Rapidly Activating Pd-Precatalyst for Suzuki-Miyaura and Buchwald-Hartwig Couplings of Aryl Esters

Article abstract of DOI:10.1021/acs.joc.7b02588

Esters are valuable electrophiles for cross-coupling due to their ubiquity and ease of synthesis. However, harsh conditions are traditionally required for the effective cross-coupling of ester substrates. Utilizing a recently discovered precatalyst, Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig reactions involving cleavage of the C(acyl)-O bond of aryl esters that proceed under mild conditions are reported. The Pd(II) precatalyst is highly active because it is reduced to the Pd(0) active species more rapidly than previous precatalysts.

Full text of DOI:10.1021/acs.joc.7b02588

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Note
A Rapidly Activating Pd-Precatalyst for Suzuki-
Miyaura and Buchwald-Hartwig Couplings of Aryl Esters
Amira H Dardir, Patrick R Melvin, Ryan M. Davis, Nilay Hazari, and Megan Mohadjer Beromi
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Dec 2017
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A Rapidly Activating Pd-Precatalyst for Suzuki-Miyaura and
Buchwald-Hartwig Couplings of Aryl Esters
Amira H. Dardir,‡ Patrick R. Melvin,‡ Ryan. M. Davis, Nilay Hazari,* and Megan Mohadjer Beromi
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[a]The Department of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut, 06520, USA
ABSTRACT: Esters are valuable electrophiles for cross-coupling due to their ubiquity and ease of synthesis. However, harsh
conditions are traditionally required for the effective cross-coupling of ester substrates. Utilizing a recently discovered precatalyst,
Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig reactions involving cleavage of the C(acyl)–O bond of aryl esters that
proceed under mild conditions are reported. The Pd(II) precatalyst is highly active because it is reduced to the Pd(0) active species
more rapidly than previous precatalysts.
Pd-catalyzed cross-coupling is one of the most powerful
synthetic methods and is widely utilized in the synthesis of
both pharmaceuticals and agrochemicals.1 Aryl halides or
pseudo halides are typically utilized as the electrophile in
cross-coupling reactions, and many catalysts that operate
under mild conditions have been developed for these
substrates.1 Nevertheless, to increase the applicability of the
method there is interest in extending cross-coupling reactions
to a broader range of electrophiles. For example Suzuki-
Miyaura reactions involving triflates,2 sulfonates,3 thioesters,4
sulfonyl chlorides,5 perfluorinated arenes,6 diazonium and
trimethylammonium salts,7 aryl methyl ethers,8 amides,9 and
nitroarenes10 have all been reported.. In particular, in the last
decade it has been demonstrated that aryl esters can be used as
the electrophile in cross-coupling reactions.11 Unactivated aryl
Figure 1. Summary of previous work on cross-coupling reactions of aryl
esters and comparison to this work.
esters are valuable substrates because they can readily be
synthesized from phenols12 or carboxylic acids,13 are bench
organometallic nucleophiles to Weinreb amides.21 Similarly,
stable, and are common intermediates in organic synthesis.
Buchwald-Hartwig reactions between aryl esters and amines
However, the use of aryl esters as electrophiles can lead to
selectivity problems as either the C(aryl)–O bond14 or
to generate amides, especially those that involve non-
C(acyl)–O bond15,16,17 can potentially be cleaved (Figure 1).18
nucleophilic amines, provide advantages over conventional
routes to these biologically relevant molecules.22 In seminal
Additionally, cleavage of the C(acyl)–O bond followed by
decarbonylation provides another alternative pathway.19
work in 2017, Newman and co-workers reported the first
Suzuki-Miyaura reactions of aryl esters.16a Using 3 mol % of
Catalysts that are selective for all three possible reactions have
(3-cinnamyl)Pd(IPr)(Cl) (IPr
=
1,3-bis(2,6-diisopropyl-
now been developed, but in general the conditions required for
aryl ester cross-coupling are harsh.20 For example, elevated
temperatures (80-130 °C), high catalyst loadings (3-15 mol %),
and a significant excess of nucleophile and base are typically
required. This limits the practicality of these reactions.
phenyl)-1,3-dihydro-2H-imidazol-2-ylidene) as the precatalyst,
they were able to couple a range of aryl esters at 90 °C.
Subsequently, the same group extended their work to
Buchwald-Hartwig reactions between aryl esters and aniline-
based substrates.16b In this case,
3 mol %
of (3-
Suzuki-Miyaura reactions involving cleavage of the
C(acyl)–O bond in aryl esters represent a straightforward
method for the synthesis of ketones from stable carboxylic
acid derivatives. They offer significant advantages in terms of
chemoselectivity, functional group tolerance, and atom
economy compared to standard stoichiometric routes for the
synthesis of aryl ketones, such as the addition of
allyl)Pd(IPr)(Cl) was used as the precatalyst, along with
elevated temperatures (110 °C), and extended times (16 hours).
These initial examples demonstrate a new type of selectivity
in cross-coupling reactions involving aryl esters, but milder
conditions and lower catalyst loadings would make the
reactions more synthetically accessible.
