Tris-ureas as versatile and highly efficient organocatalysts for Michael addition reactions of nitro-olefins: Mechanistic insight from in-situ diagnostics

Article abstract of DOI:10.1016/j.molcata.2015.01.004

Tris(2-aminoethyl)-amine, TREN based tris-ureas (1a–1d) and tris-thiourea (1e) have been explored towards a wide range of catalytic Michael addition reactions. These tris-ureas, 1a–1d efficiently catalyze the addition reaction of β-nitro styrenes (2a–2d)

Full text of DOI:10.1016/j.molcata.2015.01.004

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Tris-ureas as versatile and highly efficient organocatalysts for Michael
addition reactions of nitro-olefins: Mechanistic insight from in-situ
diagnostics
Milan Bera, Tamal Kanti Ghosh, Bidyut Akhuli, Pradyut Ghosh∗
Department of Inorganic Chemistry, India Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Tris(2-aminoethyl)-amine, TREN based tris-ureas (1a–1d) and tris-thiourea (1e) have been explored
towards a wide range of catalytic Michael addition reactions. These tris-ureas, 1a–1d efficiently cat-
alyze the addition reaction of ␤-nitro styrenes (2a–2d) with various nucleophiles such as ␤-ketoesters
(3a–3c), 1,3-dicarbonyl compound (3d), a cyanoester (3e) and a nitroester (3f) under ambient con-
ditions to produce corresponding nitro alkanes in high yields. Pentafluorophenyl attached tris-urea,
1d is found to be the most effective catalyst in the series that yields 78–98% products conversion. In
case of the reaction between ␤-nitro styrenes and malononitrile (3g) in presence of 1d, 2-amino-5-
nitro-4,6-diphenylcyclohex-1-ene-1,3,3-tricarbonitriles are also isolated as a minor product along with
the corresponding Michael adduct. The added advantage of bridge-head nitrogen center in tris-urea
organocatalysts, 1a–1d has been established by studying analogous benzene platform based tris-ureas
(1f, 1g, 1h) in similar experimental conditions. Furthermore, a plausible reaction mechanism has also
been established based on in-situ 1H NMR kinetic studies.
Received 13 November 2014
Received in revised form
26 December 2014
Accepted 2 January 2015
Available online xxx
Keywords:
Michael addition reaction
Tris-urea catalyst
Organocatalysis
Hammett plot
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
squaramide [11](a)–(e), and other asymmetric version of catalysts
[11](f) are also reported.
Organocatalysis has emerged as one of the most rapidly growing
and promising areas in synthetic organic chemistry. The advantages
of organocatalysis consist of their operational simplicity, ready
availability, low cost, and low toxicity, which confers a huge direct
benefit in the production of pharmaceutical intermediates [1]. In
current research, organocatalytic strategies include formation of
temporary covalent bond through enamine or iminium catalysis
[2], hydrogen bonding interaction through urea or thiourea cataly-
sis [3], pi-stacking interactions [4], Brønsted acid base interactions
[5] and ion-pair interactions by phase transfer catalysts [6], etc.
Combinations of different strategies may lead to an unexpected
synergistic effect to develop better organocatalysts. The Michael
reaction of nitro-olefins represents a convenient route to nitroalka-
nes which are versatile intermediates in organic synthesis [7]. This
reaction has been well studied using different organocatalysts and
In recent times, TREN based tripodal ureas/thioureas have been
extensively studied in the area of anion recognition chemistry upon
manipulating the hydrogen bonding ability of ureas/thioureas [12].
These receptors generally create a C3v-symmetric cleft for guest
species where hydrogen atoms of three urea/thiourea moieties are
directed towards the inner cavity. Apart from these urea/thiourea
moieties in such receptors, a bridge-head nitrogen atom (tertiary N
center) is located close proximity to the cleft bound guest. Herein
we explore such tris-ureas (Scheme 1) as effective catalytic scaf-
folds towards the Michael addition reaction of nitro-olefins with
various carbon nucleophiles. To the best of our knowledge this rep-
resents the first report on the Michael addition reaction by tripodal
tris-urea as organocatalyst. Moreover, control experiments have
been carried out to justify the involvement of bridge-head nitro-
gen center of tris-ureas in the catalytic activity and in-situ 1H NMR
kinetic studies to establish a plausible reaction mechanism.
ithasemergedasoneofthemostefficientandpowerfultoolstoC
C
bond formation. Several organocatalysts like modified amines and
diamines [8], substituted thiourea [9] functionalized l-proline [10],
2. Results and discussion
2.1. Selection of tris-ureas as catalysts
∗
A judicious choice of scaffold is indeed very important towards
the development of a new generation organocatalysts. Our choice
Corresponding author. Tel.: +91 3324734971.
