Chiral monodentate phosphines and bulky carboxylic acids: Cooperative effects in palladium-catalyzed enantioselective C(sp3)-H functionalization

Article abstract of DOI:10.1002/anie.201108511

Teaming up: The important indoline scaffold is provided with enantiomeric ratios of up to 98:2 in palladium(0)-catalyzed C(sp³)-H activations of aryl triflates. The key is the combination of the electron-rich monodentate Sagephos and the bulky 9H-xanthene-9-carboxylic acid. Both participate in a highly cooperative manner in the enantiodetermining concerted-deprotonation- metalation step (see scheme, Tf=triflate). Copyright

Full text of DOI:10.1002/anie.201108511

.
Angewandte
Communications
DOI: 10.1002/anie.201108511
CÀH Activation
Chiral Monodentate Phosphines and Bulky Carboxylic Acids:
Cooperative Effects in Palladium-Catalyzed Enantioselective C(sp )–H
Functionalization**
3
Tanguy Saget, Sꢀbastien J. Lemouzy, and Nicolai Cramer*
3
Advances in transition-metal catalysis are closely linked to
the development of tailored phosphine ligands enabling
lective C(sp )–H functionalizations of unactivated methyl and
methylene bonds. We reasoned that a combination of the
outstanding properties of both parent scaffolds, the Buch-
[
1]
previously impossible transformations. In this respect, the
development of the Buchwald-type ligands was a game-
[2]
wald-type backbone and the electron-rich phospholane
moiety with its inherent chirality, would lead to a new
ligand class with significant potential (Scheme 1). Further-
more, its highly modular nature would allow a rapid synthetic
access and fine-tuning to the specific reaction or substrate
needs.
[
2]
[3]
changer in cross-coupling reactions. Being monodentate,
bulky, and electron-rich ligands, they resulted in very reactive
and yet very stable palladium complexes enabling a multitude
of previously unfeasible transformations. In comparison to
the plethora of chiral bidentate phosphine ligands, there is
only a rather limited portfolio of efficient chiral monodentate
[
4]
phosphines available. By and large the most popular ones
are phosphoramidites derived from the Binol or Taddol
[
5]
backbone. Ligands mimicking the favorable electronic
properties of tricyclohexylphosphine or tri-tert-butylphos-
[
6]
phine are rarer. Besides MOP and KenPhos, other phos-
phines which are chiral at phosphorous have been used with
limited success as they are often difficult to synthesize and/or
[7]
not configurationally stable at elevated temperatures. An
increasing number of metal-catalyzed transformations func-
tion only with monodentate phosphines as ligands, thus novel,
modular, and efficient, electron-rich chiral monodentate
phosphines are highly valued for further developments in
asymmetric catalysis. The C -symmetric and electron-rich
2
Scheme 1. Design and structure of the utilized monodentate electron-
rich ligands. Cy=cyclohexyl.
phospholane module has been used with great success in
several diphosphine ligands, such as Duphos, BPE-phos, and
[
8]
related scaffolds. Despite its general utility in bidentate
phosphines, it has been surprisingly used only scarcely as
[
9]
a chirality source unit in monodentate phosphines.
The envisioned ligands were prepared in a straight-
forward manner from readily available building blocks
(Scheme 2). Metalation of different m-dialkoxybenzenes
and reaction with benzyne generated in situ gave 1. The
subsequently obtained lithiated biaryl species were treated
either directly with the chloro phospholane 3 to give L2 or
with chloro diethylphosphonate to give 2. Subsequent reduc-
Herein, we report a class of new chiral biaryl mono-
phospholanes and demonstrate their utility in combination
with a bulky carboxylic acid in highly challenging enantiose-
[
*] T. Saget, S. J. Lemouzy, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis, EPFL SB ISIC
LCSA
BCH 4305, 1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
T. Saget
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland)
[
**] This work is supported by the EPFL, the ETH Zurich (ETH-16 08-3),
and by the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007-2013)/ERC
Grant agreement no 257891. We thank Dr. R. Scopelliti for X-ray
crystallographic analysis of 9a and Dr. R. Kadyrov (Evonik Industries
AG) for generous donations of 2,5-dimethyl-1-TMS-phospholane.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108511.
