Ligand-enabled pd(ii)-catalyzed c(sp3)-h lactonization using molecular oxygen as oxidant

Article abstract of DOI:10.1021/acs.orglett.0c01243

Pd(II)-catalyzed C-H lactonization of o-methyl benzoic acid substrates has been achieved using molecular oxygen as the oxidant. This finding provides a rare example of C-H oxygenation through Pd(II)/Pd(0) catalysis as well as a method to construct biologically important benzolactone scaffolds. The use of a gas mixture of 5% oxygen in nitrogen demonstrated the possibility for its application in pharmaceutical manufacturing.

Full text of DOI:10.1021/acs.orglett.0c01243

pubs.acs.org/OrgLett
Letter
Ligand-Enabled Pd(II)-Catalyzed C(sp3)−H Lactonization Using
Molecular Oxygen as Oxidant
Shaoqun Qian, Zi-Qi Li, Minyan Li, Steven R. Wisniewski, Jennifer X. Qiao, Jeremy M. Richter,
William R. Ewing, Martin D. Eastgate, Jason S. Chen, and Jin-Quan Yu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01243
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Pd(II)-catalyzed C−H lactonization of o-methyl benzoic
acid substrates has been achieved using molecular oxygen as the
oxidant. This finding provides a rare example of C−H oxygenation
through Pd(II)/Pd(0) catalysis as well as a method to construct
biologically important benzolactone scaffolds. The use of a gas mixture
of 5% oxygen in nitrogen demonstrated the possibility for its
application in pharmaceutical manufacturing.
enzolactones are prominent scaffolds in bioactive natural
Scheme 1. Palladium-Catalyzed C−H Functionalizations
toward the Synthesis of Benzolactones
B
products and important pharmaceutical compounds-
(Figure 1).1 Additionally, the lactone structural motif is a
Figure 1. Bioactive and natural benzolactone derivatives.
common synthetic intermediate and building block for the
synthesis of complex molecules.2 Traditionally, the benzolac-
tone skeleton is constructed through the cyclization of hydroxy
acids or the halolactonization processes.3 While these methods
are well established for the synthesis of such motifs, a direct
C−H lactonization would be highly attractive. A number of
studies toward C−H lactonization using the Shilov system
have been reported.4 In 2006, Chang reported a platinum(II)-
catalyzed lactonization of benzylic C−H bonds affording
benzolactones in the presence of 3 equiv of CuCl2 as the
oxidant. Synthetically useful yields can be obtained with a di-
ortho-methylated benzoic acid substrate (Scheme 1).4d In
2011, Martin developed a palladium-catalyzed C(sp3)−H
lactonization with o-methyl benzoic acid using MPAA ligand
and stoichiometric silver(I) as an oxidant.4e Substitution at the
5- or 6-position on the benzoic acid was required to block the
C(sp2)−H bond to prevent the facile ortho-C−H activation
accelerated by the MPAA ligand. In our search for an efficient
route for the preparation of a pharmaceutical ingredient
bearing the benzolactone motif, we began to develop new
ligands and conditions to achieve such C−H lactonization of
simple mono-o-methyl benzoic acids in which a ligand will
selectively accelerate the activation of the C(sp3)−H bond
over the C(sp2)−H bond. For potential scaling up to
kilograms, the use of expensive oxidant needs to be avoided.
To be compatible with safe operation in process, O2 at low
concentration, for example, 5% in N2, will be the ideal oxidant.
In the past decade, a wide range of palladium-catalyzed C−
H functionalization reactions have been realized.5 While both
Pd(II)/Pd(IV) and Pd(II)/Pd(0) redox catalysis have been
established for C−C coupling reactions, C−O and C−N
formations are largely limited to Pd(IV) catalysis using
chalcogenide-type oxidants or bystanding oxidants.6 For
example, TBHP, Ag(I), CuCl2, K2S2O8, BQ, and PIDA have
Received: April 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01243
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
been extensively adopted.6 From the practical viewpoint, it is
highly desirable to develop Pd(II)/Pd(0) catalysis using O2 as
the sole oxidant.7 However, achieving C−H oxygenation via
Pd(II)/Pd(0) catalysis is challenging due to the lack of a ligand
that can promote both C−H activation and C−O reductive
elimination from the Pd(II) center. Herein, we report the
development of Pd(II)-catalyzed C(sp3)−H lactonization
using molecular oxygen as the oxidant. The absence of
oxidants other than oxygen provides a rare example to further
investigate the mechanism of C−H oxygenation via Pd(II)/
Pd(0) catalysis.
laboratory.10 Unfortunately, no further improvement was
observed. Guided by our recent finding that 2-pyridone
ligands can accelerate C−H activation,11 we turned to
investigate this type of ligand. Encouragingly, the yield
increased to 34% with a simple 2-pyridone ligand (L8).
