Asymmetric Michael addition reactions of aldehydes with nitrostyrenes catalyzed by functionalized chiral ionic liquids

Article abstract of DOI:10.1016/j.tet.2008.03.073

A new class of pyrrolidine-based functionalized chiral ionic liquids (FCILs) has been developed and shown to be effective and reusable catalysts for the asymmetric Michael addition reactions. For the Michael addition reaction involving various aldehydes a

Full text of DOI:10.1016/j.tet.2008.03.073

Tetrahedron 64 (2008) 5091–5097
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Tetrahedron
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Asymmetric Michael addition reactions of aldehydes with nitrostyrenes
catalyzed by functionalized chiral ionic liquids
*
*
Qianying Zhang, Bukuo Ni , Allan D. Headley
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of pyrrolidine-based functionalized chiral ionic liquids (FCILs) has been developed and
shown to be effective and reusable catalysts for the asymmetric Michael addition reactions. For the
Michael addition reaction involving various aldehydes and nitrostyrenes, FCIL 6, in combination with
trifluoroacetic acid as an additive, was found to be a very effective catalyst, compared to FCIL 3, which
varied slightly in structure. Excellent yields (up to 99%), good enantioselectivities (up to 85% ee), and high
diastereoselectivities (syn/anti ratio up to 97:3) were obtained for these reactions. The FCIL catalysts were
easily recycled and reused for at least five times without significantly losing their ability to affect the
outcome of the asymmetric reactions.
Received 29 February 2008
Accepted 18 March 2008
Available online 26 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Michael addition reactions of nitrostyrenes with aldehydes and
ketones have emerged as one of the most important and efficient
There has been considerable interest in the use of room tem-
perature ionic liquids (RTILs) as a new type of media for organic
synthesis,1 electrochemistry,2 material science,3 and green chem-
istry4 due to their unique properties. Most ionic liquids are ther-
mally stable over a wide temperature range, lack measurable vapor
pressure, incombustibility, and exhibit high ionic conductivity.5
One of the attractive properties of ionic liquids is their ‘tunable’
feature. Ionic liquids can be modified by varying the structure of
either the cation or the anion in order to make them easier to
separate from organic phases, as well as aqueous media. Recently,
such ionic liquids have been used as soluble supports for reagents,6
catalysts,7 and for the synthesis of small molecules8 and bio-
oligomers.9 Ionic liquids that contain tethered specialized groups
are known as functionalized ionic liquids (FILs), and they have been
used successfully to catalyze various organic reactions;7 in addition,
they are also recyclable. Recently, chiral ionic liquids that are also
FILs have been the focus of attention, especially their effect on
asymmetric reactions.10,11 To date, there are only a few of such
functionalized chiral ionic liquids (FCILs) that have been designed,
synthesized, and used effectively as catalysts for asymmetric re-
actions; these include hydrogenation reactions,11a–c the Michael
additons,11d–f aldol reactions,11g,h and borane reductions.11i This
‘designer’ feature of ionic liquids opens up new areas of research for
their design and use for asymmetric reaction.
methods for the preparation of g-nitrocarbonyl compounds. These
compounds are versatile synthetic building blocks since the nitro
and carbonyl groups can be easily transformed into other useful
functional groups.12 In recent years, research into finding simple
organocatalysts for asymmetric Michael addition reactions that do
not contain metals has intensified.13 Proline and its derivatives have
proven to be a very promising group of organocatalysts for various
reactions,14,15 and pyrrolidine catalysts have been used successfully
for direct asymmetric Michael addition reactions.15 A major draw-
back in the use of these catalysts is that they are typically used in
substantial quantity, and their efficient recovery and reuse have
become a major concern. Therefore, there is an urgent need to
develop a new group of catalysts that are easily recyclable and
possess enhanced catalytic abilities. FCILs11 that contain specific
functionalities should be ideal compounds to serve as effective
recyclable catalysts.
In our preliminary communication,11e we reported that FCIL 3
served as a recyclable catalyst for Michael addition reactions of b-
nitrostyrenes and aldehydes with good enantioselectivities (up to
82%) and high diastereoselectivities (syn/anti ratio up to 97:3) via
an enamine intermediate. Based on the mechanism proposed, the
acidic N–H of the FCIL 3 is believed to stabilize the transition state
via a hydrogen bond. Therefore, a new FCIL that is more acidic
should be a more efficient catalyst for the Michael reaction. Thus,
we have developed a new FCIL, in which the electron-withdrawing
group, the imidazolium cation, is separated from the sulfonyl group
by a methylene unit. FCIL 6, which contains a more acidic N–H as
well as more steric bulk closer to the catalytic site, should exhibit
the enhanced catalytic activity and selectivity for the Michael
* Corresponding authors.
E-mail addresses: bukuo_ni@tamu-commerce.edu (B. Ni), allan_headley@
tamu-commerce.edu (A.D. Headley).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.073

5092
Q. Zhang et al. / Tetrahedron 64 (2008) 5091–5097
Table 1
reaction. Herein, we report the results of the effect of our newly
designed catalyst, FCIL 6, on the Michael addition reaction, com-
pared to that of FCIL 3.
Optimization of the reaction conditions
Ph
O
Ph
O
catalyst 3 (20%)
solvent, 6 d
+
NO2
H
H
NO2
2. Results and discussion
(R)-7a
Yielda (%)
eeb (%)
2.1. Synthesis of the pyrrolidine-based FCILs 3 and 6
Entry
Solvent
Additive
T
1
2
3
4
5
6
7
8
MeOH
MeOH
i-PrOH
CH3CN
Neat
THF
DCM
THF
DCM
EtOAc
Et2O
CHCl3
Et2O
d
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4 8C
80
<5
62
22
22
17
34
<10
<10
<5
52
67
c
The pyrrolidine-based FCILs 3 and 6 were synthesized using the
‘chiral pool’ strategy from commercially available starting material
(S)-2-amino-1-N-Boc-pyrrolidine and sulfonyl chloride (Scheme 1).
