Camphor-derived C1-symmetric chiral diamine organocatalysts for asymmetric Michael addition of nitroalkanes to enones

Article abstract of DOI:10.1039/c2ob25922b

A series of stable C₁-symmetric chiral diamines (2a-2l) were conveniently synthesized by condensing exo-(-)-bornylamine or (+)-(1S,2S,5R)-menthylamine with various commercially available Cbz-protected amino acids. Among them, 2a can efficiently promote the Michael addition of nitroalkanes to a broad scope of enones with high yields (up to 96%) and excellent enantioselectivities (up to 98%) under mild conditions.

Full text of DOI:10.1039/c2ob25922b

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PAPER
Camphor-derived C1-symmetric chiral diamine organocatalysts for
asymmetric Michael addition of nitroalkanes to enones†
Yirong Zhou, Qiang Liu and Yuefa Gong*
Received 14th May 2012, Accepted 20th July 2012
DOI: 10.1039/c2ob25922b
A series of stable C1-symmetric chiral diamines (2a–2l) were conveniently synthesized by condensing
exo-(−)-bornylamine or (+)-(1S,2S,5R)-menthylamine with various commercially available Cbz-protected
amino acids. Among them, 2a can efficiently promote the Michael addition of nitroalkanes to a broad
scope of enones with high yields (up to 96%) and excellent enantioselectivities (up to 98%) under mild
conditions.
addition of acetone or acetophenone to nitroalkenes. However,
Introduction
the production of 2-nitropropanes bearing a quaternary carbon
atom are otherwise difficult to access. In light of the knowledge
of effective mechanism of iminium activation of enones by
chiral primary amines2,3e,f and our previous success in develop-
ing a group of C1-symmetric chiral secondary diamines from
L-proline and D-camphor,8a,9 we assumed that chiral primary–
secondary diamines bearing a camphor skeleton may partially
circumvent the existing limitations and enhance the enantioselec-
tivity. Herein, we disclose a highly asymmetric Michael addition
of nitroalkanes to enones catalyzed by a novel C1-symmetric
chiral primary–secondary diamine 2a derived from L-phenyl-
alanine and exo-(−)-bornylamine.
Over the past decade, asymmetric organocatalysis has become a
more and more important complement to traditional metal cata-
lysis and biocatalysis, and has found broad utility in organic syn-
thesis.1 For a long period of time, chiral secondary amines have
been undoubtedly the dominant organocatalysts for their
efficient activation of the carbonyl group, especially aliphatic
aldehydes and α,β-unsaturated aldehydes, via enamine or
iminium activation.1d,2f However, primary amines have not
attracted much attention until very recently.2 Compared with the
various well-developed chiral secondary amine organocatalyst
systems, novel chiral primary amines having strong asymmetric
induction ability for a wide substrate scope are still in high
demand.
The asymmetric Michael addition of nitroalkanes to enones,
as one of the most powerful atom-economical carbon–carbon
bond-constructing methods, furnishes useful adducts which can
be transformed into a wide variety of valuable optically active
building blocks, such as multi-substituted pyrrolidines and un-
natural amino acids.3 Therefore, the development of catalytic
asymmetric reaction variants have focused great interest and both
metal catalysis4 and organocatalysis systems have been success-
fully developed.5–7 The asymmetric additions of nitroalkanes to
chalcones5 or cyclic enones6 have already achieved excellent ee
values up to 99%. Nevertheless, there are few reports about
“cinnamones”,7 especially in the case of bulkier 2-nitropropane,
and the highest ee reported to date has been 91%.7f Meanwhile,
the nitromethane adducts can also be delivered by the conjugate
Results and discussion
Very recently, we prepared exo-(−)-bornylamine from D-camphor
and applied it to constructing a new chiral secondary diamine 2f
(Fig. 1) as a potential catalyst for enantioselective Henry re-
actions.8 In our continued synthetic efforts toward the develop-
ment of new chiral diamine catalysts, we designed and
synthesized a class of novel C1-symmetric chiral primary–
secondary diamines from primary amino acids and exo-(−)-bornyl-
amine through the route outlined in Scheme 1. Firstly, Cbz-
protected L-phenylalanine was condensed with exo-(−)-bornyl-
amine. Then the desired amide compound 1a was obtained after
the deprotection of the Cbz group. Subsequent reduction of 1a
using LiAlH4 in THF provided the desired chiral primary–
secondary diamine 2a. Using the above three-step practical
protocol, a series of chiral diamines (2a–2l) were conveniently
prepared in moderate to good yields under mild reaction con-
ditions. This synthetic route is quite simple and straightforward
and can be operable on a gram scale.
School of Chemistry and Chemical Engineering, Huazhong University
of Science and Technology, 1037 Luoyu Road, Wuhan 430074, People’s
Republic of China. E-mail: gongyf@mail.hust.edu.cn;
Fax: +86 027 87543632; Tel: +86 027 87543232
Initially, the Michael addition of 2-nitropropane (4) to 4-chloro-
benzylideneacetone (3a) was chosen as a model reaction using
20 mol% 2a as the catalyst to optimize the reaction conditions
†Electronic supplementary information (ESI) available: Detailed infor-
mation for optimization of the reaction as well as NMR spectra and
HPLC traces. See DOI: 10.1039/c2ob25922b
7618 | Org. Biomol. Chem., 2012, 10, 7618–7627
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Table 1 Optimization of reaction conditionsa
Time
(h)
Yieldb
(%)
eec
(%)
Entry
Acid additive
Solvent
1
2
3
4
5
6
7
8
PhCOOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
i-PrOH
Et2O
60
60
60
100
48
48
48
60
48
30
48
30
55
55
24
84
80
91
84
95
94
92
88
96
90
85
96
94
91
98
83
78
92
94
93
95
94
90
96
75
90
89
92
91
92
4-MeO-PhCOOH
4-NO2-PhCOOH
3,5-diNO2-PhCOOH
Boc-L-PhgOH
Boc-L-PheOH
Cbz-L-PheOH
Boc-D-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Fig. 1 Structures
of
other
C1-symmetric
chiral
diamine
9
organocatalysts.
10
11
12
13
14
15
MeCN
PhMe
Hexane
Neat
a Reactions were carried out with 0.2 mmol of 3a and 0.5 mL of 4 in
0.5 mL of solvent in the presence of 20 mol% catalyst 2a and
acid additive at room temperature for the specified time. b Isolated
yields. c Determined by chiral HPLC analysis using Chiracel AS-H as a
column; the absolute configuration was established as S by comparison
of the optical rotation with literature data.
Scheme 1 General synthesis route of the C1-symmetric chiral diamine
organocatalyst.
Table 2 Influence of other factorsa
including the acid additives and solvents at room temperature.
The results are summarized in Table 1. To our delight, the
diamine 2a show high efficiency in promoting the transformation
with the assistance of various acid additives. Electron-rich
benzoic acids gave poorer enantioselectivity than electron-poor
benzoic acids (entries 1–4). When 3,5-diNO2-PhCOOH was
used, the reaction rate became much slower albeit with a higher
ee value of 94%. The reaction could not even proceed in the
presence of stronger acids such as p-TsOH and TFA, probably
due to their interaction with the basic amine moieties of the cata-
lyst 2a being too strong.10 To further improve the reactivity and
enantioselectivity, several chiral acids deriving from amino acids
were examined for there may exist some synergistic effects
between the catalyst and acid additive (entries 5–8). Gratifyingly,
Boc-L-PheOH proved to be the best one in terms of yield and
enantioselectivity. Both Boc-L-PhgOH and Cbz-L-PheOH gave
similar results. When Boc-D-PheOH was utilized, the reaction
became sluggish and was accompanied by decreasing enantio-
selectivity. Next, a group of solvents were further assessed
(entries 9–15).10 Halogenated solvents such as dichloromethane
and chloroform gave better results than other solvents including
alcohols, ethers and alkanes. When performed in neat 2-nitropro-
pane, the reaction went to completion within 24 h with 92% ee.