Based on our previous successes with electron-deficient 2-
pyridones,11 we set out to extensively screen 2-pyridone
ligands with electron-withdrawing substituents. To our delight,
the use of 5-chloro-2-pyridone (L9) increased the yield to
50%. Further tuning the substitution at the 5-position did not
enhance the reactivity (L10−L12). We next evaluated 2-
pyridone ligands bearing 3-substituents (L13−L17). Intrigu-
ingly, the yield increased to 58% when 3-trifluoromethyl-2-
pyridone (L14) was used. Installing another trifluoromethyl
group on L14 gave slightly lower yield (L18), and the use of 5-
nitro-3-trifluoromethyl-2-pyridone (L19) resulted in loss of
reactivity. These results indicated that this lactonization is
highly sensitive to the electronic and steric environments of the
2-pyridone ligands. With L14 as the top performing ligand, we
next investigated the effect of additives toward Pd(II)-
catalyzed C(sp3)−H lactonization. To our delight, the addition
of acetic anhydride was found to be beneficial to the reaction,
and the yield was further increased to 72%. The acetic
anhydride could act as a transient protecting group for benzoic
acid and prevent the decarboxylation of the starting material.
With the optimal conditions in hand, the scope of benzoic
acids was evaluated. As shown in Scheme 3, a wide range of
functional groups are well accommodated in this trans-
formation. Benzoic acids bearing electron-donating groups,
such as methyl (2a−2c, 2i, and 2n), methoxy (2l), and phenyl
(2f) gave the desired lactones in moderate to excellent yield.
Electron-deficient benzoic acids, such as fluoro (2e and 2j),
trifluoromethyl (2k), and ketone (2g), are also well tolerated.
Furthermore, our methodology can react with C(sp3)−H
bonds selectively over C(sp2)−H (2h−2r). More interestingly,
the selectivity is not determined by steric effects since benzoic
acids without 5-substitution (2m−2q) still gave the desired
product, while the previous method4e only tolerated 5-
substituted benzoic acids. Moreover, aryl halides (2d, 2h, 2o,
and 2q) were well tolerate in the reaction, which enabled
further transformations with classical cross-coupling reactions.
Besides benzoic acid derivatives, the desired lactone product
was formed with naphthenic acid, albeit with slightly lower
yield (2r). This result showed the potential of employing our
methodology with more complex aromatic ring system.
In order to gain experimental data in support of the
involvement of Pd(II)/Pd(0) redox catalysis, a control
experiment under nitrogen atmosphere was conducted and
4% yield of the desired product was observed (Scheme 4).
This result indicated that the reductive elimination still
occurred in the absence of any oxidant, hence suggesting
that the reaction is more likely to proceed through a Pd(II)/
Pd(0) catalytic cycle.
After considerable optimization, we were pleased to observe
that using Pd(PhCN)2Cl2, K2HPO4, and chlorobenzene as the
solvent in the presence of 1 atm oxygen provided the desired
product 2a in 10% yield (Scheme 2). To ensure safe use of
a,b
Scheme 2. Ligand Optimization
a
Reaction conditions: substrate 1a (0.1 mmol), Pd(PhCN)2Cl2 (10
mol %), ligand (30 mol %), K2HPO4 (2.5 equiv), PhCl (1.0 mL), 140
b
1
°C, 20 h. The yields were determined by H NMR analysis of the
crude product using 1,3,5-trimethoxybenzene as the internal standard.
1 atm of O2. Ac2O (2.0 equiv) was used.
c
d
oxygen in process, we attempted to replace pure oxygen with
the gas mixture of 5% oxygen in nitrogen which is below the
limiting oxygen concentration (LOC) of most organic solvent8
as the oxygen source. To our delight, the same result was
obtained with the gas mixture of 5% oxygen in nitrogen under
400 psi. We next evaluated several monodentate pyridine-
based ligands (L1, L2), which have been shown to promote
C−H activation.9 Interestingly, the yield was improved to 31%
by using the pyridine-based ligand (L2). Subsequently, we
tested Ac-Leu-OH (L3) which afforded a remarkable ligand
effect in previous Martin’s work.4e However, ligand L3 only
gave a poor yield of the desired product. We then turned our
attention to bidentate ligands (L4−L7) developed in our
To demonstrate the scalability of this protocol, a gram-scale
reaction was conducted under the standard lactonization
conditions affording desired lactone product 2a in 61% yield
(Scheme 5).
