An Adverse Effect of Higher Catalyst Loading and Longer Reaction Time on Enantioselectivity in an Organocatalytic Multicomponent Reaction

Article abstract of DOI:10.1002/chem.201800278

An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones, and Meldrum's acid has been developed. A cinchona-based primary amine (1 mol %) catalyses the multicomponent reaction via the formation of the Knoevenagel product and a chiral enamine to form enantiopure δ-keto Meldrum's acids in a tandem catalytic pathway. An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides and the method is scalable on a gram quantity. DFT calculations were carried out on the proposed reaction mechanism and they were in close agreement with the experimental results.

Full text of DOI:10.1002/chem.201800278

A Journal of
Accepted Article
Title: An Adverse Effect of Higher Catalyst Loading and Longer
Reaction Time on Enantioselectivity in Organocatalytic
Multicomponent Reaction
Authors: Ramakrishna G. Bhat, Tushar M Khopade, Trimbak B. Mete,
and Jyotsna S Arora
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To be cited as: Chem. Eur. J. 10.1002/chem.201800278
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COMMUNICATION
An Adverse Effect of Higher Catalyst Loading and Longer
Reaction Time on Enantioselectivity in Organocatalytic
Multicomponent Reaction
Tushar M. Khopade, Trimbak B. Mete, Jyotsna S. Arora and Ramakrishna G. Bhat*
Abstract: Enantioselective organocatalytic multicomponent reaction
of aldehyde, ketone and Meldrum’s acid has been developed.
Cinchona based primary amine (1 mol%) catalyzes the
multicomponent reaction via the formation of Knoevenagel product
and chiral enamine to form enantiopure δ-keto Meldrum’s acids in a
tandem catalytic pathway. An adverse effect of higher catalyst
loading and longer reaction time on enantioselectivity is studied. This
mild protocol provides an easy access to enantiopure carboxylic
acids, esters and amides and the method proved to be scalable on a
gram scale. DFT calculations were carried out on the proposed
reaction mechanism and they were in close agreement with the
experimental results.
unmet challenge and this encouraged us to investigate an
appropriate catalyst system for the same.
We believed that the modularly designed organocatalyst
[
7]
assembly developed by Zhao group or cinchona based primary
[3c]
amine
catalysts
might
overcome
the
ineffective
enantiodiscrimination catalyzed by proline. In general, it is often
assumed that reactions work smoothly when aminocatalysts are
employed in the range of 10-30 mol%. However, their
counterproductive effects on the chemoselectivity and
[
8]
stereoselectivity are rarely observed and studied. To the best
of our knowledge, the counterproductive effects of high-catalyst
loading of aminocatalyst and longer reaction time in the
multicomponent reactions are not observed till date. Herein, in
this communication, we report the very first enantioselective
organocatalytic multicomponent reaction of aldehyde, ketone
and Meldrum’s acid and the study on significant effect of low-
catalyst loading on the enhancement in the enantioselectivity of
multicomponent reaction.
Aminocatalysis is one of the essential pillars in the field of
organocatalysis and is often explored in several complex
[
1-3]
multicomponent reactions.
At the dawn of asymmetric
organocatalysis, various research groups independently
discovered that the aminocatalysts possess an unprecedented
strength of catalyzing a number of diverse multicomponent
processes very efficiently and selectively to generate a broad
[
4]
At the outset, we began our investigation by treating Meldrum’s
acid 1, benzaldehyde 2a and acetone 3a with D-proline and
various other catalyst modules (Scheme 1 and see ESI for the
screening table). Initial screening with D-proline as well as
modularly designed catalysts (D-proline/D-phenylglycine and
array of diverse optically active compounds. However, to
identify a suitable catalyst and set of conditions is always crucial
for the success of enantioselective multicomponent reactions.
