A chiral amino-naphthalene-derived prolinamide catalyst for the enantioselective Michael addition of ketones to nitroolefins

Article abstract of DOI:10.3184/174751912X13332916163195

An enantioselective Michael addition of ketones to nitroolefins has been accomplished using a novel chiral aminonaphthalenederived prolinamides catalyst 1. The desired Michael adducts were obtained in high yields (up to 93%) as well as good diastereoselectivities (>99:1) and enantioselectivities (48%-99% ee).

Full text of DOI:10.3184/174751912X13332916163195

278 RESEARCH PAPER
MAY, 278–282
JOURNAL OF CHEMICAL RESEARCH 2012
A chiral amino-naphthalene-derived prolinamide catalyst for the
enantioselective Michael addition of ketones to nitroolefins
Chuanming Yu*, Ke Zhang and Xiangjun Shi
Key Laboratory for Green PharmaceuticalTechnologies and Related Equipment, Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
An enantioselective Michael addition of ketones to nitroolefins has been accomplished using a novel chiral amino-
naphthalene-derived prolinamides catalyst 1. The desired Michael adducts were obtained in high yields (up to 93%)
as well as good diastereoselectivities (>99:1) and enantioselectivities (48%-99% ee).
Keywords: amino-naphthalene-derived prolinamide, Michael addition, ketone, nitroolefins
The conjugate Michael addition1 plays an important role in
numerous asymmetric carbon–carbon bond-forming reactions
since it represents one of the most elegant and attractive ways
to introduce chirality into a Michael acceptor.2–6 In particular,
the asymmetric Michael reaction of carbonyl compounds
to nitroolefins represents an easy approach to the formation of
synthetically useful γ-nitro carbonyl compounds, which serve
as versatile intermediates for the preparation of complex
organic targets.7–9 List10 and Barbas11 firstly reported the addi-
tion of ketones to trans-β-nitrostyrene with L-proline as the
catalyst with good diastereoselectivity but very poor enanti-
oselectivities (0-23% ee). Thus, the development of enantiose-
lective catalytic protocols for this key reaction has received
considerable attention. In the past, a number of efficient and
highly selective catalytic systems have been designed for
this addition reaction, such as pyrrolidine sulfonamides,12
dehydrobietylamine,13 diamines,14 thiourea-secondary amines,15
primary amine-thioureas,16 thiourea-tertiary amine,17 bis–
secondary–tertiary triamine,18 pyrrolidinyl-camphor deriva-
tives,19 and bifunctional guanidines,20 etc. Among these, chiral
amines based on intermolecular H-bonding cores dominate
the field.
Recently the development of bifunctional asymmetric
catalysts has been a fruitful area of investigation. The basis
of these catalysis, was the synergistic activation of the
nucleophile and electrophile by two or more reactive centers
involving a combination of a Lewis acid or Lewis base work-
ing in concert. This gave high reaction rates and excellent
stereoselectivities.21 Alonso and coworkers22 reported an
example of this bifunctional asymmetric catalysts, in which a
series of amino-alcohol-derived prolinamides were applied
to the asymmetric Michael addition of ketones to trans-β-
nitrostyrene with high levels of syn-diastereoselectivity (up to
94%) and enantioselectivity (41-81% ee). Consequently, we
havedevelopednovelamino-naphthalene-derivedprolinamides
as catalysts for the asymmetric Michael addition reaction.
Scheme 1. (S)-Proline 12 was firstly protected with the
benzyloxycarbonyl (Cbz) group as (S)-N-(benzyloxycarbonyl)
proline 13.23 Then the protected proline 13 was transformed
into prolinamide derivatives 14 by reaction with the corre-
sponding chiral amine and β-amino alcohol in the presence of
Et3N and isobutyl chloroformate22. The catalysts 1-6 were
obtained by the hydrogenolysis of 14 in the presence of a Pd/C
catalyst under hydrogen at ordinary pressure. The catalyst
1 reacted with MeI to give catalyst 7 in the presence of K2CO3
as shown in Scheme 2.
We investigated the catalytic activity of 1-7 for the asym-
metric Michael additon of cyclohexanone 8a to trans-β-
nitrostyrene 9a as a model reaction (Scheme 3), and the results
were summarized in Table 1.
