Highly enantioselective Michael addition of cyclopentanone with chalcones via novel di-iminium mechanism

Article abstract of DOI:10.1039/b915852a

The highly efficient asymmetric Michael addition reactions of cyclopentanone with chalcones were catalyzed by a simple and commercially available chiral 1,2-diaminocyclohexane-hexanedioic acid, and exhibited good yields (up to 92%) and excellent enantioselectivities (up to 99% ee). A new di-iminium mechanism for the reaction was proposed.

Full text of DOI:10.1039/b915852a

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Highly enantioselective Michael addition of cyclopentanone
with chalcones via novel di-iminium mechanismw
Junfeng Wang, Xin Wang, Zemei Ge,* Tieming Cheng and Runtao Li*
Received (in Cambridge, UK) 3rd August 2009, Accepted 25th November 2009
First published as an Advance Article on the web 12th January 2010
DOI: 10.1039/b915852a
The highly efficient asymmetric Michael addition reactions of
cyclopentanone with chalcones were catalyzed by a simple and
commercially available chiral 1,2-diaminocyclohexane-hexanedioic
acid, and exhibited good yields (up to 92%) and excellent enantio-
selectivities (up to 99% ee). A new di-iminium mechanism for the
reaction was proposed.
The Michael addition reaction is widely recognized as one of
the most important carbon–carbon bond-forming reactions in
organic synthesis.1,2 The catalytic asymmetric Michael addition
Fig. 1 Catalysts screened in the Michael reactions of cyclopentanone
using metal carbanions has been developed with great success.3
In recent years, the organocatalytic asymmetric Michael
addition reaction has undergone rapid development, and
excellent results have been reported for various intermolecular
reactions.4–7 However, organocatalytic asymmetric Michael
addition reactions of simple ketones with chalcones still
remain a challenge probably due to the low reactivity and
high steric hindrance of substrates.8 To the best of our knowledge,
only one example was reported by Wang using an (S)-pyrrolidine-
sulfonamide compound as the catalyst.9 However, the reaction
with chalcones.
ketones.10 The reaction proceeded via a novel intermediate, a
three-component conjugated iminium of the corresponding
a,b-unsaturated ketone. Thus, we assume that if both simple
ketones and a,b-unsaturated ketones could be activated
simultaneously in this system by a suitable amine-acid catalyst,
the asymmetric Michael addition reactions between the two
activated pieces should be possible. Based on this hypothesis,
we screened a various amine-acid catalysts (Fig. 1) for the
reaction of cyclopentanone and chalcone 1a as the model in
MeOH at room temperature (Table 1).
of cyclopentanone and
a chalcone gave only 73% ee
(Scheme 1, 1).9 Herein, we report an asymmetric Michael
addition of cyclopentanone with various chalcones catalyzed
by chiral 1,2-diaminocyclohexane-hexanedioic acid with good
yields and excellent enantioselectivities (Scheme 1, 2).
As shown in Table 1, catalyst L-proline-TEA gave the
Michael product in high yield but with low diastereoselectivity
and enantioselectivity (Table 1, entry 1). However, neither
primary amino-acid (3) and dipeptide (4), nor proline
We previously reported that various ketones, including
C-glycosidic ketones, aryl ketones, and alkyl ketones, could
be easily activated in MeOH by catalyst proline-TEA to
react with aldehydes for the synthesis of a,b-unsaturated
Table 1 Catalyst and additive screening for the reaction of
cyclopentanone and chalcone 1a
Entry Cat. Additive
Yield (%)a drb syn : anti ee (%)b
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
8
8
8
8
8
8
8
TEA
TEA
TEA
—
96
1 : 1
—
—
—
—
—
2 : 3
2 : 3
—
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
27/26
—
—
—
—
Trace
Trace
Trace
Trace
Trace
59
Trace
Trace
58
—
AcOH
—
Scheme 1 Michael reactions of cyclopentanone with chalcones.
