NMR and DFT Insight into the Synergistic Role of Bovine Serum Albumin–Ionic Liquid for Multicomponent Cascade Aldol/Knoevenagel–thia-Michael/Michael Reactions in One Pot

Article abstract of DOI:10.1002/cctc.201600637

The synergistic combination of two catalysts is an emerging strategy towards the formation of unprecedented complex molecules, and herein bovine serum albumin (BSA) and the neutral ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) are used together for the first time towards multiple C?C and C?S bond-formation reactions in one pot under metal-free, acid-free, and base-free conditions by merging two classical named reactions, that is, aldol condensation (AC) and thia-Michael addition (TMA) for the cascade chemoselective generation of β-aryl-β-sulfido carbonyl compounds from aliphatic ketones, aromatic aldehydes, and thiols. NMR spectroscopy and DFT calculations studies provided insight into the synergism, progress, and mechanism of the reaction, and control experiments highlighted that the single catalysts (BSA or IL) alone did not allow even the first AC step to proceed. Moreover this synergistic BSA–[bmim]Br catalytic system offers the step-economical synthesis of the anticoagulant warfarin through sequential aldol–Michael addition reactions and potent pyridine analogues through a Knoevenagel–Michael route. Besides, the recyclability of the catalytic system (up to 5 times) with the generation of water as a byproduct makes our one-pot protocol more economically efficient and synthetically attractive than traditional methods.

Full text of DOI:10.1002/cctc.201600637

DOI: 10.1002/cctc.201600637
Communications
NMR and DFT Insight into the Synergistic Role of Bovine
Serum Albumin–Ionic Liquid for Multicomponent Cascade
Aldol/Knoevenagel–thia-Michael/Michael Reactions in One
Pot
Yogesh Thopate,[a, b] Richa Singh,[a] Arun K. Sinha,*[a, b] Vikash Kumar,[c] and
Mohammad Imran Siddiqi[c]
The synergistic combination of two catalysts is an emerging
strategy towards the formation of unprecedented complex
molecules, and herein bovine serum albumin (BSA) and the
neutral ionic liquid 1-butyl-3-methylimidazolium bromide
([bmim]Br) are used together for the first time towards multi-
ple CÀC and CÀS bond-formation reactions in one pot under
metal-free, acid-free, and base-free conditions by merging two
classical named reactions, that is, aldol condensation (AC) and
thia-Michael addition (TMA) for the cascade chemoselective
generation of b-aryl-b-sulfido carbonyl compounds from ali-
phatic ketones, aromatic aldehydes, and thiols. NMR spectros-
copy and DFT calculations studies provided insight into the
synergism, progress, and mechanism of the reaction, and con-
trol experiments highlighted that the single catalysts (BSA or
IL) alone did not allow even the first AC step to proceed. More-
over this synergistic BSA–[bmim]Br catalytic system offers the
step-economical synthesis of the anticoagulant warfarin
through sequential aldol–Michael addition reactions and
potent pyridine analogues through a Knoevenagel–Michael
route. Besides, the recyclability of the catalytic system (up to
5 times) with the generation of water as a byproduct makes
our one-pot protocol more economically efficient and syntheti-
cally attractive than traditional methods.
