Development and comparison of the substrate scope of Pd-catalysts for the aerobic oxidation of alcohols

Article abstract of DOI:10.1021/jo0482211

(Chemical Equation Presented) Three catalysts for aerobic oxidation of alcohols are discussed and the effectiveness of each is evaluated for allylic, benzylic, aliphatic, and functionalized alcohols. Additionally, chiral nonracemic substrates as well as chemoselective and diastereoselective oxidations are investigated. In this study, the most convenient system for the Pd-catalyzed aerobic oxidation of alcohols is Pd(OAc)₂ in combination with triethylamine. This system functions effectively for the majority of alcohols tested and uses mild conditions (3 to 5 mol % of catalyst, room temperature). Pd(IiPr)(OAc)₂(H₂O) (1) also successfully oxidizes the majority of alcohols evaluated. This system has the advantage of significantly lowering catalyst loadings but requires higher temperatures (0.1 to 1 mol % of catalyst, 60°C). A new catalyst is also disclosed, Pd(IiPr)(OPiv)₂ (2). This catalyst operates under very mild conditions (1 mol %, room temperature, and air as the O₂ source) but with a more limited substrate scope.

Full text of DOI:10.1021/jo0482211

VOLUME 70, NUMBER 9
APRIL 29, 2005
© Copyright 2005 by the American Chemical Society
Development and Comparison of the Substrate Scope of
Pd-Catalysts for the Aerobic Oxidation of Alcohols
Mitchell J. Schultz, Steven S. Hamilton, David R. Jensen, and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-8500
sigman@chem.utah.edu
Received October 8, 2004
Three catalysts for aerobic oxidation of alcohols are discussed and the effectiveness of each is
evaluated for allylic, benzylic, aliphatic, and functionalized alcohols. Additionally, chiral nonracemic
substrates as well as chemoselective and diastereoselective oxidations are investigated. In this
study, the most convenient system for the Pd-catalyzed aerobic oxidation of alcohols is Pd(OAc)2 in
combination with triethylamine. This system functions effectively for the majority of alcohols tested
and uses mild conditions (3 to 5 mol % of catalyst, room temperature). Pd(IiPr)(OAc)2(H2O) (1) also
successfully oxidizes the majority of alcohols evaluated. This system has the advantage of
significantly lowering catalyst loadings but requires higher temperatures (0.1 to 1 mol % of catalyst,
60 °C). A new catalyst is also disclosed, Pd(IiPr)(OPiv)2 (2). This catalyst operates under very mild
conditions (1 mol %, room temperature, and air as the O2 source) but with a more limited substrate
scope.
Introduction
dichromate (PDC),7 and Swern8 oxidations. These oxida-
tions have served the organic synthesis community well
as highly versatile and robust methods. Unfortunately,
most of these suffer from the use of stoichiometric toxic
reagents, cryogenic conditions, and/or the production of
copious amounts of waste. An alternative, more practical
approach is the use of a catalyst in combination with a
stoichiometric terminal oxidant. An excellent example of
this is the use of catalytic tetrapropylammonium per-
ruthenate (TPAP) with stoichiometric N-methylmorpho-
line (NMO) for the oxidation of alcohols.9 While this
The oxidation of alcohols to carbonyl compounds is an
essential functional group transformation in organic
synthesis. Countless methods have been developed to
perform this reaction, with the most popular represented
by the Collins,1 Dess-Martin,2 Jones,3 Moffatt,4 Parikh-
Doering,5 pyridinium chlorochromate (PCC),6 pyridinium
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10.1021/jo0482211 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/30/2004
J. Org. Chem. 2005, 70, 3343-3352
3343

Schultz et al.
system has proven very useful for the oxidation of a wide
variety of alcohols, the use of stoichiometric NMO is not
ideal.10
these systems are synthetically useful, several drawbacks
remain including the use of high catalyst loadings, forcing
conditions, and/or lack of substrate scope. With the hope
of addressing these issues, we have investigated the
development of new Pd(II)-catalysts for the aerobic
oxidation of alcohols.25
Significant effort has been afforded to the development
of Pd-catalysts for the aerobic alcohol oxidations.26-28 Of
these reports, Uemura’s pyridine/Pd(OAc)2 system29 and
Sheldon’s phananthroline/Pd(OAc)2 system30 under aque-
ous conditions serve as benchmarks in the development
of new catalysts: Uemura’s primarily due to the simplic-
ity of the procedure and Sheldon’s due to the effective
use of low loadings of the homogeneous catalyst.31
However, improved catalyst systems are desirable where
a combination of lower catalyst loadings, lower levels of
oxygen, and milder temperatures can be used. These
improvements would potentially allow for applications
in various areas including industrial oxidations and
oxidations of complex targets.
An attractive alternative terminal oxidant is molecular
oxygen because it is readily available, inexpensive, and
produces benign stoichiometric byproducts (H2O2 and/or
H2O). Due to these attributes, the development of cata-
lysts for the aerobic oxidation of alcohols has been
explored by using a diverse scope of metals which include
Mn,11 Fe,12 Ru,13 Co,14 Cu,15 Pt,16 Zn,17 Rh,18 V,19 Ce,20
Ni,21 Pd,22,23 and bimetallic systems.24 While many of
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3344 J. Org. Chem., Vol. 70, No. 9, 2005

Aerobic Oxidation of Alcohols
In this regard, we have recently reported two catalyst
systems for the palladium-catalyzed aerobic oxidation of
alcohols. In the first system, a mixture of Pd(OAc)2 and
triethylamine (TEA) was used to successfully oxidize a
broad scope of alcohols at room temperature.32 After
disclosing this initial study, we used data from mecha-
nistic studies performed by several groups including our
own on aerobic alcohol oxidations to design and develop
a highly active catalyst using an N-heterocyclic carbene
(NHC) as the ligand for Pd, and acetate as both the
anionic ligand and the internal base for successful
oxidation.33,34
While these two catalyst systems provided significant
advances in both practicality (room temperature and air
atmosphere) and activity (up to 1000 turnovers) for the
Pd-catalyzed aerobic oxidation of alcohols, developing a
catalyst system that can combine the use of low temper-
atures, low catalyst loadings, and an air atmosphere is
desirable. Also, the application of Pd-catalysis to the
oxidation of more complex substrates bearing alcohols
has been lacking. Herein, we report on the development
of a new Pd(II) aerobic alcohol oxidation catalyst system
and comparison of all three catalytic systems for general
substrate scope, and scope relevant to the synthesis of
complex targets.
