Sugar-derived bifunctional thiourea organocatalyzed asymmetric Michael addition of acetylacetone to nitroolefins

Article abstract of DOI:10.1002/ejoc.200800555

A bifunctional chiral thiourea organocatalyst bearing a glycosyl scaffold and a tertiary amino group proved to be an effective organocatalyst for the asymmetric Michael addition of acetylacetone to nitroolefins. The corresponding adducts were obtained in

Full text of DOI:10.1002/ejoc.200800555

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800555
Sugar-Derived Bifunctional Thiourea Organocatalyzed Asymmetric Michael
Addition of Acetylacetone to Nitroolefins
Peng Gao,[a] Chungui Wang,[a] Yang Wu,[a] Zhenghong Zhou,*[a] and Chuchi Tang[a]
Keywords: Thiourea / Michael addition / Ketones / Nitroalkenes / Enantioselectivity
A bifunctional chiral thiourea organocatalyst bearing a gly-
cosyl scaffold and a tertiary amino group proved to be an
effective organocatalyst for the asymmetric Michael addition
of acetylacetone to nitroolefins. The corresponding adducts
were obtained in good to excellent yields with excellent
enantioselectivities (up to 96%ee).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ure 1). Primary amine–thiourea catalyst 2 developed by Ja-
cobsen also demonstrated excellent catalytic activity in the
asymmetric Michael addition of ketones to nitroolefins (up
to 99%ee).[10f] Saccharide-derived bifunctional thiourea 3
bearing a primary amino group documented by Ma was
proven to be an efficient organocatalyst for the asymmetric
addition of acetophenone to nitroolefins (up to 98%ee).[10i]
In addition, chiral bifunctional thiourea 4 containing mul-
tiple hydrogen-bonding donors[10l] and 5 bearing a 2,2Ј-di-
amino-1,1Ј-binaphthalene skeleton[10b] were also efficient
Introduction
Michael addition to electron deficient nitroolefins is one
of the important reactions in organic synthesis that pro-
vides access to synthetically useful functionalized nitroal-
kanes.[1] Because of the versatile reactivity of the nitro func-
tionality, it can be conveniently transformed into a nitrile
oxide[2], amine[3] (reduction), ketone (Nef reaction),[4] car-
boxylic acid (Meyer reaction),[5] and other functionalized
compounds (nucleophilic substitution),[6] providing a wide
range of synthetically valuable compounds. Although sig-
nificant progress was achieved in substrate- or auxiliary-
controlled diastereoselective versions of this reaction,[1,7]
the development of metal[8] and organocatalysts[9,10] for the
enantioselective process has been the focus of important re-
cent research efforts. Among the variants of this strategy,
the direct asymmetric Michael addition of carbon nucleo-
philes, such as aldehydes, ketones, and methylene-active
substrates, to nitroolefins is one of the most attractive and
atom-economical processes to access functionalized enan-
tiomerically enriched nitroalkanes, and impressive progress
was recently made in this area.[8d,8g–8j,9j–9p,10] In contrast,
the use of chiral bifunctional thioureas as powerful hydro-
gen-bond-donating organocatalysts for the synthesis of op-
tically active compounds has become a new and exciting
area of contemporary synthetic organic chemistry[11] since
Jacobsen successfully develop an efficient chiral Schiff
base–thiourea catalyzed asymmetric Strecker reaction.[12]
Takemoto reported the first example of a thiourea-organ-
ocatalyzed asymmetric Michael addition to nitroolefins,
and ee values up to 94% were observed with the use of
tertiary amine–thiourea bifunctional catalyst 1[10a,10c] (Fig-
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, P. R. China
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Thiourea organocatalysts.
Eur. J. Org. Chem. 2008, 4563–4566
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P. Gao, C. Wang, Y. Wu, Z. Zhou, C. Tang
SHORT COMMUNICATION
organocatalysts for the asymmetric Michael addition to ni- Table 1. Comparison of catalytic activities of thioureas 6a–c.[a]
troolefins. As part of a program aimed at developing new
organocatalysts for asymmetric organic transformations, we
recently found that bifunctional thioureas 6 bearing both a
