A recyclable organocatalyst for asymmetric Michael addition of acetone to nitroolefins

Article abstract of DOI:10.1021/jo2002819

Based on different chiral diamine skeletons, a series of bifunctional primary amine-thiophosphoramides were synthesized and screened as the catalysts for the asymmetric Michael addition of acetone to both aromatic and aliphatic nitroolefins. Under the cat

Full text of DOI:10.1021/jo2002819

ARTICLE
pubs.acs.org/joc
A Recyclable Organocatalyst for Asymmetric Michael Addition of
Acetone to Nitroolefins
Aidang Lu, Tao Liu, Ronghua Wu, Youming Wang,* Guiping Wu, Zhenghong Zhou,* Jianxin Fang, and
Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
P. R. China
S Supporting Information
b
ABSTRACT: Based on different chiral diamine skeletons, a
series of bifunctional primary amine-thiophosphoramides were
synthesized and screened as the catalysts for the asymmetric
Michael addition of acetone to both aromatic and aliphatic
nitroolefins. Under the catalysis of a thiophosphoramide de-
rived from 1,2-diphenylethane-1,2-diamine, the corresponding adducts were obtained in high yields (up to >99%) with excellent
enantioselectivities (97ꢀ99% ee) under mild reaction conditions. Moreover, the catalyst could be recovered via simple phase
separation and reused at least five times without any loss of both catalytic activity and stereocontrol.
’ INTRODUCTION
highly efficient alternative catalysts for the asymmetric Michael
addition of acetone to both aromatic and aliphatic nitroolefins is
highly desirable. Recently, we have demonstrated that functionalized
thiophosphoramides can function as a novel type of hydrogen bond
donor catalyst in asymmetric nitro-Michael addition.5 Among them,
primary amine-thiophosphoramide catalyst 1 could promote the
asymmetric Michael addition of acetone to nitroolefin, providing the
conjugate addition product with high levels of enantioselectivity
(Scheme 1).5b Herein we report our further results on a highly
efficient and recyclable thiophosphoramide catalyst for the Michael
addition of acetone to both aromatic and aliphatic nitroolefins.
Michael addition of ketone to nitroolefins represents a con-
venient access to γ-nitroketones, which are valuable building
blocks in organic synthesis.1 Since the proline-catalyzed direct
nitro-Michael addition emerged,2 much effort has been devoted
to the development of more selective and efficient catalytic
systems for this synthetically useful transformation. In sharp
contrast to the high enantioslectivities obtained with the orga-
nocatalyzed Michael addition of cyclic ketones, especially cyclo-
hexanones, to nitroalkenes,3 acetone is still one of the most
problematic substrates for the nitro-Michael addition. To our
knowledge, only limited cases have been reported with enantio-
meric excesses of over 90% for the Michael products of acetone.4
Employing chiral primary amine-thiourea catalysts Jacobsen4a
and Tsogoeva4b,c have independently developed the highly
enantioselective conjugate addition of acetone to aromatic nitro-
olefins, affording the conjugated addition products with the
highest ee value of 99% and 92%, respectively. Feng described
an amine organocatalyst based on bispidine for this transforma-
tion and achieved an enantioselecitivity of 96% ee.4d Zhao
developed a self-assembled organocatalyst based on ionic inter-
actions between L-phenylglycine and cinchonoid thiourea that
could mediate the asymmetric nitro-Michael addition of acetone
with enantioselectivities up to 98% ee.4e In addition, chiral
primary amine-thiourea bearing a glycosyl scaffold,4f N-diphe-
’ RESULTS AND DISCUSSION
Designed primary amine-thiophosphoramides 2ꢀ5 bearing
different chiral diamine skeletons were readily synthesized via the
condensation of the corresponding diamine with thiophosphoryl
chloride in the presence of triethylamine in acceptable yields.
Thiophosphoramide 6 was prepared through the reaction of the
monolithium salt of (R)-1,10-binaphthyl-2,20-diamine with di-
phenylphosphinothioic chloride (Scheme 2).
With these catalysts in hand, screening of their catalytic
efficacy and enantioselectivity was carried out with the model
reaction between β-nitrostyrene (7a) and acetone (Table 1).
Results, listed in Table 1, clearly indicated that their catalytic
activity and enantioselectivity are highly dependent on their
chiral diamine skeleton. Moreover, the substituents on the phos-
phorus atom also have considerable influence on both catalytic
activity and enantioselectivity. In the absence of acid co-catalyst, only
moderate conversion of 7a with ee value of 89% was achieved when
nylphosphinyl-trans-1,2-diphenylethane-1,2-diamine,4g
and
Noyori’s Ts-DPEN ligand4h have also been describe as effective
catalysts for the asymmetric Michael addition of acetone to
nitroolefin, giving high levels of enantioselectivity. Despite these
recent advances, there are still some drawbacks associated with
these previously reported procedures, such as the substrate limita-
tion to aromatic nitroolefin, need of an acidic co-catalyst, and in
some cases, unsatisfactory selectivity. Therefore, the development of
thiophosphoramide
1 derived from (1R,2R)-cyclohexane-1,
Received: February 9, 2011
Published: April 05, 2011
r
2011 American Chemical Society
3872
dx.doi.org/10.1021/jo2002819 J. Org. Chem. 2011, 76, 3872–3879
|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. (R,R)-1 Catalyzed Asymmetric Michael Addition
of Acetone to β-Nitrostyrene
Table 1. Catalyst Screeninga
entry
catalyst
solvent
time
yield (%)b
ee (%)c
1
1
1d
toluene
toluene
toluene
CH3CN
THF
132 h
66 h
36 h
42 h
42 h
47
45
89
90
2
3
2
>99
50
98
4
2
93
NDe
Scheme 2. Preparation of Primary
5
2
10
Amine-thiophosphoramide Catalyst 2ꢀ6
6
2
MeOH
hexane
CH2Cl2
neat
42 h
tr
7
2
22 h
42 h
94
96
95
93
99
98
99
98
95
95
8
2
81
9
2
42 h
71
10
11
12
13
14
15
16
17
18
19
20
21
2f
2d
2d,f
2d,g
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
72 h
12 h
31 h
7 d
>99
>99
>99
93
108 h
66 h
6 d
51
3d
57
4
NRh
NRh
NRh
17
NRh
NRh
4d
5
5d
66 h
6 d
66 h
6 d
NDe
6
6d
66 h
a All reactions were carried out using acetone (0.9 mmol, 3 equiv) and 7a
(0.3 mmol) in the presence of catalyst (10 mol %) in toluene (0.5 mL) at
20 °C. b Yield of the isolated product after chromatography on silica gel.
tr = trace. c Determined by chiral HPLC analysis. d 10 mol % of
2-diamine was employed as the catalyst (Table 1, entry 1). The use of
diphenylphosphinothioamide 2 bearing (R,R)-1,2-diphenyleth-
ane-1,2-diamine skeleton resulted in a full conversion of nitros-
tyrene 7a with high enantioselectivity of 98% ee (Table 1,
entry 3). In contast, catalyst O,O-diphenyl thiophosphoramide
3 with the same chiral diamine skeleton as that of catalyst
2 afforded the desired conjugate addition product in only
51% yield with slightly lower enantioselectivity of 95% ee in
prolonged reaction time (Table 1, entry 8). Under identical
conditions, thiophosphoramide catalysts 4ꢀ6 prepared from
(þ)-cis-1,2,2-trimethylcyclopentane-1,3-diamine, (R,R)-11,12-
diamino-9,10-dihydro-9,10-ethanonanthracene, and (R)-1,10-bi-
naphthyl-2,20-diamine were completely inactive in the model
reaction and failed to afford product 8a. Addition of 10 mol % of
4-nitrophenol as acid co-catalyst significantly accelerated the reaction in
comparison with that without the co-catalyst (Table 1, entry 2 vs entry
1, entry 11 vs entry 3, and entry 15 vs entry 14). However, even with the
aid of the acidic co-catalyst thiophosphoramides 1, 3, 5 were not active
enough to ensure a full conversion of 7a over 66 h (Table 1, entries 2,
15, and 19), and catalysts 4 and 6 were still not active at all (Table 1,
entries 17 and 21). In general, the same high level of enantioselectivity
was achieved consistently with or without the acidic co-catalyst.
