Micellar promiscuity: An expeditious approach to Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2013.02.097

An accelerated and efficient method for Morita-Baylis-Hillman (MBH) reaction in aqueous cationic micellar solution under ambient conditions has been developed. The present method holds promise for future use of cyclic and acylic MBH-adducts of general uti

Full text of DOI:10.1016/j.tetlet.2013.02.097

Tetrahedron Letters 54 (2013) 2391–2394
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Micellar promiscuity: an expeditious approach to Morita–Baylis–Hillman
reaction
Bashir Ahmad Shairgojray a, Aijaz Ahmad Dar b, Bilal Ahmad Bhat a,
⇑
a Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Sanatnagar, Srinagar 190005, J&K, India
b 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:
An accelerated and efficient method for Morita–Baylis–Hillman (MBH) reaction in aqueous cationic
micellar solution under ambient conditions has been developed. The present method holds promise for
future use of cyclic and acylic MBH-adducts of general utility in total synthesis of natural products in
a robust fashion.
Received 23 January 2013
Revised 25 February 2013
Accepted 27 February 2013
Available online 7 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Micelles
MBH reaction
Reaction acceleration
CTAB
Michael–Aldol sequence
The Morita–Baylis–Hillman (MBH) reaction is a carbon–carbon
sigma bond-formation reaction between activated alkenes and
carbon electrophiles in a tandem Michael–Aldol sequence.1 The
reaction, catalysed by tertiary amines or tertiary phosphanes pro-
vides rapid access to polyfunctionalized synthons under relatively
mild conditions.2 The products of this reaction continue to lure syn-
thetic organic chemists for rapid access of versatile substrates for
the synthesis of natural products,3 heterocycles4 and drugs.5 In
recent past, the reaction has drawn increasing attention owing to
its selectivity (chemo-, regio-, diastereo-, enantio-) and atom-
economical efficiency for the generation of structurally variegated
scaffolds. Despite its promise in generating a diverse range of b-
relatively efficient manner,14b though, it was not effective during
our study for cyclic adducts. On the other hand, there are reports
in which MBH adducts of cyclic and acyclic enones can be promoted
by mild cooperative catalysis of trialkylphosphanes with hydrogen
bond donors such as phenols in anhydrous THF.15 Mechanistically,
it is believed that the p-nitrophenol (a weak Brønsted acid) in the
co-catalysed systems stabilizes the enolate intermediate in the con-
jugate addition step through its hydrogen-bonding with the enolate,
driving the reaction forward and accelerating the reaction rate.15b
We have been engaged in recent past in targeting the total
synthesis of complex natural products from cyclic and acylic
MBH adducts.16 We also suffered with the sluggish reaction rates
and low yields during our efforts despite testing most of the condi-
tions expected to accelerate the rates. We felt the dire need of an
efficient strategy of general utility in accessing a diverse range of
MBH adducts. In light of the preceding discussion, we hypothe-
sized to stabilize the enolate intermediate in the conjugate addi-
tion step of MBH reaction through self-organized aggregates such
as aqueous micellar structures instead of intermolecular hydrogen
bonding with weak Brønsted acids (Fig. 1).
hydroxy-a-methylene compounds, the reaction typically suffers
from sluggish reaction rates that vary from days to weeks.6 Various
efforts have been made to find effective catalysts and optimal exper-
imental conditions to circumvent the sluggish nature of the reaction
and to improve its overall efficiency. Most of the strategies involve
the use of organic bases like DABCO,7 DMAP,8 imidazole,9 DBU,10
etc., use of strong Lewis acids (TiCl4, Et2Al)11 or even physical meth-
ods such as high pressure12 and microwave irradiation.13 But, a gen-
eral solution with a high degree of substrate tolerance is still lacking
and desperately needed. Recently, an interesting approach on cyclic
enones by a bicyclic imidazolyl alcohol in the presence of phase
transfer additives is reported.14a Besides, a nonionic surfactant
Triton X-100 was employed to generate acyclic MBH adducts in a
Interestingly, micellar media bind the otherwise insoluble or-
ganic substrates by incorporating their hydrophobic part in the
micellar interior and exposing their polar part at the water-micelle
interface and hence offer an alternative to traditional methods of
accomplishing organic transformations. The intrinsic solubilization
ability of micelles provides a discrete reaction site at the microhet-
erogeneous interface by bringing the reacting molecules in close
proximity. Hence, the local interfacial concentrations of reactants
⇑
Corresponding author.
