Organocatalytic michael addition of 1,3-dicarbonyl indane compounds to nitrostyrenes

Article abstract of DOI:10.3390/molecules15042551

To map out the efficient organocatalyst requirements in the Michael addition of 1,3-dicarbonyl indane compounds to nitrostyrenes, a dozen different amino organocatalysts containing a p-toluenesulfonyl group (Ts) have been evaluated; excellent enantioselectivities (up to er 92:8) were obtained with a primary amine-based Ts-DPEN catalyst and a plausible catalytic reaction mechanism was proposed on the basis of the experimental results. Copyright

Full text of DOI:10.3390/molecules15042551

Molecules 2010, 15, 2551-2563; doi:10.3390/molecules15042551
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Organocatalytic Michael Addition of 1,3-Dicarbonyl Indane
Compounds to Nitrostyrenes
Zhen-Yu Jiang, Hua-Meng Yang, Ya-Dong Ju, Li Li, Meng-Xian Luo, Guo-Qiao Lai *,
Jian-Xiong Jiang and Li-Wen Xu *
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education,
Hangzhou Normal University, Hangzhou 310012, China
* Author to whom correspondence should be addressed: E-Mail: licpxulw@yahoo.com;
Tel.: +86-571-288-67756; Fax: +86-571-288-65135.
Received: 9 December 2009; in revised form: 3 March 2010 / Accepted: 19 March 2010 /
Published: 12 April 2010
Abstract: To map out the efficient organocatalyst requirements in the Michael addition of
1,3-dicarbonyl indane compounds to nitrostyrenes, a dozen different amino organocatalysts
containing a p-toluenesulfonyl group (Ts) have been evaluated; excellent enantio-
selectivities (up to er 92:8) were obtained with a primary amine-based Ts-DPEN
catalyst and a plausible catalytic reaction mechanism was proposed on the basis of the
experimental results.
Keywords: organocatalysis, Michael reaction, primary amine, diamine
1. Introduction
The addition of stabilized 1,3-dicarbonyl compounds to electro-deficient alkenes is one of the oldest
and most useful key bond construction methods in organic synthesis for the formation of new C-C
bonds [1]. Catalytic, enantioselective versions of this fundamental transformation which use metal-
based chiral complex catalysts or organocatalysts have been reported extensively [2–8]. Early studies
on organocatalytic asymmetric Michael reactions were conducted with readily available amines of
natural origin, such as (-)-quinine and (+)-quinidine [9–11]. In the case of the Michael reaction of
nitrostyrenes, the resulting 1,4-addition product is a very useful precursor to different complex organic
molecules, such as amino carbonyl compounds, which is tied to their propensity to undergo facile

Molecules 2010, 15
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α-alkylation reaction and interconversions to other important organic functional groups.[12,13]
Several attempts have been performed toward achieving asymmetric Michael addition of 1,3-
dicarbonyl compounds to nitrostyrenes in the presence of organocatalysts, such as
2-aminobenzimidazole [14], aminothiourea [15–22], guanidine [23,24], primary amine [25], and other
amino catalysts [26]. However, the development of the perfect organocatalyst based on the above
functionality is difficult because there are many factors that influence enantioselective reactions.
Although the enantioselective Michael reaction of ketoesters to nitrostyrenes is a well studied reaction
in organocatalysis, the stereocontrolled concurrent creation of adjacent quaternary and tertiary
stereocenters still remains challenging. Recently we have reported on the effective enantioselective
Michael addition of 1,3-dicarbonyl indane compounds to nitrostyrenes in the presence of Ts-DPEN
with primary amine and simple amino N-sulfonamide groups [27,28]. To establish whether the primary
amine and simple amino N-sulfonamide group was important and to map out the structural
requirements of organocatalysts, we have now carried out an extensive organocatalyst variation study.
For the synthesis of the organocatalysts, our criteria were that the chiral organocatalysts should be
derived from similar chiral diamines. Herein, we reported a full account of our investigation focusing
on the development of organocatalysts for the Michael addition of 1,3-dicarbonyl indane compounds
to nitrostyrenes.
