Photocatalytic Phenol–Arene C–C and C–O Cross-Dehydrogenative Coupling

Article abstract of DOI:10.1002/ejoc.201700211

Phenol-containing nonsymmetrical biaryls play an important role in natural-product synthesis, as ligands in metal catalysis, and in organic functional materials. Their synthesis through cross-coupling reactions by two-fold direct C–H activation are import

Full text of DOI:10.1002/ejoc.201700211

A Journal of
Accepted Article
Title: Photocatalytic Phenol-Arene C-C and C-O Cross-
Dehydrogenative Coupling
Authors: Anna Eisenhofer, Johnny Hioe, Ruth Gschwind, and Burkhard
König
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700211
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10.1002/ejoc.201700211
European Journal of Organic Chemistry
FULL PAPER
Photocatalytic Phenol–Arene C–C and C–O Cross-Dehydrogena-
tive Coupling
Anna Eisenhofer,[a] Johnny Hioe,[a] Ruth M. Gschwind,*[a] and Burkhard König*[a]
Abstract: Phenol-containing non-symmetrical biaryls play an
important role in natural product synthesis, as ligands in metal
catalysis and for organic functional materials. Cross-coupling
reactions by twofold direct C–H activation for their synthesis are
important and challenging transformations. In the last decade, a
variety of useful oxidative methods have been developed. The key
for efficiency and selectivity typically constitutes the application of
highly fluorinated solvent systems. Herein, we describe the visible
light-mediated C–C and C–O cross-coupling of electron-rich phenols
and arenes by using Ru(bpz)3(PF6)2 as photocatalyst and
ammonium persulfate as terminal oxidant. The method requires no
leaving group functionalities, which allows the use of simple
activated arenes as starting materials. Furthermore, the approach
features a good chemo- and regioselectivity as well as functional
group tolerance even by replacement of fluoroalcohols by
acetonitrile. The selectivity for the formation of the non-symmetrical
biaryls is rationalized on basis of the nucleophilicity N values and
oxidation potentials Eox of the electron-rich substrates.
at the same time a severe challenge due to the possible
formation of undesired homocoupling products, regioisomers
and overoxidation products. Metal salts such as CuII,[10] FeIII,[11]
TiIV,[12] AlIII,[13] MoV,[14] TlIII[15] have been successfully employed as
stoichiometric oxidants for the formation of biaryls. Also
combinations of metal catalysts (i.e. Pd, Fe, Cr, Cu) and a
metal-free terminal oxidant (i.e. air) are reported.[16] However,
these transformations are often limited to the homocoupling of
arenes or suffer from low chemoselectivity as well as (toxic)
metal waste. The challenge is to identify the factors that
determine the chemo- and regioselectivity and thus, to control
the formation of the anticipated cross-coupling products.
Recent developments in the field of oxidative phenol–arene C–C
cross-coupling demonstrated the applicability of hypervalent-
iodine based oxidants as reported by Kita et al.[17]
,
electrochemical methods as described by Waldvogel et al.[18]
and iron-catalyzed transformations using t-BuOOt-Bu as
terminal oxidant published by Pappo et al.[19] These strategies
provided a selective and easy access to the respective cross-
coupling products, but are typically limited in terms of efficiency
and (chemo)selectivity to highly fluorinated solvent systems, in
particular 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which are
expensive and have a large environmental footprint. Despite the
possibility of recycling of HFIP as shown for the electrochemical
protocol, the replacement of the fluorinated media would be
highly desirable. Waldvogel et al. obtained promising results by
substitution of HFIP by solvents with a strong hydrogen bonding
capability, like formic acid. The C–C cross-coupling products
were formed with good selectivity, but reduced yields.[18c, 20]
Different rationales were developed in order to explain the
observed efficiency and tendency for cross- vs. homocoupling.
Waldvogel and coworker rationalized the selectivity for C–C
cross-coupling as a result of a decoupling of oxidation potential
Eox and nucleophilicity by formation of different HFIP
solvates.[18d] Pappo et al. developed an operational simple tool
to predict the selectivity for iron-catalyzed phenol–phenol C–C
cross-coupling reactions, which proceed via a radical−anion
coupling mechanism, by comparing the Eox and nucleophilicity N
values of the phenol substrates.[19b],[21] On the basis of the model
a selective C–C cross-coupling takes place if the phenol
component a is more readily oxidized to the corresponding
phenoxyl radical a• than the phenol coupling partner b (Eox(a) <
Eox(b)), which constitutes the stronger nucleophile (Nb > Na).
In the last decade, visible light photoredox catalysis developed
as a mild and versatile method for the activation of C–H bonds
and may provide a valuable, alternative mechanistic concept for
the oxidative biaryl synthesis.[22] The feasibility of phenol
activation by photocatalysis was demonstrated by early work of
Introduction
Non-symmetrical biaryls including a phenol moiety represent an
important structural motif in natural products and pharmaceutical
active compounds,[1] as phenols, especially oxygenated
derivatives like guaiacol, are ubiquitous in nature and their
oxidation is involved in the biogenesis of biologically active,
naturally occurring products.[2] Moreover, biaryls constitute
important ligands for transition metal catalysis[3] and are versatile
building blocks for organic functional materials.[4]
Conventional C–C cross-coupling strategies for the synthesis of
biaryls, like Suzuki and Negishi coupling, are powerful and
established methods, but require the prefunctionalization of the
starting materials by introduction of leaving groups, complex
catalyst systems often based on transition metals and typically a
protection of the phenol hydroxyl group.[5] Due to the impact of
green chemistry principles in organic synthesis the demand for
the development of cross-coupling methods by direct C–H
functionalization emerged. Over the past decades a variety of
efficient protocols for the cross-coupling of arenes with only one
prefunctionalized coupling partner were developed.[6],[7]
Especially attractive in terms of atom economy and efficiency is
the cross-coupling of arenes by twofold direct C–H activation.[6c-e,
8],[9]
However, the absence of leaving functionalities constitutes
[a]
Dr. A. Eisenhofer, Dr. J. Hioe, Prof. Dr. R. M. Gschwind, Prof. Dr. B.
König
Ohkubo
et
al.;
they
described
the
photocatalytic
University of Regensburg, Faculty of Chemistry and Pharmacy,
Institute of Organic Chemistry, D-93040 Regensburg, Germany
E-mail: Ruth.Gschwind@ur.de, Burkhard.Koenig@ur.de
http://www-oc.chemie.uni-regensburg.de/gschwind/
http://www-oc.chemie.uni-regensburg.de/koenig/
homodimerization of naphthols.[23] Recent examples from the
groups of Yoon and Wang photocatalytically activated phenols
for the construction of dihydrobenzofurans.[24] Rüping et al.
developed a method for the ortho olefination of protected
phenols bearing a directing group in a dual catalytic approach.[25]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700211
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of reaction conditions for the oxidative phenol–arene cross-coupling.[a],[b]
Yield [%][c]
Conv.