chemistry and are generally accomplished by using
multicomponent reactions (MCRs),[1] which have been used for
the preparation of structurally diverse molecules, including
druglike compounds.[1b–d] As a result, more efficient multicom-
ponent cascade[2] reactions have emerged as significant tools
in the modern era of organic synthesis. Over the decade,
a large number of catalytic systems,[3] including transition met-
als,[3a] organocatalysts,[3b] and biocatalysts,[3c–e] have been ex-
plored for MCRs.[1–3] In this context, biocatalyzed MCRs are be-
coming more appealing because of inherent environmental
advantages along with the requirement for milder reaction
conditions without the generation of side products. Among
various biocatalysts, bovine serum albumin[4] (BSA or “Frac-
tion V”), a non-enzymatic transporter protein, occupies the
shelf of chemists when it comes to choosing a biocatalyst,
owing to its strong affinity to bind organic molecules by rever-
sible noncovalent complexation in its hydrophobic pockets,[4e]
whereby the organic molecules can then undergo numerous
organic transformations[4a–c] to provide products in high yields
with excellent stereoselectivity; furthermore, BSA is compatible
with green solvents[5] such as water[5b] and ionic liquids (ILs).[5c]
In many instances, the preferential use of ILs[6] over organic
solvents as reaction media for biocatalysis is due to their high
ability of dissolving a wide variety of materials besides exhibit-
ing outstanding catalytic properties through appropriate modi-
fication of the cations and anions.
The creation of multiple carbon–carbon or carbon–heteroatom
bonds in one pot provides operational simplicity, cost
effectiveness, higher yields, and energy efficiency. These bene-
fits are broadly encompassed under the periphery of green
Recently, the combination of two or more catalysts belong-
ing to pole-opposite domains has emerged as a promising
strategy owing to its synergistic cooperative effect,[7] which en-
ables access to unprecedented complex molecules otherwise
not obtainable by the use of one catalyst alone. This coopera-
tive catalysis will, in principle, not only aid to accelerate the re-
action rate and reduce the loading of expensive catalysts, but
it might also improve the efficiency of MCRs. In this context,
two privileged catalysts that is, BSA[4] and an IL[6] have been
channelized individually for many chemical/biochemical trans-
formations, including a contribution from our group;[8] howev-
er, the unification of these two catalysts for MCRs has yet not
caught the attention of chemists, although reports disclosing
molecular interaction of BSA with ILs are present in the litera-
ture.[9] Hence, the synergism of BSA with an IL was visualized
as a greener approach towards the multicomponent cascade
chemoselective synthesis of b-aryl-b-sulfido carbonyl com-
pounds (Scheme 1) by combining two known privileged
[a] Y. Thopate, R. Singh, Dr. A. K. Sinha
Medicinal and Process Chemistry Division
CSIR-Central Drug Research Institute
Sector 10, Jankipuram Extension
Sitapur Road, Lucknow 226031 (India)
E-mail: aksinha08@rediffmail.com
[b] Y. Thopate, Dr. A. K. Sinha
Academy of Scientific and Innovative Research
New Delhi110001(India)
[c] V. Kumar, Dr. M. I. Siddiqi
Molecular and Structural Biology Division
CSIR-Central Drug Research Institute
Sitapur Road, Lucknow226031 (India)
Supporting Information for this article can be found under http://
dx.doi.org/10.1002/cctc.201600637.
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Scheme 1. Concept of a synergistic BSA–[bmim]Br-catalyzed AC–TMA cascade reaction.
named reactions, that is, aldol condensation (AC) and thia-Mi-
chael addition (TMA) in one pot.
calculations (DFT) revealed for the first time that the “synergis-
tic effect” of BSA with 1-butyl-3-methylimidazolium bromide
([bmim]Br) promoted the multicomponent chemoselective syn-
thesis of b-aryl-b-sulfido carbonyl compounds (construction of
CÀC and CÀS bonds) without the formation of undesired bi-
sadducts. Further, this catalytic system was exploited for the
synthesis of the drug warfarin[14] (construction of two CÀC
bonds) from acetone, benzaldehyde, and 4-hydroxycoumarin
through sequential aldol–Michael addition reactions and the
synthesis of potent pyridine analogues[15] (construction of two
CÀC bonds, one CÀS bond, and one CÀN bond) from aromatic
aldehydes, thiophenol, and malononitrile through Knoevena-
gel–Michael reactions in one pot.
b-Aryl-b-sulfido carbonyl compounds[10] are synthetically im-
portant precursors for the generation of b-acylvinyl cations,[10a]
thiochromenes,[10c] the antiasthma agent montelukast,[10d–e] and
the calcium antagonist dilitazem[10f] (Figure 1); as a result,
there has been sustained interest in the synthesis of b-aryl-b-
sulfido carbonyl compounds by the AC and TMA reactions.
