Oxidative photocatalytic homo- And cross-coupling of phenols: Nonenzymatic, catalytic method for coupling tyrosine

Article abstract of DOI:10.1021/acscatal.0c04515

An oxidative photocatalytic method for phenol? phenol homo- and cross-coupling is described, and isolated yields of 16?97% are obtained. Measured oxidation potentials and computed nucleophilicity parameters support a mechanism of nucleophilic attack of one partner onto the oxidized neutral radical form of the other partner. Our understanding of this model permitted the development of cross-coupling reactions between nucleophilic phenols/arenes and easily oxidized phenols with high selectivity and efficiency. A highlight of this method is that one equivalent of each coupling partner is utilized. Building on these findings, a nonenzymatic, catalytic method for coupling tyrosine was also developed.

Full text of DOI:10.1021/acscatal.0c04515

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Research Article
Oxidative Photocatalytic Homo- and Cross-Coupling of Phenols:
Nonenzymatic, Catalytic Method for Coupling Tyrosine
Kyle A. Niederer, Philip H. Gilmartin, and Marisa C. Kozlowski*
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ABSTRACT: An oxidative photocatalytic method for phenol−
phenol homo- and cross-coupling is described, and isolated yields of
16−97% are obtained. Measured oxidation potentials and computed
nucleophilicity parameters support a mechanism of nucleophilic
attack of one partner onto the oxidized neutral radical form of the
other partner. Our understanding of this model permitted the
development of cross-coupling reactions between nucleophilic
phenols/arenes and easily oxidized phenols with high selectivity
and efficiency. A highlight of this method is that one equivalent of each coupling partner is utilized. Building on these findings, a
nonenzymatic, catalytic method for coupling tyrosine was also developed.
KEYWORDS: oxidative coupling, phenol coupling, photocatalysis, tyrosine dimerization, cross-coupling
Importantly, these catalytic oxidative phenolic coupling
reactions proceed via distinct mechanisms that dictate the
reactivity and selectivity. For example, the copper-catalyzed
oxidative homocoupling of phenols reported by Lumb and co-
workers is proposed to proceed via a combination of two
neutral phenoxyl radicals.16 Kozlowski and co-workers
proposed radical−anion coupling via a high spin state in the
mechanism for phenol cross-coupling a chromium catalyst.18
Pappo and co-workers also propose a radical−radical
mechanism in cross-couplings with an iron porphyrin
catalyst,17 but propose a distinct chelated radical−anion
mechanism for phenolic cross-coupling with catalytic Fe(III)
and (t-BuO)2.19 In the aforementioned cases, metal phenolates
are often invoked as key intermediates that undergo inner
sphere oxidation at a metal center. Under electrochemical
conditions, Waldvogel and colleagues propose generation of a
free phenoxyl radical by outer sphere electron transfer,
followed by trapping with an unoxidized phenol or
arene.13,14 Even though there are occasional similar outcomes,
the mechanisms for each of those homo- and cross-coupling
transformations is fundamentally different.20
INTRODUCTION
■
The biphenol scaffold is a prevalent substructure in biologically
active natural compounds (Chart 1).1−7 Since the discovery
Chart 1. Coupled Phenol Natural Products
that phenol oxidation is the key step in the synthesis of several
of these natural products, chemists have explored analogous
means to effect such transformations.
While many stoichiometric phenol homo- and cross-
couplings have been reported,8−11 Uang and co-workers
disclosed in 1999 one of the first catalytic reports of non-
naphthol−phenol homocoupling using a vanadium catalyst
under an oxygen atmosphere.12 In 2011, the Waldvogel group
revealed the homocoupling of select phenols by utilizing a
boron-doped diamond anode in yields up to 83%.13,14 In 2014,
we reported the use of a metal salen/salan catalyst library to
achieve highly selective homo- and cross-couplings of several
alkyl and alkoxy substituted phenols,15 while Lumb and co-
workers revealed a copper-catalyzed aerobic oxidation of
phenols.16 Finally, more-recent reports of cross-coupling from
Pappo and Kozlowski reveal selective, high-yielding phenol
cross-couplings using iron porphyrin and chromium salen
catalysts, respectively.17,18
While these advances in the field of oxidative coupling have
facilitated the synthesis of a diverse array of ligands and natural
products, they still require the use of high loadings of transition
metal catalysts, diamond electrodes, or stoichiometric oxidants
Received: October 19, 2020
Revised: November 9, 2020
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© XXXX American Chemical Society
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that are not atom economical.5,14,19,21,22 In addition, certain
coupling patterns are difficult to access, and couplings of
mono-substituted phenols are especially challenging.
