One-pot synthesis of α,β-epoxy ketones by palladium-catalyzed epoxidation-oxidation of terminal allylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.01.065

Described herein is a one-pot synthesis of α,β-epoxy ketones using a palladium-catalyzed epoxidation-oxidation sequence. Functionalized terminal allylic alcohols are treated with m-CPBA under mild reaction conditions to obtain the α,β-epoxy ketones. The m

Full text of DOI:10.1016/j.tetlet.2010.01.065

Tetrahedron Letters 51 (2010) 1671–1673
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One-pot synthesis of a,b-epoxy ketones by palladium-catalyzed
epoxidation–oxidation of terminal allylic alcohols
*
Fateh V. Singh, Jesus M. Pena, Hélio A. Stefani
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Described herein is a one-pot synthesis of a,b-epoxy ketones using a palladium-catalyzed epoxidation–
oxidation sequence. Functionalized terminal allylic alcohols are treated with m-CPBA under mild reaction
Received 12 December 2009
Revised 18 January 2010
Accepted 19 January 2010
Available online 1 February 2010
conditions to obtain the ,b-epoxy ketones. The main benefit of this approach is that the epoxidation of
a
the terminal double bond and the oxidation of the secondary alcohol occured in the same reaction under
mild reactions and both electron-donating and electron-withdrawing functionalities are tolerated in the
reaction sequence.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
were synthesized by the homologation of vicinal polyketones with
diazomethane.11 Lange et al.1 reported the synthesis of these
a
,b-Epoxy ketones are key intermediates in the syntheses of
chemical entities by using m-CPBA to epoxidize chalcones. Cella
et al.12 reported the tetramethylpiperadine–HCl-catalyzed epoxi-
dation–oxidation of endocyclic allylic alcohols by m-CPBA.
several biologically important synthetic and natural products. Re-
cently, aromatic compounds possessing
a,b-epoxy ketone cores
were used as synthetic intermediates in the synthesis of nitro-
gen-containing heterocycles that were reported to be potent and
selective CB1 cannabinoid receptor antagonists1 and novel non-
We previously demonstrated the oxidative cleavage of the ter-
minal double bond in 1,1-diarylethenes using m-CPBA as the oxi-
dant.13 In the context of an ongoing project in our laboratory, we
needed to cleave the terminal double bond of 1,2-diarylprop-2-
mutagenic antibacterial agents.2
a,b-Epoxy ketones have also been
used as precursors in the synthesis of optically active phenylprop-
ylene oxides.3 In addition, cyclic epoxy ketones have been identi-
fied as key starting materials for the synthesis of functionalized
isophosphinoline compounds,4 chromones5, and ipriflavones.6
Table 1
The effects of various catalysts on the epoxidation of 1,2-diphenylprop-2-en-1-ol (1a)
with m-CPBA
However, the synthesis of
oughly examined, and most of the reports on this topic focus on the
epoxidation of ,b-unsaturated ketones with peracids. Arylated
a,b-epoxy ketones has not been thor-
a
epoxy ketones can be synthesized by treating 1,2-diarylethane-
1,2-diones with dimethyloxosulfonium methylide, but this
approach suffers from the formation of side products.7 In the
mid-1980s, Griesbaum and his research group described the syn-
thesis of
a,b-epoxy ketones by ozonizing acyclic, conjugated
Entry
Catalysta
Reaction time (h)
Yieldb (%)
dienes, but this approach also leads to the formation of undesired
side products.8 Epoxy ketone cored architectures have been syn-
thesized by the nucleophilic acylation of chlorocarbonyl com-
pounds, but the products are obtained in low yields.9 In the past
1
2
3
4
5
PdCl2
4
6
7
10
8
81
69
21
12
—
Fe(acac)3
Cu(OAc)2
CuI
two decades,
a,b-epoxy ketones have been synthesized by the
NiCl2
epoxidation of chalcones using polyamino acids as catalysts; this
reaction involves a triphasic system that consists of an aqueous,
basic peroxide, an organic solvent, and an insoluble polyamino acid
6
7
8
9
10
11
Pd(OAc)2
FeCl3
FeSO4
Pd(PPh3)4
PdCl2(dppf)ÁCH2Cl2
TDBzDP
8
57
16
—
—
35
22
10
24
24
24
24
such as poly-L a,b-epoxy ketones
-leucine.10 More recently, arylated
a
5 mol % of catalyst.
The yields were determined by GC analysis.
* Corresponding author. Tel.: +55 11 818 3654; fax: +55 11 3 815 4418.
