New class of bifunctional thioureas from l-proline: Highly enantioselective Michael addition of 1,3-dicarbonyls to nitroolefins

Article abstract of DOI:10.1016/j.tetasy.2014.02.011

A new class of bifunctional tertiary amine thiourea was synthesized from l-proline. The reported thiourea is amenable to steric and electronic modifications at the stereogenic center bearing a thiourea moiety. Excellent enantioselectivity was obtained in the Michael addition of 2,4-pentanedione to various nitro olefins using the new organocatalyst. The construction of contiguous stereocenters via the Michael reaction of substituted 1,3-dicarbonyls to nitro olefins was also carried out with very good yield, enantioselectivity, and diastereoselectivity.

Full text of DOI:10.1016/j.tetasy.2014.02.011

Tetrahedron: Asymmetry 25 (2014) 568–577
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New class of bifunctional thioureas from L-proline: highly
enantioselective Michael addition of 1,3-dicarbonyls to nitroolefins
⇑
Poopathy Vinayagam, Manjunatha Vishwanath, Venkitasamy Kesavan
Chemical Biology Laboratory, Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 February 2014
Accepted 26 February 2014
A new class of bifunctional tertiary amine thiourea was synthesized from L-proline. The reported thiourea
is amenable to steric and electronic modifications at the stereogenic center bearing a thiourea moiety.
Excellent enantioselectivity was obtained in the Michael addition of 2,4-pentanedione to various nitro
olefins using the new organocatalyst. The construction of contiguous stereocenters via the Michael reac-
tion of substituted 1,3-dicarbonyls to nitro olefins was also carried out with very good yield, enantiose-
lectivity, and diastereoselectivity.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
from an inexpensive chiral pool for example, tartaric acid,8 we
continued our efforts to develop new organocatalysts from
line. We hoped that proline derived non-covalent organocatalysts
containing tertiary amines and thiourea will emulate the
catalytic efficiency of proline and its derivatives in various enantio-
selective reactions. The modularity of organocatalyst 1, allows the
possibility of changing the electronic and steric environment at the
stereogenic center bearing the thiourea functionality when
compared to other known thioureas. Herein we report the develop-
L-pro-
In recent years, asymmetric organocatalysis has grown rapidly
as an indispensable tool for the synthesis of chiral organic
molecules.1 Multipoint recognition and the activation of reactants
by weak enthalpic binding is the main advantage in non-covalent
catalysis. Chiral thioureas play a vital role as non-covalent organo-
catalysts in enantioselective transformations. The development of
thiourea organocatalysts is an expanding research area in the field
of asymmetric catalysis.2
a
ment of L-proline derived novel bifunctional thiourea 1 and its
Jacobsen et al. reported on the first example of thiourea cata-
lyzed asymmetric Mannich reactions.3 In 2003, Takemoto reported
on a bifunctional thiourea, which comprized of tertiary amine and
a thiourea moiety for the concurrent activation of both a nucleo-
phile and an electrophile.4 Among the numerous reported
thioureas, only a few can be termed as privileged organocatalysts,
which can catalyze different asymmetric transformations. More
precisely tertiary amine thiourea catalysts derived from privileged
chiral building blocks such as cyclohexyl diamine, chincona
alkaloid amine, and chiral BINAM belong to this category (see
Fig. 1).5
application in conjugate additions of 1,3-diketones and b-ketoest-
ers to nitroolefins.
2. Results and discussion
Starting from L-proline (Scheme 1), N-trityl prolinal 3 was ob-
tained using Chemla’s strategy with a change in the oxidation step
(i.e. a Parikh–Doering oxidation was performed instead of a Swern
oxidation).9 The addition of a Grignard reagent to aldehyde 3 affor-
ded phenyl substituted N-trityl prolinol 4, which was transformed
into its corresponding azide
5 under Mitsunobu conditions.
The lack of effective bifunctional organocatalysts stimulated us
to develop a new class of bifunctional tertiary amine thioureas
from L-proline. L-Proline and its derivatives are well known for
Detritylation and N-alkylation provided the phenyl substituted
azido compound 7 in good yield. Azide 7 was reduced using LiAlH4
to yield the amine, which was converted in situ into thiourea 1 by
treatment with 1-isothiocyanato-3,5-bis(trifluoromethyl) benzene
isothiocyanate.
their efficiency as organocatalysts in performing various enantio-
selective transformations via covalent catalysis.6 The Yong Tong
pyrrolidine–thiourea derived from L-proline also belongs to this
Andres et al. observed a low yield and poor enantioselectivity
when organocatalyst 1d (Fig. 2) was used, in which the thiourea
moiety was attached to a non-stereogenic carbon atom.10 Similar
results were obtained for various Michael addition reactions using
category.7 Due to our interest in generating new chiral ligands
⇑
Corresponding author. Tel.: +91 44 2257 4124; fax: +91 44 2257 4102.
E-mail address: vkesavan@iitm.ac.in (V. Kesavan).
organocatalyst 1d.11 To further prove the requirement of
a
http://dx.doi.org/10.1016/j.tetasy.2014.02.011
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
569
reported thioureas derived from priviledged chiral scaffolds:
CF3
S
S
BnHN
N
H
N
H
F3C
N
H
N
H
O
N
R
R
N
cyclohexyl diamine derived thioureas
(Takemoto and Jacobsen)
R'
R''
CF3
N
*
S
N
S
NH
N
H
N
N
H
CF3
F3C
NH
CF3
chincona alkaloid derived thioureas
(Soos, Cannon and Chen)
BINAM derived thiourea (Wang)
thiourea organocatalyst derived from L-proline: (herein)
B
tunable handles:
H
R'
N
A - nitrogen substituent (basicity and nucleophilicity)
B - proline substituent (structural motif)
S
N
CF3
CF3
A
N
D
H
C
R
C - thiourea (hydrogen bonding motif)
H
D - thiourea substituent (rigidity and binding capacity)
1
Figure 1. Various bifunctional thiourea organocatalysis.
H
H
Ph
N3
Ph
(i)
CHO
(ii)
(iii)
N
N
OH
N
N
OH
Tr
Tr
Tr
Tr
5
3
2
4
(iv)
CF3
H
Ph
N
H
Ph
N3
H
Ph
N3
S
(vi),(vii)
(v)
N
N
N
N
H
R
H
R
CF3
H
1a
1b
1c
6
R=Et
7a R=Et
7b R=Bn
7c R=Me
R=Bn
R=Me
Scheme 1. Synthesis of L-proline derived bifunctional thiourea. Reagents and conditions: (i) pyridine–SO3 complex, dry DIEA, dry DMSO, dry DCM, 0 °C, 82% ; (ii) PhMgBr, dry
THF, ꢀ78 °C, dr = 98:2, 58% ; (iii) PPh3, DEAD, DPPA, dry THF, rt, 80% ; (iv) 4 M HCl, ether, rt, 85%; (v) (a) EtBr, K2CO3, dry DMF, rt, 77%; (b) BnBr, K2CO3, dry DMF, rt, 80%; (c)
HCOOH, HCHO, H2O, 100 °C, 62%; (vi) LiAlH4, dry THF, rt; (vii) 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene, dry DCM, rt, 56–70%, over two steps.
Ph
H
Ph
HN
Ph
HN
S
CF3
CF3
S
CF3
CF3
S
CF3
CF3
N
HN
N
N
HN
HN
R
HN
1d
1a R = Et
1b R = Bn
1e
1c
R = Me
Figure 2. Various L-proline based bifunctional organocatalysts used for screening.

570
P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
stereogenic center at the carbon bearing a thiourea moiety, we
synthesized organocatalyst 1e, as shown in Scheme 2. N-Methyla-
tion of amino azide 8,12 followed by reduction using LiAlH4 gave
the amine, which was treated in situ with isothiocyanate to afford
the desired organocatalyst 1e.
Encouraged by this observation, we screened various polar and
non-polar solvents, in which methyl tert-butyl ether was identified
as the most suitable reaction medium (Table 1, entries 6–11).
Using 10 mol % of catalyst 1c, Michael adduct 11a was isolated in
98% yield with 96% enantioselectivity within 12 h at ambient
temperature in methyl tert-butyl ether. Lowering the catalyst
loading to 5 mol % did not affect either the yield or the enantiose-
lectivity (Table 1; entry 12). Further lowering of the catalyst load-
ing to 2 mol % resulted in reduction of enantioselectivity to 61%
(Table 1, entry 13). Thus the Michael addition of 2,4-pentanedione
with nitrostyrene was achieved with quantitative yield and
excellent enantioselectivity using 5 mol % of the newly designed
thiourea organocatalyst 1c.
Ph
Ph
a) HCOOH, HCHO, H2O, 100°C
S
CF3
CF3
Ph
b) LiAlH4, dry THF, rt
Ph
N3
N
HN
HN
N
H
c) 1-isothiocyanato-
3,5-bis(trifluoromethyl)benzene,
dry DCM, rt, 45%, over three steps.
1e
8
Scheme 2. Synthesis of organocatalyst 1e.