E-mail address: icpg@iacs.res.in (P. Ghosh).
http://dx.doi.org/10.1016/j.molcata.2015.01.004
1381-1169/© 2015 Elsevier B.V. All rights reserved.
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Scheme 1. TREN and mesitylene based tripodal tris-ureas.
of TREN based tripodal tris-ureas towards Michael addition reac-
tion between nitro-olefins and different carbon nucleophiles are
based on, (i) tris-ureas produce a microenvironment by forming
C3v-symmetric clefts or dimeric capsular assemblies [12]. In cases
of anionic guest, acidic H-atoms of urea NH are directed towards
the center of the cavity [12]. Thus, orientation of multiple urea pro-
tons of the catalysts might favor activation of the incoming guests
like nitro-olefins in case of the Michael addition reaction through
multiple hydrogen bonding interactions, (ii) presence of bridge-
head N-center in the catalytic scaffold can also play a synergistic
role in such addition reaction. Thus, it would be interesting to have
a new generation organocatalysts with tris-urea receptors having
bridge-head N-center in the scaffold, (iii) further scope to tune the
catalytic activity by changing the substituent on the attached aryl
unit to the urea center to study the Michael addition reactions with
closely related catalysts.
product is formed. This suggests that the reaction is going only
through homogeneous medium. The reaction in the presence of
phenyl analogue, 1a (5 mol%) provides 60% yield of the desired
Michael adduct 4a after 5 h of reaction (entry 1, Table 1). Replace-
ment of the catalyst with 1b containing 4-cyano phenyl and 1c
with 4-flluoro phenyl groups improve the yields up to 67% (entry
2, Table 1) and 70% (entry 3, Table 1), respectively. Interestingly,
pentaflurophenyl substituted catalyst 1d dramatically increases
the yield up to 95% within 4 h (entry 4, Table 1). The catalyst 1d,
bearing five fluoride atoms shows the highest catalytic activity.
This could be due to the enhancement of the overall acidity of
urea N–H groups. Gratifyingly decreasing the catalyst loading by
employing 2 mol% of the catalyst 1d, the reaction proceeds well
and we find 82% yield after 4 h of reaction (entry 5, Table 1) and
the reaction is completed after 6 h where 4a is isolated in 95%
yield, as diastereomeric mixtures (entry 6, Table 1). It is impor-
tant to mention that some racemic and unselective versions of the
Michael addition of nitro-styrene have been reported by using dif-
ferent metal/base catalysis [13], heterogeneous catalytic systems
[14], organic bases [15], etc. Remarkably, in most of the cases there
are some difficulties on the basis of high catalyst loading, limited
substrate scope, and undefined mechanism of such reaction. How-
ever, here we could explore the Michael reaction with low catalyst
loading towards a variety of substrates along with the plausible
mechanism which are discussed latter. The catalytic activity of 1d
towards the Michael addition reaction decreases in DMF where
product 4a is isolated in 60% yield after 15 h. When thiourea ana-
logue of 1d i.e., pentafluorophenyl substituted tris-thiourea, 1e
(5 mol%) is chosen as catalyst, the catalytic activity of the reac-
tion between 2a and 3a in DMSO decreases significantly. In this
case, a trace amount of the desired product is detected after 15 h
of reaction by TLC (entry 7, Table 1). Since 1e is also soluble in
2.2. Efficacy of functionalized tripodal tris-urea catalysts
Various tren-based ureas and thiourea derivatives 1a–1e have
been synthesized following the literature procedures to examine
the effect of substituents on the aryl moieties attached to urea
linkage [12]. Then the evaluation of catalytic activities of 1a–1e
towards the Michael addition of various carbon nucleophiles to
nitro-olefins are undertaken. We have carried out the Michael reac-
tion of ␤-nitro-styrene 2a with 1.5 equiv. of ethylacetoacetate 3a
as model reaction with different catalysts loading (Table 1). The
screening study has been carried out in DMSO due to insolubility
of catalysts in other solvents like THF, MeOH, DCM, etc. We have
also carried out selected Michael addition reactions with all the
catalysts (1a–1e) in different heterogeneous reaction medium (Sol-
uble substrate + insoluble catalyst). However, in all the cases no
Table 1
The Michael reaction of ␤-nitro-styrene 2a with various catalystsa.
