Enantioselective Pd0-Catalyzed C(sp2)–H Arylation for the Synthesis of Chiral Warped Molecules

Article abstract of DOI:10.1002/anie.202013303

C?H activation-based ring-forming methods are a powerful approach for the construction of complex molecular architectures, especially those containing a congested stereocenter. Therefore, this strategy seems perfectly suited to address the synthesis of ch

Full text of DOI:10.1002/anie.202013303

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Accepted Article
Title: Enantioselective Pd0-Catalyzed C(sp2)–H Arylation for the
Synthesis of Chiral Warped Molecules
Authors: David Savary and Olivier Baudoin
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Enantioselective Pd0-Catalyzed C(sp2)–H Arylation for the
Synthesis of Chiral Warped Molecules
David Savary,[a] and Olivier Baudoin*[a]
[a]
D. Savary, Prof. Dr. O. Baudoin
Department of Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: olivier.baudoin@unibas.ch
Supporting information for this article is given via a link at the end of the document.
a) Previous work
Abstract: C–H activation-based ring-forming methods constitute a
powerful approach for the construction of complex molecular
architectures, especially those containing a congested stereocenter.
Therefore, this strategy seems perfectly suited to address the
synthesis of chiral polycyclic aromatic hydrocarbons (PAHs) and
bowl-shaped molecules, which are important target molecules in the
field of organic electronic materials. Herein, we describe an
enantioselective Pd0-catalyzed C(sp2)–H arylation protocol for the
synthesis of chiral fluoradenes and other warped molecules, which
could serve to the bottom-up construction of chiral PAHs. The current
approach relies on the use of chiral bifunctional phosphine-
carboxylate ligands and delivers diverse polycyclic compounds in high
yield and with good to excellent enantioselectivity. The chiroptical
properties of the obtained products were investigated, and some of
them were found to have a strong ellipticity and an emission band
located in the visible region.
H
Pd2(dba)3•CHCl3
R1
(2.5 mol%)
Y
N
R1
R1
L9 (10 mol%)
R2
N
Y
H
Cs2CO3 (1.5 equiv)
DME, 4Å MS, 80°C
R2
R1
e.r. up to 99:1
Br
Y = CO2Me, Ts, Me
b) Synthesis of fluoradenes, working mechanistic hypothesis
F
F
Pd0 (cat.)
OMe
OMe
Br
Bifunctional Ligand (cat.)
1a
2a
Reductive
elimination
Oxidative addition
Ligand exchange
O
O
The activation of C–H bonds permits the rapid construction of
complex chemical architectures via ring construction events.[1]
The high similarity between the products and their precursors
generally translates into diminished waste generation and
improved atom-economy.[2] Moreover, C–H activation-based
CMD
O
*
OH
*
P
Pd
P
Pd
Ar
H
Ar
Ar
Ar
H
OMe
OMe
F
desymmetrisation reactions constitute
a
powerful way of
F
generating congested stereogenic centers, because they occur at
a remote position and hence do not suffer from the steric
hindrance associated to such units.[3] In this context, the use of
asymmetric Pd0/PdII-catalyzed C(sp2)–H arylation has been the
topic of many publications over the last decade, often targeting
the preparation of new potential ligands, organocatalysts
precursors or natural products.[4,5] The mechanism underlying
these transformations usually involves an enantiodetermining
concerted metalation–deprotonation (CMD) step. At the transition
state of this step, both the ligand and the base are coordinated to
the metal center. Therefore, a chiral ancillary ligand[5] and/or a
chiral base[6,7] may be used to bring in stereocontrol over the
reaction. In order to induce a more organized transition-state, and
thereby to provide higher enantioselectivities in challenging cases,
we recently developed a new family of chiral bifunctional
phosphine-carboxylate ligands (Scheme 1a).[8] Herein, we
describe the application of this approach to the enantioselective
synthesis of highly symmetrical fluoradenes[9], through the
selective activation of one enantiotopic C-H bond (scheme 1b),
and other warped molecules, which could serve to the bottom-up
preparation of buckybowls or other bowl-shaped hydrocarbons.
enantiotopic C–H bonds
c) Target molecules
R1
6-membered palladacyle
R
R1
R2
R2
5
6
5
5
6
6
R3
R3
Z
O
R3
R3
2a-2i
4a-h
6a-c
Scheme 1. Previous work, working mechanistic hypothesis to design our
enantioselective synthesis of fluoradenes and target molecules.