The reaction of 3-chloropropanesulfonyl chloride with (S)-2-
amino-1-N-Boc-pyrrolidine provided 1, which was converted to
imidazolium iodide 2 in 86% overall yield via two steps involving
iodination with NaI and alkylation of the corresponding pyrrolidine
sulfonamide with 1-methylimidazole in CH3CN. The final chiral
ionic liquid 3 was obtained by deprotecting to Boc group followed
by anion exchange with NTf2 in 88% overall yield. Using a method
analogous to that for the synthesis of FCIL 3, chiral ionic liquid 6 was
obtained in 66% overall yield from (S)-2-amino-1-N-Boc-pyrroli-
dine and chloromethanesulfonyl chloride (Scheme 1). These two
FCILs are viscous liquids at room temperature. FCIL 3 was found to
be very soluble in common solvents, such as CH2Cl2, CHCl3, EtOAc,
alcohol, DMF, and DMSO, but was immiscible in Et2O and hexane.
FCIL 6 was only soluble in more polar solvents, such as alcohol,
DMF, and DMSO, and was immiscible in CH2Cl2, CHCl3, EtOAc, Et2O,
and Hexane.
5% TFA
d
66
68
74
75
d
d
d
d
77
c
5% TsOH
5% TsOH
c
c
9
10
11
12
13d
14
d
d
d
d
d
78
76
77
82
43
20
58
Et2O
a
Yield of isolated product.
Determined by chiral HPLC analysis (Chiralpak AS-H).
Not determined.
b
c
d
The reaction was carried for 7 d using 10 mol % of catalyst 3.
Table 2
Optimization of the reaction conditions for catalyst 6
Ph
O
Ph
O
catalyst 6 (20%)
+
NO2
H
H
solvent
NO2
(R)-7a
O
S
O
H
N
O
Cl
NH2
a
72%
S
Cl
+
b
Cl
N
Boc
Entry
Solvent
Additive
T
t (d)
Yielda (%)
eeb (%)
c
N
Boc
O
86%
1
2
3
4
5
6
7
8
CH3CN
MeOH
i-PrOH
DCM/MeOH
MeOH
MeOH
MeOH
MeOH
d
rt
rt
rt
rt
rt
4 ꢀ
rt
rt
6
6
6
6
3
6
6
3
<5
86
84
80
90
<10
81
80
1
O
S
O
O
S
O
d
79
79
81
+
c
+
d
N
H
Boc
N
H
N
N
N
N
d
88%
-
I-
NTf2
N
HN
5% TFA
5% TFA
10% TFA
5% AcOH
84
3
2
c
C
79
77
O
S
O
H
N
O
Cl
NH2
a
d
a
S
O
Cl
N
+
Cl
Yield of isolated product.
Determined by chiral HPLC analysis (Chiralpak AS-H).
Not determined.
N
98%
b
c
75%
Boc
Boc
4
O
S
O
O
S
+
+
c
N
N
N
N
N
N
H
H
90%
-
Cl-
5
N
NTf2
O
6
HN
catalytic amounts of an organic acid or using ethyl acetate as sol-
vent does not result in enhanced yields (entries 8–10). However,
when the less polar solvents, such as Et2O or CHCl3, are used in
conjunction with IL 3, the Michael adduct was afforded in moderate
yields (43–52%) and good enantioselectivities (76–78%) (entries 11
and 12). When the loading of catalyst 3 was minimized to 10 mol %,
the reaction only gave 20% yield (entry 13). Finally, optimal results
were obtained at a lower temperature (4 ꢀC) with 82% ee and 58%
yield using Et2O as solvent (entry 14). The absolute configuration of
7a was determined to be R, by comparing the specific rotation of 7a
with that reported elsewhere.15b
In the presence of 20 mol % FCIL 6 as catalyst, the reaction of
isobutyraldehyde with trans-b-nitrostyrene was examined under
different conditions. As can be seen from the results shown in Table
2, when using CH3CN as solvent, only a trace amount of the desired
adduct 7a was observed (entry 1); on the other hand, in the more
polar solvents MeOH and i-PrOH, FCIL 6 promoted the addition
with a good enantioselectivity of 79% and good yields of 84–86%
(entries 2 and 3). Noteworthy, catalyst 6 exhibited superior enan-
tiocontrol, compared to catalyst 3 in MeOH and i-PrOH (Table 1,
entries 1 and 3 vs Table 2, entries 2 and 3). The introduction of the
electron-withdrawing imidazolium cation in close proximity to
the NH in catalyst 6 increases the strength of hydrogen bond
Boc
Reaction conditions: (a) Et3N, CH2Cl2; (b) (1) NaI, acetone;
(2) 1-methylimidazole, CH3CN; (c) (1) CF3COOH, CH2Cl2; (2) LiNTf2,
H2O; (d) 1-methylimidazole, neat.
Scheme 1. Synthesis of pyrrolidine-based chiral ionic liquids.
2.2. Optimization of the reaction conditions
Once synthesized, FCILs 3 and 6 were tested as catalysts utilizing
the Michael reaction of isobutyraldehyde and trans-b-nitrostyrene
in various solvents, and the results are shown in Tables 1 and 2.
Using FCIL 3 as catalyst, the reaction proceeds smoothly to give the
desired Michael adduct 7a in good yields (62–80%) and enantio-
selectivities (66–67%) in polar solvents, such as MeOH and i-PrOH
(Table 1, entries 1 and 3), but the addition of 5 mol % TFA resulted in
very poor yields (entry 2). This observation indicates that the
acidity plays a role in catalytic efficiency. Using CH3CN as the sol-
vent also resulted in low yield, but similar enantioselectivity as that
obtained in MeOH (entry 4). Higher enantioselectivities (74–78%)
were observed in a solvent-free medium or in THF and CH2Cl2 as
solvents, but the yields were poor (entries 5–7). The addition of

Q. Zhang et al. / Tetrahedron 64 (2008) 5091–5097
5093
interaction in the transition state, which results in enhanced ste-
reochemical control. A solvent mixture of CH2Cl2/MeOH resulted in
a slightly enhanced enantioselectivity of 81% (Table 2, entry 4).
