Synthesis of Triarylmethanes via Palladium-Catalyzed Suzuki-Miyaura Reactions of Diarylmethyl Esters

Article abstract of DOI:10.1021/acs.organomet.1c00085

The synthesis of triarylmethanes via Pd-catalyzed Suzuki-Miyaura reactions between diarylmethyl 2,3,4,5,6-pentafluorobenzoates and aryl boronic acids is described. The system operates under mild conditions and has a broad substrate scope, including the coupling of diphenylmethanol derivatives that do not contain extended aromatic substituents. This is significant as these substrates, which result in the types of triarylmethane products that are prevalent in pharmaceuticals, have not previously been compatible with systems for diarylmethyl ester coupling. Furthermore, the reaction can be performed stereospecifically to generate stereoinverted products. On the basis of DFT calculations, it is proposed that the oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrate occurs via an S_N2 pathway, which results in the inverted products. Mechanistic studies indicate that oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrates to (IPr)Pd(0) results in the selective cleavage of the O-C(benzyl) bond in part because of a stabilizing η³-interaction between the benzyl ligand and Pd. This is in contrast to previously described Pd-catalyzed Suzuki-Miyaura reactions involving phenyl esters, which involve selective cleavage of the C(acyl)-O bond, because there is no stabilizing η³-interaction. It is anticipated that this fundamental knowledge will aid the development of new catalytic systems, which use esters as electrophiles in cross-coupling reactions.

Full text of DOI:10.1021/acs.organomet.1c00085

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Article
Synthesis of Triarylmethanes via Palladium-Catalyzed Suzuki−
Miyaura Reactions of Diarylmethyl Esters
Amira H. Dardir, Irene Casademont-Reig, David Balcells,* Jonathan D. Ellefsen, Matthew R. Espinosa,
Nilay Hazari,* and Nicholas E. Smith
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ABSTRACT: The synthesis of triarylmethanes via Pd-catalyzed
Suzuki−Miyaura reactions between diarylmethyl 2,3,4,5,6-penta-
fluorobenzoates and aryl boronic acids is described. The system
operates under mild conditions and has a broad substrate scope,
including the coupling of diphenylmethanol derivatives that do not
contain extended aromatic substituents. This is significant as these
substrates, which result in the types of triarylmethane products that
are prevalent in pharmaceuticals, have not previously been
compatible with systems for diarylmethyl ester coupling.
Furthermore, the reaction can be performed stereospecifically to
generate stereoinverted products. On the basis of DFT calculations, it is proposed that the oxidative addition of the diarylmethyl
2,3,4,5,6-pentafluorobenzoate substrate occurs via an SN2 pathway, which results in the inverted products. Mechanistic studies
indicate that oxidative addition of the diarylmethyl 2,3,4,5,6-pentafluorobenzoate substrates to (IPr)Pd(0) results in the selective
cleavage of the O−C(benzyl) bond in part because of a stabilizing η3-interaction between the benzyl ligand and Pd. This is in
contrast to previously described Pd-catalyzed Suzuki−Miyaura reactions involving phenyl esters, which involve selective cleavage of
the C(acyl)−O bond, because there is no stabilizing η3-interaction. It is anticipated that this fundamental knowledge will aid the
development of new catalytic systems, which use esters as electrophiles in cross-coupling reactions.
are currently limited to electrophiles with extended aromatic
systems, such as naphthyls and biaryls, and are not compatible
with diphenylmethanol derivatives, which are prevalent in
natural products and pharmaceuticals.7,8b Nevertheless, they are
the first examples of a synthetically valuable transformation and
are fundamentally interesting because of their selectivity.
Specifically, the high yields of triarylmethane products suggest
that the diarylmethyl esters undergo oxidative addition
exclusively across the O−C(benzyl) bond (Figure 3a).11,13,15
In contrast, depending on the catalyst and exact nature of the
substrate some aryl esters can undergo oxidative addition across
either the O−C(aryl) (Figure 3a)16 or C(acyl)−O bond (Figure
3b),17 to give either biaryl or ketone products, respectively, after
transmetalation and reductive elimination. Furthermore, in
some cases following C(acyl)−O bond cleavage a decarbon-
ylative step can occur, which ultimately leads to biaryl products
(Figure 3c).18 At this stage, the exact reasons for the differences
in selectivity are not clear, especially with regard to why the O−
INTRODUCTION
■
Triarylmethanes are common motifs in natural products,1
fluorescent probes,2 organic dyes,3 metal ion sensors,4 and active
pharmaceutical ingredients.5 For example, triarylmethanes have
antiviral,6 antituberculosis,7 and antibreast cancer8 properties
(Figure 1). The most common method to synthesize triaryl-
methanes is through Lewis or Brønsted acid catalyzed Friedel−
Crafts reactions of diarylmethanols or their derivatives with
arenes; however, these reactions often have limited substrate
scopes and poor selectivity.5b In recent years, a number of
transition metal catalyzed C(sp2)−C(sp3) cross-coupling
reactions have been developed for the synthesis of triaryl-
methanes. These methods typically utilize nonclassical electro-
philes, such as diarylmethyl ammonium salts,9 sulfones,10 and
alcohol derivatives.11 In particular, alcohol derivatives, for
example, esters, are attractive as electrophiles for the synthesis
of triarylmethanes because alcohols are abundant, stable, and
diverse building blocks, which can easily be derivatized.12
In 2005, Kuwano et al. demonstrated that benzyl acetates can
be used in Pd-catalyzed Suzuki−Miyaura reactions to generate
diarylmethanes (Figure 2a).13 Although this work was not
extended to diarylmethyl esters, subsequent studies by Watson
et al. and Jarvo et al. showed that diarylmethyl esters can be used
in Ni-catalyzed Suzuki−Miyaura reactions to generate triaryl-
methanes stereospecifically (Figure 2b).11,14 The later reactions
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: February 10, 2021
Published: May 27, 2021
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C(benzyl) bonds of diarylmethyl esters are cleaved and not the
C(acyl)−O bonds.
