A highly chemoselective, diastereoselective, and regioselective epoxidation of chiral allylic alcohols with hydrogen peroxide, catalyzed by sandwich-type polyoxometalates: Enhancement of reactivity and control of selectivity by the hydroxy group through metal-alcoholate bonding

Article abstract of DOI:10.1021/jo0266386

Sandwich-type polyoxometalates (POMs), namely [VZnM₂(ZnW₉O₃₄)₂]^q- [M = Mn(II), Ru(III), Fe(III), Pd(II), Pt(II), Zn(II); q = 10-12], are shown to catalyze selectively the epoxidation of chiral allylic alcohols with 30% hydrogen peroxide under mild conditions (ca. 20 °C) in an aqueous/organic biphasic system. The transition metals M in the central ring of polyoxometalate do not affect the reactivity, chemoselectivity, or stereoselectivity of the allylic alcohol epoxidation by hydrogen peroxide. Similar selectivities, albeit in significantly lower product yields, are observed for the lacunary Keggin POM [PW₁₁O₃₉]^7-, in which a peroxotungstate complex has been shown to be the active oxidizing species. All these features support a tungsten peroxo complex rather than a high-valent transition-metal oxo species operates as the key intermediate in the sandwich-type POM-catalyzed epoxidations. On capping of the hydroxy functionality through acetylation or methylation, no reactivity of these hydroxy-protected substrates [1a(Ac) and 1a(Me)] is observed by these POMs. A template is proposed to account for the marked enhancement of reactivity and selectivity, in which the allylic alcohol is ligated through metal - alcoholate bonding, and the H₂O₂ oxygen source is activated in the form of a peroxotungsten complex. 1,3-Allylic strain promotes a high preference for the threo diastereomer and 1,2-allylic strain a high preference for the erythro diastereomer, whereas tungsten - alcoholate bonding furnishes high regioselectivity for the epoxidation of the allylic double bond. The estimated dihedral angle α of 50 - 70° for the metal - alcoholate-bonded template of the POM/H₂O₂ system provides the best compromise between ^1,2A and ^1,3A strain during the oxygen transfer. In contrast to acyclic allylic alcohols 1, the M-POM-catalyzed oxidation of the cyclic allylic alcohols 4 by H₂O₂ gives significant amounts of enone.

Full text of DOI:10.1021/jo0266386

A High ly Ch em oselective, Dia ster eoselective, a n d Regioselective
Ep oxid a tion of Ch ir a l Allylic Alcoh ols w ith Hyd r ogen P er oxid e,
Ca ta lyzed by Sa n d w ich -Typ e P olyoxom eta la tes: En h a n cem en t of
Rea ctivity a n d Con tr ol of Selectivity by th e Hyd r oxy Gr ou p
th r ou gh Meta l-Alcoh ola te Bon d in g
Waldemar Adam,† Paul L. Alsters,‡ Ronny Neumann,§ Chantu R. Saha-Mo¨ller,†
Dorit Sloboda-Rozner,§ and Rui Zhang*,†
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany,
Advanced Synthesis and Catalysis, DSM Fine Chemicals, 6160 MD Geleen, The Netherlands, and
Department of Organic Chemistry, Weizmann Institute of Science, Rehovet 76100, Israel
adam@chemie.uni-wuerzburg.de
Received October 31, 2002
Sandwich-type polyoxometalates (POMs), namely [WZnM2(ZnW9O34)2]q- [M ) Mn(II), Ru(III), Fe-
(III), Pd(II), Pt(II), Zn(II); q ) 10-12], are shown to catalyze selectively the epoxidation of chiral
allylic alcohols with 30% hydrogen peroxide under mild conditions (ca. 20 °C) in an aqueous/organic
biphasic system. The transition metals M in the central ring of polyoxometalate do not affect the
reactivity, chemoselectivity, or stereoselectivity of the allylic alcohol epoxidation by hydrogen
peroxide. Similar selectivities, albeit in significantly lower product yields, are observed for the
lacunary Keggin POM [PW11O39]7-, in which a peroxotungstate complex has been shown to be the
active oxidizing species. All these features support a tungsten peroxo complex rather than a high-
valent transition-metal oxo species operates as the key intermediate in the sandwich-type POM-
catalyzed epoxidations. On capping of the hydroxy functionality through acetylation or methylation,
no reactivity of these hydroxy-protected substrates [1a (Ac) and 1a (Me)] is observed by these POMs.
A template is proposed to account for the marked enhancement of reactivity and selectivity, in
which the allylic alcohol is ligated through metal-alcoholate bonding, and the H2O2 oxygen source
is activated in the form of a peroxotungsten complex. 1,3-Allylic strain promotes a high preference
for the threo diastereomer and 1,2-allylic strain a high preference for the erythro diastereomer,
whereas tungsten-alcoholate bonding furnishes high regioselectivity for the epoxidation of the
allylic double bond. The estimated dihedral angle R of 50-70° for the metal-alcoholate-bonded
template of the POM/H2O2 system provides the best compromise between 1,2A and 1,3A strain during
the oxygen transfer. In contrast to acyclic allylic alcohols 1, the M-POM-catalyzed oxidation of the
cyclic allylic alcohols 4 by H2O2 gives significant amounts of enone.
In tr od u ction
ease of preparation and facile modification.2 For this
purpose, a variety of oxygen sources may be employed,
which include iodosobenzene,3 N-oxide,4 nitrous oxide,5
periodate,6 ozone,7 dioxygen,8 hydrogen peroxide,9 and
tert-butyl hydroperoxide.10
The fine chemical industry is facing increased pressure
to develop sustainable alternatives for classical processes
that no longer meet current environmental constraints.
With respect to oxidative transformations, there is a need
for the development of effective catalytic systems that
enable the selective manufacture of oxygen-functionalized
fine chemicals based on cheap, readily available, and
environmentally benign oxidants such as hydrogen per-
oxide and nontoxic metal catalysts.1 In this context,
recently polyoxometalates (POMs), in particular their
transition-metal-substituted derivatives, have gained
importance as homogeneous and heterogeneous oxidation
catalysts due to their oxidative and hydrolytic stability,
Initially, the tungsten-based polyoxometalates
[PW12O40]3- and {PO4[W(O)(O2)2]4}3- were used to cata-
(2) For reviews, see: (a) Mizuno, N.; Misono, M. Chem. Rev. 1998,
98, 199-218. (b) Hill, C. L.; Prosser-McCartha, C. M. Coord. Chem.
