Diaryl Ether Formation Merging Photoredox and Nickel Catalysis

Article abstract of DOI:10.1021/acs.organomet.1c00018

Photoredox and Ni catalysis are combined to produce diaryl ethers under mild conditions. A broad range of aryl halides and phenol derivatives are cross-coupled in the presence of a readily available organic photocatalyst and NiBr₂(dtbpy). Symmetrical diaryl ethers have also been directly obtained from aryl bromides in the presence of water. Mechanistic investigations support the involvement of Ni(0) species at the outset of the reaction and a Ni(II)/Ni(III)-photocatalyzed single electron transfer process preceding the productive C(sp²)-OAr reductive elimination.

Full text of DOI:10.1021/acs.organomet.1c00018

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Diaryl Ether Formation Merging Photoredox and Nickel Catalysis
Le Liu and Cristina Nevado*
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ABSTRACT: Photoredox and Ni catalysis are combined to
produce diaryl ethers under mild conditions. A broad range of
aryl halides and phenol derivatives are cross-coupled in the
presence of a readily available organic photocatalyst and
NiBr2(dtbpy). Symmetrical diaryl ethers have also been directly
obtained from aryl bromides in the presence of water. Mechanistic
investigations support the involvement of Ni(0) species at the
outset of the reaction and a Ni(II)/Ni(III)-photocatalyzed single electron transfer process preceding the productive C(sp2)−OAr
reductive elimination.
(80−150 °C), and the required prefunctionalization of the
starting materials still demand further improvements.
llmann couplings rank among the most widely used
Ureactions in organometallic chemistry, providing access
to ubiquitous diaryl ether motifs.1−3 Protocols based on
stoichiometric amounts of copper reagents1a,b have been
replaced by catalytic ones capitalizing on the nature of
ligands,4 bases,5 and metals6 (Scheme 1a).7,8 Alternative
methods employing boronic acids9 or diaryliodonium species10
have also been developed. Despite significant progress,
limitations such as the need for privileged ligands involving
multistep preparation, the relatively high reaction temperatures
The combination of photoredox and transition metal
catalysis has recently emerged as a powerful strategy to
achieve challenging transformations.11 Seminal examples by
MacMillan’s group described the utilization of nickel salts and
iridium photocatalysts in the presence of nitrogen-containing
additives to forge C(sp2)−O bonds:12 aryl bromides were
successfully cross-coupled with primary or secondary alkyl
alcohols as well as with carboxylic acids to give alkyl aryl
ethers12a and aryl esters,12b respectively (Scheme 1b). An
efficient synthesis of phenols from the corresponding aryl
bromides under very similar conditions was also reported.13
The mechanisms underlying these transformations have been
studied in detail, as multiple scenarios can be envisaged to
operate under the reaction conditions used.14 Both electron
transfer12a and energy transfer12b processes have been
proposed independently for these reported C(sp2)−O bond
formations under dual catalytic systems. On the other hand,
the direct cross-coupling of aryl halides and phenol derivatives
to produce the most useful and widespread diaryl ethers is yet
to be reported in this context.15
Scheme 1. Strategies for C(sp2)−O Bond Formation
Here we present a dual photoredox/nickel-catalyzed
Ullmann-type cross-coupling to access diaryl ethers under
mild reaction conditions. The cheap and readily available
organic photocatalyst 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicya-
nobenzene (4CzIPN) is combined with nickel to couple a
broad range of aryl halides and phenol derivatives in high
yields. A straightforward route to symmetrical diaryl ethers
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: January 12, 2021
https://doi.org/10.1021/acs.organomet.1c00018
© XXXX American Chemical Society
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A

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from aryl bromides and H2O has also been devised.
