Palladium-catalyzed enantioselective oxidation of alcohols: a dramatic rate acceleration by Cs2CO3/t-BuOH.

Article abstract of DOI:10.1021/ol027463p

[reaction: see text] The addition of Cs(2)CO(3) and t-BuOH provides a dramatic rate acceleration in the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols while maintaining the selectivity of the process.

Full text of DOI:10.1021/ol027463p

ORGANIC
LETTERS
2003
Vol. 5, No. 6
835-837
Palladium-Catalyzed Enantioselective
Oxidation of Alcohols: A Dramatic Rate
Acceleration by Cs2CO /t-BuOH
3
Jeffrey T. Bagdanoff, Eric M. Ferreira, and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis,
DiVision of Chemistry and Chemical Engineering, California Institute
of Technology, Pasadena, California 91125
stoltz@caltech.edu
Received December 13, 2002
ABSTRACT
The addition of Cs2CO and t-BuOH provides a dramatic rate acceleration in the palladium-catalyzed aerobic oxidative kinetic resolution of
3
secondary alcohols while maintaining the selectivity of the process.
We recently reported the oxidative kinetic resolution of sec-
ondary alcohols using a simple protocol involving a com-
mercially available palladium complex, sparteine, and mo-
lecular oxygen (Scheme 1).1-3 Although our previously
For example, a typical reaction time was on the order of 4
days. In an effort to develop more active catalyst systems
for the oxidative kinetic resolution of nonactivated alcohols
and other asymmetric dehydrogenation reactions, we have
discovered a modified set of conditions that accomplishes
similar resolutions in a fraction of the time.4,5
During the course of our investigations into the enanti-
oselective oxidation of secondary alcohols, we prepared a
number of Pd(II)‚sparteine complexes and studied their
reactivity.6 In general, we found that the reactivity of these
complexes toward the asymmetric oxidation of alcohols was
poor when compared to the optimized method we developed,
wherein a 4-fold excess of sparteine relative to the palladium
source was used to form the complex in situ. Interestingly,
Scheme 1
described system was applied to a range of benzylic and
allylic alcohols, the reaction times required to advance the
resolutions to high conversion were often prohibitively long.
(4) Recently, Stahl has been studying the mechanistic details of related,
non-asymmetric systems; see: (a) Steinhoff, B. A.; Stahl, S. S. Org. Lett.
2002, 4, 4179. (b) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem.
Soc. 2002, 124, 766. (c) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee,
M. A. J. Am. Chem. Soc. 2001, 123, 7188.
(1) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725.
(2) Simultaneous to our publication a related system was reported; see:
Jensen., D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123,
7475.
(3) The kinetic resolutions in refs 1 and 2 were based on a non-
asymmetric alcohol oxidation employing Pd(OAc)2, pyridine, and O2; see:
Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64,
6750.
(5) For discussions on kinetic resolution, see: (a) Martin, V. S.; Woodard,
S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem.
Soc. 1981, 103, 6237. (b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih,
C. J. J. Am. Chem. Soc. 1982, 104, 7294. (c) Kagan, H. B.; Fiaud, J. C. In
Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York,
1988; Vol. 18, pp 249-330.
(6) Bagdanoff, J. T.; Ferreira, E. M.; Trend, R. M.; Stoltz, B. M.
Unpublished results.
10.1021/ol027463p CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/14/2003