Rev. 1995, 143, 407-455. (c) Kozhevinikov, I. V. Chem. Rev. 1998, 98,
171-198. (d) Neumann, R. Prog. Inorg. Chem. 1998, 47, 317-370. (e)
Finke, R. G. Polyoxoanions in Catalysis: From Record Catalytic
Lifetime Nanocluster Catalysis to Record Catalytic Lifetime Catechol
Dioxygenase Catalysis. In Polyoxometalate Chemistry; Pope, M. T.,
Mu¨ller, A., eds.; Kluwer Academic Publishers: Dordrecht, The Neth-
erlands, 2001; pp 363-390.
(3) (a) Hill, C. L.; Brown, R. B. J . Am. Chem. Soc. 1986, 108, 536-
538. (b) Mansuy, D.; Bartoli, J . F.; Battioni, P.; Lyon, D. K.; Finke, R.
G. J . Am. Chem. Soc. 1991, 113, 7222-7226. (c) Weiner, H.; Hayashi,
Y.; Finke, R. G. Inorg. Chem. 1999, 38, 2579-2591.
† University of Wu¨rzburg.
‡ DSM Fine Chemicals.
§ Weizmann Institute of Science.
(1) (a) Sheldon, R. A.; Kochi, J . K. Metal-Catalyzed Oxidation of
Organic Compounds; Academic Press: New York, 1990. (b) Catalytic
Oxidations with Hydrogen Peroxide as Oxidant; Strukul, G., Ed.;
Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992.
(4) Zhang, X.; Sasaki, K.; Hill, C. L. J . Am. Chem. Soc. 1996, 118,
4809-4816.
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10.1021/jo0266386 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/28/2003
J . Org. Chem. 2003, 68, 1721-1728
1721

Adam et al.
F IGURE 1. Structures of the sandwich-type polyoxometalate M-POM catalysts and allylic alcohols.
lyze the oxidation of organic substances by hydrogen
peroxide under phase-transfer conditions.11,12 The result-
ing tungsten peroxo complexes, derived from these poly-
oxometalate catalysts, serve as the active oxygen-transfer
agent.13 With regard to the commonly used R-Keggin and
Wells-Dawson POMs, their unfortunate property is that
they do not persist against solvolytic and oxidative
decomposition, especially in the presence of H2O2, as has
been proved by kinetic and spectral studies.2b,13
Recently, the so-called sandwich-type polytungsto-
metalates [WXM2(H2O)2(XW9O34)2]12- with X ) Zn(II) or
Co(II) (Figure 1), initially prepared by Tourne´,14 have
received attention as promising oxidation cata-
lysts.7,8a-c,9b-f,10b These anions contain two B-[XW9O34]12-
truncated Keggin fragments, linked by four coplanar
octahedrally coordinated and close-packed d transition-
metal atoms. Both the heteroatoms in the trivacant
Keggin fragments and the four transition-metal ions in
the central ring may be varied extensively,14 which pro-
vides still unexplored opportunities for the design of new
oxidation catalysts. A definite advantage of the sandwich-
type POMs is their higher resistance toward hydrolysis
as well as oxidative degradation by H2O29c than those of
most common Keggin and Wells-Dawson structures.
A good example of uniquely high catalytic activity in
hydrogen peroxide-mediated oxidations is the Mn(II)-
disubstituted POM, namely [WZnMnII2(ZnW9O34)2]12-
,
which displays high selectivity for the epoxidation of
alkenes and the oxidation of alcohols by 30% H2O2 in a
biphasic system; indeed, hundreds to thousands of cata-
lytic turnovers have been achieved.9b,c Other isostructural
noble-metal [Rh(III), Pd(II), Pt(II), and Ru(III)] disub-
stituted analogues have also been shown to exhibit
activity in alkene and alkane oxidations with H2O2 and
tBuOOH.9d,10b In fact, the ruthenium derivative was found
to be effective in the oxidation of adamantane even by
molecular oxygen.8a-c
Despite this success, conspicuous is the fact that
sandwich-type POMs have not been employed for the
epoxidation of chiral allylic alcohols.15 The chiral allylic
alcohols not only are valuable stereochemical probes for
the elucidation of oxygen-transfer transition structures,16
but also offer the opportunity to test the chemoselectivity
of the oxidation in terms of epoxide versus enone forma-
tion, that is, oxygen transfer to the double bond or oxygen
insertion into the allylic CH bond. In this context,
catalytic systems such as Ti(OiPr)4/TBHP,17 VO(acac)2/
TBHP,18 H2WO4/H2O2,19 methyltrioxorhenium (MTO)/
UHP,20 manganese(salen)/PhIO,21 and iron(porphyrin)/
PhIO,21 and the stoichiometric oxidants DMD22 and
m-CPBA18 have been used in the epoxidation of allylic
(6) (a) Neumann, R. Abu-Gnim, C. J . Chem. Soc., Chem. Commun.
1989, 1324-1325. (b) Neumann, R. Abu-Gnim, C. J . Am. Chem. Soc.
1990, 112, 6025-6031. (c) Steckhan, E.; Kandzia, C. Synlett 1992, 139-
140. (d) Bressan, M.; Morvillo, A.; Romanello, G. J . Mol. Catal. 1992,
77, 283-288.
(7) Neumann, R.; Khenkin, A. M. Chem. Coummn. 1998, 1967-
1968.
(8) (a) Neumann, R.; Khenkin, A. M.; Dahan, M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1587-1589 (b) Neumann, R.; Dahan, M. Nature
1997, 388, 353-355. (c) Neumann, R.; Dahan, M. J . Am. Chem. Soc.
1998, 120, 11969-11976. (d) Weiner, H.; Finke, R. G. J . Am. Chem.
Soc. 1999, 121, 9831-9842. (e) Khenkin, A. M.; Weiner, V.; Wang, Y.;
Neumann, R. J . Am. Chem. Soc. 2001, 123, 8531-8542. (f) Rhule, J .