Interestingly, the addition of a catalytic amount of the organic acid,
TFA, dramatically increased the reaction rate, along with an im-
provement in the enantioselectivity of 84% with MeOH as the sol-
vent (Table 2, entry 5). This observation indicates that acidic
additives in the reaction accelerate the formation of the enamine
intermediate and promote the catalytic cycle. Interestingly, catalyst
3, which is similar to catalyst 6, in combination with TFA as acidic
additive provided poorer yield, compared to that obtained for
catalyst 6 (Table 2, entry 5 vs Table 1, entry 2). It was also observed
that lowering the reaction temperature to 4 ꢀC from room tem-
perature, only a trace amount of adduct 7a resulted (Table 2, entry
6). Increasing the amount of TFA or replacing to organic acid TFA
with AcOH provided no further improvement in the enantiose-
lectivity (Table 2, entries 7 and 8).
for catalyst 6 were chosen to study the scope of the Michael
reactions using a series of aldehydes and nitrostyrenes, and the
results are summarized in Tables 3 and 4. The scope of the reaction
included a variety of a,a-disubstituted aldehyde donors and nitro-
styrene acceptors, and as shown in Table 3, all a,a-disubstituted
aldehydes, except cyclohexanecarboxaldehyde, reacted efficiently
with nitrostyrenes of variable electronic characteristics in the
presence of catalyst 6 with moderate to high yields (33–90%) and
high enantioselectivities (up to 85%). Catalyst 3 however, was found
to exhibit low reactivity for the a,a-disubstituted aldehydes and
nitrostyrene acceptors except for the reaction of isobutyraldehyde
and trans-b-nitrostyrene (entry 1). From the results in Table 3,
catalyst 6 exhibits greater reactivity and selectivity, compared to
catalyst 3 for the Michael reaction of a,a-disubstituted aldehydes
and nitrostyrenes.
Table 4
Michael reactions of a-monosubstituted aldehydes to trans-nitrostyrenes catalyzed
by 3 and 6
2.3. Study of the scope of substrates
O
Ar
Ar
O
NO2
Based on the results summarized in Tables 1 and 2, the reaction
catalyst (20%)
+
R3
H
H
conditions of entry 14 (Table 1) for catalyst 3 and entry 5 (Table 2)
NO2
7
R3
Table 3
Entry
Product
Catalysta t (d) Yieldb (%) eec (%) drd (syn/anti)
Michael reactions of a,a-disubstituted aldehydes to trans-nitrostyrenes catalyzed by
3 and 6
O
O
Ph
O
1
2
3
6
6
2
70
99
54
45
91:9
94:6
O
Ar
NO2
NO2
Ar
H
H
R1
NO2
catalyst (20%)
H
+
H
7g
Ph
NO2
R1
R2
R2
7
3
4
3
6
6
2
49 (87)f
99
64
45
89:11
93:7
Entry
Product
Catalysta t (d) Yieldb (%) eec (%)
drd
(syn/anti)
n-Pr
7h
Ph
O
O
O
O
Ph
5
6
3
6
6
2
64
99
68
46
97:3
78:22
1
2
NO2
NO2
3
6
6
3
58
90
82
84
d
d
NO2
H
H
H
H
n-Bu 7i
7a
Ph
Ph
7
8
3
6
6
2
53
99
66
33
96:4
91:9
NO2
e
3
4
3
6
6
6
<10
82
d
d
85
7j
O
O
Ph
7b
e
e
e
e
9
10
3
6
6
6
<5
<5
NO2
7k
O
O
Ph
H
e
5
6
3
6
6
6
<10
54
d
NO2
NO2
t-Bu
63 (syn); 56:44
71 (anti)
H
H
C6H4-p-Me
7c
11
12
3
6
6
2
38 (90)f
98
68
44
96:4
93:7
NO2
H
Ph
n-Pr
7l
e
7
8
3
6
6
6
<10
<10
d
O
C
6H4-p-OMe
e
d
13
14
3
6
6
2
29 (85)f
91
67
44
92:8
92:8
NO2
H
7d
n-Pr
7m
C6H4-p-Me
O
O
C6H4-p-Br
e
9
10
NO2
3
6
6
6
<10
d
e
e
15
16
3
6
6
2
<5
91
NO2
H
43 (89)f
80
d
H
41
92:8
n-Pr
7e
7n
O
C6H4-p-Br
O
C6H4-o-CF3
11
12
3
6
6
6
<10
e
d
d
NO2
17
18
3
6
6
2
<5
98
e
e
33 (85)f
83
NO2
H
H
41
93:7
n-Pr
7f
7o
a
a
Reaction conditions: catalyst 3 was carried out in Et2O at 4 ꢀC, 6 was carried out
Reaction conditions: catalyst 3 was carried out in Et2O at 4 ꢀC, 6 was carried out
in MeOH at room temperature with 5% TFA.
in MeOH at room temperature with 5% TFA.
b
b
Yield of isolated product.
Yield of isolated product.
c
c
The ee values were determined by HPLC analysis on a chiral column.
The ee values were determined by HPLC analysis on a chiral column.
Determined by 1H NMR spectroscopy (400 MHz).
Determined by 1H NMR spectroscopy (400 MHz).
d
d
e
e
Not determined.
Not determined.
f
f
Yield based on recovered starting material.
Yield based on recovered starting material.

5094
Q. Zhang et al. / Tetrahedron 64 (2008) 5091–5097
Based on these results, we examined the Michael reactions, in
of the reaction. As shown in Table 5, catalysts 3 and 6 could be
recycled and reused for at least five times without significant loss of
activity.
which a variety of a-monosubstituted aldehydes and nitrostyrenes
were used in conjunction with FCIL 3 and FCIL 6/TFA catalysts, re-
spectively (Table 4). The Michael reactions involving aldehydes
with trans-b-nitrostyrene in the presence of 20 mol % of catalyst 3
in Et2O at 4 ꢀC gave the corresponding Michael adducts 7g–j in
moderate yields (49–70%), good enantioselectivities (54–68% ee),
and high diastereoselectivities (syn/anti ratio up to 97:3).16 How-
ever, in the presence of catalyst 6 with 5 mol % of TFA in MeOH,
these reactions gave Michael adducts 7g–j in nearly quantitative
yields, but the enantioselectivities are relatively low (entries 1–8).