A number of nitroolefins 9 were subjected to a Michael addition
with 2,4-pentanedione 10 in the presence of 5 mol % of catalyst 1c
at room temperature. The results are summarized in Table 2. The
presence of halogens such as Cl or Br atoms at the ortho-, meta
and para-positions, had no influence on either the yield or the
enantioselectivity. Quantitative yields and excellent enantioselec-
tivities were obtained for Michael adducts 11b–g (Table 2; entries
2–7). Similar results were observed for 4-fluoro substituted
nitrostyrene which afforded the corresponding Michael adduct
11h (Table 2; entry 8). An electron donating group, such as a meth-
oxy group, lowered the yield of the reaction but the enantioselec-
tivity (94% ee) remained the same (Table 2; entries 9 and 10). The
presence of an electron donating methyl group at the para-position
had no negative effect on the yield or the enantiomeric excess
(Table 2; entry 11). A nitroolefin containing a heteroaromatic
moiety such as a thiophene, underwent Michael addition with
2,4-pentanedione in very good yield and enantioselectivity
(Table 2; entry 12). An electron withdrawing nitro group at the
ortho-position 9m also provided the corresponding product in
good yield and excellent enantioselectivity (Table 2; entry 13).
Various disubstituted nitroolefins yielded the corresponding
Michael adducts in good to very good yields, whereas the enanti-
oselectivity was comparable with mono substituted nitroolefins
(Table 2; entries 14–16). It is noteworthy that the presence of an
–OH in disubstituted nitrostyrene 9n lowered the yield as did
In the literature, conjugate additions were found to be suitable
reactions for examining the catalytic efficacy of new thiourea
organocatalytic systems.13 Hence, the Michael addition of 2,4-pen-
tanedione to nitrostyrene was chosen as the model reaction to
evaluate the efficiency of 1 as an organocatalyst. A solution of
nitrostyrene 9a in toluene was treated with 10 mol % of N-ethyl
thiourea 1a at room temperature, followed by the addition of
2,4-pentanedione 10. Michael adduct 11a was isolated in 72% yield
with 90% ee in 46 h (Table 1, entry 1). The N-benzyl substituted
thiourea 1b did not catalyze the reaction under identical
conditions (Table 1, entry 2). N-Methyl thiourea 1c catalyzed the
Michael addition of 2,4-pentanedione to nitrostyrene with great
efficiency to yield the product in 92% yield and with 91% enantiose-
lectivity (Table 1, entry 3). Organocatalyst 1d in which thiourea
moiety attached to the non-stereogenic carbon atom afforded
Michael adduct in 83% yield with poor enantioselectivity of 9%
(Table 1, entry 4). Only trace amounts of the Michael adduct were
observed when a similar type of organocatalyst 1e was employed
hence, no further attempts were made either to isolate or deter-
mine the enantioselectivity of the product (Table 1, entry 5). These
results demonstrate unequivocally the requirement of a stereogen-
ic center at the carbon bearing a thiourea moiety in organocatalyst
1 scaffold for its effective asymmetric induction.
Table 1
Optimization of reaction conditionsa
O
O
O
O
Ph
1
catalyst
NO2
NO2
solvent, rt, 8-46 hrs
Ph
9a
10
11a
Entry
Organocatalyst (mol %)
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (5)
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CHCl3
CH2Cl2
Hexane
Diethyl ether
Cyclohexane
THF
MTBE
MTBE
MTBE
46
48
26
30
48
30
32
24
48
28
36
12
18
20
72
25
92
83
Trace
95
92
90
84
65
90
—
91
09
—
84
79
86
82
92
89
96
96
61
9
10
11
11
12
13
68
98
95
71
1c (2)
a
Reaction conditions: 2,4-pentanedione 10 (0.5 mmol) was added to an agitated solution of nitroalkene 9a (0.15 mmol) and catalyst
1 (x mol %) in 1.5 mL of MTBE at ambient temperature for the time mentioned.
b
Isolated yields.
c
Enantiomeric excess was determined by chiral HPLC analysis.

P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
571
Table 2
Table 3
Asymmetric Michael addition of 2,4-pentanedione to nitro olefins 8 catalyzed by
Asymmetric Michael addition of various nucleophiles to nitrostyrene 9a using
organocatalyst 1ca
organocatalyst 1ca
O
O
O
O
O
COR'
1c (5 mol%)
O
O
Ph
∗
∗
R'
1c
Ar
(5 mol%)
NO2
NO2
NO2
NO2
MTBE
MTBE, rt, 18 - 36h
Ph
Ar
9a-q
Entry
10
11a-q
12(a-e)
9a
13(a-e)
drc
R
11
Yieldb (%)
eec,d (%),
Entry
1e
12
Yieldb (%)
eed
1
2
3
4
5
6
7
8
Ph 9a
11a
11b
11c
11d
11e
11f
11g
11h
11i
98
90
85
92
92
94
94
93
53
67
89
88
93
96
98
99
98
99
96
97
97
94
94
96
94
98
O
O
2-ClC6H4 9b
3-ClC6H4 9c
4-ClC6H4 9d
2-BrC6H4 9e
3-BrC6H4 9f
4-BrC6H4 9g
4-FC6H4 9h
2-MeOC6H4 9i
4-MeOC6H4 9j
4-MeC6H4 9k
O
92
95
90:10
99:1
95
99
12a
O
2f
3f
4f
5f
12b
9
OEt
O
10
11
12
13
11j
11k
11l
O
87
91
89
80:20
58:42
65:35
98
2-Thiophenyl 9l
2-NO2C6H4 9m
11m
OMe 12c
O
O
14e
11n
68
95
99/98
99/99
OEt
OEt
HO
9n
12d
Cl
F
OMe
O
O
15e
16e
11o
11p
89
80
95
95
MeO
9o
12e
Br
a
Reaction conditions: 1,3-dicarbonyl 12 (0.17 mmol) was added to an agitated
solution of nitroalkene 9a (0.15 mmol) and catalyst 1c (3.45 mg, 0.0075 mmol,
5 mol %) in 1.5 mL of MTBE at the temperature mentioned for 8–12 h.
O
b
9p
Isolated yields.
O
Diastereomeric ratio was determined by 1H NMR analysis.
c
d
a
Enantiomeric excess was determined by chiral HPLC analysis.
Reaction was carried out at 0 °C.
Reactions were carried out at ꢀ15 °C.
Reaction conditions: 2,4-pentanedione 10 (0.5 mmol) was added to an agitated
solution of nitroalkene (0.15 mmol) and catalyst 1c (3.45 mg, 0.0075 mmol,
5 mol %) in 1.5 mL of MTBE at ambient temperature for 8–20 h.
e
9
f
b
Isolated yields.
c
Enantiomeric excess was determined by chiral HPLC analysis.
The absolute configuration of the product was determined as (R) by comparing
d
the specific rotation and HPLC data with the reported literatures.
CF3
e
The absolute configuration was assigned on (R) by analogy.
H
S
NO2
N
the –OMe substituent in 9i, although the enantioselectivty was
unchanged. These disubstituted niroolefins 9n–9p are the first
examples in the literature for asymmetric Michael additions with
2,4-pentanedione. In summary, various substituents such as halo-
gens, electron withdrawing and electron donating groups are well
tolerated under the reaction conditions to afford the corresponding
Michael adducts with excellent enantioselectivity.
N
H
N
CF3
H
H
O
H
O
O
O
Ph
O
N
O
(R)-enantiomer
Ph
Figure 3. Plausible transition states for Michael addition using organocatalyst 1c.
To further expand upon the scope of bifunctional thiourea 1c in
generating contiguous stereogenic centers, the Michael addition of
various substituted 1,3-dicarbonyls to nitrostyrene 9a was
performed. It is evident that, Michael addition of 2-acetyl cyclo-
pentanone 12a with nitrostyrene 9a proceeded (Table 3; entry 1)
with ease to yield the product in good enantioselectivity and
diastereoselectivity (90:10). Encouraged by this result, various
substituted b-ketoesters were subjected to Michael additions with
nitrostyrene 9a. Among them, ethyl-2-oxocyclopentane carboxyl-
ate 12b afforded the corresponding Michael adduct in excellent
diastereoselctivity (99:1) and enantioselectivity (Table 3; entry
2). In the cases of other nucleophiles, only a variation in diastere-
oselectivity was observed while the enantioselectivity remained
as high as 98–99% ee. Substituted b-ketoesters, such as fluoro
and chloro (Table 3; entries 3-5) facilitated the reaction effectively
to yield the corresponding Michael adducts in very good yields. It is
noteworthy that separate optimization was not carried out for
these nucleophiles other than changing the temperature.
On the basis of stereoisomeric outcome, synergistic activation
model for the Michael reaction of 2,4-pentanedione to phenyl nitro-
styrene is proposed. The possible transition state for the substrate-
organocatalyst interaction is shown in Figure 3. Deprotonation of
the acidic proton from acetyl acetone by the tertiary amino group
of the catalyst, led to the formation of an ammonium ion and the
activation of nitrostyrene 9a occurs through this ammonium moiety
while the thiourea engages in H-bonding with the enolate.14 From
the absolute configuration of 11a, the new C–C bond was formed
by the nucleophilic attack on the ‘Re’ face of nitrostyrene 9a.