Accordingly, after the above extensive screening, the optimized
system was established as 2a used in combination with Boc-
L-PheOH in chloroform.
Entry Other factors
Time (h) Yieldb (%) eec (%)
1
2
3
4
5
30 mg 4 Å molecular sieves 48
0.2 eq H2O
0.2 eq brine
1.0 eq H2O
94
88
91
83
92
96
96
96
96
96
48
48
96
48
0.2 eq TFA*Morphine
a Reactions were carried out with 0.2 mmol of 3a and 0.5 mL of 4 in
0.5 mL of CHCl3 in the presence of 20 mol% catalyst 2a and Boc-L-
PheOH with some other factors at room temperature for the specified
time. b Isolated yields. c Determined by chiral HPLC analysis.
Table 2. All these factors did not have any apparent influence on
the asymmetric catalytic process, while too much water may
slow down the reaction rate (entry 4). These results mean this
organocatalytic asymmetric conjugated addition is a robust
system with good condition-tolerance ability.
Encouraged by these preliminary results, we turned our atten-
tion to investigating the effect of different chiral diamines as the
organocatalyst and hoped to improve the enantioselectivity. The
results are listed in Table 3. On the basis of our previous work,8a
different combinations were built by employing exo-(−)-bornyl-
amine or (+)-(1S,2S,5R)-menthylamine with L or D-phenylalanine
In addition, 4 Å molecular sieves, water, brine and quaternary
ammonium salt were also evaluated. The results are given in
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(entries 1–4). Evidently, the stereoselectivity was controlled by
the absolute configuration of the phenylalanine part and the
camphor scaffold showed better chiral induction than menthone.
Meanwhile, there does exist some cooperation between the two
chiral parts, which is responsible for the excellent enantioselec-
tivity. Amide compound 1a was found to be completely inert for
the Michael addition as the amide group may be unfavorable for
the formation of iminium ion the with α,β-unsaturated ketone
(entry 5). Primary–tertiary diamine 2e only afforded moderate
enantiomeric excess (entry 6). And surprisingly, chiral secondary
diamine 2f even gave almost racemic adduct (entry 7). All these
results clearly indicate that both the primary amine and the
secondary amine motifs are pivotal for the outcome of high
efficiency and enantioselectivity. As a consequence, several com-
mercially available primary amine amino acids were employed
to construct a series of chiral primary–secondary diamines
(2g–2l). Different R substituents on the chiral primary amine
position did not make obvious differences and all these catalysts
delivered comparable results (entries 9–13). Even when R was
replaced by the much smaller methyl group which was derived
from alanine, a good ee value of 80% could be produced
(entry 8). The catalyst 2k where the N position of the indole ring
was blocked by an ethyl group, showed almost the same
efficiency as 2j (entry 12 versus 11). This phenomenon indicates
that the R substituent just serves as steric function. Finally, we
tried to decrease the catalyst loading for high catalyst loading is
always an inherent shortcoming of organocatalysis. When
15 mol% or 10 mol% catalyst 2a and Boc-L-PheOH were used,
the enantioselectivity was not influenced but a longer time was
required for the reaction to complete (entries 14–15).
Table 3 Catalyst screeninga
Entry Catalyst Acid additive
Time (h) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
1a
2e
2f
2g
2h
2i
2j
2k
2l
2a
2a
Boc-L-PheOH
Boc-D-PheOH
Boc-L-PheOH
Boc-D-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
Boc-L-PheOH
48
48
48
48
100
60
60
48
48
60
48
48
48
60
72
96
91
89
85
trace
81
82
90
93
85
91
94
90
84
82
96
−80
79
−77
ndf
50
4
80
94
93
96
95
94
95
9
10
11
12
13
14d
15e
95
a Reactions were carried out with 0.2 mmol of 3a and 0.5 mL of 4 in
0.5 mL of CHCl3 in the presence of 20 mol% catalyst and acid additive
at room temperature for the specified time. b Isolated yields.
c Determined by chiral HPLC analysis. d 15 mol% catalyst and Boc-L-
With the optimized reaction parameters in hand, the substrate
scope was probed, and the results are presented in Table 4. In
general, the electronic nature and positions of the substituent on
the aromatic ring do not exert any significant influence on the
asymmetric catalytic progress (entries 1–12). All these enones
f
PheOH was used. e 10 mol% catalyst and Boc-L-PheOH was used. Not
determined.
Table 4 Enantioselective Michael addition of nitroalkanes to various enonesa
Entry
R1
R2
Enone
Product
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-ClC6H4
4-FC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
48
48
48
48
48
48
60
48
48
60
60
48
55
80
80
96
96
96
92
93
95
90
93
88
92
94
86
90
96
93
75
68
76
61
96
96
92
93
92
94
96
90
91
95
92
94
94
91
95
95
90
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
4-MeSC6H4
2-NO2C6H4
3-NO2C6H4
3-MeOC6H4
2,4-diClC6H3
3,4-(OCH2O)C6H3
Ph
2-furyl
Ph(CH)2
Ph(CH2)2
Ph
Ph
9
10
11
12
13
14
15
16
17
2-pyridyl
a Reactions were carried out with 0.2 mmol of 3 and 0.5 mL of 4 in 0.5 mL of CHCl3 in the presence of 20 mol% catalyst 2a and Boc-L-PheOH at
room temperature for the specified time. b Isolated yields. c Determined by chiral HPLC analysis.
7620 | Org. Biomol. Chem., 2012, 10, 7618–7627
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Scheme 3 Enlarged scale reaction.
Fig. 2 Possible transition state model.
stereochemical results. We envisioned that the primary–second-
ary diamine organocatalyst acts in a bifunctional fashion. The
primary amine moiety is a well-known efficient functional group
to activate the enone though the iminium activation model.
Because of the steric repulsion from the camphor skeleton, the
rigid phenyl group of the L-phenylalanine prefers to shield the
Re face of the enone. On the other hand, the secondary amine
can effectively deprotonate the 2-nitropropane and then fix the
nucleophilic nitronate by H-bonding interaction to make it attack
the enone from the exposed Si face. Thus, the corresponding
Michael adduct was generated with S configuration. At the same
time, the acid additive may facilitate the formation of the
iminium ion and its hydrolyzation process to regenerate
the organocatalyst. This proposal was hypothesized based on the
preliminary experimental results for all the three parts: primary
amine, secondary amine and chiral acid additive were respon-
sible for the high efficiency of the asymmetric catalytic Michael
reaction. However, the exact synergistic effects between the cata-
lyst and acid additive are difficult to be determined in the cata-
lytic transformation.
Scheme 2 Further investigation of the nitroalkane substrate scope.
with a considerable degree of structural variation could undergo
the asymmetric Michael addition smoothly to afford the expected
products with useful levels of enantiocontrol (above 90% ee)
under the specified reaction conditions. Heterocyclic 2-furyl
enone 3m can be tolerated and a satisfying result was generated
(entry 13). It was noteworthy that in the case of enone 3n that
derived from cinnamaldehyde bearing two conjugated carbon–
carbon double bonds, the Michael addition occurred on the
1,4 position regioselectively (entry 14).4g,5d,g,7d,11 Moreover,
aliphatic substrate 3o and chalcones 3p, 3q, can all work well in
this system with high ee values albeit with moderate yields
(entries 15–17).
In addition, other nitroalkanes including nitromethane 6,
nitroethane 9 and 1-nitropropane 11 were investigated under the
same catalytic conditions (Scheme 2). Nitromethane 6 reacted
well with 3l and 3p, the transformation proceeding smoothly to
afford the expected products in good yield and high enantio-
selectivities. Nitroethane 9 and 1-nitropropane 11 also proved to
be good substrates to react with 3a in high yields and enantio-
selectivities albeit with poor diastereoselectivities. The low di-
astereoselectivities can be partially circumvented as both the
diastereomers can be easily separated by silica gel column
chromatography.
