Synthesis of Chiral Bifunctional NHC Ligands and Survey of Their Utilities in Asymmetric Gold Catalysis

Article abstract of DOI:10.1021/acs.organomet.9b00400

The synthesis and characterization of the chiral bifunctional NHC ligands based on the imidazo[1,5-a]pyridine (ImPy) scaffold are described. These ligands possess a fluxional biaryl axis and a chiral center. The configurational stability of the biaryl axis in their gold(I) complexes is investigated. The application of these axially chiral ImPy-based AuCl complexes in a series of gold catalysis is explored, and varying degrees of asymmetric induction are observed. In most cases, the ligand (aS,R)-L8-H with its cyclohexyl group pointing to the reaction site and hence exerting asymmetric steric influence is more effective in asymmetric induction.

Full text of DOI:10.1021/acs.organomet.9b00400

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Cite This: Organometallics XXXX, XXX, XXX−XXX
Synthesis of Chiral Bifunctional NHC Ligands and Survey of Their
Utilities in Asymmetric Gold Catalysis
Jun-Qi Zhang,†,‡ Yunkui Liu,†,§ Xing-Wang Wang,‡ and Liming Zhang*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China
§State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou
310014, P. R. China
S
* Supporting Information
ABSTRACT: The synthesis and characterization of the chiral bifunc-
tional NHC ligands based on the imidazo[1,5-a]pyridine (ImPy)
scaffold are described. These ligands possess a fluxional biaryl axis and a
chiral center. The configurational stability of the biaryl axis in their
gold(I) complexes is investigated. The application of these axially chiral
ImPy-based AuCl complexes in a series of gold catalysis is explored, and
varying degrees of asymmetric induction are observed. In most cases, the
ligand (aS,R)-L8-H with its cyclohexyl group pointing to the reaction
site and hence exerting asymmetric steric influence is more effective in
asymmetric induction.
tions between the basic group and substrates and/or
nucleophiles in homogeneous gold catalysis (Figure 1A). As
such, a range of versatile and/or new gold catalyses have been
developed.1 For example, WangPhos, the first ligand of this
type and one that features a 3′-carboxamide, can accelerate the
gold-catalyzed addition of carboxylic acid to alkyne >800-fold
by comparison to JohnPhos, a ligand of similar steric and
electronic characteristics but without the remote basic group
(eq 1).1i As a result, the loading of the gold catalyst in this
reaction mixture can be decreased to a level of tens of parts per
million. This accelerative gold catalysis is also applied to
achieve for the first time accelerative asymmetric gold catalysis,
in which hexa-4,5-dien-1-ols are cyclized with an excellent
enantiomeric excess in the presence of as little as 100 ppm of
the chiral cationic gold(I) catalyst2 prepared from the
binaphthyl ligand (R)-L1 (eq 2).1e Replacing the amide
group of WangPhos with a more basic aniline or tertiary amino
group led to ligands L2−L7, among others, that are capable of
engaging novel interactions with alkyne substrates via the basic
groups and thereby enable gold catalysis1a−d,f,h that cannot be
achieved by conventional ligands. The first study in this
context is the isomerization of alkynes into 1,3-dienes (eq 3).
In this case, the remote anilinic group (pKa ∼ 4) of ligand L2 is
capable of effectively deprotonating the propargylic C−H bond
(pKa > 30) due to the synergistic Au(I) activation and the
INTRODUCTION
■
For the past several years, our lab has developed several
remotely functionalized biaryl-2-ylphosphines [i.e., WangPhos
and L1−L7 (Figure 1)] for gold catalysis.1 These novel ligands
feature a basic substituent at the bottom half of the pendant
aryl ring. Because of the approximately linear arrangement of
the P−Au−substrate coordination and the restricted rotation
of the P−C2 bond imposed by the bulky adamantyl groups,
they enable beneficiary second-coordination sphere interac-
Special Issue: Asymmetric Synthesis Enabled by Organometallic
Complexes
Figure 1. Novel biaryl-2-ylphosphines featuring a remote basic
functional group specifically designed for homogeneous gold catalysis:
(A) design and (B) a selected list of our reported ligands.
