Synthesis of ortho-Azophenols by Formal Dehydrogenative Coupling of Phenols and Hydrazines or Hydrazides

Article abstract of DOI:10.1002/chem.201701226

Azophenols are important chromophores and reagents in organic synthesis, with applications as pigments and molecular switches. Here, we describe a catalytic aerobic process that couples phenols and hydrazines or hydrazides for their synthesis. The key aromatic C?N bond is formed by condensation between the hydrazine or hydrazide and an ortho-quinone, which triggers a redox-isomerization to install the azo-functionality. Notable features include rapid access to highly functionalized azophenols with a range of electronic configurations, including “push–pull” systems, conditions that employ simple, unactivated substrates, occurrence at room temperature using an earth-abundant and commercially available copper catalyst, and production of water as the only stoichiometric byproduct.

Full text of DOI:10.1002/chem.201701226

A Journal of
Accepted Article
Title: Synthesis of ortho-Azophenols by Formal Dehydrogenative
Coupling of Phenols and Hydrazines or Hydrazides
Authors: Jean-Philip George Lumb and Kenneth Virgel N. Esguerra
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To be cited as: Chem. Eur. J. 10.1002/chem.201701226
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Synthesis of ortho-Azophenols by Formal Dehydrogenative
Coupling of Phenols and Hydrazines or Hydrazides
Kenneth Virgel N. Esguerra, [a] and Jean-Philip Lumb* [a]
Dedication ((optional))
azo-switches,15 which display exceptionally fast and quantitative
Abstract: Azophenols are important chromophores and reagents in
thermal isomerization.3 Transition metal-catalyzed ortho-
organic synthesis, with applications as pigments and molecular
oxygenation of symmetric azobenzenes has been reported
switches. Herein, we describe a catalytic aerobic process that couples
(Scheme 2A),14b-d but suffers from poor regio- and
phenols and hydrazines or hydrazides for their synthesis. The key
chemoselectivity in non-symmetrical substrates, complicating the
synthesis of “push-pull” azophenols. A mechanistically distinct,
aromatic C-N bond is formed via condensation between the hydrazine
or hydrazide and an ortho-quinone, which triggers
a redox-
but undeveloped transformation that leads selectively to ortho-
azophenols, occurs by a condensation and redox isomerization
cascade between ortho-quinones and hydrazines.16 This process
has been used to probe the chemistry of the quinone co-factor
pyrroloquinoline quinone (PQQ),16a-c but it has not been
developed as a synthetic methodology. This stems, in part, from
the limited availability of ortho-quinones, which are electrophilic,
redox-sensitive, and often difficult to prepare and store.
isomerization to install the azo functionality. Notable features include
rapid access to highly functionalized azophenols with a range of
electronic configurations, including “push-pull” systems, under
conditions that employ simple, un-activated substrates, occur at room
temperature using an earth-abundant and commercially available
copper-catalyst, and produce water as the only stoichiometric
byproduct.
Azophenols are an important class of azobenzene dyes,1 with
applications as pigments,2 ligands for transition metals,3
molecular switches,4 fluorescent probes5 and sensors (Scheme
1A).6 Relative to non-phenolic azobenzenes, they possess red-
shifted absorption spectra, and exhibit rapid rates of cis-to-trans
thermal relaxation, made possible by a facile tautomerization to
the ortho-imino-quinone (Scheme 1B). These are important
properties for fast information transmission in biologically relevant
contexts,7 which can be further fine-tuned by the degree of
polarization across the azo-linkage.1a,4,8 Azophenols possessing
a polarized or “push-pull” electronic configuration are noted for
their fast rates of switching, which is attenuated for less-polarized
derivatives possessing neutral or electron-rich aromatic rings.4
Structurally related 2-aryl-azo-carboxylates (Scheme 1A) are
widely used as electrophilic reagents,9-10 in heterocycle
synthesis,11 and also as versatile synthetic intermediates.12 The
unique properties of these two classes of azo-compounds creates
a need for new methodologies that can efficiently provide non-
symmetrical azophenols with a palette of electron releasing and
withdrawing substituents on the non-phenolic substituent.
Scheme 1. (A) Selected examples of azophenols. (B) Mechanism of
isomerization for ortho-azophenols.17
Recognizing these challenges, we envisioned that a catalytic
aerobic ortho-oxygenation of phenols could allow entry to
this transformation.18 Phenols are readily available staring
materials, but their ortho-oxygenation has historically
required a multi-step sequence,19 or a synthetic oxidant that
can be difficult to use in sequential transformations.19d In the
current context, we questioned whether our aerobic ortho-
oxygenation could be interfaced with a hydrazine / hydrazide
coupling reaction to provide ortho-azophenols in a 1-pot,
sequential process from phenols. To our knowledge, the
cross-coupling of these two nucleophilic reagents is
unknown. Hydrazines and hydrazides benefit from
widespread commercial availability, but they are
In contrast to the synthesis of azobenzenes, for which a number
of recent methodologies have been reported,7c,13 the synthesis of
azophenols remains complicated by issues of selectivity and
reactivity.14 Their classical preparation from an aryl diazonium salt
and a phenol is not regioselective (Scheme 2A),14a and can be
difficult to apply to azo-phenols containing heterocycles.
