Iron-catalyzed hydroxylation of β-ketoesters with hydrogen peroxide as oxidant

Article abstract of DOI:10.1016/j.tetlet.2008.07.157

The hydroxylation of β-ketoesters was studied using simple iron catalysts and 30 wt % hydrogen peroxide as the terminal oxidant. The highest activity and yield were achieved in the presence of iron(III) chloride. Cyclic β-ketoesters could be smoothly hydr

Full text of DOI:10.1016/j.tetlet.2008.07.157

Tetrahedron Letters 49 (2008) 5976–5979
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Tetrahedron Letters
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Iron-catalyzed hydroxylation of b-ketoesters with hydrogen peroxide as oxidant
Dongmei Li a, Kristin Schröder a, Bianca Bitterlich a, Man Kin Tse a,b, Matthias Beller a,b,
*
a Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
b Center for Life Science Automation, Universität Rostock, Friedrich-Barnewitz-Straße 8, 18119 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydroxylation of b-ketoesters was studied using simple iron catalysts and 30 wt % hydrogen peroxide
as the terminal oxidant. The highest activity and yield were achieved in the presence of iron(III) chloride.
Cyclic b-ketoesters could be smoothly hydroxylated in 75–90% yield. For linear b-ketoester and b-keto-
amide, the chloro-substituted products were obtained.
Received 21 June 2008
Revised 28 July 2008
Accepted 29 July 2008
Available online 31 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Selective oxidation
Ketoester
Hydrogen peroxide
a
-Hydroxy b-ketoester is an important scaffold found in a lot of
O
O
O
O
bioactive molecules.1 The hydroxylation of 1,3-dicarbonyl com-
pounds is a straight forward important technique in organic syn-
thesis to access these compounds. A variety of reagents including
hydrogen peroxide, m-CPBA, molecular oxygen, and (camphor-
ylsulfonyl)-oxaziridines were applied in the selective oxidation of
b-keto-carbonyl compounds.1d,2 Recently, it was reported that
CoCl2, CeCl3, and Mn(OAc)2 could be effective catalyst for this
transformation using molecular oxygen as oxidant.3 Noteworthy,
the asymmetric hydroxylation of b-ketoesters was also success-
fully demonstrated using a titanium-TADOL based catalyst and
up to 94% ee was achieved.4 Hydrogen peroxide is known to be
an environmentally benign oxidant with the ease of laboratory
handling. The development of general, simple and efficient catalyst
system using H2O2 is still a challenging goal for the hydroxylation
of b-keto-carbonyl compounds.
FeCl3 6H2O
OEt
OEt
2 equiv. 30wt%H2O2
tert-amyl alcohol
r.t.
OH
Scheme 1. Selective hydroxylation of 2-ethoxycarbonyl-1-oxo-cyclohexane.
Initial screening of the reaction conditions, that is, different iron
salts, organic solvents, and the amount of catalyst loading revealed
that 1 mol % of iron(III) chloride hexahydrate, 2 equiv of hydrogen
Table 1
Catalyst screening using 1 as model substratea
Entry
Iron salts
Con.b (%)
Yieldc (%)
Sel.d (%)
Great progress has been advanced in iron catalysis in the last
decade. Various reactions such as olefin hydroxylation,5 sulfide
oxidation,6 cross-coupling reactions,7 heterolytic RO–OH bond
cleavage,8 hydroamination,9 allylic alkylation or amination,10 and
alcohol oxidation11 were investigated. Based on our recent experi-
ence in iron-catalyzed selective oxidation of olefin to epoxide and
alcohol to aldehyde,12 here we report our new findings about iron-
catalyzed selective hydroxylation of b-ketoesters to the corres-
1
2
3
4
5
6
7
8
FeCl3
79
82
80
13
7
7
13
14
79
82
80
13
7
7
13
14
99
99
99
99
99
99
99
99
FeCl3Á6H2O
FeCl2
FeBr3
Fe(OAc)2
Fe(NO3)3Á9H2O
Fe2(SO4)3Á5H2O
FePO4Á4H2O
a
1 mmol (170 mg) 1, 1 mol % iron salt, 2 equiv (0.20 mL) 30 wt % H2O2, and
25 mL tert-amyl alcohol were added into a 50 mL reaction tube, respectively. After
being shaken, the reaction vessel was allowed to react at rt for 1 h without stirring.
1 mmol (170 mg) dodecane was added as an internal standard for quantitative
analysis.14
ponding
a-hydroxy-b-ketoesters. The selective hydroxylation of
2-ethoxycarbonyl-1-oxo-cyclohexane (1) was used as the model
reaction (Scheme 1).
b
Conversion of 1.
Calibrated GC yield.
Chemoselectivity toward the desired product with respect to consumed starting
c
d
* Corresponding author. Tel.: +49 381 1281 0; fax: +49 381 1281 5000.
E-mail address: matthias.beller@catalysis.de (M. Beller).
material.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.157