led to the development of a third system for the Pd-
catalyzed aerobic oxidation of alcohols in which acetate
has been substituted by pivalate (PivO). The resulting
catalytic system uses 1.0 mol % of catalyst loading of Pd-
(IiPr)(OPiv)2 (2) along with 0.5 mol % of PivOH under
an air atmosphere at room temperature to oxidize a
variety of alcohols.
Evaluation of Substrate Scope
Oxidation of Benzylic Alcohols with Pd(OAc)2/
TEA. Generally, benzylic alcohols oxidize well using this
system (Table 1). Electronics do not seem to play a
significant role on isolated yields with both electron-rich
and electron-poor benzylic alcohols oxidizing well. A
hindered secondary alcohol 3k also oxidizes under these
conditions, albeit with a lower yield and an extended
reaction time (entry 22). Of note, p-(methylthio)benzyl
alcohol 3f oxidizes poorly with Pd-black formation ob-
served (entries 12). A potential limitation is with alcohols
that can chelate the Pd(II) catalyst, either as a starting
material or product, resulting in observed inhibition of
oxidation (entries 28 and 30).
Oxidation of Benzylic Alcohols with 1. Benzylic
alcohols are excellent substrates for this catalyst, with
electron-rich alcohols having the fastest rates (Table 1).34
Compared with the Pd(OAc)2/TEA system, the sterically
hindered alcohol 3k oxidizes much more efficiently (entry
23). Also, p-(methylthio)benzyl alcohol 3f oxidizes well
under standard conditions, and with a slightly modified
procedure provides a 90% isolated yield of the desired
product with no oxidation of the sulfur (entries 13 and
14). Of practical significance, 1 can be prepared in situ
from commercially available starting materials by using
Pd(OAc)2, IiPr-HBF4, and KOtBu, to provide an effective
oxidation (entry 2). For the oxidation of the electronically
activated substrate, p-methoxybenzyl alcohol 3c, the
catalyst loading can be lowered to 0.1 mol % to provide
complete conversion representing 1000 turnovers (entry
8). Once again, this oxidation system is not successful
for the oxidation of 3m and 3n (entries 29 and 31).
By increasing the concentration of AcOH to 4 mol %
on a 1-mmol scale, this oxidation system can be rendered
effective for the oxidation of benzylic alcohols under an
air atmosphere (entries 3, 7, 21, and 26). This was only
the second example of a homogeneous Pd-catalyst effec-
tive for the oxidation of alcohols under ambient pressure
of air.27d By using these modified conditions and increas-
ing the AcOH additive from 4 mol % to 5 mol %, the
oxidation of secphenethyl alcohol 3a can be accomplished
on a 1-g scale in 97% isolated yield (entry 3). The ability
to modulate the catalysis by addition of AcOH allows the
use of lower oxygen pressures and potential tuning of this
system for a particular substrate.
Results and Discussion
Recently, we have disclosed a mechanistic study on the
aerobic oxidation of alcohols using Pd(IiPr)(OAc)2(H2O)
(1).33i In this study, it was found that using more basic
carboxylates as the anionic ligand for Pd resulted in
increased rates of oxidation. Applying this finding has
(31) Uemura’s system has also been applied to other oxidation
reactions: (a) For a review, see: Nishimura, T.; Ohe, K.; Uemura, S.
Synlett 2004, 201-216. (b) For ring opening of hydroxycyclopropanes,
see: Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147-149. (c) For
intramolecular oxidative amination, see: Fix, S. R.; Brice, J. L.; Stahl,
S. S. Angew. Chem., Int. Ed. 2002, 41, 164-166. (d) For Wacker
cyclizations, see: Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2003, 42, 2892-2895. (e) For annulation
of indoles, see: Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003,
125, 9578-9579.
(32) Schultz, M. J.; Park, C. C.; Sigman, M. S. Chem. Commun.
2002, 3034-3035.
(33) For mechanistic studies on Pd(II)-catalyzed aerobic alcohol
oxidations, see: (a) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem.
Soc. 2002, 124, 766-767. (b) Steinhoff, B. A.; Stahl, S. S. Org. Lett.
2002, 4, 4179-4181. (c) Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J.
Am. Chem. Soc. 2002, 124, 8202-8203. (d) ten Brink, G.-J.; Arends, I.
W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344, 355-369. (e)
ten Brink, G.-J.; Arends, I. W. C. E.; Hoogenraad, M.; Verspui, G.;
Sheldon, R. A. Adv. Synth. Catal. 2003, 345, 497-505. (f) Mueller, J.
A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005-7013. (g) Nielson,
R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A., III J. Am. Chem.
Soc. 2004, 126, 7967-7974. (h) Steinhoff, B. A.; Guzei, I. A.; Stahl, S.
S. J. Am. Chem. Soc. 2004, 126, 11268-11278. (i) Mueller, J. A.; Goller,
C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724-9734. (j)
Konnick, M. M.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126,
10212-10213.