T.; Neivert, W. A.; Hardcastle, K. I.; Do, B. T.; Hill, C. L. J . Am. Chem.
Soc. 2001, 123, 12101-12102.
(9) (a) Khenkin, A. M.; Hill, C. L. Mendeleev Commun. 1993, 140-
141. (b) Neumann, R.; Gara, M. J . Am. Chem. Soc. 1994, 116, 5509-
5510. (c) Neumann, R.; Gara, M. J . Am. Chem. Soc. 1995, 117, 5066-
5074. (d) Neumann, R.; Khenkin, A. M. J . Mol. Catal. 1996, 114, 169-
180. (e) Neumann, R.; J uwiler, D. Tetrahedron 1996, 52, 8781-8788.
(f) Neumann, R.; Khenkin, A. M.; J uwiler, D.; Miller, H.; Gara, M. J .
Mol. Catal. 1997, 117, 169-183. (g) Zhang, X.; Chen, Q.; Duncan, D.
C.; Campana, C. F.; Hill, C. L. Inorg. Chem. 1997, 36, 4208-4215. (h).
Bo¨sing, M.; No¨h, A.; Loose, I.; Krebs, B. J . Am. Chem. Soc. 1998, 120,
7252-7259. (i) Mizuno, N.; Nozaki, C. Kiyoto, I.; Misono, M. J . Am.
Chem. Soc. 1998, 120, 9267-9272. (j) Ben-Daniel, R.; Neumann, R.;
Khenkin, A. M. Chem.sEur. J . 2000, 6, 3722-3728. (k) Droege, M.
W.; Finke, R. G. J . Mol. Catal. 1991, 69, 323-338.
(10) (a) Faraj, M.; Hill, C. L. J . Chem. Soc., Chem. Commun. 1987,
1487-1489. (b) Neumann, R.; Khenkin, A. M. Inorg. Chem. 1995, 34,
5753-5760.
(15) Recently, we reported on the oxidation of cyclohexenol, mediated
by Keggin-type POMs, but neither the acyclic alcohols nor their epoxide
products persisted under these conditions: Adam, W.; Herold, M.; Hill,
C. L. Saha-Mo¨ller, C. R. Eur. J . Org. Chem. 2002, 941-946.
(16) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
(17) Adam, W.; Kumar, R.; Reddy, T. I.; Renz, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 880-882.
(18) (a) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahe-
dron Lett. 1979, 19, 4733-4736. (b) Sharpless, K. B.; Verhoeven, T.
R. Aldrichimica Acta 1979, 12, 63-74. (c) Adam, W.; Nestler, B.
Tetrahedron Lett. 1993, 34, 611-614.
(19) (a) Prat, D.; Lett, P. Tetrahedron Lett. 1986, 27, 707-710. (b)
Prat, D.; Delpech, B.; Lett, P. Tetrahedron Lett. 1986, 27, 711-714.
(20) (a) Adam, W.; Mitchell, C. M. Angew. Chem., Int. Ed. Engl.
1996, 35, 533-535. (b) Adam, W.; Mitchell, C. M. Saha-Mo¨ller, C. R.
J . Org. Chem. 1999, 64, 3699-3707.
(21) Adam, W.; Stegmann, V. R.; Saha-Mo¨ller, C. R. J . Am. Chem.
Soc. 1999, 121, 1879-1882.
(22) Adam, W.; Smerz, A. K. Tetrahedron 1995, 51, 13039-13044.
(11) (a) Ishii, Y.; Yamawaki, K.; Ura, T.; Yamada. Y.; Yoshida, T.;
Ogawa, M. J . Org. Chem. 1988, 53, 3587-3593. (b) Ishii, Y.; Yoshida,
T.; Yamawaki, K.; Ogawa, M. J . Org. Chem. 1988, 53, 5549-5552. (c)
Sakata, Y.; Ishii, Y. J . Org. Chem. 1991, 56, 6233-6235. (d) Ishii, Y.,
Ogawa, M., Eds. Hydrogen Peroxide Oxidation Catalyzed by Heteropoly
Acids Combined with Cetylpyridinium Chloride; MYU: Tokyo, 1990.
(e) Neumann, R.; Khenkin, A. M. J . Org. Chem. 1994, 59, 7577-7579.
(12) (a) Venturello, C.; Alneri, E.; Ricci, M. J . Org. Chem. 1983, 48,
3831-3833. (b) Venturello, C.; D’Aloisio, R. J . Org. Chem. 1988, 53,
1553-1557. (c) Venturello, C.; Gambaro, M. Synthesis 1989, 295-297.
(13) (a) Aubry, C.; Chottard, G.; Platzer, N.; Bre`gault, J .-M.;
Thouvenot, R.; Chauveau, F.; Huet, A.; Ledon, H. Inorg. Chem. 1991,
30, 4409-4415. (b) Duncan, D. C.; Chambers, R. C.; Hecht, E.; Hill,
C. L. J . Am. Chem. Soc. 1995, 117, 681-691.
(14) Tourne´, C. M.; Tourne´, G. F.; Zonnevijlle, F. J . Chem. Soc.,
Dalton. Trans. 1991, 143-155.
1722 J . Org. Chem., Vol. 68, No. 5, 2003

Epoxidation of Chiral Allylic Alcohols
TABLE 1. Rea ctivity, Ch em oselectivity, a n d
SCHEME 1. Ca ta lytic Ep oxid a tion of Ch ir a l
Allylic Alcoh ols Ca ta lyzed by Sa n d w ich -Typ e
P OMs w ith H2O2
Dia ster eoselectivity for th e Ca ta lytic Ep oxid a tion of
Ch ir a l Allylic Alcoh ols 1 by 30% H2O2 a n d th e
Sa n d w ich -Typ e P olyoxom eta la tes in 1,2-Dich lor oeth a n ea
alcohols and have furnished relevant information on the
transition structures of the oxygen-transfer process.
Indeed, a very recent preliminary report23 demonstrated
the efficacy of the oxidatively and solvolytically persistent
sandwich-type polyoxometalates for the epoxidation of
the chiral allylic alcohols 1 by hydrogen peroxide. High
(>95%) chemo-, regio-, and diastereoselectivities have
been achieved in the epoxidation of 1,3- or 1,2-allylically
strained alcohols.