3. Conclusion
In conclusion, we have developed a new class of bifunctional
thiourea from
L-proline, an inexpensive chiral pool material.

572
P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
Organocatalyst 1c was successfully applied to the Michael addition
of 1,3-dicarbonyl compounds and b-ketoesters to nitrostyrene with
excellent enantioinduction. Exploration of the newly developed
thiourea in other asymmetric transformations is in progress in
our laboratory. Further efforts are also being undertaken to obtain
the organocatalyst 1c in fewer synthetic steps. We expect that it is
poised to play an active role in the field of asymmetric catalysis,
which is currently being explored in our laboratory.
the solvents removed in vacuo. The resulting solid was purified
by column chromatography on silica gel (Hexane/EtOAc/Et3N,
9:1:0.2) to afford compound 4 (2.4 g, 58%) as a white foamy solid.
Analytical data matched with previously reported values. 1H NMR
(500 MHz, CDCl3): d 7.65 (d, J = 7.5 Hz, 6H), 7.18–7.34 (m, 12H),
7.14 (d, J = 7.0 Hz, 2H), 5.17 (d, J = 3.5 Hz, 1H), 3.78 (ddd, J = 8.5,
5.0, 3.5 Hz, 1H), 3.34 (br s, 1H), 3.34 (ddd, J = 12.0, 9.0, 7.0 Hz,
1H), 3.09 (ddd, J = 11.5, 8.0, 3.5 Hz, 1H), 1.49 (ddt, J = 12.0, 8.0,
5.0 Hz, 1H), 1.32–1.40 (m, 1H), 0.084 (ddt, J = 13.0, 8.5, 4.5 Hz,
1H), 0.26 (m, 1H); 13C NMR (125 MHz, CDCl3): d 144.7, 142.4,
130.0, 128.1, 127.7, 126.6, 126.5, 125.5, 78.3, 75.7, 66.2, 53.4,
25.9, 24.9.
4. Experimental
4.1. Materials and methods
4.2.3. (S)-2-((S)-Azido (phenyl)methyl)-1-tritylpyrrolidine 5
To a solution of compound 4 (1 g, 2.25 mmol) and PPh3 (1.2 g,
4.5 mmol) in dry THF (10 mL), diethyl azodicarboxylate (0.78 mL,
4.5 mmol) was added dropwise at 0 °C followed by a similar
addition of diphenyl phosphoryl azide (0.6 mL, 2.7 mmol) under
an argon atmosphere. The resulting solution was allowed to warm
and stirred for 8 h at ambient temperature. The reaction mixture
was concentrated through in vacuo, after which water was added
and extracted using EtOAc. The organic phase was separated, dried
over sodium sulfate, and concentrated in vacuo. The crude material
was purified by column chromatography on silica gel using Hex-
ane/Et3N (99.5:0.5) as eluent to obtain the product 5 (0.76 g,
All reactions were carried out in an oven dried flask. The
solvents used for the reactions and column chromatography were
of commercial grade and distilled prior to use. Toluene and THF
were dried over sodium/benzophenone, CH2Cl2 and CHCl3 over
CaH2. Solvents for HPLC were bought as analytical grade and used
without further purification. TLC was performed on pre-coated
silica gel aluminum plates with 60F254 indicator, visualized by
irradiation with UV light. Column chromatography was performed
using silica gel 60–100 mesh. 1H NMR and 13C NMR were recorded
on a 500 MHz spectrometer using CD3OD-d4 and CDCl3 as the sol-
vent; multiplicities are indicated as follows: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt
(doublet of triplet) br s (broad singlet). Coupling constants J were
reported in Hertz. High resolution mass spectra were obtained by
ESI using a Q-TOF mass spectrometer. IR spectra were recorded
in terms of frequency of absorption (cmꢀ1). The enantiomeric ex-
cess was obtained by HPLC analysis using a chiral stationary phase
column (CHIRALPAK AD-H, AS-H and OD-H). Optical rotations were
recorded using a polarimeter at a wavelength of 589 nm.
80%) as white solid. Mp: 123–126 °C; ½a D25
¼ ꢀ99:3 (c 1.0, CHCl3);
ꢁ
IR(KBr):
m = 3349, 2985, 2958, 2895, 2102, 1599, 1487, 1446,
1359, 1301, 1277, 1027, 747, 707, 698, 648 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d 7.60 (d, J = 7 Hz, 6H), 7.27 (t, J = 7.5 Hz, 6H),
7.15–7.21(m, 6H), 6.86 (d, J = 7 Hz, 1H), 5.26 (d, J = 2.5 Hz, 1H),
3.76 (dt, J = 8.5, 3 Hz, 1H), 3.38–3.44 (m,1H), 3.02–3.07 (m, 1H),
1.36–1.49 (m, 2H), 0.80–0.88 (m, 1H), 0.14–0.24 (m, 1H); 13C
NMR (125 MHz, CDCl3): d 144.8, 138.9, 129.9, 128.2, 127.6, 127.2,
126.3, 126.0, 78.4, 70.9, 67.3, 51.9, 25.5, 24.9; HRMS (ESI): m/z cal-
culated for C30H28N4+Na+: 467.2212, found: 467.2226.
4.2. Synthesis of organocatalyst 1a, 1b, 1c, and 1e
4.2.1. (S)-1-Tritylpyrrolidine-2-carbaldehyde 39
4.2.4. (S)-2-((S)-Azido(phenyl)methyl)pyrrolidine 6
A
solution of (S)-(1-tritylpyrrolidin-2-yl)methanol 2 (6 g,
To a solution of 5 (1 g, 4.9 mmol) in Et2O (10 mL) was added HCl
(4 M aqueous solution, 10 mL). After 3 h of vigorous stirring, the
two phases were separated, and the aqueous layer was washed
three times with Et2O (3 ꢂ 5 mL). The aqueous phase was cooled
and made alkaline with concentrated aqueous NaOH followed by
extraction with CHCl3 (3 ꢂ 10 mL). The extract was dried over
anhydrous sodium sulfate and the solvents were evaporated in va-
cuo. Purification was carried out by column chromatography using
silica gel (Hexane/EtOAc–75:25) to afford the title compound 6
17.4 mmol) in 20 mL of dry CH2Cl2 and 60 mL of dry DMSO (1:3)
was cooled to 0 °C under a nitrogen atmosphere. Dry diethyl
isopropyl amine (9.1 mL, 52.4 mmol) was added, then pyridine–
SO3 complex (active SO3 48–50%, 157.2 mmol) was added portion-
wise and allowed to stir at the same temperature for 6 h, after
which it was diluted with 60 mL of CH2Cl2 and 80 mL of water.
The organic layer was washed repeatedly using water and finally
with a brine solution. The organic phase was separated and dried
over anhydrous sodium sulfate, filtered, and concentrated. The
crude material was purified through silica gel column using hex-
ane/Et3N (99.5:0.5) as eluent to afford product 3 (4.9 g, 82%) as a
white solid. Analytical data matched with previously reported
values. 1H NMR (500 MHz, CDCl3): d 9.88 (d, J = 3.0 Hz, 1H), 7.59
(d, J = 7.5 Hz, 6H), 7.30 (t, J = 7.5 Hz, 6H), 7.20 (t, J = 7.5 Hz, 3H),
3.79 (dt, J = 9.0, 3.3 Hz, 1H), 3.31 (dt, J = 11.5, 7.0 Hz, 1H), 2.94
(ddd, J = 11.5, 7.0, 4.0 Hz, 1H), 1.62 (ddd, J = 17.0, 8.0, 4.0 Hz, 1H),
1.39–1.49 (m, 1H), 1,14 (ddd, J = 17.0, 12.5, 8.5 Hz, 1H), 0.76–0.86
(m, 1H); 13C NMR (125 MHz, CDCl3): d 204.4, 144.5, 129.5, 127.8,
126.5, 77.0, 68.5, 50.7, 28.1, 24.4.
(0.389 g, 85%) as a yellow oil. ½a D25
ꢁ
¼ ꢀ184:6 (c 1.0, CHCl3); IR(KBr):
m
= 3062, 2965, 2794, 2101, 1494, 1452, 1288, 1123, 741,
699 cmꢀ1
; d 7.37–7.40 (m, 2H),
1H NMR (500 MHz, CDCl3):
7.31–7.35 (m, 3H), 4.36 (d, J = 8 Hz, 1H), 3.33 (q, J = 7 Hz, 1H),
2.94–2.99 (m, 1H), 2.80–2.85 (m, 1H), 1.88–1.94 (m, 1H), 1.78–
1.86 (m, 1H), 1.63–1.77 (m, 3H); 13C NMR (125 MHz, CDCl3): d
138.3, 128.8, 128.3, 127.4, 70.3, 62.9, 46.4, 28.3, 25.0; HRMS
(ESI): m/z calculated for C11H15N4+H+: 203.1297, found: 203.1290.
