A highly efficient asymmetric Michael addition of anthrone to nitroalkenes with cinchona organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2007.06.107

A highly efficient asymmetric Michael addition of anthrone to nitroalkenes catalyzed by cinchona alkaloids was described. Up to 99% ee of the corresponding adduct was obtained.

Full text of DOI:10.1016/j.tetlet.2007.06.107

Tetrahedron Letters 48 (2007) 5743–5746
A highly efficient asymmetric Michael addition of anthrone
to nitroalkenes with cinchona organocatalysts
a,b,
a
a
a
*
Min Shi,
Zhi-Yu Lei, Mei-Xin Zhao and Jing-Wen Shi
a
School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
54 Fenglin Road, Shanghai 200032, China
3
Received 15 May 2007; revised 15 June 2007; accepted 19 June 2007
Available online 24 June 2007
Abstract—A highly efficient asymmetric Michael addition of anthrone to nitroalkenes catalyzed by cinchona alkaloids was
described. Up to 99% ee of the corresponding adduct was obtained.
Ó 2007 Elsevier Ltd. All rights reserved.
Cinchona alkaloids have long been known as very useful
and robust catalysts for many kinds of organic reactions
before the recent explosion of ‘organocatalysis’.
Anthrone usually functions as a reactive diene in the
presence of base and a variety of dienophiles, furnishing
the corresponding Diels–Alder reaction products in
1
1
0
Although the first example of asymmetric reaction cata-
good yields rather than the Michael addition adducts.
Only in few cases the corresponding Michael adducts
2
lyzed by cinchona alkaloids can be dated back to 1912,
1
1
only after 1960s, with the development of asymmetric
were isolated as by-products in Diels–Alder reactions.
3
phase transfer catalysts (chiral PTC), and asymmetric
On the other hand, nitroalkenes, as a reactive Michael
acceptor, can be transformed into a variety of function-
alities due to the strongly electron-withdrawing nitro
group, which is seldom used in the Diels–Alder reaction
as a dienophile, although few examples have been
reported using nitroalkenes as dienophiles in the Diels–
4
dihydroxylation by Sharpless, cinchona organocata-
lysts have drawn much more attention and have been
widely used in a variety of asymmetric reactions.
As a unique class of bifunctional cinchona organocata-
lysts, cupreines and cupreidines have been proved to
be powerful chiral catalysts for a wide array of asym-
1
2
Alder reactions. Therefore, we envisioned that the
reaction of anthrone with nitroalkenes, reactive Michael
acceptors, could exclusively produce the corresponding
Michael addition products in the presence of bifunc-
tional cinchona organocatalysts. In fact, we found that
the asymmetric Michael addition of anthrone to nitro-
alkenes could be achieved in good yields and ee’s in
the presence of cinchona organocatalysts. To the best
of our knowledge, this is the first report on the asymmet-
ric Michael addition of anthrone to nitroalkenes. Here-
in, we wish to report our preliminary results.
5
metric transformations only shortly after their first
application in the Baylis–Hillman reaction in 1999.6a
Compared to the previous traditional cinchona cata-
lysts, one of the most noticeable features of cupreines
and cupreidines is that they bear a phenolic OH group
0
at C -6 position, and a free hydroxy moiety at C-9 posi-
tion, which can be utilized to tune the steric conforma-
tion by further functionalization to achieve higher
efficiency in asymmetric reactions. Thus far, these dual
organocatalysts have been successfully applied in the
6
7
Baylis–Hillman reaction, conjugate addition, electro-
Initial examinations using anthrone 1a as a substrate
and nitroalkene 2a as a Michael acceptor for the asym-
metric Michael addition in the presence of a variety of
cinchona organocatalysts were aimed at determining
the optimal conditions and the results of these
experiments are summarized in Table 1. Using quinine
(Q) (10 mol %) as the catalyst in CH Cl at 20 °C, the
8
9
philic amination, and nitroaldol reaction.
