(2 S)-2-[(Phenylsulfinyl)methyl]pyrrolidine-catalyzed efficient stereoselective michael addition of cyclohexanone and cyclopentanone to nitroolefins

Article abstract of DOI:10.1055/s-0032-1316917

(2S)-2-[(Phenylsulfinyl)methyl]pyrrolidine, derived from l-proline, has been demonstrated as an efficient organocatalyst for the asymmetric Michael addition of cyclohexanone and cyclopentanone to β-nitrostyrenes. This pyrrolidine-based catalyst bearing a sulfoxide moiety was used to synthesize various γ-nitro carbonyl compounds in high yield (up to 97%) with excellent stereoselectivity (up to >99:1 dr and >99% ee) without the use of any additive.

Full text of DOI:10.1055/s-0032-1316917

1406▌
PAPER
paper
(2S)-2-[(Phenylsulfinyl)methyl]pyrrolidine-CatalyzedEfficientStereoselective
Michael Addition of Cyclohexanone and Cyclopentanone to Nitroolefins
Stereoselective Michael Addition of Cycloalkanones to Nitroolefins
Kamal Nain Singh,*a Paramjit Singh,a Amarjit Kaur,a Pushpinder Singh,a Sandeep Kumar Sharma,a Sadhika Khullar,b
Sanjay K. Mandalb
a
Department of Chemistry, Panjab University, Chandigarh 160014, India
Fax +91(172)2545074; E-mail: kns@pu.ac.in
b
Department of Chemical Sciences, Indian Institute of Science Education and Research, Mohali, Sector 81, Manauli PO, S.A.S. Nagar,
Mohali (Punjab) 140306, India
Received: 04.01.2013; Accepted after revision: 19.03.2013
in asymmetric Michael additions. Interestingly, this cata-
Abstract: (2S)-2-[(Phenylsulfinyl)methyl]pyrrolidine,
derived
lyst proved very successful for the stereoselective conju-
gate addition of cyclic ketones to various aryl-substituted
nitroolefins and afforded the corresponding adducts in
from L-proline, has been demonstrated as an efficient organocata-
lyst for the asymmetric Michael addition of cyclohexanone and cy-
clopentanone to β-nitrostyrenes. This pyrrolidine-based catalyst
bearing a sulfoxide moiety was used to synthesize various γ-nitro high yield (up to 97%) with excellent stereoselectivity (up
carbonyl compounds in high yield (up to 97%) with excellent ste-
reoselectivity (up to >99:1 dr and >99% ee) without the use of any
additive.
to >99:1 dr and >99% ee) in wet toluene. The results are
described in this paper.
The chiral catalyst (2S)-2-[(phenylsulfinyl)methyl]pyrro-
lidine (1) employed in this work was easily prepared, ac-
cording to Scheme 1. Reduction of Boc-protected L-
Key words: Michael addition reaction, organocatalyst, amino sulf-
oxide, nitroolefins, ketones
proline 2 with borane–methyl sulfide complex (BMS) af-
forded the corresponding alcohol 3 in 92% yield.8 Reac-
Organocatalysis with its asymmetric variant has emerged
tion of this alcohol 3 with p-toluenesulfonyl chloride8 and
as a powerful synthetic paradigm for the development of
subsequent treatment with sodium hydride and benzene-
new methods to prepare diverse chiral molecules.1 Or-
thiol gave thioether 5.5a Oxidation of 5 with sodium peri-
ganocatalytic conjugate addition is an important and
odate in methanol–water (1:1)9 and then deprotection5a
widely applicable strategy for asymmetric carbon–carbon
with trifluoroacetic acid furnished the catalyst 1 in 57%
bond formation using a variety of donors and acceptors.2
overall yield.
In recent years, several catalysts have been developed for
the direct asymmetric Michael addition of unmodified
BMS
p-TsCl
carbonyl compounds to nitroalkenes to produce enantio-
merically enriched γ-nitro ketones.3 Many of these are
pyrrolidine-based organocatalysts having different func-
tionalities in the side chain.4 Some examples of pyrro-
lidine-type organocatalysts bearing a sulfide/sulfone5a or
sulfonamide5b function in the side chain have also been re-
ported for the above reactions. An oxygen atom of the sul-
fone functionality in combination with a protic solvent,
such as water, provides a hydrogen-bond interaction to
improve both the reactivity and stereoselectivity of the
Michael reaction.5 β-Amino sulfoxides have been used as
effective bidentate ligands in metal-catalyzed enantiose-
lective reactions and have also served as chiral auxiliaries
in various processes promoted by transition metals;6 how-
ever, the use of β-amino sulfoxides as chiral organocata-
lysts does not seem to have been investigated so far. As
part of our interest in the development of new pyrrolidine-
based organocatalysts7a and continuing our investigations
toward the stabilization of α-amino sulfoxides,7b we ex-
plored the use of β-amino sulfoxide 1 as a chiral catalyst
OH
OTs
COOH
N
N
N
Boc
Boc
Boc
4 (91%)
2
(92%)
3
NaH
PhSH
H
H
S
H
H
NaIO4
TFA
Ph
Ph
Ph
S
S
N
H
N
N
H
H
Boc
Boc
O
O
1
(92%)
(89%)
6
(83%)
5
Scheme 1 Synthesis of catalyst 1
For initial studies, the reaction of cyclohexanone (7a) and
β-nitrostyrene (8a) in the presence of chiral catalyst 1 was
investigated. Use of 20 mol% of catalyst 1 in chloroform
at room temperature, without any other additive, gave the
desired Michael adduct 9a in 80% yield with high syn di-
astereoselectivity (dr 99:1) and good enantioselectivity
(98% ee) (Table 1, entry 1). To optimize the reaction con-
ditions, a variety of solvents were screened. Best results
were obtained using wet toluene as the solvent medium
SYNTHESIS 2013, 45, 1406–1413
Advanced online publication: 12.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316917; Art ID: SS-2013-Z0008-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereoselective Michael Addition of Cycloalkanones to Nitroolefins
1407
(Table 1, entry 8).10 In contrast, only a trace amount of the
Michael adduct was observed in protic polar solvents such
as methanol, ethanol and water (Table 1, entries 9–11).