Furthermore, we have carried out a detailed mechanistic
investigation that supports the involvement of Ni(0) species at
the outset of the catalytic cycle and postulate a Ni(II)/Ni(III)-
photocatalyzed single electron transfer (SET) process that
precedes the productive C(sp2)−OAr reductive elimination
(Scheme 1c).
in an improved 73% yield (Table 1, entry 4). 4CzIPN features
a low price (it can be prepared for ∼$6 per gram)17 and thus
was selected for further optimization. Increasing the amount of
K3PO4 to 2.0 equiv led to the formation of 3 in 85% yield
(Table 1, entry 5), while no product was observed when the
reaction was carried out in its absence (Table 1, entry 8).
When preformed NiBr2(dtbpy) was used as the catalyst, an
excellent 93% yield was obtained for this transformation
(Table 1, entry 6). Under the same conditions, [Ir(ppy)3]
furnished the product only in marginal yields (Table 1, entry
7). (For additional optimization studies, see Tables S1 and
S2). Further control experiments demonstrated that the
organic photocatalyst, the nickel complex, and light as well
as degassed reaction mixtures were critical parameters for a
successful outcome (Table 1, entries 9−11). Finally, a gram-
scale reaction (5 mmol) delivered 3 in 84% yield (Table 1,
entry 12), thus highlighting the applicability of this protocol in
a preparative context.
As shown in Table 1, our efforts to find the optimal
conditions focused on the cross-coupling of 1-bromo-4-
Table 1. Optimization of the Reaction Conditions
yield of 3
a
b
entry
conditions
(%)
c
d
1
Ir cat (1 mol %), NiCl2·glyme (5 mol %), dtbpy (5
mol %), quinuclidine (10 mol %), and K2CO3 (1.0
equiv) in MeCN
<5
With the optimized conditions in hand, we first investigated
the scope of the aryl halide component in the reaction
(Scheme 2). 1-Chloro-, 1-bromo-, and 1-iodo-4-
(trifluoromethyl)benzene were examined in parallel. While
2
3
4
5
6
7
Ir cat (1 mol %), NiCl2·glyme (5 mol %), dtbpy (5
32
54
73
85
mol %), and K2CO3 (1.0 equiv) in PhCF3
Ir cat (1 mol %), NiCl2·glyme (5 mol %), dtbpy (5
mol %), and K3PO4 (1.0 equiv) in PhCF3
4CzIPN (2 mol %), NiCl2·glyme (5 mol %), dtbpy (5
mol %), K3PO4 (1.0 equiv) in PhCF3
4CzIPN (2 mol %), NiCl2·glyme (5 mol %), dtbpy (5
mol %), and K3PO4 (2.0 equiv) in PhCF3
4CzIPN (2 mol %), NiBr2(dtbpy) (5 mol %), and K3PO4 93 (91)
(2.0 equiv) in PhCF3
[Ir(ppy)3] (2 mol %), NiBr2(dtbpy) (5 mol %), and
K3PO4 (2.0 equiv) in PhCF3
no base
no LEDs or no 4CzIPN or Ir photocatalyst
no NiBr2(dtbpy)
without degassing
Scheme 2. Reaction Scope for the Synthesis of
a
Nonsymmetrical Diaryl Ethers
d
<5
e
f
f
f
8
NR
NR
NR
10
e
9
e
10
e
11
e
12
reaction on a 5 mmol scale
84
a
1 (0.15 mmol) and 2 (0.1 mmol) in 1.0 mL of PhCF3 (0.1 M)
b
irradiated with a 34 W blue LED for 36 h. Yields were determined by
1H NMR analysis of the crude reaction mixtures using mesitylene as
an internal standard. The value in parentheses is the isolated yield
c
after column chromatography. Ir cat stands for [Ir{dF(CF3)-
ppy}2(dtbpy)]PF6. <5% indicates that a trace amount of product
was observed. Deviation from the reaction conditions in entry 6. NR
indicates that no product was detected by H NMR spectroscopy.