Finally, in order to examine the synthetic potential of this
strategy, the model reaction of 3a with 4 was performed on a
2.0 mmol scale (10 times enlarged), and the same good result
was produced without any loss of yield or enantiomeric excess
(Scheme 3). Due to its stable diamine moiety, after completion
of the reaction, the catalyst 2a could be recovered in 86% yield
by simple aqueous acid/base workup.
On the basis of the previous work reported by Jørgensen’s and
Zhao’s groups,7a,b,f a similar possible transition state model as
illustrated in Fig. 2 was proposed to account for the observed
Conclusions
In summary, starting from commercially available D-camphor
and natural amino acids, a small library of novel C1-symmetric
chiral primary–secondary diamines (2a–2l) have been success-
fully constructed with three practical protocols in moderate to
good yields. Among them, 2a as organocatalyst in combination
with acid additive Boc-L-PheOH shows high efficiency for the
asymmetric Michael addition of nitroalkanes to a wide range of
enones with high yields (up to 96%) and excellent enantio-
selectivities (up to 98%) under mild conditions. Due to its stable
diamine moiety, the chemically and optically pure catalyst 2a
could be recovered by simple aqueous acid/base workup. Further
studies of asymmetric applications of these new chiral diamines
are currently underway in our laboratory.
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reaction mixture was filtered through a pad of celite and washed
with MeOH. Then the filtrate was concentrated under reduced
pressure. The crude product was purified by column chromato-
graphy eluting with dichloromethane and methanol to afford 1a
Experimental
General methods
All the enones substrates were prepared according to the litera-
ture.12 All solvents were dried and purified prior to use. Nitro-
alkanes were dried over anhydrous CaCl2 and distilled prior to
use. Reactions were monitored by TLC analysis using silica gel
60 Å F-254 thin layer plates. Flash column chromatography was
performed on silica gel 60 Å, 10–40 μm. Optical rotations were
measured by polarimeter in the solvent indicated. Melting points
were recorded without correction. 1H NMR spectra were
recorded on instruments (400 MHz). Chemical shifts are
reported in ppm from tetramethylsilane with the solvent reson-
ance as the internal standard (CDCl3, δ = 7.26). Data are
reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad), coup-
ling constants (Hz) and integration. 13C NMR spectra were
recorded on instruments (100 MHz) with complete proton
decoupling. Chemical shifts are reported in ppm from the tetra-
methylsilane with the solvent resonance as internal standard
(CDCl3, δ = 77.0). HRMS was measured on an Apex III (7.0 T)
Fourier transform ion cyclotron resonance (FTICR) mass
spectrometer equipped with an ESI or EI source. Enantiomer
ratios were determined by chiral HPLC analysis on Daicel
Chiralcel AS-H, AD-H, OD-H and OJ-H in comparison with the
authentic racemates. Retention times are given in minutes.
The absolute configuration was assigned by comparison of the
optical rotation with literature data or by analogy to other
compounds.
as Colorless solid (2.62 g, 92% yield). m.p. 66–68 °C; [α]D20
=
−71.5 (c = 1.0 in EtOH; lit8a: [α]2D5 = −65.7, c = 0.9 in EtOH);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 0.79 (s, 3H),
0.83 (s, 3H), 0.89 (s, 3H), 1.13–1.20 (m, 1H), 1.27–1.34 (m,
1H), 1.36 (br s, 2H), 1.50–1.60 (m, 2H), 1.66–1.73 (m, 2H),
1.83 (dd, J = 13.2, 8.8 Hz, 1H), 2.68 (dd, J = 13.8, 9.4 Hz, 1H),
3.28 (dd, J = 13.8, 4.2 Hz, 1H), 3.57 (dd, J = 9.2, 4.0 Hz, 1H),
3.88 (td, J = 9.4, 5.0 Hz, 1H), 7.22–7.25 (m, 3H), 7.27–7.33 (m,
2H), 7.38–7.40 (br s, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ = 11.7, 20.0, 20.2, 27.0, 35.9, 39.0, 41.2, 44.9, 47.0,
48.4, 56.0, 56.5, 126.7, 128.6, 129.2, 138.0, 173.1; HRMS
(ESI): m/z calcd for C19H29N2O [M + H]+: 301.2275; found:
301.2272.
2a. To a stirred mixture of LiAlH4 (0.91 g, 24 mmol) in an-
hydrous THF (30 mL) was added a THF (40 mL) solution of 1a
(2.40 g, 8 mmol) at 0 °C dropwise. The mixture was warmed to
room temperature and then heated to reflux for a few hours.
After the reaction completed, saturated Na2SO4 aqueous solution
was added dropwise to quench the reaction at 0 °C. The resulting
white precipitation was removed by filtration. The filtrate was
dried over anhydrous K2CO3, and then concentrated under
reduced pressure. The crude product was purified by column
chromatography eluting with dichloromethane and methanol to
afford 2a as light yellow oil (1.56 g, 68% yield). [α]2D0 = −48.6
(c = 1.3 in EtOH; lit8a: [α]2D5 = −44.5, c = 0.9 in EtOH);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 0.80 (s, 3H),
0.88 (s, 3H), 1.02 (s, 3H), 1.04–1.08 (m, 2H), 1.32 (br s, 3H),
1.48–1.58 (m, 3H), 1.65–1.68 (m, 2H), 2.37 (dd, J = 11.6,
8.0 Hz, 1H), 2.44–2.49 (m, 2H), 2.65 (dd, J = 11.6, 4.4 Hz, 1H),
2.80 (dd, J = 13.6, 4.8 Hz, 1H), 2.98–3.05 (m, 1H), 7.19–7.22
(m, 3H), 7.28–7.31 (m, 2H); 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 12.3, 20.5, 20.6, 27.3, 36.9, 39.4, 42.8, 45.2,
46.6, 48.5, 53.1, 55.5, 67.2, 126.1, 128.4, 129.2, 139.5; HRMS
(ESI): m/z calcd for C19H31N2 [M + H]+: 287.2482; found:
287.2472.
Synthesis and characterization of the chiral diamine
organocatalysts
Exo-(−)-bornylamine and (+)-(1S,2S,5R)-menthylamine were
prepared according to our previous work.8a
General synthesis route
1a. To a stirred mixture of (S)-N-benzyloxycarbonylphenyl-
alanine (2.99 g, 10 mmol) in anhydrous dichloromethane
(40 mL), a dichloromethane (30 mL) solution of dicyclohexyl-
carbodiimide (DCC) (2.18 g, 10.5 mmol) at 0 °C was added
dropwise followed by a dichloromethane (30 mL) solution of
exo-(−)-bornylamine (1.53 g, 10 mmol). The mixture was stirred
at 0 °C for 30 minutes, and then warmed to room temperature
for another few hours. After the reaction completed, 0.5 mL
acetic acid was added and the mixture was stirred for additional
30 minutes. Insoluble dicyclohexylurea (DCU) was removed by
filtration. After removing the solvent, the residue was dissolved
in ether, and then filtered again. The filtrate was washed by satu-
rated NaHCO3 aqueous solution (2 × 50 mL) and brine (2 ×
50 mL), and the organic phase was dried over anhydrous
Na2SO4. Evaporation of the organic solvent afforded the product
as colorless oil (4.12 g, 95% yield), which was used directly in
the next steps without further purification. To a stirred solution
of the residue in MeOH (80 mL), Pd/C (0.41 g, 10% w/w) was
added and the resulting suspension was stirred under H2 atmos-
phere (1 atm.) at room temperature. After stirring overnight, the
2b. Light yellow oil (1.33 g, 62% yield). [α]2D0 = −89.1 (c =
1
1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.80 (s, 3H), 0.85 (s, 3H), 1.02 (s, 3H), 1.01–1.08 (m, 2H), 1.46
(br s, 3H), 1.52–1.54 (m, 1H), 1.55–1.56 (m, 2H), 1.67–1.68 (m,
2H), 2.36 (dd, J = 11.6, 8.8 Hz, 1H), 2.50–2.55 (m, 2H), 2.58
(dd, J = 11.6, 3.6 Hz, 1H), 2.73 (dd, J = 13.2, 5.2 Hz, 1H),
3.00–3.06 (m, 1H), 7.19–7.22 (m, 3H), 7.27–7.31 (m, 2H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 12.1, 20.5,
27.3, 36.9, 38.7, 42.5, 45.2, 46.6, 48.2, 52.7, 54.4, 66.6, 126.1,
128.3, 129.2, 139.4; HRMS (ESI): m/z calcd for C19H31N2
[M + H]+: 287.2482; found: 287.2473.
