N-Heterocyclic carbene-catalyzed oxidations

Article abstract of DOI:10.1016/j.tet.2008.10.033

N-Heterocyclic carbenes catalyze the oxidation of allylic and benzylic alcohols as well as saturated aldehydes to esters with manganese(IV) oxide in excellent yields. A variety of esters can be synthesized, including protected carboxylates. The oxidation proceeds under mild conditions, with low loadings of a simple triazolium salt pre-catalyst in the presence of base. Substrates containing potentially epimerizable centers are oxidized while preserving stereochemical integrity. The acyl triazolium intermediate generated under catalytic conditions can be employed as a chiral acylating agent in the desymmetrization of meso-diols.

Full text of DOI:10.1016/j.tet.2008.10.033

Tetrahedron 65 (2009) 3102–3109
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Heterocyclic carbene-catalyzed oxidations
*
Brooks E. Maki, Audrey Chan, Eric M. Phillips, Karl A. Scheidt
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Heterocyclic carbenes catalyze the oxidation of allylic and benzylic alcohols as well as saturated al-
dehydes to esters with manganese(IV) oxide in excellent yields. A variety of esters can be synthesized,
including protected carboxylates. The oxidation proceeds under mild conditions, with low loadings of
a simple triazolium salt pre-catalyst in the presence of base. Substrates containing potentially epimer-
izable centers are oxidized while preserving stereochemical integrity. The acyl triazolium intermediate
generated under catalytic conditions can be employed as a chiral acylating agent in the desymmetri-
zation of meso-diols.
Received 9 September 2008
Received in revised form 9 October 2008
Accepted 10 October 2008
Available online 17 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
approaches can suffer from toxic or expensive reagents as well as
non-selective oxidation of the alcohol that serves as the nucleo-
New methods employing mild conditions for efficient oxida-
tions remain an important goal in organic chemistry.1–4 Processes
that facilitate the generation and functionalization of challenging
substrates in situ are increasing in importance and use in synthesis.
Tandem oxidation strategies that accomplish multiple oxidations or
other transformations have garnered significant interest due to
their efficiency and ability to streamline synthetic routes.5 Of par-
ticular focus is the oxidation of alcohols or aldehydes to esters,
which has inspired many investigations due to the synthetic utility
of the ester products and the ready availability of the starting
materials. However, a general solution to this transformation re-
mains elusive.
In 1968, Corey reported the oxidation of alcohols to esters by
a two-step process in the presence of sodium cyanide and man-
ganese(IV) oxide (MnO2).6–8 Based on numerous pre-1960 studies
of the reactivity of acyl cyanides,9 this method has found applica-
tion in several synthetic endeavors10–12 despite its reliance on ex-
cess sodium cyanide (in some cases >20 equiv) as a promoter for
the oxidation. Other transformations of this type require harsh
oxidants such as chromium13 or iodine,14 which have both been
shown to oxidize alcohols to esters. However, these methods re-
quire super-stoichiometric amounts of toxic and difficult to handle
reagents.
phile. The standard two-step approach involves oxidation of the
aldehyde to the carboxylic acid followed by alkylation of the acid.
These transformations, such as the Pinnick oxidation, can be
complicated by over-oxidation of electron-rich aromatic rings or
undesired interactions with heteroatoms.24 Furthermore, the sub-
sequent alkylation of the carboxylate formed in the second step can
suffer from chemoselectivity complications particularly in the case
of a saturated, enolizable substrate. Saturated aldehydes pose ad-
ditional problems as reactants due to the potential for aldol side
reactions. Given this litany of potential complications, a mild oxi-
dation providing access to esters without the use of a toxic reagent
and with the potential for application to saturated substrates is
a compelling goal with potential broad utility.
2. Background
In biological systems, the thiamine-pyrophosphate cofactor has
long been known to catalyze oxidative transformations such as the
oxidative decarboxylation of pyruvic acid to form ‘active acetate’
acylating agents in the presence of oxidants such as NADþ (nico-
tinamide adenine dinucleotide), molecular oxygen, and flavins.25
Initial investigations in this area were focused on discovering al-
ternative oxidants, which could be paired with the enzyme to ac-
celerate the transformation.26,27
With the elucidation of the active component of thiamine-py-
rophosphate as a nucleophilic carbene/zwitterion,28 other work
was focused on designing an enzyme/cofactor mimic, which would
catalyze useful acylation reactions. Using a non-enzymatic thiazo-
lium-based N-heterocyclic carbene (NHC), very brief studies con-
cerning the oxidative transformation converting aromatic
aldehydes to esters were reported.29–32 More recently, Miyashita33
The single-flask oxidation of aldehydes to esters has also
attracted considerable interest.15–19 Recently, pyridinium hydro-
bromide perbromide,20 peroxides,21,22 and Oxone23 have all been
reported to function as oxidants in these transformations. These
* Corresponding author. Tel.: þ1 847 491 6659; fax: þ1 847 467 2184.
