PdII-Catalyzed Enantioselective C(sp3)?H Activation/Cross-Coupling Reactions of Free Carboxylic Acids

Article abstract of DOI:10.1002/anie.201813055

Pd^II-catalyzed enantioselective C(sp³)?H cross-coupling of free carboxylic acids with organoborons has been realized using either mono-protected amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.

Full text of DOI:10.1002/anie.201813055

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
International Edition
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Accepted Article
Title: Pd(II)-Catalyzed Enantioselective C(sp3)–H Activation/Cross-
Coupling Reactions of Free Carboxylic Acids
Authors: Liang Hu, Peng-Xiang Shen, Qian Shao, Kai Hong, Jennifer
X. Qiao, and Jin-Quan Yu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813055
Angew. Chem. 10.1002/ange.201813055
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10.1002/anie.201813055
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
C–H Activation
Pd(II)-Catalyzed Enantioselective C(sp3)–H Activation/Cross-Coupling
Reactions of Free Carboxylic Acids
Liang Hu, Peng-Xiang Shen, Qian Shao, Kai Hong, Jennifer X. Qiao and Jin-Quan Yu*
Abstract: Pd(II)-catalyzed enantioselective C(sp3)−H cross-
coupling of free carboxylic acids with organoborons has been
realized using either mono-protected amino acid (MPAA) ligands or
mono-protected aminoethyl amine (MPAAM) ligands. A diverse
range of aryl- and vinyl-boron reagents can be used as coupling
partners to provide chiral carboxylic acids. This reaction provides
an alternative approach to the enantioselective synthesis of
cyclopropanecarboxylic acids and cyclobutanecarboxylic acids
containing α-chiral tertiary and quaternary stereocenters. The
utility of this reaction was further demonstrated by converting the
carboxylic acid into cyclopropyl amine without loss of optical
activity.
E
nantioselective alkyl C(sp3)−H bond activation is
a
Scheme 1. Pd-Catalyzed Enantioselective C–H Functionalization of Free Carboxylic
longstanding goal in organic synthesis.1 Recently, Pd-catalyzed
asymmetric C−H activation reactions using chiral ligands have been
demonstrated. The combination of monodentate coordinating
substrates with chiral bidentate mono-N-protected amino acid ligand
(MPAA) has led to the development of a wide range of Pd(II)-
catalyzed enantioselective intermolecular C−H activation
reactions.2-5 Recently, chiral bidentate quinoline ligands and
oxazoline ligands were developed to realize the enantioselective
functionalization of methylene C−H bonds and methyl C−H bonds
in carboxylic acid derivatives, respectively.3c-3d However, substrates
in these reactions require preinstalled directing groups that need to
be removed after C−H functionalization.3 Therefore, the direct C−H
functionalization of free carboxylic acids would afford superior
atom and step economies in the context of protecting free synthesis.6
Acids.
developed in our laboratory. Enantioselective C−H coupling of free
carboxylic acids via Pd(II)/Pd(0) catalytic cycle offers a new avenue
to broaden the diversity of transformations.
With our previously developed β-C−H arylation of free
cyclopropyl carboxylic acid with aryl iodides in mind,7 we began
our study by investigating the reactivity of cyclopropanecarboxylic
acid under Pd(II)/Pd(0) catalysis.8-9 Initially we focused on the C−H
cross-coupling reactions with phenylboronic acid pinacol ester using
various types of bidentate chiral ligands (Table 1). While 11% yield
was obtained in the absence of ligand, we were pleased to observe
that mono-protected aminoethyl amine (MPAAM) ligand (L1)
provided the desired arylated product in 38% yield with 96:4 er.
Other ligand screening showed that our previous two classes of
chiral ligands (L2 and L3) gave poor yields or enantioselectivities.
Further optimization using other ligands did not afford significant
improvement (see supporting information). We then turned our
attention to mono-protected amino acid (MPAA) ligands. Pleasingly,
N-acetyl-L-phenylalanine (L4) afforded a 58% yield with 97:3 er.
