Mechanism of the enantioselective oxidation of racemic secondary alcohols catalyzed by chiral Mn(III)-salen complexes

Article abstract of DOI:10.1021/ja103103d

The experiments described here clarify the mechanism and origin of the enantioselectivity of the oxidation of racemic secondary alcohols catalyzed by chiral Mn(III)-salen complexes using HOBr, Br₂/H₂O/KOAc or PhI(OAc)₂/H₂O/KBr as a stoichiometric oxidant. Key points of the proposed pathway include (1) the formation of a Mn(V)-salen dibromide, (2) its subsequent reaction with the alcohol to give an alkoxy-Mn(V) species, and (3) carbonyl-forming elimination to produce the ketone via a highly organized transition state with intramolecular transfer of hydrogen from carbon to an oxygen of the salen ligand.

Full text of DOI:10.1021/ja103103d

Published on Web 07/28/2010
Mechanism of the Enantioselective Oxidation of Racemic
Secondary Alcohols Catalyzed by Chiral Mn(III)-Salen
Complexes
M. Kevin Brown, Megan M. Blewett, James R. Colombe, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge,
Massachusetts 02138
Received April 13, 2010; E-mail: corey@chemistry.harvard.edu
Abstract: The experiments described here clarify the mechanism and origin of the enantioselectivity of
the oxidation of racemic secondary alcohols catalyzed by chiral Mn(III)-salen complexes using HOBr,
2 2 2 2
Br /H O/KOAc or PhI(OAc) /H O/KBr as a stoichiometric oxidant. Key points of the proposed pathway include
(1) the formation of a Mn(V)-salen dibromide, (2) its subsequent reaction with the alcohol to give an alkoxy-
Mn(V) species, and (3) carbonyl-forming elimination to produce the ketone via a highly organized transition
state with intramolecular transfer of hydrogen from carbon to an oxygen of the salen ligand.
Introduction
Scheme 1. Enantioselective Oxidation of Racemic Secondary
a
Alcohols as Reported by Xia and Coworkers
Chungu Xia and his group showed that chiral Mn(III)-salen
complexes can catalyze the oxidation of racemic secondary
alcohols of the type R
mixture of the corresponding ketone and chiral R
excellent enantioselection under the optimized conditions.
It was reported that the addition of substoichiometric amounts
of a bromide salt to a mixture of catalyst 2a, PhI(OAc) , and a
biphasic CH Cl /H O medium is important for high enantiose-
lectivity and that krel in favorable cases can be as high as 450
1
R
2
CHOH at partial conversion to a
1 2
R
CHOH with
1
-4
2
2
2
2
1
b
5
(
Scheme 1). Kita and co-workers had earlier noted that KBr
accelerated the oxidation of secondary alcohols by PhIO. The
Xia group proposed that the active oxidant for the oxidation of
secondary alcohols may be a species having composition
salen-Mn(V)-OIPh but provided no explanation for the effect
of bromide on the enantioselectivity or for the absolute
1b
stereochemical course of the reaction. Representative examples
of the enantioselective oxidation of racemic secondary alcohols
(
(
1) (a) Sun, W.; Wang, H.; Xia, C.; Li, J.; Zhao, P. Angew. Chem., Int.
Ed. 2003, 42, 1042–1044. (b) Li, Z.; Tang, Z. H.; Hu, X. X.; Xia,
C. G. Chem.sEur. J. 2005, 11, 1210–1216. (c) Sun, W.; Wu, X.;
Xia, C. HelV. Chim. Acta 2007, 90, 623–626. (d) Cheng, Q.; Deng,
F.; Xia, C.; Sun, W. Tetrahedron: Asymmetry 2008, 19, 2359–2362.
2) (a) Kantam, M. L.; Ramani, T.; Chakrapani, L.; Choudary, B. M. J.
Mol. Catal. A: Chem. 2007, 274, 11–15. (b) Pathak, K.; Ahmad, I.;
Abdi, S. H. R.; Kureshy, R. I.; Khan, N. H.; Jasra, R. V. J. Mol. Catal.