For the reaction involving the branched aldehyde, 3,3-dime-
thylbutyraldehyde, only a trace amount of the desired adduct 7k
resulted when both catalysts 3 and 6 (entries 9 and 10), re-
spectively, are used. The reaction of substituted nitrostyrenes and
linear aldehyde n-pentanal was studied. It was observed that re-
actions involving nitrostyrenes bearing electron-donating sub-
stituents Me and MeO groups with the catalyst 3 gave the desired
adducts 7l,m with moderate yields (29–38%), good enantiose-
lectivities (67–68%), and high diastereoselectivities (syn/anti ratio
up to 96:4) (entries 11 and 13); whereas, reactions involving
nitrostyrenes bearing electron-withdrawing substituents Br and
CF3 groups with the catalyst 3 only produced a trace amount of
adducts 7l,m (entries 15 and 17). On the other hand, when catalyst
6 was used for the reactions of nitrostyrenes, bearing both electron-
donating and electron-withdrawing substituents, excellent yields
(91–98%), moderate enantioselectivities (41–44%), and high ster-
eoselectivities (syn/anti ratio up to 93:7) resulted (entries 12, 14, 16,
and 18). From the results depicted in Table 4, it can be concluded
that FCIL 6 results in higher reactivity and in a broader spectrum of
substrates than FCIL 3 in the catalysis of Michael reaction of a-
monosubstituted aldehydes and nitrostyrenes, even though lower
enantioselectivities result with FCIL 6.
Table 5
Recycling studies of FCILs 3 and 6 catalyzed Michael addition reaction between
trans-b-nitrostyrene and isobutyraldehyde under standard reaction conditions
Run
t (d)
Catalyst
Yield (%)
ee (%)
1
2
3
4
5
6
6
6
6
7
3
3
3
3
3
58
57
55
50
45
82
81
82
80
77
1
2
3
4
5
3
3
3
3
4
6
6
6
6
6
90
87
85
83
80
84
82
83
81
78
2.5. Mechanism of the reactions
Based on the results summarized in Tables 1–4, a possible
mechanism of catalysts 3 and 6 catalyzed Michael reaction of al-
dehydes with nitrostyrene should be similar to aldol reactions
catalyzed by L-proline in which the enamine intermediate is for-
med.17,13a,15k As shown in Figure 1, it is obvious that the N–H acidic
hydrogen plays an important role in the reaction by forming
hydrogen bonds to the nitrostyrene substrate in a manner that the
C–C bond formation would take place by the preferential enamine
addition to the less hindered Si-face of the nitrostyrene generating
2R,3S configuration of products (Fig. 1, mode A). For the cyclohex-
anone substrate, we speculate that the ketone-derived enamine
attacked the nitrostyrene from the less hindered Re-face to afford
the 2S,3R configuration of product due to the steric hindrance in-
duced by the ketone side chain (Fig. 1, mode B). In addition, from
FCILs 3 and 6, being bifunctional catalysts, it is expected that they
should stabilize the transition state, possibly resulting in increased
selectivity for the reaction.
The asymmetric addition of cyclohexanone to trans-b-nitro-
styrene using 3 and 6 as catalyst, respectively, was also investigated
and the results are shown in Scheme 2. It was observed that
cyclohexanone gave the desired product 8 in moderate yields (38–
40%), high enantioselectivities (88–90%), and high diaster-
eoselectivities (syn/anti up to 95:5). The absolute configuration of 8
was determined to be 2S,3R by comparison with the optical rotation
of that reported elsewhere.15k In this case, catalysts 3 and 6 showed
comparable reactivity and selectivity.
+
N
O
S
O
N
N
O
Ar
R
O
NTf2
H
H
NO2
N
O
O
H
3S
+
2R
N
O
Ph
NO2
R
O
Ar
A
Ph
NO2
catalyst (20%)
Solvent, 6 d
+
R Ar
NO2
8
+
N
O
S
O
O
N
Catalyst (additive) solvent yield(%) ee (%) dr (syn/anti)
N
O
Ar
NTf2
a
H
FCIL 3
FCIL 6 (TFA)
CH3CN 38 (88)
88
90
95/5
94/6
NO2
N
O
O
a
3R
MeOH 40 (91)
2S
N
a
Yield based on recovered starting material.
+
B
NO2
Ar
Scheme 2. The Michael addition of cyclohexanone to trans-b-nitrostyrene catalyzed
by 3 and 6.
Ar
Figure 1. Mechanism for the Michael addition using catalysts 3 and 6.
2.4. Recyclability of the FCIL catalysts
3. Conclusion
The reaction of trans-b-nitrostyrene and isobutyraldehyde un-
der standard reaction conditions was chosen as the model to ex-
amine the recyclability of catalysts FCILs 3 and 6. After the reaction
was completed, the reaction mixture was concentrated and the
residue extracted twice with ether. Removal of the solvent and
purification by chromatography column gave the Michael adduct
7a. Since catalysts 3 and 6 were insoluble in ether, they could be
easily isolated. Each catalyst was dried and reused for the next run
A new class of recyclable pyrrolidine-based functionalized chiral
ionic liquids (FCILs) has been developed for the asymmetric
Michael addition reactions. These catalysts result in high yields (up
to 99%), good enantioselectivities (up to 85%), and high diastereo-
selectivities (syn/anti ratio up to 97:3). FCIL 6, in combination with
trifluoroacetic acid as additive, was found to be more effective than
FCIL 3 in influencing the enantioselective outcome of the Michael

Q. Zhang et al. / Tetrahedron 64 (2008) 5091–5097
5095
addition reactions of a,a-disubstituted aldehydes and nitrostyrenes
to provide the Michael adducts with one quaternary carbon center.
On the other hand, FCIL 3 was found to be superior in enantiose-
lectivities for reactions involving a-monosubstituted aldehydes,
while FCIL 6 was observed to be more effective because of the
higher yields and reactivity. These FCIL catalysts were easily recy-
cled and reused up to five times without significant loss of their
ability to influence the reactivities and enantioselectivities of the
Michael reactions.
steps). [a]2D0 þ0.42 (c 0.71, MeOH); 1H NMR (400 MHz, CD3OD)
d 8.85 (s, 1H), 7.62 (t, J¼1.6 Hz, 1H), 7.57 (t, J¼1.6 Hz, 1H), 4.40 (t,
J¼7.2 Hz, 2H), 3.93 (s, 3H), 3.72–3.65 (m, 1H), 3.45 (dd, J¼15.2 and
4.4 Hz,1H), 3.40–3.25 (m, 3H), 3.21 (t, J¼7.2 Hz, 2H), 2.38 (dt, J¼14.4
and 7.2 Hz, 2H), 2.23–2.00 (m, 3H), 1.80–1.70 (m, 1H); 13C NMR
(100 MHz, CD3OD) d 138.1, 125.3, 123.6, 121.2 (q, J¼319.2 Hz, 2C),
62.0, 46.6, 44.6, 44.3, 36.6, 28.1, 25.6, 23.9; IR (neat) n¼1568, 1347,
1187, 1133, 1056 cmꢁ1
;
HRMS (ESI þ) m/z (%) calcd for
[C12H23N4OS]þ: 287.1542, found: 287.1536; HRMS (ESIꢁ) m/z (%)
calcd for [N(SO2CF3)2]ꢁ: 279.9173, found: 279.9202.