Oxidation of Benzylic Alcohols with 2. This system
compares well with both Pd(OAc)2/TEA and 1 for the
oxidation of benzylic alcohols. Once again primary,
secondary, and cyclic benzylic alcohols oxidize to comple-
tion under very mild conditions (ambient temperature
and air filled balloon) while using low catalyst loadings
(1 mol %). However, an electron-deficient benzylic alcohol
(35) This was previously illustrated by showing that the addition
of cinnamaldehyde inhibited the oxidation of 2-decanol. See ref 32 for
details.
(34) Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S.
Angew. Chem., Int. Ed. 2003, 42, 3810-3813.
J. Org. Chem, Vol. 70, No. 9, 2005 3345

Schultz et al.
TABLE 1. Oxidation of Benzylic Alcoholsa
a See Experimental Section for details. b Reactions with Pd(OAc)2/TEA: 0.3 M in 15% THF/toluene. c Reactions with 1: 0.5 M in toluene.
d Reactions with 2: 0.4 M in toluene. e Conversion measured by GC or 1H NMR. f Isolated yield in parentheses. g Catalyst 1 prepared in
situ with 0.5 mol % of Pd(OAc)2, 0.65 mol % of IiPr-HBF4, and 0.7 mol % of KOtBu. h 1.0-g scale.
3i does not oxidize well (entry 18). This system also works
well for the oxidation of p-(methylthio)benzyl alcohol 3f,
providing 92% conversion of the alcohol with no Pd-black
formation (entry 15). The sterically encumbered benzylic
alcohol 3k only oxidizes to 23% conversion under the
standard conditions showing a potential limitation of this
system (entry 24).
Oxidation of Aliphatic and Allylic Alcohols with
Pd(OAc)2/TEA. The oxidation of straight chain and
cyclic secondary aliphatic alcohols under standard condi-
tions is successful (Table 2). This includes oxidation of
the sterically encumbered alcohol, 2-adamantanol 5c, in
a slightly lower yield. A 1,4-diol 5d oxidizes to the
corresponding lactone (entry 6). The oxidation also works
well for primary aliphatic alcohols; however, the oxida-
tion of straight chain, primary aliphatic alcohols requires
modification of the standard conditions by lowering the
substrate concentration (vide infra).
As with most Pd-catalyzed alcohol oxidations, allylic
alcohols proved to be a more challenging substrate class.
Cyclic allylic alcohol 5j oxidizes well with this system but
myrtenol 5l only oxidizes to 82% conversion (entries 16
and 22). Straight chain, primary allylic alcohols do not
oxidize well with this system even under various modified
conditions (entries 19, 25, and 26). The difficulty with
oxidation of allylic alcohols is attributed to the ability of
R,â-unsaturated carbonyl compounds to chelate Pd(0),
thus inhibiting oxidation.35
Oxidation of Aliphatic and Allylic Alcohols with
1. By decreasing the AcOH concentration from 2 mol %
to 1 mol %, straight chain and cyclic aliphatic secondary
alcohols oxidize well with 0.5 mol % 1 (Table 2). As with
3346 J. Org. Chem., Vol. 70, No. 9, 2005

Aerobic Oxidation of Alcohols
TABLE 2. Oxidation of Aliphatic and Allylic Alcoholsa
a See Experimental Section for details. b Reactions with Pd(OAc)2/TEA: 0.3 M in 15% THF/toluene. c Reactions with 1 and secondary
alcohols: 0.5 M in toluene. d Reactions with 1 and primary alcohols: 0.125 M in toluene. e Reactions with 2: 0.4 M in toluene. f Conversion
measured by GC or 1H NMR. g Isolated yield in parentheses. h Product is the corresponding lactone. i 0.075 M in 20% THF/toluene with
1.0 mol % of Bu4NOAc added. j 5.4:1 mixture of isomers measured by 1H NMR.
benzylic alcohols, oxidation of secondary aliphatic alco-
hols could be performed under an air atmosphere (1 atm)
with an increase in AcOH concentration, from 1 to 2 mol
% (entry 8). Primary aliphatic alcohols proved more
challenging. Further optimization led to lowering the
molarity of the reaction and switching from AcOH to 5
mol % of Bu4NOAc to obtain decanal and octadecanal in
moderate yields (entries 12 and 13). In the case of
benzylic and secondary aliphatic alcohols, it was found
that adding small amounts of AcOH allowed for more
consistent oxidation presumably by slowing the oxidation
rate thus preventing catalyst decomposition. However,
the use of additive AcOH in the oxidation of primary
aliphatic alcohols resulted in slow oxidation possibly due
to the formation of small amounts of overoxidized prod-
uct, which would result in decreased oxidation rates.
Added acid has been shown to slow the rate of oxidation
through an inhibitory pathway.33i Additionally, while
elucidating the mechanistic details, we observed a first-
order rate dependence on [Bu4OAc] but considerable
decomposition of catalyst occurs at high levels of this
additive. Therefore, in the case of primary aliphatic
alcohols, small amounts of Bu4NOAc were used to ac-
celerate the oxidation thus resulting in improved yields
of aldehyde. Allylic alcohols oxidize better with 1 than
with Pd(OAc)2/TEA. The secondary allylic alcohol 5i and
cyclic allylic alcohol 5j both oxidize well under standard
conditions (entries 14 and 17). Myrtenol 5l and geraniol
5k require modified conditions for successful oxidations
(entries 20 and 23). Unfortunately, the oxidation product
of geraniol shows a 5.4:1 mixture of cis/trans isomers.