Received: June 17, 2019
© XXXX American Chemical Society
A
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independently and has since been adopted for the preparation
of Au(I)/Au(III) complexes with cytotoxicity5 and photo-
physical properties6 and for structural considerations7 and
catalysis.7b,8 Bifunctional ImPy ligands have also been
developed for Au,8b Pd,9 and Cu10 chemistry (Figure 2A).
Our design, as shown in Figure 2B, entails the installation of a
chiral tetrahydroisoquinoline moiety at C-5 of the ligand
imidazo[1,5-a]pyridine ring. The resulting ImPy ligand L8
should have a fluxional biaryl axis, where the two connecting
aryl groups should be mostly oriented orthogonally. It is by
design analogous to chiral phosphine ligand L7 but could offer
three distinct differences (Scheme 1). (a) The NHC is more
Scheme 1. Synthesis of [(aS,R)-L8-H]AuCl, [(aS,R)-L8-
Me]AuCl, [(aR,R)-L8-H]AuCl, and [(aR,R)-L8-Me]AuCl
likely optimal ligand framework (eq 3). The extension of this
synergistic soft propargylic deprotonation in the presence of
the more basic tertiary amine-functionalized ligands led to,
among other works,1b,d,f our recent report on asymmetric
isomerization of propargylic alcohols into 2,5-dihydrofurans
(eq 4).1a In this chemistry, chiral ligand L7 featuring a chiral
tetrahydroisoquinoline and a fluxional axis can enable gold-
catalyzed asymmetric isomerization of alkyne into chiral allene.
RESULTS AND DISCUSSION
■
Ligand Design. Encouraged by these developments, we
have recently extended the ligand design concept to the
development of bifunctional NHC-type ligands and, in
particular, their chiral versions based on the imidazo[1,5-
a]pyridine framework (Figure 2). This class of NHC ligands
(ImPy) was initially reported by Lassaletta3 and Glorius4
electron-donating and hence renders the cationic gold catalysts
potentially more robust and offers a different catalytic activity
profile. (b) The rigid imidazo[1,5-a]pyridine framework
removes issues associated with C−P rotation in the phosphine
case, including the necessity of installing bulky PAd2 and the
potential entropy penalty during reaction. (c) The carbene−
Au−substrate line is tilted away from the pendant aryl ring due
to the 5−6-fused nature of the top half of the ligand. We
anticipate that the first two differences could offer discrete
advantages to gold catalysis, but the third might diminish the
second-coordination sphere interaction due to the increasing
separation of the participating groups. Herein, we report the
synthesis of several chiral ligands of this type, their character-
izations, and a survey of their effectiveness in inducing
asymmetric gold catalysis.
Figure 2. Bifunctional imidazo[1,5-a]pyridin-3-ylidene ligands or
their precursors: (A) known examples and (B) our design and
comparison to L7.
B
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Figure 3. ORTEP drawings of [(aR,R)-L8-H]AuCl (A, solvent omitted) and [(aR,R)-L8-Me]AuCl and [(aS,R)-L8-Me]AuCl (B, solvent shown)
showing 50% thermal ellipsoid probabilities. Selected bond distances (angstroms) and angles (degrees) for [(aR,R)-L8-H]AuCl: Au1−C1,
1.977(15); Au1−Cl1, 2.268(4); C1−N1, 1.352(19); C1−N2, 1.361(18); C7−C8, 1.45(2); C1−Au1−Cl1, 177.9(5); N1−C1−N2, 104.2(12).
