Chiral squaramide-catalyzed highly enantioselective michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes

Article abstract of DOI:10.1002/adsc.201000981

A chiral squaramide-organocatalyzed, highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes has been developed. This reaction afforded the chiral naphthoquinones in excellent yields (up to 99%) and excellent enantioselectivity (up to 98% ee) under very low catalyst loading (0.25 mol%). This organocatalytic asymmetric Michael addition provides an efficient alternative route toward the synthesis of chiral functionalized naphthoquinones.

Full text of DOI:10.1002/adsc.201000981

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DOI: 10.1002/adsc.201000981
Chiral Squaramide-Catalyzed Highly Enantioselective Michael
Addition of 2-Hydroxy-1,4-naphthoquinones to Nitroalkenes
Wen Yanga and Da-Ming Dua,*
a
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, Peopleꢀs Republic of
China
Fax : (+86)-010-6891-4985; e-mail: dudm@bit.edu.cn
Received: December 30, 2010; Published online: May 12, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000981.
Abstract:
A
chiral squaramide-organocatalyzed,
nones, 5H-benzo[b]carbazole-6,11-diones, which have
antineoplastic activity.[6] In consideration of the differ-
ent bioactivities of enantiomers, the development of
highly enantioselective catalytic methodologies for
the synthesis of chiral naphthoquinone compounds is
an important synthetic target.
highly enantioselective Michael addition of 2-hy-
droxy-1,4-naphthoquinones to nitroalkenes has
been developed. This reaction afforded the chiral
naphthoquinones in excellent yields (up to 99%)
and excellent enantioselectivity (up to 98% ee)
under very low catalyst loading (0.25 mol%). This
organocatalytic asymmetric Michael addition pro-
vides an efficient alternative route toward the syn-
thesis of chiral functionalized naphthoquinones.
The asymmetric Michael addition of nitroalkenes is
À
an important C C bond-forming reaction, which pro-
vides access to synthetically useful enantioenriched
nitroalkanes and has attracted significant interest in
recent years.[7] 2-Hydroxy-1,4-naphthoquinones have
an enol moiety and may serve as good nucleophiles in
the Michael addition.[8] The asymmetric conjugate ad-
dition of 2-hydroxy-1,4-naphthoquinones to nitroal-
kenes is particularly interesting because it produces
chiral nitroalkylated compounds which are precursors
of a variety of other functionalized bioactive com-
pounds. After our first report on the chiral thiourea-
Keywords: asymmetric catalysis; Michael addition;
naphthoquinones; nitroalkenes; organocatalysis;
squaramides
Quinones and naphthoquinones are important struc- catalyzed enantioselective Michael addition of 2-hy-
tural units in many natural products.[1] Quinones and droxynaphthoquinones to nitroalkenes,[9] Xu reported
naphthoquinones exhibit redox properties that influ- an organocatalytic enantioselective Michael addition
ence various regulatory cellular processes. Many qui- of 2-hydroxy-1,4-naphthoquinone to b,g-unsaturated
none-containing compounds have biological activity a-oxo esters, which was promoted by bifunctional
owing to the presence of the quinone pharmaco- chiral amine-derived squaramides.[10] Chiral squara-
phore.[2] Quinone-containing antitumor drugs, such as mide organocatalysts pioneered by Rawalꢀs group and
mitoxantrone, ametantrone, and doxorubicin, demon- later exploited by other groups have been demon-
strate potent antitumor activity and have been used strated to be a new family of efficient and versatile bi-
clinically as one of the most effective classes of anti- functional organocatalysts for asymmetric chemical
cancer agents with broad applications in the treat- transformations such as the enantioselective Michael
ment of several leukemias and lymphomas.[3] In view addition, Friedel–Crafts reaction, and a-amination of
of their important biological features in medicinal 1,3-dicarbonyl compounds.[11] In consideration of the
chemistry, a large number of quinone derivatives and excellent performace of squaramides in asymmetric
related compounds has been prepared in order to catalysis as hydrogen-bonding organocatalysts,[11,12]
a
search for novel bioactive agents with improved phar- more powerful catalytic asymmetric Michael addition
macological properties.[4] 2-Hydroxy-1,4-naphthoqui- of 2-hydroxy-1,4-naphthoquinones to nitroalkenes
nones have received particularly attention due to may be possible using squaramide organocatalysts.