Oxidation of Aliphatic and Allylic Alcohols with
2. Catalyst 2 oxidizes secondary aliphatic alcohols suc-
cessfully, although the cyclic aliphatic alcohol 5e did not
oxidize to complete conversion (Table 2). Unfortunately,
it was concluded that this catalyst was not suitable for
J. Org. Chem, Vol. 70, No. 9, 2005 3347

Schultz et al.
TABLE 3. Oxidation of 1,3 Monoprotected Diols
the oxidation of primary aliphatic alcohols due to very
slow conversion. We hypothesize that due to the steric
bulk associated with the ligands of this catalyst, one of
the pivalates may dissociate from 2. This would render
2 the most Lewis acidic of the three catalysts explored
and thereby more susceptible to product inhibition by
good Lewis bases such as aldehydes. Although this
catalyst system was unsuccessful for the oxidation of
primary aliphatic alcohols, it performed better with
allylic alcohols. Both myrtenol 5l and a cyclic allylic
alcohol 5j oxidize to completion under standard condi-
tions (entries 18 and 24). The secondary allylic alcohol
5i only oxidizes to 62% conversion (entry 15). Geraniol
5k oxidizes to 68% conversion but in contrast to oxidation
with 1, no double bond isomerization is observed under
the milder conditions used for this catalyst system (entry
7).
Functionalized Alcohols. As observed above, alco-
hols that have the ability to chelate with metals can be
problematic substrates for oxidation. Inhibition of oxida-
tion or decomposition of the catalyst is generally associ-
ated with these substrates. Unfortunately, this limits the
use of several important substrate classes in Pd-catalyzed
aerobic oxidations. Therefore, we were not enthusiastic
about evaluating substrates that were more functional-
ized and related to the synthesis of complex targets.
However, evaluation of monoprotected 1,2- and 1,3-diols
proved fruitful, and many of these potentially chelating
substrates worked well with all three catalysts as de-
scribed below.
Oxidation of 1,3-Monoprotected Diols. For second-
ary alcohol substrates containing a protected primary
alcohol, Pd(OAc)2/TEA is the most versatile, giving excel-
lent isolated yields of TBS 8a, acetyl 8b, trityl 8c, and
benzyl 8d protected â-alkoxy-ketones (Table 3, entries
1, 4, 7, and 10). Of particular note, oxidation of 7d
proceeds well even on a 30-mmol (5.4 g) scale (entry 10)
with no special considerations for the heterogeneous (gas/
liquid) conditions employed. This system also effectively
oxidizes the sterically encumbered alcohol 7e in a 90%
isolated yield (entry 13).
Using 1 proved to be a good catalyst for the oxidation
of secondary alcohols containing a protected primary
alcohol, yielding slightly lower conversions than the TEA
system for TBS, trityl, and benzyl protected diols (Table
3, entries 2, 5, 8, and 11). Catalyst 2 did not oxidize
secondary alcohols containing a protected primary alcohol
as efficiently as the other catalysts. TBS and benzyl
protected diols oxidize to moderate conversions while the
acetyl and trityl protected alcohols are poorer substrates
(entries 3, 6, 9, and 12). For a primary alcohol containing
a protected secondary alcohol 7f, both Pd(OAc)2/TEA and
1 oxidize the trityl protected alcohol in >90% conversion
(entries 16 and 17). However, a primary alcohol with a
benzyl protected secondary alcohol 7g was not as suc-
cessful, presumably due to chelation (entries 18 and 19).
Catalyst 2 does not oxidize primary, nonbenzylic alcohols.
It is important to note, changing the nature of the
protecting group has little impact on the ability to oxidize
the substrate especially when using Pd(OAc)2/TEA.
Oxidation of 1,2-Monoprotected Diols. For second-
ary alcohols containing a TBS 9a or trityl 9c protected
alcohol, good yields of the desired ketones are achieved
by using the Pd(OAc)2/TEA oxidation system (Table 4,
a Reactions with Pd(OAc)2/TEA: 0.3 M in 15% THF/toluene.
b Reactions with 1 and secondary alcohols: 0.5 M in toluene.
c Reactions with 1 and primary alcohols: 0.125 M in toluene.
d Reactions with 2: 0.4 M in toluene. e Isolated yield in parenthe-
ses. f Conversion measured by GC or 1H NMR. g 30-mmol scale.
h 0.075 M in 20% THF/toluene.
entries 1 and 7). In contrast, secondary alcohol 9b, with
an acetyl protecting group, does surprisingly poorly with
the Pd(OAc)2/TEA but 1 promotes complete conversion
and a 99% isolated yield (entry 4). Catalyst 2 did not
oxidize these alcohols with comparable efficiency to Pd-
(OAc)2/TEA or 1. For oxidation of the enantiomerically
enriched substrate 9d, containing a primary alcohol and
a trityl protected secondary alcohol, Pd(OAc)2/TEA and
1 both perform equally well with an 85% yield of the
aldehyde when using Pd(OAc)2/TEA (entries 10 and 11).
In addition, the product was obtained with no racemiza-
3348 J. Org. Chem., Vol. 70, No. 9, 2005

Aerobic Oxidation of Alcohols
TABLE 4. Oxidation of 1,2 Monoprotected Diols and
Amino Alcohols
TABLE 5. Preventing Ester Formation of 1,2-Amino
Alcohols
entry
modified conditions
% conversion 12:13a
1b
2
0.075 M
70
75
76
77
70
70
75
69
64
56
36
4.5:1
3.1:1
2.3:1
3.6:1
6.6:1
21:1
0.1 M
3
0.125 M
4
10% THF
5
50% THF
6
100% THF
7
15 mol % of TEA
60 mol % of TEA
100 mol % TEA
100% of THF/100 mol % of TEA
3.6:1
7.0:1
9.4:1
34:1
8
9
10
11c,d Pd(liPr)(OAc)2(H2O)
33:1
a Ratio determined by GC and accounts for differences in
response factors. b No racemization is observed. c 0.75 mol % of 1.
d Complete racemization observed.
