Chiral amine-thioureas bearing multiple hydrogen bonding donors: Highly efficient organocatalysts for asymmetric Michael addition of acetylacetone to nitroolefins

Article abstract of DOI:10.1039/b718949d

New bifunctional organocatalysts amine-thioureas bearing multiple hydrogen bonding donors were synthesized and applied in catalytic asymmetric Michael addition of acetylacetone to aryl and alkyl nitroolefins. Multiple hydrogen bonding donors play a signif

Full text of DOI:10.1039/b718949d

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Chiral amine-thioureas bearing multiple hydrogen bonding donors: highly
efficient organocatalysts for asymmetric Michael addition of
acetylacetone to nitroolefinsw
Chun-Jiang Wang,* Zhi-Hai Zhang, Xiu-Qin Dong and Xiao-Jun Wu
Received (in Cambridge, UK) 10th December 2007, Accepted 26th December 2007
First published as an Advance Article on the web 23rd January 2008
DOI: 10.1039/b718949d
New bifunctional organocatalysts amine-thioureas bearing mul-
tiple hydrogen bonding donors were synthesized and applied in
catalytic asymmetric Michael addition of acetylacetone to aryl
and alkyl nitroolefins. Multiple hydrogen bonding donors play a
significant role in accelerating reactions, improving yields and
enantioselectivities.
enantioselectivities up to 99% ee using as low as to 0.1–1
mol% catalyst loading.
In the presence of 10 mol% 3a–d, the reaction of nitroolefin
(4a) with acetylacetone (5) was initially examined under
different conditions. The results are summarized in Table 1.
To our delight, the newly designed catalysts exhibited high
catalytic efficiency. The reactions were finished in less than
0.5 h at room temperature when ether was used as the solvent.8
Chiral catalyst 3a promoted the reaction with a high yield of
97% but a moderate enantioselectivity (76% ee, entry 1).
Gratifyingly, its isomer catalyst 3b afforded a superior level
of enantioselectivity with the same sense of asymmetric induc-
tion (93% ee, entry 2). This indicates that the (R,R)-1,2-
diphenylethenediamine moiety matched the (R,R)-cyclohexa-
nediamine moiety and the configurations of the products were
determined mainly by the latter, but the enantioselective
control could be greatly enhanced by the former. Replacing
the Ts group of 3b with a less bulky group (Ms) decreased the
enantioselectivity (89% ee) due to the steric flexibility of
catalyst 3c (entry 3). The highest enantioselectivity of 97%
ee was observed with 3d as catalyst (entry 4), which is
presumably attributed to the presence of the additional stron-
ger hydrogen bonding donor from sulfonamide NHSO2Ar
with two electron-withdrawing groups CF3 on the aromatic
ring. The change of solvents has a remarkable effect on the
enantioselectivity and catalytic activity. In polar solvents, the
reaction became sluggish and displayed lower ee presumably
due to the competitive activation of 4a between 3d and the
Recently, the design and application of organocatalysts have
received much attention due to asymmetric organocatalysis
emerging as a powerful and environmentally friendly metho-
dology for the catalytic production of the valuable synthetic
building blocks.1 Impressive progress has been made in the
development of small chiral molecules bearing hydrogen
bonding donors for a diverse range of reactions with high
enantioselectivities attributed to their strong activation of
carbonyl or nitro groups through efficient double hydrogen
bonding interactions.2 Of the developed organocatalysts, bi-
functional amine-thioureas have been proved to be powerful
and have been applied successfully in asymmetric Michael
addition reactions3 (Fig. 1). Nonetheless, catalyst loading of as
high as 20–30 mol% and long reaction times are usually
required to achieve good isolated yields and high enantio-
selectivities for amine-thiourea catalyzed asymmetric
reactions.1d,4 Therefore, the development of highly efficient
chiral amine-thiourea catalysts, which show high enantioselec-
tivity and fast reaction rate for a broad scope of substrates at
low catalyst loading, is still in great demand.
Considering the importance of the double hydrogen bond-
ing interactions between the thiourea moiety and substrates in
amine-thiourea catalyzed asymmetric reactions,5 we envi-
sioned that amine-thioureas bearing multiple hydrogen bond-
ing donors as shown in Scheme 1 could facilitate forming more
hydrogen bonds6 and thereby significantly enhance their cat-
alytic activity and overcome the drawback of high catalyst
loading. To the best of our knowledge, this strategy has not yet
been applied in the design and synthesis of chiral amine-thiourea
organocatalysts.7 Herein, we report a new class of amine-
thiourea catalysts bearing multiple hydrogen bonding donors
which efficiently catalyze asymmetric Michael addition of
acetylacetone to nitroolefins with both high yields and high
College of Chemistry and Molecular Sciences, Wuhan University,
430072, China. E-mail: cjwang@whu.edu.cn; Fax: +86
(0)27 68754067; Tel: +86 (0)27 65241880
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b718949d
Fig. 1 Examples of reported chiral bifunctional amine-thiourea
catalysts.
