Aryl Radical Activation of C-O Bonds: Copper-Catalyzed Deoxygenative Difluoromethylation of Alcohols

Article abstract of DOI:10.1021/jacs.1c04254

Given their ubiquity in natural products and pharmaceuticals, alcohols represent one of the most attractive starting materials for the construction of C-C bonds. We report herein the first catalytic strategy to harness the reactivity of aryl radicals for the activation of C-O bonds in alcohol-derived xanthate esters, allowing for the discovery of the first catalytic deoxygenative difluoromethylation reaction. Under copper-catalyzed conditions, a wide variety of alkyl xanthate esters, readily synthesized from alcohol feedstocks, were activated by catalytically generated aryl radicals and were converted to the alkyl-difluoromethane products via alkyl radical intermediates. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage modification of complex pharmaceutical agents. A one-pot protocol has been developed that allows for the direct use of free alcohols without purification of the xanthate esters. Mechanistic studies are consistent with the hypothesis of aryl radicals being formed and initiating the cleavage of the C-O bonds of xanthate esters, to generate alkyl radicals as the key intermediates. This aryl radical activation approach represents a new strategy for the activation of alcohols as cross-coupling partners.

Full text of DOI:10.1021/jacs.1c04254

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Aryl Radical Activation of C−O Bonds: Copper-Catalyzed
Deoxygenative Difluoromethylation of Alcohols
Aijie Cai,$ Wenhao Yan,$ and Wei Liu*
Cite This: J. Am. Chem. Soc. 2021, 143, 9952−9960
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ABSTRACT: Given their ubiquity in natural products and
pharmaceuticals, alcohols represent one of the most attractive
starting materials for the construction of C−C bonds. We report
herein the first catalytic strategy to harness the reactivity of aryl
radicals for the activation of C−O bonds in alcohol-derived
xanthate esters, allowing for the discovery of the first catalytic
deoxygenative difluoromethylation reaction. Under copper-cata-
lyzed conditions, a wide variety of alkyl xanthate esters, readily
synthesized from alcohol feedstocks, were activated by catalytically
generated aryl radicals and were converted to the alkyl-difluoro-
methane products via alkyl radical intermediates. This scalable protocol exhibits a broad substrate scope and functional group
tolerance, enabling late-stage modification of complex pharmaceutical agents. A one-pot protocol has been developed that allows for
the direct use of free alcohols without purification of the xanthate esters. Mechanistic studies are consistent with the hypothesis of
aryl radicals being formed and initiating the cleavage of the C−O bonds of xanthate esters, to generate alkyl radicals as the key
intermediates. This aryl radical activation approach represents a new strategy for the activation of alcohols as cross-coupling partners.
Alkyl xanthate esters, which are bench-stable and can be
readily prepared from the corresponding alcohols, have been
widely used in Barton-McCombie deoxygenation reactions.9
Despite the well-known formation of alkyl radicals as key
intermediates in these reactions, to date, there were very few
examples that could engage xanthate esters in cross-couplings.