Selected bond distances (angstroms) and angles (degrees) for [(aR,R)-L8-Me]AuCl: Au2−C37, 2.00(3); Au2−Cl2, 2.294(8); C37−N4, 1.36(4);
C37−N5, 1.37(3); C40−C44, 1.49(4); C37−Au2−Cl2, 178.3(9); N4−C37−N5, 99(2). Selected bond distances (angstroms) and angles
(degrees) for [(aS,R)-L8-Me]AuCl: Au1−C1, 1.93(3); Au1−Cl1, 2.266(7); C1−N1, 1.39(4); C1−N2, 1.32(3); C4−C8, 1.47(4); C1−Au1−Cl1,
177.9(9); N1−C1−N2, 107(2).
Synthesis of Chiral Bifunctional NHC Ligands and the
Structural Data of Their Au(I) Complexes. Our synthesis
of the gold(I) complexes of (R)-L8 commenced with the
condensation between 6-bromopicolinaldehyde and 2,6-
diisopropylaniline, followed by the reaction with paraformal-
dehyde in the presence of TMSBr.11 Upon workup, 5-bromo-
2-(2,6-diisopropylphenyl)imidazo[1,5-a]pyridin-2-ium 1 was
obtained as a white powder. Its Suzuki−Miyaura coupling
with the boronate (R)-2, the synthesis of which we reported
previously,1a yielded the biaryl NHC precursor salt (R)-3 by
employing a modified literature procedure.4 The gold complex
[(R)-L8-Boc]AuCl was prepared first by the synthesis of its
silver complex as a crude product from (R)-3 by using the
combination of AgCl and KOH in dichloromethane in the dark
and then by its transmetalation with AuCl·SMe2. As expected,
[(R)-L8-Boc]AuCl exhibits a mixture of diastereomeric
atropisomers (3:2 dr) due to the restricted rotation of the
biaryl axis in the presence of AuCl. To our delight, they could
be readily separated by regular silica gel flash column
chromatography. Subsequently, the Boc groups of the
separated NHC−Au(I) complexes [(aS,R)-L8-Boc]AuCl and
[(aR,R)-L8-Boc]AuCl were quantitatively removed upon
exposure to TFA at 0 °C, affording complexes [(aS,R)-L8-
H]AuCl and [(aR,R)-L8-H]AuCl, respectively, as white solids
upon subsequent aqueous NaHCO3 washing. These solids are
fully air and moisture stable. Furthermore, they underwent
reductive amination in the presence of paraformaldehyde and
NaBH(OAc)3 without incident to smoothly deliver [(aS,R)-
L8-Me]AuCl and [(aR,R)-L8-Me]AuCl, respectively, in
excellent yields. Single crystals of [(aR,R)-L8-H]AuCl and of
the 1:1 mixture of [(aR,R)-L8-Me]AuCl and [(aS,R)-L8-
Me]AuCl were successfully cultivated and subsequently
subjected to X-ray diffraction studies. Their molecular
structures and selected structural data are shown in Figure 3.
As expected, the Ccarbene−Au−Cl connection is nearly linear,
with the angle ranging from 177.9° to 178.3°. The Au−Cl
distances range from 2.266 to 2.294 Å, and their Au−carbene
bond lengths range from 1.93 to 2.00 Å.
Fluxional Nature of the Ligand Biaryl Axis. Inspired by
our previously reported work on the related phosphine
ligands,1a we speculated that these chiral ImPy-based AuCl
complexes, upon removal of the chloride, could rotate along its
biaryl axis under heating conditions. Thus, we first examined
[(aS,R)-L8-H]AuCl using our previously employed protocol:
heating a mixture of 1 equiv of the complex, 4 equiv of
NaBArF , and 20 equiv of 6-dodecyne in DCE at the specified
4
temperature and then quenching the reaction with tetrabuty-
lammonium chloride (4 equiv) after the specified time (Figure
4A). We note that this complex has the cyclohexyl group
Figure 4. Rationales for inducing chirality by the chiral bifunctional
ImPy−Au complexes.
intrude into the space of AuCl. This protocol is intended to
examine the biaryl axis fluxionality of the in situ-generated
cationic [(aS,R)-L8-H]Au+ complex. As shown in Figure 4A, a
small amount of [(aR,R)-L8-H]AuCl was observed when the
rotation was conducted at room temperature for 3 h. With a
further increase in temperature to 50 °C, more [(aR,R)-L8-
H]AuCl was detected with an (aR)/(aS) ratio of 0.19/1.00.