Entry[a]
Equiv. 1b
Catalyst
Solvent
t [h]
Oxidant
1a %][c]
1ab
30
48
52
53
50
65
66
66
59
37
68
69 (62)
0
1ab’
1abb
1
3
2 mol% [1](PF6)2
2 mol% [1]Cl2
HFIP/MeOH[d]
HFIP/MeOH[d]
MeCN
24
24
24
36
24
24
18
18
18
18
18
18
18
18
Air
43
68
73
79
81
96
96
96
96
87
97
97
-
3
-
2
3
Air
5
2
3
3
2 mol% [1](PF6)2
2 mol% [1](PF6)2
4 mol% [1](PF6)2
2 mol% [1](PF6)2
2 mol% [1](PF6)2
2 mol% [1](PF6)2
2 mol% [1](PF6)2
2 mol% [1](PF6)2
1 mol% [1](PF6)2
0.5 mol% [1](PF6)2
Air
4
1
4
3
MeCN
Air
3
2
5
3
MeCN
Air
2
1
6
3
MeCN
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
7
23
7
3
MeCN
7
24
8
2
MeCN
5
19
9
1.5
1
MeCN
4
18
10
11
12
13
14
MeCN
8
8
2
MeCN
5
26
2
MeCN
5 (5)
0
23 (23)
[e]
3
2 mol% [1](PF6)2
MeCN
-
-
2
No catalyst
MeCN
13
3
0
[a] Reaction conditions: 2-methoxy-4-methylphenol 1a (0.20 mmol, 0.25 M), 1,2,4-trimethoxybenzene 1b (1-3 equiv.), air or ammonium persulfate (1.5 equiv.)
and the respective photocatalyst were irradiated with blue LEDs open to air for entries 1-5 and under a N2-atmosphere for entries 6-14 at 23 °C in the respective
solvent (dry), unless otherwise noted. [b] The potentials of the catalyst are given in Volt vs. SCE.[26] [c] Quantitative HPLC yields using acetanilide as internal
standard. [d] HFIP + 18 Vol% MeOH. [e] Reaction under exclusion of light.
The visible light-mediated amination of phenols[27] and arenes[28]
was reported recently.
product 1ab was obtained in 30% yield along with traces of the
C–O connected cross-coupling product 1ab’ (Table 1, entry 1).
Such bis-aryl ether by-products for the oxidative cross-coupling
of phenols and arenes are rare and are reported by the groups
of Peddinti[30] and Waldvogel[18b] for very few examples. The
In this study, a visible light-mediated oxidative phenol−arene
cross-coupling reaction is described using Ru(bpz)3(PF6)2 as
photocatalyst with low catalyst loadings and ammonium
persulfate as mild terminal oxidant. The approach requires no
leaving group functionalities or protection of the phenol hydroxyl
group, which allows the use of simple electron-rich starting
materials. The observed selectivity is rationalized by comparing
the oxidation potential Eox and nucleophilicity N values of the
substrates.
-
exchange of the counterion from PF6 to Cl- improved the
solubility of the photocatalyst in the HFIP/MeOH mixture and led
to an increased product yield of 48% (Table 1, entry 2). A screen
of solvents showed that acetonitrile could substitute the highly
fluorinated solvent mixture without loss of selectivity and even a
slightly increased yield (Table 1, entries 1-3 and Table S1 in the
SI). In acetonitrile an exchange of the counterion to chloride was
detrimental (for details see SI). An enhanced reaction time or
catalyst loading could not further improve the yield, but the
replacement of air by ammonium persulfate as terminal oxidant
led to full conversion of the activated phenol 1a (Table 1, entries
4-6) and the non-symmetrical biaryl 1ab was obtained in 65%
yield. Ammonium persulfate is a reported oxidative quencher of
photoexcited ruthenium polypyridyl complexes and provide
Results and Discussion
We focused our initial studies on the oxidative cross-coupling
between 4-methylguaiacol 1a and 1,2,4-trimethoxybenzene 1b,
which are reported to undergo preferentially cross- instead of
homocoupling by electrochemical oxidation in HFIP/MeOH
solvent systems,[18b] to find and optimize suitable photocatalytic
conditions. The photoreactions were performed at 23 °C and
irradiated with blue LEDs. Ru(bpz)3(PF6)2 [1] was used as
photocatalyst, as phenols are literature known reductive
quencher of its excited state (Table 1).[29] To our delight, when
air was used as terminal oxidant, the desired cross-coupling
3+
access to the strongly oxidative Ru(bpz)3 species for the
phenol oxidation.[31] The combination of Ru(bpz)3(PF6)2 and
persulfate was also beneficial for the [3+2]-cycloaddition of
activated phenols and styrenes reported by Yoon et al.[24a] The
C–C vs C–O chemoselectivity for the biaryl products (1ab:1ab’)
almost retained under these conditions. However, the stronger
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oxidative conditions led to a higher formation of the teraryl 1abb
as a single isomer. Within the system with ammonium persulfate
as terminal oxidant the equivalents of the electron-rich coupling
partner 1b and the catalyst loading could be reduced without
loss of selectivity and yield (Table 1, entries 7-10, 11-12). A
change of the photocatalyst to the less oxidizing Ru(bpy)3(PF6)2
[2] results in slower rates and incomplete conversion (Table S2
in the SI). The homocoupling product 1bb was not detected by
HPLC under all applied conditions (< 1% with regard to the
detection limit). Control experiments in the absence of
photocatalyst or light confirmed the photocatalytic nature of the
reaction (Table 1, entries 13-14).[32]
Under consideration of the Eox and N values, the phenol–arene
pairs were divided in 3 categories (Table 2). In categories 1-2
the oxidation of the phenol a is thermodynamically favored
(Eox(a) < Eox(b)) and the nucleophilicity N of the arene coupling
partner b range from strong (category 1) to moderate (category
2). Category 3 covers the inverse region of the oxidation
potentials (Eox(a) > Eox(b)) in the presence of the strong,
electron-rich arene nucleophile 1b.
Table 3. Oxidation potentials Eox and calculated global nucleophilicity N values
of various activated phenols and arenes. The oxidation potentials are sorted in
an increasing order.
The scope of the oxidative phenol–arene cross-coupling was
investigated using the optimized reaction conditions (phenol
(1 equiv., 0.25 M in MeCN (dry), arene (2 equiv.), ammonium
persulfate (1.5 equiv.) and Ru(bpz)3(PF6)2 (0.5–2 mol%), blue
LEDs, N2, 23 °C). The results are summarized in Table 2.
The desired C–C cross-coupled biaryls ab were obtained for
various combinations of electron-rich phenols and arenes with
moderate to good yields and high functional group tolerance. To
our surprise a varying content of C–O connected biaryls ab’
were isolated, which even became the main product for some
phenol–arene pairs.[33]
In order to explain the observed product distribution for the biaryl
formation (coupling mode and cross- vs. homocoupling), the
oxidation potentials Eox and nucleophilicity N values[34],[35] of the
electron-rich substrates were determined by cyclic voltammetry
(CV) and density functional theory (DFT) methods (Table 3),
respectively, and analyzed in analogy to the electrochemical[18d]
and iron-catalyzed[19b] selectivity rationales for oxidative cross-
coupling reactions.
