Hydroxyphthalimide allied triazole-pyrrolidine catalyst for asymmetric Michael additions in water

Article abstract of DOI:10.1016/j.tetasy.2010.08.012

A new hydroxyphthalimide-coupled triazole-pyrrolidine derivative has been synthesized and demonstrated as an efficient and stereoselective organocatalyst for the asymmetric Michael addition reaction of ketones to nitro olefins at room temperature. Good yields and high selectivities were achieved when benzoic acid was used in combination with organocatalyst 1, employing water as the reaction medium.

Full text of DOI:10.1016/j.tetasy.2010.08.012

Tetrahedron: Asymmetry 21 (2010) 2372–2375
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Tetrahedron: Asymmetry
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Hydroxyphthalimide allied triazole-pyrrolidine catalyst for asymmetric
Michael additions in water
⇑
Srivari Chandrasekhar , Togapur Pavan Kumar, Kothapalli Haribabu, Chada Raji Reddy
Organic Division-I, 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 20 July 2010
Accepted 12 August 2010
A new hydroxyphthalimide-coupled triazole-pyrrolidine derivative has been synthesized and demon-
strated as an efficient and stereoselective organocatalyst for the asymmetric Michael addition reaction
of ketones to nitro olefins at room temperature. Good yields and high selectivities were achieved when
benzoic acid was used in combination with organocatalyst 1, employing water as the reaction medium.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Boc-protected proline azide 2 to afford 4, which upon deprotection
of the Boc group would yield a new hydroxyphthalimide-linked
The asymmetric Michael addition is one of the most powerful
synthetic tools for the construction of stereoselective carbon–
carbon bonds.1 In recent years, this process has gained prominence
from synthetic organic chemists working in the field of organocatal-
ysis due to the formation of stereoenriched adducts with multiple
stereogenic centres in a single step.2 In particular, the use of nitro-
olefins as Michael acceptors has received large attention for the effi-
triazole-pyrrolidine 1 (Scheme 1). Structurally it possesses a privi-
leged chiral pyrrolidine backbone as the catalytically active site,
which efficiently activates the carbonyl compounds via the forma-
tion of an enamine intermediate and planar triazole ring as the ste-
ric controller, which directs the reactivity towards the less hindered
stereotopic face of the enamine double bond furnishing the Michael
products with high stereoselectivity.14 Herein, we report the use of
a hydroxyphthalimide-linked triazole-pyrrolidine in the asymmet-
ric Michael addition reaction of ketones with various nitroolefins.
cient formation of chiral c-nitro carbonyl compounds, which serve
as versatile building blocks for the synthesis of complex organic
molecules.3 Over the past few years, various proline-based organo-
catalysts, such as pyrrolidine-triazole,4 pyrrolidine-tetrazole,5
2. Results and discussion
pyrrolidine-thiourea,6
pyrrolidine-sulfonamide,7
pyrrolidine-
pyridine,8 pyrrolidine-imidazolium,9 2,2-bipyrrolidine3b,10 have
been successfully employed for asymmetric Michael additions with
diverse range of stereoselectivities. Further work in this field to de-
velop new organocatalysts would be a useful addition to the exist-
ing methods. With our continued interest on organocatalysts,11,12
we have developed a new hydroxyphthalimide-linked triazole-pyr-
rolidine catalyst (Fig. 1) from proline using the Huisgen 1,3-dipolar
cycloaddition, ‘click reaction’.13 We envisioned that N-propa-
rgyloxyphthalimide 3 could participate in a click reaction with
The hydroxyphthalimide-linked organocatalyst 1 was synthe-
sized from the known azide 2 (readily obtained from L
-proline)15
as illustrated in Scheme 1. Accordingly, the Boc-protected proline
azide 2 was treated with commercially available N-propargyl-
oxyphthalimide 3 under click conditions to furnish the protected
derivative 4 in 92% yield, which upon deprotection of the Boc
group with 5 M HCl/EtOH resulted in the desired organocatalyst
1 (89% yield, Scheme 1). The efficiency of the catalyst 1 was eval-
uated in a model reaction of cyclohexanone 5a with b-nitrostyrene
6a (Scheme 2). Initially, the reaction was performed in THF with
10 mol % of the catalyst at rt, and it was found that the reaction
proceeded in 24 h to provide the Michael product 7a in 65% yield.
The syn/anti ratio of the product obtained was 7:3 (determined by
1H NMR of the crude product) and the enantiomeric excess was
72% (determined by chiral HPLC, Table 1, entry 1).
To further improve the yield as well as the stereoselectivity, we
investigated the effect of different solvents such as CH2Cl2, MeOH,
DMF, toluene and H2O. The results are summarized in Table 1. The
reaction proceeded well in polar solvents such as MeOH, DMF and
H2O resulting in the Michael adduct in good yield, diastereoselec-
tivity and enantioselectivity. In non-polar solvents, the reaction
O
N
N
N
N
O
N
H
O
1
Figure 1. Structure of organocatalyst 1.
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.012

