Novel aqueous phase supramolecular synthesis of 3-pyrrolyl-indolin-2-ones and pyrrolylindeno[1,2-b]quinoxalines

Article abstract of DOI:10.1002/adsc.200800121

Various 3-pyrrolylindolin-2-ones and pyrrolylindeno[1,2-b]quinoxaline were synthesized for the first time in high yields in water under neutral conditions by supramolecular catalysis involving β-cyclodextrin. The β-cyclodextrin can be recovered and reused a number of times without any loss of activity.

Full text of DOI:10.1002/adsc.200800121

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DOI: 10.1002/adsc.200800121
Novel Aqueous Phase Supramolecular Synthesis of 3-Pyrrolyl-
A
N
R. Sridhar,a B. Srinivas,a V. Pavan Kumar,a V. Prakash Reddy,a A. Vijay Kumar,a
and K. Rama Raoa,*
a
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad – 500007, India
Fax : (+91)-40-2716-0512; e-mail: kakulapatirama@gmail.com
Received: February 25, 2008; Published online: June 2, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Various 3-pyrrolylindolin-2-ones and
pyrrolylindeno[1,2-b]quinoxaline were synthesized
for the first time in high yields in water under neu-
tral conditions by supramolecular catalysis involving
b-cyclodextrin. The b-cyclodextrin can be recovered
and reused a number of times without any loss of
activity.
are important mediators of cellular signal transduc-
tion and are implicated in the transformation process-
es associated with human cancers.[5] In view of their
high significance, many methodologies have been de-
veloped for the construction of the pyrrole skeleton.[6]
The most frequently used methods include the classi-
cal Hantzsch procedure,[7] the cyclocondensation of
primary amines with 1,4-dicarbonyl compounds
(Paal–Knorr synthesis)[8] and various cycloaddition
strategies.[9] These approaches generally involve mul-
tistep synthetic operations limiting the scope of these
reactions. Recently, a few syntheses of 3-pyrrolyl-2-in-
dolinones by the condensation of trans-4-hydroxy-l-
proline with various isatins have been described.[10]
ACHTREUNG
Keywords: b-cyclodextrin; trans-4-hydroxy-l-pro-
line; indolinones; isatins; pyrroles; water
Pyrroles are an important class of compounds display- However, these methodologies also have limited
ing remarkable pharmacological properties such as scope due to the use of transition metal triflates, mi-
antibacterial, antiviral, anti-inflammatory, antitumor- crowave irradiation, acidic conditions and hazardous
al, and antioxidant activities.[1] Furthermore, they are solvents. As a consequence, the development of envi-
useful intermediates in the synthesis of natural prod- ronmentally benign practical synthetic routes under
ucts and heterocycles[2] and are also widely used in neutral conditions in water for accessing these 3-pyr-
materials science.[3] Various 3-substituted indoline-2- rolylindolin-2-ones still remains a major goal. Organic
ones have been shown to exhibit tyrosine kinase in- reactions in aqueous media have recently become the
hibitory activity.[4] Receptor tyrosine kinases (RTKs) focus in organic synthesis since they overcome the
Scheme 1.
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Table 1. b-CD-catalyzed synthesis of 3-(1H-pyrrol-1-yl)indo-
harmful effects of organic solvents and are environ-
mentally benign.[10] Aqueous reactions can be made
more sophisticated if they can be performed under
supramolecular catalysis, for example, by b-cyclodex-
trins, overcoming many of the drawbacks observed in
the previous methodologies.
lin-2-ones and 11-(1H-pyrrol-1-yl)-11H-indeno[1,2-b]qui-
A
noxaline.
Cyclodextrins (CDs) are cyclic oligosaccharides
possessing hydrophobic cavities, which bind substrates
selectively and catalyze chemical reactions with high
selectivity. They catalyze reactions by a supramolec-
ular process involving reversible formation of host-
guest complexes through non-covalent bonding as
seen in enzymes.
In continuation of our interest in the b-cyclodex-
trin-catalyzed biomimetic synthesis of heterocyclic
compounds in the aqueous phase,[12] we have ex-
plored, the aqueous phase synthesis of 3-pyrrolylindo-
lin-2-ones by condensation of trans-4-hydroxy-l-pro-
line with isatin derivatives under neutral conditions
and demonstrated the remarkable catalytic activity of
b-cyclodextrin (Scheme 1).
In general, the reactions were carried out by form-
ing in situ the b-CD complex of the isatin in water,
followed by the addition of trans-4-hydroxy-l-proline
and stirring at 608C. The corresponding 3-(1H-pyrrol-
1-yl)-indolin-2-one compounds were obtained in im-
pressive yields (90–96%) after 75–95 min. This meth-
odology is compatible with various substituted isatins
having different functionalities such as bromo, fluoro,
methyl, cyano, nitro and with 1-methyl-, 1-phenyl-
and 1-benzylisatins (Table 1, entrries a–i). It was also
found
that
11H-indeno[1,2-b]quinoxalin-11-ones
A
(Table 1, entry j) underwent condensation with trans-
4-hydroxy-l-proline to give 11-(1H-pyrrol-1-yl)-11H-
indeno[1,2-b]quinoxalines in 87% yield under similar
A
