Tetrahedron: Asymmetry
Asymmetric aldol reactions of isatins catalyzed
by phthalimido-prolinamide
a
a
Togapur Pavan Kumar a,b, , Nemali Manjula , Kumar Katragunta
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a Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective aldol reactions of isatins with acetone using phthalimido-prolinamide organocatalyst 1
are described. The protocol was effective under solvent free and additive free reaction conditions with
20 mol % of 1 leading to the desired aldol products in good yields and with good enantioselectivities.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 15 September 2015
Accepted 30 September 2015
Available online xxxx
1. Introduction
development of phthalimido-prolinamide 18 (Fig. 1) as an efficient
organocatalyst for asymmetric direct aldol reactions with ketones
The aldol reaction is one of the most explored benchmark trans-
formations using organocatalysts.1 Specifically, it ranks at the top
for testing and evaluating the efficacy of new catalyst designs.2
The products of this reaction, b-hydroxy carbonyl compounds are
important structural motifs, which are found in numerous bioac-
tive natural products and drug molecules.3 Among the various
aldol substrates, isatins attract great attention as they lead to the
formation of oxindole derivatives, which serve as valuable
templates for further derivatization to hybrid and/or designed
bioactives.4 From a literature survey, isatins were found to be
infrequent substrate partners for aldol reactions and thus drew
our attention. Although a large number of organocatalysts such
as proline derivatives, bifunctional thioureas, and others have been
reported for various asymmetric reactions, only some of them have
been evaluated for aldol reactions with isatin derivatives.5 The first
report on the enantioselective aldol reaction of isatin with acetone
was presented by Tomasini et al. in 2005 using peptide based
organocatalysts.5b Later on, Zhao et al. developed a thiourea
and aldehydes under solvent free reaction conditions. Having been
encouraged by this and in continuation of our research interests8,9
on organocatalysis, we evaluated the catalytic performance of 1 for
aldol reactions of isatins and acetone. Catalyst 1 worked well and
resulted in the formation of the corresponding aldol adducts with
good yields and selectivities under solvent free and additive free
conditions when employing 20 mol % of 1. Herein these studies
are reported.
O
O
N
H
HN
N
O
1
Figure 1. Phthalimido-prolinamide.
catalyst,5c Chen et al. developed
a carbohydrate derived
2. Results and discussion
catalyst,5d and several other catalysts were developed for this
transformation with good levels of success.5 In particular, several
proline derived organocatalytic protocols were found to be effec-
tive.6 Among the proline derivatives, prolinamides are prominent
due to their functional characteristics such as graded NH acidity
and tunable steric control.7 An investigation into new catalytic
approaches for aldol reaction of isatin substrates serves as valuable
addition to the existing methods and extends the horizons of
organocatalysis. Recently, we have reported on the design and
In order to explore the ability of 1 as an organocatalyst for aldol
reactions of isatins and acetone, a series of screening studies were
conducted to establish the optimal parameters by using isatin 2a
and acetone 3 as the model substrates (Scheme 1). Initially, exper-
iments were conducted identically in various solvents at room
temperature with 20 mol % of catalyst 1 and the results of these
studies are shown in Table 1. The enantioselective aldol reaction
between isatin 2a and acetone 3 proceeded reasonably well in all
solvents irrespective of their polar/non-polar nature resulting in
products with moderate yields and enantioselectivities (Table 1,
entries 1–12). However, when the reaction was performed under
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Corresponding author. Tel.: +91 40 27191727; fax: +91 40 27160512.
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.