the reactivity of the system could be restored upon introduc-
tion of an additional 3 equiv of sparteine relative to the
complex (particularly the chloride derivatives).7 Intrigued by
this finding, we hypothesized that the excess sparteine was
serving as a general base for the ultimate neutralization of
HCl liberated from the system, and thus investigated the
effect of other bases on the reaction. Indeed, Sigman’s kinetic
work has confirmed this hypothesis.
Table 2. Catalyst and External Alcohol Effects
time conversionb ROHc
(h) (%)
ee (%) sd
As shown in Table 1, we surveyed the effect of a variety
of external bases and additives on the oxidative kinetic
entry
additive
1
2
3
4
5
6
7
8
9
sparteine (5 mol %)
sparteine (10 mol %)
sparteine (30 mol %)
n-BuOH (1.0 equiv)
n-BuOH (2.0 equiv)
n-BuOH (10 equiv)
t-BuOH (1.0 equiv)
t-BuOH (4.0 equiv)
t-BuOH (10 equiv)
5
5
5
5.5
5.5
45
60
83
96
98
95
56
90
94
90
12
12
15
12
10
7
16
20
16
56
61
66
67
48
57
57
57
Table 1. Additive Effects on the Oxidative Kinetic Resolution
19
22.5d
11.5d
19e
a 10 mol % Pd(nbd)Cl2, 10 mol % (-)-sparteine, 1 equiv of Cs2CO3, 1
atm of O2, 0.1 M substrate concentration in PhCH3. b Measured by 1H
NMR. c Measured by chiral HPLC. d Conducted at 50 °C. e Conducted at
45 °C.
time conversionb ROHc
entry
additive
(h)
(%)
ee (%) sd
1
2
3
4
5
6
7
nonee
96
20
13
13
13
13
13
67
26
19
7
27
56
68
98
31
19
8
31
84
99
12
22
11
20
15
13
13
Et3N (0.4 equiv)
Et3N (2.0 equiv)
DABCO (0.4 equiv)
Na2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
Cs2CO3 (1.0 equiv)
provide a beneficial effect on reactivity as well. In particular,
the addition of t-BuOH increased the selectivity of the
reaction at little expense to the overall rate. At slightly
decreased temperatures (i.e., 50 °C), a selectivity factor (s)
of 20 was observed over 11.5 h, with resolution of alcohol
3 to 57% conversion and 94% ee.8
To directly compare the effect of additives on the overall
rate to that of our previous conditions, we carried out a
parallel analysis at 80 °C. As shown in Scheme 2, there is
a 10 mol % Pd(nbd)Cl2, 10 mol % (-)-sparteine, 1 atm of O2, 0.1 M
substrate concentration in PhCH3. b Measured by 1H NMR. c Measured
by chiral HPLC. d See footnote 8. e 5 mol % Pd(nbd)Cl2, 20 mol %
(-)-sparteine.
resolution and compared the results to those previously
reported (entry 1).1,2 For all trials depicted in Table 1, a 1:1
ratio of Pd(nbd)Cl2/sparteine was employed. Although ad-
dition of amine bases provided high levels of selectivity,
resolutions performed under these conditions failed to
proceed beyond low conversion (entries 2-4). The most
dramatic effect was observed upon addition of carbonate
salts. Specifically, inclusion of 1.0 equiv of powdered
anhydrous Cs2CO3 resolved benzylic alcohol 3 in just 13 h,
with comparable selectivity to our previously reported
conditions.
Scheme 2
Having observed a marked additive effect, we attempted
to further improve the system by optimizing the catalyst
loading, Pd/sparteine ratio, and by continuing to study the
effects of additives. As shown in Table 2, increased amounts
of sparteine still have a positive effect on the selectivity
and the overall rate of the reaction (entries 1-3). In fact,
by simply increasing the total amount of (-)-sparteine to
that previously employed (4:1 sparteine/Pd), we could
achieve alcohol resolution to high enantiopurity in only 5 h
(entry 3).
a clear overall rate acceleration using Cs2CO3 and t-BuOH
as additives. Specifically, under these conditions resolution
of alcohol 5 to 94% ee is observed after only 3 h.
Unfortunately, there is also a noticeable erosion in selectivity
as compared to our original conditions. Most of this
selectivity diminution can be overcome by simply performing
the reaction at a slightly lower temperature and at somewhat
increased substrate concentration in PhCH3 (see Table 3,
entry 1).
Interestingly, it was found that alcohols that are not readily
oxidized (i.e., nonactivated primary and tertiary alcohols),
Having identified a number of highly reactive catalytic
systems, we began to investigate the substrate scope using
(7) Sigman observed a similar phenomenon2 and has recently published
a kinetic study of the effect; see: Mueller, J. A.; Jensen, D. R.; Sigman,
M. S. J. Am. Chem. Soc. 2002, 124, 8202.
(8) The selectivity factor (s) was determined using the equation s )
k
rel(fast/slow) ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C )
conversion.5c
836
Org. Lett., Vol. 5, No. 6, 2003

As shown in Table 3, essentially all of the activated benzylic
and allylic alcohols that were previously good substrates
serve as excellent substrates under the new conditions. A
range of electron rich and poor benzylic alcohols can be
resolved to high enantiopurity by oxidative kinetic resolution
in well under 24 h. A particularly striking example is the
resolution of 1-phenylpropanol (entry 7). Previously, the
reaction time for this resolution required 8 days to proceed
to 59.3% conversion (93.1% ee) with a selectivity factor of
14.8.1 Using our Cs2CO3/t-BuOH-modified conditions, the
oxidation proceeds in only 4.5 h to 62.8% conVersion and
98.0% ee (s ) 16.1).
Table 3. Cs2CO3/t-BuOH-Modified Oxidative Kinetic
Resolution
In summary, we have developed a highly reactive set of
conditions for the oxidative kinetic resolution of activated
secondary alcohols. Resolutions that previously required up
to a week to proceed to high conversion and enantiopurity
can now be achieved in less than 16 h, typically with
comparable selectivity. Studies aimed at understanding the
dramatic effect of the Cs2CO3/t-BuOH system, further
improving the reactivity, and establishing conditions for the
resolution of nonactivated alcohols are currently under
investigation in our laboratory. Results toward these ends
will be published in due course.
Acknowledgment. We wish to thank the NIH-NIGMS
(R01 GM65961-01), the California Institute of Technology,
the Camille and Henry Dreyfus Foundation (New Faculty
Award to B.M.S.), the Merck Research Laboratories, Re-
search Corporation, The University of California TRDRP
(predoctoral fellowship to J.T.B.), the National Science
Foundation (predoctoral fellowship to E.M.F.), GlaxoSmith-
Kline, and Abbott Laboratories for generous financial
support.
a 5 mol % Pd(nbd)Cl2, 20 mol % (-)-sparteine, 0.5 equiv of Cs2CO3,
1.5 equiv of t-BuOH, 1 atm of O2, 0.25 M substrate concentration in PhCH3.
b Measured by GC relative to an internal standard (tridecane). The total
GC yield (alcohol + ketone) was >95% in all cases. c Measured by chiral
HPLC. d Conducted at 40 °C. e Conducted at 80 °C.
the combination of Pd(nbd)Cl2, (-)-sparteine, Cs2CO3, and
t-BuOH at 60 °C under an oxygen atmosphere,9,10 with a
substrate concentration of 0.25 M in PhCH3 (see Table 3).
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Although we have never experienced an accident, all reactions must
be performed with appropriate caution in a fume hood due to the flammable
nature of mixtures of oxygen and organic solvents.
(10) Unfortunately, reactions conducted under an atmosphere of air rather
than O2 were less effective in terms of both enantioselectivity and reactivity.
OL027463P
Org. Lett., Vol. 5, No. 6, 2003
837