Tropos biphenol derived chiral thiophosphoramide catalysed highly diastereo- and enantioselective michael addition of cyclic ketones to nitro olefins

Article abstract of DOI:10.1002/ejoc.201000892

Chirality transfer from (S)-2-(aminomethyl)pyrrolidine to the tropos biphenyl skeleton has been observed in the preparation of a chirally flexible biphenol-derived novel chiral thiophosphoramide to afford exclusively the thermodynamically favoured diaster

Full text of DOI:10.1002/ejoc.201000892

FULL PAPER
DOI: 10.1002/ejoc.201000892
Tropos Biphenol Derived Chiral Thiophosphoramide Catalysed Highly
Diastereo- and Enantioselective Michael Addition of Cyclic Ketones to Nitro
Olefins
Aidang Lu,[a] Ronghua Wu,[a] Youming Wang,*[a] Zhenghong Zhou,*[a] Guiping Wu,[a]
Jianxin Fang,[a] and Chuchi Tang[a]
Keywords: Diastereoselectivity / Enantioselectivity / Michael addition / Nitro olefins / Organocatalysts
Chirality transfer from (S)-2-(aminomethyl)pyrrolidine to the
tropos biphenyl skeleton has been observed in the prepara-
tion of a chirally flexible biphenol-derived novel chiral thio-
phosphoramide to afford exclusively the thermodynamically
favoured diastereomer. This novel secondary amine–thio-
phosphoramide has proven to be an effective bifunctional or-
ganocatalyst for the asymmetric Michael addition of cyclo-
hexanone to both aryl- and alkyl-substituted nitro olefins.
The corresponding adducts were obtained with excellent
diastereo- (up to Ͼ99:1 dr) and enantioselectivities (up to
Ͼ99% ee).
moting the asymmetric Michael addition of cyclic ketones
to nitro olefins (Scheme 1).[4] It is believed that thiophos-
phoramide (S,aR)-1 functions as a bifunctional organocata-
lyst; the “privileged” pyrrolidine backbone may serve as the
catalytic site and the thiophosphoramide moiety as hydro-
gen-bonding donor for the activation of nitro olefin sub-
strates and the formation of a well-controlled transition
state. Although excellent results have been achieved for cat-
alyst (S,aR)-1, the need for a combination of (R)-bi-
naphthol and (S)-2-(aminomethyl)pyrrolidine to afford sat-
isfactory results makes this catalyst less competitive, and
the development of a more economic chiral thiophosphor-
amide organocatalyst remains an important challenge. We
envisioned that, like transition-metal catalysis, the chirality
of the axially flexible biphenyl moiety may be controlled by
chirality transfer from (S)-2-(aminomethyl)pyrrolidine to
the tropos biphenyl group to form a thermodynamically
Introduction
Chirally flexible (tropos) ligands with a low rotation barrier
that are highly modular, versatile, and easy to synthesize
without resolution have been a focus of interest in recent
transition-metal-catalysed reactions.[1] For example, al-
though the tropos Biphep ligand [2,2Ј-bis(diphenylphos-
phanyl)-1,1Ј-biphenyl] is not resolvable at room tempera-
ture due to fast racemization, the chirality of the racemic
Biphep–metal complex can be controlled by induction of
the chiral diamine[2] or chiral diene[3] leading to the single
Biphep–metal enantiomer, and this resulting enantiopure
metal complex can behave as an efficient catalyst in asym-
metric reactions. However, to the best of our knowledge,
this strategy has never been documented in organocatalysis.
We have recently developed (S,aR)-pyrrolidine–thiophos-
phoramide (S,aR)-1 as an efficient organocatalyst for pro-
Scheme 1. Thiophosphoramide (S,aR)-1 catalysed asymmetric Michael addition of cyclic ketones to nitro olefins.
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
favourable diastereomer that can also be employed as a chi-
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
ral organocatalyst to promote the asymmetric Michael ad-
dition of ketones to nitro oelefins. Herein we describe a new
chiral catalyst bearing a tropos biphenyl skeleton for the
asymmetric conjugate addition of ketones to nitroalkenes.
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000892.
122
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 122–127

Michael Addition of Cyclic Ketones to Nitro Olefins
Results and Discussion
As shown in Scheme 2, the trifluoroacetic acid salts of
newly designed pyrrolidine–thiophosphoramide 2 were
readily prepared by the coupling of tert-butyl (S)-2-(amino-
methyl)pyrrolidine-1-carboxylate (3)[5] and O,O-(2,2Ј-bi-
phenylyl) phosphorochloridothioate (4)[6] and successive re-
moval of the protecting group with trifluoroacetic acid.
Scheme 3. Preliminary comparison of the catalytic activities of
(S,aR)-1 and (S,aS)-2.
Encouraged by this result, other parameters influencing
the reaction, such as reaction temperature and catalyst
loading, were also examined by employing benzoic acid as
the acidic additive, but the results obtained were not better
(Table 1). Similarly to the (S,aR)-1-catalysed Michael ad-
dition to β-nitrostyrene, the reaction temperature was found
to have a noticeable effect on the reaction. The enantio-
selectivity gradually increased by decreasing the reaction
temperature from 25 to –30 °C (Table 1, Entries 1 and 3–5,
90–96% ee). The reaction became quite sluggish on further
lowering of the temperature to –40 °C, and the product was
obtained in a rather low yield with a slight loss of ste-
reocontrol even after a prolonged reaction time (Table 1,
Entry 6). In addition, reduction of the amount of (S,aS)-2
from 20 to 10 mol-% led to a clear decrease in both the
turnover frequency and the stereoselectivity (Table 1, En-
try 1 vs. Entry 2).