The traditional strategy for the synthesis of b-aryl-b-sulfido
carbonyl compound involves two steps with the use of a wide
range of catalysts[11] individually for the AC[11a–c] and TMA[11d–g]
reactions. However, these catalytic systems are flanked with
limitations, namely, the use of metal Lewis acids, long reaction
times, side-product generation, cumbersome workup and pu-
rification steps, and the catalysts could not be recycled. These
drawbacks call for the exploration of new protocols in which
the first step can be incorporated with a second step to give
the AC–TMA product in one pot. In this context, there are
a few reports[12] on sequential one-pot AC–TMA product forma-
tion for which Amberlyst[12a] and base[12b] were used, whereas
there is only one successful report for tandem AC–TMA trans-
Consequently, the AC–TMA cascade was performed by stir-
ring a mixture of p-anisaldehyde (1a, 0.12 mmol), acetone (2a,
0.5 mL), and thiophenol (3a, 1 equiv.) in the presence of BSA
(50 mg) and [bmim]Br (0.5 mL) (Table 1) at 608C for 6 h in one
pot (see the Supporting Information). HPLC analysis of the
crude mixture (see the Supporting Information) revealed the
formation of desired product 4a, albeit in 18% yield (Table 1,
entry 1) along with the formation of a diaryl disulfide in 68%
yield and unreacted intermediate enone in 11% yield. The
above results led us to reason that thiophenol (ÀSH) itself had
undergone self-oxidative coupling into the disulfide (SÀS
bond) in the presence of the neutral ionic liquid[6e] and BSA,[4c]
which thus resulted in a decreased concentration of thiophe-
nol available for thia-Michael addition; thus the yield of 4a
was lowered to 18%. To this end, we thought to perform the
above AC–TMA reaction under a nitrogen atmosphere, and to
our surprise, the yield of 4a increased to 58% (product isolat-
ed in 57% yield; Table 1, entry 2) on the basis of HPLC analysis
(see the Supporting Information). Further, the amounts of thio-
phenol (Table 1, entries 3 and 4) and BSA (Table 1, entries 5
[13]
formations dealing with ZrCl4 in which both steps were per-
formed in one pot. Despite considerable efforts, a one-pot che-
moselective AC–TMA cascade reaction starting from aliphatic
ketones (over aromatic ketones) is difficult, owing to the pres-
ence of two enolizable[13] a-hydrogen atoms in acetone, which
often leads to the formation of mixtures of monoaldol and bi-
saldol adducts (undesired product); thus, column purification
is necessary before the TMA reaction can be performed
(Scheme 1).
Herein, we report a mild, economical, one-pot, and green
protocol for an AC–TMA cascade reaction, and a combination
of experimental (1H NMR spectroscopy[6e,8a]) and theoretical
Figure 1. Biologically active scaffolds containing CÀC and CÀS bonds.
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AC–TMA reaction sequence. Surprisingly, the use of 10 mol%
of TBAB led to an increase in the yield of 4a to 93% (Table 2,
entry 2), and conjointly, the reaction time was decreased from
6 h (Table 1, entry 3) to 4 h (Table 2, entry 2). Notably, PTCs
containing an anion other than bromide such as iodide and
fluoride (i.e., TBAI and TBAF) (Table 2, entries 4 and 5) did not
allow the formation of 4a, whereas if the cationic part of the
bromide-containing PTC was changed to cetylammonium (i.e.,
CTAB), desired 4a was obtained in 90% yield (Table 2, entry 6).
