Sustainable Pd(OAc)2/Hydroquinone Cocatalyst System for Cis-Selective Dibenzoyloxylation of 1,3-Cyclohexadiene

Article abstract of DOI:10.1002/anie.202108499

The 1,4-diacyloxylation of 1,3-cyclohexadiene (CHD) affords valuable stereochemically defined scaffolds for natural product and pharmaceutical synthesis. Existing cis-selective diacyloxylation protocols require superstoichiometric quantities of benzoquino

Full text of DOI:10.1002/anie.202108499

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Sustainable Pd(OAc)2 Hydroquinone Cocatalyst System for Cis-
Selective Dibenzoyloxylation of 1,3-Cyclohexadiene
Authors: Alexios G. Stamoulis, Peng Geng, Michael A. Schmidt, Martin
D. Eastgate, Alina Borovika, Kenneth J. Fraunhoffer, and
Shannon S Stahl
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202108499
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10.1002/anie.202108499
Angewandte Chemie International Edition
COMMUNICATION
Sustainable Pd(OAc)2/Hydroquinone Cocatalyst System
for Cis-Selective Dibenzoyloxylation of 1,3-Cyclohexadiene
Alexios G. Stamoulis,[a] Peng Geng,[b] Michael A. Schmidt,[b] Martin D. Eastgate,[b] Alina Borovika,[b]
Kenneth J. Fraunhoffer,[b] and Shannon S. Stahl[a]*
Abstract: The 1,4-diacyloxylation of 1,3-cyclohexadiene (CHD)
affords valuable stereochemically defined scaffolds for natural
product and pharmaceutical synthesis. Existing cis-selective
diacyloxylation protocols require superstoichiometric quantities of
benzoquinone (BQ) or MnO2, which limit process sustainability and
large-scale application. In this report, reaction development and
mechanistic studies are described that overcome these limitations by
pairing catalytic BQ with tert-butyl hydroperoxide as the stoichiometric
oxidant. Catalytic quantities of bromide enable a switch from trans to
cis diastereoselectivity. A catalyst with a 1:2 Pd:Br ratio supports high
cis selectivity while retaining good rate and product yield. Further
studies enable replacement of BQ with hydroquinone (HQ) as a
source of cocatalyst, avoiding the handling of volatile and toxic BQ in
large scale applications.
BQ reoxidizes Pd0 to PdII in these reactions,[23,24] and seminal
work by Bäckvall and coworkers has demonstrated that
cocatalysts, such as [Co(salophen)] or [Fe(phthalocyanine)],
support in situ reoxidation of HQ to BQ using O2 as the terminal
oxidant.[25 -28] These conditions are only compatible with formation
of trans-diacyloxylation products, however. Complementary
PdII/chloride catalyst systems have been identified for cis-
diacyloxylation of dienes,[5] but the chloride additive inhibits the
aerobic cocatalysts, even when used in catalytic quantities.[29,30]
Stoichiometric MnO2 is required as a terminal oxidant in order to
lower the BQ loading in these reactions.[6,31] Recently, Eastgate
and coworkers reported a complementary catalytic method, using
tert-butyl hydroperoxide (tBuOOH) as the oxidant.[7,32] The Pd
catalyst serves a dual role in these reactions (Scheme 1b),
promoting both CHD oxidation and reoxidation of HQ by tBuOOH
(DA1 is a Diels-Alder adduct obtained from reaction of CHD with
BQ). These conditions are appealing for large-scale application;
however, they similarly access only trans-diacyloxylation product
(i.e., trans-1). The present report outlines development and
Pd-catalyzed oxidations of alkenes and dienes are important
industrial processes,[ 1 ] ranging from the Wacker process for
production of acetaldehyde from ethylene,[2] to 1,4-diacetoxylation
of 1,3-butadiene, employed in the commercial synthesis of
tetrahydrofuran.[3] The latter reaction is closely related to 1,4-
diacyloxylation of 1,3-cyclohexadiene (CHD) and other cyclic
dienes,[4-7] which find utility in natural product and pharmaceutical
synthesis.[8-12] These reactions generate cis or trans diastereo-
mers, and their utility in synthetic routes (e.g., using Tsuji-Trost
characterization of
a new Pd(OAc)2/bromide/BQ cocatalyst
system that enables large-scale cis-diacyloxylation of CHD with
tBuOOH as the oxidant (Scheme 1c).
