A convenient and efficient one-pot way to synthesize α,β-epoxy ketones directly from acetophenones and arylaldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.11.110

A convenient and efficient one-pot way to synthesize α,β-epoxy ketones directly from ketones and aldehydes has been described. Reactions were carried out at room temperature and the corresponding α,β-epoxy ketones were isolated in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.11.110

Tetrahedron Letters 50 (2009) 651–655
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A convenient and efficient one-pot way to synthesize
directly from acetophenones and arylaldehydes
a,b-epoxy ketones
*
Lun-Zhi Dai, Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient one-pot way to synthesize a,b-epoxy ketones directly from ketones and alde-
Received 22 October 2008
Revised 21 November 2008
Accepted 22 November 2008
Available online 3 December 2008
hydes has been described. Reactions were carried out at room temperature and the corresponding
a,b-
epoxy ketones were isolated in moderate to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
a
,b-Epoxy ketones have played a pivotal role in many organic
reactions because they could be readily transformed into various
synthetically useful intermediates, such as - and b-hydroxy car-
bonyls,
,b-epoxy alcohols and 1,3-diols.1
The Darzens reaction2 is a well-known synthetic method for
generating ,b-epoxy ketones from -halo carbonyl compounds
and aldehydes directly. However, the limitation of Darzens reac-
size
a
,b-epoxy ketones directly in a one-pot manner for the first
time. This synthetic protocol involves two steps: (i) formation of
enone from ketone and aldehyde; (ii) epoxidation of enone with
H2O2 (Scheme 2).
a
a
The reaction was initially carried out using equimolar amounts
of ketone 1a and aldehyde 2a in the presence of catalytic amount
of 10% aqueous NaOH (0.3 equiv) under solvent free conditions.
When the starting materials were consumed completely, 1.0 mL
of 30% H2O2 was slowly added to the above system at 0 °C. To
our disappointment, the reaction gave a very poor result. However,
it was found that when the reaction was carried out in methanol,
the reaction outcome could be improved significantly. The forego-
ing experiment showed that 1.0 equiv of base was the best choice
to the reaction. It should be noted that if the solubility of the
a
a
tion is the inconvenience in the preparation of
compounds.
Epoxidation of
to synthesize
,b-epoxy ketones.3 This method usually requires
nucleophilic oxidation under basic conditions. However, various
,b-unsaturated ketones should be obtained from the aldol reac-
a-halo carbonyl
a,b-unsaturated ketones is another general way
a
a
tion of ketones and aldehydes firstly, which made this synthetic
method to be more complicated. What is more, sometimes the
formed
a,b-unsaturated ketone in methanol was poor, the more
preparation of
a
,b-unsaturated ketones from ketones and alde-
amount of solvent should be required.
hydes is troublesome according to the procedures reported before.4
For example, subjecting 1.0 equiv of 2-prop-2-ynyloxybenzalde-
hyde 1a and 2.0 equiv of 1-(4-chlorophenyl)ethanone 2a into the
aqueous NaOH solution without any other solvents, we could only
get product 3a rather than the corresponding enone (Scheme 1).
Only after the aldol reaction product 3a was dissolved in MeOH
with further addition of NaOH upon a prolonged reaction time,
the corresponding enone was then finally obtained. Further exper-
iments revealed that the formed enone could also be partially
hydrolyzed to 3a under either weak acidic or weak basic condi-
tions, causing some trouble to obtain pure enone for further use.
Therefore, we envisaged that if the formed enone could be directly
After a series of careful examination of the reaction conditions,
we found that subjecting equimolar amounts of ketone 1a, alde-
hyde 2a, and aqueous NaOH solution in methanol at room temper-
ature resulted in the production of
a,b-unsaturated ketone
exclusively without the formation of the corresponding aldol prod-
uct 3a. Then, adding excess amounts of 30% hydrogen peroxide
slowly afforded
in good yield.
a,b-epoxy ketone 4a immediately as white solid
This simple and efficient reaction procedure could be success-
fully extended to a variety of ketones and aldehydes.5 The results
of these studies are listed in Table 1. Treating 1-(4-chloro-
phenyl)ethanone 2a with aryl aldehydes such as 1a and 1b pro-
used for further epoxidation without isolation to synthesize
a,b-
duced the corresponding a,b-epoxy ketones 4a and 4b in
epoxy ketone from ketone and aldehyde in a one-pot manner,
these problems would be easily resolved.
In this Letter, we wish to report a convenient and efficient
method using ketones and aldehydes as raw materials to synthe-
moderate yields (Table 1, entries 1 and 2), although when aliphatic
aldehyde was used into this reaction, no desired product was ob-
tained along with the recovery of 54% of 2a (Table 1, entry 3). Con-
ducting other ketones such as 2b and 2c with various aldehydes
under the standard conditions afforded the corresponding
a,b-
epoxy ketones in moderate to good yields (Table 1, entries 4–9).
As for the aldehyde 1h bearing two strongly electron-donating
* Corresponding author. Tel.: +86 21 54 92 51 37; fax: +86 21 64166128.
E-mail address: Mshi@mail.sioc.ac.cn (M. Shi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.110