Scheme 2. Synthesis of chiral thiophosphoramide (S,aS)-2.
As we anticipated, when the chirally rigid binaphthalene
skeleton was replaced by a flexible biphenyl moiety, chiral-
ity transfer from (S)-2-(aminomethyl)pyrrolidine to tropos
biphenol was observed to afford exclusively a thermody-
namically favoured diastereomer 2, which corresponds to
the single peak at δ = 83.38 ppm in the 31P NMR spectrum.
The relative configuration of the thermodynamically
favourable diastereomer was determined to be (S,aS) by X-
ray analysis of a single crystal obtained from a solution of
2 in MeOH/iPrOH (2:1, v/v; Figure 1).[7]
By using the optimized reaction conditions, we next
probed the scope of the reaction with a variety of nitro
olefins. The results are summarized in Table 2.
As shown in Table 2, the reaction has a broad applica-
bility with respect to the nitro olefins. Excellent yields (up
to Ͼ99%) and stereoselectivities (up to Ͼ99:1 dr, Ͼ99% ee)
were achieved with various styrene-type nitro olefins bear-
ing either electron-donating or -withdrawing substituents
regardless of the nature and the position of the substituted
group on the benzene ring (Table 2, Entries 2–10). 1-Naph-
thyl- and 2-furyl-substituted aromatic nitroalkenes also
worked well giving satisfactory stereoselectivities (Table 2,
Entries 11 and 12). Notably, the aliphatic aldehyde derived
nitro olefin 5n also appeared to be a good candidate at an
elevated temperature, affording the desired product with the
same high levels of enantioselectivity as those found in the
aryl-substituted ones, albeit with a moderate diastereoselec-
tivity (Table 2, Entry 14, syn/anti = 79:21, 93% ee for the
syn isomer). Moreover, although a little loss of stereocon-
Figure 1. X-ray structure of the thermodynamically favoured dia-
stereomer 2. Most of the hydrogen atoms and the trifluoroacetate
anion have been omitted for clarity.
With the thermodynamically favoured diastereomer trol was observed, alkenyl-substituted nitro olefin 5m can
(S,aS)-2 in hand, the catalytic performance of (S,aS)-2 was also be employed successfully (Table 2, Entry 13). Com-
initially evaluated in the Michael addition of cyclohexanone pared with the results obtained for the previously reported
to (E)-β-nitrostyrene as the model reaction under the opti- (R)-binaphthol-derived chiral thiophosphoramide catalyst
mal reaction conditions for the thiophosphoramide catalyst (S,aR)-1, it is worth noting that comparable or even better
(S,aR)-1 (benzoic acid as the acidic co-catalyst, –30 °C in stereoselective results were obtained in some cases (Table 2,
neat cyclohexanone). Almost the same level of stereoselecti- Entries 3, 4, 6, 12 and 14) for the newly developed chiral
vity was observed for the newly developed catalyst (S,aS)-2 catalyst (S,aS)-2 bearing a tropos biphenyl skeleton. Be-
as with (S,aR)-1. The corresponding Michael adduct was cause chirally flexible (tropos) biphenols are easy to synthe-
obtained in excellent yield (Ͼ99%) with high diastereo- size without resolution, catalyst (S,aS)-2 has a great advan-
(syn/anti 99:1) and enantioselectivity (96% ee; Scheme 3).
tage over the catalyst (S,aR)-1 derived from optically active
Eur. J. Org. Chem. 2011, 122–127
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123

A. Lu, R. Wu, Y. Wang, Z. Zhou, G. Wu, J. Fang, C. Tang
Table 1. Optimization of the reaction conditions for the Michael addition with (S,aS)-2 as catalyst.[a]
FULL PAPER
Entry
2 [mol-%]
Temp. [°C]
Time [h]
Yield [%][b]
dr [syn/anti][c]
ee [%][d]
1
2
3
4
5
6
20
10
20
20
20
20
25
25
0
–15
–30
–40
1
2
4
7
22
63
Ͼ99
96
99
95
96
99:1
98:2
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
90
87
92
94
96
94
52
[a] All reactions were performed with cyclohexanone (226 mg, 2.3 mmol) and nitro olefin 5a (0.23 mmol) in the presence of catalyst
1
(S,aS)-2. [b] Yield of the isolated product after chromatography on silica gel. [c] Determined by H NMR spectroscopy. [d] Determined
by chiral HPLC analysis.