E-mail address: hstefani@usp.br (H.A. Stefani).
b
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.065

1672
F. V. Singh et al. / Tetrahedron Letters 51 (2010) 1671–1673
Table 2
Table 3
The effect of solvent on the epoxidation of 1,2-diphenylprop-2-en-1-ol (1a) with m-
CPBA
The optimization of equivalents of m-CPBA and palladium chloride in the epoxidation
of 1,2-diphenylprop-2-en-1-ol (1a) with m-CPBA
Entry
Solvent
Reaction time (h)
Yielda (%)
Entry
m-CPBA (equiv)
PdCl2 (mol %)
Reaction time (h)
Yielda (%)
1
2
3
4
5
6
7
DCM
MeOH
DMF
4
20
24
24
24
24
10
81
15
nr
nr
Trace
nr
52
1
2
3
4
5
6
7
8
1
5
5
5
5
2
5
8
10
10
10
8
8
12
4
—
1.5
2.0
3.0
2.0
2.0
2.0
2.0
35
82
70
53
82
83
80
THF
Toluene
1,4-Dioxane
CCl4
4
4
a
The yields were determined by GC analysis.
a
The yields were determined by GC analysis.
en-1-ol derivatives. In order to identify new approaches for the
oxidative cleavage of terminal double bonds, we focused our atten-
tion on the reaction between m-CPBA and the terminal double
bond of allylic alcohols.
Herein, we report a general approach for the one-pot synthesis
a,b-epoxy ketones by the palladium-catalyzed epoxidation–oxi-
dation of functionalized terminal allylic alcohols using m-CPBA un-
of
Table 4
The epoxidation of allylic alcohols 1a–k with m-CPBA
O
m-CPBA/DCM
PdCl2 (5%)
R
R
O
OH
1
2
Entry
a
Allylic alcohol (1)
Product (2)
Reaction time (h)
4
Yielda (%)
81
O
OH
OH
OH
O
Cl
Br
Cl
Br
O
b
c
5
5
85
83
O
O
O
Me
Me
O
d
e
f
8
14
8
70
64
62
OH
O
O
O
O
Cl
OH Cl
OH
OH
Cl
OH
Cl
O
g
13
12
10
72
75
64
OH Cl
OH
OH Cl
OH
OH
O
O
h
OMe
OMe
O
OMe
OMe
OMe
OMe
i
j
OH
OH
O
O
8
7
73
77
O
O
k
O
O
a
Isolated yields.

F. V. Singh et al. / Tetrahedron Letters 51 (2010) 1671–1673
1673
der mild reaction conditions. The strength of this approach is that
Acknowledgments
the epoxidation of terminal double bond and oxidation of allylic
alcohol occurring in the same reaction under mild conditions and
permits flexibility of introducing an electron-donating or elec-
tron-accepting functionality in epoxy ketone cored aromatic
architectures.
The authors are grateful to FAPESP (Grant 07/59404-2, fellow-
ship process 07/51466-9, and CNPq 300.613/2007-5) for financial
support.
Prior to developing new m-CPBA-mediated oxidation reactions,
we focused on the synthesis of functionalized allylic alcohols. We
have synthesized compounds 1a–k by the nucleophilic addition
of (1-phenylvinyl)magnesium bromide to various aldehydes.14
After preparing the necessary allylic alcohols, we turned our
attention to the m-CPBA-mediated epoxidation of the terminal
double bonds in allylic alcohols 1a–k. 1,2-Diphenylprop-2-en-1-
ol (1a) was chosen as a model substrate, and a variety of conditions
were screened (Table 1). The reactions were monitored by TLC or
GC.
In order to find an appropriate catalyst for the epoxidation of
1,2-diphenylprop-2-en-1-ol (1a), we evaluated several transition
metal catalysts. The best result was obtained with PdCl2 (Table 2,
entry 1), and the product was formed in 81% yield.
We screened a number of solvents in this epoxidation reaction
(Table 2). The best result was achieved with dichloromethane
(DCM), and the product was obtained in 81% yield (Table 2, entry
1). In contrast, no product was formed when the reaction was
run in DMF, THF, or 1,4-dioxane.
Next, we focused on determining the optimal amount of
m-CPBA for this epoxidation reaction. We performed the same
reaction using 1.0, 1.5, 2.0, and 3.0 equiv of m-CPBA (Table 3, en-
tries 1–4), and the maximum yield (82%) of the desired product
(2a) was observed with 2.0 equiv of m-CPBA (entry 3).
