Direct asymmetric Michael addition of ketones to chalcones catalyzed by a hydroxyphthalimide derived triazole-pyrrolidine

Article abstract of DOI:10.1016/j.tetasy.2013.11.002

An efficient protocol for the enantioselective Michael additions of ketones to chalcones catalyzed by a hydroxyphthalimide linked triazole-pyrrolidine derivative has been developed. The corresponding products, 1,5-dicarbonyl compounds, were obtained in good yields with high levels of stereoselectivities under mild reaction conditions employing benzoic acid as an additive.

Full text of DOI:10.1016/j.tetasy.2013.11.002

Tetrahedron: Asymmetry 24 (2013) 1615–1619
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Direct asymmetric Michael addition of ketones to chalcones
catalyzed by a hydroxyphthalimide derived triazole–pyrrolidine
⇑
Togapur Pavan Kumar , Mohammad Abdul Sattar, Vanka Uma Maheshwara Sarma
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2013
Accepted 1 November 2013
An efficient protocol for the enantioselective Michael additions of ketones to chalcones catalyzed by a
hydroxyphthalimide linked triazole–pyrrolidine derivative has been developed. The corresponding prod-
ucts, 1,5-dicarbonyl compounds, were obtained in good yields with high levels of stereoselectivities
under mild reaction conditions employing benzoic acid as an additive.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
N
N
N
O
Organocatalysis has become an area of intense investigation
over the past few years.1 One of the most significant organocatalyt-
ic transformations is the asymmetric Michael addition reaction,
which results in the formation of functionalized products with
multiple stereogenic centers in a single step. Due to its importance,
the asymmetric Michael addition reaction has gained much atten-
tion from the scientific community.2 A large number of designed
organocatalysts bearing a pyrrolidine moiety were developed and
investigated for a wide range of organic transformations and were
found to be efficient with various levels of success.3,4 The most
commonly used Michael acceptors thus far are nitroolefins5 and
sulfones,6 while other Michael acceptor substrates have been less
well explored. We noticed that enantioselective organocatalytic
Michael addition reactions of ketones to chalcones have remained
significantly less explored, probably due to the steric and reactivity
barriers of the substrates.7 Therefore, an investigation into new
catalytic methods for this relatively underexplored transformation
is highly desirable. In a continuation of our interest on organocatal-
ysis,8 we recently developed the hydroxyphthalimide derived
triazole–pyrrolidine 1 (Fig. 1) as an efficient catalyst for asymmet-
ric Michael addition reactions of ketones to nitroolefins via an
enamine mechanism using water as the reaction medium.8g
Having been encouraged by this study and considering the con-
sistency of catalytic mechanisms, wherein the privileged chiral
pyrrolidine backbone acts as the catalytically active site and the
triazole ring with a phthalimide group as the selectivity director,9
we therefore started our investigations by testing whether catalyst
1 would also catalyze asymmetric Michael addition reactions of
ketones to chalcones. Herein we report on the use of a hydroxyph-
N
H
O
1
Figure 1. Hydroxyphthalimide linked triazole–pyrrolidine.
thalimide linked triazole–pyrrolidine in asymmetric Michael
addition reaction of ketones with activated chalcones.
2. Results and discussion
In order to evaluate the efficacy of catalyst 1 for asymmetric
Michael additions of ketones to chalcones, we initiated our exper-
iments with a model reaction using cyclohexanone 2a as a donor
and chalcone 3a as an acceptor (Scheme 1) and the reaction opti-
mization involved variation of solvent, additive, and template.
Firstly, the reaction was examined in several solvents using
20 mol % of the catalyst at room temperature and the results are
summarized in Table 1. As evident from the survey, the conjugate
addition reaction proceeded well in polar solvents such as DMF,
MeOH, i-PrOH, and t-BuOH to afford the product 4a in good yields
and stereoselectivities (Table 1, entries 3, 7–9), while in other sol-
vents the reaction is relatively less productive. To our delight the
O
O
O
O
1 (10 mol%)
solvent (0.5 mL)
rt
2a
3a
4a
⇑
Corresponding author. Tel.: +91 40 27191727; fax: +91 40 27160512.
E-mail address: pavantogapur@gmail.com (T.P. Kumar).
Scheme 1. Michael addition of cyclohexanone to chalcone.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.002