The ratio increased to 1.00/0.09 when the conversion was
performed at 80 °C for 3 h. Eventually, after 24 h, the (aR)/
(aS) ratio was further increased to 1.00/0.04, which appears to
be the equilibrium point. This conclusion was supported by
C
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Scheme 2. Studying the Biaryl Axis Rotation of ImPy-Based Gold Complexes [(R)-L8-H]Au+ and [(R)-L8-H]AuCl
reaching the same ratio when [(aR,R)-L8-H]AuCl was
employed as the starting point (Figure 4B). This result
confirms that the biaryl axis is indeed fluxional and is
consistent with our previous observation, where the presumed
cationic Au(I) intermediate with the cyclohexyl group pointing
toward the gold center, i.e., with the (aS) configuration, is
thermodynamically less stable than that with the (aR)
configuration. We propose that the electrostatic attraction
between cationic gold and the partially negatively charged and
unhindered nitrogen in the case of the (aR) configuration is
responsible for the difference in stability.
To our surprise, during the protracted cultivation of single
crystals for X-ray studies, we detected epimerization of [(R)-
L8-H]AuCl at its chiral axis in solution, which is in contrast to
the configuration stability of L7AuCl.1a Subjecting either [(R)-
L8-H]AuCl atropisomer in DCE to an elevated temperature
confirmed it (Scheme 2C,D) and revealed (a) their rates of
epimerization are similar to those of the cationic counterpart
(i.e., Scheme 2A,B) and (b) the preference for the (aR)
configuration over the (aS) configuration is only 2-fold, much
lower than that of the cationic counterparts (∼25-fold),
suggesting the predominating role of electronic attraction in
favoring [(aR,R)-L8-H] in the cationic scenarios. We did not
observe, however, that either atropisomer of [(R)-L8-H]AuCl
in the solid state had undergone any epimerization while
stored at 0 °C for 1 month.
Applications in Asymmetric Gold Catalysis. Having the
four chiral ImPyAu(I) complexes in hand, we then survey their
efficacy in enabling asymmetric gold catalysis,12 albeit the
semifluxional nature of their biaryl axes. It is surmised, as
shown in Figure 4A, that with (aR,R)-L8-H as the ligand, the
electrostatic attraction between the partially negatively charged
ligand nitrogen and the cationic intermediates ubiquitous in
gold catalysis might introduce the necessary asymmetric
interaction to effectively induce product chirality. Alternatively,
as shown in Figure 4B, the chiral steric environment posed by
the protruding cyclohexyl group in the case of (aS,R)-L8-H
could likewise be conducive to asymmetric catalysis.
