A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and Phenols Applied to the Synthesis of Aryl Ethers

Article abstract of DOI:10.1002/anie.201606359

ortho-Quinones are underutilized six-carbon-atom building blocks. We herein describe an approach for controlling their reactivity with copper that gives rise to a catalytic aerobic cross-coupling with phenols. The resulting aryl ethers are generated in high yield across a broad substrate scope under mild conditions. This method represents a unique example where the covalent modification of an ortho-quinone is catalyzed by a transition metal, creating new opportunities for their utilization in synthesis.

Full text of DOI:10.1002/anie.201606359

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International Edition: DOI: 10.1002/anie.201606359
German Edition: DOI: 10.1002/ange.201606359
Copper Catalysis
Hot Paper
A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and
Phenols Applied to the Synthesis of Aryl Ethers
Zheng Huang and Jean-Philip Lumb*
Abstract: ortho-Quinones are underutilized six-carbon-atom
building blocks. We herein describe an approach for control-
ling their reactivity with copper that gives rise to a catalytic
aerobic cross-coupling with phenols. The resulting aryl ethers
are generated in high yield across a broad substrate scope
under mild conditions. This method represents a unique
example where the covalent modification of an ortho-quinone
is catalyzed by a transition metal, creating new opportunities
for their utilization in synthesis.
I
n spite of their occurrence in nature,[1] materials science,[2]
catalysis,[3] organometallic chemistry,[4] and synthesis,[5] ortho-
benzoquinones have remained underexplored functional
groups.[6,7] Their redox lability, complex coordination chemis-
try, and sensitivity towards nucleophiles are amongst the
obstacles that complicate their utilization.[8] Methods that
overcome these challenges benefit from downstream trans-
formations that dramatically alter the topology and polarity
of the ortho-quinone.[9] This can diversify chemical space
around a key functional group, which we recently illustrated
for oxindole heterocycles.[8] In this previous work, ortho-
quinones were formed by ortho-oxygenation of a phenol with
a P-type dinuclear Cu oxidant (Scheme 1).[10] This forms
a CuII semiquinone radical (Ln-SQ) following atom transfer,
which undergoes coupling with the starting phenol prior to
dissociation of LnCuI.[11] While the resulting ortho-quinones
are versatile,[12] this method is currently limited to the
homocoupling of phenols (1a to 4, Scheme 1).[13]
CuII semiquinones can also be formed by oxidation of CuI
with an ortho-quinone,[4b,10] which suggested to us that a cross-
coupling between a phenol and an ortho-quinone might
provide a more versatile fragment coupling. Existing addition
reactions to ortho-quinones are either low-yielding or limited
in scope, and have not been investigated as general synthetic
methods.[14] Successful reaction development would require
Scheme 1. Synthesis and reactivity of ortho-quinones.
ꢀ
chemoselectivity for cross-C O bond formation over oxida-
tive homocoupling[15] or ortho-oxygenation of the phenol,[16]
while avoiding decomposition of the ortho-quinone. Herein,
we overcome these challenges and describe a catalytic aerobic
synthesis of vinyl aryl ethers by an ortho-quinone/phenol
cross-coupling. Ligand and counterion effects have a pro-
nounced impact on rate and selectivity, and provide param-
eters for optimization that extend the method to a broad
selection of coupling partners. Aryl ethers are omnipresent in
natural products, pharmaceuticals, agrochemicals, and mate-
rials,[17] justifying continued efforts to improve the efficiency
of their synthesis.[18] Our reactions employ commercially
available components, occur at room temperature in 1 h, and
provide access to a diverse array of aryl ethers by post-
coupling diversification of the ortho-quinone (Scheme 1).
The challenges of utilizing ortho-quinones are highlighted
by the reaction of phenol (1a) and 4-tert-butyl-ortho-quinone
(2a; Table 1). As a homogenous solution in CH2Cl2, 1a and
2a undergo about 25% decomposition upon standing for 1 h
(entry 1). Upon addition of catalytic amounts of either N,N’-
di-tert-butyl-ethylenediamine (DBED) or 4-methoxypyridine
(4-MeO-Py; see below for why these amines were chosen),
[*] Z. Huang, Prof. Dr. J.-P. Lumb
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, Quebec, H3A 0B8 (Canada)
E-mail: jean-philip.lumb@mcgill.ca
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606359.
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Table 1: Optimization of the reaction conditions.[a]
results suggest that a similar oppor-
tunity may extend to metal semi-
quinones.