Recently, our group and others have reported Pd-catalyzed
Suzuki−Miyaura reactions of phenyl esters in which the
C(acyl)−O bond is selectively cleaved to generate ketones in
high yields.18c,19 Based in part on Kuwano et al.’s work with
benzyl acetates,13 we hypothesized that if the substrate was
changed to a diarylmethyl ester then we could instead selectively
cleave the O−C(benzyl) bond, which would ultimately lead to
the formation of triarylmethanes. Herein, we report the first
examples of Pd-catalyzed Suzuki−Miyaura reactions of diary-
lmethyl-2,3,4,5,6-pentafluorobenzoates to selectively generate
triarylmethanes (Figure 2c). Importantly, the reaction is
compatible with diphenylmethanol derivatives that do not
contain extended aromatic substituents and enantioenriched
diarylmethyl-2,3,4,5,6-pentafluorobenzoates can be coupled
with high stereospecificity to give stereoinverted products.
The latter observation, supported by DFT calculations, suggests
that oxidative addition of the substrate to the (IPr)Pd(0) active
catalyst occurs via an SN2-type mechanism, and we were able to
isolate the oxidative addition product from the reaction of a
diarylmethyl-2,3,4,5,6-pentafluorobenzoate to an (IPr)Pd(0)
complex. Additional DFT calculations demonstrate it is
kinetically and thermodynamically more favorable to cleave
the O−C(benzyl) bond of benzyl benzoate during oxidative
addition to (IPr)Pd(0) in part due to an η3-interaction between
the benzyl group and the Pd. In contrast, it is kinetically and
thermodynamically more favorable to cleave the C(acyl)−O
bond of phenyl benzoate during oxidative addition to (IPr)-
Pd(0), which proceeds via a concerted mechanism. Overall, this
work provides a notable synthetic advance due to the improved
substrate scope for the formation of triarylmethanes and
valuable fundamental information about selectivity in the
cleavage of benzoates.
Figure 1. Examples of medicinally relevant triarylmethanes.
Figure 2. Summary of previous work on Suzuki−Miyaura reactions of
diarylmethyl esters (a, b) and comparison to this work (c).11,13,15d
RESULTS AND DISCUSSION
■
Reaction Discovery and Development. In our prelimi-
nary work, we demonstrated that we could couple benzyl
benzoate with phenyl boronic acid to selectively generate a
diarylmethane product using (η3-1-tBu-indenyl)Pd(IPr)(Cl)
(IPr = 1,3-bis(2,6-diisopropyl-phenyl)-1,3-dihydro-2H-imida-
zol-2-ylidene) as a precatalyst (Figure 4). This is in agreement
with Kuwano et al.’s results13 and is indicative of selective
cleavage of the O−C(R) (R = benzyl) bond. It is notable that
when benzyl benzoate is replaced with phenyl benzoate under
the same reaction conditions that we selectively form
benzophenone, which is consistent with selective cleavage of
the C(acyl)−O bond (Figure 4). Our results with benzyl
benzoate suggested that we could leverage the observed cleavage
of the O−C(R) (R = benzyl) bond to develop a selective
Figure 3. Bonds that can be cleaved in oxidative addition reactions
involving esters.
Figure 4. Comparison of Pd-catalyzed Suzuki−Miyaura reactions of phenyl and benzyl benzoate using (η3-1-tBu-indenyl)Pd(IPr)(Cl) as the
precatalyst under identical conditions.
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Figure 5. (a) Pd-catalyzed Suzuki−Miyaura reactions of diphenylmethyl esters and halides and (b) side reaction observed with aryl halides.
aConditions: diphenylmethyl−X (0.05 mmol), 4-methoxyphenylboronic acid (0.075 mmol), K2CO3 (0.1 mmol), (η3-1-tBu-indenyl)Pd(IPr)(Cl)
(0.0005 mmol), toluene (0.4 mL), and EtOH (0.1 mL). Yields are an average of two runs determined by GC-FID using the conversion of starting
material to product.
Table 1. Optimization Table for the Pd-Catalyzed Suzuki−Miyaura Reaction of Diarylmethyl 2,3,4,5,6-Pentafluorobenzoate with
4-Methoxyphenylboronic Acid
a
entry
deviation from optimized conditions
GC yield
1
2
no change
no precatalyst
85%
0%
b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
24 h instead of 6 h
>99%
>99%
73%
64%
86%
62%
16%
40%
2%
3%
46%
<1%
69%
40 °C instead of r.t. and 4 h instead of 6 h
(η3-cinnamyl)Pd(IPr)Cl instead of (η3-1-tBu-indenyl)Pd(IPr)Cl
PEPPSI-IPr instead of (η3-1-tBu-indenyl)Pd(IPr)Cl
0.5 mol % [Pd(IPr)(μ-Cl)Cl]2 instead of (η3-1-tBu-indenyl)Pd(IPr)Cl
SIPr instead of IPr
IMes instead of IPr
IPr*OMe instead of IPr
PCy3 instead of IPr
XPhos instead of IPr
SPhos instead of IPr
toluene only
H2O instead of EtOH
MeOH instead of EtOH
iPrOH instead of EtOH
c
d
e
89%
56%
a
Conditions: diphenylmethyl ester (0.05 mmol), 4-methoxyphenylboronic acid (0.075 mmol), base (0.1 mmol), precatalyst (0.0005 mmol),
b
solvent (0.5 mL). Yields are an average of two runs determined by GC-FID using the conversion of starting material to product. Reached 64%
conversion to F5C6COOC2H5 and 36% starting material remaining. Reached 67% conversion to F5C6COOC2H5. Reached 32% conversion to
F5C6COOC2H5. Reached 9% conversion to F5C6COOCH3.
c
d
e
method for the synthesis of synthetically valuable triaryl-
methanes from diphenylmethyl esters through the careful
selection of the leaving group on the ester and the optimization
of the reaction conditions.