2. Results and Discussion
We designed a series of functional amino analogues with commonly encountered groups, such as
thiourea, amide, phenol, tertiary amine and imine, for the catalytic Michael addition of 1,3-dicarbonyl
indane compounds to nitrostyrenes. Catalysts 3a-l containing p-methylbenzene sulfonyl groups (Ts)
could be easily synthesized in several steps from chiral cyclohexane-1,2-diamine (1a) or 1,2-
diphenylethane-1,2-diamine (1b) (Scheme 1). Chiral diamines 1 reacted with p-toluenesulfonyl
chloride (TsCl) in DCM at 0 °C to afford the corresponding products 2 in good yield [29,30]. It should
be noted that an excess of diamine was necessary to achieve satisfactory yields in this step. Treatment
of compounds 2 with Ac2O, cyclohexene oxide, salicylaldehyde, and isothiocyanate under reported
conditions afforded the corresponding functional catalysts 3 in excellent yields [31–34]. Catalysts 3c,
3d, 3h, were prepared from 2a or 2b by alkylation and reduction [35,36].
To evaluate the different organocatalysts, the following conditions were adopted for the Michael
addition of 1,3-dicarbonyl indane compound 4a to nitrostyrene 5a: organocatalyst (10 mol%),
nitrostyrene 5a (0.5 mmol) and 1,3-dicarbonyl indane compound 4a (0.55 mmol) in toluene (1 mL) at
-20 °C (Scheme 2). The organocatalysts 3a-l were evaluated by using the above conditions and full
results are shown in Figure 1. The yields are good and similarly for all the cases that obtained after
purification by chromatography (70–80%). The ee values were determined by using chiral HPLC. In
the model Michael addition of 1,3-dicarbonyl indane compound 4a to nitrostyrene 5a, the diastereo-
and enantioselectivities in the reaction using these organocatalysts varied significantly with different
functional substitutes. For example, 3d, 3e, or 3h, has poor enantioselectivity for both enantiomers
(2R or 2S), while 3g or 3i gave the major 2S-enantiomer Michael adduct with good enantioselectivity.
Interestingly, 2a containing a similar functional group gave low diastereo- and enantioselectivity in
comparison to Ts-DPEN (2b) These results suggest that Ts-DPEN (2b) is the most suitable Ts-based

Molecules 2010, 15
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organocatalyst among these similar amino catalysts in this reaction, and the primary amine group
turned out to be a crucial factor to obtain high levels of enantioselectivities.
Scheme 1. The preparation of different functional organocatalysts derived from chiral diamine.
OH
OH
N
N
H
3a
NHTs
3b
NHTs
ref. 22 70%
ref.17
93%
ref.18
98%
OH
TsCl
N
H
ref.17
90% yield
NHTs
H2N
NHTs
85%
H2N
NH2
2a
3c
1a
ref. 23
75%
ref. 20
N
NHTs
AcHN
NHTs
S
3e
3d
Ph
Ph
TsHN
Ph
HN
OH
N
Bn
HN
NHTs
3g
Ph
3f
ref. 22
75%
ref.17
97%
95%
Ph
ref. 21
OH
Ph
Ph
Ph
H2N
Ph
NH2
TsCl
HN
Ph
ref.16
86% yield
H2N
NHTs
TsHN
3h
2b
1b
90%
ref. 21
96%
ref.18
ref. 20
75%
OH
NH
Ph
AcHN
Ph
Ph HN
Ph
TsHN
NHTs
N
H
S
TsHN
Ph
Ph
3k
3l
3i

Molecules 2010, 15
Scheme 2. Asymmetric Michael addition of 1,3-dicarbonyl indane compound to nitrostyrene.
2554
O
O
O
OMe
NO2
O
Organocatalyst
+
NO2
OMe
4a
5a
6a
Figure 1. Enantio- and diastereoselectivities in the Michael reaction using different organocatalysts.
We next examined the scope of this class of Michael reactions with a series of nitrostyrenes and
cyclic β-ketoesters under the optimized reaction conditions. As shown in Table 1, in the
organocatalytic asymmetric Michael reaction different substituted nitrostyrenes 5 reacted smoothly
with methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4) with good diastereoselectivities. In this
way, it was revealed that major Michael adducts with various nitrostyrenes were obtained in good
enantioselectivities (up to 92:8 er), while minor 2S,2S-isomers were obtained with moderate
enantioselectivities (up to 82:18 er). Lower temperature resulted in lower diastereo- and
enantioselectivity (Entries 18 and 8), which may be due to the poor interaction between the primary
amine group of Ts-DPEN (2b) and the 1,3-dicarbonyl compounds at lower temperature. Iinterestingly,
methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate did not react with nitrostyrene under these
reaction conditions (Entry 17).