The results summarized in Table 1 demonstrate that phos-
phoramide catalyst 2 bearing the (R,R)-1,2-diphenylethane-1,2-
diamine skeleton was highly efficient for the Michael addition of
acetone to nitroolefin 7a. The corresponding adduct 8a could be
attained quantitatively with a high enantioselectivity of 98% ee at
the catalyst loading of 10 mol % in toluene at room temperature
without an acidic co-catalyst (Table 1, entry 3). The reaction proceeded
well even at 5 mol % catalyst loading, with slight improvement in the
f
4-nitrophenol was added as co-catalyst. e ND = not determined. In
the presence of 5 mol % of catalyst 2. g In the presence of 2 mol % of
catalyst 2. h NR = no reaction occurred.
observed ee only at the expense of reaction time (Table 1, entry 10).
Solvent evaluation revealed that toluene was the best solvent for the
reaction, and no better results were obtained in other solvents (Table 1,
entries 3ꢀ9). It was gratifying that the catalyst loading could be
successfully reduced to 5 mol % without any detrimental effect on the
reaction when 10 mol % of 4-nitrophenol was added as an acidic co-
catalyst (Table 1, entry 12).6 Although the enantioselectivity remained
unaltered, further reducing the catalyst loading to 2 mol % resulted in a
very sluggish reaction (Table 1, entry 13).
On the basis of the optimized conditions for nitroolefin 7a, a
variety of nitroolefins were further examined either under condition A
(10mol%of2alone as the catalyst, in toluene, at 20 °C) or condition
B (5 mol % of 2 in combination with 10 mol % 4-nitrophenol as the
catalyst, in toluene, at 20 °C), and the results are collected in Table 2.
As shown in Table 2, the reaction has a broad substrate scope
with respect to the nitroolefins. Under either condition A or
condition B, a wide range of electron-rich and electron-deficient
aromatic nitroalkenes underwent the Michael addition reaction
of acetone with comparable high yields and enantioselectivities
(Table 2, entries 1ꢀ6, 8ꢀ14; 98ꢀ99% ee). It is more significant
that the less reactive nitroethylenes bearing a linear alkyl,
branched alkyl, and alkenyl substituent at the β-position also
proved to be suitable substrates when 20 mol % of catalyst 2 was
employed. The corresponding reactions ran smoothly, affording
the desired products in excellent yields with slightly eroded
3873
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879

The Journal of Organic Chemistry
ARTICLE
Table 2. Substrate Scope of 2 Catalyzed Asymmetric Michael Addition of Acetone to Nitroolefinsa
condition A
condition B
yield (%)b
entry
R
time (h)
yield (%)b
ee (%)c
time (h)
ee (%)c
1
Ph (a)
36
59
36
36
21
24
26
24
36
21
16
20
21
36
48
108
72
72
96
67
72
>99
99
98
99
31
49
60
60
41
36
>99
92
99
98
2
2-MeOC6H4 (b)
4-MeOC6H4 (c)
3,4-OCH2OC6H3 (d)
2-ClC6H4 (e)
4-ClC6H4 (f)
4-ClC6H4 (f)d
2-BrC6H4 (g)
2-CF3C6H4 (h)
2-NO2C6H4 (i)
4-NO2C6H4 (j)
1-naphthyl (k)
2-furyl (l)
3
94
99
99
98
4
90
98
86
99
5
>99
>99
95
99
>99
90
>99
98
6
98
7
>99
99
8
99
40
60
75
22
48
49
60
97
90
>99
>99
99
9
91
>99
>99
>99
99
10
11
12
13
14
15
16
17
18
19
20
21
95
67
>99
>99
98
>99
94
99
98
98
93
98
2-thienyl (m)
(E)-styryl (n)e
BnCH2 (o)e
Et (p)e
iBu (q)e
iBu (q)e,f
>99
90
98
87
98
98
>99
85
97
97g
98g
98g
97g
98g
95
93
Pr (r)e
Cy (s)e
86
75
a All reactions were carried out on 0.3 mmol scale. b Yield of the isolated product after chromatography on silica gel. Determined by chiral HPLC
analysis. d The reaction was performed on a 40 mmol scale. e In the presence of 20 mol % of catalyst 2. f The reaction was conducted on a 30 mmol scale.
g Determined by chiral GC analysis.
c
the Michael addition of acetone to 4-chloro-substituted trans-β-
nitrostryene (7f) on a 30 mmol scale. Gratifying, catalyst 2 could be
easily recovered via simple phase separation and reused at least five
times without any loss of efficacy and stereocontrol, giving almost
quantitative yields (average 97.4%, because of the accumulation of
the unprecipitated product in the mother liquor, yields of >100%
was observed in some cases) and excellent enantioselectivities
(>99% ee) (Table 3). The product 8f was separated at the end
after each run by precipitation from the reaction mixture with the
addition of 60 mL of hexane. The mother liquor containing catalyst
2 was evaporated under reduced pressure to remove hexane and
then reused directly in the subsequent nitro-Michael addition.
The asymmetric addition of other methyl ketones to nitros-
tyrene 7a also ran smoothly in the presence of 20 mol % of
thiophosphoramide 2 to provide the desired adducts in high yield
with both high regioselectivities and enantioselectivities
(Scheme 3). For example, methyl ethyl ketone and methyl
hydroxymethyl ketone underwent reaction with nitrostyrene
7a with excellent regioselectivity, favoring branched products
9a,b over their chromatographically separable regioisomer.
Moreover, both 9a and 9b were generated with high enantios-
electivities (98% ee) albeit with moderate diastereoselectivities
(77/23 and 74/26 dr, respectively). More sterically demanding
methyl isobutyl ketone afforded linear product (9c) exclusively
in excellent chemical yield (93%) with high degree of enantios-
electivity (96% ee).
Table 3. Catalyst Recovery and Reuse in Michael Addition of
Acetone to Nitroolefin 7f Using 10 mol % of Catalyst 2a
run
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
17
24
24
36
72
83
110
83
>99
>99
>99
>99
>99
115
96
a All reactions were performed on a 30 mmol scale in 50 mL of toluene.
b Yield of the product precipitated from the reaction mixture, average
yield 97.4%. c Determined by chiral HPLC analysis.
enantioselectivities (Table 2, entries, 97ꢀ98% ee). To demon-
strate the potential of this method for preparative purposes, the
reaction is also carried out in gram scale giving the isolated
product with unaltered enantioselectivity. For example, the
reactions of aromatic nitroolefin 7f and aliphatic nitroalkene
7q on 40 and 30 mmol scale resulted in the formation of
conjugated addition product 8f and 8q with enantiomeric excess
of >99% and 98%, respectively (Table 2, entries 7 and 19).
To further reduce the amount of catalyst, the possibility of
recovery and reuse of catalyst 2 was investigated by performing
3874
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879

The Journal of Organic Chemistry
ARTICLE
Scheme 3. Asymmetric Michael Addition of Other Ketones
Catalyzed by 2
efficacy and enantioselectivity were significantly improved with
thiophosphoramide catalyst 2 bearing the 1,2-diphenylethane-
1,2-diamine skeleton relative to other thiophosphoramides cat-
alyst derived from different chiral diamines. The reaction toler-
ated a broad substrate scope; not only aromatic but also aliphatic
nitroolefins could be converted into the corresponding adducts
in high yields with excellent enantioselectivities (97ꢀ99% ee).
Moreover, catalyst 2 can be easily recovered via simple phase
separation and reused at least five times without any lost of
catalytic activity and sterereocontrol.