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Recently, we described new bench-stable and commercially
Page 2 of 9
available precatalysts for cross-coupling based on the (3-1-
tBu-indenyl)Pd(L)(Cl) scaffold, which is compatible with both
state-of-the-art N-heterocyclic carbene (NHC) and phosphine
ligands.23 These precatalysts are typically more active for
cross-coupling reactions than related precatalysts of the form
(3-allyl)Pd(L)(Cl) and (3-cinnamyl)Pd(L)(Cl) because they
activate to monoligated L-Pd(0) more rapidly and do not form
inactive Pd(I) dimers.23-24 Here, we demonstrate that due to
their rapid activation, precatalysts of the form (3-1-tBu-
indenyl)Pd(NHC)(Cl) catalyze Suzuki-Miyaura and Buchwald-
Hartwig reactions involving cleavage of the C(acyl)–O bond of
aryl esters under mild conditions. In fact, Suzuki-Miyaura
reactions can be performed at room temperature using just 1
mol % catalyst loading, which are conditions comparable to
reactions involving aryl halides.1a,1b,1d,1f,1g,25 We note that while
our work was in progress Szostak and co-workers reported the
use of our precatalyst to perform room temperature Suzuki-
Miyaura reactions of aryl esters, but the conditions described in
this work are milder in regard to catalyst loading, time, and
equivalents of both nucleophile and base.16d
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Scheme 1. Isolated yields of products in Suzuki-Miyaura reactions using
aryl esters. Conditions: aryl ester (0.50 mmol), boronic acid (0.75 mmol),
KOH (1.0 mmol), (3-1-tBu-indenyl)Pd(IPr)(Cl) precatalyst (0.005 mmol),
THF (2 mL), water (0.5 mL). aPerformed on 1 mmol scale in relation to
benzoate. Yields are the average of two runs.
Initially, we tested (3-1-tBu-indenyl)Pd(IPr)(Cl) as a
precatalyst for the coupling of phenyl benzoate with
phenylboronic acid under the same conditions used by
Newman et al. (3 mol % [Pd], 90 °C, THF) for (3-
cinnamyl)Pd(IPr)(Cl)16a and observed excellent activity (see
Supporting Information, SI). Subsequently, we optimized the
acids, including 2-heteroaryl compounds, which readily
undergo protodeborylation,27 also afforded product in good
yield (1h-1j).
(3-1-tBu-
We also varied the aryl ester substrate in coupling reactions
with 4-methoxyphenylboronic acid (Scheme 1, 1k-1n). When
the aryl ring of the acyl group contained moderately electron-
deficient or electron-neutral substituents good yields were
obtained. However, GC analysis indicated that a lower yield
was obtained when an electron-rich aryl ester substrate such as
phenyl 4-methoxybenzoate was utilized and no attempts were
made to isolate the product from this reaction. Similarly, no
product was observed when the highly electron deficient
substrate phenyl 4-nitrobenzoate was utilized and a low yield
when methyl phenyl terephthalate was used (1m). A reduced
yield was also observed with phenyl 2-naphthoate (1n) but we
were able to isolate the product from this reaction in 50% yield.
By GC the mixed alkyl aryl ketone 4'-methoxyacetophenone
was formed in high yield using phenyl acetate as the starting
ester, but attempts to isolate this product were unsuccessful.
Our results demonstrate that (3-1-tBu-indenyl)Pd(IPr)(Cl)
is a much more active precatalyst for Suzuki-Miyaura reactions
of aryl esters compared to (3-cinnamyl)Pd(IPr)(Cl).
Furthermore, our conditions require a significantly lower
number of equivalents of boronic acid (1.5 equiv vs 4.5 equiv)
and base (2.0 equiv vs 7.2 equiv), lower catalyst loading (1
mol % vs 3 mol %), and shorter reaction time (6 hours versus
15 hours) compared to those very recently reported by Szostak
and co-workers using our precatalyst.16d We propose that our
use of water as a co-solvent greatly assists the reaction by
solubilizing the base and boronic acid and increasing the rate of
precatalyst activation (vide infra). Our results show that if the
conditions
for
ester
coupling
using
indenyl)Pd(IPr)(Cl) as the precatalyst by varying the catalyst
loading, solvent, base, and equivalents of boronic acid (see SI).
Using a 1 mol % loading of (3-1-tBu-indenyl)Pd(IPr)(Cl), a
4:1 mixture of THF/H2O as the solvent, and 2 equivalents of
KOH as the base, we were able to quantitatively couple phenyl
benzoate and phenylboronic acid to benzophenone at room
temperature in 6 hours. Other bases, such as K2CO3 or K3PO4,
were also compatible with the reaction, but required longer
reaction times (see SI). We also evaluated other ancillary
ligands on precatalysts of the form (3-1-tBu-indenyl)Pd(L)(Cl).
Although the best results were obtained with IPr, some other
NHC ligands, such as SIPr, also resulted in conversion to
product (see SI). In contrast, no product was observed with
phosphine ligands (see SI).
Using our optimized conditions, we expanded the substrate
scope to other boronic acids (Scheme 1). We were able to
couple a variety of arylboronic acids with phenyl benzoate in
good to excellent yield at room temperature (1a-1g). The
isolated yield of benzophenone (1a) was lower than expected
based on the quantitative GC yield (see SI), presumably due to
loss of product during work-up.26 The coupling reaction
involving the formation of 1d was performed on a 1 mmol
scale, indicating that the reaction can be executed on a
synthetically useful scale. The reaction was tolerant of
sterically more demanding arylboronic acids with substituents
in the 2-position of the aryl ring (1e, 1f). Although a substrate
with an electron-donating substituent on the arylboronic acid
was coupled in high yield (1b), a lower yield was observed
when an electron-withdrawing group was present on the
arylboronic acid (1g). Additionally, a very low yield of product
was observed by GC when 4-nitrophenylboronic acid was used
as a substrate with phenyl benzoate, and no attempt was made
to isolate the product from this reaction. Heteroarylboronic
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conditions and precatalyst are optimized, aryl esters can be
1
coupled under conditions comparable to those normally used
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for aryl halides.
It has been proposed that elevated temperatures are
required for cross-coupling reactions involving aryl esters
because the oxidative addition of the C(acyl)–O bond to the
metal is challenging.20 Given that the active species in our
system, monoligated IPr-Pd(0), is likely the same as in the
Newman system,16a our results provide strong evidence that the
elementary steps in the catalytic cycle are unlikely to have been
the reason for the harsh conditions. Instead, precatalyst
activation to form the active Pd(0) species may have been the
problem. To probe the rate of precatalyst activation, we
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compared
the
rate
of
reduction
of
(3-1-tBu-
indenyl)Pd(IPr)(Cl) and (3-cinnamyl)Pd(IPr)(Cl) to Pd(0)
with KOH (the base in catalysis) in a 4:1 THF/H2O mixture
(our optimized solvent mixture). Using the chelating olefin 1,3-
divinyl-1,1,3,3-tetramethyldisiloxane (dvds) as a trap for Pd(0),
all of the (3-1-tBu-indenyl)Pd(IPr)(Cl) was reduced to Pd(0)
in just 2 hours (eq 1). In contrast, for (3-cinnamyl)Pd(IPr)(Cl)
only 35% conversion to Pd(0) was achieved after 2 hours, with
the rest of the Pd still in the form of the starting precatalyst.