A working mechanistic hypoth-
esis that considers the ligand and
counterion effects, the requirement
for O2, and the complete absence of
4 is presented in Scheme 2. The
catalytic cycle begins with oxidation
of LnCuX with 2a to provide Ln-SQ-
2a. Stack, Pierpont, and our group
have previously shown that amines
influence the geometry, nuclearity,
and electronic structure of Cu semi-
quinones,[4b,21] which helps explain-
ing the pronounced ligand and
counterion effects on rate and selec-
tivity.[22] The requirement of O2 for
Entry
Phenol
Quinone
CuX
(mol%)
Amine
(mol%)
Conv. [%]
1/2
3a–3d[b]
(yield [%])
1[c]
2[c]
1a
1a
–
2a
2a
2a
2b
2a
2a
2a
2b
2b
2b
2b
2b
–
–
–
–
–
8/17
33/81
–/40
–/100
58/48
100/100
97/100
81/100
>95/>95
>95/>95
86/>95
22/>95
–
DBED (5)
DBED (20)
DBED or 4-MeO-Py (20)
DBED (5)
DBED (5)
4-MeO-Py (10)
4-MeO-Py (20)
4-MeO-Py (20)
DBED (10)
DBED (10)
4-MeO-Py (20)
3a (20)
–
–
3[c]
4[c,d]
–
5[e]
1a
1a
1a
1a
1b
1b
1c
1c
CuPF6 (4)
CuBr (4)
CuBr (4)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
3a (40)
3a (97)
3a (97)
3b (73)
3c (74)
3c (<5)
3d (79)
3d (<10)
6
7[f]
8[f,g]
9[f,g]
10[g]
11[g]
12[f,g]
ꢀ
selective C O coupling leads us to
propose an aerobic oxidation of Ln-
ꢀ
SQ-2a prior to C O bond forma-
tion, which should be accelerated
by more-coordinating counterions,
such as Cl or Br, relative to PF6. The
resulting peroxide (Ln-Per-2a)
[a] The reactions were performed with 0.5 mmol of 1 and 0.5 mmol of 2. [b] Yield determined by 1H NMR
spectroscopy using hexamethylbenzene as an internal standard. [c] Reactions performed under N2.
[d] Reaction time: 5 min. [e] Reaction time: 4 h. [f] With 4 ꢀ M.S. (100 mg). [g] 0.75 mmol of 2 were
slowly added over 10 min.
a complex mixture quickly evolves, from which 3a is isolated
in low yield (entry 2). Factors leading to decomposition
include the sensitivity of 2a towards the amine (entry 3), and
redox exchange between 3a and quinone 2a.[19] These
problems are amplified for 4-methyl-ortho-quinone (2b),
which undergoes complete decomposition within 5 min under
similar conditions (entry 4).
The addition of CuI salts and molecular oxygen (O2) has
a dramatic impact on the selectivity and rate of the reaction.
In the presence of [Cu(CH3CN)4](PF6) (abbreviated as
CuPF6), DBED, and 2 atm of O2, the addition becomes
selective for 3a at about 50% conversion after 4 h (entry 5).
By simply changing to a halide counterion, the reaction is
complete after only 1 h, and the yield of 3a is > 95%
(entry 6). An equally pronounced effect is observed for the
ligand. After an extensive survey (> 20 amines; see the
Supporting Information, Table S2), only 4-MeO-Py emerged
as an equally efficient ligand for the coupling of 1a and 2a in
the presence of 4 ꢀ molecular sieves (M.S.; entry 7).
DBED and 4-MeO-Py display a surprising, yet highly
desirable, complementarity that enables couplings of either
electron-rich or electron-poor phenols. This is illustrated with
quinone 2b, whose overall sensitivity requires slow addition
to the reaction mixture over 10 min (entry 8). 2b undergoes
a relatively clean coupling with electron-rich phenol 1b in the
presence of 4-MeO-Py (entry 9), whereas the use of DBED
leads to complete decomposition (entry 10). In contrast,
DBED promotes the coupling of 2b with electron-poor
phenol 1c (entry 11), whereas 4-MeO-Py does not (entry 12).
Fine-tuning reaction conditions by ligand design is a hallmark
of traditional metal-catalyzed cross-coupling reactions.[20] Our
Scheme 2. Mechanistic proposal for the catalytic aerobic coupling of
1a and 2a to 3a.
2
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Table 3: Quinone scope.[a]
resembles complexes of Fe,[23] Cu,[24] Co,[25] Rh,[26] and Ir,[27]
involved in both the enzymatic and non-enzymatic cleavage
of semiquinones to muconic esters.[24a,28] Oxidative cleavage is
avoided under our conditions by trapping of Ln-Per-2a with
1a, in what we tentatively describe as a radical addition.[29]
Elimination of H2O2 would then provide Ln-SQ-3a,[26–27] and
ꢀ
would form the key C O bond of the product while avoiding
redox exchange.[8] Ligand exchange with 2a would then
release 3a and close the catalytic cycle. The chemoselectivity
for 3a over 4 (Scheme 2) results from the sequestration of CuI
as a CuII semiquinone, preventing O2 activation as a P-type
oxidant, and thus ortho-oxygenation of 1a (Scheme 1).[11] This
is a rare example of chemoselective oxidation over oxygen-
ation,[16] which finds parallels in the work of Kozlowski and
Stahl.[30]
Coupling remains efficient across a broad range of
phenols (Table 2) and can include substituents that are used
in more traditional cross-coupling reactions (3i, 3j, and 3r) or
groups that are sensitive to aerobic oxidation (3g, 3j, 3m, 3p,
and 3u–3w). The scope of the ortho-quinone is equally broad
(Table 3), and includes alkyl, aryl, and heteroatom substitu-
tion (3y, 3z, 3ae, and 3ag), demonstrating regioselectivity for
either the less sterically encumbered (3ah) or more electro-
philic position of the quinone (3af). Fused quinones, includ-
ing ortho-naphthoquinone and the 4,5- and 6,7-quinones of
[a] The reactions were performed with 1 mmol of 1 and 1.5 mmol of 2. 2
was added to the reaction mixture over 10 min. [b] CuCl (20 mol%) and
4-methoxypyridine (40 mol%) were used. [c] 1 mmol of 2 was used;
reaction time: 4 h.