The catalyst loadings were also evaluated (Table 3, entries 5–8),
and the best yield (83%) was obtained with 8 mol % of PdCl2 (Table
3, entry 7). However, using 5 mol % of PdCl2 provided the product
in nearly the same yield (82%) (Table 3, entry 6). As such, all the
subsequent experiments employed 5 mol % of PdCl2.
Our next step was to optimize the synthesis of phenyl(2-pheny-
loxiran-2-yl)methanone (2a) from diphenylprop-2-en-1-ol (1a)
(Table 4). The best conditions were found to include 1.0 equivalent
of 1,2-diphenylprop-2-en-1-ol (1a), 2.0 equiv of m-CPBA, and
5 mol % of PdCl2 in DCM; this mixture was stirred at room temper-
ature under nitrogen for 4 h. Using these optimized conditions, we
prepared a series of aryl(2-phenyloxiran-2-yl)methanones (com-
pounds 2a–k) (see Table 4).15
We found that the oxidation reaction was successful with both
electron-donating and electron-withdrawing substitutions on the
benzene ring, but in general, the products were obtained in better
yields when an electron-withdrawing substituent was present.
References and notes
1. Lange, J. H. M.; Coolen, H. K. A. C.; Stuivenberg, H. H.; Dijksman, J. A. R.;
Herremans, A. H. J.; Ronken, E.; Keizer, H. G.; Tipker, K.; McCreary, A. C.;
Veerman, W.; Wals, H. C.; Stork, B.; Verveer, P. C.; den Hartog, A. P.; de Jong, N.
M. J.; Adolfs, T. J. P.; Hoogendoorn, J.; Kruse, C. G. J. Med. Chem. 2004, 47, 627.
2. Dickens, J. P.; Ellames, G. J.; Hare, N. J.; Lawson, K. R.; McKay, W. R.; Metters, A.
P.; Myers, P. L.; Pope, A. M. S.; Upton, R. M. J. Med. Chem. 1991, 34, 2356.
3. Capriati, V.; Florio, S.; Luisi, R.; Nuzzo, I. J. Org. Chem. 2004, 69, 3330.
4. Ruf, S. G.; Dietz, J.; Regitz, M. Tetrahedron 2000, 56, 6259.
5. Donnelly, J. A.; Maloney, D. E. Tetrahedron 1979, 35, 2875.
6. Varga, M.; Batori, S.; Kövari-Radkai, M.; Prohaszka-Nemet, I.; Vitanyi-Morvai,
M.; Böcskey, Z.; Bokotey, S.; Simon, K.; Hermecz, I. Eur. J. Org. Chem. 2001, 3911.
7. Pierre, J. L.; Guidoti, R.; Arnaud, P. Bull. Soc. Chim. France 1967, 4, 1439.
8. (a) Griesbaum, K.; Zwick, G. Chemische Berichte 1986, 119, 229; (b) Griesbaum,
K.; Zwick, G. Chemische Berichte 1985, 118, 3041.
9. Huenig, S.; Marschner, C. Chemische Berichte 1990, 123, 107.
10. Kroutil, W.; Lasterra-Sanchez, M. E.; Maddrell, S. J.; Mayon, P.; Morgan, P.;
Roberts, S. M.; Thornton, S. R.; Todd, C. J.; Tuter, M. J. Chem. Soc. Perkin Trans. 1
1996, 23, 2837.
11. Hartung, R. E.; Paquette, L. A. Heterocycles 2004, 64, 23.
12. Cella, J. A.; McGrath, J. P.; Kelley, J. A.; Soukkary, O. E.; Hilpert, L. J. Org. Chem.
1977, 42, 2079.
13. Singh, F. V.; Milagre, H. M. S.; Eberlin, M. N.; Stefani, H. A. Tetrahedron Lett.
2009, 50, 2312.
14. General procedure for the synthesis of 1,2-diphenylprop-2-en-1-ol derivatives 1a–
k: a solution of 1-bromo-1-phenylethylene (10 mmol) in THF (20 mL) was
added dropwise to magnesium metal (0.264 g, 11 mmol) and
a catalytic
amount of iodine at room temperature under a N2 atmosphere. After the Mg
was consumed, corresponding aldehyde (10 mmol) was added in one portion
at 0 °C, and the mixture was stirred vigorously for 4–14 h at room temperature.
