catalyst.

Full text of DOI:10.1016/j.tetlet.2017.06.040

Accepted Manuscript
Microwave-induced Bismuth(III)-catalyzed Synthesis of Linear Indoloquino-
lines
Prakash T. Parvatkar, P.S. Parameswaran, Debasish Bandyopadhyay,
Sanghamitra Mukherjee, Bimal K. Banik
PII:
S0040-4039(17)30771-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.040
TETL 49032
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 May 2017
10 June 2017
13 June 2017
Please cite this article as: Parvatkar, P.T., Parameswaran, P.S., Bandyopadhyay, D., Mukherjee, S., Banik, B.K.,
Microwave-induced Bismuth(III)-catalyzed Synthesis of Linear Indoloquinolines, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.06.040
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Microwave-induced Bismuth(III)-catalyzed Synthesis of Linear Indoloquinolines
Prakash T. Parvatkara,b, P. S. Parameswaranc, Debasish Bandyopadhyayd, Sanghamitra
Mukherjeed, Bimal K. Banikd,e*
aDepartment of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India;
bCurrent Address: Department of Chemistry and Chemical Biology, Northeastern
University, Boston, MA 02115, United States
cCSIR-National Institute of Oceanography, Regional Centre, Kochi 682 018, India
dDepartment of Chemistry, The University of Texas-Pan American, Edinburg, TX 78539,
United States; eCurrent Address: Community Health System of South Texas, 3135 South
Sugar Road, Edinburg, TX 78539, United States
Phone: +1-281-813-2104
Fax: +1-956-259-8085
Email: bimalbanik10@gmail.com
Abstract: Microwave-induced Bi(NO3)3-catalyzed one-pot synthesis of a series of linear
indoloquinolines is accomplished under mild reaction conditions. While majority of these
examples were carried out under solvent-free conditions, in a few cases, minimal quantity
of THF is used as solvent. The methodology involves several unique reaction pathways,
providing different linear indolo[2,3-b]quinolines in good yields from readily available
starting materials and using environmentally benign Bi(NO3)3.5H2O as catalyst.
Keywords: Bismuth nitrate; Domino; Indoloquinoline; Microwave; Neocryptolepine
Linear indoloquinoline alkaloids have received considerable attention in recent
years due to their wide range of biological activities such as antimalarial, cytotoxicity,
antimuscarinic, antibacterial, antiviral, antimicotic, antihyperglycemic, antitumor and
DNA interacalating properties.1 Several linear indoloquinoline alkaloids have been
isolated from the roots of Cryptolepis sanguinolenta,2 a shrub indigenous to West Africa,
which are being used in folk medicine in Central and West Africa for the treatment of
infectious diseases, amoebiasis, fever and malaria.1e,3 Major alkaloids reported from C.
sanguinolenta are cryptolepine 14 and neocryptolepine 25a (also known as
cryptotackiene5b) (Fig. 1) containing linear indolo[3,2-b]quinoline and indolo[2,3-
b]quinoline ring systems respectively and are being widely studied because of its
biological importance. 6H-Indolo[2,3-b]quinoline 3, an immediate chemical precursor of
2 is also been studied extensively in recent years as it shares many biological activities
with cryptotackieine.2 Compound 3, named norcryptotackieine is also a natural product,
being isolated recently from the leaves of Justicia betonica.6
Figure 1: Naturally occurring linear indoloquinoline alkaloids