Heterocyclic azophenols are a particularly interesting class of
[a]
K. V. N. Esguerra, Prof. Dr. J.-P. Lumb
Department of Chemistry
McGill University
801 Sherbrooke St. W., Montreal, Quebec H3A 0B8 (Canada)
jean-philip.lumb@mcgill.ca
underdeveloped for the synthesis of azobenzenes.20 Herein
2
we demonstrate their utility in a formal dehydrogenative Csp
-
2
Nsp coupling reaction, providing valuable ortho-azophenols
with a range of electronically distinct functional groups
Supporting information for this article is given via a link at the end of
the document.
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directly from phenols under mild and regioselective
conditions (Scheme 2C).
parameters that were optimized include the equivalents of 2
(2 equiv), its addition as a homogeneous solution in MeOH
(0.7 M), and the time for C-N coupling (12 h), which led to
yields of ~ 90% on scales that range from 1 to 20 mmol. An
x-ray structure of
4 confirms the regioselectivity of C-N bond
formation at the more sterically accessible C1-carbonyl of
3
,
defining the overall transformation as a formal transposition
of the C1 oxygen of the phenol to C2 with concomitant
formation of the azo at C1.
Scheme 2. (A) Classical syntheses by diazo coupling, and transition metal
catalyzed hydroxylation. (B) PQQ and hydrazine condensation. (C) Work
described therein.
At the outset of our work, we discovered two competitive
pathways for the reaction of ortho-quinones with hydrazines
(Scheme 3). For constructive C-N bond formation to occur,
condensation must out-compete a redox exchange, in which
the quinone is reduced to the corresponding catechol, and
the hydrazine is ultimately oxidized to an organic radical. The
latter pathway provides an interesting entry into arene radical
chemistry, which is discussed later in Scheme 4. To develop
the desired C-N coupling, we employed 3,5-di-tert-butyl-
Scheme 3. Initial studies on aerobic coupling of phenol 1 and hydrazine 2. [a]
Hydrogens are omitted for clarity. Blue = N, Red = O, Teal = C.
The scope of the nitrogen coupling partner was evaluated
using these optimized conditions (Table 1). Azophenols with
a push-pull electronic configuration are prepared in generally
high yields from the coupling of aryl or heteroaryl hydrazines
bearing a range of electron-withdrawing substituents. These
include fluorine, chlorine, trifluoromethyl and sulfonate
groups (entries 1-5). We highlight entries 2 and 3, as
azophenols possessing ortho-chloro substituents, and entry
5 as a heterocyclic "push-pull" azophenol, which are two
substrate classes that have attracted recent attention for
their red-shifted optical properties and their fast thermal
isomerization.4,7c The use of hydrazides as nitrogen coupling
partners is equally efficient (entries 6-11), and establishes a
phenol (
be coupled in a 1-pot, sequential process involving aerobic
oxygenation of to ortho-quinone with 8 mol% of
1) and 2,4-di-nitrophenylhydrazine (2), which could
1
3
Cu(CH3CN)4(PF6) (abbreviated as CuPF6) and 15 mol% of
di-tert-butyl-ethylenediamine (DBED).18 After 4 hours at
room temperature,
S1 and S2 in the Supporting Information for optimization
studies). The direct addition of (1 equiv) then triggers the
condensation / redox-isomerization to provide , but only in
3 is produced in > 95 % yield (see Tables
2
4
2
new Csp2-Nsp coupling reaction that is selective for the
13% yield after 4 h. We observed dramatic improvements to
the efficiency and selectivity of C-N coupling upon the
addition of MeOH, under the premise that a more protic
environment would facilitate condensation. Reaction
terminal nitrogen of the hydrazide. This complements the
regioselectivity of more traditional metal-catalyzed coupling
reactions, which are typically selective for the internal
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nitrogen.21 Aryl (entry 6) and carbamate (entry 7)
substituents on the hydrazide are tolerated, as are furan
(entry 8), isoxazole (entry 9), pyridine (entry 10), and
carbonyl of the ortho-quinone to provide single regioisomers of
“push-pull” azophenols in good yields. In cases where selectivity
during ortho-oxygenation is diminished, C-N coupling remains
selective, to provide a mixture of only two, separable azophenols,
in synthetically useful yields (entries 7 and 8).
thiophene
(entry
12)
heterocycles.
Likewise,
thiosemicarbazides (entry 12) function well.
