Selective Aromatic C-H Hydroxylation Enabled by η6-Coordination to Iridium(III)

Article abstract of DOI:10.1021/acs.organomet.5b00731

We report an aromatic C-H hydroxylation protocol in which the arene is activated through η⁶-coordination to an iridium(III) complex. η⁶-Coordination of the arene increases its electrophilicity and allows for high positional selectivity of hydroxylation at the site of least electron density. Through investigation of intermediate η⁵-cyclohexadienyl adducts and arene exchange reactions, we evaluate incorporation of arene π-activation into a catalytic cycle for C-H functionalization.

Full text of DOI:10.1021/acs.organomet.5b00731

Article
pubs.acs.org/Organometallics
Selective Aromatic C−H Hydroxylation Enabled by η6‑Coordination
to Iridium(III)
Erica M. D’Amato, Constanze N. Neumann, and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
S
* Supporting Information
ABSTRACT: We report an aromatic C−H hydroxylation protocol in which
the arene is activated through η6-coordination to an iridium(III) complex. η6-
Coordination of the arene increases its electrophilicity and allows for high
positional selectivity of hydroxylation at the site of least electron density.
Through investigation of intermediate η5-cyclohexadienyl adducts and arene
exchange reactions, we evaluate incorporation of arene π-activation into a
catalytic cycle for C−H functionalization.
traditional C−H functionalization chemistry. Herein, we
present C−H hydroxylation utilizing iridium(III) η6-arene
complexes and demonstrate the first use of oxygen nucleophiles
for C−H functionalization with transition metal η6-arene
complexes. We anticipate that these advances in stoichiometric
C−O bond formation will provide valuable insight for
translation into a catalytic cycle.
INTRODUCTION
■
Transition metal-mediated C−H functionalization methods
typically involve the formation of a metal−carbon σ-bond
through oxidative addition, σ-bond metathesis, or electrophilic
metalation.1 Slow metalation processes, due to the strength and
low polarity of the aromatic C−H bond, are difficult to
overcome and hinder the improvement of current method-
ologies. We identified η6-coordination of the aromatic π-system
to a transition metal as an alternative activation manifold that
could facilitate aromatic C−H functionalization. The catalytic
cycle we envision involves nucleophilic attack on an η6-
coordinated arene, oxidation of the resulting η5-cyclohexadienyl
adduct, and arene exchange (Scheme 1). By employing
Several strategies have been employed to form metal−carbon
σ-bonds as intermediates for subsequent functionalization,
despite the slow C−H metalation of arenes. The use of
coordinating directing groups for both ortho2 and meta3 C−H
functionalization has been thoroughly explored by several
groups to enforce intramolecularity for the difficult metalation
step. However, introduction and further modification of a
directing group increases step count and is often challenging.
On the other hand, C−H metalation without a coordinating
directing group typically requires an excess of arene (i.e., as
solvent) to increase the concentration of substrate. Notable
exceptions include iridium-catalyzed borylation4 and rhodium-
catalyzed silylation.5 An opposing strategy is to avoid formation
of a metal−carbon σ-bond altogether, such as electrophilic
aromatic substitution, radical rebound by high valent metal
complexes,6 or reactions that proceed through a radical addition
to an arene. For example, MacMillan’s iridium-catalyzed
trifluoromethylation7 and our group’s palladium and silver
cocatalyzed C−H imidation8 utilize transition metal catalysts to
form reactive radical species that interact with the aromatic
substrate. In an effort to expand upon methods that do not rely
upon formation of a metal−carbon σ-bond during catalysis, we
focused on utilizing η6-arene complexes to provide a different
mechanism for C−H functionalization.
Scheme 1. C−H Functionalization Utilizing η6-Arene
Activation
nucleophilic functionalization reagents, as opposed to the
conventionally used electrophilic reagents, the π-activation
mode is well suited for the formation of C−X bonds, where X is
an electronegative atom, such as O, N, or F. Additional benefits
of the π-activation approach include the ability to target
aromatic rings without introduction of a coordinating directing
group and the reversal of positional selectivity observed for
η6-Coordination of an arene has long been recognized as a
tool for umpolung aromatic substitution chemistry, which
facilitates nucleophilic attack on otherwise unactivated aromatic
Received: August 25, 2015
© XXXX American Chemical Society
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π-systems.9,10 Nucleophilic attack at C−H bonds is well
established with a variety of transition metal complexes, such
as η6-arene complexes of the [Cr(CO)3], [Mn(CO)3]+,
[FeCp]+, [RuCp]+, and [IrCp*]2+ fragments, and is kinetically
preferred over C−X bonds9a in most cases. Strong
nucleophiles, such as some carbanions, form stable η5-
cyclohexadienyl adducts via irreversible nucleophilic attack.9,11
Stable adducts can be oxidized in a subsequent step to provide
overall C−H-functionalized products (Scheme 2). However,
Scheme 3. Synthetic Cycle for Oxidation of Benzene to
Phenol
Scheme 2. C−H Functionalization via Nucleophilic Attack
on η6-Arene Complexes
a
Isolated as the aryl p-toluenesulfonate due to volatility of phenol.