Several methods for the synthesis of 3 and its derivatives have been reported in
the literature.2 Most important among those are one-pot domino approaches (Scheme 1 -
I2 in refluxing Ph2O,7 RuY (Ru+3 ion-exchanged zeolite) in refluxing 1,4-dioxane,8 NBS
under solvent-free condition at room temperature,9 and PivOH in refluxing Ph2O10).
However, most of these methodologies require higher temperature or much longer
reaction times, with tedious product isolation procedures, toxicity of the catalyst or low
product yields being additional impediments.
Scheme1: One-pot approaches for the synthesis of 6H-indolo[2,3-b]quinoline
Herein, we report a fast, efficient, clean and mechanistically unique microwave-
mediated one-pot method for the synthesis of 6H-indolo[2,3-b]quinolines using eco-
friendly bismuth-nitrate as a catalyst. In the recent years, bismuth(III) salts have attracted
much attention in various organic transformations due to their low toxicity, low cost, high
catalytic activity, good stability and ease of handling.11 Furthermore, in recent years,
Bi(III) compounds have been applied for efficient and atom-economic synthesis of
various heterocyclic compounds in high yields and under mild reaction conditions.12
The mixture of indole-3-carboxyaldehyde 4 and two equivalents of aniline 5 in
presence of 10 mol% of Bi(III) salt as a catalyst in tightly sealed vessel (manufactured by
CEM microwave company) under solvent-free condition were irradiated in microwave at
60°C (Table 1).

Table 1: Optimization of reaction conditionsa
Entry Bi(III) salt
Time (min) Yield of 3b (%)
1
2
3
4
5
None
Bi(NO3)3.5H2O
BiCl3
BiI3
Bi2O3
30
3
15
15
30
0
61
10
10
0
aReaction conditions: 4 (1 mmol), 5 (2 mmol, 2 equiv.), catalyst (10 mol%, 0.1 equiv.).
bYield of the isolated product.
Results revealed that, in absence of catalyst (entry 1) and with Bi2O3 (entry 5), no
product formation is observed whereas in presence of other Bi(III) salts (entry 2-4),
desired product is obtained within short period of time. However, the reason for the
failure of reaction with Bi2O3 is not known. Bi(NO3)3.5H2O gave the best results in terms
of both yield and time. Addition of different amounts of water to the reaction mixtures of
inactive bismuth salts (BiCl3, BiI3 and Bi2O3) did not yield the products. We have
attempted to prepare anhydrous bismuth nitrate, but failed as it decomposes at high
temperature and produces bismuth oxide. In order to optimize the product yield, varying
percentages of Bi(NO3)3.5H2O (5 to 20 mol%) were studied (not shown in the table).
These experiments revealed that 10 mol% loading of the catalyst furnished the highest
yield of desired products in just 3 min.
We first proposed the mechanism (Scheme 2) wherein the Bi(NO3)3 acts as a
Lewis acid to activate carbonyl to facilitate the imine formation through the condensation
of 4 and 5. Next step is different from the previously reported7-9 mechanisms, wherein
indole attacks the catalyst (I2, NBS, Ru-Y) due to its electrophilic nature to form
indolinium cation. However, attack of indole on the bulky Bi(NO3)3 to form indolinium
cation is highly unlikely. So, we thought, water generated during the imine formation and
water of crystallization present in the salt itself could have decomposed the Bi(NO3)3
under the reaction condition to form Bi(OH)3 and HNO3. In-situ generated HNO3 then
may have catalyzed the reaction further to form indolonium cation. Nucleophilic attack
by another mole of aniline on indolonium cation followed by annulation and subsequent
loss of aniline may have given dihydro-indoloquinoline, which may rapidly undergo
oxidation to give fully aromatized indoloquinoline 3.7-9

Scheme 2: Preliminary proposed mechanism catalyzed by in-situ generated HNO3.
To test this above mechanism, we performed the reaction with catalytic amount of
HNO3. However, the reaction was very sluggish and undesired products or no products
were formed. The failure of the reaction with HNO3 indicates this transformation follows
an entirely different pathway from that shown in scheme 1. This leads us to propose a
new mechanism (Scheme 3), which significantly differs from the previously reported6-8
mechanisms for this one-pot transformation. As per this postulated mechanism, Bi(NO3)3
activates the in-situ formed imine to form iminium cation.13 1,4-Addition of another mole
of aniline 4 followed by [1,3]-hydride shift will result in 2,3-disubstituted indole
derivative. Regeneration of Bi(NO3)3, subsequent ring closure and finally expulsion of
aniline will lead to 6H-indolo[2,3-b]quinoline 3.

