Titanium-salan-catalyzed asymmetric epoxidation with aqueous hydrogen peroxide as the oxidant

Article abstract of DOI:10.1002/anie.200600636

(Chemical Equation Presented) Keep it simple: A titanium complex with a salan ligand bearing phenyl groups at C3 and C3′ is an efficient catalyst for the enantioselective epoxidation of unfunctionalized olefins with aqueous hydrogen peroxide (see scheme); furthermore, the epoxidation was stereospecific. The C3 and C3′ substituents stabilize this complex and enhance the asymmetric induction.

Full text of DOI:10.1002/anie.200600636

Communications
methods for oxidation have been developed, more atom-
efficient approaches that can be carried out under mild
conditions are strongly desired from the viewpoint of
protecting the environment and conserving resources. The
choice of oxidant is an important factor in the enhancement of
the efficiency of the oxidation reaction. Among the oxidants
known, aqueous hydrogen peroxide is almost ideal, because it
is relatively cheap, commercially available, and easy to
handle; moreover, only water is generated as the by-product.
Thus, the development of a catalyst for oxidation reactions
with hydrogen peroxide has been a central theme in oxidation
chemistry.[2] In particular, much effort has been directed
toward the development of a chiral catalyst for epoxidation
because of the high utility of optically active epoxides as
versatile chiral building blocks.[3,4] However, a general and
highly enantioselective epoxidation of unfunctionalized ole-
fins with hydrogen peroxide has not been developed.
Recently, we developed a chiral di-m-oxo titanium–salalen
(salalen[5,6]: hybrid salan/salen tetradentate (ONNO)-type
ligand; salan: N,N,-bis(o-hydroxybenzyl)-1,2-diaminoethane,
salen: N,Nꢀ-bis(salicylidene)ethylenediamine) complex that
was able to catalyze the epoxidation of unfunctionalized
olefins using aqueous hydrogen peroxide with high enantio-
selectivity and a high turnover number of the catalyst.[7] The
robustness and the unique catalysis of the titanium–salalen
complex are in marked contrast with the ineffectiveness of the
corresponding di-m-oxo titanium–salen complex as an epox-
idation catalyst. These distinctive features of the former
complex have been attributed to hydrogen bonding between
the amino proton and the oxygen atom
Asymmetric Catalysis
of a putative peroxo species (Scheme 1).
Although the complex is currently one
DOI: 10.1002/anie.200600636
of the most efficient catalysts for asym-
metric epoxidation, it has a rather elab-
orate structure and its synthesis using
Meerwein–Ponndorf–Verley reduction
in situ has less flexibility in tuning the
structure. Construction of an efficient
Scheme 1. A puta-
tive peroxo species
activated by hydro-
gen bonding.
Titanium–Salan-Catalyzed Asymmetric
Epoxidation with Aqueous Hydrogen Peroxide as
the Oxidant**
catalyst that has a much simpler structure and that can be
prepared from readily available compounds is a worthy
challenge. A requirement for such a catalyst is the ability to
efficiently enhance the reactivity of a putative peroxo species
and to regulate its orientation in an asymmetric atmosphere.
Thus, we newly introduced a series of di-m-oxo titanium–salan
complexes and examined their catalysis, because salan ligands
and the corresponding titanium–salan complexes can be
readily synthesized,[8] and the catalysis of the titanium–salan
complex could be tuned by introducing an appropriate
substituent to the ligand. Moreover, the complexes also
possess amino protons to activate a putative peroxo species.
The experimental procedure for the synthesis of the di-m-
oxo titanium–salan complexes is shown in Scheme 2. Salan
ligands 1a–d were prepared by reduction of the correspond-
ing salen ligands with NaBH4. [Ti(OiPr)4] was added to a
solution of the salan ligand in dichloromethane, and subse-
quent treatment with water gave the di-m-oxo titanium–salan
complexes 2a–d.[9]
Yuji Sawada, Kazuhiro Matsumoto, Shoichi Kondo,
Hisayuki Watanabe, Tomoyuki Ozawa, Kenji Suzuki,
Bunnai Saito, and Tsutomu Katsuki*
Oxidation reactions are at the core of methods for the
conversion of bulk chemicals into useful and high-value
materials.[1] Although many economical and highly selective
[*] Y. Sawada, K. Matsumoto, Dr. B. Saito, Prof. T. Katsuki
Department of Chemistry
Faculty of Science
Graduate School, Kyushu University
Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
Fax: (+81)92-642-2607
E-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
Dr. S. Kondo, Dr. H. Watanabe, T. Ozawa, K. Suzuki
Nissan Chemical Industries, Ltd. (Japan)
[**] Financial support was provided by CRESTand the Japan Science and
Technology Agency. We are indebted to JEOL Ltd. for the coldspray
ionization mass-spectrometric (CSI-MS) measurements. K.M. is
grateful for a JSPS Research Fellowship for Young Scientists.
