Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of Inexpensive Alkylarenes Enabling Direct Access to Diarylalkanes

Article abstract of DOI:10.1021/jacs.7b03387

A Cu-catalyzed method has been identified for selective oxidative arylation of benzylic C-H bonds with arylboronic esters. The resulting 1,1-diarylalkanes are accessed directly from inexpensive alkylarenes containing primary and secondary benzylic C-H bonds, such as toluene or ethylbenzene. All catalyst components are commercially available at low cost, and the arylboronic esters are either commercially available or easily accessible from the commercially available boronic acids. The potential utility of these methods in medicinal chemistry applications is highlighted.

Full text of DOI:10.1021/jacs.7b03387

Communication
pubs.acs.org/JACS
Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of
Inexpensive Alkylarenes Enabling Direct Access to Diarylalkanes
Aristidis Vasilopoulos, Susan L. Zultanski,† and Shannon S. Stahl*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
Scheme 1. Cu-Catalyzed Benzylic C−H Arylation Method and
ABSTRACT: A Cu-catalyzed method has been identified
Its Relationship to the Kharasch−Sosnovsky Reaction
for selective oxidative arylation of benzylic C−H bonds
with arylboronic esters. The resulting 1,1-diarylalkanes are
accessed directly from inexpensive alkylarenes containing
primary and secondary benzylic C−H bonds, such as
toluene or ethylbenzene. All catalyst components are
commercially available at low cost, and the arylboronic
esters are either commercially available or easily accessible
from the commercially available boronic acids. The
potential utility of these methods in medicinal chemistry
applications is highlighted.
oluene, xylenes, and ethylbenzene are among the largest-
volume platform chemicals in the commodity chemical
T
industry, and the low cost of these molecules underlies their use
as industrial solvents and components of gasoline. In addition to
these basic feedstocks, many other alkylarenes are abundant and
inexpensive relative to reagents commonly used in organic
chemistry and, therefore, represent ideal starting materials for the
preparation of complex molecules, such as pharmaceuticals and
agrochemicals.1 Catalytic methods for selective functionalization
of benzylic C−H bonds, particularly those capable of forming
carbon−carbon bonds, would provide a strategic means to utilize
this resource.1−3 Diarylalkanes, also known as benzhydryls,
represent an important pharmacophore in drugs and other
bioactive molecules (Chart 1),4,5 and arylation of benzylic C−H
an alkoxy radical, followed by reaction of the carbon-centered
radical with a CuII−OR species to form the C−O bond (Scheme
1C, left cycle).11 Related methods for benzylic C−H oxidation
have also been developed,12 and, in collaboration with Liu and
co-workers, we recently reported a method for Cu-catalyzed
cyanation of benzylic C−H bonds.13 We speculated that benzylic
arylation could be achieved via transmetalation from an
arylboronic acid to the CuII−OR species within the catalytic
cycle en route to an aryl(benzyl)copper species that undergoes
C−C coupling (Scheme 1C, right cycle).14 The results presented
below validate this hypothesis and show that a wide range of
readily available methyl- and alkylarenes undergo arylation with
diverse arylboronic esters, including heterocyclic derivatives, to
afford medicinally important benzhydryl derivatives.
Chart 1. Pharmaceutically Important Diarylalkanes
We initiated our investigation by examining toluene as a
prototypical benzylic C−H substrate in the presence of
commonly used catalyst components for Kharasch-type
oxidations: a copper source (CuI), ligand (phenanthroline),
and peroxide-based oxidant (Table 1). Testing of trimethoxy-
phenylsilane and phenylboronic acid did not lead to appreciable
C−C coupling product (entries 1 and 2), but use of
phenylboronic pinacol ester, PhBpin, afforded a 50% yield of
diphenylmethane, with respect to PhBpin (entry 3). Increasing
bonds would provide an efficient route to such compounds.
Precedents for such reactivity are rare,6−8 and a synthetically
versatile method for benzylic C−H arylation could have
significant impact.
Kharasch−Sosnovsky reactions, which use a Cu catalyst in
combination with a peroxide-based oxidant (originally
tBuOOBz) to achieve allylic oxygenation,9,10 provided key
inspiration for this study (Scheme 1A,B). These reactions are
proposed to be initiated by abstraction of an allylic C−H bond by
Received: April 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b03387
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Journal of the American Chemical Society
Communication
Table 1. Cu-Catalyzed Benzylic C−H Arylation: Optimization
of the Reaction Conditions
Table 2. Cu-Catalyzed Arylation of Primary Benzylic C−H
Bonds: Substrate Scope
a
Reactions at 0.5 mmol scale in 1.6 mL of PhMe under N2.