When the reaction was carried out in chloroform at 0 °C,
prolonged reaction time was required for completion
(Table 1, entry 3).
Table 2 Effect of Catalyst Loadinga
Entry
Catalyst 1 Time
Yieldb
(%)
eec
(%)
drd
(syn/anti)
(mol%)
(h)
1
2
3
4
5
10
20
30
48
36
24
24
58
72
97
98
99
99
99:1
99:1
Table 1 Screening of Solventsa
>99
>99
>99:1
>99:1
O
O
a Reaction conditions: β-nitrostyrene (1.6 mmol), cyclohexanone (3.2
mmol), wet toluene (10.0 mL), 25 °C.
b Isolated yield.
NO2
1 (20 mol%)
NO2
+
solvent, 25 °C
c Determined by chiral HPLC analysis using a Chiralpak AS-H col-
umn.
7a
8a
9a
d Determined by 1H NMR analysis of crude sample.
Entry
Solvent
Time
(h)
Yieldb
(%)
eec
(%)
drd
(syn/anti)
was observed with furyl and naphthyl derivatives of ni-
troolefins (Table 3, entries 11 and 12), as was also the case
when cyclopentanone was used instead of cyclohexanone
(entries 13 and 14).
1
2
CHCl3
DCE
24
24
72
36
36
36
24
24
72
72
72
80
98
98
>99
99
99
99
93
>99
–
99:1
99:1
99:1
99:1
99:1
98:2
99:1
>99:1
–
82
3e
4
CHCl3
Et2O
92
In order to have an assessment of the role of 1 as chiral
catalyst and of the transition state involved in this process,
it was imperative to determine the stereochemistry of the
second stereogenic center at the sulfoxide sulfur generat-
ed during the periodate oxidation of 5 (Scheme 1). Clear-
ly, it cannot be expected that the conversion of 5 into 6
will occur with complete diastereoselectivity. In the
event, crystallization of Boc-protected sulfoxide 6 from
ethyl acetate–hexane (5:95) afforded a single crystal, and
a view of its single-crystal X-ray diffraction (SCXRD)
structure is shown in Figure 1. On this basis, the specifi-
cation at the sulfur atom was assigned as R; however, the
simulated powder X-ray diffraction (PXRD) of this crys-
tal differed from the experimental PXRD of 6 (Figure 2
and Figure 3), indicating that 6 may be a diastereomeric
mixture. TLC examination of 6 in several solvent systems
showed only a single spot. Thus, separation of the diaste-
reomers by column chromatography was not possible.
Chiral HPLC analysis of 6 using a Chiralpak AS-H col-
umn clearly showed the presence of two diastereomers in
a ratio of 58:42. The diastereomeric ratio could not be in-
ferred from the integration of the methylene proton
[S(O)CH2] signals in the 1H NMR spectrum of 6 as these
signals partially overlap with the (NCH2) signal of the
pyrrolidine ring; however, the single proton adjacent to
the nitrogen atom in the pyrrolidine ring (NCH) appeared
as two multiplets at δ 4.27–4.18 and 4.04–4.00, and the ra-
tio of these signals (55:45) reflects the diastereomeric ra-
88
5
THF
78
6
DMF
50
7
toluene
wet toluene
MeOH
EtOH
H2O
75
8
97
9
traces
traces
traces
10
11
–
–
–
–
a Reaction conditions: β-nitrostyrene (1.6 mmol), cyclohexanone (3.2
mmol), catalyst 1 (20 mol%), solvent (10.0 mL), 25 °C.
b Isolated yield.
c Determined by chiral HPLC analysis using a Chiralpak AS-H col-
umn.
d Determined by 1H NMR analysis of crude sample.
e Reaction was performed at 0 °C.
Next, the catalyst loading was evaluated. Decreased yield
was observed when the amount of catalyst 1 was reduced
to a half or a quarter (Table 2, entries 1 and 2). Incremen-
tal increase in the catalyst loading, up to 30 mol%, did not
show any significant effect on the reaction time, yield and
stereoselectivity (Table 2, entry 4). Hence, 20 mol% of
catalyst 1 and wet toluene as a solvent at 25 °C proved to
be the optimized reaction conditions.
1
tio. Similarly, the H NMR spectrum of 1 showed this
To further explore the scope of catalyst 1 in the asymmet-
ric Michael reaction, various nitroolefins and cyclic ke-
tones were reacted, and the results are summarized in
Table 3. The corresponding Michael adducts were gener-
ally obtained in good to excellent yields with high enan-
tiomeric excess (ee) and diastereoselectivity. The reaction
is tolerant to methoxy (Table 3, entries 2–5), chloro (en-
tries 6–8) and nitro (entry 9) substituents on the aromatic
ring of nitrostyrenes. Some decrease in stereoselectivity
proton as two multiplets at δ 3.60–3.54 and 3.43–3.31, in
a ratio of 57:43. Thus, it was concluded that in 6 and sub-
sequently in 1, the two diastereomers are present in a ratio
of ~57:43.11
For the observed stereochemical results, we propose tran-
sition states A and B (Figure 4) which are based upon
Seebach’s model11 and the model proposed by Lin and co-
workers.5a Cyclohexanone and catalyst 1 generate the chi-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1406–1413

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K. N. Singh et al.