The first selectivity determining parameter for the formation of
the biaryl products is the initiating oxidation step. Depending on
the tendency for oxidation, which can be estimated from Eox,
either the phenol a or the arene b are assumed to enter the
catalytic cycle and provide the corresponding phenoxyl radical a•
(pathway 1: Eox(a) < Eox(b)) or arene radical cation b•+ (pathway
2: Eox(a) > Eox(b)) (Scheme 1). Phenoxyl radicals a• are
resonance-stabilized and the spin density distribution depends
amongst others on the type and position of the substituents.
However, phenoxyl radicals a• with unsubstituted ortho- or para-
positions are reputed to couple via these electrophilic carbon
atoms in the first coupling step.[18b],[33],[36],[37],[38] The second
parameter, which we propose to determine the efficiency and
selectivity in analogy to the literature reported rationales,[18d, 19b]
is the nucleophilicity strength N of the coupling partner.
Entry
Substrate
Eox [V][a]
N (eV)[b]
1
4-methoxy-1-naphthol (2a)
0.87
1.01
1.02
1.02
1.10
1.10
1.11
1.15
1.23
1.32
1.34
1.35
1.36
1.48
4.05
4.07
3.81
3.82
3.64
3.68
3.70
3.63
3.37
3.09
3.55
3.38
3.51
3.46
2
1,2,4-trimethoxybenzene (1b)
2-tert-butyl-4-methoxyphenol (4a)
4-methoxy-2-methylphenol (3a)
2,6-dimethoxyphenol (5a)
3
4
5
6
2-methoxy-4-methyl-phenol (1a)
4-ethyl-2-methoxyphenol (6a)
4-allyl-2-methoxyphenol (7a)
4-chloro-2-methoxy-phenol (8a)
2-chloro-4-methylphenol (9a)
1,3,5-trimethoxybenzene (3b)
2,6-diphenylphenol (10a)
7
8
9
10
11
12
13
14
2-methoxynaphthalene (2b)
1-bromo-2,4-dimethoxybenzene (4b)
[a]
The oxidation potentials (peak potentials) were determined by CV using
tetrabutylammonium tetrafluoroborate as the supporting electrolyte in MeCN
(0.1 M) at a scan rate of 50 mV s−1. Ferrocene was used as internal standard.
The potentials are given in Volt vs. SCE.[39] [b] The energy of the HOMO of the
selected substrate was calculated by DFT methods at the B3LYP-D3/6-
311+G(d,p) level of theory[35] and the nucleophilicity N values are referenced
against the HOMO of tetracyanoethylene (TCE).
Category 1 (Eox(a) ≤ Eox(b), Nb ≥ Na). For phenol–arene pairs of
category 1 the oxidation of the phenol component (2a-4a) is
favored and the arene coupling partner 1b constitutes a strong
nucleophile, which is shown by a high N value (4.07 eV). The
expected biarylic C–C cross-coupling products (2ab-4ab) are
obtained with moderate to good yields and selectivity. The arene
1b reacted at the most nucleophilic position and no regioisomers
as well as homocoupling products or C–O coupled biaryls ab’
were formed supporting the mechanistic rationale in Scheme 1.
Interestingly, for 4-alkoxy cross-coupling products (2ab-4ab) a
prolonged irradiation time and higher catalyst loading led to a
further oxidation to the corresponding benzo- and naphtho-
quinone products (2q-4q) (see Scheme 2).[40] The profile (see
Figure S13 in the SI) of the reaction between 4-methoxy-1-
naphthol 2a and 1,2,4-trimethoxybenzene 1b indicates that the
formation of the products takes place successively and excludes
the formation of the naphthoquinone product 2q by cross-
coupling of oxidized naphthol starting material with arene 1b.
Using 2 mol% Ru(bpz)3(PF6)2 under otherwise identical condi-
tions provided 67% 2q after 18 h of irradiation with blue LEDs.
On the basis of our results we propose, that the C–C coupled
biaryls ab are formed predominately on the pathway 1 via the
intermediacy of the phenoxyl radicals a•, which are trapped by
an arene nucleophile b, if b provides a high N value. Whereas,
the C–O coupled biaryls ab’ are assumed to be accessed via
the pathway
2
with the phenol component
a
acting
predominately as O-nucleophile trapping the arene radical cation
b+•. The formation of the homocoupling products bb is proposed
to proceed via pathway 2. The final products are obtained after
another oxidation/deprotonation step (Scheme 1).
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Table 2. Scope of the photocatalytic oxidative phenol–arene cross-coupling by direct C–H activation. The phenols a are sorted in an increasing order regarding
[a]
the oxidation potentials Eox
.
Yield [%][c]
Category
Entry
1
Phenol
Arene
t [h][b]
arecov.
ab
ab’
abb
bb
78
(2ab)
[e]
3
5
-
-
-
-
-
1
61
(3ab)
[f]
2
3
5
6
24
41
-
-
Eox(a) ≤ Eox(b)
Nb ≥ Na
44
(4ab)
[g]
-
-
31
(5ab)
[l],[j]
4
22
16
18
22
-
-
traces[j]
-
24
(6ab)
5[d]
traces[j]
traces[j], [k]
-
2
Eox(a) < Eox(b)
Nb ≈ Na
23
(7ab)
30
(7abb)
6[d]
10
-
-
traces[j]
(8ab)
[l],[j]
7[d]
18
18
44
-
-
-
-
-
79
(9ab)
15
(9abb)
8[d]
-
-
-
62
(1ab)
5
23
(1abb)
9
18
18
16
21
18
40
-
(1ab’)
46
(10ab)
6
24
(10abb)
10
11
12
13
14
5
(10ab’)
3
36
(11ab)
21
(11ab’)
18
(11abb)
10
27
52
19
-
Eox(a) > Eox(b)
Nb > Na
21
(12ab)
34
(12ab’)
10
(12abb)
4
(1bb)
7
17[i]
(13ab’)
traces
25
(1bb)
[j], [k]
(13ab)
10
(14ab)
44
(14ab’)
27
(14abb)
6
(1bb)
[a] Reaction conditions: phenol (0.20 mmol, 0.25 M), arene (2 equiv.), ammonium persulfate (1.5 equiv.) and 0.5 mol% Ru(bpz)3(PF6)2 were irradiated with blue
LEDs under a N2-atmosphere at 23 °C in MeCN (dry), unless otherwise noted. [b] End of reaction was judged by TLC and/or HPLC analysis indicated by either no
further conversion of starting material or complete consumption of starting material. For 4-methoxyphenols and –naphthols a color change to dark red indicates
initiation of quinone formation and marks the end of the reaction. [c] Yield of isolated products. [d] 2 mol% Ru(bpz)3(PF6)2 were used. [e] 6% of naphthoquinone 2q
were isolated. [f] 5% of benzoquinone 3q were isolated. [g] 15% of benzoquinone 4q were isolated. [h] Local nucleophilicity index (Nk-) values from reference[34]. [i]
A second minor regioisomer was detected. [j] The product amount was too small for preparative isolation and characterization. See LC-MS data in the Supporting
Information. [k] Several teraryls as a mixture. [l] Traces of the homocoupling product of phenol a were detected by mass analytics.