Entry
Ligand (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
1a (5)
1b (5)
1c (5)
1d (5)
1d (2)
1d (2)
1e (5)
5
5
5
4
4
60
67
70
95
82
95
Trace
6
15
a
the reaction was conducted with 2a (1 equiv.), 3a (1.5 equiv.), and DMSO(1.5 mL) in the presence of various catalysts at room temperature.
isolated yield.
b
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Table 2
The Michael reaction of ␤-nitro-styrene -ketoester and 1,3-dicarbonyl compounda.
Entry
1
␤-nitrostyrene
3a–3d
Time (h)
6
Product, Yield (%)b
dr (ratio)c
1.3:1
2a
4a, 95
2
3
4
2b
2c
2d
8
8
5
4b, 93
4c, 92
4d, 97
01:01
1.2:1
01:01
5
6
2a
2d
12
10
4e, 78
4f, 82
7
8
9
2a
2b
2c
2d
7
4g, 92
4h, 86
4i, 84
4j, 94
2.3:1
02:01
01:01
4.5:1
9
10
6
10
11
2a
2c
3
4
4k, 98
4l, 93
12
a
Conditions: ␤-nitrostyrene (1 equiv.), ␤-Ketoester (1.5 equiv.), 1d (2 mol%), DMSO (1.5 mL).
b
c
isolated yield.
determined by 1H NMR.
other common solvents like DCM and THF, we have tried to eval-
(2a–2d) and a series of ␤-ketoesters and 1,3-dicarbonyl compounds
(3a–3d) are explored with 1d. All twelve reactions in this series
undergo smoothly and afford the corresponding products in good
yields (78–98%, Table 2). Table 2 clearly shows that nature of the
substituent on the aromatic ring of nitro-styrene effect the
product conversion with the following reactivity trend,
2d > 2a > 2b > 2c. This trend follows the electron withdrawing
effect of the substituents.
uate the catalytic activity of 1e in such systems. However, there
is no improvement in the reaction yield even in DCM and THF.
It is worth mentioning that the literature reports on the Michael
addition of nitro-olefins with ␤-ketoesters show better yields with
the substituted mono-thiourea organocatalysts than its mono-urea
analogue [9]. However, a reverse pattern is observed in our case
where tripodal systems are studied.
In this series, we have first investigated the addition of ␣-
unsubstituted ␤-ketoester, ethyl acetoacetate 3a to substituted
␤-nitrostyrenes 2a–2d. 3a reacts with 2a–2d in DMSO in the pres-
ence of 2 mol% of 1d that provides the desired products 4a–4d in
high yields, as diastereomeric mixtures (entries 1–4, Table 2). Next
we have examined the Michael addition by using ␣-substituted
␤-ketoesters with substituted ␤-nitrostyrenes 2a–2d.
2.3. Michael reaction with ˇ-ketoester and 1,3-dicarbonyl
compounds
We have examined the scope and limitations of this class of the
Michael reactions using the best catalyst 1d following the above
optimized conditions. A variety of functionalized ␤-nitro-styrenes
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Table 3
The Michael addition of ␤-nitrostyrene with cyanoester and nitroestera.
Entry
␤-nitrostyrene
3e–3f
Time (h)
Product, Yield (%)b
dr (ratio)c
1
2
3
4
5
6
2b
2c
2d
2a
2b
2d
3e
3e
3e
3f
3f
3f
5
6
3
3
5
3
4m, 92
4n, 90
4o, 95
4p, 95
4q, 93
4r, 96
1:1
1:1
1:1
1:1
1:1
1:1
a
Conditions: 2a–2d (1 equiv.), 3e–3f (1.5 equiv.), 1d (2 mol%), DMSO (1.5 mL).
b
c
isolated yield.
determined by 1H NMR.