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Table 3 Asymmetric Michael Addition Catalyzed by 1a
O
O
Ar
1 (20 mol%)
NO2
+
NO2
Ar
wet toluene, 25 °C
n
n
7a n = 2
7b n = 1
8a–l
9a–n
Entry
7
8
Ar
Ph
Time (h)
Product
Yieldb (%) eec (%)
drd (syn/anti)
1
2
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
8a
8b
8c
8d
8e
8f
24
34
30
24
34
30
26
24
28
24
32
25
28
24
9a
9b
9c
9d
9e
9f
97
92
90
90
85
88
93
85
92
90
82
80
85
82
>99
>99
>99
>99
92
>99:1
99:1
99:1
99:1
98:2
98:2
97:3
98:2
99:1
99:1
97:3
95:5
90:10
83:17
4-MeOC6H4
3
3,4-(MeO)2C6H3
3-MeOC6H4
4
5
3-MeO-4-EtOC6H3
4-ClC6H4
6
91
7
8g
8h
8i
3-ClC6H4
9g
9h
9i
88
8
2-ClC6H4
81
9
3-O2NC6H4
1,3-benzodioxol-5-yl
2-furyl
95
10
11
12
13
14
8j
9j
98
8k
8l
9k
9l
88
1-naphthyl
82
8a
8j
Ph
9m
9n
72
1,3-benzodioxol-5-yl
87
a Reaction conditions: nitroalkene (1.6 mmol), ketone (3.2 mmol), catalyst 1 (20 mol%), wet toluene (10.0 mL), 25 °C.
b Isolated yield.
c Determined by chiral HPLC analysis using a Chiralpak AS-H column.
d Determined by 1H NMR analysis of crude sample.
ral enamine which further reacts with nitroolefin leading
to the formation of Michael adduct via transition state A
or B. In these states, the oxygen atom of the sulfoxide
group, via hydrogen bonding with water, directs the ni-
troolefin 8 in such a manner so that the enamine attacks
the olefinic double bond from the Re-face. This ensures
the opposite orientation of the phenyl group of 1 and the
aryl group of 8, which results in highly enantio- and dia-
stereoselective Michael adducts 9. Clearly, the stereo-
chemistry at the sulfur atom in 1 has no influence on the
Figure 2 Simulated PXRD of 6 from the SCXRD structure
observed chirality of the Michael adducts 9.12 The results
obtained with chiral catalyst 1 reflect a marked improve-
ment over those reported for the precursor thioether of 1
(23% ee) and the corresponding sulfone of 1 (64% ee).5a
Furthermore, reactions of some acyclic ketones, such as
acetone (10), methyl ethyl ketone (11) and diethyl ketone
(12), with nitrostyrenes in the presence of organocatalyst
1 were investigated, and the results are shown in Table 4.
The reaction of acetone (10) with nitrostyrene 8f fur-
nished the corresponding Michael adduct 13 in 94% yield
with 83% ee under the standard reaction conditions. The
Figure 1 View of 6 as determined by single-crystal X-ray crystallog-
raphy
Synthesis 2013, 45, 1406–1413
© Georg Thieme Verlag Stuttgart · New York

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Stereoselective Michael Addition of Cycloalkanones to Nitroolefins
1409
in such reactions by using chiral bifunctional organocata-
lysts bearing both primary amine and thiourea functional-
ities has been reported.4e,10b,14 It is also noteworthy that in
the case of the unsymmetrical ketone 11, Michael adduct
formation occurred exclusively at the more substituted
site. Presumably, the intermediate enamine formation oc-
curs under thermodynamic control under these reaction
conditions.15
In summary, we have evaluated a newly designed sulfox-
ide-bearing pyrrolidine organocatalyst 1 for direct asym-
metric Michael addition. Excellent enantio- and
diastereoselectivity as well as high yields were observed
in the formation of the corresponding Michael adducts in
wet toluene in the presence of a low loading of this cata-
lyst (20 mol%), without the addition of any additive.
These results compare favorably with previous reports.4
Figure 3 Experimental PXRD of 6
R
S
S
S
O
O
N
N
Melting points were taken in open capillaries and are uncorrected.
1H NMR spectra were recorded in CDCl3 solution on a Jeol AL 300
MHz or Bruker 400 MHz spectrometer; the chemical shifts are re-
ported in parts per million (δ) relative to internal standard TMS (0
H
O
N
H
O
N
O
O
H
H
O
O
ppm) and the coupling constants (J) are reported in hertz (Hz). 13
C
Ar
Ar
B
A
NMR spectra were obtained at 75 MHz or 100 MHz and are refer-
enced to the internal solvent signals. MS and HRMS data were ob-
tained on a Q-Tof micro™ Mass Spectrometer. Chiral HPLC
analyses were carried out on a Waters 2996 system using Daicel
Chiralpak AS-H and Chiralcel OD columns. Elemental analyses
were performed with a Flash 2000 organic elemental analyzer. Ni-
Figure 4 Proposed transition states
enantioselectivity of 13 increased to 95% ee (Table 4, en-
try 1) after a single recrystallization (i-PrOH–hexane). For troolefins were prepared according to literature procedures.16 Prod-
ucts were isolated and purified by column chromatography over
silica gel (hexane–EtOAc, 9:1–8:2).
acyclic ketones 11 and 12, an excess of ketone (10 equiv)
was required along with prolonged reaction time to give
the corresponding adducts 14 and 15 (Table 4, entries 2
tert-Butyl (2S)-2-(Hydroxymethyl)pyrrolidine-1-carboxylate
and 3). Although the diastereoselectivity in both cases (3)8
To a soln of (2S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic
was excellent (dr 99:1), the enantioselectivity decreased
substantially (31% ee and 51% ee, respectively). Low en-
antioselectivity for acyclic ketones has also been observed
by others for pyrrolidine-based catalysts;13 however, a re-
markable improvement in the enantioselectivity and yield
acid (2; 1.0 g, 4.6 mmol) in anhyd THF (10 mL) was added BMS
(0.7 g, 9.2 mmol) dropwise under nitrogen atmosphere at 0 °C, and
the reaction mass was stirred at 0 °C for 5 h and then at r.t. over-
night. H2O (20 mL) was slowly added to quench the reaction and the
mixture was extracted with EtOAc (3 × 20 mL). The combined or-
Table 4 Reaction of Acyclic Ketonesa
O
Ar
O
NO2
NO2
+
Ar
R1
R2
R1
R2
10 R1 = R2 = H
13 R1 = R2 = H, Ar = 4-ClC6H4
14 R1 = H, R2 = Me, Ar = Ph
15 R1 = R2 = Me, Ar = Ph
8
11 R1 = H, R2 = Me
12 R1 = R2 = Me
Entry
Ketone
8
Ar
Time (h)
Product
Yieldb (%)
ee (%)
drc (syn/anti)
1
2
3
10
11
12
8f
4-ClC6H4
24
72
48
13
14
15
94
72
75
95d
31d
51e
–
8a
8a
Ph
Ph
>99:1
99:1
a Reaction conditions, entry 1: nitroalkene (1.3 mmol), ketone (5 equiv), catalyst 1 (20 mol%), wet toluene (10.0 mL), 25 °C; entries 2 and 3:
nitroalkene (1.6 mmol), ketone (10 equiv), catalyst 1 (20 mol%), wet toluene (10.0 mL), 25 °C.