Molecules 2010, 15
Table 1. Enantio- and Diastereoselective Michael Reactions of Nitrostyrenes in the
2555
presence of catalytic Ts-DPEN.
O
O
OMe
NO2
R2
O
R1
Ts-DPEN(10mol%)
O
n
R2
+
H
toluene
-20~ -40℃
NO2
OMe
n
R1
5
4
6
Entrya R1
R2, n
Time (h) Yield%b Drc er (minor)d er (major)d
1
2
3
4
5
6
7
8
9
H
H, n = 1
H, n = 1
H, n = 1
H, n = 1
24
24
24
24
24
24
24
24
24
24
48
6a: 87
6b: 85
6c: 81
6d: 72
6e: 78
6f: 81
6g: 79
6h: 85
6i: 77
6k: 76
6l: 72
80/20
76/24
85/15
82/18
75/25
83/17
82/18
83/17
77/23
85/15
73/27
66:34
60:40
64:36
61:39
57:43
63:37
52:48
65:35
82:18
65:35
71:29
87:13
84:16
90:10
87:17
86:14
86:14
85:15
89:11
92:8
p-Me
o-Cl
p-Br
p-OMe H, n = 1
p-Cl H, n = 1
2,4-Cl H, n = 1
p-F
H, n = 1
H, n = 1
H, n = 1
4-Me, n = 1
o-Br
p-CN
o-Br
10
11
84:16
86:14
12
13
14
15
16
17
18e
o-Br
o-Br
o-Cl
o-Cl
o-Cl
o-Cl
p-F
4-OMe, n = 1 48
6m: 87
6n: 78
6o: 83
6p: 85
6q: 87
trace
82/18
75/25
76/24
84/16
74/26
-
75:25
50:50
78:22
62:38
50:50
-
87:13
84:26
80:20
85:15
82:18
-
5-Br, n =1
48
48
4-Me, n = 1
4-OMe, n =1 48
5-Br, n =1
H, n =2
48
48
24
H, n = 1
6h: 93
57/43
51:49
77/23
a The reactions were performed with 0.5 mmol of nitrostyrene, 0.55 mmol of cyclic β-ketoester,
b
c
1
10 mol% of Ts-DPEN, in toluene (1 mL), at -20 °C. Isolated yield. Determined by H NMR.
d
The er values of major and minor prodcuts were determined by HPLC, and the absolute
configuration was not determined. e At -40 °C.
On the basis of the experimental results described in this article, a reasonable catalytic reaction
model is provided in Figure 2. In the (1), the reaction may proceed by the dual activation model, the
carbonyl group of enol intermediate of β-ketoester was assumed to interact with primary amine moiety
of Ts-DPEN via multiple H-bonds, thus increasing the nucleophilic ability of the reacting carbon
center. The H-sulfonamide activates nitrostyrenes via a single hydrogen bond and enhances the
electrophilicity of the olefin. However, an alternative mechanism with enamine catalysis is also
reasonable [37,38]. As shown in Equation (2), the reaction is preceded with the combination of
enamine activation of primary amine and hydrogen-bonding activation of Ts- group.

Molecules 2010, 15
Figure 2. Proposed catalytic reaction mode via dual activation model.
2556
OMe
O
O
H
H
S
N
O
O
R
O
N
Ph
N
H
O
N
HN
Ph
Ts
N
H
O
H
O
O
O
Ar
(1)
(2)
3. Experimental Section
3.1. General
All reagents and solvents were used directly without purification. Flash column chromatography
13
was performed over silica (200–300 mesh). 1H-NMR and C-NMR spectra were recorded at 400 and
100 MHz, respectively on Advance (Brucker) 400 MHz Nuclear Magnetic Resonance Spectromer, and
were referenced to the internal solvent signals. IR spectra were recorded using a FTIR apparatus on
Nicolet 700 spectrophotometer in KBr cells. Thin layer chromatography was performed using silica
gel; F254 TLC plates and visualized with ultraviolet light. HPLC was carried out with a Waters 2695
Millennium system equipped with a photodiode array detector. EI and CI mass spectra were performed
on a Trace DSQ GC/MS spectrometer. Data are reported in the form of(m/z). The organocatalysts were
prepared according to references [29–36]. All the Michael products were known and confirmed by
GC-MS, and usual spectral methods (NMR and IR).