d
e
f
1
(trifluoromethyl)benzene (1) and 1-(4-hydroxyphenyl)ethan-
1-one (2). We initiated the reaction screening adopting the
same protocol as previously reported for the O-arylation of
aliphatic alcohols, which employed [Ir{dF(CF3)-
ppy}2(dtbpy)]PF6 and NiCl2·glyme (1 and 5 mol %,
respectively) along with 4,4′-di-tert-butyl-2,2′-bipyridine
(dtbpy) (5 mol %) in the presence of quinuclidine (10 mol
%) and base (1.0 equiv of K2CO3) in acetonitrile as the
solvent.12a These conditions afforded only traces of the desired
product (Table 1, entry 1). Interestingly, when we switched
the solvent to PhCF3 and omitted quinuclidine, which was
reported to be the crucial additive for the alcohol cross-
coupling reaction,12a,14 diaryl ether 3 was generated in a
promising 32% yield (Table 1, entry 2). Further yield
enhancement was achieved by switching the base to K3PO4
(Table 1, entry 3). In order to ensure an effective
photocatalytic cycle, we next examined 4CzIPN, which
possesses a similar redox potential window but a longer
excited-state lifetime (5.1 μs).16 To our delight, 3 was obtained
a
Aryl halide (0.15 mmol), phenol (0.1 mmol), 4-CzIPN (0.02 mmol,
2 mol %), NiBr2(dtbpy) (0.05 mmol, 5 mol %), and K3PO4 (0.2
mmol, 2.0 equiv) in 1.0 mL of PhCF3 (0.1 M) irradiated with a 34 W
blue LED for 36 h. Isolated yields after column chromatography are
shown.
B
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similar yields of the desired product were obtained with the
bromide and iodide, only a trace amount of product 3 could be
detected with the chloride derivative. Different bromoarenes
were examined next. Aromatic rings bearing cyano (4), ester
(10), and methylsulfonyl (11) groups were well-tolerated
under the mild reaction conditions, delivering the correspond-
ing O-arylation products in high yields. When sterically
hindered ortho-substituted aryl bromides (known to be difficult
substrates for classical Cu-catalyzed Ullmann coupling
reactions18) were used as reaction partners, the coupling still
proceed smoothly to furnish adducts 9−12. Importantly, both
electron-neutral and electron-rich bromobenzenes were also
compatible with the optimized conditions, as demonstrated by
the efficient formation of diaryl ethers 5−9. Pyridine and
quinoline derivatives could also be used as nucleophiles in
these reactions to generate the corresponding heteroaryl ether
products 13 and 14, respectively.
The mechanism underlying the formation of C(sp2)−O
bonds via dual photoredox/nickel catalysis has been the focus
of numerous studies.12−14 Originally, reactions involving
aliphatic alcohols were proposed to proceed via a Ni(I)/
Ni(0) SET event at the expense of the photocatalyst.12a This
mechanism was later revised in order to rationalize the critical
role that quinuclidine plays in the reaction. Studies by Nocera
et al. showed that a self-sustained Ni(I)/Ni(III) catalytic cycle
is likely to operate in these transformations, with the amine
additive working both as a base and as a ligand to stabilize
dimeric Ni(I) species present in the reaction medium (Scheme
4e, bottom).14 In contrast, reactions involving carboxylic acids
Scheme 4. Control Experiments and Proposed Reaction
Mechanism
We then turned our attention to the phenolic component of
this etherification process. Phenols with both electron-
withdrawing and -donating groups at the para, meta, and
ortho positions were efficiently coupled, affording the
corresponding products in moderate to good yields (15−
21). 2-Naphthol proved to be a good cross-coupling partner,
producing diaryl ether 22 in 87% yield. Additionally, a bicyclic
flavanone derivative also furnished product 23 in 80% yield.