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Table 1 Screening studies of organocatalytic asymmetric Michael
addition of acetylacetone and nitroolefinsa
Entry Catalyst
Solvent Temp/1C t/h Yield (%)b ee (%)c,d
1
2
3
4
5
6
7
8
3a (10 mol%) Et2O
Rt
Rt
Rt
Rt
0.5 97
0.5 96
0.5 96
76
93
89
97
18
0
86
35
89
95
98
97
97
97
95
3b (10 mol%) Et2O
3c (10 mol%) Et2O
3d (10 mol%) Et2O
3d (10 mol%) MeOH Rt
3d (10 mol%) DMSO Rt
3d (10 mol%) MeCN Rt
3d (10 mol%) THF
3d (10 mol%) DCM
3d (10 mol%) PhMe Rt
3d (10 mol%) Et2O
3d (10 mol%) Et2O
3d (2 mol%) Et2O
3d (1 mol%) Et2O
3d (0.1 mol%) Et2O
1
97
17 69
16 72
10 90
Rt
Rt
5
96
9
0.5 97
0.5 97
0.5 97
10
11
12
13
14
15
0
À20
Rt
Rt
Rt
2
1
1
96
97
97
Scheme 1 Synthesis of amine-thiourea catalysts bearing multiple
hydrogen bonding donors.
10 81
a
Unless otherwise noted, the reaction was carried out with 0.15 mmol
b
of 4a and 0.30 mmol of 5 in 0.35 mL of solvent. Isolated yield.
c
Enantiomeric excesses were determined by chiral HPLC analysis.
The absolute configuration of the product was determined as R by
protic solvent such as methanol (entry 5), or the reduced
activity of 3d caused by strongly H-bonding acceptor solvents
such as DMSO, MeCN and THF (entries 6, 7 and 8). In
contrast, 3d in nonpolar or less polar solvents, such DCM,
PhMe and ether, efficiently promoted the reaction in high yield
with good to excellent enantioselectivities within less than 1h
(entries 4, 9 and 10). Ether was the best solvent of choice and 97%
ee was obtained. Reducing the reaction temperature from room
temperature to 0 and À20 1C did not improve the enantioselec-
tivities (entries 11 and 12). Further optimization showed that high
yield and enantioselectivity and fast reaction rate remained when
the reaction was performed with as low as 1 mol% of catalyst
loading (entry 14). Even when the catalyst loading was reduced to
0.1 mol%, a comparable result (95% ee, 85% yield) was still
achieved with extended reaction time (entry 15).9
d
comparing the optical rotation with the reported date.8
acetylacetone (5) (1 : 2 ratio) in the presence of 1 mol% 3d
afforded the product in 499% yield with 94% ee within 2 h.11
The asymmetric Michael addition of other diketones to
nitroolefin 4a using 3d as a catalyst was also investigated. As
Table 2 Asymmetric Michael addition of acetylacetone to nitro-
olefins (4) catalyzed by organocatalyst 3da
Under the optimized experimental conditions, the scope of
the reaction was explored (Table 2). A variety of aryl nitro-
olefins (4a–k) reacted smoothly with acetylacetone (5) to
afford the corresponding products (6a–k) in high yields
(87–97%) and excellent enantioselectivities (95–99% ee) in
the presence of 1 mol% of catalyst 3d at room temperature
within 1–2 h. It appears that the position and the electronic
property of the substituents on the aromatic rings have a very
limited effect on the enantioselectivities. Noticeably, alkyl
nitroolefins also work well in this reaction with 1–5 mol%
catalyst loading: alkyl nitroolefins with sterically hindered or
unhindered substitutents (4l–n) led to similar enantioselectiv-
ities of 82–85% ee (entries 12–15). To the best of our knowl-
edge, no example of the asymmetric addition of acetylacetone to
alkyl nitroolefins has been described so far, probably due to the
fact that they are less reactive than aryl nitroolefins.10 Actually,
extended reaction time and 5 mol% catalyst loading were
needed to complete the reactions compared with needing only
0.1–1 mol% catalyst and 1–2 h for aryl nitroolefins.
Entry
R
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph (4a)
97
96
95
93
96
97
87
97
96
97
96
85
81
80
83
97
95
98
98
97
95
98
95
96
96
99
85
81
83
82
4-MePh (4b)
2-MePh (4c)
4-MeOPh (4d)
3-MeOPh (4e)
2-MeOPh (4f)
3-ClPh (4g)
4-BrPh (4h)
3-BrPh (4i)
2-BrPh (4j)
4-FPh (4k)
Amyl (4l)
9
10
11
12d
13d
14e
15d
a
i-Propyl (4m)
i-Propyl (4m)
i-Butyl (4n)
Unless otherwise noted, the reactions was carried out with
0.15 mmol of 4 and 0.30 mmol of 5 in 0.35 mL of ether within
b
c
1–2 h. Isolated yield. Enantiomeric excesses were determined by
d
chiral HPLC analysis. 5 mol% catalyst was used and the reactions
e
completed in 16–28 h. 1 mol% catalyst was used and the reaction
completed in 36 h.