We initially synthesized diphenylmethyl-acetate, -benzoate,
and -2,3,4,5,6-pentafluorobenzoate via a straightforward reac-
tion between diarylmethanol and the appropriate carboxylic acid
(see the Supporting Information).17a Subsequently, using 1 mol
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Figure 6. Isolated and NMR yields for Pd-catalyzed Suzuki−Miyaura reactions of diarylmethyl 2,3,4,5,6-pentafluorobenzoates with (4-
methoxyphenyl)boronic acid. Conditions for isolated yields: ester (0.2 mmol), phenylboronic acid (0.3 mmol), K2CO3 (0.4 mmol), (η3-1-tBu-
indenyl)Pd(IPr)Cl (0.0002 mmol), toluene (1.6 mL), and ethanol (0.4 mL). Conditions for NMR yields: ester (0.05 mmol), phenylboronic acid
(0.075 mmol), K2CO3 (0.1 mmol), (η3-1-tBu-indenyl)Pd(IPr)Cl (0.0005 mmol), toluene (0.4 mL), and ethanol (0.1 mL). NMR yields were
determined using 1,2,4,5-tetramethylbenzene as an internal standard. aUsing 4 mol % (η3-1-tBu-indenyl)Pd(IPr)Cl instead of 1 mol %. bReacted for 16
h instead of 4 h. cReacted at 80 °C instead of 40 °C. dUsing water instead of ethanol.
% of (η3-1-tBu-indenyl)Pd(IPr)(Cl) as the precatalyst, a 4:1
mixture of toluene/ethanol as the solvent, and 2 equiv of K2CO3
as the base, we assessed these esters as substrates in Suzuki−
Miyaura reactions with 4-methoxyphenylboronic acid at room
temperature (Figure 5a). After 6 h, Suzuki−Miyaura reactions
with diphenylmethyl-acetate and -benzoate give 28 and 35% of
(diphenyl)(4-methoxyphenyl) methane, respectively, while the
reaction with diphenylmethyl-2,3,4,5,6-pentafluorobenzoate
yields 85% of the desired product. The observed trend in
reactivity of the diphenylmethyl esters correlates with the pKa’s
of the corresponding carboxylic acids, with acetic acid and
benzoic acid having similar pKa values and 2,3,4,5,6-penta-
fluorobenzoic acid having a much lower pKa value.20 We suggest
that the pKa values are reflective of the substrates relative ability
to be activated by the Pd center via an SN2-type mechanism, as
well as the strength of the interaction between Pd and the anion
(vide infra).15i These reactions are some of the first examples of
Suzuki−Miyaura reactions of diphenylmethanol derivatives that
do not contain extended aromatic substituents.15k,21 We also
compared the reactions using esters as electrophiles to those
using diphenylmethyl chloride and diphenylmethyl bromide as
substrates (Figure 5a). Although diphenylmethyl chloride gives
a high yield (77%), the reaction results in the formation of
(ethyl)(diphenylmethyl)ether as a side product (∼5%) (Figure
5b), presumably as a result of base-mediated nucleophilic
substitution of the alcohol solvent on the halide. In agreement
with this proposal, the more reactive diphenylmethyl bromide
gives an even lower yield (21%) and an increased quantity of the
ether side product (∼33%).
We performed a series of Suzuki−Miyaura reactions between
diphenylmethyl 2,3,4,5,6-pentafluorobenzoate and 4-methoxy-
phenylboronic acid to evaluate the factors that are important in
obtaining high yields. In the absence of precatalyst no product is
observed, and the majority of the starting material is converted
to ethyl 2,3,4,5,6-pentafluorobenzoate, indicating that the
diphenylmethyl 2,3,4,5,6-pentafluorobenzoate is not stable
under the reaction conditions (Table 1, entry 2). In the
presence of (η3-1-tBu-indenyl)Pd(IPr)(Cl), the desired cou-
pling outcompetes the side reaction and quantitative conversion
occurs in 24 h (entry 3). Increasing the temperature to 40 °C,
results in a quantitative yield after 4 h (entry 4). Other common
precatalysts, such as (η3-cinnamyl)Pd(IPr)Cl and PEPPSI-IPr,
give moderate but reduced yields relative to that with (η3-1-tBu-
indenyl)Pd(IPr)(Cl) likely due to their slower rates of activation
under our reaction conditions (entries 5 and 6).22 A similar yield
was obtained when (η3-1-tBu-indenyl)Pd(IPr)Cl was replaced
with [Pd(IPr)(μ-Cl)Cl]2, but this precatalyst was not pursued
further, as it lacks a precursor that can be readily used for ligand
screening (entry 7).23 Changing the ancillary ligand to other
frequently utilized NHC ligands, such as SIPr, IMes, and
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Figure 7. Isolated yields and enantioselectivity for Pd-catalyzed stereospecific Suzuki−Miyaura reactions of diarylmethyl 2,3,4,5,6-
pentafluorobenzoates. Conditions for isolated yields enantioenriched ester (0.05 mmol), arylboronic acid (0.075 mmol), K2CO3 (0.1 mmol), (η3-
1-tBu-indenyl)Pd(IPr)Cl (0.0005 mmol), toluene (0.4 mL), and ethanol (0.1 mL).
IPr*OMe (entries 8−10), or phosphine ligands, such as PCy3,
XPhos, or SPhos (entries 11−13), gives reduced yields
compared to IPr. We have observed similar trends in related
Suzuki−Miyaura reactions involving phenyl benzoates.19f The
choice of base is also crucial, and although high yields are
obtained with K2CO3, lower yields are observed with other
common inorganic bases, such as K3PO4 or Na2CO3 (see the
Supporting Information). In the absence of a protic cosolvent,
no product is observed (entry 14). Although the reaction
worked comparably in the presence of methanol or ethanol
(entries 16 and 1), faster transesterification occurs in methanol
to generate the methyl 2,3,4,5,6-pentafluorobenzoate by-
product, which unnecessarily consumes starting material.