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Scheme 1. Proposed predominate pathways for the photocatalytic phenol–arene C–C and C–O oxidative cross-coupling reaction for the formation of biaryls ab
and ab’.[41],[26a, 42] Ammonium persulfate oxidatively quenches the excited state of Ru(bpz)32+* generating the corresponding Ru3+ species and the oxygen-centered
sulfate radical anion SO4•–, which is a very strong oxidant capable of oxidizing Ru2+ in the ground state providing a second equivalent of Ru3+ [31], [43]
The
.
intermediacy of phenoxyl radicals was confirmed for the phenol–arene coupling between 1a and 1b by trapping with the persistent radical TEMPO.
investigated series within category 3 the arene 1b was kept
unchanged as strong nucleophile. According to the mechanistic
rationale (Scheme 1) the formation of products derived from
pathway 2, the C–O coupled product ab’ and the homocoupling
product 1bb of the arene component, are expected. However,
also the phenol–arene C–C cross-coupled biaryls (1ab, 9ab-
14ab) were formed with up to 79 % yield (9ab). Within the
category 3 the amount of C–C coupled biaryl ab decreased with
increasing oxidation potentials of the phenol a and thus,
increasing off-set in the oxidation potentials between phenol a
and arene b. The formation of the C–O coupled biaryl ab’
initiates at an off-set in the potentials of ~0.1 V, the arene
homocoupling product 1bb at an off-set of ~0.2 V. Furthermore,
the amount of ab’ and bb increased as expected with the
oxidation potential of the phenol substrate a.
Scheme 2. Photocatalytic formation of naphthoquinone–arene coupling
product 2q.
Category 2 (Eox(a) < Eox(b), Nb ≈ Na). Category 2 covers phenol–
arene pairs, for which the oxidation potential of the phenol a is
significantly lower than for the arene b, but the nucleophilicity N
values of both substrates are moderate and in the same range.
On basis of the mechanistic rationale a mixture between the
desired mixed C–C coupled biaryl ab and the homocoupling
product of the corresponding phenol aa is expected. The mixed
C–C coupled biaryls 5ab-7ab were obtained with moderate
yields. The nucleophilicity of arene 4b is not sufficient to provide
the respective cross-coupling product, determining the limit of
the method. However, no phenol homocoupling products aa
were isolated[44] and the mass balance for the component a
indicate, that the phenol components a undergo under these
conditions polymerization rather than the expected dimerization.
The absence of C–O coupled biaryls 5ab’, 7ab’ and 8ab’ in
Wenger et al. suggested that phenols can form weakly hydrogen
bonded encounter adducts with the peripheral nitrogen atoms of
2+*
the bipyrazine ligand of the Ru(bpz)3 catalyst.[29] Furthermore,
it is known that bases, e.g. pyridine or inorganic salts, lower the
oxidation potential of phenolic compounds due to a partial
deprotonation of the hydroxyl group resulting in an enhanced
electron density and a facilitated electron transfer.[45] Thus, we
propose that a pre-organization between the phenol substrates a
and the catalyst via hydrogen bonding occurs (not applicable for
compound class b). We assume further that the pre-organization
enables the selective and efficient conversion of substrates to
the C–C cross-coupled biaryls ab via pathway 1 with an offset of
ΔEox = Eox(a) - Eox(b) < 0.10 V. A similar effect was reported by
Waldvogel and coworkers,[18b] they showed that the addition of
MeOH to the HFIP solvent reduced the oxidation potential of the
phenol substrate, which allow the selective cross-coupling with
arenes even if the original potential in pure HFIP was higher.
category
2 further supports the mechanism proposed in
Scheme 1 for their formation.
Category 3 (Eox(a) > Eox(b), Nb > Na). Phenols (1a, 5a-10a) of
category 3 exhibit a higher oxidation potential than the arene
component b. The oxidation potentials of the phenolic substrate
were increased stepwise from entry 8 to 14. Throughout the
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10.1002/ejoc.201700211
European Journal of Organic Chemistry
FULL PAPER
The mechanism in Scheme 1 for the formation of C–O coupled
biaryls ab’ via an O-nucleophilic attack of the phenol on the
arene radical cation b•+ (pathway 2) is supported by comparing
the relative amount of C–O coupled biaryls ab’ and the
homocoupling product 1bb with the N values of the applied
phenols a.[46] Phenols with high nucleophilicity N value (1a, 6a-
7a) exclusively provided the biaryl ab’ and no homocoupling
product 1bb is formed, phenols (8a, 10a) with moderate N value
led to a low formation of the symmetrical biaryl 1bb in addition to
the biaryl ab’, whereas for the very poorly nucleophilic phenol 9a
25% of the by-product 1bb were isolated. However, we also
want to point out that the distribution of the spin density of
phenoxyl radicals a• is affected by the type and position of
substituents on the aromatic ring, which can lead to an
increased spin density on the O-atom and thus can serve as an
alternative explanation for the formation of the C–O cross-
coupled biaryls ab’ by a cross-coupling of electrophilic a• with a
nucleophile b via pathway 1.[36a-e, 36g, 37a, 38] For example, bulky
ortho-groups stabilize the O-radical and thus an increased
reactivity of the phenoxyl radical via the oxygen atom is
possible.[36g] Pappo et al. investigated the influence of ortho-
groups on the regioselectivity and coupling mode for the
consecutive formation of teraryls.[36d] However, due to the
dependency of the product distribution ab’:bb on the
nucleophilicity N of the phenol a, the correlation between the Eox
of the phenols a and the relative amount of C–O coupling
product ab’ as well as the high potential difference for category
3 couplings (in particular entries 12-14), we assume that the
proposed mechanism in scheme 1 is dominant. A coexistence of
both mechanisms cannot be unambiguously excluded at this
stage.
In addition to the discussed biaryls the corresponding teraryls
(1abb, 7abb, 9abb-12abb, 14abb) were obtained in most cases
as single isomeric species in minor amounts (Table 2).[47]
Overoxidation e.g. to oligomers or polymers constitutes a sever
challenge especially for the cross-dehydrogenative coupling of
oxygenated aryl compounds, because the products often exhibit
a lower oxidation potential than the corresponding starting
materials (compare Table S3 and Table S4 in the SI). For the
electrochemical protocol the formation of undefined oligomeric
and polymeric by-products is reported in some cases.[18a] We
observed a single teraryl species abb, which provide access to
complex structures within a single step.[48] In order to determine
the pathways for the formation of the teraryl 1abb, the biaryl
products (1ab, 1ab’) were isolated and subjected to the
photocatalytic conditions (Figure S7 and Scheme S3 in SI). Both,
the C–C 1ab and C–O 1ab’ cross-coupling product provided the
teraryl 1abb. Thus, for the formation of teraryl species different
pathways are possible. Consequently, the rationalization on
basis of Eox and N is not trivial and required further investigation.
The possible formation routes are presented in the SI.
functionalization of the electron-rich substrates under mild,
photocatalytic conditions. The access in a single step is very
attractive and may constitute an alternative to conventional
synthetic methods.[49] However, further investigations are
required to improve the efficiency and selectivity for the C–O
coupling.