The reaction mixture was neutralized with NH4Cl solution, and the resulting
solution was poured into water and was extracted with ethyl acetate. The
organic layer was dried over MgSO4 and was evaporated under vacuum. The
pure compound was isolated in good yield after purification via flash column
chromatography using 15–20% ethyl acetate in hexane as the eluent. 1,2-
Diphenylprop-2-en-1-ol (1a): Yield: 81%; yellow oil; 1H NMR (300 MHz, CDCl3)
d 2.18 (br s, 1H, OH), 5.45 (s, 1H, CH), 5.48 (s, 1H, CH), 5.67 (s, 1H, CH), 7.18–
7.39 (m, 10H, ArH); 13C NMR (75.5 MHz, CDCl3) d 74.24, 114.24, 127.19, 127.25,
127.84, 127.97, 128.46, 128.66, 139.59, 142.08; CG/MS: m/z (relative, %) 210
(27), 107 (42), 104 (100), 79 (44), 77 (48). 1-(4-Chlorophenyl)-2-phenylprop-2-
en-1-ol (1b): Yield: 78%; yellow oil; 1H NMR (300 MHz, CDCl3) d 2.18 (br s, 1H,
OH), 5.46 (s, 1H, CH), 5.50 (s, 1H, CH), 5.68 (s, 1H, CH), 7.22–7.40 (m, 9H, ArH);
13C NMR (75.5 MHz, CDCl3) d 75.18, 114.11, 126.80, 127.62, 128.10, 128.14,
128.38, 133.27, 138.74, 140.08, 150.03; CG/MS: m/z (relative, %) 244 (36), 104
(100), 93 (41), 77 (67).
15. General procedure for the synthesis of a,b-epoxy ketones 1a–k: a solution of the
olefinic alcohol (1a–k) (0.5 mmol) in dichloromethane (5 mL) in a two-necked
round-bottomed flask was cooled to À78 °C under a nitrogen atmosphere. A
solution of m-chloroperbenzoic acid (172 mg, 1.0 mmol) in dichloromethane
(5 mL) was added dropwise. Next, PdCl2 (4.4 mg, 5 mol %) was added, and the
reaction solution was stirred for 4–14 h at room temperature. The reaction
mixture was diluted with DCM and was washed sequentially with brine and
10% NaOH solution. The organic layer was dried over MgSO4 and then was
evaporated under vacuum. The crude product was purified by flash column
chromatography using 8–10% ethyl acetate in hexane as the eluent. Phenyl(2-
phenyloxiran-2-yl)methanone (2a)8: Yield: 81%; colorless oil; 1H NMR
(300 MHz, CDCl3) d 3.09 (d, J = 5.4 Hz, 2H, 2CH), 3.24 (d, J = 5.4 Hz, 2H, 2CH),
7.20–7.35 (m, 10H, ArH); 13C NMR (75.5 MHz, CDCl3) d 55.07, 125.39, 127.92,
129.29, 128.55, 128.59, 128.84, 130.00, 130.07, 132.42, 133.78, 134.54, 137.63,
196.78; CG/MS: m/z (relative, %) 224 (17), 208 (12), 121 (63), 105 (100), 91
(39), 77 (33). (4-Chlorophenyl)(2-phenyloxiran-2-yl)methanone (2b): Yield: 85%;
colorless oil; 1H NMR (300 MHz, CDCl3) d 2.99 (d, J = 5.4 Hz, 1H, CH), 3.31 (d,
J = 5.4 Hz, 1H, CH), 7.18–7.41 (m, 7H, ArH), 7.90 (d, J = 9.0 Hz, 2H, ArH); 13C
NMR (75.5 MHz, CDCl3) d 55.13, 63.10, 125.29, 128.42, 128.62, 129.10, 129.97,
131.38, 132.26, 135.26, 140.34, 193.53; CG/MS: m/z (relative, %) 258 (13), 242
(6), 165 (15), 141 (32), 139 (100), 119 (62), 105 (26), 91 (60).
This reaction was also successful with
a-alkyl olefinic alcohols 1j
and 1k.
2. Conclusion
In summary, we have identified a simple and useful approach
for synthesizing ,b-epoxy ketones by palladium-catalyzed
a
a
epoxidation–oxidation sequence; this process uses functionalized
terminal allylic alcohols as substrates and m-CPBA as the stoichi-
ometric oxidant. The strength of this approach is that the epoxida-
tion of terminal double bond and oxidation of allylic alcohol
occurring during same reaction under mild conditions and permits
flexibility of introducing an electron-donating or electron-accept-
ing functionality in epoxy ketone cored aromatic architectures.