Synthesis of Complex Phenols Enabled by a Rationally Designed Hydroxide Surrogate

Article abstract of DOI:10.1002/anie.201700244

The conversion of aryl halides to phenols under mild reaction conditions is a longstanding and formidable challenge in organic chemistry. Herein, we report the rational design of a broadly applicable Pd-catalyzed method to prepare phenols with benzaldehyde oxime as a hydroxide surrogate. These reactions occur under mildly basic conditions and enable the late-stage hydroxylation of several functionally-dense drug-like aryl halides.

Full text of DOI:10.1002/anie.201700244

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700244
German Edition: DOI: 10.1002/ange.201700244
Synthetic Methods
Synthesis of Complex Phenols Enabled by a Rationally Designed
Hydroxide Surrogate
Patrick S. Fier* and Kevin M. Maloney*
Abstract: The conversion of aryl halides to phenols under mild
reaction conditions is a longstanding and formidable challenge
in organic chemistry. Herein, we report the rational design of
a broadly applicable Pd-catalyzed method to prepare phenols
with benzaldehyde oxime as a hydroxide surrogate. These
reactions occur under mildly basic conditions and enable the
late-stage hydroxylation of several functionally-dense drug-
like aryl halides.
P
henols and their derivatives are prevalent across many
chemical disciplines, and are components of several pharma-
ceutical, agrochemical, and material products.[1] Phenols are
also versatile intermediates in organic chemistry for a multi-
tude of transformations. Yet, few methods allow for the
À
formation of Ar OH bonds in the presence of sensitive
functionality found in complex molecules.
Scheme 1. Synthesis of phenols from aryl halides.
The hydroxylation of aryl halides is among the most
attractive strategies to prepare phenols due to the ubiquity of
haloarenes.[2] Both copper- and palladium-catalyzed reactions
have been developed to prepare phenols from unactivated
aryl halides (Scheme 1A).[3,4] However, Cu-catalyzed hydrox-
ylation reactions typically require high temperatures, strong
bases, and are predominantly limited to aryl iodides and
bromides. Palladium catalysts can promote the conversion of
unactivated aryl bromides and chlorides to phenols; however
the use of KOH, CsOH, or an organic superbase[4,5] is still
necessary for high yields. Due to the strongly basic conditions,
these reactions are not applicable to substrates containing
base-sensitive functionality.
Furthermore, a major drawback of reported Pd-catalyzed
hydroxylation methods is the lack of hydroxide coupling in
the presence of functional groups that can undergo N- or O-
arylation, such as amides, amines, and alcohols. This problem
is inherent in coupling reactions with hydroxide, as Ar-Pd-OH
complexes react readily with functional groups containing
hydroxylation reactions by avoiding strongly basic conditions
and circumventing Ar-Pd-OH species as catalytic intermedi-
ates.
We proposed that the limitations of previously reported
Pd-catalyzed hydroxylation reactions would be overcome
with a suitable hydroxide surrogate in place of KOH or
CsOH. The criteria in identifying a hydroxide replacement
were that it would: 1) couple under mildly basic conditions,
2) form an intermediate that would liberate the phenol
product in situ with an innocuous byproduct, 3) be tolerant
of electrophilic and base-sensitive functionality, 4) react in the
presence of the phenol products and nucleophilic sites in the
substrates, and 5) be readily available, stable, and inexpen-
sive.
With the above considerations in mind, benzaldoxime was
identified as a mild hydroxide surrogate that would react to
form O-aryl oxime intermediates (Scheme 1B). Base-induced
elimination in situ would reveal the phenol product with the
concomitant generation of benzonitrile.[10] It was presumed
that benzaldoxime would react under mildly basic conditions
due to its similar acidity to phenol (pKa values in DMSO:
benzaldoxime, 20; phenol, 18) and significantly reduced
basicity compared to hydroxide (H2O has a pKa of 31 in
DMSO). Furthermore, it was anticipated that the benzaldox-
ime anion, which has enhanced nucleophilicity from the
alpha-effect and is sterically unencumbered, would couple to
form phenols in the presence of pendant nucleophilic
functionality.
À
À
N H and O H bonds to form water and the corresponding
Ar-Pd-NR2 or Ar-Pd-OR complexes faster than undergoing
Ar-OH reductive elimination.[6–9] Herein, we report the
rational design of an enabling Pd-catalyzed method to
prepare phenols that addresses the shortcomings of previous
[*] Dr. P. S. Fier, Dr. K. M. Maloney
Department of Process Research and Development
Merck & Co., Inc.
Rahway, NJ (USA)
E-mail: patrick.fier@merck.com
kevin_maloney@merck.com
Several challenges exist in developing the proposed
reaction with benzaldoxime. First, there have been no reports
on the Pd-catalyzed O-arylation of aldoximes to date, and it
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201700244.