After protonation of 2 and heating at 80 °C in acetonitrile,
phenol is recovered in 75% isolated yield and tris(acetonitrile)
complex 3 is isolated in 85% yield. The iridium can be recycled
to convert complex 3 into 1 in 81% yield by heating in a 1:1
mixture of benzene and acetone. In this way, all steps of the
proposed catalytic cycle have been demonstrated individually.
Upon discovery of the above C−H oxidation protocol, the
effect of arene substitution on selectivity was investigated
(Table 1). Interestingly, C−O bond formation occurs
Table 1. Effect of Arene Substitution on Site Selectivity of
C−H Hydroxylation
−
the use of heteroatomic nucleophiles (HNR2, OR, etc.) for
this two-step sequence is quite limited, because η5-cyclo-
hexadienyl adduct formation is usually reversible with
equilibrium favoring the starting materials.12,13 Furthermore,
an example where nucleophilic attack and oxidation have
occurred in the same reaction vessel at the same time, as is
necessary for a catalytic reaction and is reported here, is
unprecedented. We targeted C−H hydroxylation as a reaction
that would be an advancement of known stoichiometric η6-
arene chemistry, as well as a desirable synthetic trans-
formation.14
RESULTS AND DISCUSSION
■
a
We identified air- and moisture-stable arene complex 115 as a
good target for studying the desired oxidation reaction, due to
its high electrophilicity.16 Complex 1 is readily synthesized
from commercially available [Cp*IrCl2]2 by chloride abstrac-
tion with AgBF4 (Scheme 3). Upon addition of NaClO2, in
Isolated as the aryl p-toluenesulfonate due to volatility of phenol.
b
iPrCN used instead of MeCN for step 2; isolated as a 95:5 mixture of
meta:para isopropoxyphenol.
selectively ortho to electron-withdrawing groups, as in the
case of trifluorotoluene complex 1b and ethyl benzoate
complex 1c. Only one isomeric product was observed in the
reactions of both 1b and 1c. C−O bond formation was
observed primarily meta to the resonance electron-donating
group in isopropoxybenzene complex 1d. A small amount (5%)
of the para hydroxylation product was also isolated from the
reaction of 1d.
conjunction with 2-methyl-2-butene as an HOCl scavenger,17
1
is converted directly into η5-phenoxo complex 218 within 3 h at
23 °C in 85% yield. The conversion of 1 into 2 is an overall
aromatic C−H to C−O bond transformation that represents
both the nucleophilic attack and oxidation steps of the
proposed catalytic cycle from Scheme 1. Importantly, the
control reaction using uncoordinated benzene instead of
complex 1 results in no formation of phenol. By increasing
the electrophilicity of the arene complex and identifying the
appropriate functionalization reagent (NaClO2), nucleophilic
attack and oxidation occur concurrently, which circumvents
issues of an unfavorable equilibrium for the initial attack step.
To the best of our knowledge, no other transition metal η6-
arene complex has afforded hydroxylated aromatic products
through initial nucleophilic attack at a C−H bond.
While nucleophilic addition of carbanions to η6-arene
complexes has been shown to occur with similar selectivi-
ty,9a,b,19 typical C−H hydroxylation chemistry does not proceed
in such high selectivity. In addition, the positional selectivity of
the products in Table 1 is opposite that of most C−H oxidation
protocols, which broadly rely on the arene to act as nucleophile.
For example, Siegel reported aromatic C−H hydroxylation
using phthaloyl peroxide and observed only ortho and para
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products (o:p = 1.4:1.0) for anisole, a substrate with a single
resonance donor.20 Similarly, Sanford reported a palladium-
catalyzed acetoxylation that gives C−O bond formation
predominantly meta to the electron-withdrawing trifluorometh-
yl group (o:m:p = 1:78:21).21 In contrast, by enhancing the
electrophilicity of the arene through η6-coordination, our
protocol has the potential to complement these selectivities,
with hydroxylation occurring at the position of least electron
density.
With the goal of catalysis in mind, we examined more closely
the mechanism of the promising C−H hydroxylation protocol
described above. The C−H to C−O transformation can be
divided into two general steps: nucleophilic attack to form an
η5-cyclohexadienyl adduct, followed by oxidation to form η5-
phenoxo complex 2 (Scheme 4a). While there are reports of
with 1 to learn about the nucleophilic attack and oxidation
steps that lead to C−O bond formation.
In a reaction analogous to that with NaClO2, complex 1
reacts with m-chloroperbenzoic acid (mCPBA) in the presence
of Na2CO3 to give η5-phenoxo complex 2 in 85% yield
(Scheme 4b). Furthermore, an η5-cyclohexadienyl adduct of m-
chloroperbenzoate (5) was observed when the reaction was
1
followed by H NMR spectroscopy. Adduct 5 could not be
isolated due to its propensity to form complex 2, but it was
distinguished by the significant upfield shift of the observed 1H
NMR and 13C NMR signals, compared to those of η6-arene
complex 1, a feature characteristic of all known η5-cyclo-
hexadienyl adducts.22 After comparing adduct 5 with the
proposed η5-cyclohexadienyl adduct of chlorite, we hypothe-
sized that a cyclic five- or six-membered transition state for syn
elimination might facilitate oxidation.