Conclusions
In conclusion, an efficient and mild photocatalytic C–C and C–O
cross-dehydrogenative coupling of electron-rich phenols and
arenes in a single step under visible light irradiation was
reported, using low catalyst loadings of Ru(bpz)3(PF6)2 and
ammonium persulfate as terminal oxidant. The direct C–H
activation avoids the pre-functionalization of the electron-rich
starting materials and thus enables the use of simple arenes.
Furthermore, the photocatalytic cross-coupling method has a
high functional group tolerance (e.g. halogen-moieties are
conserved) and provides good synthetic yields. The tendency
and efficiency for cross- vs. homocoupling and the coupling
mode were rationalized on basis of the oxidation potentials Eox
and nucleophilicity N values.
Experimental Section
General: NMR-spectra were recorded on a Bruker Avance 400 (III HD)
(1H: 400 MHz, 13C: 101 MHz; T = 300 K, if not stated otherwise), Bruker
Avance 300 (1H: 300 MHz, 13C: 75 MHz, T = 295 K) or a Bruker III 600
(1H: 600 MHz, 13C: 151 MHz, T = 295 K) using the solvent residual peak
as internal reference (CDCl3: δ H 7.26; δ C 77.0). Chemical shifts δ are
reported in ppm. Multiplicities are indicated, s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), sept (septet), m (multiplet); coupling
constants (J) are given in Hertz (Hz). Reactions were monitored by thin-
layer chromatography using silica gel plates ALUGRAM Xtra SIL
G/UV254 from Macherey-Nagel; visualization was accomplished with UV
light (254 nm or 366 nm). Flash column chromatography was performed
on a Biotage Isolera One automated flash purification system with UV-Vis
detector using Sigma Aldrich MN silica gel 60 M (0.040-0.063 mm, 230-
400 mesh) for normal phase chromatography. Cyclic voltammetry (CV)
measurements were performed with the three-electrode potentiostat
galvanostat PGSTAT302N from Metrohm Autolab. Mass spectra were
recorded on Finnigan MAT95 (EI-MS), Agilent Q-TOF 6540 UHD (ESI-
MS, APCI-MS), Finnigan MAT SSQ 710
ThermoQuest Finnigan TSQ 7000 (ES-MS, APCI-MS) spectrometer.
HPLC analytics were performed on HPLC 1220 from Agilent
A (EI-MS, CI-MS) or
a
technologies fitted with a C18 analytical column (Phenomenex Luna,
particle size 3 μm, 150 x 2.0 mm, 100 Å) and VWD. HPLC was calibrated
by the internal standard method (multi-level calibration, internal standard:
acetanilide). Gradient elution was done with water (millipore, 0.05 v/v%
trifluoroacetic acid) (solvent A) and acetonitrile (solvent B) at a constant
flow rate of 0.3 mL/min. A gradient profile with the following proportions
of solvent B was applied [t (min), % B]: (0, 10), (25, 90), (30, 90). The
injection volume was 1 μL. Column oven temperature was set to 40°C.
The chromatograms were monitored with wavelength switching [t (min), λ
(nm)]: (0, 260), (10, 280). For irradiation with blue light Osram Oslon SSL
80 LEDs (λPeak = 440 nm, royal blue, operated at 700 mA) were used.
Within the constraints of ΔEox < 0.10 V the efficiency and
selectivity of the phenol–arene C–C cross-coupling for the
formation of biaryls is competitive with previously reported
systems under consideration of the replacement of HFIP. The
C–O coupling, initiating at an off-set in the potentials of ~0.1 V,
enables the formation of the bis-aryl ethers ab’ without pre-
General procedure for the photocatalytic phenol-arene coupling: In
a
crimp cap vial the appropriate phenol (1.0 equiv., 200 µmol),
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10.1002/ejoc.201700211
European Journal of Organic Chemistry
FULL PAPER
Ru(bpz)3(PF6)2 (0.5 - 2 mol %, see Table 2), ammonium persulfate
(1.5 equiv.) and the arene coupling partner (2 equiv.) were dissolved in
dry MeCN (0.25 M) equipped with a magnetic stir bar. The solution was
degassed by three freeze-pump-thaw cycles. The resulting mixture was
irradiated (blue LEDs) through the vial’s plane bottom side for the
indicated time. The temperature was kept constant at 23 °C. After the
irradiation period the reaction mixture was diluted with EtOAc and filtered
over a plug of silica gel. The filtrate was concentrated in vacuum and
purified by automated flash column chromatography (silica gel,
hexane/EtOAc).
56.19, 55.70, 16.87. HRMS (ESI): calcd. for C17H21O5 (M+H)+, m/z =
305.1384; found 305.1387.
2',4',5'-Trimethoxy-3-methyl-[1,1'-biphenyl]-2,5-dione (3q): Rf = 0.22
(hexane/EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 6.76 (d, J = 2.7 Hz,
1H), 6.72 (s, 1H), 6.63 (dq, J = 3.0, 1.6 Hz, 1H), 6.58 (s, 1H), 3.93 (s, 3H),
3.84 (s, 3H), 3.76 (s, 3H), 2.11 (d, J = 1.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ = 187.84, 186.40, 152.04, 151.12, 146.28, 145.30, 142.99,
133.99, 132.98, 113.93, 97.55, 56.57, 56.52, 56.07, 16.41. HRMS (ESI):
calcd. for C16H17O5 (M+H)+, m/z = 289.1071; found 289.1076.
2-Hydroxy-2',3,4',5'-tetramethoxy-5-methylbiphenyl (1ab):[18a] 1H
NMR (300 MHz, CDCl3): δ = 6.85 (s, 1H), 6.71 (d, J = 1.9 Hz, 1H), 6.69
(d, J = 1.9 Hz, 1H), 6.65 (s, 1H), 5.98 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H),
3.86 (s, 3H), 3.81 (s, 3H), 2.33 (s, 3H). 13C NMR (75 MHz, CDCl3): δ =
150.25, 149.17, 147.34, 143.48, 140.79, 129.13, 125.10, 123.30, 118.47,
114.92, 111.13, 98.34, 57.17, 56.35, 56.03, 55.89, 21.05. MS (EI): m/z
(%): 304.2 (100), 289.1 (17), 272.1 (5), 261.1 (11), 257.2 (34), 229.0 (7),
152.1 (12), 115.1 (7).
3-(tert-Butyl)-2-hydroxy-2',5,4',5'-tetramethoxy-biphenyl (4ab):[17d] Rf
= 0.33 (hexane/EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 6.93 (d, J =
3.1 Hz, 1H), 6.86 (s, 1H), 6.67 – 6.64 (m, 2H), 6.09 (s, 1H), 3.95 (s, 3H),
3.87 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 1.45 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ = 152.81, 149.71, 149.65, 146.41, 144.33, 139.13, 127.28,
119.17, 115.52, 113.38, 112.67, 98.61, 57.54, 56.51, 56.24, 55.67, 35.19,
29.65. HRMS (ESI): calcd. for C20H27O5 (M+H)+, m/z 347.1853; found
347.1860.