A: Chem. 2007, 274, 120–126. (c) Kureshy, R. I.; Ahmad, I.; Pathak,
K.; Khan, N. H.; Abdi, S. H. R.; Prathap, J. K.; Jasra, R. V. Chirality
a
For further details, see ref 1 and the Supporting Information.
6
are displayed in Scheme 1. There are limitations of the Xia
method with R
similar steric bulk. Alcohols such as 1-phenylpropanol (11), for
example, are oxidized with only poor selectivity.
Our group recently proposed a logical mechanistic explanation
for the absolute stereochemical course of the Mn(III)-salen-
catalyzed epoxidation of olefins (Jacobsen epoxidation) that
1 2 1 2
R CHOH substrates in which R and R have
2
007, 19, 352–357. (d) Han, F.; Zhao, J.; Zhang, Y.; Wang, W.; Zho,
Y.; An, J. Carbohydr. Res. 2008, 343, 1407–1413.
1
d
(
3) In one example, Katsuki and co-workers reported an enantioselective
oxidation of 3,3-dimethyl-1-indanol with Mn-salen-based complexes,
but low selectivities were observed. See: Hamada, T.; Irie, R.; Mihara,
J.; Hamachi, K.; Katsuki, T. Tetrahedron 1998, 54, 10017–10028.
4) For non-enantioselective oxidation of alcohols promoted by Mn-salen
complexes, see: (a) Kumbhat, V.; Sharma, P. K.; Banerji, K. K.
J. Chem. Res., Synop. 2001, 5, 179–181. (b) Kim, S. S.; Borisova, G.
Synth. Commun. 2003, 33, 3961–3967. (c) Mardani, H. R.; Golchou-
bian, H. Tetrahedron Lett. 2006, 47, 2349–2352.
7
(
8
is in cases highly enantioselective. The key features of this
pathway are as follows: (1) the epoxidation involves electrophilic
(5) (a) Tohma, H.; Maegawa, T.; Takizawa, S.; Kita, Y. AdV. Synth. Catal.
(6) For reviews regarding kinetic resolution, see: (a) Keith, J. M.; Larrow,
J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5–26. (b) Vedejs,
E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974–4001.
2002, 344, 328–337. (b) Tohma, H.; Maegawa, T.; Kita, Y. Synlett
2003, 723–725.
10.1021/ja103103d  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 11165–11170 9 11165

A R T I C L E S
Brown et al.
Table 1. Survey of Reaction Conditions for the Biphasic Oxidation
of 1
a
b
c
entry
solvent
additive
conv (%)
ee (%)
k
rel
1
2
3
4
5
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
/H
/H
/H
/H
2
2
2
2
O (1:2) 8 mol % KBr
O (1:2) 8 mol % KCl
O (1:2) 8 mol % KI
68
12
29
13
63
49
>99
<2
22
<2
55
-
>13
1.0
4.1
1.0
3.2
O (1:2)
-
4
8 mol % Et NBr
d
6
/H
2
O (1:2) 8 mol % KBr
-
a
Determined by 1H NMR (500 MHz) analysis of the unpurified
b
Figure 1. An explanation for the origin of enantioselectivity in the Jacobsen
epoxidation.
reaction mixtures. Determined by HPLC analysis with a chiral column.
rel ) ln[(1 - conv)(1 - ee)]/ln[(1 - conv)(1 + ee)]. The reaction
was carried out in the absence of catalyst 2a.
c
d
k
attack by the oxygen of a salen-Mn(V)-oxo complex on one
of the olefinic carbons to form the more stable carbocationic
intermediate; (2) the relative orientation of the olefinic substrate
and the Mn(V)-oxo complex is determined by the electrostatic
attraction between the cationic carbon and one of the oxygens
of the salen ligand; and (3) the olefinic π-face selectivity arises
from differences in steric repulsion for the two diastereomeric
complexes. This model leads, for example, to the pre-transition-
state assembly shown in Figure 1 for the epoxidation of indene
by Mn-salen complex 2a.
the data are noteworthy (see Table 1). Reactions in which
potassium bromide was replaced by potassium chloride afforded
only low conversion of (()-1-indanol (1) (Table 1, entry 2).