This is consistent with our hypothesis that (3-1-tBu-
indenyl)Pd(IPr)(Cl) is a more efficient precatalyst because it
activates rapidly. Additionally, slower activation of (3-1-tBu-
indenyl)Pd(IPr)(Cl) was observed when THF was used as the
sole solvent, supporting our hypothesis that the use of water as
Scheme 2. Isolated yields of products in Buchwald-Hartwig reactions using
aryl esters and 4-methoxyaniline. Conditions: aryl ester (0.50 mmol), 4-
methoxyaniline (0.60 mmol), Cs2CO3 (0.75 mmol), (3-1-tBu-
indenyl)Pd(SIPr)(Cl) precatalyst (0.005 mmol), water (2 mL), THF (0.5 mL).
aPerformed on 1 mmol scale in relation to aryl ester. Yields are the
average of two runs.
precatalyst we were able to couple phenyl benzoate and aniline
in essentially quantitative yield at 40 °C, in 4 hours, using a 4:1
H2O/THF solvent mixture (Table 1). A number of different
bases, including Cs2CO3, K3PO4, K2CO3, and Na2CO3, could be
used with no significant change in activity. The reaction was
extremely sensitive to the ancillary ligand, and under our
optimized conditions no activity was observed when SIPr was
replaced with other common NHC or phosphine ligands.
Additionally, under our standard conditions (1 mol %
precatalyst, 40 °C, 4:1 H2O/THF, 2 equiv Cs2CO3), no activity
was seen using precatalysts of the type (3-allyl)Pd(L)(Cl) (L =
IPr or SIPr), which have previously been used for this reaction
with more forcing conditions.16b Control experiments indicated
that, in an analogous fashion to the Suzuki-Miyaura reaction,
this was due to slow activation under our optimized conditions,
whereas (3-1-tBu-indenyl)Pd(SIPr)(Cl) activated rapidly (see
SI).
The substrate scope for the coupling of 4-methoxyaniline
with a variety of phenyl esters was examined (Scheme 2).
Phenyl benzoates containing both electron rich and electron
poor substituents on the aryl ring of the acyl group were
successfully coupled (2a-2e). In some cases slight
modifications to our optimized conditions were required to
achieve isolated yields of approximately 90%, but there were
no clear trends based on the electronic properties of the acyl
group. Nevertheless, we did not observe any product when 4-
nitrobenzophenone or methyl phenyl terephthalate, both of
which contain electron withdrawing groups, were used as
substrates. Phenyl 2-methylbenzoate (2f), which contains an
ortho-substituent on the aryl ring of the acyl group, and phenyl
2-naphthoate (2g) were also coupled in high yield. However,
presumably due to the increased steric congestion, no product
was observed when phenyl 2,6-dimethylbenzoate was used as a
substrate. The reaction was tolerant to oxygen containing
heterocycles on the ester as phenyl furan-2-carboxylate (2h)
was successfully coupled. In contrast, no reaction was observed
using phenyl picolinate, likely due to coordination of the
nitrogen atom of the pyridine ring to the catalyst. The reaction
a
co-solvent increases the rate of activation (see SI).
Previously, we have described how protic solvents can play a
large role in the activation of precatalysts of the type (3-1-tBu-
indenyl)Pd(L)(Cl), and our observations here are in agreement
with those results.24
Given
the
exceptional
activity
of
(3-1-tBu-
indenyl)Pd(IPr)(Cl) for Suzuki-Miyaura reactions involving
aryl esters, we explored systems based on the (3-1-tBu-
indenyl)Pd(L)(Cl) framework for Buchwald-Hartwig couplings.
Using 1 mol % (3-1-tBu-indenyl)Pd(SIPr)(Cl) (SIPr = 1,3-
bis(2,6-diisopropyl-phenyl)imidazolidin-2-ylidene) as the
Table 1. Yields for screening of Pd-catalyzed Buchwald-Hartwig reactions
of phenyl benzoate.
entry
1
deviation from optimized conditions
None
yield (%)a
> 99
0
(3-allyl)Pd(SIPr)(Cl) instead of (3-1-tBu-
indenyl)Pd(SIPr)(Cl)
2
3
(3-allyl)Pd(IPr)(Cl) instead of (3-1-tBu-
indenyl)Pd(SIPr)(Cl)
0
> 99
> 99
> 99
0
4
5
K3PO4 instead of Cs2CO3
K2CO3 instead of Cs2CO3
Na2CO3 instead of Cs2CO3
IPr instead of SIPr
6
7
0
8
SIMes instead of SIPr
IPr*OMe instead of SIPr
XPhos instead of SIPr
P(o-tol)3 instead of SIPr
PtBu3 instead of SIPr
0
9
0
10
11
12
0
0
Conditions: phenyl benzoate (0.20 mmol), aniline (0.24 mmol), Cs2CO3
(0.3 mmol), (3-1-tBu-indenyl)Pd(L)(Cl) (0.002 mmol), solvent (1 mL).
aYields are the average of two runs and were determined by GC
conversion. SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-
ylidene.
IPr*OMe
=
1,3-bis(2,6-bis(diphenylmethyl)-4-
methoxyphenyl)imidazol-2-ylidene. XPhos
2’,4’,6’-triisopropylbiphenyl.
=
2-dicyclohexylphosphino-
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which may be a more common problem than is currently
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1
realized.