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 21 (2010) 2372–2375
2373
O
O
N
Cu (turnings)
aq. CuSO4
N
N
N3
N
O
O
N
N
N
EtOH, reflux
2h, 92%
Boc
O
3
Boc
4
2
O
O
N
N
N
5M HCl/EtOH
N
O
0 oC-rt, 2h, 89%
N
H
1
O
Scheme 1. Synthesis of catalyst 1.
with cyclohexanone (Table 3, entries 1–8) and also equally with
cyclopentanone (Table 3, entries 9 and 10) to give the correspond-
ing Michael adducts in good yields with high diastereoselectivity
and enantioselectivity. The reaction of b-nitrostyrene with acetone
was very sluggish and afforded the desired product in low yield
with low selectivity even after prolonged reaction time (Table 3,
entries 11 and 12).
O
O
NO2
1 (10 mol%)
NO2
rt
5a
6a
7a
Scheme 2. Michael addition of cyclohexanone to nitrostyrene.
Based on the above-mentioned experimental results, we
propose two potential transition states (Fig. 2) to rationalize the
stereochemical outcome of the asymmetric Michael addition reac-
tion performed by catalyst 1. TS-1 is an acyclic synclinal transition
state in which the planar triazole ring effectively shields the Si face
of the enamine double bond in the ketone and allows the reaction
to occur via Re–Re approach.16,9a The addition of water improved
the efficiency of catalyst towards yield and selectivity, this sug-
gests that TS-2 may be more favorable.
Table 1
Screening of solvents
Entry
Solvent
Time (h)
Yielda (%)
syn/antib
eec (%)
1
2
3
4
5
6
7
THF
CH2C12
DMF
Toluene
MeOH
H2O
24
24
18
24
18
18
18
65
68
84
56
87
92
80
7:3
6:4
8:2
6:4
9:1
9:1
9:1
72
70
79
61
82
88
85
—
3. Conclusions
a
b
c
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
In conclusion, we have developed a new hydroxyphthalimide
linked triazole-pyrrolidine organocatalyst by employing click
reaction for the asymmetric Michael addition of ketones to nitro
olefins. The reactions were performed in water with the aid of an
acid co-catalyst leading to the desired products in good yield and
high selectivity. Further investigations to extend the scope of this
catalyst are under way in our laboratory.
was slow and the products were formed in low yield with less
stereoselectivity. The reaction was also performed under solvent-
free conditions, in which the reaction was completed in 18 h with
80% yield (9:1, 85% ee) (Table 1, entry 7). The best result was ob-
served when H2O was used as the solvent (Table 1, entry 6). With
the hope of improving the yield and selectivity, we next examined
the effect of various acid additives such as CSA, TFA, pTSA, PhOH,
PhCOOH and formic acid. From these experiments, we found that
the use of PhCOOH as an additive improved the selectivity as well
as the yield, as shown in Table 2.
4. Experimental section
4.1. General
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 Perkin–Elmer 683
spectrometer. Optical rotations were obtained on Jasco Dip 360
digital polarimeter. 1H and 13C NMR spectra were recorded in
CDCl3 solution on a Varian Gemini 200 and a Brucker Avance
300. Chemical shifts were reported in parts per million with
respect to internal TMS. Coupling constants (J) are quoted in Hertz.
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.
Table 2
Screening of additives
Entry
Additived (5 mol %)
Yielda (%)
syn/antib
eec (%)
1
2
3
4
5
6
CSA
TFA
p-TSA
PhOH
PhCOOH
HCOOH
85
82
87
86
95
90
92:8
93:7
94:6
92:8
96:4
94:6
84
80
85
82
91
89
a
b
c
Isolated yields.
Determined by the 1H NMR of the crude product.
Determined by chiral HPLC.
d
Reactions performed in water for 18 h.
4.1.1. (S)-tert-Butyl-2-((4-((1,3-dioxoisoindolin-2-yloxy)-1H-
1,2,3-triazol-1-yl)methyl)pyrrolidine-1-carboxylate 4
To a mixture of N-propargyloxyphthalimide 3 (200 mg, 0.99
With the established reaction conditions in hand, a series of
mmol) in ethanol (5 ml) was added N-Boc-proline azide
2
nitroolefins (Michael acceptors) with different ketones (Michael
donors) were examined to expand the substrate scope and the
results are summarized in Table 3. All b-nitrostyrenes irrespective
of the nature of substituents on aryl group were reacted smoothly
(240 mg, 1.09 mmol), Cu turnings (5 mg), aq saturated copper
sulfate solution (0.1 mL) and refluxed for 2 h. After completion of
the reaction (monitored by TLC), ethanol was removed in vacuo