’ EXPERIMENTAL SECTION
All reagents and solvents were commercial grade and purified prior to
use when necessary. NMR spectra were acquired on a 400 MHz
instrumental. Chemical shifts are measured relative to residual solvent
peaks as an internal standard set to δ 7.26 and δ 77.0 (CDCl3).
Enantiomeric excesses were determined on a HPLC instrument
(chiral column; mobile phase hexane/i-PrOH). Column chromatogra-
phy was performed on silica gel (100ꢀ200 mesh).
Scheme 4. Asymmetric Michael Addition to (E)-r-Methyl
β-Nitrostyrene Catalyzed by 2
Preparation of Thiophosphoramides 2ꢀ5. To a stirred
solution of chiral diamine (11 mmol) and triethylamine (1.11 g, 11
mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of
thiophosphoryl chloride (10 mmol) in dry CH2Cl2 (50 mL) at 0 °C over
a period of 2 h. The reaction mixture was allowed to warm to room
temperature and stirred for 2 h. The resulting mixture was washed with
water, and the separated organic phase was dried over anhydrous
magnesium sulfate. After removal of solvent the crude product was
purified through column chromatography on silica gel (100ꢀ200 mesh,
petroleum ether/ethyl acetate = 6:1ꢀ3:1) to afford the desired thiopho-
sphoramides 2ꢀ5.
Data for 2. White solid, 3.64 g, 85% yield, mp 112ꢀ113 °C,
[R]2D0 ꢀ23.4 (c 1.0, CHCl3). H NMR (CDCl3, 400 MHz): δ 1.56
1
(br. s, 2 H), 4.10ꢀ4.13 (m, 1 H), 4.23 (d, J = 5.6 Hz, 1 H), 4.45ꢀ4.51
(m, 1 H), 7.05ꢀ7.15 (m, 5 H), 7.17ꢀ7.21 (m, 2 H), 7.23ꢀ7.39
(m, 9 H), 7.58ꢀ7.63 (m, 4 H). 31P NMR (CDCl3, 161.7 MHz):
δ 59.12. 13C NMR (CDCl3, 100.6 MHz): 61.3 (d, J = 7.4 Hz), 61.8,
131.0, 131.1, 131.2, 131.3, 131.7, 131.8, 133.6, 133.9, 134.6, 134.9, 141.0,
142.5. HRMS (ESI) m/z calcd for C26H25N2PS [M þ H]þ: 429.1549,
found 429.1545.
Figure 1. Possible transition state.
The reaction of less reactive trans-β-methyl-β-nitrostyrene
(10), an interesting acceptor, since two contiguous tertiary
stereocenters will be created in the Michael reaction, can afford
the desired product 11 in good yield at the expense of reaction
time. Compound 11 was obtained almost quantitatively as a pair
of separable diastereomers with an syn/anti selectivity of 5.6/1,
and the ee value of the syn-isomer was 93% (Scheme 4).
The relative configurations of the major diastereomer were
assigned by comparison of 1H and/or 13C NMR of the products
with the known compounds. The absolute configuration of the
major isomer was established by comparison to the literature
value of optical rotation.
Data for 3. White solid, 3.45 g, 75% yield, mp 110ꢀ112 °C,
[R]2D0 ꢀ9.5 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.52 (br.
s, 2 H), 4.36 (br. s, 1 H), 4.81 (dt, J = 3.2 and 9.2 Hz, 1 H), 5.17 (dd, J =
9.2 and 16.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 6.78 (d, J = 8.0 Hz, 2 H),
7.06ꢀ7.19 (m, 6 H), 7.28ꢀ7.44 (m, 10 H). 31P NMR (CDCl3, 161.7
MHz): δ 62.73. 13C NMR (CDCl3, 100.6 MHz): 60.7 (d, J = 8.7 Hz),
62.6, 120.7, 120.8, 120.9, 121.0, 124.6, 124.7, 126.9, 127.3, 127.6, 128.3,
128.5, 129.1, 129.2, 141.3, 141.9, 150.9, 151.0. HRMS (ESI) m/z calcd
for C26H25N2PO2S [M þ H]þ: 461.1447, found 461.1444.
Similar to our previous report,5b thiophosphoramide 2 is
believed to function as a bifunctional catalyst. The primary amine
first reacts with a carbonyl compound to form an enamine with or
without the aid of acidic co-catalyst. Subsequently, the acidic
hydrogen orientates the nitro group via hydrogen-bonding
interaction so that the enamine will nucleophilic attack the
nitroolefin from the si face to give the desired highly enantiose-
lective conjugate addition product.
Data for 4. Brown solid, 3.30 g, 92% yield, mp 97ꢀ100 °C,
[R]2D0 þ57.6 (c 1.0, CHCl3). H NMR (CDCl3, 400 MHz): δ 0.77
1
(s, 3 H, CH3), 1.04 (s, 3 H, CH3), 1.05 (s, 3 H, CH3), 1.12 (br. s, 2 H,
NH2), 1.53ꢀ1.60 (m, 1 H), 1.65ꢀ1.72 (m, 1 H), 1.92ꢀ2.00 (m, 1 H),
2.09ꢀ2.18 (m, 1 H), 3.26ꢀ3.34 (m, 1 H), 4.89 (t, J = 9.6, 10.4 Hz, 1 H),
7.39ꢀ7.43 (m, 6 H), 7.93ꢀ8.01 (m, 4 H). 31P NMR (CDCl3, 161.7
MHz): δ 55.06. 13C NMR (CDCl3, 100.6 MHz): δ 17.7, 24.3, 26.4, 31.1,
38.0, 47.4 (d, J = 6.8 Hz), 61.7, 61.9, 128.0 (d, J = 5.9 Hz), 128.2 (d, J =
5.7 Hz), 131.4 (d, J = 10.9 Hz), 131.6 (d, J = 10.9 Hz), 135.1 (d, J = 90.5
Hz), 136.1 (d, J = 88.3 Hz). HRMS (ESI) m/z calcd for C20H27N2PS
[M þ H]þ: 359.1705, found 359.1704.
’ CONCLUSION
The chiral diamine skeleton was found to be crucial to both
the catalytic activity and chiral induction ability of the primary
amine-thiophosphoramide catalyst for the asymmetric Michael
addition of problematic acetone to nitroolefins. Both the catalytic
Data for 5. Pale yellow solid, 2.40 g, 53% yield, mp 84ꢀ86 °C,
[R]2D0 ꢀ48.0 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.48 (br. s,
2 H), 3.01ꢀ3.08 (m, 2 H), 4.13 (d, J = 2.4 Hz, 1 H), 4.37 (d, J = 2.4 Hz,
1 H), 7.10ꢀ7.16 (m, 4 H), 7.22ꢀ7.24 (m, 1 H), 7.30ꢀ7.32 (m, 2 H),
3875
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879

The Journal of Organic Chemistry
ARTICLE
7.37ꢀ7.50 (m, 7 H), 7.92ꢀ8.02 (m, 4 H). 31P NMR (CDCl3, 161.7
MHz): δ 58.08. 13C NMR (CDCl3, 100.6 MHz): δ 51.2 (d, J = 5.8 Hz),
51.8, 61.6 (d, J = 4.7 Hz), 62.3, 124.3, 124.4, 126.0, 126.1, 126.4, 126.5,
126.7, 128.4, 128.5, 128.6, 131.5, 131.6, 131.8, 133.5, 133.7, 134.6, 134.7,
138.3, 139.0, 140.6, 142.3. HRMS (ESI) m/z calcd for C28H25N2PS
[M þ H]þ: 453.1549, found 453.1547.
7.6 Hz, 1 H). 13C NMR (CDCl3, 100.6 MHz): 30.1, 35.2, 44.4, 55.25, 77.7,
110.9, 120.8, 126.3, 128.9, 129.2, 157.0, 206.1. HPLC analysis (Chiralpak
AS-H column, hexane/2-propanol = 85:15, flow rate = 1.0 mL/min,
wavelength = 210 nm): tR = 17.50 (major) and 19.98 min (minor), 99%
ee (condition A); tR = 17.42 (major) and 19.93 min (minor), 98% ee
(condition B).