E-mail address: bilal@iiim.ac.in (B.A. Bhat).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.097

2392
B. A. Shairgojray et al. / Tetrahedron Letters 54 (2013) 2391–2394
tant 4 and 5 at or above CMC had a dramatic enhancement in both
HO
R
reaction rates as well as yields of the reactions. Contrary to this, the
two phase transfer additives 6 and 7, did not have any appreciable
effect on the reaction rates. From the initial screening of surfac-
tants and delightful results with 4 and 5 we ventured to explore
the role of 4 in this reaction for further optimization of conditions
while varying the organocatalyst.
O
O
R
O
O
aq. micelle
O
H
R
n
n
N
R
n
R
Current work
HO
R
During our initial study, we tested the reaction of acrylonitrile
with 2-nitrobenzaldehyde in water as solvent and 4 as a surfactant
(at or above CMC), and varied the bases such as DABCO, DBU,
DMAP, imidazole and Ph3P (Table 1). From the results, it was inter-
esting to note that the base DABCO under micellar conditions
accelerated the reaction rates and reaction efficiency remarkably
while DMAP only accelerated the reaction kinetics. DABCO/4-
condition was found to be the best in terms of kinetics and yields
compared to controlled reaction in which only DABCO was used.
On the other hand, in case of cyclic enones which are weak
Michael acceptors and are generally less reactive towards MBH
reaction, it was observed that the reaction between the cyclohex-
en-2-one (11b) and 2-nitrobenzaldehyde (8e) was highly efficient
and accelerated in DMAP/4 condition compared to other bases like
DABCO, DBU and imidazole. DMAP/4 condition resulted into the
formation of MBH-product (12e) between 11b and 8e in 95% in
6 h compared to bare DMAP, 69% yield in 21 h (Table 2).
Having the reaction conditions optimized and based on these
observations, we synthesized an array of MBH adducts from acyclic
and cyclic enones under the established conditions. In our study,
we studied the MBH reaction of acrylonitrile with a range of aro-
matic aldehydes (8a–8h) having both electron donating and elec-
tron withdrawing group/s. It was observed that in a controlled
condition, that is, without micellar media, all the reactions took
longer reaction time (especially those with electron donating
groups) with relatively low yields compared to reactions in micel-
lar media. Among the four surfactants (1, 2, 4 and 5), the reactions
proceeded better in 4 and 5 followed by 1 and 2, respectively (Ta-
ble 3). It is clear from the results that the protocol works equally
good for aliphatic aldehydes like formaldehyde (8i), pentanal (8j)
and heptanal (8k).18 It is to be mentioned that the protocol also
works effectively with other enones like acrylates in addition to
acrylonitrile. Since our proposed hypothesis is working, we believe
that the self-organized micellar aggregates are playing a role in the
R
THF
B
H
O
H
R
N
R
n
R
Previous work
Figure 1. Schematic representation of catalysis in MBH reaction.
get enhanced compared to their stoichiometric concentration. The
energy of activation is therefore, lowered presumably due to in-
creased collisions between such interfacially concentrated
reactants.17
During our venture on total synthesis programme starting from
MBH adducts, we herein, disclose our efforts towards the establish-
ment of an efficient protocol for MBH reaction in micellar media.
We developed an interesting method of general utility to access
a diverse range of MBH adducts on cationic micellar media under
ambient conditions. Initially, we screened a range of cationic and
anionic surfactants including SDS (1), SDBS (2), sodium cholate
(3), CTAB (4) and penanediyl-1,5-bis(dimethylcetylammoniumbro-
mide), 16-5-16 (5) along with two phase transfer additives TEAB
(6) and TBAB (7) for the purpose (Fig. 2). Initially, it was observed
that the surfactants 1–5 enhanced the reaction kinetics to some ex-
tent, especially with 1, 2, 4 and 5, the results were on better side.
Encouraged with these observations, we further investigated 1, 2,
4 and 5 at, below and above critical micellar concentration-CMC
(concentration above which a surfactant leads to the formation
of self aggregates). To our delight, it was observed that the surfac-
O
O
S
Na
O
O
SDS (1)
O
O
S
Na
O
O
Table 1
2
SDBS ( )
Results of MBH adduct of acrylonitrile with 2-nitrobenzaldehyde with various organic
bases in the presence of 4 as micellar media
O
OH
Yielda (%)
O
Na
S. no.
Base/CTAB
Reaction time (h)
1
2
3
4
5
6
DABCO
DABCO/4
DBU/4
DMAP/4
Imidazole/4
Ph3P/4
5.0
0.7
4.0
1.2
No reaction
No reaction
72
95
10
40
—
HO
OH
Sodium cholate (3)
Br
—
N
N
4
CTAB ( )
a
Yields reported are isolated yields.