Keywords: Michael addition; Nitroalkenes; Anthrone; Cinchona
alkaloids.
*
Corresponding author. Fax: +86 21 64166128; e-mail: mshi@mail.
sioc.ac.cn
2
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.107

5744
M. Shi et al. / Tetrahedron Letters 48 (2007) 5743–5746
a
Table 1. Catalysts Screening
O
O
NO2
1
0 mol% catalyst
+
Me
CH Cl , 2-24 h
NO2
2
2
1
a
2a
3a
Me
Catalysts:
OMe
OMe
OMe
H
H
N
H
N
H
HO
H
N
O
COPh
OH
N
N
H
N
Quinidine (QD)
O-Benzoylquinine (BzQ)
Quinine (Q)
OH
N
OH
OH
H
H
N
N
H
O
H
H
H
N
OH
OCOPh
N
N
β-Isocupreidine
β-ICPD)
Cupreine (CPN)
O-Benzoylcupreine
(
(
BzCPN)
b
c
Entry
Catalysts
Temperature (°C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Q
Q
Q
QD
BzQ
BzQ
CPN
b-ICPD
BzCPN
20
ꢀ10
ꢀ40
ꢀ40
ꢀ40
20
ꢀ40
ꢀ40
ꢀ40
2
4
8
8
24
8
8
8
8
97
99
99
99
13
58
95
99
97
22 (ꢀ)
44 (ꢀ)
51 (ꢀ)
50 (+)
0
0
80 (+)
32 (ꢀ)
95 (+)
a
All reactions were carried out with anthrone 1a (0.24 mmol), nitroalkene 2a (0.2 mmol) and cinchona alkaloid (0.02 mmol) in CH
2
Cl
2
(3.0 mL) for
the specified time.
Yield of isolated product.
b
c
The enantiomeric excess (ee) was determined by HPLC on a chiral stationary phase (Chiracel AS-H) and the sign of the optical rotation was shown
in the parenthesis.
corresponding adduct 3a was obtained in 97% yield and
2% ee (Table 1, entry 1). Lowering the reaction temper-
ature to ꢀ10 °C and ꢀ40 °C improved the ee of 3a to
4% and 51%, respectively (Table 1, entries 2 and 3).
As quinine’s pseudo-enantiomer, quinidine (QD) pro-
duced 3a in similar ee but with opposite enantioselectiv-
ity under otherwise identical conditions (Table 1, entry
for the Baylis–Hillman reactions due to its high nucleo-
philicity and a phenolic OH group. When using O-ben-
6
2
zoylcupreine (BzCPN) as the catalyst, the highest ee
(95%) was obtained for this Michael addition (Table 1,
4
9
c
entry 9). These results suggest that both the phenolic
0
hydroxy group at C -6 position and the steric structure
around C-9 position played important roles in this
asymmetric Michael addition.
4
). Using O-benzoylquinine (BzQ), which does not have
free hydroxy group, as the catalyst, the reaction became
sluggish, affording 3a in lower yields with no enantio-
selectivities at 20 °C or ꢀ40 °C (Table 1, entries 5 and
Next, we further optimized the reaction conditions with
O-benzoylcupreine (BzCPN) as the catalyst by examin-
ing the solvent effect, the influence of reaction tempera-
ture and the catalyst loading. As shown in Table 2,
whether in nonpolar or in polar nonprotic solvents, 3a
was produced in high yields (>95%), but in dichloro-
methane (CH Cl ), 3a was produced in higher ee
(90%) at ꢀ10 °C (Table 2, entries 1–4). The lowest yield
and ee were obtained by use of ethanol (EtOH) as a sol-
vent presumably due to that the protic solvent disturbed
the hydrogen-bonding between the catalyst and the sub-
strates (Table 2, entry 5). Lowering the reaction temper-
6
). However, cupreine (CPN) that bears a hydroxy OH
0
group at C-9 position and a phenolic OH group at C -
6
position was found to be a more effective organocata-
lyst in this reaction, affording 3a in much higher ee than
others (Table 1, entry 7 vs entries 3–6). Encouraged by
this result, we further explored cupreine and cupreidine
derivatives as catalysts for this reaction. With the cage-
like conformationally rigid structure, b-isocupreidine (b-
ICPD), as a catalyst, 3a was formed in only 32% ee
2
2
(
Table 1, entry 8), although it was an effective catalyst

M. Shi et al. / Tetrahedron Letters 48 (2007) 5743–5746
5745
a
Table 2. Optimization of the reaction conditions
Table 3. Asymmetric Michael addition of anthrone 1a to nitroalkenes
2
a
b
c
Entry Cat.
