Ferrocene-based planar chiral imidazopyridinium salts for catalysis

Article abstract of DOI:10.1002/anie.201410118

Planar chirality remains an underutilized control element in asymmetric catalysis. Factors that have limited its broader application in catalysis include poor catalyst performance and difficulties associated with the economical production of enantiopure p

Full text of DOI:10.1002/anie.201410118

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Chemie
DOI: 10.1002/anie.201410118
Asymmetric Catalysis
Ferrocene-Based Planar Chiral Imidazopyridinium Salts for
Catalysis**
Christopher T. Check, Ki Po Jang, C. Benjamin Schwamb, Alexander S. Wong,
Michael H. Wang, and Karl A. Scheidt*
Abstract: Planar chirality remains an underutilized control
element in asymmetric catalysis. Factors that have limited its
broader application in catalysis include poor catalyst perfor-
mance and difficulties associated with the economical produc-
tion of enantiopure planar chiral compounds. The construction
of planar chiral azolium salts that incorporate a sterically
demanding iron sandwich complex is now reported. Applica-
tions of this new N-heterocyclic carbene as both an organo-
catalyst and a ligand for transition-metal catalysis demonstrate
its unprecedented versatility and potential broad utility in
asymmetric catalysis.
cantly differs from that of IMes, and they have only recently
been employed in asymmetric transformations.[8]
A major challenge in carbene catalysis is the design and
implementation of a chiral IMes analogue with competent
ligand and/or catalyst characteristics. Whereas C2-symmetric
chiral imidazolium salts are rapidly accessible through the
condensation of stereodefined amines with glyoxal,[9] these
NHCs rarely deliver high levels of selectivity as ligands in TM
catalysis and are typically unsuitable as organocatalysts.[10]
Most notably, structurally rigid NHCs that invoke planar
chirality are scarce in the literature, with most contemporary
examples featuring pendant planar chiral motifs with various
degrees of free rotation.[6a,b] Encouraged by the potential
opportunity to develop a versatile chiral IMes equivalent and
the documented successes of chiral ferrocenyl-based ligands
and catalysts as control elements in asymmetric transforma-
tions,[11,12] we set out to create imidazolium-inspired NHCs
featuring the fusion of a metal sandwich complex with the
core structure of an NHC framework (Figure 1).[13]
N-Heterocyclic carbenes (NHCs) are unique and enabling
ligands for transition metal (TM) catalysis and have emerged
as highly selective organocatalysts for a remarkably diverse
array of transformations.[1–3] Given the importance of these
strongly nucleophilic Lewis bases in chemistry, major efforts
by many laboratories have produced numerous classes of
structurally and electronically diverse NHC structures.[4]
Within this truly broad family of heteroatom-stabilized
divalent carbon species, two major classes of NHCs derived
from triazolium and imidazolium salts have demonstrated
applicability as Lewis base catalysts and TM ligands.
Although triazolium salts have seen broad application in
asymmetric organocatalysis, their success in metal-based
transformations has been limited.[2e] In contrast, imidazo-
lium-derived NHCs (imidazol-2-ylidenes) have been widely
deployed as successful ligands for TM catalysis and are unique
platforms for organocatalytic transformations. The archetype
imidazol-2-ylidene, IMes [1,3-bis(2,4,6-trimethylphenyl)imi-
dazol-2-ylidene], was introduced by Arduengo in 1992.[5]
Surprisingly, in over two decades since the disclosure of
IMes, only few chiral scaffolds based on this important species
have been reported.[6] As one notable example, the saturated
analog of IMes, SIMes (4,5-dihydro-1,3-dimesityl-1H-imida-
zolium) has been translated into multiple chiral ligands for
TM catalysis,[7] but their reactivity in organocatalysis signifi-
[*] Dr. C. T. Check, Dr. K. P. Jang, C. B. Schwamb, A. S. Wong,
M. H. Wang, Prof. Dr. K. A. Scheidt
Department of Chemistry Center for Molecular Innovation and Drug
Discovery, Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
[**] Financial support was provided by the NSF (CHE-1152010). We
thank FMC Lithium and Umicore KG for their generous supply of
organometallic reagents and rhodium salts, respectively. A.W.
thanks NU for a Summer Research Grant.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410118.
Figure 1. Chiral imidazolium strategy.