Reactions with potassium iodide gave poorer conversion than
reactions with potassium bromide (Table 1, entry 3). Reactions
carried out in the absence of any halide ion or with added
chloride ion were inefficient (Table 1, entry 4). Water is a
necessary component for high enantioselectivity (Table 1, entry
10
5
). There is a significant Mn-independent background reaction,
since the oxidation of 1 with PhI(OAc) and potassium bromide
2
We believe that some features of this model for the Jacobsen
epoxidation of olefins carry over to the enantioselective oxida-
without any Mn complex 2a was nearly complete within 30
min (Table 1, entry 6). The enantioselective oxidation of 1 in
the presence of Mn complex 2a and KBr is much faster and
was complete in less than 10 min. This acceleration of the
Mn-salen oxidation by bromide ion is clearly large enough to
dominate over the competing, nonenantioselective background
process (without any Mn-salen) and thus leads to enantiose-
lectivity.
1
tion of secondary alcohols developed by Xia. This line of
8
analysis based on our earlier work together with the experi-
ments described herein have led to a new and rational explana-
tion for the Mn-salen-catalyzed enantioselective oxidation of
secondary alcohols. We have followed a heuristic that has been
extremely useful in many of our previous research efforts on
the design and understanding of enantioselective chemical
9
Because one possible role of bromide might be the conversion
of the salen-Mn-chloro complex 2a into the corresponding
salen-Mn-Br complex 12, we prepared complex 12. As
expected and as indicated in Table 2, oxidation of 1 catalyzed
by 12 under the optimized conditions gave results identical to
those for 2a (compare Table 1, entry 1 with Table 2, entry 1).
However, the use of additional potassium bromide with
salen-Mn-Br complex 12 is essential for achieving optimum
stereoselection in the oxidation of 1 (Table 2, entry 2), as it is
reactions. In its simplest form, that heuristic is as follows: (1)
for cases in which a chemical reaction is highly enantioselective
and also wide in scope, the pre-transition-state assembly is likely
to be highly organized in the sense that there is one preferred
three-dimensional assembly of the atoms involved; (2) that
condition very sharply limits the number of mechanistic
pathways by which the reaction can occur; and (3) the favored
pathway can often be derived from three-dimensional modeling
and an analysis of the steric, electrostatic, and stereoelectronic
effects that determine the reaction energetics and rates.
1
for the corresponding salen-Mn-chloro complex. The bromide
attached to Mn in 12 provides only a modest improvement in
oxidative enantioselection relative to catalyst 2a in the absence
of additional potassium bromide (compare Table 1, entry 4 with
Results and Discussion
Role of the Additive Bromide Ion. We start by examining
1
1
Table 2, entry 2).
We determined experimentally that bromide ion is oxidized
by PhI(OAc) to Br (and therefore to HOBr, which in the
presence of H O is known to be in equilibrium with Br
according to reactions R1 and R2:
the role of the additive bromide ion on enantioselectivity in the
oxidation of racemic secondary alcohols since Xia et al.
reported that potassium bromide is absolutely crucial for fast
and highly enantioselective oxidation. Several points regarding
1
2
2
2
2
)
1
2
(
7) For a review regarding the Cr- and Mn-promoted epoxidation of
olefins, see: McGarrigle, E. M.; Gilheany, D. G. Chem. ReV. 2005,
(10) In accordance with results published by Xia and coworkers (ref 1),
enantioselective oxidation of 1-phenylethanol under the conditions
presented in entry 3 of Table 1 resulted in <10% conversion.
(11) Enantioselective oxidation of 1-phenylethanol under the conditions
presented in entry 2 of Table 2 resulted in 33% conversion and <10%
ee.
1
05, 1563–1602.
(
8) K u¨ rti, L.; Blewett, M. M.; Corey, E. J. Org. Lett. 2009, 11, 4592–
595.
9) For example, see: Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100–
117.
