A biomimetic catalytic aerobic functionalization of phenols

Article abstract of DOI:10.1002/anie.201311103

The importance of aromatic C-O, C-N, and C-S bonds necessitates increasingly efficient strategies for their formation. Herein, we report a biomimetic approach that converts phenolic C-H bonds into C-O, C-N, and C-S bonds at the sole expense of reducing dioxygen (O₂) to water (H ₂O). Our method hinges on a regio- and chemoselective copper-catalyzed aerobic oxygenation to provide ortho-quinones. ortho-Quinones are versatile intermediates, whose direct catalytic aerobic synthesis from phenols enables a mild and efficient means of synthesizing polyfunctional aromatic rings. The direct approach: Polyfunctional aromatic rings have been generated by direct functionalization of C-H bonds to C-O, C-N, and C-S bonds at the sole expense of reducing O₂ to H₂O. The method hinges on a regio- and chemoselective, copper-catalyzed aerobic oxygenation of phenols to provide ortho-quinones (see scheme), thus mimicking the ubiquitous biosynthetic pathway of melanogenesis.

Full text of DOI:10.1002/anie.201311103

Angewandte
Chemie
DOI: 10.1002/anie.201311103
Synthetic Methods
A Biomimetic Catalytic Aerobic Functionalization of Phenols**
Kenneth Virgel N. Esguerra, Yacoub Fall, and Jean-Philip Lumb*
Dedicated to Professor Allan Hay on the occasion of his 85th birthday
À
À
À
Abstract: The importance of aromatic C O, C N, and C S
bonds necessitates increasingly efficient strategies for their
formation. Herein, we report a biomimetic approach that
À
À
À
À
converts phenolic C H bonds into C O, C N, and C S bonds
at the sole expense of reducing dioxygen (O2) to water (H2O).
Our method hinges on a regio- and chemoselective copper-
catalyzed aerobic oxygenation to provide ortho-quinones.
ortho-Quinones are versatile intermediates, whose direct
catalytic aerobic synthesis from phenols enables a mild and
efficient means of synthesizing polyfunctional aromatic rings.
T
he reduction of molecular oxygen (O2) to water (H2O)
provides a sustainable source of chemical energy for the
synthesis of a myriad of molecules and materials in nature.[1]
Numerous biochemical processes harness the energy of O2 by
converting phenols into ortho-quinones (Scheme 1a).[2] ortho-
Quinones are versatile synthetic intermediates,[3] whose
innate reactivity[4] enables cycloaddition, condensation, addi-
tion, and redox reactions. This makes them the centerpiece of
biomimetic strategies for the synthesis of materials,[5] natural
products,[6] biologically active heterocycles,[7] dyes, and pig-
ments.[8] Phenols are readily available feedstock chemicals[9]
that are potentially derived from renewable sources of
carbon.[10] However, their conversion into ortho-quinones
currently requires stoichiometric amounts of an oxidant other
than O2.[3c–e]
Catalyzing the aerobic oxygenation/dearomatization of
phenols has remained an unresolved challenge in biomimetic
copper chemistry for more than 50 years.[11] In nearly all living
organisms, the type-III copper enzyme tyrosinase oxygenates
phenols to ortho-quinones, thereby triggering melanogenesis
(Scheme 1a).[2,11–13] Under stoichiometric conditions, biomim-
etic complexes recreate the enzymeꢀs mechanism of O2
Scheme 1. a) Principle steps of melanogenesis leading to eumelanin
and the reactive oxygen species of the enzyme tyrosinase. b) Previous
examples of phenolic oxygenation/functionalization reactions. c) The
catalytic aerobic dearomatization of phenols reported herein.
activation and oxygen atom transfer (species P in Scheme 1a,
inset),[14] but extending these mechanistic studies to catalytic
reactions has met with limited success. In early studies,
Bulkowski,[15] Rꢁglier et al.,[16] and Casella et al.[17] oxygen-
ated phenols using dinuclear Cu catalysts and excess triethyl-
amine (2 equiv Et3N), and more recently, Tuczek and co-
workers[18] as well as Stack, Herres-Pawlis, and co-workers[19]
employed similar conditions with mononuclear CuI catalysts.