4. Experimental section
4.4. Synthesis of compound 4
4.1. Synthesis of compound 1
N-Boc-(S)-2-aminomethylpyrrolidine (0.5 g, 2.5 mmol) and
Et3N (0.46 mL, 3.3 mmol) in CH2Cl2 (15 mL) were reacted with 3-
Chloromethanesulfonyl chloride (0.45 g, 3.0 mmol) according to
the procedure described for the preparation of 1 to give product 4
(0.77 g, 98%) as a white solid. Mp: 86–88 ꢀC; [a]D20 ꢁ31.0 (c 1.15,
CH2Cl2); 1H NMR (400 MHz, CDCl3) d 6.87–6.75 (br, 1H), 4.49 (s,
2H), 4.17–3.96 (m, 1H), 3.50–3.17 (m, 4H), 2.12–2.02 (m, 1H), 1.92–
1.80 (m, 3H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) d 156.6, 80.5,
57.0, 55.2, 49.5, 47.3, 29.6, 28.4, 23.9; IR (neat) n¼1645, 1414,
1159 cmꢁ1; HRMS (ESI) m/z (%) calcd for C11H21ClN2O4S (MNaþ):
335.0803, found: 335.0813.
To a solution of N-Boc-(S)-2-aminomethylpyrrolidine (1.00 g,
5.0 mmol) in CH2Cl2 (20 mL) was added Et3N (0.7 mL, 5.5 mmol),
the solution was cooled to 0 ꢀC and 3-chloropropanesulfonyl
chloride (0.89 g, 5.0 mmol) was added. Following the addition, the
reaction mixture was warmed to room temperature while stirring
for 17 h. The solution was diluted with CH2Cl2 (60 mL) and washed
with 0.5 M HCl (15 mL), saturated aqueous NaHCO3 (15 mL), and
then brine (15 mL); the organic phase was dried with Na2SO4 and
purified by flash chromatography on silica gel (hexane/ethyl
acetate¼2:1) to afford the product 1 (1.22 g, 72%). [a]2D0 ꢁ24.4
(c 0.55, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 6.33–6.18 (br, 1H),
4.02–3.85 (br, 1H), 3.66 (t, J¼6.0 Hz, 2H), 3.50–3.05 (m, 6H), 2.35–
2.20 (m, 2H), 2.08–1.97 (m, 1H), 1.92–1.76 (m, 2H), 1.74–1.62 (m,
1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d 156.5, 80.4, 57.0, 49.1,
48.5, 47.3, 42.9, 29.5, 28.4, 26.9, 23.8; IR (neat) n¼2976, 1670, 1397,
1148, 1111 cmꢁ1; HRMS (ESI) m/z (%) calcd for C13H26ClN2O4S
(MHþ): 341.1296, found: 341.1286.
4.5. Synthesis of compound 5
To a solution of compound 4 (2.4 g, 7.58 mmol) and 1-methyl-
imidazole (0.62 g, 7.58 mmol) in toluene (2 mL), which was
refluxed under N2 for 3 d, was added ethyl acetate to precipitate the
solid, which was collected to give the compound 5 (2.24 g, 75%). 1H
NMR (400 MHz, CD3OD) d 9.16 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 5.59
(s, 2H), 3.99 (s, 3H), 3.87–3.78 (br, 1H), 3.37–3.24 (m, 3H), 3.08 (dd,
J¼13.6 and 7.6 Hz, 1H), 2.00–1.70 (m, 4H), 1.45 (s, 9H). This com-
pound was used for the next step without further characterization.
4.2. Synthesis of compound 2
To a solution of compound 1 (1.22 g, 3.58 mmol) in acetone
(15 mL), NaI (5.3 g, 35.3 mmol) was added under N2 atmosphere.
The reaction mixture was stirred at reflux for 24 h and the solvent
removed; the concentrate was diluted with CH2Cl2 (60 mL) then
washed with water followed by brine. The organic phase was dried
over Na2SO4, filtrated, and concentrated to give the crude iodine
product (1.45 g, 96%), which was used for the next step directly
without further characterization.
The above iodine compound (1.45 g, 3.36 mmol) and 1-meth-
ylimidazole (0.30 g, 3.69 mmol) were dissolved in CH3CN (2 mL)
and the solution was stirred for 14 h at 65 ꢀC, followed by removal
of the solvent under reduced pressure. The residue was washed
with Et2O (2ꢂ5 mL) and dried to give the compound 2 (1.55 g, 90%).
1H NMR (400 MHz, CD3OD) d 9.01 (s, 1H), 7.69 (d, J¼1.6 Hz,1H), 7.59
(d, J¼1.6 Hz, 1H), 4.43 (t, J¼7.2 Hz, 2H), 3.94 (s, 3H), 3.87–3.79 (m,
1H), 3.37–3.23 (m, 3H), 3.15 (t, J¼7.2 Hz, 2H), 3.11–3.02 (m,1H), 2.36
(dt, J¼14.4 and 7.2 Hz, 2H), 2.00–1.77 (m, 4H), 1.45 (s, 9H); 13C NMR
(100 MHz, CD3OD) d 156.7, 156.3,138.0,125.2,123.6, 81.2, 80.9, 58.8,
58.5, 45.9, 36.9, 29.6, 29.2, 28.8, 25.9, 24.4, 23.6. This compound
was used for the next step without further characterization.