Ethyl-2-methyl acetoacetate, 3b reacts with 2a and 2d that
conditions. The Michael reaction of aryl substituted nitro olefins
2a–2d with the cyanoester 3e and the nitroester 3f undergo with
excellent yields (90–96%, entries 1–6, Table 3). Electron donating
groups such as methyl and methoxy on the aryl ring 2b and 2c
prolong the reaction time without affecting the yields (entries 1,
2, and 5, Table 3). Nitrostyrenes 2a and 2d react with 3e and 3f
very effectively and reactions are completed within 3 h with high
yields (entries 3, 4, and 6, Table 3). In all the cases we have observed
diastereomeric mixture of products (1:1) which is determined from
the integration of 1H NMR spectra.
afford the desired products 4e and 4f in moderate to good yields
(entry 5 & 6, Table 2). Next we turned our attention towards the
cyclic ketoester as one of the reaction partners. It is revealed that
ethyl 2-oxocyclopentane carboxylate 3c combines to 2a–2d which
results 4g–4j adducts in high yields, respectively, as a diastere-
omeric mixture (entries 7–10, Table 2). Notably products 4g–4j are
found as a diasteriomeric mixture, possibly due to conformational
isomers of cyclopentane moiety. By similar fashion, acetyl acetone
3d reacts with ␤-nitrostyrene 2a and 2c to afford the correspond-
ing adducts 4k and 4i in 98% and 93% yields, respectively (entry 11
& 12, Table 2).
2.5. Michael reaction with malononitrile
2.4. Reaction with cyanoester and nitroester
The Michael reaction of nitro-olefins with malononitrile in the
presence of 2 mol% 1d is performed under similar experimental
conditions. Nitro-styrenes 2a–2c has found to be excellent sub-
strates for the Michael reaction with malononitrile 3g where 2a–2c
react with 3g very efficiently and complete the reaction within
5–6 h. However, in these cases, we have observed two product
spots in the TLC instead of exclusive product formation as in previ-
Catalytic activity of 1d is further explored towards the Michael
addition of nitro-olefins with other nucleophiles like cyanoester
and nitro esters. Surprisingly, 1d also acts as an efficient cata-
lyst towards such reactions. Table 3shows the details of catalytic
activity of 1d where high conversions are observed under ambient
Scheme 2. The Michael reaction of ␤-nitrostyrene with malononitrile.
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Scheme 3. The Michael reaction of 2a and 3a in Presence of 1f, 1g and 1h.
ous cases. After purification, corresponding Michael adducts 4s–4u
as major products, and uncommon cyclic compounds 2-amino-5-
nitro-4,6-diphenylcyclohex-1-ene-1,3,3-tricarbonitriles 4v–4x as
minor products (Scheme 2) are isolated. In literature, exclusive syn-
theses of polysubstituted cyclohexene derivatives such as 4v–4x
are achieved by convenient three components reactions of aromatic
aldehyde, nitromethane and malononitrile [16]. In the present
cases, the tandem cyclization is obtained through two components
reaction of nitrostyrene and malononitrile. Inspired by the efficacy
of the catalyst 1d towards the Michael reaction of nitro-olefins with
various nucleophiles, here we aim to explore the mechanism of
catalysis for better understanding of the initial bond-breaking and
bond-making processes and to identify the controlling factors in
the catalytic steps.
In the mechanistic front, following studies have been under-
taken (i) to search the positive role of bridge-head nitrogen center
in TREN based tris-urea organocatalysts by studying two analogous
benzene platform based tris-ureas (1f, 1g) in similar experimental
conditions, (ii) by evaluating the individual experimental order of
substrates and catalyst using 1H NMR kinetic studies with respect
to excess use of one of the reaction partners and vice-versa, (iii)
by calculating the Hammett reaction constant (ꢀ) that determine
the substituent dependent electronic perturbation in the transition
state.