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EXPERIMENTAL SECTION
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General. Experiments were performed under a dinitrogen
atmosphere in an M-Braun dry box or using standard Schlenk
techniques unless otherwise stated. Under standard glovebox
conditions purging was not performed between uses of diethyl
ether, pentane, benzene, toluene and THF; thus when any of
these solvents were used, traces of all these solvents were in
the atmosphere and could be found intermixed in the solvent
bottles. Moisture- and air-sensitive liquids were transferred by
stainless steel cannula on a Schlenk line or in a dry box. NMR
spectra were recorded on Agilent-400, -500 and -600
spectrometers at ambient probe temperatures unless noted.
Chemical shifts are reported with respect to residual internal
protio solvent for 1H and 13C NMR spectra. Gas
chromatography (GC) analyses were performed on a Shimadzu
GC-2010 Plus apparatus equipped with a flame ionization
detector and a Shimadzu SHRXI-5MS column (30 m, 250 m
inner diameter, film: 0.25 m). The following conditions were
utilized for GC analyses: flow rate 1.23 mL/min constant flow,
column temperature 50 °C (held for 5 min), 20 °C/min increase
to 300 °C (held for 5 min), total time 22.5 min. THF was dried
by passage through a column of activated alumina followed by
storage under dinitrogen. H2O was degassed by sparging with
dinitrogen for 1 hour and stored under dinitrogen. All
commercial chemicals were used as received except where
noted. Ethyl acetate and hexanes (Fisher Scientific) were used
as received. SIPr, IPr*OMe, IMes, and SIMes were purchased
from Strem Chemicals. SIPr was stored in a -35 °C fridge in
dinitrogen-filled glovebox. IPr was either synthesized
according to a literature procedure,28 or purchased from Strem
Chemicals. XPhos, RuPhos, and PtBu3 were purchased from
Sigma-Aldrich and stored in a dinitrogen-filled glovebox; P(o-
tolyl)3 was purchased from Strem Chemicals and stored in a
dinitrogen-filled glovebox. Esters were all prepared from acyl
chlorides or carboxylic acids using literature procedures.16a
Palladium precatalysts were synthesized by methods previously
reported.23,29
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Scheme 3. Isolated yields of products in Buchwald-Hartwig reactions using
phenyl benzoate and different substituted anilines. Conditions: aryl ester
(0.50 mmol), substituted aniline (0.60 mmol), Cs2CO3 (0.75 mmol), (3-1-
tBu-indenyl)Pd(SIPr)(Cl) precatalyst (0.005 mmol), water (2 mL), THF (0.5
mL). Yields are the average of two runs. a2.5 equiv of amine and 3 equiv of
Cs2CO3 were utilized.
is also compatible with phenyl esters containing alkyl acyl
groups. Phenyl isobutyrate (2i) and phenyl pivalate (2j) were
coupled with yields of 67 and 80%, respectively. It is
noteworthy that all of the esters used in in this work are
relatively unactivated, and as shown by Newman, will not form
amides under basic conditions without a catalyst.16b
We also explored the substrate scope for the coupling of
phenyl benzoate with different substituted aniline nucleophiles
(Scheme 3). The reaction was tolerant to anilines with electron
donating and electron withdrawing substituents (3a-3h).
However, lower yields or more forcing conditions were
required with substrates with more electron withdrawing
substituents such as 4-trifluoromethylaniline (3f) and methyl 4-
aminobenzoate (3g). The steric properties of the aniline
affected the reaction, and significantly reduced yields were
observed with 2,6-dimethylaniline (3d). Both 1- and 2-
naphthylamine (3j, 3j) were coupled in high yield, but the
reaction was not very tolerant to anilines with heteroatoms. For
example, 2-aminopyridine (3k) was coupled, but more forcing
conditions were required, and the yield was lowered
significantly. Additionally, no product was observed when 4-
aminopyridine was used as the nucleophile. Overall, our
conditions represent a substantial improvement over those
previously described in the literature in terms of catalyst
loading (1 mol % vs 3 mol %), temperature (40 °C vs 110 °C),
and time (4 hours vs 16 hours). These results indicate that
Buchwald-Hartwig reactions of aryl esters can be performed at
temperatures only slightly above room temperature, which
presents the opportunity to increase the synthetic applications
of this reaction.
In conclusion, we have demonstrated that, because our (1-
tBu-indenyl)Pd(L)(Cl) precatalysts activate rapidly, they can be
used for Suzuki-Miyaura and Buchwald-Hartwig couplings
involving aryl ester substrates without the need for forcing
conditions. Our conditions are the mildest reported to date for
these synthetically relevant reactions and indicate that the
barriers for the elementary steps in catalysis do not require
elevated temperatures.20 In fact, cross-coupling reactions
involving aryl ester electrophiles may actually be as facile as
those involving aryl halides. In future work we will attempt to
use our fast activating systems to improve other reactions
where precatalyst activation is the limiting factor in catalysis,
Substrate Scope for Pd-Catalyzed Suzuki-Miyaura
Reactions (Scheme 1). The following general procedure was
used to determine the substrate scope unless otherwise stated:
Electrophile (0.5 mmol), boronic acid (0.75 mmol), KOH
(1.0 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005
mmol) were added to a 4 dram vial equipped with a magnetic
stir bar. THF (2 mL) and H2O (0.5 mL) were added in a
glovebox. The vial was stirred at rt for 6 h. At this time, the
vial was opened to air and the crude mixture was concentrated
under vacuum, dissolved in toluene (1 mL), and 3M KOHaq (3
mL) was added and stirred for 1 h at rt. The organic layer was
extracted with ethyl acetate (3 x 5 mL), washed with brine,
dried (MgSO4), and concentrated. Purification was performed
using silica column chromatography.