2c. Light yellow oil (1.46 g, 55% yield). [α]2D0 = +26.0 (c =
1
1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.84–0.90 (m, 12H), 1.18 (qd, J = 12.8, 3.2 Hz, 1H), 1.36 (br s,
3H), 1.49–1.57 (m, 1H), 1.61–1.72 (m, 3H), 1.89 (ddd, J = 13.4,
5.6, 3.2 Hz, 1H), 2.47–2.54 (m, 2H), 2.55 (s, 1H), 2.79 (dd, J =
13.4, 5.0 Hz, 1H), 2.86 (d, J = 3.2 Hz, 1H), 3.01–3.07 (m, 1H),
7.20–7.22 (m, 3H), 7.28–7.31 (m, 2H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 20.8, 21.4, 22.5, 24.9, 25.6, 28.9,
35.4, 38.2, 42.5, 48.4, 52.9, 53.4, 53.5, 126.1, 128.4, 129.2,
7622 | Org. Biomol. Chem., 2012, 10, 7618–7627
This journal is © The Royal Society of Chemistry 2012

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139.6; HRMS (ESI): m/z calcd for C19H33N2 [M + H]+:
289.2638; found: 289.2635.
45.2, 46.6, 48.4, 55.9, 56.7, 66.8, 126.3, 126.9, 128.3, 145.0;
HRMS (ESI): m/z calcd for C18H29N2 [M + H]+: 273.2325;
found: 273.2323.
2d. Light yellow oil (1.09 g, 60% yield). [α]2D0 = +9.5 (c = 1.0
in EtOH); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.84–0.90 (m, 12H), 1.18 (qd, J = 12.8, 3.2 Hz, 1H), 1.38 (br s,
3H), 1.49–1.57 (m, 1H), 1.61–1.72 (m, 3H), 1.89 (ddd, J = 13.4,
5.6, 3.2 Hz, 1H), 2.47–2.54 (m, 2H), 2.56 (s, 1H), 2.78 (dd, J =
13.4, 5.0 Hz, 1H), 2.86 (d, J = 3.2 Hz, 1H), 3.01–3.17 (m, 1H),
7.19–7.22 (m, 3H), 7.28–7.31 (m, 2H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 20.7, 21.4, 22.5, 24.8, 25.5, 28.9,
35.4, 38.1, 42.5, 48.3, 52.8, 53.3, 53.5, 126.1, 128.3, 129.2,
139.5; HRMS (ESI): m/z calcd for C19H33N2 [M + H]+:
289.2638; found: 289.2634.
2j. Light yellow oil (0.49 g, 45% yield). [α]2D0 = −45.0 (c =
1
1.1 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.80 (s, 3H), 0.88 (s, 3H), 1.01 (s, 3H), 0.99–1.07 (m, 2H),
1.47–1.49 (m, 1H), 1.54–1.58 (m, 2H), 1.65–1.66 (m, 2H),
1.86 (br s, 3H), 2.42 (dd, J = 11.6, 8.0 Hz, 1H), 2.49 (dd, J =
7.6, 5.6 Hz, 1H), 2.62 (dd, J = 14.2, 8.6 Hz, 1H), 2.72 (dd, J =
11.6, 4.4 Hz, 1H), 2.94 (dd, J = 14.2, 4.6 Hz, 1H), 3.10–3.15
(m, 1H), 6.98 (s, 1H), 7.07–7.11 (m, 1H), 7.14–7.18 (m, 1H),
7.32 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 8.88 (br s,
1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 12.2, 20.4,
20.5, 27.3, 31.8, 36.8, 39.4, 45.2, 46.6, 48.5, 51.9, 55.5, 67.2,
111.2, 112.8, 118.8, 119.0, 121.7, 122.6, 127.6, 136.4; HRMS
(ESI): m/z calcd for C21H32N3 [M + H]+: 326.2591; found:
326.2585.
2e. Yellow solid (0.45 g, 65% yield). m.p. 58–60 °C; [α]D20
=
+17.8 (c = 1.0 in EtOH; lit13: [α]D25 = +21, c = 1.0 in MeOH);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.68 (br s, 2H),
2.23–2.30 (m, 2H), 2.32–2.38 (m, 2H), 2.47–2.56 (m, 3H), 2.73
(dd, J = 13.4, 4.6 Hz, 1H), 3.17–3.24 (m, 1H), 3.65–3.74
(m, 4H), 7.20–7.23 (m, 3H), 7.28–7.32 (m, 2H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 42.1, 48.8, 53.9, 65.3,
67.0, 126.1, 128.3, 129.1, 139.0; HRMS (ESI): m/z calcd for
C13H21N2O [M + H]+: 221.1649; found: 221.1643.
2k. Light yellow oil (0.67 g, 46% yield). [α]2D0 = −48.8 (c =
1
1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.80 (s, 3H), 0.88 (s, 3H), 1.02 (s, 3H), 1.04–1.08 (m, 2H), 1.44
(t, J = 7.2 Hz, 3H), 1.50–1.52 (m, 1H), 1.56–1.58 (m, 2H),
1.59–1.66 (m, 2H), 1.79 (br s, 3H), 2.43 (dd, J = 11.6, 7.6 Hz,
1H), 2.50 (dd, J = 7.2, 6.0 Hz, 1H), 2.63 (dd, J = 14.2, 8.6 Hz,
1H), 2.73 (dd, J = 11.6, 4.4 Hz, 1H), 2.95 (dd, J = 14.2, 4.6 Hz,
1H), 3.10–3.17 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 6.98 (s, 1H),
7.09 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.32 (d,
J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 12.3, 15.4, 20.5, 20.6, 27.3, 31.9,
36.9, 39.3, 40.7, 45.2, 46.6, 48.5, 51.9, 55.5, 67.2, 109.2, 111.8,
118.6, 119.1, 121.4, 125.4, 128.2, 136.1; HRMS (ESI): m/z
calcd for C23H36N3 [M + H]+: 354.2904; found: 354.2897.
2l. Light yellow oil (0.52 g, 50% yield). [α]2D0 = −34.5 (c =
2f. Light yellow oil (0.99 g, 48% yield). [α]2D5 = −61.1 (c =
1
1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.80 (s, 3H), 0.87 (s, 3H), 1.02 (s, 3H), 1.04–1.08 (m, 2H),
1.28–1.37 (m, 1H), 1.45–1.56 (m, 3H), 1.65–1.74 (m, 4H),
1.81–1.89 (m, 1H), 2.11 (br s, 2H), 2.39 (dd, J = 11.4, 7.8 Hz,
1H), 2.50 (t, J = 6.6 Hz, 1H), 2.59 (dd, J = 11.4, 5.0 Hz, 1H),
2.84–2.98 (m, 2H), 3.11–3.18 (m, 1H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 12.2, 20.5, 20.6, 25.6, 27.4, 29.7,
36.9, 39.1, 45.3, 46.5, 46.7, 48.4, 53.8, 58.9, 67.1; HRMS (ESI):
m/z calcd for C15H29N2 [M + H]+: 237.2325; found: 237.2315.