4
(
2
1
1166 J. AM. CHEM. SOC. 9 VOL. 132, NO. 32, 2010

Enantioselective Oxidation of Racemic Secondary Alcohols
A R T I C L E S
Table 2. Biphasic Oxidation of 1 with salen-Mn(III)-Br Catalyst 12
a
b
c
entry
solvent
additive
oxidant
conv (%)
ee (%)
k
rel
1
2
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
/H
/H
/H
2
2
2
O (1:2)
O (1:2)
O (1:2)
8 mol % KBr
PhI(OAc)
2
2
65
64
65
27
69
66
66
>99
72
98
<5
97
98
89
>16
4.8
14
1.3
9.5
13
-
PhI(OAc)
d
e
3
2.0 equiv of KOAc
Br
Br
2
d
e
4
4
2.0 equiv of n-Bu NOAc
2
d
f
5
/H
2
/H
2
/H
2
O (1:2)
O (1:2)
O (1:2)
1.3 equiv of KOAc
1.0 equiv of KOAc
1.0 equiv of NaHCO
HOBr
d
g
g
6
t-BuOBr
t-BuOBr
d
7
3
7.4
a
Determined by 1H NMR (500 MHz) analysis of the unpurified reaction mixtures. Determined by HPLC analysis with a chiral column.
b
c
k
rel
)
d
ln[(1 - conv)(1 - ee)]/ln[(1 - conv)(1 + ee)]. The reaction was carried out with 10 mol % 12 and oxidant added over 30 min. See the Supporting
Information for details. Using 0.75 equiv of Br . Using 0.90 equiv of HOBr. Using 0.80 equiv of t-BuOBr.
2
e
f
g
PhI(OAc) + 2KBr f PhI + Br + 2KOAc
(R1)
2
2
PhI(OAc) + KBr + H O f PhI + HOBr + HOAc +
2
2
KOAc (R2)
The fact that a positive Br species is formed under the Xia
conditions suggests that PhI(OAc) can be replaced by Br or
2
2
HOBr as the stoichiometric oxidant in the enantioselective
oxidation. Indeed, highly enantioselective oxidations can be
Figure 2. Pre-transition-state assembly with the Mn(V)-oxo complex
predicts an incorrect absolute stereochemistry for the recovered alcohol.
carried out with Br
2
or HOBr as the stoichiometric oxidant [no
PhI(OAc) added] provided that sufficient potassium acetate is
2
under the most effective Xia procedure, with comparable
used to neutralize the HBr generated during the oxidation and
buffer the reaction mixture (Table 2, entries 3 and 5). Sodium
bicarbonate can also be used to neutralize HBr in the enanti-
oselective oxidation of 1 (Table 2, entry 7). It is important that
the oxidant be added slowly enough to prevent the detrimental
reaction conditions (1:2 CH
PhI(OAc) in the presence of bromide ion in the Xia procedure
is to generate HOBr and Br . There is no obvious reason why
2 2 2
Cl /H O, 23 °C). The role of
2
2
it needs to be invoked as an integral component of the transition-
1
state assembly for enantioselective oxidation.
2
build up of HBr. Reactions carried out with Br or HOBr as
It should be emphasized that the Xia process for the
enantioselective oxidation of secondary alcohols is biphasic with
the stoichiometric oxidant in the absence of potassium acetate
were nonselective because of the adverse effect of HBr, and
lower selectivities were observed (krel ≈ 4-9) when the oxidant
a CH
and the PhI(III) oxidant are concentrated in the CH
as are 1-indanol and the product 1-indanone. Any bromide ion
is concentrated in the aqueous phase, whereas Br and HOBr
are probably available in both the CH Cl and water layers.
Essentially all of the acetate ion buffer is in the water layer,
2
Cl
2
layer and a water layer. The Mn(V)-salen catalyst
1
2
2
Cl phase,
2
was added rapidly. As evidenced by the experiment sum-
marized in Table 2, entry 4, the presence of water in the biphasic
reaction mixture is necessary for the highly enantioselective
reaction to occur. Our best procedure involved the slow addition
2
2
2
1
2
of Br
secondary alcohol (1.0 equiv), potassium acetate (2.0 equiv for
Br or 1.0 equiv for HOBr), and salen-Mn-Br complex 12
10 mol %) in 1:2 CH Cl /H O with stirring. Under the
optimized reaction conditions, t-BuOBr afforded results that
were almost identical to those for Br or HOBr (Table 2, entry
2
or HOBr (0.75-0.90 equiv; see Table 2) to a mixture of
and for this reason among others, this species is unlikely to be
involved in the oxidation itself. Furthermore, under the Xia
conditions, acetate ion is not present and therefore cannot be
involved in the transition state for secondary alcohol oxidation.