(a) Current conditions en route to drug candidate
NHtBu
OBz
Pd(OAc)2 (2 mol%)
BzOH (4.0 equiv)
10 steps
[13 -16 ]
[17 -19 ]
allylic substitution
or enzymatic desymmetrization
)
depends on selective formation of a single diastereomer.
Recently, 1,4-dibenzoyloxylation of CHD was used to access cis-
1 on 150 kg scale as the first step in the synthesis of an anticancer
drug candidate (Scheme 1a).[11,12] The reaction, based on a
published method by Bäckvall and coworkers,[20] employs 2.2
equiv of benzoquinone (BQ), requiring the handling of nearly 500
kg of BQ in this process. BQ is toxic[21] and readily sublimes, even
at room temperature,[22] and the mixture of superstoichiometric
BQ and hydroquinone (HQ) byproducts formed in the reaction
complicate purification efforts and lower the product yield. These
challenges motivated efforts to develop improved reaction
conditions. The safety hazards and operational complexities
evident in this process highlight the need for a cis-selective
dibenzoyloxylation method capable of using catalytic quantities of
BQ, or ideally hydroquinone (HQ), as a cocatalyst.
BQ (2.2 equiv)
acetone
NHAc
tBu
CHD
OBz
N
O
rt, 24 h
150 kg
scale
HN
N
cis-1
75% solution yield
55% isolated yield
HN
N
N
(b) Recent trans-selective diacyloxylation protocol
OBz
Pd(OAc)2 (2.5 mol%)
DA1 (10 mol%), HQ (5 mol%)
H O
H
BzOH (2.2 equiv), LiOH (0.2 equiv)
tBuOOH (2.0 equiv)
3:1 iPrOH/acetone
rt, 16 h
DA1
OBz
trans-1
73% yield
93% trans
O
Dual-function Pd catalyst: substrate oxidation & HQ reoxidation
PdII
tBuOOH
HQ
BQ
CHD
+ 2 BzOH
PdII
k1
k2
tBuOH
+ H2O
trans-1
+ 2 H+
Pd0
[a] A. G. Stamoulis, and Prof. S. S. Stahl*
Department of Chemistry, University of Wisconsin-Madison, Madison,
WI 53706 (USA), E-mail: stahl@chem.wisc.edu
(c) Goal: Scalable, cis-selective diacyloxylation, catalytic hydroquinone
OBz
Low [Pd]
HQ (rather than BQ)
+
2 BzOH
cis-1
[b] P. Geng, Dr. M. A. Schmidt, Dr. M. D. Eastgate, Dr. A. Borovika, Dr. K.
J. Fraunhoffer
Chemical Process Development, Bristol-Myers Squibb, New Brunswick,
New Jersey 08903 (USA).
Scalable oxidant
Benign solvent
OBz
Scheme 1. Cis- and trans-selective diacyloxylation of 1,3-cyclohexadiene
(CHD), including a (a) process-scale application leading to a drug candidate,[12]
(b) trans-selective diacyloxylation using tBuOOH and catalytic benzoquinone
(BQ), with a dual-function Pd catalyst,[7] and (c) goals of the present work.
Supporting Information for this article is given via a link at the end of the
document.
1
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10.1002/anie.202108499
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COMMUNICATION
Reaction screening efforts were initiated with the previously
reported tBuOOH/catalytic BQ conditions, evaluating the effect of
various additives (base, DA1, etc.; see section 3 of the Supporting
Information for screening data). Replacing DA1/HQ (10 mol%
each; entry 1, Table 1) with 20 mol% BQ gives almost identical
yield and diastereoselectivity, favoring trans-1 (entry 2). Addition
of chloride to this mixture leads to higher cis-1 (entries 3 and 4),
accessing 72% cis with 10 mol% Bu4NCl. Bromide and iodide lead
to even higher cis selectivity (entries 5-8, also see Tables S3 and
S6 in the Supporting Information), and an optimal balance of yield
and cis selectivity is obtained with 5 mol% Bu4NBr (72% yield,
94% cis). Efforts to replace BQ with HQ were unsuccessful
(entries 9 and 10). These reactions exhibit catalyst decomposition
via Pd black formation and low product yields.
