Stereospecific cross-coupling of secondary organotrifluoroborates: Potassium 1-(benzyloxy)alkyltrifluoroborates

Article abstract of DOI:10.1021/ja307861n

Potassium 1-(alkoxy/acyloxy)alkyltrifluoroborates have been synthesized through a copper-catalyzed diboration of aldehydes and subsequent conversion of the resulting potassium 1-(hydroxy)alkyltrifluoroborates. The palladium-catalyzed Suzuki-Miyaura reaction employing the potassium 1-(benzyloxy)alkyltrifluoroborates with aryl and heteroaryl chlorides provides access to protected secondary alcohols in high yields. The β-hydride elimination pathway is avoided through use of the benzyl protecting group, which is proposed to stabilize the diorganopalladium intermediate by coordination of the arene to the metal center. This cross-coupling is stereospecific with complete retention of stereochemistry.

Full text of DOI:10.1021/ja307861n

Article
pubs.acs.org/JACS
Stereospecific Cross-Coupling of Secondary Organotrifluoroborates:
Potassium 1‑(Benzyloxy)alkyltrifluoroborates
Gary A. Molander* and Steven R. Wisniewski
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: Potassium 1-(alkoxy/acyloxy)alkyltrifluoro-
borates have been synthesized through a copper-catalyzed
diboration of aldehydes and subsequent conversion of the
resulting potassium 1-(hydroxy)alkyltrifluoroborates. The
palladium-catalyzed Suzuki−Miyaura reaction employing the
potassium 1-(benzyloxy)alkyltrifluoroborates with aryl and
heteroaryl chlorides provides access to protected secondary alcohols in high yields. The β-hydride elimination pathway is
avoided through use of the benzyl protecting group, which is proposed to stabilize the diorganopalladium intermediate by
coordination of the arene to the metal center. This cross-coupling is stereospecific with complete retention of stereochemistry.
with reliably high asymmetric induction (>97% ee) across a
broad class of substructures. Thus, the levels of enantiomeric
excess can be highly variable within a subset of molecules, as
transformations relying on conversion of planar, prochiral
systems to tetrahedral configurations are often highly substrate
dependent and substrate variable, even within groups of
reactants that are structurally quite similar.
In terms of C−C bond-forming routes to benzylic alcohols,
the high nucleophilicity of Grignards and organolithiums
prevents the preparation of highly functionalized reagents,
and enantioselective additions to aldehyde substrates with
consistently high ee’s are virtually unknown.4
INTRODUCTION
■
Secondary benzylic alcohols represent an important class of
organic compounds whose inherent reactivity makes them both
important synthetic intermediates and components in bio-
logically active molecules. The vast majority of routes to such
systems rely upon conversion of the sp2 prochiral center of a
carbonyl to the sp3 stereocenter containing the hydroxyl
functional group, the main disconnections for which are
summarized in Scheme 1. Thus, the addition of an aryl or
Scheme 1. Disconnections To Access Secondary Alcohols
The asymmetric addition of diorganozinc species to
aldehydes, in contrast, is an efficient method to generate
enantioenriched secondary alcohols, as several systems allow
access to the desired products in high yield and with a range of
ee’s up to 99%. However, there remains a challenge of
obtaining high enantioselectivity in the addition of organozincs
to alkyl aldehydes, which often requires the use of a Lewis acid
in addition to the catalyst. The addition of external Lewis acids
is also common when employing less reactive dialkylzinc
species, such as dimethylzinc. Additionally, these methods
suffer from the need to generate the active organozinc species
in situ, and excess organozinc reagents are often required.
Furthermore, the synthesis of many organozinc species often
requires the use of pyrophoric diethylzinc and/or trialkylbor-
anes.4
alkyl organometallic reagent to the requisite aldehyde
comprises one general protocol to access alcohols via
carbon−carbon bond formation (route a).1 Another method
for the generation of the product involves reduction of a ketone
(route b),2 which can be carried out by a variety of methods3
(e.g., transition metal-catalyzed hydrogenation,3a transfer
hydrogenation,3b hydrosilylation,3b catalytic hydroboration,3b
reduction with metal hydrides or boranes,2 or enzymatic
methods3c).
The vast majority of these methods provide excellent product
yields, and of course each of these protocols possesses
individualized sets of advantages and limitations. Perhaps
most importantly, however, these approaches can be limited in
terms of their access to enantioenriched secondary alcohols
Triarylboranes5 and triarylalanes6 have been also employed
in enantioselective additions to both alkyl and aryl aldehydes
with reasonable success. However, these reagents are not
readily available, they deliver only a single aryl group, and they
are pyrophoric, greatly diminishing their appeal. The more
Received: August 7, 2012
Published: October 1, 2012
© 2012 American Chemical Society
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readily available and easily handled arylboronic acids have been
employed in Ru(II)-catalyzed reactions with aryl aldehydes,7
but to the best of our knowledge addition to alkanals has not
been examined.
of a Lewis acid), respectively, proceeds with retention of
configuration through a conventional four-membered transition
structure, whereas prior research by our group14 and
Suginome13b demonstrated that cross-coupling of potassium
β-trifluoroboratoamides and α-(acylamino)alkylboronic esters
(the latter in the absence of Lewis acids), respectively, proceeds
with inversion of configuration. The inversion phenomenon has
been ascribed to the presence of a strongly coordinating group
to bind the boronate during the reaction.