3.2. General Procedure for Michael Addition of 1,3-Dicarbonyl Indane Compounds to Nitroolefins
A catalytic amount of Ts-DPEN (10 mol %) was added to a vial containing olefins (0.5 mmol) and
1,3-dicarbonyl compounds (0.55 mmol) in toluene (1 mL). After vigorous stirring at -20 °C or -40 °C
for the times shown in the Table, the reaction mixture was poured into an extraction funnel containing
brine, diluted with distilled water, and EtOAc. The aqueous phase was extracted with EtOAc. The
combined organic phases were dried with Na2SO4 and the solvent was removed under reduced
pressure. The crude product was purified by silica gel column chromatography to furnish the desired
Michael products. All the diastereomers could not be separated and were confirmed by GC-MS, NMR
and IR, the ees of the Michael products were determined by chiral-phase HPLC analysis using a
Chiralcel OD-H column and the indicated eluent systems [27,28]. The relative configuration of
1
products was determined by comparison of the H-NMR spectra and HPLC with literature
data [39,40].

Molecules 2010, 15
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Methyl 2-(2-nitro-1-phenylethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1, entry 1) 6a
[20]: yellow amorphous solid; 1H-NMR (CDCl3) (ppm): δ = 3.14–3.19 (d, J = 17.6 Hz,1H), 3.47–3.51
(d, J=17.2 Hz, 1H), 3.70 (s, 3H), 4.47–4.50 (dd, J = 11.2, 3.2 Hz,1H), 5.05–5.09 (dd, J = 13.6, 3.6 Hz,
1H), 5.17–5.23 (m, 1H), 7.13–7.26 (m, 6H), 7.34–7.38 (t, J = 7.6 Hz, 1H), 7.49–7.53 (t, J = 7.6 Hz,
13
1H), 7.76–7.78 (d, J = 7.6 Hz, 1H); C-NMR (CDCl3, ppm): δ = 202.1, 199.9, 171.2, 169.9, 152.4,
136.2, 135.9, 135.8, 135.7, 134.8, 134.0, 129.07, 129.02, 128.9, 128.7, 128.4, 128.08, 128.03, 126.1,
125.2, 124.5, 62.8, 61.8, 53.3, 47.6, 47.1, 36.6. GC-MS: m/z :339 (M); HPLC: hexane/2-propanol =
80/20, 0.8 mL/min, λ= 210 nm, retention times: (major enantiomer) 14.8 min, (minor enantiomer)
31.5 min, (minor diastereomers) [13.1, 54.6 min].
Methyl 2-(2-nitro-1-p-tolylethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1, entry 2) 6b:
1H-NMR (CDCl3) (ppm): δ = 2.21 (s, 3H), 3.18–3.27 (d, J = 17.2 Hz, 1H), 3.49–3.53 (d, J = 17.2 Hz,
1H), 3.71 (s, 3H), 4.46–4.49 (dd, J = 11.2, 3.2 Hz, 1H), 5.04–5.08 (dd, J = 13.6, 3.2 Hz, 1H), 5.17–
13
5.23 (m, 1H), 7.04–7.43 (m, 7H) ,7.78–7.80 (d, J = 7.6 Hz, 1H); C-NMR (CDCl3, ppm): δ = 202.1,
199.9, 171.2, 169.9, 152.5, 138.1, 136.2, 135.9, 135.7, 134.8, 134.1, 132.7, 131.7, 129.6, 129.4, 128.9,
128.8, 128.0, 127.9, 126.2, 125.2, 124.5, 62.9, 61.9, 53.2, 47.3, 36.5, 21.0. MS (EI):m/z =353.03;
HPLC: hexane/2-propanol = 80/20, 0.8 mL/min, λ= 210 nm, retention times: (major enantiomer)
13.3 min, (minor enantiomer) 28.4 min, (minor diastereomers) [12.5, 48.6 min].
Methyl 2-(1-(2-chlorophenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
1
entry 3) 6c:: H-NMR (CDCl3) (ppm): δ = 3.10–3.17 (dd, J = 17.6, 7.6 Hz, 1H), 3.44–3.56 (dd,
J = 29.6, 17.6 Hz,1H), 3.72 (s, 3H), 5.20–5.44 (m, 3H), 6.89–7.06 (m, 3H) ,7.19–7.51 (m, 4H), 7.75–
13
7.81(dd, J = 19.2, 8 Hz, 1H); C-NMR (CDCl3, ppm): δ = 202.6, 171.5, 152.5, 136.3, 135.9, 135.8,
132.9, 130.1, 129.4, 128.4, 128.0, 127.1, 126.0, 124.4, 62.9, 61.2, 53.3, 42.0, 36.7. MS (EI): m.z =
338.01; HPLC: hexane/2-propanol = 80/20, 0.8 mL/min, λ= 210 nm, retention times: (major
enantiomer) 11.8 min, (minor enantiomer) 33.6 min, (minor diastereomers) [11.3, 16.5 min].