The reaction was first carried out at room temperature in the
presence of catalyst 1 with benzoic acid as the additive and
ethanol as the solvent. However, it afforded the adduct with
poor enantioselectivity (40% ee), albeit with good diastereose-
lectivity (94:6 dr) and high yield (91%). Fortunately, excellent
enantioselectivitie (>99% ee) was obtained (Table 1, entry 2),
when the reaction temperature was decreased to 0 °C. The
other catalysts 2–7 were examined in this Michael reaction,
but the enantioselectivities decreased, only 38–89% ee
(Table 1, entries 3–8). When phenolic hydroxyl of catalyst
7 was protected by a methyl group, the enantioselectivity was
only 38%. Obviously, the presence of the phenolic hydroxyl
was important for the selectivity of the process (Table 1, entries
4 and 8). Catalysts 2 and 3 derived from (R)-1-(amino(phenyl)
methyl)naphthalen-2-ol and race-1-(amino(phenyl)methyl)na
phthalen-2-ol were not effective compared with catalyst 1.
Double H-bonding did not combine the catalyst with trans-
β-nitrostyrene, when electron-donating groups increased the
electronic density of chiral amide. A series of solvents and
additives were also investigated. In general, the catalyst
exhibited higher activity in protic solvent such as EtOH com-
pared with aprotic solvent and both a higher yield (91%)
and higher enantioselectivity (>99%) were obtained (Table 1,
entry 2). The reactions proceeded more rapidly in the presence
of strong acids as additives, but the enantioselectivities were
poor (Table 1, entries 16 and 17).
With the optimal conditions to hand, the reactions of a vari-
ety of nitroolefins with ketones were investigated, and the
results were shown in Table 2. Firstly, different nitroolefins
were probed and the reactions reached completion, affording
good yields (up to 93%). However, the reaction involving
2-nitrovinylcyclohexane or butan-2-one produced a trace of
products (Table 2, entries 12 and 14). To our surprise, results
show moderate enantioselectivities (48–67% ee), when the
nitroolefins possessed different substituents. The possible
reason is that both the amide NH and the phenolic hydroxyl in
the catalyst activate the nitro alkene by the combination of
upto three hydrogen bonds, favouring the approach of the
nitroalkene from the Re face of the anti enamine. But another
Results and discussion
We synthesised the novel derived prolinamide catalysts 1–7
which were similar to amino-alcohol-derived prolinamide.
These catalysts contained a pyrrolidine ring as a Brønsted
base to generate the nucleophile, and also included another
Brønsted base and acidic phenolic hydroxyl group. When
these two groups combined with the electrophile by double
H-bonding, classical electrostatic effects served to decrease
the electron density of these species, activating it towards
nucleophilic attack,21 furthermore, it plays an active part in
enantioselectivity inducement.
Chiral amino-naphthalene-derived prolinamides catalysts
1–6 were easily prepared from (S)-proline 12 as shown in
* Correspondent. E-mail: pharmlab@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 279
Scheme 1
Experimental
The chiral amino-napthalenes were synthesised according to the
published procedures.24 All other reagents are commercially available.
Melting points were measured on a Büchi B-540 capillary melting
point apparatus and are uncorrected. IR spectra were recorded on a
Nicolet Aviatar-370 instrument; as KBr discs. 1H NMR and 13C NMR
spectra were recorded on a Varian 400 MHz instrument using CDCl3
or DMSO-d6 as the solvent, and chemical shifts were expressed in
parts per million (ppm) using TMS as an internal standard. Mass
spectra were obtained on a Thermo Finnigan LCQ-Advantage spec-
trometer. Flash column chromatography was carried out on 200–300
mesh silica gel.
Scheme 2
Synthesis of catalysts 1–7; general procedure
Cbz-protected proline 13 (5.00 g, 20 mmol) and Et3N (2.02 g, 20 mmol)
were dissolved in THF (60 mL) and cooled to 0 °C. Isobutyl chlorofor-
mate (2.17 g, 20 mmol) dissolved in THF (40 mL), was added slowly,
the solution was stirred for 0.5 h. Then (S)-1-[amino(phenyl)methyl]
naphthalen-2-ol (5.00 g, 20 mmol) dissolved in THF (40 mL) was
added slowly and the reaction temperature was maintained at 0 °C.
After being stirred for 3 h, the solution was filtered and the solvent
was removed in vacuo to give a thick yellow oil that was purified
by flash chromatography on silica gel (pentane/ethyl acetate, 1:1) to
yield the desired white solid 14 (7.7 g, 80%). Compound 14 (4.8 g,
10 mmol) was dissolved in anhydrous MeOH (30 mL), and Pd/C
(10%, w/w) (0.48 g) was added to the solution. The mixture was
stirred under a hydrogen atmosphere for 6 h. The solution was filtered
and the filtrate was concentrated under reduced pressure. The residue
which was obtained was then subjected to flash chromatography
on silica gel (pentane/ethyl acetate = 1:2, v/v) to afford yellow solid
1 (3.11g, 90%).