Reported herein is the synthesis of potassium 1-(hydroxy)-
alkyltrifluoroborates and their conversion to potassium 1-
(alkoxy)alkyl- and 1-(acyloxy)alkyltrifluoroborates, the former
of which have been successfully cross-coupled stereospecifically
with diverse aryl and heteroaryl chlorides. By extending the
paradigm of employing a hemilabile ligand to avoid β-hydride
elimination, this method demonstrates the development of an
effective and straightforward route to obtain protected
secondary alcohols in enantiopure form.
The asymmetric reduction of prochiral ketones provides
another approach to enantioenriched secondary alcohols in
high yield and ee, but again this approach has its own set of
limitations. For example, the use of excess reducing agent
commonly employed provides a drawback for large-scale
reactions in terms of separation and purification.3 Additionally,
although aryl alkyl ketones are able to undergo addition with
reasonable stereochemical induction, their diaryl ketone
counterparts are more challenging. Thus, the reduction of
diaryl ketones requires electronically differentiated aryl groups
or ortho-substituted aryl rings,4 because the enantiomeric excess
of the reaction is mainly determined by the difference in steric
bulk of the two substituents.
One means to avoid these drawbacks would be to employ a
stereospecific cross-coupling between an enantiopure, config-
urationally stable 1-(alkoxy)alkyl organometallic species and an
aryl halide (route c). This strategically complementary mode of
reactivity would move the challenge of asymmetric synthesis to
a reliable early stage assembly of enantiopure reagents, and
would alleviate the vagaries associated with the late-stage
conversion of prochiral centers to stereocenters, permitting the
direct insertion of chirality into molecules with configurational
integrity and reliability.
RESULTS AND DISCUSSION
■
Seeking to develop a general method for the synthesis of
enantioenriched potassium 1-(alkoxy)alkyltrifluoroborates, our
initial efforts focused on a directed lithiation sequence, utilizing
a carbamate-directed borylation to form potassium 1-(N,N-
diisopropylcarbamoyl)-3-phenylpropyltrifluoroborate (2) (eq
1).15
To the best of our knowledge, only one such cross-coupling
based on this bond connection has been reported in the
literature.8 Thus, a Stille reaction requiring the use of
organostannanes, prepared using 4 equiv of tributyltin hydride
and 4 equiv of diethylzinc,9 has been previously reported. The
published research outlines the cross-coupling of 3-phenyl-1-
(tri-n-butylstannyl)propyl 4-(trifluoromethyl)benzoate
(TFMB) with an array of (hetero)aryl and alkenyl iodides
and bromides, with yields ranging from 52 to 86%. The
coupling of enantioenriched α-(acyloxy)-tri-n-butylstannanes,
such as 3-phenyl-1-(tri-n-butylstannyl)propyl benzoate, was
shown to proceed with complete retention of stereochemistry.
To reduce exposure to potentially toxic reagents and to use a
more atom economical protecting group that can be cleaved
under mild reaction conditions, the synthesis and cross-
coupling of potassium 1-(alkoxy)alkyltrifluoroborates was
envisioned as a general approach to secondary benzylic alcohols
via a complementary bond connection. The Suzuki−Miyaura
cross-coupling reaction has become one of the most powerful
transformations in organic synthesis for the generation of
carbon−carbon bonds.10 Organotrifluoroborates11 are often
preferred coupling reagents because of their favorable proper-
ties, which include low toxicity, air and water stability, and
functional group compatibility.
In optimizing the cross-coupling reaction, we sought to find a
system where high stereochemical fidelity could be translated
from the starting organometallic to the cross-coupled product.
In addition to the value of a new synthetic approach to optically
enriched benzylic alcohols, the development of the cross-
coupling of an enantioenriched potassium 1-(alkoxy)-
alkyltrifluoroborate would be of interest to elucidate further
the contributing factors that lead to retention or inversion of
configuration at the boron center in cross-coupling of such
systems. Prior research by Crudden12 and Suginome13a
revealed that cross-coupling of α-methylbenzylboronic esters
and α-(acylamino)alkylboronic esters (the latter in the presence
This synthetic route would allow an enantioenriched
organotrifluoroborate to be synthesized by replacing TMEDA
with (−)-sparteine.15 Although successful, the directed
lithiation route does not permit diverse organotrifluoroborates
to be synthesized because it requires a directing group and
employs very basic conditions that limit functional group
tolerance. Therefore, attention was turned to a copper-
catalyzed diboration of aldehydes.16 The original Sadighi
protocol for this transformation called for the reaction to be
run for 22 h in benzene and required an oxygen and moisture-
free atmosphere for the workup and isolation of the unstable
products. Isolated alkyl-, aryl-, and heteroaryldibora compounds
with yields up to 95% were reported. It was anticipated that this
method could be directly applied to access the desired
organotrifluoroborates, as quenching this reaction with aqueous
KHF2 would not only transform the pinacol boronate to the
corresponding trifluoroborate, but would also cleave the borate
O−B bond, converting the dibora compounds to the
corresponding potassium 1-(hydroxy)alkyltrifluoroborate, thus
allowing the workup and isolation to be performed outside a
glovebox.
The protocol for the previously reported diboration of
aldehydes17 and ketones18 did not involve the addition of
methanol. In the absence of methanol, intermediate 3c
(Scheme 2) undergoes transmetalation with a molecule of
bis(pinacolato)diboron in the rate determining step to generate
the desired dibora compound 3d and regenerate the active
catalyst 3a. Because methanol has been shown to facilitate
protolytic turnover of the catalyst in other diboration
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Scheme 2. Proposed Catalytic Cycle for Diboration of
Aldehydes with Methanol
Table 1. Preparation of Potassium 1-
(Hydroxy)alkyltrifluoroborates
reactions,19 the original Sadighi diboration was optimized by
performing the reaction in toluene with the addition of
methanol, thereby greatly accelerating the reaction, resulting in
complete conversion in only 1.5 h. The proposed catalytic cycle
(Scheme 2) starts with the active copper complex 3a, generated
by subsequent transmetalation with NaOt-Bu and B2pin2.