1,2,4-Trimethoxy-5-(2-methoxy-4-methylphenoxy)benzene
(1ab’):
3-(tert-Butyl)-2',4',5'-trimethoxy-[1,1'-biphenyl]-2,5-dione (4q): Rf
=
Rf = 0.31 (hexane/EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 6.78 (d,
J = 1.8 Hz, 1H), 6.64 (s, 1H), 6.63 – 6.60 (m, 1H), 6.59 (s, 1H), 6.56 (d,
J = 8.1 Hz, 1H), 3.89 (s, 6H), 3.80 (s, 3H), 3.73 (s, 3H), 2.31 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ = 149.30, 145.56, 145.07, 144.92, 143.34,
138.41, 132.50, 120.89, 116.29, 113.27, 106.29, 100.48, 57.39, 56.52,
55.93, 21.10. HRMS (ESI): calcd. for C17H21O5 (M+H)+, m/z = 305.1384;
found 305.1387.
0.33 (hexane/EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 6.72 (s, 1H),
6.68 (d, J = 2.6 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.58 (s, 1H), 3.93 (s,
3H), 3.85 (s, 3H), 3.75 (s, 3H), 1.33 (s, 9H). 13C NMR (101 MHz, CDCl3):
δ = 188.32, 186.53, 157.18, 151.92, 151.43, 148.32, 143.26, 131.71,
130.99, 114.96, 113.61, 97.67, 56.60, 56.52, 56.15, 35.52, 29.24. HRMS
(ESI): calcd. for C19H23O5 (M+H)+, m/z 331.1540; found 331.1545.
1-(2-Hydroxy-3-methoxy-5-methylphenyl)-2-methoxynaphthalene
(5ab):[18a] 1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 9.0 Hz, 1H), 7.85 –
7.81 (m, 1H), 7.52 – 7.46 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.38 – 7.32
(m, 2H), 6.80 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 5.38 (s, 1H),
3.95 (s, 3H), 3.90 (s, 3H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3): δ =
154.21, 146.67, 141.29, 133.48, 129.52, 129.13, 128.86, 127.87, 126.37,
125.20, 124.31, 123.55, 122.09, 120.37, 113.82, 111.12, 56.92, 55.87,
21.22. MS (ESI): m/z (%) = 295.1 (100, MH+), 312.2 (34, MNH4+), 611.2
(30, 2MNa+).
2',3,4',5'-Tetramethoxy-5-methyl-2-(2,4,5-trimethoxyphenoxy)-1,1'-
biphenyl (1abb): Rf = 0.32 (hexane/EtOAc, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 6.77 (s, 1H), 6.77-6.73 (m, 2H), 6.44 (s, 1H), 6.41 (s, 1H),
6.19 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.70 (s, 3H), 3.68 (s,
3H), 3.61 (s, 3H), 3.60 (s, 3H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ = 152.21, 150.69, 148.59, 142.92, 142.72, 142.27, 142.16, 141.95,
139.31, 134.15, 132.50, 124.34, 117.87, 114.66, 112.24, 101.46, 100.91,
97.33, 57.38, 56.62, 56.58, 56.21, 56.03, 55.93, 55.85, 21.46. HRMS
(ESI): calcd. for C26H31O8 (M+H)+, m/z = 471.2013; found 471.2011.
2-Hydroxy-2',3,4',6'-tetramethoxy-5-methyl-biphenyl (6ab):[18a] 1H
NMR (300 MHz, CDCl3): δ = 6.68 (d, J = 1.9 Hz, 1H), 6.60 (d, J = 1.8 Hz,
1H), 6.25 (s, 2H), 5.37 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.74 (s, 6H),
2.31 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 160.98, 158.66, 146.59,
141.17, 128.33, 124.56, 120.34, 110.99, 107.34, 91.06, 56.06, 55.75,
55.34, 21.26. MS (ESI): m/z (%) = 305.1 (100, MH+), 631.3 (22, 2MNa+).
1-Hydroxy-4-methoxy-2-(2,4,5-trimethoxyphenyl)naphthalene
(2ab):[17b] 1H NMR (300 MHz, CDCl3): δ = 8.39 – 8.32 (m, 1H), 8.26 –
8.19 (m, 1H), 7.59 – 7.47 (m, 2H), 6.97 (s, 1H), 6.73 (s, 1H), 6.72 (s, 1H),
6.70 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ = 149.64, 149.59, 149.45, 144.56, 142.82,
126.53, 126.04, 125.88, 125.67, 122.75, 121.52, 119.53, 117.97, 115.37,
106.42, 98.96, 57.87, 56.61, 56.20, 55.82. MS (ESI): m/z (%) = 341.1 (43,
MH+), 703.3 (21, 2MNa+).
4-Hydroxy-2',3,4',5,6'-pentamethoxy-biphenyl (7ab):[36d] Rf
= 0.11
(hexane/EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 2H), 6.23
(s, 2H), 5.50 (s, 1H), 3.87 (s, 6H), 3.87 (s, 3H), 3.74 (s, 6H). 13C NMR
(101 MHz, CDCl3): δ = 160.35, 158.41, 146.41, 133.50, 124.75, 112.46,
107.99, 90.95, 56.20, 55.93, 55.38. HRMS (ESI): calcd. for C17H21O6
(M+H)+, m/z = 321.1333; found 321.1337.
2-(2,4,5-Trimethoxyphenyl)naphthalene-1,4-dione (2q):[50] 1H NMR
(600 MHz, CDCl3): δ = 8.17 – 8.09 (m, 2H), 7.78 – 7.73 (m, 2H), 7.05 (s,
1H), 6.83 (s, 1H), 6.62 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H).
13C NMR (151 MHz, CDCl3): δ = 185.32, 183.93, 152.27, 151.27, 147.31,
143.09, 136.46, 133.64, 133.53, 132.70, 132.15, 126.94, 125.92, 114.27,
114.19, 97.72, 56.64, 56.60, 56.12. MS (ESI): m/z (%) = 325.1 (100,
MH+), 671.2 (28, 2MNa+).
2,3',4,5',6-Pentamethoxy-4'-(2,4,6-trimethoxyphenoxy)-1,1'-biphenyl
(7abb):[36d] Rf = 0.08 (hexane/EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ
= 6.53 (s, 2H), 6.21 (s, 2H), 6.15 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.72
(s, 6H), 3.70 (s, 6H), 3.69 (s, 6H). 13C NMR (101 MHz, CDCl3): δ =
160.27, 158.40, 155.31, 152.29, 150.77, 136.45, 132.35, 127.88, 112.96,
109.72, 92.56, 91.33, 56.81, 56.66, 55.99, 55.42, 55.35. HRMS (ESI):
calcd. for C26H31O9 (M+H)+, m/z = 487.1963; found 487.1970.
2-Hydroxy-2',5,4',5'-tetramethoxy-3-methylbiphenyl (3ab): Rf = 0.23
(hexane/EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 6.85 (s, 1H), 6.75
(d, J = 2.9 Hz, 1H), 6.66 (s, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.09 (s, 1H),
3.95 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 2.32 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ = 153.05, 149.62, 149.54, 145.82, 144.29,
127.35, 126.19, 118.94, 115.77, 115.26, 113.47, 98.47, 57.53, 56.47,
4-Hydroxy-2',3,4',5,5'-pentamethoxy-biphenyl (9ab):[18b] 1H NMR (300
MHz, CDCl3) δ = 6.86 (s, 1H), 6.73 (s, 2H), 6.62 (s, 1H), 5.61 (s, 1H),
3.92 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.76 (s, 3H). 13C
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10.1002/ejoc.201700211
European Journal of Organic Chemistry
FULL PAPER
NMR (75 MHz, CDCl3) δ = 150.51, 148.67, 146.53, 143.11, 133.68,
129.30, 122.45, 114.46, 106.25, 98.47, 56.70, 56.59, 56.20, 56.06. MS
(ESI): m/z (%) = 321.1 (100, MH+), 663.2 (11, 2MNa+).