[
5]
List and co-worker reported an efficient proline-catalyzed three
component Knoevenagel-Michael addition reaction of Meldrum’s
acid, aldehyde and ketone (see Fig 1 A). Although this elegant
C-C bond forming reaction is highly diastereoselective, it lacks
enantioselectivity. Furthermore, in addition to the desired
reaction sequence, numerous pathways are possible which can
compete by leading to the undesired products. For example,
[7]
chiral thiourea catalyst) afforded the desired product 4a with
extremely poor enantioselectivity (4-5% ee). Hayashi-Jørgensen
catalyst and other catalyst assemblies comprising of chiral
thiourea and amino acids such as D-aspartic acid, D-glutamic
acid, D-pipecolic acid led to unsatisfactory results. After
exhaustive screening, we turned our attention towards cinchona
based primary amine bi-functional catalyst Q2. Gratifyingly,
quinine based bi-functional primary amine catalyst Q2 (10 mol%)
furnished the desired product 4a in 75% yield with very good
enantioselectivity (89 % ee) with considerably shorter reaction
time at room temperature (6 h, rt, see ESI). After establishing
the suitable catalyst system, further, the effect of solvents on
enantioselectivity was examined (see ESI). Screening of various
solvents revealed that chloroform is the best solvent for the
desired transformation. Primary amine catalyst (Q2, 10 mol%) in
chloroform at room temperature was established as optimized
reaction conditions.
[
6]
Barbas and co-worker demonstrated a very same reaction that
furnished four products when pyrrolidine was used as a catalyst
(
see Fig 1, B).
Scheme 1. Bifunctional amine catalyzed model reaction
Figure 1. Multicomponent reaction of ketones, aldehydes and Meldrum’s acid
Having optimized the reaction conditions in hand, we planned to
extend the scope of the reaction using various aldehydes and
ketones for the generality of the protocol. Initially, the reaction of
Meldrum’s acid 1, 4-methoxybenzaldehyde 2b and acetone 3a
To our surprise, this highly efficient C-C bond forming
enantioselective three component process still remained an
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under optimized reaction conditions afforded the corresponding
product 4b in 50% yield with 72% ee after 6 h. However, when
we tried to increase the yield by stirring the reaction for an
extended period of time, to our surprise, the enantioselectivity
was drastically lowered from 72% ee at 6 h to 10% ee at 48 h.
This unanticipated observation indicated the probable negative
influence of longer reaction time on the enantioselectivity. In
order to validate this finding, further, we repeated the same
reaction and recorded the enantiomeric excess of the product 4b
at different time intervals as summarized in Figure 2 (black line).
Surprisingly, we observed that the initial very good
enantioselectivity (86% ee at 1.5 h) was found to be eroding
continuously over a period of time and virtually became racemic
after 72 h (Fig. 2, black line 10 mol% Q2). However, unlike Q2
D-proline catalyzed reaction led to the racemic product in a short
period of time (1 h). Prior to unravel the root cause of
catalyst Q2 (10 mol%). Interestingly, the anticipated aldol
condensation product 6b (p-methoxybenzylidene acetone) was
not obtained. Surprisingly, 20 mol% of Meldrum’s acid 1 along
with Q2 (10 mol%) catalyzed the formation of 6b in trace amount
(see ESI eq. 2, S23). These findings unambiguously infer that
the reaction is proceeding via Knoevenagel-Michael reaction
pathway (path a).
racemization over
a period of time, it was important to
understand the possible pathways of this transformation.
Scheme 3. Possible routes for the racemization
Further, in the quest for finding the reason for the erosion in
enantioselectivity over a period of time we conceived two
probable hypotheses
hypotheses, enantiopure compound 4b may be undergoing
racemizing equilibrating retro-Michael-Michael addition.