Table 2. Substrate scope of the (S,aS)-2-catalysed asymmetric Michael addition of cyclohexanone to nitro olefins.[a]
Entry
R
Time [h]
Yield [%][b]
dr [syn/anti][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph (a)
3-CF3C6H4 (b)
4-CF3C6H4 (c)
4-FC6H4 (d)
22
24
30
19
21
21
21
19
19
40
19
16
17
4
Ͼ99
87
83
90
Ͼ99
95
99:1 (Ͼ99:1)
98:2 (98:2)
Ͼ99:1 (Ͼ99:1)
Ͼ99:1 (99:1)
99:1 (98:2)
Ͼ99:1 (Ͼ99:1)
99:1 (Ͼ99:1)
99:1 (99:1)
96 (96)
95 (96)
Ͼ99 (99)
99 (97)
95 (98)
98 (97)
97 (98)
96 (96)
96 (97)
97 (98)
96 (97)
96 (95)
87 (89)
93 (91)
4-ClC6H4 (e)
2-BrC6H4 (f)
4-BrC6H4 (g)
2-MeOC6H4 (h)
4-MeC6H4 (i)
97
Ͼ99
Ͼ99
95
Ͼ99
Ͼ99
90
99:1 (99:1)
benzo[d][1,3]dioxol-5-yl (j)
1-naphthyl (k)
2-furyl (l)
Ͼ99:1 (Ͼ99:1)
98:2 (Ͼ99:1)
Ͼ99:1 (98:2)
92:8 (93:7)
(E)-styryl (m)[e]
2-phenylethyl (n)[e]
89
79:21 (73:27)
[a] All reactions were performed with cyclohexanone (226 mg, 2.3 mmol) and nitro olefin 5 (0.23 mmol) in the presence of catalyst (S,aS)-
1
2. [b] Yield of the isolated product after chromatography on silica gel. [c] Determined by H NMR spectroscopy. Values in parentheses
1
were obtained with catalyst (S,aR)-1. The relative configurations were assigned by comparison of the H and 13C NMR spectra of the
products with those of the known compounds. [d] Determined by chiral HPLC analysis. Values in parentheses were obtained with catalyst
(S,aR)-1. The absolute configuration of the major isomer was established by comparison with the literature value of the optical rotation.
[e] The reaction was carried out at room temperature (25 °C).
binaphthol and may be potentially useful for the prepara-
tion of enantiomerically enriched γ-nitro ketones.
We also carried out preliminary investigations on the
asymmetric addition of other ketones to nitrostyrene 5a
using (S,aS)-2 as catalyst. For example, the challenging cy-
clopentanone worked well to provide the desired product 7
in 89% yield with excellent enantioselectivity (91% ee for
syn-7 and 93% ee for anti-7, respectively) and good dia-
stereoselectivity (syn/anti = 83:17; Scheme 4) at room tem-
perature. Cyclohexane-1,4-dione monoethylene acetal also
reacted smoothly with 4a in THF at –30 °C to give the cor-
responding adduct 8 in quantitative yield with excellent
stereoselectivities (syn/anti = 98:2, 95% ee for the major
stereoisomer). These results are also comparable to those
observed for catalyst (S,aR)-1.
Scheme 4. Reactions of other ketones in the Michael addition reaction.
124
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Eur. J. Org. Chem. 2011, 122–127

Michael Addition of Cyclic Ketones to Nitro Olefins
and the reaction mixture was stirred for 15 min. The nitro olefin
(0.23 mmol) was added to the resulting mixture at the required tem-
perature. After the reaction was complete (monitored by TLC), the
mixture was purified by column chromatography on silica gel (200–
300 mesh, PE/EtOAc = 15:1) to afford the product.
Conclusions
We have reported that a thiophosphoramide bearing a
biphenyl skeleton can acquire axial chirality by the reaction
of the corresponding achiral thiophosphoryl chloride with
the chiral inducer tert-butyl (S)-2-(aminomethyl)pyrrolid-
(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (6a):[8] White solid,
ine-1-carboxylate. The single thermodynamically favoured 57 mg, Ͼ99% yield, m.p. 124–126 °C, [α]2D0 = –30.5 (c = 1.0,
1
CHCl3), syn/anti = 99:1, 96% ee. H NMR (CDCl3, 300 MHz): δ
= 1.10–1.22 (m, 1 H, one proton of CH2), 1.47–1.73 (m, 4 H, 2
CH2), 1.98–2.04 (m, 1 H, one proton of CH2), 2.26–2.44 (m, 2 H,
CH2), 2.61 (m, 1 H, CH), 3.69 (dt, J = 4.5 and 9.9 Hz, 1 H, CH),
4.56 (dd, J = 9.9 and 12.6 Hz, 1 H, one proton of NCH2), 4.87
(dd, J = 4.5 and 12.6 Hz, 1 H, one proton of NCH2), 7.08–7.11 (m,
2 Har), 7.19–7.27 (m, 3 Har) ppm. 13C NMR (CDCl3, 75.0 MHz): δ
= 25.1, 28.5, 33.2, 42.8, 44.0, 52.6, 78.9, 127.8, 128.2, 128.9, 137.8,
211.9 ppm. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 254 nm):
tR = 8.06 (minor), 9.74 (major) min.
diastereomer formed has proven to be an efficient bifunc-
tional organocatalyst for promoting the highly diastereo-
and enantioselective Michael addition of cyclic ketones to
both aryl and alkyl nitro olefins. Further investigations into
the application of this catalyst in asymmetric catalysis are
in progress.
Experimental Section
General Methods: All reagents and solvents were of commercial
grade and purified prior to use when necessary. NMR spectra were
acquired with either a Bruker AMX-300 or Varian 400 MHz in-
strument. Chemical shifts were measured relative to residual sol-
vent peaks as internal standard [δ = 7.26 and 77.0 ppm (CDCl3)].
Specific rotations were measured with a Perkin–Elmer 341MC po-
larimeter. Enantiomeric excesses were determined by using an HP-
1100 instrument (chiral column; mobile phase: hexane/iPrOH).