4.2.5. (S)-2-((S)-Azido (phenyl)methyl)-1-ethylpyrrolidine 7a
To a solution of compound 6 (0.5 g, 2.1 mmol) in dry DMF,
K2CO3 (0.348 g, 2.5 mmol) was added and stirred for a few min-
utes, after which ethyl bromide (0.19 mL, 2.5 mmol) was added
and stirred overnight at ambient temperature. The reaction
mixture was diluted with water and extracted using CH2Cl2. The
organic phase was washed three times with water, separated, dried
over sodium sulfate, and concentrated. Purification was carried out
by column chromatography using silica gel (Hexane/EtOAc–97:3)
4.2.2. (R)-Phenyl ((S)-1-tritylpyrrolidin-2-yl)methanol 49
To aldehyde 3 (3.41 g, 10 mmol) in dry Et2O (100 mL) under ar-
gon was added PhMgBr solution (30 mmol) at ꢀ80 °C. The reaction
was followed by TLC. After 5 h of stirring, the reaction was hydro-
lyzed at ꢀ80 °C with a 2:1 mixture of a saturated aqueous NH4Cl
solution and NH3 (28% in water). The layers were separated, and
the aqueous layer was extracted twice with CH2Cl2. The combined
organic phases were dried over anhydrous sodium sulfate and
to give compound 7a (0.438 g, 77%) as
a
colorless liquid.
½
a 2D5
ꢁ
¼ ꢀ165:3 (c 1.0, CHCl3); IR (KBr):
m = 3421, 2924, 2854,

P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
573
2106, 1628, 1444, 1377, 1275, 1110, 770, 703, 650 cmꢀ1
;
1H NMR
chromatography using silica gel (Hexane/EtOAc–85:15) to afford
(500 MHz, CDCl3): d 7.33–7.36 (m, 2H), 7.27.7.32 (m, 3H), 4.70 (d,
J = 3.5 Hz, 1H), 3.23 (td, J = 9, 2 Hz, 1H), 2.79–2.88 (m, 1H), 2.71–
2.75 (m, 1H), 2.27–2.34 (m, 1H), 2.16–2.21 (m, 1H), 1.84–1.91
(m, 1H), 1.75–1.83 (m, 1H), 1.64–1.70 (m, 1H), 1.50–1.58 (m,
1H), 1.10 (t, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 138.5,
128.4, 127.6, 126.9, 69.7, 67.0, 53.6, 48.6, 25.7, 23.2, 13.8; HRMS
(ESI): m/z calculated for C13H18N4+H+: 231.1610, found: 231.1615.
the title compound 1a (0.266 g, 56%) as a colorless foamy solid.
Mp: 73–76 °C; ½a 2D5
ꢁ
¼ ꢀ82:2 (c 1.0, CHCl3); IR (KBr):
m = 3251,
2972, 1600, 1543, 1473, 1384, 1273, 1176, 1134, 1000, 960, 885,
700, 681 cmꢀ1 1H NMR (500 MHz, CD3OD): d 8.22 (s, 2H), 7.63
;
(s, 1H), 7.25–7.34 (m, 5H), 5.71 (s,1H), 3.25 (t, J = 4.0 Hz, 1H),
2.94–3.01 (m, 2H), 2.3(br s, 2H), 1.76 (br s, 4H), 1.10 (t, J = 7 Hz,
3H); 13C NMR (125 MHz, CD3OD): d 183.2, 143.4, 141.5, 132.7 (q,
J = 33.75 Hz), 129.6, 128.0, 17.5, 124.7 (q, J = 270 Hz), 121.5,
117.8, 70.2, 59.2, 54.1, 49.6, 26.9, 23.0, 13.6; HRMS (ESI): m/z
calculated for C22H23F6N3S+H+: 476.1595, found: 476.1591.
4.2.6. (S)-2-((S)-Azido(phenyl)methyl)-1-benzylpyrrolidine 7b
To a solution of compound 6 (0.5 g, 2.1 mmol) in dry DMF,
K2CO3 (0.348 g, 2.5 mmol) was added and stirred for a few min-
utes, after which benzyl bromide (0.29 mL, 2.5 mmol) was added
and stirred overnight at ambient temperature. The reaction
mixture was diluted with water and extracted using CH2Cl2. The
organic phase was washed three times with water, separated, dried
over sodium sulfate, and concentrated. Purification was carried out
by column chromatography using silica gel (Hexane/EtOAc–98:2)
4.2.10. 1-((S)-((S)-1-Benzylpyrrolidin-2-yl)(phenyl)methyl)-3-
(3,5-bis(trifluoromethyl)phenyl)thiourea 1b
Prepared according to general procedure using compound 7b
(293.2 mg, 1 mmol). Purification was carried out by column
chromatography using silica gel (Hexane/EtOAc–90:10) to afford
the title compound 1b (0.349 g, 65%) as a colorless foamy solid.
to give compound 7b (0.585 g, 81%) as
¼ ꢀ105:0 (c 1.0, CHCl3); IR (KBr):
2101, 1494, 1452, 1288, 1123, 741, 699 cmꢀ1
a
colorless liquid.
= 3295, 2965, 2794,
1H NMR (500 MHz,
Mp: 52–55 °C; ½a 2D5
ꢁ
¼ ꢀ127:2 (c 1.0, CHCl3); IR (KBr):
m = 3251,
½
a 2D5
ꢁ
m
3030, 2969, 1599, 1538, 1473, 1384, 1277, 1175, 1133, 1075,
;
885, 847, 699 cmꢀ1 1H NMR (500 MHz, CD3OD): d 8.11 (s, 2H),
;
CDCl3): d 7.32–7.36 (m, 6H), 7.25.7.29 (m, 4H), 4.59 (d, J = 2 Hz,
1H), 3.95 (d, J = 13 Hz, 1H), 3.51 (d, J = 13 Hz, 1H), 3.05 (t,
J = 7.5 Hz, 1H), 2.95–2.97 (m, 1H), 2.26–2.30 (m, 1H), 1.91–1.96
(m, 1H), 1.76–1.86 (m, 1H), 1.60–1.71 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 139.5, 138.5, 128.9, 128.4, 128.3, 127.6,
127.1, 127.0, 69.7, 67.3, 59.8, 54.9, 26.1, 23.6; HRMS (ESI): m/z
calculated for C18H20N4+H+: 293.1766, found: 293.1766.
7.53(s, 1H), 7.07–7.24(m, 10H), 5.73(s, 1H), 4.00(br, d, J = 12.5 Hz,
1H), 3.20(br, 1H), 2.85–2.93(m, 2H), 2.20(br, 1H), 1.57–1.72(m,
4H); 13C NMR (125 MHz, CD3OD): d 182.0, 161.9, 141.9, 140.2,
138.6, 131.3(q, J = 32.5 Hz), 129.0, 128.3, 128.1, 126.9, 125.2(q,
J = 298 Hz), 120.1, 116.6, 68.0, 58.2, 53.6, 26.5, 25.7, 21.7; HRMS
(ESI): m/z calculated for
538.1750.
C
27H25F6N3S+H+: 538.1752, found:
4.2.7. (S)-2-((S)-Azido(phenyl)methyl)-1-methylpyrrolidine 7c
Amino azide 6 (0.5 g, 2.1 mmol) was dissolved in water (2 mL),
and HCOOH (98%, 1 mL) and HCHO (37% aqueous solution, 1.5 mL)
were added. The reaction mixture was stirred for 3 h at reflux and
then cooled and made alkaline with concentrated aqueous NaOH,
followed by extraction with CH2Cl2. The extract was dried over so-
dium sulfate and the solvent evaporated in vacuo. The residue was
purified over silica gel hexane/EtOAc (92:8) as eluent to afford the
4.2.11. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-((S)-1-methyl
pyrrolidin-2-yl)(phenyl)methyl)thiourea 1c
Prepared according to general procedure using compound 7c
(217.2 mg, 1 mmol). Purification was carried out by column
chromatography using silica gel (Hexane/EtOAc–85:15) to afford
the title compound 1c (0.325 g, 70%) as a colorless foamy solid.
Mp: 56–59 °C; ½a 2D5
ꢁ
¼ ꢀ43:5 (c 1.0, CHCl3); IR (KBr):
m = 3287,
2924, 2854, 1744, 1470, 1384, 1277, 1176, 1134, 885, 700,
title compound 7c (0.331 g, 62%) as
¼ ꢀ119:0 (c 1.0, CHCl3); IR (KBr):
1633, 1453, 1277, 1176, 1136, 742, 702 cmꢀ1
a
m
slightly yellow oil.
