Are phosphines viable ligands for Pd-Catalyzed aerobic oxidation reactions? Contrasting insights from a survey of six reactions

Article abstract of DOI:10.1021/acscatal.8b01009

Phosphines are the broadest and most important class of ligands in homogeneous catalysis, but they are typically avoided in Pd-catalyzed aerobic oxidation reactions because of their susceptibility to oxidative degradation. Recent empirical reaction-development efforts have led to a growing number of Pd/phosphine catalyst systems for aerobic oxidative coupling reactions, but few of these studies have assessed the fate of the phosphine ligand. Here, we assess six different oxidative coupling reactions, including the homocoupling of boronic acids, amino- and alkoxycarbonylation reactions, intramolecular C-H annulation, and enantioselective Fujiwara-Moritani C-C coupling. The fate and role of the phosphine, analyzed by ³¹P NMR spectroscopy throughout the reaction time course in each case, varies in different reactions. In one case, the phosphine has an inhibitory effect and leads to lower selectivity relative to ligand-free conditions. In other cases, the phosphine ligands have a beneficial effect on the reaction but undergo oxidative decomposition in parallel with productive catalytic turnover. Inclusion of MnO₂ in one of the reactions slows phosphine oxidation by catalyzing disproportionation of H₂O₂ and thereby supports productive catalytic turnover. Negligible oxidation of the chiral phosphine (S,S)-chiraphos is observed during the enantioselective C-C coupling reaction, due to strong chelation of the ligand to Pd^II. The results of this study suggest that phosphines warrant broader attention as ligands for Pd-catalyzed aerobic oxidation reactions, particularly by implementing strategies identified for ligand stabilization.

Full text of DOI:10.1021/acscatal.8b01009

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Are Phosphines Viable Ligands for Pd-Catalyzed Aerobic Oxidation
Reactions? Contrasting Insights from a Survey of Six Reactions
Stephen J. Tereniak, Clark R. Landis, and Shannon S. Stahl
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01009 • Publication Date (Web): 21 Mar 2018
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Are Phosphines Viable Ligands for Pd-Catalyzed
Aerobic Oxidation Reactions? Contrasting Insights
from a Survey of Six Reactions
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Stephen J. Tereniak, Clark R. Landis, and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin - Madison, 1101 University Ave, Madison,
Wisconsin, 53706, United States
Abstract
Phosphines are the broadest and most important class of ligands in homogeneous catalysis, but
they are typically avoided in Pd-catalyzed aerobic oxidation reactions because of their
susceptibility to oxidative degradation. Recent empirical reaction-development efforts have led to
a growing number of Pd/phosphine catalyst systems for aerobic oxidative coupling reactions, but
few of these studies assess the fate of the phosphine ligand. Here, we assess six different oxidative
coupling reactions including the homocoupling of boronic acids, amino- and alkoxycarbonylation
reactions, intramolecular C–H annulation, and enantioselective Fujiwara-Moritani C–C coupling.
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The fate and role of the phosphine, analyzed by P NMR spectroscopy throughout the reaction
time course in each case, varies in the different reactions. In one case, the phosphine has an
inhibitory effect and leads to lower selectivity relative to ligand-free conditions. In other cases, the
phosphine ligands have a beneficial effect on the reaction, but undergo oxidative decomposition
in parallel with productive catalytic turnover. Inclusion of MnO2 in one of the reactions slows
phosphine oxidation by catalyzing disproportionation of H2O2 and thereby supports productive
catalytic turnover. Negligible oxidation of the chiral phosphine, (S,S)-chiraphos, is observed
during the enantioselective C–C coupling reaction, due to strong chelation of the ligand to PdII.
The results of this study suggest that phosphines warrant broader attention as ligands for Pd-
catalyzed aerobic oxidation reactions, particularly by implementing strategies identified for ligand
stabilization.