2374
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 21 (2010) 2372–2375
Table 3
Asymmetric Michael addition of ketones to nitroolefins using organocatalyst 1
Entry
Ketone
Nitroolefin
NO2
Time (h)
Product
Yielda (%)
95
syn/antib
eec (%)
91
O
O
1
18
96:4
6a
7a
7b
7c
NO2
NO2
5a
NO2
6b
CH3
H3C
2
3
5a
18
18
94
96
95:5
97:3
90
87
O
O
O
NO2
OCH3
6c
H3CO
5a
NO2
NO2
NO2
6d
O2N
O2N
4
5
5a
5a
18
18
93
95
98:2
94:6
95
94
7d
7e
NO2
NO2
NO2
6e
O
O
O
O
O
NO2
NO2
6f
6
7
5a
5a
20
20
92
89
93:7
94:6
86
85
NO2 7f
NO2 7g
NO2 7h
NO2
6g
S
S
NO2
6h
O
8
9
5a
20
24
90
86
92:8
93:7
86
84
O
O
5b
6a
NO2
NO2
7i
7j
CH3
10
11
5b
6b
24
82
90:10
82
O
O
5c
6a
6e
48
48
75
64
—
—
41
36
O
O
7k
7l
NO2
NO2
12
5c
NO2
a
b
c
Isolated yields.
Determined by 1H NMR and HPLC analysis.
Determined by chiral HPLC using chiral pak-IA, IC or OD-H columns.
and purified by silica-gel column chromatography to afford Boc-
22.6; ESIMS: m/z 428 [M+H]+; HRMS calcd for C21H26N5O5:
protected triazole 4 (380 mg, 92% yield) as a white solid: mp:
428.1928, found: 428.1945.
122–124 °C; ½a 2D7
ꢀ
¼ ꢁ39:6 (c 0.6, CHCl3); IR (Neat):
m 2927, 2361,
1791, 1732, 1698, 1465, 1397, 1170, 1050 cmꢁ1
;
1H NMR (CDCl3,
4.1.2. (S)-2-((1-(Pyrrolidin-2-ylmethyl)-1H-1,2,3-triazol-4-
yl)methoxy)isoindoline-1,3-dione 1
Five molar HCl (0.5 mL) was added to a solution of triazole 4
(100 mg) in ethanol at 0 °C and stirred for 2 h at rt. After comple-
tion of the reaction, the solvent was removed in vacuo and the
300 MHz): d 7.76–7.72 (m, 5H), 5.35–5.31 (m, 2H), 4.61–4.58 (m,
2H), 4.12–4.08 (m, 1H), 3.45–3.41 (m, 2H), 1.88–1.83 (m, 3H),
1.52 (s, 10H); 13C NMR (CDCl3, 75 MHz): d 163.1, 134.2, 129.1,
125.3, 124.9, 123.5, 79.9, 70.1, 57.2, 52.6, 51.5, 47.0, 29.7, 28.7,