E-mail address: scheidt@northwestern.edu (K.A. Scheidt).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.033

B.E. Maki et al. / Tetrahedron 65 (2009) 3102–3109
3103
has demonstrated that other NHCs derived from triazolium and
benzimidazolium salts are capable of catalyzing the oxidation of
aryl aldehydes. These processes generally employed organic oxi-
dants such as substituted nitrobenzenes, azobenzene derivatives,
and flavin. These reports represent the initial discovery of this re-
activity, but the full potential of this carbene-catalyzed oxidative
reaction pathway remains unrealized. In light of this observation,
we sought to expand the scope of NHC-catalyzed oxidation re-
actions by utilizing a more efficient oxidant and exploring our ex-
tensive catalyst library. At the onset of these investigations, we
hoped to develop a mild, efficient, Lewis base-catalyzed oxidation
protocol for facile access to esters from readily available substrates.
alcohol is capable of undergoing oxidation43 by a selective oxidant
such as MnO2.
3.1. Reaction development
The initial aim was to establish the catalyst core structure that
most efficiently catalyzed the proposed oxidation pathway. A va-
riety of simple imidazolium, benzimidazolium, thiazolium, and
triazolium salts were screened as pre-catalysts in this trans-
formation (Scheme 3). Commercially available imidazolium salts B,
C, and D showed no conversion to ester in either reaction manifold,
although using IMes (A) did result in a low amount of conversion to
the desired ester product. Simple triazolium salts H and J gave
excellent results with reduced catalyst loading. The simpler and
more readily accessible of the effective catalysts (J) were employed
going forward in the explorations of this reaction.
3. Results and discussion
Our proposed pathway for this carbene-catalyzed reaction is
initiated by a standard oxidation of the allylic alcohol (Scheme 1) by
MnO2. The resulting aldehyde combines with the NHC catalyst in
order to form a tetrahedral intermediate, which is itself an allylic
alcohol.
azolium (20 mol %),
O
DBU (20 mol %)
MnO2, MeOH
Ph
OH
H
Ph
Ph
OMe
OMe
1
R1
azolium (20 mol %),
DBU (1.2 equiv)
O
R1
O
O
O
R2
R
R
H
OR4
N
N
X
R2
MnO2, MeOH (5 equiv)
CH2Cl2
Ph
R3
R3
MnO2
2
R1
R4OH
Cl
R2
BF4
BF4
t -Bu
BF4
Ad
OH
Cy
Cy
t-Bu
Ad
R3
N
Mes
Mes
N
N
N
N
N
N
D
N
R1
O
H
R1
O
A
B
C
R
R
R2
N
N
R2
1: 41%
2: 22%
1: 0%
2: 0%
1 : 0%
2 : 0%
1 : 0%
2 : 0%
X
X
R3
N
R3
N
R
Me
N
R
BF4
Mes
G
I
I
Me
Me
F
S
N
N
N
N
MnO2
Scheme 1. Pathway of oxidation of allylic alcohols.
N
Me
E
Me
Me
1: N/A
2: 0%
Me
1: 0%
2: 9%
1: 0%
2: 23%
Br
I
This intermediate is oxidized by MnO2 to yield an acyl azolium
intermediate, which we have employed as an activated acylating
agent in many recent new reactions.34–40 The nucleophilic alcohol
is acylated, generating the ester product and regenerating the NHC
catalyst in the presence of a base. The initial addition of the NHC to
the aldehyde is similar to Umpolung processes catalyzed by these
Lewis base catalysts,41,42 but importantly, the oxidation must be
fast enough to preclude the formation of any acyl anion or homo-
enolate equivalents.