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The synthesis of such an NHC began from iron sandwich
complex 1, which was first described by Fu and co-workers
and can be prepared on multigram scale in six steps starting
from ethyl acetoacetate, cyclopentanone, and ammonium
acetate (Scheme 1, see the Supporting Information for
details).[14] Initial efforts towards the preparation of enantio-
pure aldehyde 3 from 1 involved the use of chiral preparative
HPLC, but we felt that a practical separation of diastereomers
would be advantageous for larger-scale preparations and
would ultimately allow ease of access for the catalysis
community. After extensive investigation of different meth-
ods to produce diastereomers amenable to purification/
separation, we discovered that pseudoephedrine amides 2a
and 2b could be easily separated by flash column chromatog-
raphy on silica gel (1:1 EtOAc/hexanes) on multigram scale.
Notably, this method of resolution does not result in an
increase in the number of synthetic steps over that of the
synthesis of the racemates (see the Supporting Information
for details). Ultimately, a direct palladium-catalyzed amino-
carbonylation of aryl chloride 1 provided a straightforward
route to pseudoephedrine amide 2 and enabled the crucial
separation.[15] Subsequent reduction with DIBAL-H yielded
the enantiopure aldehyde (> 99:1 e.r. by HPLC analysis on
a chiral stationary phase, see the Supporting Information for
details). The formation of the planar chiral NHC architecture
was achieved through an annulation described by Aron and
Hutt with the corresponding aniline and formaldehyde,
followed by anion exchange with AgBF4.[16] The absolute
configurations of the catalysts were then determined by X-ray
crystallography (Scheme 1).
With an optimal route to enantiopure ferrocene-based
azolium salts, we set out to explore the reactivity and
versatility of these new NHCs. Our long-standing program
towards the discovery of NHC-catalyzed transformations
compelled us to investigate the competency of these azolium
salts as organocatalyst precursors.[17] We initially focused on
the NHC-catalyzed homoenolate addition to a-ketoesters
owing to the previously documented challenge associated
with performing this transformation with high levels of
enantioselectivity.[18] Encouragingly, our initial attempt to
promote this transformation using catalyst 4a was successful,
providing the annulation product in good yield (74%). The
major and minor diastereomers were obtained in modest
enantioselectivities (66:44 and 62:38 e.r., respectively;
Scheme 2). Catalysts 4b and 4d afforded only 20% con-
version; this insufficient reactivity may be due to the lack of
ortho substituents on the pendant aromatic ring, which is
considered to be crucial for catalyst performance.[19] Catalyst
4c provided the highest levels of enantioselectivity (85:15 e.r.
for the cis diastereomer), but without any diastereoselectivity
(1:1 d.r.). While computational and experimental investiga-
tions are underway to probe the influence of the subtle
differences of the pendant aromatic ring, these new NHCs
have the potential to be capable Lewis base catalysts for the
promotion of homoenolate reactivity. The exploration of the
Scheme 1. Synthesis of planar chiral NHCs. Reaction conditions:
a) [Pd(dppf)Cl2], Cs2CO3, (+)-pseudoephedrine, toluene, CO (balloon),
65% (overall yield for both diastereomers); b) DIBAL-H, THF, 78%;
À
c) Ar NH2, formaldehyde, EtOH, HCl, THF, 51–70%; d) AgBF4,
MeCN, 74–95%. See the Supporting Information for further details.
DIBAL-H=diisobutylaluminum hydride, dppf=1,1’-bis(diphenylphos-
phanyl)ferrocene.
Scheme 2. Organocatalytic annulation. TBD=1,5,7-triazabicyclo-
[4.4.0]dec-5-ene.
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aryl substituent as well as other structural factors is ongoing
with the aim of imparting higher levels of selectivity and
reactivity in umpolung transformations.
The use of NHCs as ligands in metal-catalyzed trans-
formations has dramatically increased over the last two
decades.[1] In particular, IMes and related structures have
been found to be successful ligands for a variety of important
transformations, including olefin metathesis,[20] cross-cou-
pling,[21] and hydrogenation[22] as well as many others.[23]
A
recent report by Montgomery et al. demonstrated the ability
of saturated imidazolium NHCs to impart high levels of
enantioselectivity in nickel-catalyzed reductive couplings,
whereby the C2-symmetric NHCs first reported by Grubbs
and co-workers proved to be efficient ligands for the coupling
of simple alkynes and aldehydes.[7a,24] Although moderate to
high selectivity has been reported for reductive couplings of
alkynes and aldehydes, there remains room for further
enhancement of the enantioselectivity and scope of these
reactions.[25,26] Inspired by this report and others (see below),
we viewed this particular transformation as an excellent
opportunity to evaluate the chiral environment engendered
by 4 when bound to a transition metal such as nickel. Under
reaction conditions developed by Montgomery, NHC 4a
proved to be a capable ligand for the Ni-catalyzed reductive
coupling of 1-phenyl-1-propyne with benzaldehyde and cyclo-
hexanecarboxaldehyde using triethylsilane as the reducing
agent (Scheme 3). In both cases, the allylic alcohol product
Scheme 4. Copper catalysis.
