Chiral Bifunctional Phosphine-Carboxylate Ligands for Palladium(0)-Catalyzed Enantioselective C?H Arylation

Article abstract of DOI:10.1002/anie.201712061

Previous enantioselective Pd⁰-catalyzed C?H activation reactions proceeding via the concerted metalation-deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes th

Full text of DOI:10.1002/anie.201712061

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Accepted Article
Title: Introducing Chiral Bifunctional Phosphine-Carboxylate Ligands
for Palladium(0)-Catalyzed Enantioselective C-H Arylation
Authors: Lei Yang, Markus Neuburger, and Olivier Baudoin
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Angewandte Chemie International Edition
10.1002/anie.201712061
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
C–H Activation
Introducing Chiral Bifunctional Phosphine-Carboxylate Ligands for
Palladium(0)-Catalyzed Enantioselective C–H Arylation
Lei Yang, Markus Neuburger, and Olivier Baudoin*
0
Abstract: Previous enantioselective Pd -catalyzed C–H activation
reactions proceeding via the concerted metalation-deprotonation
0
a) general mechanism of Pd -catalyzed C–H activation/C–C coupling:
mechanism employed either a chiral ancillary ligand, a chiral base,
or a bimolecular mixture thereof. This study describes the
development of new chiral bifunctional ligands based on a
binaphthyl scaffold and incorporating both a phosphine and a
carboxylic acid moiety. The optimal ligand provided high yields
C
C
C
X
C
H
Pd0
L
reductive
elimination
oxidative
addition
2
C
C
C
C
H
and enantioselectivities for the desymmetrizing C(sp )–H arylation
PdII
L
PdII
L
leading to 5,6-dihydrophenanthridines, whereas the corresponding
monofunctional ligands showed low enantioselectivities. The
bifunctional system proved applicable to a range of substituted
dihydrophenanthridines, and allowed the parallel kinetic resolution
of racemic substrates.
X
O
(CO32–
)
O
ligand
exchange
decoordination
Y
Y
O–
R
C
OH
‡
deprotonation
R
X–
L
C
O
L
C
O
C
H
Ι
n recent years, catalytic enantioselective C–H activation has
Pd
PdII
emerged as a simple and powerful method to construct different
types of stereogenic elements (central, planar or axial) and generate
O
O
H
Y
Y
R
[
1]
R
high value-added enantioenriched molecules. In the context of
palladium(0)-catalyzed C–H activation/C–C coupling reactions
proceeding via the catalytic cycle depicted in Scheme 1a, the
enantiodetermining step is usually the C–H activation, which occurs
via the concerted metalation-deprotonation (CMD, aka AMLA)
CMD
C–H activation
b) known chiral catalysts inducing enantioselectivity:
chiral ancillary ligand: phosphine,
L
phosphoramidite, phosphonite, N-heterocyclic
[
2]
carbene...
O
Y
mechanism. According to the latter, the substrate, an ancillary
–
chiral base: carboxylate (Y = C), phosphate (Y = P)
2
ligand (L) and the base performing the C–H bond cleavage (RYO )
O–
R
are all coordinated to the palladium center at the transition state.
Consistent with this mechanism, two types of chiral catalysts have
c) current system:
L
C
0
been successfully employed to induce enantioselectivity in Pd -
C
Pd
Ar O
2
3
P
H
catalyzed C(sp )–H and C(sp )–H activation reactions (Scheme 1b):
O
Y
Ar
O
1
. chiral ancillary ligands, more specifically phosphorus(III)
O
O–
C
[3,4]
[5]
R
compounds
carboxylates
and NHCs,
and 2. chiral bases, e. g.
[
4a,b]
[6]
and Binol-derived phosphates. The union of an
chiral bifunctional ligand
phosphine/carboxylate
proposed mechanism
ancillary ligand and base in the same bifunctional molecule has not
0
been achieved so far in the context of Pd -catalyzed
0
[
7]
Scheme 1. State-of-the-art and current chiral catalysts for Pd -
catalyzed C–H arylation.
enantioselective C–H activation, and is the subject of the current
work (Scheme 1c). Such a bifunctional ligand would possess a
more organized structure compared to the corresponding
bimolecular system, and might be broadly applicable to various
types of asymmetric C–H activation reactions operating via a
similar mechanism.
scaffold (Schemes 1c, 2). A series of phosphine-carboxylic acid pre-
3
7
ligands L -L with a variable number (1-5) of methylene groups
separating the carboxylic acid and the binaphthyl core were
prepared from (R)-Binol by adapting literature procedures from
At the onset of our work, we chose to focus on phosphine-
carboxylate bifunctional ligands based on the classic binaphthalene
[
8,9]
Uozumi, Hayashi and co-workers (Scheme 2).
