Reagent Design and Ligand Evolution for the Development of a Mild Copper-Catalyzed Hydroxylation Reaction

Article abstract of DOI:10.1021/acs.orglett.7b01403

Parallel synthesis and mass-directed purification of a modular ligand library, high-throughput experimentation, and rational ligand evolution have led to a novel copper catalyst for the synthesis of phenols with a traceless hydroxide surrogate. The mild reaction conditions reported here enable the late-stage synthesis of numerous complex, druglike phenols.

Full text of DOI:10.1021/acs.orglett.7b01403

Letter
pubs.acs.org/OrgLett
Reagent Design and Ligand Evolution for the Development of a Mild
Copper-Catalyzed Hydroxylation Reaction
Patrick S. Fier* and Kevin M. Maloney*
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: Parallel synthesis and mass-directed purification of a modular ligand library, high-throughput experimentation, and
rational ligand evolution have led to a novel copper catalyst for the synthesis of phenols with a traceless hydroxide surrogate. The
mild reaction conditions reported here enable the late-stage synthesis of numerous complex, druglike phenols.
dehydration of alcohols.4b,e,k Furthermore, no publications on
ross-coupling reactions have revolutionized synthetic
Cchemistry, with broad-reaching applications across many
copper-catalyzed coupling have demonstrated the synthesis of
disciplines.1 However, many of these reactions operate under
strongly basic conditions and with reagents that are intolerant of
common electrophilic and protic functionalities and cannot be
applied to complex molecules. As a result, the number of
protecting group manipulations in synthesis has increased
significantly in recent years.2 Therefore, the design of new
catalysts and reagents that enable reactions to occur under mild
conditions without protecting groups can improve efficiency in
complex molecule synthesis.
phenols in the presence of free X−H bonds of amines,
unhindered amides, carbamates, sulfonamides, or aliphatic
alcohols, as these groups can undergo competitive Ar−N and
Ar−O bond formation with aryl halides under the reaction
conditions. To address these limitations, herein we report a novel
Cu-catalyzed method for the hydroxylation of complex aryl
halides.
We have recently developed a new paradigm to form phenols
under mild conditions through the use of traceless hydroxide
surrogates.3d,5i The hallmarks of the hydroxide surrogate
reactions are (i) mildly basic conditions made possible by acidic
O−H bonds, (ii) tolerance of protic and electrophilic
functionality, (iii) selective coupling of the α-aza oxyanion in
the presence of nucleophilic groups (NuH) prone to competitive
Ar-Nu formation, (iv) the direct synthesis of phenol products
without a separate deprotection step, and (v) the use of readily
available, inexpensive reagents with the formation of innocuous
byproducts.
The use of strongly basic conditions is particularly problematic
in the conversion of aryl halides to phenols.3−5 Phenols are
versatile synthetic intermediates and components of over 200
approved drugs and 100000 natural products.6 Thus, the forcing
conditions of current methods limit which phenol targets and
intermediates can be efficiently accessed in drug discovery and
total synthesis. Specifically, in copper-catalyzed methods (Figure
1), hydroxide nucleophiles have been shown to result in the
hydrolysis of esters and amides, hydration of nitriles, and
Our previous work revealed that benzaldehyde oxime can act
as a hydroxide surrogate in Pd/RockPhos-catalyzed cross-
coupling, with the coupling and phenol-forming elimination
steps occurring under mild conditions.5i While the Pd-catalyzed
reactions occur with broad scope, the high cost of RockPhos
($545/mmol),7 difficulty of purging Pd from complex molecules,
and low yields with substrates containing primary amino groups
limit the applicability of this method. A related Cu-catalyzed
hydroxylation reaction could address these concerns, as Cu
catalysts are typically inexpensive, Cu is readily removed from
target compounds with simple aqueous workups, and Cu-
catalyzed reactions can occur with complementary scope to
analogous Pd-catalyzed reactions.8
However, the development of a Cu-catalyzed reaction with
benzaldoxime faces several challenges not present with Pd. First,
Received: May 9, 2017
Figure 1. Copper-catalyzed synthesis of phenols from aryl halides.