Molander has nicely shown that O-benzyl xanthates could be
activated by photogenerated sec-butyl radicals and readily
participated in Ni-catalyzed coupling reactions.10 Very
recently, the Rousseaux group reported that nickel alone
could also catalyze the cross-couplings of finely tuned
carbamothioates with aryl halides.11 These two neat methods
allowed for the construction of Csp3−Csp2 bonds using
alcohol-derived xanthate analogues although only derivatives of
primary benzylic alcohols or tertiary 1-phenylcyclopropanols
were amenable with the reaction conditions. In addition,
Altman12 and Cook13 have shown that in the presence of
superstoichiometric amounts of copper(0) or copper(III)
complexes, respectively, xanthate esters could be efficiently
converted to alkyl-trifluoromethanes. These elegant ap-
proaches could provide easy access to trifluoromethylated
INTRODUCTION
■
The development of transition metal-catalyzed cross-coupling
reactions for the construction of C−C bonds continues to be a
central topic in the field of synthetic organic chemistry.1 In this
area, the identification of stable, easily handled, yet reactive
alkyl electrophiles as well as novel activation modes that can
engage new coupling partners in these reactions remains an
important goal. Recent years have witnessed continuous efforts
devoted to the use of alcohols and their derivatives as coupling
partners,2 largely owing to the fact that alcohols are among the
most naturally abundant organic compounds and are
ubiquitous in bioactive molecules. In particular, the activation
of alcohol-based C−O bonds for the construction of C−C
bonds via the formation of alkyl radical intermediates offers a
promising yet challenging opportunity for the diversification of
alcohol feedstocks. For instance, pioneering work by Over-
man,3 MacMillan,4 Gong,5 and Shu6 has shown that alkyl
oxalates, readily synthesized from alcohols, could be engaged
as radical fragments in Ni catalysis or metallophotoredox
catalysis. Li et al. have reported an electrochemically enabled,
nickel-catalyzed protocol that can directly use free alcohols in
the coupling reactions with aryl bromides.7 The Diao group
has very recently discovered that a dihydropyridine-derived
auxiliary could activate the anomeric C−O bonds of
carbohydrates for the synthesis of aryl glycosides via the
formation of glycosyl radical intermediates.8 In spite of these
breakthroughs, the discovery of new activation modes that can
engage easily accessed alcohol derivatives in C−C bond-
forming coupling reactions remains highly desirable.
Received: April 23, 2021
Published: June 28, 2021
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© 2021 American Chemical Society
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Figure 1. A new aryl radical activation/copper capture mechanism could engage alkyl xanthate esters in transition metal-catalyzed cross-coupling
reactions and allow for the development of a copper-catalyzed deoxygenative difluoromethylation reaction for the rapid synthesis of bioisosteres of
alcohols. TM: transition metals.
products from alcohols although the high loading of copper
and a special copper(III) complex14 could dampen the
generality of these methods. Therefore, new catalytic strategies
that employ alkyl xanthate esters as coupling partners for the
construction of C−C bonds could offer new opportunities for
the functionalization of alcohols and the late-stage modifica-
tion of pharmaceutical agents. Herein, we report a unique aryl
radical activation/copper capture mechanism for the catalytic
conversion of alkyl xanthate esters to their corresponding alkyl-
difluoromethanes (Figure 1).
The difluoromethyl (CF2H) group has received increasing
attention in medicinal chemistry community due to its unique
hydrogen-bonding ability.15 Recent work has shown that,
depending on the attached functional groups, CF2H groups
can act as hydrogen-bond donors on a scale comparable to (in
most cases, weaker than) that of hydroxyl groups.16 Therefore,
CF2H groups can be considered as lipophilic bioisosteres of
alcohols, replacing the hydroxyl groups of the parent drug
candidates to modify their pharmacokinetic and pharmacody-
namic profiles.