As a prototypical
reaction, we chose to investigate the enantioselective C–H arylation
of aryl bromide 1a to give 5,6-dihydrophenanthridine 2a. This
structural motif is present in various biologically active substances,
in particular fluorogenic probes for the detection of reactive oxygen
[
*]
Dr. L. Yang, Dr. M. Neuburger, Prof. Dr. O. Baudoin
University of Basel, Department of Chemistry, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
[10]
0
2
E-mail: olivier.baudoin@unibas.ch
species.
Related Pd -catalyzed desymmetrizing C(sp )–H
[3a,c]
[11]
[3b,h]
Dr. L. Yang
arylations generating carbon,
phosphorus
or silicon
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, P.R. China
stereocenters have been reported using a chiral phosphorus ligand
and an achiral base, but such an enantioselective synthesis of 5,6-
[12,13]
dihydrophenanthridines has not been described.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201712061
1
2
bimolecular systems composed of L or L and AcOH or PivOH. Of
note, we also tested other chiral ligands such as BINAP, TADDOL-
derived phosphoramidites, and NHCs, which were previously
MeO C
2
Pd dba (2.5 mol%)
ligand (10 mol%)
2
3
N
N
CO Me
0
[3-4]
2
employed in asymmetric Pd -catalyzed C–H activation reactions,
Cs CO (3 equiv),
2
3
3
[9]
Br
DME, 4Å MS, 120 °C, 20h
but they provided lower enantioselectivities than L .
In search for a further improvement of the enantioselectivity, we
2a[a]
1
a
8
9
first synthesized MOP-pivalic acid hybrids L and L , but the
3
5
enantioselectivity was reduced compared to ligands L and L
deprived of gem-dimethyl groups. The modification of aryl sub-
PPh
2
PPh
2
stituents on the phosphorus atom turned out to be more successful
O
O
CO Et
2
1
0
13
10
11
(
L -L ), with dimethyl and dimethoxy-substituted ligands L -L
affording the highest enantiomeric ratio. Further refinement of
L1 (MOP)
L2
10
reaction conditions was performed using L , including other
+ PivOH:[b] 87%, e.r. 58.5:41.5
7
8%, e.r. 51:49
[9]
[
b]
[b]
carbonate bases, solvents and temperatures. These studies allowed
+
PivOH: 96%, e.r. 63.5:36.5
AcOH:[b] 85%, e.r. 57:43
+ AcOH: 95%, e.r. 54:46
to decrease the amount of Cs CO to 1.5 equiv and the temperature
2
3
+
to 80 °C, and to achieve an e.r. of 98.5:1.5 with a 92% yield on a 1
mmol (fivefold) scale (Scheme 3a). Importantly, control
PPh
2
a
PPh
2
O
experiment performed with 1 equiv of the potassium salt derived
(
)n
O
CO
2
H
CO H
10
2
(
)
from L and in the absence of cesium carbonate still furnished
n
[9]
product 2a in 92% yield and a slightly reduced e.r. of 95.5:4.5.
8
9
L
L
n = 0: 95%, e.r. 81:19
n = 2: 85%, e.r. 79.5:20.5
L3 n = 1: 91%, e.r. 93.5:6.5
This experiment further supports our hypothesis that this ligand is
not a mere bidentate ligand, but it also acts as the base participating
in the CMD mechanism (Scheme 1c). In this case the main role of
the stoichiometric carbonate is to regenerate the active carboxylate
ligand after the C–H activation step.