Notably, the crucial role of TBAB in accelerating our AC–TMA
reactions was also corroborated by the literature, in which the
use of TBAB as a catalyst enhanced the aldol condensation.[17]
With the optimized reaction conditions in hand, the scope
and generality of the AC–TMA cascade reaction were investi-
gated by using different aromatic aldehydes, aliphatic ketones,
and thiols, the results of which are summarized in Table 3. The
electronic effects of the substituents on the arenethiol (Table 3,
see products 4a–e) or aryl aldehyde (Table 3, see products 4i–
n) did not have any clear impact on the yield. Similarly, aliphat-
ic thiols (Table 3, see products 4 f–h), a heteroaromatic alde-
hyde (Table 3, see product 4o), and hydroxylated aromatic al-
dehydes without a protection–deprotection strategy (Table 3,
see products 4p–q) provided the corresponding AC–TMA
products in moderate to good yields. Additionally, an allylated
aromatic aldehyde successfully afforded the desired product
(Table 3, see product 4r) without interference of hydrothiola-
tion[8a] of the allyl side chain by thiophenol. Aliphatic ketones
other than acetone, namely, 2-hexanone and cyclopropyl
methyl ketone (Table 3, see products 4s and 4t), provided the
desired products after a longer reaction time[5c] of 48 h
through sequential AC–TMA reactions (see the Supporting In-
formation). Unfortunately, no thia-Michael product was ob-
tained with heterocyclic thiols, as 2-mercaptopyridine (Table 3,
see product 4u) may deprotonate the C2 hydrogen atom of
the imidazolium cation of [bmim]Br to generate a reactive Ar-
duengo-type carbene.[18] Interestingly, the neutral biocatalytic
Table 1. Effect of varying the amounts of thiophenol and BSA and the
effect of temperature on the AC–TMA cascade reaction.[a]
Entry
BSA
PhSH
Yield of 4a[b]
[mg]
[equiv.]
[%]
1
2
3
4
5
6
7[d]
8
9[e]
50
50
50
50
75
100
50
–
1
1
1.5
2
1.5
1.5
1.5
1.5
1.5
18[c]
57 (58)[c]
63 (65)[c]
60
60
57
37
n.d.
n.d.
50
[a] Reaction conditions: 1a (0.12 mmol), 2a (0.5 mL), 3a (1.0–2.0 equiv.).
Reactions for entries 2–8 were performed under a N2 atmosphere; n.d.=
not detected. [b] Yield of isolated product. [c] Yield determined by HPLC.
[d] Reaction was performed at 808C. [e] Reaction was performed in the
absence of [bmim]Br.
and 6) were varied as was the temperature (Table 1, entry 7).
Among the screened reaction conditions, the use of 1.5 equiv-
alents of thiophenol (3a) proved to be marginally efficacious,
as it improved the yield of 4a to 63% (isolated product) in the
presence of 50 mg of BSA and 0.5 mL of [bmim]Br at 608C
(Table 1, entry 3) under a nitrogen atmosphere, whereas an in-
crease in the reaction temperature (808C) reduced the yield of
4a (Table 1, entry 7). In control experiments for which the
AC–TMA reaction was conducted with either
system offered chemoselective formation of
a series of
[bmim]Br (Table 1, entry 8) or BSA (Table 1, entry 9)
Table 2. Screening of different phase-transfer catalysts (PTCs) for the AC–TMA cascade
as the catalyst, the formation of 4a was not ob-
served, which clearly indicated the role of a BSA–
[bmim]Br combination as an activator for the AC–
TMA cascade (see the Supporting Information). Fur-
ther, replacing BSA with other albumins (i.e., sheep
serum, pig serum, rabbit serum, etc.) also did not im-
prove the yield of 4a (see the Supporting Informa-
tion). Next, the replacement of [bmim]Br with acidic,
basic, or even other neutral ILs provided 4a in lower
yields, wherein the type of anion (Br vs. Cl) and alkyl
chain of the cation in the IL also played decisive
roles in the AC–TMA reactions (see the Supporting
Information).
reaction.[a]
Entry
PTC
Amount
[mol%]
Yield of 4a[b]
[%]
1
2
3
4
5
6
TBAB
TBAB
TBAB
TBAI
TBAF
CTAB
5
10
15
10
10
10
85
93
89
n.d.
n.d.