their biological properties and their potential as syn- Herein, we describe our successful applications of
thetic precursors of complex carbocyclic and hetero- squaramide organocatalysts to the highly efficient
cyclic quinones,[5] such as bisannulated indoloqui- enantioselective Michael addition of 2-hydroxy-1,4-
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Table 1. Screening of organocatalysts for the asymmetric Mi-
chael addition of 2-hydroxy-1,4-naphthoquinone to b-nitro-
styrene.[a]
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
I
II
94
96
96
96
95
96
97
97
91
92
-87
-86
89
87
97
98
III
IV
V
VI
VII
VIII
Figure 1. Structures of the screened organocatalysts.
naphthoquinones to nitroalkenes at very low catalyst
loading (0.25 mol%), and excellent yields and enan-
tioselectivities (up to 98% ee) could be achieved for
most substrates.
A series of chiral squaramide-based organocatalysts
I–VIII (Figure 1) was synthesized to promote the Mi-
chael addition of 2-hydroxy-1,4-naphthoquinones to
nitroalkenes. Remarkably, these squaramides, possess-
ing a high modular nature, can be easily prepared in
two or three steps from commercially available di-
methyl squarate, aromatic amines and chiral amines
[a]
Unless noted otherwise, reactions were carried out with
b-nitrostyrene (0.2 mmol) and 2-hydroxy-1,4-naphthoqui-
none (0.2 mmol) in CH2Cl2 (0.5 mL).
Isolated yields after column chromatography purifica-
tion.
[b]
[c]
Determined by HPLC using a Daicel Chiralcel OJ-H
column.
(Cinchona alkaloids or 1,2-diaminocyclohexane). The factorily, catalysts VII and VIII gave access to the de-
highly modular nature and the facile synthesis of sired products in excellent yields with excellent enan-
chiral squaramides facilitate the fine-tuning of their tioselectivities (97% ee and 98% ee) (Table 1, en-
catalytic activity for asymmetric catalysis. Initially, we tries 7 and 8). Catalyst VIII was slightly better than
selected the Michael addition of 2-hydroxy-1,4-naph- catalyst VII, and was selected as the best catalyst for
thoquinone to b-nitrostyrene as a model reaction and further optimization.
examined the catalytic effects of various squaramide-
With the best catalyst in hand, we further screened
based organocatalysts. The model reaction was per- the effect of solvents, catalyst loading, substrate con-
formed in CH2Cl2 in the presence of 5 mol% catalyst centration and temperature for the optimal reaction
loading at 308C, and the screening results are given in conditions. The screening results are summarized in
Table 1. To our delight, quinine-derived squaramides Table 2. Variation of the solvents had a limited effect
I and II gave the desired products in excellent yields on the yields and enantioselectivities of the reaction.
with high enantioselectivities (91% ee and 92% ee) in The common solvents such as CH2ClCH2Cl, CHCl3,
20 min (Table 1, entries 1 and 2). When quinidine-de- toluene and THF gave excellent yields and enantiose-
rived squaramides III and IV were used, the products lectivities (96–98% ee) (Table 2, entries 2–5). As ex-
with the opposite configuration were obtained in pected, MeOH led to a decrease in the enantioselec-
lower enantioselectivities (À87% ee and À86% ee) tivity (92% ee) because it is often a poor solvent in
(Table 1, entries 3 and 4). We then turned our atten- hydrogen bond-controlled organocatalysis (Table 2,
tion to those squaramides derived from chiral 1,2-di- entry 6). No solvent tested was found to be obviously
ACHTUNGTRENNUNGaminocyclohexane. Disappointingly, inferior results superior to CH2Cl2. The above observation demon-
(89% ee and 87% ee) were achieved when catalysts V strated that the catalytic system for the Michael addi-
and VI were employed (Table 1, entries 5 and 6). For tion was not very sensitive to solvents. Subsequently,
investigation of the effect of the tertiary amino group, the effect of catalyst loading was investigated. The ex-
squaramide-based catalysts VII and VIII containing a cellent enantioselectivities were still maintained with