Coordination of the carbonyl of the aldehyde to copper results
in the formation of 3b, where the boron then undergoes
addition to the aldehyde to provide intermediate 3c.
Protonation of this complex with methanol yields the 1-
(hydroxy)alkylboronic acid pinacol ester from the aldehyde as
well as 3e. Transmetalation with another molecule of B2pin2
regenerates the active catalyst 3a, completing the catalytic cycle.
This one-pot procedure, starting from aldehydes, provided
access to the desired products (4a−4t) after subsequent
treatment of the 1-(hydroxy)alkyl pinacolboronates with KHF2
(Table 1), and both aryl and alkyl aldehydes were successfully
employed to provide the corresponding trifluoroborates in
modest to excellent yield. Unlike the corresponding dibora
compounds 3d, which oxidize back to the aldehyde starting
material upon prolonged exposure to air,16 the organo-
trifluoroborates 4 are all solids that can be stored on the
benchtop without particular precautions. Alkyl aldehydes of
various carbon chain lengths (entries 1−13, 18−20) as well as
substituted aryl (entries 14−16) or naphthyl (entry 17)
aldehydes can be used in this reaction with yields of the
desired products as high as 98%. Both sterically hindered alkyl
and aryl aldehydes (entries 4, 16) provide the desired
trifluoroborates in good yields. Terminal and internal alkenes,
as well as protected alcohols and amines, do not interfere with
the diboration, as evident by the generation of the desired
product in high yields from substrates bearing these functional
groups (entries 6, 7, 9, 19, 20). The diboration of chiral
aldehydes was examined, resulting in the diastereoselective
formation of the corresponding trifluoroborates. Garner’s
aldehyde afforded a single diastereomer (entry 20), whereas
(S)-(−)-citronellal provided a 1:1 mixture of diastereomers
(entry 19), and 2-phenylpropionaldehyde reacted with a 4:1
Reaction conditions (unless otherwise noted): 1.0 equiv of aldehyde,
1.0 equiv of B2pin2, equiv of base/Cu ratio = 2, toluene, rt, 1.5 h.
a
b
Reaction stirred overnight at rt. Isolated as a diasteromeric mixture
c
1
1
(4:1 by H NMR). Isolated as a diastereomeric mixture (1:1 by H
d
e
NMR). Isolated as a single diastereomer by 1H NMR. Reaction
performed on 1 g scale.
(entry 18). Substitution beta to the aldehyde, as in the
diboration of 3-phenylbutanal (entry 12) results in a 1:1
1
mixture of diastereomers as determined by H NMR spectros-
copy.
The next step in performing the desired cross-coupling
would be the installation of a suitable protecting group on the
alcohol of the potassium 1-(hydroxy)alkyltrifluoroborates. This
group should be readily cleavable, but should also be capable of
complexation with the intermediate diorganopalladium species
to prevent β-hydride elimination. Although many advances
1
diastereoselectivity as determined by H NMR spectroscopy
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have been made in C(sp2)−C(sp3) bond-forming reactions, the
possibility of β-hydride elimination remains an inherent
obstacle in cross-coupling of alkyl compounds.20 After
transmetalation of the nucleophilic partner, β-hydride elimi-
nation competes with the product-forming reductive elimi-
nation (Scheme 3).
carbonyl to the organopalladium as well as an electron-
withdrawing inductive effect). Therefore, initial efforts focused
on the synthesis and palladium-catalyzed coupling reactions of
such organotrifluoroborates with aryl halides. From the readily
available 1-(hydroxy)alkyltrifluoroborates, representative exam-
ples of 1-(acyloxy)alkyltrifluoroborates were synthesized (Table
2) by treatment with acyl chlorides (entries 1−3) or anhydrides
Scheme 3. Possible Pathways after Transmetalation of the
Organoboron
Table 2. Preparation of Potassium 1-
(Acyloxy)alkyltrifluoroborates
To ensure success in such an alkyl cross-coupling reaction, a
means must be found to favor reductive elimination over β-
hydride elimination. Prior research has demonstrated that one
successful paradigm for accomplishing this is to perform cross-
couplings and related reactions in the presence of electron-
donating groups21 that can serve as hemilabile ligands for the
intermediate organometallics. These hemilabile ligands can
serve several roles. First, they donate electron density to the
coordinatively unsaturated metal center, thereby minimizing
the electron deficiency on the metal and reducing agostic
interactions with neighboring hydrogens that would sub-
sequently lead to β-hydride elimination. Complexing groups
incorporated within the substrate can also enforce conforma-
tions that inhibit syn β-hydride elimination. For example, the
success of the cross-coupling of alkyl β-trifluoroboratoamides14
has been credited in part to stabilization provided by the
carbonyl,8,13 which complexes to the diorganopalladium
intermediate after transmetalation (Scheme 4). Calculations
Reaction conditions (unless otherwise noted): 1.0 equiv of
trifluoroborate, 1.5 equiv of KH, 1.5 equiv of electrophile, THF, rt,
a
overnight. Cb = CONiPr2. K2CO3 as base, 0 °C to rt, Ac2O in place
Scheme 4. Proposed Mechanism for the Coupling of Alkyl β-
Trifluoroboratoamides
of AcCl.
