Palladium catalyzed Csp2-H activation for direct aryl hydroxylation: The unprecedented role of 1,4-dioxane as a source of hydroxyl radicals

Article abstract of DOI:10.1039/c4cc06864e

A novel strategy for direct aryl hydroxylation via Pd-catalysed C_sp²-H activation through an unprecedented hydroxyl radical transfer from 1,4-dioxane, used as a solvent, is reported with bio relevant and sterically hindered heterocycles and various acyclic functionalities as versatile directing groups.

Full text of DOI:10.1039/c4cc06864e

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DOI: 10.1039/C4CC06864E
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Palladium Catalyzed Csp2-H Activation for Direct Aryl
Hydroxylation: Unprecedented Role of 1,4-Dioxane as
Source of Hydroxyl Radical
Cite this: DOI: 10.1039/x0xx00000x
Received
Accepted
Kapileswar Seth, Manesh Nautiyal, Priyank Purohit, Naisargee Parikh, and Asit K.
Chakraborti*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel strategy for direct aryl hydroxylation by Pd-
catalysed Csp2-H activation through an unprecedented
hydroxyl radical transfer from 1,4-dioxane, used as solvent, is
reported with bio relevant and sterically hindered
heterocycles and various acyclic functionalities as versatile
directing groups.
15 to Pd), poor selectivity, and harsh reaction conditions (15
atm O2, 15 atm CO, 180 °C, AcOH) do not make it attractive.
The strategy of Kim et al4b on the use of 2-pyridyl moiety as
the directing group (DG) for Csp2-H activation though affords
good yields requires excess oxidant (5 equiv), is applicable to
highly substituted DG (2-pyridyl), and does not work with aryl
The wide occurrence of hydroxylated aromatics (phenols) in
bioactive compounds1 makes them highly sought for synthetic
targets. Aryl hydroxylation through C-H activation has emerged
as new synthetic route to phenols.2 However, these represent
indirect hydroxylation as the reaction proceeds via the
intermediate formation of the acyloxy arenes that are converted
to the hydroxyaromatics during the workup or on further
hydrolytic transformation.3 The issue on direct aryl
hydroxylation remains inadequately addressed (Scheme 1).4
moiety bearing o-substitution. The use of carboxylic acid as DG
by Yu et al4c requires excess of base, benzoquinone as
additional oxidant (in addition to O2 at 1-5 atm), and leads to
decarboxylation (e.g. 1-naphthoic acid). The tandem C-S
coupling-hydroxylation strategy of Pan et al4d requires special
ligand, excess of base, and aryl bromide/iodide as the reaction
partner (additional reagent). The recent report on 2-pyridyl
directed Csp2-H activation by Jiao et al 4e
the limitations of the protocol of Kim et al 4b
,
though circumvents
requires
,
N-
hydroxyphthalimide (NHPI) and toluene as additional reagent
system (in addition to O2 at 1 atm) to form benzyl radical that
acts as the effective agent/species for hydroxyl radical
generation and leads to the formation of high boiling by-
products (benzaldehyde/benzoic acid).
Functionalised 2-(benzoxazol-2-yl)phenols have diverse
biological activities.5 Thus, it would be attractive to use the 2-
benzoxazolyl scaffold as the DG for Csp2-H activation for direct
aryl hydroxylation to further potentiate their biological activity6
and as there is no report on direct aryl hydroxylation with 2-
7
benzoxazolyl moiety as the DG. 2-Phenylbenzoxazole (1a
)
was considered as model substrate for oxidative hydroxylation
via aryl Csp2-H activation under various conditions (Scheme 2).
Scheme 2. Direct hydroxylation of 1a to form 2a
.
Scheme 1. Different strategies for direct aryl hydroxylation.
It appears that the limited reports on direct hydroxylation
involve the generation of oxygen/hydroxyl radical4b-d that adds
on to the metal centre at its higher oxidation state in the
Fujiwara et al4a revealed the feasibility of direct aryl
hydroxylation but the low yield (~5%) and turnover ratio (10-
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Table 1. Substrate scope for direct aryl hydroxylation via C-H activation
with bio relevant and sterically hindered DGs.
cyclometallated intermediate and acts as the effective species
for C-O bond formation. 1,4-Dioxane is reported to generate
hydroxyl radical on pyrolysis.8 However, high temperature
(1550-2100 K) is required to generate the hydroxyl radical by
ring opening (homolytic C-O cleavage), isomerisation, and
dissociation of the resulting linear species. We reasoned that the
hydroxyl radical generation from 1,4-dioxane may be achieved
under milder condition in the presence of an oxidant that would
abstract H from 1,4-dioxane and facilitate its dissociation via
ring opening C-O cleavage involving free radical mechanism.