4.6. Synthesis of compound 6
Compound 5 (2.24 g, 5.69 mmol) reacted with 1:1 mixture of
trifluoroacetic acid and dichloromethane (20 mL) according to the
procedure described for the preparation of 3 to give product 6
(2.80 g, 90% for two steps). [a]2D0 ꢁ2.88 (c 1.25, MeOH); 1H NMR
(400 MHz, CD3OD) d 8.95 (s, 1H), 7.69 (d, J¼2.0 Hz, 1H), 7.66 (d,
J¼2.0 Hz, 1H), 5.64 (s, 2H), 3.98 (s, 3H), 3.68–3.60 (m, 1H), 3.50 (dd,
J¼15.2 and 4.4 Hz, 1H), 3.42–3.23 (m, 3H), 2.23–2.14 (m, 1H), 2.10–
1.98 (m, 2H), 1.77–1.66 (m, 1H); 13C NMR (100 MHz, CD3OD) d 138.1,
125.4, 124.9, 121.1 (q, J¼319.3 Hz, 2C), 63.6, 62.0, 46.7, 44.5, 37.0,
28.2, 23.7; IR (neat) n¼1346, 1187, 1054 cmꢁ1; HRMS (ESIþ) m/z (%)
calcd for [C10H19N4OS]þ: 259.1229, found: 259.1222; HRMS (ESIꢁ)
m/z (%) calcd for [N(SO2CF3)2]ꢁ: 279.9173, found: 279.9179.
4.7. Typical experimental procedure for Michael addition
reaction. Synthesis of (R)-2,2-dimethyl-4-
nitrophenylbutanal 7a15b
4.3. Synthesis of compound 3
To a solution of catalyst FCIL 6 (23 mg, 0.04 mmol) in MeOH
(1 mL) were added trifluoroacetic acid solution of MeOH (16 mL,
14 mL/mg, 5 mol %) and isobutyraldehyde (87 mg, 1.2 mmol). After
stirring for 10 min at room temperature, and trans-b-nitrostyrene
(30 mg, 0.2 mmol) was added and the reaction mixture was stirred
at room temperature for 3 d. The reaction mixture was concen-
trated and the residue was extracted with ether for two times.
Removal of the solvent and purification by silica gel column (elu-
ent: hexane/ethyl acetate¼4:1) gave the Michael adduct (40 mg,
90%) as a colorless oil. The residue was ether insoluble catalyst FCIL
6, which was dried under vacuum for 1 h and used directly for the
Compound 2 (1.55 g, 3.02 mmol) was dissolved in a 1:1 mixture
of trifluoroacetic acid and dichloromethane (10 mL) and the solu-
tion was stirred for 2 h at room temperature, at which time the
solvent was evaporated under reduced pressure. The pH was ad-
justed to 8 with aqueous NaHCO3, and LiNTf2 (0.87 g, 3.02 mmol)
was added and the mixture was stirred for 1 h at room tempera-
ture, extracted with CH2Cl2 (3ꢂ20 mL) and the organic phase was
dried over NaSO4 and purified by flash chromatography on silica gel
(CH2Cl2/MeOH¼10:1) to afford the product 3 (1.51 g, 88% for two

5096
Q. Zhang et al. / Tetrahedron 64 (2008) 5091–5097
next run. [a]2D0 ꢁ15.0 (c 0.01, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 9.50 (s, 1H), 7.40–7.15 (m, 5H), 4.83 (dd, J¼13.0 and 11.4 Hz, 1H),
4.67 (dd, J¼13.0 and 4.0 Hz,1H), 3.76 (dd, J¼11.4 and 4.0 Hz,1H),1.11
(s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) d 204.2, 135.3, 129.0,
128.7, 128.1, 76.3, 48.4, 48.2, 21.6, 18.8; HPLC (Chiralpak AS-H,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 203.2, 137.8, 129.1,
128.2, 128.1, 128.0, 78.4, 53.8, 43.2, 29.5, 19.8, 13.9; HPLC (Chiralcel
OD-H, i-propanol/hexane¼20:80, flow rate 1 mL/min, l¼254 nm):
tminor¼11.9 min, tmajor¼15.5 min; ee¼64%.
i-propanol/hexane¼5:95, flow rate 0.5 mL/min, l¼238 nm): tminor
¼
4.14. (R)-2-[(S)-2-Nitro-1-phenylethyl]hexanal 7i14i
33.1 min, tmajor¼34.5 min; ee¼84%.
[a]2D0 ꢁ5.5 (c 0.22, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.69 (d,
J¼2.8 Hz, 1H), 7.38–7.15 (m, 5H), 4.73–4.62 (m, 2H), 3.78 (dt, J¼9.6
and 5.2 Hz, 1H), 2.73–2.67 (m, 1H), 1.53–1.11 (m, 6H), 0.78 (t,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 203.2,136.8,129.1,128.1,
128.0, 78.4, 53.9, 43.1, 28.5, 27.0, 22.4, 13.6; HPLC (Chiralcel OD-H, i-
4.8. 1-((R)-2-Nitro-1-phenylethyl)cyclopentanecarb-
aldehyde 7b15d
[a]2D0 ꢁ12.7 (c 0.28, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.49 (s,
1H), 7.33–7.19 (m, 5H), 4.96 (dd, J¼13.8 and 11.6 Hz, 1H), 4.70 (dd,
J¼13.8 and 3.2 Hz, 1H), 3.71 (dd, J¼11.2 and 3.6 Hz, 1H), 2.10–2.00
(m, 1H), 1.94–1.84 (m, 1H), 1.74–1.40 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 204.4, 136.3, 128.8, 128.1, 60.2, 49.3, 32.6, 31.5, 24.8, 24.6;
HPLC (Chiralcel OD-H, i-propanol/hexane¼20:89, flow rate 1 mL/
min, l¼254 nm): tminor¼14.7 min, tmajor¼10.7 min; ee¼85%.
propanol/hexane¼15:85, flow rate 1 mL/min, l¼254 nm): tminor
¼
12.8 min, tmajor¼16.0 min; ee¼68%.