90
However, determined to improve the yield of 4a
and further encouraged by our recent report in
which a phase-transfer catalyst (PTC)[16] improved the
yield of a desired aldol–Suzuki adduct, we decided
to use tetrabutylammonium bromide (TBAB) in our
[a] Reaction conditions: 1a (0.12 mmol), 2a (0.5 mL), 3a (1.5 equiv.), BSA (50 mg),
[bmim]Br (0.5 mL), PTC, 608C, 4 h, N2 atmosphere; n.d.=not detected. [b] Yield of iso-
lated product.
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The present neutral BSA–[bmim]Br catalytic system also al-
lowed the bridging of two molecules of an enone with a bi-
functional alkane dithiol towards the exclusive formation of an
AC–double-TMA product (Scheme 2) under the optimized,
one-pot conditions; alkane dithiols[19] are known to be suscep-
tible to dithioacetal formation with aryl aldehydes in acidic
media (see the Supporting Information).
Table 3. Substrate scope of aromatic aldehydes, ketones, and thiols for
the BSA–[bmim]Br-catalyzed AC–TMA cascade reaction.[a]
Similarly, the BSA–[bmim]Br catalytic system was exploited
to catalyze a MCR between 4-hydroxycoumarin, a carbon nu-
cleophile, and an aryl aldehyde and acetone to generate the
anticoagulant drug warfarin[14] (8a) and analogue 8b in good
yields through sequential aldol–Michael reactions (Scheme 3)
in one pot. On the other side, it was previously reported that
BSA alone is unable[14] to catalyze the synthesis of warfarin,
which thus strengthens the importance of the synergism of
the BSA–[bmim]Br catalyst.
Further venturing into the robustness of our developed pro-
tocol, we investigated the reaction of malononitrile with an ar-
omatic aldehyde and thiophenol (Scheme 4) in the same cata-
lytic system. However, the expected product was not obtained;
rather, the NMR spectroscopy and mass spectrometry data re-
vealed the formation of polysubstituted pyridine derivatives
10a and 10b possessing a “privileged medicinal scaffold”
through a Knoevenagel–Michael reaction route in one pot in-
stead of Knoevenagel–thia Michael reactions (see the Support-
ing Information).
To properly address the synergism between BSA and
[bmim]Br towards the formation of the AC–TMA products,
NMR (1H and 13C) spectroscopy was used to visualize the in situ
generation of the intermediate and to monitor the progress of
the reaction to provide deeper insight into the mechanism[6e,8a]
of the reaction pathway. Towards this goal, however, a problem
arose, as BSA is practically insoluble in most organic solvents,
whereas it is soluble in D2O, in which the acidic C2 proton of
[bmim]Br might undergo deuterium exchange with D2O. After
some trials, we were able to establish synergistic interaction
between [bmim]Br and BSA in [D6]acetone, for which the C2
proton (resonance a) of the imidazolium cation of [bmim]Br
[a] Reaction conditions: 1 (0.12 mmol), 2 (0.5 mL), 3 (1.5 equiv.), [bmim]Br
(0.5 mL), 608C, 4 h; n.d.=not detected. [b] Yield of isolated product.
[c] Sequential AC (48 h)–TMA (4 h) addition in one pot.
1
AC–TMA products preferentially with aliphatic ketones (Table 3,
see products 4a–t) over an aromatic ketone (Table 3, see prod-
uct 4v).
shifted from d=10.209 to 10.067 ppm in the 500 MHz H NMR
spectrum (Figure 2). Notably, this first observation into
the synergistic interaction of BSA with [bmim]Br by 1H NMR
Scheme 2. Synthesis of dithia-Michael adduct by AC–double-TMA reaction.