(S)-4-(4-Methoxyphenyl)-5-nitropentan-2-one (8c)4a,d,7. White so-
lid, 67 mg, 94% yield for condition A, 70 mg, 99% yield for condition B,
Preparation of Thiophosphinamide 6. To a stirred solution of
(R)-1,10-binaphthyl-2,20-diamine (0.57 g, 2 mmol) in dry THF (5 mL)
was added dropwise a solution of BuLi in THF (0.8 mL, 2 mmol, 2.5 M)
at ꢀ40 °C. After being stirred for 1 h the resulting mixture was allowed
to warm to 0 °C. Then a solution of diphenylphosphinothioic chloride
(0.51 g, 2 mmol) in dry THF (5 mL) was added dropwise. After addition
the reaction mixture was allowed to warm to room temperature and
stirred for 2 h. The reaction was quenched with slowly addition of
saturated aqueous NaHCO3 and extracted twice with methylene
chloride (15 mL). The combined organic phase was dried over
anhydrous magnesium sulfate. After removal of solvent the crude
product was purified through column chromatography on silica gel
(100ꢀ200 mesh, petroleum ether/ethyl acetate = 6:1) to afford the
desired thiophosphinamide 6 as a yellow solid: 0.40 g, 40% yield, mp
mp 84ꢀ86 °C, [R]2D0 ꢀ2.3 (c 1.0, CHCl3). H NMR (CDCl3, 400
1
MHz): δ 2.10 (s, 3 H), 2.88 (d, J = 6.8 Hz, 2 H), 3.77 (s, 3 H), 3.95
(quintet, J = 6.8 Hz, 1 H), 4.55 (dd, J = 7.6 and 12.0 Hz, 1 H), 4.65 (dd,
J = 7.2 and 12.4 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.13 (d, J = 8.8 Hz,
2 H). 13C NMR (CDCl3, 100.6 MHz): 30.4, 38.4, 46.2, 55.2, 79.7, 114.4,
128.4, 130.6, 159.1, 205.5. HPLC analysis (Chiralpak AD-H column,
hexane/2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
210 nm): tR = 14.19 (major) and 15.77 min (minor), 99% ee (condition A);
tR = 14.08 (major) and 15.72 min (minor), 98% ee (condition B).
(S)-4-(Benzo[d][1,3]dioxol-5-yl)-5-nitropentan-2-one (8d)7. Pale
brown solid, 68 mg, 90% yield for condition A, 65 mg, 86% yield for
condition B, mp 62ꢀ63 °C, [R]2D0 ꢀ2.8 (c 1.0, CHCl3). H NMR
1
101ꢀ103 °C, [R]2D0 ꢀ26.1 (c 1.0, CHCl3). H NMR (CDCl3, 400
1
(CDCl3, 400 MHz): δ 2.11 (s, 3 H), 2.85 (d, J = 7.2 Hz, 2 H), 3.91
(quintet, J = 7.2 Hz, 1 H), 4.53 (dd, J = 8.0 and 12.4 Hz, 1 H), 4.63 (dd,
J = 6.8 and 12.4 Hz, 1 H), 5.92 (s, 2 H), 6.65ꢀ6.68 (m, 2 H), 6.73 (d, J =
7.6 Hz). 13C NMR (CDCl3, 100.6 MHz): 30.3, 38.8, 46.2, 79.6, 101.2,
107.6, 108.6, 120.7, 132.4, 147.1 148.1, 205.3. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min,
wavelength = 210 nm): tR = 18.83 (major) and 20.59 min (minor), 98%
ee (condition A); tR = 18.57 (major) and 20.44 min (minor), 99% ee
(condition B).
MHz): δ 3.55 (br. s, 2 H), 5.14 (d, J = 7.6 Hz, 1 H), 7.11ꢀ7.16 (m, 2 H),
7.23ꢀ7.46 (m, 11 H), 7.55ꢀ7.64 (m, 3 H), 7.74ꢀ7.84 (m, 6 H). 31P
NMR (CDCl3, 161.7 MHz): δ 52.29. 13C NMR (CDCl3, 100.6 MHz):
110.6, 118.2, 119.2, 119.3, 119.7, 119.8, 122.6, 124.0, 124.1, 124.8, 126.9,
127.2, 128.3, 128.5, 128.6, 128.9, 129.9, 130.2, 130.8, 130.9, 131.6, 131.7,
131.8, 133.0, 133.3, 133.7, 133.8, 134.4, 134.8, 137.3, 143.0. HRMS
(ESI) m/z calcd for C32H25N2PS [M þ H]þ: 501.1549, found
501.1541.
(S)-4-(2-Chlorophenyl)-5-nitropentan-2-one (8e)4h. White solid, 72
mg, >99% yield for condition A, 72 mg, >99% yield for condition B, mp
57ꢀ59 °C, [R]2D0 þ18.8 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ 2.14 (s, 3 H), 2.94 (dd, J = 6.0 and 18.4 Hz, 1 H), 3.03 (dd, J = 8.0 and
18.0 Hz, 1 H), 4.41ꢀ4.49 (m, 1 H), 4.64ꢀ4.74 (m, 2 H), 7.18ꢀ7.23 (m,
3 H), 7.36ꢀ7.39 (m, 1 H). 13C NMR (CDCl3, 100.6 MHz): 30.1, 35.6,
44.4, 77.2, 127.3, 128.2, 128.9, 130.3, 133.6, 135.9, 205.3. HPLC analysis
(Chiralpak AD-H column, hexane/2-propanol = 90:10, flow rate =
1.0 mL/min, wavelength = 210 nm): tR = 14.29 (major) and 16.78 min
(minor), 99% ee (condition A); tR = 14.14 (major) and 16.46 min
(minor), >99% ee (condition B).
General Procedure for 2 Catalyzed Asymmetric Michael
Addition to Nitroolefins. Condition A: A mixture of the catalyst 2
(12.9 mg, 0.03 mmol) and acetone (52 mg, 0.9 mmol, 3 equiv) in
toluene (0.5 mL) was stirred at 20 °C to form a clear solution. Then, to
the resulting solution was added nitroolefin (0.3 mmol) at the same
temperature. After the reaction was complete (monitored by TLC), the
mixture was purified by column chromatography on silica gel (100ꢀ200
mesh, PE/EtOAc = 5:1) to afford the desired product. The enantiomeric
excess of the pure product was determined by chiral HPLC analysis.
Condition B: A mixture the catalyst 2 (6.4 mg, 0.015 mmol),
4-nitrophenol (4.2 mg. 0.03 mmol) and acetone (52 mg, 0.9 mmol,
3 equiv) in toluene (0.5 mL) was stirred at 20 °C to form a clear solution.
Then, to the resulting solution was added nitroolefin (0.3 mmol) at the
same temperature. After the reaction is complete (monitored by TLC),
the mixture was purified by column chromatography on silica gel
(100ꢀ200 mesh, PE/EtOAc = 5:1) to afford the desired product. The
enantiomeric excess of the pure product was determined by chiral HPLC
analysis.
(S)-4-(4-Chlorophenyl)-5-nitropentan-2-one (8f)4e. White solid, 72
mg, >99% yield for condition A, 65 mg, 90% yield for condition B, mp
89ꢀ91 °C, [R]2D0 þ5.5 (c 1.1, CHCl3). 1H NMR (CDCl3, 400 MHz): δ
2.12 (s, 3 H), 2.88 (d, J = 7.2 Hz, 2 H), 3.98 (quintet, J = 7.2 Hz, 1 H),
4.56 (dd, J = 7.2 and 12.4 Hz, 1 H), 4.67 (dd, J = 6.4 and 12.4 Hz, 1 H),
7.16 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H). 13C NMR (CDCl3,
100.6 MHz): 30.3, 38.4, 45.9, 79.1, 128.8, 129.2, 133.7, 137.3, 205.0.
HPLC analysis (Chiralpak AD-H column, hexane/2-propanol = 90:10,
flow rate = 1.0 mL/min, wavelength = 210 nm): tR = 12.21 (major) and
14.06 min (minor), 98% ee (condition A); tR = 12.28 (major) and 14.12
min (minor), 98% ee (condition B).