We first investigated the gold-catalyzed alkoxycyclization of
1,6-enyne 4a [X = C(CO2Me)2],13 and the results are
summarized in Table 1 (entries 1−6). With [(aR,R)-L8-
H]AuCl as the catalyst precursor and AgSbF6 as the chloride
D
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a
Table 1. Au-Catalyzed Alkoxycyclization of 1,6-Enynes
Scheme 3. Gold-Catalyzed Enantioselective Cyclization of
4-Allen-1-ol 7
b
c
yield
ee
entry enyne
catalyst
chloride scavenger
AgSbF6
(%)
(%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4b
4b
[(aR,R)-L8-H]
AuCl
[(aR,R)-L8-Me]
AuCl
[(aS,R)-L8-H]
AuCl
[(aS,R)-L8-Me]
AuCl
[(aS,R)-L8-H]
AuCl
[(aS,R)-L8-H]
AuCl
[(aS,R)-L8-H]
AuCl
[(aR,R)-L8-H]
AuCl
52
33
AgSbF6
AgSbF6
AgSbF6
trace
99
−
−73
−66
−18
−77
−
99
NaBArF
82
4
cyclohexyl group pointing away from gold induced no chirality;
on the other hand, its atropoisomer [(aS,R)-L8-H]AuCl led to
the formation of vinyltetrahydrofuran 9 with 29% ee, which
was determined by chiral HPLC analysis of its cross-coupling
product 10. We previously reported that with a remotely
amide-functionalized binaphthyl-2-ylphosphine as the ligand
an accelerative asymmetric gold catalysis permits the
cyclization of 8 with excellent ee.1e In that chemistry, the
amide group, behaving as a general base, enables the drastic
rate acceleration and thereby the asymmetric induction. The
lack of such acceleration in the case of (aR,R)-L8-H is not
entirely surprising as the basic nitrogen is most likely
positioned too far from the HO group during cyclization.
The [2+2] cycloaddition between α-methylstyrene and
phenylacetylene has been realized asymmetrically by using
non-C2-chiral Josiphos digold(I) complexes as the catalyst.17
However, neither (aR,R)-L8-H nor (aS,R)-L8-H was able to
induce much chirality in this reaction; however, the reaction
was efficient (eq 6). Notably, in this case, the same enantiomer
was preferred.
[Ag(CH3CN)2]+
BARF−
AgSbF6
97
trace
71
AgSbF6
21
a
Reaction conditions: 0.1 mmol scale, 5 mol % catalyst based on Au
center, 5 mol % chloride scavenger, 1 mL of mixed solvent (1:1
b
c
DCM/MeOH). Isolated yields. Determined by chiral HPLC. The
absolute stereochemistry is assigned upon the comparison of its
specific rotation to the literature data, and the negative ee values
indicate the opposite configuration of the product.
scavenger, desired product 5a was formed in 52% yield and
with 33% ee (entry 1). On the other hand, the N-methyl
counterpart of [(aR,R)-L8-H]AuCl, i.e., [(aR,R)-L8-Me]AuCl,
led to only a trace amount of reaction (entry 2). Significant
increases in enantioselectivity and yield in the presence of
either of the (aS) ligands, i.e., [(aS,R)-L8-H] or [(aS,R)-L8-
Me], were observed (entry 3 or 4, respectively). We note that
the sense of chirality is opposite and the ee can reach a
respectable value of −73%. The chloride scavenger appears to
be important, as NaBArF led to poor ee (entry 5) but
4
[Ag(MeCN)2]+ BARF− improved it to −77% (entry 6).
Because (R)-L8-H performed better than (R)-L8-Me, the
former ligands were employed in the subsequent studies.
12
Sulfonamide substrate 4b,11
,
however, reacted quite
c
differently, with (aR,R)-L8-H performing instead much better
than [(aS,R)-L8-H] in terms of reaction yield (entries 7 and
8), but the ee remained poor.
We then evaluated the asymmetric cyclopropanation of
styrene by the gold carbene generated from methyl phenyl-
diazoacetate 6. Despite this reaction has been widely reported
by employing chiral Rh catalysts,14 the gold counterpart15 has
not been achieved with good enantiomeric excess, despite
success in related studies.16 To our delight, both ligands
(aS,R)-L8-H and (aR,R)-L8-H could promote the reaction
with high efficiency and decent enantiomeric excess. The
absolute stereochemistry of 7 is assigned upon the comparison
of its specific rotation to the literature data.14 Again, the ligand
atropisomers led to the selective formation of the enantiomer
of 7 and hence to the negative ee value (eq 5).