conditions. These reactions proceeded efficiently
under neutral conditions. No by-product formation
was observed. b-Cyclodextrin can be easily recovered
and reused.
1
The H NMR spectra (D2O) of b-CD, the b-CD:isa-
tin complex and a freeze-dried reaction mixture of
the b-CD:isatin complex with the trans-4-hydroxy-l-
proline were studied. It was observed from Figure 1
that there was an upfield shift of the H3 (0.02 ppm)
and H5 (0.02 ppm) protons of cyclodextrin in the b-
CD:isatin complex as compared to b-CD, indicating
the formation of an inclusion complex of isatin with
b-CD from the secondary side of cyclodextrin.[13] In
the spectra of the reaction mixture of the b-CD:isatin
complex with trans-4-hydroxy-l-proline at 50 min we
also observed an upfield shift of the CD H6 proton by
0.045 ppm. This indicated that the reaction proceeded
by complexation of trans-4-hydroxy-l-proline from
[a]
All products were identified by IR, NMR, mass spectros-
copy and elemental analysis.
Yields of products isolated after column chromatography.
[b]
the primary side of cyclodextrin (Figure 1). This clear- in the hydrophobic microenvironment of b-cyclodex-
ly demonstrates that the isatin is ideally located for trin cavity (Figure 2).
the condensation with the trans-4-hydroxy-l-proline
The catalytic activity of cyclodextrins for these re-
actions is established by the fact that no reaction was
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Novel Aqueous Phase Supramolecular Synthesis of 3-Pyrrolylindolin-2-ones
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11-(1H-pyrrol-1-yl)-11H-indeno[1,2-b]quinoxaline and
G
3-(1H-pyrrol-1-yl)indolin-2-one compounds by the
condensation of trans-4-hydroxy-l-proline with
11Hindeno[1,2-b]quinoxalin-11-one or isatin deriva-
E
tives under biomimetic conditions in the presence of
b-cyclodextrin. This straightforward, environmentally
benign methodology may find widespread applica-
tions in organic and medicinal chemistry.
Experimental Section
General Information
1H NMR spectra were recorded on Gemini-200 MHz or
Avance-300 MHz spectrometers in CDCl3 or DMSO-d6 with
TMS as internal standard. Mass spectra were recorded on a
Finnigan MAT 1020 mass spectrometer operating at 70 eV.
IR spectra were recorded on Nicolet FT-IR. spectrometer.
Melting points were recorded on Büchi R-535 apparatus
and are uncorrected.
Figure 1. 1H NMR spectra of a) b-CD, b) b-CD:isatin com-
plex and c) reaction mixture after 50 min. The spectra were
recorded in D2O at 258C.
General Procedure for the Synthesis of 3-(1H-Pyrrol-
1-yl)-indolin-2-ones
b-CD (1 mmol) was dissolved in water (15 mL) by warming
to 608C until a clear solution was formed. Then, isatin
(1 mmol) was added portionwise followed by trans-4-hy-
droxy-l-proline (1 mmol) and the mixture was stirred at
608C until the reaction was complete (as monitored by
TLC) (Table 1). However in the case of indenoquinoxali-
none (entry j, Table 1), this compound was dissolved in
methanol (0.5 mL methanol/mmol) and added dropwise to
the aqueous solution of cyclodextrin. It is observed that
isatin forms a clear solution in water at 608C whereas inden-
oquinoxalinone is insoluble in water at this temperature ne-
cessitating its dissolution in methanol before the addition.
After completion of the reaction, the mixture was extracted
with ethyl acetate, and the extract was filtered. The organic
layer was dried over anhydrous Na2SO4, the solvent was re-
moved under reduced pressure, and the resulting product
was further purified by column chromatography. The aque-
ous layer was cooled to 58C to recover b-CD by filtration.
This b-CD was recycled for five times without any loss of ac-
tivity and change in the yield in the cases of 3a and 3c. All
the compounds were characterized by 1H NMR, IR, MS
analyses and compared with the authentic compounds.[10]
Figure 2.
observed in the absence of cyclodextrin. The com-
plexation with b-CD increases the reactivity of both
the keto and amino groups of isatin and trans-4-hy-
droxy-l-proline due to intermolecular hydrogen bond-
ing with the CD hydroxy groups facilitating the estab-
lished sequence of reactions such as condensation, de-
carboxylation, dehydration, and aromatization of the
product.[10] Here, b-CD not only forms the inclusion
complex with isatin and trans-4-hydroxy-l-proline but
is also involved in the intermolecular hydrogen bond-
ing with the guests promoting the condensation and
dehydration reactions.
Preparation of b-CD:Isatin Inclusion Complex
b-CD (1 mmol) was dissolved in water (15 mL) by warming
to 608C until a clear solution was formed, and then isatin
(1 mmol) was added portionwise and the mixture was al-
lowed to cool to room temperature. It was cooled to 58C for
12 h and the orange precipitate was filtered and dried.
Acknowledgements
In conclusion, we have presented the first neutral
We thank CSIR, New Delhi, India, for fellowships to RS, BS,
aqueous phase synthesis of functionalized pyrroles, VPK, VPR and UGC for a fellowship to AVK.
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