Thus, it was hypothesised that the use of 1,4-dioxane in
combination with persulfate would serve the dual purpose of
the reaction medium and the oxo/hydroxyl transfer agent
without the requirement of any additional oxidant/reactant and
base.
Treatment of 1a with different variation of the reaction
parameters (ESI: Tables 1A-1E)† revealed the use of Pd(OAc)2
(2.5 mol%) and Na2S2O8 (1.25 equiv) in 1,4-dioxane at 80 °C
for 14 h to be the best operative reaction condition affording 2a
in 62% yield which could be further improved to 82% after
reusing the unreacted 1a recovered after the first use. The lack
of formation of 2a in any other solvent (ESI: Tables 1D and
1E)† suggested 1,4-dioxane to be the hydroxyl transfer agent as
the comparable results with commercial grade as well as dry
and degassed 1,4-dioxane under N2 or O2 eliminated the
possibility of hydroxyl transfer from any dissolved
oxygen/moisture. That the reaction forms the hydroxyarene
directly was demonstrated by the fact that 2a was obtained in
comparable yield (64%) avoiding aqueous work up. However,
the Pd(OAc)2-catalysed reaction of 1a with Na2S2O8 (1.5 equiv)
in HOAc-Ac2O (1:1) or Ac2O instead of 1,4-dioxane afforded
aThe figure in the parenthesis is the total yield based on recovery and reuse
of the unreacted starting material after the first attempt.
the
O-acetylated 2a following non-aqueous workup in 53 and
55% yields, respectively (ESI: Table 2A).† Thus, the persulfate-
dioxane combination constitutes a novel reagent system for Pd-
catalysed direct aryl hydroxylation.
The results of Table 2 demonstrate further scope with
acyclic DGs such as azo, amide, anilide, carbamate, and
unsymmetrical urea. The F and Cl substituted azo benzenes
produced the corresponding azoxy-benzene in 40 and 24%
yields, respectively, along with the desired hydroxylated
products. The chemoselective hydroxylation with substrates
bearing halogen provide scope of structural modification
through Suzuki coupling11 to broaden the chemical space. The
catalyst [Pd(OAc)2] was recovered and reused for five
consecutive reactions affording comparable yields.†
Treatment of 1a under the reported conditions for
acetoxylation/hydroxylation and minor variation (using 1,4-
dioxane as solvent) did not produce significant amount of 2a
(ESI: Tables 3A and 3B)† and established the distinctiveness of
the present work.
The direct hydroxylation protocol is applicable to
benzoxazoles bearing substituent in the 2-aryl moiety as well as
in the benzenoid ring of the benzoxazole scaffold (Table 1).
The applicability of the direct hydroxylation towards various
substituted 2-arylbenzothiazoles (Table 1),9 another bio
relevant and sterically hindered DG, demonstrated the
versatility with respect to the DG.10 The presence of Cl, Br,
CF3, and NO2 in the 2-aryl moiety appears to be beneficial as
such substrates afforded the corresponding hydroxyarenes in
better yields compared to that of the unsubstituted analogue
Table 2. Scope of acyclic DGs for direct aryl hydroxylation.
1a/3a. The effect of these substituents was more pronounced
with 2-benzothiazolyl moiety as the DG. The presence of
electron donating substituent such as the Me group decreased
the yield.
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DOI: 10.1039/C4CC06864E
and
D
/
E
(m/z 71) (ESI: 10.2.2) that compared well with the
GC-MS and ms2 (of the ion at m/z 71) spectra of an authentic
sample of THF.† Some of the daughter ions observed in the ms2
of the ion at m/z 71 were also observed in the ms2 of the ion at
m/z 87 (e.g. 70.81 vs. 70.82; 42.93 vs. 42.87) suggesting the
ion with m/z 71 to derive from the ion of m/z 87 through loss of
active oxygen species. The GC-MS spectra of aliquots of the
reaction mixture during the treatment of 2-phenylbenzoxazole
(
1a) with Na2S2O8 and 1,4-dioxane at 80 °C revealed the
presence of the ion peaks at m/z 87 and 71 corresponding to
and
, respectively (ESI:10.5.3 and 10.5.2).†
B
aThe figure in the parenthesis is the total yield based on recovery and reuse
of the unreacted starting material after the first attempt
D/E
.