To probe the hypothesis of a cyclic transition state, we next
evaluated hydrogen peroxide, a nucleophilic oxidant that would
not be expected to readily undergo syn elimination after attack
on complex 1. Reaction of 1 with H2O2 and Na2CO3 resulted in
a dialkylated peroxide η5-cyclohexadienyl adduct (6b), which,
unlike 5, could be isolated and characterized (Scheme 4c).
Monoalkylated peroxide adduct 6a could be observed by NMR
and is likely on-path in the formation of 6b. Adduct 6b was
observed to form complex 2 in low conversion (5%) over the
course of 5 days, which suggests a different mechanism for
oxidation, or at least one that was significantly slowed when
using H2O2, and supported our hypothesis of syn elimination in
the cases of NaClO2 and mCPBA.
Scheme 4. C−O Bond Formation via η5-Cyclohexadienyl
a
Adducts
To further probe possible mechanisms for C−H oxidation,
we attempted to decouple the nucleophile and oxidant but
maintain the possibility for a cyclic transition state for syn
elimination. Reaction of complex 1, H2O, Na2CO3, and [4-
NHAc-TEMPO]BF4, a reagent known for oxidation of alcohols
to aldehydes or ketones,23 results in isolation of complex 2 in
79% yield. Formation of adduct 7a is observed, and the adduct
can be isolated if the reaction is run in the absence of oxidant.
Previously reported mechanistic investigations for alcohol
oxidation with [4-NHAc-TEMPO]BF4 suggest that oxidation
proceeds through a five-membered transition state.24
Based on the observed positional selectivity and the
formation of η5-cyclohexadienyl adducts with oxygen nucleo-
philes, our mechanistic hypothesis for the C−O bond forming
reaction involves nucleophilic attack of chlorite on arene
complex 1 in analogy to nucleophilic attack of chlorite on an
aldehyde in the Lindgren−Pinnick oxidation.25 Nucleophilic
attack is quickly followed by oxidation, possibly through a syn
elimination, to generate η5-phenoxo complex 2 and hypo-
chlorous acid.
Ultimately, our goal is to develop the selective C−H
oxidation described above into a catalytic reaction. Initial
experiments have indicated that each step in the cycle shown in
Scheme 3 involves conditions that are not compatible with
those for the other steps. For example, NaClO2 is known to
decompose under acidic conditions (pH < 2 in aqueous
solutions),26 while complex 2 requires strong acid for
protonation and displacement from iridium. In addition,
tris(acetonitrile) complex 3 forms readily from 2 under acidic
conditions. However, benzene does not easily displace
acetonitrile ligands to re-form 1 unless a solvent less
coordinating than acetonitrile is used (e.g., acetone).
Preliminary progress toward a catalytic cycle has shown that
use of 3-methyl-2-oxazolidinone, a solvent with high dielectic
a
b
[Ir] = [Cp*Ir(III)]. Complex 7a may be isolated in the absence of
[4-NHAc-TEMPO]BF4. See the SI for details.
nucleophilic attack on complex 1, albeit with stronger
nucleophiles than NaClO2,16b the oxidation step is unprece-
dented. Only starting material (1) and final product (2) could
be observed in the NaClO2 oxidation reaction when monitored
by H NMR spectroscopy. We, therefore, were prompted to
investigate other nucleophile/oxidant combinations that react
1
C
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constant,27 allows for direct conversion of complex 2 into
starting arene complex 1, with release of phenol (Scheme 5).
and Et2O (10 mL) was added. Centrifugation followed by decantation
of the supernatant yielded a residue, which was washed with Et2O (10
mL) and dried under high vacuum to afford 86.7 mg of the title
1
compound as a colorless solid (85% yield). NMR spectroscopy: H
Scheme 5. Direct Formation of 1 from 2
NMR (500 MHz, CD3CN, 23 °C, δ): 6.38 (t, J = 5.5 Hz, 1H), 6.27
(dd, J = 7.5, 5.5 Hz, 2H), 5.54 (d, J = 7.5 Hz, 2H), 2.18 (s, 15H). 13C
NMR (125 MHz, CD3CN, 23 °C, δ): 163.8, 100.7, 96.0, 84.6, 81.5,
10.2. FT-IR spectroscopy (neat, cm−1): 3091, 3033, 1633, 1597, 1470,
1392, 1050, 1036, 694, 522, 454. Anal. Calcd for C16H20BF4IrO: C,
37.88; H, 3.97. Found: C, 37.68; H, 4.25. HRMS-FIA (m/z): calcd for
C16H20OIr [M]+, 421.1143; found 421.1147. Spectroscopic data match
that reported for related compounds [(η5-phenoxo)IrCp*]PF6 and
[(η5-phenoxo)IrCp*]I.18b
a
b
1
Yield determined by H NMR. Isolated as the aryl p-toluenesulfo-
[Cp*Ir(MeCN)3](BF4)2·H2O (3). Complex 2 (50.8 mg, 0.100 mmol,
1.00 equiv) was added to a flame-dried round-bottom flask equipped
with a reflux condenser. Acetonitrile (10 mL) and HBF4·OEt2 (27 μL,
0.20 mmol, 2.0 equiv) were added. The mixture was allowed to stir at
80 °C for 24 h. After cooling to ambient temperature, the reaction
mixture was poured into Et2O (100 mL). The oily precipitate was
allowed to settle, and the supernatant was decanted and saved (see
below). The residue was washed with Et2O (10 mL) to afford crude
nate due to volatility of phenol. 3-Me-Ox = 3-methyl-2-oxazolidinone.