© XXXX American Chemical Society
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Letter
Cu-catalyzed reactions typically require higher temperatures
than Pd-catalyzed reactions, a formidable challenge due the
instability of benzaldoxime toward thermal dehydration.9
Second, the nucleophilic benzaldoxime anion may lead to the
displacement of auxiliary ligands and the formation of
“ligandless” cuprate species, [Cu(OR)2]−, which are generally
inert toward coupling with aryl halides.10 Finally, and most
significantly, is that several Cu salts are known to promote facile
hydrolysis, dehydration, and/or rearrangement of benzaldoxime,
which would effectively preclude the development of the
proposed reaction.11 In line with these challenges, only a single
example of Cu-catalyzed coupling of oximes with aryl halides has
been reported.12 Due to the observed sensitivity of the oximes
toward degradation, the C−O coupled products were formed in
particularly poor yields with no functional group tolerance
demonstrated.
identity of the oxime was predicted to have a significant impact
on the outcome of the targeted hydroxylation reaction. Thus,
four benzaldoxime derivatives were surveyed to expand the
breadth of the screening effort beyond a single hydroxide
surrogate (384 reactions in total) (Scheme 2)
Scheme 2. High-Throughput Screening of Oximes with
a
Custom Ligand Library
Despite the above-mentioned challenges, Cu-catalyzed
reactions with benzaldoxime were investigated with compound
1. This substrate contains a base-sensitive methyl ester and
epimerizable stereocenter and would probe the ability of copper
complexes to catalyze the coupling of an unactivated aryl
bromide under mild conditions. Notably, compound 1 underwent
complete ester hydrolysis and variable degrees of epimerization under
the mildest conditions for the Cu-catalyzed coupling of aryl bromides
with hydroxide salts.4 Initially, reactions with benzaldoxime as the
hydroxide surrogate were screened with weak bases and with
catalysts prepared in situ from CuI and 12 commonly used
ligands (see the Supporting Information) (Scheme 1). Even after
a
Scheme 1. Initial Screening of Cu Catalysts
a
Reaction conditions: 5.0 μmol of 1, 2.0 equiv of oxime, 2.5 equiv of
Cs2CO3, 5 mol % of CuI and ligand, DMSO (0.2 M), 80 °C, 18 h.
Structures of all 96 ligands and yields for all 384 reactions are provided
in the Supporting Information.
The 384 microscale reactions formed compound 2 in 0−61%
yield and provided valuable insight into the factors that impact
the targeted hydroxylation reaction. Reactions with benzaldox-
ime as the hydroxide surrogate provided the highest yields,
followed by p-(trifluoromethyl)benzaldoxime and p-methox-
ybenzaldoxime. Across all reactions, no ester hydrolysis or
epimerization side products were observed. Many cases were
identified where minor variations in the ligand structure had
profound impacts on the yields of the reaction. Reactions with
previously reported oxamide ligands occurred in modest yields
(0−39%), underscoring the importance of investigating an
expansive ligand set for the development of new transformations.
The reaction with benzaldoxime catalyzed by CuI/L1
(Scheme 3) provided the highest yield of 2 (61%). The related
ligand where the oxazoline in L1 is replaced by a phenyl ring
formed 2 in only 18% yield with benzaldoxime. We propose that
the additional coordination site (i) prevents the formation of
inactive copper species formed by ligand displacement by the
benzaldoxime anion and/or (ii) prevents the formation of
unligated copper species that mediate benzaldoxime decom-
position. The modest yield is a due to the formation of 11% of
diaryl ether product and incomplete consumption of 1. To
address these issues, derivatives of L1 were prepared, wherein the
oxazoline was replaced by other coordinating groups. Reactions
of 1 with the ligand bearing an oxadiazole moiety (L2) formed
a
Reaction conditions: 5.0 μmol of 1, 1.2 equiv of benzaldoxime, 2.0
equiv of Cs2CO3, 5 mol % CuI and ligand, DMSO (1.0 M), 80 °C, 18
h. Additional details are available in the Supporting Information.
extensive screening, the phenol product was formed in poor
yields. In all cases, incomplete conversion of 1 was observed,
which could not be overcome through traditional screening
efforts. Thus, it was imperative to pursue an alternative strategy
that went beyond merely screening known ligands.13
Of the 12 ligands investigated, the highest yields of 2 were
observed for reactions containing an oxamide ligand.4k,14 We
proposed that varying the two ends of the oxamide ligand could
lead to a series of novel ligands for the targeted hydroxylation
reaction. Due to the modular nature of oxamide ligands, these
ligands are ideally suited for combinatorial synthesis. A library of
96 oxamide ligands was prepared through parallel synthesis and
mass-directed purification (eq 1). The 96 unique ligands were
prepared from a diverse collection of primary and secondary
amines and anilines and encompassed both symmetrical and
unsymmetrical oxamides.
