A simple and versatile method for alkene epoxidation using aqueous hydrogen peroxide and manganese salophen catalysts

Article abstract of DOI:10.1016/j.tetlet.2006.01.074

We describe a simple and versatile method for the catalytic epoxidation of a broad range of olefins (e.g., ketones, esters, and alkyl halides) with aqueous H₂O₂ using manganese salophen catalysts. Low catalyst loading, short reaction times, and a simple reaction setup (e.g., no pH buffer is required) are salient features of the system, which unites the benefits of H₂O₂ as an oxidant with the versatility and modularity of salen-based catalysts.

Full text of DOI:10.1016/j.tetlet.2006.01.074

Tetrahedron Letters 47 (2006) 1923–1926
A simple and versatile method for alkene epoxidation using
aqueous hydrogen peroxide and manganese salophen catalysts
Shih-Yuan Liu and Daniel G. Nocera*
Department of Chemistry, 6-335, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4307, USA
Received 29 October 2005; accepted 17 January 2006
Abstract—We describe a simple and versatile method for the catalytic epoxidation of a broad range of olefins (e.g., ketones, esters,
and alkyl halides) with aqueous H2O2 using manganese salophen catalysts. Low catalyst loading, short reaction times, and a simple
reaction setup (e.g., no pH buffer is required) are salient features of the system, which unites the benefits of H2O2 as an oxidant with
the versatility and modularity of salen-based catalysts.
Ó 2006 Elsevier Ltd. All rights reserved.
The discovery of manganese salen complexes as epoxi-
dation catalysts by Kochi1 and their subsequent devel-
opment in asymmetric catalysis, most notably by
Jacobsen2 and Katsuki,3 represent landmark achieve-
ments in catalytic oxidation chemistry. High chemo-,
stereo-, and regio-selectivities have been achieved when
these salen catalyst platforms are used in concert with
iodosylbenzene, sodium hypochlorite, and m-chloroper-
benzoic acid as the primary oxidants. Recently, there
has been a burgeoning interest in the development of
catalytic epoxidation systems that employ ‘green’ oxi-
dants such as H2O2.4–20 The successful implementation
of such systems becomes a worthwhile objective when
issues of environmental compatibility,21 high atom econ-
omy,22,23 availability, and expense24,25 are considered.
Surprisingly, manganese salen complexes have only
rarely been employed as epoxidation catalysts in con-
junction with H2O2 as the primary oxidant.26–32 In the
few examples, turnover numbers (TON) are low (typi-
cally ꢀ20), and the substrate scope is limited. We envi-
sioned that more efficient oxidations may be realized
when H2O2 is activated with catalysts that precisely
position (or hang) an acid–base functionality over the
face of a redox-active macrocycle.33,34 Proton delivery
from an acid–base functional group to a hydroperoxide
bound to the metal unmasks the high-valent metal-
oxo, that is, the active species in many oxidation cycles.
We have shown this to be the case for ‘Hangman’ por-
phyrin complexes, which function as mono-oxygenase
mimics,35–37 and ‘Hangman’ salophen complexes,38
which function as catalase mimics. During the course
of these studies, we discovered that simple manganese
salophen complexes, such as MnClSaloph and MnCl-
Saloph-Br in Chart 1, could also promote, under certain
conditions, the epoxidation of olefins using H2O2. In
this letter, we show that olefin epoxidations can be effi-
ciently performed with 30% H2O2 solutions and manga-
nese salophen as the catalyst. Using our catalytic
system, a broad range of olefins (e.g., ketones, esters,
and alkyl halides are well tolerated) can be epoxidized
at high turnover and in good yield. The results described
herein add to the emerging literature of using H2O2 as a
primary oxidant and unite the benefits of employing an
environmentally benign oxidant with the versatility and
modularity of salen-based catalysts.
*
Corresponding author. Tel.: +1 617253 5537; fax: +1 617253 7670;
e-mail: nocera@mit.edu
Chart 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.074