Chiral fullerene fragments such as buckybowls (including
corannulene, sumanene and dicyclopentaperylene) and other
polycyclic aromatic hydrocarbons (PAHs) or bowl-shaped
hydrocarbons are interesting targets which have received a lot of
attention due to their photophysical and chiroptical properties and
their potential applications as organic electronic materials.[10,11]
However, these molecules are often synthesized in racemic form,
and enantiomerically pure samples obtained by chromatographic
separation on a small scale. This synthetic gap drove us to
1
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develop
a
general C–H activation-based protocol for the
based our optimization exclusively on the observed enantiomeric
ratios. The design of our bifunctional ligands allows for an easy
modification of the linker attaching the carboxylic acid to the
binaphthyl scaffold. Ligand L1 with a single methylene unit in this
tether gave the best results. When the length of this chain was
increased (L2, L3) the enantiomeric ratio of 2a dropped rapidly
and dramatically. For longer chains (L4-L6), a slightly higher
induction was observed, but for the opposite enantiomer,
suggesting a change in the mechanism along this series. Of note,
when L7, wherein the carboxylic acid is directly linked to the 1,1’-
binaphthyl scaffold, was used, the obtained product was racemic.
A control experiment with monofunctional ligand L8, used in
combination with pivalic acid, confirmed the superiority of our
enantioselective synthesis of diverse polycyclic aromatic-rich
warped molecules via the formation of ring systems of different
sizes (scheme 1c).[12] We herein report the development of this
method, as well as a preliminary study of the photophysical and
chiroptical properties of some of the synthesized compounds.
F
F
Conditions A or B
OMe
OMe
Br
1a
2a[a]
bifunctional ligand for this transformation compared to
a
a) Initial ligand screening and control experiments (using conditions A, unless
otherwise noted)
bimolecular approach. We then turned our attention to the
modification of the substituents on the phosphorous atom.
Different 3,5-disubtituted aryl groups were introduced (L9-L13),
with dimethyl substituted ligand L9 giving the highest
enantiomeric ratio. Introducing a phenyl (L14) or methyl (L15)
substituent at the 3’ position of the binaphthyl scaffold was found
to be detrimental to the selectivity of this transformation. At this
point, a new round of condition optimization was conducted (see
the Supporting Information for details). Optimized conditions
CO2H
CO2Et
O
CO2H
PAr2
O
n
PPh2
PPh2
L1 n = 1, e.r. 80:20
L2 n = 2, e.r. 56:44
L3 n = 3, e.r. 57:43
L4 n = 4, e.r. 37:63
L5 n = 5, e.r. 38:62
L6 n = 6, e.r. 37:63
L7,[b] e.r. 50:50
Ar=4-F-3,5-diMePh
L8 +PivOH,[b,c] e.r. 63:37
involved
a
combination of the ligand (20 mol%) with
Pd2dba3∙CHCl3 (5 mol%), cesium carbonate (1.5 equiv) and
toluene as the solvent at 140 °C, in the presence of molecular
sieves. Using this new set of conditions, the effect of the
substituents on the phosphorous atom was further investigated.
Ligands L16-L18 possessing an increased aromatic surface
attached to the phosphine moiety were prepared and tested.