681 cmꢀ1 1H NMR (500 MHz, CD3OD): d 8.23 (s, 2H), 7.62 (s,
;
½
a 2D5
ꢁ
= 3417, 2854, 2102,
1H), 7.33–7.36 (m, 4H), 7.24–7.27 (m, 1H), 5.75 (s, 1H), 3.12 (t,
J = 7.0 Hz, 1H), 2.71 (s, 1H), 2.41 (s, 3H), 2.31 (d, J = 7.0 Hz, 1H),
1.64–1.78 (m, 4H); 13C NMR (125 MHz, CD3OD): d 183.1, 143.4,
141.6, 132.7 (q, J = 32.5 Hz), 129.5, 128.3, 127.9, 124.7 (q,
J = 270 Hz), 133.4, 117.7, 71.6, 58.9, 58.1, 41.1, 27.0, 22.9 ; HRMS
;
1H NMR (500 MHz,
CDCl3): d 7.35–7.38 (m, 2H), 7.28.7.33 (m, 3H), 4.71 (d, J = 4 Hz,
1H), 3.11–3.14 (m, 1H), 2.48–2.51 (m, 1H), 2.34 (s, 3H),
2.21–2.26 (m, 1H), 1.88–1.94 (m, 1H), 1.74–1.83 (m, 1H),
1.62–1.68 (m, 1H), 1.56–1.62 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 138.4, 128.6, 127.8, 127.0, 71.0, 66.6, 57.5, 40.9, 25.9, 22.8; HRMS
(ESI): m/z calculated for C12H16N4+H+: 217.1453, found: 217.1450.
(ESI): m/z calculated for
C
21H21F6N3S+H+: 462.1439, found:
462.1434.
4.2.12. Synthesis and characterization of thiourea organano
catalyst 1e
4.2.8. General procedure for synthesis of thiourea 1a, 1b, and 1c
from the corresponding N-alkyl azide 7
Amino azide 8 (0.5 mg, 1.8 mmol) was dissolved in water
(2 mL), after which HCOOH (98%, 1 mL) and HCHO (37% aqueous
solution, 1.5 mL) were added. The reaction mixture was stirred
for 3 h at reflux, cooled, and then made alkaline with concentrated
aqueous NaOH, followed by extraction with CH2Cl2. To LiAlH4
(68.4 mg, 1.8 mmol) in 1 mL of dry THF, a solution of crude product
in 2 mL of dry THF was slowly added under ice cold conditions
under an argon atmosphere. The resulting mixture was stirred at
room temperature for 1.5 h, and then quenched using 5% aqueous
sodium potassium tartarate solution. The reaction mixture was
filtered through a short Celite pad, dried over sodium sulfate, and
concentrated in vacuo. The resulting yellowish liquid was
dissolved in dry CH2Cl2 (4 mL), after which 1-isothiocyanato-3,5-
bis(trifluoromethyl) benzene (0.33 mL, 1.8 mmol) was added and
allowed to stir for 18 h at room temperature. The volatiles are
removed in vacuo and purified by column chromatography using
silica gel. The residue was purified over silica gel (Hexane/
EtOAc–98:2) to afford compound 1e (0.434 g, 45% yield) as a foamy
To LiAlH4 (38 mg, 1 mmol) in 1 mL of dry THF, a solution of
compound 7 (1 mmol) in 2 mL of dry THF was slowly added under
ice cold conditions under an argon atmosphere. The resulting
mixture was stirred at room temperature for 1.5 h and then
quenched using 5% aqueous sodium potassium tartarate solution.
The reaction mixture was filtered through a short Celite pad, dried
using sodium sulfate, and concentrated in vacuo. The resulting
yellowish liquid was dissolved in dry CH2Cl2 (3 mL), after which
1-isothiocyanato-3,5-bis (trifluoromethyl) benzene (0.22 mL,
1.2 mmol) was added and allowed to stir for 18 h at room temper-
ature. Volatiles are removed in vacuo and purified by column
chromatography using silica gel.
4.2.9. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-((S)-1-ethyl
pyrrolidin-2-yl)(phenyl)methyl)thiourea 1a
Prepared according to general procedure using compound 7a
(231.31 mg, 1 mmol). Purification was carried out by column

574
P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
white paste. [
a
]
26 = +300.0 (c 1.0, CHCl3); IR (KBr):
m
= 3263, 2989,
1H
desired product was obtained as a white solid (36.18 mg, 85% yield).
Analytical data matched with previously reported values. 1H NMR
(500 MHz, CDCl3): d 7.42–7.44 (t, J = 2.0 Hz, 1H), 7.22–7.31(m, 2H),
7.15–7.19 (m, 1H), 4.82–4.88 (dd, J = 6.5 Hz, 11.5 Hz, 1H), 4.73–4.79
(m, 1H), 4.69–4.70 (d, J = 3.5 Hz, 1H), 4.61–4.66 (dd, J = 3.5 Hz,
7.5 Hz, 1H), 2.31 (s, 3H), 2.05 (s, 3H); 13C NMR (125 MHz, CDCl3): d
201.9, 200.9, 133.8, 133.4, 130.7, 129.7, 129.0, 127.7, 76.2, 69.0,
38.8, 30.9, 28.4; HPLC (AD-H, hexane/2-propanol = 97/3, flow rate-
0.8 mL/min, 210 nm): tminor = 23.6 min, tmajor = 26.8 min, ee = 99%.
D
2832, 1732, 1510, 1311, 1239, 1102, 1176, 879, 721, 679 cmꢀ1
;
NMR (500 MHz, CD3OD): d 7.93 (s, 2H), 7.59 (s, 1H), 7.52 (d,
J = 8.0 Hz, 4H), 7.34 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 7.21
(t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.68 (dd, J = 9.5, 3.5 Hz,
1H), 3.10–3.06 (m, 1H), 2.71 (m, 1H), 2.49 (s, 3H), 2.40–2.32 (m,
1H), 2.03–2.01 (m, 1H), 1.91–1.85 (m, 1H); 13C NMR (125 MHz,
CD3OD): d 183.6, 147.2, 143.9, 143.4, 132.8 (q, J = 33 Hz), 130.1,
129.4, 128.7, 128.4, 128.2, 127.4, 124.7 (q, J = 270 Hz), 123.4,
118.0, 75.9, 72.4, 59.3, 45.1, 31.4, 25.5; HRMS (ESI): m/z calculated
for C27H25F6N3S+H+: 538.1746, found: 538.1761.
4.2.18. (R)-3-(1-(4-Chlorophenyl)-2-nitroethyl)pentane-2,4-
dione 11d13b
4.2.13. General procedure A for the enantioselective Michael
addition of 2,4-pentanedione to nitroolefins
Prepared according to general procedure A using b-nitrostyrene
9d (27.5 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 11 h. After column chromatogra-
phy, the desired product was obtained as a white solid (39.16 mg,
92% yield). Analytical data matched with previously reported val-
ues. 1H NMR (500 MHz, CDCl3): d 7.29–7.33(m, 2H), 7.12–7.16(m,
2H), 4.60–4.62(t, J = 2 Hz, 2H), 4.32–4.35(d, J = 11 Hz, 1H), 4.19–
4.27(m, 1H), 2.30(s, 3H), 1.98(s, 3H); 13C NMR (125 MHz, CDCl3):
d 201.4, 200.6, 134.6, 134.5, 129.6, 129.3, 77.9, 70.5, 42.1, 30.5,
29.7; HPLC (AS-H, hexane/2-propanol = 85/15, flow rate-1 mL/
min, 210 nm): tminor = 12.8 min, tmajor = 23.2 min, ee = 98%.
To a stirred solution of 1c (3.45 mg, 0.0075 mmol, 5 mol %) and
nitroalkene 9 (0.15 mmol) in MTBE (1.5 mL), 2,4-pentanedione 10
(0.5 mmol) was added under argon. The solution was stirred at
ambient temperature for 8–20 h. After the reaction was completed
(monitored by TLC), the resulting mixture was concentrated under
reduced pressure and the residue was purified by column chroma-
tography on silica gel to give the product.
4.2.14. General procedure B for the enantioselective Michael
addition of substituted 1,3-dicarbonyls to nitrostyrene
To a stirred solution of 1c (3.45 mg, 0.0075 mmol, 5 mol %)
and nitroalkene 9a (0.15 mmol) in MTBE (1.5 mL), substituted
1,3-dicarbonyl 12 (0.17 mmol) was added under argon. The
solution was stirred at the mentioned temperature for 8–12 h.
After the reaction was completed (monitored by TLC), the resulting
mixture was concentrated under reduced pressure and the residue
was purified through column chromatography on silica gel.
4.2.19. (R)-3-[1-(2-Bromophenyl)-2-nitroethyl]-pentane-2,4-
dione 11e13i,18
Prepared according to general procedure A using b-nitrostyrene
9e (34.21 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 8 h. After column chromatogra-
phy, the desired product was obtained as a pale brown solid
(45.3 mg, 92% yield). Analytical data matched with previously re-
ported values. 1H NMR (500 MHz, CDCl3): d 7.64 (dd, J = 8, 1.5 Hz,
1H), 7.29 (td, J = 7.5, 1.5 Hz, 1H), 7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.14
(dd, J = 8, 1.5 Hz, 1H), 4.84 (dd, J = 12.0, 6.5 Hz, 1H), 4.75 (ddd,
J = 10, 6.5, 4.0 Hz, 1H), 4.68 (dd, J = 12.5, 4.0 Hz, 1H), 4.61 (d,
J = 9.5 Hz, 1H), 2.32 (s, 3H), 2.05 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 202.0, 200.9, 134.0, 130.0, 128.7, 128.3, 124.6, 76.2,
69.1, 41.0, 31.0, 28.3; HPLC (OD-H, hexane/2-propanol = 95/5, flow
rate-0.8 mL/min, 254 nm): tminor = 37.5 min, tmajor = 46.7 min,
ee = 99%.