Calibrated GC yield with tetradecane as the internal standard. Phd
b
c
used as the ligand instead of phen.
the ligand loading decreased formation of the biphenyl
byproduct, while simultaneously increasing the product yield
to 68% (entry 4; see Figure S1 in the Supporting Information
(SI) for full analysis of the product distributions at different
ligand:Cu ratios). This improvement in yield may be rationalized
by attenuation of the rate of aryl transmetalation from boron to
Cu, thereby decreasing the steady-state concentration of a Cu−
Ar intermediate, which could undergo unproductive biphenyl
formation. A number of other CuI sources (e.g., CuBr, CuCl,
CuCN) were effective, with only a moderate drop in yield (see SI
for full screening data), but we chose to proceed with a copper
iodide−dimethyl sulfide complex (CuI·DMS, entry 5) because it
has good solubility, has good physical properties for weighing
and dispensing, and led to reproducibly good yields. A final
improvement in yield was achieved by using the 4,4,6-trimethyl-
1,3,2-dioxaborinane ester, PhBdiol. This boronic ester led to a
9% increase in yield relative to PhBpin (entry 6) and is readily
accessed in one step from 2-methyl-2,4-pentanediol and the
corresponding commercially available arylboronic acid (see
Figure S2 for a comparison of their reactivity). 1,10-Phenanthro-
line-5,6-dione (phd) was screened for efficacy as a ligand, as it has
higher solubility in toluene, but it led to a lower yield of the
desired product. In selected reactions described below, however,
use of phd as a ligand proved to be advantageous.
The optimized reaction conditions were then tested with a
number of different Bdiol-derived boronic esters bearing diverse
functional groups. The reaction appears to be relatively
insensitive to electronic properties of the boronic ester: both
electron-rich (e.g., 2 and 3) and electron-deficient (e.g., 4, 6, and
23) boronic esters undergo effective coupling in similarly good
yields. This favorable outcome was not necessarily expected, as
rates of transmetalation of aryl groups from arylboronic esters to
CuII have been shown to exhibit relatively strong electronic
effects,14a and different relative rates of transmetalation could
favor formation of biaryl and/or bibenzyl side products owing to
changes in steady-state concentrations of organocopper inter-
mediates. Reactive functional groups, including methyl ester
(13), N-methylamide (16), methylthioether (25), and halides
(F, Cl, Br, I; 5−8) are conserved in the reactions and provide
potential points for further elaboration of the 1,1-diarylmethane
a
Calibrated 1H NMR yields using dibromomethane as an internal
b
standard (isolated yields in parentheses). Reaction yield at 74% by 1H
NMR after 24 h. Product obtained as a mixture with biphenyl or
biaryl byproduct; see SI for details. Reaction used 20 mol% or more
of phen; see SI for details. Prices obtained from vendors listed on
c
d
e
SciFinder.
products. Steric effects were also evaluated. The reactions
tolerate both para and meta substitution well, but the presence of
an ortho substituent reduces the yield (cf. 3 vs 9). Boronic esters
bearing heterocycles are also competent coupling partners (cf.
11, 12, 15, 18−22). Benzofuran derivative 18 is a key
intermediate en route to a sphingosine-1 phosphate receptor
subtype-1 agonist,15 and a single-step route to this and other
heterocyclic diarylmethane derivatives offers an appealing
alternative to traditional pathways to these molecules.
In addition to toluene, many other methylarene derivatives are
very inexpensive (2−35¢/gram), which makes them amenable to
use in large excess relative to the valuable boronic esters. The
xylene isomers (cf. 26, 27, and 28) proved to be even more
effective coupling partners with PhBdiol than toluene. Because
xylene is the solvent, this outcome could reflect an increase in the
effective concentration of benzylic C−H bonds. Toluene
derivatives with dimethylamino and acetyl functional groups
are not effective oxidative coupling partners with PhBdiol (<10%
yield); however, halogenated toluene derivatives are quite
effective (5′, 7′, 29−31). Halogens at the ortho, meta, and para
positions are all well tolerated. The importance of the latter
results is readily apparent in the context of the active
B
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Journal of the American Chemical Society
Communication
reagents in a glovebox was not needed. This larger-scale reaction
proceeded in 70% yield, which is even higher than the yield of the
small-scale reaction. The good yield and ease of recovery of the
unreacted alkylarene starting material (see SI for details) suggests
that this reaction could be used in the arylation of other valuable
alkylarenes.