High conversion of this reaction was not observed due to an
unfavorable equilibrium constant for arene exchange. However,
the conversion could be improved by removing the phenol
product and resubjecting the mixture of complexes 1 and 2 to
the reaction conditions. While the change in solvent can
promote direct transformation of 2 into 1, the issue of
incompatibility between NaClO2 and strong acid remains
unsolved.
1
material of 93% purity, as judged by H NMR. The major impurity
observed was the starting material, complex 2. The crude material was
added to a flame-dried round-bottom flask equipped with a reflux
condenser. Acetonitrile (10 mL) and HBF4·OEt2 (27 μL, 0.20 mmol,
2.0 equiv) were added. The mixture was allowed to stir at 80 °C for 24
h. After cooling to ambient temperature, the reaction mixture was
poured into Et2O (100 mL). The oily precipitate was allowed to settle,
and the supernatant was decanted. The residue was washed with Et2O
(10 mL) and dried under high vacuum to afford 54.4 mg of the title
compound as a pale yellow solid (85% yield). NMR spectroscopy:18a
1H NMR (500 MHz, CD3CN, 23 °C, δ): 1.96 (s, 9H), 1.75 (s, 15H).
13C NMR (125 MHz, CD3NO2, 23 °C, δ): 124.6, 94.7, 9.1, 3.7. FT-IR
CONCLUSION
■
In conclusion, we present aromatic C−H bond hydroxylation
enabled by η6-coordination to an iridium(III) complex that
proceeds with high positional selectivity through nucleophilic
attack, followed by oxidation. By conceptually reversing the role
of the arene in C−H functionalization chemistry (from
nucleophile to electrophile), π-arene activation provides a
new platform for the synthesis of arenes that makes use of
nucleophilic functionalization reagents and gives products with
complementary selectivity to traditional approaches. We believe
that catalytic activation of the aromatic π-system has great
potential as an alternative approach to C−H functionalization
chemistry.
spectroscopy (neat, cm−1): 3638, 3011, 2944, 2329, 2300, 1544, 1460,
1426, 1389, 1048, 1019, 520, 469. Anal. Calcd for C16H24B2F8IrN3O:
C, 29.92; H, 4.08; N, 6.54. Found: C, 30.22; H, 3.95; N, 6.64. LRMS-
FIA (m/z): calcd for C11H15IrNaO2 [M − (CH3CN)3 − H+ + Na+ +
(HCO2)−]+, 395.0599; found 395.1087. Isolation of phenyl tosylate
(4a): Due to the volatility of phenol, the supernatant was concentrated
to 20 mL, and p-toluenesulfonyl chloride (57.3 mg, 0.300 mmol, 3.00
equiv), 4-dimethylaminopyridine (12.2 mg, 0.100 mmol, 1.00 equiv),
and triethylamine (123 μL, 0.900 mmol, 9.00 equiv) were added. The
mixture was allowed to stir for 3 h at 23 °C. DCM (20 mL) and H2O
(20 mL) were added, and the reaction mixture was poured into a
separatory funnel. The layers were separated. The aqueous layer was
extracted with DCM (2 × 10 mL). The combined organic layers were
washed with 1 M HCl(aq) (10 mL) and brine (10 mL), dried over
MgSO4, filtered, and concentrated. The residue was purified by
column chromatography on silica gel eluting with a solvent mixture of
Et2O/pentane (5:95 (v/v)) to afford 18.6 mg of the title compound as
a colorless solid (75% yield). Spectroscopic data matched those
described in the SI for compound 4a (p S8).
Regeneration of Complex 1 from 3. Iridium complex 3 (62.4
mg, 0.100 mmol, 1.00 equiv) was added to a 20 mL scintillation vial.
Acetone (2 mL) and benzene (2 mL) were added. The vial was sealed,
and the reaction mixture was allowed to stir at 80 °C for 24 h. After
cooling to ambient temperature, Et2O (15 mL) was added to the
reaction mixture. Centrifugation, followed by decantation of the
supernatant, gave a yellow-brown residue. Acetonitrile (3 mL) was
added to the crude material, and the mixture was filtered through glass
wool to give a yellow filtrate. Et2O (10 mL) was added to the filtrate to
afford a colorless precipitate. Centrifugation, followed by decantation
of the supernatant, yielded a residue that was washed with Et2O (10
mL) and dried under high vacuum to afford 46.8 mg of 1 as a colorless
solid (81% yield). Spectroscopic data matched those described above
for compound 1.
EXPERIMENTAL SECTION
■
General Procedure for Synthesis of Arene Complexes 1a−d.
[Cp*IrCl2]2 (300 mg, 0.377 mmol, 1.00 equiv) and AgBF4 (293 mg,
1.51 mmol, 4.00 equiv) were added to a flame-dried round-bottom
flask. The flask was evacuated and backfilled with N2. Acetone (6 mL)
was then added. The mixture was allowed to stir for 30 min at 23 °C,
affording a yellow solution and an off-white precipitate (AgCl).
