Synthesis and Suzuki-Miyaura cross-coupling of enantioenriched secondary potassium β-trifluoroboratoamides: Catalytic, asymmetric conjugate addition of bisboronic acid and tetrakis(dimethylamino)diboron to α,β- unsaturated carbonyl compounds

Article abstract of DOI:10.1002/adsc.201300640

Enantioenriched potassium β-trifluoroboratoamides have been synthesized via an asymmetric, copper-catalyzed 1,4-addition of tetrahydroxydiboron (BBA) and tetrakis(dimethylamino)-diboron to α,β-Unsaturated amides. These dibora reagents provide access to the desired organotri-fluoroborates using effective and atom economical sources of boron. The copper-catalyzed β-boration is extended to α,β- Unsaturated ketones and esters. The desired potassium organotrifluoroborates are synthesized with yields up to 92% and enantiomeric ratios up to 98:2. The enantioenriched potassium btrifluoroboratoamides are successfully cross-coupled with an array of aryl and heteroaryl chlorides in high yield with complete stereochemical fidelity as the transmetalation proceeds through an SE2 mechanism via an open transition state.

Full text of DOI:10.1002/adsc.201300640

UPDATES
DOI: 10.1002/adsc.201300640
Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched
Secondary Potassium b-Trifluoroboratoamides: Catalytic,
Asymmetric Conjugate Addition of Bisboronic Acid and
Tetrakis(dimethylamino)diboron to a,b-Unsaturated Carbonyl
Compounds
Gary A. Molander,a,* Steven R. Wisniewski,a and Mona Hosseini-Sarvaria,b
a
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of
Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA
Fax : (+1)-215-573-7165; e-mail: gmolandr@sas.upenn.edu
Current address: Department of Chemistry, Faculty of Science, Shiraz University, Shiraz 71454, Iran
b
Received: July 22, 2013; Revised: September 3, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300640.
Abstract: Enantioenriched potassium b-trifluoro-
boratoamides have been synthesized via an asym-
metric, copper-catalyzed 1,4-addition of tetrahy-
droxydiboron (BBA) and tetrakis(dimethylamino)-
diboron to a,b-unsaturated amides. These dibora re-
agents provide access to the desired organotri-
a,b-unsaturated amides with ees up to 99% after oxi-
dation of the pinacol boronate to the corresponding
alcohol.[1] Additionally, two enantioenriched potassi-
um b-trifluoroboratoamides[2] have been synthesized
by a method based on the pioneering work of Yun,[1]
utilizing a copper-catalyzed 1,4-borylation of a,b-un-
saturated amides with B2pin2 [Eq. (1)]. Although ex-
tremely effective in providing the enantioenriched
boronates, these methods suffer from the use of the
atom inefficient B2pin2 as the borylating agent.
ACHTUNGTRENNUNGfluoroACHTUNGTRENNUNGborates using effective and atom economical
sources of boron. The copper-catalyzed b-boration
is extended to a,b-unsaturated ketones and esters.
The desired potassium organotrifluoroborates are
synthesized with yields up to 92% and enantiomeric
ratios up to 98:2. The enantioenriched potassium b-
trifluoroboratoamides are successfully cross-coupled
with an array of aryl and heteroaryl chlorides in
high yield with complete stereochemical fidelity as
the transmetalation proceeds through an SE2 mech-
anism via an open transition state.
Keywords: asymmetric borylation; catalytic reac-
tion; potassium organotrifluoroborate; stereospecif-
ic Suzuki–Miyaura cross-coupling; tetrahydroxydi-
boron; tetrakis(dimethylamino)diboron
Several other transition metal complexes, such as
those based on rhodium,[3] palladium,[4] platinum,[5]
and nickel,[6] have been shown to mediate the conju-
Introduction
The synthesis of b-borylated carbonyl compounds via gate addition of bis(pinacolato)diboron across a,b-un-
metal-catalyzed conjugate addition of a dibora species saturated carbonyl compounds. Additionally Fernan-
to an a,b-unsaturated carbonyl compound represents dez[7] and Hoveyda[8] have published asymmetric,
an important transformation in organic synthesis, as it metal-free additions of B2pin2, catalyzed by chiral
provides access to a useful class of synthetic inter- phosphines or chiral N-heterocyclic carbenes, respec-
mediates. Yun reported two examples of the asym- tively. However, copper has been shown to be quite
metric addition of bis(pinacolato)diboron (B2pin2) to effective and is also the cheapest and least toxic of
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Gary A. Molander et al.
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the transition metals[9] shown to facilitate this trans-
formation.
BBA and tetrakis(dimethylamino)diboron are capa-
ble of undergoing many of the same types of transfor-
Recently, tetrahydroxydiboron[10] (bisboronic acid mations as B2pin2, including Miyaura borylation.[10a,b,11]
or BBA) and tetrakis(dimethylamino)diboron[11] have BBA can also undergo conjugate additions to a,b-un-
been demonstrated to be more sustainable and more saturated carbonyl compounds in a racemic man-
atom economical dibora species as compared to bis- ner.[10c] The goal of the current project was to employ
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
dary organometallic reagents has gained much atten-
tion over the past few years.[14] The synthesis of chiral,
non-racemic organotrifluoroborates is particularly ap-
pealing owing to their favorable properties.[15] Be-
cause of their tetracoordinate nature, trifluoroborates
are stable to both air and moisture, and thus they are
capable of being stored on the bench indefinitely
without decomposition. Trifluoroborates are less
prone to protodeboronation during cross-coupling re-
actions than their boronic acid or boronate ester
counterparts, which can require an excess of up to
1 equivalent.[16] Consequently, trifluoroborates can be
used in near stoichiometric amounts in these impor-
tant transformations.[15]
Recently, Matteson homologation chemistry was
utilized to synthesize enantioenriched potassium 1-
Figure 1. Structures and atom economy of dibora sources.
(benzyloxy)-3-phenylpropyltrifluoroborate
in
an
enantiopure form.[17] The use of this material was
demonstrated in its cross-coupling with aryl and het-
no)diboron is synthesized in a three-step sequence eroaryl chlorides, with the reactions proceeding in
starting from boron tribromide.[12] Addition of pinacol high yield with complete stereochemical fidelity. The
and HCl provides B2pin2, and reaction with aqueous synthesis of related materials in an enantioenriched
HCl affords BBA. Because B
synthetic precursor to B2pin2, the use of the latter is of a stereogenic center via a cross-coupling.
inherently wasteful because the addition of pinacol is Reported herein is the asymmetric synthesis of po-
2ACHTUGNTRENN(GNU NMe2)4 is the direct form is therefore appealing for the rapid installation
completely unnecessary. If the desired product of tassium b-trifluoroborato carbonyl compounds via
a borylation reaction is a boronic acid (or an organo- a copper-catalyzed 1,4-addition of bisboronic acid and
trifluoroborate), less than 10% of the mass of B2pin2 tetrakis(dimethylamino)diboron to a,b-unsaturated
is incorporated into the final product because of the amides, esters, and ketones. To the best of our knowl-
two equivalents of pinacol generated upon hydrolysis edge, this method represents the first asymmetric ad-
of the boronate ester. Aside from generating an exor- dition of bisboronic acid and tetrakis(dimethylamino)-
bitant amount of waste in the form of pinacol, this diboron. The potassium b-trifluoroboratoamides gen-
diol is not an easy by-product to remove from reac- erated therefrom are successfully cross-coupled ste-
tion mixtures.[13] Replacing the dibora reagent with reospecifically with aryl and heteroaryl chlorides. The
BBA (3) or tetrakis(dimethylamino)diboron (4) paradigm of employing a hemilabile ligand to avoid
allows the direct installation of a boronic acid, thus b-hydride elimination is further expanded to include
avoiding these problems. In the case of the conversion a wide array of amides, which provides an effective
to the trifluoroborate, the by-products are water or di- route to the direct installation of a stereocenter
methylamine in place of pinacol, thus greatly facilitat- through cross-coupling.
ing isolation of the final product.
Even accounting for the two equivalents of BBA
required for the optimized conjugate borylation using Results and Discussion
BBA, the latter is a much more atom economical
dibora species than B2pin2, because on this basis Seeking to develop a synthesis of enantioenriched po-
a >50% reduction in the mass of the starting material tassium b-trifluoroboratoamides utilizing BBA and/or
can be achieved (Figure 1). Both BBA and tetrakis- tetrakis(dimethylamino)diboron, we hoped to utilize
A
high throughput experimentation (HTE) to determine
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Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
the optimal reaction conditions.[18] (E)-N-(4-Methoxy- croscale reactions. The ratios of product to internal
phenyl)but-2-enamide was chosen as the model sub- standard (P/IS) and starting material to internal stan-
strate (1) as it was previously shown to undergo the dard (SM/IS) can be directly compared for microscale
copper-catalyzed conjugate addition with B2pin2 to reactions in one screen. If the same internal standard
provide the corresponding organotrifluoroborate with and HPLC conditions are used for future screens, the
an enantiomeric ratio of 93:7 [Eq. (1)].[2]
One of the benefits in utilizing HTE in the devel- tion conditions.
results can be correlated to determine the ideal reac-
opment of synthetic methods is the minimal use of ex-
Some of the results of the initial screen are dis-
pensive chiral ligands. Performing the reaction on played in Figure 2. The enantiomeric ratios were de-
a 10-mmol scale allows the use of minute amounts of termined for those reactions with high P/IS ratios by
ligand over a range of reaction conditions.
subjecting those reactions to supercritical fluid chro-
The purpose of the initial screening was to deter- matographic (SFC) analysis. The P/IS ratios were nor-
mine if there was an ideal ligand for the desired trans- malized to the highest hit for ease of comparison.
formation. Yun reported bidentate phosphine ligands Only the top twelve ligands that provided an appreci-
that coordinate to a single copper as being the most able amount of desired product are shown; see the
effective for the conjugate borylation with B2pin2. For Supporting Information for the screening results with
the asymmetric addition, chiral ligands whose back- all 50 ligands.
bones or chain lengths are similar to those effective in
the racemic borylation (dppbz or dppp) provided the
desired product in high yield. Specifically, (R,S)-Josi-
phos provided two enantioenriched products in high
yield (81%) and enantiomeric ratio (up to 99:1).[1]
Therefore, 50 different chiral ligands, based largely
on Yunꢁs platform, but also including several structur-
ally diverse ligands, were screened under various reac-
tion conditions with BBA as the borylating agent.
Several copper sources were screened in this reaction,
including CuCl, which was shown to be effective in
the racemic synthesis of potassium b-trifluoroborato-
ACHTUNGTRENNUNG
amides.[10c] As a protic solvent is required to promote
catalytic turnover as well as for esterification of BBA
and tetrakis(dimethylamino)diboron, which are con-
verted to the tetraACTHNUTRGNEUNG
(alkoxy)dibora species in situ,[10a]
several alcohol solvents were tested. The final varia-
ble screened was the source and amount of alkoxide
base. Base is required to form a [Cu]-OR complex,
which then undergoes transmetalation with the dibora
species to form the active [Cu]-B(OR)2 catalyst. In
the case of the racemic addition of BBA, excess NaO-
t-Bu served to sequester the produced B(OR)3 in the
form of NaB(OR)4.[10c]
Figure 2. Graphical summary of screen 1. Reaction condi-
tions: 1.0 equiv. of 1, 2.0 equiv. of BBA, 0.05 equiv. of CuCl,
0.05 equiv. of ligand, 0.30 equiv. of NaO-t-Bu or KOMe,
EtOH, room temperature, 24 h; L1=1,2-bis
ACHTUNGTREN[NUGN (2S,5S)-2,5-di-
A
ACHTUNGTRENNUNG
diphenylpyrrolidin-1-yl]methylene}-2,5-diphenylpyrrolidini-
um tetrafluoroborate.
Because the reaction generates an alkylboron spe-
cies, this intermediate was converted to the corre-
As shown in Figure 2, out of the 50 ligands tested
sponding alcohol via oxidation with NaBO3·4H2O to in the reaction, the three ligands providing the highest
facilitate analysis [Eq. (2)].
enantiomeric excess were ROPhos,[19] Taniaphos
The relative amounts of product and unreacted T001,[20] and (2R,5R)-1-{[(2R,5R)-2,5-diphenylpyrroli-
starting material were compared by addition of an in- din-1-yl]methylene}-2,5-diphenylpyrrolidinium tetra-
ternal standard followed by HPLC analysis of the mi- fluoroborate (L2)[21] (Figure 3). With BBA as the bor-
ylating agent, (R,S)-Josiphos, which proved successful
for the addition of B2pin2, was not effective in the
borylation of a,b-unsaturated amides, and led to a tri-
fluoroboratoamide with modest yield and enantiomer-
ic ratio.
With ROPhos as the ligand, an enantiomeric ratio
of 86:14 was obtained, whereas Taniaphos T001 pro-
vided an enantiomeric excess of >99:1. Further opti-
mization with ROPhos did not lead to an enantiomer-
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Gary A. Molander et al.
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Figure 3. Structures of Taniaphos T001, ROPhos, and L2.
Figure 4. Graphical summary of screen 2. Reaction condi-
tions: 1.0 equiv. of 1, 2.0 equiv. of BBA, 0.05 equiv. of CuCl,
0.05 equiv. of L2, 1.0 or 2.0 equiv. of base, room tempera-
ture, 24 h.
ic excess higher than that shown here, and attempts at
optimizing the conjugate addition with Taniaphos
T001 as the ligand resulted in only 50% yield of the
oxidized product 6.[22]
Figure 2 shows L2 to be the only ligand that provid-
Although it seems as if several different systems
ed both high levels of enantiomeric induction as well provide a high P/IS ratio, the base and solvent system
as a high P/IS ratio. L2 is a carbene precursor, form- only marginally affect the enantioselectivity of the re-
ing a carbene upon deprotonation, which then coordi- action.[23] SFC analysis of the top reactions yielded
nates copper. Two structurally similar ligands provid- one set of conditions that provided both high P/IS
ed low levels of enantioselectivity, and therefore L2 ratio and a high enantiomeric ratio, with the (R) alco-
was chosen for further study.
hol predominating. The conditions of CuCl as the
Optimization with this ligand was completed with copper source, NaO-t-Bu as the base, and L2 as the
the aid of HTE and required only one additional ligand in a solvent system of 1:1 THF/EtOH resulted
screen, which employed CuCl as the copper source in complete conversion of the starting material with
with L2 as the ligand in the presence of three differ- an enantiomeric ratio of 93:7. This enantiomeric ratio
ent bases (KOMe, NaO-t-Bu, LiOMe) and four differ- is the same as that reported using Yunꢁs conditions
ent solvents (EtOH, MeOH, THF/EtOH, toluene/ with bis(pinacolato)diboron as the borylation reagent
EtOH).