Notably, replacing acetyl with other protecting groups (L5–L9) led
to either low yields or no reaction. Ligands with different side
chains were also examined. The yield decreased when the benzyl
group was replaced with other alkyl groups (L10–L14). On the
other hand, only 13% yield and 88:12 er was obtained when we
replaced benzyl side chain with phenyl substituent (L15) in this
reaction, suggesting the importance of the benzyl group. We then
focused on the modification of the benzyl group. Though para-OMe
substituted N-acetyl-L-phenylalanine (L17) slightly improved the
yield to 60%, other groups, such as tert-butyl, naphthalenyl and
fluoro (L16, L18–L19), introduced to the para or ortho positions
To date, there exists
a single example of enantioselective
intermolecular C(sp3)–H activation of carboxylic acids without
using exogenous directing groups (Scheme 1).7 Key to the
development of this method was the design of a novel mono-
protected aminoethyl amine (MPAAM) chiral ligand to match the
weakly coordinating carboxylic acid for stereocontrol. However,
only arylation via a Pd(II)/Pd(IV) catalytic cycle is compatible with
this chiral catalyst. In addition, this method was not compatible with
cyclobutane substrates, an important class of cycloalkane in
synthesis. Herein, we report the first chiral catalyst for the
enantioselective
C(sp3)–H
cross-coupling
of
both
cyclopropanecarboxylic acids and cyclobutanecarboxylic acids with
both aryl and vinyl boron reagents. Both chiral ligands (L25, L36)
were conveniently synthesized by C−H activation reactions
[]
L. Hu, P.-X Shen, Q. Shao, K. Hong, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
gave
lower
yields.
Gratifyingly,
N-acetyl-L-(2,6-di-
phenyl)phenylalanine (L20) gave
a
better yield and high
Dr. J. X. Qiao
Discovery Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000,
Princeton, NJ 08543 (USA)
enantioselectivity (64% yield. 94:6 er). Since this type of ligand can
be synthesized by our sulfonamide-directed C−H cross-coupling
reaction10, we prepared a series of 2,6-di-substituted phenylalanine-
derived ligands (L20–L28) for optimization. Among those 2,6-di-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201813055
Angewandte Chemie International Edition
Table 2. The Scope of Enantioselective Arylation of Cyclopropanecarboxylic Acids a,b
substituted ligands, the [2,6-di-(4-tert-butylphenyl)] phenylalanine
ligand (L25) gave the best yield and enantioselectivity (70% yield,
97:3 er).
Table1. Ligand Screening for Enantioselective Arylation of Cyclopropanecarboxylic
Acid a,b
[a] Conditions: 1 (0.1 mmol), 2 (1.5 equiv), Pd(OAc)2 (10 mol%), L25 (20 mol%),
Ag2CO3 (1.5 equiv), K2HPO4 (1.5 equiv), BQ (0.5 equiv), H2O (10.0 equiv), t-BuOH
(1.0 mL), 80 °C, air, 12 h. [b] Isolated yields. [c] Using L36 instead of L25.
[a] Conditions: 1a (0.1 mmol), 2a (1.5 equiv), Pd(OAc)2 (10 mol%), ligand (20 mol%),
Ag2CO3 (1.5 equiv), K2HPO4 (1.5 equiv), BQ (0.5 equiv), H2O (10.0 equiv), t-BuOH
(1.0 mL), 80 °C, air, 12 h. [b] 1H NMR yields, using CH2Br2 as an internal standard. BQ
= benzoquinone.
Table 3. Ligand Screening for Enantioselective Arylation of Cyclobutanecarboxylic Acid
a,b
With the optimized reaction conditions in hand, we next
explored the substrate scope of this method. The reaction was
compatible with a wide range of aryl-boronic acid pinacol esters
(Table 2). The coupling of 1a with electron-withdrawing
arylboronic acid pinacol esters afforded the arylated products in
good yields with excellent enantioselectivities (3a–3g). On the other
hand, arylboronic acid pinacol esters containing electron-rich groups
tended to give the desired arylated products in slightly lower yields
with similar enantioselectivities (3h–3i). In addition, both meta-
substituted and ortho-substituted arylboron reagents were also
viable coupling partners (3j–3l). We were also pleased to find that
heteroaryl boronic ester can also participate in the reaction, albeit in
a lower yield (3o). Furthermore, the reaction worked well with
various 1-substituted 1-cyclopropanecarboxylic acids (3p–3u) to
give similar enantioselectivity despite the drastic change of sterics.
1-Aryl-1-cyclopropanecarboxylic acids (3p–3q) were arylated to
give the desired products in good yields with good
enantioselectivities. 1-Butyl (3r), phenylpropyl (3s), chloropentyl
[a] Conditions: 4a (0.1 mmol), 2a (1.5 equiv), Pd(OAc)2 (10 mol%), ligand (20 mol%),
Ag2CO3 (2.0 equiv), K2HPO4 (1.5 equiv), BQ (0.5 equiv), H2O (5.0 equiv), t-BuOH (1.0
mL), 60 °C, air, 12 h. [b] 1H NMR yields, using CH2Br2 as an internal standard.