In particular, efficacious nonenzymatic catalytic methods for
the direct oxidative ortho−ortho coupling of L-tyrosine have
remained an elusive goal for chemists (Scheme 1). Many
activates phenols toward oxidative coupling and blocks
additional reactive sites,29−32 to effect the synthesis of several
arylomycin analogues via an intermolecular iron-catalyzed
tyrosine coupling (Scheme 1d).33 Herein, we disclose a
photocatalytic process to accomplish such couplings without
the aid of a directing group (Scheme 1e).34
Our initial approach involved screening our library of
oxidizing transition metal catalysts in the coupling of tyrosine
and related phenols but revealed no reactivity and recovery of
starting material. Reasoning that these catalysts did not have
sufficiently high oxidation potentials, we turned to photoredox
catalysts, which have a wide range of reported oxidation
potentials. By pairing a photoredox catalyst with a stoichio-
metric oxidant to generate controlled amounts of the oxidized
intermediate, the coupling of phenols should be feasible. While
net-oxidative photoredox processes are less common overall,35
we were encouraged by reports of the photo-cross-linking of
tyrosine-residues in various polymers.36 Although there was no
direct evidence of tyrosine−tyrosine couplings, it appeared that
tyrosine was within the oxidation range of known photo-
Scheme 1. Previous Approaches to Inter- and
Intramolecular Tyrosine Coupling
catalysts.36,37
38
Notably, in 2017, Konig and Xia39 disclosed the
̈
photocatalytic cross-coupling of phenols with arenes and
amines, respectively. In the former case, control of C−C vs C−
O coupling was a challenge. In the latter case, a very electron-
rich phenol was oxidized by persulfate and the amine was
oxidized by the photocatalyst. While there are limited examples
of photocatalytic naphthol−phenol cross-couplings,40 to the
best of our knowledge, there are no reports describing
photocatalytic phenol−phenol cross- or homocouplings.
Challenges associated with such processes include identifying
an appropriate terminal oxidant that does not act on phenols
directly, preventing decomposition of the products, controlling
cross-selectivity by selective oxidation, and controlling
regioselectivity.
Herein, we disclose the transition-metal-free photocatalytic
oxidative homo- and cross-coupling of phenols. The use of
high-throughput experimentation (HTE) allowed for the rapid
identification of optimal photocatalyst, oxidant, and solvent
combination for the transformation. Hallmarks of the reaction
include good scope for homo- and cross-coupling, use of a
mild, readily available oxidant, a 1:1 ratio of coupling partners
in cross-coupling, and excellent control of regioselectivity in
cross-coupling based on nucleophilicity and oxidation potential
parameters of phenol partners. Mechanism experiments
support a mechanism wherein a neutral phenol radical is
attacked by a nucleophilic phenol or arene, followed by
subsequent oxidation by photocatalyst or H2O2 to furnish the
biphenol product. Given the importance of the dityrosine
motif, an additional HTE screen was undertaken to develop
photocatalytic conditions for the coupling of tyrosine.
attempts have been made to effect such a coupling, as it would
engender a biomimetic approach to the dityrosine motif found
in several natural products, including mycocyclosin3 and RP-
66453.4 However, most efforts have culminated in Suzuki type
cross-couplings to forge the biaryl bond, as is the case in all
efforts to generate mycocyclosin (Scheme 1a),3,23 a natural
product that is also a key intermediate to the herqulines.24−26
Notably, Baran deployed an intramolecular oxidative coupling
of tyrosine and para-hydroxyphenylglycine by employing a
stoichiometric CuIII-TMEDA complex (Scheme 1b).27 In spite
of these efforts, reports of intermolecular tyrosine coupling are
limited. In 2001, Rieker and co-workers disclosed that
superstoichiometric [bis(trifluoroacetoxy)iodo]benzene
(PIFA) couples tyrosine in less than 40% isolated yield
(Scheme 1c).28 Additionally, they reported a 90% yield using
horseradish peroxidase enzyme and H2O2, for which material
throughput was an issue.