4.15. (2R,3S)-2-(Methylethyl)-4-nitro-3-phenylbutanal 7j14i
[a]2D0 þ32.7 (c 0.15, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.93 (d,
J¼2.4 Hz, 1H), 7.40–7.13 (m, 5H), 4.70–4.53 (m, 2H), 3.90 (dt, J¼10.4
and 4.4 Hz, 1H), 2.80–2.73 (m, 1H), 1.75–1.67 (m, 1H), 1.10 (d,
J¼7.2 Hz, 3H), 0.89 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 204.3, 137.1, 129.1, 128.1, 127.9, 79.0, 58.8, 41.9, 27.9, 21.6, 17.0;
HPLC (Chiralpak AS-H, i-propanol/hexane¼5/95, flow rate 0.5 mL/
min, l¼254 nm): tminor¼30.3 min, tmajor¼31.8 min; ee¼66%.
4.9. (2R,3S)-2-Ethyl-2-methyl-4-nitro-3-phenylbutanal 7c15b
[a]2D0 þ4.0 (c 0.15, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.54
(syn) and 9.52 (anti) (s, 1H), 7.38–7.27 (m, 3H), 7.24–7.15 (m, 2H),
4.90–4.60 (m, 2H), 3.78 (dt, J¼11.2 and 4.0 Hz, 1H), 1.78–1.24 (m,
2H), 1.11 (s, 3H), 0.89 (anti) and 0.82 (syn) (t, J¼7.2 Hz, 3H); HPLC
(Chiralcel OD-H, i-propanol/hexane¼10:90, flow rate 1 mL/min,
4.16. (R)-2-[(S)-1-(4-Methylphenyl)-2-nitroethyl]-
l¼254 nm): tmajor¼13.4 min (anti), tmajor¼15.9 min (syn), tminor
¼
pentanal 7l11e
17.5 min (anti), tminor¼23.8 min (syn); ee¼63% (syn), ee¼71% (anti).
4.10. (R)-2,2-Dimethyl-4-nitro-3-p-tolylbutanal 7e15k
[a]2D0 þ41.8 (c 0.11, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.69 (d,
J¼2.8 Hz, 1H), 7.14 (d, J¼8.0 Hz, 2H), 7.05 (d, J¼8.0 Hz, 2H), 4.68 (dd,
J¼12.8 and 5.6 Hz, 1H), 4.61 (d, J¼12.8 and 9.6 Hz, 1H), 3.73 (dt, J¼
9.6 and 5.2 Hz, 1H), 2.70–2.64 (m, 1H), 2.33 (s, 3H), 1.60–1.10 (m,
4H), 0.81 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 203.4,
137.9, 133.6, 129.8, 127.8, 78.5, 53.9, 42.9, 29.4, 21.1, 19.8, 13.9; HPLC
(Chiralcel OD-H, i-propanol/hexane¼20:80, flow rate 1 mL/min,
l¼254 nm): tminor¼10.4 min, tmajor¼12.6 min; ee¼68%.
Mp: 54–56 ꢀC; [a]D20 þ1.7 (c 0.18, CH2Cl2); 1H NMR (400 MHz,
CDCl3) d 9.53 (s, 1H), 7.13 (d, J¼8.0 Hz, 2H), 7.08 (d, J¼8.0 Hz, 2H),
4.83 (dd, J¼13.2 and 11.6 Hz, 1H), 4.67 (dd, J¼13.2 and 4.4 Hz, 1H),
3.74 (dd, J¼10.8 and 4.0 Hz,1H), 2.32 (s, 3H),1.13 (s, 3H),1.01 (s, 3H);
13C NMR (100 MHz, CDCl3) d 204.4, 137.9, 132.1, 129.4, 128.9, 76.4,
48.2, 21.6, 21.0, 18.9; HPLC (Chiralcel OD-H, i-propanol/
hexane¼20:80, flow rate 1 mL/min, l¼254 nm): tminor¼14.1 min,
tmajor¼10.1 min; ee¼80%.
4.17. (R)-2-[(S)-1-(4-Methoxyphenyl)-2-nitroethyl]-
pentanal 7m15j
4.11. (3S)-(4-Bromo-phenyl)-2,2-dimethyl-4-nitro-
[a]2D0 þ29.2 (c 0.12, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.70 (d,
J¼2.8 Hz, 1H), 7.08 (d, J¼8.8 Hz, 2H), 6.87 (d, J¼8.8 Hz, 2H), 4.70–
4.55 (m, 2H), 3.80–3.69 (m, 1H), 2.70–2.60 (m, 1H), 1.60–1.10 (m,
4H), 0.81 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 203.4,159.3,
129.0, 128.5, 114.5, 78.6, 55.2, 54.0, 42.5, 29.4, 19.8, 13.9; HPLC
(Chiralcel OD-H, i-propanol/hexane¼10:90, flow rate 1 mL/min,
l¼254 nm): tminor¼20.5 min, tmajor¼22.4 min; ee¼67%.
butanal 7f18
[a]2D0 þ11.4 (c 0.09, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.50 (s,
1H), 7.48 (d, J¼2.0 Hz, 2H), 7.46 (d, J¼2.0 Hz, 2H), 4.82 (dd, J¼13.2
and 11.2 Hz, 1H), 4.67 (dd, J¼13.2 and 4 Hz, 1H), 3.75 (dd, J¼11.2 and
4.0 Hz, 1H), 1.12 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 203.8, 134.5, 131.9, 130.7, 122.3, 76.1, 48.1, 48.0, 21.8, 18.9; HPLC
(Chiralpak AS-H, i-propanol/hexane¼10:90, flow rate 0.7 mL/min,
l¼220 nm): tminor¼21.4 min, tmajor¼23.1 min; ee¼83%.
4.18. (R)-2-[(S)-1-(4-Bromophenyl)-2-nitroethyl]pentanal 7n
[a]2D0 þ3.47 (c 0.38, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.70 (d,
J¼2.4 Hz,1H), 7.48 (d, J¼6.8 Hz, 2H), 7.07 (d, J¼6.8 Hz, 2H), 4.72–4.58
(m, 2H), 3.75 (dt, J¼10.0 and 5.2 Hz,1H), 2.72–2.66 (m,1H),1.52–1.14
(m, 4H), 0.82 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 202.7,
135.9, 132.3, 129.7, 122.1, 78.1, 53.5, 42.5, 29.5, 19.7, 13.9; HRMS (ESI)
m/z (%) calcd for [C13H16BrNO3þHþ]: 314.0386, found: 314.0372;
HPLC (Chiralcel OD-H, i-propanol/hexane¼10:90, flow rate 1 mL/
min, l¼254 nm): tminor¼20.1 min, tmajor¼21.8 min; ee¼44%.