(S)-5-Nitro-4-phenylpentan-2-one (8a)4a. White solid, 62 mg, >99%
yield for condition A, 62 mg, >99% yield for condition B, mp
110ꢀ112 °C, [R]2D0 þ4.3 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ 2.12 (s, 3 H), 2.92 (d, J = 7.2 Hz, 2 H), 4.06 (quintet, J = 7.2 Hz, 1 H),
4.59 (dd, J = 7.6 and 12.4 Hz, 1 H), 4.69 (dd, J = 6.8 and 12.4 Hz, 1 H),
7.21ꢀ7.30 (m, 2 H), 7.31ꢀ7.35 (m, 3 H). 13C NMR (CDCl3, 100.6
MHz): 30.4, 39.0, 46.1, 79.4, 127.4, 127.9, 129.0, 138.8, 205.3. HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, wavelength = 220 nm): tR = 10.15 (major) and 10.89
min (minor), 98% ee (condition A); tR = 9.90 (major) and 10.63 min
(minor), 99% ee (condition B).
(S)-4-(2-Bromophenyl)-5-nitropentan-2-one (8g)4e. Pale yellow oil,
85 mg, 99% yield for condition A, 83 mg, 97% yield for condition B,
[R]2D0 þ14.9 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.18 (s,
3 H), 2.96 (dd, J = 6.0 and 18.0 Hz, 1 H), 3.05 (dd, J = 8.0 and 18.0 Hz,
1 H), 4.44ꢀ4.52 (m, 1 H), 4.68ꢀ4.77 (m, 2 H), 7.14ꢀ7.22 (m, 2 H),
7.28ꢀ7.32 (m, 1 H), 7.61 (dd, J = 1.2 and 8.0 Hz, 1 H). 13C NMR
(CDCl3, 100.6 MHz): 30.1, 37.8, 44.7, 77.4, 124.3, 128.0, 129.2, 129.4,
133.7, 137.5, 205.2. HPLC analysis (Chiralpak AS-H column, hexane/2-
propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): tR =
18.99 (major) and 23.15 min (minor), 99% ee (condition A); tR = 19.02
(major) and 23.21 min (minor), >99% ee (condition B).
(S)-4-(2-Methoxyphenyl)-5-nitropentan-2-one (8b)7. Pale yellow
oil, 70 mg, 99% yield for condition A, 65 mg, 92% yield for condition
B, [R]2D0 þ23.4 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.12 (s, 3
H), 2.95 (dd, J = 6.4 and 18.0 Hz, 1 H), 3.02 (dd, J = 7.6 and 18.0 Hz, 1 H),
3.85 (s, 3 H), 4.21 (quintet, J = 6.8 Hz, 1 H), 4.68ꢀ4.76 (m, 2 H), 6.89 (t,
J = 8.4 Hz, 2 H), 7.13 (dd, J = 1.6 and 7.6 Hz, 1 H), 7.24 (dt, J = 1.6 and
(S)-5-Nitro-4-(2-(trifluoromethyl)phenyl)pentan-2-one (8h)8. Col-
orless oil, 75 mg, 91% yield for condition A, 74 mg, 90% yield for
3876
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879

The Journal of Organic Chemistry
ARTICLE
condition B, [R]2D0 þ12.8 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ 2.14 (s, 3 H), 2.90 (dd, J = 5.2 and 18.0 Hz, 1 H), 2.99 (dd, J = 8.4 and
18.0 Hz, 1 H), 4.41 (quintet, J = 6.8 Hz, 1 H), 4.72 (dd, J = 2.8 and 6.8
Hz, 2 H), 7.35ꢀ7.40 (m, 2 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.68 (d, J = 8.0
Hz, 1 H). 13C NMR (CDCl3, 100.6 MHz): 29.9, 34.2, 46.1, 78.2, 122.7,
125.5, 126.7 (q, J = 5.7 Hz), 127.5, 127.8, 132.4, 137.7, 204.9. HPLC
analysis (Chiralpak AD-H column, hexane/2-propanol = 90:10, flow
rate = 1.0 mL/min, wavelength = 210 nm): tR = 7.99 (major) and 8.67
min (minor), >99% ee (condition A); tR = 8.17 (major) and 8.88 min
(minor), >99% ee (condition B).
205.0. HPLC analysis (Chiralpak AD-H column, hexane/2-propanol =
90:10, flow rate = 1.0 mL/min, wavelength = 210 nm): tR = 11.54
(major) and 12.96 min (minor), 98% ee (condition A); tR = 11.31
(major) and 12.73 min (minor), 98% ee (condition B).
(S,E)-4-(Nitromethyl)-6-phenyl-5-hexen-2-one (8n)9. White solid,
63 mg, 90% yield, mp 111ꢀ113 °C, [R]2D0 ꢀ7.0 (c 1.0, CHCl3),
97.5% ee. 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3 H), 2.75 (d, J =
6.8 Hz, 2 H), 3.48ꢀ3.57 (m, 1 H), 4.52 (dd, J = 7.2 and 12.0 Hz, 1 H),
4.59 (dd, J = 6.4 and 12.0 Hz, 1 H), 6.08 (dd, J = 8.8 and 16.0 Hz, 1 H),
6.53 (d, J = 16.0 Hz, 1 H), 7.24ꢀ7.34 (m, 5 H). 13C NMR (CDCl3, 100.6
MHz): 30.5, 37.0, 44.9, 78.6, 126.2, 126.4, 128.0, 128.6, 133.4, 136.1,
205.5. HPLC analysis (Chiralpak AS-H column, hexane/2-propanol =
85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): tR = 24.96
(major) and 30.40 min (minor).
(S)-5-Nitro-4-(2-nitrophenyl)pentan-2-one (8i)4e,7. Yellow oil, 72
mg, 95% yield for condition A, 51 mg, 67% yield for condition B,
[R]2D0 ꢀ32.2 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.13 (s,
3 H), 3.03 (d, J = 6.8 Hz, 2 H), 4.51 (quintet, J = 6.8 Hz, 1 H), 4.80 (dd,
J = 4.0 and 6.8 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.42 (t, J = 7.2 Hz,
1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.85 (dd, J = 0.8 and 8.0 Hz, 1 H). 13C
NMR (CDCl3, 100.6 MHz): 30.00, 33.71, 45.24, 78.84, 125.12, 128.41,
128.65, 133.25, 133.45, 149.80, 204.77. HPLC analysis (Chiralpak
AD-H column, hexane/2-propanol = 90:10, flow rate = 1.0 mL/min,
wavelength = 210 nm): tR = 22.61 (major) and 25.04 min (minor),
>99% ee (condition A); tR = 21.80 (major) and 24.20 min (minor),
99% ee (condition B).
(R)-4-(Nitromethyl)-6-phenylhexan-2-one (8o)9. Yellow oil, 70 mg,
>99% yield, [R]2D0 þ6.6 (c 1.0 CHCl3). 1H NMR (CDCl3, 400 MHz): δ
1.70ꢀ1.76 (m, 2 H), 2.16 (s, 3 H), 2.59ꢀ2.73 (m, 5 H), 4.48ꢀ4.51 (m, 2
H), 7.16ꢀ7.22 (m, 3 H), 7.28ꢀ7.31 (m, 2 H). 13C NMR (CDCl3, 100.6
MHz): 30.4, 32.6, 32.9, 33.1, 44.5, 78.02 126.2, 128.2, 128.6, 140.7,
206.5. HPLC analysis (Chiralpak AS-H column, hexane/2-propanol =
85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): tR = 13.67
(major) and 15.70 min (minor), 97% ee.