For instance, Burton has successfully used this bioisosteric
replacement approach in the development of a DAF-12
receptor antagonist: compared to the parent hydroxyl-
containing molecule, the CF2H analogue exhibited improved
in vivo activity, retained the antagonist activity, and was devoid
of residual agonist activity.17 However, as traditional
difluoromethylation reactions required CF2H groups to be
installed at a very early stage of the synthesis, development of a
CF2H analogue of an alcohol typically required lengthy denovo
synthesis. Thus, the direct conversion of a hydroxy group into
a CF2H group at a late stage could be a highly desirable
approach to the rapid evaluation of bioisosteres of drug
candidates and the synthesis of previously difficult-to-access
CF2H molecules as potent medicines. To this end, the Xiao
group has recently reported an ingenious copper-mediated
dehydroxylative difluoromethylation reaction although the
requirement of superstoichiometric amounts of copper(I)
salts and the limitation to only primary alcohols might prevent
a wide application of this method.18
RESULTS AND DISCUSSION
■
Hypothesis. Our recent work on the carbo-difluoromethy-
lation of alkenes as well as early work by Goossen19 has shown
that aryl radicals could be generated from the reactions
between aryl diazonium salts and [CuI−CF2H] species. Given
the precedented reactions between aryl radicals and
thiocarbonyl groups,2e,20 we questioned whether in situ
generated aryl radicals could activate xanthate esters in a
fashion similar to how stannyl,9b silyl,21 or ethyl radicals22
activate them in Barton-McCombie-type reactions in which
alkyl radicals were formed via the cleavage of the C−O bonds
of xanthate esters. We expect that the alkyl radicals could then
engage in our recently discovered copper-CF2H capture/
reductive elimination mechanism to afford alkyl-difluoro-
methanes.23 It is worth noting that despite a diverse range of
synthetic transformations that involved aryl radical intermedi-
ates, the use of aryl radicals for the activation of functional
groups has remained an untapped field in organic synthesis.24
Therefore, we anticipated that the successful execution of this
concept would not only provide a general platform to engage
xanthate esters in coupling reactions and catalytically access
alkyl-difluoromethanes from alcohols but also open a new
avenue for the development of novel synthetic transformations
that can manipulate the reactivity of aryl radicals.
Our proposed mechanism for the aryl radical-activated,
copper-catalyzed deoxygenative difluoromethylation protocol
is outlined in Figure 2. The transmetalation from a
nucleophilic CF2H reagent, (DMPU)2Zn(CF2H)2 (i.e., Vicic-
Mikami reagent) 1,25 to a copper(I) catalyst 2 could generate a
reactive [CuI−CF2H] species 3.19,25b,26 This species 3 should
undergo a single electron transfer with an aryl diazonium salt 4
to give an aryl radical 5 and a [CuII−CF2H] complex 6. We
hypothesized that this aryl radical 5 would attack the CS π
bond of an alcohol 7-derived xanthate ester 8 to form a radical
intermediate 9. The ensuing homolytic cleavage of the C−O
bond of 9 and the concurrent formation of a new CO π
bond could generate an alkyl radical 10 and a S-aryl
dithiocarbonate 11. Facile oxidative trapping of the alkyl
radical 10 by the [CuII−CF2H] intermediate 6 would then
furnish a formally alkyl-copper(III) complex 12.27 Reductive
elimination of 12 would afford the alkyl-difluoromethane
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a
Table 1. Reaction Optimization
Figure 2. Proposed catalytic cycle for the aryl radical-activated,
copper-catalyzed deoxygenative difluoromethylation reaction.
b
entry
variation from standard conditions
None
L2 instead of L1
L3 instead of L1
L4 instead of L1
4b instead of 4a
4c instead of 4a
4d instead of 4a
4e instead of 4a
[Cu(OTf)]2·C6H6 instead of Cu(OTf)2
Cu(OAc)2 instead of Cu(OTf)2
DMSO: THF (2:1)
DMSO: ACN (2:1)
no Cu(OTf)2 or no 4a
yield (%)
1
2
3
4
5
6
7
8
89
76
14
16
42
24
69
20
46
48
54
32
N.D.
product 13 and regenerate the CuI catalyst 2,28 effectively
closing the catalytic cycle. We realized that this proposed
catalytic cycle would pose two major challenges: (i) the
potential binding of sulfur atoms in xanthate esters with copper
catalysts could inhibit the reactivity, and (ii) the high reactivity
of aryl diazonium salts and aryl radicals could lead to undesired
side reactions. We reasoned that these challenges could be
circumvented by modifying the binding environment of copper
catalysts and tuning the electronic properties of diazonium
salts.