5-Allyl-2',3,4',5'-tetramethoxy-2-(2,4,5-trimethoxyphenoxy)-1,1'-
biphenyl (11abb): 1H NMR (400 MHz, CDCl3): δ = 6.81 – 6.78 (m, 2H),
6.77 (d, J = 2.0 Hz, 1H), 6.44 (s, 1H), 6.42 (s, 1H), 6.19 (s, 1H), 6.03 (ddt,
J = 16.7, 10.0, 6.6 Hz, 1H), 5.17 – 5.07 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H),
3.77 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H), 3.61 (s, 3H), 3.60 (s, 3H), 3.42 (d,
J = 6.6 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ = 152.43, 150.76, 148.68,
143.04, 142.75, 142.35, 142.14, 142.04, 139.90, 137.28, 136.29, 132.62,
123.99, 117.91, 115.97, 114.72, 111.59, 101.60, 100.93, 97.46, 57.42,
56.66, 56.65, 56.30, 56.09, 55.99, 55.93, 40.10. HRMS (ESI): calcd. for
C28H36O8N (M+NH4)+, m/z = 514.2435; found 514.2441.
2,3',4,5,5'-Pentamethoxy-4'-(2,4,5-trimethoxyphenoxy)-1,1'-biphenyl
(9abb): Rf = 0.29 (hexane/EtOAc, 1:1). 1H NMR (400 MHz, 213 K, CDCl3)
δ = 6.90 (s, 1H), 6.78 – 6.74 (m, 2H), 6.62 (s, 1H), 6.61 (s, 1H), 6.24 (s,
1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H),
3.79 (s, 6H), 3.66 (s, 3H). 13C NMR (101 MHz, 213 K, CDCl3): δ =152.32,
149.51, 147.94, 142.44, 141.82, 141.28, 140.87, 139.92, 135.08, 129.19,
120.19, 112.63, 105.35, 98.94, 97.01, 95.78, 56.72, 56.27, 56.07, 56.02,
55.99, 55.95, 55.88. HRMS (ESI): calcd. for C26H31O9 (M+H)+, m/z =
487.1963; found 487.1966.
2,2',4,4',5,5'-Hexamethoxy-1,1'-biphenyl (1bb):[18a] 1H NMR (300 MHz,
CDCl3): δ = 6.82 (s, 2H), 6.63 (s, 2H), 3.93 (s, 6H), 3.84 (s, 6H), 3.76 (s,
6H). 13C NMR (75 MHz, CDCl3): δ = 151.16, 148.71, 142.79, 118.80,
115.17, 98.20, 56.81, 56.45, 56.02.
5-Ethyl-2-hydroxy-2',3,4',5'-tetramethoxybiphenyl (10ab): 1H NMR
(400 MHz, CDCl3): δ = 6.87 (s, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.72 (d, J =
2.0 Hz, 1H), 6.66 (s, 1H), 5.97 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.86 (s,
3H), 3.81 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ = 150.39, 149.26, 147.42, 143.57, 141.04,
135.69, 125.12, 122.20, 118.68, 115.12, 109.99, 98.48, 57.23, 56.47,
56.12, 55.99, 28.54, 15.71. HRMS (ESI): calcd. for C18H23O5 (M+H)+, m/z
= 319.1540; found 319.1546.
5-Chloro-2-hydroxy-2',3,4',5'-tetramethoxybiphenyl (12ab): 1H NMR
(400 MHz, CDCl3): δ = 6.89 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H),
6.82 (s, 1H), 6.64 (s, 1H), 6.08 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.86 (s,
3H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 150.35, 149.74,
148.15, 143.71, 141.96, 126.39, 124.46, 122.81, 117.11, 114.74, 110.69,
98.41, 57.29, 56.50, 56.27, 56.14. HRMS (ESI): calcd. for C16H18ClO5
(M+H)+, m/z = 325.0837; found 325.0842.
1-(4-Ethyl-2-methoxyphenoxy)-2,4,5-trimethoxybenzene (10ab’): 1H
NMR (400 MHz, CDCl3): δ = 6.80 (d, J = 1.9 Hz, 1H), 6.64 (dd, J = 8.2,
1.9 Hz, 1H), 6.64 (s, 1H), 6.61 (s, 1H), 6.58 (d, J = 8.1 Hz, 1H), 3.91 (s,
3H), 3.89 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.23
(t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ = 149.28, 145.63,
145.31, 145.03, 143.33, 138.90, 138.25, 119.59, 116.06, 112.08, 106.48,
100.41, 57.42, 56.54, 56.51, 55.97, 28.53, 15.66. HRMS (ESI): calcd. for
C18H23O5 (M+H)+, m/z = 319.1540; found 319.1549.
1-(4-Chloro-2-methoxyphenoxy)-2,4,5-trimethoxybenzene (12ab’): 1H
NMR (400 MHz, CDCl3): δ = 6.93 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6,
2.4 Hz, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 6.55 (d, J = 8.6 Hz, 1H), 3.90 (s,
3H), 3.89 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ = 149.81, 146.40, 146.15, 145.01, 143.33, 137.12, 127.16, 120.29,
116.35, 112.73, 106.60, 100.09, 57.17, 56.51, 56.47, 56.16. HRMS (ESI):
calcd. for C16H18ClO5 (M+H)+, m/z = 325.0837; found 325.0839.
5-Ethyl-2',3,4',5'-tetramethoxy-2-(2,4,5-trimethoxyphenoxy)-1,1'-
biphenyl (10abb): 1H NMR (400 MHz, CDCl3): δ = 6.81 - 6.79 (m, 2H),
6.78 (d, J = 2.0 Hz, 1H), 6.44 (s, 1H), 6.42 (s, 1H), 6.20 (s, 1H), 3.84 (s,
3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.69 (s, 3H), 3.61 (s, 3H),
3.60 (s, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ = 152.30, 150.76, 148.61, 142.99, 142.76, 142.34,
142.24, 142.03, 140.46, 139.47, 132.49, 123.12, 118.10, 114.75, 111.04,
101.64, 100.99, 97.49, 57.44, 56.68, 56.65, 56.30, 56.07, 55.97, 55.92,
28.73, 15.30. HRMS (ESI): calcd. for C27H36O8N (M+NH4)+, m/z =
502.2435; found 502.2446.