A distinctive advantage of this potential pathway is that the
oxidation of saturated aldehydes to esters is possible due to the
generation of an activated alcohol by the addition of the NHC
generated in situ. In this particular case, the aromatic nature of the
azolium core of the catalyst serves to activate the secondary alcohol
generated by addition to the aldehyde (Scheme 2). This activated
Me
Me
Me
H
N
N
N
N
N
N
J
1 (10 mol %): 72%
2 (10 mol %): 90%
1(10 mol %): 93%
2(10 mol %): 98%
CO2Me
Scheme 3. Catalyst screen for NHC-catalyzed oxidation.
Additionally, different sources of MnO2 were surveyed. It was
found that commercial activated MnO2 (purchased from Sigma–
Aldrich) was capable of effecting this transformation in a timely
manner (18 h for 1, 3 h for 2). When freshly prepared MnO2 was
employed44–46 there was a mild rate enhancement observed (12 h
for 1, 2–3 h for 2). Unless otherwise noted, the work reported
herein was carried out with commercial MnO2.
3.2. Reaction scope
O
NHC
catalyst
R
With the simple triazolium salt J established as the optimal
catalyst precursor, we began our investigation of this oxidation
pathway by subjecting allylic and benzylic alcohols to man-
ganese(IV) oxide.47
O
R1
transient benzylic
alcohol
R1
R2
N
H
X
R2 R3
R3
N
R
MnO2
R
3.2.1. Oxidation of allylic and benzylic alcohols to esters
Potential substrates were surveyed with a variety of different
nucleophilic alcohols. Two different methods can be employed for
this catalytic oxidation. The nucleophilic alcohol can be used as the
solvent (method A) providing an excess of the nucleophile to un-
dergo addition to the acylating intermediate. Alternatively, the
oxidation could be run in toluene (method B) with a more modest
O
O
ROH
R1
acyl azolium
intermediate
R1
R2
N
R3
R
X
OR
R2
R3
N
Scheme 2. Oxidation of unactivated aldehydes.

3104
B.E. Maki et al. / Tetrahedron 65 (2009) 3102–3109
Table 1
Oxidation of allylic and benzylic alcohols to estersa
I
Me
Me
R1
R1
O
N
N
N
, DBU
+
ROH
R2
R2
OH
OR
MnO2, Method A or B,
R3
R3
6-36h
Entry
Product
Method
Yield (%)
Entry
10
Product
Method
A
Yield (%)
91
O
O
1
2
A
B
93
95
O
Me
OMe
Me
Ph
O
O
O
O
3
4
A
B
93
91
11
12
A
A
90
85
Me
Me
Ph
O
O
O
O
5
6
A
B
81
89
Me
Me
Ph
Ph
O
7
8
9
A
A
A
91b
88c
73
O
Me
Ph
O
O
Me
13
14
A
A
87
85
Me
Me
Me
O
Me
O
Ph
O
O
O
O
EtO
Me
O
O
Method A: 10 mol % triazolium salt, 10 mol % DBU, 15 equiv MnO2, 0.2 M in ROH at 23 ꢁC. Method B: 10 mol % triazolium, 1.1 equiv DBU, 3–5 equiv ROH, 15 equiv MnO2, 0.2 M in
toluene at 23 ꢁC (see Section 5 for full details).
a
Isolated yields.
Triazolium/DBU (25 mol %).
Triazolium/DBU (50 mol %).
b
c
3–5 equiv of the nucleophilic alcohol. These two methods give
similar results in most cases, with little difference in other aspects
of the process (i.e., reaction time, purification procedure, etc.), and
can be used interchangeably. Methanol generates the most efficient
reaction (complete in 6 h, Table 1, entries 1, 2), but 1-butanol and
other primary alcohols provide the ester product in similar reaction
times and yield (Table 1, entries 3, 4). Secondary alcohols can also
be employed, although reaction times are prolonged (up to 36 h)
due to the difficult addition of the hindered nucleophile to the
congested acylating agent (Table 1, entries 5, 6).
3.2.2. Oxidation of saturated aldehydes to esters
The success of the tandem oxidation of allylic alcohols led us to in-
vestigate further applications of the combination of NHCs and man-
ganese(IV) oxide. Namely, we became interested in the oxidation of
saturated, unactivated substrates through the generation of an activated
substrate in situ via addition of the nucleophilic triazolium catalyst.48
A wide variety of alcohols and aldehydes can be employed in
this oxidation. Methanol is once again the most efficient nucleo-
phile (Table 2, entry 1), generally resulting in better yields than
other primary alcohols (entry 2) or secondary alcohols (entries 3,
4). It is important to note, however, that increased substitution of
the nucleophilic alcohol does not preclude access to synthetically
useful yields of the ester products.