Furthermore, the yield suffered when water or isopropanol is
used instead of ethanol (entries 15 and 17). The role of the
alcohol cosolvent may be in solubilizing the reagents, assisting in
precatalyst activation,22b or facilitating transmetalation by
displacing the carboxylate with an alkoxy ligand.13
Substrate Scope. Given the success of Suzuki−Miyaura
reactions involving diphenylmethyl 2,3,4,5,6-pentafluoroben-
zoate, we explored the substrate scope for the coupling of a range
of diarylmethyl 2,3,4,5,6-pentafluorobenzoates with phenyl-
boronic acid under our optimized conditions (Figure 6).
Electron-neutral diarylmethyl esters (6a and 6b), including
fluorene-9-ester (6b), result in high yields of the desired
product, 96 and 94%, respectively. The latter result is notable
because fluorenes are important motifs in biologically active
molecules,24 as monomers in polymer chemistry,25 and as dyes
for solar cell applications, and our system provides a facile
method for functionalization.26 Additionally we were able to
generate 6a on a 1 mmol scale in 95% isolated yield (see the
Supporting Information), which demonstrates that our method
is scalable. The reaction is also compatible with esters containing
electron-donating (6c) and -withdrawing (6d and 6e)
substituents. This includes the doubly cyano-substituted ester
(6e) which is coupled in 86% yield. This is significant because
cyano groups often coordinate to Pd and inhibit catalysis. It is
more difficult to couple substrates with ortho-substitution on an
aryl group of the diarylmethyl ester, such as 6f. Even with higher
precatalyst loading (4 mol %) and longer reactions times (16 h),
when ethanol is used as the cosolvent, transesterification to
generate the ethyl 2,3,4,5,6-pentafluorobenzoate competes with
the desired cross-coupling reaction, and only a 40% NMR yield
of cross-coupled product is observed. However, an 87% yield is
obtained by increasing the precatalyst loading to 4 mol %, the
temperature to 80 °C, the time to 16 h, and switching to water as
the cosolvent to prevent transesterification. Consistent with the
challenges in coupling ortho-substituted substrates, (1-
naphthyl)(phenyl)methyl 2,3,4,5,6-pentafluorobenzoate (6g)
gives minimal yield under the optimized conditions (6% NMR
yield). When more forcing conditions are utilized, with the use
of water in place of ethanol as a cosolvent, a yield of 77% is
obtained. Under the same conditions, the even more sterically
bulky bis(1-naphthyl)methyl 2,3,4,5,6-pentafluorobenzoate
(6h) gives an 87% yield. In contrast, we are able to couple the
less sterically bulky substrate (2-naphthyl)(phenyl)methyl
2,3,4,5,6-pentafluorobenzoate (6i) without major modification
to our optimized conditions (16 h instead of 4 h). Pyridyl groups
are common in pharmaceuticals but are often difficult substrates
for cross-coupling reactions due to coordination of the
heterocycle to Pd.27 Using our more forcing conditions,
including the replacement of ethanol with water as a cosolvent,
we can couple a 2-pyridyl containing electrophile (6j) in 49%.
Enantiomers of chiral molecules often have different bio-
logical activity due to variations in their binding affinity with
chiral targets.28 Therefore, there are advantages to accessing
single enantiomers of triarylmethanes.1 We hypothesized that
our method could be compatible with producing single
enantiomers of triarylmethanes if enantioenriched diarylmethyl
2,3,4,5,6-pentafluorobenzoates esters were utilized as substrates.
The enantioenriched substrates, (S)-(2-naphthyl)(phenyl)-
methyl 2,3,4,5,6-pentafluorobenzoate and (S)-(4-
methylphenyl)(phenyl)methyl 2,3,4,5,6-pentafluorobenzoate,
were readily synthesized from the appropriate (S)-diary-
lmethanol by following a literature procedure involving the
reaction of an in situ generated phenylzinc species and an
aldehyde catalyzed by a chiral pyrrolidine ligand (see the
Supporting Information).29 The subsequent coupling of (S)-(2-
naphthyl)(phenyl)methyl 2,3,4,5,6-pentafluorobenzoate with 3-
furylboronic acid under our optimized conditions results in the
formation of triarylmethane 7a in 97% yield and 99% es,
indicating that the reaction proceeds with high enantiospeci-
ficity (Figure 7). Comparison of the polarimetry data of isolated
7a ([α]2D0 −23.25 (c 0.400, CDCl3)) with literature data ([α]D29
−22.0 (c 1.00, CDCl3))11a suggests the formation of the (R)-
isomer, which is consistent with a pathway involving inversion.
Similarly, the reaction of (S)-(4-methylphenyl)(phenyl)methyl
2,3,4,5,6-pentafluorobenzoate with (4-methoxy)phenylboronic
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Figure 8. Isolated and NMR yields for Pd-catalyzed Suzuki−Miyaura reactions of diphenylmethyl 2,3,4,5,6-pentafluorobenzoate with boronic acids.