Benzophenone (1a). Following the general procedure above,
a
mixture of phenyl benzoate (99.1 mg, 0.5 mmol),
phenylboronic acid (91.4 mg, 0.75 mmol), KOH (56.1 mg, 1.00
mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005
mmol) in THF (2.0 mL) and H2O (0.5 mL) were stirred at rt for
6
h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 1%
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The Journal of Organic Chemistry
EtOAc/99% hexanes. The average of two runs provided a yield
(3.5 mg, 0.005 mmol) in THF (2.0 mL) and H2O (0.5 mL) were
stirred at rt for 6 h. The crude mixture was concentrated under
vacuum, dissolved in toluene (1 mL) and 3 mL of 3M KOHaq
was added to the reaction mixture and stirred for 1 hour at rt.
The residue was concentrated under reduced pressure,
dissolved in 1:1 THF/KOHaq (0.1M) and stirred at 60 °C for 1
hour. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 5%
EtOAc/95% hexanes. The average of two runs provided a yield
1
of 51% (46.5 mg). H and 13C NMR data were consistent with
1
2
3
4
5
6
7
8
that published in the literature.16a
4-methoxyphenyl(phenyl)methanone (1b). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), 4-methoxyphenylboronic acid (114.0 mg, 0.75
mmol), KOH (56.1 mg, 1.00 mmol), and (3-1-tBu-
indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005 mmol) in THF (2.0 mL)
and H2O (0.5 mL) were stirred at rt for 6 h. No column
purification was needed. The average of two runs provided a
1
of 67% (83.8 mg). H and 13C NMR data were consistent with
9
1
yield of 86% (91.2 mg). H and 13C NMR data were consistent
that published in the literature.16a
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with that published in the literature.30
Furan-2-yl(phenyl)methanone (1h). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), furan-2-ylboronic acid (83.9 mg, 0.75 mmol), KOH
(56.1 mg, 1.00 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5
mg, 0.005 mmol) in THF (2.0 mL) and H2O (0.5 mL) were
stirred at rt for 6 h. At this time, the vial was opened to air and
the organic layer was extracted with ethyl acetate (3 x 5 mL),
washed with brine, dried (MgSO4), and concentrated. The
crude mixture was dissolved in 1 mL of CH2Cl2, and 2 mL of
KOHaq (3M) was added and stirred for 1 hour at rt. The organic
layer was extracted with CH2Cl2 (3 x 5 mL), washed with brine,
dried (MgSO4), and concentrated. No further purification was
needed. The average of two runs provided a yield of 83% (71
mg). 1H and 13C NMR data were consistent with that published
in the literature.33
Furan-3-yl(phenyl)methanone (1j). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), furan-3-ylboronic acid (83.9 mg, 0.75 mmol), KOH
(56.1 mg, 1.00 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5
mg, 0.005 mmol) in THF (2.0 mL) and H2O (0.5 mL) were
stirred at rt for 6 h. Purification was performed using silica
column chromatography by using a gradient of 100% hexanes
to 5% EtOAc/95% hexanes. The average of two runs provided
a yield of 74% (63.7 mg). 1H and 13C NMR data were
consistent with that published in the literature.16a
Naphthalen-1-yl(phenyl)methanone (1c). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), naphthalen-1-ylboronic acid (129.0 mg, 0.75
mmol), KOH (56.1 mg, 1.00 mmol), and (3-1-tBu-
indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005 mmol) in THF (2.0 mL)
and H2O (0.5 mL) were stirred at rt for 6 h. At this time, 0.1 M
KOHaq (2 mL) was added and the mixture was stirred at 60 °C
for 2 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 1%
EtOAc/99% hexanes. The average of two runs provided a yield
of 91% (105.7 mg). 1H and 13C NMR data were consistent with
that published in the literature.31
Naphthalen-2-yl(phenyl)methanone (1d). Following the
general procedure above, a mixture of phenyl benzoate (198.2
mg, 1.00 mmol), naphthalen-2-ylboronic acid (258.0 mg, 1.50
mmol), KOH (112.2 mg, 2.00 mmol), and (3-1-tBu-
indenyl)Pd(IPr)(Cl) (7.0 mg, 0.01 mmol) in THF (4.0 mL) and
H2O (1.0 mL) were stirred at rt for 6 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 1% EtOAc/99% hexanes. The
1
average of two runs provided a yield of 65% (152.0 mg). H
and 13C NMR data were consistent with that published in the
literature.32
(2-methoxyphenyl)(phenyl)methanone (1e). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), 2-methoxyphenylboronic acid (114.0 mg, 0.75
mmol), KOH (56.1 mg, 1.00 mmol), and (3-1-tBu-
indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005 mmol) in THF (2.0 mL)
and H2O (0.5 mL) were stirred at rt for 6 h. At this time, 0.1 M
KOHaq (2 mL) was added and the mixture was stirred at 60 °C
for 2 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 1%
EtOAc/99% hexanes. The average of two runs provided a yield
Phenyl(thiophen-2-yl)methanone (1j). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), thiophen-2-ylboronic acid (96.0 mg, 0.75
mmol), KOH (56.1 mg, 1.00 mmol), and (3-1-tBu-
indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005 mmol) in THF (2.0 mL)
and H2O (0.5 mL) were stirred at 50 °C for 6 h. At this time,
the vial was opened to air and the organic layer was extracted
with ethyl acetate (3 x 5 mL), washed with brine, dried
(MgSO4), and concentrated. The crude mixture was dissolved
in 1 mL of CH2Cl2, and 2 mL of KOHaq (3M) was added and
stirred for 1 hour at rt. The organic layer was extracted with
CH2Cl2 (3 x 5 mL), washed with brine, dried (MgSO4), and
concentrated. No further purification was needed. The average
1
of 88% (93.4 mg). H and 13C NMR data were consistent with
that published in the literature.16a
Phenyl(o-tolyl)methanone (1f). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), o-tolylboronic acid (102.0 mg, 0.75 mmol), KOH (56.1
mg, 1.00 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5 mg,
0.005 mmol) in THF (2.0 mL) and H2O (0.5 mL) were stirred
at rt for 6 h. No column purification was needed. The average
1
of two runs provided a yield of 81% (76.0 mg). H and 13C
NMR data were consistent with that published in the
literature.34
(4-methoxyphenyl)(p-tolyl)methanone (1k). Following the
1
of two runs provided a yield of 86% (84.4 mg). H and 13C
general procedure above,
methyl)benzoate (106.1
a
mg,
mixture of phenyl(4-
0.5 mmol), (4-
NMR data were consistent with that published in the
literature.16a
methoxyphenyl)boronic acid (114.0 mg, 0.75 mmol), KOH
(56.1 mg, 1.00 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5
mg, 0.005 mmol) in THF (2.0 mL) and H2O (0.5 mL) were
stirred at rt for 6 h. Purification was performed using silica
column chromatography by using a gradient of 100% hexanes
to 10% EtOAc/99% hexanes. The average of two runs provided
Phenyl(4-(trifluoromethyl)phenyl)methanone
Following the general procedure above, a mixture of phenyl
benzoate (99.1 mg, 0.5 mmol), (4-
(1g).