The catalyst 1 (1.7 g, 5 mmol), MeI (1.42 g, 10 mmol) and K2CO3
(2.76 g, 20 mmol) were dissolved in MeCN (20 mL) and the solvent
was stirred for 5 h. Then the reaction solution was filtered and the
filtrate was concentrated under reduced pressure. The obtained residue
was then subjected to flash chromatography on silica gel (pentane/
ethyl acetate = 1:1, v/v) to afford yellow solid 7 (1.44 g, 80%).
(S)-N-((S)-(2-Hydroxynaphthalen-1-yl)(phenyl)methyl)pyrrolidine-
2-carboxamide (1): Yellow solid; m.p. 204.4–205.9 °C; IR (KBr):
νmax = 3321, 1631, 1526, 1271 cm–1; 1H NMR (400 MHz, DMSO-d6)
δ = 9.46 (s, 1H), 7.80 (s, 1H), 7.82–7.75 (m, 2H), 7.46 (t, J = 6.4 Hz,
Scheme 3
enantiomer is also formed through a Si approach of the
nitroalkene to the anti enamine.22 However, catalyst 1 had a
high catalytic activity for the reaction of cyclohexanone
with nitrostyrene with excellent enantioselectivity (>99% ee).
The results show that electronic effect are not important
for asymmetric Michael addition reactions in the presence of
catalyst 1 (Scheme 4).
The possible mechanism of asymmetric Michael addition
reactions of cyclohexanone to nitrostyrene catalysed by 1 is
considered as follows (Scheme 5).
In summary, a series of chiral amino-naphthalene-derived
prolinamides were examined as the catalysts in the asymmetric
Michael addition reactions of ketones to nitroolefins. Among
these catalysts, the organocatalyst 1 showed the highest
catalytic activity toward this reaction to furnish the corre-
sponding adducts in excellent yields (up to 93%) and useful
stereoselectivities (48–99% ee).

280 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Catalytic asymmetric Michael reaction of cyclohexanone to nitrostyrene under various conditionsa
Entry
Catalyst
Solvents
Additives
Time/h
Yieldb/%
drc(syn/anti)
eed/%
1e
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
free
DMSO
CH2Cl2
THF
AcOEt
n-hexane
EtOH
EtOH
EtOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
free
48
48
48
48
48
48
48
48
60
48
48
48
48
72
48
18
18
91
93
89
90
80
89
91
88
90
95
87
91
89
85
86
90
92
94:6
99:1
96:4
>99:1
95:5
98:2
>99:1
98:2
97:3
99:1
94:6
99:1
98:2
99:1
98:2
96:4
95:5
40
>99
57
89
38
56
53
51
50
53
34
77
47
40
50
41
48
HCl
p-TSA
a Reaction conditions: 8a (5 mmol), 9a (0.5 mmol), catalyst (10 mol%), additive (10 mol%) and solvent (1 mL) at 0 °C.
b Isolated yield.
c Determined by 1H NMR spectroscopy or HPLC.
d Determined by chiral HPLC analysis.
e The reaction was carried out at room temperature.
Table 2 Asymmetric Michael addition reactions of ketones to nitroolefinsa
Entry
R1, R2
R3
Time /h
Products
Yield/%b
drc(syn/anti)
eed/%
1
2
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
Me, H
C6H5
48
72
72
48
48
48
72
48
72
48
48
72
72
72
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
93%
83%
86%
87%
88%
88%
90%
87%
91%
86%
81%
Trace
73%
Trace
>99:1
>99:1
97:3
96:4
98:2
92:8
>99:1
>99:1
98:2
97:3
98:2
–
>99
53
52
56
55
51
55
67
59
50
52
–
4-OMeC6H4
3,4-Me2C6H3
4-ClC6H4
4-BrC6H4
3-O2NC6H4
3-OHC6H4
2-FC6H4
3
4
5
6
7
8
9
2-OMeC6H4
1-Naphthyl
2-Furanyl
Cyclohexyl
C6H5
10
11
12
13
14
95:5
–
48
–
Et, H
C6H5
a Reaction conditions: 8 (5 mmol), 9 (0.5 mmol), 1 (0.05 mmol), benzoic acid (0.05 mmol) and EtOH (1 mL) at 0 °C.
b Isolated yield.
c Determined by 1H NMR spectroscopy or HPLC.
d Determined by chiral HPLC analysis.