These examples, which are limited to small scales (25 mmol),
high dilution (0.001m), and incomplete conversion, under-
score the well-known challenges of catalyzing aerobic oxida-
tions of phenols,[11c,20–22] for which Hayꢀs polymerization[21] is
the only example that has found practical application.[1b,11b]
Herein, we show how this long-standing challenge can be
overcome, and describe a practical method for the Cu-
[*] K. V. N. Esguerra, Dr. Y. Fall, Prof. J.-P. Lumb
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, QC, H3A 0B8 (Canada)
E-mail: jean-philip.lumb@mcgill.ca
[**] We thank Prof. Allan Hay and Prof. Xavier Ottenwaelder for
extensive discussions during the development of this project and
during the preparation of this manuscript. Financial support was
provided by the Natural Sciences and Engineering Council of
Canada (Discovery Grant to J.-P.L.), the Fonds de Recherche du
Quꢀbec–Nature et Technologies (Team Grant to J.-P.L), McGill
University-Canadian Institutes of Health Drug Development Trainee
Program (doctoral fellowship to K.V.N.E.), Centre in Green
Chemistry and Catalysis at McGill University, and McGill University
(start-up funds to J.-P.L.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311103.
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catalyzed aerobic oxygenation of phenols to ortho-quinones
that gives rise to the site-selective functionalization of two
(compare entries 1 and 3), suggesting that 2 was hydrolyzed
over the course of the reaction to hydroxy para-quinone 4 and
phenol 1 [Eq. (1)]. Attempts to isolate 4 from catalytic
À
aromatic C H bonds (Scheme 1c). Our study builds upon the
examples from the research groups of Brackman,[23]
Maumy,[24] and Sayre,[25] who demonstrated that phenols
undergo oxygenation and oxidative coupling when exposed to
excess CuI and O2 (Scheme 1b), thereby providing ortho-
quinones that are stable to work-up and purification. Since
phenolic oxidations are frequently associated with complex
product mixtures,[11c,26] we opted to investigate the conversion
of 4-tert-butylphenol (1) into substituted ortho-quinone 2
(Table 1), which can be purified by chromatography (see the
Supporting Information).
reactions were precluded by its instability to Cu in the
presence of O2.[27] However, control experiments under N2
returned a 90% yield of isolated 4 when 2 was exposed to
[Cu(CH3CN)4]PF6 (3) and H2O [Eq. (1)]. Hydroxy ketones
related to 4 are inhibitors of the enzyme tyrosinase,[28] and
when the structurally related para-quinone lawsone (Table 1,
inset) was added to our standard reaction conditions, catalysis
was inhibited (entry 4). This suggested that a conjugate
addition/elimination of H2O onto 2, which would regenerate
starting phenol 1 and release 4, could account for the trends in
conversion observed across entries 1–3. This hypothesis,
which identified H2O as a problematic by-product, was
substantiated by the beneficial effects of 4 ꢂ molecular
sieves (entry 5), whose inclusion led to complete and quanti-
tative formation of 2. Somewhat surprisingly, the beneficial
effects of molecular sieves were observed across a range of
iminopyridine catalysts[18] (Table 1, inset: L1–L6 yields with
and without molecular sieves), thus prompting us to inves-
tigate the background oxygenation of 1 with 3 and Et3N in the
absence of additional ligands (entry 6). Remarkably, a fully
catalytic oxygenation of 1 could be optimized to give a 96%
yield of 2 by the addition of 4 ꢂ molecular sieves (entries 7
and 8), thus demonstrating that a catalytic aerobic oxygen-
ation can be conducted under surprisingly simple conditions
that do not require sophisticated ligands.[11a,29] This result is
particularly significant since excess Et3N has been employed
as a Brønsted base in each of the previous attempts to
catalyze the aerobic oxygenation of phenols,[16–19] and yet its
role as a ligand has not been described.[29]
A 60% conversion of 1 into 2 was observed under slightly
modified conditions to those reported by Rꢁglier et al.