Subjecting an alcohol with a potentially sensitive stereogenic
center such as (S)-(ꢀ)-methyl lactate (97% ee) to the reaction
conditions results in acylation without significant epimerization;
the ester is afforded in 93% ee. The lack of epimerization under
these mild oxidation conditions demonstrates the potential for
application of this method to more complex and sensitive sub-
strates prevalent in target-oriented synthesis.
The allylic alcohol substrate can be varied to create a range of
acylating agents. Substitution at the a-position (Table 1, entries 7, 8)
requires increased catalyst loading to effectively generate the un-
saturated esters. Benzylic alcohol substrates result in the most
difficult oxidation, requiring increased catalyst loading (up to
50 mol %). However, with an inexpensive catalyst, the utility is not
compromised as the yield is still synthetically useful. Electron-rich
alcohols, such as 4-methoxybenzyl alcohol, yield only aldehyde as
the product with increased catalyst loading and prolonged reaction
times. The electron-rich furfuryl alcohol (entry 9) undergoes oxi-
dation to the ester under the standard conditions, but the ester is
isolated in an uncharacteristically mediocre yield. The naphthyl
substrates (entries 10, 11) are the most successful of the benzylic
alcohol substrates, providing the esters in excellent yields. Prop-
argyl alcohols are easily oxidized in this system (entry 12). Alkyl
substitution (entry 13) as well as electron withdrawing groups
(entry 14) is tolerated. It is interesting to note that no evidence of
transesterification of the ethyl ester is observed under these protic
conditions.
A variety of saturated aldehydes can be employed in this oxi-
dation. In contrast to the benzylic oxidation, substitution at the
a-position (entries 6, 7) of the less rotationally restricted saturated
aldehydes is tolerated without any change in the efficiency of the
process. Steric considerations are still important, as increased
substitution (entry 8) does result in a decreased yield. This is at-
tributed to the difficulty of the addition of the triazolium catalyst to
the congested aldehyde. Unsurprisingly, substitution at the
sition (entry 9) has no effect on the yield of the oxidation.
b-po-

B.E. Maki et al. / Tetrahedron 65 (2009) 3102–3109
3105
Table 2
Oxidation of saturated aldehydes to esters
I
Me
Me
O
O
N
N
N
R1
R2
R1
R2
(10 mol %), DBU (1.1 equiv)
+
ROH
OR
H
R3
R3
MnO2, CH2Cl2, 0.5-3 h
Entry
1
Product
Yielda
98
Entry
Product
Yielda
93
O
Me
Me O
9
OMe
Me
Ph
OMe
O
O
O
2
3
82
88
10
11
94
95
Me
OMe
Ph
TBSO
O
O
O
OMe
TBDPSO
Ph
CO2Me
O
Me
CO2Me
4
5
74b
91
12
13
90
88
N
Me
O
O
Ph
O
O
OMe
O
Me
OMe
N
OMe
6
7
96
14
15
99
92
OMe
OMe
MeO
OMe
O
O
91c
O
S
OMe
TBSO
Me
OMe
Me
O
O
8
56
16
96
OMe
OMe
Me
Me
a
Isolated yield, 5 equiv ROH, 5 equiv MnO2 (see Section 5 for full details).
b
c
Use of methyl (S)-(ꢀ)-lactate (97% ee) furnished the ester in 93% ee.
Triazolium (25 mol %) was employed to give the methyl ester in 92% ee from enantiopure aldehyde.
Previous reports in the area of carbene catalysis have shown
(Scheme 4), chlorination of the aromatic ring was a prevalent side
reaction. In contrast, by employing the NHC-catalyzed process the
same aldehyde is oxidized to the methyl ester as the sole product in
nearly quantitative yield (Table 2, entry 14). Other electron-rich
heterocycles such as furans (entry 15) and thiophenes (entry 16) are
also successfully oxidized in very good yields.
O–Si bonds to be cleavable in the presence of an NHC catalyst and an
aldehyde.49,50 Under our oxidation reaction conditions, no depro-
tection of silyl ethers was observed with –TBS (entries 7, 10) and
–TBDPS (entry 11) ethers. It seems that the rate of oxidation is faster
than any possible rate of desilylation for these substrates using
these conditions. Additionally, the potentially epimerizable Roche
ester derivative ((S)-3-hydroxy-2-methylpropionic acid methyl es-
ter, entry 7) could be obtained without significant loss of stereo-
chemical information. The ester was accessed in 92% ee from
enantiopure aldehyde. In this reaction the amount of the triazolium
catalyst is increased to 25 mol % in order to decrease the reaction
time to 0.5–0.75 h. If the reaction is allowed to continue beyond that
point, the integrity of the stereogenic center is eroded to <90% ee.