Scheme 2. Synthesis of the phosphine ligands L2–L7.
2
238
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tion to the phosphane and double S 2 displacement using the
classical cyclic sulfate route provides access to congenerꢀs
metalation has proceeded as discussed above, palladacycle 8,
N
[
8]
can then reductively eliminate to give indoline 9 and
0
L3–L7 having bulkier phospholane units.
regenerate the Pd catalyst.
3
The direct enantioselective functionalization of C(sp )ÀH
With aryl triflate 5a as initial screening substrate, we
evaluated the different parameters of the reaction (Table 1).
The best and most reactive source of palladium(0) proved to
bonds with a palladium(0) system is a prime challenge to
evaluate the potential of the prepared ligands
[
10–14]
3
[18]
(
Scheme 3).
Mechanistic studies as well as theoretical
be [h -cinnamyl)PdCp] (Cp = C H ).
In contrast to the
5
5
[
14,19]
findings of previous studies using aryl bromide substrates,
the aryl triflates display a different trend with respect to the
inorganic bulk base, with sodium phosphate being the most
[20]
efficient. The carboxylic acid additive employed is critically
important to the catalyst performance and to the enantiose-
lectivity. An amount of 10 mol% is optimal. Lower amounts
reduced the catalytic efficiency and enantioselectivity,
whereas higher amounts slightly decreased the conversion.
A screening of several simple carboxylic acids of different
steric demand with L2 revealed their influence on the
enantioselectivity (Table 1, entries 1–9). 9H-Xanthene-9-car-
boxylic acid (A1) showed a robust performance and con-
stantly superior selectivity and was used in the further
evaluation of the phosphine ligands. The size of the ether
substituent of the shielding aromatic ring (R’ = iPr or Cy is
better than R’ = Me) of the ligand has an effect on the
selectivity without disturbing the reactivity of the catalyst.
The large isopropyl substituent on the phospholane has
a strong effect on the selectivity, but at the same time
decreases the reactivity (Table 1, entries 12–14). Ligands
having other backbone structures, such as L8–L11, were less
Scheme 3. Proposed catalytic cycle and hypothesis for the cooperative
ligand effects in the synthesis of indolines 9. Tf=triflate.
investigations on the operative concerted-deprotonation-
metalation (CMD) pathway, suggest that only a single
coordination site of on the palladium atom is available.
Table 1: Optimization of the reaction conditions for the enantioselective
C(sp )--H activation.
3
[a]
[
15,16]
Hence, only a monodentate ligand would lead to a competent
catalyst. Moreover, according to the mechanism (Scheme 3),
a carboxylate base is required as a second ligand on the metal
center, playing a critical role in the proton abstraction step
leading to formation of the palladium–carbon bond. It has
been shown by Fagnou et al. that pivalate is optimally suited
[b]
[c]
Entry Carboxylic acid
L*
% Yield
e.r.