(3t)
and
benzyl-protected
1-hydroxymethyl
(3u)
We next investigated the hitherto unreported coupling of
cyclobutanecarboxylic acids with arylboronic acid pinacol esters.
Asymmetric synthesis of diverse chiral cyclobutanes remains a
significant challenge.11 Previous attempts to enantioselectively
cyclopropanecarboxylic acids were also smoothly arylated in
moderate to good yields with good enantioselectivities.
2
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10.1002/anie.201813055
Angewandte Chemie International Edition
functionalize cyclobutyl C−H bonds require the installation of a
directing group.12 Through ligand screening, we found that the
mono-protected aminoethyl amine (MPAAM) ligand (L1) was
promising for enantioselective C−H activation of cyclobutane
carboxylic acid, affording a moderate yield and enantioselectivity.
Though MPAA ligands worked well for cyclopropanecarboxylic
enantioselectivities. The reaction also worked well with other 1-
substituted 1-cyclobutanecarboxylic acids (5p–5t). 1-Aryl-1-
cyclobutanecarboxylic acid and 1-alkyl cyclobutanecarboxylic acid
(5p–5r) were arylated to give the desired products in moderate
yields and enantioselectivities. Substrates containing either an ether
(5s) or a protected amine group (5t) were also compatible with this
reaction conditions. Surprisingly, α-hydrogen cyclobutanecarboxylic
acid (5u) gave poor enantioselectivity with this MPAAM ligand (57%
yield, 64:36 er). Interestingly, the use of MPAA ligand L25 afforded
the desired product 5u in 61% yield with 92:8 er. The absolute
configuration of the product 5u was confirmed by X-ray
crystallographic analysis (see Supporting Information).
acids,
poor
enantioselectivity
was
obtained
with
cyclobutanecarboxylic acid (L4 and L25) in this reaction. We thus
decided to focus on the modification of MPAAM ligands to further
optimize this transformation (L29–L39). Changing the benzyl
group to other alkyl groups (L30–L33) led to lower yields and
moderate er. Remarkably, 2,6-di-aryl substituents on the phenyl ring
(L36–L39) dramatically improved both the yield and er. Of the
ligands prepared, the 2,6-phenyl substituted MPAAM ligand (L36)
gave the best yield and enantioselectivity of 62% and 94:6 er,
respectively.
Table 5. The Scope of Enantioselective Vinylation of free carboxylic Acids a,b
Table 4. The Scope of Enantioselective Arylation of Cyclobutanecarboxylic Acids a,b
[a] Conditions: 6 (0.1 mmol), 7 (2.0 equiv), [Pd(allyl)Cl]2 (5 mol%), L28 (20 mol%),
Ag2CO3 (1.5 equiv), K2HPO4 (1.5 equiv), BQ (0.5 equiv), H2O (2.0 equiv), t-BuOH (1.0
mL), 80 °C, air, 12 h. [b] Isolated yields. [c] 60 °C.
Subsequently,
we
explored
the
Pd(II)-catalyzed
enantioselective C(sp3)−H vinylation of free carboxylic acids (Table
5) as this transformation will provide access to a broader range of
chiral carboxylic acids. Through extensive experimentation, we
established the optimal reaction conditions that consisted of 2 equiv.
of vinyl boronic ester with 20% ligand L28 as the chiral ligand (8a).
A number of disubstituted and trisubstituted (Z)-vinylboron reagents
(8a–8e) were effective coupling partners for this reaction. Moreover,
1-cyclohexenyl-Bpin (8f) was compatible with this reaction,
affording a lower yield with good er. We were also pleased to see
that the heterocyclohexenyl boronic ester (8g) could also be
subjected in the vinylation, giving the desired product in moderate
yield with excellent enantioselectivity. Furthermore, this protocol
was also successfully extended to the vinylation of
cyclobutanecarboxylic acid, affording the desired product in 61%
yield with 88:12 er (8h). Such olefin-containing chiral acids could
provide valuable scaffold for organic synthesis and medicinal
chemistry.