The oxidation is also compatible with a variety of heterocycles
and electron-rich aromatic rings. Nitrogen-containing indole and
pyridine substrates (entries 12, 13) are smoothly oxidized in excel-
lent yields. Electron-rich aromatic rings can pose problems in tra-
ditional oxidations of aldehydes, due to the potential for reactions
with electrophilic chlorine.51,52 In fact, upon treatment of 3-(2,4,6-
trimethylphenyl)propanal with Pinnick oxidation conditions24
OMe
OMe
O
OH
OH
3
MeO
OMe
OMe
OMe
O
NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH/H2O (5:2)
H
O
Cl
MeO
OMe
4
MeO
89% yield
3:4 2.5:1 (by 1H NMR)
Scheme 4. Chlorination of electron-rich aromatic rings.

3106
B.E. Maki et al. / Tetrahedron 65 (2009) 3102–3109
Table 3
Although it is possible to access saturated aldehydes through
Synthesis of protected carboxylate derivatives
a variety of methods (ozonolysis of olefins, periodate cleavage of
diols, reduction of Meldrum’s acid derivatives,53 etc.) the most
common procedure is oxidation of the corresponding alcohol. Thus
we sought to apply our oxidation protocol to a sequence that would
allow easy access to an ester from any alcohol.
Entry
Substrate
Product
Yield
85a
O
O
1
CCl3
Ph
H
Ph
O
O
Manganese(IV) oxide, the most effective oxidant for the NHC-cat-
alyzedprocess, isaninefficientoxidizingagentfor unactivated alcohols,
thus a one-pot procedure was impractical. However, simple TPAP oxi-
dation54 of the alcohol, followed by filtration and immediate treatment
with the triazolium/MnO2 system (Scheme 5) gives facile access to the
ester with only a single chromatographic purification carried out at the
conclusion of the procedure. The yield for this transformation is com-
parable to that reported for the oxidation of the aldehyde.
O
2
3
4
87a
82b
82b
SiMe3
H
Ph
Ph
Ph
O
O
OH
Ph
O
O
CCl3
OMe
Ph
Ph
OH
OH
Ph
O
O
O
5
74b
O
SiMe3
i) TPAP, NMO
Ph
OH
R
CH2Cl2
ii) triazolium,
MnO2, MeOH,
CH2Cl2
H
R
a
Isolated yield, see Table 2 for conditions.
Isolated yield, see Table 1, method B for conditions.
after filtration
b
R = Ph 92%
R = OTBS 89%
R = OTBDPS 88%
O
Access to the protected carboxylates can be accomplished either
OMe
from the saturated aldehyde (Table 3, entries 1, 2) or the allylic
alcohol (entries 3–5). The trichloroethyl (Troc),59,60 (trimethylsilyl)-
ethyl (TMSE),61 and methoxyethyl (ME)62 derivatives are synthe-
sized in very good yields following the general procedures for the
corresponding starting substrates.
R
Scheme 5. Oxidation of alcohols to esters.
3.2.3. Comparative analysis
The acyl triazolium intermediate presents a further opportunity
for application of this method toward asymmetric reactions. The
use of a chiral triazolium pre-catalyst creates a chiral acylating
agent. With that inspiration, we applied the reaction to the
desymmetrization of meso-diols.63
A variety of chiral acylating agents generated by the combina-
tion of various allylic or benzylic alcohols and benzimidazolium or
triazolium catalysts have proved incapable of selectively acylating
primary diols (Scheme 7). The low levels of enantiomeric excess
observed upon the isolation of the desired monoacylation product
indicate the presence of a nontrivial background rate.