However, while ester formation was observed for other
primary aliphatic alcohols, the relative ratios of aldehyde
to ester were much less significant (>20:1). In the case
of N-boc-valinol, substantially more ester is formed under
these conditions (Table 5, entry 1). We reasoned the
undesired enhancement of ester formation is attributed
to the ability of the resulting aldehyde to chelate to the
Pd catalyst. Lewis acid activation allows for nucleophilic
attack of an alcohol on the aldehyde to result in a new
Pd-alkoxide derived from the hemiacetal. Subsequent
â-hydride elimination leads to ester formation. Presum-
ably, this mechanism is responsible for lactone formation
from a γ-diol via an intramolecular path (Table 2, entry
6). In the current study, ester formation is not a desirable
product but the design of a system that converts alcohols
directly to the acid oxidation state is currently under
study.36
a Isolated yield in parentheses. b Reactions with Pd(OAc)2/TEA:
0.3 M in 15% THF/toluene. c Reactions with 1: 0.5 M in toluene.
d Reactions with 2: 0.4 M in toluene. e Conversion measured by
GC or by 1H NMR. f No racemization of the product is observed.
g 0.1 M. h 0.125 M. i Racemized from 99% to 97% ee.
To test if chelation is the most likely contributor to the
increased ester formation, we evaluated several modified
reaction conditions. It was found that ester formation can
be limited by increasing the concentration of competing
ligands in the reaction by raising the THF and/or TEA
concentration (Table 5, entries 4-10). Additionally,
lowering the entropic barrier by decreasing the molarity
of the substrate leads to modest improvements (Table 5,
entries 1-3). While improvements in the ratio of alde-
hyde to ester are observed, a corresponding slowing of
the oxidation rate also results, leading to a more selective
but inefficient oxidation. The use of 1 for the oxidation
of N-boc-valinol was also ineffective and leads to complete
racemization of the aldehyde product. This N-boc pro-
tected R-amino primary alcohol is a difficult substrate
for these Pd-catalyzed alcohol oxidations.
tion. Overall, 1,2-monoprotected diols are viable sub-
strates for Pd-catalyzed aerobic oxidative protocols.
Protected 1,2-Amino Alcohols. While unprotected
amino alcohols will not oxidize with these catalyst
systems, protecting the amine may allow for facile alcohol
oxidation. To test this, norephedrine was Boc protected
and submitted to the oxidation conditions (Table 4,
entries 12-14). As with most functionalized alcohols, Pd-
(OAc)2/TEA outperformed the other catalysts providing
a 97% yield of the desired R-amino-ketone. No racem-
ization of 10e is observed with the two methods at room
temperature but a slight erosion of enantiomeric excess
(99% to 97% ee) is observed with catalyst 1 at 60 °C. A
more difficult substrate, N-boc-valinol 11, was tested with
the Pd(OAc)2/TEA catalyst system where the aldehyde
is obtained in modest conversion with no loss of stereo-
chemical integrity. However, a major byproduct 13, the
ester formed from two molecules of N-boc-valinol, was
observed (Table 5). This observation was not entirely
surprising considering primary aliphatic alcohols re-
quired modified reaction conditions for effective oxidation.
Chemoselective Alcohol Oxidations. Chemoselec-
tivity in alcohol oxidations avoids the use of protecting
groups and streamlines the chemical synthesis process.
There are very few examples of highly chemoselective
(36) Mueller, J. A.; Heaton, A. L.; Sigman M. S. Unpublished results.
J. Org. Chem, Vol. 70, No. 9, 2005 3349

Schultz et al.
TABLE 6. Chemoselective Alcohol Oxidations
TABLE 7. Diastereoselective Oxidations of
Methylcyclohexanols
entry
1
conditions
% conversion 15:16:17a
3 mol % of Pd(OAc)2/6% TEA
0.3 M, 15% THF/toluene
3 Å MS, O2, rt, 15 h
3 mol % of Pd(OAc)2/18% TEA
0.075 M, 20% THF/toluene
3 Å MS, O2, rt, 15 h
0.75 mol % of 1, 5 mol % of
Bu4NOAc 0.7 M, toluene
3 Å MS, O2, 60 °C, 15 h
88
98
75
2.3:0.4:1
0.8:0.7:1
2.6:2.4:1
2
3
entry
catalyst
alcohol time conversiona trans:cis sb
1
2
3
4
5
6
7
8
9
Pd(OAc)2/TEA
15
13
16
15
13
16
15
13
16
>99
48
NA
NA
11
23
NA
7
1
20c
21d
22e
65:1
575:1
NA
2
45
Pd(OAc)2/TEA
>99
51
a Ratio determined by GC and does not account for differences
in response factors.
1
2
1:22
1:25
NA
10:1
11:1
40
19
NA
7
Pd(OAc)2/TEA
1
2
99
49
catalysts for alcohol oxidations.37 Chemoselectivity, be-
tween a primary and a secondary alcohol, was tested by
submitting 1,6-heptanediol 14 to oxidation with all three
catalyst systems (Table 6). Conditions developed to
oxidize secondary alcohols for the Pd(OAc)2/TEA system
lead to a chemoselective oxidation of the secondary
alcohol to yield a nearly 6 to 1 ratio of 15 to 16 (entry 1).