b Isolated yield.
c Determined by 1H NMR analysis of crude sample.
d Determined by chiral HPLC analysis using a Chiralpak AS-H column.
e Determined by chiral HPLC analysis using a Chiralcel OD column.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1406–1413

1410
K. N. Singh et al.
PAPER
ganic layer was washed with sat. NaHCO3 soln (20 mL), H2O (20
mL) and brine (20 mL), dried over anhyd Na2SO4 and concentrated
under reduced pressure to afford 3 as an oil which spontaneously
crystallized as a white solid when left at r.t.; yield: 0.859 g (92%);
mp 58–60 °C (Lit.8 58–59 °C).
1H NMR (300 MHz, CDCl3): δ = 3.85 (br s, 1 H), 3.58–3.49 (m, 2
H), 3.40–3.32 (m, 1 H), 3.28–3.20 (m, 1 H), 1.97–1.88 (m, 1 H),
1.79–1.69 (m, 2 H), 1.51–1.46 (m, 1 H), 1.40 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 152.8, 152.5, 145.2, 144.5, 130.7,
129.2, 128.9, 127.4, 124.0, 123.8, 79.9, 79.3, 61.4, 60.7, 55.0, 53.8,
47.1, 46.3, 31.6, 28.5, 23.9, 23.7.
(2S)-2-[(Phenylsulfinyl)methyl]pyrrolidine (1)
To a soln of tert-butyl (2S)-2-[(phenylsulfinyl)methyl]pyrrolidine-
1-carboxylate (6; 0.10 g, 0.32 mmol) in anhyd CH2Cl2 (2.0 mL) was
added TFA (0.36 g, 3.2 mmol). The resulting mixture was stirred at
r.t. for 5 h, then solvent and excess TFA were removed under re-
duced pressure. The residue was dissolved in H2O (20 mL) and ba-
sified with 20% KOH (20 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layer was washed
with brine (20 mL), dried over anhyd Na2SO4 and concentrated un-
der reduced pressure to afford 1 as a pale yellow oil; yield: 0.059 g
(89%).
tert-Butyl (2S)-2-[(Tosyloxy)methyl]pyrrolidine-1-carboxylate
(4)8
tert-Butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3;
0.76 g, 3.7 mmol) was dissolved in pyridine (5.0 mL) and cooled to
0 °C. p-TsCl (0.86 g, 4.5 mmol) was added and the mixture was
stirred at r.t. overnight. The reaction mass was diluted with EtOAc
(20 mL) and the organic layer was washed with 10% HCl (3 × 10
mL), sat. NaHCO3 soln (10 mL) and brine (10 mL), then dried over
anhyd Na2SO4. The solvent was evaporated under reduced pressure
to afford 4 as a thick, colorless oil; yield: 1.22 g (91%).
IR (CHCl3): 3431, 3060, 2968, 1443, 1216, 1069, 1033, 665 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.57–7.52 (m, 2 H), 7.43–7.38 (m,
3 H), 3.60–3.54 (m, 0.57 H), 3.43–3.31 (m, 0.43 H), 2.94–2.85 (m,
2 H), 2.83–2.61 (m, 2 H), 2.22 (br s, 1 H), 1.99–1.82 (m, 1 H), 1.76–
1.65 (m, 2 H), 1.48–1.33 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 144.7, 144.6, 130.7, 130.5, 129.2,
129.1, 123.9, 123.8, 64.5, 63.2, 54.2, 52.7, 46.4, 46.1, 31.7, 31.6,
25.2, 24.4.
1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 8.1 Hz, 2 H), 7.26 (d,
J = 7.5 Hz, 2 H), 3.98–3.81 (m, 3 H), 3.22–3.17 (m, 2 H), 2.35 (s, 3
H), 1.92–1.69 (m, 4 H), 1.37 (s, 9 H).
tert-Butyl (2S)-2-[(Phenylsulfanyl)methyl]pyrrolidine-1-car-
boxylate (5)17
MS (ESI): m/z = 210.1 [M + H]+.
Into a flame-dried 50-mL two-neck round-bottom flask equipped
with a stir bar, septum cap and a nitrogen bubbler, a suspension of
60% NaH (washed with hexane before use; 0.540 g, 13.5 mmol) in
anhyd THF (15 mL) was placed under nitrogen atmosphere. After
cooling to 0 °C, PhSH (1.19 g, 10.8 mmol) was added dropwise and
the mixture was stirred at 0 °C for 5 min, then brought to r.t. Stirring
was continued until evolution of hydrogen ceased. A soln of tert-bu-
tyl (2S)-2-[(tosyloxy)methyl]pyrrolidine-1-carboxylate (4; 3.2 g,
9.0 mmol) in anhyd THF (20 mL) was then added and the resulting
mixture was heated under reflux for 5 h. The reaction mixture was
brought to r.t., quenched with H2O (20 mL) and extracted with
CHCl3 (3 × 20 mL). The combined organic layer was washed with
brine (20 mL), dried over anhyd Na2SO4 and concentrated under re-
duced pressure to afford 5 as a colorless oil; yield: 2.2 g (83%).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 2 H), 7.21–7.15 (m,
2 H), 7.09–7.03 (m, 1 H), 3.95–3.84 (m, 1 H), 3.46–3.25 (m, 3 H),
2.66–2.53 (m, 1 H), 1.96–1.74 (m, 4 H), 1.37 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 154.1, 153.9, 136.4, 136.0, 129.3,
129.0, 128.8, 128.0, 127.4, 127.0, 126.0, 125.3, 79.5, 79.0, 56.4,
56.3, 47.1, 46.6, 36.8, 35.4, 30.0, 29.4, 28.6, 23.6, 22.7.