2g. Light yellow oil (1.12 g, 51% yield). [α]2D5 = −51.9 (c =
1
0.9 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
1
1.1 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.80 (s, 3H), 0.88 (s, 3H), 1.01 (s, 3H), 1.03–1.08 (m, 2H),
1.47–1.66 (m, 8H), 2.35 (dd, J = 11.6, 7.8 Hz, 1H), 2.42 (dd,
J = 13.4, 8.6 Hz, 1H), 2.47 (dd, J = 7.8, 5.4 Hz, 1H), 2.64 (dd,
J = 11.6, 4.4 Hz, 1H), 2.72 (dd, J = 13.8, 4.8 Hz, 1H),
2.93–3.00 (m, 1H), 5.02 (s, 2H), 6.88–6.92 (m, 2H), 7.09–7.24
(m, 2H), 7.28–7.32 (m, 1H), 7.34–7.39 (m, 2H), 7.41–7.43 (m,
2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 12.2, 20.4,
20.5, 27.2, 36.8, 39.3, 41.6, 45.1, 46.6, 48.4, 53.1, 55.2, 67.1,
69.9, 114.7, 127.3, 127.8, 128.4, 130.0, 131.5, 137.0, 157.2;
HRMS (ESI): m/z calcd for C26H37N2O [M + H]+: 393.2901;
found: 393.2893.
0.80 (s, 3H), 0.88 (s, 3H), 1.01 (s, 3H), 1.03–1.09 (m, 5H),
1.48–1.69 (m, 9H), 2.27 (dd, J = 11.6, 8.0 Hz, 1H), 2.48 (dd,
J = 8.0, 5.2 Hz, 1H), 2.55 (dd, J = 11.8, 4.6 Hz, 1H), 2.86–2.93
(m, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 12.3,
20.5, 20.7, 21.9, 27.4, 36.9, 39.5, 45.3, 46.7, 47.2, 48.5,
57.7, 67.2; HRMS (ESI): m/z calcd for C13H27N2 [M + H]+:
211.2169; found: 211.2161.
2h. Light yellow oil (1.52 g, 56% yield). [α]2D0 = −42.4 (c =
1
1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.80 (s, 3H), 0.90 (s, 3H), 0.88–0.92 (m, 6H), 1.01 (s, 3H),
1.05–1.09 (m, 2H), 1.48–1.54 (m, 2H), 1.55–1.58 (m, 2H),
1.59–1.62 (m, 3H), 1.65–1.69 (m, 3H), 2.26 (dd, J = 11.4,
9.0 Hz, 1H), 2.46–2.53 (m, 2H), 2.65 (dd, J = 11.4, 3.8 Hz, 1H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 12.3, 17.8,
19.4, 20.4, 20.5, 27.3, 32.1, 36.9, 39.4, 45.2, 46.6, 48.5, 53.5,
57.0, 67.3; HRMS (ESI): m/z calcd for C15H31N2 [M + H]+:
239.2482; found: 239.2477.
General procedure for the catalytic Michael addition
To a mixture of enone 3 (0.2 mmol), catalyst 2a (0.04 mmol,
20 mol%) and Boc-L-PheOH (0.04 mmol, 20 mol%) in CHCl3
(0.5 mL) was added 2-nitropropane 4 (0.5 mL) under an aerobic
atmosphere, taking no precaution to exclude moisture. After 48 h
of stirring at room temperature (about 25 °C), the reaction
mixture was quenched with 1 mL 1 M aqueous HCl solution and
extracted with EtOAc three times. The combined organic layer
was dried over Na2SO4, filtered, and concentrated to afford the
corresponding Michael adduct 5 after purification by column
chromatography on silica gel, eluting with petroleum ether and
ethyl acetate.
2i. Light yellow oil (1.08 g, 63% yield). [α]2D0 = −56.7 (c =
1
1.1 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
0.79 (s, 3H), 0.83 (s, 3H), 0.97 (s, 3H), 1.01–1.04 (m, 2H),
1.46–1.51 (m, 1H), 1.54–1.59 (m, 5H), 1.65–1.69 (m, 2H),
2.50 (t, J = 6.6 Hz, 1H), 2.59 (dd, J = 11.6, 7.8 Hz, 1H), 2.79
(dd, J = 11.6, 4.4 Hz, 1H), 3.98 (dd, J = 7.8, 4.6 Hz, 1H),
7.22–7.26 (m, 1H), 7.32–7.33 (m, 4H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 12.1, 20.4, 20.5, 27.3, 36.8, 39.2,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7618–7627 | 7623

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The large scale reaction (Scheme 3) was carried out on a scale
of 2.0 mmol of 3a under identical conditions. After the reaction
completed, 1 M HCl aqueous solution was added and stirred for
a few minutes. The mixture was then extracted with EtOAc, and
the organic layers were combined, washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated to afford the
corresponding Michael adduct 5a after purification by column
chromatography on silica gel. The water layer was neutralized by
4 M NaOH aqueous solution until pH = 11 and subsequently
extracted by CH2Cl2, and the organic phase was dried over an-
hydrous Na2SO4 and evaporated under reduced pressure. The
crude recovered catalyst 2a (86% yield) was directly character-
ized by NMR, and the 1H and 13C NMR spectra are also
enclosed in the ESI.†
HPLC (Chiralcel OJ-H, hexane–isopropanol 90 : 10, 0.5 mL min−1,
UV λ = 254 nm): tR(major) = 45.26 min, tR(minor) = 42.51 min.
(S)-4-(4-Methoxyphenyl)-5-methyl-5-nitrohexan-2-one
(5e).
Colorless oil (Table 4, entry 5, 90% yield, 92% ee). [α]D20
=
−33.0 (c = 1.0 in EtOH; lit7f: [α]D22 = −22.7, c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.47 (s, 3H),
1.54 (s, 3H), 2.02 (s, 3H), 2.67 (dd, J = 16.8, 3.6 Hz, 1H), 3.04
(dd, J = 16.8, 10.8 Hz, 1H), 3.77 (s, 3H), 3.87 (dd, J = 10.8,
3.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 22.3,
25.6, 30.2, 44.1, 48.1, 55.1, 91.1, 113.8, 129.3, 130.1, 159.0,
205.3; HPLC (Chiralcel AS-H, hexane–isopropanol 90 : 10,
0.5 mL min−1, UV λ = 254 nm): tR(major) = 34.27 min, tR(minor)
=
40.64 min.
(S)-4-(4-Chlorophenyl)-5-methyl-5-nitrohexan-2-one (5a). Color-
less oil (Table 4, entry 1, 96% yield, 96% ee). [α]2D0 = −31.2 (c =
(S)-5-Methyl-4-(4-(methylthio)phenyl)-5-nitrohexan-2-one (5f).
Yellow oil (Table 4, entry 6, 93% yield, 94% ee). [α]2D0 = −29.7
1
1.0 in EtOH; lit7f: [α]D18 = −35.2, c = 1.0 in CHCl3); H NMR
1
(c = 1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS):
(400 MHz, CDCl3, 25 °C, TMS): δ = 1.48 (s, 3H), 1.54 (s, 3H),
2.04 (s, 3H), 2.74 (dd, J = 17.4, 3.4 Hz, 1H), 3.04 (dd, J = 17.4,
10.6 Hz, 1H), 3.90 (dd, J = 10.6, 3.4 Hz, 1H), 7.13 (d, J =
8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 22.6, 25.5, 30.3, 43.9, 48.1, 90.7,
128.7, 130.4, 133.7, 136.2, 204.7; HPLC (Chiralcel AS-H,
hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ = 254 nm):
δ = 1.48 (s, 3H), 1.54 (s, 3H), 2.03 (s, 3H), 2.46 (s, 3H), 2.69
(dd, J = 17.0, 3.4 Hz, 1H), 3.05 (dd, J = 16.8, 10.8 Hz, 1H),
3.88 (dd, J = 10.8, 3.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.17
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = 15.4, 22.4, 25.7, 30.3, 43.9, 48.3, 90.9, 126.3, 129.5, 134.1,
138.3, 205.0; HRMS (ESI): m/z calcd for C14H19NO3SNa
[M + Na]+: 304.0978; found: 304.0978; HPLC (Chiralcel AS-H,
hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ = 254 nm):
tR(major) = 40.63 min, tR(minor) = 49.58 min.
tR(major) = 34.87 min, tR(minor) = 29.68 min.