AcOHc
—
86/64
31/13
—
87/71
87/71
91/71
92/81
95/87
9
CF3COOHc
o-Cl-PhCOOHc
State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
100191, Beijing, P. R. China. E-mail: Lirt@mail.bjmu.edu.cn,
Zmge@bjmu.edu.cn; Fax: +86-10-82716956; Tel: +86-10-82801504
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and spectral data for compounds M-1 to
M-13; CIF file for M-13b. CCDC 743201. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
b915852a
10
11
12
13
14
a-naphthylacetic acidc 50
PhCH2COOHc
(E)-butene diacid
Hexanedioic acid
56
59
59
a
b
Isolated yield of the corresponding product. Determined by chiral-
c
phase HPLC. The loading of acid additives was 40 mol%.
ꢀc
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Chem. Commun., 2010, 46, 1751–1753 | 1751

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derivatives (5 and 6) showed any catalytic activity (Table 1,
entries 2–5). Then, the simple chiral primary amine (7) and
primary di-amine (8) were also tested as catalysts with HOAc
as an additive. Much to our delight, 20 mol% of (1S,2S)-1,2-
diaminocyclohexane 8 and HOAc catalyzed the reaction
efficiently in 59% yield with 2 : 3 dr and up to 86% ee
(Table 1, entry 7). It is worthy to note that the acid played
an important role in this reaction because catalyst 8 lost
almost all its catalytic capability in the absence of acid
(Table 1, entry 8). This result encouraged us to further
investigate the effect of different kinds of acid additives on
the reaction. It is clear that utilization of a strong acid as the
additive, such as trifluoroacetic acid (TFA), led to the almost
complete loss of the catalytic activity (Table 1, entry 9). In
contrast, all the weak carboxylic acids exhibited significant
catalytic efficiency, and the hexanedioic acid demonstrated the
best promoting capability for the catalysts compared with
other screened acid additives (Table 1, entries 9 to 14).
Table 3 Organocatalyzed direct Michael addition reactions of cyclo-
pentanone to chalcones
drb
Entry Ar1
Ar2
Yield (%)a anti : syn ee (%)b
1c
2c
3c
4c
5c
6c
7c
8c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
69(M-1)
73(M-2)
43(M-3)
83(M-4a) 3 : 2
92(M-5) 3 : 1
87(M-6a) 3 : 2
73(M-7a) 2 : 1
1 : 1
51(M-9a) 3 : 2
3 : 2
2 : 1
2 : 1
97/99
97/98
96/98
98/>99
>99/>99
99/98
>99/>99
95/98
98/99
—/99
98/—
4-CH3Ph
4-MeOPh
4-FPh
4-CNPh
3-ClPh
3-CF3Ph
2-thiophene 61(M-8)
9c
4-MeOPh 2-thiophene M-9a1e
2 : 98
98 : 2
4-NO2Ph 2-thiophene 29(M-10) 1 : 1
M-9a2e
10c
11c
12c
13d
>99/98
97/98
Subsequently, the effect of different solvents on the reaction
was studied in the presence of 20 mol% catalyst 8 and
hexanedioic acid. Solvent screening revealed that the reaction
only proceeded smoothly in protic polar solvents (Table 2,
entries 1–3), which is consistent with our previous discovery
for the aldol condensation reactions.10 The addition of CHCl3 is
favorable for the increase of yield and enantioselectivity, which
may due to the solubility improvement of chalcone substrates
(Table 2, entry 11). Thus, 20 mol% of chiral 1,2-diaminocyclo-
hexane catalyst and 20 mol% of hexanedioic acid additive in a
mixed solvent of CHCl3–MeOH (1: 1) at room temperature
were found to be the most suitable reaction conditions.