(2S)-N-((2-Hydroxynaphthalen-1-yl)(phenyl)methyl)pyrrolidine-2-
carboxamide (3): Yellow solid; m.p. 205.2–207.0 °C; IR (KBr):
νmax = 3321, 1615, 1526, 1271 cm–1; 1H NMR (400 MHz, DMSO-d6)
δ = 9.41 (s, 1H), 7.84 (s, 1H), 7.82–7.79 (m, 2H), 7.50–7.49 (m, 1H ),
7.30–7.14 (m, 6H), 7.05 (s, 1H), 3.83–3.71 (m, 1H), 2.92–2.79 (m,
1H), 2.52–2.48 (m, 1H), 2.08–2.01 (m, 1H), 1.71–1.57 (m, 3H); 13C
NMR (100 MHz, DMSO-d6): δ = 171.3, 153.4, 141.3, 133.5, 129.2,
128.8, 128.3, 126.3, 126.2, 125.5, 122.3, 121.4, 115.6, 63.4, 49.1,
45.6, 30.9, 24.4; MS (ESI): m/z (%) = 347 (100) [M+1]+. HRMS-ESI:
m/z (M++1) Calcd for C22H23N2O2: 347.1762; found: 347.1764.
(S)-N-((S)-2-Hydroxy-1-phenylethyl)pyrrolidine-2-carboxamide
(4): Yellow solid; m.p. 121.3–123.7 °C; IR (KBr): νmax = 3306, 1648,
Scheme 4
1H ), 7.28 (t, J = 7.2 Hz, 1H), 7.24-7.11 (m, 7H), 7.05 (s, 1H), 3.63–
3.60 (m, 1H), 2.98–2.92 (m, 1H), 2.85–2.79 (m, 1H), 2.07–1.99 (m,
1H), 1.89–1.82 (m, 1H), 1.60–1.59 (m, 2H); 13C NMR (100 MHz,
DMSO-d6): δ = 173.6, 153.0, 142.6, 132.0, 129.0, 128.5, 127.9, 126.7,
126.0, 125.5, 122.4, 121.8, 118.4, 60.3, 47.1, 46.8, 30.7, 26.1; MS
(ESI): m/z (%) = 347 (100) [M+1]+. HRMS-ESI: m/z (M++1) Calcd
for C22H23N2O2: 347.1762; found: 347.1764.
1
1551, 1256 cm–1; H NMR (400 MHz, DMSO-d6) δ = 8.35 (d, J =
8 Hz, 1H), 7.30–7.18 (m, 5H), 4.80–4.75 (m, 1H), 3.59–3.52 (m, 3H),
2.84–2.80 (m, 2H), 2.00–1.91 (m, 1H), 1.69–1.56 (m, 3H); 13C NMR
(100 MHz, DMSO-d6): δ = 173.6, 141.0, 127.9, 126.6, 64.5, 60.22,
54.3, 46.7, 30.5, 25.8; MS (ESI): m/z (%) = 235 (100) [M+1]+. HRMS-
ESI: m/z (M++1) Calcd for C13H19N2O2: 235.1441; found: 235.1442.
(S)-N-((S)-(2-Hydroxynaphthalen-1-yl)(4-methoxyphenyl)methyl)
pyrrolidine-2-carboxamide (5): Yellow solid; m.p. 213.2–215.1 °C;
(S)-N-((R)-(2-Hydroxynaphthalen-1-yl)(phenyl)methyl)pyrrolidine
-2-carboxamide (2): Yellow solid; m.p. 205.4–206.8 °C; IR (KBr):
1
νmax = 3321, 1615, 1515, 1463 cm–1; H NMR (400 MHz, DMSO-d6)
δ = 9.48 (s,1H), 7.98 (s,1H), 7.82–7.74 (m, 2H), 7.45(t, J = 6.8 Hz,
1H), 7.30–7.19 (m, 5H), 7.16–7.11 (m, 2H), 7.04 (s, 1H), 3.75–3.60
(m, 1H), 2.98–2.80 (m, 1H), 2.65–2.50 (m, 1H), 2.08–1.82 (m, 1H),
1.75–1.38 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 172.5, 153.2,
142.1, 132.7, 129.1, 128.6, 128.1, 126.5, 126.1, 125.5, 122.4, 121.6,
117.2, 60.7, 48.1, 46.4, 30.8, 25.1; MS (ESI): m/z (%) = 347 (100)
[M+1]+. HRMS-ESI: m/z (M++1) Calcd for C22H23N2O2: 347.1762;
found: 347.1764.
