Cationic chiral surfactant based micelle-guided asymmetric Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.catcom.2016.05.010

Cationic chiral surfactant (1R, 2S)-(-)-N-dodecyl-N-methylephedrinium bromide (DMEB) was utilized for the first time in inducing asymmetry to Morita-Baylis-Hillman reaction in aqueous medium. Proton NMR studies carried out to determine the locus of the re

Full text of DOI:10.1016/j.catcom.2016.05.010

Catalysis Communications 83 (2016) 58–61
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
Cationic chiral surfactant based micelle-guided asymmetric
Morita-Baylis-Hillman reaction
Bashir Ahmad Shairgojray a, Aijaz Ahmad Dar b, Bilal A. Bhat a,
⁎
a
CSIR-Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, J&K, India
b
Physical Chemistry Division, Department of Chemistry, University of Kashmir, Srinagar 190006, J&K, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cationic chiral surfactant (1R, 2S)-(−)-N-dodecyl-N-methylephedrinium bromide (DMEB) was utilized for the
first time in inducing asymmetry to Morita-Baylis-Hillman reaction in aqueous medium. Proton NMR studies car-
ried out to determine the locus of the reaction in micro-heterogeneous micellar environment, were found useful
in proposing a plausible model for asymmetric induction. This work demonstrates that under such mild and non-
hazardous reactions conditions, the reaction rates increase, good yields are favored and above all reasonable en-
antiomeric excesses are obtained.
Received 17 February 2016
Received in revised form 31 March 2016
Accepted 17 May 2016
Available online 18 May 2016
Keywords:
Ephedrinium salts
© 2016 Elsevier B.V. All rights reserved.
Morita-Baylis-Hillman reaction
Asymmetric induction
Enantiomeric excess
Micellar micro-environment
1. Introduction
solubilization in water, increase the local concentration and reactivity
of reagents and promote chemo- regio- & stereo-selectivities [23,24].
Morita-Baylis-Hillman (MBH) reaction is a powerful chemical trans-
formation where simple starting materials are converted into highly
functionalized molecular synthons in a catalytic process [1–2]. As a re-
sult this reaction has been applied to synthesis of natural products [3,
4], biologically relevant heterocycles [5,6] and more importantly in syn-
thesizing versatile chiral building blocks [7–9]. However, the reaction
has traditionally suffered from low reaction rates leading to limited sub-
strate scope, but recent developments have focused on improving rates
[10–14] and changed its scope considerably. In our own efforts towards
synthesizing natural products using MBH-adducts as building blocks,
we also suffered with its sluggish reaction rates and lower yields [15–
18]. It is important to mention that over the years many chiral catalysts
have been employed to develop asymmetric versions of MBH-reaction
to produce variety of chiral building blocks. The diversity of chiral cata-
lysts tested include Lewis acids and Lewis bases, Bronsted acids, thio-
ureas, bulky ammonium salts, ionic liquids, phosphines and many
more bi-functional organocatalysts including proline [19–22].
Keeping in view these features of micellar-guided reactions, we earlier
developed an expeditious protocol for MBH-reaction that utilizes the
cationic surfactant cetyltrimethylammonium bromide (CTAB) as cata-
lyst enhancing its reaction kinetics substantially. A plausible model
was proposed that explains the stabilization of enolate-intermediate
in the conjugate addition step of MBH- reaction through the positive
charge on the self-organized aggregates of these cationic micellar struc-
tures thereby driving the reaction faster. To further capitalize on the
utility of the micelles as catalysts in MBH-reaction, we sought to devel-
op a generalized, fast and enantioselective variant of this reaction with
the use of an enantiopure cationic surfactant, (1R,2S)-(−)-N-dodecyl-
N-methylephedrinium bromide (DMEB) [25] which is expected to in-
duce enantio-selectivity in addition to increase the reactions kinetics.
2. Experimental
2.1. Representative procedure for MBH reaction of 4-nitrobenzaldehyde
with acrylonitrile in presence of chiral DMEB surfactant
During the endeavour to increase efficiency of chemical reactions,
micellar catalysis is gaining considerable attention among scientific
community owing to their efficient outcome and involvement of
green protocols [23]. These micellar environments are considered to
be the nano-reactors having unique features that include isolation of
the substrates from bulk solvent, enhancement of organic species
The micellar solution was prepared by dissolving DMEB (100 mg,
0.22 mmol) in distilled water (4 mL) and the resulting solution was
stirred for 20 min at room temperature. To this solution, 4-
nitrobenzaldehyde (30 mg, 0.19 mmol), acrylonitrile (14 μL, 0.19 mmol)
and DABCO (4 mg, 0.038 mmol) were added followed by continuous stir-
ring till the reaction was over in 6 h. After the completion of reaction
(monitored by TLC), the crude product was extracted with ethylacetate
⁎
Corresponding author.
E-mail address: bilal@iiim.ac.in (B.A. Bhat).
http://dx.doi.org/10.1016/j.catcom.2016.05.010
1566-7367/© 2016 Elsevier B.V. All rights reserved.