4
L
L
L
L
n = 2: 95%, e.r. 75:25
n = 3: 95%, e.r. 80.5:19.5
n = 4: 90%, e.r. 48:52
n = 5: 83%, e.r. 46:54
R
5
6
7
R
R
P
Employing these optimal conditions, we studied the scope and
limitations of the catalytic enantioselective synthesis of 5,6-
O
R
H
1
0
CO
2
dihydrophenanthridines catalyzed by Pd/L (Scheme 3). For less
reactive substrates, the reaction was performed at higher
temperatures as indicated. First, the optimal leaving group was
found to be a bromide (Scheme 3a). Lower yields of 2a were
obtained from the corresponding iodide and chloride, whereas the
triflate underwent decomposition and no desired product was
observed. Next, we studied the impact of the nitrogen substituent on
the reaction (Scheme 3b). The best results were obtained with
alkoxycarbonyl groups (2a-c). With a tosyl group (2d), a diminished
enantioselectivity was observed, whereas with methyl (2e) and
trifluoroacetyl (2f) groups the reaction was sluggish and gave
several decomposition products. With bromide as the leaving group
1
0
L
L
L
L
R = Me: 92%, e.r. 97.5:2.5
R = OMe: 96%, e.r. 97:3
R = t-Bu: 94%, e.r. 91:9
11
1
1
2
3
R = CF : 87%, e.r. 89:11
3
Scheme 2. Synthesized bifunctional ligands and their effect in
enantioselective C(sp )–H arylation. [a] The absolute configuration of
a was deduced from the Xray crystal structure shown in Scheme 3.
2
2
[
b] 15 mol%.
Standard reaction conditions involved the combination of the
ligand (10 mol%) with Pd dba as a carboxylate-free Pd source (5
1
and methoxycarbonyl as the N-substituent, different types of R
2
3
mol% Pd), stoichiometric cesium carbonate, which is able to both
deprotonate the carboxylic acid function of the ligand to generate
the active carboxylate in situ and regenerate it after the C–H
activation step (see Scheme 1a), and DME as the solvent at 120 °C
in the presence of molecular sieves to remove traces of potentially
groups were introduced on the bromine-containing aromatic ring,
with equally excellent yields and enantioselectivities (Scheme 3c,
2g-m). Of note, the X-ray diffraction analysis of a single crystal of
[15]
2k allowed determination of its absolute configuration as (R). In
addition, substrates containing a naphthalene (2n) or a pyridine (2o)
ring performed with similar efficiency and enantioselectivity.
[6b]
deleterious water molecules. The enantioselectivity obtained with
bifunctional ligands was compared to the one obtained with the
2
Similarly, the reaction was compatible with R substituents at
1
[14]
2
corresponding monofunctional ligands
L
(MOP)
and
L
various positions of the other aryl rings (Scheme 3d, 2p-v). In the
case of 2s, the C–H arylation occurred selectively at the most
containing an ethyl ester instead of the carboxylic acid. All
3
7
[16]
1
19
bifunctional ligands L -L enabled the reaction in very good yield,
but with various levels of enantioselectivities, showing the effect of
the carbon spacer length (Scheme 2). The enantioselectivity was
reactive ortho position to the fluorine atom, as shown by H- F
[9]
HOESY. On the other hand, a limitation was found when the
connection of the rings undergoing C–C coupling was changed
3
maximal for MOP-acetic acid hybrid ligand L containing one
(
Scheme 3e). A drop in the yield and the enantioselectivity was
methylene spacer, which furnished 5,6-dihydrophenanthridine 2a in
indeed observed for compounds 2w-y containing a different 6- or 7-
membered bridging ring. Achieving efficient enantioselective
syntheses of these motifs would likely require further optimization
of the ligand structure. For instance, using t-Bu-substituted ligand
9
1% yield and 93.5:6.5 e.r.. Importantly, the enantioselectivity was
much lower in control experiments performed with monofunctional
1
2
ligands L and L both in the absence and in the presence of pivalic
or acetic acid additive. Moreover, although the enantioselectivity
12
10
L
instead of L significantly improved the enantioselectivity in
6
7
was low with ligands L -L bearing a longer carbon spacer, the
the formation of sultam 2y.