Methyl 2-(1-(4-bromophenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
Entry 4) 6d: 1H-NMR (CDCl3) (ppm): δ = 3.09–3.13 (d, J = 17.6 Hz, 1H), 3.48–3.52 (d, J = 17.6 Hz,
1H), 3.69 (s, 3H), 4.44–4.47 (dd, J = 11.2, 3.6 Hz, 1H), 5.02–5.06 (dd, J = 13.2, 3.2 Hz, 1H), 5.17–
5.23 (dd, J = 13.6, 11.2 Hz, 1H), 7.02–7.04 (d, J = 8.4 Hz, 2H), 7.25–7.29 (m, 3H), 7.34–7.42 (m, 1H),
7.53–7.57 (t, J = 7.2 Hz, 1H), 7.76–7.78 (d, J = 8 Hz,1H); 13C-NMR (CDCl3, ppm): δ = 201.8, 171.0,
152.2, 136.0, 133.9, 131.9, 130.7, 128.2, 126.2, 124.6, 122.6, 100.0, 61.5, 53.4, 47.0, 36.6; MS (EI):
m/z =416.98; HPLC: hexane/2-propanol = 80/20, 1 mL/min, λ= 210 nm, retention times: (major
enantiomer) 17.7 min, (minor enantiomer) 41.4 min, (minor diastereomers) [13.2, 78.6 min].
Methyl 2-(1-(4-methoxyphenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
1
Entry 5) 6e: H-NMR (CDCl3) (ppm): δ = 3.17–3.26 (t, J = 17.6Hz, 1H), 3.48–3.53 (d, J = 17.6 Hz,
1H), 3.69–3.75 (dd, J = 16, 7.2 Hz, 6H), 4.20–4.47 (m, 1H), 5.03–5.41 (m, 2H), 6.67–6.78 (dd, J =
35.2, 8.4 Hz, 2H), 7.07–7.21 (dd, J = 46.4, 8.8 Hz, 2H, 7.26–7.60 (m, 3H), 7.69–7.79 (dd, J = 34.4, 7.6
13
Hz, 1H); C-NMR (CDCl3, ppm): δ = 202.2, 200.0, 171.3, 169.9, 159.3, 152.4, 136.2, 135.9, 135.8,
130.2, 130.1, 128.0, 128.1, 127.5, 126.5, 126.1, 125.2, 124.5, 114.2, 114.1, 63.1, 62.0, 55.1, 53.2, 47.0,

Molecules 2010, 15
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36.6; MS (EI): m/z =369.06; HPLC: hexane/2-propanol = 80/20, 0.5 mL/min, λ = 210 nm, retention
times: (major enantiomer) 29.6 min, (minor enantiomer) 73.6 min, (minor diastereomers)
[28.7, 124.4 min].
Methyl 2-(1-(4-chlorophenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
1
Entry 6) 6f: H-NMR (CDCl3) (ppm):δ = 3.09–3.14 (d, J = 17.6 Hz, 1H), 3.48–3.52 (d, J = 17.6 Hz,
1H), 3.69 (s, 3H), 4.45–4.49 (dd, J = 10.8, 3.2 Hz, 1H), 5.03–5.07 (dd, J = 13.6, 3.6 Hz, 1H), 5.13–
5.19 (dd, J = 13.6, 11.2 Hz, 1H), 7.08–7.27 (m, 5H), 7.36–7.56 (m, 2H), 7.76–7.78 (d, J = 8 Hz, 1H);
13C-NMR (CDCl3, ppm): δ = 201.8, 171.0, 152.2, 136.0, 134.4, 133.4, 130.4, 128.9, 128.2, 126.2,
124.5, 61.6, 53.3, 46.9, 36.6; MS (EI): m/z =373.03; HPLC: hexane/2-propanol = 80/20, 0.8 mL/min,
λ= 210 nm, retention times: (major enantiomer) 20.6 min, (minor enantiomer) 50.7 min, (minor
diastereomers) [14.9, 96.6 min].