1924
S.-Y. Liu, D. G. Nocera / Tetrahedron Letters 47 (2006) 1923–1926
For initial optimization studies, we chose to investigate
the olefin epoxidation of the common benchmark, styr-
ene. Table 1 illustrates the solvent effect on the efficacy
of the epoxidation reaction in the presence of 1,5-dicy-
clohexylimidazole (DCI) as an additive. Of all the sol-
vents used (Table 1, entries 1–9), DMF seems to be
the only one that can promote efficient epoxidation (en-
try 7). In order to prevent potential solubility problems
that can arise from using hydrophobic hydrocarbon
substrates in a hydrophilic solvent such as DMF,
CH2Cl2/DMF solvent mixtures were used. Indeed, the
use of a CH2Cl2/DMF mixture in a ratio of 1 to 3 signifi-
cantly improves conversion yields (entry 10). Interest-
ingly, a higher CH2Cl2 concentration results in complete
loss of epoxidation reactivity (entry 11).
ligands with pKa < 7 (entries 1 and 2) are employed.
Enhanced activity is observed, however, when the
epoxidation reaction is carried out using bases with
pKa > 7 (entries 3–5). No product was observed when
the reaction is carried out in the absence of an additive
(entry 6).
One of the more attractive features of using salen-based
catalysts is the ability to tune reactivity by altering the
X-substituent on the macrocyclic ring.1,42–44 We sought
to probe the electronic effects on catalyst performance
for various X substituents appended to the salen at the
5 and 50 positions of the macrocycle. Table 3 illustrates
that epoxidation reactivity is reduced significantly for a
catalyst bearing an electron-rich salophen ligand (i.e.,
X = OMe). On the other hand, good reactivity can be
achieved with catalysts containing less electron donating
groups (i.e., X = t-Bu or Br).
With an optimal solvent system established, we turned
our attention to address additive effects. In the presence
of 0.5% catalyst, different ligands with pKa values rang-
ing from 0.8 to 11 were surveyed. As can be seen from
Table 2, the nucleophilicity/basicity of the added ligands
is a critical factor for the efficacy of epoxidation.
Although many reactions employ 4-phenylpyridine N-
oxide (PPO) as an additive,39–41 a negligible amount of
product is obtained when PPO or other coordinating
Control experiments were performed with unligated
manganese since it is known that simple manganese salts
can catalyze olefin epoxidations. For instance, Burgess
et al. described olefin epoxidations in the presence of
Mn2+ salts in a hydrogen carbonate buffer,45,46 and
moreover, olefin epoxidations have been reported in
the absence of transition metal catalysts.47 Notwith-
standing, our experiments indicate that Mn2+ and
Mn3+ salts are ineffective catalysts under our experimen-
tal conditions (Table 4). In addition, no product was ob-
served in the absence of any transition metals. The
results in Table 3, as well as in Table 4, stress the impor-
tance of the metal-supporting salophen scaffold. Pre-
sumably, a high valent salophen MnV oxo species48–51
is involved in the catalytic epoxidation reaction.
Table 1. Manganese salophen catalyzed epoxidation of styrene:
solvent screen
Entry
Solvent
GC yield (%)
The epoxidation method can be applied to a wide range
of olefins. As can be seen from Table 5, unfunctionalized
1
2
3
4
5
Toluene
CH2Cl2
THF
CH3CN
CH3NO2
MeOH
<5
<5
<5
<5
<5
7
Table 3. Electronic effects on the epoxidation of styrene
6
7
8
DMF
DMA
85
5
9
NMP
6
10
11
CH2Cl2/DMF (1:3)
CH2Cl2/DMF (1:1)
99
6
X
GC yield (%)
t-Bu
OMe
Br
97
6
94
Table 2. Additive effect in manganese salophen catalyzed epoxidation
of styrene
Table 4. Control experiments using simple manganese salts as epox-
idation catalysts
Entry
Additive
pKa
GC yield (%)
1
2
3
4
5
6
4-PPO
Pyridine
DCIa
DMAP
Quinuclidine
—
0.8
5.2
7.0
9.2
11.0
—
<5
5
97
88
73
<5
Catalyst
GC yield (%)
Mn(OAc)2Æ4H2O
MnCl2
Mn(OAc)3Æ2H2O
—
0
0
0
0
a pKa reported for imidazole.