Whereas the use of ligand L18 did not give satisfactory results,
ligands L16 and L17 both performed very well. Removing one
methyl substituent from L9 to get L19 was slightly beneficial, but
L19 failed to outcompete L17. However, ligand L20, retaining the
3,5-dimethyl substitution with an additional fluorine substituent at
the para position to the phosphorous atom gave the same
selectivity as L17 on this model substrate. Finally, replacing the
1,1’-binaphthyl scaffold with its octahydro analogue (L21) did not
furnish a promising way to improve the selectivity.
R2
CO2H
CO2H
R1
R1
O
P
O
P
R1
R1
L9 R1 = Me, e.r. 85:15
L14 R2 = Ph, e.r. 53:47
L15 R2 = Me, e.r. 53:47
L10 R1 = H, e.r. 80:20
L11[d] R1 = OMe, e.r. 77:23
L12[d] R1 = CF3, e.r. 70:30
L13[d] R1 = t-Bu, no conversion
b) Further optimization (using conditions B)
O
CO2H
O
CO2H
PAr2
PPh2
Next, the best ligands L17 and L20 were chosen to study
the reaction scope to generate different types of scalemic warped
molecules, starting with fluoradenes (Scheme 3). The diversity
and accessibility were the main criteria underlying the choice of
employed substrates. Model substrate 1a was transformed into
2a in excellent yield and with good enantioselectivity under the
optimized conditions employing ligand L20. The absolute
configuration of 2a was determined by X-ray diffraction
analysis.[13] The latter also revealed that fluoradene 2a adopts a
bowl-like structure with a bowl depth of 1.36 Å, measured
between the stereogenic carbon atom and the plane defined by
the 3 most remote carbon atoms (see Scheme 3). An additional
phenyl ring at the para position of the bromine of substrate 1b was
L9 Ar = 3,5-diMePh, e.r. 87:13
L16 Ar = naphtalen-2-yl, e.r. 90:10
L17 Ar = 1,1'-biphenyl-4-yl, e.r 91:9
L18 Ar = 1,1'-biphenyl-3-yl, e.r. 79:21
L19 Ar = m-tolyl, e.r. 89:11
L21, e.r. 18:82
L20 Ar = 4-F-3,5-diMePh, e.r. 91:9
Scheme 2. Synthesized bifunctional ligands and their effect in enantioselective
C(sp2)–H arylation. Conditions A: ligand (10 mol%), Pd2dba3∙(CHCl3) (5 mol%),
Cs2CO3 (1.5 equiv), 4Å MS, DME (0.1 M), 140 °C, 18h. Conditions B: ligand (20
mol%), Pd2dba3∙(CHCl3) (5 mol%), Cs2CO3 (1.5 equiv), 4Å MS, toluene (0.1 M),
140 °C, 18h [a] The absolute configuration of 2a was deduced from the X-ray
crystal structure shown in Scheme 3. [b] Conditions B were used. [c] 20 mol%.
[d] 2.5 mol% Pd2dba3·CHCl3. dba
dimethoxyethane, MS = molecular sieves.
= dibenzylideneacetone, DME = 1,2-
well tolerated to furnish product 2b, which contains
a
quaterphenyl substructure. An electron-donating group at the
same position was also tolerated, as demonstrated by the
synthesis of 2c, albeit with a reduced enantioselectivity.[14]
Modification of the fluorene scaffold did not impact the reactivity
nor the selectivity (2d) and it was possible to replace the methoxy
group on the stereocenter by a larger propoxy substituent (2e).
Compound 1a was chosen as a model substrate to start our
optimization (Scheme 2). Standard conditions for the initial ligand
screening involved a combination of the ligand (10 mol%) with
Pd2dba3∙(CHCl3) (5 mol%), cesium carbonate (1.5 equiv) and
DME as the solvent at 140 °C in the presence of molecular sieves.