To further our understanding of this new class of NHCs,
we examined the electronic properties of the various aryl-
substituted planar chiral ferrocenyl azolium salts through the
use of the Tolman electronic parameter (TEP).[4,29] Synthesis
of the corresponding [(NHC)Rh(CO)2Cl] complexes allowed
for a comparison of the electron-donating properties of the
planar chiral NHCs 15a–15d with those of selected known
NHCs (Figure 2).[30] These new ferrocenyl-imidazo[1,5-a]pyr-
idine NHCs have distinctive degrees of donating abilities
depending on the N-aryl substituent. Surprisingly, the mesityl-
substituted NHC (15a) possesses similar electronic properties
to the parent IMes, which is fortuitous in light of our initial
goal of creating a new chiral IMes equivalent for catalysis.
The 2,6-dimethoxyphenyl-substituted carbene 15c provided
the largest donor capacity (TEP = 2047 cmÀ1), which exceeds
that of most common imidazolium and dihydroimidazolium
carbenes. In contrast, the complex bearing a bis(trifluorome-
thyl)phenyl substituent (15d) demonstrated the smallest
donor capacity (TEP = 2054 cmÀ1), which is comparable to
that of dihydroimidazolium complexes. The current range of
modulation in the donating capability of our NHCs demon-
strates that these NHCs are versatile in their steric environ-
ments as well as electronic properties.
In conclusion, a novel NHC scaffold that incorporates an
iron sandwich complex into the azolium framework has been
developed. This new class of planar chiral imidazopyridinium-
based NHCs has proven to be highly competent as both Lewis
base catalysts and as ligands for transition-metal complexes.
Significantly, these new planar chiral NHCs impart high levels
of stereoselectivity across three challenging platforms with
distinct requirements for asymmetric induction (organocatal-
ysis, nickel(I) and copper(I) catalysis), underscoring the
potential generality of these systems.[7a,18b,27b–e] The late-
stage formation of the key azolium core allows for a modular
Scheme 3. Nickel catalysis. cod=cyclooctadiene, Cy=cyclohexyl.
was formed with excellent regioselectivity (> 20:1 and 10:1)
and enantiomeric excess (86% and 82% ee). To the best of
our knowledge, these reactions provide some of the highest
selectivities for this transformation to date and highlight the
opportunity to explore both known and unreported Ni0-
catalyzed transformations with these NHC ligands.
To further investigate the potential versatility of 4 in
additional metal-catalyzed processes, we explored the copper-
catalyzed borylation of olefins.[27] The preparation of the
enantiopure Cu/NHC complex (À)-4a-CuCl was accom-
plished following a literature procedure, and a crystal struc-
ture was obtained (Scheme 4).[28] Gratifyingly, the isolated
Cu/NHC complex catalyzed the borylation of a variety of
substrates without the need for any reaction optimization and
provided the products in good yields with high stereoselec-
tivities (Scheme 4).
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Received: October 15, 2014
Revised: November 14, 2014
Published online: && &&, &&&&
Keywords: asymmetric synthesis · N-heterocyclic carbenes ·
.
organocatalysis · transition-metal catalysis
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Communications
Asymmetric Catalysis
C. T. Check, K. P. Jang, C. B. Schwamb,
A. S. Wong, M. H. Wang,
K. A. Scheidt*
&&& — &&&
Ferrocene-Based Planar Chiral
Imidazopyridinium Salts for Catalysis
Planar chiral azolium salts that incorpo-
rate a sterically demanding iron sandwich
complex are synthesized. These newN-
heterocyclic carbenes can be employed
both as organocatalysts and as ligands
for transition-metal catalysis, which
demonstrates their unprecedented ver-
satility and potential broad utility in
asymmetric catalysis.
6
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