652
L.-Z. Dai, M. Shi / Tetrahedron Letters 50 (2009) 651–655
O
O
OH
O
O
10% aq. NaOH
+
Cl
O
Cl
1a
2a
3a
Scheme 1. Aldol reaction between 2-Prop-2-ynyloxybenzaldehyde 1a and 1-(4-Chlorophenyl)ethanone 2a in the aqueous NaOH solution.
donating group substituted acetophenones 2d, 2e, and 2f as the
O
O
O
O
step 1
step 2
substrate to react with various aryl aldehydes, affording the de-
sired products in good to excellent yields (Table 1, entries 11–20).
Further examination of the scope and limitations of the reaction
surprisingly revealed that treatment of 3-phenylpropenal 1l and 1-
phenylethanone 2c under the optimized conditions only afforded
1-phenyl-3-(3-phenyloxiranyl)propenone 5 in 35% yield rather
O
+
R1
R2
R1
R2
R2
R1
Scheme 2. Protocol for the one-pot synthesis of a,b-epoxy ketones.
methoxy groups on the aromatic ring, no reaction occurred (Table
1, entry 10). The best results were obtained by using one electron-
than the corresponding
a,b-epoxy ketone (Scheme 3). Moreover,
using 2-butenal 1m as the substrate under identical conditions
Table 1
Scope of the one-pot reaction for the synthesis of a,b-epoxy ketones from ketones and aldehydes
Entry
1
Aldehyde
Ketone
Product
Yielda (%)
O
O
O
O
78
O
Cl
O
Cl
1a
4a
2a
O
O
O
2
3b
4
2a
68
Cl
4b
1b
Cl
Cl
O
O
O
2a
—
1c
4c
Cl
O
O
O
1a
71
56
60
O
2b
4d
O
O
O
O
5
4e
1d
2c
O
O
O
7
1b
2c
4g
Cl
Br
O
O
8
2c
62
Br
4h
1f
(continued on next page)

L.-Z. Dai, M. Shi / Tetrahedron Letters 50 (2009) 651–655
653
Yielda (%)
62
Table 1 (continued)
Entry
Aldehyde
Ketone
Product
O
O
O
9
10
11
2c
Me
4i
1g
Me
O
O
O
2c
—
O
O
O
O
1h
4j
O
O
O
O
O
1b
78
Cl
4k
2d
O
Cl
O
O
13
14
2d
2d
91
80
Cl
1i
O
O
4m
O
1d
O
4n
O
O
O
15
16
17
18
1g
2d
2d
2d
2d
77
87
75
Me
4o
O
O
MeO
O
O
OMe
1j
4p
O
O
O
O
1a
4q
O
O
O
O
54
N
N
1k
4r
(continued on next page)

654
L.-Z. Dai, M. Shi / Tetrahedron Letters 50 (2009) 651–655
Table 1 (continued)
Entry
Aldehyde
Ketone
Product
Yielda (%)
92
O
O
Me
O
19
20
1a
Me
O
O
O
4s
2e
O
1b
90
O
O
Cl
2f
4t
a
Isolated.
b
54% of 1-(4-chlorophynyl)ethanone 2a was recovered.
O
O
O
1) NaOH, MeOH
2) H2O2, 0 oC - rt
O
+
1l
2c
2c
5: 35%
O
O
O
1) NaOH, MeOH
2) H2O2, 0 oC - rt
+
O
1m
6: 0%
Scheme 3. One-pot synthesis of 1-phenyl-3-(3-phenyloxiranyl)propenone.
O
Cl
Cl
7: 19%
O
1) NaOH, MeOH
2) H2O2, 0 oC - rt
O
+
+
O
Cl
1.0 equiv
2.0 equiv
1b
Cl
8
: 6%
Scheme 4. One-pot reaction between 4-chlorobenzaldehyde and acetone under the optimized reaction procedure.
did not result in the formation of product 6. Compared with the
Acknowledgments
synthetic methods reported before, our new synthetic procedure
is very simple to produce these kinds of products.6
Financial support from Shanghai Municipal Committee of Sci-
ence and Technology (06XD14005, 08dj1400100-2), National Basic
Research Program of China (973)-2009CB825300, the National Nat-
ural Science Foundation of China (20872162, 20472096 and
20672127), and Cheung Kong Scholar Program is greatly
appreciated.
We have also attempted the one-pot synthesis of a,b-epoxy ke-
tone from 4-chlorobenzaldehyde 1b and acetone under the similar
reaction conditions. But, it was found that products 7 and 8 were
obtained in 19% yield and in 6% yield, respectively, rather than
the corresponding a,b-epoxy ketone (Scheme 4).
Inspired by the above results, we next examined the reaction of
benzaldehyde with nitroethane under identical conditions. To our
disappointment, complex product mixtures were formed without
the formation of the desired product.
In conclusion, we have developed a one-pot synthetic approach
to synthesize a,b-epoxy ketones from aldehydes and acetophenon-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.110.
es in moderate to excellent yields. Compared with the previously
reported methods, our approach has several advantages, for exam-
ple, easily available starting materials (aldehydes and ketones),
mild reaction conditions, simple procedures, and highly improved
yields. The scope and limitations of this one-pot procedure are still
under progress in our laboratory.
References and notes
1. (a) Jacobsen, E. N. Acc. Chem. Res 2000, 33, 421; (b) Porter, M. J.; Skidmore, J.
Chem. Commun. 2000, 1215; (c) Yadav, V. K.; Kapoor, K. K. Tetrahedron 1995, 51,
8573.
2. For a review, see: Rosen, T.. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 409.