(entry 4). All of these trifluoroborates were isolated as
colorless, free-flowing solids, capable of being stored open to
air indefinitely without undergoing protodeboronation or other
side reactions. Thus, because of their tetracoordinate nature,
they demonstrate the same inherent stability as all other
organotrifluoroborates.
The first reaction screened was the cross-coupling of 5c with
4-chloroanisole (eq 2). Electron donation from both the
have revealed that the hydrogens on the most substituted
carbon undergo β-hydride elimination most readily.22 Upon
coordination of the stabilizing carbonyl group, the alkyl chain is
rotated in such a way that the β-hydrogens at the most
substituted carbons are no longer able to become coplanar, thus
preventing β-hydride elimination.14 Finally, electron-withdraw-
ing groups in the substrate have also been found to inhibit β-
hydride elimination. The success of the aforementioned cross-
coupling of β-trifluoroboratoamides can also be attributed to
some degree to the inductive effect of the amide substituent in
the organopalladium intermediate. The carbonyl of the amide
withdraws electron density from the hydrogens β to the
palladium, disfavoring β-hydrogen agostic interactions with the
metal, thereby further inhibiting β-hydride elimination.22
Potassium 1-(acyloxy)alkyltrifluoroborates possess a struc-
tural motif analogous to that of the β-trifluoroboratoamides.
Consequently, an inherent resistance to β-hydride elimination
was expected in these substrates owing to the same factors
found in the β-trifluoroboratoamides (i.e., complexation of the
nitrogen and oxygen of the carbamate was anticipated to
increase the electron density on the carbonyl oxygen. This
increased electron density was expected to aid in the
complexation of the carbonyl moiety to palladium after
transmetalation of the organoboron reagent, thereby preventing
β-hydride elimination. The carbamate can also be viewed as an
electron-withdrawing group on the reactant, which would also
help disfavor β-hydride elimination.
Initial screening of the coupling reaction led to a set of
conditions that appeared promising, but which led to an
interesting product. Instead of observing the desired cross-
coupled product, low yields of the oxidized ketone 6 of the
expected product were obtained. Because of the high
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temperature and amount of base required for the Suzuki−
Miyaura reaction, the protecting group was hydrolyzed, and the
corresponding alcohol was oxidized under the reaction
conditions. The mechanistic pathway to this product was
envisioned to transpire via deprotonation of the deprotected
alcohol and formation of an alkoxypalladium species, with
subsequent β-hydride elimination forming the ketone.
Oxidation of secondary alcohols in the presence of palladium
and aryl chlorides has been reported in the literature.23 The
feasibility of this oxidative process under the conditions utilized
was confirmed upon subjection of an authentic sample of the
alcohol to the initially developed reaction conditions (eq 3).
Therefore, potassium 1-(benzyloxy)-3-phenylpropyltrifluor-
oborate 7a was synthesized. Initial screening results of the
cross-coupling of 7a with 4-chloroanisole were promising,
providing evidence that this stabilization was aiding in the
prevention of β-hydride elimination during the cross-coupling
reaction. After these encouraging initial results, several
representative 1-(arylmethyleneoxy)- and 1-(heteroarylmethyl-
eneoxy)alkyltrifluoroborates were assembled (Table 3). 1-
(Arylmethyleneoxy)alkyltrifluoroborates bearing electron-with-
drawing (entries 2, 3) and electron-donating (entries 5−8)
groups were synthesized in high yields. Aryl rings with both
ortho- and meta-substituents were also employed in the
reaction, providing the desired products with yields up to
81% (entries 6, 8, 9). It is important to note that the p-
methoxybenzyl (PMB)-protected alcohol can be prepared in
90% yield (entry 7). Heteroaryl-containing trifluoroborates
were also prepared in moderate yields (entries 10, 11). Other
ether-containing alkyl trifluoroborates were synthesized by
reacting 4a with allyl bromide or iodomethane to provide the
corresponding ethers in excellent yield (entries 12, 13).
As the carbamate was deprotected under the reaction
conditions, attention was turned to the cross-coupling of the
pivalate-protected trifluoroborate 5b with 4-chloroanisole (eq
2). Prior research had shown that an alkyltrifluoroborate with a
terminal alcohol protected with a pivalate could be cross-
coupled in 10:1 toluene/H2O with Pd(OAc)2, RuPhos, and
K2CO3 as base.24 However, attempts to couple 5b with 4-
chloroanisole did not result in product formation, presumably
owing to deprotection and oxidation as observed for the
carbamate. It became clear from these results that carbonyl-
containing protecting groups could not be employed as a
stabilizing moiety because of their facile hydrolysis under the
reaction conditions.
Based on prior reports of the ability of aromatic rings to
coordinate palladium through an ipso-carbon or η2 binding
mode,25 it was believed that a benzyl group could act as a
stabilizing entity (Figure 1). The benzyloxy group is also
inductively electron withdrawing, and therefore would further
aid in disfavoring β-hydride elimination.
The Suzuki−Miyaura cross-coupling reaction of 7a with 4-
chloroanisole was subsequently optimized, aided by high-
throughput experimentation.27 Many screens were performed, a
few of which are detailed below. For each screen, the reactions
were run for 24 h at either 105 or 110 °C. The purpose of the
first screen was to investigate general conditions to determine
which type of solvent, cosolvent, ligand, and base would be best
for the reaction. Therefore, a 96-well plate was run with four
different bases, four different ligands, and six different solvents.
The results of the screen are displayed in Figure 2.