1
2
3
4
5
6
7
8
9
Acetic acid
Benzoic acid
Pivalic acid
Phenylacetic acid
Diphenylacetic acid
Triphenylacetic acid
2,2-Diphenylpropanoic acid
Anthracene-9-carboxylic acid
L2
L2
L2
L2
L2
L2
L2
L2
35
67
86
88
83
73
91
84
75
38.5:61.5
41:59
37:63
40:60
41.5:58.5
51:49
42.5:57.5
35.5:64.5
36:64
[
17]
for this task for the achiral reaction. We reasoned that the
chiral space crafted by the single phosphine ligand around the
metal center of 7 would be too weak and too far away to
provide high levels of asymmetric induction. We based the
design of our experiments on the hypothesis that the chiral
space created by the phosphine ligand could be relayed to the
spatial orientation of the specific carboxylate co-ligand. It is
much closer to reactive center and directly involved in the
enantioselectivity determining step by addressing the enan-
tiotopic proton atoms. This approach would open intriguing
opportunities to combine a chiral phosphine with an achiral
bulky carboxylic acid or cooperatively use a chiral carboxylic
acid to maximize selectivity. A further requirement of the
reaction is a bulky ligand to prevent aggregation of additional
phosphine units around the metal and at the same time
ensuring a high stability of the complex even with thermally
forcing reaction conditions. Using aryl triflates 5 has the
benefit of giving a cationic aryl palladium species 6, which in
turn reacts rapidly with catalytic amounts of the respective
9H-xanthene-9-carboxylic acid L2
A1)
(
1
1
12
13
1
1
1
1
1
0
1
A1
A1
A1
A1
A1
A1
A1
A1
A1
ent-L1
L4
L5
L6
L7
L8
ent-L9
ent-L10 76
L11 70
81
79
72
66
40
71
25
73.5:26.5
62:38
91:9
97.5:2.5
>97.5:2.5
78.5:21.5
43:57
[
d]
4
5
6
7
8
31:69
25:75
[
5
a] Reaction conditions: 50 mmol 5a, 5 mmol of the carboxylic acid,
mmol [(h -cinnamyl)PdCp], 10 mmol L*, 1.2 equiv Na PO , 0.6m in
3 4
cumene at 1358C for 12 h. [b] Yield of isolated product 9a. [c] Deter-
mined by GC with a chiral stationary phase; e.r.=(2R,3S)/(2S,3R). [d] In
p-xylene as solvent.
3
[
13b]
carboxylate to give the crucial intermediate 7.
Once the
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2239

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Angewandte
Communications
suitable (entries 15–18). The combination of L6 and A1 is the
best match, providing 9a in 66% yield with e.r. 97.5:2.5
(
Table 1, entry 13). L7 displays a slightly higher selectivity
albeit at expense of the reactivity (entry 14).
The effect of the carboxylic acid on the selectivity
supported our hypothesis of relaying the chirality of the
ligand. This prompted us to evaluate the direct influence of
chiral carboxylic acids. Indeed, a significant cooperative effect
was observed for the pair of enantiomers of acid A2 and L2
(
Scheme 4). For instance, the matching (S)-isomer of A2
Scheme 4. Cooperative ligand effects: domination of the chiral acid.
provides 82:18 e.r. in favor of (2R,3S)-9a whereas the
mismatched (R)-A2 overrides the selectivity of the phosphine
and reverses the sense of induction and gives 71:29 e.r. for
Table 2 outlines the scope of the reaction under the
optimized conditions. In general, the process provides high
enantiomeric ratios for a range of substrates. Apart from
different substituents on the aryl ring, pyridine as a coordi-
nating heterocycle is tolerated providing azaindoline 9i
(2S,3R)-9a. Using an enantiopure carboxylic acid as the sole
source of chirality also led to a noteworthy asymmetric
[21]
induction.
Table 2: Enantioselective synthesis of indolines 9 from triflates 5.
[
c]
[d]
[c]
[d]
Entry Aryl triflate 5
Indoline 9
% Yield
e.r.
Entry Aryl triflate 5
Indoline 9
% Yield
e.r.
[
a]
[b]
1
2
3
4
5a
66
97.5:2.5
97:3
9
55
94:6
96:4
[
a]
[b]
54
46
75
10
64
85
76
[
[
a]
a]
[b]
96:4
11
86.5:13.5
97.5:2.5
[a]
97:3
12
[
a]
[a]
5
64
97:3
13
71
97.5:2.5
[
[
[
a]
a]
b]
[a]
6
7
8
58
74
57
96:4
96:4
96:4
14
75
60
70
98:2
97.5:2.5
81:19
[a]
15
[a,e]
16
3
[
[
a] Conditions A: 0.1 mmol 5, 10 mmol of A1, 10 mmol [(h -cinnamyl)PdCp], 20 mmol L7, 1.2 equiv Na PO , 0.6m in cumene at 1358C for 12 h.
3 4
3
b] Conditions B: 0.1 mmol 5, 5 mmol of A1, 5 mmol [(h -cinnamyl)PdCp], 12 mmol L6, 1.2 equiv Na PO , 0.6m in p-xylene at 1358C for 12 h. [c] Yield
3
4
of isolated product 9. [d] Determined by HPLC or GC using a chiral stationary phase. [e] with L4 instead of L6.