1
2
sense of the induction was inverted compared to L -L . All together,
3
7
these results strongly indicate that ligands L -L operate in a
3
bifunctional mode. In addition, the most selective ligand L
provided
a much higher enantioselectivity than comparable
2
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Angewandte Chemie International Edition
10.1002/anie.201712061
R2
R1
R2
Z
Pd dba (2.5 mol%)
R2
2
3
N
L10 (10 mol%)
N
R1
Z
Cs CO (1.5 equiv),
2
3
R2
X
DME, 4Å MS, 80 °C, 20-72h
1a-v
2a-v
a) variation of X
b) variation of Z (X = Br)
MeO C
Z
2
N
N
2
a
X = Br: 92%, e.r. 98.5:1.5 (1 mmol)
2b Z = CO Et: 91%, e.r. 98.5:1.5
2
[
a]
[b]
X = Cl: 16%, e.r. 94.5:5.5
X = I: 42%, e.r. 98:2
2c Z = CO i-Bu: 89%, e.r. 98.5:1.5
2
2d Z = Ts: 88%, e.r. 93:7
2e Z = Me: 44%, e.r. 82.5:17.5
[b]
[b]
X = OTf: n.d.
2
f Z = COCF : traces
3
X-ray structure of 2k[e]
c) variation of R1 (X = Br)
Me CO Me
MeO2C
N
MeO2C
N
MeO C
MeO C
2
2
2
R
N
N
N
R
Me
N
c]
2
2
g R = Me: 75%, e.r. 98:2[
2i R = Me: 83%, e.r. 98.5:1.5
2j R = F: 90%, e.r. 98:2[
2m 82%, e.r. 97:3
2n 93%, e.r. 98:2
2o 73%, e.r. 94:6
c]
h R = CF : 90%, e.r. 98.5:1.5
3
2
2
k R = Cl: 92%, e.r. 96.5:3.5
l R = CO Me: 80%, e.r. 98.5:1.5
d) variation of R2 (X = Br)
2
Me
R
R
MeO C
MeO C
MeO C
MeO C
2
2
2
2
N
N
N
N
F
Me
R
F
Me
Me
R
[b]
2
2
2
p R = Me: 80%, e.r. 97.5:2.5
q R = F: 93%, e.r. 98.5:1.5
r R = OMe: 78%, e.r. 98.5:1.5
2s 87%, e.r. 96.5:3.5
2t 83%, e.r. 96.5:3.5
2u R = Me: 78%, e.r. 88:12
2v R = F: 81%, e.r. 95:5[
c]
e) unsuccessful examples (X = Br)
O
O
Me
N
O
Me
S
N
O
w 10%, e.r. 58:42[
d]
2x traces[d]
2y 76%, e.r. 52:48[d]
2%, e.r. 67:33[f]
2
8
Scheme 3. Scope and limitations of the enantioselective synthesis of 5,6-dihydrophenanthridines. [a] NMR yield. [b] Performed at 120 °C.
1
2
10
[
c] Performed at 100 °C. [d] Performed at 140 °C. [e] Thermal ellipsoids at the 50% probability level. [f] Using ligand L instead of L . The
absolute configurations of other products were ascribed by analogy to 2k. n.d. = not detected.
[
5b]
R
Finally, inspired from the work of Kündig and more recently
R
[17]
3
2
MeO C
MeO C
Cramer
parallel kinetic resolution (PKR) of racemic substrates 3-4 (Scheme
). This behavior is based on the fact that differently substituted aryl
in C(sp )–H and C(sp )–H arylation, we examined the
2
2
standard
N
N
[
a]
conditions
N
CO Me
4
2
groups undergo C–H arylation at similar rates. Since a given
enantiomer of the chiral catalyst always selects the same
enantiotopic aryl group, two enantioenriched constitutional isomers
with the same absolute configuration can be obtained with a
maximum of 50% yield each. Indeed, reacting 3 and 4 under
standard conditions led to ca. 1:1 mixtures of highly enantioenriched
isomers 5a/5b and 6a/6b in excellent combined yields. This result is
Br
R
(
±)-3 R = F
(±)-4 R = Me
5a R = F
6a R = Me
5b R = F
6b R = Me
[
b]
5a/5b 1:1, 87%, e.r 99:1 & 97.5:2.5
a/6b 1:1, 85%, e.r 98.5:1.5 & 98:2
[
b]
6
[5b,17]
Scheme 4. Parallel kinetic resolution of racemic substrates. [a]
10
in line with previous reports,
hence tending to indicate the
0
Pd
0 °C. [b] Combined yield of the isolated mixture of inseparable
isomers.
2 3 2 3
dba (2.5 mol%), L (10 mol%), Cs CO (1.5 equiv), DME, 4Å MS,
general character of PKR via Pd -catalyzed C–H activation.