At the outset of this study, perhaps the most obvious pathway
for enantioselective oxidation of secondary alcohols by the
2
(
2
2
2
2
1
3
6
).
Our experimental results indicate that either Br
2
reagents Mn(III)-salen, KBr, and PhI(OAc) under the condi-
2
or HOBr
1
tions of Xia et al. that would follow from our earlier
alone can convert the chiral (S,S)-Mn(III)-salen complex 12
into an oxidizing species that catalyzes the transformation of
8
mechanistic proposal for the Jacobsen epoxidation (Figure 1)
seemed to be the one summarized in Figure 2. Such a pathway
involving abstraction of the carbinol C-H by the oxygen of a
salen-Mn(V)-oxo complex with H bonding of the hydroxyl
proton and one of the oxygens of the salen ligand can definitely
be ruled out, as this process would lead to the wrong enantio-
preference. As illustrated in Figure 2, such a model incorrectly
predicts that (S)-1-indanol would oxidize in preference to (R)-
(
()-1-indanol into a mixture of 1-indanone and (S)-1-indanol
with essentially the same enantioselectivity as that achieved
(
(
12) See the Supporting Information for details.
13) It is recommended that HOBr be generated in situ from t-BuOBr in
1
:2 CH
of Br and HgO in H
latter procedure. For the preparation of HOBr from HgO and Br
2
Cl
2
/H
2
O rather than from the previously described reaction
O because the yield of HOBr can vary with the
, see:
2
2
2
1
-indanol with (S,S)-Mn(III)-salen complexes, which is con-
Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M. AdVanced
Inorganic Chemistry, 6th ed.; Wiley-Interscience: New York, 1999.
trary to fact.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 32, 2010 11167

A R T I C L E S
Brown et al.
Scheme 2. Stoichiometric Reactions with salen-Mn(III)-Br
Complex 12
Scheme 3. Plausible Catalytic Cycle
We have obtained strong evidence that any mechanism
involving direct C-H abstraction by a Mn(V)-oxo complex
is unlikely on the basis of the following observations: (1)
under conditions that are conducive to formation of
Mn(V)-oxo complexes (and epoxidation of olefins), enan-
tioselective oxidation of secondary alcohols is inefficient and
nonselective, since treatment of Mn complex 2a (1.1 equiv)
Pathway for Enantioselective Mn-salen-Catalyzed Oxidation
of Secondary Alcohols. All of our data are in accord with a
pathway in which HOBr or Br /H O converts the Mn(III)-salen
2
2
complex (I) into a brominated Mn(V)-salen species, such as
1
4
15
+
with m-CPBA or PhIO (1.0 equiv) in 1:2 CH
2
Cl
2
/H
2
O at
[salen-Mn(V)-Br2] (II), which then reacts reversibly with
2
3 °C followed by addition of 1 (1.0 equiv) led to poor
the secondary alcohol to form the alkoxy complex
1
2
+
conversion and enantioselectivity (<25% conv, <10% ee);
2) treatment of salen-Mn-Br complex 12 (1.1 equiv) with
t-BuOBr (1.0 equiv) and KOAc (1.0 equiv) in 1:2 CH Cl
O (optimal conditions for enantioselective oxidation of 1)
converted indene to dibromide 13 rather than to the epoxide
[salen-Mn(V)-Br-OR] (III) as the key reaction intermediate
(
and precursor of the ketonic product, as shown in Scheme 3.