5-Chloro-2',3,4',5'-tetramethoxy-2-(2,4,5-trimethoxyphenoxy)-1,1'-
biphenyl (12abb): 1H NMR (400 MHz, CDCl3): δ = 6.98 (d, J = 2.4 Hz,
1H), 6.93 (d, J = 2.4 Hz, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 6.41 (s, 1H), 6.16
(s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H),
3.64 (s, 3H), 3.61 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 153.16,
150.62, 149.12, 143.32, 142.68, 142.37, 142.04, 141.46, 140.59, 133.91,
129.38, 123.88, 116.30, 114.42, 111.75, 101.31, 100.59, 97.07, 57.26,
56.67, 56.57, 56.17, 56.11, 56.10, 55.98. HRMS (ESI): calcd. for
C25H31ClO8N (M+NH4)+, m/z = 508.1733; found 508.1735.
3-Chloro-2-hydroxy-2',4',5'-trimethoxy-5-methyl-biphenyl (13ab):[18b]
1H NMR (300 MHz, CDCl3): δ = 7.20 – 7.16 (m, 1H), 6.98 – 6.94 (m, 1H),
6.81 (s, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.84 (s,
3H), 2.31 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 149.79, 147.12, 144.03,
130.60, 130.23, 129.39, 127.05, 121.66, 117.89, 114.95, 98.19, 57.43,
56.51, 56.17, 20.41. MS (ESI): m/z (%) = 309.1 (100, MH+), 639.2 (7,
2MNa+).
5-Allyl-2-hydroxy-2',3,4',5'-tetramethoxybiphenyl (11ab): 1H NMR
(400 MHz, CDCl3): δ = 6.86 (s, 1H), 6.73 – 6.69 (m, 2H), 6.65 (s, 1H),
6.06 – 5.94 (m, 2H), 5.16 – 5.04 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.86
(s, 3H), 3.80 (s, 3H), 3.37 (d, J = 6.8 Hz, 2H). 13C NMR (101 MHz,
CDCl3): δ = 150.41, 149.32, 147.53, 143.58, 141.43, 137.67, 131.46,
125.21, 123.05, 118.52, 115.63, 115.11, 110.52, 98.50, 57.26, 56.49,
56.13, 56.01, 39.94. HRMS (ESI): calcd. for C19H23O5 (M+H)+, m/z =
331.1540; found 331.1545.
1-(2-Chloro-4-methylphenoxy)-2,4,5-trimethoxybenzene (13ab’): 1H
NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.5,
2.1 Hz, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 6.58 (d, J = 8.3 Hz, 1H), 3.89 (s,
3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ = 151.81, 146.19, 145.05, 143.55, 137.61, 132.69, 130.76, 128.07,
122.61, 116.32, 106.60, 100.75, 57.65, 56.53, 56.48, 20.36. HRMS (ESI):
calcd. for C16H18ClO4 (M+H)+, m/z = 309.0888; found 309.0887.
1-(4-Allyl-2-methoxyphenoxy)-2,4,5-trimethoxybenzene (11ab’): 1H
NMR (400 MHz, 213 K, CDCl3): δ = 6.77 (d, J = 1.9 Hz, 1H), 6.69 (s, 1H),
6.64 – 6.56 (m, 2H), 6.43 (d, J = 8.2 Hz, 1H), 5.93 (ddt, J = 16.8, 10.0,
6.8 Hz, 1H), 5.15 – 5.01 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.79 (s, 3H),
3.76 (s, 3H), 3.34 (d, J = 6.8 Hz, 2H). 13C NMR (101 MHz, 213 K, CDCl3):
δ = 147.96, 145.45, 145.12, 144.73, 141.50, 137.38, 134.59, 133.64,
119.65, 115.90, 113.43, 111.22, 105.99, 96.63, 56.23, 55.92, 55.60,
39.75. HRMS (ESI): calcd. for C19H23O5 (M+H)+, m/z = 331.1540; found
331.1547.
3'-Chloro-2,2'',4,4'',5,5''-hexamethoxy-5'-methyl-[1,1':4',1''-terphenyl]-
2'-ol (13abb): Main regioisomer. 1H NMR (300 MHz, CDCl3): δ = 7.08 (s,
1H), 6.90 (s, 1H), 6.68 – 6.65 (m, 3H), 6.47 (s, 1H), 3.96 (s, 6H), 3.89 (s,
6H), 3.84 (s, 3H), 3.77 (s, 3H), 2.06 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ = 150.83, 150.01, 149.71, 149.21, 147.35, 143.93, 143.15, 136.95,
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10.1002/ejoc.201700211
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130.25, 130.20, 125.49, 122.37, 119.14, 118.09, 115.21, 114.20, 98.15,
98.03, 57.31, 56.85, 56.56, 56.52, 56.20, 56.02, 20.05. HRMS (ESI):
calcd. for C25H28ClO7 (M+H)+, m/z = 475.1518; found 475.1527.
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NMR (400 MHz, CDCl3): δ = 7.64 – 7.59 (m, 4H), 7.53 – 7.47 (m, 4H),
7.47 (s, 2H), 7.43 – 7.37 (m, 2H), 6.93 (s, 1H), 6.64 (s, 1H), 5.43 (s, 1H),
3.94 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3): δ =
150.67, 148.80, 148.21, 143.33, 137.70, 130.90, 130.81, 129.44, 128.84,
128.41, 127.62, 121.67, 114.47, 98.29, 56.67, 56.65, 56.22. HRMS (ESI):
calcd. for C27H25O4 (M+H)+, m/z = 413.1747; found 413.1748.
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2'-(2,4,5-Trimethoxyphenoxy)-1,1':3',1''-terphenyl (14ab’): 1H NMR
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J = 8.5, 6.5 Hz, 1H), 7.31 – 7.24 (m, 4H), 7.24 – 7.18 (m, 2H), 6.29 (s,
1H), 6.01 (s, 1H), 3.70 (s, 3H), 3.60 (s, 3H), 3.52 (s, 3H). 13C NMR (101
MHz, CDCl3): δ = 149.57, 143.18, 142.68, 142.14, 141.72, 137.92,
136.19, 130.60, 129.11, 127.83, 127.05, 125.21, 102.23, 100.92, 57.51,
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596.2646.
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X-ray Crystallographic Details for Compounds 2q and 3q: CCDC
1510097 (for 2q) and 1510098 (for 3q) provide the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
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Acknowledgements
This work was financially supported by the German Science
Foundation (DFG) (GRK 1626, Chemical Photocatalysis). A. E.
thanks the Deutsche Bundesstiftung Umwelt (DBU) for a
graduate scholarship. We thank Dr. Rudolf Vasold (University of
Regensburg) for his assistance in LC and GC-MS
measurements, Regina Hoheisel (University of Regensburg) for
her assistance in CV measurements.
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Keywords: cross-dehydrogenative coupling • photocatalysis •
phenols • biaryls • C–O coupling
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700211
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201700211
European Journal of Organic Chemistry
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FULL PAPER
No leaving groups required – C–C
vs C–O cross-coupling driven by
visible light. Formation of C–C and
C–O cross-coupling products of
phenol and arenes by direct C–H
activation was accomplished by
visible light photoredox catalysis.
The efficiency and chemoselectivity
(homo- vs. cross-coupling and C–C
vs. C–O) were rationalized on basis
of the oxidation potentials Eox and
Photoredox catalysis*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
nucleophilicity
N
values of the
aromatic substrates.
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