HRMS (ES+): m/z [M + H]+ calcd for C11H15NOS: 210.0947; found:
210.0946.
Enantioselective Michael Addition of Cycloalkanones to Ni-
troolefins Catalyzed by Organocatalyst 1; General Procedure
Cyclic ketone 7 (2 equiv) was added to a stirred soln of organocat-
alyst 1 (20 mol%) in wet toluene10 (10 mL) and the reaction mixture
was stirred at r.t. for 15–20 min. A trans-β-nitrostyrene (1 equiv)
was added and the reaction mixture was stirred at 25 °C for 24–34
h. The progress of the reaction was monitored by TLC (hexane–
EtOAc, 7:3). After consumption of the nitrostyrene, indicated by
TLC, the solvent was evaporated under reduced pressure and the
residue was dissolved in CHCl3 (20 mL). The organic layer was
washed with 10% HCl soln (10 mL), sat. NaHCO3 soln (10 mL) and
brine (10 mL), and dried over anhyd Na2SO4. The solvent was evap-
orated under reduced pressure to afford the crude product which
was purified by column chromatography over silica gel (hexane–
EtOAc, 9:1–8:2). The configuration of chiral centers in the Michael
adducts was assigned on the basis of a comparison of retention
times in chiral HPLC analysis with those reported in the litera-
ture.13d,e,18–21
tert-Butyl (2S)-2-[(Phenylsulfinyl)methyl]pyrrolidine-1-carbox-
ylate (6)17
(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (9a)13d
Yield: 0.4 g (97%); white solid; mp 123–126 °C (Lit.18a 124–
126 °C).
To a soln of NaIO4 (0.145 g, 0.68 mmol) in H2O (5 mL) at 0 °C was
added a soln of tert-butyl (2S)-2-[(phenylsulfanyl)methyl]pyrro-
lidine-1-carboxylate (5; 0.2 g, 0.68 mmol) in MeOH (5 mL). The re-
action mass was stirred at 0 °C for 9 h and then at r.t. for 24 h. The
mixture was diluted with H2O (20.0 mL) and then extracted with
CHCl3 (3 × 10 mL). The combined organic layer was washed with
brine (10 mL), dried over anhyd Na2SO4 and concentrated under re-
duced pressure. Purification by column chromatography (hexane–
EtOAc, 9:1) afforded 6 as a colorless oil which solidified on tritu-
rating with hexane to give a white solid; yield: 0.193 g (92%); mp
87–89 °C.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 227.4 nm): tR (minor) = 16.7 min, tR (major) = 19.8
min; syn/anti >99:1; >99% ee.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.15 (m, 3 H), 7.09 (d,
J = 7.2 Hz, 2 H), 4.86 (dd, J = 4.8, 12.6 Hz, 1 H), 4.58 (dd, J = 9.6,
12.6 Hz, 1 H), 3.70 (dt, J = 4.8, 9.6 Hz, 1 H), 2.65–2.56 (m, 1 H),
2.42–2.25 (m, 2 H), 2.03–1.98 (m, 1 H), 1.74–1.43 (m, 4 H), 1.21–
1.09 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 211.4, 137.7, 128.9, 128.1, 127.7,
78.8, 52.5, 44.0, 42.7, 33.2, 28.6, 25.0.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 95:5, flow rate 0.5
mL·min–1, λ = 254.0 nm): tR (1st diastereomer) = 54.6 min, tR (2nd
diastereomer) = 62.5 min.
IR (neat): 3053, 2972, 1687, 1476, 1393, 1170, 1040, 771, 692 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.52 (m, 2 H), 7.44–7.38 (m,
3 H), 4.27–4.18 (m, 0.55 H), 4.04–4.00 (m, 0.45 H), 3.37–3.04 (m,
3 H), 2.92–2.57 (m, 1 H), 2.20–1.76 (m, 4 H), 1.39 (s, 9 H).
(S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone
(9b)18a
Yield: 0.35 g (92%); white solid; mp 152–154 °C (Lit.18e 153–
154 °C).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 85:15, flow rate 0.5
mL·min–1, λ = 229.4 nm): tR (minor) = 21.0 min, tR (major) = 23.5
min; syn/anti 99:1; >99% ee.
Synthesis 2013, 45, 1406–1413
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereoselective Michael Addition of Cycloalkanones to Nitroolefins
1411
1H NMR (300 MHz, CDCl3): δ = 7.07 (d, J = 8.2 Hz, 2 H), 6.86 (d,
J = 8.2 Hz, 2 H), 4.88 (dd, J = 4.8, 12.3 Hz, 1 H), 4.59 (dd, J = 9.9,
12.3 Hz, 1 H), 3.76 (s, 3 H), 3.70–3.63 (m, 1 H), 2.63–2.62 (m, 1 H),
2.39–2.35 (m, 2 H), 2.04–2.03 (m, 1 H), 1.77–1.20 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 211.5, 159.0, 129.5, 129.1, 114.3,
79.0, 55.0, 52.6, 43.2, 42.7, 33.1, 28.5, 25.0.
(m, 2 H), 2.04–1.80 (m, 1 H), 1.70–1.48 (m, 4 H), 1.18–1.13 (m, 1
H).
13C NMR (75 MHz, CDCl3): δ = 211.0, 136.3, 133.7, 129.5, 129.1,
78.5, 52.4, 43.3, 42.6, 33.1, 28.4, 25.1.
(S)-2-[(R)-1-(3-Chlorophenyl)-2-nitroethyl]cyclohexanone
(9g)18d
Yield: 0.35 g (93%); brownish oil.
(S)-2-[(R)-1-(3,4-Dimethoxyphenyl)-2-nitroethyl]cyclohexa-
none (9c)13e
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 232.5 nm): tR (minor) = 20.7 min, tR (major) = 23.0
min; syn/anti 97:3; 88% ee.