4.2.15. (R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione 11a13a,15
Prepared according to general procedure A using b-nitrostyrene
9a (22.37 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 10 h. After column chromatogra-
phy, the desired product was obtained as a white solid (36.62 mg,
98% yield). Analytical data matched with previously reported
values. 1H NMR (500 MHz, CDCl3):
d 7.28–7.36 (m, 3H),
7.16–7.21 (m, 2H), 4.65 (dd, J = 12.5, 7.5 Hz, 1H), 4.60 (dd,
J = 12.5, 5.0 Hz, 1H), 4.16–4.27 (m, 2 H), 4.37 (d, J = 11 Hz, 1H),
4.19–4.27 (m, 1H), 2.29 (s, 3H), 1.93 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 201.7, 200.9, 135.8,129.3, 128.6, 127.8, 78.2, 70.7, 42.8,
30.4, 29.5; HPLC (AD-H, hexane/IPA = 90/10, flow rate-1.0 mL/
min, 210 nm): tminor = 9.2 min, tmajor = 12.1 min; ee = 96%.
4.2.20. (R)-3-[1-(3-Bromophenyl)-2-nitroethyl]-pentane-2,4-
dione 11f17,18
Prepared according to general procedure A using b-nitrostyrene
9f (34.21 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 9 h. After column chromatogra-
4.2.16. (R)-3-(1-(2-Chlorophenyl)-2-nitroethyl)pentane-2,4-
dione 11b13b
phy, the desired product was obtained as a white solid
(46.28 mg, 94% yield). Analytical data matched with previously re-
ported values. 1H NMR (500 MHz, CDCl3): d 7.42 (ddd, J = 8.0, 1.5,
1.0 Hz, 1H), 7.34 (t, J = 1.5 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.11
(dt, J = 7.0, 1.0 Hz, 1H), 4.63 (dd, J = 13.0, 7.5 Hz, 1H), 4.59 (dd,
J = 13.0, 5.0 Hz, 1H), 4.33 (d, J = 10.5 Hz, 1H), 4.19 (ddd, J = 10.5,
7.5, 5.0 Hz, 1H), 2.28 (s, 3H), 1.99 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 201.2, 200.4, 138.4, 131.7, 131.0, 130.8, 126.5, 123.3,
77.7, 70.3, 42.2, 30.5, 29.8; HPLC (AS-H, hexane/2-propanol = 85/
15, flow rate-1 mL/min, 210 nm): tminor = 14.6 min, tmajor = 26.4 min,
ee = 96%.
Prepared according to general procedure A using b-nitrostyrene
9b (27.5 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 10 h. After column chromatogra-
phy, the desired product was obtained as a white solid (38.30 mg,
90% yield). Analytical data matched with previously reported val-
ues. 1H NMR (500 MHz, CDCl3): d 7.42–7.44 (t, J = 2.0 Hz, 1H),
7.21–7.30 (m, 2H), 7.14–7.18 (m, 1H), 4.81–4.87 (dd, J = 6.5 Hz,
11.5 Hz, 2H), 4.72–4.78 (m, 1H), 4.59–4.69 (m, 1H), 2.30 (s, 3H),
2.04 (s, 3H); 13C NMR (125 MHz, CDCl3): d 201.9, 200.9, 133.8,
133.4, 130.7 129.7, 129.0, 127.7, 76.2, 69.0, 38.8, 30.9, 28.4; HPLC
(AS-H, hexane/IPA = 90/10, flow rate-0.6 mL/min, 210 nm):
tminor = 20.6 min, tmajor = 22.3 min, ee = 98%.
4.2.21. 3-((R)-1-(4-Bromophenyl)-2-nitroethyl)pentane-2,4-
dione 11g13h,23
Prepared according to general procedure A using b-nitrostyrene
9g (34.21 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 8 h. After column chromatogra-
4.2.17. (R)-3-(1-(3-Chlorophenyl)-2-nitroethyl)pentane-2,4-
dione 11c13b,16
Prepared according togeneral procedureA using b-nitrostyrene 9c
(27.5 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg, 0.5 mmol),
the reaction time was 12 h. After column chromatography, the
phy, the desired product was obtained as a white solid
(46.28 mg, 94% yield). Analytical data matched with previously re-
ported values. 1H NMR (500 MHz, CDCl3): d 7.47 (d, J = 8.5 Hz, 2H),

P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
575
7.08 (d, J = 8.5 Hz, 2H), 4.66–4.59 (m, 2H), 4.33 (d, J = 10.5 Hz, 1H),
4.26–4.19 (m, 1H), 2.29 (s, 3H), 1.98 (s, 3H); 13C NMR (125 MHz,
CDCl3): d = 201.3, 200.5, 135.0, 132.5, 129.6, 122.6, 77.8, 70.4,
42.1, 30.4, 29.7; HPLC (AS-H, hexane/2-propanol = 85/15, flow
rate-1 mL/min, 210 nm): tminor = 14.6 min, tmajor = 26.4 min,
ee = 97%.
4.2.26. (S)-3-(2-Nitro-1-(thiophen-2-yl)ethyl)pentane-2,4-dione
11l13b,g
Prepared according to general procedure A using b-nitrostyrene
9l (23.27 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 12 h. After column chromatogra-
phy, the desired product was obtained as
a colorless solid
(33.70 mg, 88% yield). Analytical data matched with previously
reported values. 1H NMR (500 MHz, CDCl3) d 7.16 (dd, J = 5.0,
1.0 Hz, 1H), 6.86 (dd, J = 5.0, 3.5 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H),
4.58 (m, 2H), 4.47 (m, 1H), 4.32 (d, J = 10.0 Hz, 1H), 2.22 (s, 3H),
2.01 (s, 3H); 13C NMR (125 MHz, CDCl3) d 200.5, 199.6, 137.4,
126.4, 126.0, 124.7, 77.5, 70.0, 37.2, 29.5, 28.6; HPLC (AS-H,
hexane/2-propanol = 90/10, flow rate-0.6 mL/min, 210 nm):
tminor = 32.8 min, tmajor = 42.4 min, ee = 94%.
4.2.22. (R)-3-(1-(4-Fluorophenyl)-2-nitroethyl)pentane-2,4-dione
11h13b
Prepared according to general procedure A using b-nitrostyrene
9h (25.07 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 8 h. After column chromatogra-
phy, the desired product was obtained as
a white solid
(37.29 mg, 93% yield). Analytical data matched with previously
reported values. 1H NMR (500 MHz, CDCl3): d 7.15–7.20 (m, 2H),
7.00–7.06 (m, 2H), 4.60–4.62 (t, J = 1.0 Hz, 2H), 4.32–4.36 (d,
J = 10.5 Hz, 1H), 4.20–4.28 (m, 1H), 2.30 (s, 3H), 1.97 (s, 3H); 13C
NMR (125 MHz, CDCl3): d 201.9, 200.9, 133.8, 133.4, 130.7, 129.7,
129.0, 127.7, 76.2, 69.0, 38.8, 30.9, 28.4; HPLC (OD-H, hexane/2-
propanol = 85/15, flow rate-1 mL/min, 210 nm): tminor = 14.1 min,
tmajor = 15.6 min, ee = 97%.
4.2.27. (R)-3-[2-Nitro-1-(2-nitro-phenyl)-ethyl]-pentane-2,4-
dione 11m18
Prepared according to general procedure A using b-nitrostyrene
9m (29.12 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 10 h. After column chromatogra-
phy, the desired product was obtained as a pale yellow solid
(41.05 mg, 93% yield). Analytical data matched with previously re-
ported values.1H NMR (500 MHz, CDCl3): d 7.94 (dd, J = 8.0, 1.5 Hz,
1H), 7.59 (td, J = 8.0, 1.5 Hz, 1H), 7.49 (td, J = 8.0, 1.5 Hz, 1H), 7.37
(dd, J = 8.0, 1.5 Hz, 1H), 4.98 (dd, J = 13.0, 7.0 Hz, 1H), 4.85 (dd,
J = 13.0, 3.5 Hz, 1H), 4.74 (ddd, J = 8.5, 7.0, 3.5 Hz, 1H), 4.68 (d,
J = 8.5 Hz, 1H), 2.32 (s, 3H), 2.14 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 201.5, 200.5, 149.8, 133.5, 131.2, 129.3, 129.2, 125.6,
76.5, 69.1, 37.1, 31.3, 29.2; HPLC (OD-H, hexane/2-propanol = 90/
4.2.23. 3-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)pentane-2,4-
dione 11i16,23
Prepared according to general procedure A using b-nitrostyrene
9i (26.87 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 20 h. After column chromatogra-
phy, the desired product was obtained as an oil (22.20 mg, 53%
yield). Analytical data matched with previously reported values.