Table 2. Scope of Di- and Tri-Substituted Phenols a
Table 1. Scope of Hydrazines and Hydrazides
[a] Conducted with 1.0 mmol of 1. Isolated yields are reported for each entry. [b]
Ratio of regioisomers.
The balance between condensation and redox exhange
sways to the latter for hydrazines that are more electron-rich,
such that the attempted coupling of phenyl hydrazine with
1
[a] Reaction conditions: 1 (1.0 mmol), CuPF6 (8 mol%), DBED (15 mol%), O2 (1
atm), CH2Cl2 (0.1 M), rt, 4 h; then, hydrazine/hydrazide (2 equiv.) in MeOH (3
mL), rt, 12 h. Isolated yields are reported for each entry. [b] Hydrogens are
removed for clarity. Red = O, Blue = N, Yellow = F and Teal = C.
returns catechol at complete conversion, without evidence
5
of C-N coupling (Scheme 4A). While the fate of the hydrazine
is difficult to discern under these conditions, control
Our conditions also tolerate phenols bearing 3,5-di-silyl groups, to
provide azophenols with attractive functional handles (Table 2,
entry 1). Likewise, 3,4,5-tri-phenyl phenol provides the
corresponding penta-substituted azophenol in good yield (entry
2). The coupling of unsymmetrical phenols is also possible, in
spite notorious difficulties of controlling the regioselectivity of C-H
oxygenation when O2 is the atom-transfer agent.22 Under our
conditions,23 oxygenation occurs within a dinuclear Cu(III)-µ-oxo
experiments between quinone
intermediacy of arene radical 10, which can be intercepted
either by the quinone to provide aryl ether 7 26
or by benzene
to provide biaryl (Scheme 4B). Despite extensive
investigations into the oxidation of hydrazines,27 little is
known about their redox-exchange with ortho-quinones. The
plausibility of a 2 electron / 2 proton exchange to provide aryl
2 and hydrazine 6 suggest the
,
8
phenolate (see Scheme S2 and
S3 in the Supporting
Information),24 such that oxygenation is regioselective for the
sterically least demanding ortho-position of phenols possessing
differentiated substituents at C3 and C5 (entries 3-6).25 The
subsequent amination occurs exclusively at the less encumbered
diazene
9 is supported by literature precedent, in so far as
related diazenes are known to serve as precursors to arene
radicals.28
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room temperature, using an earth-abundant and
commercially available Cu-catalyst, with the added benefit of
generating H2O as the sole stoichiometric byproduct
.
Scheme 4. (A) Redox reaction of 1 with phenylhydrazine. (B) Mechanistic
studies on quinone / hydrazine redox exchange.
While the redox chemistry of hydrazines and ortho-quinones
presents an interesting entry into arene radical chemistry, it
also creates a practical limitation for the synthesis of more
electron rich azophenols, which we sought to overcome by
exploiting a coupling reaction with para-toluenesulfonyl
Scheme 5. Synthesis of electron-rich azophenols from diazobenzoquinones.
Acknowledgements
hydrazide (Scheme 5). This provides diazobenzoquinone 12
following the spontaneous elimination of toluene sulfinic acid
from N-tosyl-azo phenol 11 29
The ortho-azo-quinone
,
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 Québec—Nature et
Technologies (FRQNT, Team Grant to J.-P.L.), the FRQNT
Center for Green Chemistry and Catalysis at McGill University,
the NSERC CREATE Program in Green Chemistry at McGill
University, and the McGill University-Canadian Institutes of
Health Drug Development Trainee Program (doctoral fellowship
to K.V.N.E.). Dr. Thierry Maris (University of Montreal) for help
with X-ray crystallography.
.
structure of 12 was confirmed by x-ray crystallography, and
is consistent with previously reported structures of azo-
naphthoquinones29a,29b and azo-para-quinones,30 which
have been synthesized from the corresponding aminophenol
by diazotization.30c-f Diazobenzoquinones have applications
in photolithography31 and as precursors to carbenes.30c,32 In
the current context, we explored the reactivity of 12 towards
Grignard reagents, with the hope of accessing less-polarized
azophenols by nucleophilic addition to the terminal
nitrogen.33 Gratifyingly, this provides a two-step alternative
for the synthesis of azophenols possessing aromatic rings
(entries 1-3), or even an alkyl substituent (entry 4), that
cannot be incorporated using our standard phenol /
hydrazine coupling conditions. We anticipate a number of
opportunities to exploit ortho-azobenzoquinones, which,
unlike their para-isomers or naphthalene / phenanthrene
analogues, have not previously been synthesized.
Keywords: Azophenol • Aerobic Copper Catalysis • Phenol • Hydrazine • C-H
Functionalization
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10.1002/chem.201701226
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Kenneth Virgel N. Esguerrra, Prof. Dr.
Jean-Philip Lumb*
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Synthesis of ortho-Azophenols by
Formal Dehydrogenative Coupling of
Phenols and Hydrazines or
Hydrazides
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