Solvent Temperature Time Yield
ee
(mol %)
(°C)
(h)
(%)
(%)
O
O
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
5
Toluene ꢀ10
8
8
8
8
16
8
12
12
16
97
96
95
98
70
97
97
94
80
65
84
81
90
5
95
94
91
91
5
mol% BzCPN
NO2
CH
3
CN ꢀ10
+ R
o
CH Cl , -40 C, 12 h
2
2
THF
CH Cl
EtOH
ꢀ10
ꢀ10
ꢀ10
ꢀ40
ꢀ40
ꢀ40
ꢀ40
NO2
1
a
2
2
2
R
3
b
c
CH
CH
CH
CH
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
Entry
2
R
3
Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
C
6
H
5
3b
3c
3d
3e
3f
3g
3h
3i
94
98
99
99
98
99
99
99
96
95
94
96
91
96
98
97
99
97
94
99
98
98
95
91
80
3
1
d
4-MeOC
4-FC
3-FC H
6
H
4
6
H
4
a
All reactions were carried out with anthrone 1a (0.24 mmol), nitro-
alkene 2a (0.2 mmol), and O-benzoylcupreine (0.02–0.002 mmol) in
solvent (3.0 mL) for the specified time.
Yield of isolated product.
The enantiomeric excess (ee) was determined by HPLC on a chiral
stationary phase (Chiracel AS-H).
6
4
4-ClC H
6
4
2g
2h
2i
2 6
2,4-Cl C H
3
b
c
6 4
2-ClC H
d
e
6 4
4-BrC H
2j
4-NO C H
2
6
4
3j
10
11
12
13
2k
2l
3-NO
2
C
6
H
4
3k
3l
1-Naphthyl
2-Furyl
2m
2n
2o
3m 93
e
e
ature to ꢀ40 °C can significantly improve the enantio-
selectivity of 3a to 95% ee without scarifying the yield
n-C
(E)-C H CH@CH
3
H
7
3n
3o
91
96
14
6
5
(
97%) (Table 2, entry 6). Catalyst loading was also
a
All reactions were carried out with anthrone 1a (0.24 mmol), nitro-
alkenes 2 (0.2 mmol), and O-benzoylcupreine (0.01 mmol) in CH Cl
3.0 mL) at ꢀ40 °C for 12 h.
examined and it was found that 5 mol % was ideal for
this reaction (Table 2, entries 6–9).
2
2
(
b
c
Yield of isolated product.
With these optimized reaction conditions in hand, the
scope and limitations of this interesting asymmetric
Michael addition were explored. A variety of nitro-
alkenes, including those bearing aryl, hetero-aromatic
or alkyl substituents, reacted with anthrone 1a smoothly
to afford the corresponding adducts 3 in high yields in
the presence of 5 mol % of O-BzCPN at ꢀ40 °C in
CH Cl (Table 3). As for aryl nitroalkenes with elec-
Otherwise specified, the enantiomeric excess (ee) was determined by
HPLC on a chiral stationary phase (Chiracel AS-H).
The enantiomeric excess (ee) was determined by HPLC on a chiral
stationary phase (Chiracel OD-H).