piperidinyl group were prepared and screened. Satis- a reduced catalyst loading from 1 to 0.1 mol%, and
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Chiral Squaramide-Catalyzed Highly Enantioselective Michael Addition of 2-Hydroxy-1,4-naphthoquinones
Table 2. Optimization of the reaction conditions for the
asymmetric Michael addition of 2-hydroxy-1,4-naphthoqui-
none to b-nitrostyrene.[a]
Table 3. Scope of the Michael addition of 2-hydroxy-1,4-
naphthoquinones to nitroalkenes.[a]
Entry R1
R2
Product Yield ee
[%][b] [%][c,d]
Entry Solvent
Loading
[mol%]
Time Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
C6H5
4-FC6H4
3a
3b
3c
3d
3e
3f
3g
3h
96
98
95 98
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CH2ClCH2Cl 5
CHCl3
PhCH3
THF
5
20 min 97
20 min 96
20 min 97
20 min 99
20 min 98
20 min 98
98
97
97
96
97
92
98
98
98
98
98
98
98
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-ClC6H4
2-MeOC6H4
99
94
97
95
92
90
89
92
93
89
78
95
96
75
97
98 (R)
97
97
98
5
5
5
5
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
95
1
1 h
97
96
94
91
96
91
70
9
3,4-(MeO)2C6H3 3i
96[e]
97
0.50
0.25
0.10
0.25
0.25
0.25
3 h
10
11
12[f]
13[f]
14
15
16
2-furanyl
2-thienyl
2-phenylethyl
cyclohexyl
C6H5
3j
3k
3l
3m
3n
3o
3p
6 h
98
24 h
6 h
97 g]
96[e]
98
11[d] CH2Cl2
12[e] CH2Cl2
24 h
24 h
13[f]
CH2Cl2
4-MeC6H4
97
97
[a]
Unless noted otherwise, reactions were carried out with
b-nitrostyrene (0.20 mmol) and 2-hydroxy-1,4-naphtho-
quinone (0.20 mmol) in solvent (0.5 mL).
Isolated yields after column chromatography purifica-
tion.
Determined by HPLC using a Daicel Chiralcel OJ-H
column.
0.25 mL of CH2Cl2 was used.
OMe C6H5
[a]
Unless noted otherwise, reactions were carried out with
nitroalkenes (0.20 mmol) and 2-hydroxy-1,4-naphthoqui-
nones (0.20 mmol) in CH2Cl2 (0.25 mL) for 6 h.
Isolated yields after column chromatography purifica-
tion.
[b]
[c]
[b]
[c]
[d]
[d]
[e]
[f]
Determined by HPLC using a Daicel Chiralcel OJ-H
column.
1.0 mL of CH2Cl2 was used.
Reaction was carried out at 08C.
The configuration of product 3d was assigned by compa-
ration with the previous X-ray crystal structure of its
enantiomer, others were assigned by analogy.[9]
Determined by HPLC using a Chiralpak IA column
through its O-methyl derivative.
Reaction was carried out for 12 h.
Determined by HPLC using a Daicel Chiralcel OJ-H
column through its O-methyl derivative.
[e]
high yields were also achieved in the corresponding
extended reaction times (Table 2, entries 7–10). Com-
promising with the yield and reaction time,
0.25 mol% catalyst loading was chosen for further op-
timization. Variation of the substrate concentration
did not affect the enantioselectivities, but had a slight
[f]
[g]
effect on the yields (Table 2, entries 11 and 12). As with 2-hydroxy-1,4-naphthoquinone to afford the de-
expected, a high substrate concentration led to a sired products with excellent yields (90–99%) and
slight increase in the yield. When the reaction was enantioselectivities (95–98% ee) (Table 3, entries 2–
performed at 08C, a moderate yield (70%) and com- 8). When the 3,4-dimethoxy-substituted nitroalkene
parable enantioselectivity were observed in a pro- was used as an acceptor, a comparable result (89%
longed time (Table 2, entry 13).
yield and 96% ee) was observed (Table 3, entry 9). In
The scope of this Michael reaction was explored the cases of other aromatic nitroalkenes derived from
under the optimized reaction conditions, and the re- furan and thiophene, the desired products were also
sults are summarized in Table 3. Various nitroalkenes obtained with high yields and excellent enantioselec-
bearing either electron-withdrawing or electron-do- tivities (Table 3, entries 10 and 11). The aliphatic ni-
nating groups (F, Cl, Br, Me and OMe) at the para or troalkenes can also gave comparable excellent enan-
ortho position on the phenyl ring reacted smoothly tioselectivities (97% and 96% ee), which were deter-
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Wen Yang and Da-Ming Du
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Scheme 1. Further investiagtion of the substrate scope.
