Convenient preparation of chiral α,β-epoxy ketones via claisen-schmidt condensation-epoxidation sequence

Article abstract of DOI:10.1002/adsc.200600592

A novel Clasisen-Schmidt condensation-epoxidation sequence of aldehydes and ketones was developed to produce a series of chiral α,β-epoxy ketones under asymmetric phase-transfer catalytic conditions. The organocatalytic method reported here can afford chiral α,β-epoxy ketones under mild conditions with moderate to good yields and up to 96% ee.

Full text of DOI:10.1002/adsc.200600592

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DOI: 10.1002/adsc.200600592
Convenient Preparation of Chiral a,b-Epoxy Ketones via
Claisen–Schmidt Condensation-Epoxidation Sequence
Yongcan Wang,a Jinxing Ye,b,* and Xinmiao Lianga,b,*
a
Dalian Institute of Chemical Physics, Chinese Academy of Science, 457 Zhongshan Road, Dalian 116023, Peopleꢀs
Republic of China
Phone: (+86)-411-8437-9519; fax: (+86)-411-8437-9539; e-mail: liangxm@dicp.ac.cn
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, Peopleꢀs
b
Republic of China
Phone/Fax: (+86)-21-6425-1830
Received: November 14, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A novel Clasisen–Schmidt condensation-
epoxidation sequence of aldehydes and ketones was
developed to produce a series of chiral a,b-epoxy
ketones under asymmetric phase-transfer catalytic
conditions. The organocatalytic method reported
here can afford chiral a,b-epoxy ketones under
mild conditions with moderate to good yields and
up to 96% ee.
of enones. The reaction of a ketone and an aldehyde
can occur under aqueous or alcoholic alkaline condi-
tions. Since a base is needed in both condensation
and epoxidation, we envisioned that it would be possi-
ble to combine the two reactions into a one-pot se-
quential process. We hoped that the CSC products
could be directly converted to epoxy ketones through
asymmetric phase-transfer catalytic epoxidation with-
out any isolation. Such a one-pot reaction sequence is
a highly efficient and economic method in organic
synthesis. To the best of our knowledge, this combina-
tion of condensation and epoxidation process has not
been reported before. We herein present our results
on the one-pot CSC-asymmetric epoxidation reaction
to access chiral a,b-epoxy ketones. The aldehyde and
Keywords: aldehydes; asymmetric catalysis; con-
densation; epoxidation; ketones; one-pot
Chiral epoxides are important intermediates and pre- ketone were treated with aqueous potassium hydrox-
cursors for further chemical transformations.[1] In ide to yield the enone. TCCA and chiral quaternary
recent years, a clean and efficient asymmetric phase- ammonium salt were then added to this mixture to
transfer catalytic epoxidation access to chiral a,b- afford the corresponding a,b-epoxy ketone with mod-
epoxy ketones has become particularly attractive in erate to high yield and satisfactory enantioselectivity
the development of asymmetric processes.[2–9] A series (Scheme 1).
of chiral quaternary ammonium salts such as Cincho-
na alkaloid derivatives and N-spiro C2-symmetric bi-
naphthyl derivatives have shown high catalytic effi-
ciency and remarkable asymmetric control. In these
bi- or triphase catalytic systems, a variety of oxidants
such as hydrogen peroxide, sodium or potassium hy-
pochlorite have demonstrated different reaction activ-
ities and selectivities under different reaction condi-
tions. Recently, we have reported that a novel oxida-
tion system, trichloroisocyanuric acid (TCCA) with
an inorganic base such as potassium hydroxide, could
serve as an efficient alternative for these oxidants in
the epoxidation of enones with high activity and