9
10
11
12
13
Reaction Optimization. To test this hypothesis, a
xanthate ester 14, easily synthesized from the corresponding
alcohol on a gram scale, was used as the model substrate. After
exposing 14 to a variety of conditions, we were pleased to find
that in the presence of catalytic amounts of Cu(OTf)2, tritert-
butyl-terpyridine L1 and (DMPU)2Zn(CF2H)2 1, along with a
diazonium salt 4a, 14 could be selectively converted to the
corresponding difluoromethylated product 15 in an 89% yield
at room temperature (Table 1, entry 1 and SI). Consistent
with our hypothesis, the ligands played a vital role in this
reaction; the use of bidentate ligands had a deleterious effect
on the reactions, and the use of other tridentate ligands led to
diminished yields (entries 2−4). Although the unique role of
terpyridine in this reaction remains unclear, it is likely that the
tridentate ligand could help to stabilize the [Cu−CF2H]
species, thus preventing other unproductive pathways.29 The
choice of a diazonium salt 4a bearing electron-donating groups
was another crucial factor to the success of this reaction
(entries 5−8). Lower yields were attained when less electron-
rich aryl diazonium salts were used. The use of a trimethoxy
substituted diazonium salt 4e led to a decreased yield, largely
due to its moderate solubility in DMSO. It is noteworthy that
4a could be easily prepared from the inexpensive aniline (∼
$0.4/g) on a decagram scale and be stored in a −20 °C freezer
for at least 3 months without noticeable decomposition. Other
copper(I) and copper(II) salts could also be used (entries 9−
10), albeit with lower efficiency. We postulated that copper(II)
salts were reduced in situ by the zinc reagents to form the
reactive copper(I) catalysts. Of all solvents screened, DMSO
was found to be the optimal solvent and the addition of other
cosolvents led to diminished yields (entries 11−12). Control
experiments showed that no products were formed in the
absence of either copper catalysts or diazonium salts (entry
13).
a
Reactions were conducted with 14 (0.1 mmol, 1.0 equiv), diazonium
salt (0.2 mmol, 2.0 equiv), 1 (0.12 mmol, 1.2 equiv), Cu(OTf)2 (20
b
mol %), and ligand (20 mol %) in DMSO (0.6 mL) at RT. Yields
were determined by 19F NMR using 1-fluoro-3-nitrobenzene as the
internal standard.
Substrate Scope. We then explored the scope of this
deoxygenative difluoromethylation reaction (Table 2). Com-
mon functional groups, including esters (15−17), nitriles (18),
imides (19), amides (20, 21), and carbamates (34), were well-
tolerated under the reaction conditions. Alkenes (22−23) and
terminal alkynes (24) were also tolerated under the standard
conditions, despite their tendency to react with carbon-
centered radicals, highlighting the selectivity of aryl radials
toward the C=S bonds. Interestingly, despite the reactions
between aryl radicals with xanthate groups, this transformation
was tolerant of thioesters (25). Nitrogen containing hetero-
cycles, which are core structures in drug synthesis, including
piperidine (26), morpholine (27−29), pyrrolidine (30),
azepane (31), tetrahydroisoquinoline (32), azetidine (33),
and piperazine (34), were all accommodated in this protocol.
Moreover, this system could be applied to the difluoromethy-
lation of secondary benzylic and heterobenzylic alcohols (35−
39), complementing our previously developed decarboxylati-
ve23b and deaminative difluoromethylation protocols,23c in
which the scope of secondary benzylic carboxylic acids or
secondary benzylic pyridinium salts was limited. The scalability
of this reaction was demonstrated through the gram scale
synthesis of compound 15.
Xanthate esters derived from primary alcohols were also
evaluated in this difluoromethylation protocol. Phenyl alcohols
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a
Table 2. Substrate Scope of the Aryl Radical-Activated, Copper-Catalyzed Deoxygenative Difluoromethylation
a
Unless otherwise noted, reactions were run with 0.25 mmol of xanthate esters, 0.5 mmol of diazonium salt (2.0 equiv), 0.3 mmol of 1 (1.2 equiv),
b
L1 (20 mol %) and Cu(OTf)2 (20 mol %) in 1.5 mL of DMSO at RT. Isolated yields based on xanthate esters. Reactions were run with 0.25
c
mmol of alcohols. Isolated yields based on alcohols. Yield was determined by 19F NMR due to the volatility of the product.