4-MeOPh 2-furan
4-CH3Ph Ph
Ph
56(M-11a) 3 : 1
85(M-12a) 3 : 1
81(M-4b) 3 : 2
97/>99
ꢁ98/ꢁ98
—/ꢁ98
ꢁ98/—
ꢁ98/ꢁ99
oꢁ99/oꢁ99
ꢁ97/ꢁ99
ꢁ98/ꢁ98
—/ꢁ98
ꢁ98/—
ꢁ96/oꢁ99
4-FPh
M-4b1e
M-4b2e
3 : 97
99 : 1
14d
15d
16d
17d
Ph
Ph
3-ClPh
3-CF3Ph
85(M-6b) 3 : 2
71(M-7b) 3 : 2
54(M-11b) >2 : 1
86(M-12b) 3 : 2
4-MeOPh 2-furan
4-CH3Ph Ph
M-12b1e
M-12b2e
76(M-13b) 3 : 2
1 : 99
98 : 2
18d
Ph
4-NO2Ph
M-13b2f
>99 : 1 ꢁ99.9/—f
a
b
Isolated yield of the corresponding product. Determined by chiral-
c
phase HPLC. The catalyst used in the reactions was (1R,2R)-1,2-
Under the optimized reaction conditions, the scope of the
reaction was then explored (Table 3). It appears that cyclo-
pentanone could react with various kinds of chalcones, affording
the corresponding Michael addition products in good yields
and excellent enantioselectivities. When Ar1 was a phenyl
group (Table 3, entries 1–8), the property of the substituents
on Ar2 in chalcones did not influence the enantioselectivities,
d
diamino cyclohexane 8. The catalyst used in the reactions was
e
(1S,2S)-1,2-diamino cyclohexane 9. The product was purified by
f
TLC. The product was purified by recrystallization.
but the electron-withdrawing group on Ar2 is obviously
favorable for the increase of the yields. Therefore, chalcones
with 4-cyano substituted Ar2 gave 92% yield, while chalcones
with 4-methoxyl substituted Ar2 gave 43% yields (Table 3,
entries 5 and 3). On the contrary, a higher yield was achieved
for the chalcones with electron-donating substituents on Ar1
than for those with electron-withdrawing groups on Ar1
(Table 3, entries 8–12). Having obtained the satisfactory
results with catalyst 8, we then examined the efficiency of
catalyst 9, the enantiomer of catalyst 8, and the corresponding
opposite enantiomers were obtained with the same results as
well (Table 3, entries 13–18). Moreover, the excellent diastereo-
selectivities (up to >99 : 1) could also be obtained after simple
purification of the crude product by preparative TLC chromato-
graphy (Table 3, entries 9, 13 and 17) or recrystallization
(Table 3, entry 18). Other ketone substrates, such as cyclo-
hexanone and acetophenone were also explored, but almost no
Michael products were discovered. The possible explanation is
that other ketones might be unfavorable for the formation of
the di-iminium intermediate due to the instability or steric
effect of other ketoiminiums.
Table 2 Solvent screening for the Michael reaction of cyclopentanone
to chalcone 1a
Entry
Solvent
Yield (%)a
drb syn : anti
ee(%)b
1
2
3
4
5
6
7
8
EtOH
49
37
30
2 : 3
1 : 2
2 : 3
—
—
—
—
—
—
—
90/79
85/78
96/93
—
—
—
—
—
—
—
Me2CHOH
HOCH2CH2OH
CH2Cl2
CHCl3
PhCH3
THF
CH3CN
DMF
DMSO
Trace
Trace
Trace
Trace
Trace
Trace
Trace
69
9
10
11c
CHCl3–MeOH
2 : 3
99/97
a
Isolated yield of the corresponding product. The reactions were
conducted in the presence of 20 mol% of catalyst 8 and acid additive
To account for the present efficient organocatalytic
asymmetric Michael addition reactions catalyzed by the novel
chiral 1,2-diaminocyclohexane-hexanedioic acid, we propose
b
hexanedioic acid at r.t. for 4 days. Determined by chiral-phase
c
HPLC. At r.t. in dark, CHCl3–MeOH = 1 : 1, for 6 days.