A and B (Scheme 3). In both the
However, based on the earlier NMR experiments, hypothesis A
seems to be unlikely as 4-methoxybenzylidene Meldrum’s acid
5
b
disappeared over
a
period of time. Instead, 4-
Scheme 2. Possible pathways for the product 4b
methoxybenzylidene acetone 6b formed over a period of time
via the racemizing equilibrating retro-Michael-Michael addition
starting from enantiopure 4b. Further, in order to validate the
possible reversible retro-Michael/Michael addition reaction
We firmly believed that three-component reaction of 1, 2b and
3
a
can proceed via either Knoevenagel-Michael reaction
pathway (path a) or Aldol-Michael reaction pathway (path b)
Scheme 2). In order to investigate the most plausible pathway,
(
Hypothesis B), we carried out a cross-over experiment of
(
1
enantiopure product 4b and benzylidene acetone 6a in the
presence of 10 mol% of catalyst Q2 in chloroform (18 h, Scheme
4
we carried out the time-dependent H NMR experiments of the
reaction mixture (see ESI for the stacked spectrum). It was very
interesting to observe that an intense peak (s, 8.32 ppm)
corresponding to alkylidene Meldrum’s acid 5b appeared
immediately within 10 minutes. This peak disappeared over a
period of time, while the characteristic peak (dd, 3.01 ppm)
corresponding to the product 4b intensified gradually over a
A, see ESI). The formation of 4-methoxybenzylidene acetone
6b and product 4a unambiguously supported the hypothesis B
for the reversible retro-Michael/Michael addition pathway. This
clearly gives an insight that compound 4b undergoes an
elimination process to afford Meldrum’s acid
methoxybenzylidene acetone 6b over period of time.
Interestingly, longer reaction time also resulted in spiro
compound 6b’ (4+2 cycloaddition of 5b and 6b, 35% yield)
along with racemic 4b (see Scheme 4 B) and this finding further
1 and 4-
1
a
period of time (10 min - 8 h). Likewise, the time-dependent H
NMR experiments of the reaction mixture of 4a gave a similar
pattern of results. However, interestingly we also noticed that
[
6]
initially
absent
or
insignificant
characteristic
peaks
[
9]
supported the hypothesis B. This unexpected finding led us to
believe that possibly the higher concentration of the catalyst Q2
may be the key factor (acting as a base) for the retro-
Michael/Michael addition thus causing erosion of enantiopurity.
In order to overcome this problem, we planned to add acidic
additive such as trifluoroacetic acid (20 mol% TFA, pKa 0.23)
along with the catalyst to reduce the undesirable base effect of
the catalyst. However, interestingly we observed that the initial
excellent enantioselectivity eroded over the time (see red line,
corresponding to benzylidene acetone 6a (d, 6.72 ppm) and 4-
methoxybenzylidene acetone 6b (d, 6.61 ppm) slowly appeared
along with the product peak (see ESI). Based on this interesting
observation we surmised that either the initially formed products
4a/4b (via Knoevenagel-Michael pathway, path a) slowly
underwent elimination of Meldrum’s acid 1 thus leading to 6a/6b
or aldol condensation competed meekly with the path a. In order
to validate further, we carried out the reaction of 4-
methoxybenzaldehyde 2b and acetone 3a in the presence of
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COMMUNICATION
Fig 2). Nevertheless, erosion of enantioselectivity was found to
be relatively slower than in the presence of sole catalyst Q2 (see
black line, Fig 2).
Based on[ our experimental observations and literature
8c,8d]
precedents
we propose that under higher catalyst loading
the initially formed enantiopure product 4b, slowly undergoes
equilibrating retro Michael-Michael addition process thus leading
to racemization (Step 2, Scheme 2). The more favourable
increase in entropy could be the driving force for the irreversible
racemization and would reach the completion[10]when
thermodynamic equilibrium is achieved (ee ≈ 0 %).
This
assumption was further revalidated by the reaction of Meldrum’s
acid 1 and 4-methoxy benzylidene acetone 6b in presence of 10
[11]
mol% of Q2 and 20 mol% TFA (see Scheme 4C).