Based on the results outlined in Figure 4, it is evi-
[Eq. (1)].
Having conditions in which there was complete
dent that both KOMe and NaO-t-Bu are superior conversion of the starting material, final optimization
bases to LiOMe. Also apparent is that the solvent was conducted on a 0.5-mmol scale at the bench in
system of 1:1 THF/EtOH provides the highest P/IS order to synthesize the desired organotrifluoroborate
ratio, slightly greater than that of 1:1 toluene/EtOH.
product (Table 1). Despite screening with CuCl, the
Table 1. Final optimization of the asymmetric, conjugate addition of BBA.
[a]
Enantiomeric excess determined by oxidation of 2a to 6 followed by SFC analysis
of 6.
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Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
copper source was changed to the air-stable ing the active complex by adding the copper salt,
CuACHTUNGTRENNUNG(MeCN)4PF6 so that a glovebox would not be re- ligand, and base in THF before adding BBA and the
quired to set up these reactions. It is important to amide in EtOH provided the same yield and enantio-
note that changing the copper source did not have an meric ratio of product as when the complex was not
effect on the yield or enantiomeric excess. Varying preformed. Additionally, CuACHTNUGRTNEUNG(MeCN)4PF6 was deter-
the concentration of the reaction also had little effect mined to be necessary, as the reaction conducted in
on the yield or the enantiomeric excess of this reac- the absence of the copper salt did not result in prod-
tion (entries 1–3). Decreasing the equivalents of BBA uct formation.
in the reaction resulted in modestly lower yields of
The optimized conditions were applied to an array
the desired trifluoroborate (entries 4 and 5). Lowering of a,b-unsaturated amides, providing the desired
the temperature to 08C did not improve the enantio- enantioenriched b-trifluoroboratoamides in high
selectivity of the reaction and provided the desired yields and enantiomeric ratios (Table 2). Enantiomer-
product in lower yield (entry 6). Therefore, the opti- ic ratios were determined by oxidation and SFC anal-
mized conditions were established as CuACTHNUGTRNEG(UN MeCN)4PF6 ysis of the corresponding alcohol. Installation of
as the copper source (5 mol%), L2 as the ligand a phenyl group on the terminal olefin resulted in a de-
(5 mol%), NaO-t-Bu as the base (1 equiv.) in a solvent crease in the enantiomeric excess in most cases (en-
system of THF/EtOH (1:1). These conditions provid- tries 13 and 14); however, changing the group to
ed the desired product in 90% yield with an enantio- a longer carbon chain provided high levels of enantio-
meric ratio of 93:7 (R:S). The enantiomeric excess of meric excess (entries 2 and 6). Secondary and tertiary
these reactions was determined by oxidation of 2a to amides subjected to the reaction conditions afforded
6, followed by SFC analysis.
the desired products. An N-cyclopropylamide provid-
As the carbene-catalyzed, asymmetric conjugate ad- ed the desired trifluoroborate with a yield of 51%
dition of B2pin2 to a,b-unsaturated carbonyl com- and an enantiomeric ratio of 93:7 (entry 5). Hetero-
pounds is known,[8] it was important to confirm that
ACHTUNGTRENaNGNU toms, as appearing in the heterocyclic amide derived
the current borylation was copper-catalyzed. Preform- from morpholine, do not interfere with the catalysis,
Table 2. Scope of the catalytic, asymmetric borylation of a,b-unsaturated amides with BBA.
[a]
Enantiomeric excess was determined by oxidation of 2 followed by SFC analysis of the corresponding alcohol.
[b]
Reaction performed on a 5.5-mmol scale with 2.5 mol% Cu
ACHTUNGRTEN(NUNG MeCN)4PF6, 2.5 mol% L2.
[c]
Reaction performed on a 3-mmol scale.
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Gary A. Molander et al.
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as the corresponding trifluoroborate can be synthe- oped for BBA. The desired b-trifluoroboratoamide
sized in a yield of 84% (entry 8). Unsymmetrical terti- was synthesized in 19% yield. However, simply
ary amides can also be subjected to the borylation, changing the co-solvent from EtOH to MeOH result-
obtaining the desired product in 71% yield (entry 10). ed in an increased yield of 91% with an enantiomeric
The borylation was scaled to 5.5 mmol, with the cata- ratio of 93:7. A similar solvent trend has been ob-
lyst loading cut in half to 2.5 mol%. The desired prod- served in the Miyaura borylation with BBA and tetra-
uct was isolated in 85% yield with an enantiomeric kis(dimethylamino)diboron, where improved yields
ratio of 93:7 (entry 1). Lowering the equivalents of were obtained with MeOH as the solvent.[10a,b,11]
BBA on a 3-mmol scale resulted in a decreased yield Using these conditions, the yield obtained with BBA
of the b-trifluoroboratoamide (entry 4).
The reaction conditions were extended to the b-bo- using B CTHUNGTRENNUNG
as the borylating agent is practically the same as that
2A(NMe2)4, whereas the enantiomeric ratio ob-
ration of other a,b-unsaturated carbonyl compounds, tained is the same for both dibora sources. Therefore,
including esters and ketones (Table 3). Different sub- these modified conditions were applied to an array of
stitution patterns on the substrates, including cyclic a,b-unsaturated amides (Table 4). For the most part,
and acyclic partners, proved to work well in the reac- the use of tetrakis(dimethylamino)diboron led to sim-
tion, providing the corresponding enantioenriched tri- ilar or improved enantiomeric ratios but a lower yield
fluoroborates in high yield and enantiomeric ratios of the isolated product as compared to analogous re-
(as judged by oxidation and SFC analysis of the re- actions with BBA.
sulting alcohols). The presence of a phenyl ring on
the terminal carbon of the olefin led to a drop of verted to a tetra
enantiomeric excess in these reactions (entry 4). action, up to four equivalents of dimethylamine are
Because tetrakis(dimethylamino)diboron is con-
AHCTUNGTRENNUNG
Tetrakis(dimethylamino)diboron was tested as the released per equivalent of the dibora species. In an at-
borylating agent under the reaction conditions devel- tempt to determine whether an amine could be used
as an additive to improve the enantiomeric ratio of
some borylations, one equivalent of dimethylamine or
N-methylaniline was added to the reaction with BBA
as the borylating agent. In the case of dimethylamine,
Table 3. Scope of the catalytic, asymmetric borylation of
a,b-unsaturated ketones and esters.
only starting amide was recovered after 24 h. Al-
though the desired product was observed when N-
methylaniline was added to the reaction with BBA,
the same enantiomeric ratio was observed as when
the amine was absent.
After synthesizing enantioenriched potassium b-tri-
fluoroboratoamides, research focused on their
Suzuki–Miyaura cross-coupling with aryl and hetero-
aryl chlorides. The Suzuki–Miyaura cross-coupling re-
action[24] has become one of the most utilized reac-
À
tions for the construction of C C bonds in organic
synthesis. The cross-coupling of potassium b-trifluoro-
boratoamides has increased importance in the synthe-
sis of enantioenriched b-arylated amides owing to the
complementarity of its implementation relative to ex-
isting methods. Thus, the main disconnections to syn-
thesize b-arylated amides are summarized in
Scheme 1.
One common method to synthesize these types of
substrates is a transition metal-catalyzed hydrogena-
tion (route a).[25] In the case of b,b-diaryl substituted
amides, an asymmetric reduction provides the desired
product with an enantiomeric excess up to 74%.[26]
Perhaps the most common method for the generation
of b-arylated amides is a transition metal-catalyzed
conjugate addition of an arylmetallic species to an
a,b-unsaturated amide (route b).[27] A rhodium-cata-
lyzed addition of arylboronic acids to lactams pro-
[a]
vides the desired b-arylated products in yields and
Enantiomeric excess was determined by oxidation of 7
followed by SFC analysis of the corresponding alcohol.
enantiomeric excess up to 99%.[27b] However, the rho-
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Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
Table 4. Scope of the catalytic, asymmetric borylation of
a,b-unsaturated amides with tetrakis(dimethylamino)dibor-
on.
Scheme 1. Disconnections to access b-arylated amides.
agents thus allows the direct installation of a stereo-
genic center into a molecule with complete stereo-
chemical integrity. Furthermore, the polarity-inverted
mode of coupling increases the diversity of products
that can be accessed owing to the tremendous availa-
bility of readily accessible and highly functionalized
aryl and heteroaryl halide partners.
The cross-coupling of potassium b-trifluoroborato-
AHCTUNGTREGUNaNN mides has been demonstrated to proceed in high
yield with complete inversion of stereochemistry.[2]
This stereochemical outcome, first demonstrated by
Suginome,[28] is surmised to occur from the presence
of a strongly coordinating carbonyl group, which can
interact with the boron center to disfavor a four-cen-
tered transmetalation pathway. We sought to extend
the scope of this type of cross-coupling by demon-
strating that diverse, enantioenriched potassium b-tri-
fluoroboratoamides, with various substitution pat-
terns, cross-couple without loss of stereochemical in-
tegrity through inversion of configuration. Further-
more, there was a desire to extend the coupling to
heteroaryl chlorides, which had not been examined
previously.
Reported conditions for the coupling of 2a with
chlorobenzene incorporated 10 mol% of PdACHTUNGTRENNUNG(OAc)2
and 20 mol% of XPhos with 3 equiv. of Cs2CO3 in
a solvent system of CPME/H2O, resulting in an 82%
yield of the desired product [Eq. (3)].[2] With the
report of Buchwaldꢁs second and third generation pre-
catalysts,[29] which rapidly form the active L1Pd(0)
species by reductively eliminating carbazole after loss
[a]
Enantiomeric excess was determined by oxidation of 2
followed by SFC analysis of the corresponding alcohol.
dium-catalyzed addition of phenylboronic acid to an
acyclic amide provided the desired product in only
40% yield with an enantiomeric ratio of 90:10.[27c] As
noted by this analysis, the most challenging aspect of
asymmetric synthesis is the late stage conversion of
a prochiral center to a stereocenter with high enantio-
meric excess and yield. Utilizing a stereospecific
cross-coupling as outlined herein moves the asymmet-
ric step to a more reliable stage through the prepara-
tion of enantioenriched starting materials (route c).
The assembly of enantioenriched nucleophilic re-
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Gary A. Molander et al.
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Table 5. Optimization of the cross-coupling of 2a with
chlorobenzene.
[a]
Starting material:product:side products.
of HX (X=Cl or OMs), an attempt was made to
lower the catalyst loading by changing the palladium
source to one of these complexes.
The general reaction conditions were applied to
a representative set of heteroaryl chlorides with po-
Optimization with the Buchwald precatalysts is out- tassium N-(4-methoxyphenyl)-3-(trifluoroborato)-but-
lined in Table 5. Side products include the sum of ma- anamide 2a as the nucleophilic partner in the cross-
terials resulting from protodeboronation of the potas- coupling reaction (Table 6).
AHCTUNGTRENNUNG
sium b-trifluoroboratoamide, homocoupling of the
When the electrophile was 3-chloropyridine, the
aryl chloride, and unidentifiable side products. The coupled product was obtained in 56% yield (entry 1).
original conditions for this cross-coupling are shown Isomeric thiophenes provide the desired products
in entry 7. Decreasing the catalyst load of Pd
resulted in incomplete consumption of the aryl halide noline was also an efficient electrophile for this reac-
(entry 6). Switching from Pd(OAc)2/XPhos to XPhos- tion, affording the desired product in 56% yield
ACHTUNGRTEN(NGNU OAc)2 with yields up to 60% (entries 2 and 3). A chloroqui-
AHCTUNGTRENNUNG
Pd-G2, the XPhos derivative of Buchwaldꢁs 2nd gener- (entry 4). An unprotected chloroindole did not result
ation precatalyst, provided a superior ratio of product in product formation; however, an N-Boc protected
to side-product at the same temperature (entry 2). chloroindole was successfully cross-coupled in 43%
Cutting the catalyst load in half to 5 mol% resulted in yield (entry 5). The cross-coupling was performed on
a similar ratio (entry 1). No advantage was gained in a 1-g scale of 2a using 3-chloropyridine as a coupling
utilizing the 3rd generation XPhos precatalyst partner with a catalyst loading of 2.5 mol%, and the
(entry 4), and lowering the temperature to 808C re- desired product was obtained in 52% yield. Most im-
sulted in incomplete conversion of the chlorobenzene portantly, however, is that all of the cross-couplings
after 24 h (entry 5).
with heteroaryl chlorides proceed with virtually com-
Therefore, based on this optimization, the palladi- plete stereochemical integrity.
um loading was decreased to 5 mol% with XPhos-Pd-
The compatibility of the cross-coupling was next ex-
G2 as the palladium source. XPhos-Pd-G2 is easily amined for diverse electrophilic partners (Table 6,
synthesized from the aminobiphenyl palladium m-Cl entry 6). When iodobenzene was employed as the
dimer in 90% yield [Eq. (4)].[30]
electrophilic partner in the reaction, none of the de-
With this new palladium source, the desired cross- sired product was obtained after 24 h. However, sev-
coupled product was obtained in 85% yield without eral other electrophiles tested provided the desired
loss of stereochemical integrity [Eq. (5)]. These re- product in moderate to high yield. Chlorobenzene
sults are comparable to those reported previously was previously shown to work efficiently [Eq. (4)].
[Eq. (3)].[2]
When changing the electrophile to bromobenzene,
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Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
Table 6. Cross-coupling of 2a with heteroaryl chlorides and diverse aryl electrophiles.
[a]
Reaction performed on a 3.33 mmol scale with 2.5 mol% XPhos-Pd-G2.
No product observed.
[b]
a lower yield of 68% was obtained. Aryl bromides 89%. The unsymmetrical amide 2j was efficient in
have been previously shown to be effective coupling this reaction, as the cross-coupled product was ob-
partners with potassium b-trifluoroboratoamides.[2] tained in 81% yield. As with the heteroaryl chlorides,
À
These coupling conditions are also efficient for C O these couplings proceed with little to no loss of enan-
activation as both phenyl mesylate and triflate provid- tioselectivity and are presumed to proceed with inver-
ed the cross-coupled product in good yield. Most im- sion of configuration based on previously established
portantly, these couplings proceed with virtually com- precedents.
plete stereochemical fidelity regardless of the type of
electrophile.
The inversion of configuration for the cross-cou-
pling reaction has been attributed to the presence of
To expand the range of nucleophiles, the general the electron-donating group on the nucleophilic spe-
reaction conditions were then applied to several dif- cies. Chiral benzylstannanes,[31] silanes,[32] and a-(acyl-
ferent enantioenriched potassium b-trifluoroborato-
ACHTUNGTRENNUNGamides with 1-chloro-4-fluorobenzene as the electro- couple with inversion of configuration. However,
amino)benzyl boronates[28] have all been shown to
ACHTUNGTRENNUNG
phile (Table 7). Secondary and tertiary amides both enantioenriched secondary benzylic pinacol boronates
provide the desired product with yields between 81– proceed through retention of configuration.[33] As re-
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Gary A. Molander et al.