Scheme 3. Synthesis of warfarin derivatives by sequential aldol–Michael reactions (double CÀC bond formation in one pot).
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Scheme 4. Synthesis of pyridine analogues by using BSA–[bmim]Br.
Figure 2. 1H NMR spectra of i) [bmim]Br and ii) interaction between BSA and [bmim]Br at 500 MHz.
spectroscopy was concordant with a literature report,[9a] in
which a UV study showed molecular interaction of BSA with an
IL. Encouraged by the above NMR spectroscopy observations,
interactions of the individual reactants [i.e., p-anisaldehyde
(1a), acetone (2a), and thiophenol (3a)] and the intermediate
enone (standard) with the catalytic system were recorded by
using NMR spectroscopy (see the Supporting Information),
which provided insight into the activating effect of the catalyt-
ic system[20] on the reactants and intermediate and helped in
predicting a plausible mechanism for the reaction.
(TMA reaction), which thus resulted in the formation of the
characteristic resonance d of AC–TMA product 4a at
d=4.782 ppm (Figure 3viii) as compared with standard 4a
(Figure 3ix). The above shifts could be taken as evidence for
synergism of the catalyst and its interaction with the reactants
and intermediate. Further, it was realized that the rate of the
AC–TMA reaction sequence decreased upon using BSA with
a deuterated IL[6h] (C2 proton of the IL), which further empha-
sized the synergism of the BSA–IL catalytic system. On the
basis of the above experiments and NMR spectroscopy obser-
vations, a plausible mechanism to account for the present mul-
ticomponent AC–TMA cascade reaction is proposed in
Figure 4.
We next proceeded to study the course of the one-pot AC–
TMA reaction cascade among 1a, 2a, and 3a in BSA–[bmim]Br,
for which in situ progress of the reaction was monitored at dif-
1
ferent time intervals (0 to 6 h) by utilizing H NMR spectrosco-
To understand the synergism of the BSA–IL system better
and to validate the dual activating role of the catalytic system
for the AC–TMA cascade reaction as observed by NMR spec-
troscopy, we planned to perform DFT[21] studies. However, no
reference, as per our knowledge, on DFT studies of BSA with
other molecule were found in the literature owing to the large
number of atoms associated with BSA itself; thus, the DFT
calculations became too complex, although DFT calculations of
lysine and other amino acids in the form of the active site of
BSA were successfully studied. Therefore, the lysine residue of
BSA, which is known to interact with the IL,[9a] was chosen to
py (Figure 3). Interestingly, the C2 proton (resonance a) (Fig-
ure 3,iv) of BSA–[bmim]Br shifted progressively from
d=10.067 to 10.049, 9.996, 9.958, and 10.005 ppm at time in-
tervals of t=0, 2, 4, and 6 h, respectively (Figure 3v–viii), which
clearly indicated the involvement of the C2 proton of [bmim]Br
of the catalytic system in the reaction, whereas the aldehyde
proton (resonance b) (d=9.937 ppm) (Figure 3v) of 1a
disappeared with time with simultaneous appearance/
disappearance of the intermediate enone (resonance c)
(d=6.658–6.690 ppm) (Figure 3vi) after its reaction with thiol
Figure 3. Progress of the AC–TMA cascade reaction at different time intervals.
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tive enol form III stabilized by the bromide anion of the cata-
lytic system through H-bonding, which in fact prevents tauto-
merization of III back into II. Activated enol form III reacts with
anisaldehyde (1a) to generate aldol product IV, which is fur-
ther converted into enone V with release of water as a byprod-
uct under the influence of the bromide anion[24] of the syner-
gistic BSA–IL system. The released water along with the bro-
mide anion of the catalytic system help to increase the nucleo-
philicity of thiophenol (3a) (also shown by a control experi-
ment, see the Supporting Information), which undergoes thia-
Michael addition with enone V to generate intermediate VI;
this intermediate tautomerizes into stable keto form VII, which
leads to the formation of 4a. Interestingly, DFT studies showed
that the bromide anion of the IL rather than the C2 proton (on
the basis of NMR spectroscopy) of the IL is directly involved in
catalyzing the AC–TMA cascade reaction.