The first screen indicated that alcoholic solvents were not
ideal for this reaction, even as a cosolvent, and water as a
cosolvent provided the product in the highest yield. This screen
conveyed that cataCXium A [di-(1-adamantyl)-n-butylphos-
phine] is the ligand that worked the best, and also showed that
Cs2CO3 and K3PO4 were effective bases for this reaction. Based
on these conclusions, another screen was conducted that
focused solely on cataCXium A as the ligand and used the two
best bases from the previous screen. An array of palladium
sources was analyzed, and the ratio of the cosolvent was
changed to determine the importance of water in the
reaction.28 The results of this screen are depicted in Figure 3.
An analysis of the screen results revealed that an increased
amount of water in the reaction led to an increase of the desired
product, and therefore, subsequent screens focused on a 1:1
solvent/H2O ratio. An increase in the amount of water often
increases the rate of cross-coupling relative to protodeborona-
tion of the organotrifluoroborate.28
Through this second screen, it was determined that the
nature of the palladium precursor is very important for the
coupling. The palladium source resulting in the best conversion
and yield was the cataCXium A derivative of Buchwald’s second
generation catalyst 9 (cataCXium A-Pd-G2).29 This catalyst
benefits from a rapid reductive elimination to form carbazole
with concomitant formation of the active L1Pd(0) complex,
which is believed to be the most reactive species for cross-
coupling.30 This precatalyst was synthesized from the amino-
biphenyl palladium μ-Cl dimer 8 in 92% isolated yield (eq 5).31
After determining the optimal solvent, source of palladium,
and base, the choice of ligand was the only variable left to be
investigated. Examination of 48 different ligands with [Pd-
(allyl)Cl]2, 3 equiv of Cs2CO3, and a solvent system of 1:1
Figure 1. Proposed coordination from benzyl stabilizing group.
In fact, Fu reported a nickel-catalyzed coupling of
homobenzylic bromides, citing the high levels of enantiomeric
induction as being attributed to a secondary interaction
between the benzyl substituent and the organonickel
intermediate (eq 4).26 Although unmentioned, it seems likely
that the aromatic substituent also stabilizes the diorganometal-
lic intermediate, preventing β-hydride elimination.
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Table 3. Preparation of Potassium 1-
(Alkoxy)alkyltrifluoroborates
Figure 2. Graphical summary of Screen 1. Reaction conditions: 1.0
equiv of 7a, 1.0 equiv of 4-chloroanisole, 0.1 equiv of palladium, 110
°C, 3.0 equiv of Cs2CO3, 24 h. Pd-L = L-Pd-G2, Cat A = cataCXium
A, tamylOH = tert-amyl alcohol.
Figure 3. Graphical summary of Screen 2. Reaction conditions: 1.0
equiv of 7a, 1.0 equiv of 4-chloroanisole, 0.1 equiv of palladium, 0.2
equiv of cataCXium A, 3.0 equiv of Cs2CO3, 110 °C, 24 h.
THF/H2O was carried out. For those ligands which were also
precatalysts, [Pd(allyl)Cl]2 was not added to the reaction.
The results of this screen, as shown in Figure 4, confirmed
that the ideal ligand for the desired transformation was
cataCXium A. Although some other ligands provided product,
there were only two reactions where there was both high
conversion and enhanced product formation. These two
systems both employed cataCXium A as the ligand. The
difference between the top two hits from the screen was the
palladium source, for which the top result was from cataCXium
A-Pd-G2 9, and the second hit utilized [Pd(allyl)Cl]2 as the
source of palladium. At this point, the initial optimization of the
reaction was deemed complete. This extensive screening
process led us to the following conditions: a 1:1 cyclopentyl
Reaction conditions (unless otherwise noted): 1.0 equiv of
trifluoroborate, 1.5 equiv of KH, 1.5 equiv of electrophile, THF, 50
a
b
°C, overnight. Room temperature, overnight. MeI in place of R-Br.
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impedes the reaction. CsOH·H2O was a much better base than
Cs2CO3, and increasing the equiv of base from 3 to 5 led to a
better conversion and product formation. Although several
different ethereal solvents can be used, it is clear that when 5
equiv of CsOH·H2O is employed, the best solvent is CPME.
Based on these results, a 1:1 CPME/H2O solvent mixture,
reaction temperature of 105 °C, cataCXium A-Pd-G2 9 catalyst
system (7.5 mol %), and CsOH·H2O (5 equiv) base were
adopted as the standard conditions for the subsequent studies
and applied to representative aryl and heteroaryl chlorides.
To investigate the method fully, both electron-poor (Table 4,
entries 1−6) and electron-rich (entries 7−20) aryl chlorides
were examined. All of these aryl chlorides were successfully
cross-coupled, providing the desired benzyl-protected secon-
dary alcohols with yields of 39−95%. Both 1- and 2-
chloronaphthalene were successfully engaged in this reaction
with yields of 95% and 85%, respectively (entries 19, 20).
Electron-donating groups can be present in any position of
the aryl chloride, as evident by the couplings of o-, m-, and p-
chloroanisole as well as o-, m-, and p-chlorotoluene (entries 7−
9, 16−18). Several common functional groups were tolerated,
including carbamates (entry 13), amines (entries 14, 15), and
ketones (entry 6). Two methyl ester-substituted aryl chlorides
were successfully cross-coupled by changing the base to
Cs2CO3 to avoid hydrolysis of the ester by CsOH·H2O
(entries 4, 5).