Yield: 0.33 g (90%); white solid; mp 134–135 °C (Lit.18f 133–
135 °C).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 95:5, flow rate 0.5
mL·min–1, λ = 247.3 nm): tR (major) = 30.5 min, tR (minor) = 33.3
min; syn/anti 99:1; >99% ee.
1H NMR (300 MHz, CDCl3): δ = 6.72 (d, J = 7.8 Hz, 1 H), 6.61–
6.57 (m, 2 H), 4.80 (dd, J = 4.5, 12.3 Hz, 1 H), 4.56 (dd, J = 9.6,
12.3 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.64–3.54 (m, 1 H), 2.61–
2.54 (m, 1 H), 2.42–2.24 (m, 2 H), 2.23–1.99 (m, 1 H), 1.73–1.40
(m, 4 H), 1.19–1.16 (m, 1 H).
1H NMR (300 MHz, CDCl3): δ = 7.20–7.12 (m, 2 H), 7.08 (s, 1 H),
7.01–6.96 (m, 1 H), 4.83 (dd, J = 4.5, 12.6 Hz, 1 H), 4.52 (dd,
J = 9.9, 12.6 Hz, 1 H), 3.67 (dt, J = 4.5, 9.9 Hz, 1 H), 2.65–2.52 (m,
1 H), 2.36–2.19 (m, 2 H), 1.96–1.93 (m, 1 H), 1.72–1.45 (m, 4 H),
1.24–1.08 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 210.4, 140.2, 134.6, 130.0, 129.8,
128.6, 126.5, 78.2, 52.1, 43.5, 42.4, 33.0, 28.3, 25.0.
13C NMR (75 MHz, CDCl3): δ = 210.7, 149.1, 148.7, 130.8, 120.7,
114.4, 112.4, 78.7, 56.0, 52.7, 43.6, 42.6, 33.1, 28.5, 25.2.
(S)-2-[(R)-1-(2-Chlorophenyl)-2-nitroethyl]cyclohexanone
(9h)18d
Yield: 0.32 g (85%); brownish viscous mass.
(S)-2-[(R)-1-(3-Methoxyphenyl)-2-nitroethyl]cyclohexanone
HPLC (Chiralpak AS-H, hexane–i-PrOH, 85:15, flow rate 0.5
mL·min–1, λ = 214.7 nm): tR (minor) = 12.8 min, tR (major) = 15.3
min; syn/anti 98:2; 81% ee.
1H NMR (300 MHz, CDCl3): δ = 7.29 (dd, J = 0.9, 6.9 Hz, 1 H),
7.15–7.07 (m, 3 H), 4.79–4.77 (m, 2 H), 4.24–4.16 (m, 1 H), 2.86–
2.39 (m, 1 H), 2.38–2.06 (m, 2 H), 2.05–1.94 (m, 1 H), 1.77–1.44
(m, 4 H), 1.31–1.18 (m, 1 H).
(9d)18c
Yield: 0.34 g (90%); white solid; mp 133–135 °C (Lit.18b 133–
134 °C).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 236.8 nm): tR (minor) = 22.7 min, tR (major) = 31.1
min; syn/anti 99:1; >99% ee.
1H NMR (300 MHz, CDCl3): δ = 7.15 (t, J = 7.8 Hz, 1 H), 6.69–
6.58 (m, 3 H), 4.80 (dd, J = 4.8, 12.3 Hz, 1 H), 4.54 (dd, J = 9.6,
12.3 Hz, 1 H), 3.71 (s, 3 H), 3.63–3.55 (m, 1 H), 2.62–2.57 (m, 1 H),
2.41–2.27 (m, 2 H), 1.98–1.95 (m, 1 H), 1.71–1.16 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 211.0, 135.4, 134.4, 130.1, 129.3,
128.7, 127.2, 77.4, 51.5, 42.6, 40.7, 32.8, 28.3, 25.1.
(S)-2-[(R)-2-Nitro-1-(3-nitrophenyl)ethyl]cyclohexanone (9i)18b
Yield: 0.34 g (92%); white solid; mp 111–113 °C.
13C NMR (75 MHz, CDCl3): δ = 210.6, 160.0, 139.5, 129.9, 120.2,
114.4, 112.8, 78.6, 55.0, 52.5, 44.0, 42.6, 33.1, 28.5, 25.2.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 241.9 nm): tR (minor) = 20.8 min, tR (major) = 30.9
min; syn/anti 99:1; 95% ee.
1H NMR (300 MHz, CDCl3): δ = 8.09 (dd, J = 1.8, 4.2 Hz, 1 H),
7.99 (s, 1 H), 7.50–7.42 (m, 2 H), 4.91 (dd, J = 4.8, 12.9 Hz, 1 H),
4.65 (dd, J = 9.9, 12.9 Hz, 1 H), 3.87 (dt, J = 4.8, 9.6 Hz, 1 H), 2.72–
2.63 (m, 1 H), 2.44–2.25 (m, 2 H), 2.08–2.04 (m, 1 H), 1.68–1.49
(m, 4 H), 1.26–1.14 (m, 1 H).
(S)-2-[(R)-1-(4-Ethoxy-3-methoxyphenyl)-2-nitroethyl]cyclo-
hexanone (9e)
Yield: 0.3 g (85%); white solid; mp 123–125 °C.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 240.9 nm): tR (minor) = 20.0 min, tR (major) = 26.8
min; syn/anti 98:2; 92% ee.
1H NMR (300 MHz, CDCl3): δ = 6.94 (d, J = 8.7 Hz, 1 H), 6.55–
6.53 (m, 2 H), 4.77 (dd, J = 4.8, 12.3 Hz, 1 H), 4.55 (dd, J = 9.6,
12.3 Hz, 1 H), 4.00 (q, J = 6.9 Hz, 2 H), 3.77 (s, 3 H), 3.70 (dt,
J = 4.8, 9.6 Hz, 1 H), 2.57–2.53 (m, 1 H), 2.41–2.28 (m, 2 H), 1.99–
1.95 (m, 1 H), 1.72–1.53 (m, 4 H), 1.40 (t, J = 6.9 Hz, 3 H), 1.96–
1.65 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 209.8, 148.8, 140.4, 134.8, 129.8,
122.9, 78.0, 52.3, 43.8, 42.6, 33.2, 28.3, 25.3.