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Figure 3. Copper-catalyzed late-stage deoxygenative difluoromethylation of pharmaceutical derivatives. See Supporting Information for detailed
experimental conditions.
were generally competent, with a diverse range of electron-
withdrawing, electron-donating, and electron-neutral func-
tional groups tolerated on the aryl rings (40−49). Steric
hindrance had little effect on the reactivity and a good yield
was observed for a 2,6-dichloro substituted substrate (45).
Notably, the compatibility of aryl bromides (51) and iodides
(43) with this reaction could allow for the further
diversification of the products. The aldehyde group, which
could be problematic under nucleophilic difluoromethylation
conditions, was compatible with this protocol (44). A boronic
ester was tolerated under the copper-catalyzed mild conditions,
albeit in a moderate yield (49). A substrate that contained two
hydroxyl groups was doubly difluoromethylated (52). In
addition, different heterocycles including dioxole (54),
pyrazole (55), furan (56), were tolerated on the phenyl
rings. Furthermore, this method was applied to the
difluoromethylation of a diverse range of heterobenzylic
(58−65) and propargylic alcohols (66 and 67), affording the
CF2H derivatives of thiophene, quinoline, benzofuran,
benzothiazole and indazole. Finally, this protocol could also
be extended to a nonbenzylic primary alcohol (68), albeit in a
fair yield.
Limitations. Although diazonium salts were required for all
the difluoromethylation reactions shown in Table 1, xanthate
esters derived from allylic alcohols could be converted to the
corresponding allyl-difluoromethanes in the absence of
diazonium salts (Figure S1). The similar reactivity has also
been reported by Mikami for the copper-catalyzed difluor-
omethylation of allyl carbonates in which the formation of π-
allyl copper(III) species has been proposed.30 We expected
that such intermediates were also formed between the
reactions of [CuI−CF2H] with the allylic xanthate esters,
which reductively eliminated to form allyl-difluoromethanes.
Similarly, secondary propargylic xanthate esters were converted
to difluoromethylated allenes when no diazoniums salts were
used (Figure S2). Copper-catalyzed difluoromethylation of
conjugated propargyl bromides has been recently reported by
Shen using a silver-difluoromethyl reagent.31 Finally, a
limitation of this protocol is its incompatibility with xanthate
esters derived from cyclic alcohols (see Figure S3 for a list of
unsuccessful substrates). Nonetheless, this complements our
previously reported decarboxylative difluoromethylation re-
actions23b in which the cyclic carboxylic acids were more
competent than the acyclic counterparts.
One-Pot Deoxygenative Difluoromethylation. An
ideal deoxygenative difluoromethylation reaction would
obviate the need to separate the xanthate intermediates and
directly use alcohols in the reactions. Therefore, to further
facilitate the broader application of this method in the field of
medicinal chemistry, we developed conditions for the one-pot
conversion of alcohols to the difluoromethylated products.
Specifically, substrates that did not contain base-sensitive
functional groups could be readily converted to their xanthate
esters in a biphasic NaOH/CS2 system within a few minutes.
After the completion of the reactions, the aqueous layers could
be easily removed by simple pipetting, and the crude xanthate
esters were used in the next step without further purification.
The generality of this one-pot procedure has been evaluated on
different alcohols (31, 36, 41, 42, 45, 62), including primary,
secondary, and heterobenzylic alcohols, all of which were
converted to the corresponding CF2H products in workable
yields.
Late-Stage Difluoromethylation of Pharmaceuticals.