The effects of steric hindrance were tested with mono- or di-
ortho-substituted electrophiles (entries 7, 16, 22, 23). The
standard conditions proved to be very efficient for mono-ortho-
substituted electrophiles, as both 2-chloroanisole and 2-
chlorotoluene provided the product in high yield. 2-Chloro-5-
methoxy-1,3-dimethylbenzene as well as 2-chloro-1,3-dimethyl-
benzene are known to be difficult substrates, owing to the
presence of two methyl groups in the ortho positions;35
however, both were coupled in modest yields of 57% and 39%,
respectively.
The ability to conduct the reaction with various electrophilic
partners was then analyzed (entries 9−11). 4-Bromo- and 4-
iodoanisole afforded the desired product in modest yields. 4-
Methoxyphenyl methanesulfonate did not provide any of the
desired product under the reaction conditions. Only unreacted
starting material was detected after 24 h.
Figure 4. Graphical summary of Screen 3. Only the top 10 ligands are
shown. Reaction conditions: 1.0 equiv of 7a, 1.0 equiv of 4-
chloroanisole, 0.1 equiv of palladium, 0.2 equiv of L, 3.0 equiv of
Cs2CO3, 110 °C, 24 h. Pd-L = L-Pd-G2.
methyl ether (CPME)/H2O solvent mixture, a temperature of
105 °C, cataCXium A-Pd-G2 precatalyst 9 (7.5 mol %), and
Cs2CO3 (3 equiv).
Attempts to apply these conditions to a collection of aryl
chlorides resulted in yields ranging from 53 to 75%.32 An
evaluation of the crude reactions revealed that the low and
variable yields were a result of incomplete conversion of the
starting material. To avoid increasing the temperature and/or
reaction time, optimization continued, and it was soon realized
that simply replacing the base with CsOH·H2O greatly
increased the yield of the reaction. Jutand and Hartwig have
revealed that for couplings wherein transmetalation is the rate-
determining step, hydroxide bases are most effective, as the
higher concentration of hydroxide leads to the more active
ArPd(OH)L complex, which undergoes transmetalation faster
than the corresponding ArPd(X)L complex.33,34 To demon-
strate the importance of CsOH·H2O, one last screen was
completed that probed the amount and type of base. As
CsOH·H2O is very hygroscopic, 3 and 5 equiv of base were
compared in the reaction. The palladium source, both with and
without the addition of extra ligand, was also examined.
Analysis of this screen (Figure 5) confirmed the importance
of cataCXium A-Pd-G2 precatalyst (9), which led to the highest
amount of product independent of the nature or amount of
base in the reaction. Also evident is that excess cataCXium A
The cross-coupling with 4-chloroanisole was performed on a
1 g scale by reducing the catalyst loading in half to provide the
desired product in 79% isolated yield (entry 9).
To expand the range of electrophiles, the potassium 1-
(benzyloxy)-3-phenylpropyltrifluoroborate (7a) was coupled
with a variety of heteroaryl chlorides (Table 5). The optimized
conditions proved to be efficient for these couplings, resulting
in yields of up to 88% for nine heteroaryl chlorides. A variety of
substrates was examined, including pyridine, with and without
substituents, as well as isomeric chloropyridines (entries 1−3,
9). Chloroquinolines were also efficient electrophiles for this
reaction, as the chloride could be located at the 4-, 6-, and 8-
positions. Substitution of the quinoline did not seem to impact
the reaction (entry 4−6). A sulfur-containing heterocycle can
also be coupled, albeit in a lower yield of 41% (entry 8).
To demonstrate the versatility of this method, other
potassium 1-(benzyloxy)alkyltrifluoroborates were synthesized
using the same conditions for the synthesis of 7a (Table 6).
Conversion of 1-(hydroxy)alkyltrifluoroborates yielded the
desired products after heating overnight at 50 °C. The products
Figure 5. Graphical summary of Screen 4. Reaction conditions: 1.0
equiv of 7a, 1.0 equiv of 4-chloroanisole, 0.075 equiv of palladium, 105
°C, 24 h. A = [Pd(allyl)Cl]2 with cataCXium A; B = cataCXium A-Pd-
G2; 1:0/1:1/1:2 = palladium:ligand ratio.
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Table 4. Scope of the Cross-Coupling with Aryl Chlorides
Reaction conditions (unless otherwise noted): 1.0 equiv of trifluoroborate, 1.0 equiv of electrophile, 7.5 mol % Pd, 5.0 equiv of base, 1:1 CPME/
a
b
H2O, 105 °C, 24 h. 3 equiv of Cs2CO3 as base. 3 mmol scale, 3.75 mol % Pd.
These potassium (1-benzyloxy)alkyltrifluoroborates were
Table 5. Scope of the Cross-Coupling with Heteroaryl
subsequently subjected to cross-coupling reactions under the
standard reaction conditions (Table 7). Straight chain alkyl
groups can be cross-coupled in good yield (entry 1), as well as
other substituted alkyltrifluoroborates (entries 2−4). 1-
(Benzyloxy)(phenyl)methyltrifluoroborate 12k yielded the
desired product in 52% yield with the use of Cs2CO3 as base,
while the use of CsOH·H2O resulted primarily in proto-
deboronation (entry 5). Other potassium 1-(arylmethyl-
eneoxy)alkyltrifluoroborates were also subjected to the cross-
coupling reaction. Substitution at the ortho-, meta-, and para-
positions of the aryl ring does not interfere with the cross-
coupling, resulting in the desired products with yields ranging
from 61 to 89% (entries 6−8). It is important to note that this
method can be extended to other protected alcohols, as it has
been shown that the PMB-protected organotrifluoroborate 7g
is also an efficient nucleophile for this coupling reaction (entry
8). A limitation of the current method is that branching α to
the alkoxy group (e.g., as in organotrifluoroborates 12a-12c)
cannot be tolerated in the cross-coupling.