UPDATES
Table 7. Cross-coupling of various potassium b-trifluorobor-
atoamides.
Scheme 2. Rationale for the sense of asymmetry observed in
the cross-coupling reaction to access b-arylated amides.
lectively binds to the Lewis acid, resulting in coupling
that proceeds with retention of configuration.[28] To
determine if ZrACTHUNTRGNE(UNG O-i-Pr)4·i-PrOH was a suitable Lewis
acid to invert the stereochemistry in the present
study, the cross-coupling of a potassium b-trifluoro-
boratoamide with chlorobenzene was performed with
ZrACTHUNTRGNE(UGN O-i-Pr)4·i-PrOH as an additive [Eq. (6)]. Unfortu-
nately, the desired cross-coupled product was not
formed under these conditions. The reaction showed
consumption of the aryl halide; however, an array of
side products formed, including some b-hydride elimi-
nation product.
Conclusions
ported by Suginome[28] and then by our group,[2] the
stereochemical-determining step in this cross-coupling The synthesis of enantioenriched b-trifluoroborato
reaction is the transmetalation, which does not occur carbonyl compounds was developed utilizing an asym-
through the traditional four-centered transition struc- metric copper-catalyzed conjugate addition of bisbor-
ture.[34] Because the carbonyl of the amide can coordi- onic acid and tetrakis(dimethylamino)diboron. The
nate to the intermediate boronate species after hy- enantioenriched b-trifluoroboratoamides were suc-
drolysis of the trifluoroborate, the transmetalation cessfully cross-coupled with 1-chloro-4-fluorobenzene
proceeds through an SE2 mechanism via an open tran- in high yield, and potassium N-(4-methoxyphenyl)-3-
sition structure to provide the product with inversion (trifluoroborato)butanamide was successfully coupled
of configuration (Scheme 2). Borate substrates that to an array of heteroaryl chlorides in good yield. The
proceed with inversion of configuration through SE2- carbonyl group on the amide contributes to the ste-
type reaction pathways have been previously revealed reochemical outcome of the coupling reaction. The
in the literature.[35]
Suginome reported that the addition of a Lewis stereochemistry, as the carbonyl group on the nucleo-
acid, such as Zr(O-i-Pr)4·i-PrOH, changes the stereo- philic species coordinates the boronate intermediate,
cross-coupling proceeds with complete inversion of
ACHTUNGTRENNUNG
chemistry of the reaction. Thus, with enantioenriched allowing the transmetalation to proceed through an
a-(acylamino)benzyl boronate esters the carbonyl se- SE2 mechanism.
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Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
8H), 0.79 (t, J=7.0 Hz, 3H), 0.62 (brs, 1H); 13C NMR
Experimental Section
(90.5 MHz, DMSO-d6): d=174.8, 154.9, 133.7, 120.8, 114.0,
55.5, 32.9, 31.8, 28.83, 22.7, 14.5; 19F NMR (338.8 MHz,
General Considerations
DMSO-d6): d=À141.73; 11B NMR (128.4 MHz, DMSO-d6):
All starting materials, reagents, and catalysts were used as
received. THF, EtOH, MeOH and CPME were distilled
from sodium/benzophenone prior to use. Both solvents and
H2O were degassed prior to use. Tetrakis(dimethylamino)di-
boron was distilled prior to use and stored under Ar. Stan-
dard benchtop techniques were employed for handling air-
sensitive reagents. Melting points (8C) are uncorrected.
19F NMR chemical shifts were referenced to external CFCl3
(0.0 ppm). 11B NMR spectra at 128.4 MHz were obtained on
a spectrometer equipped with the appropriate decoupling
accessories. All 11B NMR chemical shifts were referenced to
external BF3·OEt2 (0.0 ppm) with a negative sign indicating
an upfield shift. Determination of the absolute configura-
tions was based on our previous work.[2]
d=4.92; IR (neat): n=3290, 2953, 2920, 2851, 1650, 1523,
1409, 1247, 1080, 980, 825, 657, 636 cmÀ1; HR-MS (ESI):
m/z=308.1833, calcd. for C16H24BFNO3 [MÀ
ACHTUNGTRENNUNG(KF2)+
(CH2O)]À: 308.1833; [a]20: À3.5 (c=0.2, MeOH).
Potassium
(R)-N-pDhenyl-3-(trifluoroborato)butanamide
(2c): According to the general procedure using (E)-N-phe-
nylbut-2-enamide (0.0805 g, 0.5 mmol), the product was ob-
tained as a white crystalline solid; yield: 108 mg (80%); mp
135–1388C; 1H NMR (300 MHz, acetone-d6): d=8.99 (s,
1H), 7.76–7.64 (m, 2H), 7.24 (d, J=8.5 Hz, 2H), 6.90–7.05
(m, 1H), 2.46 (dd, J=13.8, 5.1 Hz, 1H), 2.09–2.17 (m, 1H),
0.83–0.95 (m, 4H); 13C NMR (75.4 MHz, acetone-d6): d=
174.6, 139.9, 128.2, 122.4, 119.1, 41.9, 15.43; 19F NMR
(282.4 MHz,
acetone-d6):
d=À147.18;
11B NMR
(128.4 MHz, acetone-d6): d=5.74; IR (neat): n=3290, 2949,
2876, 1639, 1599, 1513, 1441, 1308, 1244, 1059, 1010, 907,
748, 690, 656 cmÀ1; HR-MS (ESI): m/z=222.1102, calcd. for
General Procedure for the Preparation of Enantio-
enriched Potassium b-Trifluoroboratoamides with
BBA
C11H14BFNO2 [MÀ
(KF2)+(CH2O)]À: 222.1102; [a]2D0: +18.8
ACHTUNGTRENNUNG
(c=0.26, MeOH).
Potassium
(R)-N-cyclohexyl-3-(trifluoroborato)butan-
An oven-dried microwave vial with stir bar was charged
amide (2d):[2] According to the general procedure using (E)-
N-cyclohexylbut-2-enamide (0.0836 g, 0.5 mmol), the prod-
uct was obtained as a white crystalline solid; yield: 113 mg
with Cu
ACHTUNGTRENNUNG
t-Bu (0.0480 g, 0.5 mmol, 1 equiv.), (2R, 5R)-1ACHTUNGTRENNUNG
diphenylpyrrolidin-1-yl]methylene}2,5-diphenylpyrrolidini-
um tetrafluoroborate (0.0136 g, 0.025 mmol, 5 mol%),
(HO)2B-B(OH)2 (0.0896 g, 1 mmol, 2 equiv.), and amide
(0.5 mmol, 1 equiv.). The vial was sealed with a cap lined
with a disposable Teflon septum, evacuated under vacuum
and purged with argon (three times). Anhydrous THF
(0.5 mL) was added under argon followed by anhydrous
EtOH (0.5 mL), and the reaction mixture was stirred at
room temperature for 24 h. After cooling to 08C, MeOH
(1 mL) and saturated aqueous KHF2 (3 mmol, 6 equiv.) was
added dropwise. The reaction mixture was stirred at room
temperature until deemed complete by 11B NMR (about
10 min), concentrated, and placed on the high vacuum over-
night. The crude product was isolated by filtration with hot
acetone (3ꢂ10 mL), then concentrated to a minimal amount
(~2 mL), and precipitating with Et2O (20 mL).
Potassium (R)-N-(4-methoxyphenyl)-3-(trifluoroborato)-
butanamide (2a):[2] According to the general procedure
using (E)-N-(4-methoxyphenyl)but-2-enamide (0.0955 g,
0.5 mmol), the product was obtained as a white crystalline
solid; yield: 135 mg (90%); mp 168–1708C;1H NMR
(360 MHz, acetone-d6): d=8.82 (br s, 1H), 7.56 (d, J=
8.7 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 3.73 (s, 3H), 2.26–2.42
(m, 1H), 1.99–2.03 (m, 1H), 0.82 (m, 4H); 13C NMR
(125.8 MHz, acetone-d6): d=174.2, 155.2, 133.2, 120.6, 113.4,
54.6, 41.8, 15.5; 19F NMR (338.8 MHz, acetone-d6): d=
À147.17; 11B NMR (128.4 MHz, acetone-d6): d=5.25; [a]2D0:
+10.8 (c=0.34, MeOH).
1
(82%); mp 213–2158C; H NMR (300 MHz, DMSO-d6): d=
7.19 (d, J=8.0 Hz, 1H), 3.37–3.58 (m, 1H), 1.99 (dd, J=
13.7, 3.8 Hz, 1H), 1.47–1.72 (m, 6H), 1.16 (m, 5H), 0.43–
0.65 (m, 4H); 13C NMR (75.4 MHz, DMSO-d6): d=174.5,
47.3, 40.7, 33.0, 25.6, 25.0, 15.9; 19F NMR (282.4 MHz,
DMSO-d6): d=À128.4; 11B NMR (128.4 MHz, DMSO-d6):
d=5.25; [a]2D0: À8.0 (c=0.1, MeOH).
Potassium
(R)-N-cyclopropyl-3-(trifluoroborato)butan-
amide (2e):[10c] According to the general procedure using
(E)-N-cyclopropylbut-2-enamide (0.0.625 g, 0.5 mmol), the
product was obtained as a white crystalline solid; yield:
1
60 mg (51%); mp 165–1678C; H NMR (500 MHz, DMSO-
d6): d=7.42 (d, J=5.0 Hz, 1H), 2.53–2.56 (m, 1H), 1.95–
2.07 (m, 1H), 1.53–1.66 (m, 1H), 0.55–0.65 (m, 4H), 0.50–
0.56 (m, 2H), 0.33 (s, 2H); 13C NMR (125.8 MHz, DMSO-
d6): d=176.9, 22.4, 16.0, 6.1, 5.9; 19F NMR (470.8 MHz,
DMSO-d6): d=À144.97; 11B NMR (128.4 MHz, DMSO-d6):
d=5.76; [a]2D0: +19.0 (c=0.2, MeOH).
Potassium
(R)-N-cyclohexyl-3-(trifluoroborato)pentan-
amide (2f):[10c] According to the general procedure using
(E)-N-cyclohexylpent-3-enamide (0.0906 g, 0.5 mmol), the
product was obtained as a white crystalline solid; yield:
1
124 mg (86%); mp 237–2398C; H NMR (300 MHz, DMSO-
d6): d=7.13 (d, J=7.9 Hz, 1H), 3.47 (m, 1H), 1.96 (dd, J=
14.1, 4.6 Hz, 1H), 1.46–1.74 (m, 6H), 0.97–1.28 (m, 7H),
0.75 (t, J=7.4 Hz, 3H), 0.45 (br s, 1H); 13C NMR
(75.4 MHz, DMSO-d6): d=174.8, 47.3, 33.1, 32.9, 25.8, 25.1,
24.0, 14.3; 19F NMR (338.8 MHz, DMSO-d6): d=À141.10;
11B NMR (128.4 MHz, DMSO-d6): d=4.94; [a]2D0: À14.6 (c=
0.13, MeOH).
Potassium (R)-N-(4-methoxyphenyl)-3-(trifluoroborato)-
methyloctanamide (2b): According to the general procedure
using (E)-N-(4-methoxyphenyl)oct-2-enamide (0.1235 g,
0.5 mmol), the product was obtained as a white crystalline
solid; yield: 146 mg (82%); mp 224–2268C; 1H NMR
(360 MHz, DMSO-d6): d=9.31 (s, 1H), 7.47 (d, J=8.6 Hz,
2H), 6.80 (d, J=8.5 Hz, 2H), 3.68 (s, 3H), 2.19 (dd, J=14.0,
4.8 Hz, 1H), 1.90 (dd, J=14.0, 9.8 Hz, 1H), 1.00–1.31 (m,
Potassium
1-(piperidin-1-yl)-3-(trifluoroborato)butan-1-
one (2g):[2] According to the general procedure for the race-
mic preparation using (E)-1-(piperidin-1-yl)but-2-en-1-one
(0.0765 g, 0.5 mmol), the product was obtained as a light
yellow amorphous solid; yield: 107 mg (82%); 1H NMR
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Gary A. Molander et al.
UPDATES
(500 MHz, acetone-d6): d=3.33–3.58 (m, 4H), 2.22–2.29 (m,
1H), 2.24–210 (m, 1H), 1.43–1.63 (m, 6H), 0.76–0.79 (m,
3H), 0.71 (br s, 1H); 13C NMR (125.8 MHz, acetone-d6): d=
173.7, 46.5, 41.7, 38.4, 26.3, 25.4, 24.4, 16.2; 19F NMR
Potassium
(R)-N,N-dibenzyl-3-(trifluoroborato)butan-
amide (2l):[2] According to the general procedure for the
racemic preparation using (E)-N,N-dibenzylbut-2-enamide
(0.1865 g, 0.5 mmol), the product was obtained as a white
crystalline solid; yield: 149 mg (80%); mp 236–2388C;
1H NMR (360 MHz, DMSO-d6): d=7.09–7. 44 (m, 10H),
4.67 (d, J=15.2 Hz, 2H), 4.59 (d, J=17.1 Hz, 2H), 4.31 (d,
J=17.0 Hz, 1H), 4.18 (d, J=15.1 Hz, 1H), 2.40 (dd, J=13.9,
3.1 Hz, 1H), 1.80 (dd, J=13.9, 11.1 Hz, 1H), 0.72 (d, J=
6.9 Hz, 3H), 0.59 (br s, 1H); 13C NMR (90.5 MHz, DMSO-
d6): d=176.1, 138.2, 129.0, 128.7, 127.8, 127.5, 127.2, 126.8,
126.4, 50.1, 47.5, 37.6, 16.5; 19F NMR (338.8 MHz, acetone-
d6): d=À148.19; 11B NMR (128.4 MHz, acetone-d6): d=
5.46; [a]2D0: À7.0 (c=0.1, MeOH).
(470.8 MHz,
acetone-d6):
d=À147.68;
11B NMR
(128.4 MHz, acetone-d6): d=5.46; [a]2D0: À13.0 (c=0.1,
MeOH).
Potassium (R)-1-morpholino-3-(trifluoroborato)butan-1-
one (2h):[10c] According to the general procedure for the rac-
emic preparation using (E)-1-morpholinobut-2-en-1-one
(0.0775 g, 0.5 mmol), the product was obtained as a white
crystalline solid; yield: 111 mg (84%); mp 175–1778C;
1H NMR (500 MHz, DMSO-d6): d=3.46–4.00 (m, 4H),
3.27–3.46 (m, 4H), 2.29 (d, J=13.7 Hz, 1H), 1.66–1.86 (m,
1H), 0.66 (d, J=6.9 Hz, 3H), 0.45 (brs, 1H); 13C NMR
(125.8 MHz, DMSO-d6): d=174.2, 66.6, 46.3, 41.5, 37.3,
16.3; 19F NMR (470.8 MHz, DMSO-d6): d=À145.78;
11B NMR (128.4 MHz, acetone-d6): d=4.25; [a]2D0: +2.9 (c=
0.34, MeOH).