Herein, we present our detailed study on the epoxida-
tion of chiral allylic alcohols 1 with aqueous hydrogen
peroxide as the oxygen source, catalyzed by the sandwich-
type polyoxometalates, in particular {WZn[M(H2O)]2-
(ZnW9O34)2}q- [M-POM; M ) Mn(II), Ru(III), Fe(III),
Pd(II), Pt(II), and Zn(II); Figure 1]. Besides chemoselec-
tivity and stereoselectivity, also the regioselectivity was
assessed with the help of 1-methylgeraniol (1h ) and
geraniol (1i) as substrates. For mechanistic comparison,
the catalytic epoxidation of the same set of chiral allylic
alcohols 1 was also conducted with the lacunary Keggin-
type POM [PW11O39]7- as catalyst. To acquire structural
information on the transition-state geometry in the
M-POM-catalyzed epoxidation, a set of cyclic allylic
alcohols 4 with varying ring size and defined dihedral
angles R (CdCsCsOH) were selected as substrates in
this work.
a
All reactions were carried out at ca. 20 °C for 6 h with allylic
alcohol 1 (0.50 mmol), M-POM (0.1 mol %), and 2 equiv of 30%
H2O2. Conversions (allylic alcohol), yields of epoxy alcohol 2
b
(adjusted to 100% conversion), and product ratios were determined
by 1H NMR analysis on the crude reaction mixture with dimethyl
isophthalate as internal standard, ca. 5% error of the stated value.
For ratios >95%, only one product was observed in the 1H NMR
analysis. In parentheses are given the yields of isolated material
after silica gel chromatography. c About 10-12% isomerized ep-
oxide (E)-2f was observed in a threo:erythro ratio of ca. 12:88.
Resu lts
The polyoxometalates used in the present studies and
their corresponding hydrophobic methyltricaprylammo-
nium salts,24 as well as the racemic allylic alcohols 1,
were synthesized according to literature procedures (see
the Experimental Section). The epoxidations (Scheme 1)
were conducted at ca. 20 °C with an M-POM:allylic
alcohol:H2O2 (30%) ratio of 1:1000:2000 in a biphasic
system of water and 1,2-dichloroethane (Table 1); similar
results have been obtained in toluene (data not shown).
The results in Table 1 reveal that these sandwich-type
POMs effectively catalyze the epoxidation of the allylic
alcohols 1 to the epoxy alcohols 2, most of them in
excellent conversions (>95%). A comparatively low re-
activity (30-50% conversion) was observed for the 1,2-
allylically strained substrate 1c (entries 11-13), which
is due to the poorer nucleophilicity of the terminal double
bond. Allylic oxidation (CH insertion) to the R,â-unsatur-
ated enone 3 was observed to a minor extent (ca. 5-17%)
only for derivative 1g (Table 1, entries 23-25). Thus, the
epoxidation of allylic alcohols by M-POM is highly
chemoselective. Fortunately, the usual undesirable sec-
ondary reactions of the epoxides, i.e., hydrolysis, cleavage,
and rearrangement, were not observed under the present
reaction conditions.25
The M-POM-catalyzed epoxidation of allylic alcohols
is not only chemoselective, but also highly diastereose-
lective. The alcohols 1a ,b with 1,3-allylic strain were
exclusively epoxidized by Mn(II)-POM predominately to
the threo-epoxy alcohols 2a ,b in excellent chemoselectiv-
ity (no enone formation) and high reactivity (>90%
conversion) within 6 h (entries 1 and 7). It should be
noted that the substituting transition metal in the
sandwich POM displays little effect on the catalytic
activity and selectivity. This indicates that redox-type
transition metals are not directly involved in the M-POM-
catalyzed epoxidation of allylic alcohols by H2O2.
The allylic alcohols 1c,d with 1,2-allylic strain were
epoxidized less efficiently by these POM catalysts; mecha-
nistically more significant, the erythro-epoxides 2c,d were
(23) Adam, W.; Alsters, P. L.; Neumann, R.; Saha-Mo¨ller, C. R.;
Sloboda-Rozner, D.; Zhang, R. Synlett 2002, 2011-2014.
(25) In this study, no buffer was used in the epoxidation, despite
the relatively high acidity (pH ca. 2) of the aqueous phase of the
biphasic system. Fortunately, for the substrates reported herein, the
acid-catalyzed decomposition of both the allyl alcohols and their
epoxides was not appreciable during the relatively short reaction time.
The material balance was good to excellent under the present reaction
conditions.
(24) Catalysis with polyoxometalates is commonly conducted by
transferring the polyoxoanion into an organic solvent by means of a
quaternary ammonium cation. Upon extraction into the organic
solvent, the labile H2O ligand, initially coordinated to the transition
metal, is displaced, to afford the preferred salt Qq[ZnWM2(ZnW9O34)2]
[Q ) (n-C8H17)3CH3N+]; see ref 9c.
J . Org. Chem, Vol. 68, No. 5, 2003 1723

Adam et al.
TABLE 2. Rea ctivity, Ch em oselectivity, a n d
Dia ster eoselectivity for th e Ca ta lytic Ep oxid a tion of
Ch ir a l Allylic Alcoh ols 1 by 30% H2O2 a n d th e La cu n a r y
Keggin -Typ e P olyoxom eta la tea
tageous than lacunary Keggin-type POMs for the selec-
tive catalytic epoxidation of chiral allylic alcohols.26
To assess the regioselectivity of the M-POM-catalyzed
epoxidation by H2O2 as the oxygen source, 1-methylge-
raniol 1h and geraniol 1i were employed as substrates;
the former also permits one to probe the diastereoselec-
tivity (Table 3).27 Both substrates were epoxidized
exclusively at the allylic alcohol site by the sandwich-
type POMs (entries 1-9, 11, and 12). Essentially the
same regioselectivity was observed in the epoxidation of
substrate 1h by the Keggin-type POM [PW11O39]7- (entry
10). As expected, analogous to the related 1,3-allylically
strained alcohols 1a ,b, also a very high threo selectivity
was obtained for the 3,4-epoxide in the epoxidation of 1h
by the M-POMs (entries 1-9) and with the lacunary
Keggin-type POM (entry 10). In toluene (entry 2), the
results are essentially the same as in 1,2-dichloroethane
(entry 1), whereas in methanol (entry 3), the selectivities
are the same as those in the nonprotic solvents, yet the
reactivity dropped considerably, i.e., to only 20% conver-
sion from 95%. Significantly, similar catalytic activity and
identical selectivities were observed when 0.01 mol %
instead of 0.1 mol % Mn(II)-POM and only 1.0 equiv of
H2O2 were employed in the catalytic epoxidation of
substrate 1h (entry 4). These findings illustrate the very
high catalytic efficiency (ca. 8000 TON) of the sandwich-
type POMs in the selective epoxidation of allylic alcohols.