A more hindered nucleophile was sought that would engender
a more selective reaction with the acyl azolium intermediate. The
secondary hydroxyl groups of cis-1,2-cyclohexanediol were par-
ticularly promising. In fact, triazolium salts M and N yielded the
monoacylated product in 20 and 41% ee, respectively (Table 4, en-
tries 3, 4). The non-nucleophilic K2CO3/18-crown-6 base system
was employed in an effort to suppress the degradation of ee
through acyl transfer. Unfortunately, a stoichiometric amount of
this base was required, and upon treatment of the enantioenriched
product with K2CO3/18-crown-6 racemic material was observed in
Our method represents the most general and efficient NHC-
catalyzed oxidation reaction reported to date. Several reports exist
of thiazolium or benzimidazolium reagents catalyzing the oxida-
tion of aromatic aldehydes to esters.29–33,35 A representative ex-
ample is the recent disclosure by Connon and co-workers of an
approach utilizing a thiazolium catalyst and azobenzene as an ox-
idant.55 While this method gives good yields for the oxidation of
substituted benzaldehydes (46–97% yield, 8 substrates), application
to unactivated substrates results in poor yields of the ester.
Employing the thiazolium/azobenzene system, hexanal is oxidized
to methyl hexanoate in 16% yield after 48 h. Under our triazolium/
MnO2 conditions outlined in the previous section, hexanal (Table 2,
entry 5) is oxidized to the methyl ester in 91% yield in under 3 h.
Our NHC-catalyzed reaction compares favorably to other methods
for the oxidation of activated substrates to esters as well. The use of
a catalytic amount of the non-toxic triazolium NHC precursor rep-
resents an attractive alternative to the Corey–Gilman oxidation,6–8
that, while efficient and high yielding, employs a full equivalent of
sodium cyanide as a nucleophilic promoter of the oxidation. Taylor
has reported the tandem oxidation of alcohols to methyl esters using
sodium cyanide,56,57 but the use of nucleophilic alcohols other than
methanol results in prolonged reaction times (up to 7 days) and sig-
nificantly depressed yields. Further, the cyanide-promoted process
shows no activity in the oxidation of saturated aldehydes (Scheme 6).
azolium salt
(30 mol %)
MnO2
chiral monoacylated
product
+
diol
OH
R
3.2.4. Applications
OH
R = cinnamyl,
1-naphthyl,
2-naphthyl
O
OH
OH
Me
Me
As a simple oxidation procedure providing access to ester de-
rivatives, this method presents the opportunity to synthesize pro-
tected carboxylate derivatives.58 The carboxylic acid, which is the
common precursor in the standard synthesis of these esters, often
presents potential problems with isolation and/or handling, while
this method does not proceed through the acid intermediate.
diols:
Ph
OH
O
azolium salts:
Ph
Ph
O
Me
Cl
BF4
N
N
Cl
N
N
N
Ph
R
N
O
N
N
NaCN (1 equiv),
MnO2
MeOH, THF
O
Me
O
R = Ph, M, 38-58% yield,
10-16% ee
L, 59-70% yield,
Ph
0-4% ee
H
Ph
0% yield, 36 h
Ph
OMe
K, 0% yield
R = Mes, N, 49-62% yield,
6-13% ee
Scheme 6. Cyanide-promoted oxidation.
Scheme 7. Desymmetrization of primary diols.

B.E. Maki et al. / Tetrahedron 65 (2009) 3102–3109
3107
Table 4
reaction products was carried out by flash chromatography using
EM Reagent silica gel 60 (230–400 mesh). Analytical thin layer
chromatography was performed on EM Reagent 0.25 mm silica gel
60-F plates. Visualization was accomplished with UV light and
anisaldehyde, ceric ammonium nitrate stain, potassium perman-
ganate, or phosphomolybdic acid followed by heating. Infrared
spectra were recorded on a Perkin Elmer 1600 series FT-IR spec-
trometer. 1H NMR spectra were recorded on a Varian Inova 500
(500 MHz) or Mercury 400 (400 MHz) spectrometer and are
reported in parts per million using solvent as an internal standard
(CDCl3 at 7.26 ppm). Data are reported as ap¼apparent, s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad; coupling
constant(s) in hertz; integration. Proton-decoupled 13C NMR
spectra were recorded on a Varian Inova 500 (125 MHz) or Mercury
400 (100 MHz) spectrometer and are reported in parts per million
using solvent as an internal standard (CDCl3 at 77.0 ppm). Mass
spectra data were obtained on a Varian 1200 Quadrupole Mass
Spectrometer and Micromass Quadro II Spectrometer.