Potassium (S)-N-cyclohexyl-3-phenyl-3-(trifluoroborato)-
propanamide (2m):[10c] According to the general procedure
for the racemic preparation using N-cyclohexylcinnamide
(0.1145 g, 0.5 mmol), the product was obtained as a white
crystalline solid; yield: 130 mg (77%); mp 168–1708C;
1H NMR (500 MHz, DMSO-d6): d=7.10–7.00 (m, 4H), 6.96
(d, J=8.2 Hz, 1H), 6.87 (t, J=6.9 Hz, 1H), 3.28–3.36 (m,
1H), 2.27–2.36 (m, 2H), 1.99–2.02 (m, 1H), 1.41–1.62 (m,
4H), 1.31–1.41 (m, 1H), 0.85–1.18 (m, 5H); 13C NMR
(125.8 MHz, DMSO-d6): d=173.5, 149.4, 128.5, 126.9, 122.7,
47.1, 39.3, 38.7, 32.7, 25.6, 24.8, 24.8; 19F NMR (470.8 MHz,
DMSO): d=À142.19; 11B NMR (128.4 MHz, DMSO-d6):
d=5.22; [a]2D0: +5.0 (c=0.2, MeOH).
Potassium (S)-3-phenyl-1-(pyrrolidin-1-yl)-3-(trifluorobor-
ato)propan-1-one (2n):[2] According to the general proce-
dure for the racemic preparation using (E)-3-phenyl-1-(pyr-
rolidin-1-yl)prop-2-en-1-one (0.1545 g, 0.5 mmol), the prod-
uct was obtained as a white amorphous solid; yield: 131 mg
(85%); 1H NMR (500 MHz, acetone-d6): d=7.20 (d, J=
7.0 Hz, 2H), 7.08 (t, J=6.7 Hz, 2H), 6.93 (t, J=8.1 Hz, 1H),
3.39 (s, 1H), 3.23–3.34 (m, 3H), 2.63 (dd, J=13.2, 7.2 Hz,
1H), 2.45 (dd, J=14.0, 7.5 Hz, 1H), 2.21 (s, 1H), 1.70–1.82
(m, 4H); 13C NMR (125.8 MHz, acetone-d6): d=173.3,
149.6, 128.3, 126.9, 122.9, 46.1, 45.0, 38.2, 25.7, 23.9;
19F NMR (470.8 MHz, acetone-d6): d=À144.31; 11B NMR
(128.4 MHz, acetone-d6): d=5.14; [a]2D0: +37.1 (c=0.1,
MeOH).
Potassium (S)-N-(4-methoxyphenyl)-3-phenyl-3-(trifluoro-
borato)propanamide (2i): According to the general proce-
dure using N-(4-methoxyphenyl)cinnamide (0.1265 g,
0.5 mmol), the product was obtained as a white crystalline
solid; yield: 166 mg (92%); mp 176–1798C; 1H NMR
(300 MHz, acetone-d6): d=8.66 (s, 1H), 7.45 (d, J=8.6 Hz,
2H), 7.26 (d, J=7.6 Hz, 2H), 7.10 (t, J=7.5 Hz, 2H), 6.89–
6.98 (m, 1H), 6.77 (d, J=8.5 Hz, 2H), 3.73 (s, 3H), 2.61–
2.84 (m, 2H), 2.36–2.39 (m, 1H); 13C NMR (75.4 MHz, ace-
tone-d6): d=173.2, 155.3, 148.9, 133.0, 128.1, 127.0, 122.9,
120.6, 113.3, 54.6, 40.2; 19F NMR (282.4 MHz, DMSO-d6):
d=À144.72; 11B NMR (128.4 MHz, DMSO-d6): d=5.46; IR
(neat): n=3367, 3342, 1658, 1641, 1515, 1241, 980, 824, 703,
659, 640 cmÀ1; HR-MS (ESI): m/z=322.1223, calcd. for
C16H16BF3NO2 [M]À: 322.1222; [a]2D0: +21.0 (c=0.2, MeOH).
Potassium N-ethyl-N-(o-tolyl)-3-(trifluoroborato)butan-
amide (2j):[2] According to the general procedure for the
racemic preparation using (E)-N-ethyl-N-(o-tolyl)but-2-en-
amide (0.1015 g, 0.5 mmol), the product was obtained as
a white crystalline solid; yield: 110 mg (71%); mp 228–
1
2308C; H NMR (300 MHz, asterisk denotes minor rotamer
peaks, DMSO-d6): d=7.31–7.33 (m, 1H), 7.16–7.29 (m, 2H),
7.01–7.07 (m, 1H), 3.88–3.99 (m, 1H), 3.11–3.23* (m, 1H),
2.96–3.01 (m, 1H), 2.08–2.14 (m, 3H), 1.72–1.91 (m, 1H),
1.48* (dd, J=14.6, 9.8 Hz, 1H), 1.32 (dd, J=15.7, 10.3 Hz,
1H), 0.96–1.08 (m, 3H), 0.56–0.77 (m, 4H); 13C NMR
(75.4 MHz, asterisk denotes rotamer peaks, DMSO-d6): d
174.6, 174.2*, 142.1, 141.9*, 136.1, 135.6*, 131.4, 131.3*,
129.9, 129.8*, 127.9, 127.8*, 127.1, 42.6, 42.2*, 38.4, 37.1*,
17.5, 16.5, 16.3*, 13.4, 13.2*; 19F NMR (470.8 MHz, DMSO-
d6): d=À147.65; 11B NMR (128.4 MHz, DMSO-d6): d=4.97;
[a]2D0: À8.1 (c=0.16, MeOH).
Potassium ethyl (R)-3-(trifluoroborato)butanoate (7a):[10c]
According to the general procedure using ethyl (E)-but-2-
enoate (0.0720 g, 0.5 mmol), the product was obtained as
a white crystalline solid: yield; 100 mg (91%); mp 128–
1308C; 1H NMR (500 MHz, DMSO-d6): d=4.48 (q, J=
7.1 Hz, 2H), 2.71–2.80 (m, 1H), 2.31–2.42 (m, 1H), 1.63 (t,
J=7.1 Hz, 3H), 1.17–1.32 (m, 4H); 13C NMR (125.8 MHz,
acetone-d6): d=176.2, 59.1, 38.7, 15.57, 14.1; 19F NMR
(470.8 MHz,
acetone-d6);
d=À148.24;
11B NMR
(128.4 MHz, acetone-d6): d=5.96; [a]2D0: +4.0 (c=0.25,
MeOH).
Potassium
(R)-N,N-dimethyl-3-(trifluoroborato)butan-
amide (2k):[10c] According to the general procedure for the
racemic preparation using (E)-N,N-dimethylbut-2-enamide
(0.0565 g, 0.5 mmol), the product was obtained as a yellow
Potassium ethyl (R)-3-(trifluoroborato)octanoate (7b):
According to the general procedure using ethyl (E)-oct-2-
enoate (0.0851 g, 0.5 mmol), the product was obtained as
a white crystalline solid; yield: 77 mg (55%); mp 220–
2228C; 1H NMR (500 MHz, acetone-d6): d=4.01 (q, J=
7.0 Hz, 2H), 2.23 (dd, J=13.9, 6.2 Hz, 1H), 2.00 (dd, J=
13.9, 8.9 Hz, 1H), 1.07–1.45 (m, 11H), 0.85 (t, J=7.1 Hz,
3H), 0.75 (br s, 1H); 13C NMR (125.8 MHz, acetone): d=
176.3, 58.5, 36.7, 32.6, 31.4, 22.5, 13.6, 13.5; 19F NMR
1
amorphous solid; yield: 95 mg (86%); H NMR (500 MHz,
acetone-d6): d=3.00 (s, 3H), 2.83 (s, 3H), 2.24–2.31 (m,
1H), 2.05 (s, 1H), 0.79 (m, 4H); 13C NMR (125.8 MHz, ace-
tone-d6): d=175.9, 37.6, 37.0, 34.4, 15.9; 19F NMR
(470.8 MHz,
acetone-d6):
d=À147.34;
11B NMR
(128.4 MHz, DMSO-d6): d=5.42; [a]2D0: À5.6 (c=0.34,
MeOH).
(470.8 MHz,
acetone-d6):
d=À145.99;
11B NMR
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3037 – 3057

Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
(128.4 MHz, acetone-d6): d=5.79; IR (neat): n=2949, 2924,
2851, 2356, 2332, 1717, 1467, 1445, 1368, 1249, 1217, 1126,
1073, 996, 937, 643 cmÀ1; HR-MS (ESI): m/z=251.1631,
calcd. for C11H22BF2O3 [MÀ(KF)+(MeO)]À: ; [a]D20: +5.7
(c=0.2, MeOH).
concentrated, and placed on the high vacuum overnight.
The crude product was isolated by hot filtration with ace-
tone (3ꢂ10 mL), concentrating to
(~2 mL), and precipitating with Et2O (20 mL).
Spectral data for the enantioenriched cross-coupled prod-
a minimal amount
AHCTUNGTRENNUNG
Potassium
(R)-3-trifluoroborato-1-phenylbutan-1-one
ucts is the same as the racemic products and can be seen
above in the “General Procedure for the Preparation of
Enantioenriched Potassium b-Trifluoroboratoamides with
BBA.”
(7c): According to the general procedure using (E)-1-phe-
nylbut-2-en-1-one (0.0730 g, 0.5 mmol), the product was ob-
tained as a white crystalline solid; yield: 95 mg (75%); mp
1
110–1128C; H NMR (300 MHz, acetone-d6): d=8.00 (d, J=
7.5 Hz, 2H), 7.38–7.3861 (m, 3H), 3.13 (m, 1H), 2.56 (m,
1H), 1.07–0.92 (br s, 1H), 0.83 (d, J=6.9 Hz, 3H); 13C NMR
(75.4 MHz, acetone-d6): d=203.3, 137.8, 131.9, 128.1, 128.1,
42.9, 15.2; 19F NMR (282.4 MHz, acetone-d6): d=À148.08;
11B NMR (128.4 MHz, acetone-d6): d=5.03; IR (neat): n=
2937, 2868, 1667, 1597, 1446, 1306, 1278, 1073, 1014, 924,
893, 690, 645 cmÀ1; HR-MS (ESI): m/z=251.0934, calcd. for
C10H11BF3O [MÀK]À: 251.0855; [a]2D0: +61.0 (c=0.1,
MeOH).
Determination of Absolute Configuration and
Enantiomeric Ratio of Enantioenriched Potassium
Trifluoroboratoamides
The purpose of the oxidation of the enantioenriched potassi-
um trifluoroboratoamides was to determine the enantiomer-
ic ratio of the corresponding alcohol. Therefore a small
sample of the potassium trifluoroboratoamide was oxidized
with oxone. After confirming the product by NMR, the
sample was subjected to SFC analysis.
Potassium (S)-1,3-diphenyl-3-(trifluoroborato)butan-1-one
(7d):[10c] According to the general procedure using (E)-chal-
cone (0.104 g, 0.5 mmol), the product was obtained as
a white crystalline solid; yield: 82 mg (52%); mp 147–
1508C; 1H NMR (500 MHz, acetone-d6): d=7.94 (d, J=
8.0 Hz, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.41 (t, J=7.8 Hz, 2H),
7.21 (d, J=9.5 Hz, 2H), 7.00–7.14 (m, 2H), 6.83–6.99 (m,
1H), 3.39 (d, J=7.7 Hz, 2H), 2.44–2.59 (m, 1H); 13C NMR
(125.8 MHz, acetone-d6): d=202.0, 148.5, 137.8, 131.9, 128.1,
128.1, 128.0, 127.1, 123.0, 41.3; 19F NMR (470.8 MHz, ace-
tone-d6): d À144.96; 11B NMR (128.4 MHz, acetone-d6): d=
4.57; [a]2D0: +27.3 (c=0.23, MeOH).
General Procedure for the Oxidation of Enantio-
enriched Potassium b-Trifluoroboratoamides
Method A: To a flask containing a mixture of potassium b-
trifluoroboratoamides, esters, or ketones (1 mmol, 1 equiv.)
and acetone (2.5 mL) (MeOH was added dropwise in the
case of insoluble trifluoroborates), was added Oxone
(2.5 mL of a 0.2M solution in H2O, 1 equiv.) in one portion.
The reaction mixture was stirred at room temperature until
11B NMR indicated completion of the reaction (~10 min).
To the crude reaction mixture was added H2O (2.5 mL) and
aqueous HCl (0.3M, 3 mL), and the aqueous layer was ex-
tracted with CH2Cl2 (3ꢂ15 mL). The combined organic
layers were dried (MgSO4), filtered, concentrated under
vacuum.
Potassium (R)-3-(trifluoroborato)cyclohexanone (7e):[10c]
According to the general procedure using cyclohex-2-enone
(0.0480 g, 0.5 mmol), the product was obtained as a white
crystalline solid; yield: 92 mg (90%); mp 235–2378C;
1H NMR (360 MHz, DMSO-d6): d=2.13–2.22 (m, 1H),
2.11–1.87 (m, 4H), 1.56–1.59 (m, 1H), 1.36–1.53 (m, 1H),
1.21–1.32 (m, 1H), 0.47 (br s, 1H); 13C NMR (90.5 MHz, General Procedure for the Preparation of Both (R)-
DMSO-d6): d=215.4, 45.21, 42.3, 30.2, 27.7; 19F NMR
and (S)-MTPA Ester Enantiomers
(338.8 MHz, DMSO-d6); d À145.3; 11B NMR (128.4 MHz,
acetone-d6): d=5.25; [a]2D0: +55.0 (c=0.34, MeOH).
Method B: To a solution of b-hydroxy amides or ketones
(which was prepared by method A) (0.027 mmol) in CH2Cl2
(1.8 mL) in a round-bottom flask under argon were added
Et3N (19 mL, 0.137 mmol), (R)-MTPA chloride (25.5 mL,
0.137 mmol), and DMAP (3.6 mg, 0.030 mmol). The result-
ing mixture was stirred for 16 h at room temperature and
General Procedure for the Preparation of Enantio-
enriched Potassium b-Trifluoroboratoamides with
Tetrakis(dimethylamino)diboron
then the solvent was concentrated under vacuum. Enantio-
An oven-dried microwave vial with stir bar was charged
with Cu(MeCN)4PF6 (0.0093 g, 0.025 mmol, 5 mol%), NaO-
t-Bu (0.0480 g, 0.5 mmol, 1 equiv.), and (2R, 5R)-1{[(2R,5R)-
meric ratios were determined by 19F NMR of the unpurified
material.