1616
T. P. Kumar et al. / Tetrahedron: Asymmetry 24 (2013) 1615–1619
Table 1
loading or reaction temperature resulted in longer reaction time
with no substantial effect on the yield and selectivity (Table 3,
entries 1 and 3).
Screening of solventsa
Entry
Solvent
Time (d)
Yieldb (%)
syn/antic
eed (%)
Having established the optimal reaction conditions for Michael
addition of cyclohexanone 2a with chalcone 3a, we then examined
the scope and limitation of this reaction with different ketones and
chalcones under solvent free reaction conditions using catalyst 1
(20 mol %) in combination with benzoic acid (10 mol %) at room
temperature. As shown in Tables 4 and 5, chalcones 3b–k reacted
smoothly with cyclohexanone 2a (Table 4, entries 1–10) and other
six-membered ring ketones 2b–d (Table 5, entries 1–3) under the
established reaction conditions and the corresponding Michael
products were obtained in good yields with high levels of diastere-
oselectivities and enantioselectivities regardless of the nature of
substitution pattern in chalcones. However, reactions with cyclo-
pentanone and acetone were less compatible, and the resultant
products are obtained in moderate yields and selectivities (Table 5,
entries 4 and 5). Overall, there is a good substrate scope for the
conjugate addition of ketones to chalcones using hydroxyphthali-
mide derived triazole–pyrrolidine catalyst, providing access to a
variety of 1,5-dicarbonyl compounds in high selectivities.
The absolute stereochemical outcome of this transformation
can be explained by considering the possible transition state model
as shown in Figure 2. The pyrrolidine moiety of the catalyst acts as
an activation site leading to the formation of enamine on reaction
with ketone and the planar triazole ring as a steric controller,
which effectively shields the Si face of the enamine and allows
the reaction to occur via Re–Re approach.10 While the phthalimide
group might participate in H-bonding interaction with the car-
bonyl group by the intermediacy of benzoic acid resulting in a cav-
ity like arrangement, thus bringing about a tighter transition state
and leading to the formation of desired products with high
stereoselectivities.
1
2
3
4
5
6
7
8
9
10
CHC13
Toluene
DMF
CH3CN
THF
6
6
4
5
5
3
4
3
3
5
58
65
73
70
66
78
73
71
69
45
88:12
85:15
91:9
93:7
91:9
94:6
9:1
92:8
95:5
8:2
63
61
70
65
68
81
72
76
74
67
Neat
MeOH
iPrOH
tBuOH
H2O
a
b
c
Reaction conditions: cyclohexanone (5 mmol), chalcone (1 mmol).
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
d
reaction performed under solvent free conditions has resulted in
the product with best yield (78%) and stereoselectivities (94:6
syn/anti and 81% ee) among the conditions tested (Table 1, entry 6).
Encouraged by solvent screening survey, we then directed our
investigations to test the effect of acid additive in the above trans-
formation. As evident from the literature, the presence of an acid
additive enhances the efficiency of catalytic cycle by accelerating
enamine formation. In anticipation, we examined the effect of var-
ious acid additives such as TFA, HCOOH, PhCOOH, PhCH2COOH,
PhOH, pTSA, CSA, and HCl. As illustrated in Table 2, from these
experiments we found PhCOOH as the best additive in combination
with catalyst 1 (89% yield, 97:3 syn/anti, and 86% ee, Table 2, entry
3) and it was selected as the additive for further investigation.
Table 2
Screening of additivesa
Yieldb (%)
syn/antic
eed (%)
3. Conclusions
Entry
Additive
Time (d)
1
2
3
4
5
6
7
8
TFA
5
3
3
3
3
3
5
3
Trace
75
89
82
78
72
Trace
76
—
—
In conclusion, we have demonstrated the application of hydrox-
yphthalimide derived triazole–pyrrolidine as an effective organo-
catalyst for the asymmetric Michael addition of ketones to
chalcones. The process was found to be productive in terms of yield
and stereoselectivities, when performed under solvent-free reac-
tion conditions using benzoic acid as an additive. Further investi-
gations to extend the scope of this valuable transformation and
development of new organocatalysts are underway in our
laboratory.
HCOOH
PhCOOH
PhCH2COOH
PhOH
pTSA
HCl
93:7
97:3
94:6
91:9
93:7
—
77
86
83
80
74
—
CSA
86:14
63
a
Reaction conditions: cyclohexanone (5 mmol), chalcone (1 mmol), additive
(10 mol %).
b
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
c
d
4. Experimental section
4.1. General
We then studied the effect of temperature and catalyst loading
to further optimize the reaction conditions and however none of
these variations could further improve the reaction either in terms
of yield or selectivity. As shown in Table 3, a decrease in catalyst
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 60–120 mesh. IR spectra were recorded on a Perkin–Elmer
Table 3
Effect of temperature and catalyst loadinga
Entry
Catalyst (mol %)
Temp. (°C)
Time (d)
Yieldb (%)
syn/antic
eed (%)
1
2
3
4
20
20
10
30
0
50
RT
RT
6
2
5
3
85
71
83
90
94:6
8:2
91:9
97:3
84
58
81
86
a
b
c
Reaction conditions: cyclohexanone (5 mmol), chalcone (1 mmol), PhCOOH (10 mol %), neat.
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
d