2
240 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012, 51, 2238 –2242

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(
Table 2, entry 9). For 6-membered-ring substrates with Experimental Section
a substituent in the 4-position, both, trans-isomer 5e and
cis-isomer 5 f provide comparable selectivities (Table 2,
entries 5 and 6). Isopropyl amine substrates with enantiotopic
Representative procedure for the enantioselective cyclization
3
(Table 2, entry 7): [h -cinnamyl)PdCp] (2.88 mg, 10.0 mmol), A1
2.24 mg, 10.0 mmol), substrate 5g (49.1 mg, 0.10 mmol), and sodium
(
phosphate (19.7 mg, 0.12 mmol) were weighed into a vial equipped
with a magnetic stir bar. The vial was sealed with a rubber septum and
flushed with nitrogen. L6 (8.79 mg, 20.0 mmol) was added as
a solution in 0.2 mL p-xylene. The mixture was degassed and
subsequently heated to 1358C. After 12 h, the reaction mixture was
cooled to 238C and directly purified on silica gel (EtOAc/pentane
CH groups perform well and give access to a variety of 2-
3
methyl-indolines 9g–9n (Table 2, entries 7–14). The reactivity
could be further extended to non-cyclic methylene groups
providing compounds 9o in high selectivity (Table 2,
entry 15). Even in this case, the trans-isomer of the indoline
is exclusively observed, underlying the critical importance of
a proper spatial arrangement of the hydrogen atom in the
reactive conformation 7b for the reactivity. To investigate this
idea, we tested smaller rings which impose cis-fused products.
For instance, benzocyclopentyl substrate 5p readily cyclizes
and gives rise to 9p in good yields albeit with diminished
enantioselectivity (Table 2, entry 16).
1
9
:15, R =0.45) yielding 25.2 mg (74 %) of 9g with an e.r. value of
6:4.
f
Received: December 2, 2011
Published online: February 3, 2012
Keywords: asymmetric catalysis · CÀH activation ·
.
cooperative effects · palladium · phosphines
The relative and absolute configuration of the cyclized
products was unambiguously established by X-ray crystallo-
[22]
graphic analysis of product 9a. (2R,3S)-Configured indo-
line 9a is obtained when the reaction is performed with (R,R)-
SagePhos [(R,R)-L6]. The absolute configuration might be
rationalized by the stereochemical pathway illustrated in
Scheme 5. The sterically demanding residue of the carboxylic
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[
3
C(sp )–H activations. The ligands are sterically demanding,
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aryl triflates and provides access to the important indoline
scaffold in a highly enantioselective fashion. Moreover, we
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1
2
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II
ever, the palladium source utilized, Pd (OAc) , is reduced to the
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0
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[
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enantioselectivities albeit in significantly diminished yields.
21] In a preliminary experiment, we found that chiral carboxylic acid
A3 as sole source of chirality and a stabilizing achiral carbene
ligand (IPr) provides indoline 9a with 71:29 e.r.
133, 19598 – 19601.
[
13] For our activities in enantioselective CÀH and CÀC functional-
izations see: a) T. Seiser, N. Cramer, Angew. Chem. 2008, 120,
9
435 – 9438; Angew. Chem. Int. Ed. 2008, 47, 9294 – 9297; b) T.
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Albicker, N. Cramer, Angew. Chem. 2009, 121, 9303 – 9306;
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[
22] See Supporting Information. CCDC 852462 contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via href = “http://www.ccdc.cam.ac.uk/cgi-
bin/catreq.cgi” > www.ccdc.cam.ac.uk/data_request/cif.
8
1
181 – 8184; h) T. Seiser, N. Cramer, Angew. Chem. 2010, 122,
0361 – 10365; Angew. Chem. Int. Ed. 2010, 49, 10163 – 10167;
i) M. Waibel, N. Cramer, Chem. Commun. 2011, 47, 346 – 348;
j) D. N. Tran, N. Cramer, Angew. Chem. 2011, 123, 11294 – 11298;
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[
14] During our studies and the preparation of this manuscript,
3
a report on highly enantioselective C(sp )-H functionalizations
2
242 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 2238 –2242