It is
interesting to note that initially formed enatiomerically pure
product (+)-4b (94% ee) was susceptible to the erosion of
enantiopurity over a period of time (30 h, 72% ee). Further,
treatment of isolated enantiopure product (+)-4b with 10 mol% of
Q2 over a period of time (72 h) resulted in almost racemic (±)-
4b. On the other hand, under the lower catalytic loading (1 mol%
Q2 and 2 mol% TFA) due to the slower reaction rate Michael
addition favours over racemizing retro-Michael/Michael pathway
(
Step 2, Scheme 2) resulting in the enantiomerically pure
product (+)-4b. Further, the reaction of 4-methoxybenzylidene
Meldrum’s acid 5b with acetone 3a in the presence of 10 mol%
of Q2 and 20 mol% TFA afforded the enantiopure desired
product (+)-4b in 2 h. However, prolonging this reaction (40 h)
resulted in erosion in enantioselectivity leading to 4b (72% ee)
along with small amount of Meldrum’s acid 1 and 4-methoxy
benzylidene acetone 6b (see Scheme 4D). Based on the above
experiments and especially from scheme 4C & 4D, we can
propose that enantiopure (+)-4b slowly undergoes retro-Michael-
Michael reaction equilibrium to give racemic 4b over the period
of time.
(
a-d)
Table 1. Substrate scope
Scheme 4. Crossover experiment to validate hypothesis B
This led us to believe that reducing the catalyst loading instead
of compromising the reaction time would be more beneficial. It
was gratifying to note that the reaction of 1, 2b and 3a in
presence of 1 mol% of Q2 in chloroform (24 h) afforded the
corresponding product 4b in excellent enantioselectivity (93%
ee), however, over a period of time very slow erosion of
enantioselectivity was inevitable (see green line, Fig. 2).
Gratifyingly, the addition of 2 mol% of TFA along with Q2 (1
mol%) found to be highly effective and the enantiopurity of 4b
remained almost unchanged even after prolonged reaction time
72 h (see blue line, Fig. 2).
a
Optimized Reaction Conditions: Meldrum’s acid 1 (1 equiv.), aldehyde 2 (1.05
equiv.), ketone 3 (5 equiv.) catalyst Q2 (1 mol%), TFA as an additive (2 mol%),
b
Figure 2. Effect of catalyst loading and time on enantioselectivity of 4b
in chloroform at rt; isolated yield after purification by column chromatography
given in parenthesis; dr was calculated based H NMR; ee was determined
c
1
d
by HPLC using chiral column.
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Based on the available experimental evidences we can surmise
the most probable mechanistic pathway for the erosion in the
enantioselectivity. After re-establishing the optimum catalytic
loading (1 mol% Q2 and 2 mol% TFA) we explored the
generality of the reaction by using various aldehydes and
ketones. The aromatic aldehydes, both electron-rich and -
deficient were found to be compatible under the optimized
reaction conditions by affording the corresponding products (4a-
The molecular structure of compounds 4a and 4q (relative
configuration) were established using single crystal X-ray
[
13]
diffraction analysis (Table 1).
The proposed mechanism was computationally studied using
the density functional theoretical calculations (see ESI for results
and details). Initially protonated primary amine Q2 catalyzes
Knoevenagel condensation via iminium ion intermediate (I) and
intermediate (II) to generate a heterodiene (5a). In the second
step catalyst Q2 forms chiral enamine (S-ENM) with acetone 3a
that further reacts with the heterodiene (5a) via [4+2]-hetero-
4j, Table 1) in good yields with excellent enantioselectivity up to
[
14]
99% ee. However, we observed that aromatic aldehydes such
Diels-Alder cycloaddition pathway. The transition states (TS’s)
for the [4+2] cycloaddition step could follow the enamine/5a si
facial attack or enamine/5a re facial attack, thus resulting in
TS1-S and TS1-R TS’s, respectively (Fig. 3). Of these two TS’s
formed, TS1-S is 7.53 kcal/mol more stable than the TS1-R
resulting in product 4a (R configutation) with high
as 4-methoxy benzaldehyde and 3,4-dimethoxy benzaldehyde
[9]
reacted relatively slow (36 h) affording 4b and 4i.