1H NMR (500 MHz, CDCl3): d 7.26 (dd, J = 16.0 Hz, 1.5 Hz, 1H),
7.07(dd, J = 8.0 Hz, 1.5 Hz, 1H), 6.94–6.85 (m, 2H), 4.77 (dd,
J = 12.5 Hz, 8.0 Hz, 1H), 4.62–4.55 (m, 2H), 4.51–4.45 (m, 1H),
3.87 (s, 3H), 2.27 (s, 3H), 1.93 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 202.3, 201.6, 157.0, 130.2, 129.7, 123.4, 121.1, 111.2, 76.5, 68.9,
55.4, 38.9, 30.4, 28.7; HPLC (AD-H, hexane/2-propanol = 99/1, flow
rate-0.5 mL/min, 210 nm): tminor = 61.7 min, tmajor = 96.7 min,
ee = 94%.
10, flow rate-1 mL/min, 230 nm): tminor = 30.0 min, tmajor
=
35.6 min, ee = 98%.
4.2.28. (R)-3-(1-(4-Hydroxy-3-methoxyphenyl)-2-nitroethyl)
pentane-2,4-dione 11n
Prepared according to general procedure A using b-nitrostyrene
9n (29.27 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 20 h. After column chromatogra-
phy, the desired product was obtained as a light yellow paste
4.2.24. 3-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)pentane-2,4-
dione 11j16,23
(30.12 mg, 68% yield). ½a D25
ꢁ
¼ ꢀ38:1 (c 0.25, CHCl3); IR (KBr):
m
= 3391, 2957, 2925, 2337, 1695, 1637, 1568, 1384, 1333, 846,
Prepared according to general procedure A using b-nitrostyrene
9j (26.87 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 19 h. After column chromatogra-
phy, the desired product was obtained as an oil (28.07 mg, 67%
yield). Analytical data matched with previously reported values.
769, 741, 702, 590 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 6.85 (d,
J = 8.5 Hz, 1H), 6.68 (dd, J = 8.0, 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz,
1H), 4.55–4.62 (m, 2H), 4.34 (d, J = 11 Hz, 1H), 4.14–4.18 (m, 1H),
3.86 (s, 3H), 2.28 (s, 3H), 1.95 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 201.8, 201.2, 146.9, 145.8, 127.7, 120.5, 115.1, 110.8, 78.5,
70.9, 56.0, 42.6, 30.3, 29.5; HRMS (ESI): m/z calculated for
1H NMR (500 MHz, CDCl3):
d
7.10 (d, J = 8.5 Hz, 2H), 6.84
(d, J = 8.5 Hz, 2H), 4.61–4.57 (m, 2H), 4.35 (d, J = 11.0 Hz, 1H),
4.24–4.18 (m, 1H), 3.78 (s, 3H), 2.29 (s, 3H), 1.95 (s, 3H); 13
C
14H17NO6+Na+: 318.0954, found: 318.0940; HPLC (AS-H, hexane/
C
2-propanol = 75/25, flow rate-0.3 mL/min, 220 nm): tminor = 59.3
min, tmajor = 64.6 min, ee = 95%. Configuration assignment: The
absolute stereochemistry was assigned as (R) by analogy.
NMR (125 MHz, CDCl3): d 201.8, 201.1, 159.4, 129.0, 127.5, 114.6,
78.4, 70.8, 55.1, 42.0, 30.3, 29.4; HPLC (AD-H, hexane/2-propa-
nol = 85/15, flow rate-1 mL/min, 210 nm): tminor = 9.5 min,
tmajor = 14.2 min, ee = 94%.
4.2.29. (R)-3-(1-(3-Bromo-4-methoxyphenyl)-2-nitroethyl)
pentane-2,4-dione 11o
Prepared according to general procedure A using b-nitrostyrene
9o (38.71 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 19 h. After column chromatogra-
4.2.25. (R)-3-(2-Nitro-1-p-tolylethyl)pentane-2,4-dione 11k13b,16
Prepared according to general procedure A using b-nitrostyrene
9k (24.48 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 14 h. After column chromatogra-
phy, the desired product was obtained as
a
colorless solid
phy, the desired product was obtained as
a
colorless solid
(47.82 mg, 89% yield). Mp: 131–134 °C; ½a D25
ꢁ
¼ ꢀ118:1 (c 1.0,
(35.15 mg, 89% yield). Analytical data matched with previously re-
ported values. 1H NMR (500 MHz, CDCl3): d 7.12 (d, J = 8.0 Hz, 2H),
7.06 (d, J = 8.0 Hz, 2H), 4.58–4.65 (m, 2H), 4.36 (d, J = 11.0 Hz, 1H),
4.24–4.17 (m, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 1.94 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 201.9, 201.1, 138.3, 132.7, 130.0, 127.7, 78.3,
70.8, 42.4, 30.4, 29.4, 21.0; HPLC (AD-H, hexane/2-propanol = 90/
CHCl3); IR (KBr): m = 3397, 3009, 2926, 2839, 2764, 1735, 1705,
1605, 1551, 1504, 1361, 1261, 1138, 1052, 951, 821, 737,
675 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.38 (d, J = 2.5 Hz, 1H),
;
7.09 (dd, J = 7.5, 2.0 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.58–4.59 (m,
2H), 4.31 (d, J = 11 Hz, 1H), 4.14–4.19 (m, 1H), 3.86 (s, 3H), 2.29
(s, 3H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3): d 201.5, 200.7,
155.9, 132.6, 129.3, 128.2, 112.4, 112.3, 78.1, 70.6, 56.2, 41.7,
30.4, 29.6; HRMS (ESI): m/z calculated for C14H16NO5Br+Na+:
10, flow rate-0.8 mL/min, 210 nm): tminor = 10.7 min, tmajor
=
17.5 min, ee = 96%.

576
P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
380.0110, found: 380.0117; HPLC (AS-H, hexane/2-propanol = 85/
15, flow rate-1 mL/min, 220 nm): tminor = 25.7 min, tmajor = 44.8 -
min, ee = 95%. Configuration assignment: The absolute stereo-
chemistry was assigned as (R) by analogy
values. 1H NMR (500 MHz, CDCl3): d 7.76 (d, J = 7.5 Hz, 0.20H),
7.67 (d, J = 7.5 Hz, 0.80H), 7.58 (t, J = 7.5 Hz, 0.8H), 7.50 (d,
J = 7.5 Hz, 0.2H), 7.40–7.32 (m, 2H), 7,26–7.14 (m, 5H), 5.44 (dd,
J = 3.5, 13.5 Hz, 0.8H), 5.24–5.16 (m, 1H), 5.07 (dd, J = 3.5,
13.5 Hz, 0.2H), 4.48 (dd, J = 3.5, 11.0 Hz, 0.2H), 4.21 (dd, J = 3.5,
11.2 Hz, 0.8H), 3.75 (s, 2.4H), 3,70 (s, 0.6H), 3.64 (d, J = 17.5 Hz,
0.8H), 3.49 (d, J = 17.5 Hz, 0.2H), 3.24–3.13 ppm (m, 1H); 13C
NMR (125 MHz, CDCl3): d = 202.0, 199.9, 171.2, 169.8, 152.3,
152.2, 136.1, 135.8, 135.7, 135.6, 134.8, 134.0, 129.0, 128.9,
128.8, 128.6, 128.3, 128.0, 127.9, 126.05, 126.04, 125.2, 124.4,
77.0, 76.9, 62.7, 61.8, 53.2, 53.1, 47.3, 47.0, 36.5, 35.2; HPLC (OD-
H, hexane/2-propanol = 80/20, flow rate-0.8 mL/min, 254 nm): Ma-
jor diastereomer: tminor = 11.5 min, tmajor = 59.1 min, ee = 98%;
Minor diastereomer: tminor = 13.3 min, tmajor = 33.6 min, ee = 97%.
The absolute stereochemistry was not assigned.