The yield of the desired product being excellent in most cases, we
2
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surface was isolated by recrystallization and obtained with a very
high enantiomeric ratio. The structure and the absolute
configuration of this compound were confirmed by X-ray
diffraction analysis.[13] The latter revealed that 4h adopts a bowl-
like structure too, with a slightly shorter bowl depth (1.30 Å)
compared to 2a, due to the presence of the 6-membered pyran
ring. Finally, our protocol could also be used for the preparation
of anthrone-derived compound 4g, albeit with
a reduced
enantioselectivity.
Scheme 3. Scope of the enantioselective synthesis of fluoradenes. Reactions
were performed on a 0.1 mmol scale. [a] Using L20. [b] Thermal ellipsoids
shown at 50% probability. The absolute configurations of other products were
assigned by analogy to 2a. [c] Using L17. [d] Determined from the
corresponding monodemethylated aniline. [e] Determined form the
corresponding free phenol. [f] After recrystallization from i-PrOH.
Scheme 4. Scope of the enantioselective C(sp2)–H arylation of xanthone- and
anthrone-derived substrates. Reactions were performed on a 0.1 mmol scale.
[a] Performed on a 0.05 mmol scale, isolated by recrystallization from i-PrOH.
[b] Thermal ellipsoids shown at 50% probability. The absolute configurations of
other products were assigned by analogy to 4h.
Four fluoradenes containing a quaternary all-carbon stereocenter
were also prepared (2f-2i). In these cases, ligand L17 was found
to provide higher enantiomeric ratios than L20. Pleasingly, aniline
2f was obtained in good yield and excellent enantiomeric ratio.
The oxygen-containing fused tetraphenylmethane products 2g-2i
were also obtained in excellent yield and good enantioselectivity,
and the methoxy group of 2g was readily cleaved to afford the
corresponding phenol, which could serve as a handle for further
functionalization. Furthermore, the enantiomeric ratio of 2i could
be easily increased to 96:4 upon recrystallisation from
isopropanol.
To further demonstrate the applicability of our protocol to the
preparation of warped molecules containing an extended
aromatic system, helix-shaped products 6a-6c containing an all-
carbon quaternary stereocenter and a formed 6-membered ring
(vs. 5-membered for previous products 2 and 4) were synthesized
by C–H arylation from substrates 5a-5c. Electron-donating and -
withdrawing substituents were again well tolerated and did not
significantly influence the selectivity of the reaction. Moreover, the
enantiomeric ratio of 6a could be increased upon recrystallization
from isopropanol to reach an enantiomeric ratio of 98:2. The
structure and the absolute configuration of this compound were
confirmed by X-ray diffraction analysis.[13] Interestingly, 6a adopts
a right-handed helical shape induced by the stereogenic center
and the extended aromatic surface, which is similar to the
configurationally unstable[15] oxa[5]helicene (angle between the
two edge rings: 6a, 54°, oxa[5]helicene, 53°).[16]
In addition to fluorenes, xanthone-derived substrates (3a-3f,
3h), were successfully transformed into the corresponding
products (4a-4f, 4h), which contain an all-carbon quaternary
stereocenter. An excellent enantioselectivity was achieved in
most cases using L20 as the ligand. Aryl bromides bearing
electron-withdrawing (3a) or electron-donating (3b, 3c)
substituents at the para position to the bromine atom provided
good results. Meta-substituted (3d, 3f) and unsubstituted (3e) aryl
bromides also gave excellent yields and enantioselectivities.
Moreover, compound 4h displaying an increased aromatic
3
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R
a)
R
Pd2(dba)3•CHCl3 (5 mol%)
Br
100
50
0
1
L20 (20 mol%)
Cs2CO3 (1.5 equiv)
PhMe, 4Å MS, 140°C, 18h
O
O
5a-c
6a-c
0,5
R
54°
0
200
250
300
350
400
450
500
550
O
Wavelength [nm]
6a R = H: 96%, e.r. 90:10 (e.r. 98:2)[a]
6b R = F: 75%, e.r. 91:9
6c R = OMe: 51%, e.r. 89:11
b)
X-ray structure of 6a[b]
85
Scheme 5. Scope of the enantioselective synthesis of helix-shaped xanthone-
derived products. Reactions were performed on a 0.1 mmol scale. [a] After
recrystallization from i-PrOH. [b] Thermal ellipsoids shown at 50% probability.