Filtration through glass wool afforded a clear yellow solution, to which
arene (3 mL) was added. The mixture was stirred for 1 h at 23 °C to
give a pale yellow solution and the formation of a colorless precipitate.
Et2O (5 mL) was added to this mixture. Centrifugation followed by
decantation of the supernatant yielded a colorless solid, which was
washed with Et2O (10 mL). This solid was dissolved in acetonitrile
(10 mL). Et2O (10 mL) was added to the solution, affording a
colorless precipitate. Centrifugation followed by decantation of the
supernatant and drying under high vacuum yielded the title compound
as a colorless solid.
[Cp*Ir(η5-phenoxo)](BF4) (2). Complex 1 (116 mg, 0.200 mmol,
1.00 equiv) was added to a flame-dried round-bottom flask.
Acetonitrile (10 mL), a solution of 2-methyl-2-butene in THF
(0.800 mL, 1.60 mmol, 8.00 equiv, 2.0 M), and freshly powdered
sodium chlorite (45.2 mg, 0.400 mmol, 2.00 equiv) were then added.
The mixture was allowed to stir for 3 h at 23 °C. Filtration through
glass wool afforded a clear, pale yellow solution. The filtrate was
concentrated to 3 mL. Et2O (10 mL) was added to the filtrate.
Centrifugation followed by decantation of the supernatant yielded a
tan residue. The residue was extracted with DCM (100 mL). The
extracts were filtered through glass wool and concentrated to 10 mL,
General Procedure for the Synthesis of Hydroxylated
Arenes 4a−d. Iridium complex 1 (116 mg, 0.200 mmol, 1.00
equiv) was added to a flame-dried round-bottom flask. Acetonitrile (10
mL), a solution of 2-methyl-2-butene in THF (0.800 mL, 1.60 mmol,
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8.00 equiv, 2.0 M), and freshly powdered sodium chlorite (45.2 mg,
0.400 mmol, 2.00 equiv) were then added. The mixture was allowed to
stir for 3 h at 23 °C. Filtration through glass wool afforded a clear, pale
yellow solution. The filtrate was concentrated to 2 mL, and Et2O (15
mL) was added. The mixture was centrifuged, and the supernatant
decanted. The precipitate was dissolved in acetonitrile (10 mL) and
transferred to a flame-dried round-bottom flask equipped with a reflux
condenser. HBF4·OEt2 (55 μL, 0.40 mmol, 2.0 equiv) was then added.
The mixture was allowed to stir for 24 h at 80 °C. After cooling to
ambient temperature, the reaction mixture was filtered over a plug of
silica and washed with Et2O (200 mL). The filtrate was concentrated,
and the residue was purified by column chromatography on silica gel
to afford the title compound. If the organic product was volatile, the
compound was tosylated before isolation (see the SI for details).
Reaction of 1 with mCPBA. Iridium complex 1 (57.9 mg, 0.100
mmol, 1.00 equiv) and sodium carbonate (106 mg, 1.00 mmol, 10.0
equiv) were added to a round-bottom flask. Acetonitrile (5 mL) was
added, followed by a solution of mCPBA in DCM (1.00 mL, 0.100
mmol, 1.00 equiv, 0.10 M). The reaction mixture was allowed to stir
for 3 h at 23 °C, during which time the mixture became cloudy with a
colorless precipitate. The reaction mixture was filtered over glass wool.
The filtrate was then concentrated to 2 mL, and Et2O (10 mL) was
added, affording a colorless precipitate. Centrifugation, followed by
decantation of the supernatant, yielded a colorless solid. The solid was
extracted with DCM (100 mL). The extracts were filtered through
glass wool and concentrated to 10 mL, and Et2O (10 mL) was added.
Centrifugation, followed by decantation of the supernatant, yielded a
colorless solid, which was washed with Et2O (10 mL) and dried under
high vacuum to afford 43.0 mg of 2 as a colorless solid (85% yield).
Spectroscopic data matched those described above for compound 2.
η5-Cyclohexadienyl Adduct of mCPBA and 1 (5). Complex 1
(17.3 mg, 0.0300 mmol, 1.00 equiv) and Na2CO3 (63.6 mg, 0.600
mmol, 20.0 equiv) were added to an NMR tube. A solution of mCPBA
in CD3CN (1.00 mL, 0.0300 mmol, 1.00 equiv, 0.030 M) was added,
and the tube was inverted once and immediately placed into the
23 °C, δ): 6.38 (t, J = 5.3 Hz, 2H), 5.38 (dd, J = 5.9 Hz, 5.9 Hz, 4H),
4.26 (t, J = 5.9 Hz, 2H), 4.18 (dd, J = 6.1 Hz, 6.1 Hz, 4H), 2.15 (s,
30H). 13C NMR (125 MHz, CD3CN, 23 °C, δ): 99.0, 88.8, 87.6, 70.9,
47.4, 10.3. Anal. Calcd for C32H42B2F8Ir2O2: C, 37.80; H, 4.16. Found:
C, 38.03; H, 4.14. Adduct 6b decomposes to give complex 2 upon
standing in CD3CN solution. Complex 2 is generated in 5% yield after
5 d at 23 °C.
