Design, preparation, and implementation of an imidazole-based chiral biaryl P,N-ligand for asymmetric catalysis

Article abstract of DOI:10.1021/ja407689a

A new strategy for increasing the barrier to rotation in biaryls has been developed that allows for the incorporation of 5-membered aromatic heterocycles into chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A³-coupling, demonstrating the potential of this new design element.

Full text of DOI:10.1021/ja407689a

Communication
pubs.acs.org/JACS
Design, Preparation, and Implementation of an Imidazole-Based
Chiral Biaryl P,N-Ligand for Asymmetric Catalysis
Flavio S. P. Cardoso, Khalil A. Abboud, and Aaron Aponick*
Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, United States
S
* Supporting Information
adjacent aromatic group due to the modified bond angles of the
ABSTRACT: A new strategy for increasing the barrier to
rotation in biaryls has been developed that allows for the
incorporation of 5-membered aromatic heterocycles into
chiral atropisomers. Using this concept, an imidazole-
based biaryl P,N-ligand has been designed and prepared as
a single enantiomer. This ligand performs exceptionally
well in the enantioselective A3-coupling, demonstrating the
potential of this new design element.
ring system. This may lead to a reduced barrier to rotation and
loss of chirality. In his seminal work, Brown encountered this
difficulty when 4, an indole version of QUINAP, was prepared
and found not to be configurationally stable (Figure 1).11 While
he chiral biaryl structural motif is an important
T
component found in a diverse array of catalysts for
enantioselective synthesis.1 Ligands built on the binaphthalene
and biphenyl backbones are regularly employed in a variety of
reactions, with such success that BINAP (1) and BINOL are
referred to as privileged ligands.2 The atropisomeric backbone
in the vast majority of chiral biaryl ligands is comprised of
substituted or fused benzenoid aromatics that rely on ortho-
substitution to hinder rotation about the biaryl bond.3 Although
reducing the steric demand by removing substituents from the
2- or 8-position lowers the barrier to rotation and hence
reduces configurational stability,4 P,N-ligands such as QUINAP
(2)5 and PINAP (3)6 have successfully been prepared and
employed in enantioselective transformations.7,8 It is well-
known that changing the dihedral and bite angles of the biaryl
can drastically affect ligand performance, and the success of 2
and 3 can be attributed to modifying these parameters as well
as changing the donating properties of the ligand.9
Figure 1. Configurationally unstable ligand 4.
this may potentially be overcome by the incorporation of
increasingly large ortho-substituents,12 the central dogma for
inducing atropisomerism, we hypothesized that a fundamental
new approach to increasing the barrier to rotation could be
developed to enable new classes of highly reactive and selective
catalysts. More specifically, we hypothesized that the barrier to
rotation in biaryls can be increased by stabilizing the chiral ground-
state conformation instead of destabilizing the planar transition
state, leading to racemization (Figure 1). Surprisingly, to the best
of our knowledge, this strategy has never been explored. Herein
we report our findings in this area including the design,
synthesis, deracemization, and successful implementation of a
chiral imidazole-based biaryl P,N-ligand for enantioselective
copper acetylide addition.
The design of our ligand centers around the incorporation of
a 5-membered electron-rich aromatic heterocycle that contains
a coordinating atom and functional elements that stabilize the
chiral conformation. At the outset we envisioned an imidazole-
based system, providing a basic coordination site and a second
nitrogen atom that could be appended with a group to stabilize
the chiral conformation 7 through π-stacking interactions
(Figure 2). This would provide a unique P,N-ligand with
modified bite and dihedral angles.
The synthesis of racemic 7 was achieved in several
straightforward steps starting with 2-hydroxy-1-naphthaldehyde
8, whereby the requisite heterocycle and phosphino groups
were readily introduced (Scheme 1). In the event, condensation
of 8 with ammonium acetate and benzil furnished 9 in 80%
Atropisomeric P,N-ligands have proven to be highly
selective,7 but making structural modifications for fine-tuning
of the ligand is challenging, and relatively few derivatives are
known.8 In contrast to the substituted or fused 6-membered
aromatics commonly encountered, 5-membered heteroaro-
matics would offer a new, unexplored chemical diversity and
be much easier to prepare and modify using established
methods.10 One potential problem is that ortho-substituents on
5-membered rings are not held as closely in space to the
Received: August 6, 2013
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
converted to a single enantiomer in a two-step process, in effect
deracemizing it. To achieve this, rac-7 was treated with complex
14 and KPF6 in refluxing acetone for 24 h to provide 15 in 81%
yield as a single diastereomer whose structure was confirmed by
X-ray crystallography (Scheme 2).19,20 The free ligand was then
obtained in high yield and 98% ee after treatment with dppe.21
Figure 2. Stabilization of the chiral conformation in 7.