HRMS was performed with a Varian QFT-ESI instrument. Melt-
ing points were determined with a Taike X-4 melting-point appara-
tus. IR spectra were recorded with Bruker FT-IR Equinox 55 and
TENSOR 27 instruments.
(S)-2-[(R)-2-Nitro-1-(3-trifluoromethylphenyl)ethyl]cyclohexanone
(6b):[5] Pale-yellow oil, 63 mg, 87% yield, [α]2D0 = –19.4 (c = 1.6,
1
CHCl3), syn/anti = 98:2, 95% ee. H NMR (CDCl3, 300 MHz): δ
= 1.56–1.83 (m, 5 H, 2 CH2 and one proton of CH2), 2.04–2.13
(m, 1 H, one proton of CH2), 2.33–2.51 (m, 2 H, CH2), 2.70 (m, 1
H, CH), 3.86 (dt, J = 4.8 and 9.6 Hz, 1 H, CH), 4.67 (dd, J = 9.6
and 12.9 Hz, 1 H, one proton of NCH2), 4.96 (dd, J = 4.5 and
12.9 Hz, 1 H, one proton of NCH2), 7.38–7.55 (m, 4 Har) ppm. 13
C
NMR (CDCl3, 75.0 MHz): δ = 25.1, 28.3, 33.2, 42.7, 43.8, 52.4,
78.3, 124.7, 124.7, 124.8, 124.8, 124.9, 124.9, 124.9, 125.0, 129.5,
131.7, 139.1, 211.1 ppm. HPLC analysis (Chiralpak AS-H column,
hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
254 nm): tR = 13.63 (minor) and 26.94 (major) min.
Preparation of Chiral Thiophosphoramide (S,aS)-2: A solution of
thiophosphoryl chloride 4 (707 mg, 2.5 mmol) in dry CH2Cl2
(5 mL) was added dropwise to a stirred solution of tert-butyl (S)-2-
(aminomethyl)pyrrolidine-1-carboxylate (3; 501 mg, 2.5 mmol) and
triethylamine (5.0 mmol) in dry CH2Cl2 (5 mL) at room tempera-
ture. The reaction mixture was heated at reflux until complete con-
sumption of 4 (monitored by TLC). The resulting mixture was al-
lowed to cool to room temperature, and washed successively with
2 m HCl and saturated NaHCO3. After removal of the solvent, the
crude product was used directly in the next step without purifica-
tion. The crude product was dissolved in a mixture of trifluoro-
acetic acid and dichloromethane (4 mL, v/v = 1:1), and the re-
sulting solution was stirred at room temperature for 2 h. After re-
moval of the solvent, the crude product was purified by column
chromatography on silica gel (200–300 mesh; ethyl acetate) to af-
ford the target compound 2. White solid, 1.00 g, 87% yield (two
(S)-2-[(R)-2-Nitro-1-(4-trifluoromethylphenyl)ethyl]cyclohexanone
(6c):[9] White solid, 60 mg, 83% yield, m.p. 79–81 °C, [α]2D0 = –27.5
1
(c = 2.5, CHCl3), syn/anti = Ͼ99:1, Ͼ99% ee. H NMR (CDCl3,
300 MHz): δ = 1.22–1.30 (m, 1 H, one proton of CH2), 1.59–1.82
(m, 4 H, 2 CH2), 2.06–2.10 (m, 1 H, one proton of CH2), 2.32–
2.50 (m, 2 H, CH2), 2.65–2.74 (m, 1 H, CH), 3.86 (dt, J = 4.5 and
9.6 Hz, 1 H, CH), 4.66 (dd, J = 9.9 and 12.6 Hz, 1 H, one proton
of NCH2), 4.96 (dd, J = 4.5 and 12.6 Hz, 1 H, one proton of
NCH2), 7.31 (d, J = 8.1 Hz, 2 Har), 7.58 (d, J = 8.1 Hz, 2 Har)
ppm. 13C NMR (CDCl3, 75.0 MHz): δ = 25.1, 28.3, 33.2, 42.7,
43.8, 52.4, 78.3, 125.9 (q, J = 3.8 Hz), 128.7, 129.9, 130.3, 142.1,
211.1 ppm. HPLC analysis (Chiralpak AS-H column, hexane/2-
propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm):
tR = 12.15 (minor) and 20.25 (major) min.
(S)-2-[(R)-1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone (6d):[10]
Pale-yellow solid, 55 mg, 90% yield, m.p. 64–66 °C, [α]2D0 = –29.2
(c = 0.8, CHCl3), syn/anti = Ͼ99:1, 99% ee. 1H NMR (CDCl3,
400 MHz): δ = 1.10–1.25 (m, 1 H, one proton of CH2), 1.56–1.82
(m, 4 H, 2 CH2), 2.01–2.10 (m, 1 H, one proton of CH2), 2.34–
2.49 (m, 2 H, CH2), 2.65 (m, 1 H, CH), 3.77 (dt, J = 4.0 and
9.6 Hz, 1 H, CH), 4.60 (t, J = 11.2 Hz, 1 H, one proton of NCH2),
4.93 (dd, J = 4.0 and 12.4 Hz, 1 H, one proton of NCH2), 7.01
(dd, J = 8.0 and 8.4 Hz, 2 Har), 7.15 (dd, J = 5.6 and 6.8 Hz, 2
Har) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 24.0, 27.4, 32.1,
41.7, 42.3, 51.5, 77.8, 114.9 (d, J = 21.4 Hz), 128.8 (d, J = 8.0 Hz),
132.5 (d, J = 3.2 Hz), 161.1 (d, J = 246.7 Hz), 210.7 ppm. HPLC
analysis (Chiralpak AS-H column, hexane/2-propanol = 90:10,
flow rate = 1.0 mL/min, wavelength = 254 nm): tR = 22.85 (minor)
and 34.24 (major) min.