Significant oxidation to 17 is also observed making this
a less practical method for chemoselective oxidation. In
contrast, using conditions developed to oxidize primary
alcohols yields almost equal amounts of 15, 16, and 17
(entry 2). In comparison, using conditions developed for
oxidation of primary aliphatic alcohols with catalyst 1,
no chemoselectivity for the initial oxidation to 15 and 16
is observed but the oxidation to 17 is slower (entry 3).
Testing of other conditions with catalysts 1 and 2 was
severely limited by the solubility of the substrate in
toluene.
Diastereoselective Oxidations of Substituted Cy-
clohexanols. When oxidizing 4-methylcyclohexanol with
catalyst 1, the cis isomer oxidized rapidly while the trans
isomer oxidized considerably slower. An initial hypothesis
was the alcohol must assume the axial position to
undergo â-hydride elimination. A cis/trans mixture of
4-tert-butylcyclohexanol 18 was chosen as a model sub-
strate to test this hypothesis. The cis diastereomer of the
mixture, which is locked in the axial position, was
expected to oxidize faster than the trans diastereomer.
However, submitting the isomeric mixture of 18 to
standard conditions for catalyst 1 gave no oxidation. In
contrast, Pd(OAc)2/TEA oxidizes 18 effectively but no
diastereoselectivity is observed (eq 1).
47
9
a GC conversion. b s ) Ln(([minor]/[minor]o)/([major]/[major]o))
where [major]o and [minor]o are initial concentrations of each
isomer. c Starting material trans/cis ratio ) 2.4:1, ratios measured
by GC. d Starting material cis/trans ratio ) 2.2:1, ratios measured
by 1H NMR. e Starting material trans/cis ratio ) 1.6:1, ratios
measured by 1H NMR.
cis/trans mixtures of the three constitutional isomers of
methyl cyclohexanol (Table 7). Using Pd(OAc)2/TEA,
complete oxidation of the mixture of diastereomers
results and no diastereoselectivity is observed even at
low conversions. In contrast, catalyst 1 promotes a highly
diastereoselective oxidation of each alcohol. For 2- and
4-methylcyclohexanol, the cis isomer oxidizes faster
whereas the trans isomer of 3-methylcyclohexanol oxi-
dizes faster. The isomers corresponding to the fast
reacting diastereomers contain a substituent in an axial
position. Out of the three constitutional isomers, cis/
trans-2-methylcyclohexanol results in the best resolu-
tions. Using catalyst 1 a 65 to 1 ratio (selectivity factor
) 11) of trans to cis diastereomers at 48% conversion is
observed (entry 2). Catalyst 2 oxidizes all three alcohols
in higher diastereoselectivity than catalyst 1 with 20
giving an excellent resolution of 575 to 1 ratio (selectivity
factor ) 23) of trans to cis diastereomers at 45% conver-
sion (entry 3).
Interactions between the ligand, carboxylate, and
substrate play a role in diastereoselectivity of the oxida-
tion. As the substitution on the cyclohexane ring becomes
closer to the site of oxidation, higher selectivity factors
are observed. The size difference between the carboxy-
lates on 1 and 2 leads to an enhancement of the
selectivity factor as well. Even with these trends, it is
difficult to propose a model when a change in rate-
limiting step from â-hydride elimination to deprotonation
for the different isomers is possible. Considering the
implications to asymmetric catalysis, investigation of
these possibilities will be a subject of future research.
Considering substrate 18 does not oxidize with catalyst
1, we chose to explore the original hypothesis by oxidizing
Conclusions
The current systems compare favorably to the bench-
marks established by Uemura and Sheldon. Chief among
(37) For a recent review, see: Arterburn, J. B. Tetrahedron 2001,
57, 9765-9788.
3350 J. Org. Chem., Vol. 70, No. 9, 2005

Aerobic Oxidation of Alcohols
powdered and activated by placing them under vacuum in a
flask and heating with a Bunsen burner for ca. 2 min. GC
conversions for reactions with <99% conversion were deter-
mined relative to undecane or tetradecane as internal stan-
dard.
the advantages are the mild conditions employed and
higher catalytic activity for 1 and 2. The mild nature of
the reaction conditions presented herein allows oxidation
of functionalized substrates with protecting groups which
would likely not withstand the forcing conditions in other
Pd-catalyzed aerobic alcohol oxidations.
Preparation of Pd(IiPr)(OPiv)2 (2). To a 20-mL scintil-
lation vial was added 30 mg of [Pd(IiPr)Cl2]2 (0.027 mmol, 1.0
equiv) and 22.7 mg of AgOPiv (0.108 mmol, 4.025 equiv). In
the dark (wrapped in aluminum foil), 6 mL of cooled CH2Cl2
(0 °C) was added and the mixture was allowed to slowly warm
to room temperature. After 12 h, the reaction mixture was
concentrated to ca. 2 mL and placed in a 2-mL microcentrifuge
tube. The tube was placed in a centrifuge and spun for ca. 3
min. The yellow solution was transferred into a 10-mL flask
and the solvent removed in vacuo to yield 35 mg of a yellow
solid (96% yield). Mp >161 °C dec; IR (KBr) 2967, 2928, 2868,
1628, 1559, 1477, 1465, 1415, 1363, 1207 cm-1; 1H NMR (CD2-
Cl2) δ 0.91 (s, 18 H), 1.1 (d, J ) 7.25 Hz, 12H), 1.4 (d, J ) 6.87
Hz, 12H), 2.70 (apparent sept., J ) 6.78 Hz, 4H), 7.17 (s, 2H),
7.40-7.49 (m, 4H), 7.55-7.65 (m, 2H); 13C NMR (CD2Cl2) δ
23.0, 25.7, 27.1, 28.5, 39.5, 124.3, 126.2, 130.5, 135.0, 146.3,
148.7, 192.5. Elemental Anal. Calcd: C 63.74, H 7.81, N 4.02.