D. Li et al. / Tetrahedron Letters 49 (2008) 5976–5979
5977
peroxide, and 25 mL of tert-amyl alcohol were suitable for the
hydroxylation of 1a;13 86% conversion with 70% yield could be
obtained with magnetic stirring in 1 h. The usage of other solvents,
such as THF, dioxane, ethanol, acetonitrile, and N-methyl-2-pyrro-
lidinone, caused lower selectivity. However, the yield of the reac-
tion varied significantly in some cases. With careful investigation
of the possible factors, it was surprisingly found that the selectivity
of the reaction significantly increased from 81% to >99% with sim-
ilar conversion without stirring. The addition of more iron chloride
or hydrogen peroxide and with longer reaction time gave no
improvement of the reaction but instead more byproducts. The re-
sults under the reaction conditions without stirring are highly
reproducible, but the effect of stirring in this reaction is still not
clear at this moment. Hence, all the following reactions were
carried out without any stirring except specifically mentioned.
The catalytic activity of different iron salts was investigated in
the presence of 1 mol % catalyst and 2 equiv, 30 wt % hydrogen per-
oxide (Table 1). The counter anions of iron salts highly affect the
catalytic activity (Table 1, entries 1–8). The corresponding hydr-
oxylation product was obtained in high yield when using iron
chlorides as the catalysts, no matter anhydrous or hydrated, Fe(II)
90
80
70
60
50
40
30
20
10
0
0
200
400
600
t/min
Figure 1. Yield of 1b against time.
Table 2
Selective oxidation of diketone compounds catalyzed by iron(III) chloridea
Entry
Substrate
Product
t (h)
Conv.b (%)
Yieldc (%)
Sel.d (%)
O
O
O
O
OEt
OH
OEt
1
1
82
82
99
1a
1b
O
O
O
O
O
O
OMe
OMe
2
3
4
0.75
75
98
98
75
90
84
99
92
86
OH
2b
2a
O
O
O
O
OEt
OEt
OH
8
3a
3b
O
O
OMe
O
OMe
OH
6
4a
4b
O
O
O
OEt
OH
OEt
5
0.75
89
85e
96
Me
Me
5a
5b
O
O
O
O
OMe
OMe
6f
24
90
81
90
HO
(continued on next page)
6b
6a

5978
D. Li et al. / Tetrahedron Letters 49 (2008) 5976–5979
Table 2 (continued)
Entry
Substrate
Product
t (h)
Conv.b (%)
91
Yieldc (%)
80
Sel.d (%)
88
O
O
O
O
7g
0.2
O
O
Me
Me
OEt
O
OH
7a
7b
O
O
O
Cl
OEt
8h
4
57
38
67
N
O
N
H
H
8a
8c
O
O
O
Cl
Me
OEt
Me
OEt
9i
15
82
60
73
Ph
Ph
9c
9a
a
The same reaction conditions as given in Table 1.
Conversion of starting material.
Calibrated GC yield.
b
c
d
e
f
Chemoselectivity toward the desired product with respect to consumed starting material.
A mixture of diastereomers in ꢀ1:1 (GC–MS) was obtained.
The substrates and 2 equiv 30 wt % H2O2 were dissolved in 5 mL tert-amyl alcohol, and 10 mol % FeCl3Á6H2O (27 mg/20 mL tert-amyl alcohol) was added in 24 h.
10 mol % FeCl3Á6H2O.
g
h
1 mol % FeCl3Á6H2O, 2 equiv 30 wt % H2O2, and 15 mL tert-amyl alcohol were added initially. 19 mol % FeCl3Á6H2O (51 mg/10 mL tert-amyl alcohol) and 6 equiv 30 wt %
H2O2 were added in 4 h.
i
35 mol % FeCl3Á6H2O/20 mL tert-amyl alcohol and 6 equiv H2O2 were added in 15 h.
or Fe(III) (Table 1, entries 1–3). This small difference in all iron
chloride catalysts indicates the reaction may be catalyzed by sim-
ilar intermediates as oxidation of iron(II) chloride to iron(III) chlo-
ride by hydrogen peroxide readily takes place. Noteworthy, this
reaction is also easy to be scaled up in laboratory scale. ꢀ80% yield
and ꢀ99% selectivity maintained when 13 mmol (2.21 g) 1a was
employed.15
catalyst loading (10 mol %), 7a can be hydroxylated in 80% yield
with 91% conversion (Table 2, entry 7).
It is interesting to note that chlorination occurred when the cat-
alyst loading increased. In the presence of 5 mol % iron chloride,
the conversion of 8a was ꢀ20% with ꢀ50% selectivity to the
a-hydroxylated 8b. When the amount of iron chloride increased
to 20 mol %, the conversion could reach to 57%. However, the major
product under such conditions was -chloro-b-ketoester 8c in 38%
yield (Table 2, entry 8). For the non-cyclic b-ketoester 9a, -chloro-
An interesting phenomenon was also observed during the reac-
tion when using iron(III) chloride as catalyst. At the early stage of
reaction, the color of the reaction mixture was yellow due to the
color of FeCl3Á6H2O. It turned brown immediately after the addi-
tion of b-ketoester. This color stays during the reaction even after
H2O2 has been added. When the conversion was above 80%, the
reaction mixture changed back to yellow in color. This color change
was not observed in the reactions with low conversion. Hence, the
formation of a new iron complex from iron chloride and b-ketoes-
ter is suspected. This phenomenon provides an opportunity to de-
velop high throughput screening methods with direct visual aids.
Close monitoring of the reaction showed that the reaction fin-
ished fast and smoothly in 1 h (Fig. 1). Although our reaction con-
ditions constitute typical Fenton reagent recipe,16 the product is
stable in our reaction system after its formation within 10 h.
The selective oxidation of other b-ketocarbonyl compounds was
further studied (Table 2). In most of the cases, the reaction can be
finished overnight. However, shorter reaction time is also feasible.
The time necessary to achieve high conversion is substrate depen-
dent, as also demonstrated in other reports.3a,4 While 1a and 2a,
gave higher than 75% conversion in less than 1 h, more than 6 h
should be used in order to get high conversion and yield using
3a and 4a as starting materials (Table 2, entries 1–4). The reactivity
of the preformed intermediate from iron chloride and b-ketoesters
(1a or 2a) governs the productivity. More iron chloride (10 mol %)
and longer reaction time (24 h) can be used to produce 6b from
unreactive 6a in good yield (81%) (Table 2, entry 6). With higher
a
a
b-ketoester 9c was the main product even with only 10 mol % of
FeCl3Á6H2O. Up to 60% of 9c could be obtained when 35 mol % of
catalyst was used (Table 2, entry 9). Therefore, this system has
potential to develop a new oxidative chlorination protocol for the
synthesis of
In summary, a simple and highly effective iron catalyst system
was developed for the -oxidation of b-ketoesters. 75–90% yield of
a-chloro-b-ketocarbonyl compounds.
a
the hydroxylation products could be obtained using cyclic b-keto-
esters as starting material.
Acknowledgments
This work was supported by the State of Mecklenburg-Western
Pommerania, the Deutsche Forschungs-gemeinschaft (SPP 1118
and Leibniz prize) and the Bundesministerium für Bildung und
Forschung (BMBF). Mrs. M. Heyken, Mr. H. M. Kaiser, Dr. K. Anirban
and Mr. M. Naveenkumar are acknowledged for their valuable
support in the laboratory.
Supplementary data
The detailed characterization results for all the products are
available. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.07.157.