(S)-5-Nitro-4-(4-nitrophenyl)pentan-2-one (8j)4h,7. Pale yellow so-
lid, 75 mg, >99% yield for condition A, 75 mg, >99% yield for condition
B, mp 50ꢀ51 °C, [R]D20 þ4.8 (c 1.0, CHCl3). 1H NMR (CDCl3, 400
MHz): δ 2.14 (s, 3 H), 2.95 (dd, J = 2.4 and 7.2 Hz, 2 H), 4.13 (quintet,
J = 7.2 Hz, 1 H), 4.63 (dd, J = 8.4 and 12.8 Hz, 1 H), 4.74 (dd, J = 8.4 and
12.8 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 2 H), 8.17 (d, J = 8.8 Hz, 2 H). 13C
NMR (CDCl3, 100.6 MHz): 30.2, 38.5, 45.6, 78.5, 124.1, 128.5, 146.4,
147.4, 204.4. HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol = 80:20, flow rate = 1.0 mL/min, wavelength = 210 nm):
tR = 17.68 (major) and 24.11 min (minor), >99% ee (condition A); tR =
16.95 (major) and 23.27 min (minor), 99% ee (condition B).
(R)-4-(Nitromethyl)hexan-2-one (8p)9. Yellow oil, 41 mg, 85% yield,
[R]2D0 ꢀ8.3 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.95 (t, J =
7.2 Hz, 3 H), 1.40ꢀ1.47 (m, 2 H), 2.17 (s, 3 H), 2.52ꢀ2.62 (m, 3 H),
4.44 (d, J = 4.8 Hz, 2 H). 13C NMR (CDCl3, 100.6 MHz): 11.0, 24.34
30.4, 34.5, 44.2, 78.0, 206.6. GC analysis (BETA DEX 120 column, from
40 to 200 °C at a rate of 1 °C/min): tR = 65.54 (minor) and 65.72 min
(major), 97% ee.
(R)-6-Methyl-4-(nitromethyl)heptan-2-one (8q)4a. Yellow oil, 53
mg, 95% yield, [R]2D0 ꢀ8.8 (c 1.0, CHCl3). H NMR (CDCl3, 400
1
MHz): δ 0.87 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 1.15ꢀ1.24
(m, 2 H), 1.56ꢀ1.66 (m, 1 H), 2.15 (s, 3 H), 2.47ꢀ2.71 (m, 3 H), 4.42
(d, J = 5.6 Hz, 2 H). 13C NMR (CDCl3, 100.6 MHz): 22.3, 22.4, 25.0,
30.4, 30.8, 40.5, 44.7, 78.5, 206.7. GC analysis (Chiralsil-DEX CB
column, from 40 to 160 °C at a rate of 1 °C/min): tR = 62.02
(minor) and 62.18 min (major), 98% ee.
(S)-4-(Naphthalen-1-yl)-5-nitropentan-2-one (8k)4d,h
. Colorless
oil, 77 mg, >99% yield for condition A, 73 mg, 94% yield for condition
B, [R]2D0 þ17.6 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.14 (s,
3 H), 3.08ꢀ3.12 (m, 2 H), 4.79ꢀ4.80 (m, 2 H), 4.95 (quintet, J = 6.8 Hz,
1 H), 7.33 (d, J = 7.2 Hz, 1 H), 7.43 (t, J = 7.2 Hz, 1 H), 7.53 (t, J = 7.2 Hz,
1 H), 7.61 (dt, J = 1.2 and 6.8 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.89 (d,
J = 8.4 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H). 13C NMR (CDCl3, 100.6
MHz): 30.9, 33.4, 46.0, 78.8, 122.3, 123.6, 125.2, 126.1, 126.9, 128.5,
129.3, 130.9, 134.1, 134.7, 205.5. HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol = 80:20, flow rate = 1.0 mL/min, wave-
length = 210 nm): tR = 18.09 (major) and 21.89 min (minor), 99% ee
(condition A); tR = 18.13 (major) and 22.02 min (minor), 98% ee
(condition B)
(R)-4-(Nitromethyl)heptan-2-one (8r)4a. Pale yellow oil, 45 mg, 86%
yield, [R]2D0 ꢀ14.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.92
(t, J = 6.8 Hz, 3 H), 1.33ꢀ1.37 (m, 4 H), 2.17 (s, 3 H), 2.52ꢀ2.63 (m,
3 H), 4.44 (d, J = 5.6 Hz, 2 H). 13C NMR (CDCl3, 100.6 MHz): 13.9,
19.8, 30.5, 32.8, 33.6, 44.6, 78.4, 206.7. GC analysis (Chiralsil-DEX CB
column, from 40 to 160 °C at a rate of 1 °C/min): tR = 82.28 (minor)
and 82.80 min (major), 97% ee.
(S)-4-Cyclohexyl-5-nitropentan-2-one (8s). Colorless oil, 48 mg,
75% yield, [R]2D0 ꢀ12.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ 0.89ꢀ0.99 (m, 2 H), 1.08ꢀ1.26 (m, 3 H), 1.36ꢀ1.44 (m, 1 H),
1.64ꢀ1.76 (m, 5 H), 2.16 (s, 3 H), 2.48ꢀ2.64 (m, 3 H), 4.42 (d, J = 6.0
Hz, 2 H). 13C NMR (CDCl3, 100.6 MHz): 26.2, 29.7, 30.0, 30.3, 38.1,
38.7, 42.2, 76.9, 206.7. HRMS (ESI) m/z calcd for C11H19NO3
[MþNa]þ: 236.1257, found 236.1264. GC analysis (Chiralsil-DEX
CB column, from 40 to 160 °C at a rate of 1 °C/min): tR = 59.99
(minor) and 60.72 min (major), 98% ee.
(R)-4-(Furan-2-yl)-5-nitropentan-2-one (8l)4a,7. Brown solid, 58 mg,
98% yield for condition A, 55 mg, 93% yield for condition B, mp
48ꢀ49 °C, [R]2D0 þ5.7 (c 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz): δ
2.15 (s, 3 H), 2.88 (dd, J = 7.2 and 18.0 Hz, 1 H), 2.96 (dd, J = 6.4 and
18.0 Hz, 1 H), 4.08 (quintet, J = 6.8 Hz, 1 H), 4.64ꢀ4.67 (m, 2 H), 6.12
(d, J = 3.2 Hz, 1 H), 6.27 (dd, J = 2.0 and 3.2 Hz, 1 H), 7.32 (d, J = 1.2 Hz,
1 H). 13C NMR (CDCl3, 100.6 MHz): 30.1, 32.8, 43.4, 107.0, 110.4,
142.2, 151.6, 205.1. HPLC analysis (Chiralpak AD-H column, hexane/
2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 210 nm): tR =
9.73 (major) and 11.08 min (minor), 98% ee (condition A); tR = 9.55
(major) and 10.86 min (minor), 98% ee (condition B).