A plaussible mechanism is depicted in Scheme 3. The Pd-
catalyst forms the complex through coordination with the
I
nitrogen centre of the DG and trigers aryl Csp2-H activation and
ligand-assisted intra-molecular aryl proton abstraction in II to
form the cyclopalladated species III. Oxidative addition of the
hydroxyl radical, formed by degradation of 1,4-dioxane with
the persulfate anion, (Scheme 4) generates the Pd(IV) species
Scheme 4. Generation of OH radical from 1,4-dioxane and Na2S2O8.
The influence of ligand/counter anion on the catalytic
potential of the Pd-compounds (ESI: Table 1B)† and the lack of
improvement of yield in using NH4OAc, KOAc and (KOAc +
18-C-6) as external base (ESI: Table 5A)† during the Pd-
catalysed reactions implicate that the abstraction of the aryl
proton during the C-H activation step occurs via intramolecular
process involving II. Thus the strong electron withdrawing CF3
IV12 or the PdIII-PdIII species V 13
reductive elimination from IV
.
/
The aryl C-O bond forming
V leads to the hydroxyarene
(phenol) and brings the Pd(II) compound back to the catalytic
cycle to form through ligand exchange (facilitated by
I
16
group reduces the HB acceptor property of TFA in Pd(TFA)2
intramolecular hydrogen bond formation between the newly
inserted OH and the nitrogen atom of the DG).14
making it inferior catalyst compared to Pd(OAc)2. The HB
formation ability of the counter anion plays key role in the
formation of the reaction intermediate (transition state) in
various organic reactions.17 The importance of the HB has also
been realised in forming metal centred transition state.18
The involvement of radical species was corroborated by the
fact that a drastic decrease in the product (2a) yield (17%) was
observed in performing the Pd(OAc)2-catalysed reaction of 1a
in the presence of radical scavenger (TEMPO) (ESI: Scheme
5C).† The indispensable role of 1,4-dioxane is reflected in its
ability to form radical species in the presence of persulfate15 or
other oxidant.19
The present work provides a novel strategy for direct aryl
hydroxylation via palladium-catalysed aryl Csp2-H activation
with bioactive and sterically hindered heterocylic moieties and
other acyclic functionalities (azo, amide, anilide, carbamate,
and urea) as versatile directing groups through unprecedented
generation of hydroxyl radical, as the effective aryl
hydroxylation species, from 1,4-dioxane (used as solvent).
Financial support from DST (SR/S1/OC-33/2008) and
CSIR [senior research fellowship to KS], New Delhi, India
is acknowledged.
Scheme 3. Plaussible pathway for the direct aryl hydroxylation.
The generation of hydroxyl radical from Na2S2O8 and 1,4-
dioxane is visualized in Scheme 4. The sulfate anion radical,
generated from persulfate anion,15 has the ability to abstract C-
H hydrogen15a and reacts with 1,4-dioxane (
dioxan-2yl radical (
produces the radical
cleavage is converted to the tetrahydrofuran-2-yl radical
A
) to form the 1,4-
). Homolytic ring C-O cleavage8 of
which on further homolytic C-O
. The
B
B
Notes and references
C
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062,
Punjab, India. E-mail: akchakraborti@niper.ac.in;
D
liberated oxygen diradical is converted to the hydroxyl radical
through H-abstraction from another molecule of 1,4-dioxane
akchakraborti@rediffmail.com
generating the radical
B to propagate the radical chain reaction.
†
Electronic Supplementary Information (ESI) available: Spectroscopic
The relevant intermediates could be identified in the GC-MS
spectra of aliquot samples (withdrawn at an interval of 2 h) of
the reaction mixture of 1,4-dioxane and Na2S2O8 at 80 °C that
data of all compounds, scanned spectra of new compounds. See
DOI: 10.1039/b000000x/
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showed ion peaks corresponding to
B (m/z 87) (ESI: 10.2.3)
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