Further expansion of the scope was carried out by combination
of electron-neutral and -rich aryl bromides with phenols (24−
28). Etherifications of tyrosine and estrone derivatives were
also successful (29−32), again highlighting the potential of this
method in late-stage functionalization campaigns.19 In
addition, we found that both primary and secondary alcohols
are also effectively coupled to generate the corresponding alkyl
aryl ethers under these conditions (33, 34), showcasing the
generality of this protocol.
Symmetrical diaryl ethers were targeted next. It is well-
established that water can act as a nucleophile to form phenols
from aryl bromides under dual photoredox/nickel catalysis.13
A
fast survey of reaction parameters led to the optimal
conditions, which included ([Ir{dF(CF3)ppy}2(dtbpy)]PF6
(1 mol %) and NiBr2(dtbpy) (5 mol %) in the presence of
K3PO4 and H2O (2.0 equiv) in PhCF3 as the solvent.
Bromoarenes bearing both electron-withdrawing and elec-
tron-donating substituents delivered the corresponding sym-
metrical diaryl ethers 35−42 in moderate to excellent yields
under the above-mentioned conditions (Scheme 3).20
as oxygen partners12b seem to proceed through an excited
[ArNi(II)OC(O)R]* intermediate generated via energy trans-
fer from the photocatalyst, which thereby functions as a
sensitizer rather than as an electron shuttle (Scheme 4e, left).
Intrigued by how subtle differences in the reaction conditions
can affect both the scope and mechanism of these trans-
formations, we designed a number of control experiments to
better understand the individual steps operating in this
C(sp2)−OAr bond-forming process. At the outset, we
investigated the reaction of a Ni(0)−dtbpy complex in the
presence and absence of the photoredox catalyst. Importantly,
in the presence of 4CzIPN, the cross-coupled product 3 was
obtained in a yield comparable to that obtained when a Ni(II)
precatalyst was used. In contrast, in the absence of the
photocatalyst, only trace amounts of the diaryl ether could be
detected, even after prolonged heating (Scheme 4a). The high
efficiency of the C(sp2)−O bond formation in the presence of
a Ni(0) complex and 4CzIPN indicated that low-valent nickel
species, which can be formed in situ from NiBr2(dtbpy) at the
expense of the photocatalyst (Er1e/d2[4CzIPN*/[4CzIPN]−] =
+1.35 V vs SCE, Er1e/d2[NiII/Ni0] = −1.20 V vs SCE), are likely
a
Scheme 3. Reaction Scope for Symmetrical Diaryl Ethers
a
Aryl halide (0.2 mmol), H2O (0.2 mmol), 4-CzIPN (0.04 mmol, 2
mol %), NiBr2(dtbpy) (0.01 mmol, 5 mol %) and K3PO4 (0.4 mmol,
2.0 equiv) in 1.0 mL PhCF3 (0.2 M) irradiated with 34 W blue LED
for 36 h. Isolated yields from column chromatography are shown.
C
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to be involved in the reaction’s catalytic cycle. Moreover, the
fact that our protocol proceeds in the absence of nitrogen-
containing bases and the strong dependence of the reaction on
light irradiation observed in a light on/off experiment (see
Figure S3) further support this notion and disfavor a chain-
sustained Ni(I)/Ni(III) process.14
provides a complementary avenue to both symmetrically and
nonsymmetrically substituted diaryl ether skeletons. This study
also sheds light on the mechanism underlying these trans-
formations. The reactions, carried out in the absence of
nitrogen-based additives, proceed via a SET process aided by
the photocatalyst in which unreactive ArNi(II)OAr species are
transformed into ArNi(III)OAr, prone to undergo reductive
elimination to form the new C(sp2)−OAr bond.