Microscale reactions of the 96 ligands were conducted with
substrate 1, CuI (5 mol %), and Cs2CO3 in DMSO. In Cu-
catalyzed reactions, the nucleophilic coupling partner is generally
bound to Cu prior to reaction with the aryl halide. As such, the
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a
a
Scheme 3. Ligand Evolution from L1
Scheme 4. Representative Substrate Scope
a
Yields shown for the conversion of 1 to 2. Reaction conditions: 1 (1.0
equiv), benzaldoxime (2.0 equiv), Cs2CO3 (2.5 equiv), CuI (5 mol %),
ligand (5 mol %), DMSO (0.2 M), 80 °C, 18 h.
phenol 2 in the highest yield among the ligands prepared (73%
yield).
For L1 and L2, amide cleavage of the anilide portion was
observed during the reaction, with ligand decomposition
preventing full conversion of 1. A methyl group was installed
adjacent to the C−N bond (L3) to slow ligand decomposition,
resulting in enhanced ligand stability and an improved yield of 2.
Finally, an additional set of 11 ligands were prepared that
contained groups other than benzyl. Of the ligands investigated,
p-methoxybenzyl ligand L4 provided the highest yield of 2 with
trace diaryl ether formation.
With the novel ligand L4 in hand, the scope of the
hydroxylation reaction was investigated with a collection of
aryl halides (Scheme 4). Several electron-rich, electron-poor, and
ortho-substituted aryl halides reacted in high yields under the
standard conditions. The use of a weak base enabled the
hydroxylation to occur in the presence of several sensitive
functional groups, including enolizable ketones, aldehydes,
nitriles, and aryl halides that are susceptible to benzyne formation
under strongly basic conditions (3e and 3f). These results are in
stark contrast to previously developed Cu-catalyzed reactions
with hydroxide salts that result in ester hydrolysis and nitrile
hydration. Several Lewis basic heterocycles were well tolerated.
The formation of the phenol product from substrate 3r
provides insight into the reaction mechanism.15 The successful
coupling is consistent with a mechanism proceeding via a two-
electron oxidative addition/reductive elimination process,
opposed to one-electron mechanisms that have been invoked
for certain Cu-catalyzed reactions.
During the development of the related Pd-catalyzed method,
we found that those reaction conditions are only moderately
tolerant of primary amines and anilines, with significant amounts
of Ar−N bond formation products being formed.5i A significant
driver to developing this Cu-catalyzed system was to identify a
catalyst system that could form phenols in the presence of
primary amino groups. Indeed, spiking experiments of PhBr with
1 equiv of aniline or butylamine demonstrated that the CuI/L4
system forms phenol in significantly higher yields, with minimal
C−N coupling, compared to the same reactions with Pd/
RockPhos as the catalyst (Scheme 5). This is the first example for
the Cu-catalyzed synthesis of phenols from aryl halides in the
presence of these functional groups and further highlights the
utility of the hydroxide surrogate approach.
a
Assay yields shown for reactions performed on 1.0 mmol scale.
Scheme 5. Comparison of Cu- and Pd-Catalyzed Methods
Next, the hydroxylation of more challenging druglike aryl
halides was investigated (Scheme 6). Significantly, the phenol
products were formed with substrates containing free O−H and
N−H bonds of alcohols, acids, amides, sulfonamides, and
carbamates. Each of the products contained less than 10 ppm of
Cu after purification, an important finding for applications of this
work toward drug synthesis. Together, these results highlight the
synthetic utility of the Cu-catalyzed hydroxide surrogate reaction
for the late-stage synthesis of highly functionalized phenols under
mild reaction conditions.
In summary, we have developed a mild Cu-catalyzed reaction
to form phenols from aryl halides with a traceless hydroxide
surrogate. The development of this reaction was enabled through
a custom ligand library and subsequent ligand evolution. The
methodology reported here is highlighted by the late-stage
hydroxylation of several complex aryl halides.
C
DOI: 10.1021/acs.orglett.7b01403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01403.
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Experimental details and characterization data for new
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: patrick.fier@merck.com.
*E-mail: kevin_maloney@merck.com.
ORCID
Patrick S. Fier: 0000-0002-6102-815X
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Younong Yu and Mike DiMaso (both at Merck) for
help preparing the ligand library. We thank Ian Davies and Becky
Ruck (both at Merck) for their feedback.
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DOI: 10.1021/acs.orglett.7b01403
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