tertiary amino group and a saccharide scaffold are efficient
organocatalysts for the asymmetric aza-Henry reaction be-
Entry Catalyst
t [h]
Yield [%][b]
ee[c]
Config.[d]
tween N-Boc imine and nitroalkanes, especially for catalyst
6a, which demonstrated a broad substrate scope. In most
cases, almost perfect stereocontrol (Ͼ99%ee) was
achieved.[13] To further extend the application of this novel
type of organocatalyst, herein, we report their ability to
serve as catalysts in the asymmetric Michael addition of
acetylacetone to nitroolefins.
1
2
3
6a
6b
6c
3
18
6
96
98
96
87
67
78
R
R
R
[a] All reactions were performed in 0.5 mL of solvent on a 0.2-
mmol scale. [b] Yield of the isolated product after chromatography
on silica gel. [c] Determined by chiral HPLC analysis. [d] The abso-
lute configuration of the major isomer was established by compar-
ing the measured optical rotation to a know literature value.[10b]
Table 2. Optimization of the reaction conditions.[a]
Results and Discussion
Following the literature procedure,[13] bifunctional thio-
ureas 6 were synthesized by coupling of the corresponding
isothiocyanate with N-[(1R,2R)-2-aminocyclohexyl]-N,N-
dimethylamine starting from α--glucopyranose, galactose,
and lactose, respectively (Scheme 1).
Entry 6a [mol-%]
Solvent
T [°C]
t [h] Yield [%][b] ee[c]
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
5
THF
Hexane
Et2O
EtOAc
CH2Cl2
Toluene
Toluene
Toluene –20
Toluene –40
Toluene –60
Toluene –40
Toluene –40
20
20
20
20
20
20
0
3
3
3
3
3
90
96
86
94
98
96
88
85
93
95
90
92
66
67
74
64
78
87
89
92
96
89
74
93
3
8
12
23
66
60
19
9
10
11
12
15
[a] All reactions were performed in 0.5 mL of solvent on a 0.2-
mmol scale. [b] Yield of the isolated product after chromatography
on silica gel. [c] Determined by chiral HPLC analysis.
Scheme 1. Synthesis of thioureas 6.
sults were observed when toluene was used (Table 2, en-
tries 6; 87%ee). Moreover, the reaction temperature was
With these catalysts in hand, we initially examined the found to be an essential factor to the enantioselectivity of
effect of the different saccharide scaffolds in the catalyst this reaction. The stereoselectivity was gradually increased
structure on the reaction. The reaction of β-nitrostyrene by decreasing the reaction temperature from 20 to –40 °C
with acetylacetone was performed in toluene at room tem- (Table 2, entries 6–9; 87–96%ee). However, a further de-
perature (20 °C) by using 10 mol-% of 6 as the catalyst. As crease in the temperature to –60 °C resulted in a decrease
shown in Table 1, all the tested catalysts exhibited good in the enantiomeric excess of the reaction (Table 2, entry 10;
catalytic activity. The corresponding adduct was obtained 89%ee). In addition, catalyst loading proved to be particu-
in excellent chemical yield. In terms of enantioselectivity, larly important. For example, smaller and larger amounts
thiourea 6a bearing a glycosyl scaffold provided the best of thiourea organocatalyst led to an obvious loss of ste-
results (Table 1, entry 1).
reocontrol (Table 2, entries 11 and 12; 74 and 93%ee,
In further experiments, other factors, such as solvent, respectively).
catalyst loading, and reaction temperature, influencing the
Further studies revealed that the concentration of the β-
reaction were thoroughly investigated by employing 6a as nitrostyrene substrate had an important effect on the reac-
the catalyst and the reaction between β-nitrostyrene with tion rate and enantioselectivity. The best result was ob-
acetylacetone as the model. The results are listed in Table 2. tained when the reaction was carried out at with a β-nitro-
A survey of six solvents revealed that a variety of sol- styrene concentration of 0.4  in toluene (Table 3, entry 2;
vents were tolerated by this Michael addition reaction. All 96%ee). An increase or decrease in the substrate concentra-
the tested solvents afforded the desired product in excellent tion led to slightly lower ee values (Table 3, entries 1 and 3;
yield and good ee values (Table 2, entries 1–6). The best re- 88 and 90%ee, respectively).
4564
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Eur. J. Org. Chem. 2008, 4563–4566