Reaction of 1 with H2O, Na2CO3, and [4-NHAc-TEMPO]BF4.
Iridium complex 1 (57.9 mg, 0.100 mmol, 1.00 equiv), sodium
carbonate (212 mg, 2.00 mmol, 20.0 equiv), and [4-NHAc-
TEMPO]BF4 (60.0 mg, 0.200 mmol, 2.00 equiv) were added to a
20 mL scintillation vial. Acetonitrile (5 mL) and water (9.0 μL, 0.50
mmol, 5.0 equiv) were added. The reaction mixture was allowed to stir
for 4 h at 23 °C. The reaction mixture was filtered over glass wool. The
filtrate was then concentrated to 2 mL, and Et2O (15 mL) was added,
affording a colorless precipitate. Centrifugation, followed by decant-
ation of the supernatant, yielded a colorless solid. The solid was
extracted with DCM (50 mL). The extracts were filtered through glass
wool and concentrated. The solid residue was dissolved in acetonitrile
(2 mL) and Et2O was added (10 mL) to afford a colorless precipitate.
Centrifugation, followed by decantation of the supernatant, yielded a
colorless solid, which was washed with Et2O (10 mL) to afford 40.1
mg of 2 as a colorless solid (79% yield). Spectroscopic data matched
those described above for compound 2.
Arene Exchange Reaction. Iridium complex 1 (10.2 mg, 0.0200
mmol, 1.00 equiv), benzene (0.20 mL), 3-methyl-2-oxazolidinone
(0.20 mL), and HBF4·OEt2 (5.0 μL, 0.040 mmol, 2.0 equiv) were
added to a 4 mL scintillation vial. The reaction mixture was allowed to
stir at 80 °C for 2 d. After cooling to room temperature, Et2O (3 mL)
was added. Centrifugation, followed by decantation of the supernatant,
afforded a brown oil. The supernatant was set aside and saved (see
below). The brown oil was dissolved in 3-methyl-2-oxazolidinone
(0.20 mL). Benzene (0.20 mL) and HBF4·OEt2 (5.0 μL, 0.040 mmol,
2.0 equiv) were added. The reaction mixture was again allowed to stir
at 80 °C for 2 d. The workup described above was repeated, and the
supernatant was again saved. The resulting brown oil was dissolved in
3-methyl-2-oxazolidinone (0.20 mL) for a final time. Benzene (0.20
mL) and HBF4·OEt2 (5.0 μL, 0.040 mmol, 2.0 equiv) were added. The
reaction mixture was allowed to stir at 80 °C for 2 d. The workup
described above was repeated, and the supernatant was saved. The
brown oil was dissolved in acetonitrile (0.50 mL), and Et2O (3 mL)
was added. Centrifugation, followed by decantation and drying under
1
precooled (−40 °C) NMR machine. NMR spectroscopy: H NMR
(500 MHz, CD3CN, 23 °C, δ): 7.87 (s, 1H, H6), 7.79 (d, J = 7.9 Hz,
1H, H9), 7.68 (d, J = 8.1 Hz, 1H, H7), 7.51 (dd, J = 8.0, 8.0 Hz, 1H,
H8), 6.47 (t, J = 5.2 Hz, 1H, H4), 5.50 (dd, J = 5.8, 5.8 Hz, 2H, H3),
4.89 (t, J = 6.0 Hz, 1H, H1), 4.43 (dd, J = 6.1 Hz, 6.1 Hz, 2H, H2),
2.14 (s, 15H, H5). 13C NMR (125 MHz, CD3CN, 23 °C, δ): 134.4
(C7), 131.3 (C8), 129.2 (C6), 128.1 (C9), 88.5 (C3), 87.3 (C4), 72.8
(C1), 45.9 (C2), 9.9 (C5). NMR spectra also contain complex 1,
complex 2, mCPBA, and m-chlorobenzoic acid.
1
high vacuum, afforded a colorless solid, which was analyzed by H
NMR spectroscopy to contain 1, 2, 3-methyl-2-oxazolidinone, and
protonated N-methylethanolamine. The yield of 1 was determined by
integration against an internal standard (dioxane, 2 μL) to be 66%.
Isolation of phenyl tosylate (4a): Due to the volatility of phenol, the
supernatant was concentrated to 5 mL, and p-toluenesulfonyl chloride
(34.2 mg, 0.180 mmol, 9.00 equiv), 4-dimethylaminopyridine (7.2 mg,
0.060 mmol, 3.0 equiv), and triethylamine (75 μL, 0.54 mmol, 27
equiv) were added. The mixture was allowed to stir for 15 h at 23 °C.
DCM (10 mL) and H2O (10 mL) were added, and the reaction
mixture was poured into a separatory funnel. The layers were
separated. The aqueous layer was extracted with DCM (2 × 10 mL).
The combined organic layers were washed with 1 M HCl(aq) (10 mL)
and brine (10 mL), dried over MgSO4, filtered, and concentrated. The
residue was purified by column chromatography on silica gel eluting
with a solvent mixture of Et2O/pentane (5:95 (v/v)) to afford 2.7 mg
of the title compound as a colorless solid (54% yield). Spectroscopic
data matched those described in the SI for compound 4a (p S8).