Scheme 2. Deracemization of Ligand 7
Scheme 1. Synthesis of Racemic Ligand 7
Interestingly, the inclusion of KPF6 is vital to the success of
the reaction, as two non-interconverting diastereomers are
observed in the absence of this additive. Control experiments
were performed to study this issue, and an equal mixture of two
diastereomers was formed when KPF6 was omitted but under
otherwise identical reaction conditions. Additionally, re-
complexation of 7 (98% ee) to 14 results in a single
diastereomer that does not revert to the same 1:1 mixture of
diastereomers upon heating.
It is important to note that 7 is configurationally stable, and
samples of the ligand have been stored for several months with
no loss of optical purity. One further question regarding the
structure involves the role of the C6F5 group and π-stacking.
Evidence of π-stacking was obtained early on when X-ray-
quality single crystals were grown from a sample of rac-7 and
the structure was solved (Figure 3).19 The F5-phenyl group is
yield.13 The free alcohol was then protected as the TBS ether,
and the resulting imidazole was alkylated with pentafluor-
obenzyl bromide to yield 10. The alcohol was then deprotected,
converted to the triflate, and coupled14 to produce rac-7 in ca.
33% overall yield from commercial materials. We were
encouraged to find an AB pattern for the benzylic protons in
the 1H NMR spectrum of rac-7, indicating that they are
diastereotopic on the NMR time scale.
With a good source of 7 established, albeit racemic, it seemed
prudent to perform a preliminary ligand acceleration effect
study. To this end, rac-7 was employed in a copper-catalyzed
A3-coupling15 of butyraldehyde, trimethylsilylacetylene, and
dibenzylamine (eq 1). Much to our delight, amine product 13
was isolated in 97% yield after 24 h at room temperature.
Structurally, ligand 7 is significantly different than the known
biaryl P,N-ligands such as QUINAP, where 13 is obtained in
88% after 120 h.6,16 Extended reaction times of several days to a
week are commonly observed using these ligands.17 With rac-7,
the reactivity was enhanced to such an extent that the reaction
could even be performed at 0 °C, providing 13 in 92% yield
after 24 h (eq 1). This should be advantageous for achieving
high selectivities, and attempts were next made to obtain the
ligand as a single enantiomer.
For QUINAP and derivatives containing only axial chirality,
non-racemic material is typically obtained by resolution
involving coordination to a chiral Pd salt, crystallization, and
decomplexation.5,11,18 Unfortunately, this strategy did not
provide satisfactory results, and 7 could only be obtained in
85−90% ee. Fortunately, instead of resolving 7, after extensive
optimization it was found that the racemic compound could be
Figure 3. X-ray crystal structure showing π-stacking.
π-stacking with the naphthalene ring at a mean distance of 3.36
Å in a parallel, offset stack.22 This demonstrates that π-stacking
is possible in the solid state, but does not necessarily indicate
that it has any influence on the barrier to rotation in solution.
Literature protocols used to study π-stacking involve
modification of the substitution on one of the aromatic
rings.22 To probe this issue, a comparison of barrier heights
between 7 and a compound that would maintain the steric
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Journal of the American Chemical Society
Communication
a
Table 1. Enantioselective A3-Coupling Employing 7
profile but perturb the ability to π-stack was needed. In accord
with literature precedent, the corresponding non-fluorinated
compound was chosen because if the effect was purely steric, no
significant difference would be expected. If π-stacking is indeed
involved in the solution phase, a significant difference in barrier
height should be observed.