(S)-4-(4-Fluorophenyl)-5-methyl-5-nitrohexan-2-one (5b). Color-
less oil (Table 4, entry 2, 92% yield, 96% ee). [α]2D0 = −34.1 (c =
(S)-5-Methyl-5-nitro-4-(2-nitrophenyl)hexan-2-one (5g). Yellow
oil (Table 4, entry 7, 88% yield, 96% ee). [α]2D0 = −65.8 (c = 1.0
1
1.0 in EtOH; lit7f: [α]D22 = −32.7, c = 1.0 in CHCl3); H NMR
1
(400 MHz, CDCl3, 25 °C, TMS): δ = 1.48 (s, 3H), 1.55 (s, 3H),
2.04 (s, 3H), 2.74 (dd, J = 17.2, 3.2 Hz, 1H), 3.05 (dd, J = 17.2,
10.8 Hz, 1H), 3.92 (dd, J = 10.6, 3.4 Hz, 1H), 6.98–7.02 (m,
2H), 7.15–7.19 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ = 22.6, 25.5, 30.3, 44.0, 48.0, 90.8, 115.3, 115.5,
130.5, 130.6, 133.3, 133.4, 160.9, 163.4, 204.8; HPLC (Chiralcel
AS-H, hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ =
254 nm): tR(major) = 54.38 min, tR(minor) = 31.46 min.
in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.57
(s, 3H), 1.67 (s, 3H), 2.05 (s, 3H), 2.97–3.11 (m, 2H), 4.58 (dd,
J = 10.0, 4.0 Hz, 1H), 7.23–7.25 (m, 1H), 7.40–7.44 (m, 1H),
7.54 (td, J = 7.8, 1.2 Hz, 1H), 7.82 (dd, J = 8.4, 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 23.6, 26.5,
29.8, 41.0, 45.3, 90.6, 124.9, 128.1, 128.5, 132.6, 133.0, 151.6,
204.7; HRMS (EI): m/z calcd for C13H16N2O5 [M]+: 280.1059;
found: 280.1055; HPLC (Chiralcel AS-H, hexane–isopropanol
70 : 30, 0.5 mL min−1, UV λ = 254 nm): tR(major) = 21.42 min,
(S)-5-Methyl-5-nitro-4-(4-nitrophenyl)hexan-2-one (5c). Yellow
solid (Table 4, entry 3, 93% yield, 92% ee). m.p. 90–92 °C, lit7f:
89–91 °C; [α]2D0 = −40.1 (c = 1.0 in EtOH; lit7f: [α]2D2 = −43.0,
tR(minor) = 24.38 min.
(S)-5-Methyl-5-nitro-4-(3-nitrophenyl)hexan-2-one (5h). Color-
1
less oil (Table 4, entry 8, 92% yield, 90% ee). [α]2D0 = −31.9 (c =
c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3, 25 °C, TMS):
1
δ = 1.53 (s, 3H), 1.58 (s, 3H), 2.09 (s, 3H), 2.87 (dd, J = 18.0,
3.2 Hz, 1H), 3.12 (dd, J = 18.0, 10.4 Hz, 1H), 4.03 (dd, J =
10.6, 3.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 22.6, 25.5,
30.3, 43.9, 48.1, 90.7, 128.7, 130.4, 133.7, 136.2, 204.7; HPLC
1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
1.53 (s, 3H), 1.59 (s, 3H), 2.10 (s, 3H), 2.86 (dd, J = 17.6,
3.2 Hz, 1H), 3.15 (dd, J = 18.0, 10.8 Hz, 1H), 4.06 (dd, J =
10.4, 3.2 Hz, 1H), 7.49–7.58 (m, 2H), 8.07–8.06 (m, 1H),
8.14–8.16 (m, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = 23.1, 25.3, 31.4, 43.8, 48.1, 90.4, 123.0, 123.3, 129.6,
135.8, 140.2, 148.2, 204.2; HRMS (EI): m/z calcd for
C13H16N2O5 [M]+: 280.1059; found: 280.1054; HPLC (Chiralcel
AS-H, hexane–isopropanol 70 : 30, 0.5 mL min−1, UV λ =
254 nm): tR(major) = 31.65 min, tR(minor) = 29.11 min.
(Chiralcel AS-H, hexane–isopropanol 70 : 30, 0.5 mL min−1
UV λ = 254 nm): tR(major) = 42.22 min, tR(minor) = 31.59 min.
,
(S)-5-Methyl-5-nitro-4-p-tolylhexan-2-one (5d). Colorless oil
(Table 4, entry 4, 95% yield, 93% ee). [α]2D0 = −28.0 (c = 1.0 in
1
EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.47 (s,
3H), 1.54 (s, 3H), 2.01 (s, 3H), 2.30 (s, 3H), 2.68 (dd, J = 16.8,
3.2 Hz, 1H), 3.07 (dd, J = 16.8, 10.8 Hz, 1H), 3.89 (dd, J =
10.8, 3.6 Hz, 1H), 7.06–7.11 (m, 4H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 20.9, 22.3, 25.6, 30.2, 43.9, 48.4,
91.1, 128.9, 129.1, 134.3, 137.4, 205.2; HRMS (ESI): m/z calcd
for C14H19NO3Na [M + Na]+: 272.1257; found: 272.1252;
(S)-4-(3-Methoxyphenyl)-5-methyl-5-nitrohexan-2-one (5i).
Colorless oil (Table 4, entry 9, 94% yield, 91% ee). [α]D20
=
1
−23.3 (c = 1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.49 (s, 3H), 1.56 (s, 3H), 2.03 (s, 3H), 2.69 (dd, J =
17.0, 3.4 Hz, 1H), 3.07 (dd, J = 17.0, 10.6 Hz, 1H), 3.78 (s,
3H), 3.91 (dd, J = 10.8, 3.6 Hz, 1H), 6.77–6.81 (m, 2H),
7624 | Org. Biomol. Chem., 2012, 10, 7618–7627
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1
6.73–6.74 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 22.4, 25.8, 30.3, 44.0,
48.7, 55.1, 91.0, 112.6, 115.5, 121.4, 129.4, 139.1, 159.4, 205.0;
HRMS (ESI): m/z calcd for C14H19NO4Na [M + Na]+:
288.1206; found: 288.1202; HPLC (Chiralcel AD-H, hexane–
−11.6 (c = 0.8 in EtOH); H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.58 (s, 3H), 1.59 (s, 3H), 2.12 (s, 3H), 2.50 (dd,
J = 16.4, 3.2 Hz, 1H), 2.61 (dd, J = 16.6, 9.8 Hz, 1H), 3.44 (td,
J = 9.6, 3.2 Hz, 1H), 5.86 (dd, J = 15.8, 9.4 Hz, 1H), 6.55 (d,
J = 15.6 Hz, 1H), 7.24–7.26 (m, 1H), 7.30–7.35 (m, 4H); 13C
NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 22.8, 25.1, 30.5,
43.8, 46.8, 90.4, 125.3, 126.4, 127.9, 128.5, 135.3, 136.2,
205.1; HRMS (EI): m/z calcd for C15H19NO3 [M]+: 261.1359;
found: 261.1353; HPLC (Chiralcel AS-H, hexane–isopropanol
90 : 10, 0.5 mL min−1, UV λ = 254 nm): tR(major) = 22.15 min,
isopropanol 90 : 10, 0.5 mL min−1, UV λ = 254 nm): tR(major)
17.63 min, tR(minor) = 16.32 min.