Scheme 3: Plausible mechanism catalyzed by Bi(NO3)3 through activation of imine.
After optimising the reaction conditions, we next investigated the substrate scope
of this reaction with various aromatic/hetero-aromatic amines 5a-h and indole-3-
carboxyaldehyde 4 (Table 2).
In case of liquid aryl amines (entry a – e), the reaction is performed under solvent
free condition while for solid aryl amines (entry f – h), THF is used as a solvent. Aryl
amines containing electron-donating or electron-withdrawing groups and heteroaryl
moiety are compatible with the reaction condition yielding desired products in good
yields within short period of time (3-5 min). In contrast to all available methods, this is
the fastest method reported so far for the synthesis of linear indoloquinolines. Mild
reaction conditions, simplified reaction work-up and purification procedure, good yields
and use of environmental-friendly catalyst besides interesting mechanism (different from
other reported Lewis acid catalyst for this transformation) makes this methodology very
attractive. While iodine can react with the aromatic amine and imine (two substrates
involved in this reaction) readily, however, a similar reaction with bismuth nitrate is not
possible.7 p-Nitroaniline and p-hydroxyaniline (not shown in Table 2) did not form the
product, probably due to the reduced nucleophilicity of the NH2-group. For p-
nitroaniline, reduced nucleophilicity is due to the presence of NO2-substituent at 4-
position whereas in case of p-hydroxyaniline, nucleophilicity could have reduced due to
the formation of polymer hydrogen bonds between –OH and –NH2 groups.

Table 2: Microwave-mediated Bi(NO3)3-catalyzed synthesis of indoloquinolinesa
aReaction conditions: 4 (1 mmol), 5a-h (2 mmol), Bi(NO3)3.5H2O (10 mol%, 0.1
equiv.).14 bYield of the isolated product.c0.5 mL THF is used.

In summery, we have developed an expeditious microwave-mediated one-pot
methodology for the synthesis of linear indolo[2,3-b]quinolines using eco- and user-
friendly Bi(NO3)3.5H2O as catalyst. Short reaction time; use of inexpensive, non-toxic &
commercial availability of catalyst; ease of product isolation; good yields and mild
reaction conditions are vital advantages of this methodology. Detailed mechanistic
studies of this reaction and more transformations using different substituted indole-3-
carboxyaldehydes are currently underway in our laboratory. We anticipate that this
methodology will find more synthetic utility in other biologically important related
indoloquinolines like indolo[3,2-b]quinolines.
Acknowledgements:
BKB is grateful to NIH and NCI for the support of this work.
References and Notes:
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14. General procedure for the synthesis of linear indoloquinolines 3a-h: Indole-3-
carboxyaldehyde 4 (1 mmol), aryl amines 5a-h (2 mmol, 2 equiv.) and Bi(NO3)3 (10
0
mol%, 0.1. equiv.) were taken in a vessel, sealed tightly and irradiated at 60 C and 300
watt power in microwave reactor (CEM Discover) for 3 - 5 min. For solid aryl amines,
THF (0.5 mL) was added. Reaction mixture was diluted with THF, filtered, concentrated
and purified by silica gel column chromatography using 30% EtOAc in hexanes as the
eluent to afford corresponding indoloquinolines 3a-h. All the synthesised compounds
1
3a-h were characterized by H NMR, 13C NMR and confirmed by comparison with the
reported NMR data.7,9

Highlight:
 An efficient microwave-mediated synthesis of indoloquinolines is reported.
 Reaction uses an environmentally benign bismuth nitrate as a catalyst.
 Mechanistically, this one-pot transformation is unique.
 Proposed plausible mechanism for this one-pot transformation.

Microwave-induced Bismuth(III)-catalyzed Synthesis of Linear Indoloquinolines
Prakash T. Parvatkar, P. S. Parameswaran, Debasish Bandyopadhyay, Sanghamitra
Mukherjee and Bimal K. Banik
CHO
NH2
Bi(NO3)3.5H2O
(10 mol%)
+
MW
300 W, 60 0C
2 - 5 min
N
X
X
R
X = CH, N
H
N
N
R
H
(52 - 61%)
R = H; 2-Me; 3-Me; 4-Me; 2-Br; 2,3-benzo; 3,4-benzo