First, asymmetric epoxidation of 1,2-dihydronaphthalene
with 30% hydrogen peroxide in the presence of 5 mol% of a
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Angewandte
Chemie
catalyst prepared in situ from [Ti(OiPr)4] and ligand 1d gave
an almost comparable enantioselectivity to the pre-made
catalyst 2d, but slightly diminished yield was obtained
(entry 7).[10] Although prolonged reaction time led to ring-
opening of the epoxide to give a mixture of the corresponding
1- or 2-hydroperoxy 2- or 1-alcohol and 1,2-diol, the
enantiomeric excess of the remaining epoxide did not
change. Furthermore, when hydrogen peroxide was added
to the reaction medium with a syringe pump over 4 h, a
significant amount of ring-opened products was obtained
(entry 8). These results suggested that 2d decomposed under
the reaction conditions into a Lewis acid complex that did not
carry the salan ligand and did not promote epoxidation but
ring-opening.
The substrate scope of the epoxidation using 2d was
investigated using 1.5 equivalents of hydrogen peroxide
(Table 2). The epoxidation of terminal, cis-disubstituted,
Scheme 2. Synthesis of di-m-oxo titanium–salan complexes 2a–d.
di-m-oxo titanium–salan complex was investigated (Table 1). and trisubstituted olefins proceeded with high enantioselec-
Titanium–salan complexes (2a and 2b) with a diphenylethy-
lenediamine moiety were found not to be efficient catalysts
tivity. It is noteworthy that the epoxidation was stereospecific
and no formation of the trans epoxide was detected in the
epoxidation of cis-1-phenylpent-3-en-1-yne (entry 4). How-
Table 1: Asymmetric epoxidation of 1,2-dihydronaphthalene (3) with a
Ti–salan complex as the catalyst.[a]
Table 2: Asymmetric epoxidation catalyzed by 2d.[a]
Entry
1[d]
Substrate
Yield [%][b] ee [%] Configuration[c]
Entry
Catalyst
t
T [8C]
Yield [%][b]
ee [%][c]
Config.[d]
1
2
3
4
2a
2b
2c
2d
24
24
24
6
25
25
25
25
25
0
NR
<5
19
73
87
79
80
4
5
6
72
44
47
95[e]
97[f]
82[g]
1S,2R
5S,6R
S
44
82
95
96
98
94
95
1S,2R
1S,2R
1S,2R
1S,2R
1S,2R
1S,2R
1S,2R
2
3
5[e]
6[e]
7[e]
8[e,g]
2d
6
2d
24
6
2d[f]
2d[h]
25
25
5
24 (30, 21)
4
5
7
8
69
77
90[h]
99[i]
2R,3S
3S,4S
[a] Reaction conditions: catalyst (5 mmol), 1,2-dihydronaphthalene
(0.1 mmol), and aqueous H2O2 (30%, 0.12 mmol) in CH2Cl2 (1.0 mL).
[b] Determined by 1H NMR (400 MHz) spectroscopic analysis; the yields
of the ring-opened products (1,2-diol, 1- or 2-hydroperoxy 2- or 1-
alcohols) are given in brackets. [c] Determined by HPLC analysis on a
chiral stationary-phase column (Daicel chiralcel OB-H, hexane/iPrOH=
99:1). [d] Determined by comparison of the elution order with that of the
authentic sample in HPLC analysis. [e] Amount of aqueous H2O2 =
1.5 equivalents. [f] The catalyst was generated in situ. [g] Hydrogen
peroxide was added with a syringe pump over 4 h. [h] Amount of complex
2d: 3 mmol. NR=no reaction.
6[d]
7
9
55
25
95[j]
55[k]
1R,2S
10
R
[a] Reaction conditions: catalyst 2d (5 mmol), olefin (0.1 mmol), and
aqueous H2O2 (30%, 0.15 mmol) in CH2Cl2 (1.0 mL) at 258C for 24 h.
[b] Determined by 1H NMR (400 MHz) spectroscopic analysis. [c] Deter-
mined by comparison of the elution order with that of the authentic
sample in HPLC analysis and/or comparison of the chiroptical data with
the literature value. [d] Reaction time was 5 h. [e] Determined by HPLC
analysis on a chiral stationary-phase column (Daicel Chiracel OB-H;
hexane/iPrOH=90:10). [f] Determined by HPLC analysis on a chiral
stationary-phase column (Daicel Chiralpak AS-H; hexane/iPrOH=
99.9:0.1). [g] Determined by HPLC analysis on a chiral stationary
phase column (Daicel Chiracel OD-H; hexane/iPrOH=99.9:0.1).
[h] Determined by HPLC analysis on a chiral stationary phase column
(Daicel Chiracel OD-H; hexane/iPrOH=99:1). [i] Determined by HPLC
analysis on a chiral stationary phase column (Daicel Chiracel OJ-H;
hexane/iPrOH=70:30). [j] Determined by HPLC analysis on a chiral
stationary-phase column (Daicel Chiracel OB-H; hexane/iPrOH=99:1).
[k] Determined by 1H NMR spectroscopic analysis using a chiral shift
reagent [Eu(hfc)3] (hfc=3-(heptafluoropropylhydroxymethylene)-d-cam-
phorate).