=
(S)-4-(2,4-Dichlorophenyl)-5-methyl-5-nitrohexan-2-one (5j).
Colorless oil (Table 4, entry 10, 86% yield, 95% ee). [α]D20
=
1
−45.7 (c = 1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.53 (s, 3H), 1.59 (s, 3H), 2.05 (s, 3H), 2.89 (dd, J =
17.2, 4.0 Hz, 1H), 2.99 (dd, J = 17.2, 10.4 Hz, 1H), 4.55 (dd,
J = 10.4, 3.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.21 (dd, J =
8.4, 2.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 22.3, 26.1, 30.0, 42.8, 44.6, 90.9,
127.4, 128.8, 130.0, 134.1, 134.7, 136.8, 204.6; HRMS (EI):
m/z calcd for C13H15Cl2NO3 [M]+: 303.0424; found: 303.0421;
HPLC (Chiralcel OJ-H, hexane–isopropanol 90 : 10, 0.5 mL
t
R(minor) = 23.77 min.
(R)-4-(2-Nitropropan-2-yl)-6-phenylhexan-2-one (5o). Color-
less oil (Table 4, entry 15, 68% yield, 95% ee). [α]2D0 = −18.0
(c = 1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS):
1
δ = 1.36–1.43 (m, 1H), 1.51 (s, 3H), 1.52 (s, 3H), 1.69–1.77 (m,
1H), 2.17 (s, 3H), 2.42 (dd, J = 18.2, 6.2 Hz, 1H), 2.51–2.62 (m,
3H), 2.82–2.88 (m, 1H), 7.12–7.14 (m, 2H), 7.17–7.21 (m, 1H),
7.25–7.29 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = 23.6, 24.0, 30.0, 33.4, 34.3, 41.1, 45.0, 91.4, 126.1, 128.3,
128.4, 141.2, 206.0; HRMS (EI): m/z calcd for C15H21NO3
[M]+: 263.1516; found: 263.1512; HPLC (Chiralcel AS-H,
hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ = 254 nm):
min−1, UV λ = 254 nm): tR(major) = 38.86 min, tR(minor)
=
46.97 min.
(S)-4-(Benzo[d][1,3]dioxol-6-yl)-5-methyl-5-nitrohexan-2-one (5k).
Colorless oil (Table 4, entry 11, 90% yield, 92% ee). [α]D20
=
tR(major) = 19.38 min, tR(minor) = 18.23 min.
1
−20.5 (c = 1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.49 (s, 3H), 1.55 (s, 3H), 2.05 (s, 3H), 2.67 (dd, J =
17.0, 3.4 Hz, 1H), 3.01 (dd, J = 16.8, 10.8 Hz, 1H), 3.84 (dd,
J = 10.8, 3.6 Hz, 1H), 5.94 (s, 2H), 6.64–6.67 (m, 2H), 6.73 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ
= 22.5, 25.6, 30.3, 44.1, 48.5, 91.1, 101.1, 108.2, 109.2, 122.6,
131.1, 147.1, 147.7, 205.1; HRMS (ESI): m/z calcd for
C14H17NO5Na [M + Na]+: 302.0999; found: 302.0992; HPLC
(S)-4-Methyl-4-nitro-1,3-diphenylpentan-1-one
(5p). White
solid (Table 4, entry 16, 76% yield, 95% ee). m.p. 148–150 °C,
lit7f: 147–149 °C; [α]D20 = −75.3 (c = 1.0 in EtOH; lit7f: [α]D24
=
1
−77.5, c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.54 (s, 3H), 1.63 (s, 3H), 2.57 (dd, J = 17.2, 3.2 Hz,
1H), 3.68 (dd, J = 17.2, 10.4 Hz, 1H), 4.15 (dd, J = 10.4, 3.6
Hz, 1H), 7.21–7.29 (m, 5H), 7.42 (t, J = 3.6 Hz, 2H), 7.52–7.56
(m, 1H), 7.85–7.87 (m, 2H); 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 22.6, 26.1, 39.1, 49.0, 91.2, 127.7, 127.9,
128.4, 128.6, 129.2, 133.2, 136.6, 137.9, 196.7; HPLC (Chiral-
cel AS-H, hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ =
254 nm): tR(major) = 26.20 min, tR(minor) = 21.76 min.
(Chiralcel AS-H, hexane–isopropanol 70 : 30, 0.5 mL min−1
UV λ = 254 nm): tR(major) = 30.66 min, tR(minor) = 43.17 min.
,
(S)-5-Methyl-5-nitro-4-phenylhexan-2-one (5l). White solid
(Table 4, entry 12, 96% yield, 94% ee). m.p. 90–91 °C, lit7f:
92–94 °C; [α]2D0 = −26.2 (c = 1.0 in EtOH; lit7f: [α]2D2 = −30.9,
1
c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3, 25 °C, TMS):
(S)-4-Methyl-4-nitro-3-phenyl-1-(pyridin-2-yl)pentan-1-one (5q).
Yellow oil (Table 4, entry 17, 61% yield, 90% ee). [α]2D0 = −77.2
(c = 1.0 in EtOH); H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ = 1.48 (s, 3H), 1.55 (s, 3H), 2.03 (s, 3H), 2.71 (dd, J = 17.0,
3.4 Hz, 1H), 3.09 (dd, J = 17.0, 10.6 Hz, 1H), 3.93 (dd, J =
10.6, 3.4 Hz, 1H), 7.19–7.21 (m, 2H), 7.27–7.32 (m, 3H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 22.4, 25.7,
30.3, 44.0, 48.7, 91.0, 127.8, 128.5, 129.1, 137.5, 205.1; HPLC
1
δ = 1.53 (s, 3H), 1.68 (s, 3H), 3.31 (dd, J = 22.8, 12.0 Hz, 1H),
4.16–4.25 (m, 2H), 7.19–7.29 (m, 5H), 7.42–7.45 (m, 1H), 7.74
(td, J = 7.6, 1.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 8.66–8.67
(m, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 22.7,
25.3, 37.8, 48.7, 91.4, 121.8, 127.3, 127.5, 128.2, 129.3, 136.8,
138.0, 148.8, 152.8, 198.4; HRMS (ESI): m/z calcd for
C17H19N2O3 [M + H]+: 299.1390; found: 299.1395; HPLC
(Chiralcel OD-H, hexane–isopropanol 98 : 2, 0.5 mL min−1
UV λ = 254 nm): tR(major) = 37.09 min, tR(minor) = 39.89 min.
,
(R)-4-(Furan-2-yl)-5-methyl-5-nitrohexan-2-one (5m). Color-
less oil (Table 4, entry 13, 93% yield, 94% ee). [α]2D0 = −22.9
(c = 1.0 in EtOH; lit7f: [α]D22 = −28.3, c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.51 (s, 3H),
1.58 (s, 3H), 2.08 (s, 3H), 2.53 (dd, J = 17.0, 3.0 Hz, 1H), 3.10
(dd, J = 17.0, 11.0 Hz, 1H), 4.12 (dd, J = 11.0, 3.0 Hz, 1H),
6.18 (d, J = 3.2 Hz, 1H), 6.29–6.31 (m, 1H), 7.32–7.33 (m, 1H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 22.3, 25.6,
30.0, 42.0, 42.5, 90.4, 109.1, 110.4, 142.1, 151.1, 204.6; HPLC
(Chiralcel AD-H, hexane–isopropanol 90 : 10, 0.5 mL min−1
UV λ = 254 nm): tR(major) = 21.49 min, tR(minor) = 24.50 min.