(trifluoromethyl)phenyl)boronic acid (142.4 mg, 0.75 mmol),
KOH (56.1 mg, 1.00 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl)
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a yield of 64% (72.1 mg). 1H and 13C NMR data were
Phenyl benzoate (39.6 mg, 0.2 mmol), aniline (22 L, 0.24
mmol), base (0.3 mmol), and (3-1-tBu-indenyl)Pd(L)(Cl)
(0.002 mmol) were added to a 1 dram vial equipped with a stir
bar. THF (0.2 mL) and H2O (0.8 mL) were added in a glovebox.
The vial was stirred at 40 °C for 4 h. At this time, the vial was
opened to air, extracted with ethyl acetate, and filtered through
a silica plug. Conversion was determined by comparison of the
GC responses of phenyl benzoate starting material and
benzanilide product.
consistent with that published in the literature.35
1
2
3
4
5
6
7
8
(4-methoxyphenyl)(4-trifluoromethylphenyl)methanone
(1l). Following the general procedure above, a mixture of
phenyl(4-trifluoromethyl)benzoate (133.1 mg, 0.5 mmol), (4-
methoxyphenyl)boronic acid (114.0 mg, 0.75 mmol), KOH
(56.1 mg, 1.00 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5
mg, 0.005 mmol) in THF (2.0 mL) and H2O (0.5 mL) were
stirred at rt for 6 h. Purification was performed using silica
column chromatography by using a gradient of 100% hexanes
to 10% EtOAc/90% hexanes. The average of two runs provided
a yield of 64% (89.3 mg). 1H and 13C NMR data were
consistent with that published in the literature.36
Substrate Scope for Pd-Catalyzed Buchwald-Hartwig
9
Reactions (Schemes
2 and 3). The following general
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procedure was used to determine the substrate scope unless
otherwise stated:
Methyl 4-(4-methoxybenzoyl)benzoate (1m). Following the
Electrophile (0.5 mmol), amine (0.6 mmol), Cs2CO3 (244.4
mg, 0.75 mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg,
0.005 mmol) were added to a 2 dram vial equipped with a
magnetic stir bar. THF (0.5 mL) and H2O (2 mL) were added
in a glovebox. The vial was stirred at 40 °C for 4 h. After this
time, the vial was opened to air and the aqueous layer was
extracted with EtOAc (5 x 4 mL) and concentrated under
vacuum. The resulting solid was dissolved in toluene (2-4 mL)
and stirred at rt with 1 M HClaq (4 mL) for 30 minutes. The
aqueous layer was extracted with EtOAc (5 x 4 mL). The
combined organic layer was washed with NaHCO3(aq) and
concentrated. Purification was performed using silica column
chromatography.
general procedure above,
a mixture of methyl phenyl
terephthalate (128.1 mg, 0.5 mmol), (4-methoxyphenyl)boronic
acid (114.0 mg, 0.75 mmol), KOH (56.1 mg, 1.00 mmol, and
(3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005 mmol) in THF
(2.0 mL) and H2O (0.5 mL) were stirred at rt for 16 h.
Purification
was
performed
using
silica
column
chromatography by using a gradient of 100% hexanes to 5%
EtOAc/95% hexanes. The average of two runs provided a yield
1
of 32% (43.9 mg). H and 13C NMR data were consistent with
that published in the literature.37
(4-methoxyphenyl)(naphthalene-2-yl)methanone
(1n).
Following the general procedure above, a mixture of phenyl(2-
naphthoate) (124.1 mg, 0.5 mmol), (4-methoxyphenyl)boronic
acid (114.0 mg, 0.75 mmol), KOH (56.1 mg, 1.00 mmol), and
(3-1-tBu-indenyl)Pd(IPr)(Cl) (3.5 mg, 0.005 mmol) in THF
(2.0 mL) and H2O (0.5 mL) were stirred at rt for 6 h.