(entries 1 and 2).[16] Interestingly, both the yield of 2 and the
reaction conversion decreased as the reaction time increased
Table 1: Reaction optimization.[a]
Entry
Catalyst
(mol%)
Amine
(mol%)
t
[h]
M.S.
[mg]
Conversion[b]
[%]
Yield
[%]
1
2
3
4
5
6
7
8
9
L2 (10)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
3 (10)
3 (10)
3 (8)
Et3N (200)
Et3N (50)
Et3N (200)
Et3N (50)
Et3N (50)
Et3N (50)
Et3N (50)
Et3N (50)
DBED (5)
4
4
24
4
4
4
4
4
4
–
–
–
–
200
–
200
200
–
60
55
58[b]
54[b]
18[b]
<5[c]
97[b]
26[b]
86[b]
96[d]
98[d]
33
<5[c]
99
32
90
>95
>95
3 (4)
Although the precise role of molecular sieves remains
unclear,[30] the negative impact of H2O on the reaction
outcome prompted us to investigate the more hydrolytically
stable complex of
3 with di-tert-butylethylenediamine
(DBED) developed by Hay[31] and extensively studied by
Stack and co-workers.[14c] Remarkably, ratios of DBED/3
greater than 1:1 afford a robust catalyst that does not require
the use of excess Et3N or a desiccant (entry 9), and even
promotes oxidation in common, undried solvents under open-
flask conditions (see the Supporting Information). This
catalyst system remains efficient on a multigram scale
(60 mmol of 1), high concentrations (up to 2.0m), and low
catalyst loadings (2 mol% Cu, 4 mol% of DBED; see the
Supporting Information), thereby setting the stage for its
development into a versatile and practical tool for syn-
thesis.[32]
[a] Reactions were performed on a 1.0 mmol scale of 1. [b] Yields and
ratios are based on 1H NMR integration relative to an internal standard
(hexamethylbenzene). [c] Reaction performed in the presence of lawsone
(25 mol%). [d] Yields of isolated and purified 2. [e] Reactions using L1,
L3–L6 (10 mol%) were performed on a 1.0 mmol scale of 1 using Et3N
(50 mol%) in CH2Cl2 (0.1m) under O2 (1 atm) at 238C in the presence
and absence of molecular sieves (4 ꢁ M.S, 200 mg). Yields in the
absence of sieves are reported first (in black), and with molecular sieves
Both Et3N- and DBED-mediated oxidations retain excel-
lent regio- and chemoselectivity for ortho-, meta-, or para-
substituted phenols displaying a range of common functional
1
are reported second (in blue). Yields are based on H NMR integration
relative to an internal standard (hexamethylbenzene).