tris-urea, control experiments are performed by two closely related
catalysts 4-cyano phenyl and 3,5-di trifluoromethyl phenyl sub-
stituted benzene platform based tris-ureas (1f, 1g, respectively),
towards the addition reaction of 2a with 3a under similar reaction
conditions (Scheme 3). Our effort to carry out the above addition
reaction with the pentafluorophenyl substituted benzene based
analogue (1h) of 1d in DMSO is unsuccessful due to poor solu-
bility of 1h in the reaction conditions. Above Michael addition
reaction in heterogeneous reaction condition results no product
formation. Scheme 3 shows that the catalytic activities of 1f and 1g
are decreased significantly and product 4a is isolated with 25–30%
yield after 10 h of reaction. These experimental results clearly
show that the reaction could not be completed without a tertiary
nitrogen center in the catalytic scaffold. By correlating this data
with the optimized results of catalyst 1a–1d in Table 1, we do think
there might be a positive role of the bridge-head nitrogen center
along with the extensive hydrogen bonding interactions from mul-
tiple urea groups in the scaffold with the substrate towards such
addition reaction. Further, we think a dual activation model for
the Michael addition reaction (Fig. 1) might be operative where
the six urea N–H and bridge-head nitrogen of tris-urea scaffold are
involved in hydrogen bonding interactions with the nitro group of
the nitro-olefins and ketoester simultaneously. The tertiary amine
nitrogen acts as a base center to de-protonate ␣-carbon of the car-
bonyl group to form the enolate and that attacks the electrophile.
To obtain further information about the reaction mechanism, we
have carried out kinetic studies of the Michael addition reactions.
This study is attempted by monitoring the product formation (vide
1H NMR, with 1,3,5-trimethoxybenzene as the internal reference)
for the initial part of the Michael reaction. When the reaction is
carried out between 2a and a large excess of ethylacetoacetate 3a,
a straight line curve 2A is generated from the data plotted with ln
2.6. Reaction mechanism
Based on the observed reactivity with various catalysts 1a–1d,
we believe that multiple urea N–H of tris-urea scaffolds interact
with the nitro group of the nitro-olefins via extensive hydrogen
bonding interactions that enhances the electrophilicity of the nitro-
olefins. To find out the role of bridge-head nitrogen center in the
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Scheme 4.
Then we have evaluated the Hammett reaction constant (ꢀ) to
determine the extent of electronic perturbation in the transition
state of the reaction. The effect of substituent on the reaction
kinetics is often derived from the Hammett linear free energy rela-
tionship [log (kR/kH) = ꢀꢁ]. From the Hammett plot of relative rate
constant values (kR/kH) versus the substituent constant (ꢁ), one
can obtain the Hammett reaction constant ꢀ, which is the mea-
sure of the sensitivity of a reaction upon electronic perturbation
due to substituent effect. In other words, it is a measure of the rela-
tive susceptibility of a reaction to the electron-donating or electron
withdrawing effect exerted by a substituent. We have under-
taken the Hammett study to look into the influence of substituent
in nitrostyrene on the Michael addition. This is attempted by
monitoring the product formation (vide 1H-NMR, with 1,3,5-
trimethoxy benzene as the internal reference) for the initial part
of the reaction between ethylacetoacetate 3a and para-substituted
phenyl ␤-nitrostyrenes 2a–2d in the presence of 2 mol% 1d
(Scheme 4, Table 4). The data is fitted well with pseudo-first-order
rate plots, from which rate constants are evaluated.
Fig. 1. Dual activation model with 1d.
(Ct–C␣)/(C0–C␣) versus time (t). This clearly indicates that the reac-
tion is first-order with 2a. Similarly, it is found that with excess of
nitrostyrene 2a, the reaction is also maintained first-order kinetics
in 3a (Fig. 2B).
To know the order of the reaction w. r. t. the catalyst, a set of
Michael addition reactions between constant amount of reactants,
2a and 3a with varying concentrations of the catalyst 1d are carried
out in similar experimental conditions. A set of rate constants (kobs
)
that obtained from above reactions are plotted against the concen-
trations of 1d which results a straight line, indicative of first-order
kinetics w. r. t. the catalyst 1d (Fig. 2C).
Fig. 2. Kinetics studies based on the integration values obtained from 1H-NMR (1,3,5-trimethoxybenzene as the internal reference); (A) Plot of ln (Ct–C␣)/(C0–C␣) v/s time
where 2a (0.083 mmol), 1d (0.0015 mmol) and 3a (0.83 mmol); (B) Plot of ln (Ct–C␣)/(C0–C␣) v/s time where 2a (0.5 mmol), 1d (0.001 mmol) and 3a (0.05 mmol); (C) Plot of
Kobs v/s catalyst loading where 2a (0.083 mmol), 3a (0.83 mmol) and various amount of 1d (2 mol%, 4 mol%, 6 mol%, 8 mol% and 10 mol%) (See ESI for details).