Keywords: palladium, aerobic, oxidation, catalysis, phosphine, ligand, carbonylation,
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Introduction
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Ligand-supported Pd catalysts have been the focus of growing attention for selective aerobic
oxidation of organic molecules, with applications including alcohol oxidation, Wacker-type intra-
and intermolecular functionalization of alkenes, and C–H oxidations.1 Most of the reactions follow
a general catalytic mechanism that consists of two redox half-reactions consisting of PdII-mediated
oxidation of the organic substrate (SubH2) followed by aerobic oxidation of the reduced Pd0
catalyst (Figure 1). Ancillary ligands have been shown to play important roles in these reactions
ranging from controlling chemo-, regio- and stereoselectivity to stabilization of Pd0 and promoting
its reoxidation by O2. The majority of these ligands consist of nitrogen donors, including pyridine
and bipyridine derivatives and alkylamines (e.g., NEt3, sparteine), and dimethyl sulfoxide,
thioethers and N-heterocyclic carbenes (NHCs) have also been used.1d These ligands exhibit
(meta)stability under the oxidative reaction conditions and, therefore, are well suited to support
the Pd-based catalysts.
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LnPdIIX2
SubH2
H2O
Subox
+ 2 HX
1/2 O2
+ 2 HX
LnPd0
Figure 1. Simplified mechanism for ligand-supported Pd catalyzed aerobic oxidation reactions.
Phosphines have found widespread use as ancillary ligands in other classes of Pd-catalyzed
reactions, 2 but they are typically avoided in the present oxidation reactions owing to their
susceptibility to formation of phosphine oxides under aerobic conditions. In the 1960s, two groups
reported that Pd(PPh3)4 reacts with O2 to afford the !2-peroxopalladium(II) complex,
(Ph3P)2Pd(O2), and further showed that Pd(PPh3)4 catalyzes efficient aerobic oxidation of
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triphenylphosphine to triphenylphosphine oxide (eq 1),3,4 and similar reactivity has been reported
with Pd(OAc)2 as the catalyst.5 Nevertheless, several aerobic Pd catalytic reactions have been
reported with phosphine-based ligands.6 The fate of the phosphine under the catalytic conditions
has seldom been probed,6j however, raising questions about not only the fate but also the potential
role of this ligand. Answers to these questions have important implications for the field of Pd-
catalyzed aerobic oxidation chemistry because phosphines represent a very broad and versatile
class of ligands that are seldom used to support these reactions.
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cat. Pd(PPh3)4
Ph3P=O
(1)
Ph3P + 1/2 O2
! 500 TON
In the present study, we examine six previously reported examples of Pd-catalyzed aerobic
oxidation reactions that employ phosphine ligands. These reactions include two examples of
oxidative homocoupling of boronic acid derivatives (Figure 2A),6b,e alkoxycarbonylation of an
alkyne C–H bond and aminocarbonylation of an arylboronic acid (Figure 2B),6c,q aromatic C–S
bond formation via intramolecular C–H functionalization (Figure 2C),6f and an asymmetric
oxidative C–C coupling reaction (Figure 2D).6d In each case, the fate of the phosphine has been
analyzed throughout the reaction by 31P NMR spectroscopy. Phosphine oxidation is found to occur
in some, but not all, of these reactions. In one case, the phosphine is detrimental to the reaction
outcome, with better performance achieved in the absence of an ancillary ligand. The diverse roles
and fates of the phosphine ligand in this set of representative reactions shows that phosphine
ligands warrant further consideration in Pd-catalyzed aerobic oxidation reactions, even though the
oxidative sensitivity of this ligand class remains an important consideration.
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cat. Pd/L1 or L2
A.
Ar–Ar
2 Ar–B(OR)2
O2
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8
O
cat. Pd/L1
R–M/H + CO + H–Nu
M = B(OH)2
B.
C.
D.
O2
R
Nu
H
S
N
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cat. Pd/L1
O2
S
NR2
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N
H
NR2
CO2Me
CO2Me
cat. Pd/L3
Ar–B(OR)2 +
Ar
*
O2
PPh2
PPh3
Ph2P
PPh2
Ph2P
L1
L2
L3
Figure 2. The reaction classes investigated in this study: (A) homocoupling of arylboronic acids
or esters, (B) oxidative alkoxy- and aminocarbonylation, (C) oxidative annulation of an aromatic
C–H bond, and (D) asymmetric Fujiwara-Moritani (oxidative Heck) coupling.