B.A. Shairgojray et al. / Catalysis Communications 83 (2016) 58–61
59
Table 2
Range of non-racemic MBH-adducts synthesized using DMEB as a chiral surfactant.
Producta
Reaction time in h
6
Percentage yieldb
72
ee (%)
Fig. 1. Structure of ephedrinium slats, (1R,2S)-(−)-N-dodecyl-N-methylephedrinium
bromide, DMEB (1) and (1R, 2S)-(−)-N-benzyl-N-methylephedrinium bromide (2) used
in this study.
Entry
1
56.0c (S)
5
6
2
3
5
75
70
40.0c (S)
42.0c (R)
37
7
8
9
4
5
6
18
15
16
71
70
73
44.0c (R)
44.0c (R)
22.0c (R)
Scheme 1. MBH-reaction of 4-nitrobenzaldehyde with acrylonitrile in presence of DABCO
and micellar medium.
(3 × 10 mL). The combined organic layer was dried over Na2SO4, concen-
trated under vacuum and purified by column chromatography (60–120
mesh; eluent, 7:3 petroleum ether and ethylacetate).
10
7
13
78
44.3e (S)
3. Results and discussion
In light of the above discussion, we proposed that the chiral micellar
environment could be the potential alternative strategy in carrying out
the rapid asymmetric version of MBH-reaction. For this purpose,
two ephedrinium based enantiopure salts were used to validate our
concept. A well known and commercially available chiral surfactant,
(1R, 2S)-(−)-N-dodecyl-N-methylephedrinium bromide (DMEB), 1, and
its non-surfactant variant, (1R, 2S)-(−)-N-benzyl-N-methylephedrinium
bromide, 2, were used in this study (Fig. 1).
We initially attempted the reaction of 4-nitrobenzaldehyde and ac-
rylonitrile in presence of DABCO in CTAB and proline mixture
(Scheme 1). To our surprise, a marginal enantioselectivity was achieved
in the MBH-adduct 5 with ee = 18% (entry 1, Table 1). We next utilized
the chiral surfactant 1 for this reaction. In order to ensure the presence
of micelles in the reaction medium we determined the critical micelle
concentration (cmc) of DMEB in water using the surface tension meth-
od. The cmc of DMEB was obtained from the plot of surface tension vs
logarithm of surfactant concentration and observed to be 4.11 mM. To
our delight, it was observed that an aqueous micellar solution of 1
above its cmc, the enantiomeric excess (ee) of adduct 5 was enhanced
upto 52% (Table 1, entry 2). In order to further confirm that the ee was
achieved due to micellar micro-environment, the ee was also carried
out in presence of a non-surfactant enantiopure ephedrinium salt 2. It
was interesting to observe that under these conditions, both ee and
chemical yield of adduct 5 were poor (Table 1, entry 3).
11d
12d
8
9
21
19
70
70
40.6e (S)
42.8e (R)
13d
14d
10
11
23
15
71
72
47.6e (R)
45.7e (R)
15d
16d
12
13
17
22
77
68
43.9e (R)
48.4e (R)
17d
a
All reactions were carried out in presence of aqueous solution of DMEB surfactant
above its CMC at room temperature using DABCO as a catalyst.
Table 1
b
Yields reported are isolated yields.
Formation of MBH-adduct 5 under various conditions.
c
Enantiomeric excess (ee) of MBH- adducts were determined by chiral HPLC using a
Chiralcel OD-H column.
Entry Conditions
Yield of 5 ee (%)
d
For the synthesis of adducts 11–17, DMAP was used as a tertiary amine catalyst.
Enantiomeric excess of adducts 11–17 were calculated from their specific rotation
e
1.
2.
CTAB + L-proline
(1R,2S)-(−)-N-dodecyl-N-methylephedrinium
70
72
18
52
when compared to enantiopure adducts in literature and absolute configuration of all
MBH-adducts were also assigned based on literature reports [9,26–29].
bromide
3.
(1R,2S)-(−)-N-Benzyl-N-methylephedrinium
43
03
bromidea
After optimizing the reaction conditions, a wide range of substrates
were screened for carrying out the MBH-reaction under DMEB-micellar
conditions in presence of DABCO as a catalyst. All the reactions showed a
a
In order to ensure the solubility of reactants under this reaction condition, THF:H2O
(1:1) were taken as the solvent for the reaction.