ACHTUNGTRENNUNG
G
3-Hydroxy-N-(4-methoxyphenyl)butanamide:[2] According
to the general procedure (Method A) using potassium
(R)-N-(4-methoxyphenyl)-3-(trifluoroborato)butanamide
(0.299 g, 1 mmol) the title compound was obtained as
a white crystalline solid; yield: 188 mg (90%); mp 134–
2,5-diphenylpyrrolidin-1-yl]methylene}2,5-diphenylpyrrolidi-
nium tetrafluoroborate (0.0136 g, 0.025 mmol, 5 mol%). The
vial was sealed with a cap lined with a disposable Teflon
septum, evacuated under vacuum and purged with argon
(three times). Anhydrous THF (0.5 mL) was added under
argon followed by tetrakis(dimethylamino)diboron (1 mmol,
2 equiv.) in anhydrous MeOH (0.5 mL). The reaction was
stirred at room temperature for 5 min before adding the
amide (0.5 mmol, 1 equiv.). The reaction mixture was stirred
at room temperature for 24 h. After cooling to 08C, MeOH
(1 mL) and saturated aqueous KHF2 (3 mmol, 6 equiv.) was
added dropwise. The reaction mixture was stirred at room
temperature until complete by 11B NMR (about 10 min),
1
1368C; H NMR (300 MHz, CDCl3): d=7.68 (s, 1H), 7.33
(d, J=8.9 Hz, 3H), 6.79 (d, J=8.9 Hz, 2H), 4.17–4.27 (m,
1H), 3.72 (s, 3H), 2.90 (s, 1H), 2.50–2.32 (m, 2H), 1.22 (d,
J=6.3 Hz, 3H); 13C NMR (90.5 MHz, CDCl3): d=170.2,
156.5, 130.5, 122.0, 114.1, 64.9, 55.4, 44.9, 29.6, 22.9. A
method was developed to separate the enantiomers using
SFC analysis (column OD-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=8.76 min and (R)-isomer reten-
tion time=9.80 min.
Adv. Synth. Catal. 2013, 355, 3037 – 3057
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3049

Gary A. Molander et al.
UPDATES
(R)-3-Hydroxy-N-(4-methoxyphenyl)butanamide
(2a-
having an absolute configuration of R: (S)-isomer retention
time=8.51 min and (R)-isomer retention time=10.11 min.
N-Cyclohexyl-3-hydroxybutanamide:[2] According to the
general procedure (Method A) using potassium N-cyclohex-
yl-3-(trifluoroborato)butanamide (0.274 g, 1 mmol) the title
compound was obtained as a white crystalline solid; mp
134–1368C; 1H NMR (300 MHz, CDCl3): d=5.74 (s, 1H),
4.16 (m, 1H), 3.95 (s, 1H), 3.78 (m, 1H), 2.16–2.40 (m, 2H),
1.84–1.99 (m, 2H), 1.54–1.80 (m, 3H), 1.04–1.48 (m, 8H);
13C NMR (75.4 MHz, CDCl3): d=171.3, 64.7, 48.0, 43.8,
32.9, 25.3, 24.6, 22.6. A method was developed to separate
the enantiomers using SFC analysis (column OD-H, 10% i-
PrOH, 2 mL, 10 MPa): (S)-isomer retention time=5.27 min
and (R)-isomer retention time=5.57 min.
OH): Following the procedure described above for oxida-
tion using the enantioselective borylated intermediate, the
title compound was obtained as a white crystalline solid
with spectra in accordance with that described above for the
racemate (0.25 mmol scale); yield: 46 mg (88%); mp 135–
1368C; [a]2D0: 31.5 (c=1.0, MeOH). A method was devel-
oped to separate the enantiomers using SFC analysis
(column OD-H, 10% i-PrOH, 2 mL, 10 MPa): the enantio-
meric ratio was measured to be 5:95, the major enantiomer
having an absolute configuration of R; (S)-isomer retention
time=8.64 min and (R)-isomer retention time=9.55 min.
3-Hydroxy-N-(4-methoxyphenyl)octanamide: According
to the general procedure (Method A) using potassium
N-(4-methoxyphenyl)-3-(trifluoroborato)methyloctanamide
(0.355 g, 1 mmol) the title compound was obtained as
(R)-N-Cyclohexyl-3-hydroxybutanamide (2d-OH):[2] Fol-
lowing the procedure described above for oxidation using
the enantioselective borylated intermediate, the title com-
pound was obtained as a white crystalline solid with spectra
in accordance with those described above for the racemate;
mp 134–1368C; [a]2D0: À17.0 (c=0.2, MeOH). Using SFC
analysis (column AS-H, 10% i-PrOH, 2 mL, 10 MPa): the
enantiomeric ratio was measured to be 5:95; the major
enantiomer having an absolute configuration of R: (S)-
isomer retention time=6.19 min and (R)-isomer retention
time=6.93 min.
1
a white solid; mp 120–1228C; H NMR (300 MHz, CDCl3):
d=7.67 (s, 1H), 7.39 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz,
2H), 4.07 (d, J=11.3 Hz, 1H), 3.79 (s, 3H), 3.19 (s, 1H),
2.37–2.60 (m, 2H), 1.70–1.17 (m, 8H), 0.90 (t, J=6.9 Hz,
3H); 13C NMR (125.8 MHz, CDCl3): d=170.3, 1566.4, 130.5,
123.4, 121.8, 114.0, 113.0, 68.6, 55.3, 43.4, 36.8, 31.6, 25.0,
22.4, 13.9; IR (neat): n=3314, 2957, 2924, 2855, 1655, 1548,
1513, 1250, 1031, 825, 665, 648 cmÀ1; HR-MS (ESI): m/z=
266.1751, calcd. for C15H24NO3 [M+H]+: 266.1756.
A
method was developed to separate the enantiomers using
SFC analysis (column OD-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=9.47 min and (R)-isomer reten-
tion time=11.55 min.
N-Cyclopropyl-3-hydroxyoctanamide: According to the
general procedure (Method A) using potassium N-(4-me-
thoxyphenyl)-3-(trifluoroborato)methyloctanamide (0.233 g,
1 mmol) the title compound was obtained as a yellow oil;
1H NMR (500 MHz, CDCl3): d=6.20 (s, 1H), 4.03–4.22 (m,
1H), 3.56 (br s, 1H), 2.64 (s, 1H), 2.12–2.29 (m, 2H), 1.15 (t,
J=5.5 Hz, 3H), 0.71 (t, J=6.6 Hz, 2H), 0.44 (t, J=6.3 Hz,
2H); 13C NMR (125.8 MHz, CDCl3): d=173.9, 64.7, 43.6,
22.7, 22.3, 8.0, 6.4; IR (neat): n=3283, 2965, 2920, 1641,
1542, 1455, 1376, 1302, 1196, 1123, 852, 664, 638 cmÀ1; HR-
MS (ESI): m/z=143.0948, calcd. for C7H13NO2 [M]+:
143.0946. A method was developed to separate the enantio-
mers using SFC analysis (column AS-H, 10% i-PrOH, 2 mL,
10 MPa): (S)-isomer retention time=6.87 min and (R)-
isomer retention time=7.81 min.
(R)-N-Cyclopropyl-3-hydroxyoctanamide (2e-OH): Fol-
lowing the procedure described above for oxidation using
the enantioselective borylated intermediate, the title com-
pound was obtained as a yellow oil with spectra in accord-
ance with those described above for the racemate; [a]2D0:
À25.0 (c=0.1, MeOH). Using SFC analysis (column AS-H,
10% i-PrOH, 2 mL, 10 MPa): the enantiomeric ratio was
measured to be 7:93; the major enantiomer having an abso-
lute configuration of R: (S)-isomer retention time=6.07 min
and (R)-isomer retention time=7.44 min.
(R)-3-Hydroxy-N-(4-methoxyphenyl)octanamide
(2b-
OH): Following the procedure described above for oxida-
tion using the enantioselective borylated intermediate, the
title compound was obtained as a white solid with spectra in
accordance with those described above for the racemate;
mp 119–1228C; [a]2D0: À20.8 (c=0.25, MeOH). Using SFC
analysis (column AS-H, 10% i-PrOH, 2 mL, 10 MPa): the
enantiomeric ratio was measured to be 3:97; the major
enantiomer having an absolute configuration of R: (S)-
isomer retention time=9.67 min and (R)-isomer retention
time=11.71 min.
3-Hydroxy-N-phenylbutanamide:[36] According to the gen-
eral procedure (Method A) using potassium (R)-N-phenyl-
3-(trifluoroborato)butanamide (0.269 g, 1 mmol) the title
compound was obtained as a white crystalline solid; mp 92–
1
948C; H NMR (500 MHz, acetone-d6): d=9.19 (s, 1H), 7.64
(d, J=8.7 Hz, 2H), 7.22–7.34 (m, 2H), 7.09–6.98 (m, 1H),
4.19–4.30 (m, 1H), 4.10 (br s, 1H), 2.39–2.53 (m, 2H), 1.19
(d, J=6.4 Hz, 3H); 13C NMR (125.8 MHz, acetone-d6): d=
170.1, 139.1, 128.48, 123.14, 119.17, 64.33, 45.70, 22.60. A
method was developed to separate the enantiomers using
SFC analysis (column OD-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=8.51 min and (R)-isomer reten-
tion time=10.49 min.
(R)-3-Hydroxy-N-phenylbutanamide (2c-OH): Following
the procedure described above for oxidation using the enan-
tioselective borylated intermediate, the title compound was
obtained as a white crystalline solid with spectra in accord-
ance with those described above for the racemate; mp 93–
958C; [a]2D0: À14.8 (c=0.25, MeOH). A method was devel-
oped to separate the enantiomers using SFC analysis
(column OD-H, 10% i-PrOH, 2 mL, 10 MPa): the enantio-
meric ratio was measured to be 8:92; the major enantiomer
N-Cyclohexyl-3-hydroxypentanamide: According to the
general procedure (Method A) using potassium N-cyclohex-
yl-3-(trifluoroborato)pentanamide (0.289 g, 1 mmol) the title
compound was obtained as a white crystalline solid; yield:
1
151 mg (76%); mp 106–1088C; H NMR (300 MHz, CDCl3):
d=5.98 (br s, 1H), 3.79–3.88 (m, 2H), 3.6174–3.74 (m, 1H),
2.05–2.32 (m, 2H), 1.78–1.86 (m, 2H), 1.70–0.96 (m, 10H),
0.86 (t, J=7.4 Hz, 3H); 13C NMR (75.4 MHz, CDCl3): d=
171.6, 69.9, 48.0, 41.8, 32.9, 29.6, 25.3, 24.6, 9.7; IR (neat):
n=3292, 2932, 2852, 1639, 1556, 1445, 1386, 1194, 1125, 984,
870, 699, 630 cmÀ1; HR-MS (ESI): m/z=200.1651, calcd. for
C11H22NO2 [M+H]À: 200.1651. A method was developed to
3050
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3037 – 3057

Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
separate the enantiomers using SFC analysis (column AS-H,
10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention time=
8.77 min and (R)-isomer retention time=10.67 min.
3-Hydroxy-N-(4-methoxyphenyl)-3-phenylpropanamide:
According to the general procedure (Method A) using po-
tassium (S)-N-(4-methoxyphenyl)-3-phenyl-3-(trifluorobora-
to)propanamide (0.361 g, 1 mmol) the title compound was
(R)-N-Cyclohexyl-3-hydroxypentanamide (2f-OH): Fol-
lowing the procedure described above for oxidation using
the enantioselective borylated intermediate, the title com-
pound was obtained as a white crystalline solid with spectra
in accordance with that described above for the racemate;
mp 105–1068C; [a]2D0: À17.0 (c=0.2, MeOH). Using SFC
analysis (column AS-H, 10% i-PrOH, 2 mL, 10 MPa): the
enantiomeric ratio was measured to be 2:98; the major
enantiomer having an absolute configuration of R: (S)-
isomer retention time=8.75 min and (R)-isomer retention
time=9.21 min.
obtained as
a white crystalline solid; mp 144–1468C;
1H NMR (500 MHz, DMSO-d6): d=9.73 (s, 1H), 7.50 (d,
J=8.8 Hz, 2H), 7.30–7.47 (m, 4H), 7.24 (m, 1H), 6.86 (d,
J=8.5 Hz, 2H), 5.06 (dd, J=8.9, 4.7 Hz, 1H), 3.71 (s, 3H),
3.40 (br s, 1H), 2.62–2.66 (m, 1H), 2.46–2.59 (m, 1H);
13C NMR (125.8 MHz, DMSO-d6): d=168.9, 155.4, 145.7,
132.7, 128.4, 127.2, 126.0, 121.0, 114.1, 70.1, 55.4, 47.2; IR
(neat): n=3326, 2953, 2916, 2851, 1653, 1536, 1511, 1469,
1409, 1244, 1030, 1018, 822, 756, 701, 689, 656 cmÀ1; HR-MS
(ESI): m/z=272.1296, calcd. for C16H18NO3 [M+H]+:
272.1287. Both (R)- and (S)-MTPA esters were prepared ac-
cording to general procedure B, and the enantiomeric ratio
was determined by 19F NMR (338.8 MHz, CDCl3): (R)-
MTPA derivative of (S) enantiomer d=À71.73, (R) enantio-
mer d=À71.50.
3-Hydroxy-1-(piperidin-1-yl)butan-1-one:[37] According to
the general procedure (Method A) using potassium 1-(piper-
idin-1-yl)-3-(trifluoroborato)butan-1-one (0.261 g, 1 mmol)
1
the title compound was obtained as a yellow oil; H NMR
(500 MHz, CDCl3): d=4.20 (s, 1H), 3.98–4.2 (m, 1H), 3.49–
3.61 (m, 2H), 3.27–3.44 (m, 2H), 2.49 (d, J=16.0 Hz, 1H),
2.31 (dd, J=16.5, 9.4 Hz, 1H), 1.64–1.72 (m, 2H), 1.51–1.60
(m, 4H), 1.10–1.28 (m, 3H); 13C NMR (125.8 MHz, CDCl3):
d=170.6, 64.1, 46.2, 42.3, 40.5, 26.1, 25.3, 24.2, 22.0. A
method was developed to separate the enantiomers using
SFC analysis (column AD-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=6.04 min and (R)-isomer reten-
tion time=5.51 min.