Results and Discussion
The first reactions investigated consisted of aerobic oxidative homocoupling of arylboronic
acid derivatives that afford symmetrical biaryls. Many reactions of this type have been reported,7
and, in 2006, Amatore and Jutand presented a mechanistic study of Pd-catalyzed homocoupling of
three different 4-X-phenylboronic acids (X = MeO, H, CN) to the corresponding biphenyls.6e This
study revealed the involvement of (Ph3P)2Pd(O2) in transmetalation of the aryl group from boron
to Pd, and this peroxo species was shown to be an effective precatalyst. The fate of PPh3 under the
catalytic reaction conditions was not reported, however. In order to probe this issue, the
homocoupling of 4-methoxyphenylboronic acid 1 to 4,4’-dimethoxybiphenyl 2 was analyzed by
1H and 31P NMR spectroscopy (Figure 3). The reaction proceeds with nearly complete conversion
of 1 within 2 h, affording 2 and 4-methoxyphenol 3 in a net yield of 86% (65% and 21% yields,
respectively). Partial phosphine oxidation occurs in parallel with the productive reaction, with 24%
conversion of the initial PPh3 (1.2 mol% with respect to substrate) to the phosphine oxide at the
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employed (Ph3P)2Pd(O2) as a well-defined Pd catalyst precursor, and reaction 6 is excluded
because asymmetric catalysis is not possible without the ancillary ligand.
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The extent of phosphine oxidation shows more diverse behavior among the reactions.
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Reactions 1–3 show only partial oxidation of the phosphine ligand during the reaction, and P
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NMR spectroscopic data from these reactions show that the unoxidized phosphines are coordinated
to Pd. Moreover, in each of these cases, phosphine oxidation no longer occurs when the reaction
is complete. Although multiple pathways are available for oxidation of phosphines in the presence
of Pd,3,5,17 these data suggest that reactive intermediates generated during catalyst turnover are
responsible for ligand oxidation. Probable intermediates consist of peroxide species generated
during two-electron oxidation of Pd0 by O2, such as Pd(O2), Pd-OOH, H2O2, and X2BOOH
species.18 Reactions 4 and 5 resemble reactions 1 and 3 in that phosphine oxidation proceeds in
parallel with active catalytic turnover, but they differ in that phosphine ligand oxidation is nearly
complete by the end of the reaction. Reaction 6 is unique and noteworthy among the reactions
investigated here, as virtually no oxidation of the chelating chiral phosphine ligand is observed.
Once again, the 31P NMR spectroscopic data show that the ligand present is entirely coordinated
to Pd. This observation, together with the complementary observations from reactions 1–3,
suggests that restriction of ligand lability, e.g., via chelation, represents a strategy to enhance
phosphine stability under the reaction conditions. Reaction 2 also features a diphosphine, but dppp
forms a less stable chelate than chiraphos. A similar concept underlies the successful use of NHC
ligands in Pd-catalyzed aerobic oxidation reactions, as free NHCs undergo rapid oxidation to the
corresponding ureas in the presence of O2.19
Pd-catalyzed aerobic oxidative carbonylation reactions commonly employ phosphine
ligands.6c,g-i,l-m,o,q-r The two reactions of this type in the present study (reactions 3 and 4) show a
clear beneficial effect of the phosphine ligand (e.g., Figure 10), even though phosphine oxidation
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occurs during the reaction. CO is a good reductant for PdII (e.g., forming CO2 in the presence of
water),11a,b,20 and it can nucleate the formation of reduced Pd clusters,21 ultimately generating Pd
black.22 The relatively "hard" nitrogen donor ligands commonly used in other classes of Pd-
catalyzed aerobic oxidation reactions are probably less effective in stabilizing Pd0 or competing
with CO to prevent aggregation of Pd, thereby accounting for the prevalent use of phosphines in
these reactions.23,24
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A final highlight from this study concerns the beneficial effect of MnO2 in the Pd(PPh3)4-
catalyzed intramolecular C–H functionalization reaction (reaction 5). Sigman and coworkers had
previously reported the use of MnO2 as an additive in the coupling of organostannanes and styrene
under aerobic conditions with Pd[(–)-sparteine)]Cl2 as the catalyst.25 The reaction was conducted
in the presence of a 16-fold excess of sparteine relative to the Pd catalyst, and MnO2 was proposed
to catalyze H2O2 disproportionation12 and to slow the rate of background oxidation of sparteine.