4.2.30. (R)-3-(1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)pen-
tane-2,4-dione 11p
Prepared according to general procedure A using b-nitrostyrene
9p (28.97 mg, 0.15 mmol) and 2,4-pentanedione 10 (50 mg,
0.5 mmol), the reaction time was 20 h. After column chromatogra-
phy, the desired product was obtained as
a
colorless solid
(35.20 mg, 80% yield). Mp: 86–89 °C; ½a D25
ꢁ
¼ ꢀ102:0 (c 0.5, CHCl3);
IR (KBr):
m ;
= cmꢀ1 1H NMR (500 MHz, CDCl3): d 6.74 (d, J = 7.5 Hz,
1H), 6.63–6.65 (m, 2H), 5.95 (s, 2H), 4.56 (d, J = 6.5 Hz, 2H), 4.30 (d,
J = 11 Hz, 1H), 4.14–4.18 (m, 1H), 2.29 (s, 3H), 1.99 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 201.7, 200.9, 148.4, 147.7, 129.4, 121.4, 108.9,
108.1, 101.4, 78.4, 70.9, 42.6, 30.4, 29.4; HRMS (ESI): m/z calculated
for C14H15NO6+Na+: 316.0797, found: 316.0811; HPLC (AS-H, hex-
4.2.34. Ethyl 2-acetyl-2-chloro-4-nitro-3-phenylbutanoate 13d
Prepared according to general procedure B using nitrostyrene
9a (22.37 mg, 0.15 mmol) and ethyl 2-chloro-3-oxobutanoate
12d (27.98 mg, 0.17 mmol), the reaction time was 10 h. After
column chromatography, the desired product was obtained as an
oil (42.83 mg, 91% yield); dr = 58:42 (determined by 1H NMR); Ma-
jor diastereomer: 1H NMR (500 MHz, CDCl3): d 7.30–7.33 (m, 5H),
5.13 (dd, J = 13.5, 4.0 Hz, 1H), 5.04 (dd, J = 13.5, 4.1 Hz, 1H), 4.60
(dd, J = 10.0, 4.0 Hz, 1H), 4.20–4.29 (m, 2H), 1.97 (s, 3H), 1.25 (t,
J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 199.6, 166.5, 133.0,
129.8, 129.0, 128.8, 76.6, 75.9, 63.6, 48.6, 27.2, 13.7. Minor diaste-
reomer: 1H NMR (500 MHz, CDCl3): d 7.33–7.36 (m, 5H), 4.94 (dd,
J = 12.0, 4.0 Hz, 1H), 4.87 (dd, J = 15.5, 10.5 Hz, 1H), 4.66 (dd,
J = 10.5, 4.0 Hz, 1H), 3.94–4.07 (m, 2H), 2.31 (s, 3H), 1.08 (t,
J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 196.5, 164.8, 133.7,
129.3, 129.0, 128.7, 77.1, 76.9, 63.8, 46.7, 25.6, 13.6; HRMS (ESI):
m/z calculated for C14H16NO5Cl+Na+: 336.0607, found: 336.0615;
HPLC (OD-H, hexane/2-propanol = 90/10, flow rate-0.5 mL/min,
210 nm): Major diastereomer: tminor = 13.9 min, tmajor = 21.9 min,
ee = 99% Minor diastereomer: tminor = 15.1 min, tmajor = 16.9 min,
ee = 98%. The absolute stereochemistry was not assigned.
ane/2-propanol = 70/30,
flow
rate-1 mL/min,
220 nm):
tminor = 25.2 min, tmajor = 45.1 min, ee = 95%. Configuration assign-
ment: The absolute stereochemistry was assigned as (R) by
analogy.
4.2.31. ((S)-2-Acetyl-2-((S)-2-nitro-1-phenylethyl) cyclopenta-
none 13a13g,19,21
Prepared according to general procedure B using nitrostyrene
9a (22.37 mg, 0.15 mmol) and 2-acetyl cyclopentanaone 12a
(21.45 mg, 0.17 mmol), the reaction time was 12 h. After column
chromatography, the desired product was obtained as colorless
solid (38 mg, 92% yield); dr = 90:10 (determined by 1H NMR); Ana-
lytical data matched with previously reported values. 1H NMR
(500 MHz, CDCl3): 7.20–7.32 (m, 5H), 4.87 (t, J = 11.5 Hz, 1H),
4.50 (dd, J = 4.0 and 13.0 Hz, 1H), 4.40 (dd, J = 4.0 and 11.5 Hz,
1H), 2.56–2.61 (m, 1H), 2.34 (s, 3H), 2.15–2.28 (m, 1H), 1.93–
2.03 (m, 1H), 1.65–1.80 (m, 3H); 13C NMR (125 MHz, CDCl3): d
213.3, 203.0, 134.4, 129.7, 129.1, 128.7, 75.8, 71.4, 46.6, 38.9,
27.5, 26.8, 19.7; HPLC (OD-H, hexane/2-propanol = 80/20, flow
rate-1 mL/min, 220 nm): Major diastereomer: tminor = 10.8 min,
tmajor = 40.8 min, ee = 95%; Minor diastereomer: tminor = 13.4 min,
tmajor = 18.9 min, ee = 94%.
4.2.35. Ethyl 2-acetyl-2-fluoro-4-nitro-3-phenylbutanoate
13e20,22
Prepared according to general procedure B using nitrostyrene
9a (22.37 mg, 0.15 mmol) and ethyl 2-fluoro-3-oxobutanoate 12e
(25.18 mg, 0.17 mmol), the reaction time was 8 h. After column
chromatography, the desired product was obtained as a paste
(39.69 mg, 89% yield); dr = 64:36 (determined by 1H NMR); Analyt-
ical data matched with previously reported values. 1H NMR
(500 MHz, CDCl3): d 7.31–7.26 (m, 8.5H), 4.84–4.88 (m, 2H),
4.74–4.51 (m, 2.8H), 4.31 (dq, J = 7.0, 1.5 Hz, 2H) (major), 3.97 (q,
J = 7.0 Hz, 1.1H) (minor), 2.32 (d, J = 4.5 Hz, 1.7H) (minor), 1.85
(d, J = 5.5 Hz, 3H) (major), 1.32 (t, J = 7.0 Hz, 3H) (major)), 0.98 (t,
J = 7.0 Hz, 1.7H) (minor); 13C NMR (125 MHz, CDCl3): d 201.3,
201.1, 199.6, 199.4, 164.6, 164.4, 163.8, 163.6, 133.1, 132.4,
129.52, 129.51, 129.18, 129.17, 129.0, 128.9, 128.9, 101.7, 101.3,
100.0, 99.7, 75.3, 75.2, 63.6, 63.1, 47.2, 47.1, 46.5, 46.3, 26.3,
25.7,13.9, 13.6; HPLC (OD-H, hexane/2-propanol = 90/10, flow
rate-0.5 mL/min, 210 nm): Major diastereomer: tminor = 19.5 min,
tmajor = 28.9 min, ee = 99%; Minor diastereomer: tminor = 22.1 min,
tmajor = 24.3 min, ee = 99%. The absolute stereochemistry was not
assigned.
4.2.32. (R)-Ethyl 1-((S)-2-nitro-1-phenylethyl)-2-oxocyclopen-
tanecarboxylate 13b13b,g
Prepared according to general procedure B using nitrostyrene
9a (22.37 mg, 0.15 mmol) and ethyl 2-oxocyclopentanecarboxylate
12b (26.55 mg, 0.17 mmol), the reaction time was 9 h. After
column chromatography, the desired product was obtained as an
oil (43.51 mg, 95% yield); dr = 99:1 (determined by 1H NMR); Ana-
lytical data matched with previously reported values. 1H NMR
(500 MHz, CDCl3):
d 7.25–7.34(m, 5 H), 5.18(dd, J = 4.0 Hz,
13.5 Hz, 1H), 5.02(dd, J = 11.0 Hz, 13.5 Hz, 1H), 4.17–4.24(m, 2H),
4.08 (dd, J = 4.0 Hz, 11.0 Hz, 1H), 2.31–2.41(m, 2H), 1.78–2.08(m,
4H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 212.3,
169.3, 135.3, 129.3, 128.7, 128.2, 76.4, 62.4, 62.1, 46.1, 37.8, 31.2,
19.3, 13.9; HPLC (OD-H, hexane/2-propanol = 90/10, flow rate-
0.7 mL/min, 220 nm): Major diastereomer: tminor = 14.1 min,
tmajor = 20.2 min, ee = 99%.
4.2.33. Methyl 2-(2-nitro-1-phenylethyl)-1-oxo-2,3-dihydro-1H-
indene-2-carboxylate 13c13e
Prepared according to general procedure B using nitrostyrene
9a (22.37 mg, 0.15 mmol) and methyl 1-oxo-2,3-dihydro-1H-in-
dene-2-carboxyla 12c (32.33 mg, 0.17 mmol), the reaction time
was 8 h. After column chromatography, the desired product was
obtained as an oil (44.28 mg, 87% yield); dr = 80:20 (determined
by 1H NMR); Analytical data matched with previously reported
Acknowledgements
This work was supported by Department of Science & Technol-
ogy, Government of India, New Delhi (Grant No. SR/S1/OC-60/
2006). Vinayagam thanks Council for Scientific and Industrial

P. Vinayagam et al. / Tetrahedron: Asymmetry 25 (2014) 568–577
577
Res. 2004, 37, 548–557; (f) Liu, X.; Lin, L.; Feng, X. Acc. Chem. Res. 2011, 44, 574–
587.
Research, India for the research fellowship. We thank Dr. M. S.
Moni and Dr. C. Baby at Sophisticated Analytical Instrument
Facility (SAIF), IIT Madras for NMR analysis.
7. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904.
8. (a) Balaraman, K.; Vasanthan, R.; Kesavan, V. Synthesis 2012, 44, 2455–2462;
(b) Balaraman, K.; Vasanthan, R.; Kesavan, V. Tetrahedron: Asymmetry 2013, 24,
919–924; (c) Balaraman, K.; Vasanthan, R.; Kesavan, V. Tetrahedron 2013, 69,
6162–6169; (d) Balaraman, K.; Vasanthan, R.; Kesavan, V. Tetrahedron Lett.
2013, 54, 3613–3616.
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