To make the necessary comparisons, 7-H5 was prepared
from 8 using the route outlined above.19 Interestingly, the
penultimate non-flourinated palladium complex 15-H5 was
configurationally unstable, and the 1:1 diastereomeric mixture
of complexes prepared from racemic 7-H5 converged on a
single diastereomer upon standing at room temperature for 24
h. When 7-H5 was liberated from the Pd complex, it was
obtained in 52% ee, in stark contrast to 7 which was isolated in
98% ee. Racemization studies were performed23 on both 7-H5
and 7 to obtain their barriers to rotation, and it was found that
7-H5 has a half-life of 22 min at 75 °C in DCE, whereas 7 has a
half-life of 8.70 h.19 This corresponds to ΔΔG⧧75°C = 2.2 kcal/
mol,19 a value that is within the range of previously reported
values for π-stacking,22 and demonstrates that the electronic
perturbation by simple inclusion of the fluorine atoms
significantly increases the barrier to rotation.
With the new chiral non-racemic ligand 7 in hand, we turned
our attention to testing its performance in an enantioselective
transformation. To this end, 7 was employed in the
enantioselective A3-coupling. As can be seen in Table 1, the
reactions were highly enantioselective over a range of
aldehydes. As might be expected,15 with aliphatic aldehydes
α-substitution increases selectivity (e.g., entry 1 vs 4). It is also
noteworthy that, using 7, these conditions work well for
aromatic aldehydes, which are the most challenging substrates
for the reaction.17 Remarkably, the presence of electron-
donating or -withdrawing groups has little effect on selectivity
(entries 5−9), nor does the reaction temperature. When 16g
was allowed to react at 0 °C, the reaction was very slow,
yielding 17g in only 15% after 4 days, but in 95% ee (entry 8).
Increasing the temperature to 22 °C restored the reactivity to
an acceptable level (70% yield after 24 h) and had little effect
on the ee (entry 9). In comparison, the previous best yield
obtained with this electron-deficient aldehyde was 43% after 4
days to obtain the product in 63% ee.17a
a
b
See Supporting Information for full experimental details. Isolated
c
d
yields of purified compounds. Determined after desilyation. Reaction
allowed to run for 4 days at 0 °C. Reaction allowed to run for 24 h at
22 °C.
e
Scheme 3. Alkyne Addition with 19
Carreira has also developed modified conditions to employ
the amine 19, which is readily deprotected.24 With these
conditions, using the PINAP ligand, they report that aromatic
aldehydes do not provide satisfactory results.24 In contrast,
ligand 7 enables the use of both aliphatic and aromatic
aldehydes with high enantioselectivity (Scheme 3). These
results lead to the conclusion that 7 is the best ligand for the
enantioselective A3-coupling to date, displaying the highest
levels of reactivity and selectivity over the broadest range of
substrates. More importantly, these results demonstrate the
potential of the new design element exemplified by 7.
In summary, we have developed a new concept for increasing
the barrier to rotation in biaryls whereby the chiral ground-state
conformation is stabilized by π-stacking interactions. This
strategy was successfully applied to the design of ligand 7, a
C
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Journal of the American Chemical Society
Communication
(10) Li, J. J. Name Reactions in Heterocyclic Chemistry; Wiley-VCH:
Weinheim, 2004.
new chiral biaryl P,N-ligand incorporating a 5-membered
electron-rich heteroaromatic. The ligand is straightforward to
prepare and has been demonstrated to be a superb catalyst for
the enantioselective A3-coupling reaction. More importantly,
this design concept should be broadly applicable and enable a
new class of 5-membered heteroaromatic biaryls to be prepared
as catalysts for a range of reactions. Further studies on this are
underway in our laboratories and will be reported in due
course.
(11) Claridge, T. D. W.; Long, J. M.; Brown, J. M.; Hibbs, D.;
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■
̀
S
* Supporting Information
̀
Full experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2000, 65, 8340−8347. (f) Andersen, N. G.; Parvez, M.; Keay, B. A.
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AUTHOR INFORMATION
Corresponding Author
aponick@chem.ufl.edu
Notes
■
(13) Eseola, A. O.; Obi-Egbedi, N. O Spectrochim. Acta A 2010, 75,
693−701.
The authors declare no competing financial interest.
(14) Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Tetrahedron 2000, 56,
8893−8899.
ACKNOWLEDGMENTS
(15) (a) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V.
Chem. Soc. Rev. 2012, 41, 3790−3807. (b) Yoo, W.-J.; L. Zhao, L.; Li,
C.-J. Aldrichim. Acta 2011, 44, 43−51.
■
The authors thank the University of Florida for their generous
support of our programs and Prof. Jon Stewart (UF) for the
loan of HPLC equipment.
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