Methyl 2-(1-(2,6-dichlorophenyl)-2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
Entry 7) 6g:1H-NMR (CDCl3) (ppm):δ = 3.05–3.12 (dd, J = 17.6, 8.4 Hz, 1H), 3.35–3.60 (m, 2H),
3.72 (s, 3H), 5.14–5.39 (m, 2H), 6.91–7.42 (m, 5H), 7.50–7.55 (dd, J = 14.8, 7.6 Hz, 1H), 7.75–7.82
13
(m, 1H); C-NMR (CDCl3, ppm): δ = 202.3, 199.4, 171.3, 152.3, 136.7, 136.1, 135.5, 134.6, 131.7,
130.0, 128.2, 127.8, 127.5, 126.6, 126.2, 124.7, 124.3, 61.1, 53.4, 41.7, 36.7, 30.3; MS (EI): m/z
=407.08; HPLC: hexane/2-propanol = 80/20, 0.8mL/min, λ= 210 nm, retention times: (major
enantiomer) 13.0 min, (minor enantiomer) 51.6 min, (minor diastereomers) [10.5 ,21.1 min].
Methyl 2-(1-(4-fluorophenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
1
Entry 8) 6h: H-NMR (CDCl3) (ppm):δ = 3.10–3.15 (d, J = 17.6 Hz, 1H), 3.47–3.52 (d, J = 17.6 Hz,
1H), 3.70 (s, 3H), 4.45–4.49 (dd, J = 11.2, 3.6 Hz, 1H), 5.03–5.08 (dd, J = 13.6, 3.6 Hz, 1H), 5.14–
5.20 (dd, J = 13.6, 11.2 Hz, 1H), 6.80–6.86 (m, 2H), 7.10–7.15 (m, 2H), 7.24–7.27 (m, 1H), 7.35–7.39
13
(m, 1H), 7.51–7.55 (m, 1H), 7.75–7.77 (d, J = 8 Hz, 1H). C-NMR (CDCl3, ppm): δ = 201.9,199.8,
171.1, 152.3, 136.0, 130.1, 128.2, 126.1, 124.5,115.6, 61.9, 53.3, 46.9, 36.6; MS (EI): m/z =357.05;
HPLC: hexane/2-propanol = 80/20, 0.8mL/min, λ= 210 nm, retention times: (major enantiomer) 17.2
min, (minor enantiomer) 43.7 min, (minor diastereomers) [13.1, 83.3 min].
Methyl 2-(1-(2-bromophenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
1
Entry 9) 6i: H-NMR (CDCl3) (ppm):δ = 3.13–3.20 (dd, J = 17.6, 8.8 Hz, 1H), 3.40–3.49 (m, 1H),
3.73 (s, 3H), 5.20–5.42 (m, 3H), 6.93–7.05 (m, 2H) , 7.19–7.68 (m, 5H), 7.75–7.81 (m, 1H); 13C-NMR
(CDCl3, ppm): δ = 202.6, 199.4, 171.5, 152.5, 136.3, 135.8, 135.5,134.6, 133.5, 129.6, 128.4, 128.0,
127.8, 126.6,126.0, 124.8,124.3, 62.9, 61.2, 53.3, 44.8, 36.7, 30.3; MS (EI): m/z = 418.21; HPLC:
hexane/2-propanol = 80/20, 0.8 mL/min, λ= 210 nm, retention times: (major enantiomer) 12.3 min,
(minor enantiomer) 35.8 min, (minor diastereomers) [11.8, 16.0 min].
Methyl 2-(1-(4-cyanophenyl) -2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (Table 1,
Entry 10) 6k: 1H-NMR (CDCl3) (ppm): δ = 3.05–3.09 (d, J = 17.6 Hz, 1H), 3.50–3.55 (d, J = 17.6 Hz,
1H), 3.70 (s, 3H), 4.53–4.56 (dd, J = 11.2, 3.6 Hz, 1H), 5.07–5.12 (dd, J = 14, 3.6 Hz, 1H), 5.16–5.22
(dd, J = 14, 11.2 Hz,1H), 7.25–7.46 (m, 6H), 7.53–7.58 (m, 1H), 7.76–7.78(d, J= 8Hz, 1H); 13C-NMR

Molecules 2010, 15
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(CDCl3, ppm): δ = 201.3, 170.7, 151.9, 140.5, 136.2, 135.9, 132.4, 129.9, 128.4, 126.2, 124.7, 118.0,
112.5, 61.4, 53.4, 47.4, 36.6; MS (EI): m/z =363.95; HPLC: hexane/2-propanol = 80/20, 0.8 mL/min,
λ= 210 nm, retention times: (major enantiomer) 47.2 min, (minor enantiomer) 101.4 min, (minor
diastereomers) [24.8, 182.7 min].