Scheme 2. The gram-scale preparation of 3a and its synthetic transformations.
mined through their O-methyl derivatives, but these ing heterocyclic-substituted chiral naphthoquinone 7
compounds required a longer time (12 h) due to their in 65% yield with 96% ee.
lower reactivity (Table 3, entries 12 and 13). 2-Hy-
On the basis of the experimental results described
droxy-1,4-naphthoquinones with electron-donating above, a possible transition state model was hypothe-
groups (Me and OMe) on the 6-position were also sized and shown in Figure 2. The model has no signifi-
tested, and the corresponding products were obtained cant difference with the one in our previous report.
with excellent enantioselectivities (Table 3, entries 14– We envisioned that the chiral squaramide VIII acts as
16).
a bifunctional catalyst. The 2-hydroxy-1,4-naphthoqui-
As shown in Scheme 1, further exctension of the none is deprotonated by the basic nitrogen atom of
substrate scope to a nitrodiene was investigated. The the tertiary amine. Meanwhile, the nitroalkene is
catalytic asymmetric addition of 2-hydroxy-1,4-naph- fixed and activited by the squaramide moiety through
thoquinone 3a to [(1E,3E)-4-nitrobuta-1,3-dienyl]ben- double hydrogen bonding between the NH groups
zene 4 was also effective to give the desired product 5 and the nitro group. The deprotonated 2-hydroxy-1,4-
in good yield with excellent enantioselectivity (95%
ee) under the above optimized conditions for 12 h.
To further evaluate the synthetic potential of the
catalytic system, the gram-scale preparation of 3a was
performed in the presence of 0.25 mol% of catalyst
VIII under the optimized conditions. As shown in
Scheme 2, the catalytic asymmetric Michael addition
of 1a to 2a was accomplished with excellent results
(3.12 g, 97% yield, 98% ee). In addition, the product
3a can also be easily transformed into the optically
active product 6 in 92% yield with 97% ee. Com-
pound 6 may serve as a versatile building block owing
to the existence of carbonyl, chloro, and nitro groups.
For example, the nucleophilic substitution of com-
pound 6 with morpholine can afford the correspond- Figure 2. Proposed transition state model.
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Chiral Squaramide-Catalyzed Highly Enantioselective Michael Addition of 2-Hydroxy-1,4-naphthoquinones
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thoquinones to nitroalkenes. Significantly, only
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Experimental Section
General Procedure for the Enantioselective Michael
Addition Reaction
Organocatalyst VIII (8.4 mg) was added to dichloromethane
to afford a solution of catalyst VIII (10.0 mL, 2.0 mmol/L).
To a solution of nitroalkenes 2 (0.20 mmol) in 0.25 mL of
the above catalyst VIII solution (0.0005 mmol) was added 2-
hydroxy-1,4-naphthoquinone 1 (0.20 mmol). The reaction
mixture was stirred at 308C for 6 h or 12 h. Then the mix-
ture was concentrated and purified by silica gel column
chromatography (CH2Cl2) to afford the desired products 3.
2-Hydroxy-3-(2-nitro-1-phenylethyl)naphthalene-1,4-dione
(3a): Compound 3a was obtained according to the general
procedure as an orange solid; yield: 61.9 mg (96%); mp
152–1538C. The enantiomeric excess was determined by
HPLC with a Daicel Chiralcel OJ-H column (n-hexane:2-
propanol 70:30 v/v, flow rate 1.0 mL·minÀ1, 254 nm): minor
enantiomer tr =17.3 min, major enantiomer tr =31.6 min,
98% ee; [a]2D5: À34.0 (c 1.46 g/100 mL, CH3COCH3);
1H NMR (500 MHz, CDCl3): d=8.11 (d, J=7.5 Hz, 1H),
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J2 =7.5 Hz, 1H), 7.69 (dt, J1 =1.0 Hz, J2 =7.5 Hz, 1H), 7.47
(d, J=7.5 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.28–7.25 (m,
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Major Projects Cultivating Special Program in Technology
Innovation Program (Grant No. 2011CX01008) and the De-
velopment Program for Distinguished Young and Middle-
aged Teachers of Beijing Institute of Technology.
Adv. Synth. Catal. 2011, 353, 1241 – 1246
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Adv. Synth. Catal. 2011, 353, 1241 – 1246