1
IR (KBr): νmax = 1651, 1511, 1248, 1274 cm–1; H NMR (400 MHz,
DMSO-d6) δ = 7.81–7.71 (m, 2H), 7.37–6.96 (m, 6H), 6.84–6.80 (m,
2H), 3.70 (s, 3H), 3.42–3.38 (m, 1H), 2.88–2.72 (m, 1H), 2.30–1.50
(m, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 173.7, 157.5, 153.8,
131.9, 131.4, 199.8, 128.9, 128.5, 127.1, 126.7, 122.3, 118.4, 115.2,
67.9, 64.4, 54.9, 47.6, 29.9, 23.4; MS (ESI): m/z (%) = 377 (100)

JOURNAL OF CHEMICAL RESEARCH 2012 281
Scheme 5
[M+1]+. HRMS-ESI: m/z (M++1) Calcd for C22H23N2O2: 377.1863;
found: 377.1860.
added. The mixture was stirred at 0 °C and the reaction was monitored
by TLC. The product was purified by silica gel column chromatography
(petroleum ether:EtOAc = 6:1, v/v).
(S)-N-((S)-1-(2-Hydroxynaphthalen-1-yl)ethyl)pyrrolidine-2-car-
boxamide(6):Whitesolid;m.p.113.8–115.5°C;IR(KBr):νmax = 2969,
1631, 1517, 1272 cm–1; 1H NMR (400 MHz, DMSO-d6) δ = 8.03 (m,
1H), 7.72–7.70 (m, 2H),7.39–7.24 (m, 4H), 6.00 (s, 1H), 4.13–4.08
(m, 1H), 2.90–2.89 (m, 2H), 2.08–2.01 (m, 2H), 1.26–1.22 (m, 6H);
13C NMR (100 MHz, DMSO-d6): δ = 171.0, 153.4, 133.5, 128.8,
128.3, 126.3, 123.8, 123.2, 118.9, 115.4 , 63.4, 45.6, 45.3 , 30.9, 24.9,
22.2; MS (ESI): m/z (%) = 285 (100) [M+1]+. HRMS-ESI: m/z (M++1)
Calcd for C17H21N2O2: 285.1596; found: 285.1598.
(S)-N-((S)-(2-methoxynaphthalen-1-yl)(phenyl)methyl)pyrrolidine-
2-carboxamide (7): White solid; m.p. 113.8–115.5 °C; IR (KBr):
νmax = 2969, 1631, 1517, 1272 cm–1; 1H NMR (400 MHz, DMSO-d6)
δ = 8.85 (d, J = 9.6 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.82–7.87 (m,
2H), 7.17–7.53 (m, 9H), 3.80 (m, 1H), 3.63 (m, 1H), 2.83–2.79 (m,
1H), 2.47–2.35 (m, 1H), 2.09–1.98 (m, 1H), 1.75–1.59 (m, 3H); 13C
NMR (100 MHz, DMSO-d6): δ = 172.3, 155.8, 142.6, 132.8, 130.3,
129.9, 129.0, 128.5, 127.6, 126.9, 126.4, 124.3, 123.7, 114.7, 62.9,
57.8, 49.1, 45.6, 30.9, 24.4; MS (ESI): m/z (%) = 361 (100) [M+1]+.
HRMS-ESI: m/z (M++1) Calcd for C23H25N2O2: 361.1917; found:
361.1919.
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (10a): White solid;
m.p. 128.2–130.1 °C (lit.25 124–126 °C); 1H NMR (400 MHz, CDCl3)
δ = 7.34–7.18 (m, 5H), 4.94 (dd, J = 12.4, 4.4 Hz, 1H), 4.63 (dd,
J = 12.4, 10.0 Hz, 1H), 3.76 (td, J = 10.0, 4.4Hz, 1H), 2.72–2.63
(m, 1H), 2.50–2.35 (m, 2H), 2.09–2.06 (m, 1H), 1.77–1.56 (m, 4H),
1.28–1.94 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 211.9, 137.8,
129.0, 128.3, 127.9, 79.1, 52.8, 44.2, 43.1, 33.6, 28.9, 25.4; MS (ESI):
m/z (%) = 253 (100) [M+1]+; HPLC (Chiralcel AS-H, i-PrOH/n-
hexane = 15/85, flow rate = 1.0 mL min–1, λ = 206 nm): tminor =10.5
min, tmajor = 15.3 min, >99% ee. [α]D20 = –16.4° (c = 0.28, CH2Cl2).