(S)-2-[(R)-1-(1,3-Benzodioxol-5-yl)-2-nitroethyl]cyclohexanone
(9j)13d
Yield: 0.33 g (90%); white solid; mp 143–145 °C (Lit.18a 144–
145 °C).
13C NMR (75 MHz, CDCl3): δ = 210.7, 149.8, 148.2, 130.2, 120.1,
113.2, 112.2, 78.8, 64.2, 55.9, 52.8, 43.7, 42.6, 33.1, 28.5, 25.2,
15.0.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 236.5 nm): tR (minor) = 47.1 min, tR (major) = 51.9
min; syn/anti 99:1; 98% ee.
MS (ESI): m/z = 344.2 [M + Na]+.
1H NMR (300 MHz, CDCl3): δ = 6.63 (d, J = 7.5 Hz, 1 H), 6.57–
6.50 (m, 2 H), 5.87 (s, 2 H), 4.80 (dd, J = 4.5, 12.3 Hz, 1 H), 4.49
(dd, J = 9.9, 12.3 Hz, 1 H), 3.64 (dt, J = 4.5, 10.0 Hz, 1 H), 2.57–
2.48 (m, 1 H), 2.42–2.24 (m, 2 H), 2.03–1.99 (m, 1 H), 1.75–1.49
(m, 4 H), 1.25–1.12 (m, 1 H).
Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C,
63.22; H, 7.11; N, 4.58.
(S)-2-[(R)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone
(9f)13d
Yield: 0.33 g (88%); white solid; mp 92–95 °C (Lit.18c 93–96 °C).
13C NMR (75 MHz, CDCl3): δ = 211.2, 148.2, 147.2, 131.4, 121.6,
HPLC (Chiralpak AS-H, hexane–i-PrOH, 85:15, flow rate 0.5
mL·min–1, λ = 235.7 nm): tR (minor) = 16.2 min, tR (major) = 19.6
min; syn/anti 98:2; 91% ee.
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 9.0 Hz, 2 H), 7.05 (d,
J = 9.0 Hz, 2 H), 4.86 (dd, J = 4.8, 12.3 Hz, 1 H), 4.52 (dd, J = 9.9,
12.3 Hz, 1 H), 3.69–3.62 (m, 1 H), 2.61–2.39 (m, 1 H), 2.38–2.09
108.6, 108.0, 101.1, 78.9, 52.7, 43.8, 42.7, 33.1, 28.5, 25.1.
(S)-2-[(S)-1-(Furan-2-yl)-2-nitroethyl]cyclohexanone (9k)13d
Yield: 0.34 g (82%); brown oil.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 230.9 nm): tR (minor) = 15.5 min, tR (major) = 16.2
min; syn/anti 97:3; 88% ee.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1406–1413

1412
K. N. Singh et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.26–7.25 (m, 1 H), 6.21–6.19 (m,
1 H), 6.10–6.08 (m, 1 H), 4.72 (dd, J = 4.8, 12.3 Hz, 1 H), 4.60 (dd,
J = 9.3, 12.3 Hz, 1 H), 3.91 (dt, J = 4.8, 9.3 Hz, 1 H), 2.69–2.40 (m,
1 H), 2.37–2.05 (m, 2 H), 2.03–1.79 (m, 1 H), 1.79–1.53 (m, 4 H),
1.23–1.18 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 210.3, 150.9, 142.1, 110.2, 108.8,
76.9, 50.9, 42.3, 37.4, 32.3, 28.0, 25.0.
12.3 Hz, 1 H), 3.91 (quintet, J = 6.9 Hz, 1 H), 2.81–2.77 (m, 2 H),
2.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 203.9, 137.4, 134.0, 129.3, 128.8,
79.0, 45.9, 38.4, 30.2.
(3S,4R)-3-Methyl-5-nitro-4-phenylpentan-2-one (14)20a
Yield: 0.26 g (72%); white solid; mp 79–81 °C (Lit.20b 81–82 °C).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 237.5 nm): tR (minor) = 14.9 min, tR (major) = 16.2
min; syn/anti >99:1; 31% ee.
1H NMR (300 MHz, CDCl3): δ = 7.27–7.18 (m, 3 H), 7.08–7.05 (m,
2 H), 4.61–4.48 (m, 2 H), 3.59 (dt, J = 4.8, 9.3 Hz, 1 H), 2.94–2.89
(m, 1 H), 2.15 (s, 3 H), 0.93 (d, J = 7.2 Hz, 3 H).
(S)-2-[(R)-1-(1-Naphthyl)-2-nitroethyl]cyclohexanone (9l)18d
Yield: 0.29 g (80%); white creamy solid; mp 116–119 °C (Lit.18a
116–119 °C).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 85:15, flow rate 0.5
mL·min–1, λ = 231.1 nm): tR (minor) = 17.7 min, tR (major) = 23.2
min; syn/anti 95:5; 82% ee.
1H NMR (300 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.78 (d, J = 8.1 Hz,
1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.51–7.42 (m, 4 H), 5.02 (dd, J = 4.5,
12.6 Hz, 1 H), 4.87 (dd, J = 9.3, 12.6 Hz, 1 H), 4.67 (br s, 1 H), 2.80
(br s, 1 H), 2.46–2.19 (m, 2 H), 2.04–1.98 (m, 1 H), 1.64–1.37 (m,
4 H), 1.23–1.12 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 210.0, 137.6, 129.0, 127.9, 127.3,
78.3, 48.9, 45.8, 29.0, 15.9.
(4S,5R)-4-Methyl-6-nitro-5-phenylhexan-3-one (15)21
Yield: 0.29 g (75%); brownish viscous mass.