Br
5
Table 2
N
Br
Results of MBH adduct of cyclohexenone with 2-nitrobenzaldehyde with various
organic bases in the presence of 4 as micellar media
Penanediyl-1,5-bis(dimethylcetylammonium
bromide),16-5-16 (5)
S. no.
Base/CTAB
Reaction time (h)
Yielda (%)
1
2
3
4
5
DMAP
DMAP/4
DBU/4
Imidazole/4
DABCO/4
21
6.0
10
10
69
95
20
82
—
Br
Br
N
N
TEAB (6)
Figure 2. Structure of cationic and anionic micellar structures.
TBAB (7)
No reaction
a
Yields reported are isolated yields.

B. A. Shairgojray et al. / Tetrahedron Letters 54 (2013) 2391–2394
2393
Table 3
Results of MBH adducts of acyclic alkenes with various aldehydes with and without aqueous micelles 1, 2, 4 and 5
OH
EWG
EWG
DABCO
aq. micelle
R
Aldehyde
+
8
9
10
S. no.
Aldehyde
EWG
MBH
Reaction without micelle;
time, h (yield %)b
Reaction with 1;
time, h (yield %)
Reaction with 2;
time, h (yield %)
Reaction with 4;
time, h (yield %)
Reaction with 5;
time, h (yield %)
adducta
1
2
3
4-ClPh (8a)
4-BrPh (8b)
4-MeOPh
(8c)
–CN
–CN
–CN
10a
10b
10c
25 (65)
27 (62)
74 (59)
7.0 (79)
6.0 (81)
33 (73)
8.0 (72)
8.0 (68)
36 (64)
5.5 (89)
5.0 (92)
30 (82)
4.0 (91)
4.0 (92)
19 (83)
4
3-MeOPh
(8d)
2-NO2Ph
(8e)
4-NO2Ph
(8f)
2,4-di
NO2Ph (8g)
4-MePh
(8h)
Formalin
soln. (8i)
Pentanal
(8j)
–CN
–CN
–CN
–CN
–CN
–CN
–CN
–CN
10d
10e
10f
10g
10h
10i
62 (59)
5.0 (72)
6.0 (70)
4.0 (70)
23 (61)
6.0 (70)
9.0 (65)
12 (71)
30 (70)
1.2 (82)
1.3 (79)
1.2 (86)
7.5 (77)
4.0 (80)
5.0 (70)
6.0 (75)
33 (65)
2.4 (79)
2.6 (76)
1.3 (78)
8.0 (69)
NTc
18 (89)
0.7 (95)
0.9 (93)
0.6 (93)
3.5 (89)
2.0 (95)
2.2 (91)
3 0 (87)
13 (89)
0.4 (95)
0.5 (94)
0.3 (93)
3.0 (89)
1.2 (95)
2.0 (91)
2.2(87)
5
6
7
8
9
10
11
10j
NT
Heptanal
(8k)
10k
NT
12
13
8a
8e
–CO2Et
–CO2Et
10l
10m
21 (65)
4.0 (75)
6.2 (80)
2.0 (80)
NT
NT
5.0 (89)
0.6 (95)
3.6 (90)
0.3 (95)
a
b
c
General reaction conditions: 8 (1.0 mmol), acrylonitrile (1.0 mmol), DABCO (0.1 mmol), micelle (CMC concentration), water (2 mL).
Yields reported are isolated yields.
NT = not tested.