(S)-3-Hydroxy-N-(4-methoxyphenyl)-3-phenylpropana-
mide (2i-OH): Following the procedure described above for
oxidation using the enantioselective borylated intermediate,
the title compound was obtained as a white crystalline solid
with spectra in accordance with those described above for
the racemate; mp 144–1478C; [a]2D0: À18.0 (c=0.2, MeOH).
Both (R)- and (S)-MTPA esters were prepared according to
general procedure B, and the enantiomeric ratio was deter-
mined by 19F NMR (338.8 MHz, CDCl3): (R)-MTPA deriva-
tive of (S) enantiomer d=À71.78, (R) enantiomer d=
À71.52. The enantiomeric ratio was measured to be 4:96;
the major enantiomer having an absolute configuration of S.
N-Ethyl-3-hydroxy-N-(o-tolyl)butanamide: According to
the general procedure (Method A) using potassium N-ethyl-
N-(o-tolyl)-3-(trifluoroborato)butanamide (0.311 g, 1 mmol)
the title compound was obtained as a yellow oil; yield:
(R)-3-Hydroxy-1-(piperidin-1-yl)butan-1-one
(2g-OH):
Following the procedure described above for oxidation
using the enantioselective borylated intermediate, the title
compound was obtained as a yellow oil with spectra in ac-
cordance with those described above for the racemate; [a]2D0:
À24.4 (c=0.25, MeOH). A method was developed to sepa-
rate the enantiomers using SFC analysis (column AD-H,
10% i-PrOH, 2 mL, 10 MPa): the enantiomeric ratio was
measured to be 8:92; the major enantiomer having an abso-
lute configuration of R: (S)-isomer retention time=6.10 min
and (R)-isomer retention time=5.49 min.
1
199 mg (90%); H NMR (500 MHz, asterisk denotes minor
rotamer peaks, CDCl3): d=7.19–7.31 (m, 3H), 7.03 (t, J=
8.9 Hz, 1H), 4.21 (s, 1H), 4.00–4.17 (m, 2H), 3.21 (m, 1H),
2.19 (d, J=7.9 Hz, 3H), 1.77–2.16 (m, 2H, 1H*), 1.09–1.13
(m, 3H), 1.03 (dd, J=6.4, 2.9 Hz, 3H); 13C NMR
(125.8 MHz, asterisk denotes minor rotamer peaks, CDCl3):
d=172.5, 172.3*, 140.1, 140.0*, 135.6, 135.3*, 131.5, 131.4*,
129.1, 128.8*, 128.4, 127.1, 127.1*, 64.4, 64.2*, 42.7, 42.7*,
41.6, 22.1, 22.1*, 17.3, 12.7, 12.6*; IR (neat): n=3436, 2977,
2929, 2876, 1712, 1631, 1493, 1447, 1409, 1293, 1255, 1138,
1091, 958, 77, 728, 648 cmÀ1; HR-MS (ESI): m/z=222.1493,
calcd. for C13H20NO2 [M+H]À: 222.1494. A method was de-
veloped to separate the enantiomers using SFC analysis
(column AD-H, 10% i-PrOH:CH3CN=85:15, 2 mL,
10 MPa): (S)-isomer retention time=4.63 min and (R)-
isomer retention time=5.22 min.
3-Hydroxy-1-morpholinobutan-1-one:[38] According to the
general procedure (Method A) using potassium morpholi-
no-3-(trifluoroborato)butan-1-one (0.263 g, 1 mmol) the title
compound was obtained as a colorless oil; yield: 60 mg
1
(35%); H NMR (360 MHz, CDCl3): d=4.19–4.23 (m, 1H),
4.10 (s, 1H), 3.51–3.75 (m, 6H), 3.44 (dd, J=5.9, 3.8 Hz,
2H), 2.45 (dd, J=16.4, 2.6 Hz, 1H), 2.30 (dd, J=16.4,
9.4 Hz, 1H), 1.22 (d, J=5.3 Hz 3H); 13C NMR (90.5 MHz,
CDCl3): d=171.1, 66.7, 66.4, 64.1, 45.6, 41.7, 40.7, 22.2. A
method was developed to separate the enantiomers using
SFC analysis (column AD-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=4.96 min and (R)-isomer reten-
tion time=5.61 min.
(R)-3-Hydroxy-1-morpholinobutan-1-one (2h-OH): Fol-
lowing the procedure described above for oxidation using
the enantioselective borylated intermediate, the title com-
pound was obtained as a colorless oil with spectra in accord-
ance with those described above for the racemate; [a]2D0:
À10.7 (c=1.0, MeOH). A method was developed to sepa-
rate the enantiomers using SFC analysis (column AD-H,
10% i-PrOH, 2 mL, 10 MPa): the enantiomeric ratio was
measured to be 28:72; the major enantiomer having an ab-
solute configuration of R: (S)-isomer retention time=
4.85 min and (R)-isomer retention time=5.11 min.
(R)-N-Ethyl-3-hydroxy-N-(o-tolyl)butanamide (2j-OH):
Following the procedure described above for oxidation
using the enantioselective borylated intermediate, the title
compound was obtained as a yellow oil with spectra in ac-
cordance with those described above for the racemate; [a]2D0:
À18.0 (c=0.1, MeOH). A method was developed to sepa-
rate the enantiomers using SFC analysis (column AD-H,
10% i-PrOH/CH3CN=85:15, 2 mL, 10 MPa): the enantio-
meric ratio was measured to be 28:72; the major enantiomer
having an absolute configuration of R: (S)-isomer retention
time=4.85 min and (R)-isomer retention time=5.38 min.
Adv. Synth. Catal. 2013, 355, 3037 – 3057
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3051

Gary A. Molander et al.
UPDATES
3-Hydroxy-N,N-dimethylbutanamide:[39] According to the
general procedure (Method A) using potassium N-(4-me-
thoxyphenyl)-3-(trifluoroborato)methyloctanamide (0.221 g,
1 mmol) the title compound was obtained as a yellow oil;
1H NMR (500 MHz, CDCl3): d=4.39 (br s, 1H), 4.13–4.23
(m, 1H), 2.98 (s, 3H), 2.95 (s, 3H), 2.47 (dd, J=16.5, 2.4 Hz,
1H), 2.29 (dd, J=16.5, 9.6 Hz, 1H), 1.21 (d, J=6.4 Hz, 3H);
13C NMR (125.8 MHz, CDCl3): d=172.6, 64.0, 40.7, 36.9,
35.0, 22.0. A method was developed to separate the enantio-
mers using SFC analysis (column R,R-Whelk, 10% i-PrOH,
2 mL, 10 MPa): (S)-isomer retention time=12.41 min and
(R)-isomer retention time=11.87 min.
(R)-3-Hydroxy-N,N-dimethylbutanamide (2k-OH): Fol-
lowing the procedure described above for oxidation using
the enantioselective borylated intermediate, the title com-
pound was obtained as a yellow oil with spectra in accord-
ance with those described above for the racemate; [a]2D0:
+11.7 (c=1.0, MeOH). Using SFC analysis (column R,R-
Whelk, 10% i-PrOH, 2 mL, 10 MPa): the enantiomeric ratio
was measured to be 30:70; the major enantiomer having an
absolute configuration of R: (S)-isomer retention time=
12.41 min and (R)-isomer retention time=11.47 min.
N,N-Dibenzyl-3-hydroxybutanamide: According to the
general procedure (Method A) using potassium (R)-N,N-di-
benzyl-3-(trifluoroborato)butanamide (0.373 g, 1 mmol) the
title compound was obtained as a white crystalline solid;
yield: 277 mg (98%); mp 64–668C; 1H NMR (500 MHz,
CDCl3): d=7.27–7.42 (m, 6H), 7.23 (d, J=5.0 Hz, 2H), 7.16
(d, J=5.0 Hz, 2H), 4.71 (d, J=14.8 Hz, 1H), 4.55 (d, J=
14.8 Hz, 1H), 4.40–4.52 (m, 1H), 4.27–4.31 (m, 2H), 4.22 (br
s, 1H), 2.60 (dd, J=16.4, 2.5 Hz, 1H), 2.42–2.54 (m, 1H),
1.23 (dd, J=6.6, 3.0 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3): d=173.3, 136.7, 135.8, 128.9, 128.6, 128.1, 127.7,
127.4, 126.2, 64.3, 49.7, 47.9, 40.8, 22.1. A method was devel-
oped to separate the enantiomers using SFC analysis
(column OD-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer re-
tention time=12.11 min and (R)-isomer retention time=
11.15 min.
calcd. for C15H22NO2 [M+H]À: 248.1651. A method was de-
veloped to separate the enantiomers using SFC analysis
(column OD-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer re-
tention time=11.16 min and (R)-isomer retention time=
10.69 min.
(S)-N-Cyclohexyl-3-hydroxy-3-phenylpropanamide (2m-
OH): Following the procedure described above for oxida-
tion using the enantioselective borylated intermediate, the
title compound was obtained as a white crystalline solid
with spectra in accordance with that described above for the
racemate; mp 131–1348C; [a]2D0: +140.5 (c=0.2, MeOH). A
method was developed to separate the enantiomers using
SFC analysis (column OD-H, 10% i-PrOH, 2 mL, 10 MPa):
the enantiomeric ratio was measured to be 28:72; the major
enantiomer having an absolute configuration of S: (S)-
isomer retention time=10.95 min and (R)-isomer retention
time=10.50 min.
3-Hydroxy-3-phenyl-1-(pyrrolidin-1-yl)propan-1-one:[38]
According to the general procedure (Method A) using po-
tassium (S)-3-phenyl-1-(pyrrolidin-1-yl)-3-(trifluoroborato)-
propan-1-one (0.309 g, 1 mmol) the title compound was ob-
tained as a white crystalline solid; mp 48–508C; 1H NMR
(500 MHz, CDCl3): d=7.32–7.53 (m, 4H), 7.25–7.32 (m,
1H), 5.18 (s, 1H), 4.93 (s, 1H), 3.49–3.51 (m, 2H), 3.27–3.43
(m, 2H), 2.51–2.76 (m, 2H), 1.91 (m, 4H); 13C NMR
(75.4 MHz, CDCl3): d=170.0, 143.0, 128.3, 127.3, 125.6, 70.2,
46.5, 45.4, 42.9, 25.8, 24.2. A method was developed to sepa-
rate the enantiomers using SFC analysis (column OD-H,
10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention time=
13.12 min and (R)-isomer retention time=14.10 min.
(S)-3-Hydroxy-3-phenyl-1-(pyrrolidin-1-yl)propan-1-one
(2n-OH): Following the procedure described above for oxi-
dation using the enantioselective borylated intermediate, the
title compound was obtained as a white crystalline solid
with spectra in accordance with those described above for
the racemate; mp 48–518C; [a]2D0: À12.0 (c=0.1, MeOH). A
method was developed to separate the enantiomers using
SFC analysis (column OD-H, 10% i-PrOH, 2 mL, 10 MPa):
the enantiomeric ratio was measured to be 22:78; the major
enantiomer having an absolute configuration of S: (S)-
isomer re=14.41 min and (R)-isomer retention time=
15.11 min.
(R)-N,N-Dibenzyl-3-hydroxybutanamide (2l-OH): Follow-
ing the procedure described above for oxidation using the
enantioselective borylated intermediate, the title compound
was obtained as a white crystalline solid with spectra in ac-
cordance with those described above for the racemate; mp
65–668C; [a]2D0: À5.0 (c=0.3, MeOH). A method was devel-
oped to separate the enantiomers using SFC analysis
(column OD-H, 10% i-PrOH, 2 mL, 10 MPa): the enantio-
meric ratio was measured to be 34:66; the major enantiomer
having an absolute configuration of R: (S)-isomer retention
time=12.20 min and (R)-isomer retention time=11.09 min.
N-Cyclohexyl-3-hydroxy-3-phenylpropanamide: Accord-
ing to the general procedure (Method A) using potassium
(S)-N-cyclohexyl-3-phenyl-3-(trifluoroborato)propanamide
(0.337 g, 1 mmol) the title compound was obtained as
a white crystalline solid; yield: 219 mg (89%); mp 132–
Ethyl 3-hydroxybutanoate:[40] According to the general
procedure using potassium (R)-ethyl 3-(trifluoroborato)but-
AHCTUNGTERGaNNUN noate (0.222 g, 1 mmol) the title compound was obtained
1
as a yellow oil; yield: 129 mg (98%); H NMR (300 MHz,
CDCl3): d=4.11–4.26 (m, 3H), 3.07 (s, 1H), 2.35–2.53 (m,
2H), 1.27 (t, J=7.1 Hz, 3H), 1.22 (d, J=6.3 Hz, 3H);
13C NMR (75.4 MHz, CDCl3): d=172.7, 64.1, 60.5, 42.6,
22.3, 14.0. A method was developed to separate the enantio-
mers using SFC analysis (column OD-H, 10% i-PrOH,
2 mL, 10 MPa): (S)-isomer retention time=10.3 min and
(R)-isomer retention time=11.29 min.
Ethyl (R)-3-Hydroxybutanoate (7a-OH): Following the
procedure described above for oxidation using the enantio-
selective borylated intermediate, the title compound was ob-
tained as a yellow oil with spectra in accordance with those
described above for the racemate; [a]2D0: À6.7 (c=0.55,
MeOH). A method was developed to separate the enantio-
mers using SFC analysis (column OD-H, 10% i-PrOH,
2 mL, 10 MPa): the enantiomeric ratio was measured to be
5:95, the major enantiomer having an absolute configuration
1
1348C; H NMR (300 MHz, CDCl3): d=7.17–7.41 (m, 5H),
6.30 (s, 1H), 4.97 (dd, J=7.4, 4.6 Hz, 1H), 4.74 (s, 1H),
3.66–3.69 (m, 1H), 2.36–2.54 (m, 2H), 1.30–1.82 (m, 2H),
1.49–1.74 (m, 3H), 1.27–1.31 (m, 2H), 1.05–1.17 (m, 3H);
13C NMR (75.4 MHz, CDCl3): d=170.9, 143.1, 128.2, 127.4,
125.5, 70.7, 48.1, 44.5, 32.74, 25.3, 24.6; IR (neat): n=3395,
3299, 2932, 2847, 1635, 1552, 1445, 1359, 1206, 1052, 1016,
984, 891, 755, 696, 646 cmÀ1; HR-MS (ESI): m/z=248.1650,
3052
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3037 – 3057

Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
of R: (S)-isomer retention time=10.71 min and (R)-isomer
retention time=11.64 min.
pound was obtained as a yellow oil with spectra in accord-
ance with those described above for the racemate; [a]2D0:
+8.0 (c=0.25, MeOH). A method was developed to sepa-
rate the enantiomers using SFC analysis (column R,R-
Whelk, 10% i-PrOH, 2 mL, 10 MPa): the enantiomeric ratio
was measured to be 21:79; the major enantiomer having an
absolute configuration of S: (R)-isomer retention time=
8.82 min and (S)-isomer retention time=11.47 min.