In conclusion, Pd(II)-catalyzed C(sp3)−H lactonizations of
a range of benzoic acids using molecular oxygen as the oxidant
have been developed with a broad functional group tolerance.
The reaction is conducted under a pressurized gas mixture of
5% oxygen in nitrogen (below the limiting oxygen concen-
tration for most organic solvents) which meets the safety
B
https://dx.doi.org/10.1021/acs.orglett.0c01243
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
Scheme 3. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01243.
Detailed experimental procedures and characterization
of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jin-Quan Yu − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-3560-5774; Email: yu200@
scripps.edu
Authors
Shaoqun Qian − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Zi-Qi Li − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Minyan Li − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States;
orcid.org/0000-0001-8120-6294
Steven R. Wisniewski − Chemical & Synthetic Development,
Bristol-Myers Squibb, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0001-6035-4394
Jennifer X. Qiao − Discovery Chemistry, Bristol-Myers Squibb,
Princeton, New Jersey 08543, United States
Jeremy M. Richter − Research & Development, Bristol-Myers
Squibb, Hopewell, New Jersey 08534, United States;
orcid.org/0000-0002-8313-7154
William R. Ewing − Discovery Chemistry, Bristol-Myers Squibb,
Princeton, New Jersey 08543, United States
Martin D. Eastgate − Chemical & Synthetic Development,
Bristol-Myers Squibb, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0002-6487-3121
Jason S. Chen − Automated Synthesis Facility, The Scripps
Research Institute, La Jolla, California 92037, United States
a
Reaction conditions: substrate 1a (0.2 mmol), Pd(PhCN)2Cl2 (10
mol %), L8 (30 mol %), K2HPO4 (2.5 equiv), Ac2O (2.0 equiv), PhCl
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01243
b
(2.0 mL), 140 °C, 20 h. Isolated yield.
Notes
Scheme 4. Control Experiment with N2
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the NSF under the CCI Center for
Selective C−H Functionalization (CCHE-1700982), The
Scripps Research Institute, and Bristol-Myers Squibb for
financial support. We gratefully acknowledge the NIH
grant(1S10OD025208) for the robotic pressure system. We
thank Ms. Brittany Sanchez, and Ms. Emily Sturgell (Scripps
Automated Synthesis Facility) for assistance with HRMS
analysis.
Scheme 5. Gram-Scale Reaction
REFERENCES
■
(1) (a) Khawaled, R.; Bruening-Wright, A.; Adelman, J. P.; Maylie, J.
Bicuculline Block of Small-Conductance Calcium-Activated Potas-
sium Channels. Pfluegers Arch. 1999, 438, 314−321. (b) Yang, X.-L.;
Zhang, S.; Hu, Q.-B.; Luo, D.-Q.; Zhang, Y. Phthalide Derivatives
with Antifungal Activities against the Plant Pathogens Isolated from
the Liquid Culture of Pestalotiopsis Photiniae. J. Antibiot. 2011, 64,
723−727. (c) Zhao, J.; Feng, J.; Tan, Z.; Liu, J.; Zhao, J.; Chen, R.;
requirement in process chemistry. This rare example of
catalytic C−H oxygenation reaction via Pd(II)/Pd(0) catalysis
using O2 as the sole oxidant also provides a valuable example
for probing the mechanism of the C−O reductive elimination
from a Pd(II) center in C−H activation reactions.
C
https://dx.doi.org/10.1021/acs.orglett.0c01243
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Xie, K.; Zhang, D.; Li, Y.; Yu, L.; Chen, X.; Dai, J. Stachybotrysins A−
G, Phenylspirodrimane Derivatives from the Fungus Stachybotrys
Chartarum. J. Nat. Prod. 2017, 80, 1819−1826. (d) Masiulis, S.;
Using Environmentally Benign Oxidants, O2 and H2O2. Acc. Chem.
Res. 2012, 45, 803−813.
(8) Osterberg, P. M.; Niemeier, J. K.; Welch, C. J.; Hawkins, J. M.;
Martinelli, J. R.; Johnson, T. E.; Root, T. W.; Stahl, S. S. Experimental
Limiting Oxygen Concentrations for Nine Organic Solvents at
Temperatures and Pressures Relevant to Aerobic Oxidations in the
Pharmaceutical Industry. Org. Process Res. Dev. 2015, 19, 1537−1543.