Monoalkylated η5-Cyclohexadienyl Adduct of H2O2 and 1
(6a). Complex 1 (29.0 mg, 0.0500 mmol, 1.00 equiv), Na2CO3 (10.6
mg, 0.100 mmol, 2.00 equiv), CD3CN (1.0 mL), and H2O2(aq) (28
μL, 0.25 mmol, 5.0 equiv, 30 wt %) were added to a 4 mL scintillation
vial. The mixture was allowed to stir for 1.5 h at 23 °C. The mixture
was filtered through glass wool into an NMR tube. The yield of the
title compound was determined by internal standard (dioxane) to be
68%. Dimeric adduct 6b (see below) was observed in 8% yield. NMR
spectroscopy: 1H NMR (600 MHz, CD3CN, 23 °C, δ): 9.78 (br, 1H),
6.40 (t, J = 5.2 Hz, 1H), 5.39 (dd, J = 5.8 Hz, 5.8 Hz, 2H), 4.35 (t, J =
5.9 Hz, 1H), 4.26 (dd, J = 5.9 Hz, 5.9 Hz, 2H), 2.15 (s, 15H). 13C
NMR (125 MHz, CD3CN, 23 °C, δ): 98.9, 88.8, 87.5, 71.9, 47.2, 10.3.
Bisalkylated η5-Cyclohexadienyl Adduct of H2O2 and 1 (6b).
Complex 1 (116 mg, 0.200 mmol, 1.00 equiv), Na2CO3 (106 mg, 1.00
mmol, 5.00 equiv), acetonitrile (10 mL), and H2O2(aq) (14 μL, 0.12
mmol, 0.60 equiv, 30 wt %) were added to a 20 mL scintillation vial.
The mixture was allowed to stir for 3 h at 23 °C. The mixture was
filtered through glass wool, and the filtrate was concentrated to 3 mL.
The solid residue was extracted with DCM (50 mL) and filtered, and
the filtrate was concentrated. The solid residue was dissolved in
acetonitrile (10 mL), and NaBF4 (400 mg) was added. The mixture
was stirred for 3 h at 23 °C. The mixture was filtered through glass
wool, and the filtrate was concentrated. The solid residue was
extracted with DCM (50 mL) and filtered, and the filtrate was
concentrated to afford 77.8 mg of the title compound as a colorless
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00731.
Additional experimental procedures and characterization
data for all new compounds (PDF)
1
solid (76% yield). NMR spectroscopy: H NMR (600 MHz, CD3CN,
E
DOI: 10.1021/acs.organomet.5b00731
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Crystallographic data (CIF)
Article
M. N.; Grotjahn, D. B. Organometallics 2008, 27, 67−71. (b) Shirin,
Z.; Pramanik, A.; Ghosh, P.; Mukherjee, R. Inorg. Chem. 1996, 35,
3431−3433. (c) Kvietok, F.; Allured, V.; Carperos, V.; DuBois, M. R.
Organometallics 1994, 13, 60−68. (d) Robertson, D. R.; Robertson, I.
W.; Stephenson, T. A. J. Organomet. Chem. 1980, 202, 309−318.
(e) Bailey, N. A.; Blunt, E. H.; Fairhurst, G.; White, C. J. Chem. Soc.,
Dalton Trans. 1980, 829−836.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ritter@chemistry.harvard.edu.
■
Notes
(14) For reviews discussing transition metal-mediated aromatic C−H
hydroxylation: (a) Lucke, B.; Narayana, K. V.; Martin, A.; Jahnisch, K.
The authors declare no competing financial interest.
̈
̈
Adv. Synth. Catal. 2004, 346, 1407−1424. (b) Punniyamurthy, T.;
ACKNOWLEDGMENTS
We thank Claudia Kleinlein, Hang Shi, and Jonas Borgel for
■
Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329−2363. (c) Alonso,
̈
́
D. A.; Najera, C.; Pastor, I. M.; Yus, M. Chem. - Eur. J. 2010, 16,
helpful discussions, Jessica Xu for the synthesis of an authentic
sample of 4d, Gregory B. Boursalian for assistance with low-
temperature NMR, and Dr. Shao-Liang Zheng and Heejun Lee
for assistance with X-ray crystallography. We thank the NIH-
NIGMS (GM088237) and UCB Pharma for funding.
5274−5284.
(15) White, C.; Thompson, S. J.; Maitlis, P. M. J. Chem. Soc., Dalton
Trans. 1977, 1654−1661.
(16) (a) Bush, R. C.; Angelici, R. J. J. Am. Chem. Soc. 1986, 108,
2735−2742. (b) Grundy, S. L.; Smith, A. J.; Adams, H.; Maitlis, P. M.
J. Chem. Soc., Dalton Trans. 1984, 1747−1754.
(17) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825−4830.
(18) (a) White, C.; Thompson, S. J.; Maitlis, P. M. J. Organomet.
Chem. 1977, 127, 415−421. (b) Amouri, H.; Le Bras, J.; Vaissermann,
J. Organometallics 1998, 17, 5850−5857.
REFERENCES
■
(1) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 10236−10254.