Chlorides
For each cross-coupling reaction, regardless of the electro-
phile or nucleophile, only 1.0 equiv of the starting potassium
organotrifluoroborate was engaged. The robust yields achieved
indicate that little to no protodeboronation is occurring under
the reaction conditions. The high yields of the cross-coupled
products reveal that the β-hydride elimination pathway is
virtually nonexistent as well.
Reaction conditions: 1.0 equiv of trifluoroborate, 1.0 equiv of
electrophile, 7.5 mol % Pd, 5.0 equiv of base, 1:1 CPME/H2O, 105
°C, 24 h.
An intramolecular Suzuki−Miyaura cross-coupling was also
successful with the potassium 1-(arylmethyleneoxy)-3-phenyl-
propyltrifluoroborates. Thus, 7i underwent an intramolecular
coupling, wherein the trifluoroborate acted as the nucleophile
were isolated as colorless solids, with yields ranging from 52 to
96%.
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Table 6. Preparation of Various Potassium 1-
(Benzyloxy)alkyltrifluoroborates
Table 7. Scope of the Cross-Coupling of Various Potassium
1-(Benzyloxy)alkyltrifluoroborates
Reaction conditions: 1.0 equiv of trifluoroborate, 1.5 equiv of KH, 1.5
equiv of electrophile, THF, 50 °C, overnight.
and the aryl chloride on the same molecule served as the
electrophile, providing access to a 1,3-dihydroisobenzofuran
derivative 14 through an unusual bond connection (eq 6).
Reaction conditions (unless otherwise noted): 1.0 equiv of
trifluoroborate, 1.0 equiv of electrophile, 7.5 mol % Pd, 5.0 equiv of
a
base, 1:1 CPME/H2O, 105 °C, 24 h. Reaction with 3 equiv of
Cs2CO3.
Substrate 12f underwent a similar intramolecular cross-coupling
to yield a five-membered carbocycle 15 in 73% yield (eq 7).
This umpoled route to cycloalkanol derivatives is comple-
mentary to that of intramolecular Barbier-type routes to the
same class of molecules.
To test the importance of the benzyl group on the success of
the cross-coupling, the corresponding methyl ether, 16, was
subjected to the optimized cross-coupling conditions with 4-
chloroanisole (eq 8). Only unreacted aryl chloride and none of
the desired product 17 was observed after 24 h, demonstrating
the significant role played by the benzyl group as a hemilabile
ligand stabilizing the organopalladium intermediate.
To validate the method as a means to synthesize secondary
alcohols, the benzyl protecting group would need to be
removed selectively. Deprotection of a primary benzyl group in
the presence of a secondary benzyl group has substantial
precedence in the literature.36 Utilizing standard conditions of
10 mol % Pd/C in ethanol under an atmospheric pressure of
H2, clean removal of the primary benzyl group was observed,
yielding the secondary alcohol 18 in an unoptimized yield of
79% (eq 9).
The importance of the cross-coupling approach to secondary
benzylic alcohol synthesis stems from the complementary mode
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Table 8. Scope of the Cross-Coupling of Enantioenriched 22
with (Hetero)Aryl Chlorides
of bond connection compared to those normally employed as
well as the availability of organoboron reagents that are
configurationally stable and storable. Because a stereogenic
center is being incorporated, it was important to determine the
stereospecificity of the reaction and whether the transformation
occurred with retention or inversion of stereochemistry. To
conduct these studies, an enantiomerically enriched potassium
(S)-1-(benzyloxy)-3-phenylpropyltrifluoroborate 2237 was syn-
thesized through Matteson homologation chemistry (Scheme
5).38
Scheme 5. Synthesis of Enantioenriched Potassium (S)-1-
(Benzyloxy)-3-phenylpropyltrifluoroborate
Reaction conditions (unless otherwise noted): 1.0 equiv of
trifluoroborate, 1.0 equiv of electrophile, 7.5 mol % Pd, 5.0 equiv of
a
base, 1:1 CPME/H2O, 105 °C, 24 h. Reaction with 5 equiv of
Cs2CO3.
The starting (S,S)-DICHED phenethylboronate (19) yielded
the (R)-chloride intermediate 20 after the homologation, which
underwent inversion of configuration upon displacement by
LiOBn. The (4S,5S)-2-((S)-1-(benzyloxy)-3-phenylpropyl)-
4,5-dicyclohexyl-1,3,2-dioxaborolane (21) with an ee of greater
than 99% can subsequently be converted to its corresponding
trifluoroborate 22 by addition of KHF2 dissolved in MeOH/
H2O. The ee of 20 and 21 was determined via SFC analysis.
After synthesizing the enantioenriched trifluoroborate 22, it
was reacted under the standard reaction conditions with 4-
chloroanisole. Examination of the reaction product revealed
that the transformation proceeds with complete stereo-
specificity and retention of stereochemistry (eq 10).39
results show that there is little to no erosion of ee based on the
aryl halide, as both electron poor (entries 1−2, 5−6) and
electron rich (entries 3, 7) aryl chlorides can be subjected to
the cross-coupling with high levels of enantiomeric excess. Two
different heteroaryl chlorides (entries 4, 8) were also coupled
with little, if any, loss of enantioselectivity. These coupling
reactions are presumed to proceed with retention of stereo-
chemistry.
