Organocatalyzed highly enantioselective michael additions of malonates to enones by using novel primary-secondary diamine catalysts

Article abstract of DOI:10.1002/chem.200801749

A novel primary-secondary diamine catalyst readily available from primary amino acids in three steps for the highly enantioselective Michael additions of malonates to α,β-unsaturated ketones was reported. The Michael reaction of dimethyl malonate with benzylideneacetone was selected as a model reaction for catalyst evaluation. The length of the alkyl chain is found to influence the catalytic abilities of the catalysts and the n-propylated catalyst gave the highest yield and ee value. The addition of a series of malonates to enone performed under the optimized conditions is found to be sensitive to the steric hinderance on the malonates. Heterocyclic furan enone is found to perform well to give the desired product in 92% yield and 99% ee, while no decrease in yield and ee value is observed for sterically hindered enone.

Full text of DOI:10.1002/chem.200801749

DOI: 10.1002/chem.200801749
Organocatalyzed Highly Enantioselective Michael Additions of Malonates to
Enones by Using Novel Primary–Secondary Diamine Catalysts
Ying-Quan Yang[a] and Gang Zhao*[a, b]
The Michael reaction is one of the fundamental bond-
forming processes in organic chemistry and its asymmetric
version offers an extremely powerful tool for the synthesis
of a variety of useful chiral functionalized organic mole-
cules.[1] Particularly, the catalytic asymmetric addition reac-
tion of malonates to a,b-unsaturated ketones would produce
useful products which could be easily converted to syntheti-
cally useful optically active d-ketoesters after simple decar-
boxylation procedures.[2] As a result, a variety of chiral
metal catalysts[3] as well as organocatalysts[2,4] have been de-
veloped for this transformation. However, only very recently
did Kobayashi et al. report the highest enantioselectivity
(mostly >95% ee) for this reaction with di-n-propyl malo-
nates and chalcones using a new strontium based catalysts.[5]
In the field of organocatalysis, imidazoline catalyst,[2a] pro-
line-derived tetrazole catalysts,[2b,c] phase-transfer catalysts,[6]
and Cinchona alkaloid-derived chiral thioureas[7] have been
introduced to catalyze this reaction. Nevertheless, these cat-
alytic systems more or less suffer several drawbacks such as
long reaction times (2–6 d), the need for a large excess of
malonates, and unsatisfactory enantioselectivities (generally
below 95% ee). Therefore, the development of a more effi-
cient organocatalyst system is highly desirable in order to
make this transformation more practical for use in organic
synthesis.
cessful applications in organocatalysis.[8] Despite the recent
inspiring successful applications of primary amine salts in
the iminium catalysis of enones,[9] little examples have been
reported for the use of primary–secondary diamine catalysts
in the Michael addition reactions of enones. As part of our
ongoing efforts in developing efficient organocatalysts for
the asymmetric reactions of a,b-enones,[10] we report herein
a novel primary–secondary diamine catalyst readily avail-
able from primary amino acids in three steps[11] for the Mi-
chael additions of malonates to a,b-unsaturated ketones.
Initially, the Michael reaction of dimethyl malonate 1a
with benzylideneacetone 2a was selected as a model reac-
tion for catalyst evaluation (Table 1). While catalyst 3a
(Figure 1) bearing two primary amino groups derived from
Figure 1. Structures of the catalysts studied.
On the other hand, chiral diamines, especially those bear-
ing a primary amine moiety, have recently found many suc-
l-phenylalanine promoted this reaction with poor yield and
enantioselectivity, its monomethylated analogue 3b provid-
ed much better results (Table 1, entries 1 and 2). The length
of the alkyl chain was found to influence the catalytic abili-
ties of the catalysts and the n-propylated catalyst 3d gave
the highest yield and ee value (Table 1, entry 4).[12] Surpris-
ingly, the primary–tertiary 3 f exhibited very low activity in
this reaction, which highlighted the importance of the secon-
dary amine moiety in the catalyst (Table 1, entry 6). More-
over, variation of the benzyl group of 3d yielded the opti-
mum catalyst 3i derived from l-tryptophan, which provided
the desired product 4aa with 91% ee (Table 1, entry 9).
Next, we are pleased to find that decreasing the amount of
1a to 2 equiv had little influence on both the yield and ee
[a] Y.-Q. Yang, Prof. Dr. G. Zhao
Department of chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
Fax : (+86)21-64166128
E-mail: zhaog@mail.sioc.ac.cn
[b] Prof. Dr. G. Zhao
Laboratory of modern synthetic chemistry
Shanghai institute of organic chemistry
354 Fenglin Road, Shanghai, 200032 (China)
Chinese Academy of Sciences
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801749.
10888
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10888 – 10891