Organocatalyzed Asymmetric Michael Addition of Acetylacetone to Nitroolefins
Table 3. The influence of substrate concentration on the reaction.
hydrogen-bonding interaction of this nitro group with the
thiourea moiety of the catalyst, which to some extent pro-
hibits the activation of the electrophilic nitroolefin (Table 4,
entry 16). In addition, the reaction of a nitroolefin bearing
an aliphatic β-substituent, such as 1-nitro-1-pentene (E/Z =
10.1:1), was very sluggish even at room temperature
(Table 4, entry 17). However, an alkyl nitroolefin containing
a conjugated double bond demonstrated good reactivity un-
der the otherwise same conditions. For example, the corre-
sponding Michael addition product of (E)-4-nitro-1-phenyl-
1,3-butadiene was attained in good yield and good stereose-
lectivity (Table 4, entry 15).
Entry
Nitroolefin Conc. [mol/L]
t [h]
Yield [%][a]
ee[b]
1
2
3
0.8
0.4
0.2
8
23
70
90
93
90
88
96
90
[a] Yield of the isolated product after chromatography on silica gel.
[b] Determined by chiral HPLC analysis.
With the optimal reaction conditions in hand (10 mol-%
6a as the catalyst, at –40 °C in toluene, 0.4  substrate con-
centration), we investigated the scope and limitations of this
asymmetric Michael addition reaction. The results are sum-
marized in Table 4. Thiourea 6a exhibited excellent per-
formance for a broad range of nitroolefins bearing aryl and
heteroaryl groups in terms of catalytic activity and enantio-
selectivity. Generally, electron-donating groups on the ben-
zene ring prolonged the reaction time, but did not affect the
yield and selectivity (Table 4, entries 2–7). The reaction of
1-naphthyl or electron-rich heteroaryl-substituted nitroole-
fins also ran smoothly to give the desired products in both
excellent yields and enantioselectivities (Table 4, entries 12–
14). The reaction of nitro-substituted aryl nitroolefin did
not proceed at all. This may be attributed to the competitive
Conclusions
Thiourea catalyst 6a worked well as a bifunctional or-
ganocatalyst to promote the asymmetric Michael reaction
of acetylacetone to various nitroolefins. The reaction was
highly efficient in terms of productivity (up to Ͼ99% yield)
and enantioselectivity (up to 96%ee) and may be useful for
preparing enantiomerically enriched nitroketone deriva-
tives. Further studies on the Michael addition of other car-
bon and heteroatom nucleophiles are now in progress.
Experimental Section
General Procedure for Asymmetric Michael Addition of Acetyl-
acetone to Nitroolefins Catalyzed by 6a: To a solution of the ni-
troolefin (0.2 mmol) and thiourea catalyst 6a (10.7 mg, 0.02 mmol)
in toluene (0.5 mL) was added acetylacetone (40 mg, 0.4 mmol) in
one portion at the temperature depicted in the text. The resulting
mixture was stirred at the same temperature, and the reaction was
monitored by TLC. The solution was concentrated, and the residue
was purified by column chromatography on silica gel (200–
300 mesh; ethyl acetate/petroleum ether, 1:10 to 1:5) to furnish the
desired products. The ee values were determined by chiral HPLC
analysis.
Table 4. Chiral thiourea 6a catalyzed asymmetric Michael addition
of acetylacetone to various nitroolefins.[a]
Entry
R
t [h]
Yield [%][b] ee[c] Config.[d]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures; characterization of the catalysts;
copies of 1H NMR spectra and chiral HPLC spectra of the Michael
addition adducts.
1
2
3
4
5
6
7
8
Ph (7a)
23
48
60
70
70
60
60
16
12
16
50
40
50
48
48
48
48
93
80
96
Ͼ99
Ͼ99
89
Ͼ99
76
82
81
91
97
96
89
85
88
92
92
84
91
89
95
88
95
94
85
81
R
R
R
R
R
R
R
R
R
R
R
R
S
4-MeC6H4 (7b)
4-BnOC6H4 (7c)
4-MeOC6H4 (7d)
3-MeOC6H4 (7e)
2-MeOC6H4 (7f)
2,4-(MeO)2C6H4 (7g)
4-F3COC6H4 (7h)
3-F3COC6H4 (7i)
2-F3COC6H4 (7j)
4-ClC6H4 (7k)
Acknowledgments
9
We are grateful to the National Natural Science Foundation of
China (No. 20772058) for generous financial support of our pro-
grams.
10
11
12
13
14
15
16
17
1-Naphthyl (7l)
2-Furyl (7m)
Ͼ99
Ͼ99
85
5-Me-2-furyl (7n)
(E)-PhCH=CH (7o)
2-NO2C6H4
S
S
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P. Gao, C. Wang, Y. Wu, Z. Zhou, C. Tang
SHORT COMMUNICATION
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Received: June 10, 2008
Published Online: August 8, 2008
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Eur. J. Org. Chem. 2008, 4563–4566