RESULTS AND DISCUSSION
■
Reaction Optimization. Our initial strategy to explore this
nascent field focused on the use of Ru(bpy)3Cl2 and a
persulfate oxidant.36 Initial efforts in coupling N-AcTyrOMe
were unsuccessful, motivating us to screen a series of
photocatalysts and oxidants with simpler phenols at microscale
against an internal standard (full results found in Supporting
Information). The screen revealed four potent photocatalysts,
MesAcr+BF4−, 3,6-di-tert-butyl-MesAcr+BF4−, [Ir{dF-
(CF3)2ppy}2(dtbbpy)]PF6, and [Ru(bpm)3](PF6)2], for the
homocoupling transformation. Upon validation at a larger
More recently, in 2020, the Pappo group leveraged the
presence of a tert-butyl activating group on tyrosine, which had
been reported by us and others as a removable group that
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scale, MesAcr+BF4− was identified as the most effective catalyst
due to its ability to convert several phenols into their dimers in
higher conversions (Table 1). For certain phenol substrates,
initial screen, a notable decrease in yield was observed (Table
3, entry 2 vs 1). Thus, 4,4′-di-tert-butylbiphenyl (BP) was
Table 3. Evidence of Biphenyl as a Photocatalyst
Table 1. Benchtop Photocatalyst Screen
entry
x
y
light source
result (%)
1
2
3
4
5
2
2
0
0
0
25
0
25
25
0
blue LEDs
blue LEDs
blue LEDs
none
45
25
30
0
entry
photocatalyst
NMR yield (%)
MesAcr+BF4
55
50
41
33
−
1
2
3
4
3,6-di-tert-butyl-MesAcr+BF4
−
Ru(bpm)3[PF6]2
[Ir{dF(CF3)2ppy}2(dtbbpy)]PF6
blue LEDs
0
the use of MesAcr+BF4 in the presence of O2 led to the
formation of oxidized by-products, such as the para-
peroxyquinols of the dimeric product (3) or the phenol
monomer (4) (Table 2), the latter of which was confirmed
−
included in all subsequent reactions. Notably, reactions
conducted without the photocatalyst but with the internal
standard resulted in significant amounts of product in the case
of 1b (entry 3), suggesting that the internal standard can itself
act as a photocatalyst. Supporting this observation, there is
precedent that even simple arenes, such as dicyanoanthracene
and benzophenone, can serve as photocatalysts.43 Controls
Table 2. Phenolic Coupling By-products
−
without light (entry 4) and without MesAcr+BF4 or 4,4′-di-
tert-butylbiphenyl (entry 5) confirmed that both light and a
photocatalyst are needed to effect the coupling reaction.
Homocoupling Scope. Under the optimized conditions,
substrates with 2,4-, 2,4,5-, or 3,4,5-substitution patterns
exhibited good reactivity, affording dimers in isolated yields
up to 76% (Figure 1). There was limited tolerance for bromo-
substitution, as 2d was achieved in only 16% isolated yield.
The conditions were effective with aryl-substituted phenols
(2j-2q). Remarkably, electron-poor CF3-aryl-substituted phe-
nols (2l, 2o) provided higher conversion and yield than
electron-rich MeO-aryl-substituted phenols (2j, 2m), which is
an unexpected outcome, as electron-poor phenols are typically
less easily oxidized (vide infra). Additionally, the ortho-tert-
butyl-substituted tyrosine substrate (2r) afforded the highest
isolated yield, indicating the synthetic utility of this method as
found independently by Pappo and co-workers.33 In certain
cases, 1,2-dichloroethane was added as a cosolvent with HFIP
to ensure complete solubility of reaction components over the
time course of the reaction. Unfortunately, methoxy-
substituted phenols, which are more easily oxidized, and
substrates lacking a 4-substituent proved untenable for
dimerization, as no significant yields (<5%) were achieved.
Mechanism. Previous reports in the area of oxidative
phenol photocatalysis propose two distinct types of inter-
mediates (see the Supporting Information for alternative
mechanisms). In many electrochemical and photocatalytic
reports,38,40,41,44,45 single-electron oxidation of the phenol
partner generates a radical cation, which then reacts to form a
C−C bond either as the phenol radical cation or the neutral
phenoxyl radical. Alternatively, it has been proposed that the
phenol may undergo two serial single-electron oxidations
under photocatalytic or electrochemical conditions to generate
a phenoxonium, which then reacts to form C−C bonds with
the appropriate partner.46,47 Additionally, the identification of
para-peroxyquinol products (4) in the reaction (Table 2)
raised the possibility that these compounds may serve as
with a crystal structure (see the Supporting Information).
Other oxidants (DDQ, persulfates, peroxides, CBrCl3) were
also screened (not shown), but were less effective.