COMMUNICATION
Table 2. Examination of different malonates 1 with the 3i/TFA combina-
values (Table 1, entry 10). Our further optimizing efforts
were shifted to the examination of the effect of several acid
additives, which are well-documented to be beneficial for
the formation of an iminium intermediate.[9] To our delight,
the addition of acid additives not only improved the yield
and ee values, but also decreased the reaction time signifi-
cantly from 48 to 24 h (Table 1, entries 11–15). Thus, the re-
action was best performed using a 1:1 combination of 3i/
TFA (trifluoro acetic acid) with 99% yield and 97% ee
(Table 1, entry 13). The absolute configuration of the prod-
uct 4aa was determined by comparison of the specific opti-
cal rotation with that of the literature data.
tion.[a]
Entry
1
R1
Product
Yield [%][b]
ee [%][c]
1
2
3
4
1a
1b
1c
1d
1e
1 f
Me
Et
iPr
allyl
Bn
4aa
4ba
4ca
4da
4ea
–
99
97
72
99
99
–
97
98
>99
98
99
–
5
6[d]
tBu
[a] Reaction conditions: 2a (1.0 equiv), 1 (2.0 equiv), 3i/TFA (20 mol%),
CHCl3 (1.0 mL). [b] Yield of the isolated product after column chroma-
tography. [c] The ee value was determined by HPLC on a chiral phase.
[d] No reaction was detected.
Table 1. Screening of catalysts for the asymmetric Michael addition of di-
methyl malonate 1a to benzylideneacetone 2a.[a]
nature or positions of the substituents on the phenyl ring
(Table 3, entries 1–10). Heterocyclic furan enone 2j also per-
formed well to give the desired product in 92% yield and
99% ee (Table 3, entry 11). No decrease in yield and ee
value was observed for the slightly sterically hindered enone
2l (Table 3, entry 12). Interestingly, chalcone 2m, which was
presumed to be a better Michael acceptor for this type of re-
action,[4–7] was found to react rather slowly and a longer re-
action time was required to obtain good yield, however, ex-
cellent enantioselectivity was still achieved (Table 3,
entry 13). Poor reactivity was also observed for the alkyl-
substituted enone 2n and 2-cyclohexenone 2o, in which only
moderate yields were obtained while still in excellent enan-
tioselectivities with prolonged reaction times (Table 3, en-
tries 14 and 15).
Entry
Catalyst 3
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3i
3i
3i
3i
none
none
none
none
none
none
none
none
27
43
51
93
85
trace
77
55
92
90
98
99
99
93
97
36
79
81
90
87
–
82
36
91
91
93
94
97
96
96
9
none
none
10[d]
11[d,e]
12[d,e]
13[d,e]
14[d,e]
15[d,e]
PhCO2H
CH3CO2H
CF3CO2H
CF3SO3H
d-CSA
3i
3i
A bifunctional iminium mechanism similar to those previ-
ously proposed for the primary amine salt catalysts in the
iminium catalysis[9] of enone may be invoked to explain the
observed enantioselectivity. We presume that the reaction
may proceed via the iminium ion I (Figure 2), in which the
primary amine moiety of the catalyst 3i activates the enone
2 via the formation of an iminum ion while the secondary
amine activates the nucleophile malonate 1. The Re face of
the enone in this pretransition state assembly I is shielded
by the bulky indolyl group driving the malonate to attack
the Si face of the enone 2. The strong acid additives may fa-
cilitate the formation of the iminium ion and foster the re-
generation of the catalyst in the hydrolysis of the enamine
intermediate after the addition step. However, the exact ex-
isting or functioning forms of the strong acid additives in
the reaction system are difficult to be determined.
In summary, we have devel-
oped a novel readily available
primary–secondary diamine cat-
alyst system for the Michael ad-
ditions of malonates to enones.
Excellent yields and enantiose-
lectivities were achieved for a
range of both malonates and
enones. Efforts are being fo- Figure 2. Pretransition state I.
[a] Reaction conditions: 2a (1.0 equiv), 1a (10.0 equiv), 3 (20 mol%),
CHCl3 (1.0 mL). [b] Yield of the isolated product after column chroma-
tography. [c] The ee value was determined by HPLC on a chiral phase.
[d] Two equiv of 1a was used. [e] The reaction was run for 24 h. d-CSA:
d-camphor sulfonic acid.
Subsequently, the addition of a series of malonates 1 to
enone 2a was performed under the optimized conditions
(Table 2). It seems that the reaction was quite sensitive to
the steric hindrance on the malonates. While excellent
yields and enantioselectivity were obtained for the less steri-
cally demanding malonates 1a, b, d, and e, a lower yield was
observed for the diisopropyl malonate 1c but still with up to
>99% ee (Table 2, entry 3). The reaction even failed to pro-
ceed when the more sterically demanding di-tert-butyl malo-
nates 1 f was employed (Table 2, entry 6). The use of diben-
zyl malonate 1e furnished the best results with up to 99%
yield and ee value (Table 2, entry 5). Notably, it is favorable
to use dimethyl or dibenzyl malonates for further useful
conversions of the Michael adducts in organic synthesis.[2]
Then the scope of the addition of dibenzyl malonate to a
variety of enones 2 was explored (Table 3). For 4-aryl-3-
buten-2-ones 2a–j, almost optically pure products could be
obtained in excellent yields, irrespective of the electronic
Chem. Eur. J. 2008, 14, 10888 – 10891
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10889