1
steps), m.p. 124–126 °C, [α]2D0 = –5.2 (c = 1.0, MeOH). H NMR
(CD3OD, 400 MHz): δ = 1.71–1.80 (m, 1 H, CHH), 1.92–2.03 (m,
2 H, CH2), 2.06–2.14 (m, 1 H, CHH), 3.18–3.31 (m, 2 H, NCH2),
3.38 (dd, J = 6.4 and 10.4 Hz, 2 H, NCH2), 3.58–3.66 (m, 1 H,
NCH), 7.21 (d, J = 8.0 Hz, 2 Har), 7.35 (t, J = 7.6 Hz, 2 Har), 7.43
(t, J = 7.6 Hz, 2 Har), 7.57 (dd, J = 7.6 and 1.2 Hz, 2 Har) ppm.
13C NMR (CD3OD, 100.6 MHz): δ = 24.1, 28.4, 43.9, 46.7, 62.5,
123.1, 127.7, 130.5, 131.0, 131.1, 149.5, 149.6, 149.7, 163.0,
163.3 ppm. 31P NMR (CD3OD, 161.7 MHz): δ = 83.38 ppm. IR
(KBr): ν = 3647, 3246, 2950, 1680, 1434, 1202, 1134, 1094, 925,
˜
897, 772, 751 cm–1. HRMS (ESI): calcd. for C19H20F3N2O4PS [M –
CF3CO2H + H]+ 347.0978; found 347.0976.
General Procedure for Thiophosphoramide (S,aS)-2 Catalysed
Asymmetric Michael Addition to Nitro Olefins: A mixture of the
catalyst (S,aS)-2 (0.046 mmol) and triethylamine (0.046 mmol) in
cyclohexanone (226 mg, 2.3 mmol) was stirred at room temperature
for 30 min. Then benzoic acid (2.8 mg, 0.023 mmol) was added,
(S)-2-[(R)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone (6e):[11]
Pale-yellow solid, 64.7 mg, Ͼ99% yield, m.p. 93–96 °C, [α]2D0
=
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125

A. Lu, R. Wu, Y. Wang, Z. Zhou, G. Wu, J. Fang, C. Tang
FULL PAPER
–27.7 (c = 1.9, CHCl3), syn/anti = 99:1, 95% ee. 1H NMR (CDCl3,
400 MHz): δ = 1.17–1.23 (m, 1 H, one proton of CH2), 1.55–1.81
211.1 ppm. HPLC analysis (Chiralpak AS-H column, hexane/2-
propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm):
(m, 4 H, 2 CH2), 2.06–2.11 (m, 1 H, CH), 2.33–2.48 (m, 2 H, CH2), tR = 12.73 (minor) and 21.92 (major) min.
2.61–2.68 (m, 1 H, CH), 3.75 (dt, J = 4.4 and 10.0 Hz, 1 H, CH),
(S)-2-[(R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl]cyclohexanone
4.60 (dd, J = 10.4 and 12.4 Hz, 1 H, one proton of NCH2), 4.93
(dd, J = 4.4 and 12.4 Hz, 1 H, one proton of NCH2), 7.11 (d, J =
8.0 Hz, 2 Har), 7.29 (d, J = 8.0 Hz, 2 Har) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 25.0, 28.4, 33.1, 42.7, 43.4, 52.4, 78.6, 129.1, 129.6,
133.6, 136.4, 211.4 ppm. HPLC analysis (Chiralpak AS-H column,
hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
254 nm): tR = 17.91 (minor) and 28.63 (major) min.
(6j):[8] Pale-brown solid, 64 mg, 95 % yield, m.p. 144–145 °C,
[α]2D0 = –20.0 (c = 1.0, CHCl3), syn/anti = Ͼ99:1, 97% ee. 1H NMR
(CDCl3, 400 MHz): δ = 1.19–1.22 (m, 1 H, one proton of CH2),
1.56–1.69 (m, 2 H, CH2), 1.78 (br. s, 2 H, CH2), 2.06 (br. s, 1 H,
one proton of CH2), 2.33–2.48 (m, 2 H, CH2), 2.58–2.62 (m, 1 H,
CH), 3.65–3.68 (m, 1 H, CH), 4.54 (t, J = 11.2 Hz, 1 H, one proton
of NCH2), 4.89 (dd, J = 2.8 and 12.0 Hz, 1 H, one proton of
NCH2), 5.94 (s, 2 H, OCH2O), 6.61 (d, J = 7.6 Hz, 1 Har), 6.64 (s,
1 Har), 6.73 (d, J = 7.6 Hz, 1 Har) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 25.0, 28.5, 33.1, 42.7, 43.7, 52.7, 79.0, 101.2, 108.0,
108.6, 121.7, 131.3, 147.1, 148.1, 211.9 ppm. HPLC analysis (Chi-
ralpak AD-H column, hexane/2-propanol = 90:10, flow rate =
0.5 mL/min, wavelength = 254 nm): tR = 36.91 (minor) and 38.90
(major) min.