Found: C 63.76, H 7.72, N 3.91.
Pd(OAc)2/TEA-Catalyzed Oxidation of Benzylic, Sec-
ondary Aliphatic, and Cylic Allylic Alcohols. To a 25-mL
round-bottom flask equipped with a stir bar was added 6.7
mg of Pd(OAc)2 (0.03 mmol, 0.03 equiv) and 200 mg of
powdered, freshly activated 3 Å molecular sieves. To this was
added 0.5 mL of THF, 2.83 mL of toluene, and 8.4 µL of TEA
(0.06 mmol, 0.06 equiv). A balloon of oxygen was attached via
a three-way joint. The flask was evacuated and refilled with
oxygen three times followed by vigorous stirring for 30 min
at room temperature under O2. To this solution was added 1
mmol of alcohol and the mixture was stirred vigorously at
room temperature under a balloon of O2. The reaction progress
was monitored by GC. After 12 h, the reaction mixture was
placed directly on a plug of silica, washed with pentane to
remove toluene, and eluted with diethyl ether. The ether was
removed in vacuo to yield the desired carbonyl product. For
alcohols with incomplete oxidation, the desired carbonyl
product was isolated via column chromatography with mix-
tures of diethyl ether/hexanes as the eluting solvent. Purity
was confirmed by NMR.
Pd(OAc)2/TEA-Catalyzed Oxidation of Primary Ali-
phatic Alcohols. To a 50-mL round-bottom flask equipped
with a stir bar was added 6.7 mg of Pd(OAc)2 (0.03 mmol, 0.03
equiv) and 250 mg of powdered, freshly activated 3 Å molecular
sieves. To this was added 2.6 mL of THF, 9.4 mL of toluene,
1.0 mL of 0.01 M Bu4NOAc/toluene (0.01 mmol, 0.01 equiv),
and 25 µL of TEA (0.18 mmol, 0.18 equiv). A balloon of oxygen
was attached via a three-way joint. The flask was evacuated
and refilled with oxygen three times followed by vigorous
stirring for 30 min at room temperature under O2. To this
solution was added 1 mmol of alcohol and the mixture was
stirred vigorously at room temperature under a balloon of
O2. The reaction progress was monitored by GC. After 12 h,
the reaction mixture was placed directly on a plug of silica,
washed with pentane to remove toluene, and eluted with
diethyl ether. The ether was removed in vacuo to yield the
desired carbonyl product. For alcohols with incomplete oxida-
tion, the desired carbonyl product was isolated via column
chromatography with diethyl ether/hexanes as the eluting
solvent. Purity was confirmed by NMR.
Of the three catalysts, catalyst 2 uses the mildest
reaction conditions (room temperature, 1 mol % of
catalyst, and air as the O2 source) but the substrate scope
of this catalyst is the most limited. In comparison,
catalyst 1 and Pd(OAc)2/TEA both prove quite effective
for a broad scope of substrates. The advantages of
catalyst 1 are (1) low catalyst loadings for a Pd-catalyzed
alcohol oxidation (0.1 to 1.0 mol %), (2) replacement of
O2 with ambient air by raising [AcOH] (2 to 5 mol %),
(3) a diastereoselective oxidation of substituted cyclohex-
anols, and (4) effective oxidation of allylic alcohols. The
advantages of the Pd(OAc)2/TEA system are (1) simplicity
of the reaction procedure, (2) the use of ambient temper-
ature, (3) lack of racemization of nonracemic substrates,
(4) moderately chemoselective oxidations, (5) easy scal-
ability (30 mmol), and (6) generally excellent yields for
functionalized alcohols. The main limitations of these
systems are (1) the use of basic groups inhibit the
oxidation and (2) substrate solubility in the reaction
solvent. Even though catalysts 1 and 2 are more efficient
in terms of catalyst loading and oxygen concentration,
Pd(OAc)2/TEA is the easiest system for evaluating a new
substrate due to readily available reagents and good
substrate scope. However, catalyst 1 has the greatest
ability to be modulated through changing temperature,
the oxygen concentration, and amounts of additive AcOH
or Bu4NOAc. Overall, these systems showed diverse scope
and excellent reactivity under mild conditions.
The major challenge in developing efficient catalysts
for Pd-catalyzed aerobic alcohol oxidations has been the
identification of effective and stable ligands, especially
considering that phosphine ligands are susceptible to
oxidation under aerobic conditions. However, the current
study showcases that the careful selection of ligand/base
leads to excellent results in Pd-catalyzed aerobic oxida-
tions. Using the knowledge that excess tertiary amine is
necessary for effective oxidations and leads to inhibition
of oxidation rates, we designed a catalyst that uses a
single NHC ligand on Pd(OAc)2. This allowed for signifi-
cantly lower catalyst loadings. In addition, the catalytic
activity of 1 was improved by changing the nature of the
carboxylate anionic ligand from acetate to pivalate. Not
only can the carboxylate be tuned, it is also possible to
modify the NHC ligands electronically and structurally
for development of desired reactivity. Considering this,
future work in our laboratory is focused on the discovery
of new Pd(II)-catalyzed oxidation reactions with applica-
tions in asymmetric catalysis with related ligands and
catalyst design approaches.
Pd(IiPr)(OAc)2(H2O)-Catalyzed Oxidation of Benzylic
and Secondary Allylic Alcohols. To a 10-mL round-bottom
flask equipped with a stir bar was added 3.2 mg of Pd(IiPr)-
(OAc)2(H2O) (0.005 mmol, 0.005 equiv) and 150 mg of pow-
dered, freshly activated 3 Å molecular sieves. To this was
added 1.6 mL of toluene and 0.4 mL of 0.1 M AcOH/toluene
(0.02 mmol, 0.02 equiv) followed by 1 mmol of alcohol. A reflux
condenser was attached to the flask and a balloon of oxygen
was attached to the top of the condenser via a three-way joint.