4.12. (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal 7g14i
[a]2D0 ꢁ2.7 (c 0.47, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.71 (s,
1H), 7.36–7.15 (m, 5H), 4.80 (dd, J¼12.8 and 5.6 Hz, 1H), 4.68 (dd,
J¼12.8 and 9.2 Hz,1H), 3.81 (dt, J¼9.2 and 5.6 Hz,1H), 2.81–2.73 (m,
1H), 1.00 (d, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 202.2,
136.5,129.1,128.1,128.0, 78.1, 48.4, 44.0,12.1; HPLC (Chiralcel OD-H,
i-propanol/hexane¼9:91, flow rate 1 mL/min, l¼237 nm): tminor
¼
24.5 min, tmajor¼33.4 min; ee¼45%.
4.19. (R)-2-[(S)-1-(2-Trifluoromethylphenyl)-2-
nitroethyl]pentanal 7o15k
4.13. (R)-2-[(S)-2-Nitro-1-phenylethyl]pentanal 7h15d
[a]2D0 þ7.7 (c 0.71, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.76
(d, J¼2.8 Hz, 1H), 7.73 (d, J¼7.6 Hz, 1H), 7.59 (d, J¼8.0 Hz, 1H), 7.44
(t, J¼7.6 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H), 4.83–4.73 (m, 1H), 4.65
(dd, J¼13.2 and 5.2 Hz, 1H), 4.19–4.14 (m, 1H), 2.97–2.92 (m, 1H),
[a]2D0 ꢁ13.3 (c 0.15, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 9.70 (d,
J¼2.8 Hz, 1H), 7.38–7.15 (m, 5H), 4.75–4.61 (m, 2H), 3.77 (dt, J¼9.6
and 4.2 Hz, 1H), 2.75–2.67 (m, 1H), 1.53–1.10 (m, 4H), 0.80 (t,

Q. Zhang et al. / Tetrahedron 64 (2008) 5091–5097
5097
1.62–1.18 (m, 4H), 0.82 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 203.0, 136.3, 132.6, 129.4 (q), 128.0, 126.9, 125.4, 122.7, 77.8, 54.0,
38.6, 30.3, 20.1, 13.9; HPLC (Chiralcel OD-H, i-propanol/hexane¼
9. (a) Peptides: Miao, W.; Chan, T. H. J. Org. Chem. 2005, 70, 3251; (b) Oligosac-
charides: He, X.; Chan, T. H. Synthesis 2006, 1645; (c) Oligonucleotides: Donga,
R. A.; Khaliq-Uz-Zaman, S. M.; Chan, T. H.; Damha, M. J. J. Org. Chem. 2006, 71,
7907; (d) He, X.; Chan, T. H. Org. Lett. 2007, 9, 2681.
10. For reviews, see: (a) Headley, A. D.; Ni, B. Aldrichimica Acta 2007, 40, 107; (b)
Miao, W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897; (c) Ding, J.; Armstrong, D. W.
20:80, flow rate 1 mL/min, l¼254 nm): tminor¼10.1 min, tmajor
¼
8.9 min; ee¼41%.
´
Chirality 2005, 17, 281; (d) Baudequin, C.; Bregeon, D.; Levillain, J.; Guillen, F.;
Plaqueventa, J.-C.; Gaumontb, A.-C. Tetrahedron: Asymmetry 2005, 16, 3921.
11. (a) Kawasaki, I.; Tsunoda, K.; Tsuji, T.; Yamaguchi, T.; Shibuta, H.; Uchida, N.;
Yamashita, M.; Ohta, S. Chem. Commun. 2005, 2134; (b) Lee, A.; Zhang, Y.; Piao,
J.; Yoon, H.; Song, C.; Choi, J.; Hong, J. Chem. Commun. 2003, 2624; (c) Geldbach,
T.; Dyson, P. J. Am. Chem. Soc. 2004, 126, 8114; (d) Luo, S.; Mi, X.; Zhang, L.; Liu,
S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093; (e) Ni, B.; Zhang, Q.;
Headley, A. D. Green Chem. 2007, 9, 737; (f) Ni, B.; Zhang, Q.; Headley, A. D.
Tetrahedron Lett. 2008, 49, 1249; (g) Miao, W.; Chan, T. H. Adv. Synth. Catal. 2006,
348, 1711; (h) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Tetrahedron
2007, 63, 1923; (i) Yang, S.-D.; Shi, Y.; Sun, Z.-H.; Zhao, Y.-B.; Liang, Y.-M.
Tetrahedron: Asymmetry 2006, 17, 1895.
4.20. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone 815k
[a]2D0 ꢁ28.0 (c 0.05, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.34–
7.23 (m, 3H), 7.17 (d, J¼6.8 Hz, 2H), 4.94 (dd, J¼12.4 and 4.4 Hz, 1H),
4.63 (dd, J¼12.4 and 10.0 Hz, 1H), 3.76 (dt, J¼10.0 and 4.8 Hz, 1H),
2.72–2.65 (m, 1H), 2.52–2.34 (m, 2H), 2.13–2.04 (m, 1H), 1.83–1.50
(m, 4H), 1.30–1.18 (m, 1H); 13C NMR (100 MHz, CDCl3) d 211.9, 137.7,
128.9, 128.2, 127.8, 78.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0; HPLC
(Chiralpak AS-H, i-propanol/hexane¼10:90, flow rate 0.7 mL/min,
l¼238 nm): tminor¼22.8 min, tmajor¼34.5 min; ee¼88%.
12. For recent reviews, see: (a) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171;
(b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877; (c) Sibi,
M. P.; Manyem, S. Tetrahedron 2000, 56, 8033; (d) Christoffers, J.; Baro, A.
Angew. Chem., Int. Ed. 2003, 42, 1688.
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16. For the Michael reaction of aliphatic nitroolefin 1-nitro-1-cyclohexene with
n-pentanal using FCIL 3 as catalyst under standard reaction conditions for 7 d,
the TLC showed that less than 10% yield of product was formed.
Acknowledgements
We are grateful to the Robert A. Welch Foundation (T-1460) for
financial support of this research.
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