Table 4
Results of MBH adducts of cyclic enones with various aldehydes with and without aqueous micelle 4 and 5
O
O
OH
DMAP
aq. micelle
R
+
Aldehyde
n
n
11
12
8
n = 1; 11a
n = 2; 11b
n = 3; 11c
S No Cyclic enone Aldehyde MBH adducta Reaction without micelle time, h (yield %)b Reaction with 4; time, h (yield %) Reaction with 5; time, h (yield %)
1
2
3
4
5
6
7
8
9
11a
11a
11a
11b
11b
11b
11b
11c
11c
11c
8c
8e
8i
8c
8e
8i
12a
12b
12c
12d
12e
12f
12g
12h
12i
23 (65)
19 (70)
9.0 (73)
29 (65)
21 (69)
24 (70)
27 (60)
61 (47)
36 (58)
36 (30)
6.5 (83)
5.0 (90)
1.2 (95)
9.0 (87)
6.0 (95)
1.5 (98)
2.3 (92)
23 (85)
7.5 (85)
4.0 (90)
5.0 (83)
3.3 (89)
0.8 (92)
6.0 (87)
4.6 (89)
1.0 (95)
2.0 (92)
16 (88)
5.0 (82)
2.8 (90)
8j
8c
8e
8i
10
12j
a
General reaction conditions: 8 (1.0 mmol), cyclic enone (1.0 mmol), DMAP (0.1 mmol), micelle (CMC concentration), water (2 mL).
Yields reported are isolated yields.
b

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B. A. Shairgojray et al. / Tetrahedron Letters 54 (2013) 2391–2394
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stability of the enolate intermediate in the conjugate addition step
of the reaction which is also supported by the fact that the
reactions are much faster in cationic micellar aggregates than in
anionic media.
In the case of cyclic enones, since the reaction works better
when DMAP is used as the base, we synthesized the MBH adducts
of 11a, 11b and 11c under the established conditions using 4 and 5.
We were delighted to observe that the reactions work smoothly in
all the three enones with various aldehydes (Table 4). It is to be
noted that the MBH adduct, 12j, derived from 11c and 8i was a
pain in the neck in our earlier efforts.16c We were delighted to ob-
tain this adduct 12j, in just 4.0 and 2.8 h (yield, 90%) using 4 and 5,
respectively, compared to the reaction without micellar media in
36 h (yield, 20–30%). Besides, the protocol also works equally good
for aromatic aldehydes having electron donating or electron with-
drawing group/s attached.
In summary, we have developed an efficient and accelerated
MBH reaction system in an aqueous cationic micellar media for
acyclic conjugated alkenes and cyclic enones using 4 and 5. The
present method is a general strategy that holds promise for future
use of MBH-adducts in total synthesis of natural products in an
expeditious and green fashion. Efforts are also underway to inves-
tigate the detailed mechanism of this acceleration and to develop
an enantio-selective variant of the reaction in a chiral micellar
media.
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Acknowledgments
We highly acknowledge Dr. Ram Vishwakarma, Director, Indian
Institute of Integrative Medicine-Jammu for his encouragement
and support in establishing a synthetic chemistry laboratory in Sri-
nagar campus of IIIM. One of the authors, B.A.S. acknowledges UGC
for the financial support through junior research fellowship.
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18. In a typical reaction procedure, a mixture of 11c (110 mg, 1.0 mmol) and
aqueous 37% solution 8i (2.0 mmol) was added to an aqueous solution of 4 (at
or above CMC; 2 mL). To this mixture, DMAP (12.2 mg, 0.1 mmol) was added
and the reaction was stirred at ambient temperature till its completion,
monitored by TLC. The crude reaction mixture was diluted with water and
extracted with ethylacetate to yield the pure MBH adduct. Spectral data of
representative compounds; compound 12j: IR: 3433, 3056, 1653, 1263,
References and notes
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742 cmÀ1 1H NMR (CDCl3, 400 MHz): d 1.80 (m, 4H), 2.47 (q, 2H, J = 8.0 Hz),
;
2.63 (m, 2H), 2.90 (br s, –OH), 4.23 (s, 2H), 6.77 (t, 1H, J = 8.0 Hz); 13C NMR
(100 MHz): d 21.4, 25.2, 27.9, 43.0, 64.8, 141.7, 144.9, 205.6; ESI-MS, 163.18
[M+Na]; compound 10e: IR: 3054, 2306, 1527, 1266, 741 cmÀ1 1H NMR
;
(CDCl3, 400 MHz): d 3.31 (br s, ÀOH); 6.03 (s, 1H), 6.13 (s, 1H), 6.16 (s, 1H);
7.57 (t, 1H, J = 7.5 Hz), 7.75 (t, 1H, J = 7.5 Hz), 7.86 (d, 1H, J = 7.6 Hz), 8.05 (d,
1H, J = 7.6 Hz); 13C NMR (100 MHz): d 67.5, 114.6, 122.6, 123.5, 127.5, 128.2,
130.6, 132.6, 146.1, 151.7; ESI-MS, 227.06 [M+Na].