60
B.A. Shairgojray et al. / Catalysis Communications 83 (2016) 58–61
marked enhancement in reaction kinetics as expected in cationic micel-
lar media. It is to mention here that this MBH-reaction was carried out
with a range of aldehydes (having electron withdrawing and electron
donating groups) and electron deficient alkenes (including acrylonitrile,
ethyl acrylate and cyclic enones), Table 2. All the reactions proceeded
smoothly to deliver the corresponding MBH-adducts in descent yields
with moderate to good ee. The ee of the MBH- adducts were determined
either by HPLC using a Chiralcel OD-H column or based on specific
rotation of known enantiopure MBH-adducts and their absolute
configuration was assigned based on literature reports. It was generally
observed that the ee of most of these MBH-adducts were on average 40%
with compound 5 having the maximum ee of 56%. Further, it is to men-
tion that the absolute configuration of most of the adducts were found
to be R except adducts 5, 6, 11 and 12 that were found to have S-config-
uration (Table 2).
In order to understand the possible mechanism of induction of
enantioselectivity in the reaction, we attempted to find the locus of
the reaction in DMEB micellar environment using the NMR technique.
Fig. 2. Proton NMR of DMEB in D2O (top) and proton NMR of DMEB + naphthaldehyde (1:1 ratio) in D2O (down).

B.A. Shairgojray et al. / Catalysis Communications 83 (2016) 58–61
61
Fig. 3. Plausible explanation of the role of DMEB (1) in asymmetric induction in presence of tertiary amine base.
It is to note here that the interaction between catalyst, substrate and mi-
cellar aggregates could be efficiently determined by the NMR studies
[30]. Examination of the change in chemical shift of the surfactant and
the analyte in the solutions of increasing relative concentration provides
reliable information about portions of the molecules which interact
[31–33]. In this conception, we recorded the proton NMR of DMEB in
D2O in presence and absence of model substrate, naphthaldehyde (Fig.
2). Our analysis of the proton NMR spectra of DMEB and
DMEB + naphthaldehyde (1:1 ratio) in D2O indicated that there is a sig-
nificant change in chemical shift of protons on ephedrinium moiety of
DMEB in presence of naphthaldehyde. For example, the hydroxyl at-
tached proton of DMEB shifted from δ 5.59 to δ 5.71 in presence of
naphthaldehyde. Similarly the protons on aromatic ring δ 7.33–7.47
(multiplet) merged to δ 7.33 (singlet). These are the strong evidences
that the naphthaldehyde finds itself near the polar head group of
DMEB surfactant where it reacts with activated olefins to deliver the
non-racemic MBH-adducts guided by the chirality of the surfactant
head group.
Based on these observations and in light of the literature evidence
[34,35] we finally attempted to assign the plausible enantioselective
model of this reaction in DMEB environment. In presence of a DMEB
micellar solution, the water insoluble compounds enter into the mi-
cellar structure. In this environment, the hydroxyl group of the mi-
celle 1 stabilizes the zwitter-ionic intermediate generated after the
Michael addition of the tertiary amine base over an activated olefin
and subsequent reaction of the zwitterionic adduct with electrophile
by means of hydrogen bonding interactions (Fig. 3). The stabilization
of the zwitterionic intermediate in the micellar phase leads to an in-
crease in the rate of both the electrophile addition and proton trans-
fer steps in addition to being guided by the chirality of the
ephedrinium head group of the surfactant, consequently delivering
the non-racemic MBH-adducts rapidly.
fellowship. We also wish to acknowledge the support of Mr. Manjeet
Kumar (IIIM Jammu) and Mr. Ali Mohd Lone for rendering their support
in HPLC studies and compilation of the supporting data respectively
(IIIM communication no. IIIM/1885/2016).
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.catcom.2016.05.010.
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In conclusion, we developed a rapid and generalized strategy in gen-
erating non-racemic MBH-adducts using chiral DMEB surfactant. Proton
NMR studies suggest that the reaction occurs near the polar head group
of DMEB micellar media that was helpful in predicting the plausible
enantioselective model for this reaction. The outcomes of these results
are expected to be useful in designing the better catalysts based on sur-
factants for asymmetric MBH-reaction in future studies.
Acknowledgement
We are grateful to DST (GAP-1199) for financial support. One of the
authors, BAS would like to acknowledge the UGC for Senior Research