The enantiomeric excess (ee) was determined by HPLC on a chiral
stationary phase (Chiracel AD-H).
d
e
1
3
2
2
tron-withdrawing substituents on the benzene ring,
slightly higher enantiomeric excesses than those bearing
electron-donating ones were observed (Table 3, entries
1
–10). 1-Naphthyl, hetero-aromatic and aliphatic group
substituted nitroalkenes gave the corresponding adducts
l–o in good to high enantioselectivities and high yields
3
as well (Table 3, entries 11–14). The absolute configura-
tion of 3 using O-BzCPN as a catalyst was unambigu-
ously determined by an X-ray diffraction of 3i as R-
1
4
configuration (Fig. 1).
Subsequently, we further investigated the Michael addi-
tion of 1,8-disubstituted anthrone 1b with nitroalkene.
The reaction of 1,8-dihydroxyanthrone 1b with nitroalk-
ene 2f proceeded smoothly to give the corresponding ad-
duct 3p in high yield but only with 9% ee (Scheme 1).
This control experiment suggests that the phenolic hy-
droxy groups in 1,8-dihydroxyanthrone might disturb
the hydrogen-bonding of catalyst with nitroalkenes
resulting in the corresponding adduct 3p with lower
enantioselectivity.
Figure 1. X-ray crystal structure of compound 3i.
0
lysts without free phenolic OH group at C-6 position
or with rigid conformation at C-9 position. In this reac-
tion, anthrone functions as a nucleophile rather than
an active diene, exclusively affording the corresponding
Michael addition products in up to 99% ee and yields.
Efforts to elucidate the mechanistic details of this
catalytic system and to further extend the scope and
limitations of this kind of bifunctional organocatalysts
are currently in progress.
In conclusion, we have developed a highly efficient
asymmetric Michael addition of anthrone to nitroalk-
enes catalyzed by cinchona alkaloid, O-benzoylcupreine
0
(
BzCPN). Both the free phenolic OH group at C-6 po-
sition and the steric bulkiness and structure at C-9 posi-
tion in BzCPN are crucial in this reaction to give the
corresponding adducts in higher ee than those of cata-

5746
M. Shi et al. / Tetrahedron Letters 48 (2007) 5743–5746
OH
O
OH
OH
O
OH
NO2
5
mol% BzCPN
+
Cl
o
CH Cl , -40 C,
2
2
NO2
1
b
2f
12 h
Cl
3
p
9
9% yield; 9% ee.
Scheme 1. Michael addition of substituted anthrone 1b with nitroalkene 2f.
Acknowledgments
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We thank the Shanghai Municipal Committee of Sci-
ence and Technology (04JC14083, 06XD14005), Chi-
nese Academy of Sciences (KGCX2-210-01), and the
National Natural Science Foundation of China for
financial support (20472096, 203900502, and 20672127)
and Cheung Kong Scholar program.
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1
165–1169; (d) Angew. Chem., Int. Ed. 2006, 45, 1147–
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Experimental details and characterization data, chiral
HPLC, X-ray crystallographic files in CIF format. Sup-
plementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
7
1
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6
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3
number 631349. Empirical Formula: C22H16BrNO ; for-
(
1
e) Shi, M.; Xu, Y.-M.; Shi, Y.-L. Chem. Eur. J. 2005, 11,
794–1802.
mula weight: 422.27; crystal color, habit: colorless, pris-
matic; crystal system: orthorhombic; lattice type:
˚
7
. (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
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Ed. 2005, 44, 105–108; (d) Li, H.; Song, J.; Liu, X.; Deng,
primitive; lattice parameters: a = 13.7487(13) A, b =
˚
˚
12.4288(12) A, c = 22.033(2) A, a = 90°, b = 90°, c = 90°,
˚
3
V = 3765.0(6) A ; space group: P2(1)2(1)2(1); Z = 8;
calc = 1.490 g/cm ; F000 = 1712; diffractometer: Rigaku
3
D
AFC7R; residuals: R; Rw: 0.0427, 0.0929.