Again, the type of transition metal in the polyoxometalate
does not affect the reactivity, chemoselectivity, or ste-
reoselectivity of the allylic alcohol oxidation by hydrogen
peroxide (entries 1 and 5-9).
To acquire structural information on the transition-
state geometry in the M-POM-catalyzed epoxidation, a
set of chiral cyclic allylic alcohols 4 with varying ring size
and defined dihedral angles R (CdCsCsOH) in their
favored ground-state conformations were oxidized by Mn-
(II)-POM with H2O2 as the oxygen source (Table 4). In
contrast to acyclic allylic alcohols 1, for which only small
amounts, if at all, of the R,â-unsaturated enones were
observed (cf. Table 1), the M-POM-catalyzed oxidation
of the cyclic allylic alcohols 4 by H2O2 gave significant
amounts of enone. In the case of the cyclopentenol 4a ,
the epoxide 5a was obtained as the major product with
exclusive cis diastereoselectivity, but as much as 12%
enone was also formed (entry 1). However, in the oxida-
tion of 2-cyclohexen-1-ol (4b) by Mn(II)-POM, the enone
6b was produced as the major product, albeit the cis-
epoxy alcohol 5b was obtained in a high diastereoselec-
tivity (entry 2). This product selectivity and stereochem-
ical course is independent of the transition metal in the
M-POM catalyst, since nearly the same results were
obtained with the Zn(II)-POM catalyst (entry 3). In the
oxidation of the conformationally rigid cis- and trans-5-
tert-butyl-2-cyclohexenols (cis-4c and trans-4c), more
enone is formed from the cis isomer (OH pseudo equato-
rial, R ) 140°) than the trans one (OH pseudo axial, R )
110°), although very high diastereoselectivities were
a,b
For details see Table 1. c Only a trace of epoxide 2a was
d
observed. In the presence of pyridine (1.0 mol %).
produced in excellent diastereoselectivity (entries 11-
16). This reveals that both 1,2- and 1,3-allylic strains
dominate in the stereocontrol of the oxygen transfer to
chiral allylic alcohols in the M-POM-catalyzed epoxida-
tion. Consequently, substrates 1e,f (entries 17-22) with
both 1,2- and 1,3-allylic strain were epoxidized in low
diastereoselectivity because of the opposing sense in the
stereodifferentiation displayed by these two types of
allylic strain. Expectedly, poorer diastereoselectivity was
also observed for the alcohol 1g (entries 23-25) with no
allylic strain.
To gain mechanistic insight, the catalytic epoxidation
of the same set of chiral allylic alcohols 1 has also been
conducted with the lacunary Keggin-type POM [PW11O39]7-
as catalyst under identical reaction conditions, in which
the peroxotungstate complex {PO4[W(O)(O2)2]4}3- has
been shown to serve as the active oxidizing species.13
Although this POM does not contain a redox-active
transition metal, chemoselectivities and diastereoselec-
tivies (Table 2) similar to those of the transition-metal-
substituted M-POMs were observed (Table 1). However,
compared to the M-POM-catalyzed epoxidations, signifi-
cantly lower product yields were obtained for the la-
cunary Keggin POM, especially in the case of the
substrate 1a , for which only traces of epoxide were
observed upon 86% conversion (Table 2, entry 2). Control
experiments showed that acid-sensitive allylic alcohols
and their epoxides do not persist under these reaction
conditions. Presumably, appreciable acidity of this cata-
lytic system led to the decomposition of both the substrate
and the epoxide, which is responsible for the low yields
in these epoxidations. Indeed, the use of pyridine as
buffer dramatically increased the product yields in the
epoxidation of allylic alcohol 1a by the lacunary Keggin
POM (Table 2; cf. entries 2 and 3). These results
demonstrate that sandwich-type POMs are more advan-
(26) A full comparison of the catalytic activity of the sandwich-type
POMs with the simple R-Keggin POMs and tungstic acid (H2WO4) is
beyond the scope of this paper. It is certainly an advantage, however,
that the sandwich POMs catalyze the epoxidation of the allylic alcohols
in up to 10000 turnovers compared to the R-Keggin POMs, which are
irreversibly inactivated already after several hundred turnovers.
(27) Adam, W.; Mitchell, C. M.; Paredes, R. Smerz, A. K.; Veloza,
L. A. Liebigs Ann./Recl. 1997, 1365-1369.
1724 J . Org. Chem., Vol. 68, No. 5, 2003

Epoxidation of Chiral Allylic Alcohols
TABLE 3. Ca ta lytic Ep oxid a tion of 1h a n d 1i by 30% H 2O2 a n d th e Sa n d w ich -Typ e P olyoxom eta la te M-P OMa
selectivity
convn
(%)
yieldb
(%)
chemo
(2:3)
diastereo
(threo:erythro)
entry
R
catalyst
solvent
regioc
1
2
Me
Mn(II)-POM
ClCH2CH2Cl
C6D5CD3
CD3OD
>95
95
20
95 (86)
95
95
92
90
95 (93)
95
95
95
90
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
93:7
90:10
95:5
93:7
92:8
94:6
94:6
94:6
94:6
93:7
3
4d
5
Me
Me
Me
Me
Me
Me
Me
H
Mn(II)-POM
Ru(III)-POM
Fe(III)-POM
Zn(II)-POM
Pd(II)-POM
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
85
>95
>95
95
>95
>95
76
6
7
8
9
10
11
12
Pt(II)-POM
7-
[PW11O39
]
Mn(II)-POM
Zn(II)-POM
>95
>95
95 (90)
>95
H
a,b
For details see Table 1, except that the reaction time was 3 h. c Entries 1-10 for 2h (3,4:7,8 ratio) and entries 11 and 12 for 2i
d
(2,3:6,7 ratio). The reaction was run with 0.01 mol % catalyst and 1.0 equiv of 30% H2O2 for 6 h.