The absolute configurations of other products were assigned by analogy to 6a.
0
A tentative model to rationalize the stereochemical outcome
of the reaction furnishing fluoradene 2a using ligand L20 based
on preliminary modelling is shown in Figure 1. At the transition
state of the enantiodetermining C–H activation step, the fluorene
ring of the substrate is presumably oriented inside the chiral
pocket to maximize dispersion interactions with the ligand. With
this orientation, the M configuration of the rigid bifunctional ligand
L20 imposes C–H activation to occur at the pro-R hydrogen atom
of the fluorene ring, thereby generating product 2a as the major R
enantiomer after reductive elimination.
-85
200
250
300
Wavelength [nm]
350
400
Figure 2. a) Absorption (solid trace) and emission (dotted trace) spectra of 4h
(red traces, λex = 280 nm) and 6a (blue traces, λex = 354 nm) recorded in de-
aerated CH3CN at 22 °C. b) Circular dichroism spectra of 2a (green trace), 2b
(orange trace), 4h (red trace) and 6a (blue trace), recorded in CH3CN at 25 °C.
Me
Me
F
In conclusion, a protocol for the enantioselective synthesis of
original chiral warped molecules via Pd0-catalyzed C(sp2)–H
arylation was developed. Our approach relies on the use of chiral
bifunctional phosphine-carboxylate ligands that play a unique role
in the enantiodetermining C–H activation step. A diverse array of
polycyclic compounds could be synthesized in high yields and
with good to excellent enantioselectivities. Moreover, the e.r. of
the obtained products could easily be increased by
recrystallization. The chiroptical properties of the synthesized
compounds were investigated and compound 6a, possessing a
right-handed helical shape, was shown to have a strong ellipticity
in solution and to emit in the visible region.
F
F
M
Me
F
P
OMe
Me
O
R
O
Pd
H
O
pro-S
2a
Me
O
H
pro-R
Figure 1. Proposed stereochemical model.
Finally, the absorption and emission spectra of selected
compounds 4h and 6a were obtained and are shown in Figure 2a.
Interestingly, 6a emits in the visible region with a maximum at 405
nm, and its quantum yield was determined to be 13.4% (see the
Supporting Information for details). The circular dichroism spectra
for compounds 2a, 2b, 4h and 6a are shown in Figure 2b. The
large molar ellipticity values observed for compound 6a in solution
(–81400 M–1 cm–1 at 298 nm, +73500 M–1 cm–1 at 368 nm) seem to
correlate with the helical shape observed in the solid state.
Moreover, the CD spectrum of compound 2b seems to differ
significantly from those of the other synthesized fluoradenes,
which could be due to its quaterphenyl substructure.
Acknowledgements
This work was financially supported by the Swiss National
Science Foundation (200021_165987) and the University of
Basel. We thank Dr. M. Pfeffer and S. Mittelheisser for MS
measurements, Dr. A. Prescimone for X-ray diffraction analyses,
B. Pfund, A. Di Silvestro and M. Meyer for assistance with
spectroscopy experiments. We also thank P. Knecht and A.
Cavadini who contributed to this project during internships.
Keywords: asymmetric catalysis • C–H activation•
enantioselectivity • palladium • polycyclic aromatic hydrocarbons
4
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10.1002/anie.202013303
Angewandte Chemie International Edition
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Enantioselective Pd0-catalyzed C(sp2)–H arylation allows the synthesis of warped molecules possessing congested stereocenters. The
polycyclic compounds were obtained in high yields and with good to excellent enantioselectivitiesπ using chiral bifunctional ligands, and could
serve to the bottom-up construction of chiral polycyclic aromatic hydrocarbons.
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