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nitrostyrene electrophile and build up a negative (ı−) charge in
the transition state [17]. In this context, it is important to mention
that Myar et al. have reported the kinetics of the Michael reac-
tion of ␤-nitrostyrenes with stabilized carbanions (pottasium salts)
[18].
By correlating all control experiments and kinetic studies,
a plausible mechanism is proposed for the present tris-ureas
catalyzed Michael addition reaction (Scheme 5). Firstly, cata-
lyst 1d activates both nitro-olefins and ethylacetoacetate through
hydrogen bonding interactions simultaneously to form inter-
mediate C. Then the nucleophilic attack from enolate to nitro
olefins generates a new intermediate D. From the Hammett plot
we have found a positive ꢀ value which strongly recommends
the formation of the intermediate D with the development of
negative charge. Finally, the nitronate takes the proton from the
tertiary nitrogen of the catalyst to provide the product 4a along
with the regeneration of catalyst 1d.
Table 4
Rate constant (kR) for the reaction ethylacetoacetate and p-substituted phenyl ␤-
nitrostyrene.
Entry
R
ꢁ
104 kR (min−1
)
kR/kH
log(kR/kH)
1
2
3
4
OMe
Me
H
−0.268
−0.17
0
9.49
10.4
16.7
25.6
0.5682
0.6227
1
−0.2454
−0.2057
0
Cl
0.22
1.5329
0.1855
The Michael reaction of nitrostyrenes with the malononitrile
provides corresponding nitro alkanes 4s–4u as major products and
polysubstituted cyclohexene derivatives 4v–4x as minor products
in different reactions (Scheme 2). To support these products for-
mation, a reasonable reaction mechanism has also been proposed
in Scheme 6.
Formation of product 4s is followed by the similar mechanism
of the Michael reaction of nitrostyrene with ketoester via interme-
diate F. Simultaneously, in the reaction medium, intermolecular
nucleophilic attack of intermediate F to benzylidenemalononitrile
E produces intermediate G. We think that benzylidenemalononi-
trile E could form in-situ when both nitrostyrene and malononitrile
are present [19]. The intramolecular nucleophilic addition of newly
formed anion to one nitrile group in G produces the six-membered
intermediate H. The nitrogen anion in the intermediate H abstracts
the proton from malononitrile to provide the intermediate I and
generates the malononitrile anion which can participate for the
Fig. 3. Hammett plot of the Michael reaction of p-substituted phenyl ␤-nitrostyrene
with 3a.
The linear free energy relationship between the relative rate
constant (kR/kH) and the substituent constant (ꢁ) (Fig. 3) resulted
in a positive Hammett reaction constant ꢀ-value (0.925) indicating
a nucleophilic mechanism for the present reaction. This positive
ꢀ value suggests that the nucleophilic attack of enolate to the
Scheme 5. Proposed mechanism for the present Michael addition.
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Scheme 6. A plausible reaction mechanism for the Michael addition of nitrostyrene with malononitrile.
formation of intermediate F. The tautomerization (1,3-H shift) of
intermediate I furnishes the final product 4v.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2015.01.004.
3. Conclusions
In summary, we have demonstrated a number of TREN based
functionalized tripodal tris ureas that can act as efficient cata-
lysts towards the Michael addition of substituted ␤-nitrostyrenes
with a varieties of nucleophiles such as ketoester, 1,3-dicarbonyl,
cyanoester, nitroester under ambient condition to provide the
corresponding nitroalkanes with excellent yields. We have investi-
gated the structure-activity relationship of these catalysts in the
Michael reaction and found that pentafluorophenyl-substituted
tris-urea 1d is the best in the series. We have succeeded the
Michael reaction of ␤-nitrostyrene with malononitrile that lead
to the formation of nitroalkanes and polysubstituted cyclohexene
derivatives with 1d. Finally, control experiments and kinetic stud-
ies are investigated to propose the probable reaction mechanism.
We believe that the synthetic and mechanistic description that is
presented in this account will aid in the future development of cav-
ity/cleft scaffold based organocatalysts having superior efficiency
and selectivity. Some efforts are underway to broaden the scope of
chiral version of these organocatalysts towards different types of
Michael addition reactions.
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P. G. gratefully acknowledges the Department of Science and
Technology (DST), New Delhi, India for financial support through
Swarnajayanti Fellowship. TKG and BA acknowledge CSIR for
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