Experimental Section
General Considerations. The alcohols used as substrates,
HOAc, and Bu4NOAc were purchased and used as received.
[Pd(IiPr)Cl2]228f and 134 were prepared according to literature
methods. PhCH3 used as solvent was dried before use by
passing through a column of activated alumina. THF was dried
by distilling from sodium benzophenone ketyl. TEA is purified
via distillation from CaH2. The 3 Å molecular sieves were
J. Org. Chem, Vol. 70, No. 9, 2005 3351

Schultz et al.
The flask was evacuated and refilled with oxygen three times
followed by vigorous stirring for ca. 10 min. The apparatus
was placed in a 60 °C oil bath. The reaction progress was
monitored by GC. After completion, the reaction mixture was
cooled to ambient temperature and placed directly on a plug
of silica, washed with pentane to remove toluene, and eluted
with diethyl ether. The diethyl ether was removed in vacuo to
yield the desired carbonyl product. For alcohols with incom-
plete oxidation, the desired carbonyl product was isolated via
column chromatography with mixtures of diethyl ether/hex-
anes as the eluting solvent. Purity was confirmed by NMR.
Pd(IiPr)(OAc)2(H2O)-Catalyzed Oxidation of Second-
ary Aliphatic Alcohols. To a 10 mL round-bottom flask
equipped with a stir bar was added 3.2 mg of 1 (0.005 mmol,
0.005 equiv) and 150 mg of powdered, freshly activated 3 Å
molecular sieves. To this was added 1.8 mL of toluene and 0.2
mL of 0.1 M AcOH/toluene (0.01 mmol, 0.01 equiv) followed
by 1 mmol of alcohol. A reflux condenser was attached to the
flask and a balloon of oxygen was attached to the top of the
condenser via a three-way joint. The flask was evacuated and
refilled with oxygen three times followed by vigorous stirring
for ca. 10 min. The apparatus was placed in a 60 °C oil bath.
The reaction progress was monitored by GC. After completion,
the reaction mixture was cooled to ambient temperature and
placed directly on a plug of silica, washed with pentane to
remove toluene, and eluted with diethyl ether. The diethyl
ether was removed in vacuo to yield the desired carbonyl
product. For alcohols with incomplete oxidation, the desired
carbonyl product was isolated via column chromatography
with mixtures of diethyl ether/hexanes as the eluting solvent.
Purity was confirmed by NMR.
Pd(IiPr)(OAc)2(H2O)-Catalyzed Oxidation of Primary
Aliphatic and Allylic Alcohols. To a 50-mL round-bottom
flask equipped with a stir bar was added 4.7 mg of Pd(IiPr)-
(OAc)2(H2O) (0.0075 mmol, 0.0075 equiv), 15.1 mg of Bu4NOAc
(0.05 mmol, 0.05 equiv), and 200 mg of powdered, freshly
activated 3 Å molecular sieves. To this was adde 10.0 mL of
toluene followed by 1 mmol of alcohol. A reflux condenser was
attached to the flask and a balloon of oxygen was attached to
the top of the condenser via a three-way joint. The flask was
evacuated and refilled with oxygen three times followed by
vigorous stirring for ca. 10 min. The apparatus was placed
in a 60 °C oil bath. The reaction progress was monitored by
GC. After completion, the reaction mixture was cooled to
ambient temperature and placed directly on a plug of silica,
washed with pentane to remove toluene, and eluted with
diethyl ether. The diethyl ether was removed in vacuo to yield
the desired carbonyl product. For alcohols with incomplete
oxidation, the desired carbonyl product was isolated via column
chromatography with mixtures of diethyl ether/hexanes as the
eluting solvent. Purity was confirmed by NMR.
Pd(IiPr)(OPiv)2-Catalyzed Oxidation of Benzylic, Al-
lylic, and Secondary Aliphatic Alcohols. To a 25-mL
round-bottom flask equipped with a stir bar was added 7.2
mg of Pd(IiPr)(OPiv)2 (0.01 mmol, 0.01 equiv) and 250 mg of
powdered, freshly activated 3 Å molecular sieves. To this was
added 2.45 mL of toluene and 0.05 mL of 0.1 M PivOH/toluene
(0.005 mmol, 0.005 equiv). A balloon of air was attached via a
three-way joint and the mixture was allowed to stir for 5 min.
To the mixture was added 1 mmol of alcohol and the reaction
mixture was stirred vigorously. The reaction progress was
monitored by GC. After completion, the reaction mixture was
cooled to ambient temperature and placed directly on a plug
of silica, washed with pentane to remove toluene, and eluted
with diethyl ether. The diethyl ether was removed in vacuo to
yield the desired carbonyl product. For alcohols with incom-
plete oxidation, the desired carbonyl product was isolated via
column chromatography with mixtures of diethyl ether/hex-
anes as the eluting solvent. Purity was confirmed by NMR.
Acknowledgment. This work was supported by the
National Institutes of Health (NIGMS #RO1 GM63540),
Pfizer GRD, and the Dreyfus Foundation (Teacher-
Scholar Award). D.R.J. thanks the University of Utah
and the ACS Organic Division Fellowship sponsored by
the Schering Plough Research Institute for graduate
research fellowships. S.S.H. thanks Pfizer GRD for a
summer research fellowship. We thank Johnson
Matthey for supplies of various palladium salts. We
thank Professor Ilya Zharov for designing the cover
artwork.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0482211
3352 J. Org. Chem., Vol. 70, No. 9, 2005