N-(4-methoxyphenyl)benzamide (2a, 3h). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), 4-methoxyaniline (73.9 mg, 0.6 mmol),
Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 4 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 20% EtOAc/80% hexanes. The
Purification
was
performed
using
silica
column
chromatography by using a gradient of 100% hexanes to 1%
EtOAc/99% hexanes. Organic solvents were evaporated under
reduced pressure and the residue was dissolved in 1 mL of
CH2Cl2, and 2 mL of KOHaq (3M) was added and stirred for 1
hour at rt. The organic layer was extracted with CH2Cl2 (3 x 5
mL), washed with brine, dried (MgSO4), and concentrated. The
1
average of two runs provided a yield of 95% (107.6 mg). H
and 13C NMR data were consistent with that published in the
literature.39
1
average of two runs provided a yield of 50% (65 mg). H and
N-(4-methoxyphenyl)benzamide (2a, 3h) was also isolated
on a 1 mmol scale of phenyl benzoate. Following the general
procedure above, a mixture of phenyl benzoate (198.2 mg, 1.0
mmol), 4-methoxyaniline (147.8 mg, 1.2 mmol), Cs2CO3
(488.8 mg, 1.5 mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (7.0
mg, 0.01 mmol) in THF (1 mL) and H2O (4 mL) were stirred at
40 °C for 4 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 20%
EtOAc/80% hexanes. The average of two runs provided a yield
of 91% (206.0 mg). 1H and 13C NMR data were consistent with
that published in the literature.39
13C NMR data were consistent with that published in the
literature.38
bis(4-methoxyphenyl) methanone. Following the general
procedure above, a mixture of phenyl(4-methoxy)benzoate
(45.6 mg, 0.2 mmol), (4-methoxyphenyl)boronic acid (36.5 mg,
0.3 mmol), KOH (22.4 mg, 0.4 mmol), and (3-1-tBu-
indenyl)Pd(IPr)(Cl) (1.4 mg, 0.002 mmol) in THF (0.8 mL)
and H2O (0.2 mL) were stirred at rt for 6 h. Comparison of the
GC responses of phenyl(4-methoxy)benzoate starting material
and bis(4-methoxyphenyl) methanone product indicated 60%
conversion. Isolation of this product was not attempted.
1-(4-methoxyphenyl)ethan-1-one. Following the general
procedure above, a mixture of phenyl acetate (27.2 mg, 0.2
mmol), (4-methoxyphenyl)boronic acid (45.6 mg, 0.3 mmol),
K2CO3 (55.3 mg, 0.4 mmol), and (3-1-tBu-indenyl)Pd(IPr)(Cl)
(1.4 mg, 0.001 mmol) in THF (0.8 mL) and H2O (0.2 mL) were
stirred at rt for 6 h. Comparison of the GC responses of
phenyl(4-methoxy)benzoate starting material and bis(4-
methoxyphenyl) methanone product indicated > 99%
conversion. Successful isolation of this product was not
achieved.
N-(4-methoxyphenyl)-4-methoxybenzamide
(2b).
Following the general procedure above, a mixture of phenyl 4-
methoxy benzoate (114.1 mg, 0.5 mmol), 4-methoxyaniline
(73.9 mg, 0.6 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), and 3-
1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5
mL) and H2O (2 mL) were stirred at 40 °C for 8 h. Purification
was performed by filtering with minimal EtOAc and collecting
the solid. The average of two runs provided a yield of 95%
1
(122.4 mg). H and 13C NMR data were consistent with that
published in the literature.40
N-(4-methoxyphenyl)-4-methylbenzamide (2c). Following
the general procedure above, a mixture of phenyl 4-methyl
benzoate (106.1 mg, 0.5 mmol), 4-methoxyaniline (73.9 mg,
Screening Conditions for Pd-Catalyzed Buchwald-
Hartwig Reactions (Table 1).
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The Journal of Organic Chemistry
0.6 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu- 13C NMR data were consistent with that published in the
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 4 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 20% EtOAc/80% hexanes. The
literature.46
N-(4-methoxyphenyl)-isobutyramide (2i). Following the
1
2
3
4
5
6
7
8
general procedure above, a mixture of phenyl isobutyrate (82.0
mg, 0.5 mmol), 4-methoxyaniline (73.9 mg, 0.6 mmol),
Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 8 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 20% EtOAc/80% hexanes. The
1
average of two runs provided a yield of 97% (117.3 mg). H
and 13C NMR data were consistent with that published in the
literature.41
N-(4-methoxyphenyl)-4-fluorobenzamide (2d). Following
the general procedure above, a mixture of phenyl 4-fluoro
benzoate (108.1 mg, 0.5 mmol), 4-methoxyaniline (73.9 mg,
0.6 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 60 °C for 4 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 20% EtOAc/80% hexanes. The
9
1
average of two runs provided a yield of 68% (65.6 mg). H and
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13C NMR data were consistent with that published in the
literature.47
N-(4-methoxyphenyl)-tertbutyramide (2j). Following the
general procedure above, a mixture of phenyl tertbutyrate (89.1
mg, 0.5 mmol), 4-methoxyaniline (73.9 mg, 0.6 mmol),
Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 8 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 20% EtOAc/80% hexanes. The
1
average of two runs provided a yield of 89% (109.0 mg). H
and 13C NMR data were consistent with that published in the
literature.42
N-(4-methoxyphenyl)-4-trifluoromethylbenzamide
(2e).
Following the general procedure above, a mixture of phenyl 4-
trifluoromethyl benzoate (114.1 mg, 0.5 mmol), 4-
methoxyaniline (73.9 mg, 0.6 mmol), Cs2CO3 (244.4 mg, 0.75
mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005
mmol) in THF (0.5 mL) and H2O (2 mL) were stirred at 40 °C
for 8 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 50%
EtOAc/50% hexanes. The average of two runs provided a yield
of 91% (133.9 mg). 1H and 13C NMR data were consistent with
that published in the literature.43
1
average of two runs provided a yield of 80% (82.5 mg). H and
13C NMR data were consistent with that published in the
literature.48
N-phenylbenzamide (3a). Following the general procedure
above, a mixture of phenyl benzoate (99.1 mg, 0.5 mmol),
aniline (55.9 mg, 0.6 mmol), Cs2CO3 (244.4 mg, 0.75 mmol),
and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in
THF (0.5 mL) and H2O (2 mL) were stirred at 40 °C for 4 h.