ꢀc
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1752 | Chem. Commun., 2010, 46, 1751–1753

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Crystal data for M-13b: C20H19NO4, M = 337.36, triclinic,
a = 8.061(2), b = 10.513(3), c = 11.444(3) A, U = 884.1(4) A3,
Dc = 1.267 g cmꢁ3, m(Mo-Ka) = 0.089 mmꢁ1, T = 296 K, F(000) =
356, space group P1, Z = 2, 6605 reflections measured, 3262 unique
(Rint = 0.0416) which were used in all calculations. The final
R = 0.0416 and wR = 0.0931 for 2394 observed reflections with
I > 2s(I).
1 P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992.
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and M. Shoji, J. Am. Chem. Soc., 2005, 127, 16028;
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2001, 171.
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in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen,
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Scheme 2 Proposed di-iminium activation of both substrates in the
Michael reactions of cyclopentanone with chalcones.
4 For reviews, see: (a) P. I. Dalko and L. Moisan, Angew. Chem., Int.
Ed., 2004, 43, 5138; (b) A. Berkessel and H. Groger, Asymmetric
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116, 4048; M. T. Hechavarria Fonseca and B. List, Angew. Chem.,
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(d) P. Melchiorre and K. A. Jørgensen, J. Org. Chem., 2003, 68,
4151.
Fig. 2 X-ray structure of product M-13b.
6 Intermolecular Michael reactions of a,b-unsaturated carbonyl
derivatives, see: (a) M. Malmgren, J. Granander and
M. Amedjkouh, Tetrahedron: Asymmetry, 2008, 19, 1934;
(b) G. Szanto, P. Bombicz, A. Grun and I. Kadas, Chirality,
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Loh, Tetrahedron Lett., 2008, 49, 5389; (d) J. W. Xie, W.
Chen, R. Li, M. Zeng, W. Du, L. Yue, Y. C. Chen, Y. Wu,
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Lett., 2007, 9, 4151; (f) L. Hojabri, A. Hartikka,
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M. Ohkubo and H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47,
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that both the Michael donator (ketone) and the receptor
(a,b-unsaturated ketones) could be activated simultaneously
in this reaction system to form the di-iminium transition states
TS1 and TS2 (Scheme 2). It could be seen clearly that TS1 is
sterically unfavorable and TS2 is more feasible leading to the
product with (2R, 10S) configuration, which is consistent with
the X-ray crystal data of product M-13b (Fig. 2).z
In conclusion, we have developed a new method for the
asymmetric Michael addition reactions of cyclopentanone with
chalcones utilizing the simple and commercially available
chiral 1,2-diaminocyclohexane-hexanedioic acid as the
cooperative catalyst. The reaction was highly efficient in terms
of yields (up to 92%), enantioselectivities (up to 99% ee). The
new di-iminium catalytic mechanism proposed herein might
promote the discovery of more potential organocatalysts for
related reactions. Further studies to extend the scope of this
reaction and the design of new catalysts are now in progress.
We are grateful for financial support from the National
Natural Science Foundation of China (No. 20572004) and the
National Key Technology R&D Program (No. 2007BAI34B00).
8 Y. C. Chen, Synlett, 2008, 1919.
9 J. Wang, H. Li, L. S. Zu and W. Wang, Adv. Synth. Catal., 2006,
348, 425.
10 J. F. Wang, M. Lei, Q. Li, Z. M. Ge, X. Wang and R. T. Li,
Tetrahedron, 2009, 65, 4826.
Notes and references
z Single crystals of M-13b were recrystallised from a mixture solvent of
petroleum ether : EtOAc (2 : 1), mounted in inert oil and transferred to
the cold gas stream of the diffractometer.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 1751–1753 | 1753