Hydroxyl groups are ubiquitous in pharmaceuticals and can
also be easily transformed from other functional groups. We
anticipated that this deoxygenative difluoromethylation
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method could offer a general strategy for the rapid synthesis of
CF2H analogues of pharmaceutical agents. Therefore, we
performed a series of late-stage modifications on medicinally
relevant molecules (Figure 3). The xanthate esters of
derivatives of lonidamine, an antispermatogenic and anticancer
agent,32 as well as adapalene, a topical retinoid for the
treatment of acne,33 were converted to their CF2H analogues
(69 and 70) in 46% and 64% yield, respectively. The
difluoromethylation of a precursor to rosuvastatin, a medicine
used to lower cholesterol,34 allowed for the incorporation of a
CF2H group on the sterically hindered heterobenzylic position
of a pyrimidine ring in a 65% yield (71). The analogue of
rimonabant, an anorectic antiobesity drug,35 was converted to
the CF2H analogue in a 72% yield, with three aryl chloride
bonds remaining unaffected (72).
In addition, the CF2H analogue of the protected DOPA
(73), an amino acid made as part of the human biology and
used in the clinical treatment of Parkinson’s disease,36 could be
synthesized in an 85% yield from its xanthate ester.
Levothyroxine, one of the top-selling drugs for the treatment
of thyroid hormone deficiency and thyroid tumors,37 was
converted to its CF2H analogue (74) via the xanthate
intermediate in a 52% yield. It is worth noting that the
tolerance of multiple aryl iodides on electron-rich phenyl rings
further highlighted the mild conditions of this copper-catalyzed
protocol. Moreover, an analogue of lisdexamfetamine, one of
the most prescribed medications in the United States for
treating attention deficit hyperactivity disorder and binge
eating disorder,38 was converted to its CF2H analogue (75) in
a synthetically useful yield.
Finally, we aimed to synthesize the CF2H bioisostere of
ezetimibe, one of the top-selling pharmaceuticals to treat high
blood cholesterol.39 A main metabolic pathway of ezetimibe
involves the oxidation of its benzylic hydroxyl group to form
the ketone metabolite.40 We expected that the replacement of
the benzylic hydroxyl group with a CF2H group should block
such a metabolic pathway while partially retaining the original
hydrogen-bonding ability. To our delight, the xanthate ester of
the benzyl-protected ezetimibe was converted to the
difluoromethylated product (76) under the standard con-
ditions in a 50% yield. These examples further highlighted the
potential of this copper-catalyzed protocol for the rapid
synthesis of CF2H-containing pharmaceuticals.
Mechanistic Studies. Mechanistic experiments were
conducted to shed light on this deoxygenative difluoromethy-
lation reaction. The addition of a radical-trapping reagent
TEMPO (2 equiv) to the difluoromethylation of 14 led to a
suppression of the formation of 15, while the generation of an
aryl-TEMPO adduct (77) was detected by GC. 77 was also
formed when the reactions were conducted without the
xanthate esters, supporting the notion that aryl radicals were
formed in the reactions between aryl diazonium salts and
[Cu−CF2H] species (Figure 4A). In addition, to establish the
involvement of alkyl radicals in these reactions, we conducted
the difluoromethylation of a cyclopropyl-bearing substrate
(78). The difluoromethylation of this radical clock substrate
afforded the unrearranged product (79), along with the ring-
opened product (80), consistent with the hypothesis that
short-lived alkyl radicals were involved in the reactions (Figure
4B). More importantly, this result ruled out the alternative
pathway which involved the direct nucleophilic substitution of
a [CuI−CF2H] species with the xanthate ester via a SN2
mechanism.
Figure 4. Mechanistic studies supported the proposed aryl radical
activation mechanism.
Moreover, the proposed mechanism in Figure 2 was further
supported by the detection of the S-aryl dithiocarbonate side
product (81) in all the difluoromethylation reactions (Figure
4C). We were able to isolate this compound, the structure of
which was unambiguously confirmed by NMR. The isolation
of 81, together with the fact that no difluoromethylated
products were formed in the absence of diazonium salts,
supported the postulation that aryl radicals were the key to the
activation of xanthate esters.