Purification
was
performed
using
silica
column
N-(4-methoxyphenyl)-2-methylbenzamide (2f). Following
chromatography by using a gradient of 100% hexanes to 20%
EtOAc/80% hexanes. The average of two runs provided a yield
the general procedure above,
a mixture of phenyl 2-
1
methylbenzoate (106.1 mg, 0.5 mmol), 2-methylaniline (73.9
mg, 0.6 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 8 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 20% EtOAc/80% hexanes. The
of 90% (88.7 mg). H and 13C NMR data were consistent with
that published in the literature.39
N-(4-methylphenyl)benzamide (3b). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), p-toluidine (64.3 mg, 0.6 mmol), Cs2CO3 (244.4 mg,
0.75 mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg,
0.005 mmol) in THF (0.5 mL) and H2O (2 mL) were stirred at
40 °C for 4 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 50%
EtOAc/50% hexanes. The average of two runs provided a yield
1
average of two runs provided a yield of 89% (107.8 mg). H
and 13C NMR data were consistent with that published in the
literature.44
N-(4-methoxyphenyl)-2-naphthylamide (2g). Following the
general procedure above, a mixture of phenyl 2-naphthoate
(124.1 mg, 0.5 mmol), 4-methoxyaniline (73.9 mg, 0.6 mmol),
Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 60 °C for 4 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 30% EtOAc/70% hexanes. The
1
of 92% (96.8 mg). H and 13C NMR data were consistent with
that published in the literature.39
N-(2-methylphenyl)benzamide (3c). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), o-toluidine (64.3 mg, 0.6 mmol), Cs2CO3 (244.4 mg,
0.75 mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg,
0.005 mmol) in THF (0.5 mL) and H2O (2 mL) were stirred at
40 °C for 4 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 50%
EtOAc/50% hexanes. The average of two runs provided a yield
of 96% (101.2 mg). 1H and 13C NMR data were consistent with
that published in the literature.39
N-(2,6-dimethylphenyl)benzamide (3d). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), 2,6-dimethylaniline (72.7 mg, 0.6 mmol),
Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 8 h. Purification was
performed using silica column chromatography by using a
1
average of two runs provided a yield of 84% (116.2 mg). H
and 13C NMR data were consistent with that published in the
literature.45
N-(4-methoxyphenyl)-2-furylamide (2h). Following the
general procedure above, a mixture of phenyl furan 2-
carboxylate (94.1 mg, 0.5 mmol), 4-methoxyaniline (73.9 mg,
0.6 mmol), Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 4 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 30% EtOAc/70% hexanes. The
1
average of two runs provided a yield of 87% (94.6 mg). H and
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gradient of 100% hexanes to 30% EtOAc/70% hexanes. The
of 82% (101.4 mg). 1H and 13C NMR data were consistent with
1
that published in the literature.52
1
2
3
4
5
6
7
8
average of two runs provided a yield of 56% (63.5 mg). H and
13C NMR data were consistent with that published in the
N-(2-pyridyl)benzamide (3k). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), 2-pyridylamine (56.5 mg, 0.6 mmol), Cs2CO3 (244.4
mg, 0.75 mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg,
0.005 mmol) in THF (0.5 mL) and H2O (2 mL) were stirred at
60 °C for 8 h. The resulting solid was not stirred with HClaq.
literature.49
N-(p-fluorophenyl)benzamide (3e). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), 4-fluoroaniline (66.7 mg, 0.6 mmol), Cs2CO3 (244.4
mg, 0.75 mmol), and (3-1-tBu-indenyl)Pd(SIPr)(Cl) (3.5 mg,
0.005 mmol) in THF (0.5 mL) and H2O (2 mL) were stirred at
40 °C for 4 h. Purification was performed using silica column
chromatography by using a gradient of 100% hexanes to 50%
EtOAc/50% hexanes. The average of two runs provided a yield
of 95% (102.1 mg). 1H and 13C NMR data were consistent with
that published in the literature.39
Purification
was
performed
using
silica
column
chromatography by using a gradient of 100% hexanes to 30%
EtOAc/ 70% hexanes. The average of two runs provided a
9
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26
27
28
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45
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54
55
56
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60
1
yield of 32% (31.6 mg). H and 13C NMR data were consistent
with that published in the literature.53
N-(p-trifluoromethylphenyl)benzamide (3f). Following the
general procedure above, a mixture of phenyl benzoate (99.1
mg, 0.5 mmol), 4-trifluoromethylaniline (96.7 mg, 0.6 mmol),
Cs2CO3 (244.4 mg, 0.75 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 60 °C for 8 h. After this time,
the vial was opened to air and the aqueous layer was extracted
with EtOAc (5 x 4 mL) and concentrated under vacuum. The
resulting solid was dissolved in toluene (2 mL) and stirred at rt
with 1 N HClaq (4 mL) for 2 h. The aqueous layer was
extracted with EtOAc (5 x 4 mL). The combined organic layer
was washed with NaHCO3(aq) and concentrated. Purification
was performed using silica column chromatography by using a
gradient of 100% hexanes to 50% EtOAc/50% hexanes. The
ASSOCIATED CONTENT
Supporting Information
Supporting Information containing additional details of
screening and activation experiments, and NMR spectra is
available free of charge at the ACS Publications website at
http://pubs.acs.org.
AUTHOR INFORMATION
‡These authors made equal contribution to this work.
Corresponding Author
*Email: nilay.hazari@yale.edu
Notes
The authors declare no competing financial interests.
1
average of two runs provided a yield of 70% (92.2 mg). H and
ACKNOWLEDGMENT
13C NMR data were consistent with that published in the
literature.50
Research reported in this publication was supported by the
NIHGMS under Award Number R01GM120162. RMD, PRM
and MM thank the NSF for support as Graduate Research
Fellows.
Methyl 4-benzamidobenzoate (3g). Following the general
procedure above, a mixture of phenyl benzoate (99.1 mg, 0.5
mmol), methyl 4-aminobenzoate (189.5 mg, 1.25 mmol),
Cs2CO3 (488.7 mg, 1.5 mmol), and (3-1-tBu-
indenyl)Pd(SIPr)(Cl) (3.5 mg, 0.005 mmol) in THF (0.5 mL)
and H2O (2 mL) were stirred at 40 °C for 16 h. Purification was
performed using silica column chromatography by using a
gradient of 100% hexanes to 30% EtOAc/70% hexanes. The
References
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average of two runs provided a yield of 93% (119.0 mg). H
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