Heteroaromatic aldehyde such as furfural, worked well under the
reaction conditions and afforded the corresponding 4k in good
yield with relatively lower enantioselectivity (77% ee). In order to
have a wider scope, further, we examined the feasibility of
reaction on the aliphatic aldehydes. It was found that even the
enolizable aldehydes were well tolerated in the presence of
primary amine catalyst Q2, affording the products (4l and 4m) in
good yields with moderate enantioselectivity (60-73% ee). The
scope of the reaction was extended further towards substituted
Michael donors such as cyclohexanone, cyclopentanone and 3-
pentanone with various aldehydes. In all the cases
corresponding products (4n-4s) were obtained as single
diastereomers with moderate to excellent enantioselectivity (up
to 94% ee). Notably, this protocol tolerated a wide variety of
aldehydes under very mild reaction conditions. The strength and
practicality of this protocol was also demonstrated on a gram
scale synthesis of product 4a (74% yield) without loss of
enantioselectivity (94% ee) under optimized reaction conditions.
stereoselectivity (Theoretical ee
= 98% is in very good
agreement with the experimental ee = 95% see ESI).
In conclusion, we demonstrated highly enantioselective
organocatalytic multicomponent reaction of aldehyde, ketone
and Meldrum’s acid for the first time since its discovery. We
carried out a systematic study on the adverse effect of higher
catalytic loading and longer reaction time on the outcome of
enantioselectivity. In order to understand the mechanism of
racemization in depth further detailed investigation is needed.
The protocol worked efficiently under very low catalyst loading (1
mol%) and proved to be scalable. The protocol is practical as it
gives a quick access to very useful precursors and intermediates
such as enantiopure δ-keto esters, carboxylic acids and amides.
This mild and useful reaction may find a wider application in
future.
In order to show the wider applicability of this protocol we Acknowledgements
demonstrated enantiopure synthesis of some of the important
precursors of many useful molecules such as carboxylic acid,
ester and amide starting from 4a (see ESI, page S25). The
synthesis of ester also helped to identify the absolute
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India
for the generous research grant. T. M. K. and T. B. M. thank
CSIR for the fellowship. J. S. A. thanks DST for the fellowship.
Authors thank IISER Pune for the financial assistance. Authors
thank Dr. Rajesh G. Gonnade, NCL, Pune and Mr. Amod Desai,
IISER Pune for the useful discussions and kind help in obtaining
crystal data.
[
12]
configuration of 4a (see ESI).
Based on these findings the
absolute configuration of 4a was assigned as ‘R’.
Keywords: Multicomponent reaction
•
Organocatalysis
•
Adverse effect
cycloaddition
•
Enantioselectivity
• Hetero-Diels-Alder
[
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a
Transition state structures for the addition of enamine S-ENM to 5a (both si
[
9] We observed that reactions were neat and afforded compounds 4a, 4c
h, 4j-4s with a negligible amount of corresponding spiro compounds.
However, 4-methoxy benzaldehyde and 3,4-dimethoxy benzaldehyde
b
and re face); selected bond distances are in Å; relative free energies are
4
-
1
given in parenthesis (kcal·mol ); M06-2X/6-311++G(d,p)/SMD//M06-2X/6-
1G(d). Most of the H-atoms have been omitted for the sake of clarity.
3
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afforded corresponding compounds 4b, 4i along with modest amount
(30-35%) of corresponding spiro compounds.
[
[
[
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These numbers contain all crystallographic details of this publication and
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05.
available
free
of
charge
at
[
9
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Chemistry - A European Journal
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COMMUNICATION
Layout 1:
COMMUNICATION
An adverse effect of higher catalyst
loading and longer reaction time on
Tushar M. Khopade, Trimbak B. Mete,
Jyotsna S. Arora and Ramakrishna G.
Bhat*
enantioselectivity
Enantioselective
is
studied.
organocatalytic
Page No. – Page No.
multicomponent reaction of aldehyde,
ketone and Meldrum’s acid is developed
An Adverse Effect of Higher Catalyst
Loading and Longer Reaction Time
on Enantioselectivity in
Organocatalytic Multicomponent
Reaction
(up to 99% ee). This mild protocol
provides an easy access to enantiopure
carboxylic acids, esters and amides with
very high enantioselectivities and the
method proved to be scalable.
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