3-Hydroxycyclohexan-1-one: According to the general
procedure using potassium (R)-3-(trifluoroborato)cyclohexa-
none (0.204 g, 1 mmol) the title compound was obtained as
a yellow oil; yield: 99 mg (87%); 1H NMR (500 MHz,
CDCl3): d=4.18–4.22 (m, 1H), 2.67 (dd, J=14.0, 4.4 Hz,
1H), 2.40–2.45 (m, 1H), 2.30–2.40 (m, 2H), 2.18–1.98 (m,
2H), 1.62–1.90 (m, 3H); 13C NMR (125.8 MHz, CDCl3): d=
209.4, 69.6, 50.3, 40.7, 32.7, 20.51.
(R)-3-Hydroxycyclohexane-1-one (7e-OH): Following the
procedure described above for oxidation using the enantio-
selective borylated intermediate, the title compound was ob-
tained as a yellow oil with spectra in accordance with those
described above for the racemate; [a]2D0: À1.4 (c=0.1,
MeOH). Both (R)- and (S)-MTPA esters were prepared ac-
cording to general procedure B, and the enantiomeric ratio
was determined by 19F NMR (338.8 MHz, CDCl3): (R)-
MTPA derivative of (R) enantiomer d=À71.89, (S) enantio-
mer d=À71.33. The enantiomeric ratio was measured to be
26:74; the major enantiomer having an absolute configura-
tion of R.
Ethyl 3-Hydroxyoctanoate:[41] According to the general
procedure using potassium ethyl (R)-3-(trifluoroborato)oct-
ACHTUNGTRENNUNGanoate (0.278 g, 1 mmol) the title compound was obtained
1
as a colorless oil; H NMR (500 MHz, CDCl3): d=4.36–4.10
(m, 2H), 4.10–3.93 (m, 1H), 3.01 (br s, 1H), 2.45 (m, 2H),
1.65–1.16 (m, 11H), 1.02–0.80 (m, 3H); 13C NMR
(125.8 MHz, CDCl3): d=172.9, 67.9, 60.5, 41.2, 36.4, 31.6,
25.0, 22.4, 14.0, 13.8. A method was developed to separate
the enantiomers using SFC analysis (column AD-H, 10% i-
PrOH, 2 mL, 10 MPa): (S)-isomer retention time=3.97 min
and (R)-isomer retention time=3.09 min.
Ethyl (R)-3-Hydroxyoctanoate (7b-OH): Following the
procedure described above for oxidation using the enantio-
selective borylated intermediate, the title compound was ob-
tained as a colorless oil with spectra in accordance with
those described above for the racemate; [a]2D0: À4.61 (c=
0.26, MeOH). A method was developed to separate the
enantiomers using SFC analysis (column AD-H, 10% i-
PrOH, 2 mL, 10 MPa); the enantiomeric ratio was measured
to be 12:88; the major enantiomer having an absolute con-
figuration of R: (S)-isomer retention time=3.93 min and
(R)-isomer retention time=2.99 min.
3-Hydroxy-1-phenylbutan-1-one:[42] According to the gen-
eral procedure using potassium (R)-3-trifluoroborato-1-phe-
nylbutan-1-one (0.254 g, 1 mmol) the title compound was
obtained as a yellow oil; yield: 106 mg (65%); 1H NMR
(300 MHz, CDCl3): d=7.96 (d, J=7.1 Hz, 2H), 7.53–7.64
(m, 1H), 7.42–7.53 (m, 2H), 4.41 (m, 1H), 3.40 (br s, 1H),
3.23–2.98 (m, 2H), 1.31 (d, J=6.3 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3): d=200.6, 136.6, 133.4, 128.5, 127.9, 76.5,
63.9, 46.4, 22.3. A method was developed to separate the
enantiomers using SFC analysis (column AS-H, 10% i-
PrOH, 2 mL, 10 MPa): (S)-isomer retention time=3.13 min
and (R)-isomer retention time=3.47 min.
(R)-3-Hydroxy-1-phenylbutan-1-one (7c-OH): Following
the procedure described above for oxidation using the enan-
tioselective borylated intermediate, the title compound was
obtained as a yellow oil with spectra in accordance with
those described above for the racemate; [a]2D0: À1.53 (c=
0.26, MeOH). A method was developed to separate the
enantiomers using SFC analysis (column AS-H, 10% i-
PrOH, 2 mL, 10 MPa): the enantiomeric ratio was measured
to be 14:86; the major enantiomer having an absolute con-
figuration of R: (S)-isomer retention time=3.17 min and
(R)-isomer retention time=3.47 min.
General Procedure for the Suzuki–Miyaura Cross-
Coupling with Aryl Electrophiles
To
a Biotage microwave vial was added precatalyst
(0.0125 mmol, 5 mol%), K2CO3 (0.1037 g, 0.75 mmol,
3 equiv.), aryl electrophile (0.25 mmol, 1 equiv.), and potassi-
um b-trifluoroboratoamide (0.25 mmol, 1 equiv.). This mix-
ture was sealed in the microwave vial and purged with
argon (three times). To the vial was added CPME (1.0 mL)
and H2O (0.15 mL), and then the reaction was heated to
1008C for 24 h. The reaction mixture was allowed to cool to
room temperature and diluted with H2O (1 mL). The reac-
tion mixture was extracted with EtOAc (3ꢂ3 mL) and dried
(MgSO4). The solvent was removed under vacuum, and the
product was purified by flash column chromatography on
silica gel.
Determination of Absolute Configuration and
Enantiomeric Ratio of Enantioenriched Cross-
Coupled Products
3-Hydroxy-1,3-diphenylpropan-1-one:[43] According to the
general procedure using potassium (S)-1,3-diphenyl-3-(tri-
fluoroborato)butan-1-one (0.316 g, 1 mmol) the title com-
pound was obtained as a yellow oil; 1H NMR (360 MHz,
CDCl3): d=7.97 (d, J=7.1 Hz, 2H), 7.55–7.65 (m, 1H),
7.28–7.53 (m, 7H), 5.34–5.41 (m, 1H), 3.58 (s, 1H), 3.39 (d,
J=6.0 Hz, 2H); 13C NMR (90.5 MHz, CDCl3): d=200.1,
142.9, 136.6, 133.6, 128.7, 128.5, 128.1, 127.6, 125.7, 70.0,
47.4. A method was developed to separate the enantiomers
using SFC analysis (column R,R-Whelk, 10% i-PrOH, 2 mL,
10 MPa): (R)-isomer retention time=8.79 min and (S)-
isomer retention time=11.35 min.
N-(4-Methoxyphenyl)-3-(pyridin-3-yl)butanamide: Using the
general procedure described for the Suzuki–Miyaura cross-
coupling of potassium N-(4-methoxyphenyl)-3-(trifluorobor-
ato)butanamide and 3-chloropyridine, the title compound
was obtained as a pale yellow oil after silica gel column
chromatography; yield: 38 mg (56%); 1H NMR (300 MHz,
CDCl3): d=8.42–8.58 (m, 2H), 7.76 (br s, 1H), 7.59 (d, J=
7.8 Hz, 1H), 7.33 (d, J=8.9 Hz, 2H), 7.22–7.27 (m, 1H),
6.82 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.36–3.51 (m, 1H),
2.60 (d, J=7.4 Hz, 2H), 1.40 (d, J=7.0 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3): d=169.1, 156.3, 148.3, 147.7, 141.1,
134.7, 130.7, 123.5, 121.8, 114.0, 55.3, 45.7, 34.5, 21.0. Using
(S)-3-Hydroxy-1,3-diphenylpropan-1-one (7d-OH): Fol-
lowing the procedure described above for oxidation using
the enantioselective borylated intermediate, the title com-
Adv. Synth. Catal. 2013, 355, 3037 – 3057
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3053

Gary A. Molander et al.
UPDATES
SFC analysis (column OJ-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=16.82 min and (R)-isomer reten-
tion time=14.60 min.
(S)-N-(4-Methoxyphenyl)-3-(thiophen-2-yl)butanamide
(12c): Using the general procedure described for the
Suzuki–Miyaura cross-coupling of potassium (R)-N-(4-me-
thoxyphenyl)-3-(trifluoroborato)butanamide (2a) and 2-
chlorothiophene, the title compound was obtained as a pale
yellow solid with spectral data in accordance with those de-
scribed for the racemate; yield: 37 mg (56%); mp 82–858C;
[a]2D0: +15.0 (c=0.1, MeOH). The title compound was found
to have an enantiomeric ratio of >99:1 with an absolute
configuration of S for the major enantiomer using SFC anal-
ysis (column OJ-H, 10% i-PrOH, 2 mL, 10 MPa); (S)-
isomer retention time=9.5 min.
N-(4-Methoxyphenyl)-3-(quinolin-6-yl)butanamide: Using
the general procedure described for the Suzuki–Miyaura
cross-coupling of potassium N-(4-methoxyphenyl)-3-(tri-
fluoroborato)butanamide and 6-chloroquinoline, the title
compound was obtained as a pale yellow oil after silica gel
column chromatography; yield: 47 mg (58%); mp 132–
1358C; 1H NMR (500 MHz, CDCl3): d=8.87 (br s, 1H),
8.03- 8.14 (m, 2H), 7.62 À7.70 (m, 2H), 7.37–7.45 (m, 1H),
7.23 (d, J=9.0 Hz, 2H), 7.09 (s, 1H), 6.78 (d, J=9.0 Hz,
2H), 3.76 (s, 3H), 3.62 (q, J=7.0 Hz, 1H), 2.66–2.69 (m,
2H), 1.47 (d, J=7.0 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3): d=169.6, 156.3, 149.7, 147.0, 144.1, 135.9, 130.8,
129.3, 128.8, 128.2, 125.0, 121.9, 121.1, 114.0, 113.9, 55.3,
45.9, 36.7, 21.4; IR (neat): n=3290, 3054, 2965, 2924, 1654,
1601, 1510, 1243, 1173, 1035, 833, 685, 635 cmÀ1; HR-MS
(ESI): m/z=321.1606, calcd. for C20H21N2O2 [M+H]+:
321.1603. Using SFC analysis (column OJ-H, 10% i-PrOH,
2 mL, 10 MPa): (S)-isomer retention time=7.75 min and
(R)-isomer retention time=8.51 min.
(S)-N-(4-Methoxyphenyl)-3-(quinolin-6-yl)butanamide
(12d): Using the general procedure described for the
Suzuki–Miyaura cross-coupling of potassium (R)-N-(4-me-
thoxyphenyl)-3-(trifluoroborato)butanamide (2a) and 6-
chloroquinoline, the title compound was obtained as a white
solid with spectral data in accordance with those described
for the racemate; yield: 47 mg (58%); mp 133–1358C; [a]2D0:
+47.3 (c=0.15, MeOH). The title compound was found to
have an enantiomeric ratio of 92:7 with an absolute configu-
ration of S for the major enantiomer using SFC analysis
(column OJ-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer re-
tention time=7.73 min and (R)-isomer retention time=
8.51 min.
(S)-N-(4-Methoxyphenyl)-3-(pyridin-3-yl)butanamide
(12a): Using the general procedure described for the
Suzuki–Miyaura cross-coupling of potassium (R)-N-(4-me-
thoxyphenyl)-3-(trifluoroborato)butanamide (2a) and 3-
chloropyridine, the title compound was obtained as a pale
yellow oil with spectral data in accordance with those de-
scribed for the racemate; yield: 38 mg (56%); [a]2D0: +33.8
(c=0.54, MeOH). The title compound was found to have an
enantiomeric ratio of 9:91 with an absolute configuration of
S for the major enantiomer using SFC analysis (column OJ-
H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention
time=16.59 min and (R)-isomer retention time=14.99 min.
N-(4-Methoxyphenyl)-3-(thiophen-3-yl)butanamide:
Using the general procedure described for the Suzuki–
Miyaura cross-coupling of potassium N-(4-methoxyphenyl)-
3-(trifluoroborato)butanamide and 3-chlorothiophene, the
title compound was obtained in as a pale yellow solid after
silica gel column chromatography; yield: 41 mg (60%); mp
102–1058C; 1H NMR (300 MHz, CDCl3): d=7.23–7.36 (m,
3H), 7.03–7.05 (m, 3H), 6.83 (d, J=8.9 Hz, 2H), 3.79 (s,
3H), 3.51 (q, J=7.2 Hz, 1H), 2.44–2.65 (m, 2H), 1.38 (d, J=
6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3): d=169.6, 156.3,
146.5, 130.6, 126.4, 125.9, 121.8, 119.6, 113.9, 55.3, 46.3, 32.3,
21.2; IR (neat): n=3279, 2961, 2933, 2835, 1649, 1603, 1531,
1510, 1245, 1032, 828, 776, 640 cmÀ1; HR-MS (ESI): m/z=
276.1051, calcd. for C15H18NO2S [M+H]+: 276.1058. Using
SFC analysis (column OJ-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=10.2 min and (R)-isomer reten-
tion time=11.8 min.
(S)-N-(4-Methoxyphenyl)-3-(thiophen-3-yl)butanamide
(12b): Using the general procedure described for the
Suzuki–Miyaura cross-coupling of potassium (R)-N-(4-me-
thoxyphenyl)-3-(trifluoroborato)butanamide (2a) and 3-
chlorothiophene, the title compound was obtained as a pale
yellow oil with spectral data in accordance with those de-
scribed for the racemate; yield: 41 mg (60%); mp 102–
1048C; [a]2D0: +9.5 (c=0.23, MeOH). The title compound
was found to have an enantiomeric ratio of >99:1 with an
absolute configuration of S for the major enantiomer using
SFC analysis (column OJ-H, 10% i-PrOH, 2 mL, 10 MPa);
(S)-isomer retention time=10.2 min.