We surmise further that the Mn(V)-alkoxide complex III is
converted to the Mn(III) species V by intramolecular hydrogen
transfer from the carbinol C-H to the neighboring phenolic
oxygen along a five-membered cyclic pathway via IV. This
cyclic pathway is reasonable because the electron lone pair
density on one of the metal-bound phenoxy oxygens is properly
oriented to facilitate the carbonyl-forming elimination process
in a fashion analogous to the electrostatic effect of that oxygen
in organizing the transition state and stabilizing the positive
charge during the Jacobsen epoxidation of olefins, as pictured
2
2
/
H
2
(
<2% observed), as would be expected if a Mn-oxo complex
16
were generated (Scheme 2).
Further evidence against direct catalytic involvement of a
salen-Mn(V)-oxo complex in the enantioselective oxidation
of alcohols was obtained from an experiment showing that
bromideionisrapidlyoxidizedtoBr bythesalen-Mn(V)-oxo
2
species. Experimentally, the salen-Mn(V)-oxo complex was
generated by reaction of the corresponding Mn(III) complex
with 1.0 equiv of m-CPBA and then treated with 2.0 equiv
of aqueous KBr. Addition of indene and isolation of indene
dibromide as outlined in eq 1 established that bromide ion
8
in Figure 1. There is also an obvious analogy with the
Westheimer chromate ester pathway for oxidation of secondary
1
7
alcohols by Cr(VI) reagents. The mechanism outlined in
Scheme 3 is attractive because it provides a uniquely simple
explanation for the absolute stereocourse of the Mn-salen-
promoted enantioselective oxidation. Intermolecular processes
for proton abstraction from the Mn(V)-alkoxide complex III
2
is indeed oxidized to Br by the Mn(V)-oxo salen complex.
(
2 2 2
e.g., deprotonation by any H O present in the CH Cl layer)
seems a highly unlikely alternative, as that would lead to a large
number of geometrical paths for oxidation and provide no
rational basis for the enantioselectivity. We do not rule out the
(
(
(
14) Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett.
995, 36, 5457–5460.
15) Feichtinger, D.; Plattner, D. A. Angew. Chem., Int. Ed. 1997, 36, 1718–
1
1
719.
16) The identical reaction carried out in the absence of Mn complex 12
leads to a mixture of trans-dibromide, cis-dibromide, and trans-
bromohydrin in a 33:17:10 ratio.
(
17) Westheimer, F. H. Chem. ReV. 1949, 45, 419–451.
1
1168 J. AM. CHEM. SOC. 9 VOL. 132, NO. 32, 2010

Enantioselective Oxidation of Racemic Secondary Alcohols
A R T I C L E S
Table 3. Effect of Catalyst Structure on the Efficiency of
Enantioselective Oxidation
a
Determined by 1H NMR (500 MHz) analysis of the unpurified
b
reaction mixtures. Determined by HPLC analysis with a chiral column.
rel ) ln[(1 - conv)(1 - ee)]/ln[(1 - conv)(1 + ee)].
c
k
replaced by CH
and 3), led to much-diminished enantioselectivity (krel
.9-2.6). Further support for the mechanistic model came from
3
and H, respectively (see Table 3, entries 2
Figure 3. Plausible pre-transition-state assemblies for the (a) favored and
)
(
b) disfavored modes of oxidation.
1
the study of catalyst 2d (Table 3) having nitro in place of t-Bu
as a substituent at C5 of the benzenoid ring. As indicated in
Table 3, entry 4, the effect of the change was greatly diminished
possibility that a water molecule may be involved in the
formation of ketone from IV.
We have obtained evidence that the rate-limiting step of the
oxidation involves C-H cleavage (III f V), as might be
anticipated, and not alcohol-Mn(V) complexation (II f III).
Measurement of the relative rates of oxidation of 1-deuterio-
labeled 1-indanol and 1-indanol indicated a small but definite
enantioselectivity (krel ) 1.6) for catalyst 2d relative to the
8,21
standard catalyst 2a (Table 3, entry 1).