A solvent screen revealed that halogenated solvents gave
good conversion (ClCH2CH2Cl, CH2Cl2) of phenol mono-
mer, with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) providing
the highest yields. The increased yield of the reaction using
HFIP as a solvent was not unexpected, as recent literature
reports on oxidative phenol coupling17,19,33,41 disclose the use
of this solvent due to its ability to stabilize radical/charged
intermediates.42 Even so, the conditions shown in Table 1 also
generated undesired side products 3 and 4. Reasoning that
lower oxygen concentrations would prevent direct oxygenation
to yield para-peroxyquinol products, reactions under an
atmosphere of air were attempted. This change indeed
curtailed the formation of these side products considerably,
as 2a was observed in 80% yield (vs 70% under O2; Table 2,
entry 1).
When attempting to attain isolated yields of 2b on larger
scale without the biphenyl internal standard included in the
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overall homo- and cross-coupling transformation but is a
consequence of an unproductive off-cycle reaction.
To further probe whether a phenoxonium was involved, two
key experiments were performed. First, easily oxidized 2-tert-
butyl-4-methoxyphenol (1u) was subjected to the reaction
conditions in the presence of stoichiometric methanol as a
nucleophile. When treated with hypervalent iodine and
methanol, this same phenol undergoes trapping of methanol
at the para-position to give a dimethoxy quinone ketal product
via a two-electron oxidation to the phenoxonium.50 Under the
−
optimized conditions with the strongly oxidizing MesAcr+BF4
photocatalyst, none of the quinone ketal product was observed,
pointing away from the intermediacy of a phenoxonium cation.
Furthermore, the less oxidizing photocatalyst Eosin Y (EOx
=
0.83 V),51 which operates below the oxidation potential
needed to generate the phenoxonium,52,53 is effective in the
coupling reaction (see the Supporting Information). This
finding further supports the intermediacy of radical cations or
phenoxyl radicals arising from one-electron oxidation, as
opposed to phenoxonium species arising from two-electron
oxidation.
The analysis of the aqueous extract from a completed
reaction revealed the presence of significant quantities of
hydrogen peroxide (see the Supporting Information), support-
ing a mechanism that proceeds with the generation of
superoxide anion and peroxyl radicals. The introduction of
an exogenous base (organic or inorganic) to the system also
decreased the rate of reaction, indicating that a radical−anion
coupling was not likely. In light of these findings, the reaction
pathway most likely commences with the oxidation of the
phenol by MesAcr+BF4 (EOx = 2.06 V)54 in the excited state
−
(IVa to V, Scheme 2). The reduced photocatalyst can then be
Scheme 2. Proposed Mechanism for the Photocatalytic
Coupling of Phenols
Figure 1. Scope of photocatalytic homocoupling of phenols. Reported
yields are of isolated material; yields in parentheses are based on
recovery of starting material. Values in brackets are yields from
a
b
reactions run without biphenyl. Solvent = ClCH2CH2Cl; Solvent =
ClCH2CH2Cl: HFIP (1:2).
intermediates in the overall transformation.48,49 As such, all
three mechanistic possibilities were considered.
Reactions conducted in the absence of O2 resulted in
monomer conversion consistent with photocatalyst loading
(see the Supporting Information). No para-peroxyquinol or
para-quinol ether products were observed in the absence of O2.
To further probe whether an additional pathway under air
involving para-peroxyquinols can occur, 2-tert-amyl-4-methyl
phenol and para-peroxyquinol 4a were subjected to reaction
conditions in a 1:1 ratio. This phenol substrate serves as a
proxy for 1a, with similar electronic and steric features. Under
the optimized conditions, the tert-amyl phenol partner
completely decomposed, while the peroxyquinol 4a was largely
unreacted. When light or the photocatalyst were omitted,
neither phenol nor peroxyquinol reacted (see the Supporting
Information). Taken together, these experiments indicate that
the para-peroxyquinol is not a putative intermediate in the
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reoxidized by dioxygen (III to I) to afford a superoxide anion
likely: (1) direct oxidation of the phenol occurs by excited
state MesAcr+BF4 (Scheme 2) or (2) the biphenyl quenches
−
and ground state MesAcr+BF4 (I). Thereafter, the oxidized
−
phenol radical cation V (pKa ∼ −2.0)55 is deprotonated by a
the photocatalyst to yield a biphenyl radical cation, which then
oxidizes the phenol monomer. The advantages afforded by the
latter pathway likely arise from the longer lifetime of the
biphenyl radical cation. This proposed case of redox mediation
is reminiscent of other oxidative processes,60 both biological
and synthetic, and could potentially be leveraged in the
development of more effective redox mediation pairs by
altering biphenyl steric and electronic parameters.