,
(S)-5-Nitro-4-phenylpentan-2-one (7). 0.5 mL Nitromethane 6
was used instead under the same catalytic conditions described
in the general procedure. White solid (Scheme 2, eqn (1), 87%
yield, 92% ee). m.p. 113–115 °C, lit7f: 109–111 °C; [α]D20 = +2.9
(c = 1.0 in EtOH; lit7f: [α]D18 = +3.3, c = 1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 2.12 (s, 3H), 2.91 (d, J =
7.2 Hz, 2H), 4.01 (p, J = 7.2 Hz, 1H), 4.60 (dd, J = 12.4,
8.0 Hz, 1H), 4.69 (dd, J = 12.4, 6.8 Hz, 1H), 7.20–7.23 (m, 1H),
7.24–7.29 (m, 1H), 7.32–7.35 (m, 2H); 13C NMR (100 MHz,
(Chiralcel OJ-H, hexane–isopropanol 90 : 10, 0.5 mL min−1
UV λ = 254 nm): tR(major) = 41.20 min, tR(minor) = 36.94 min.
,
(S,E)-4-(2-Nitropropan-2-yl)-6-phenylhex-5-en-2-one
(5n).
Colorless oil (Table 4, entry 14, 75% yield, 91% ee). [α]D20
=
This journal is © The Royal Society of Chemistry 2012
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CDCl3, 25 °C, TMS): δ = 30.3, 39.0, 46.1, 79.4, 127.3, 127.9,
129.0, 138.8, 205.4; HPLC (Chiralcel AD-H, hexane–isopro-
0.95 (t, J = 7.4 Hz, 3 H), 1.77 (dqd, J = 14.8, 7.4, 3.6 Hz, 1H),
1.84–1.94(m, 1 H), 2.11 (s, 3H), 2.82 (dd, J = 17.6, 7.6 Hz, 1H),
2.99 (dd, J = 17.6, 6.4 Hz, 1H), 3.71 (dt, J = 7.2, 6.8 Hz, 1H),
4.67 (ddd, J = 10.6, 7.2, 3.6 Hz, 1H), 7.07–7.10 (m, 2H),
7.25–7.29 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = 10.4, 24.6, 30.6, 43.0, 45.1, 92.8, 128.8, 129.5, 133.7,
136.6, 205.2; HPLC (Chiralcel AS-H, hexane–isopropanol
90 : 10, 0.5 mL min−1, UV λ = 254 nm): tR(major) = 25.89 min,
panol 90 : 10, 0.5 mL min−1, UV λ = 254 nm): tR(major)
20.98 min, tR(minor) = 22.61 min.
=
(S)-4-Nitro-1,3-diphenylbutan-1-one (8). 0.5 mL Nitro-
methane 6 was used instead under the same catalytic conditions
described in the general procedure. White solid (Scheme 2, eqn
(2), 65% yield, 98% ee). m.p. 89–90 °C, lit5g: 87–88 °C; [α]D20
=
tR(minor) = 27.20 min.
−23.3 (c = 1.0 in EtOH; lit4g: [α]D28 = −23.2, c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.53 (s, 3H),
1.68 (s, 3H), 3.38–3.51 (m, 2H), 4.19–4.26 (m, 1H), 4.68 (dd,
J = 12.4, 8.0 Hz, 1H), 4.82 (dd, J = 12.4, 6.4 Hz, 1H),
7.25–7.28 (m, 3H), 7.31–7.35 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H),
7.54–7.59 (m, 1H), 7.89–7.92 (m, 1H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 39.2, 41.5, 79.5, 127.4, 127.8, 128.0,
128.7, 129.0, 133.5, 136.3, 139.1, 196.8; HPLC (Chiralcel
AD-H, hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ =
254 nm): tR(major) = 29.20 min, tR(minor) = 40.06 min.
Acknowledgements
This work was supported by grants from National Natural
Science Foundation of China (no. 21172082, 20872041).
The Analysis and Testing Centre of Huazhong University of
Science and Technology is acknowledged for characterization of
the new compounds.
Notes and references
4-(4-Chlorophenyl)-5-nitrohexan-2-one (10). 0.5 mL Nitroethane
9 was used instead under the same catalytic conditions described
in the general procedure. Diastereomers I and II were isolated by
silica gel column chromatography, respectively.14 Diastereomer I
(anti major): Yellow oil (Scheme 2, eqn (3), 47% yield, 94% ee).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.33 (d, J =
6.8 Hz, 3H), 2.03 (s, 3H), 2.75 (dd, J = 17.4, 4.2 Hz, 1H), 2.94
(dd, J = 17.2, 9.6 Hz, 1H), 3.71 (td, J = 9.6, 4.0 Hz, 1H), 4.74
(dq, J = 9.6, 6.8 Hz, 1H), 7.13–7.16 (m, 2H), 7.29–7.33 (m,
2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 17.6, 30.3,
44.6, 46.0, 86.7, 129.2, 129.5, 133.7, 136.8, 204.5; HPLC (Chir-
alcel AS-H, hexane–isopropanol 90 : 10, 0.5 mL min−1, UV λ =
254 nm): tR(major) = 31.88 min, tR(minor) = 38.51 min. Diastereo-
mer II (syn minor): Yellow oil (Scheme 2, eqn (3), 40% yield,
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1
93% ee). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.48
(d, J = 6.8 Hz, 3H), 2.12 (s, 3H), 2.86 (dd, J = 17.6, 7.6 Hz,
1H), 3.02 (dd, J = 18.0, 6.4 Hz, 1H), 3.70 (dt, J = 7.6, 6.4 Hz,
1H), 4.85 (apparent p, J = 6.8 Hz, 1H), 7.07–7.09 (m, 2H),
7.28–7.29 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = 16.8, 30.5, 43.9, 44.8, 85.7, 128.9, 129.5, 133.8, 136.4,
205.2; HPLC (Chiralcel AS-H, hexane–isopropanol 90 : 10,
0.5 mL min−1, UV λ = 254 nm): tR(major) = 31.53 min, tR(minor)
=
35.25 min.
4 For selected examples of asymmetric metal catalyzed conjugate additions,
see: (a) K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai and
M. Shibasaki, Tetrahedron Lett., 1998, 39, 7557; (b) G. Sundararajan and
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8933; (b) T. Bakó, P. Bakó, Á. Szöllõsy, M. Czugler, G. Keglevich and
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4-(4-Chlorophenyl)-5-nitroheptan-2-one (12). 0.5 mL 1-Nitro-
propane 11 was used instead under the same catalytic conditions
described in the general procedure. Diastereomers I and II were
isolated by silica gel column chromatography, respectively. Di-
astereomer I (anti major): Yellow oil (Scheme 2, eqn (4), 49%
1
yield). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 0.85 (t,
J = 7.4 Hz, 3 H), 1.47 (dqd, J = 14.8, 7.4, 3.2 Hz, 1H),
1.77–1.85 (m, 1 H), 2.00 (s, 3H), 2.69 (dd, J = 17.4, 3.6 Hz,
1H), 2.94 (dd, J = 17.4, 10.0 Hz, 1H), 3.69 (td, J = 10.0, 3.6 Hz,
1H), 4.55 (td, J = 10.8, 3.2 Hz, 1H), 7.14–7.16 (m, 2H),
7.30–7.32 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = 10.2, 25.4, 30.4, 43.8, 46.0, 93.9, 129.2, 129.4, 133.6,
137.1, 204.5; the ee value was not determined for the chiral
HPLC separations for the product was not fully resolved. Di-
astereomer II (syn minor): Yellow oil (Scheme 2, eqn (4), 32%
1
yield, 92% ee). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
7626 | Org. Biomol. Chem., 2012, 10, 7618–7627
This journal is © The Royal Society of Chemistry 2012

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