N-(4-Methoxyphenyl)-3-(thiophen-2-yl)butanamide:
tert-Butyl 5-{4-[(4-Methoxyphenyl)amino]-4-oxobutan-2-
yl}-1H-indole-1-carboxylate: Using the general procedure
described for the Suzuki–Miyaura cross-coupling of potassi-
Using the general procedure described for the Suzuki–
Miyaura cross-coupling of potassium N-(4-methoxyphenyl)-
3-(trifluoroborato)butanamide and 2-chlorothiophene, the
title compound was obtained as a pale yellow solid after
silica gel column chromatography; yield: 37 mg (53%); mp
84–868C; 1H NMR (360 MHz, CDCl3): d=7.28 (d, J=
9.0 Hz, 2H), 7.17 (d, J=6.1 Hz, 1H), 7.07 (br s, 1H), 6.92–
6.94 (m, 1H), 6.87–6.92 (m, 1H), 6.82 (d, J=9.0 Hz, 2H),
3.82 (s, 3H), 3.67–3.75 (m, 1H), 2.55–2.68 (m, 2H), 1.44 (d,
J=6.9 Hz, 3H); 13C NMR (90.5 MHz, CDCl3): d=169.3,
156.5, 149.7, 130.7, 126.8, 123.3, 123.1, 122.0, 114.0, 55.4,
47.4, 32.6, 22.6; IR (neat): n=3281, 2961, 2933, 2831, 1648,
1605, 1528, 1508, 1247, 1034, 825, 695, 686, 633 cmÀ1; HR-
MS (ESI): m/z=298.0876, calcd. for C15H17NO2NaS [M+
Na]+: 298.0878. Using SFC analysis (column OJ-H, 10% i-
PrOH, 2 mL, 10 MPa); (S)-isomer retention time=9.5 min
and (R)-isomer retention time=11.5 min.
um
N-(4-methoxyphenyl)-3-(trifluoroborato)butanamide
and tert-butyl 5-chloro-1H-indole-1-carboxylate, the title
compound was obtained as a pale yellow oil after silica gel
column chromatography; yield: 44 mg (43%); 1H NMR
(500 MHz, CDCl3): d=8.10 (br s, 1H), 7.59 (d, J=3.7 Hz,
1H), 7.45 (s, 1H), 7.16–7.26 (m, 3H), 6.83–6.98 (m, 1H),
6.79 (d, J=8.9 Hz, 2H), 6.52 (d, J=3.7 Hz, 1H), 3.76 (s,
3H), 3.46–3.49 (m, 1H), 2.61–2.66 (m, 2H), 1.68 (s, 9H),
1.42 (d, J=6.9 Hz, 3H); 13C NMR (90.5 MHz, CDCl3): d=
169.9, 156.3, 149.7, 140.1, 134.0, 130.9, 130.7, 126.2, 123.1,
121.9, 118.9, 115.3, 114.8, 114.0, 107.2, 83.6, 55.4, 47.0, 37.0,
28.2, 22.2; IR (neat): n=3277, 2973, 2933, 1734, 1656, 1511,
1450, 1368, 1345, 1244, 1157, 1130, 1083, 1023, 835, 789, 764,
725, 686, 636 cmÀ1; HR-MS (ESI): m/z=409.2119, calcd. for
C24H29N2O4 [M+H]+: 409.2127. Using SFC analysis (column
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3037 – 3057

Synthesis and Suzuki–Miyaura Cross-Coupling of Enantioenriched Secondary Potassium b-Trifluoroboratoamides
AS-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention
time=14.4 min and (R)-isomer retention time=15.3 min.
tert-Butyl (S)-5-{4-[(4-Methoxyphenyl)amino]-4-oxobut-
an-2-yl}-1H-indole-1-carboxylate (12e): Using the general
procedure described for the Suzuki–Miyaura cross-coupling
of potassium (R)-N-(4-methoxyphenyl)-3-(trifluoroborato)-
butanamide (2a) and tert-butyl 5-chloro-1H-indole-1-carbox-
ylate, the title compound was obtained as a yellow oil with
spectral data in accordance with those described for the
racemate; yield: 44 mg (43%); [a]2D0: +38.8 (c=0.43,
MeOH). The title compound was found to have an enantio-
meric ratio of >99:1 with an absolute configuration of S for
the major enantiomer using SFC analysis (column AS-H,
10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention time=
15.3 min.
a white solid with spectral data in accordance with those de-
scribed for the racemate; yield: 64 mg (89%); mp 107–
1108C; [a]2D0: +26.5 (c=0.2, MeOH). The title compound
was found to have an enantiomeric ratio of 9:91 with an ab-
solute configuration of S for the major enantiomer using
SFC analysis (column AS-H, 10% i-PrOH, 2 mL, 10 MPa):
(S)-isomer retention time=19.47 min and (R)-isomer reten-
tion time=21.15 min.
3-(4-Fluorophenyl)-N-phenylbutanamide: Using the gen-
eral procedure described for the Suzuki–Miyaura cross-cou-
pling of potassium 3-(trifluoroborato)-N-phenylbutanamide
and 4-chlorofluorobenzene, the title compound was ob-
tained as a yellow solid after silica gel column chromatogra-
1
phy; yield: 57 mg (88%); mp 80–828C; H NMR (500 MHz,
CDCl3): d=7.29–7.44 (m, 2H), 7.13–7.28 (m, 2H), 7.04–7.08
(m, 1H), 6.97–7.03 (m, 2H), 6.81–6.87 (m, 2H), 3.36–3.40
(m, 1H), 2.57 (dd, J=7.4, 3.1 Hz, 2H), 1.34 (d, J=6.8 Hz,
3H); 13C NMR (125.8 MHz, CDCl3): d=169.8, 161.3 (d, J=
243.2 Hz), 141.2, 137.5, 128.8, 128.1 (d, J=7.8 Hz), 124.3,
120.0, 115.3 (d, J=21.3 Hz), 46.6, 36.1, 21.6; 19F NMR
(470.8 MHz, CDCl3): d=À116.51; IR (neat): n=3241, 3196,
3135, 3075, 2965, 1649, 1598, 1555, 150 1442, 1311, 1224, 833,
757, 692, 658 cmÀ1; HR-MS (ESI): m/z=258.1291, calcd.. for
C16H17NOF [M+H]+: 258.1294. Using SFC analysis (column
OJ-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention
time=11.19 min and (R)-isomer retention time=11.85 min.
(S)-3-(4-Fluorophenyl)-N-phenylbutanamide (13b): Using
the general procedure described for the Suzuki–Miyaura
cross-coupling of potassium (R)-3-(trifluoroborato)-N-phe-
nylbutanamide (2c) and 4-chlorofluorobenzene, the title
compound was obtained as a white solid with spectral data
in accordance with those described for the racemate; yield:
57 mg (88%); mp 80–828C; [a]2D0: +17.5 (c=0.2, MeOH).
The title compound was found to have an enantiomeric
ratio of 7:93 with an absolute configuration of S for the
major enantiomer using SFC analysis (column OJ-H, 10% i-
PrOH, 2 mL, 10 MPa): (S)-isomer retention time=
11.18 min and (R)-isomer retention time=11.83 min.
N-(4-Methoxyphenyl)-3-phenylbutanamide:[2] Using the
general procedure described for the Suzuki–Miyaura cross-
coupling of potassium N-(4-methoxyphenyl)-3-(trifluorobor-
ato)butanamide and chlorobenzene, the title compound was
obtained in as a white solid after silica gel column chroma-
tography¸yield: 57 mg (85%); mp 125–1288C; 1H NMR
(360 MHz, CDCl3): d=7.21–7.25 (m, 7H), 6.98 (br s, 1H),
6.80 (d, J=9.0 Hz, 2H), 3.76 (s, 3H), 3.34–3.40 (m, 1H),
2.55–2.59 (m, 2H), 1.37 (d, J=7.0 Hz, 3H); 13C NMR
(90.5 MHz, CDCl3): d=169.8, 156.6, 145.7, 130.7, 128.7,
126.8, 126.6, 122.0, 113.9, 55.4, 46.6, 37.1, 21.6. Using SFC
analysis (column OJ-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-
isomer retention time=11.19 min and (R)-isomer retention
time=12.13 min.
(S)-N-(4-Methoxyphenyl)-3-phenylbutanamide (8): Using
the general procedure described for the Suzuki–Miyaura
cross-coupling of potassium (R)-N-(4-methoxyphenyl)-3-(tri-
fluoroborato)butanamide (2a) and chlorobenzene the title
compound was obtained as a white solid in with spectral
data in accordance with those described for the racemate;
yield: 57 mg (85%); mp 123–1268C; [a]2D0: +57.5 (c=0.2,
MeOH). The title compound was found to have an enantio-
meric ratio of 8:92 with an absolute configuration of S for
the major enantiomer using SFC analysis (column OJ-H,
10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention time=
10.61 min and (R)-isomer retention time=11.35 min.
N-Ethyl-3-(4-fluorophenyl)-N-(o-tolyl)butanamide: Using
the general procedure described for the Suzuki–Miyaura
cross-coupling of potassium N-ethyl-3-(trifluoroborato)-N-
(o-tolyl)butanamide and 4-chlorofluorobenzene, the title
compound was obtained in as a colorless oil; yield: 61 mg
3-(4-Fluorophenyl)-N-(4-methoxyphenyl)butanamide:[2]
Using the general procedure described for the Suzuki–
Miyaura cross-coupling of potassium N-(4-methoxyphenyl)-
3-(trifluoroborato)butanamide and 4-chlorofluorobenzene,
the title compound was obtained as a pale yellow solid after
silica gel column chromatography; yield: 64 mg (89%); mp
107–1098C; 1H NMR (300 MHz, CDCl3): d=7.27 (d, J=
8.9 Hz, 2H), 7.18–7.25 (m, 2H), 7.10 (s, 1H), 7.00 (t, J=
8.7 Hz, 2H), 6.82 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.33–3.44
(m, 1H), 2.54 (d, J=7.4 Hz, 2H), 1.35 (d, J=7.0 Hz, 3H);
13C NMR (75.4 MHz, CDCl3): d=169.5, 156.4, 141.3, 130.5,
128.1 (d, J=7.8 Hz), 128.0, 121.9, 115.4, 115.1, 113.9, 55.3,
46.5, 36.2, 21.6; 19F NMR (282.4 MHz, CDCl3): d=À116.58.
Using SFC analysis (column AS-H, 10% i-PrOH, 2 mL,
10 MPa): (S)-isomer retention time=19.29 min and (R)-
isomer retention time=20.82 min.
1
(81%); H NMR (360 MHz, asterisk denotes minor rotamer
peaks, CDCl3): d=6.90–7.24 (m, 8H), 6.46–6.48* (m, 1H),
4.05–4.09 (m, 1H), 3.37–3.41 (m, 1H), 3.09–3.15 (m, 1H),
2.20 (s, 3H), 2.07–2.17 (m, 2H), 1.93* (s, 3H), 1.16–1.19 (m,
3H), 1.08–1.12 (t, J=7.1 Hz, 3H), 1.00–1.04* (t, J=7.1 Hz,
3H); 13C NMR (90.5 MHz, asterisk denotes rotamer peaks,
CDCl3): d=171.0, 170.9*, 140.7, 135.9, 131.4, 131.2*, 129.4,
129.3*, 128.5, 128.4*, 128.3, 128.2*, 126.9, 126.8*, 115.1,
115.0*, 114.8, 114.7*, 43.0, 42.9*, 42.8, 42.7*, 35.8, 35.5*,
21.6, 21.5*, 17.5, 17.2*, 12.8: 19F NMR (338.8 MHz, CDCl3):
d=À117.30; IR (neat): n=2965, 2929, 2864, 1712, 1651,
1510, 1361, 1220, 769, 727, 686, 639 cmÀ1; HR-MS (ESI):
m/z=300.1759, calcd. for C19H23NOF [M+H]+: 300.1764.
Using SFC analysis (column OD-H, 10% i-PrOH, 2 mL,
10 MPa): (S)-isomer retention time=14.4 min and (R)-
isomer retention time=15.3 min.
(S)-3-(4-Fluorophenyl)-N-(4-methoxyphenyl)butanamide
(13a): Using the general procedure described for the
Suzuki–Miyaura cross-coupling of potassium (R)-N-(4-me-
thoxyphenyl)-3-(trifluoroborato)butanamide (2a) and 4-
chlorofluorobenzene, the title compound was obtained as
(S)-N-Ethyl-3-(4-fluorophenyl)-N-(o-tolyl)butanamide
(13c): Using the general procedure described for the
Suzuki–Miyaura cross-coupling of potassium (R)-N-ethyl-3-
Adv. Synth. Catal. 2013, 355, 3037 – 3057
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Gary A. Molander et al.
UPDATES
(trifluoroborato)-N-(o-tolyl)butanamide (2j) and 4-chloro-
fluorobenzene, the title compound was obtained as a color-
less oil with spectral data in accordance with those described
for the racemate; yield: 61 mg (81%); [a]2D0: À3.2 (c=0.7,
MeOH). The title compound was found to have an enantio-
meric ratio of 15:85 with an absolute configuration of S for
the major enantiomer using SFC analysis (column OD-H,
10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention time=
11.75 min and (R)-isomer retention time=14.4 min.
spectral data in accordance with those described for the
racemate; yield: 59 mg (85%), mp 102–1048C; [a]2D0: +109.5
(c=0.2, MeOH). The title compound was found to have an
enantiomeric ratio of 10:90 with an absolute configuration
of (S) for the major enantiomer using SFC analysis (column
AS-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-isomer retention
time=19.11 min and (R)-isomer retention time=14.4 min.
N-Cyclohexyl-3-(4-fluorophenyl)butanamide.[2] Using the
general procedure described for the Suzuki–Miyaura cross-
coupling of potassium N-cyclohexyl-3-(trifluoroborato)buta-
namide and 4-chlorofluorobenzene, the title compound was
obtained as a white solid after silica gel column chromatog-
raphy; yield: 55 mg (83%); mp 132–1348C; 1H NMR
(300 MHz, CDCl3): d=7.12–7.26 (m, 2H), 6.90–7.04 (m,
2H), 5.32 (d, J=9.1 Hz, 1H), 3.60–3.81 (m, 1H), 3.26–3.30
(m, 1H), 2.31–2.47 (m, 2H), 1.79–1.93 (m, 1H), 1.50–1.76
(m, 4H), 1.27 (d, J-7.0 Hz, 3H), 0.83–1.25 (m, 5H);
13C NMR (75 MHz, CDCl3): d=170.2, 162.9 (d, J=
243.5 Hz), 141.4, 128.10 (d, J=7.8 Hz), 115.0 (d, J=
21.1 Hz), 47.8, 46.0, 36.3, 32.9, 32.8, 25.3, 24.7, 24.6, 21.5;
19F NMR (282.4 MHz, CDCl3): d=À116.94. Using SFC anal-
ysis (column AS-H, 10% i-PrOH, 2 mL, 10 MPa): (S)-
isomer retention time=8.41 min and (R)-isomer retention
time=9.81 min.
Acknowledgements
This research was supported by the NIGMS (R01 GM-
081376) and an NSF GOALI grant. Melvin Lim and Dr.
Sarah Trice (University of Pennsylvania) are acknowledged
for their assistance in the initial optimization with Taniaphos
T001. BASF and AllyChem Co. Ltd. are acknowledged for
their generous donations of bisboronic acid. BASF is also ac-
knowledged for their generous donation of tetrakis(dimethyl-
AHCTUNGTREGaNNUN mino)diboron. Frontier Scientific is acknowledged for their
donation of palladium salts. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HR-MS data.
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Using the general procedure described for the Suzuki–
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