56
−
superoxide anion (pKa of HO2• → O2 • = 4.9) (V to VI)
and attacked by a neutral phenol (VI to VII). A peroxyl radical
−
or the excited state MesAcr+BF4 subsequently oxidizes
intermediate VII to provide VIII. Tautomerization of VIII
then affords the product IX. The superoxide/peroxyl radical
pathway shown in Scheme 2 is used to illustrate a balanced
chemical equation and to account for the formation of
hydrogen peroxide in situ.
An additional implication of the mechanism proposed in
Scheme 2 is that a cross-coupling should be feasible provided
that one phenol is more readily oxidized (intermediate IVa,
outlined in blue), while the other possesses a reactive site that
is more nucleophilic (intermediate IVb, outlined in red).
Stern−Volmer fluorescence quenching experiments (Figure 2)
with two phenol monomers, 2-tert-butyl-4-methoxyphenol
(more oxidizable, less nucleophilic) and 2-tert-butyl-5-
methylphenol (less oxidizable, more nucleophilic) revealed
that both are capable of quenching the excited state
photocatalyst, which is expected, as both substrates have
oxidation potentials lying within the oxidizing range of the
The proposed mechanism for C−C bond formation can be
classified as a radical−neutral coupling between a neutral
phenoxyl radical (VI) and a neutral nucleophilic phenol
partner (IVb). This mechanism is akin to phenol cross-
coupling under electrochemical conditions, but is unique in
that the photocatalyst serves two roles: (1) from the excited
state, it is a single-electron oxidant that acts on the phenol and
(2) it acts as the reductant for the in situ production of a
second stoichiometric oxidant (hydrogen peroxyl radical). One
critical implication of the mechanism in Scheme 2 is that the
coupling will proceed best when a monomer can be readily
oxidized (IVa to V) and can act as a nucleophile (IVb to VII).
Experiments conducted in the absence of the biphenyl
internal standard revealed its influence on the conversion of
phenol monomer to dimer (Figure 1, yields in brackets). While
the biphenyl can act as a photocatalyst to some extent and
effect the coupling transformation in the absence of
MesAcr+BF4− (Table 3, entry 3), a more compelling argument
suggests that the biphenyl serves as a radical mediator or
excited state of MesAcr+BF4 (Figure 2). Furthermore, the
−
steeper slope for the more oxidizable 2-tert-butyl-4-methox-
yphenol is consistent with more effective quenching. When
both substrates are combined with the biphenyl additive and
MesAcr+BF4 , differential quenching is likely. Due to the
−
relative abundance of phenols vs biphenyl additive, the
differences in oxidation potentials, and the differences in
lifetimes, it is most probable that the blue phenol is oxidized by
either the excited photocatalyst or the biphenyl radical cation
before the red phenol.
35,43
−
cosensitizer in the presence of MesAcr+BF4 .
Previous
reports propose a mechanism wherein a biphenyl compound
rapidly quenches the photocatalyst, inducing a biphenyl radical
cation that can then serve as an oxidant.57,58 Interestingly,
these reports indicate that the biphenyl may have a longer
lifetime in its oxidized state than a photocatalyst in its excited
state.43
Stern−Volmer fluorescence quenching experiments revealed
that the biphenyl does in fact participate in photocatalyst
quenching (Figure 2).59 Therefore, two separate pathways are
Cross-Coupling Scope. A number of recent reports have
centered on phenolic cross-couplings;17−19,40,41 the limitations
include a reliance on an excess of one partner17,38,41,61,62 and/
or poor selectivity due to competitive homocoupling, as well as
mixtures of ortho- vs para-coupled products.17,38 The
homocoupling reaction (Figure 1) requires specific substitu-
tion patterns, which include an alkyl group at the para-position.
In our recent report on chromium-catalyzed phenolic
couplings, we leveraged site nucleophilicity to predict the
regioselectivity of coupling.18 The calculated values revealed
that open para-positions are significantly more nucleophilic
than open ortho-positions. Consequently, a high-yielding cross-
coupling can be induced by selecting one substrate without a
para-substituent (red phenol). The poor homocoupling of
such substrates (vide supra) and the high nucleophilicity of the
para-position make these substrates excellent candidates for
cross-coupling.