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 21 (2010) 2372–2375
2375
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N
N
O
N
O
N
N
N
N
NO2
H
H
O
O
H
O
N
N
N
N
R
O
O
O
H
O
Ar
TS -1
TS -2
Figure 2. Proposed transition state for Michael additions.
reaction mixture was dissolved in CH2Cl2 (10 mL) and quenched
with saturated NaHCO3 solution. The aqueous layer was extracted
with CH2Cl2 (3 ꢂ 10 mL) and the combined organic layer was dried
over Na2SO4, concentrated in vacuo and purified by silica-gel
column chromatography to afford organocatalyst 1 (67 mg, 89%
yield) as a white solid: mp: 128–131 °C; ½a D27
¼ ꢁ18:4 (c 0.3,
ꢀ
CHCl3); IR (Neat):
m 2924, 1731, 1694, 1462, 1217, 1133,
1051 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 7.74–7.70 (m, 5H),
5.35–5.32 (s, 2H), 4.68 (br s, 1H), 4.24–4.21 (m, 2H), 3.86–3.82
(m, 1H), 2.85–2.82 (m, 2H), 1.79–1.74 (m, 4H); 13C NMR (CDCl3,
75 MHz): d 163.4, 134.6, 129.2, 125.3, 124.9, 123.2, 70.3, 57.7,
51.5, 46.8, 30.9, 23.4; ESIMS: m/z 328 [M+H]+; HRMS calcd for
C
16H18N5O3: 328.1404, found: 328.1415.
4.1.3. General procedure for the Michael addition of
cyclohexanone to b-nitrostyrene
To a mixture of catalyst 1 (10 mol %), PhCOOH (5 mol %) and
corresponding nitroolefin in water (0.5 mL) was added cyclohexa-
none (5 equiv) and stirred for appropriate time (Table 3) at rt. After
completion of the reaction (monitored by TLC), the reaction
mixture was extracted with CH2Cl2 (3 ꢂ 5 mL) and the combined
organic layer was dried over Na2SO4, concentrated in vacuo and
purified by silica-gel column chromatography to afford the desired
product. Relative and absolute configurations of the products
were determined by comparison of 1H NMR, 13C NMR and specific
rotation values with those reported in the literature.
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liquid; ½a 2D5
ꢀ
¼ ꢁ12:8 (c 0.5, CHCl3); IR (Neat):
m 2924, 2862, 1708,
1552, 1437, 1373, 1251 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 7.12
(d, 2H, J = 7.6 Hz), 7.02 (d, 2H, J = 7.6 Hz), 4.86 (dd, 1H, J = 4.7,
12.4 Hz), 4.58 (dd, 1H, J = 9.6, 12.4 Hz), 3.32 (td, 1H, J = 4.6, 9.4,
14.2 Hz), 2.48 (td, 1H, J = 4.5, 9.8, 14.6 Hz), 2.24 (s, 3H), 2.10–2.01
(m, 4H), 1.92–1.88 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 216.6,
135.5, 134.2, 126.4, 125.2, 75.8, 64.3, 39.5, 28.8, 23.8, 17.6, 14.4;
ESIMS: m/z 248 [M+H]+; HRMS calcd for C14H18NO3: 248.1614,
found: 248.1511; HPLC: chiral pak-IA, hexane/isopropanol = 95:5,
1.0 mL/min, Rt = 17.7 (major) and 20.8 (minor), 82% ee, syn/anti =
90/10.
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Acknowledgements
T.P.K. thanks CSIR, New Delhi for the award of research fellow-
ship. The authors thank DST, New Delhi for funding the research
grant (SR/S1/OC-65/2009).
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