Methyl 2-(1-(2-bromophenyl)
-2-nitroethyl)-4-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
1
(Table 1, Entry 11) 6l: H-NMR (CDCl3) (ppm):δ = 2.37 (s, 3H), 3.06–3.13 (dd, J = 17.6, 10.8 Hz,
1H), 3.37–3.47 (dd, J = 24, 17.6 Hz, 1H), 3.72 (s, 3H), 5.19–5.41 (m, 3H),6.95–7.17 (m, 3H) , 7.30–
13
7.34 (t, J = 8 Hz ,1H), 7.47–7.68 (m, 3H); C-NMR (CDCl3, ppm): δ = 202.6, 200.2, 171.6, 150.0,
138.3, 138.1, 137.5, 137.1, 136.5, 134.7, 133.6, 133.5, 129.7, 129.6, 128.4, 127.8, 127.4, 126.0, 125.7,
125.3, 124.6,124.2 ,63.2, 61.5, 53.3, 44.7, 36.4, 29.7, 21.1; MS (EI): m/z = 352.23; HPLC: hexane/2-
propanol = 60/40, 0.4mL/min, λ= 210 nm, retention times: (major enantiomer) 15.5 min, (minor
enantiomer) 43.8 min, (minor diastereomers) [16.1, 17.7 min].
Methyl 2-(1-(2-bromophenyl)
-2-nitroethyl)-4-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
1
(Table 1, Entry 12) 6m: H-NMR (CDCl3) (ppm):δ = 3.04–3.08 (d, J = 17.6 Hz, 1H), 3.22–3.36 (m,
1H), 3.49–3.54 (dd, J = 17.2, 4 Hz, 1H), 3.79 (s, 3H), 3.90 (s, 3H),5.17–5.43 (m, 2H), 6.92–7.27 (m,
5H) , 7.67–7.75 (m, 2H); 13C-NMR (CDCl3, ppm): δ = 200.3, 197.4, 171.7,169.9, 156.7, 155.7, 134.8,
133.4, 129.6, 128.5, 127.8, 126.4, 126.1, 116.3, 116.0, 109.6, 108.9, 63.1, 61.4, 55.8, 53.4, 44.7, 36.6,
30.3, 25.4; MS (EI): m/z = 368.02; HPLC: hexane/2-propanol = 80/20, 0.8 mL/min, λ= 210 nm,
retention times: (major enantiomer) 19.5 min, (minor enantiomer) 32.6 min, (minor diastereomers)
[14.9, 17.2 min].
Methyl 5-bromo-2-(1-(2-bromophenyl)
-2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
1
(Table 1, Entry 13) 6n: H-NMR (CDCl3) (ppm):δ = 3.11–3.18 (dd, J = 17.6, 8.8 Hz, 1H), 3.41–3.54
13
(m, 1H), 3.73 (s, 3H), 5.18–5.40 (m, 3H), 7.05–7.09 (m, 2H), 7.47–7.74 (m, 5H); C-NMR (CDCl3,
ppm): δ = 201.4, 198.9, 171.1, 153.9, 135.1, 134.4, 133.7, 132.0, 131.8, 131.4, 129.8, 129.4, 128.3,
127.9, 127.4, 126.6, 125.4, 62.9, 61.3, 53.4, 44.5, 36.2, 31.6, 25.4; MS (EI): m/z = 418; HPLC:
hexane/2-propanol = 80/20, 0.8 mL/min, λ= 210 nm, retention times: (major enantiomer) 15.0 min,
(minor enantiomer) 37.0 min, (minor diastereomers) [12.7, 18.4 min].