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groups including alcohol, amide, aldehyde, and nitrile func-
tionalities (Scheme 2).[29] The selective ortho-functionaliza-
tion of aryl ethers (8 and 9) complements stoichiometric
methods that afford para-quinones or quinone ketals, and
demonstrates compatibility with phenols bearing heteroatom
substituents.[22b,c] In the case of ortho- and meta-substituted
phenols, our conditions override the preference of phenols to
oxidize to the para-quinone under aerobic conditions.[11b] The
observed regioselectivity is consistent with an inner-sphere
mechanism of oxygen atom transfer.[11a,b,12,14c] In nonsymmet-
ric substrates, regioselectivity is influenced by steric and
electronic factors to afford 4,5-disubstituted ortho-quinones
(18–22) or 3,4,5-trisubstitued ortho-quinones after two oxi-
dative coupling reactions (23–25). ortho-Substituted phenols
selectively form 3,4,5-trisubstituted ortho-quinones, and che-
moselectivity for ortho-oxygenation is retained in the pres-
Naphthol and tetrahydro-2-naphthol undergo selective oxy-
genation at C1 (29 and 30), in contrast with stoichiometric
oxidants that afford mixtures of regioisomeric quinones[6d] or
À
catalytic aerobic reactions that favor C C coupled pro-
ducts.[11b,33] A preliminary mechanistic interpretation of these
results supports an inner-sphere ortho-oxygenation of the
starting phenol, where the newly introduced oxygen atom is
derived from O2.[32] Subsequent oxidative coupling with the
starting phenol affords the coupled product, thereby releasing
the Cu catalyst and closing the catalytic cycle. The details of
this mechanism are currently under investigation, and will be
reported in due course.[32]
Our catalytic aerobic oxidation enables a direct synthesis
of polyfunctional heterocycles that extends our method
beyond a phenolic homocoupling (Scheme 3). For example,
À
ence of benzylic or aryl C H bonds (26–28), which have been
susceptible to oxidation in related Cu/O2 systems.[14b] 2-
Scheme 3. Cross-aerobic coupling. Reagents and conditions: a) Syn-
thesis of 34 and 35: 3 (4 mol%), DBED (5 mol%), EtOAc (0.5m),
open flask. Synthesis of 36 from 33: 3 (4 mol%), DBED (5 mol%),
CH2Cl2 (0.1m), O2 (1 atm); then EtSH (4 equiv), para-toluenesulfonic
acid (1 equiv). Synthesis of 37: 3 (4 mol%), DBED (5 mol%), CH2Cl2
(0.1m), O2 (1 atm); then EtSH (4 equiv), DBED (1 equiv).
primary alcohols and sulfonamides are suitable nucleophiles
for intramolecular cyclization, thus enabling the direct syn-
thesis of furano- and indoloquinones 34 and 35. While our
standard conditions are amenable to the synthesis of 34 and
35, this transformation can even be conducted under open
flask conditions in reagent-grade ethyl acetate, which are
significantly milder conditions than those typically required
for heteroatom–carbon coupling reactions.[34] Most impor-
tantly, the ortho-quinone products can be employed in
additional bond-forming reactions, thereby enabling one-
pot, sequential processes that avoid traditional work-up and
purification. For example, indoloquinone 35 is reduced by
ethanethiol (EtSH) under acidic conditions to afford 3,4-
dihydroxydihydroindole 36 in 71% yield, in a one-pot,
sequential process starting from 33. Alternatively, the addi-
Scheme 2. Substrate scope. Standard Et3N conditions (isolated yields
of products are shown first, in black): phenol (1.0 mmol), O2 (1 atm),
3 (8 mol%), Et3N (50 mol%), 4 ꢁ molecular sieves (200 mg), CH2Cl2
(0.1m) at 258C for 4 h. Standard DBED conditions (isolated yields of
products are shown second, in blue): phenol (1.0 mmol), O2 (1 atm), 3
(4 mol%), DBED (5 mol%), CH2Cl2 (0.1–0.5m) at 238C for 4 h.
[a] Reaction performed in THF (0.1m) because of issues of solubility.
À
tion of EtSH under basic conditions triggers regioselective C
S bond formation, and generates pentasubstituted catechol 37
in 78% yield in one pot starting from phenol 33. The synthesis
of functionalized ortho-quinones and catechols under such
operationally simple conditions is noteworthy, since their use
in applied fields of chemistry is currently limited to a small
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selection of commercially available derivatives.[35] Moreover,
our method establishes an exceptionally efficient route to
highly oxidized furan and indole heterocycles that converts
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À
À
À
À
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In conclusion, we have described a practical catalytic
aerobic oxygenation of phenols to ortho-quinones, which had
remained an unresolved challenge in homogeneous copper
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À
a growing trend in synthetic chemistry, which aims to drive C
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Received: December 21, 2013
Published online: April 17, 2014
Keywords: copper · ortho-quinones · oxidation ·
.
synthetic methods · tyrosinase
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