CONCLUSION
■
The Barton-McCombie reaction has taught the synthetic
community that the formation of alkyl xanthate esters is an
efficient strategy for the activation of alcohols via radical
intermediates. However, the synthetic utility of xanthates has
been significantly limited to the deoxygenation reactions,
largely due to the lack of suitable activation modes that could
engage them in transition metal-catalyzed coupling reactions.
Due to the high reactivity of aryl radicals, they have been
widely used in organic synthesis as building blocks for the
installation of aryl groups. However, the synthetic utility of aryl
radicals as reagents for the activation of functional groups
remains an underexplored yet highly promising approach in
synthetic organic chemistry.
By tuning the electronic properties of aryl diazonium salts,
we disclose herein a unique aryl radical activation approach to
engage alcohol-derived xanthate esters in cross-coupling
reactions via copper catalysis, allowing for the discovery of
the first catalytic deoxygenative difluoromethylation reaction.
Mechanistic studies were consistent with an aryl radical
activation pathway. Despite the current limitations and the
additional work required to extend the scope of alcohols
beyond ones bearing radical stabilizing groups, we expect that
this protocol could find its wide application in the
pharmaceutical industry for the rapid construction of CF2H-
containig drug candidates. Furthermore, this unique aryl
radical activation approach should inspire novel C−C and
C−heteroatom bond-forming reactions using xanthate esters as
coupling partners as well as transformations that could
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C.; Overman, L. E. Oxalates as Activating Groups for Alcohols in
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manipulate the reactivity of aryl radicals. These studies are
currently ongoing in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04254.
■
sı
General information, experimental details, character-
izations of new compounds, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wei Liu − Department of Chemistry, University of Cincinnati,
Cincinnati, Ohio 45221, United States; orcid.org/0000-
0001-6249-3179; Email: liu2w2@uc.edu
(4) Zhang, X.; MacMillan, D. W. C. Alcohols as Latent Coupling
Fragments for Metallaphotoredox Catalysis: sp3−sp2 Cross-Coupling
of Oxalates with Aryl Halides. J. Am. Chem. Soc. 2016, 138 (42),
13862−13865.
(5) Ye, Y.; Chen, H.; Sessler, J. L.; Gong, H. Zn-Mediated
Fragmentation of Tertiary Alkyl Oxalates Enabling Formation of
Alkylated and Arylated Quaternary Carbon Centers. J. Am. Chem. Soc.
2019, 141 (2), 820−824.
Authors
Aijie Cai − Department of Chemistry, University of Cincinnati,
Cincinnati, Ohio 45221, United States
Wenhao Yan − Department of Chemistry, University of
Cincinnati, Cincinnati, Ohio 45221, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04254
(6) Guo, P.; Wang, K.; Jin, W.-J.; Xie, H.; Qi, L.; Liu, X.-Y.; Shu, X.-
Z. Dynamic Kinetic Cross-Electrophile Arylation of Benzyl Alcohols
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Author Contributions
$These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(8) Wei, Y.; Ben-zvi, B.; Diao, T. Diastereoselective Synthesis of Aryl
C-Glycosides from Glycosyl Esters via C−O Bond Homolysis. Angew.
Chem., Int. Ed. 2021, 60 (17), 9433−9438.
■
W.L. acknowledges financial support from the University of
Cincinnati. NMR experiments were performed using a Bruker
AVANCE NEO 400 MHz NMR spectrometer (funded by
NSF-MRI grant CHE-1726092). We also thank Mr. Sam
Tyndall for proofreading the manuscript and Dr. Hairong
Guan and Dr. Yujie Sun for the use of their chemicals.
(9) (a) Barton, D. H. R.; McCombie, S. W. A New Method for the
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