(S)-2-[(R)-1-(2-Bromophenyl)-2-nitroethyl]cyclohexanone (6f):[8]
Pale-yellow solid, 71 mg, 95% yield, m.p. 80–82 °C, [α]2D0 = –50.8
(c = 1.0, CHCl3), syn/anti = Ͼ99:1, 98% ee. 1H NMR (CDCl3,
400 MHz): δ = 1.26–1.35 (m, 1 H, one proton of CH2), 1.51–1.76
(m, 4 H, 2 CH2), 2.01–2.04 (m, 1 H, one proton of CH2), 2.27–
2.47 (m, 2 H, CH2), 2.83 (br. s, 1 H, CH), 4.24 (br. s, 1 H, CH),
4.82 (s, 2 H, NCH2), 7.05 (t, J = 7.6 Hz, 1 Har), 7.14 (d, J = 7.6 Hz,
1 Har), 7.22–7.24 (m, 1 Har), 7.50 (d, J = 8.0 Hz, 1 Har) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ = 25.3, 28.5, 33.0, 42.8, 52.1, 77.2,
128.0, 129.1, 133.7, 137.2, 211.5 ppm. HPLC analysis (Chiralpak
AS-H column, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min,
wavelength = 238 nm): Rt = 16.85 (minor) and 22.87 min (major).
(S)-2-[(R)-1-Naphthyl-2-nitroethyl]cyclohexanone (6k):[8] Pale-
brown solid, 68 mg, Ͼ99% yield, m.p. 116–119 °C, [α]2D0 = –115.5
(c = 1.0, CHCl3), syn/anti = 98:2, 96 % ee. 1H NMR (CDCl3,
400 MHz): δ = 1.20–1.30 (m, 1 H, one proton of CH2), 1.50–1.69
(m, 4 H, 2 CH2), 2.06–2.09 (m, 1 H, one proton of CH2), 2.37–
2.52 (m, 2 H, CH2), 2.87 (s, 1 H, CH), 4.77 (s, 1 H, CH), 4.91 (dd,
J = 9.2 and 12.4 Hz, 1 H, one proton of NCH2), 5.07 (dd, J = 4.0
and 12.4 Hz, 1 H, one proton of NCH2), 7.38 (d, J = 7.6 Hz, 1
Har), 7.44–7.58 (m, 3 Har), 7.78 (d, J = 8.0 Hz, 1 Har), 7.86 (d, J =
8.0 Hz, 1 Har), 8.17 (s, 1 Har) ppm. 13C NMR (CDCl3, 100.6 MHz):
δ = 24.3, 27.7, 32.3, 35.8, 41.9, 52.8, 77.7, 121.8, 122.6, 124.4, 124.9,
125.6, 127.2, 128.0, 131.4, 133.0, 133.7, 211.3 ppm. HPLC analysis
(Chiralpak AS-H column, hexane/2-propanol = 75:25, flow rate =
1.0 mL/min, wavelength = 238 nm): tR = 12.85 (minor) and 18.58
(major) min.
(S)-2-[(R)-1-(4-Bromophenyl)-2-nitroethyl]cyclohexanone (6g):[8]
White solid, 73 mg, 97% yield, m.p. 120–122 °C, [α]2D0 = –24.2 (c =
1.0, CHCl3), syn/anti = 99:1, 97% ee. 1H NMR (CDCl3, 400 MHz):
δ = 1.17–1.27 (m, 1 H, one proton of CH2), 1.52–1.81 (m, 4 H, 2
CH2), 2.07–2.10 (m, 1 H, one proton of CH2), 2.33–2.41 (m, 1 H,
CHH), 2.45–2.49 (m, 1 H, CHH), 2.61–2.68 (m, 1 H, CH), 3.74
(dt, J = 4.4 and 9.6 Hz, 1 H, CH), 4.60 (t, J = 11.2 Hz, 1 H, one
proton of NCH2), 4.93 (dd, J = 4.4 and 12.4 Hz, 1 H, one proton
of NCH2), 7.06 (d, J = 8.0 Hz, 2 Har), 7.57 (d, J = 8.0 Hz, 2 Har)
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 25.1, 28.4, 33.1, 42.7,
43.4, 52.3, 78.5, 121.7, 129.9, 132.1, 136.8, 211.4 ppm. HPLC
analysis (Chiralpak AS-H column, hexane/2-propanol = 90:10,
flow rate = 1.0 mL/min, wavelength = 238 nm): Rt = 18.90 (major)
and 32.01 min (minor).
(S)-2-[(S)-1-(2-Furyl)-2-nitroethyl]cyclohexanone (6l):[8] Brown oil,
54 mg, Ͼ99% yield, [α]2D0 = –9.3 (c = 1.0, CHCl3), syn/anti = Ͼ99:1,
1
96% ee. H NMR (CDCl3, 400 MHz): δ = 1.29–1.32 (m, 1 H, one
proton of CH2), 1.61–1.84 (m, 4 H, 2 CH2), 2.08–2.09 (m, 1 H, one
proton of CH2), 2.32–2.47 (m, 2 H, CH2), 2.71–2.77 (m, 1 H, CH),
3.93–3.99 (m, 1 H, CH), 4.63–4.69 (m, 1 H, one proton of NCH2),
4.78 (dd, J = 4.0 and 12.4 Hz, 1 H, one proton of NCH2), 6.17 (s,
1 Har), 6.27 (s, 1 Har), 7.37 (s, 1 Har) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 25.1, 27.2, 32.5, 37.6, 42.6, 51.1, 76.7, 109.0, 110.3,
142.3, 151.0, 211.0 ppm. HPLC analysis (Chiralpak AS-H column,
hexane/2-propanol = 85:15, flow rate = 0.7 mL/min, wavelength =
230 nm): tR = 15.20 (major) and 17.41 (minor) min.