100
80
60
40
20
0
100
80
60
40
20
0
cis selectivity
rate(cis)
rate(trans)
0
1
2
3
4
5
6
Ratio Br:Pd
Table 1. Reaction screening data and effect of halide additives on yield and
diastereoselectivity
100
80
60
40
20
0
100
80
60
40
20
0
cis selectivity
rate(cis)
rate(trans)
Total
cis
Quinone/Alkene
(mol %)
Additive
(mol %)
Reaction[a]
product selectivity
(%)[b]
(%)[b]
DA1 (10 mol%)
+ HQ (10 mol%)
1
--
70
8
0
1
2
3
4
5
6
2
3
4
5
6
7
8
9
BQ (20 mol%)
BQ (20 mol%)
BQ (20 mol%)
BQ (20 mol%)
BQ (20 mol%)
BQ (20 mol%)
BQ (20 mol%)
HQ (20 mol%)
--
68
28
67
72
48
14
6
7
Ratio Cl:Pd
Bu4NCl (5 mol%)
Bu4NCl (10 mol%)
Bu4NBr (5 mol%)
Bu4NBr (10 mol%)
Bu4NI (5 mol%)
Bu4NI (10 mol%)
Bu4NBr (5 mol%)
56
72
94
98
99
99
95
Figure 1. Effect of bromide (a) and chloride (b) on the rate and
diastereoselectivity of the CHD diacetoxylation reaction. Conditions: [CHD] =
420 mM, [BzOH] = 1680 mM, [Pd(OAc)2] = 10.5 mM, [BQ] = 84 mM, [Et3N] =
315 mM, [tBuOOH] = 840 mM, [biphenyl] = 42 mM (internal standard). Reaction
aliquots analyzed by UPLC. The data in gray for chloride plot reflect reactions
with significant insoluble solids and they are not included in the empirical curve
fits (see Supporting Information for curve fitting equations).
3
probe the origin of this effect, 1,4-diacetoxylation of CHD was
analyzed by H NMR spectroscopy throughout the reaction time
DA1 (10 mol%)
+ HQ (10 mol%)
1
10
Bu4NBr (5 mol%)
5
98
[a]
course to track formation of the product cis-2 and quinone
speciation (Figure 2a and Figure S7). Cis-2 forms steadily
throughout the reaction, while the quinone speciation never
reaches steady state. BQ is slowly consumed during the first 18
h, together with the appearance of HQ and DA1. Formation of
DA1 is irreversible and consumes approximately 50% of the
original BQ, lowering the amount of BQ/HQ available to support
catalytic turnover (Figure S7). At late stages of the reaction, the
rate of HQ oxidation is competitive with BQ consumption, and a
small increase in [BQ] is evident.
The rate of HQ oxidation evident during catalysis is much
slower than expected from the previously reported study of
Pd(OAc)2-catalyzed oxidation of HQ by tBuOOH.[7] This behavior
was traced to the inhibitory effect of catalytic additives (Bu4NBr,
AcOH and/or TEA) on HQ oxidation. As shown in Figure 2b, HQ
undergoes efficient Pd(OAc)2-catalyzed oxidation to BQ in the
absence of these additives, as expected,[7] while each of the
individual additives slow or inhibit the reaction. When all three
additives are combined, slow HQ oxidation is observed together
with Pd catalyst decomposition (Pd black formation). Pd
decomposition under these conditions can arise from the
reversible reaction of PdII with HQ to form Pd0 (see ref. [38] and
dashed arrows in Figure 2c), followed by irreversible
[CHD] = 420 mM, [BzOH] = 1680 mM, [Pd(OAc)2] = 10.5 mM, [Et3N] = 315
mM, [tBuOOH] = 840 mM, [biphenyl] = 42 mM (internal standard). [b] Yield and
selectivity determined by UPLC. See Supporting Information for details.