This result is readily
understandable on the basis of the internal proton transfer from
carbon to oxygen that is shown in structure VI. Since the nitro
substituent at C5 of the benzenoid ring of catalyst 2d is para to
the phenolic oxygen serving as the proton acceptor in VI, it
markedly decreases the electron density at that oxygen and hence
reduces the rate of the enantioselective pathway. Dramatic
confirmation of this rate retardation was obtained in a competi-
tion experiment involving a 1:1 mixture of the S,S enantiomer
of 2a and the R,R enantiomer of catalyst 2d (eq 2). As indicated
in eq 2, the presence of an equimolar amount of the nitro-
substituted catalyst 2d had virtually no effect on the enantiose-
lective oxidation of 1 by catalyst 2a. Thus, it can be concluded
that the effect of the nitro substituent in 2d is to decrease the
rate of oxidation of 1 as well as to negate the enantioselective
1
2
primary kinetic isotope effect, with k
H
/k
D
D
) 2.7 ( 0.6.
Although this is below the values of k /k
H
generally observed
1
7
for the Cr(VI)-mediated oxidation of secondary alcohols, we
believe that it is entirely consistent with expectations for a more
exothermic process for the Mn(V) oxidation and an earlier, and
1
8,19
bent, transition state.
The above pathway involves the same canted (i.e., nonplanar)
geometry for the Mn(V)-salen complex III as proposed recently
7,8
for the Jacobsen epoxidation. That canted conformation places
2 2
one of the ortho tert-butyl groups above and one below the N O
ligand plane, with the further assumption that the hydrogen is
transferred to that phenoxy oxygen with the proper orientation
2
2
pathway.
2
0
of the one electron pair acceptor. Two possible stereoelec-
tronically favorable pre-transition-state structures emerge, one
for the R enantiomer and one for the S enantiomer (VI and VII,
respectively; Figure 3). This model leads to the expectation that
the oxidation of the S enantiomer (via VII) should be slower
than the oxidation of the R enantiomer (via VI) because of the
serious repulsive steric clash of the indanol aryl subunit in VII
with the tert-butyl group next to the chelate ring.
In accord with this proposal was the finding that catalysts
b and 2c, in which the proximate tert-butyl group (at C3) is
Although our mechanistic model is not based on the X-ray
2
crystal structure of the Mn(III)-alkoxide complex 14 (measured
2
3
in this work ) or that of the Mn(IV)-alkoxide complex 15
(
18) Small kinetic isotope effects (k
H
/k
D
≈ 1.3) for the carbinol C-H were
24
(
previously reported ), which appear in Figures 4 and 5,
observed in Pd-catalyzed oxidation of primary and secondary alcohols.
These studies concluded that ketone formation was rate-determining.
For example, see: Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc.
(21) (a) Pospisil, P. J.; Carsten, D. H.; Jacobsen, E. N. Chem.sEur. J.
1996, 2, 974–980. (b) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Guler,
M. L.; Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948–
954.
2
003, 125, 7005–7013.
(
(
19) Westheimer, F. H. Chem. ReV. 1961, 61, 265–273.
20) The canted structure has been proposed for salen-Mn(V)-oxo
complexes in the Jacobsen epoxidation (see refs 7 and 8). This
conformation has been observed in X-ray crystal structures of both
Mn(III)-and Mn(IV)-salen complexes (see ref 24); two examples
are presented in Figures 4 and 5. The canted conformation of the Mn-
salen complex forces the phenolic oxygen lone pairs to adopt
pseudoaxial and pseudoequatorial arrangements.
(22) We also examined briefly the effect of replacing the C5 tert-butyl
substituent in catalyst 2a by methoxy and found that there is very
little change in the rate of oxidation and a modest decrease in
enantioselectivity, which is not inconsistent with the similarity of the
Hammett σ constants (-0.20 for t-Bu and -0.27 for OMe). See:
Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165–195.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 32, 2010 11169

A R T I C L E S
Brown et al.
2
5
might involve a Mn(IV)-salen complex and a Mn(IV) a
Mn(II) redox cycle (as in the MnO oxidation of secondary
2
alcohols to ketones), experimental evidence argues against this
possibility. In a typical experiment, it was found that the
stoichiometric reaction of the Mn(II)-salen complex (0.50
equiv) and HOBr (0.50 equiv) in 1:2 CH
2 2 2
Cl /H O at 23 °C with
1
(1.0 equiv) was ineffective, as there was very little reaction
1
2
and the recovered 1-indanol was racemic.