(S)-2-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]cyclohexanone (6m):[5]
Pale-yellow solid, 57 mg, 90% yield, m.p. 78–81 °C, [α]2D0 = –42.1
(c = 1.2, CHCl3), syn/anti = 92:8, 87 % ee. 1H NMR (CDCl3,
400 MHz): δ = 1.42–1.51 (m, 1 H, one proton of CH2), 1.66–1.71
(m, 3 H, CH2 and one proton of CH2), 2.16–2.20 (m, 2 H, CH2),
2.33–2.48 (m, 2 H, CH2), 3.35–3.38 (m, 1 H, CH), 4.56–4.76 (m, 2
H, NCH2), 6.03 (dd, J = 9.6 and 15.6 Hz, 1 H, =CH), 6.50 (d, J =
15.6 Hz, 1 H, =CH), 7.25–7.34 (m, 5 Har) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 25.0, 28.1, 32.5, 41.9, 42.6, 51.7, 78.0, 125.7, 126.4,
127.9, 128.6, 134.4, 136.3, 211.2 ppm. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol = 98:2, flow rate = 0.5 mL/min,
wavelength = 254 nm): tR = 50.27 (minor) and 52.28 (major) min.
(S)-2-[(R)-1-(2-Methoxyphenyl)-2-nitroethyl]cyclohexanone (6h):[12]
White solid, 64 mg, 60 mg, Ͼ99% yield, m.p. 97–100 °C, [α]2D0
=
–28.8 (c = 1.0, CHCl3), syn/anti = 99:1, 96% ee. 1H NMR (CDCl3,
400 MHz): δ = 1.19–1.22 (m, 1 H, one proton of CH2), 1.56–1.79
(m, 4 H, 2 CH2), 2.05–2.08 (m, 1 H, one proton of CH2), 2.34–
2.49 (m, 2 H, CH2), 2.97 (dt, J = 4.8 and 11.2 Hz, 1 H, CH), 3.84
(s, 3 H, OCH3), 3.93–3.99 (m, 1 H, CH), 4.78–4.87 (m, 2 H,
NCH2), 6.87 (d, J = 8.4 Hz, 1 Har), 6.88 (t, J = 8.4 Hz, 1 Har), 7.08
(d, J = 7.2 Hz, 1 Har), 7.24 (t, J = 8.0 Hz, 1 Har) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 25.2, 28.6, 33.3, 41.3, 42.7, 50.7, 55.4,
77.5, 111.0, 120.9, 125.4, 128.9, 131.0, 157.6, 212.5 ppm. HPLC
analysis (Chiralpak AS-H column, hexane/2-propanol = 90:10,
flow rate = 1.0 mL/min, wavelength = 254 nm): tR = 15.78 (minor)
and 18.02 (major) min.
(S)-2-[(R)-1-(4-Methylphenyl)-2-nitroethyl]cyclohexanone (6i):[11]
White solid, 60 mg, Ͼ99% yield, m.p. 123–126 °C, [α]2D0 = –28.3 (c
= 1.0, CHCl3), syn/anti = 99:1, 96 % ee. 1H NMR (CDCl3,
400 MHz): δ = 1.19–1.26 (m, 1 H, one proton of CH2), 1.54–1.80
(m, 4 H, 2 CH2), 2.05–2.09 (m, 1 H, one proton of CH2), 2.31 (s,
3 H, CH3), 2.34–2.49 (m, 2 H, CH2), 2.63–2.70 (m, 1 H, CH), 3.71
(dt, J = 4.4 and 10.0 Hz, 1 H, CH), 4.60 (dd, J = 10.4 and 12.0 Hz,
(S)-2-[(S)-1-Nitro-4-phenylbutan-2-yl]cyclohexanone (6n):[5] Colour-
1 H, one proton of NCH2), 4.91 (dd, J = 4.4 and 12.4 Hz, 1 H, less oil, 56 mg, 89% yield, [α]2D0 = –9.4 (c = 1.5, CHCl3), syn/anti =
1
one proton of NCH2), 7.04 (d, J = 7.6 Hz, 2 Har), 7.12 (d, J =
79:21, 93% ee. H NMR (CDCl3, 400 MHz): δ = 1.43–1.53 (m, 1
7.6 Hz, 2 Har) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 20.0, 24.0, H, one proton of CH2), 1.64–1.70 (m, 3 H, CH2 and one proton
27.5, 32.2, 41.7, 42.6, 51.6, 78.0, 127.0, 128.6, 133.6, 136.4, of CH2), 1.81–1.86 (m, 1 H, one proton of CH2), 1.93–1.95 (m, 1
126
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 122–127

Michael Addition of Cyclic Ketones to Nitro Olefins
H, one proton of CH2), 2.09–2.14 (m, 2 H, CH2), 2.28–2.39 (m, 2
Supporting Information (see footnote on the first page of this arti-
H, CH2), 2.51–2.55 (m, 1 H, CH), 2.63–2.72 (m, 3 H, CH2 and cle): NMR, IR and HR mass spectra of the catalyst as well as the
CH), 4.36 (dd, J = 6.0 and 12.4 Hz, 0.21 H, anti), 4.46 (dd, J = 6.0
and 12.4 Hz, 0.79 H, syn), 4.62 (dd, J = 6.0 and 12.4 Hz, 1 H, one
proton of NCH2), 7.17–7.22 (m, 3 Har), 7.28–7.31 (m, 2 Har) ppm.