The effect of halide:Pd ratio on initial rate and cis selectivity of
the diacyloxylation was investigated more thoroughly (Figure 1).
The halide loading was varied between 0–6 equiv relative to Pd
and the initial rate and cis selectivity were monitored by UPLC. A
1:1 Br:Pd ratio exhibits the highest rate for cis-1 formation, but
ratios between 2–3:1 Br:Pd show improved selectivity while
maintaining good rates (Figure 1a). Chloride does not inhibit
trans-1 formation as strongly as bromide, and, even at higher
Cl:Pd ratios, only moderate diastereoselectivity is observed
(Figure 1b). Iodide strongly inhibits formation of trans-1, allowing
for very high cis selectivity (99% cis), but it also inhibits the rate of
cis-1 formation (see Table 1 and Table S7). The relative impact of
the different halide ions correlates with the relative binding affinity
of the halides for PdII (I > Br > Cl),[33-36] and bromide provides the
best balance of rate, selectivity, and overall catalyst performance.
For large-scale applications, it would be ideal to use HQ as
the source of cocatalyst to avoid handling of large quantities of
BQ;[37] however, the data in Table 1 show that poor results are
obtained with HQ as the cocatalyst (entries 9–10). In order to
2
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10.1002/anie.202108499
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COMMUNICATION
decomposition of Pd0 into Pd black. Kinetically competent
oxidation of HQ is observed, however, if 1 equiv of BQ is included
in the reaction mixture, owing to improved Pd0 stability. Complete
conversion of HQ to BQ under these conditions is complete in 16
h, commensurate with the catalytic time course shown in Figure
2a (see section 7b of the Supporting Information for details).
and lead to low product yields unless BQ is included at the start
of the reaction. Nonetheless, the results in Figure 2b offer an
alternative strategy for use of HQ as the source of cocatalyst. The
process is initiated by combining the Pd(OAc)2 catalyst and
tBuOOH oxidant with HQ in the absence of other additives. These
conditions enable efficient oxidation of HQ to BQ. The other
reaction components (NBu4Br, NEt3, BzOH and CHD) may then
be added to this "pre-oxidation mixture" to achieve the desired
1,4-dibenzoyloxylation of CHD. Preliminary optimization of this
concept on small scale set the stage for demonstration on larger
scale (Figure 3). Minor changes identified as beneficial in this
effort include use of a slightly higher Br:Pd ratio (2.25:1) to
enhance the cis selectivity (deemed more important than rate or
total yield of mixed isomers) and use of a higher proportion of
acetone in the cosolvent mixture to ensure all components remain
soluble throughout the reaction. Implementation of the optimized
conditions led to a 75% in-process yield of cis-1, with 94% cis
selectivity, based on HPLC analysis of product mixture. Work-up
and crystallization of the reaction stream led to a significant
upgrade in the diastereomeric purity (>99.9% cis, based on HPLC
analysis) and delivered 137 g of the final product (67% yield).
300
cis-2
250
200
150
100
BQ
HQ
50
0
0
5
10
15
20
25
time (h)
in situ
pre-oxidation
HO
OH
O
HQ (20 mol%)
Pd(OAc)2 (2 mol%)
tBuOOH (2.0 equiv)
OBz
OBz
O
BzOH
(4 equiv)
cis-1
+
Bu4NBr (4.5 mol%)
Et3N (0.75 equiv)
1:2 iPrOH/acetone
rt, 49 h
366 mM
75% in-process yield, 94% cis
80
60
40
20
0
Max thoretical [BQ]
67% isolated yield (137 g)
>99.9% cis
Figure 3. Pre-oxidation concept that enables HQ to be used as the cocatalyst
(gray box), and demonstration of this sequential process to access 137 g of
product, with >99.9% cis selectivity, following isolation.