(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone (10b):
1
White solid; m.p. 153.5–154.8 °C (lit.26 153-154 °C); H NMR (400
MHz, CDCl3) δ = 7.08 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H),
4.91 (dd, J = 12.4, 4.4 Hz, 1H), 4.58 (dd, J = 12.4, 10.0 Hz, 1H), 3.78
(s, 3H), 3.71 (td, J = 10.0, 4.8Hz, 1H), 2.68–2.61 (m, 1H), 2.49–2.34
(m, 2H), 2.15–2.10 (m, 1H), 1.81–1.58 (m, 4H), 1.28–1.18(m, 1H);
13C NMR (100 MHz, CDCl3) δ = 212.0, 159.0, 129.5, 129.1, 114.26,
79.1, 55.2, 52.6, 43.2, 42.7, 33.1, 28.5, 25.0; MS (ESI): m/z (%) = 278
(100) [M+1]+; HPLC (Chiralcel AS-H, i-PrOH/n-hexane = 15/85,
flow rate = 1.0 mL min–1, λ = 206 nm): tminor =14.4 min, tmajor = 16.9
min, 53% ee. [α]D20 = –7.5° (c = 0.50, CH2Cl2).
Synthesis of 10a–n; general procedure
The catalyst 1 (10 mol %), PhCOOH (10 mol %) and ketones (5 mmol)
were mixed in EtOH (1 mL), and the nitro olefin (0.5 mmol) was
(S)-2-((R)-1-(3,4-Dimethylphenyl)-2-nitroethyl)cyclohexanone (10c):
White solid; m.p. 137.6–138.3 °C (lit.18 not reported); 1H NMR (400 MHz,

282 JOURNAL OF CHEMICAL RESEARCH 2012
CDCl3) δ = 7.07 (d, J = 7.6 Hz, 1H), 6.90-6.87 (m, 2H), 4.91 (dd,
J = 12.4, 4.4 Hz, 1H), 4.60 (dd, J = 12.4, 10.0 Hz, 1H), 3.68
(td, J = 10.0, 4.4 Hz, 1H), 2.69–2.62 (m, 1H), 2.50–2.36 (m, 2H), 2.22
(d, J = 4.8 Hz, 6H), 2.10–2.04 (m, 1H), 1.80–1.60 (m, 4H), 1.29–1.18
(m, 1H); 13C NMR (100 MHz, CDCl3) δ = 212.2, 137.1, 136.0, 135.0,
130.0, 129.4, 125.3, 79.0, 52.6, 43.6, 42.7, 33.2, 28.6, 25.0, 19.9,
19.4.; MS (ESI): m/z (%) = 276 (100) [M+1]+; HPLC (Chiralcel
AS-H, i-PrOH/n-hexane = 15/85, flow rate = 1.0 mL min–1, λ = 206 nm):
(S)-2-((R)-1-(Naphthalen-1-yl)-2-nitroethyl)cyclohexanone (10j):
White solid; m.p. 136.5–137.9 °C (lit.26 133–134 °C); 1H NMR
(400 MHz, CDCl3) δ = 8.15–8.14 (m, 1H), 7.84 (d, J = 8 Hz, 1H),
7.76 (d, J = 8.4 Hz), 7.56–7.42 (m, 3H), 7.36 (d, J = 7.2 Hz, 1H), 5.06
(dd, J = 12.8, 4.4 Hz), 4.93–4.88 (m, 1H), 4.76–4.73 (m, 1H), 2.87–
2.85 (m, 1H), 2.53–2.38 (m, 2H), 2.11–2.05 (m, 1H), 1.72–1.47
(m, 4H), 1.3–1.2 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 212.3,
136.2, 134.5, 132.6, 128.4, 128.3, 128.1, 127.1, 126.9, 126.5, 124.7,
78.2, 55.4, 43.3, 40.7, 28.5, 25.6, 23.6; MS (ESI): m/z (%) = 298 (100)
[M+1]+; HPLC (Chiralcel AS-H, i-PrOH/n-hexane = 15/85, flow
rate = 1.0 mL min–1, λ = 206 nm): tminor =13.6 min, tmajor = 19.3 min,
50% ee. [α]D20 = –13.9° (c = 0.50, CH2Cl2).
t
minor = 8.4 min, tmajor = 13.1 min, 52% ee. [α]D20 = –7.6° (c = 0.50,
CH2Cl2).