HPLC (Chiralcel OD, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 219.7 nm): tR (minor) = 19.3 min, tR (major) = 23.9
min; syn/anti 99:1; 51% ee.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.18 (m, 3 H), 7.08–7.05 (m,
2 H), 4.61–4.46 (m, 2 H), 3.61–3.54 (m, 1 H), 2.97–2.87 (m, 1 H),
2.59–2.46 (m, 1 H), 2.39–2.26 (m, 1 H), 1.02 (t, J = 7.2 Hz, 3 H),
0.91 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 209.8, 134.3, 131.2, 129.3, 128.1,
126.6, 125.9, 125.3, 123.5, 122.7, 78.6, 52.9, 42.8, 35.7, 33.3, 28.7,
25.2.
(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclopentanone (9m)13d
Yield: 0.33 g (85%); white solid; mp 116–118 °C (Lit.18a 116–
119 °C).
13C NMR (75 MHz, CDCl3): δ = 212.8, 137.7, 129.0, 128.8, 127.9,
78.1, 48.2, 46.1, 35.3, 16.3, 7.6.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 85:15, flow rate 0.5
mL·min–1, λ = 228.9 nm): tR (minor) = 17.2 min, tR (major) = 23.6
min; syn/anti 90:10; 72% ee.
1H NMR (300 MHz, CDCl3): δ = 7.25–7.14 (m, 3 H), 7.07–7.05 (m,
2 H), 5.23 (dd, J = 5.7, 12.9 Hz, 1 H), 4.62 (dd, J = 9.0, 12.9 Hz, 1
H), 3.63 (dt, J = 5.4, 9.0 Hz, 1 H), 2.33–2.19 (m, 2 H), 2.16–1.90
(m, 1 H), 1.88–1.56 (m, 3 H), 1.48–1.34 (m, 1 H).
Crystal Structure Determination
For compound 6, X-ray data were collected on a Bruker Kappa
APEX II diffractometer equipped with a CCD detector (with the
crystal-to-detector distance fixed at 60 mm) and sealed-tube mono-
chromated Mo Kα radiation using the program APEX2.22 The im-
ages were interpreted and integrated using SAINT. The crystal
structures were solved and refined using SHELX 97.23 Positions of
most of the non-hydrogen atoms were obtained from a direct meth-
ods solution. Several full-matrix least-squares/difference Fourier
cycles were performed, locating the remainder of the non-hydrogen
atoms. All non-hydrogen atoms were refined with anisotropic dis-
placement parameters. All hydrogen atoms were placed in ideal po-
sitions and refined as riding atoms with individual isotropic
displacement parameters. Crystal data for 6 (CCDC 928286):24
C16H23NO3S, M = 309.41, orthorhombic, a = 5.7931(4) Å,
b = 13.0408(7) Å, c = 22.0601(16) Å, α = 90°, β = 90°, γ = 90°,
V = 1666.57(19) Å3, T = 296(2) K, space group P212121, Z = 4, ab-
sorption coefficient = 0.203 mm–1, 11858 reflections collected,
2920 independent reflections [R(int) = 0.0992]. A set of 1656 re-
flections were included in calculations, giving a final standard re-
sidual R1 value of 0.0612 (wR2 = 0.1277) for observed data
[I > 2σ(I)] and 0.1308 for all data (wR2 = 0.1567); GOF = 1.002.
13C NMR (75 MHz, CDCl3): δ = 218.4, 137.8, 128.9, 128.8, 127.9,
78.2, 51.2, 44.2, 38.5, 28.4, 20.3.
(S)-2-[(R)-1-(1,3-Benzodioxol-5-yl)-2-nitroethyl]cyclopenta-
none (9n)
Yield: 0.29 g (82%); white solid; mp 98–100 °C.
HPLC (Chiralpak AS-H, hexane–i-PrOH, 95:5, flow rate 0.5
mL·min–1, λ = 227.7 nm): tR (major) = 41.0 min, tR (minor) = 56.5
min; syn/anti 83:17; 87% ee.
1H NMR (300 MHz, CDCl3): δ = 6.65 (d, J = 7.5 Hz, 1 H), 6.55–
6.50 (m, 2 H), 5.87 (s, 2 H), 5.20 (dd, J = 5.4, 12.6 Hz, 1 H), 4.54
(dd, J = 9.9, 12.6 Hz, 1 H), 3.53 (dt, J = 5.4, 9.9 Hz, 1 H), 2.32–2.23
(m, 2 H), 2.20–2.00 (m, 1 H), 1.89–1.66 (m, 3 H), 1.48–1.40 (m, 1
H).
13C NMR (75 MHz, CDCl3): δ = 216.9, 148.2, 147.1, 131.5, 121.5,
108.6, 108.0, 101.1, 78.3, 50.5, 44.1, 38.5, 28.5, 20.4.
MS (ESI): m/z = 300.1 [M + Na]+.
Acknowledgment
Anal. Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C,
60.45; H, 5.46; N, 5.16.
We acknowledge financial support via scheme no. SR/SI/OC-
31/2007 from DST, New Delhi. S.K.S. is thankful to DST, New
Delhi for providing a research fellowship (DST/INSPIRE fellow-
ship/2011/150). Pushpinder Singh and S.K. thank CSIR for a re-
search fellowship. The X-ray facility at IISER, Mohali is gratefully
acknowledged.
(R)-4-(4-Chlorophenyl)-5-nitropentan-2-one (13)19
Yield: 0.3 g (94%); white solid; mp 76–77 °C (Lit.8 75–77 °C).
HPLC (Chiralpak AS-H, hexane–i-PrOH, 90:10, flow rate 0.5
mL·min–1, λ = 229.2 nm): tR (minor) = 27.9 min, tR (major) = 34.9
min; 95% ee.
1H NMR (300 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 2 H), 7.08 (d,
J = 8.4 Hz, 2 H), 4.60 (dd, J = 6.9, 12.3 Hz, 1 H), 4.49 (dd, J = 7.5,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. SnufpgIorpi
o
nmitSartunpIoofprimntgirat
Synthesis 2013, 45, 1406–1413
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereoselective Michael Addition of Cycloalkanones to Nitroolefins
1413
(8) Morris, D. J.; Partridge, A. S.; Manville, C. V.; Racys, D. T.;
Woodward, G.; Docherty, G.; Wills, M. Tetrahedron Lett.
2010, 51, 209.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1406–1413