Conditions for isolated yields: ester (0.2 mmol), boronic acid (0.3 mmol), K2CO3 (0.4 mmol), (η3-1-tBu-indenyl)Pd(IPr)Cl (0.0002 mmol), toluene
(1.6 mL), and ethanol (0.4 mL). Conditions for NMR yields: diphenylmethyl 2,3,4,5,6-pentafluorobenzoate ester (0.05 mmol), (4-
methoxyphenyl)boronic acid (0.075 mmol), K2CO3 (0.1 mmol), (η3-1-tBu-indenyl)Pd(IPr)Cl (0.0005 mmol), toluene (0.4 mL), and ethanol
(0.1 mL). NMR yields were determined using 1,2,4,5-tetramethylbenzene as an internal standard. aReacted for 8 h instead of 4 h. bReacted for 16 h
instead of 4 h. cUsing 4 mol % (η3-1-tBu-indenyl)Pd(IPr)Cl instead of 1 mol %.
acid generates enantioenriched triarylmethanes 7b in 88% yield
and 90% es. Given that we propose the mechanism of the
reaction involves oxidation addition, transmetalation, and
reductive elimination (vide infra), the stereochemical inversion
of the (S)-diarylmethyl 2,3,4,5,6-pentafluorobenzoates to the
(R)-triarylmethanes suggests that oxidative addition proceeds
via an SN2 pathway. This is because transmetalation and
reductive elimination typically occur with retention of
configuration in Suzuki−Miyaura reactions;30 therefore, the
stereochemistry of the product is likely based on oxidative
addition. Our work is consistent with previous studies utilizing
NHC−Ni catalysts for the stereoselective coupling of naphthyl
and biaryl diarylmethyl esters, which also proceed with inversion
and propose that oxidative addition is responsible for the
observed stereochemistry.11a,15i
4-acetyl-phenylboronic acids (8g) give yields of 87 and 70%,
respectively, which are not only electron-withdrawing but can be
further functionalized, for example, via nucleophilic addition
reactions.31 The reaction is tolerant of ortho-substituted aryl
boronic acids (8i−j). However, while 2,6-dimethoxyphenyl
boronic acid (8l) could be coupled in high yield (although
difficulty in isolation resulted in a lower isolated yield), minimal
product is observed with 2,4,6-trimethylphenyl boronic acid
(8m) even with higher precatalyst loadings. The 1- and 2-
naphthyl boronic acids (8j and 8k) are coupled in yields of 83
and 80%, respectively. Heteroaryl-substituted triarylmethanes
derivatives are common in pharmaceutical compounds,7b,32 but
cross-coupling reactions of diarylmethanol derivatives with
heteroaryl boronic acids are limited,11a,33 possibly due to the
instability of heteroaryl nucleophiles.34 Our system is able to
couple 2-furyl (8n) and 3-thiophene (8o) boronic acids in yields
of 98 and 97%, respectively, but 2-substituted thienyl boronic
acid gives low conversion (see the Supporting Information).
Benzo[b]thien-2-yl- (8p) and boc-protected pyrrole- (8q)
boronic acids give yields of 80 and 70%, respectively, but
The scope of the boronic acid coupling partner was evaluated
using diphenylmethyl 2,3,4,5,6-pentafluorobenzoate as the
electrophile (Figure 8). The reaction is compatible with
electron-neutral, -donating, and -withdrawing aryl boronic
acids (8a−h). In a noteworthy result, 4-methylester- (8f) and
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require longer reaction times. Unfortunately, pyridyl boronic
acids could not be coupled (see the Supporting Information),
likely due to protodeborylation or coordination of the nitrogen
atom of the pyridine ring to the catalyst.
Overall, our substrate scope demonstrates that we have
developed a mild and general method for the synthesis of
triarylmethanes, containing both extended and nonextended
aromatic groups, from readily available diarylmethyl esters. In
particular, the ability of our system to couple diphenylmethyl
esters that do not contain extended aromatic substrates is
significant, as these substrates have not previously been utilized.
Furthermore, our system is tolerant of a variety of different
functional groups, is compatible with heterocyclic substrates and
is stereospecific. As a result, we expect that it will be valuable for
the synthesis of medicinally relevant triarylmethanes.
Mechanistic Studies. The high yields of triarylmethanes
that are observed in Suzuki−Miyaura reactions involving
diarylmethyl 2,3,4,5,6-pentafluorobenzoates indicate that the
reaction must be proceeding with high selectivity, consistent
with the selective cleavage of the O−C(benzyl) bond.
Furthermore, there is no evidence for cleavage of the
C(acyl)−O bond, which presumably occurs readily when a
phenyl ester is utilized instead of a benzyl ester (Figure 4).
Previous studies have hypothesized that oxidative addition to
Pd(0) is responsible for the differences in selectivity between
phenyl- and benzyl-esters, but there are few well-defined
examples of the oxidative addition of these substrates and the
reaction pathways (e.g., concerted versus SN2) have not been
probed.35 In seminal work, Yamamoto et al. demonstrated
differences in oxidative addition for aryl- and benzyl-
trifluoroacetates to phosphine ligated Pd(0) complexes.15b,35b,c
Specifically, aryl trifluoroacetates were shown to oxidatively add
across the C(acyl)−O bond, while benzyl trifluoroacetates
underwent oxidative addition across the O−C(benzyl) bond.
However, the mechanistic origins for this difference were not
elucidated and their applicability to our system, which features a
different ester and ancillary ligand, was unclear. Therefore, we
studied the oxidative addition of the type of esters used in this
work, such as phenyl- and benzyl-benzoates, to the proposed
active catalytic species (IPr)Pd(0).36
Initial evaluation of the oxidative addition of phenyl benzoate
with the Pd(0) source (IPr)Pd(0)(styrene)2 resulted in slow
decomposition to Pd black and (IPr)2Pd. The use of more
electron-withdrawing electrophiles is known to result in more
facile oxidative addition and also stabilize the resulting transition
metal complexes.37 In this case, treatment of phenyl 2,3,4,5,6-
pentafluorobenzoate with (IPr)Pd(styrene)2 at room temper-
ature resulted in the slow formation of new product(s) as
determined by NMR spectroscopy, but this was followed by
decomposition, which prevented full characterization. We
hypothesized that an ortho-coordinating ligand on the benzoate
group, such as diphenylphosphine, would stabilize the putative
three-coordinate oxidative addition complex by binding to the
open coordination site on the metal center. The reaction of
phenyl 2-(diphenylphosphino)benzoate with (IPr)Pd(styrene)2
at room temperature resulted in the clean formation of a
product, 1, with a single resonance in the 31P NMR spectrum at
50.4 ppm, which was isolated in 75% yield (Figure 9a). X-ray
crystallography confirmed that 1 is the result of oxidative
addition of the C(acyl)−O bond to (IPr)Pd(0) with
coordination of the phosphine (Figure 9b). Interestingly, the
crystal structure shows that the C(acyl) ligand is trans to the
OPh ligand and that the phosphine ligand is trans to the IPr
Figure 9. (a) Oxidative addition of phenyl 2-(diphenylphosphino)-
benzoate to (IPr)Pd(0) to form 1. (b) ORTEP (30% probability) of 1.