D. Li et al. / Tetrahedron Letters 49 (2008) 5976–5979
5979
13. The effect of N-ligands, such as pyrrolidine and imidazoles, in Refs. 12a and 12b
was also tested. No better activity and yield were obtained in comparison with
the merely iron chloride addition system.
References and notes
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14. Typical procedure for the hydroxylation of 1: 1 mmol (170 mg) of 1, 1 mol %
(2.7 mg) of iron(III) chloride hexahydrate, 2 equiv of (0.2 mL) 30 wt % H2O2 and
25 mL tert-amyl alcohol were added into a 50 mL reaction tube, respectively.
After being sealed and shaken, the reaction was allowed to react at rt for 1 h
without stirring. After the reaction, 1 mmol (170 mg) of dedecane was added as
an internal standard for quantitative analysis. Then the solvent was removed
under reduced pressure and the residue was purified by column
chromatography to afford the desired product. Compound 1b: Rf = 0.19
(hexane/ethyl acetate = 90:10); colorless liquid; 1H NMR (300.1 MHz, CDCl3):
d = 1.11–1.27 (t, J = 7.2 Hz, 3H), 1.48–1.84 (m, 4H), 1.87–2.06 (m, 1H), 2.38–
2.66 (m, 3H), 4.06–4.19 (q, J = 7.2 Hz, 2H), 4.19–4.28 (s, 1H); 13C NMR
(75.5 MHz, CDCl3): d = 14.3, 22.2, 27.3, 38.0, 39.2, 62.3, 80.9, 170.4, 207.7; MS
(EI): m/z (rel. int.) 186 (31), 168 (20), 142 (62), 140 (32), 130 (19), 114 (29), 113
(72), 112 (44), 111 (123), 101 (35), 95 (15), 86 (15), 85 (95), 84 (35), 83 (20), 73
(17), 68 (57), 67 (96), 57 (30), 56 (35), 55 (100), 45 (13), 43 (38), 42 (34), 41
(45), 39 (21), 29 (54), 27 (30); HRMS calcd for C9H14O4 m/z 186.0887, found m/z
186.0890.
15. Scaling up testing for the hydroxylation of 1a: 13 mmol (2.21 g) of 1a, 1 mol %
(35.1 mg) of iron(III) chloride hexahydrate, 2 equiv (2.6 mL) of 30 wt % H2O2
and 325 mL tert-amyl alcohol were added into a 500 mL round-bottomed
bottle. After being sealed and shaken, the reaction was allowed to react at rt for
2 h without stirring. After the reaction, 13 mmol (2.2 g) of dodecane was added
as an internal standard for quantitative analysis. The reactions were repeated
two times. ꢀ80% conversion, ꢀ99% selectivity and ꢀ80% yield were obtained.
Caution! Although we have never faced any problem during our experiments, it
needs to be mentioned that large scale usage of hydrogen peroxide may cause
explosion.
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