(entries 1 and 2). On the other hand, the complexes (2c and
2d) bearing a cyclohexanediamine moiety showed the desired
catalysis (entries 3 and 4). The presence of a cyclohexane ring
was considered to provide a more suitable structure for
hydrogen bonding of the amino proton with the oxygen atom
of the peroxo group. Furthermore, introduction of a phenyl
substituent at C3 and C3’ was found to remarkably enhance
catalytic activity and improve enantioselectivity (entry 4).
The use of 1.5 equivalents of hydrogen peroxide improved the
yield to some extent (entry 5). Lowering the reaction temper-
ature to 08C slightly increased enantioselectivity, although
the yield was decreased somewhat (entry 6). Moreover, the
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ever, the reaction of a nonconjugated terminal olefin was slow
(entry 7).
The reaction mechanism is unclear at present. It is,
Keywords: asymmetric catalysis · enantioselectivity ·
epoxidation · hydrogen peroxide · titanium
.
however, of note that the catalyst prepared in situ from
[Ti(OiPr)4] and an N,N’-dimethylated derivative of 1d did not
show any catalytic activity for the epoxidation of styrene. This
result agreed with our proposal that a titanium–peroxo
species is activated through hydrogen bonding. Moreover,
when a solution of 2d in dichloromethane was treated with
aqueous hydrogen peroxide, a new species was obtained.
Analysis by cold-spray ionization mass-spectrometry (CSI-
MS) indicated a m-peroxo-m-oxo species (Mr = 1097.3); how-
ever, this species was also detected by CSI MS in the presence
of hydrogen peroxide and 1,2-dihydronaphthalene. Accord-
ingly, it is very likely that the active species is not the dimeric
m-peroxo-m-oxo species but a monomeric peroxo or dimeric
di-m-peroxo species.
In summary, the titanium–salan-catalyzed asymmetric
epoxidation of unfunctionalized olefins using aqueous hydro-
gen peroxide has been developed. High enantioselectivity of
up to 98% ee was achieved for several olefins. We have
demonstrated that a more efficient catalyst of lower molec-
ular weight could be constructed for asymmetric epoxidation
using hydrogen peroxide as the oxidant by appropriately
considering the mechanism of activation of a peroxo species.
Further improvements in the catalytic activity and detailed
mechanistic studies are now in progress.
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Springer, Heidelberg, 1999, chap. 21, pp. 649 – 677; b) T. Katsuki
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[9] CCDC-297268 (for complex 2d) contains the supplementary
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[10] A catalyst prepared in situ from [Ti(OiPr)4] and a salan ligand
with other substituents at C3 gave inferior results (H: 36%,
93% ee; Me: 69%, 93% ee; tBu: 15%, 83% ee).
Experimental Section
2d: [Ti(OiPr)4] (1.3 mmol) was added to a solution of salan ligand 1d
(1.2 mmol) in dichloromethane (3.5 mL), and the solution was stirred
at room temperature. A few drops of H2O were added after 5 h, and
the resultant mixture was stirred overnight. Volatiles were removed
under reduced pressure, and the residue was recrystallized from
dichloromethane to give the desired complex 2d in 46% yield.
Elemental analysis (%) for C64H64N4O6Ti2·H2O·1.5CH2Cl2: C 64.15,
H 5.67, N 4.57; found: C 64.03, H 5.49, N 4.55; CSI MS: m/z: calcd for
C64H64N4O6Ti2: 1080.38; found: 1081.32 [M++H].
Typical procedure for epoxidation using a pre-made catalyst:
Titanium complex 2d (5 mmol) and 1,2-dihydronaphthalene
(0.1 mmol) were dissolved in dichloromethane (1.0 mL) in an nitro-
gen atmosphere. The resultant mixture was stirred at room temper-
ature after 30% aqueous hydrogen peroxide (0.15 mmol) had been
added. The solvent was removed in vacuo, and the residue was
purified by column chromatography on silica gel (pentane/Et2O, 40:1)
to give the corresponding epoxide. The ee value was determined by
HPLC on a chiral stationary phase.
Typical procedure for epoxidation using a catalyst prepared
in situ: Salan ligand 1d (10 mmol) was added to a solution of
[Ti(OiPr)4] (10 mmol) in dichloromethane (1.0 mL, 10 mm), and the
solution was stirred at room temperature. A drop of water was added
after 30 min, and the resultant mixture was stirred for 30 min. The
reaction mixture was stirred at room temperature for 6 h after 1,2-
dihydronaphthalene (0.1 mmol) and 30% aqueous hydrogen perox-
ide (0.15 mmol) were added. The solvent was removed in vacuo, and
the residue was purified by column chromatography on silica gel
(pentane/Et2O 40:1) to give the corresponding epoxide. The ee value
was determined by HPLC on a chiral stationary phase.
Received: February 17, 2006
Published online: April 24, 2006
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Angew. Chem. Int. Ed. 2006, 45, 3478 –3480