(4S)-3-Methyl-5-nitro-4-phenylpentan-2-one (9a)3j. Colorless oil,
54 mg, 82% yield, [R]2D0 ꢀ6.5 (c 1.0, CHCl3), syn/anti: 77/23, 98% ee for
syn-isomer and 71% ee for anti-isomer. 1H NMR (CDCl3, 400 MHz): δ
0.98 (d, J = 7.2 Hz, 2.38 H, syn-isomer), 1.21 (d, J = 6.8 Hz, 0.71 H, anti-
isomer), 1.94 (s, 0.66 H, anti-isomer), 2.23 (s, 2.20 H, syn-isomer),
2.94ꢀ3.02 (m, 1 H), 3.65ꢀ3.81 (m, 1 H), 4.60ꢀ4.81 (m, 2 H),
7.15ꢀ7.20 (m, 2 H), 7.27ꢀ7.35 (m, 3 H). 13C NMR (CDCl3, 100.6
MHz): 14.2 (anti-isomer), 15.9 (syn-isomer) 29.2 (syn-isomer), 29.4
(anti-isomer), 45.7 (anti-isomer), 45.8 (syn-isomer), 49.1 (syn-isomer),
49.8 (anti-isomer), 77.6 (anti-isomer), 78.4 (syn-isomer), 127.8 (anti-
isomer), 127.9 (syn-isomer), 128.9 (anti-isomer), 129.0 (syn-isomer),
(R)-5-Nitro-4-(thiophen-2-yl)pentan-2-one (8m)4c. Brown solid, 64
mg, >99% yield for condition A, 56 mg, 87% yield for condition B, mp
37ꢀ38 °C, [R]2D0 ꢀ21.7 (c 1.0, CHCl3), 95% ee. 1H NMR (CDCl3, 400
MHz): δ 2.16 (s, 3 H), 2.97 (d, J = 6.8 Hz, 2 H), 4.32 (quintet, J = 6.8 Hz,
1 H), 4.61 (dd, J = 7.6 and 12.4 Hz, 1 H), 4.71 (dd, J = 6.4 and 12.4 Hz,
1 H), 6.86ꢀ6.95 (m, 2 H), 7.20 (dd, J = 1.2 and 5.2 Hz, 1 H). 13C NMR
(CDCl3, 100.6 MHz): 30.3, 34.5, 46.8, 79.7, 124.7, 125.5, 127.1, 141.5,
3877
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879

The Journal of Organic Chemistry
ARTICLE
137.4 (syn-isomer), 137.9 (anti-isomer), 209.8 (anti-isomer), 210.7
(syn-isomer). HPLC analysis (Chiralpak AD-H column, hexane/
2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength = 220 nm):
tR = 14.28 (minor, syn-isomer), 17.40 (major, syn-isomer), 22.91 (major,
anti-isomer) and 25.36 min (minor, anti-isomer).
removal of 8f through filtration, the mother liquor was evaporated under
reduced pressure to remove hexane, and the resulting mixture was used
for subsequent reaction.
’ ASSOCIATED CONTENT
(4S)-3-Hydroxy-5-nitro-4-phenylpentan-2-one (9b)10. White solid,
60 mg, 90% yield, mp 35ꢀ36 °C, [R]2D0 þ6.9 (c 0.87, CHCl3), anti/syn:
S
Supporting Information. Copies of NMR spectra and
b
1
HPLC analysis. This material is available free of charge via the
74/26, 98% ee for anti-isomer and 88% ee for syn-isomer. H NMR
(CDCl3, 400 MHz): δ 1.99 (s, 2.27 H, anti-isomer), 2.10 (s, 0.80 H, syn-
isomer), 3.69 (br. s, 1 H, OH), 3.73ꢀ3.78 (m, 1 H), 4.31 (d, J = 5.2 Hz,
0.74 H, anti-isomer), 4.45 (d, J = 2.8 Hz, 0.26 H, syn-isomer), 4.58 (dd,
J = 8.4 and 13.6 Hz, 0.81 H, anti-isomer), 4.66 (dd, J = 7.2 and 13.6 Hz,
0.31 H, syn-isomer), 4.75 (dd, J = 6.4 and 13.6 Hz, 0.79 H, anti-isomer),
4.95 (dd, J = 8.0 and 13.6 Hz, 0.29 H, syn-isomer), 7.16ꢀ7.25 (m, 2 H),
7.28ꢀ7.31 (m, 3 H). 13C NMR (CDCl3, 100.6 MHz): 25.8 (syn-
isomer), 26.7 (anti-isomer) 46.0 (syn-isomer), 47.1 (anti-isomer), 77.2
(syn-isomer), 77.3 (anti-isomer), 78.9, 128.3 (anti-isomer), 128.7 (syn-
isomer), 128.8 (anti-isomer), 128.9 (syn-isomer), 129.2 (syn-isomer),
129.6 (anti-isomer), 134.0 (syn-isomer), 137.4 (anti-isomer), 206.6 (syn-
isomer), 208.3 (anti-isomer). HPLC analysis (Chiralpak AD-H column,
hexane/2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength =
220 nm): tR = 41.13 (minor, syn-isomer), 45.26 (major, syn-isomer)
63.04 (major, anti-isomer) and 77.72 min (minor, anti-isomer).
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: z.h.zhou@nankai.edu.cn; youmingwang@eyou.com.
’ ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (Nos. 20772058, 20972070), the National Basic research
Program of China (973 program 2010CB833300), and the Key
laboratory of Elemento-Organic Chemistry for generous finan-
cial support for our programs.
(S)-6-Methyl-1-nitro-2-phenylheptan-4-one (9c)4a. Yellow oil, 70
’ REFERENCES
1
mg, 93% yield, [R]2D0 þ3.1 (c 1.0, CHCl3). H NMR (CDCl3, 400
(1) For reviews, see: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur.
J. Org. Chem. 2002, 1877. (b) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701.
(2) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
(b) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III
Tetrahedron Lett. 2001, 42, 4441. (c) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260. (d) Enders, D.; Seki,
A. Synlett 2002, 26.
MHz): δ 0.83 (d, J = 6.8 Hz, 6 H), 2.01ꢀ2.11 (m, 1 H), 2.16ꢀ2.27 (m,
2 H), 2.79ꢀ2.90 (m, 2 H), 4.01 (quintet, J = 7.2 Hz, 1 H), 4.58 (dd, J =
8.0 and 12.4 Hz, 1 H), 4.68 (dd, J = 6.8 and 12.4 Hz, 1 H), 7.19ꢀ7.24
(m, 3 H), 7.29ꢀ7.32 (m, 2 H). 13C NMR (CDCl3, 75.0 MHz): 22.3,
22.4, 24.4, 39.0, 45.7, 52.2, 79.4, 127.3, 127.7, 128.9, 138.9, 207.4. HPLC
analysis (Chiralpak AS-H column, hexane/2-propanol = 98:2, flow
rate = 0.7 mL/min, wavelength = 210 nm): tR = 14.00 (minor) and
17.06 min (major), 96% ee.
(3) For selected examples of organocatalytic asymmetric Michael
additions of cyclohexanone to nitro olefins, see: (a) Xu, Y.; Zou, W.;
Sundꢀen, H.; Ibrahem, I.; Cꢀordova, A. Adv. Synth. Catal. 2006, 348, 418.
(b) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem.,
Int. Ed. 2006, 45, 3093. (c) Xu, Y.; Cꢀordova, A. Chem. Commun.
2006, 460. (d) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem.
Commun. 2006, 3687. (e) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.;
Wang, W. Chem.—Eur. J. 2006, 12, 4321. (f) Ishii, T.; Fujioka, S.;
Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558. (g) Mase,
N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J.
Am. Chem. Soc. 2006, 128, 4966. (h) Pansare, S. V.; Pandya, K. J. Am.
Chem. Soc. 2006, 128, 9624. (i) Luo, S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.;
Cheng, J.-P. J. Org. Chem. 2006, 71, 9244. (j) Zu, L.; Wang, J.; Li, H.;
Wang, W. Org. Lett. 2006, 8, 3077. (k) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.;
Tang, Y. Org. Lett. 2006, 8, 2901. (l) Vishnumaya; Singh, V. K. Org. Lett.
2007, 9, 1117. (m) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericꢁas, M. A.
Org. Lett. 2007, 9, 3717. (n) Clarke, M. L.; Fuentes, J. A. Angew. Chem.,
Int. Ed. 2007, 46, 930. (o) Alma-si, D.; Alonso, D. A.; Goꢀmez-Bengoa, E.;
Nagel, Y.; Nꢀajera, C. Eur. J. Org. Chem. 2007, 2328. (p) Xu, D. Q.; Yue,
H. D.; Luo, S. P.; Xia, A. B.; Zhang, S.; Xu, Z. Y. Org. Biomol. Chem. 2008,
6, 2054. (q) Quintard, A.; Bournaud, C.; Alexakis, A. Chem.—Eur. J.