Desymmetrization of cis-1,2-cyclohexanediol
chiral azolium
(30 mol %)
K2CO3,
OH
OH
OH
O
18-crown-6
MnO2 (15 equiv)
solvent
O
+
H
Ph
O
Ph
Entry
Conditionsa
P, toluene, 23 ꢁ
Q, toluene, 23 ꢁ
M, toluene, 23 ꢁ
N, toluene, 23 ꢁ
N, Proton Sponge, toluene, 23 ꢁC
N, Proton Sponge, CH2Cl2, 23 ꢁ
Yield
% ee
1b
2b
3b
4b
5
6
7
8
9
C
C
C
C
43
40
53
47
62
78
67
58
38
5
9
20
41
60
59
65
80
73
C
N, Proton Sponge, CH2Cl2, 0 ꢁ
C
N, Proton Sponge, CH2Cl2, ꢀ30 ꢁ
C
C
N, Proton Sponge, CH2Cl2, ꢀ40 ꢁ
Me
Me
Me
5.2. General procedure for oxidation of allylic alcohols
to esters (Table 1)
R = Ph, M
R = Mes, N
BF4
R = Ph, P
R = Mes, Q
O
N
N
O
5.2.1. Method A
N
R
N
N
BF4
A flame-dried round bottom flask was charged with triazolium
salt J (22 mg, 0.10 mmol). The flask was sealed with a septum and
put under positive pressure of nitrogen. The allylic alcohol
(1 mmol) and the nucleophilic alcohol (5 mL) were added. The
septum was removed and to the flask was added MnO2 (1.304 g,
15 mmol). The flask was then sealed with septum and DBU
(0.015 mL, 0.10 mmol) was added via syringe. The reaction stirred
at ambient temperature until allylic alcohol and aldehyde were
consumed (monitored by GC). The mixture was filtered through
a thin pad of Celite. The Celite was washed with ethyl acetate
(15 mL). The filtrate was then concentrated in vacuo. The resulting
residue was purified by flash chromatography on silica gel.
N
R
a
K2CO3 30 mol %, 15 mol % 18-crown-6, 1 equiv Proton Sponge, 0.25 M in solvent.
K2CO3 1.5 equiv, 20 mol % 18-crown-6, 0.25 M in solvent. Proton
Sponge¼N,N,N0,N0-tetramethyl-1,8-naphthalenediamine.
b
less than 2 h. This result identified base-catalyzed acyl transfer as
a significant obstacle to the successful application of this method.
The acyl transfer was successfully suppressed by the reduction
of K2CO3/18-crown-6 to substoichiometric quantities and adding
a full equivalent of Proton SpongeÔ (N,N,N0,N0-tetramethyl-1,8-
naphthalenediamine) as a weaker non-nucleophilic base (Table 4,
entry 5). A screen identified methylene chloride as the most ideal
solvent for the reaction (entry 6). Reducing the temperature of the
reaction (entries 7–9) suppressed the background rate and any
remaining acyl transfer reactions to give the monoacylated diol in
w60% yield and 80% ee (entry 8). This successful desymmetrization
demonstrates the potential of this method as an alternative to re-
actions of nucleophiles with acid chlorides and anhydrides.
5.2.2. Method B
A flame-dried round bottom flask was charged with triazolium
salt J (34 mg, 0.15 mmol). The flask was sealed with a septum and
put under positive pressure of nitrogen. Toluene (5 mL), the allylic
alcohol (1 mmol), and the nucleophilic alcohol (5 mmol) were
added. The septum was removed and to the flask was added MnO2
(1.304 g, 15 mmol). The flask was then sealed with septum and DBU
(0.165 mL, 1.1 mmol) was added via syringe. The reaction stirred at
ambient temperature until allylic alcohol and aldehyde were con-
sumed (monitored by GC). Upon consumption of allylic alcohol and
aldehyde, methanol (10 mL) was added to the reaction. The mixture
was then quickly filtered through a thin pad of Celite (prolonged
stirring with methanol resulted in transesterification to the methyl
ester). The Celite was washed with ethyl acetate (15 mL). The fil-
trate was then concentrated in vacuo. The resulting residue was
purified by flash chromatography on silica gel.
4. Conclusions
The oxidation described herein utilizes a simple and readily
available catalyst and proceeds under mild conditions with easily
accessible starting materials. The potentially problematic isolation,
handling, and functionalization of carboxylic acids or, in some
cases, aldehydes have been obviated by the ability of this reaction
to access higher oxidation states in a single-flask operation. Sen-
sitive substrates, i.e., those prone to epimerization or electrophilic
chlorination, are smoothly oxidized by this protocol. This carbene-
catalyzed oxidation manifold compares favorably to other pub-
lished strategies for similar transformations and presents unique
opportunities due to the potential to generate a catalytic chiral
acylating agent in situ. The NHC-catalyzed oxidation of alcohols and
aldehydes with manganese(IV) oxide is a potentially powerful tool
that will undoubtedly find use in organic synthesis.