(9) For selected examples of pyridine-based ligand promoted C−H
activation, see: (a) Wasa, M.; Chan, K. S. L.; Zhang, X.-G.; He, J.;
Miura, M.; Yu, J.-Q. Ligand-Enabled Methylene C(sp3)−H Bond
Activation with a Pd(II) Catalyst. J. Am. Chem. Soc. 2012, 134,
18570−18572. (b) Li, S.; Zhu, R.-Y.; Xiao, K.-J.; Yu, J.-Q. Ligand-
Enabled Arylation of γ-C−H Bonds. Angew. Chem., Int. Ed. 2016, 55,
4317−4321.
́
Desai, R.; Uchanski, T.; Martin, I. S.; Laverty, D.; Karia, D.;
Malinauskas, T.; Zivanov, J.; Pardon, E.; Kotecha, A.; Steyaert, J.;
Miller, K. W.; Aricescu, A. R. GABAA Receptor Signalling
Mechanisms Revealed by Structural Pharmacology. Nature 2019,
565, 454−459.
(2) (a) Faul, M. M.; Huff, B. E. Strategy and Methodology
Development for the Total Synthesis of Polyether Ionophore
Antibiotics †. Chem. Rev. 2000, 100, 2407−2474. (b) Kang, E. J.;
Lee, E. Total Synthesis of Oxacyclic Macrodiolide Natural Products.
Chem. Rev. 2005, 105, 4348−4378.
(3) Yudin, A. K. Catalyzed Carbon-Heteroatom Bond Formation;
Wiley-VCH: Weinheim, 2011.
(10) For selected examples of bidentate ligand promoted C−H
̈
activation, see: (a) Chen, G.; Gong, W.; Zhuang, Z.; Andra, M. S.;
(4) (a) Kao, L.-C.; Sen, A. Platinum(II) Catalysed Selective Remote
Oxidation of Unactivated C−H Bonds in Aliphatic Carboxylic Acids.
J. Chem. Soc., Chem. Commun. 1991, 1242−1243. (b) Shilov, A. E.;
Shul’pin, G. B. Activation of C−H Bonds by Metal Complexes. Chem.
Rev. 1997, 97, 2879−2932. (c) Dangel, B. D.; Johnson, J. A.; Sames,
D. Selective Functionalization of Amino Acids in Water: A Synthetic
Method via Catalytic C−H Bond Activation. J. Am. Chem. Soc. 2001,
123, 8149−8150. (d) Lee, J. M.; Chang, S. Pt-Catalyzed sp3 C−H
Bond Activation of o-Alkyl Substituted Aromatic Carboxylic Acid
Derivatives for the Formation of Aryl Lactones. Tetrahedron Lett.
Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q.
Ligand-Accelerated Enantioselective Methylene C(sp3)−H Bond
Activation. Science 2016, 353, 1023−1027. (b) Wu, Q.-F.; Shen, P.-
X.; He, J.; Wang, X.-B.; Zhang, F.; Shao, Q.; Zhu, R.-Y.; Mapelli, C.;
Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Formation of A-Chiral Centers by
Asymmetric beta-C(sp3)−H Arylation, Alkenylation, and Alkynyla-
tion. Science 2017, 355, 499. (c) Shen, P.-X.; Hu, L.; Shao, Q.; Hong,
K.; Yu, J.-Q. Pd(II)-Catalyzed Enantioselective C(sp3)−H Arylation
of Free Carboxylic Acids. J. Am. Chem. Soc. 2018, 140, 6545−6549.
(d) Zhuang, Z.; Yu, C.-B.; Chen, G.; Wu, Q.-F.; Hsiao, Y.; Joe, C. L.;
Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Ligand-Enabled β-C(sp3)−H
Olefination of Free Carboxylic Acids. J. Am. Chem. Soc. 2018, 140,
10363−10367. (e) Hu, L.; Shen, P.-X.; Shao, Q.; Hong, K.; Qiao, J.
X.; Yu, J.-Q. PdII-Catalyzed Enantioselective C(sp3)−H Activation/
Cross-Coupling Reactions of Free Carboxylic Acids. Angew. Chem.,
Int. Ed. 2019, 58, 2134−2138.
́
2006, 47, 1375−1379. (e) Novak, P.; Correa, A.; Gallardo-Donaire,
J.; Martin, R. Synergistic Palladium-Catalyzed C(sp3)−H Activation/
C(sp3)-O Bond Formation: A Direct, Step-Economical Route to
Benzolactones. Angew. Chem., Int. Ed. 2011, 50, 12236−12239.
(5) For book Chapters on C−H functionalization, see: (a) Negishi,
E. Handbook of Organopalladium Chemistry for Organic Synthesis; John
Wiley and Sons: Hoboken, NJ, 2002. (b) van Leeuwen, P. W. N. M.