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone (10d):
White solid; m.p. 93.7–96.4 °C (lit.25 93–96 °C); 1H NMR (400 MHz,
CDCl3) δ = 7.30 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 4.94
(dd, J = 12.6, 4.5 Hz, 1H), 4.60 (dd, J = 12.6, 10.1 Hz, 1H), 3.76 (td,
J = 9.9, 4.5 Hz, 1H), 2.68–2.61 (m, 1H), 2.50–2.34 (m, 2H), 2.12–
2.05 (m, 1H), 1.82–1.58 (m, 4H), 1.28–1.17 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ = 211.1, 136.1, 133.4, 129.4, 129.0, 78.5, 52.4,
43.4, 42.8, 33.2, 28.5, 25.1; MS (ESI): m/z (%) = 281 (100) [M+1]+;
HPLC (Chiralcel AS-H, i-PrOH/n-hexane = 15/85, flow rate =
1.0 mL min–1, λ = 206 nm): tminor =10.4 min, tmajor = 16.3 min, 56% ee.
[α]D20 = –13.4° (c = 0.50, CH2Cl2).
(S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)cyclohexanone (10e):
White solid; m.p. 117.4–119.1 °C (lit.25 120–122 °C); 1H NMR (400 MHz,
CDCl3) δ = 7.43 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 4.92
(dd, J = 12.4, 4.4 Hz, 1H), 4.59 (dd, J = 12.4, 10.0 Hz, 1H), 3.74 (td,
J = 10.0, 4.4 Hz, 1H), 2.67–2.61 (m, 1H), 2.49–2.33 (m, 2H), 2.09–
2.04 (m, 1H), 1.81–1.56 (m, 4H), 1.27–1.17 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ = 211.1, 136.6, 131.9, 129.7, 121.6, 78.5, 52.4,
43.5, 42.8, 33.2, 28.5, 25.2. MS (ESI): m/z (%) = 326 (100) [M+1]+;
HPLC (Chiralcel AS-H, i-PrOH/n-hexane = 15/85, flow rate =
1.0 mL min–1, λ = 206 nm): tminor =11.4 min, tmajor = 18.5 min, 55% ee.
[α]D20 = –13.4° (c = 0.50, CH2Cl2).
(S)-2-((R)-1-(Furan-2-yl)-2-nitroethyl)cyclohexanone (10k): Brown
1
oil; H NMR (400 MHz, CDCl3) δ = 7.35–7.34 (m, 1H), 6.29 (dd,
J = 3.2, 2.0 Hz, 1H), 6.18 (d, J = 3.2, 1H), 4.79 (dd, J = 12.4, 4.8 Hz,
1H), 4.67 (dd, J = 12.4, 9.6 Hz, 1H), 3.97 (td, J = 9.2, 4.8 Hz, 1H),
2.79–2.72 (m, 1H), 2.49–2.33 (m, 2H), 2.13–2.08 (m, 1H), 1.86–1.62
(m, 4H), 1.34–1.24(m, 1H); 13C NMR (100 MHz, CDCl3) δ = 211.2,
211.1, 151.3, 142.6, 110.6, 109.3, 77.6, 51.4, 42.8, 37.9, 32.7,
28.5, 25.4; MS (ESI): m/z (%) = 237 (100) [M+1]+; HPLC (Chiralcel
AS-H, i-PrOH/n-hexane = 15/85, flow rate = 1.0 mL min–1, λ = 206 nm):
t
minor = 11.8 min, tmajor = 13.2 min, 52% ee. [α]D20 = –8.3° (c = 0.24,
CH2Cl2).
(S)-5-Nitro-4-phenylpentan-2-one (10m): Colourless oil; 1H NMR
(400 MHz, CDCl3) δ = 7.35–7.21 (m, 5H), 4.70 (dd, J = 12.4, 6.8 Hz,
1H), 4.60 (dd, J = 12.4, 7.6 Hz, 1H), 4.05-3.95 (m, 1H), 2.92 (d,
J = 7.2 Hz, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 205.0,
138.4, 128.7, 127.5, 127.0, 79.1, 45.8, 38.7, 30.0; MS (ESI): m/z
(%) = 237 (100) [M+1]+; HPLC (Chiralcel AS-H, i-PrOH/n-
hexane = 15/85, flow rate = 1.0 mL min–1, λ = 206 nm): tminor =14.2
min, tmajor = 20.3 min, 48% ee. [α]D20 = –4.8° (c = 0.50, CH2Cl2).