No additives
Bu4NBr
In summary, the results described herein introduce a new
catalyst system for cis-selective 1,4-diacyloxylation of 1,3-
cyclohexadiene, highlighting the efficacy of bromide to alter the
stereochemical course of the reaction. The PdII catalyst serves a
dual role, catalyzing both 1,4-diacyloxylation of CHD and
oxidation of HQ by tBuOOH. The ability of this catalyst to operate
in the presence of halides contrasts other cocatalyst systems,
such as Pd(OAc)2/BQ/Co(salophen)/O2, that are poisoned by
halides. This feature is crucial to achieve the desired cis
All additives
AcOH
TEA
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
time (h)
diastereoselectivity with
a process-friendly and sustainable
oxidant amenable to large-scale application. The insights from
these studies have important implications for development of
other industrially relevant Pd-catalyzed oxidation methods.
Figure 2. (a) Full reaction 1H NMR time course showing cis-2 formation and
quinone speciation. Conditions: [CHD] = 420 mM, [AcOH-d4] = 1680 mM,
[Pd(OAc)2] = 10.5 mM, [Bu4NBr] = 21 mM, [BQ] = 84 mM, [Et3N] = 315 mM,
[tBuOOH] = 840 mM, [methyl 3,5-dinitrobenzoate] = 21 mM (internal standard).
Reaction conducted inside an NMR spectrometer at 24 °C using a 3:1 mixture
of iPrOD-d8/acetone-d6 employing AcOD-d4 as the nucleophile to ensure
solubility throughout the entire 24-hour time course.39 (b) HQ oxidation studies
under catalytically relevant conditions. Conditions: [HQ] = 84 mM, [AcOH] =
1680 mM, [Pd(OAc)2] = 8.4 mM, [Bu4NBr] = 16.8 mM, [Et3N] = 315 mM,
[tBuOOH] = 840 mM, [methyl 3,5-dinitrobenzoate] = 8.4 mM (internal standard).
(c) Simplified mechanistic cycle showing trade-off between HQ oxidation and
product formation.
Acknowledgements
We would like to thank Dr. Antonio Ramirez and Dr. Michaël
Fenster for useful discussions. Financial support was provided by
Bristol Myers Squibb and by the NSF (CHE-1953926).
Spectroscopic instrumentation was supported by the NSF (CHE-
1048642), the NIH (R01GM100143 and R01GM127545) and a
generous gift from Paul J. and Margaret M. Bender.
The above observations rationalize the ineffectiveness of HQ
as a source of cocatalyst (cf. Table 1, entries 9 and 10): because
HQ oxidation is relatively slow, the Pd catalyst will decompose
3
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10.1002/anie.202108499
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COMMUNICATION
Keywords: homogeneous catalysis, palladium, oxidation,
Conflict of interest:
difunctionalization, synthetic methods.
The authors declare no conflict of interest.
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4
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Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Pd(OAc)2
HO OH
cocatalysts
/
Known
We report an efficient and scalable cis-
selective diacyloxylation protocol that
employs catalytic hydroquinone with
tBuOOH as a benign terminal oxidant.
A bromide additive was crucial to
obtaining good yields and excellent cis
selectivity. The study culminates in the
implementation of the optimized
reaction on large scale.
BzO
BzO
OBz
Alexios G. Stamoulis, Peng Geng,
Michael A. Schmidt, Martin D.
Eastgate, Alina Borovika, Kenneth J.
Fraunhoffer, and Shannon S. Stahl*
trans-1
Scalable oxidant
Benign solvent
OBz
cocatalytic
NBu4Br
cis-1
>130 g isolated
Page No. – Page No.
Dual-function Pd catalyst: substrate oxidation & HQ reoxidation
PdII
tBuOOH
HQ
CHD
Sustainable
+ 2 BzOH
Pd(OAc)2/Hydroquinone-Cocatalyst
System for Cis-Selective Dibenzoyl-
oxylation of 1,3-Cyclohexadiene
PdII
Br-
tBuOH
+ H2O
cis-1
Pd0
BQ
+ 2 H+
Institute and/or researcher Twitter usernames: @Stahl_Lab, @UWMadisonChem
5
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