Hydrogen atoms and methyl groups associated with the isopropyl
substituents of IPr omitted for clarity. Selected bond distances (Å) and
angles (deg): Pd1−C1 1.971(9), Pd1−C46 1.975(7), Pd1−P1
2.287(2), Pd1−O1 2.107(6); C46−Pd1−O1 90.2(2), C1−Pd1−C46
89.5(3), P1−Pd1−O1 96.0(1), P1−Pd1−C1 84.0(2).
ligand. It would be expected, however, that after concerted
oxidative addition the C(acyl) ligand and OPh ligand would be
cis to one another, which suggests that the ligands can rearrange
on the metal center either by decoordination of the phosphine or
OPh ligands. Nevertheless, the formation of 1 indicates that
(IPr)Pd(0) is capable of facile cleavage of the C(acyl)−O bond
of a phenyl ester. Notably, this is the first example of a well-
defined oxidative addition product from the addition of a phenyl
ester to Pd(0) that does not undergo decarbonylation.
Next, we investigated the reaction of benzyl benzoate
derivatives with (IPr)Pd(styrene)2. In an analogous fashion to
the reaction with the unsubstituted phenyl benzoate, the
reaction of benzyl benzoate with (IPr)Pd(styrene)2 resulted in
slow decomposition to Pd black and (IPr)2Pd. However, when
we performed the reaction of (IPr)Pd(styrene)2 with 2,3,4,5,6-
pentafluorobenzoate, a substrate used in catalysis, one new
product, 2, is formed and isolated in a 65% yield (Scheme 1).38
In the 1H NMR spectrum of 2, the resonance associated with the
methine proton of the benzyl group is shifted upfield relative to
that of the free ester (4.78 vs 7.19 ppm), consistent with the
presence of a metal center in close proximity to the methine
proton.39 The 13C NMR spectrum includes a resonance at 177.0
ppm and two new peaks are observed in the IR spectrum at 1633
and 1343 cm−1. This is indicative of the presence of a carbonyl
group. Overall, our NMR data suggests that 2 is the oxidative
addition product from cleavage of the O−C(benzyl) bond of
2,3,4,5,6-pentafluorobenzoate. However, we were unable to
identify the exact structure of 2 despite repeated unsuccessful
attempts to obtain single crystals for X-ray diffraction. Possible
structures of 2 include those with the diarylmethyl ligand
binding in either an η1- or η3-fashion, and the 2,3,4,5,6-
pentafluorobenzoate ligand binding in a κ1- or κ2-manner
(Scheme 1). Furthermore, it is possible that the 2,3,4,5,6-
pentafluorobenzoate anion is not coordinated to Pd and that an
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Scheme 1. Formation of Oxidative Addition Complex (IPr)Pd(CHPh2)(OOCC6F5) (2) and Possible Structures of 2
Figure 10. DFT calculations comparing the oxidative addition of phenyl benzoate via C(acyl)−O and O−C(aryl) bond cleavage. Relative energies in
kcal/mol.
Figure 11. DFT calculations comparing the oxidative addition of benzyl benzoate via concerted C(acyl)−O and O−C(aryl) bond cleavage and also an
SN2 pathway. Relative energies in kcal/mol.
ion pair is generated. Nevertheless, our results indicate that
oxidative addition of 2,3,4,5,6-pentafluorobenzoate with cleav-
age of the O−C(benzyl) bond is facile, and we suggest that this is
the first step in catalysis. Consistent with this proposal, when 2 is
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used as a catalyst in the coupling of diphenylmethyl 2,3,4,5,6-
pentafluorobenzoate with (4-methoxy)phenylboronic acid
under our optimized conditions (eq 1), complete conversion
to (2- methoxyphenyl)(diphenyl)methane is observed, indicat-
ing that 2 is a kinetically competent catalyst.
lower than that observed for TSBz(O−CBz) (12.5 vs 20.7 kcal/
mol).
The cleavage of the O−C(benzyl) bond can also occur via an
SN2 pathway. The SN2 mechanism follows a lower energy
pathway than either the concerted O−C(benzyl) or C(acyl)−O
bond cleavage, as the barrier associated with the SN2-TSBz(O−
CBz) transition state, 6.4 kcal/mol, is the lowest found for this
substrate (Figure 11). The two main structural features of SN2-
TSBz(O−CBz) are as follows: (1) The η3-interaction between
the metal center and the CBz (2.32 Å), Cipso (2.29 Å), and Cortho
(2.25 Å) atoms is similar to that of the concerted TSBz(O−CBz)
transition state. (2) A linear arrangement exists between the
forming Pd−CBz (2.32 Å) and the breaking CBz−O (2.08 Å)
bonds, with a Pd−CBz−O angle of 173.6°, and CBz adopts a
distorted trigonal bipyramid geometry. The preference for the
SN2 pathway is in agreement with the inversion of configuration
observed in the Pd-catalyzed Suzuki−Miyaura reactions of
enantioenriched (diaryl)methyl 2,3,4,5,6-pentafluorobenzoate
(Figure 7), as well as that seen in the literature with (NHC)Ni
catalysts.11b,15i The product of the SN2 pathway, SN2-PBz(O−
CBz), is an ion pair between the (IPr)Pd(η3-Bz)+ cation and the
PhCO2− anion (with a natural charge q = 0.78 value). This ion
pair is more stable than the PBz(CAc−O) complex (1.6 vs 6.0
kcal/mol) and can be further stabilized by rearranging into the
PBz(O−CBz) complex (1.6 vs −9.7 kcal/mol).43 Thus, O−
C(benzyl) cleavage is both kinetically and thermodynamically
preferred over C(acyl)−O cleavage. Overall, the computational
results explain the experimental observation that for phenyl
benzoate the C(acyl)−O bond is cleaved, whereas for benzyl
benzoate the O−C(benzyl) bond is cleaved.