T. P. Kumar et al. / Tetrahedron: Asymmetry 24 (2013) 1615–1619
1617
Table 4
Substrate scope of chalconesa
Ar1
O
O
O
O
1 (20 mol%)
Ar2
PhCOOH (10 mol%)
Ar1
Ar2
neat, rt
4b-k
3b-k
2a
Entry
1
Product
Time (d)
Yieldb (%)
syn/antic
eed (%)
Cl
3
3
3
86
92:8
84
91
87
O
O
O
O
Ph
Ph
Ph
4b
4c
Me
2
3
89
90
96:4
93:7
NO2
O
O
O
O
4d
Ph
Ph
Ph
Ph
4
5
6
7
3
3
85
87
89
92
97:3
91:9
93:7
95:5
91
85
90
88
4e
NO2
O
O
O
O
O
O
4f
Cl
3.5
3
4g
4h
OMe
Me
O
O
O
Ph
Ph
Ph
O
O
O
8
3.5
3
86
85
87
92:8
97:3
94:6
83
86
85
4i
4j
Cl
9
Cl
10
3
4k
a
b
c
Reaction conditions: cyclohexanone (5 mmol), chalcone (1 mmol).
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
d
683 spectrometer. Optical rotations were obtained on a Jasco Dip
360 digital polarimeter. 1H and 13C NMR spectra were recorded
in CDCl3 solution on a Varian Gemini 200 and Brucker Avance
300. Chemical shifts were reported in parts per million with re-
spect to internal TMS. Coupling constants (J) are quoted in Hz.
Mass spectra were obtained on an Agilent Technologies LC/MSD
Trap SL. Chiral HPLC analysis was carried out on chiral pak OD-H,
IC, or IA columns using a mixture of isopropanol and hexanes as
the eluent.
4.1.1. General procedure for the Michael addition of cyclohexa
none to chalcones
To a mixture of catalyst 1 (20 mol %), and cyclohexanone
(5 mmol) was added PhCOOH (10 mol %) and stirred for 20 min.
at room temperature. Then, chalcone (1 mmol) was added to the
resulting mixture and stirred for appropriate time (Table 3) at
room temperature. After completion of the reaction (monitored
by TLC), the mixture was purified by silica-gel column chromatog-
raphy to afford the desired product. Relative and absolute

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T. P. Kumar et al. / Tetrahedron: Asymmetry 24 (2013) 1615–1619
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O
O
Ph
O
O
1 (20 mol%)
PhCOOH (10 mol%)
Ph
Ph
Ph
neat, rt
4l-p
3a
2b-f
Entry Product
Time (d) Yieldb (%) syn/antic eed (%)
O
Ph
O
Ph
Ph
4l
1
2
4
4
84 92:8
82 91:9
81
79
O
O
Ph
O
O
4m
O
Ph
4n
Ph
3
4.5
83 93:7
80
N
O
Ph
Ph
O
O
4o
4p
4
5
5
5
79
38
7:3
62
47
Ph
Ph
O
—
a
b
c
Reaction conditions: cyclohexanone (5 mmol), chalcone (1 mmol).
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
d
N
N
O
N
O
N
N
O
H
O
O
Ar2
O
Ar1
Figure 2. Proposed transition state.
configuration of the products was determined by comparison of 1H
NMR, 13C NMR, and specific rotation values with those reported in
the literature.11
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T.P.K. thank DST New Delhi for INSPIRE Faculty Award (IFA12-
CH-30). M.A.S. thank UGC, New Delhi for the award of research fel-
lowship. Authors thank Dr. J. S. Yadav and Dr. S. Chandrasekhar for
valuable suggestions.
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