Based on the cross-coupling model discussed above, it was
anticipated that different di- and tri-substitution patterns on
both the nucleophilic (red phenol) and more readily oxidized
(blue phenol) partners would be effective (Figure 3) in cross-
coupling. Remarkably, monosubstituted phenols, which are
difficult to couple due to multiple reactive sites and high
oxidation potentials,33 were compatible (6a-u through 6d-
u).15,17,18 In contrast to the homocoupling, a high level of
success was also achieved with a halogenated substrate, as 6h-y
was isolated in 73% yield. Furthermore, a more easily oxidized
(blue phenol) 3,4-di-substituted phenol also provided both
good reactivity and regioselectivity, perhaps due to steric
effects, with 6h-z being isolated in 71% yield. As in the case of
homocoupling, cross-coupling reactions conducted in the
Figure 2. Steady-state Stern−Volmer plot for the emission quenching
of excited state Mes-Acr+BF4− (λex = 450 nm, λmax = 534 nm) by two
phenol monomers and 4,4′-di-tert-butylbiphenyl. I0 and I are the
luminescence intensities in the absence and presence of the specific
quencher at variable concentrations, respectively.
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6h-aa, 6i-u) in the cross-coupling reaction (Figure 3, results in
brackets).
Notably, no homocoupling products were observed and only
trace amounts (0−5%) of the ortho−ortho coupling were found
in all but one case (6l-u; 9% ortho−ortho vs 52% ortho−para).
The greater site nucleophilicity of the para-position accounts
for these observed differences. These results also accentuate
the difference between the mechanisms proposed in this and
recent reports.17,18 For instance, the iron porphyrin coupling
reported by Pappo in 2017 proceeds via a radical−radical
pathway, which does not rely on site nucleophilicity and
exhibits lower regioselectivity.17 Specifically, that report
revealed ∼1:1 ratio of the ortho−ortho and ortho−para adducts
for the substrates corresponding to 6j-u and 6k-u. Here, 6j-u
and 6k-u form with high ortho−para selectivity (Figure 3).
Furthermore, reactions of other known compounds proceed in
similar or higher yields than other reports and use a 1:1 molar
ratio of phenols, rather than an excess of one phenol. For
example, the formation of 6h-u with our prior reported Cr
catalyst18 gave 50% yield, whereas the protocol herein
provided 97% of the same product.
Additionally, selective modifications can be made to the
biphenol products obtained from the photocatalytic coupling
reaction (Figure 4). For example, the methoxy group of 6a-u
Figure 4. Selective transformations of dimeric products.
can be selectively deprotected to generate para-dihydroxy
compound 7a-u using BBr3. Alternatively, the tert-butyl groups
of the same compound can be selectively removed in the
presence of the methoxy group using AlCl3 to generate
monosubstituted biphenol compound 8a-u, a motif that would
be difficult to access via conventional oxidative coupling
methods.32 Furthermore, the tert-butyl and methyl ether
groups can be simultaneously cleaved with AlCl3 at longer
reaction times (7h-v). Therefore, the abundance of tert-butyl
and methoxy-substituted substrates could be leveraged to
access a more diverse array of biphenyl compounds.
Figure 3. Scope of the photocatalytic phenol cross-coupling.
Conditions: 2.0 mol % MesAcr+BF4−, 25 mol % 4,4′-di-tert-
butylbiphenyl, HFIP, air, blue LEDs, 35 °C, 48 h. Reported yields
are of isolated material; yields in parentheses are based on recovered
starting material. Values in brackets are isolated yields in the absence
of the biphenyl. aReaction stopped at 24 h; bSolvent = ClCH2CH2Cl:
c
HFIP (1:1); ortho−ortho product recovered in 9% yield.
Tyrosine Coupling. Our final endeavor aimed to achieve
the direct catalytic coupling of tyrosine. Although a highly
efficient oxidative and catalytic method for coupling tyrosine
derivatives was recently reported, a tert-butyl group positioned
absence of the biphenyl cosensitizer revealed that the additive
either had little effect (6e-u) or facilitated conversion (6h-u,
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ortho to the phenol was required to obtain a high conversion,33
which we had also observed independently (Figure 1, 2r, 2s,
2t). While this group can be readily removed in excellent yield,
its use is not ideal due to the decrease in step-economy.