Interestingly, this Michael addition reaction could also be
carried out without solvent. Mixing nitroolefin (4a) with
ꢀc
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45, 1520; (b) R. P. Herrera, V. Sgarzani, L. Bernardi and A. Ricci,
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Scheme 2 Asymmetric Michael addition of other diketones to
nitroolefin 4a catalyzed by 3d.
shown in Scheme 2, 1,3-diphenylpropane-1,3-dione gave the
desired product in 95% yield with 85% ee, which is the first
report using this diketone in this asymmetric Michael addi-
tion. Unsymmetrical 2-acetylcyclopentanone also worked well
to give the desired products with good diastereoselectivity
(85 : 15) and excellent enantioselectivty (96 and 90% ee for
the major and the minor diastereomer respectively) which is
comparable with the two best results reported in the
literature.5d,12
In order to evaluate the role of the multiple hydrogen
bonding donors played in this system, a control experiment
was carried out using 10 mol% 3e as catalyst (Scheme 1) in
which the sulfonamide NMeSO2Ts is methylated. In the
Michael addition of acetylacetone to 4a, the reaction became
sluggish and the corresponding product was formed in 80%
yield with only 68% ee even in 16 h. This indicates that the
third NH of sulfonamide on the 1,2-diphenylethenediamine
moiety indeed play a significant role in this Michael addition
reaction.13
6 Y. H. Liu, L. H. Chen and M. Shi, Adv. Synth. Catal., 2006, 348,
973.
7 Other kinds of organocatalysts having multiple hydrogen
bonding donors have already been developed, see: (a) R. P.
Herrera, V. Sgarzani, L. Bernardi and A. Ricci, Angew. Chem.,
Int. Ed., 2005, 44, 6576; (b) Y. Sohtome, A. Tanatani, Y.
Hashimoto and K. Nagasawa, Tetrahedron Lett., 2004, 45, 5589;
(c) A. Berkessel, K. Roland and J. M. Neudorfl, Org. Lett., 2006, 8,
4195.
8 The best results for asymmetric Michael addition of acetylacetone
to aryl nitroolefins were obtained with 10 mol% catalyst
loading (80% yield and 89% ee in 1 h), see ref. 5d, or 1 mol%
catalyst loading (87% yield and 95% ee in 26 h), see: J. Wang,
H. Li, W. Duan, L. Zu and W. Wang, Org. Lett., 2005, 7,
4713.
9 For organocatalytic transformations with catalyst loadings of less
than 1 mol%, see: (a) M. Rueping and A. P. Antonchick, T.
Theissmanna, Angew. Chem., Int. Ed., 2006, 45, 6751; (b) P.
Krattiger, R. Kovasy, J. D. Revell, S. Ivan and H. Wennemers,
Org. Lett., 2006, 8, 2901; (c) M. Terada, K. Machioka and K.
Sorimachi, Angew. Chem., Int. Ed., 2006, 45, 2254; (d) S. Shiraka-
wa, K. Yamamoto, M. Kitamura, T. Ooi and K. Maruoka, Angew.
Chem., Int. Ed., 2005, 44, 625; (e) M. Kitamura, S. Shirakawa and
K. Maruoka, Angew. Chem., Int. Ed., 2005, 44, 1549; (f) P. Vachal
and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 10012; (g) S.
Saaby, M. Bella and A. K. Jørgensen, J. Am. Chem. Soc., 2004,
126, 8120.
In conclusion, a new class of bifunctional amine-thiourea
catalysts bearing multiple hydrogen bonding donors was
synthesized and evaluated for their ability to catalyze the
Michael addition of acetylacetone to nitroolefins. We found
that multiple hydrogen bonding donors play a key role in
accelerating reactions, improving yields and improving enan-
tioselectivities. Further investigation of the efficacy of these
organocatalysts in other catalytic asymmetric reactions and
the design of new bifunctional catalysts bearing multiple
hydrogen bonding donors are ongoing in our lab and will be
reported in due course.
The authors thank Dr Wei-Liang Duan and Dr Bo Xu for
helpful discussions. This work is supported by the National
Natural Science Foundation of China (20642005) and the
start-up fund from Wuhan University.
10 C. L. Cao, M.-C. Ye, X.-L. Sun and Y. Tang, Org. Lett., 2006, 8,
2901.
11 Due to a lot of precipitate formed in the reaction mixture, this
reaction became a little sluggish under no solvent conditions.
12 H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo, B. M. Foxman
and L. Deng, Angew. Chem., Int. Ed., 2005, 44, 105.
13 At present, we could not rule out the possibility that the sulfona-
mide proton facilitates the proton shift during the catalytic cycle,
see: G. Masson, C. Housseman and J. Zhu, Angew. Chem., Int. Ed.,
2007, 46, 4614.
Notes and references
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L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (d) A.
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Wiley-VCH, Weinheim, 2004; (e) J. Seayad and B. List, Org.
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Chem. Commun., 2008, 1431–1433 | 1433