2008, 14, 7504. (r) Ni, B.; Zhang, Q.; Dhungana, K.; Headley, A. D. Org.
Lett. 2009, 11, 1037. (s) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G.
Org. Lett. 2009, 11, 1927. (t) Wu, J.; Ni, B.; Headley, A. D. Org. Lett.
2009, 11, 3354. (u) Lu, A. D.; Gao, P; Wu, Y.; Wang, Y. M.; Zhou, Z. H.;
Tang, C. C. Org. Biomol. Chem. 2009, 7, 3141. (v) Han, B.; Xiao, Y. C.;
He, Z. Q.; Chen, Y. C. Org. Lett. 2009, 11, 4660. (w) Freund, M.;
Schenker, S.; Tsogoeva, S. B. Org. Biomol. Chem. 2009, 7, 4279. (x) Lo,
C.-M.; Chow, H.-F. J. Org. Chem. 2009, 74, 5181. (y) Cao, X.-Y.; Zheng,
J.-C.; Li, Y.-X.; Shu, Z.-C.; Sun, X.-L.; Wang, B.-Q.; Tang, Y. Tetrahedron
2010, 66, 9703. (z) Agarwal, J.; Peddinti, R. K. Tetrahedron Lett. 2011,
52, 117.
(S)-5-Nitro-4-phenylhexan-2-one (11)11,12. Yellowish-green oil, 65
mg, 98% yield, [R]2D0 þ6.4 (c 1.0, CHCl3) (diastereomer mixture),
þ10.0 (c 1.0, CHCl3) (syn-isomer), 85/15 dr, 93% ee for syn-isomer. 1H
NMR (CDCl3, 400 MHz): diastereomer mixture, δ 1.31 (d, J = 6.4 Hz,
2.52 H, syn-isomer), 1.48 (d, J = 6.4 Hz, 0.45 H, anti-isomer), 2.01 (s,
2.36 H, syn-isomer), 2.11 (s, 0.42 H, anti-isomer), 2.73 (dd, J = 4.4 and
17.2 Hz, 0.84 H, syn-isomer), 2.89 (dd, J = 7.6 and 17.6 Hz, 0.16 H, anti-
isomer), 2.97 (dd, J = 9.6 and 17.2 Hz, 0.84 H, syn-isomer), 3.04 (dd, J =
6.8 and 17.6 Hz, 0.15 H, anti-isomer), 3.68ꢀ3.75 (m, 1 H), 4.72ꢀ4.80
(m, 0.84 H, syn-isomer), 4.84ꢀ4.91 (m, 0.16 H, anti-isomer), 7.13ꢀ7.20
(m, 2 H), 7.26ꢀ7.34 (m, 3 H); syn-isomer, 1.31 (d J = 6.4 Hz, 3 H), 2.01
(s, 3 H), 2.73 (dd, J = 3.2 and 16.8 Hz, 1 H), 2.97 (dd, J = 9.6 and 16.8
Hz, 1 H), 3.71 (dt, J = 2.8 and 8.0 Hz, 1 H), 4.72ꢀ4.80 (m, 1 H), 7.19 (d,
J = 7.6 Hz, 2 H), 7.26ꢀ7.30 (m, 3 H). 13C NMR (CDCl3, 100.6 MHz):
diastereomer mixture, 16.7 (anti-isomer), 17.7 (syn-isomer), 30.4 (syn-
isomer), 30.5 (anti-isomer), 44.5 (anti-isomer), 44.7 (anti-isomer), 45.3
(syn-isomer), 46.2 (syn-isomer), 85.8 (anti-isomer), 87.1 (syn-isomer),
127.8 (syn-isomer), 127.9 (anti-isomer), 128.10 (anti-isomer), 128.15
(syn-isomer), 128.7 (anti-isomer), 129.0 (syn-isomer), 137.8 (anti-
isomer), 138.2 (syn-isomer), 204.4 (anti-isomer), 204.9 (syn-isomer);
syn-isomer, 17.7, 30.4, 45.3, 46.2, 87.1, 127.8, 128.1, 129.0, 138.2, 204.8.
GC analysis (Chiralsil-DEX CB column, from 40 to 160 °C at a rate of
1 °C/min): tR = 75.90 (major, syn-isomer), 76.44 (minor, syn-isomer),
78.14 (minor, anti-isomer) and 78.70 min (major, anti-isomer).
Recovery and Reuse of Catalyst 2. A mixture the catalyst 2
(12.9 mg, 0.03 mmol) and acetone (523 mg, 90 mmol, 3 equiv) in
toluene (50 mL) was stirred at 20 °C to form a clear solution. Then, to
the resulting solution was added nitroolefin 7f (5.51 g, 30 mmol) at the
same temperature. After the reaction was complete (monitored by
TLC), 60 mL of hexane was added, and the whole mixture was allowed
to cool to 0 °C to precipitate the conjugate addition product 8f. After
(4) (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(b) Tsogoeva, S. B.; Wei, S. W. Chem. Commun. 2006, 1451. (c) Yalalov,
3878
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879

The Journal of Organic Chemistry
ARTICLE
D. A.; Tsogoeva, S. B.; Schmatz, S. Adv. Synth. Catal. 2006, 348, 826. (d)
Yang, Z. G.; Liu, J.; Liu, X. H.; Wang, Z.; Feng, X. M.; Su, Z. S.; Hu, C. W.
Adv. Synth. Catal. 2008, 350, 2001. (e) Mandal, T.; Zhao, C. G. Angew.
Chem., Int. Ed. 2008, 47, 7714. (f) Gu, Q.; Guo, X.-T.; Wu, X.-Y.
Tetrahedron 2009, 65, 5265. (g) Morris, D. J.; Partridge, A. S.; Manville,
C. V.; Racys, D. T.; Woodward, G.; Docherty, G.; Wills, M. Tetrahedron
Lett. 2010, 51, 209. (h) Peng, L.; Xu, X.-Y.; Wang, L.-L.; Huang, J.; Bai,
J.-F.; Huang, Q.-C.; Wang, L.-X. Eur. J. Org. Chem. 2010, 1849.
(5) (a) Lu, A.; Wu, R.; Wang, Y.; Zhou, Z.; Wu, G.; Fang, J.; Tang, C.
Eur. J. Org. Chem. 2010, 2057. (b) Lu, A.; Liu, T.; Wu, R.; Wang, Y.;
Zhou, Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org. Chem. 2010, 5777. (c)
Lu, A.; Wu, R.; Wang, Y.; Zhou, Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org.
Chem. 2011, 122. (d) Wu, Y.; Lu, A.; Liu, Y.; Yu, X.; Wang, Y.; Wu, G.;
Song, H.; Zhou, Z.; Tang, C. Tetrahedron: Asymmetry 2010, 2988–2992.
(6) Co-catalyst, time, yield, ee value: acetic acid, 19 h, 65%, 97% ee;
phenol, 26 h, 99%, 98% ee; water, 26 h, 98%, 98% ee.
(7) Xue, F.; Zhang, S. L.; Duan, W. H.; Wang, W. Adv. Synth. Catal.
2008, 350, 2194.
(8) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.;
Barbas, C. F., III Synthesis 2004, 1509.
(9) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.;
Duan, W.; Wang, W. Org. Lett. 2009, 11, 2864.
(10) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003,
5, 2559.
(11) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N.
J. Am. Chem. Soc. 2005, 127, 1313.
(12) Mitchell, C. E. T.; Brenner, S. E.; García-Fortanet, J.; Ley, S. V.
Org. Biomol. Chem. 2006, 4, 2039.
3879
dx.doi.org/10.1021/jo2002819 |J. Org. Chem. 2011, 76, 3872–3879