8
3
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Angewandte Chemie International Edition
10.1002/anie.201712061
In conclusion, chiral bifunctional phosphine/carboxylate ligands
based on a binaphthyl scaffold showed high efficiency and
Sato, C. Takagi, R. Shintani, K. Nozaki, Angew. Chem. Int. Ed. 2017,
5
6, 9211; j) C. He, M. Hou, Z. Zhu, Z. Gu, ACS Catal. 2017, 7, 5316.
3
2
[4]
Selected examples in C(sp )–H activation: a) S. Anas, A. Cordi, H. B.
Kagan, Chem. Commun. 2011, 47, 11483; b) T. Saget, S. J. Lemouzy,
N. Cramer, Angew. Chem. Int. Ed. 2012, 51, 2238; c) N. Martin, C.
Pierre, M. Davi, R. Jazzar, O. Baudoin, Chem. Eur. J. 2012, 18, 4480;
d) T. Saget, N. Cramer, Angew. Chem. Int. Ed. 2012, 51, 12842; e) J.
Pedroni, M. Boghi, T. Saget, N. Cramer, Angew. Chem. Int. Ed. 2014,
enantioselectivity for the desymmetrizing C(sp )–H arylation
leading to 5,6-dihydrophenanthridines. In contrast, the corre-
sponding monofunctional ligands deprived of carboxylic acid
function induced only low enantioselectivities, thereby
demonstrating the added value of bifunctionality. This new ligand
type might show broad applicability to various types of asymmetric
C–H activation reactions operating via the CMD mechanism.
5
3, 9064; f) P. M. Holstein, M. Vogler, P. Larini, G. Pilet, E. Clot, O.
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Acknowledgements
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5] a) M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig, Angew. Chem.
Int. Ed. 2011, 50, 7438; b) D. Katayev, M. Nakanishi, T. Bürgi, E. P.
Kündig, Chem. Sci. 2012, 3, 1422; c) E. Larionov, M. Nakanishi, D.
Katayev, C. Besnard, E. P. Kündig, Chem. Sci. 2013, 4, 1995.
This work was financially supported by the People Programme
(
Marie Curie Actions) of the European Union's Seventh Framework
Programme FP7/2007–2013/ under REA grant agreement no.
23605, and by the University of Basel. We thank Dr. D.
[
[
6]
a) S. Zhang, J. Lu, J. Ye, W.-L. Duan, Chin. J. Org. Chem. 2016, 36,
7
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2
017, 8, 1344.
Häussinger for NMR experiments, S. Mittelheisser and Dr. H. Nadig
for MS analyses. L. Y. acknowledges the support from the National
Natural Science Foundation of China (Grant No. 21372231).
II
7]
Selected references on the use of bifunctional ligands in Pd -catalyzed
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Conflict of interest
The authors declare no conflict of interest.
2
3
5
7
[
8]
9]
Compounds L -L and L -L have been previously synthesized, but
only used as intermediates for the synthesis of supported MOP
ligands: a) Y. Uozumi, H. Danjo, T. Hayashi, Tetrahedron Lett. 1998,
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
3
9, 8303; b) H. Hocke, Y. Uozumi, Tetrahedron 2004, 60, 9297; c) Y.
Uozumi, T. Hayashi, Jpn. Kokai Tokkyo Koho, JP11147890, 1999.
See the Supporting Information for details.
[
[
Keywords: arylation · asymmetric catalysis · C–H activation ·
palladium ·P ligands
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Organometal. Chem. 2017, e3820.
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[
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Angewandte Chemie International Edition
10.1002/anie.201712061
C–H Activation
R2
R2
Z
0
R2
Pd /L cat.
N
Cs CO , DME, 80 °C
2
3
N
R1
L. Yang, M. Neuburger, O.
Z
R1
Me
Baudoin*__________ Page – Page
R2
Br
Me
Me
25 examples
e. r. up to 99:1
Introducing
Chiral
Bifunctional
P
Phosphine-Carboxylate Ligands for
Palladium(0)-Catalyzed Enantioselective
C–H Arylation
O
Me
CO H
2
Chiral chimera: Bifunctional ligands incorporating both a phosphine and a
carboxylate moiety provide high enantioselectivities in the synthesis of 5,6-
dihydrophenanthridines, whereas the corresponding bimolecular systems are poorly
stereoselective.
5
This article is protected by copyright. All rights reserved.