Conclusions
In conclusion, we have presented evidence to explain the
mechanistic and stereochemical pathway for the enantioselective
Mn-salen-catalyzed oxidation of racemic secondary alcohols
1
reported by Xia et al. The salient features of the proposed
mechanism are as follows: (1) A positive bromine species is
generated under the reaction conditions by oxidation of bromide
ion with PhI(OAc) . (2) It is the positive bromine species that
2
oxidizes the Mn(III)-salen complex to a Mn(V)-salen com-
plex. (3) The most likely composition of the Mn(V)-salen
complex is that of a dibromo-Mn(V) species (II, Scheme 3).
2
3
Figure 4. X-ray crystal structure of Mn(III) complex 14. Selected
distances (Å): Mn -O , 2.25; H -O , 2.59.
1
1
1
2
(
4) An additional effect of added bromide ion arises from its
ability to reduce the salen-Mn(V)-oxo complex with formation
of Br . (5) The dibromo-Mn(V) species II undergoes reversible
2
ligand exchange with (()-1-indanol as the substrate to generate
a Mn(V)-alkoxy complex (III, Scheme 3). (6) Oxidation of
the secondary alcohol occurs by intramolecular hydrogen
transfer from carbon to a phenoxy oxygen of the salen ligand.
(7) The stereochemical course of the enantioselective oxidation
is easily rationalized by comparing the degree of steric repulsion
in the structures VI and VII that are shown in Figure 3.
Acknowledgment. We thank the National Institutes of Health
for a postdoctoral fellowship to M.K.B. and Dr. Shao-Liang Zheng
(
Harvard University) for X-ray diffraction analysis. M.M.B. and
Figure 5. X-ray crystal structure of Mn(IV) complex 15 (structure originally
J.R.C. are Harvard Undergraduate Research Scholars.
24
reported by Fujii and co-workers ). Selected distances (Å): Mn
-O , 2.22.
1 1
-O , 1.88;
H
1
2
Supporting Information Available: Experimental procedures,
analytical data for all compounds, and crystallographic data
respectively, it is interesting to note that in each structure the
alkoxy ligand is oriented with the carbinol C-H aligned over
a phenolic oxygen, similar to the arrangement that we have
proposed for the pre-transition-state assembly VI in Figure 3.
This fact may be entirely coincidental but is nonetheless worth
mentioning.
(
CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA103103D
(
25) For references regarding Mn(IV)-salen complexes, see: (a) Fujiwara,
M.; Matsushita, T.; Shono, T. Polyhedron 1985, 4, 1895–1900. (b)
Law, N. A.; Machonkin, T. E.; McGorman, J. P.; Larson, E. J.; Kampf,
J. W.; Pecoraro, V. L. J. Chem. Soc., Chem. Commun. 1995, 2015–
Although a priori it is not unreasonable that the enantiose-
lective Mn-salen-mediated oxidation of secondary alcohols
2
016. (c) Asada, H.; Fujiwara, M.; Matsushita, T. Polyhedron 2000,
(
23) Solvent molecules and the counterion have been omitted for clarity.
A second molecule of Mn complex 14 that exists in a helical
conformation is present in the unit cell. See the Supporting Information
for structural data.
19, 2039–2048. (d) Campbell, K. A.; Lashley, M. R.; Wyatt, J. K.;
Nantz, M. H.; Britt, R. D. J. Am. Chem. Soc. 2001, 123, 5710–5719.
(e) Feth, M. P.; Bolm, C.; Hildebrand, J. P.; K o¨ hler, M.; Beckmann,
O.; Bauer, M.; Ramamonjisoa, R.; Bertagnolli, H. Chem.sEur. J.
2003, 9, 1348–1359. (f) Kurahashi, T.; Fujii, H. Inorg. Chem. 2008,
47, 7556–7567. (g) Reference 24.
(
24) Kurahashi, T.; Hada, M.; Fujii, H. J. Am. Chem. Soc. 2009, 131,
1
2394–12405. The solvent molecule has been omitted for clarity.
1
1170 J. AM. CHEM. SOC. 9 VOL. 132, NO. 32, 2010