Tyrosine derivatives lacking the activating tert-butyl substituent
achieved isolated yields of only 10% under the optimized
photocatalytic conditions described above, with significant
amounts of by-products observed. Specifically, when 1ee was
subjected to the photocatalytic conditions reported in Figure 1,
only the para-peroxyquinol 4ee was observed. A further HTE
screen of photocatalysts was thus undertaken to determine
whether different photocatalysts could be more effective in
producing the important dityrosine derivative 2ee. This screen
revealed that Ru(bpz)3[PF6]2 paired with O2 converts 1ee into
2ee while attenuating the formation of by-products. A larger
scale reaction (Figure 5) confirmed this result, affording a 40%
isolated yield of 2ee with no detected by-products (73% based
on recovered starting material).
Table 4. Selected Oxidation Potentials of Phenol Monomers
and Dimers
a
a
monomer
Eox (V)
dimer
Eox (V)
yield (%)
1ee
1m
1n
1o
5h
1u
1.13
0.78
0.84
0.92
0.89
0.52
2ee
2m
2n
2o
6h-u
1.07
0.71
0.96
1.03
0.56
40
36
56
70
97
a
Oxidation potentials obtained in HFIP, defined by the potential at
half peak height of local minimum for first oxidation wave.
shows poor reversibility, indicating that decomposition likely
occurs via overoxidation.
The oxidation potentials of substrates from Figure 1 further
suggest a correlation between the difference in oxidation
potentials of monomer/dimer and conversion. For example,
1o, which is more readily oxidized than its dimeric product,
affords 2o in 70% isolated yield. Conversely, 1m, which is less
readily oxidized than its dimeric product, provides 2m in only
36% yield. This model likely also accounts for the observation
that 1u, while more readily oxidized and nucleophilic at the
ortho-position than 1a, does not form dimer under the
coupling conditions described in Figure 1. However, 1u
(0.52 V) is more readily oxidized than its coupling partner 5h
(0.89 V) and the corresponding cross-coupling dimer 6h-u
(0.56 V), allowing for a high isolated yield of 6h-u (97%).
Based on these findings, it is evident that phenol nucleophil-
icity and oxidation potential are key factors in determining
overall reactivity and selectivity, but the oxidation potential of
the biphenol products should also be considered.
CONCLUDING REMARKS
■
In summary, a photocatalytic method for coupling phenols was
developed using MesAcr+BF4 . Mechanism studies suggest
−
that an oxidation of the phenol followed by the nucleophilic
addition of a neutral phenol is a plausible pathway. This
mechanistic paradigm may be relevant to biosynthetic phenol
coupling and is more plausible than two phenol radicals
reacting in a termination event, as is often proposed.63,64 With
the additional mechanistic understanding of how product
oxidation potential factors into the outcome, the design of new
catalytic systems can be undertaken.
The mechanistic model provided an insight into the
development of a cross-coupling method with the same
photocatalyst. The resultant process afforded a range of new
compounds in high yields and selectivities, as well as known
compounds with higher yields and selectivities. The method
permitted more diverse substitution patterns on the
nucleophilic coupling partner. Finally, the first nonenzymatic,
catalytic coupling of tyrosine was achieved with a ruthenium
photocatalyst.
Figure 5. Homocoupling of para-substituted phenols. Yields in
parentheses are based on recovery of starting material. Conditions: 0.5
mol % Ru(bpz)3[PF6]2, 25 mol % 4,4′-di-tert-Butylbiphenyl, HFIP,
O2, blue LEDs, 35 °C, 24 h.
The proposed radical−nucleophile coupling paradigm
(Scheme 2), which implies that reactivity relies solely on
oxidation potentials and site nucleophilicity parameters, fails to
explain the modest yields observed in the tyrosine homocou-
pling. In the chromium- and iron-catalyzed couplings reported
by Kozlowski and Pappo,17,18 covalently bound metal
phenolates are proposed and the product, which is more
sterically hindered, binds to the catalyst less readily. In
contrast, photo-oxidative processes do not proceed via inner
sphere oxidation, but through outer sphere electron transfer.
Therefore, we postulate that differences in oxidation potentials
between phenol monomers (1) and their corresponding
dimers (2) may lead to reaction inhibition. Cyclic voltammetry
(Table 4) reveals that the tyrosine dimer 2ee (1.07 V) is more
readily oxidized than the tyrosine monomer 1ee (1.13 V),
suggesting that the dimer can selectively quench the photo-
catalyst, accounting for lower conversion upon product
formation. Further, in the oxidation return sweep, the dimer
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c04515.
Experimental protocols and spectroscopic data (PDF).
Crystallographic data for 8054 (CIF)
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ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Density Factors on the Product Composition in the Oxidations of 3,5-
Dimethylphenol and Phenol. J. Chem. Soc. Perkin Trans. 1983, 2,
563−568.