5.3. General procedure for oxidation of saturated aldehydes
to esters (Table 2)
A flame-dried round bottom flask was charged with triazolium
salt J (11 mg, 0.05 mmol). The flask was sealed with a septum and
put under positive pressure of nitrogen. Dichloromethane (2.5 mL)
and DBU (82 mL, 0.55 mmol) were added followed by the aldehyde
5. Experimental
5.1. General
(0.5 mmol). The septum was removed and to the flask was added
MnO2 (217 mg, 2.5 mmol). The flask was then sealed with septum
and methanol (0.100 mL, 2.5 mmol) was added via syringe. The
reaction stirred at ambient temperature until aldehyde was con-
sumed (monitored by GC or TLC). The mixture was filtered through
a thin pad of silica, which was washed with ethyl acetate (15 mL).
All reactions were carried out under a nitrogen atmosphere in
flame-dried glassware with magnetic stirring. Purification of

3108
B.E. Maki et al. / Tetrahedron 65 (2009) 3102–3109
The filtrate was then concentrated in vacuo. The resulting residue
was purified by flash chromatography on silica gel.
(50 mL, 0.397 mmol) was added via syringe. The reaction was
allowed to stir at ꢀ30 ꢁC under a positive pressure of nitrogen until
the aldehyde was consumed as determined by TLC. Upon con-
sumption of the aldehyde, the mixture was filtered through a thin
pad of Celite and washed with ethyl acetate (25 mL). The filtrate
was then concentrated in vacuo and the resulting residue was
purified by flash chromatography on silica gel.
5.4. Pinnick oxidation of 3-(2,4,6-trimethoxyphenyl)propanal
(Scheme 4)
A flame-dried round bottom flask was charged with aldehyde
(56 mg, 0.25 mmol) and sealed with a septum and put under pos-
itive pressure of nitrogen. A 5:2 mixture of tert-butanol and water
(1.0 mL) was added and the mixture was cooled to 0 ꢁC. 2-Methyl-
Acknowledgements
2-butene (66 mL, 0.625 mmol), NaH2PO4$H2O (86 mg, 0.625 mmol),
Financial support was provided by NIH/NIGMS (GM73072),
Northwestern University, the PRF (Type-G), Abbott Laboratories,
Amgen, AstraZeneca, 3M, GlaxoSmithKline, the Sloan Foundation,
and Boerhinger-Ingelheim (New Investigator Awards). B.E.M. was
supported by a GAANN Fellowship. A.C. is the recipient of a Dow
Chemical Company Fellowship. E.M.P. is the recipient of an Amer-
ican Chemistry Society Division of Organic Chemistry Graduate
Fellowship sponsored by Organic Reactions (2008–2009). We
thank FMCLithium, Sigma–Aldrich, and BASF for providing reagents
used in this research. Funding for the NU Integrated Molecular
Structure Education and Research Center (IMSERC) has been fur-
nished in part by the NSF (CHE-9871268). The authors wish to
thank John M. Roberts for assistance in the synthesis of triazolium
salt H.
and sodium chlorite (80%) (70 mg, 0.625 mmol) were added se-
quentially and stirring was continued at 0 ꢁC for 1.5 h. The reaction
was warmed to ambient temperature and allowed to stir for an
additional 1.5 h, then quenched with saturated ammonium chlo-
ride, diluted with dichloromethane and extracted with dichloro-
methane (3ꢂ10 mL) and ethyl acetate (1ꢂ10 mL). The organic layers
were combined, dried with Na2SO4, and concentrated to give an
inseparable mixture (56 mg) of 3-(2,4,6-trimethoxyphenyl)-
propionic acid (3) and 3-(3-chloro-2,4,6-trimethoxyphenyl)-
propionic acid (4). The 1H NMR spectrum of the residue showed 3
and 4 in a 2.5:1 mixture favoring 3 based on integration of the
protons attached to the aromatic rings; 3: d 6.12 (s, 2H); 4: d 6.05 (s,
1H). LRMS (APCI): Mass calculated for 3, C12H16O5 [MþH]þ 241.1.
Found 241.0. Mass calculated for 4, C12H15O5Cl [MþH]þ 275.1.
Found 274.8.
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