13C NMR (CDCl3, 100.6 MHz): δ = 25.1 (anti), 25.2 (syn), 27.3
(anti), 27.6 (syn), 29.8 (anti), 30.2 (syn), 30.8 (anti), 31.3 (syn), 33.5
(syn), 33.7 (anti), 36.9 (anti), 37.0 (syn), 42.4 (anti), 42.5 (syn), 51.1
(anti), 51.4 (syn), 76.9, 126.1, 128.2, 128.5, 141.1, 211.1 ppm. HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol = 98:2, flow
rate = 0.5 mL/min, wavelength = 254 nm): tR = 34.61 (major),
39.40 (minor) min.
chiral HPLC data of the Michael addition products.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Nos. 20772058 and 20972070), the National Basic Research
Program of China (973 program 2010CB833301) and the Key Lab-
oratory of Elemento-Organic Chemistry for generous financial sup-
port of our programs.
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(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclopentanone (7):[8] White solid,
56 mg, 89% yield, m.p. 116–119 °C, [α]2D0 = –18.5 (c = 1.0, CHCl3),
syn/anti = 83:17, 91% ee (syn), 93% ee (anti): 1H NMR (CDCl3,
400 MHz): δ = 1.43–1.52 (m, 1 H, one proton of CH2), 1.68–1.75
(m, 1 H, one proton of CH2), 1.85–1.96 (m, 2 H, CH2), 2.08–2.18
(m, 1 H, one proton of CH2), 2.32–2.43 (m, 1.83 H, syn), 2.49–2.55
(m, 0.17 H, anti), 3.66–3.72 (m, 0.83 H, syn), 3.82–3.85 (m, 0.17
H, anti), 4.71 (dd, J = 10.0 and 12.8 Hz, 1 H, one proton of NCH2),
5.34 (dd, J = 5.6 and 12.8 Hz, 1 H, one proton of NCH2), 7.15–
7.19 (m, 2 Har), 7.28–7.34 (m, 3 Har) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 20.3 (syn), 20.6 (anti), 28.3 (syn), 29.7 (anti), 38.7
(syn), 39.3 (anti), 44.0 (anti), 44.2 (syn), 50.5 (syn), 51.4 (anti), 77.2
(anti), 78.3 (syn), 127.9 (anti), 128.0 (anti), 128.0 (syn), 128.5 (syn),
128.8 (syn), 128.9 (syn), 129.0 (anti), 130.9 (anti), 137.4 (anti), 137.5
(syn), 218.5 (syn), 219.1 (anti) ppm. HPLC analysis (Chiralpak AD-
H column, hexane/2-propanol = 95:5, flow rate = 1.0 mL/min,
wavelength = 220 nm): tR = 12.34 (major, anti), 14.06 (minor, anti),
15.46 (minor, syn) and 21.01 (major, syn) min.
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(S)-7-[(R)-2-Nitro-1-phenylethyl]-1,4-dioxaspiro[4.5]decan-8-one
(8):[13] White solid, 70 mg, Ͼ99% yield, m.p. 125–127 °C, [α]2D0
=
–9.5 (c = 1.0, CHCl3), syn/anti = 98:2, 95% ee. 1H NMR (400 MHz,
CDCl3): δ = 1.57 (t, J = 12.8 Hz, 1 H, one proton of CH2), 1.62–
1.72 (m, 1 H, one proton of CH2), 1.97 (dt, J = 5.2 and 13.2 Hz,
1 H, one proton of CH2), 2.03–2.09 (m, 1 H, one proton of CH2),
2.48 (dt, J = 4.4 and 13.6 Hz, 1 H, one proton of CH2), 2.72 (dt,
J = 6.4 and 13.6 Hz, 1 H, one proton of CH2), 3.05–3.12 (m, 1 H,
CH), 3.81–4.00 (m, 5 H, 2 OCH2 and CH), 4.63 (dd, J = 10.0 and
12.4 Hz, 1 H, one proton of NCH2), 4.96 (dd, J = 4.8 and 12.4 Hz,
1 H, one proton of NCH2), 7.17–7.19 (m, 2 Har), 7.28–7.36 (m, 3
Har) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.0, 38.6, 39.3, 43.4,
48.1, 64.5, 64.7, 78.9, 106.9, 127.8, 128.2, 129.0, 137.2, 210.3 ppm.
HPLC analysis (Chiralpak AS-H, hexane/iPrOH = 80:20, flow rate
1.0 mL/min, wavelength = 210 nm): tR = 17.20 (minor) and 27.08
(major) min.
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Received: June 21, 2010
Published Online: November 12, 2010
Eur. J. Org. Chem. 2011, 122–127
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
127