Figure 4. Proposed mechanism for the AC–TMA cascade reaction (see the
Supporting Information).
performed the DFT studies.[22] The DFT calculations indicated
synergism of lysine with the IL through the bromide anion of
the IL, and thus, this complex behaves as a contact-ion pair[23]
(Figure 5i). Further, the surface diagram of this complex depicts
a cavity in which all the catalytic activity occurs (Figure 5ii).
The DFT study (Figure 6) demonstrated that the carbonyl
oxygen atom of acetone (2a) initially interacts with catalytic
system I to generate II, which then tautomerizes into the reac-
From an economical point, recyclability of the catalytic
system is an important factor, and we hence turned our
attention towards the reusability of BSA–IL for the AC–TMA
cascade reaction for the synthesis of 4a. The catalytic system
retained its high reactivity over five cycles without any appreci-
able loss in yield of 4a (see the Supporting Information).
In summary, we developed a metal-free, base-free, and acid-
free protocol for which, for the first time, NMR spectroscopy
Figure 5. Synergism of lysine with IL established by i) DFT and ii) surface diagram of the synergistic catalytic system.
Figure 6. Computational prediction of the reaction mechanism of the AC–TMA cascade reaction by using Gaussian 09. Energy in a.u.
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and DFT calculations were used to prove that the synergism of
the bovine serum albumin (BSA)/1-butyl-3-methylimidazolium
bromide ([bmim]Br) system promoted the multicomponent
aldol condensation/thia-Michael addition (AC–TMA) cascade re-
action through the CÀC and CÀS bonds. Further, the same cat-
alytic system was explored for the synthesis of the drug war-
farin through the formation of two CÀC bonds and the synthe-
sis of bioactive pyridine analogues through the formation of
two CÀC bonds, one CÀS bond, and one CÀN bond in one
pot. Meritoriously, our neutral catalytic system presented excel-
lent chemoselectivity for aliphatic ketones, which led to the ex-
clusive formation of intermediate enones without the forma-
tion of dienones, in contrast to traditional methods that do
not show any such discrimination. Further, the crucial roles of
the bromide anion of the ionic liquid of the catalytic system
and the in situ generated water during the AC–TMA reaction
sequence were established by DFT calculations. Furthermore,
the added benefit of the recyclability of the catalytic system
up to five cycles makes our protocol wastefree, atom economi-
cal, and overall greener than traditional methods.
[7] a) Y. Deng, S. Kumar, H. Wang, Chem. Commun. 2014, 50, 4272–4284;
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Received: May 25, 2016
Published online on && &&, 0000
ChemCatChem 2016, 8, 1 – 8
www.chemcatchem.org
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

COMMUNICATIONS
Y. Thopate, R. Singh, A. K. Sinha,*
V. Kumar, M. I. Siddiqi
&& – &&
NMR and DFT Insight into the
Synergistic Role of Bovine Serum
Albumin–Ionic Liquid for
Multicomponent Cascade Aldol/
Knoevenagel–thia-Michael/Michael
Reactions in One Pot
Synergistic catalysis: Synergistic cataly-
sis of bovine serum albumin (BSA) and
the neutral ionic liquid 1-butyl-3-meth-
ylimidazolium bromide ([bmim]Br) to-
wards multiple CÀC and CÀS bond for-
mations by cascade aldol condensation
and thia-Michael addition is reported.
The reaction generously leads to the
chemoselective generation of b-aryl-b-
sulfido carbonyl compounds from ali-
phatic ketones, aromatic aldehydes, and
thiols in one pot.
&
ChemCatChem 2016, 8, 1 – 8
www.chemcatchem.org
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!