S.-Y. Liu, D. G. Nocera / Tetrahedron Letters 47 (2006) 1923–1926
1925
Table 5. Manganese salophen catalyzed epoxidation of olefins
We have scaled up the catalytic epoxidation of 1,2-dihy-
dronaphthalene (Eq. 1). Using just 0.2% catalyst, the
reaction goes to completion within 100 min, and the
desired product can be obtained in 76% isolated yield,
corresponding to a TON of 380.
Entry Olefin
1
Additive Yield (%)a TON
DCI
90
77
180
154
2
3
4
DMAP
ð1Þ
DMAP
DMAP
70
140
118
In conclusion, we have developed a simple and versatile
method for alkene epoxidation employing manganese
salophen catalysts and aqueous H2O2 as the primary
oxidant. Implementing the experimental conditions de-
scribed here, a wide range of unfunctionalized and func-
tionalized olefins can be epoxidized with high TON. The
method is distinguished from sodium hypochlorite
oxidations inasmuch as it is not necessary to precisely
control the pH.52 Additionally, the oxidation features
a high atom economy and the reaction does not
suffer from the undesirable organic by-products of
iodosylbenzene and organic peracid oxidations. Our
results establish that hydrogen peroxide may be used
effectively as an oxidant for salophen-mediated oxida-
tion catalysis.
59b
5
6
DCI
DCI
51
102
120
60c
7
8
DCI
DCI
78
69
78
69
Acknowledgements
We are grateful to Professor Gregory C. Fu for permit-
ting the use of gas chromatography instrumentation in
his laboratory. This work was supported by funding
from the National Institutes of Health GM 47274.
9
DCI
39
78
10
11
DCI
DCI
62
61
62
61
Supplementary data
Synthesis and characterization of salophen complexes
and procedures for epoxidation reactions. This material
is available free of charge via the Internet at http://
pubs.acs.org. Supplementary data associated with this
article can be found, in the online version, at doi:10.
1016/j.tetlet.2006.01.074.
12
DCI
68
136
a Isolated yields.
b 1.1:1 cis:trans ratio of products obtained (see SI).
c 79% oxidized product obtained, 19% of which was 2-phenyl-pro-
pionaldehyde (see SI).
References and notes
1. Srinivasan, K.; Michaud, P.; Kochi, J. K. J. Am. Chem.
Soc. 1986, 108, 2309–2320.
2. Zhang, W.; Loebach, J. L.; Wilson, D. R.; Jacobsen, E. N.
J. Am. Chem. Soc. 1990, 112, 2081–2083.
3. Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T.
Tetrahedron Lett. 1990, 31, 7345–7348.
4. Beller, M. Adv. Synth. Catal. 2004, 346, 107–108.
5. Jacobsen, E. N. Adv. Synth. Catal. 2004, 346, 109.
6. Venturello, C.; Alneri, E.; Ricci, M. J. Org. Chem. 1983,
48, 3831–3833.
aromatic (entries 1–6) as well as aliphatic (entries 7–9)
olefins are suitable substrates. Furthermore, our condi-
tions tolerate functional groups such as ketones (entry
10), alkyl bromides (entry 11), and esters (entry 12).
The low catalyst loading, the short reaction time, sim-
plicity of reaction setup (e.g., no pH buffer is required),
and the broad substrate scope are salient features of our
catalytic system. The TONs that have been achieved
with our method are among the highest reported for
manganese-salen-catalyzed epoxidation using H2O2.
7. Sato, K.; Aoki, M.; Ogawa, M.; Hashimoto, T.; Noyori,
R. J. Org. Chem. 1996, 61, 8310–8311.