AUTHOR INFORMATION
Corresponding Author
Marisa C. Kozlowski − Department of Chemistry, Roy and
Diana Vagelos Laboratories, University of Pennsylvania,
Philadelphia, Pennsylvania 19014, United States;
orcid.org/0000-0002-4225-7125; Email: marisa@
sas.upenn.edu
■
(10) Morimoto, K.; Sakamoto, K.; Ohnishi, Y.; Miyamoto, T.; Ito,
M.; Dohi, T.; Kita, Y. Metal-Free Oxidative Para Cross-Coupling of
Phenols. Chem. − Eur. J. 2013, 19, 8726−8731.
(11) More, N. Y.; Jeganmohan, M. Solvent-Controlled Selective
Synthesis of Biphenols and Quinones: Via Oxidative Coupling of
Phenols. Chem. Commun. 2017, 53, 9616−9619.
(12) Hwang, D. R.; Chen, C. P.; Uang, B. J. Aerobic Catalytic
Oxidative Coupling of 2-Naphthols and Phenols by VO(Acac)2.
Chem. Commun. 1999, 1207−1208.
Authors
Kyle A. Niederer − Department of Chemistry, Roy and Diana
Vagelos Laboratories, University of Pennsylvania,
Philadelphia, Pennsylvania 19014, United States;
orcid.org/0000-0001-9213-8303
Philip H. Gilmartin − Department of Chemistry, Roy and
Diana Vagelos Laboratories, University of Pennsylvania,
Philadelphia, Pennsylvania 19014, United States;
orcid.org/0000-0002-4052-9705
(13) Kirste, A.; Schnakenburg, G.; Stecker, F.; Fischer, A.;
Waldvogel, S. R. Anodic Phenol-Arene Cross-Coupling Reaction on
Boron-Doped Diamond Electrodes. Angew. Chem., Int. Ed. 2010, 49,
971−975.
(14) Kirste, A.; Schnakenburg, G.; Waldvogel, S. R. Anodic Coupling
of Guaiacol Derivatives on Boron-Doped Diamond Electrodes. Org.
Lett. 2011, 13, 3126−3129.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c04515
(15) Lee, Y. E.; Cao, T.; Torruellas, C.; Kozlowski, M. C. Selective
Oxidative Homo- and Cross-Coupling of Phenols with Aerobic
Catalysts. J. Am. Chem. Soc. 2014, 136, 6782−6785.
Notes
(16) Esguerra, K. V. N.; Fall, Y.; Petitjean, L.; Lumb, J. P.
Controlling the Catalytic Aerobic Oxidation of Phenols. J. Am. Chem.
Soc. 2014, 136, 7662−7668.
The authors declare no competing financial interest.
(17) Shalit, H.; Libman, A.; Pappo, D. Meso-Tetraphenylporphyrin
Iron Chloride Catalyzed Selective Oxidative Cross-Coupling of
Phenols. J. Am. Chem. Soc. 2017, 139, 13404−13413.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (CHE1764298) and the NIH (R35
GM131902) for the financial support of this research. Partial
instrumentation support was provided by the NIH and NSF
(1S10RR023444, 1S10RR022442, CHE-0840438, CHE-
0848460, 1S10OD011980, CHE-1827457). P.H.G. thanks
NSF for fellowship support (DGE-1845298). Dr. Charles W.
Ross III (UPenn) is acknowledged for obtaining accurate mass
data. We thank Dr. Patrick Carroll (UPenn) for X-ray analysis
and Dr. Sergei Tcyrulnikov (UPenn) for calculations of site
nucleophilicity values. We are grateful to William Neuhaus
(UPenn) for helpful discussions.
(18) Nieves-Quinones, Y.; Paniak, T. J.; Lee, Y. E.; Kim, S. M.;
Tcyrulnikov, S.; Kozlowski, M. C. Chromium-Salen Catalyzed Cross-
Coupling of Phenols: Mechanism and Origin of the Selectivity. J. Am.
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(19) Libman, A.; Shalit, H.; Vainer, Y.; Narute, S.; Kozuch, S.;
Pappo, D. Synthetic and Predictive Approach to Unsymmetrical
Biphenols by Iron-Catalyzed Chelated Radical-Anion Oxidative
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ACS Catal. 2018, 9, 521−555.
(21) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Total Synthesis
of Chiral Biaryl Natural Products by Asymmetric Biaryl Coupling.
Chem. Soc. Rev. 2009, 38, 3193−3207.
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