enantioselectivity under chiral phase-transfer condi-
tions.[10]
It is well known that the Claisen–Schmidt conden-
sation (CSC) is a convenient method for the synthesis quence for the preparation of chiral a,b-epoxy ketones.
Scheme 1. Claisen–Schmidt condensation-epoxidation se-
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Yongcan Wang et al.
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Table 1. Condensation of benzaldehyde and acetophenone.
Entry
Conditions
Time [h]
Conversion [%][a]
1
2
3
toluene/10% KOH aq./4 (5% mol)
toluene/50% KOH aq./4 (5% mol)
10% KOH aq.
2415
2486
2496
420% KOH aq.
24 94
5
6
40% KOH aq.
50% KOH aq.
6
2
97
98
[a]
The values of conversion were obtained by GC analysis base on acetophenone.
Table 2. One-pot condensation-epoxidation of benzaldehyde and acetophenone.
Entry
KOH [equivs.]
TCCA [equivs.]
Catalyst%
Time [h][a]
Conversion [%][b]
ee [%][c]
1
2
3
46.0
5
3.0
3.0
6.0
1.0
6.0
12.0
0.67
0.67
1.0
5
1.0
2.0
10
5
10
8
1
1
24
2488
8
>99
85
84
>99
>99
87
87
2472
2477
86
87
6
[a]
The epoxidation time.
[b]
[c]
The values of conversion were obtained by HPLC analysis based on chalcone.
Determined by HPLC using a Chiralpakꢂ OD-H column.
Preliminary studies focused on the investigation of um hydroxide solution was used, the condensation
the condensation of benzaldehyde and acetophenone was completed (>98% conversion) in 2 h to yield the
under phase-transfer catalytic conditions. The reaction chalcone in 92% isolated yield. This encouraging
condition was similar to the epoxidation that we had result indicates that the direct conversion of benzalde-
reported using chiral quaternary ammonium salt 4 as hyde and acetophenone to a chiral epoxy chalcone
phase-transfer catalyst.[10a] But under the toluene/ under one-pot conditions is feasible.
aqueous biphasic conditions, the reaction was time-
Further studies show that this one-pot condensa-
consuming with a low conversion (Table 1, entries 1 tion-epoxidation sequence can be simply achieved.
and 2). Then we turned our interest to the CSC reac- The condensation mixture was transferred to PTC ep-
tion under aqueous conditions. It has been reported oxidation conditions similar to our reported proce-
that the CSC reaction could take place under aqueous dure by adding toluene, TCCA and catalyst 4, and the
conditions by using cetyltrimethylammonium bromide corresponding epoxide was obtained after 24h with
(CTMAB) as a surfactant.[11] Unfortunately, such a 85% ee (Table 2, entry 1). The epoxidation was in-
process was unsuitable in our CSC-asymmetric epoxi- complete using 0.67 equivalents of TCCA and 3.0
dation sequence because the epoxidation of enones equivalents of potassium hydroxide with 5% mol of
could be catalyzed by CTMAB as well,[12] which catalyst. However, the reaction was efficiently com-
would cause low enantioselectivity. Our experiment plete within 8 h with only 5% mol of catalyst using
indicated that the condensation of benzaldehyde and 1.0 equivalent of TCCA and 6.0 equivalents of 50%
acetophenone could take place in 10% potassium hy- potassium hydroxide aqueous (Table 2, entries 2–4).
droxide aqueous at room temperature without We reasoned that the dichloroisocyanuric acid pro-
CTMAB, but the reaction rate was slow (Table 1, duced by TCCA with one molecule of potassium hy-
entry 3). Further experiments showed that the reac- droxide is not an efficient reagent to produce the oxi-
tion rate increased with higher concentrations of dant hypochlorite. While using 1.0 equivalent of
aqueous potassium hydroxide. When a 50% potassi- TCCA, only highly active TCCA was involved in the
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Adv. Synth. Catal. 2007, 349, 1033 – 1036