1926
S.-Y. Liu, D. G. Nocera / Tetrahedron Letters 47 (2006) 1923–1926
8. Herrmann, W. A.; Fischer, R. W.; Marz, D. W. Angew.
31. Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R.; Patel, S. T.;
Jasra, R. V. Tetrahedron: Asymmetry 2001, 12, 433–437.
32. Berkessel, A.; Frauenkron, M.; Schwenkreis, T.; Stein-
metz, A.; Baum, G.; Fenske, D. J. Mol. Catal. A 1996,
113, 321–342.
Chem., Int. Ed. Engl. 1991, 30, 1638–1641.
9. Rudolph, J.; Reddy, K. L.; Chiang, J. P.; Sharpless, K. B.
J. Am. Chem. Soc. 1997, 119, 6189–6190.
10. Battioni, P.; Renaud, J. P.; Bartoli, J. F.; Reina-Artiles,
M.; Fort, M.; Mansuy, D. J. Am. Chem. Soc. 1988, 110,
8462–8470.
33. Yeh, C.-Y.; Chang, C. J.; Nocera, D. G. J. Am. Chem.
Soc. 2001, 123, 1513–1514.
11. Thellend, A.; Battioni, P.; Mansuy, D. J. Chem. Soc.,
Chem. Commun. 1994, 1035–1036.
34. Chang, C. J.; Yeh, C.-Y.; Nocera, D. G. J. Org. Chem.
2002, 67, 1403–1406.
12. Rebelo, S. L. H.; Simoes, M. M. Q.; Neves, M. G. P. M.
˜
35. Chang, C. J.; Chng, L. L.; Nocera, D. G. J. Am. Chem.
Soc. 2003, 125, 1866–1876.
36. Chng, L. L.; Chang, C. J.; Nocera, D. G. Org. Lett. 2003,
5, 2421–2424.
37. Chang, C. J.; Chang, M. C. Y.; Damrauer, N. H.; Nocera,
D. G. Biochim. Biophys. Acta 2004, 1655, 13–28.
38. Liu, S.-Y.; Nocera, D. G. J. Am. Chem. Soc. 2005, 127,
5278–5279.
S.; Silva, A. M. S.; Cavaleiro, J. A. S. Chem. Commun.
2004, 608–609.
13. De Vos, D.; Bein, T. Chem. Commun. 1996, 917–918.
14. Bolm, C.; Kadereit, D.; Valacchi, M. Synlett 1997, 687–
688.
15. Berkessel, A.; Sklorz, C. Tetrahedron Lett. 1999, 40, 7965–
7968.
16. Francis, M. B.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 937–941.
39. Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320–
4323.
17. White, M. C.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem.
Soc. 2001, 123, 7194–7195.
40. Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem.
1993, 58, 6939–6941.
18. Tse, M. K.; Do¨bler, C.; Bhor, S.; Klawonn, M.; Ma¨ger-
lein, W.; Hugl, H.; Beller, M. Angew. Chem., Int. Ed. 2004,
43, 5255–5260.
19. Matsumoto, K.; Sawada, Y.; Saito, B.; Sakai, K.; Katsuki,
T. Angew. Chem., Int. Ed. 2005, 44, 4935–4939.
20. Tse, M. K.; Klawonn, M.; Bhor, S.; Do¨bler Anilkumar,
G.; Hugl, H.; Ma¨gerlein, W.; Beller, M. Org. Lett. 2005, 7,
987–990.
21. Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003,
1977–1986.
22. Lane, B. S.; Burgess, K. Chem. Rev. 2003, 103, 2457–2473.
23. Grigoropoulou, G.; Clark, J. H.; Elings, J. A. Green
Chem. 2003, 5, 1–7.
41. Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59,
4378–4380.
42. Sivasubramanian, V. K.; Ganesan, M.; Rajagopal, S.;
Ramaraj, R. J. Org. Chem. 2002, 67, 1506–1514.
43. Jacobsen, E. N.; Zhang, W.; Guler, M. L. J. Am. Chem.
¨
Soc. 1991, 113, 6703–6704.
44. Palucki, M.; Finney, N. S.; Pospisil, P. J.; Guler, M. L.;
¨
Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
948–954.
45. Lane, B. S.; Burgess, K. J. Am. Chem. Soc. 2001, 123,
2933–2934.
46. Lane, B. S.; Vogt, M.; DeRose, V. J.; Burgess, K. J. Am.
Chem. Soc. 2002, 124, 11946–11954.
24. Kirk–Othmer Encyclopedia of Chemical Technology, 4th
ed.; Kroschwitz, J. I., Howe-Grant, M., Eds.; John Wiley
& Sons: New York, 1995; Vol. 13, p 961.
25. Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed.;
Elvers, B., Hawkins, S., Ravenscroft, M., Schulz, G., Eds.;
VCH: New York, 1989; Vol. A13, p 443.
26. Schwenkreis, T.; Berkessel, A. Tetrahedron Lett. 1993, 34,
4785–4788.
27. Irie, R.; Hosoya, N.; Katsuki, T. Synlett 1994, 255–256.
28. Pietika¨inen, P. Tetrahedron Lett. 1994, 35, 941–944.
29. Pietika¨inen, P. Tetrahedron 1998, 54, 4319–4326.
30. Pietika¨inen, P. J. Mol. Catal. A 2001, 165, 73–79.
47. Chen, Y.; Reymond, J.-L. Tetrahedron Lett. 1995, 36,
4015–4018.
48. Strassner, T.; Houk, K. N. Org. Lett. 1999, 1, 419–421.
49. Cavallo, L.; Jacobsen, H. Angew. Chem., Int. Ed. 2000, 39,
589–592.
50. Cavallo, L.; Jacobsen, H. Eur. J. Inorg. Chem. 2003, 892–
902.
51. Feth, M. P.; Bolm, C.; Hildebrand, J. P.; Ko¨hler, M.;
Beckmann, O.; Bauer, M.; Ramamonjisoa, R.; Berta-
gnolli, H. Chem. Eur. J. 2003, 9, 1348–1359.
52. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296–
2298.