TABLE 4. Ca ta lytic Ep oxid a tion of Cyclic Allylic
Alcoh ols 4 by 30% H2O2 a n d th e Sa n d w ich -Typ e
P olyoxom eta la te M-P OMa
oxygen source 30% H2O2, catalyzed by the oxidatively and
solvolytically persistent sandwich-type polyoxometalates.
As for the mechanism of the oxygen transfer, in view of
the structural composition of these sandwich-type POMs,
the reaction may occur at either the substituting metal
center or the framework tungsten site of the intactcata-
lyst;9c however, possibly also W-containing fragments
derived from the sandwich-type POM may function as
the active oxidant.9k The following facts constitute evi-
dence that a tungsten peroxo complex serves as the likely
oxidant rather than a high-valent transition-metal oxo
species:29 The transition metal in the central ring of these
sandwich-type POMs (Mn, Ru, Fe, Pd, Pt) does not
notably affect the reactivity and selectivity of these
catalysts (Tables 1 and 3); the oxidatively inactive Zn
metal (Tables 1 and 3) performs just as effectively in this
epoxidation as the former redox metals; the purely
tungsten containing lacunary Keggin POM [PW11O39]7-
epoxidizes the same set of chiral allylic alcohols in similar
selectivities (Table 2). The advantage of epoxidations
catalyzed by the sandwich-type POMs compared to the
phospho-Keggin POMs is the higher persistence of the
former against degradation, such that very high catalytic
activity (ca. 8000 TON) may be achieved. Moreover, the
lower Lewis acidity of the sandwich POMs circumvents
the need of adding a basic buffer (e.g., pyridine), as is
required for tungstic acid-catalyzed epoxidations of allylic
alcohols.19 Be this as it may, it must be emphasized that,
irrespective of these mechanistic options, the preparative
value of this expoxidation methodology should be evident.
The present stereochemical (Table 1) and regiochemical
data (Table 3) shall now be analyzed to propose a
catalytic cycle for the sandwich-type POM-catalyzed
epoxidation of the chiral allylic alcohols. First, the
question arises about the electronic nature of the interac-
tion between the substrate and the POM catalyst, that
is, hydrogen bonding versus metal-alcoholate binding,
a,b
For details see Table 1. c Dihedral angle of CdCsCsOH.
d
The descriptors cis and trans pertain to the configuration of the
epoxide functionality relative to the allylic hydroxy group.
observed in both cases, again in favor of the cis-epoxides
(entries 4 and 5). The exclusive trans selectivity for the
cyclooctenol 4d (entry 6) speaks for purely steric interac-
tions in the conformer of minimal transannular strain,
as reported for other oxidants.28
Discu ssion
The present results (Tables 1 and 3) conspicuously
demonstrate that chiral allylic alcohols may be epoxidized
in high selectivities with the environmentally benign
(28) Adam, W.; Mitchell, C. M.; Saha-Mo¨ller, C. R. Eur. J . Org.
Chem. 1999, 785-790.
(29) A tungsten hydroperoxy species [W(OOH)+] may not be ex-
cluded as oxidant, since the present catalytic system is strongly acidic.
J . Org. Chem, Vol. 68, No. 5, 2003 1725

Adam et al.
SCHEME 2. P r op osed Ca ta lytic Cycle for th e
M-P OM-Ca ta lyzed Ep oxid a tion of Ch ir a l Allylic
Alcoh ols by Hyd r ogen P er oxid e
The transition-state geometry of this oxygen-transfer
process shall now be considered in terms of the depen-
dence of the diastereoselectivity on the dihedral angle
OsCsCdC (R) between the π plane of the double bond
and the hydroxy group of the allylic alcohols. The R
angles assume characteristic values for catalytic and
stoichiometric epoxidations of chiral allylic alcohols with
allylic strain. Typical dihedral angles for some pertinent
established oxidants and their threo/erythro diastereo-
selectivities are listed in Table 5, with which the data
for the POM catalysts in Tables 1 and 2 shall be
compared.
For the POM/H2O2 catalytic system, the threo diaste-
reomer is highly preferred in the epoxidation of sub-
strates 1a and 1b with 1,3-allylic strain (entries 1 and
2). Mechanistically significant, for the substrates 1c and
1d with only 1,2-allylic strain, also excellent diastereo-
selectivity is expressed, but the erythro diastereomer is
now favored (entries 3 and 4). When 1,2- and 1,3-allylic
strains are both competing in the same molecule, as in
the stereochemical probe 1f, the epoxidation is nondias-
tereoselective (entry 5) because of the opposing sense in
the stereodifferentiation displayed by these two types of
allylic strain. Comparison of these POM diastereoselec-
tivities with the ones of established oxidants in Table 5
discloses that the POM data fit qualitatively well with
both the Ti(OiPr)4/TBHP and VO(acac)2/TBHP oxidants,
for which also a template with metal-alcoholate bonding
applies. Therefore, this stereochemical comparison sug-
gests that the dihedral angle in the transition structure
with the POM oxidants lies between those for VO(acac)2/
TBHP (40-50°) and Ti(OiPr)4/TBHP (70-90°), and may
be estimated to be 50-70° (Figure 2). Evidently, the
intermediate R angle for the metal-alcoholate-bonded
structure III [a peroxy-type structure (WOOH+) would
also qualify] in the case of the POM/H2O2 system provides
the best compromise between 1,2A and 1,3A strain during
the oxygen transfer.
The R angle of 50-70° estimated for the POM-
catalyzed epoxidation of the acyclic allylic alcohols (Fig-
ure 2) also provides a clue to why so much enone is
formed with the cyclohexenol substrates 4b,c (Table 4).