The retention of stereochemistry observed is consonant with
prior cross-coupling studies of isotopically labeled primary
organoborons by Soderquist and Woerpel,40 as well as the
cross-coupling of secondary benzylic systems by Crudden
(Scheme 6, I)12 but contrasts with prior research in the
Molander14 and Suginome groups13 in which inversion of
configuration was observed (Scheme 6, II and III). The
stereochemically differentiating step of the cross-coupling in
these latter studies is the transmetalation, which proceeds with
inversion of configuration via an open transition structure. Both
examples resulting in inversion of configuration take advantage
of intramolecular coordination of a carbonyl to the boron in the
transmetalation transition structure. The strong complexation
of the carbonyl to the boron species appears to facilitate a
process whereby the transmetalation proceeds through an SE2
mechanism, wherein the boron center undergoes electrophilic
attack of the L(Ar)PdY species.13a,14 Examples of SE2-type
The other enantiomer of 22 was prepared through the same
synthetic pathway, except the opposite enantiomer of the 1,2-
dicyclohexyl-1,2-ethanediol was utilized as the starting material
(Scheme 5). The two enantiomerically enriched organo-
trifluoroborates were subjected to the cross-coupling with
several aryl and heteroaryl chlorides to determine the effect of
the aryl halide on the enantiomeric excess (Table 8). The
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IV). The addition of a Lewis acid was postulated to disrupt the
intramolecular coordination between the carbonyl and
boronate species. The argument was made that with a vacant
coordination site on boron, the transmetalation transpired
through a four-membered transition structure in which the lone
pair of Y (Y = halogen or OH) of the L(Ar)PdY species
coordinated to boron. This transformation resulted in retention
of configuration for the cross-coupling, as the electrophilic
attack of the organopalladium occurred from the same side as
boron.13b In a similar manner, the cross-coupling of
enantioenriched 22 proceeds with retention of configuration
(Scheme 6, V). Because the potassium 1-(benzyloxy)-
alkyltrifluoroborates lacks a strongly coordinating group to
induce SE2 reactivity, the transmetalation proceeds through a
four-membered transition structure with retention.
Scheme 6. Stereospecificity of Various Suzuki−Miyaura
Cross-Coupling Reactions
As the reaction developed herein proceeds with near
complete stereospecificity, an efficient and facile synthesis of
enantioenriched potassium 1-(benzyloxy)alkyltrifluoroborates
should prove exceedingly useful for the ultimate synthesis of
enantiomerically enriched secondary benzylic alcohols. Inves-
tigations on the catalytic asymmetric synthesis of such materials
are currently underway. These organotrifluoroborates would
serve as metal-centered “stereocenters in a bottle”, i.e.,
enantioenriched nucleophiles that could be stored indefinitely
on the benchtop, with a known configuration, allowing the
reliable installation of a defined stereocenter independent of the
structure of the electrophilic partner.
CONCLUSIONS
■
The synthesis of potassium 1-(hydroxy)alkyltrifluoroborates
and their conversion to potassium 1-(alkoxy)alkyltrifluoro-
borates and 1-(acyloxy)alkyltrifluoroborates have been re-
ported. Potassium 1-(benzyloxy)alkyltrifluoroborates undergo
a palladium-catalyzed cross-coupling reaction with a variety of
aryl and heteroaryl chlorides in high yields, using stoichiometric
quantities of the two partners. The success of this cross-
coupling is attributed to the presence of the benzyl protecting
group, which is believed to prevent β-hydride elimination in
two ways: by coordinating to the palladium center of the
diorganopalladium intermediate after transmetalation of the
alkyl group and by an electron-withdrawing inductive effect.
The cross-coupling proceeds with complete retention of
configuration, and therefore, enantioenriched organotrifluor-
oborates can be used as the nucleophilic species with virtually
no loss of enantiomeric excess regardless of the cross-coupling
partner. A method for a direct installation of a secondary
alcohol through a Suzuki−Miyaura reaction (after deprotec-
tion) has thus been developed.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectral characterization, and 1H, 13C,
19F, and 11B NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
reactions of tetracoordinate boron “ate” complexes with soft
electrophiles such as I2 and Br2, proceeding with inversion of
configuration, have been reported previously.41 With the
approach of the arylpalladium electrophile occurring from the
opposite side of boron and reductive elimination transpiring
with retention, the result of this transformation is overall
inversion of configuration.13,14
AUTHOR INFORMATION
■
Corresponding Author
gmolandr@sas.upenn.edu
Notes
Suginome subsequently studied the effect of Lewis acid
additives in stereospecific cross-coupling reactions (Scheme 6,
The authors declare no competing financial interest.
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(12) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J.
Am. Chem. Soc. 2009, 131, 5024.
(13) For references on the cross-coupling of carbonyl-containing
organometallics, see: (a) Ohmura, T.; Awano, T.; Suginome, M. J. Am.
Chem. Soc. 2010, 132, 13191. (b) Awano, T.; Ohmura, T.; Suginome,
M. J. Am. Chem. Soc. 2011, 133, 20738.
(14) Sandrock, D. L.; Jean-Gerard, L.; Chen, C.-Y.; Dreher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108.
(15) Beckmann, E.; Desai, V.; Hoppe, D. Synlett 2004, 13, 2275.
(16) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R0I GM-081376)
and an NSF GOALI grant. Dr. Simon Berritt, Dr. Jason
Schmink, and Dr. Cornell Stanciu (University of Pennsylvania)
are acknowledged for their assistance in performing the high
throughput experiments. BASF is acknowledged for their
generous donation of bis(pinacolato)diboron. Dr. Matthew
Tudge (Merck) is acknowledged for synthesis of the amino-
biphenyl palladium μ-Cl dimer. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
(17) Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc.
2008, 130, 5586.
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