(S)-2-((R)-2-Nitro-1-(3-Nitrophenyl)ethyl)cyclohexanone (10f): White
solid; m.p. 78.6–79.9 °C (lit.27 76–79 °C); 1H NMR (400 MHz, CDCl3)
δ = 8.13–8.06 (m, 2H), 7.56–7.48 (m, 2H), 4.99 (dd, J = 12.8, 4.4 Hz,
1H), 4.67 (dd, J = 12.4, 10.0 Hz, 1H), 3.95–3.87 (m, 1H), 2.75–2.68
(m, 1H), 2.49–2.33 (m, 2H), 2.11–2.08 (m, 1H), 1.82–1.70 (m, 1H),
1.69–1.56 (m, 3H), 1.30–1.23 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ = 211.7, 136.5, 133.8, 129.7, 129.3, 78.8, 52.6, 43.5, 42.9, 33.4,
28.7, 25.3; MS (ESI): m/z (%) = 293 (100) [M+1]+; HPLC (Chiralcel
AS-H, i-PrOH/n-hexane = 15/85, flow rate = 1.0 mL min–1, λ = 206 nm):
Received 17 January 2012; accepted 27 February 2012
Paper 1201110 doi: 10.3184/174751912X13332916163195
Published online: 10 May 2012
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t
minor = 30.3 min, tmajor = 55.1 min, 51% ee. [α]D20 = –13.3° (c = 0.50,
CH2Cl2).
(S)-2-((R)-1-(3-Hydroxyphenyl)-2-nitroethyl)cyclohexanone (10g):
White solid; m.p. 123.1–125.3 °C (lit.29 not reported); 1H NMR
(400 MHz, CDCl3) δ = 7.24–7.13 (m, 2H), 6.73–6.64 (m, 2H), 4.89
(dd, J = 12.8, 3.6 Hz, 1H), 4.57 (dd, J = 12.8, 10.0 Hz, 1H), 3.71–3.65
(m, 1H), 2.64–2.60 (m, 1H), 2.47–2.31 (m, 2H), 2.05–2.04 (m,
1H),1.85–1.55 (m, 4H), 1.23–1.21 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ = 212.7, 156.4,139.7, 130.4, 120.4, 115.4, 115.1, 79.0,52.7,
44.0, 43.0, 42.2, 33.4, 28.8, 27.2, 25.2, 25.1; MS (ESI): m/z (%) =
264 (100) [M+1]+; HPLC (Chiralcel AS-H, i-PrOH/n-hexane = 15/85,
flow rate = 1.0 mL min–1, λ = 206 nm): tminor = 13.3 min, tmajor = 22.8 min,
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(S)-2-((R)-1-(2-Fluorophenyl)-2-nitroethyl)cyclohexanone (10h):
White solid; m.p. 93.7–95.4 °C (lit.28 95–96 °C); 1H NMR (400 MHz,
CDCl3) δ = 7.36 (d, J = 8.0 Hz,1H), 7.22–7.17(m, 2H), 4.92–4.86 (m,
2H), 4.31–4.25 (m, 1H), 2.94–2.87 (m, 1H), 2.49–2.34 (m, 1H),
2.11–2.04 (m, 1H), 1.83–1.61 (m, 2H), 1.38–1.29 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ = 211.5, 135.5, 134.6, 130.4, 129.5, 129.0,
127.5, 76.9, 52.0, 43.1, 41.3, 33.4, 28.9, 25.6; MS (ESI): m/z (%) =
278 (100) [M+1]+; HPLC (Chiralcel AS-H, i-PrOH/n-hexane = 15/85,
flow rate = 1.0 mL min–1, λ = 206 nm): tminor = 9.9 min, tmajor = 12.0 min,
67% ee. [α]D20 = –13.2° (c = 0.50, CH2Cl2).
(S)-2-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)cyclohexanone (10i):
White solid; m.p. 107.3–108.8 °C (lit.25 97–100 °C); 1H NMR (400 MHz,
CDCl3) δ = 7.27–7.22 (m, 1H), 7.08 (dd, J = 7.4, 1.6 Hz, 1H), 6.91–
6.86 (m, 2H), 4.85–4.79 (m, 2H), 3.99–3.93 (m, 1H), 3.84 (s, 3H),
3.01–2.94 (m, 1H), 2.49–2.35 (m, 2H), 2.10–2.05 (m, 1H), 1.80–1.60
(m, 4H), 1.25–1.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 212.4,
157.4, 130.8, 128.8, 125.2, 120.7, 110.8, 77.3, 55.2, 50.4, 42.5,
41.1, 33.1, 28.4, 25.0; MS (ESI): m/z (%) = 278 (100) [M+1]+; HPLC
(Chiralcel AS-H, i-PrOH/n-hexane = 15/85, flow rate = 1.0 mL min–1,
λ = 206 nm): tminor =15.7 min, tmajor = 17.4 min, 59% ee. [α]D20 = –22.9°
(c = 0.50, CH2Cl2).
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