The fact that about twice as much enone is formed for
the cis-4c (OH pseudo equatorial) than for the trans-4c
(OH pseudo axial) demonstrates that the product selec-
tivity depends on the dihedral angle R (Table 4, entries
4 and 5). Clearly, the larger the deviation from this
optimal R angle of 50-70° in the metal-alcoholate
template, the more competitive the allylic oxidation.
Thus, more enone is expected to be formed from the cis-
4c (R 140°) than from the trans-4c (R 110°) cyclic allylic
alcohols (Table 4, entries 4 and 5). The high cis diaste-
reoselectivity for the epoxidation of these cyclic substrates
is independent of the R angle, because the conformation-
ally fixed geometry and metal-alcoholate bonding oblige
that the oxygen atom is transferred to the double bond
from the side at which the allylic hydroxy functionality
is located.
to account for the observed high selectivities. The need
of the hydroxy functionality is demonstrated by the total
lack of epoxidation reactivity of the ester and ether
derivatives 1a (Ac) and 1a (Me) under the present reac-
tion conditions. Furthermore, the finding that in protic
solvents such as methanol the regioselectivity and dias-
tereoselectivity are not affected, although the reactivity
drops considerably (Table 3, entry 3), indicates that the
hydrogen-bonding mechanism does not operate in the
present POM system.16 As for the low reactivity in the
methanol, it is known that the epoxidation activity of the
peroxo species of tungsten or molybdenum is inhibited
by strongly coordinating solvents.30
The high regioselective preference for the allylic alcohol
double bond in the 1-methylgeraniol and geraniol (Table
3) substantiates the fact that the allylic hydroxy group
is ligated to the catalytic species by means of a metal-
alkoxide bond to give the 3,4 or 2,3 regioisomer as the
epoxide product. Such binding favors the oxygen transfer
to the proximate allylic double bond rather than to the
remote unfunctionalized double bond. This is analogous
to the known catalytic oxidants Ti(OiPr)4/TBHP and VO-
(acac)2/TBHP, typical for metal-alcoholate binding, which
also afford the 3,4 epoxide in high preference (95:5) in
the epoxidation of 1h or 1i; in contrast, the characteristic
hydrogen-bonding systems m-CPBA and DMD favor the
7,8 regioisomer.27
Clearly, a template effect operates, in which metal-
alkoxide bonding of the allylic substrate and metal
activation of the oxygen donor H2O2 through a tungsten
peroxo species assist the oxygen-transfer process [a
peroxy-type structure (WOOH+) would also qualify]. This
accounts for the remarkable enhancement of reactivity
and selectivity in the M-POM-catalyzed epoxidation of
allylic alcohols, as displayed in the proposed catalytic
cycle in Scheme 2.
Con clu sion
From our work on the sandwich-type POM-catalyzed
epoxidation of allylically strained chiral alcohols 1, a
highly efficient, selective and mild oxyfunctionalization
(30) (a) Mimoun, H.; De Roch, I. S.; Sajus, L. Tetrahedron 1970, 26,
37-50. (b) Mimoun, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 734-
750.
1726 J . Org. Chem., Vol. 68, No. 5, 2003

Epoxidation of Chiral Allylic Alcohols
TABLE 5. Dia ster eoselectivities (th r eo:er yth r o) for th e Ep oxid a tion of Allylic Alcoh ols 1 by P olyoxom eta la tes a n d
Oth er P er tin en t Ca ta lytic a n d Stoich iom etr ic Oxid a n ts
a
b
d
Data from this work; see Tables 1 and 2. See ref 18. c See ref 17. See ref 22. e Dihedral angle of CdCsCsOH.
Sta r tin g Ma ter ia ls. The sandwich-type polyoxometalate
Na12{ZnW[Zn(H2O)]2[ZnW9O34]2}‚44H2O, and other isostruc-
tral disubstituted transition-metal derivatives with the Mn-
(II), Fe(III), Pd(II), and Pt(II) metals were synthesized and
characterized by a literature procedure.14 The ruthenium(III)
analogue Na11{ZnW[Ru2(H2O)(OH)](ZnW9O34)2}‚42H2O was
likewise prepared by a known procedure.10b The lacunary
R-Keggin Na7[PW11O39] was obtained according to a procedure
as reported.31 The known and fully characterized allylic
alcohols 1a ,32 1a (Ac),33 1a (Me),34 1b,35 1c,36 1d ,37 1e,32 1f,37
1g,38 and 1h 27 and the conformationally fixed cis- and trans-
5-tert-butyl-2-cyclohexenols (4c)39 were synthesized according
to known methods. The 2-cyclopentenol (4a ) and 2-cyclooctenol
(4d ) were prepared by photooxygenation of the corresponding
cycloalkenes and subsequent reduction with triphenylphos-
phine according to a literature procedure.40 Geraniol (1i) and
2-cyclohexenol (4b) were commercially available. Hydrogen
peroxide was employed as a 30% aqueous solution, whose
concentration was determined by iodometry.41
F IGURE 2. Proposed transition structures with the optimal
dihedral angles for the epoxidation of the chiral allylic alcohols
by VO(acac)2/TBHP (I), Ti(OiPr)4/TBHP (II), and POM/H2O2
(III).
has become available, in which the reactivity and selec-
tivity derive from template formation with the tungstate
metal. In this template, the allylic alcohol is ligated
through metal-alcoholate bonding and the hydrogen
peroxide oxygen source is activated in the form of a
peroxotungsten complex. 1,3-Allylic strain expresses a
high preference for the threo diastereomer and 1,2-allylic
strain a high preference for the erythro diastereomer,
whereas tungsten-alcoholate bonding accelerates the
reaction rate and furnishes high regioselectivity for the
epoxidation of the allylic double bond. Evidently, the
catalysis by the readily available sandwich-type polyoxo-
metalates provides a valuable synthetic method for the
selective catalytic epoxidation of allylic alcohols by H2O2
as the oxygen source.
P r ep a r a tion of Stock Solu tion s of Hyd r op h obic P OM
Ca ta lysts. The catalytic reactions with the polyoxometalates
were performed by transferring the polyoxoanion into the
organic solvents with a quaternary ammonium cation. For this
purpose, the alkali metals of all transition-metal-substituted
(31) Brevard, C.; Schimpf, R.; Tourne´, G. F.; Tourne´, C. M. J . Am.