L.-Z. Dai, M. Shi / Tetrahedron Letters 50 (2009) 651–655
655
3. (a) Miyashita, M.; Suzuki, T.; Yoshikoshi, A. Chem. Lett. 1987, 285; (b) Straub, T. S.
Tetrahedron Lett. 1995, 36, 663; (c) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem.
1995, 60, 3887; (d) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599;
(e) McQuaid, K. M.; Pettus, T. R. R. Synlett 2004, 2403; (f) Garcia, R. J. L.; Fajardo,
C.; Fraile, A.; Martin, M. R. J. Org. Chem. 2005, 70, 4300; (g) Yang, S. G.; Hwang, J.
P.; Park, M. Y.; Lee, K.; Kim, Y. H. Tetrahedron 2007, 63, 5184.
4. (a) Wurtz, A. Bull. Soc. Chim. Fr. 1872, 17, 436; (b) Nielsen, A. T.; Houlihan, W. J.
Org. React. 1975, 16, 1; (c) Heathcock, C. H. Science 1981, 214, 395; (d)
Mukaiyama, T. Org. React. 1982, 28, 203; (e) Cravotto, G.; Demetri, A.; Nano, G.
M.; Palmisano, G.; Penoni, A.; Tagliapietra, S. Eur. J. Org. Chem. 2003, 4438.
5. Typical reaction procedures: 2-Prop-2-ynyloxybenzaldehyde 1a (3.0 mmol,
480 mg) and 1-(4-chlorophenyl)ethanone 2a (3.0 mmol, 462 mg) were
dissolved in 10 mL of MeOH, and then 1.2 mL of 10% aqueous NaOH
(3.0 mmol, 120 mg) solution was added at room temperature. The reaction
was monitored by TLC. When the starting materials were consumed completely,
1.0 mL of 30% hydrogen peroxide (16.7 mmol) was slowly added at 0 °C. The
reaction was returned to room temperature. After the reaction completed on the
basis of TLC examination, the mixture was extracted with EtOAc and the
combined organic layers were washed with water for several times to remove
MeOH, dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give a viscous oil, which was purified by chromatography on silica
gel (EtOAc/PE = 1:10) to give 4a as a white solid (0.74 g, 78%). Compound 4a:
Mp. 109–111 °C; IR (NaCl)
m
3295, 3068, 3042, 2924, 2870, 1917, 1694, 1589,
1492, 1456, 1444, 1289, 1239, 1092, 1009 cmÀ1
;
1H NMR (CDCl3, 300 MHz, TMS)
d 2.50 (1H, t, J = 2.4 Hz), 4.12 (1H, d, J = 1.8 Hz), 4.36 (1H, d, J = 1.8 Hz), 4.73 (2H,
d, J = 2.4 Hz), 7.02–7.07 (2H, m), 7.31–7.38 (2H, m), 7.46 (2H, d, J = 8.4 Hz), 8.01
(2H, d, J = 8.4 Hz); 13C NMR (CDCl3, 75 MHz, TMS) d 55.6, 55.8, 60.4, 75.9, 78.0,
111.8, 121.7, 124.6, 125.7, 129.1, 129.6, 129.8, 133.7, 140.3, 155.8, 192.4; MS (EI)
m/z 111 (M+À218, 49.6), 113 (M+À199, 17.4), 139 (M+À173, 100.0), 141
(M+À171, 32.7), 191 (M+À122, 14.9), 193 (M+À120, 5.0), 312 (M+, 1.6); Anal.
Calcd for C18H13ClO3: C, 69.13; H, 4.19. Found: C, 69.08; H, 4.25.
6. (a) Ley, S. V.; Wright, E. A. J. Chem. Soc., Perkin Trans. 1 2000, 1677; (b) Levai, A.;
Silva, A. M. S.; Cavaleiro, J. A. S.; Patonay, T.; Silva, V. L. M. Eur. J. Org. Chem. 2001,
3213; (c) Zhang, J.-L.; Che, C.-M. Chem. Eur. J. 2005, 11, 3899.