In our experimental work, we demonstrated that a Suzuki−
Miyaura reaction with diphenylmethyl 2,3,4,5,6-pentafluoro-
benzoate is more efficient than the corresponding reaction with
diphenylmethyl benzoate (Figure 5). To investigate this
observation, the transition state for cleavage of O−C(benzyl)
bond of benzyl 2,3,4,5,6-pentafluorobenzoate via an SN2-type
oxidative addition pathway was calculated using DFT. The
barrier is 2.1 kcal/mol lower in energy than that of the benzyl
benzoate consistent with our experimental results (Figure 12).
However, in both cases the barrier for oxidative addition is very
low (4.3 and 6.4 kcal/mol), suggesting that oxidative addition is
facile. The SN2 product of the oxidative addition of benzyl
2,3,4,5,6-pentafluorobenzoate to (IPr)Pd(0), PFBz(O−CBz), is
DFT calculations were performed to help us understand the
observed selectivity in the oxidative addition of phenyl- and
benzyl-benzoates to (IPr)Pd(0).40 Phenyl- and benzyl-benzoate
were used as model substrates given our results in Figure 4,
showing that they undergo selective cleavage of the C(acyl)−O
bond and O−C(benzyl) bond, respectively. For both substrates,
the concerted oxidative addition pathway was computed for the
heterolytic cleavage of the C(acyl)−O and the O−C(aryl)
bonds. In the case of benzyl benzoate, an SN2 pathway was also
calculated for the cleavage of the O−C(benzyl) bond.
The oxidative addition transition state for C(acyl)−O
cleavage in phenyl benzoate, TSPh(CAc−O), is shown in Figure
10. In addition to the C(acyl)−O bond cleavage (1.71 Å), this
transition state also involves the concerted formation of the Pd−
C(acyl)Ph (2.08 Å) and Pd−OPh (2.16 Å) bonds. The three
atoms involved in the bond rearrangement form a three-
membered Pd−O−C metallacycle, consistent with literature
precedent.17a In contrast, the transition state for O−C(aryl)
bond cleavage, in phenyl benzoate TSPh(O−CAr), has a five-
membered metallacycle geometry, in which one of the two
carboxylate O atoms breaks the bond with the Ph ring (2.04 Å),
whereas the other forms a new bond with Pd (2.20 Å). The full
relaxation of these two transition states to the oxidative addition
products yields the complexes PPh(CAc−O) and PPh(O−CAr)
with the expected Ph(O)C−Pd−OPh and Ph(O)CO−Pd−Ph
moieties, respectively (Figure 10).41 Importantly, the cleavage of
the C(acyl)−O bond in phenyl benzoate is both kinetically (8.8
vs 19.0 kcal/mol) and thermodynamically (−4.0 vs 4.6 kcal/
mol) preferred compared with cleavage of the O−C(aryl) bond,
consistent with our experimental results (Figure 4).
The concerted transition states associated with cleavage of the
C(acyl)−O and O−C(benzyl) bond of benzyl benzoate are
shown in Figure 11, along with the transition state associated
with cleavage of the O−C(benzyl) bond via an SN2 mechanism.
The geometry of TSBz(CAc−O) is very similar to TSPh(CAc−O),
with the cleavage and formation of the C(acyl)−O (1.96 Å),
Pd−C(acyl)Ph (2.02 Å), and Pd−OBz (2.11 Å) bonds in a
three-membered palladacycle. The transition state for O−
C(aryl) bond cleavage, TSBz(O−CBz), is also similar to
TSPh(O−CAr), involving both O atoms of the carboxylate
group, one cleaving the bond to the benzyl (1.99 Å), and the
other forming a new bond with Pd (2.41 Å). However, TSBz(O−
CBz) has a distinct feature. Specifically, there is an η3-interaction
between the metal center and the benzyl moiety, with Pd−C
interatomic distances of 2.71, 2.34, and 2.17 Å for the CBz, Cipso
,
and Cortho atoms, respectively.42 This interaction becomes a
covalent η3-bond in the PBz(O−CBz) product, with distances
shortened to 2.09, 2.27, and 2.39 Å, respectively. This is likely
the main reason why the PBz(O−CBz) product is lower in energy
than the PBz(CAc−O) product (−9.7 vs 6.0 kcal/mol), although
the transition state energy associated with TSBz(CAc−O) is still
Figure 12. DFT calculations comparing the oxidative addition of the
O−C(benzyl) bond in benzyl benzoate and benzyl 2,3,4,5,6-
pentafluorobenzoate to (IPr)Pd(0). Relative energies are given in
kcal/mol.
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also an ion pair (i.e., (IPr)Pd(η3-FBz)+PhCO2 , with q =
0.82e), which is significantly more stable than that formed by
the nonfluorinated substrate (−6.1 vs 1.6 kcal/mol), likely due
to the fluorides promoting charge separation.44 We propose that
the outersphere 2,3,4,5,6-pentafluorobenzoate anion in
−
PFBz(O−CBz) may lead to faster transmetalation, the likely
next elementary step in the mechanism after oxidative addition
(Figure 13), in part because the formation of PFBz(O−CBz) is
not as thermodynamically favorable as the formation of PBz(O−
CBz) (see the Supporting Information). Thus, utilizing the
2,3,4,5,6-pentafluorobenzoate as the leaving group may result in
improvements to multiple elementary steps on the catalytic
cycle. By analogy to other cross-coupling reactions,45 we expect
that the final step reductive elimination is facile, suggesting that
transmetalation is the turnover-limiting step.