Methyl 2-(1-(2-chlorophenyl)
-2-nitroethyl)-5-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(Table 1, Entry 14) 6o: 1H-NMR (CDCl3) (ppm):δ = 2.37 (s, 3H), 3.04–3.10 (dd, J = 17.6, 9.2 Hz, 1H),
3.37–3.49 (dd, J = 30, 17.6 Hz, 1H), 3.72 (s, 3H), 5.20–5.41 (m, 3H), 6.93–7.10 (m, 3H),7.30–7.67 (m,
4H); 13C-NMR (CDCl3, ppm): δ = 202.6, 200.2, 171.6, 149.9, 138.4, 138.1, 137.5, 137.1, 136.5, 136.0,
130.0, 130.2, 129.4, 128.4, 127.8, 127.1, 126.0, 125.7, 125.3, 124.2, 63.2, 61.5, 53.3, 42.0, 36.4, 21.1;
MS (EI): m/z = 351.94; HPLC: hexane/2-propanol = 60/40, 0.4mL/min, λ = 210 nm, retention times:
(major enantiomer) 15.0 min, (minor enantiomer) 42.5 min, (minor diastereomers) [15.8, 18.2 min].
Methyl 2-(1-(2-chlorophenyl)
-2-nitroethyl)-5-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
1
(Table 1, Entry 15) 6p: H-NMR (CDCl3) (ppm):δ = 3.01–3.06 (d, J = 17.6 Hz, 1H), 3.28–3.40 (m,
1H), 3.49–3.54 (dd, J = 17.2, 4 Hz, 1H), 3.79 (s, 3H), 3.90 (s, 3H), 5.18–5.43 (m, 2H), 6.85–7.40 (m,

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5H), 7.67–7.74 (m, 2H); 13C-NMR (CDCl3, ppm): δ = 200.2, 197.5, 171.8, 169.9, 156.7, 155.7, 135.9,
133.0, 130.0, 129.6, 129.3, 128.5, 127.1, 127.0, 126.4, 126.0, 116.3, 116.0, 109.6, 109.0, 61.4, 55.8,
53.4, 41.9, 36.6, 30.3, 25.4; MS (EI): m/z = 367.96; HPLC: hexane/2-propanol = 80/20, 0.8 mL/min,
λ =210 nm, retention times: (major enantiomer)15.0 min, (minor enantiomer) 36.3 min, (minor
diastereomers) [12.5, 20.1 min].
Methyl 5-bromo-2-(1-(2-chlorophenyl)
-2-nitroethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(Table 1, Entry 16) 6q: 1H-NMR (CDCl3) (ppm):δ = 3.08–3.15 (dd, J = 18, 8Hz, 1H), 3.41–3.52 (dd, J
= 28, 18Hz, 1H), 3.73 (s, 3H), 4.58–4.62 (m, 1H), 5.18–5.40 (m, 2H), 6.96–7.11 (m, 2H), 7.33–7.67
13
(m, 5H); C-NMR (CDCl3, ppm): δ = 201.4, 198.9, 171.1, 153.9, 135.9, 135.1, 132.7, 131.8, 131.4,
130.3, 129.6, 129.4, 128.3, 127.3, 126.6, 125.5, 62.9, 61.3, 53.4, 41.8, 36.2, 29.8, 25.4; MS (EI): m/z =
416.4; HPLC: hexane/2-propanol = 80/20, 0.8 mL/min, λ= 210 nm, retention times: (major
enantiomer)15.0 min, (minor enantiomer) 36.3 min, (minor diastereomers) [12.5, 20.1min].
4. Conclusions
In summary, a study of a dozen of different organocatalysts in the Michael reaction of
1,3-dicarbonyl indane compounds to nitrostyrenes has identified a satisfactory primary amine
organocatalyst. A primary amine-based catalyst, Ts-DPEN, bearing an amino sulfonamide moiety and
with a primary amino group on a chiral scaffold was found to be a simple and efficient bifunctional
organocatalyst for the asymmetric Michael addition of 1,3-dicarbonyl indane compounds to
nitrostyrenes, which gave highly functional Michael adducts with quaternary stereocenters in good
enantioselectivities (up to 92:8 er) and good dr (up to 81:15 dr). Surprisingly, the introduction of
thiourea, amide, phenol, tertiary amine, and imine groups in Ts-DPEN did not lead to higher
enantioselectvities, indicating the importance of the primary amine group in controlling the
enantioselectivity in this Michael reaction. A reasonable catalytic reaction mechanism was proposed
on the basis of the experimental results.
Acknowledgements
This work was supported by the National Natural Science Founder of China (No. 20572114 and
20973051) and Zhejiang Provincial Natural Science Foundation of China (Y4090139).
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Sample Availability: Samples of the compounds available from authors.
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