As to the actual nickel species responsible for the reductive
elimination step, the aryl-Ni(II)OAr complex 43 was prepared,
and its reactivity was explored in detail. It is important to note
that displacement of bromide ligands on Ni(II) with phenols
under the reaction conditions is a rather facile process (see
Figure S1). After exposure to an LED light source, 43
furnished only negligible amounts of the cross-coupled
product, implying that no productive reductive elimination to
create the C(sp2)−O bond can occur from either this Ni(II)
complex or its excited form by direct light irradiation alone. In
contrast, in the presence of 4CzIPN, a 35% yield of diaryl ether
9 was obtained after 10 h. While the formation of an excited
aryl-alkoxo-Ni(II) complex via energy transfer can be
invoked,12b several control experiments rule out this possibility.
First, the reaction is highly effective with an organic
photocatalyst featuring high oxidizing power (Er1e/d2[4CzIPN*/
[4CzIPN]−] = +1.35 V vs SCE) (Table 1, entry 6), while the
same reaction in the presence of [Ir(ppy)3] featuring a lower
oxidation potential (Er1e/d2[Ir(III)*/Ir(II)] = +0.31 V vs SCE)
but high triplet energy (53.6 kcal/mol) furnishes the desired
product in only marginal yield (Table 1, entry 7). Second, it
has been reported that cerium ammonium nitrate (CAN) can
act as a single electron transfer oxidant to oxidize Ni(II) to
Ni(III) species.21 In fact, when CAN was used as the oxidant,
diaryl ether 9 could be isolated from complex 43 in 30% yield
(Scheme 4b). These results support the generation of transient
Ni(III) species via single electron transfer during the reaction
as key intermediates for productive C(sp2)−O bond
formation.22 Stern−Volmer fluorescence quenching studies
showed that the emission intensity of the excited state of
4CzIPN decreased with increasing concentration of 43,
following linear Stern−Volmer behavior. In contrast, phenol
2 did not display efficient quenching (Scheme 4d).23 Cyclic
voltammetry of 43 showed an irreversible peak at +0.80 V vs
Ag/AgCl in acetonitrile, which is ascribed to the oxidation of
Ni(II) to Ni(III) (see Figure S8).24 These results provide
further support for a single electron transfer between Ni(II)
and the excited-state photocatalyst, which should be both
kinetically and thermodynamically favorable under the reaction
conditions (Er1e/d2[NiIII/NiII] = +0.80 V vs Ag/AgCl).24 Finally,
complex 43 turned out to be an effective catalyst to mediate
the cross-coupling reaction under the standard conditions,
which supports the regeneration of the active Ni species with
the photocatalyst after reductive elimination (Er1e/d2[NiI/Ni0] =
−1.10 V vs SCE and E1re/d2[4CzIPN/[4CzIPN]−] = −1.21 V vs
SCE)25 (Scheme 4c). To summarize, all of these results favor a
mechanism in which oxidation of Ni(II) complex 43 to Ni(III)
occurs at the expense of the excited photocatalyst to enable
reductive elimination and formation of the new C(sp2)−OAr
bond. The Ni(I) species produced thereby react with the
reduced form of the photocatalyst to produce Ni(0)
complexes, thus restarting the catalytic cycle according to the
mechanism proposed in Scheme 4e (highlighted in gray).
In summary, here we have demonstrated the power of
merging photoredox and nickel catalysis to produce diaryl
ethers under mild conditions. This method expands the
existing portfolio of C(sp2)−OAr bond-forming reactions and
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental procedures, characterization of products,
and control experiments (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Cristina Nevado − Department of Chemistry, University of
Zurich, CH-8057 Zurich, Switzerland; orcid.org/0000-
0002-3297-581X; Email: cristina.nevado@chem.uzh.ch
Author
Le Liu − Department of Chemistry, University of Zurich, CH-
8057 Zurich, Switzerland; orcid.org/0000-0001-8954-
9478
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00018
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Swiss National Science Foundation (SNF
200020_146853) and the Forschungskredit of the University
of Zurich (FK-18-111) for financial support. This publication
was created as part of NCCR Catalysis, a National Centre of
Competence in Research funded by the Swiss National Science
Foundation.
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Organometallics
pubs.acs.org/Organometallics
Communication
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