To further probe the nature of the turnover-limiting step in
catalysis we investigated the oxidative addition of (diphenyl)-
methyl-2,3,4,5,6-pentafluorobenzoate (14a) and (2-
methylphenyl)(phenyl)methyl-2,3,4,5,6-pentafluorobenzoate
(14b) to (IPr)Pd(styrene)2. Our substrate scope showed that
the use of diarylmethylesters with ortho-substitution, such as
14b, on the aryl groups results in reduced yields under optimized
conditions and necessitates the use of harsher reaction
conditions to obtain satisfactory yields (Figure 6). However,
the rates of oxidative addition of 14a and 14b are comparable
(Figure 14), with both occurring at room temperature. This is
not consistent with oxidative addition being the reason that
harsher conditions are required for the coupling of 14b and
suggests that a subsequent step in the catalytic cycle is turnover-
limiting. It also provides further evidence that oxidative addition
is facile.
Figure 14. NMR yields of oxidative addition product over time for the
reaction of diarylmethyl pentafluorobenzoate with (IPr)Pd(styrene)2.
C(acyl)−O bond. DFT calculations show that cleavage of the
O−C(benzyl) bond in benzyl electrophiles is both kinetically
and thermodynamically preferred. This is because oxidative
addition of benzyl electrophiles to (IPr)Pd(0) via an SN2
mechanism provides a low barrier pathway for cleavage of the
O−C(benzyl) bond, while the formation of products with an η3-
benzyl interaction thermodynamically stabilizes the Pd(II)
products. In fact, in our reactions the oxidative addition of the
2,3,4,5,6-pentafluorobenzoate electrophiles is so facile that
transmellation is likely the turnover-limiting step in catalysis.
Phenyl ester electrophiles cannot readily undergo oxidative
addition via an SN2 pathway or form products which are
stabilized via chelation and as a result cleavage of the C(acyl)−O
bond is kinetically and thermodynamically preferred. Overall,
apart from the development of a more general method for the
synthesis of triarylmethanes, our work provides fundamental
information on the selectivity of oxidative addition of ester
electrophiles. Given the currently high level of interest in using
esters as electrophiles in cross-coupling, this is likely to be
valuable for the design of new and improved synthetic methods.
CONCLUSIONS
■
We have developed a broad method for synthesizing triaryl-
methanes under mild conditions via Pd-catalyzed Suzuki−
Miyaura coupling reactions involving 2,3,4,5,6-pentafluoroben-
zoate electrophiles. Importantly, our method is not limited to
electrophiles containing extended aromatic systems, such as
naphthyl or biaryl groups, and as a result represents a significant
advance over previous methods. Furthermore, the reaction is
stereospecific and is able to generate chiral triarylmethanes with
inversion of configuration. Intriguingly, while the Suzuki−
Miyaura reaction of diarylmethyl esters involves the cleavage of
the O−C(benzyl) bond, the reaction featuring closely related
phenyl ester electrophiles involve selective cleavage of the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00085.
■
sı
Additional information about selected experiments and
calculations, characterizing data including NMR spectra
(PDF)
Cartesian coordinates (XYZ)
Accession Codes
CCDC 2045209 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
Figure 13. Proposed catalytic cycle for Pd-catalyzed Suzuki−Miyaura
reactions of diphenylmethyl 2,3,4,5,6-pentafluorobenzoate.
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CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
David Balcells − Hylleraas Centre for Quantum Molecular
Sciences, Department of Chemistry, University of Oslo, N-0315
Oslo, Norway; orcid.org/0000-0002-3389-0543;
Email: david.balcells@kjemi.uio.no
Nilay Hazari − Department of Chemistry, Yale University, New
Haven, Connecticut 06520, United States; orcid.org/0000-
0001-8337-198X; Email: nilay.hazari@yale.edu
(6) Bossche, H. V.; Willemsens, G.; Roels, I.; Bellens, D.; Moereels,
H.; Coene, M.-C.; Jeune, L. L.; Lauwers, W.; Janssen, P. A. J. R 76713
and Enantiomers: Selective, Nonsteroidal Inhibitors of the Cytochrome
P450-Dependent Oestrogen Synthesis. Biochem. Pharmacol. 1990, 40,
1707−1718.
Authors
Amira H. Dardir − Department of Chemistry, Yale University,
New Haven, Connecticut 06520, United States
Irene Casademont-Reig − Hylleraas Centre for Quantum
Molecular Sciences, Department of Chemistry, University of
Oslo, N-0315 Oslo, Norway; Donostia International Physics
Center (DIPC), 20018 Donostia, Euskadi, Spain; Kimika
Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU),
20080 Donostia, Euskadi, Spain
Jonathan D. Ellefsen − Department of Chemistry, Yale
University, New Haven, Connecticut 06520, United States
Matthew R. Espinosa − Department of Chemistry, Yale
University, New Haven, Connecticut 06520, United States
Nicholas E. Smith − Department of Chemistry, Yale University,
New Haven, Connecticut 06520, United States; orcid.org/
0000-0003-2504-0191
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00085
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.H. acknowledges support from the NIHGMS under Award
Number R01GM120162. I.C.R. acknowledges the Basque
Government for funding through a predoctoral fellowship
(PRE_2016_1_0159). D.B. acknowledges the support from the
Research Council of Norway through its Centers of Excellence
Scheme (project number 262695) and the Norwegian Super-
computing Program (NOTUR; project number NN4654K).
We thank Dr. Scott J. Miller for access to his group’s chiral
HPLC and Orven Mallari for the synthesis of diphenylmethyl
benzoate.
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(41) For the O−C(aryl) bond cleavage, one additional transition state
was found on the potential energy surface, although at a higher energy
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(42) One additional transition state was also found in the O−C(aryl)
bond cleavage pathway, although at a higher energy level (Figure S2). A
pre-reaction complex was also found.
(43) Figure S3 provides a complete list of possible isomers of this
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(44) Figure S4 provides a complete list of possible isomers of this
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