(2) For reviews related to directed ortho C−H functionalization:
(a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879−5918. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624−655. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147−1169. (d) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094−5115. (e) Ritleng, V.;
Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731−1769.
(3) (a) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle,
K. M.; Yu, J.-Q. Nature 2015, 519, 334−338. (b) Tang, R.-Y.; Li, G.;
Yu, J.-Q. Nature 2014, 507, 215−220. (c) Dai, H.-X.; Li, G.; Zhang, X.-
G.; Stepan, A. F.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 7567−7571.
(d) Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. J. Am. Chem. Soc.
2013, 135, 18056−18059. (e) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q.
Nature 2012, 486, 518−522.
(19) (a) Kundig, E. P.; Desobry, V.; Simmons, D. P.; Wenger, E. J.
̈
Am. Chem. Soc. 1989, 111, 1804−1814. (b) Sutherland, R. G.;
Chowdhury, R. L.; Piorko, A.; Lee, C. C. Can. J. Chem. 1986, 64,
́
2031−2037. (c) Semmelhack, M. F.; Garcia, J. L.; Cortes, D.; Farina,
R.; Hong, R.; Carpenter, B. K. Organometallics 1983, 2, 467−469.
(20) Yuan, C.; Liang, Y.; Hernandez, T.; Berriochoa, A.; Houk, K. N.;
Siegel, D. Nature 2013, 499, 192−196.
(21) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew.
Chem., Int. Ed. 2011, 50, 9409−9412.
(22) Notably, adduct 5 features the most downfield shifts for the ipso
and ortho protons and carbons of any reported adduct formed from
complex 1 (ref 16b), which is likely due to the electron-withdrawing
nature of the m-chloroperbenzoate group.
(23) Mercadante, M. A.; Kelly, C. B.; Bobbitt, J. M.; Tilley, L. J.;
Leadbeater, N. E. Nat. Protoc. 2013, 8, 666−676.
(4) (a) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew.
Chem., Int. Ed. 2002, 41, 3056−3058. (b) Cho, J.-Y.; Tse, M. K.;
Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III. Science 2002, 295,
305−308.
(24) Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B. J. Org. Chem. 2007,
72, 4504−4509.
(25) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888−890. (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091−2096.
(5) Cheng, C.; Hartwig, J. F. Science 2014, 343, 853−857.
(6) (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879−
2932. (b) Dolphin, D.; Traylor, T. G.; Xie, L. Y. Acc. Chem. Res. 1997,
30, 251−259.
(26) (a) Krapcho, A. P. Org. Prep. Proced. Int. 2006, 38, 177−216.
́ ́
(b) Horvath, A. K.; Nagypal, I.; Peintler, G.; Epstein, I. R.; Kustin, K. J.
(7) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224−228.
(8) Boursalian, G. B.; Ngai, M.-Y.; Hojczyk, K. N.; Ritter, T. J. Am.
Chem. Soc. 2013, 135, 13278−13281.
Phys. Chem. A 2003, 107, 6966−6973.
(27) Huffman, H. L., Jr.; Sears, P. G. J. Solution Chem. 1972, 1, 187−
196.
(9) For reviews related to nucleophilic attack on η6-arene complexes:
(a) Semmelhack, M. F.; Chlenov, A. Top. Organomet. Chem. 2004, 7,
43−69. (b) Kane-Maguire, L. A. P.; Honig, E. D.; Sweigart, D. A.
Chem. Rev. 1984, 84, 525−543. (c) Davies, S. G.; Green, M. L. H.;
Mingos, D. M. P. Tetrahedron 1978, 34, 3047−3077. (d) Rose-Munch,
F.; Gagliardini, V.; Renard, C.; Rose, E. Coord. Chem. Rev. 1998, 178−
180, 249−268. (e) Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem.
̈
Rev. 2000, 100, 2917−2940. (f) Pike, R. D.; Sweigart, D. A. Coord.
Chem. Rev. 1999, 187, 183−222.
(10) η2-Arene complexes have also been used for umpolung aromatic
substitution chemistry: Harman, W. D. Chem. Rev. 1997, 97, 1953−
1978.
(11) Semmelhack, M. F.; Hall, H. T., Jr.; Farina, R.; Yoshifuji, M.;
Clark, G.; Bargar, T.; Hirotsu, K.; Clardy, J. J. Am. Chem. Soc. 1979,
101, 3535−3544.
(12) (a) For an exception that uses a nitrogen nucleophile: Keller,
L.; Times-Marshall, K.; Behar, S.; Richards, K. Tetrahedron Lett. 1989,
30, 3373−3376. (b) For an exception that uses an oxygen
nucleophile: Le Bras, J.; El Amouri, H.; Vaissermann, J. Organo-
metallics 1996, 15, 5706−5712.
(13) For examples where heteroatomic nucleophiles are used to form
η5-cyclohexadienyl adducts, but are not oxidized to aromatic products:
(a) Moussa, J.; Chamoreau, L.-M.; Boubekeur, K.; Amouri, H.; Rager,
F
DOI: 10.1021/acs.organomet.5b00731
Organometallics XXXX, XXX, XXX−XXX