Table 2: Phenol scope.[a]
[a] The reactions were performed with 1.0 mmol of 1 and 1.0–1.5 mmol of 2. [b] 4-Methoxypyridine (10 mol%) with 200 mg of 4 ꢀ M.S. [c] DBED
(10 mol%) without 4 ꢀ M.S. [d] Reaction performed on 0.1 mmol scale, with a catalyst loading of 15 mol%.
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Norathyriol and its C-glycosylated analogue mangiferin[36]
are xanthone natural products isolated from the skin of
mangoes that exhibit a broad range of biological activities.[37]
The synthesis of 13 is accomplished by cross-coupling of
phloroglucinol 10 with 2a on multigram scale (Scheme 3B).
Oxidation of the C5 methyl group to the carboxylic acid
provides 12, which is subsequently converted into 13 by
a Friedel–Crafts acylation.
In summary, we have developed a mild and diversifiable
synthesis of aryl ethers that highlights the synthetic value of
ortho-quinones. An important future direction will explore
the reactivity of metal–quinone complexes more generally, as
they provide a unique mechanism for controlling covalent
modification. Metal semiquinones have been studied as non-
innocent ligands with unique electronic properties, but mainly
for applications in materials science. Our work makes an
important departure from this precedent, and demonstrates
that these non-innocent ligands can also be viewed as redox-
active substrates that are suitable for dehydrogenative
coupling.[38] This highlights the increasingly popular trend of
controlling organic radical chemistry with organometallic
complexes as the reactivity of these species can be carefully
tuned by ligand design.[39]
Acknowledgements
Financial support was provided by the Natural Sciences and
Engineering Council of Canada (NSERC, Discovery Grant to
J.-P.L.), the Fonds de Recherche du Quꢁbec—Nature et
Technologies (FRQNT, Team Grant to J.-P.L.), the FRQNT
Center for Green Chemistry and Catalysis at McGill Uni-
versity (graduate fellowship for Z.H.), and the NSERC
CREATE Program in Green Chemistry at McGill University.
We wish to thank Prof. James Gleason, Prof. Bruce Arndtsen,
and Prof. Xavier Ottenwaelder for helpful discussions.
Scheme 3. Diversification of ortho-quinone 5 and synthesis of norathyr-
iol (13). Conditions: a) Pb(OAc)2 (2.2 equiv), MeOH/PhMe, RT, 18 h,
62%; b) Deoxofluor, CHCl3, 08C!RT, 1 h, then NaBH4, DBU, MeOH,
508C, 30 min, 40%; c) [Cu(MeCN)4](PF6) (4 mol%), CH2N2, THF,
=
ꢀ788C!RT, 30 min, 60%; d) Ph3P CHCO2Et (2 equiv), CH2Cl2, 40!
1008C, 4 h, 62%; e) benzoyl peroxide (10 mol%), N-bromosuccinimide
(1.2 equiv), CCl4, 808C, 4 h, then N-methylmorpholine N-oxide
(3 equiv), MeCN, RT, 12 h, 73% yield; f) NaClO2 (3 equiv), NaH2PO4,
DMSO/H2O, RT, 2 h, 71% yield; g) (CF3CO)2O (2 equiv), CH2Cl2, RT,
30 min, then BF3·Et2O (5 equiv), RT, 2 h, 87%; h) K2CO3 (5 equiv), RT,
12 h, 87% yield over two steps.
Keywords: aerobic oxidation · aryl ethers · copper catalysis ·
ortho-quinones · phenols
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[19] Redox exchange between 2a and cat-3a is low-yielding:
Received: June 30, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Copper Catalysis
Z. Huang, J.-P. Lumb*
&&&& — &&&&
A Catalyst-Controlled Aerobic Coupling of
ortho-Quinones and Phenols Applied to
the Synthesis of Aryl Ethers
The reactivity of ortho-quinones can be
controlled with copper, and a catalytic
aerobic cross-coupling with phenols was
developed that provides access to
conditions. This reaction is a unique
example of covalently modifying an ortho-
quinone in the presence of a transition-
metal catalyst, creating new opportuni-
ties for their utilization in synthesis.
a broad range of aryl ethers under mild
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!