Homogeneous Catalysis: Understanding the Art; Kluwer Academic
Publishers: Dordrecht, 2004. For selected reviews on C−H
functionalization, see: (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Pd(II)-Catalyzed C−H Activation/C−C Cross-Coupling
Reactions: Versatility and Practicality. Angew. Chem., Int. Ed. 2009,
48, 5094−5115. (d) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q.
Weak Coordination as Powerful Means for Developing Broadly
Useful C−H Functionalization Reactions Acc. Acc. Chem. Res. 2012,
45, 788−802. (e) Engle, K. M.; Yu, J.-Q. Developing Ligands for
Palladium(II)-Catalyzed C−H Functionalization: Intimate Dialogue
between Ligand and Substrate. J. Org. Chem. 2013, 78, 8927−8955.
(f) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-
Catalyzed Transformations of Alkyl C−H Bonds. Chem. Rev. 2017,
(11) For selected examples of 2-pyridone ligand promoted C−H
activation, see: (a) Wang, P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.;
Shen, P.-X.; Yu, J.-Q. Ligand-Promoted Meta -C−H Amination and
Alkynylation. J. Am. Chem. Soc. 2016, 138, 14092−14099. (b) Wang,
P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.-X.; Yu, J.-Q.
Ligand-Promoted Meta -C−H Amination and Alkynylation. J. Am.
Chem. Soc. 2016, 138, 14092−14099. (c) Wang, P.; Farmer, M. E.;
Yu, J.-Q. Ligand-Promoted Meta -C−H Functionalization of Benzyl-
amines. Angew. Chem., Int. Ed. 2017, 56, 5125−5129. (d) Li, G.-C.;
Wang, P.; Farmer, M. E.; Yu, J.-Q. Ligand-Enabled Auxiliary-Free
Meta -C−H Arylation of Phenylacetic Acids. Angew. Chem., Int. Ed.
2017, 56, 6874−6877. (e) Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao,
J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-
S.; Yu, J.-Q. Ligand-Accelerated Non-Directed C−H Functionaliza-
tion of Arenes. Nature 2017, 551, 489−493. (f) Zhu, R.-Y.; Li, Z.-Q.;
Park, H. S.; Senanayake, C. H.; Yu, J.-Q. Ligand-Enabled γ-C(sp3)−H
Activation of Ketones. J. Am. Chem. Soc. 2018, 140, 3564−3568.
(g) Farmer, M. E.; Wang, P.; Shi, H.; Yu, J.-Q. Palladium-Catalyzed
Meta -C−H Functionalization of Masked Aromatic Aldehydes. ACS
Catal. 2018, 8, 7362−7367. (h) Chen, Y.-Q.; Wang, Z.; Wu, Y.;
Wisniewski, S. R.; Qiao, J. X.; Ewing, W. R.; Eastgate, M. D.; Yu, J.-Q.
Overcoming the Limitations of γ- and δ-C−H Arylation of Amines
through Ligand Development. J. Am. Chem. Soc. 2018, 140, 17884−
17894.
̈
117, 8754−8786. (g) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-
Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.;
Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A
̈
Comprehensive Overview of Directing Groups Applied in Metal-
Catalysed C−H Functionalisation Chemistry. Chem. Soc. Rev. 2018,
47, 6603−6743.
(6) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. A Highly Selective
Catalytic Method for the Oxidative Functionalization of C−H Bonds.
J. Am. Chem. Soc. 2004, 126, 2300−2301. (b) Tsang, W. C. P.; Zheng,
N.; Buchwald, S. L. Combined C−H Functionalization/C−N Bond
Formation Route to Carbazoles. J. Am. Chem. Soc. 2005, 127, 14560−
14561. (c) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. Pd(II)-Catalyzed
Hydroxyl-Directed C−H Activation/C−O Cyclization: Expedient
Construction of Dihydrobenzofurans. J. Am. Chem. Soc. 2010, 132,
12203−12205. (d) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q.
Bystanding F+ Oxidants Enable Selective Reductive Elimination from
High-valent Metal Centers in Catalysis. Angew. Chem., Int. Ed. 2011,
50, 1478−1491.
(7) (a) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Green,
Catalytic Oxidation of Alcohols in Water. Science 2000, 287, 1636−
1639. (b) Stahl, S. S. Palladium-catalyzed Oxidation of Organic
Chemicals with O2. Science 2005, 309, 1824−1826. (c) Vedernikov,
A. N. Direct Functionalization of M−C (M = Pt II, Pd II) Bonds
D
https://dx.doi.org/10.1021/acs.orglett.0c01243
Org. Lett. XXXX, XXX, XXX−XXX