Convenient Preparation of Chiral a,b-Epoxy Ketones
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Table 3. One-pot condensation-epoxidation of aldehydes and ketones.
Entry
R1
R2
Time [h][a]
Yield [%]
ee [%][b9
1
2
3
44
5
6
7
8
4-ClC6H4
4-BrC6H4
4-ClC6H4
6H4
2-ClC6H4
4-NO2C6H4
Ph
Ph
Ph
4-ClC6H4
Ph
Ph
Ph
10 (3)
12 (4)
14(6)
10 (3)
9 (4)
12 (10)
24(6)
24(10)
68
75
73
82
61
68
66
64
75
80
93
84
77
96
91
81
eC
c
d,e
e
4-MeOC6H4
Ph
1-Naphthyl
[a]
The value in parentheses is the CSC reaction time.
[b]
[c]
[d]
[e]
Determined by HPLC using a Chiralpakꢂ OD-H column or a Chiralpakꢂ OJ-H column.
10% KOH aqueous was used.
The conversion of epoxidation is 81%.
10% mol of catalyst was used.
epoxidation. More experiments showed that the epox- action mixture was stirred at 08C until the enone disap-
peared (detected by TLC). To the resultant mixture was
added water (3 mL) and the whole was extracted with ether
(3”15 mL). The organic phase was dried over anhydrous
Na2SO4 and evaporated under vacuum. The residue was pu-
rified on silica gel column with petroleum ether/ethyl ace-
tate as eluent giving the corresponding epoxyketone. For
more details, see Supporting Information.
idation was incomplete with 1 mol% catalyst even
when using 2.0 equivalents of TCCA and 12.0 equiva-
lents of 50% potassium hydroxide solution.
To test the generality of this procedure, a series of
aldehydes and ketones was examined. As shown in
Table 3, all of the benzaldehydes and acetophenones
were converted to the corresponding chiral epoxy ke-
tones with satisfactory yields and enantioselectivities
up to 96% ee. The enantioselectivity of the one-pot
condensation-epoxidation reactions was comparable
to that of the previous asymmetric phase-transfer cat-
alytic epoxidation of enones. Other kinds of aryl alde-
hyde, such as 2-naphthaldehyde, also gave good re-
sults, while alkyl ketones or alkyl aldehydes gave
poor epoxidation results (not shown in Table 3).
In summary, a novel one-pot Claisen–Schmidt con-
densation-asymmetric phase-transfer catalytic epoxi-
dation procedure was developed to prepare chiral
a,b-epoxy ketones. The method reported here allows
us to obtain chiral a,b-epoxy ketone simply from an
aldehyde and a ketone under mild conditions with
high enantioselectivity. It is a valuable alternative
method for the synthesis of chiral a,b-epoxy ketones.
References
[1] For recent representative reviews, see: a) V. K. Aggar-
wal, in: Comprehensive Asymmetric Catalysis, (Ed.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, p 679; b) Asymmetic Organocatalysis,
(Ed.: A. Berkessel, H. Grçger), Wiley-VCH, Wein-
heim, 2005, p 290; c) M. J. Porter, J. Skidmore, Chem.
Commun. 2000, 1215; d) W. Adam, C. R. Saha-Mçller,
P. A. Ganeshpue, Chem. Rev. 2001, 101, 34 99; e) P. I.
Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43,
5138; f) Q.-H Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, K.-X.
Su, Chem. Rev. 2005, 105, 1603.
[2] a) B. Lygo, P. G. Wainwright, Tetrahedron Lett. 1998,
39, 1599; b) B. Lygo, P. G. Wainwright, Tetrahedron
1999, 55, 6289; c) B. Lygo, D. C. M. To, Tetrahedron
Lett. 2001, 42, 1343; d) B. Lygo, D. C. M. To, Chem.
Commun. 2002, 2360.
Experimental Section
[3] a) S. Arai, H. Tsuge, T. Shioiri, Tetrahedron Lett. 1998,
39, 7563; b) S. Arai, M. Oku, M. Miura, T. Shioiri, Syn-
lett 1998, 1201; c) S. Arai, H. Tsuge, M. Oku, M. Miura,
T. Shioiri, Tetrahedron 2002, 58, 1623.
General Procedure for the One-Pot Condensation-
Epoxidation
A
suspension of aldehyde (1.00 mmol) and ketone
[4] E. J. Corey, F.-Y. Zhang, Org. Lett. 1999, 1, 1287.
[5] W. Adam, P. B. Rao, H. G. Degen, A. Levai, T. Pato-
nay, C. R. Saha-Mçller, J. Org. Chem. 2002, 67, 259.
[6] M. T. Allingham, A. Howard-Jones, P. J. Murphy, D. A.
Thomas, P. W. R. Caulkett, Tetrahedron Lett. 2003, 44,
8677.
(1.00 mmol) in 50% KOH aqueous solution (0.67 g,
6.00 mmol KOH) was stirred at 258C until the reaction was
complete (detected by GC). Toluene (3.0 mL) and catalyst 4
(0.05 mmol) were then added to the resulted mixture and
cooled to 08C. TCCA was added in one portion and the re-
Adv. Synth. Catal. 2007, 349, 1033 – 1036
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Yongcan Wang et al.
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[7] T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am.
Chem. Soc. 2004, 126, 6844.
[8] S. Jew, J.-H. Lee, B.-S. Jeong, M.-S. Yoo, M.-J. Kim, Y.-
J. Lee, J. Lee, S. Choi, K. Lee, M. S. Lah, H. Park,
Angew. Chem. Int. Ed. 2005, 44, 1385.
[10] a) J. Ye, Y. Wang, R. Liu, G. Zhang, Q. Zhang, J. Chen,
X. Liang Chem. Commun. 2003, 2714; b) J. Ye, Y.
Wang, X. Liang, Adv. Synth. Catal. 2004, 346, 691.
[11] a) F. Fringuelli, G. Pani, O. Piermatti, F. Pizzo Tetrahe-
dron 1994, 50, 11499; b) C. D. Mudaliar, K. R. Nivalkar,
S. H. Mashraqui, Org. Prep. Proced. Int. 1997, 29, 584.
[12] F. Toda, H. Takumi, M. Nagami, K. Tanaka, Heterocy-
cles 1998, 47, 469.
[9] K. Hori, M. Tamura, K. Tani, N. Nishiwaki, M. Ariga,
Y. Tohda, Tetrahedron Lett. 2006, 47, 3115.
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