The asymmetric cyclizations of 4-allen-1-ol 8 was next
examined. As shown in Scheme 3, [(aR,R)-L8-H]AuCl with its
We next turned to the reactions of allenamides, which have
been subjected to asymmetric gold catalysis in several
E
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reports.18 As shown in eq 7, both atropisomers of (R)-L8-H
smoothly promoted the intermolecular [2+2] cycloaddition
between allenamide 13 and p-methoxystyrene to afford the
cyclobutane 14 in >80% yields. For the asymmetric induction,
similar to the observations in Table 1, they led to opposite
stereoselectivities and (aS,R)-L8-H was substantially better
than its (aR) counterpart. The reaction of 13 with 1-phenyl-
1,3-butadiene was the most enantioselective with either of the
(R)-L8-H isomers among the screened reactions (eq 8). Again,
(aS,R)-L8-H is better, albeit moderately, and an 84%
unoptimized ee was achieved for cyclohexene product 15. In
these two cases, the product absolute configurations were also
assigned upon comparison of their specific rotations to
literature data.18
site and hence posing a chiral steric environment is more
effective in inducing chirality than its atropisomer (aR,R)-L8-
H, which relies on electrostatic attraction for enantioselectivity.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00400.
■
S
General procedures, procedure for the preparation of
gold complexes, Au-catalyzed enantioselective trans-
1
formations, X-ray structures of gold catalysts, H and
13C NMR spectra, HPLC chromatograms, and refer-
ences (PDF)
With acetal 16 as the substrate, the gold-catalyzed
cycloisomerization led to indanone product 17 upon hydrolysis
in good yields (Scheme 4).19 Interestingly, in this case, (aR,R)-
Accession Codes
CCDC 1910598 and 1913712 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Gold(I)-Catalyzed Enantioselective
Carboalkoxylation of Alkyne
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhang@chem.ucsb.edu.
■
ORCID
Yunkui Liu: 0000-0001-8614-458X
Xing-Wang Wang: 0000-0002-6004-8458
Liming Zhang: 0000-0002-5306-1515
Notes
L8-H induced much higher enantiomeric excesses than that of
its (aS,R) counterpart, in contrast to the trend observed in
Table 1, Scheme 3, and eqs 5, 7 and 8, where the latter ligand
was more effective in asymmetric induction. The configuration
of 18 was assigned on the basis of chiral HPLC behavior
comparable to that of the literature.19
These results reveal that both the attractive interaction and
the steric repulsion outlined in Figure 4 can indeed provide
asymmetric induction. In most cases, the chiral steric
environment posed by (aS,R)-L8-H is more effective in
controlling the stereochemical outcomes. However, in the
case of Scheme 4, the development of a discrete oxocarbenium
intermediate prior to the enantiodetermining step apparently
allows better stereocontrol by the electronic mode, therefore
affording a much higher ee in the case of (aR,R)-L8-H.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.-Q.Z. and Y.L. thank the China Scholarship Council for a
scholarship. The authors are thankful for National Institute of
General Medical Sciences Grant R01GM123342 and National
Science Foundation Grant CHE 1800525 for financial support
and National Institutes of Health Shared Instrument Grant
S10OD012077 for the purchase of a 400 MHz NMR
spectrometer.
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CONCLUSIONS
■
We have synthesized and characterized four new chiral
bifunctional NHC ligands based on the imidazo[1,5-a]pyridine
(ImPy) scaffold. These ligands possess a fluxional biaryl axis, a
chiral center, and a remote alkylamino group. Upon
coordination to Au(I), the rotation around the biaryl axis is
hindered, but the equilibria between the atropisomers can be
established upon moderate heating. Despite the semistable
axial chirality, these gold complexes are demonstrated to
induce chirality with a range of gold-catalyzed transformations,
and enantiomeric excesses can reach 84%. Two modes of
imparting asymmetry by these ligands are chiral steric
hindrance and asymmetric electrostatic attraction, the choice
of which is dictated by the ligand axial chirality and often leads
to opposite asymmetric induction. In most cases, ligand
(aS,R)-L8-H with its cyclohexyl group pointing to the reaction
F
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