This concept has been rarely used in Pd-catalyzed aerobic oxidation reactions, but the observations
of Batey and coworkers and the associated data in Figure 8 suggest that this approach could be a
particularly valuable tactic to mitigate oxidative decomposition of phosphines in such reactions.
Conclusion
Phosphine ligands have been evaluated empirically in a wide range of Pd-catalyzed aerobic
oxidation reactions, but the present study provides the first broader assessment of the viability of
these ligands. The data show that the role and fate of the phosphine ligands varies for different
reactions. In most cases, however, the phosphine exhibited a beneficial effect on the reactions. Of
the six reactions investigated here, all but one were more effective in the presence of the phosphine
ligand. On the other hand, oxidation of phosphine ligand was found to proceed in parallel with the
desired catalytic reaction in five of the six reactions. This metastablity will be especially important
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to consider in larger scale applications when lower catalyst loadings and higher turnover numbers
are needed. The asymmetric C–C coupling reaction with (S,S)-chiraphos as an ancillary ligand is
noteworthy because virtually no phosphine oxidation was observed during the reaction. This result
shows that strong coordination/chelation of the phosphine ligand can slow or eliminate ligand
decomposition. This strong-coordination strategy and broader use of MnO2 as an additive represent
two important opportunities to expand the utility of phosphine ligands in Pd-catalyzed aerobic
oxidation reactions. In light of the widespread availability of phosphine ligands, including
enantioselective variants, these insights have important implications for future developments in
this field.
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Qualitative insights of the type described here are relatively straightforward to acquire, and
they provide valuable insights into the fate and role of the phosphine ligands. The field would
benefit significantly if at least this minimal level of analysis is included in future reports of Pd-
catalyzed aerobic oxidation reactions that employ phosphine ligands.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI:
Experimental details for syntheses of compounds, data acquisition, and spectroscopic data,
including Figures S1-S32, are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* stahl@chem.wisc.edu
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We are grateful for financial support from the NIH through an NRSA fellowship for SJT (F32
GM119214). Additional support for this project was provided by the NSF through the CCI Center
for Selective C–H Functionalization (CHE-1205646 and CHE-1700982). The WiHP-NMRR is
supported by the Dow Chemical Company. We acknowledge the NSF (CHE-9709065) and the
Paul and Margaret Bender Fund for support of the NMR facility.
References
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Gligorich, K. M.; Sigman, M. S. Recent Advancements and Challenges of PalladiumII-
Catalyzed Oxidation Reactions with Molecular Oxygen as the Sole Oxidant. Chem. Commun.
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Strategies to Use O2 as the Oxidant in Organometallic C–H Oxidation Reactions Catalyzed by
Pd (and Cu). Acc. Chem. Res. 2012, 45, 851-863. (d) Wang, D.; Weinstein, A. B.; White, P.
B.; Stahl, S. S. Ligand-Promoted Palladium-Catalyzed Aerobic Oxidation Reactions. Chem.
Rev. 2018, 118, 2636-2679.
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Palladium-Catalyzed Amination. Angew. Chem., Int. Ed. 2008, 47, 6338-6361. (b)
Fleckenstein, C. F.; Plenio, H. Sterically Demanding Trialkylphosphines for Palladium-
Catalyzed Cross Coupling Reactions—Alternatives to PtBu3. Chem. Soc. Rev. 2010, 39, 694-
711. (c) Gildner, P. G.; Colacot, T. J. Reactions of the 21st Century: Two Decades of
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8. See Figure S2 in the Supporting Information for details.
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10. See Section IIIF in the Supporting Information for analysis of 31P NMR spectroscopic data.
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on MnO2—III. The Kinetics and the Mechanism for the Catalytic Decomposition of H2O2 over
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Cinnamate.” J. Chem. Soc., Dalton Trans. 2001, 690-698. (c) Marson, A.; van Oort, A. B.;
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Ligand and Solvent Effects in the Alternating Copolymerization of Carbon Monoxide and
Olefins by Palladium–Diphosphine Catalysis. Organometallics 2002, 21, 16-33. (e)
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16. See Sections IIIK, IV, and V in the Supporting Information for details.
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