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was unclear whether such a reaction could be developed.[11]
Second, the initially formed O-aryl oximes could participate
in unproductive side-reactions, as Pd0 has been shown to
[12]
À
oxidatively insert into the N O bond of oximes. Finally, it
was unclear how facile the syn-elimination would occur with
unactivated aryloxy groups under mildly basic reaction
conditions (Scheme 1B).[10]
In order to develop the proposed reaction, we carried out
several high-throughput experiments. We chose to investigate
reactions with 1, as this substrate contains a reactive aliphatic
ester, and an aryl fluoride that can undergo SNAr reactions. Of
particular importance, this substrate underwent complete
ester hydrolysis even under the mildest conditions[4] reported
for the Pd-catalyzed hydroxylation of aryl halides (CsOH, rt).
After initial screening of solvents, bases, temperatures, and
stoichiometries, we performed 96 experiments where we
investigated the most promising leads of: two bases (Cs2CO3,
K3PO4), two solvents (DMF, 2-MeTHF), along with 24 Pd G3
precatalysts (Scheme 2 and Supporting Information). The
Scheme 3. General scope for the conversion of aryl halides to phenols
with benzaldoxime. Reactions were performed on 1.0 mmol scale with
RockPhos Pd G3 as the precatalyst. [a] tBuBrettPhos Pd G3 was used
as the precatalyst. Yields were determined by HPLC against authentic
product standards. Isolated yield shown in parentheses. Catalyst
loadings and reaction times were not optimized for each substrate.
to couple both aryl bromides and chlorides (Scheme 3). As
shown, the reaction provides the phenol products in high
yields in the presence of esters, ketones, aldehydes, nitriles,
and common heterocycles. Ortho-alkyl substituted aryl hal-
ides coupled in modest yield (65%) with RockPhos as the
ligand, however, switching to the less bulky tBuBrettPhos
ligand allowed for the coupling of 2-bromotoluene in 88%
yield.
Monitoring the catalytic reactions by HPLC revealed that
intermediate species were present at 3–10% relative to the
starting concentration of the aryl halide. The mass spectrum
of the intermediate was obtained by LC/MS analysis of
a reaction with bromobenzene, and was consistent with the
proposed O-aryloxime species. To confirm the identity, O-
phenyl benzaldoxime was prepared from the condensation of
O-phenylhydroxylamine with benzaldehyde (Scheme 4A).
This species was identical by HPLC and LC/MS analysis to
the species observed during a reaction with bromobenzene as
the substrate under our catalytic reaction conditions. The
isolated oxime reacted with Cs2CO3 in DMF at 808C over
30 minutes with the formation of equimolar amounts of
PhOH and PhCN in quantitative yield. In all of our
hydroxylation reactions, an equimolar amount of benzonitrile
and the phenol product was observed. Control reactions
confirmed that phenol is not formed in the absence of
benzaldoxime or the Pd precatalyst. Taken together, these
results are consistent with a mechanism proceeding via the
Pd-catalyzed formation of O-aryl benzaldoxime species,
followed by Cs2CO3-mediated elimination to form the
phenol product and benzonitrile. Performing the Pd-cata-
lyzed reaction with toluene in place of DMF suppressed the
Scheme 2. High-throughput reaction development. Reaction condi-
tions: 5.0 mmol of 1, 1.3 equiv benzaldehyde oxime, 2.2 equiv of base,
5 mol% Pd G3 precatalyst, solvent (0.2m), 808C, 18 h. Structures of
all 24 precatalysts investigated are illustrated in the Supporting
Information. Yields were determined by HPLC against an authentic
product standard.
combination of Pd/RockPhos, Cs2CO3, and DMF provided
the product in 95% assay yield. Critically, less than 1% of
ester hydrolysis or SNAr displacement of the aryl fluoride was
observed. Reactions performed with a combination of
[(allyl)PdCl]2 or Pd2(dba)3 with RockPhos provided similar
results to those performed with RockPhos Pd G3 precatalyst.
K3PO4 could be used in place of Cs2CO3 with a slight decrease
in the yield of 2 (73% yield). RockPhos/Pd-catalyzed
reactions conducted in 2-MeTHF also provided the phenol
product in synthetically useful yields with either Cs2CO3
(86% yield) or K3PO4 (73% yield).
After lowering the catalyst loading and increasing the
reaction concentration, we explored the generality of the
reaction with respect to the inherent properties of the aryl
halide, tolerance of common functional groups, and the ability
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Scheme 4. Studies on the reaction mechanism.
rate of the elimination reaction, and allowed for the synthesis
of O-phenyl benzaldoxime in 89% yield (Scheme 4B).