G. Zhao and Y.-Q. Yang
Table 3. Enantioselective Michael addition of dibenzyl malonate 1e to enones 2 catalyzed by the 3i/TFA com-
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2007, 18, 299.
bination.[a]
Entry
R2
R3
Product
Yield [%][b]
ee [%][c]
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1
2
3
4
5
6
7
8
Ph
Me, 2a
Me, 2b
Me, 2c
Me, 2d
Me, 2e
Me, 2 f
Me, 2g
Me, 2h
Me, 2i
Me, 2j
Me, 2k
Et, 2l
4ea
4eb
4ec
4ed
4ee
4ef
4eg
4eh
4ei
4ej
4ek
4el
4em
4en
4eo
99
91
92
91
90
99
96
90
93
96
92
91
82
66
71
99
99
99
>99
99
99
99
>99
>99
99
99
99
>99
98
90
2-naphthyl
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
2-furyl
9
10
11
12
13[d]
14[d]
15[e]
Ph
Ph
Ph, 2m
Me, 2n
n-C4H9
2-cyclohexenone (2o)
[a] Reaction conditions: 2 (1.0 equiv), 1e (2.0 equiv), 3i/TFA (20 mol%), CHCl3 (1.0 mL). [b] Yield of the iso-
lated product after column chromatography. [c] The ee value was determined by HPLC on a chiral phase.
[d] The reaction was run for 120 h. [e] The reaction was run for 120 h at 08C.
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Experimental Section
Typical procedure: To a mixture of enone 2a (0.5 mmol), catalyst 3i
(0.1 mmol) and TFA (0.1 mmol) in CHCl3 (1.0 mL) was added dibenzyl
malonate 1e (1.0 mmol) at ambient temperature. After 24 h of stirring,
the reaction mixture was quenched with 1m aqueous HCl, and extracted
with EtOAc. The combined organic layer was dried over anhydrous
Na2SO4, filtered, concentrated and purified by flash column chromatogra-
phy on silica gel (petroleum ether/Et2O 10:1) to afford the Michael
adduct 4ea[2a] (213 mg, 99%) as a white solid.
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Acknowledgements
The generous financial support from the National Natural Science Foun-
dation of China, QT Program, Shanghai Natural Science Council, and
Excellent Young Scholars Foundation of NNSF are gratefully acknowl-
edged.
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Keywords: asymmetric catalysis · enones · malonates ·
Michael addition · organocatalysis
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10890
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Highly Enantioselective Michael Additions
COMMUNICATION
Chem. 2007, 72, 288; c) H. Cui, Y. Li, C. Zheng, G. Zhao, S. Zhu, J.
Fluorine Chem. 2008, 129, 45.
toluene (95% yield, 83% ee), n-hexane (93% yield, 80% ee),
CH2Cl2 (84% yield, 88% ee).
[11] See the Supporting Information for details.
[12] Several other solvents were also screened for catalyst 3d with inferi-
or results: DMF (94% yield, 66% ee), THF (85% yield, 83% ee),
Received: August 23, 2008
Published online: November 10, 2008
Chem. Eur. J. 2008, 14, 10888 – 10891
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10891