Table 3. Cu-Catalyzed Arylation of Secondary Benzylic C−H
Bonds: Substrate Scope
Finally, we examined the functionalization of 3-chloro-1-
phenylpropane (Table 4), another inexpensive arylalkane
Table 4. Direct Access to Derivatized 1,1-Diarylalkane
Pharmacophores
a
Calibrated 1H NMR yields using dibromomethane as an internal
b
standard (isolated yields in parentheses). Product obtained as a
mixture with homocoupled C−H substrate; see SI for details.
c
Reaction run using 3 mol% CuI·DMS with 15 mol% phd as the
ligand instead of phen.
pharmaceuticals shown in Chart 1. For example, use of o-
iodotoluene as a C−H substrate provides an opportunity to
access derivatives of bifemelane5a by employing different Bdiol
coupling partners and through coupling reactions of the aryl
iodide. In other cases, the halogen substituents themselves are
valuable. For example, the potency of a diarylalkane-derived
antihistamine increases by an order of magnitude upon
introduction of a p-Cl or p-Br substitutent.16 More generally,
the activated methylene position in all of the products in Table 2
provides a site for elaboration, as demonstrated by a number of
recent carbon−carbon17 and carbon−heteroatom18 bond-
forming methods.
After assessing the reactivity of methylarenes, we chose to
examine other alkylarenes (Table 3). Anticipating that such
substrates will typically have higher cost than the methylarenes in
Table 2, we investigated these reactions with only 10 equiv of the
alkylarene partner. Optimization of the reagent concentration
and ligand:Cu ratio resulted in a 69% yield of cross-coupled
product 32 in the reaction of PhBdiol and ethylbenzene (see SI
for full optimization data). These reactions are similarly
compatible with substituted boronic esters (35 and 36). For
certain C−H substrates, however, modified conditions proved to
be optimal. For example, the highest yields of 34, 37, and 38 were
obtained with phd as the ligand rather than phen. These
conditions provide a single-step route to the racemic anti-cancer
isoerianin analogue 34.5b,c In order to demonstrate the
preparative utility of the method, we performed this reaction
on half-gram scale (Scheme 2). The reaction was conducted on
the benchtop to demonstrate that the typical protocol of loading
a
Reactions run on 0.5 mmol scale with 10 equiv of 3-phenyl-1-
b
chloropropane. Isolated yields in parentheses. Product obtained as a
mixture with homocoupled C−H substrate; see SI for details.
substrate (28¢/gram). The product of the arylation reaction is
a direct precursor to pharmaceutically relevant 3,3-diarylpropyl-
amine derivatives (cf. Chart 1).4b−e,19 Slightly modified reaction
conditions, most notably the use of a higher concentration of
oxidant, enabled optimized yields to be attained for the benzylic
arylation reaction. Reaction with the parent PhBdiol affords 39 in
good yield, and similar reactivity was observed with other
boronic ester derivatives. As observed in Table 2, potentially
reactive functional groups, such as an aryl iodide and a ketone, are
compatible with the reaction (cf. 40, 42, and 43). These results
further demonstrate how the direct benzylic C−H arylation
method could be used in the discovery of new drug candidates.
Mechanistic studies are the focus of ongoing investigation, but
several observations are worth noting. As might be expected,
several factors contribute to the selectivity of the reactions,
including substrate sterics, electronics, and stoichiometry.
Competition studies reveal that the relative reactivity of
alkylarenes follow the order 2° (ethyl) > 1° (methyl) ≫ 3°
(isopropyl) (see Figure S4). Experiments with toluene and
diphenylmethane show that the diarylmethanes are compara-
tively unreactive and do not undergo arylation in the presence of
excess toluene (Figure S5). Further control experiments show
that tertiary diarylalkanes do not react under the catalytic
conditions (Figure S6). Collectively, these observations ration-
alize selective formation of the products in Tables 2−4.
Scheme 2. Half-Gram-Scale, Glove-Box-Free Synthesis of an
Isoerianin Analogue (34)
In summary, the Cu-catalyzed oxidative arylation reactions
described herein provide efficient access to highly important
diarylalkane derivatives from inexpensive, readily available
methyl- and alkylarenes. This new C−C coupling method
represents an important extension of traditional Kharasch−
Sosnovsky methods for C−H functionalization, and they offer a
compelling complement to benzylic arylation reactions that
employ more-traditional nucleophile/electrophile coupling
partners.20
C
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Journal of the American Chemical Society
Communication
(8) The following examples of Ir photoredox catalysis focus on
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03387.
■
S
Experimental procedures, screening tables, compound
characterization data, and spectra of new compounds,
including Figures S1−S6 (PDF)
AUTHOR INFORMATION
Corresponding Author
*stahl@chem.wisc.edu
■
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ORCID
Shannon S. Stahl: 0000-0002-9000-7665
Present Address
†S.L.Z.: Department of Process Chemistry, Merck & Co., Inc.,
Rahway, NJ 07065, United States
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Scott McCann for valuable discussions and
assistance with data collection. This work was supported by the
DOE (DE-FG02-05ER15690) and the NIH (Ruth L. Kirschstein
National Research Service Award F32-GM109569 to S.L.Z.).
Spectroscopic instrumentation was partially supported by the
NIH (1S10 OD020022-1) and the NSF (CHE-1048642).
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