hetaryl halides. Recently, we demonstrated the Suzuki-
Miyaura cross-coupling reactions of ꢀ-trifluoroborato ke-
tones, esters, and amides, which led to the construction of
ꢀ-aryl/hetaryl carbonyls.5 The ꢀ-trifluoroborato carbonyl
reagents are attractive cross-coupling partners because of
their functional group tolerance and minimal toxicity.6 As a
family, potassium organotrifluoroborates have been shown
to possess increased stability compared to their boronic acid/
boronate counterparts in Suzuki-Miyaura reactions, includ-
ing an indefinite stability to ambient moisture and a low
tendency to protodeboronate during cross-coupling.7
Scheme 2
.
Synthesis and Suzuki-Miyaura Cross-Coupling of
Chiral ꢀ-Trifluoroboratoamides
examples.10 In only one of these examples did the stereogenic
center reside in the organoboron component.
Related cross-coupling reagents have been utilized in
similar contexts. Thus, Negishi cross-coupling has proven
particularly effective for the construction of arylated alanyl
derivatives utilizing enantiomerically enriched R-chiral or-
ganozinc coupling partners.8 However, zinc homoenolates
are generally unstable to moisture and air, and consequently
they must be prepared in situ and maintained under an inert
atmosphere. Furthermore, these organozinc reagents exhibit
reactivity with a variety of electrophiles and thus may not
be tolerant of other functional groups in desired cross-
coupling transformations.9
To prepare the enantiomerically enriched ꢀ-trifluoroborato
amides 6a-d, (1S,1S)-(+)-pseudoephedrine was used as the
chiral auxiliary11 in a modification of a Matteson protocol.12
Thus the chirality was successfully installed via alkylation
of the enolate using iodomethylpinacolboronate. The alky-
lated products 5a-d were obtained in relatively high yields.
The diastereomeric ratios of 5a-d were determined to be
1
>95:5 by H NMR of the pinacolboronate intermediate.
Subsequent addition of KHF2 provided enantiomerically
enriched potassium trifluoroborato amides 6a-d in moderate
to excellent yields. The prepared ꢀ-trifluoroborato amides
6a-d were moisture- and air-stable solids and thus stored
on the bench indefinitely without detectable epimerization
or decomposition (Scheme 3).
We envisioned that an extension of our previous work on
ꢀ-trifluoroboratoamides to their enantiomerically enriched
counterparts, prepared by employing chiral auxiliaries, would
be a valuable tool in asymmetric synthesis. We report herein
a protocol for the synthesis of enantioenriched R-chiral
ꢀ-trifluoroborato amide substrates and their cross coupling
with a variety of aryl- and hetaryl chlorides (Scheme 2). To
the best of our knowledge, this chiral reagent class has not
previously been prepared or cross-coupled.
Scheme 3. Preparation of R-Chiral ꢀ-Trifluoroboratoamides
One of the concerns in being able to conduct the desired
transformation is retention of the stereochemical integrity
of the R stereocenter under the aqueous basic conditions at
elevated temperatures required for the organotrifluoroborate
cross-coupling. The use of enantiomerically enriched materi-
als in Suzuki-Miyaura cross-coupling reactions where the
stereocenter resides R to a carbonyl is limited to only a few
With the enantiomerically enriched ꢀ-trifluoroborato amides
in hand, we first investigated their application in Suzuki-Miyaura
cross-coupling reactions employing 6a with chlorobenzene to
determine optimal conditions. After screening several ligands,
bases, solvents, and reaction times, the combination of 5 mol
% of Pd(OAc)2 and 10 mol % of RuPhos in the presence of 3
equiv of K2CO3 in toluene/H2O (4:1, 0.25 M) for 22 h emerged
as the best conditions, leading to 7a in 70% isolated yield (Table
1, entry 1).
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cross-coupling events.
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