Chem. Soc. 1983, 105, 7059-7063.
(32) House, H. O.; Wilkins, J . M. J . Org. Chem. 1978, 43, 2443-
2454.
(33) Bonazza, B. R.; Lillya, C. P.; Magyar, E. S.; Scholes, G. J . Am.
Chem. Soc. 1979, 101, 4100-4106.
(34) Lodge, E. P.; Heathcock, C. H. J . Am. Chem. Soc. 1987, 109,
3353-3361.
Exp er im en ta l Section
(35) Shalley, C. A.; Schro¨der, D.; Schwarz, H. J . Am. Chem. Soc.
1994, 116, 11089-11097.
Gen er a l Asp ects. The conversions, yields, and product
ratios were determined by 1H NMR spectroscopy with dimethyl
isophthalate as internal standard. TLC analysis was conducted
on precoated silica gel foils 60 F254 (20 × 20 cm). Spots were
visualized by treatment with polymolybdic acid (5% solution
in ethanol) test spray. Silica gel (32-63 µm) was used for flash
chromatography. For peroxide tests, potassium iodide/starch
indicator paper was used. Solvents were dried by standard
methods and purified by distillation before use. Commercially
available chemicals were used without further purification,
unless otherwise stated.
(36) Ho, N.-H.; leNoble, W. J . J . Org. Chem. 1989, 54, 2018-2021.
(37) House, H. O.; Ro, R. S. J . Am. Chem. Soc. 1958, 80, 2428-
2433.
(38) Morgan, B.; Oehlschlager, A. C.; Stokes, T. M. J . Org. Chem.
1992, 57, 3231-3236.
(39) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J . Chem. Soc.
B 1970, 1374-1381.
(40) Smerz, A. K. Ph.D. Thesis, University of Wu¨rzburg, Germany,
1996.
(41) Lucas, J .; Kennedy, E. R.; Formo, M. W. Org. Synth. 1955, 3,
483-485.
J . Org. Chem, Vol. 68, No. 5, 2003 1727

Adam et al.
POMs were exchanged with hydrophobic quaternary am-
monium salts (Aliquot 336), analogous to literature protocol.9b-f
Thus, the stock solution (1.0 mM) was prepared by dissolving
required reaction time, the organic phase of the reaction
medium was separated and dried over Na2SO4, and the solvent
was removed (20 °C, 50 mbar). The conversions, yields, and
1
the particular sandwich M-POM (0.1 mmol), namely Na12
-
product ratios were determined by H NMR analysis directly
{ZnW[Zn(H2O)]2(ZnW9O34)2}‚44H2O [Zn(II)-POM], Na12{ZnW-
[Mn(H2O)]2(ZnW9O34)2}‚46H2O [Mn(II)-POM], Na10{ZnW[Fe-
(H2O)]2(ZnW9O34)2}‚46H2O [Fe(III)-POM], Na11{ZnW[Ru2(H2O)-
(OH)](ZnW9O34)2}‚42H2O [Ru(III)-POM], K12{ZnW[Pd(H2O)]2-
(ZnW9O34)2}‚38H2O [Pd(II)-POM], or K12{ZnW[Pt(H2O)]2-
(ZnW9O34)2}‚36H2O [Pt(II)-POM] or the lacunary Keggin POM
Na7(PW11O39) (0.1 mmol) and methyltricaprylammonium chlo-
ride (1.25 mmol) in a 1:1 mixture of water and 1,2-dichloro-
ethane (200 mL). Under gentle heating at 40 °C and magnetic
stirring, the color of the organic phase turned yellow [except
for Zn(II)-POM and lacunary Keggin POM], whereas the
aqueous phase was decolorized. The organic layer was sepa-
rated, dried over anhydrous Na2SO4, and used as such.
Gen er a l P r oced u r e for th e Ca ta lytic Ep oxid a tion of
Ch ir a l Allylic Alcoh ols 1 by P OM Ca ta lysts. For the
epoxidation of the allylic alcohols 1 with 30% H2O2, the reac-
tions were carried out in a 5 mL flask, equipped with a mag-
netic stirring bar. In a typical reaction, the specific substrate
1 (0.50 mmol) and dimethyl isophthalate (0.20 mmol), as
internal standard, were dissolved in the stock solution of the
particular M-POM catalyst (0.50 mL, 1.0 mM). The reaction
was initiated by addition of 30% hydrogen peroxide (110 µL,
1.0 mmol) to the solution at ca. 20 °C with magnetic stirring.
The resulting biphasic mixture was stirred at a constant rate
(ca. 1000 rpm) for all runs. The reaction progress was
monitored by 1H NMR spectroscopy or TLC, and after the
on the crude mixture and are given in Tables 1-4. In some
cases, the epoxides 2 were purified by silica gel chromatogra-
phy with a 1:1 mixture of ethyl ether and petroleum ether (30-
50 °C) as eluent. The epoxides 227,42-47 and 522,39 are both
known and have been identified by comparison of their
characteristic NMR signals with the literature reported data.
Ack n ow led gm en t. We thank the European Com-
mission (SUSTOX grant, G1RD-CT-2000-00347) and the
Fonds der Chemischen Industrie for generous financial
support. R.Z. is grateful to the Alexander-von-Humboldt
Foundation for a postdoctoral fellowship (2001-2002).
R.N. is the Rebecca and Israel Sieff Professor of Organic
Chemistry.
J O0266386
(42) Kurth, M. J .; Abreo, M. A. Tetrahedron 1990, 46, 5085-5092.
(43) Fuji, H.; Oshima, K.; Utimoto, K. Chem. Lett. 1992, 967-970.
(44) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J . Am. Chem.
Soc. 1990, 112, 5276-5290.
(45) Adam, W.; Nestler, B. J . Am. Chem. Soc. 1993, 115, 5041-
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(46) Pettersson, H.; Gogoll, A.; Ba¨ckvall, J .-E. J . Org. Chem. 1992,
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1728 J . Org. Chem., Vol. 68, No. 5, 2003