À
Notably, this is the first example of a Pd-catalyzed C O
coupling to prepare an O-aryl aldehyde oxime.[11]
Having demonstrated the reaction on simple substrates
with an understanding of the reaction mechanism, the
reaction was then performed in the presence of functional
groups that can undergo competitive N- or O-arylation
reactions. The coupling reaction of bromobenzene was
carried out with an equimolar amount of various additives
(Nu-H) and the amounts of PhOH and Ph-Nu formed in the
reactions were determined.[13] This experimental design
allows for the clear and unambiguous interpretation of the
results, and avoids any biasing impact of the nucleophilic
groups on the properties of the aryl halide. As shown in
Scheme 5, benzaldoxime coupled in preference to common
nucleophilic functionality present in drug-like molecules. It
was found that primary amino groups couple competitively
with benzaldoxime under the standard conditions, likely due
to the low concentration of the oxime anion in solution in the
presence of a weak heterogeneous base. Pre-forming the
cesium salt of benzaldoxime in situ enabled synthetically
useful yields of phenol in the presence of primary amino
groups (see Supporting Information for details). Phenol was
formed in high yield in the presence of secondary amines,
anilines, and amides, and in > 90% yield in the presence of
indole, a phenol, and alcohols. The results from these
experiments are significant, as these nucleophilic groups are
known to couple under similar reaction conditions to those
reported here,[14] and showcase the utility of benzaldoxime
over hydroxide salts[15] for the synthesis of phenols from poly-
functional aryl halides without the need for protecting groups.
To supplement the results from the additive experiments,
and to demonstrate this methodology on complex substrates,
we carried out our new reaction on a chemistry informer
library. The chemistry informer library consists of 18 poly-
functional drug-like aryl halides that are representative of
drug-like space designed to test reactions on challenging
substrates (see Supporting Information for structures).[16]
With the reaction conditions reported here, the phenol
products were formed in good yields with both ortho-
substituted and electron-rich aryl halides (Scheme 6). Several
common functional groups were tolerated, including esters,
Scheme 5. Coupling benzaldehyde oxime in the presence of common
nucleophilic functional groups. Phenol is formed in 99% yield under
the standard reaction conditions in the absence of any added
nucleophiles. [a] Reactions were performed with 2.0 equiv of in situ
formed benzaldoxime cesium salt. Yields were determined by HPLC
against authentic product standards.
À
À
free O H bonds of phenols and alcohols, free N H bonds of
amines, amides, and sulfonamides, and several basic hetero-
cycles. The use of DMF as the reaction solvent allows for the
conversion of several complex substrates (3n, 3p, 3s) that
have negligible solubility in solvents that are more commonly
used in cross-coupling, such as toluene and 1,4-dioxane.
Across the informer library, the phenol products were formed
in > 20% yield in 11/18 cases, and in > 50% isolated yield for
8/18 substrates (Scheme 6, and Supporting Information).[17]
To put these results in context, N-arylation of the 18 aryl
halides with piperidine under the most advanced Pd-catalyzed
À
C N coupling conditions provided only 6/18 of the cross-
coupled products in > 20% yield, and only 4/18 in > 50%
yield.[16] These results highlight the synthetic utility of the
reaction reported here, as highly complex phenols bearing
common functionality can be prepared without the need for
protecting groups.
In summary, we have designed benzaldoxime as a syntheti-
cally useful hydroxide surrogate for the preparation of
phenols from aryl halides. High-throughput experimentation
identified conditions that allow for the synthesis of complex
phenols bearing sensitive functional groups and pendant
nucleophilic functionality. Mechanistic studies support a reac-
tion pathway via initial Pd-catalyzed O-arylation of benzal-
doxime, followed by base-induced elimination of the phenol
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Scheme 6. Selected scope for the synthesis of complex drug-like
phenols. Isolated yields for reactions performed on 0.5 mmol scale.
[a] Reaction performed with 1.0 equiv of benzaldoxime. [b] tBuBrett-
Phos Pd G3 was used as the precatalyst. [c] Reaction performed at
1008C. See Supporting Information for additional substrates.
product and benzonitrile. We anticipate that this method-
ology will be rapidly adopted due to the mild conditions and
the ability to perform the reaction on functionally-dense
complex molecules.
Acknowledgements
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Conflict of interest
The authors declare no conflict of interest.
À
[11] Other C O coupling reactions with oximes: a) T. J. Maimone,
Keywords: cross-coupling · hydroxylation ·
medicinal chemistry · palladium · phenols
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À
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Manuscript received: January 9, 2017
Final Article published: && &&, &&&&
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Communications
Synthetic Methods
The conversion of aryl halides to phenols
under mild reaction conditions is a long-
standing and formidable challenge in
organic chemistry. The rational design of
a broadly applicable Pd-catalyzed method
to prepare phenols with benzaldehyde
oxime as a hydroxide surrogate is now
reported. These reactions occur under
mildly basic conditions and enable the
late-stage hydroxylation of functionally
dense aryl halides.
P. S. Fier,*
K. M. Maloney*
&&&& — &&&&
Synthesis of Complex Phenols Enabled by
a Rationally Designed Hydroxide
Surrogate
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!