[a] Conditions: 4 (0.1 mmol), 2 (1.5 equiv), Pd(OAc)2 (10 mol%), L36 (20 mol%),
Ag2CO3 (2.0 equiv), K2HPO4 (1.5 equiv), BQ (0.5 equiv), H2O (5.0 equiv), t-BuOH (1.0
mL), 60 °C, air, 12 h. [b] Isolated yields. [c] Using L25 instead of L36.
With the optimized reaction conditions in hand, the scope of
substrates and coupling partners was evaluated (Table 4). Electron-
withdrawing groups (5a–5g), such as methoxycarbonyl, acetyl, nitro,
cyano and phenyl groups provided the arylated products in moderate
yields and with good enantioselectivities. On the other hand, the
coupling of 4a with electron-rich arylboronic acid pinacol esters (5h
and 5i) afforded the desired products in slightly lower yields and
with similar enantioselectivities. Pleasingly, 1- and 2-
naphthylboronic acid pinacol esters (5l and 5m) were also
successful coupling partners, albeit in moderate yield and with good
Scheme 2. Synthesis of Cis-Chiral Amine from Carboxylic Acid
To demonstrate the synthetic utility of these C(sp3)−H
arylation products, the cross-coupling product 3f was further
transformed into chiral amine 9 without loss of optical activity
(Scheme 2).13 It should be noted that 2-substituted
cyclopropanamines and 2-substituted cyclopropanecarboxylic acids
are important structural motifs in biologically active molecules and
natural products.
3
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10.1002/anie.201813055
Angewandte Chemie International Edition
Kꢀndig. Angew. Chem. Int. Ed. 2011, 50, 7438; Angew. Chem. 2011,
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In summary, we have developed an efficient Pd(II)-catalyzed
enantioselective C(sp3)−H cross-coupling reaction of free carboxylic
acids. The key to the success of this method was the use of the
bidentate MPAA ligands or MPAAM ligands. This reaction is also
compatible with aryl and vinyl coupling partners and affords aryl
and olefin-containing chiral acids in high enantioselectivities. The
synthetic utility of this reaction was also demonstrated by
converting the chiral carboxylic acid into the chiral cyclopropyl
amine without loss of optical activity.
[5] For Pd(II)-catalyzed enantioselective C–H functionalization using
phosphoric acids/amides ligands, see: a) S.-B. Yan, S. Zhang, W.-L.
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Acknowledgement
We gratefully acknowledge The Scripps Research Institute, the NIH
(NIGMS 2R01 GM084019) and Shanghai RAAS Blood Products
Co. Ltd. for financial support. We thank Dr. Jason Chen from
Automated Synthesis Facility, The Scripps Research Institute for his
assistance with 2D HPLC/SFC analysis. We also thank China
Scholarship Council (fellowship to L.H., Hunan University, China).
[6] P. S. Baran, T. J. Maimone. J. M. Richter. Nature 2007, 446, 404.
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2018, 140, 6545.
[8] For selected reviews and reactions of asymmetric cyclopropanation,
see: a) M. P. Doyle, M. A. McKervey, T. Ye. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998; b) M. P. Doyle, M.
N. Protopopova. Tetrahedron 1998, 54, 7919; c) S. E. Denmark, G.
Beutner. In Cycloaddition Reactions in Organic Synthesis; Kobayashi,
S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002;
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2017, 139, 1049.
Conflict of interest
The authors declare no conflict of interest.
Keywords: arylation · vinylation · C–H activation · palladium
[1] For selected reviews of enantioselective C–H Functionalization: a) R.
Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu. Chem. Soc. Rev.
2009, 38, 3242; b) C. G. Newton, S.-G. Wang, C. C. Oliveira, N.
Cramer. Chem. Rev. 2017, 117, 8908; c) T. G. Saint-Denis, R.-Y. Zhu,
G. Chen, Q.-F. Wu, J.-Q. Yu. Science 2018, 359, eaao4798.
[9] For
Rh(I)-catalyzed
intramolecular
enantioselective
C−H
functionalization of cyclopropanes, see: T. Lee, J. F. Hartwig. Angew.
Chem. Int. Ed. 2016, 55, 8723; Angew. Chem. 2016, 128, 8865.
[2] For the early observation of enantioselective C(sp3)−H
functionalization using mono-N-protected amino acid ligands
(MPAA) and pyridine directing group, see: B.-F. Shi, N. Maugel, Y.-
H. Zhang, J.-Q. Yu. Angew. Chem. Int. Ed. 2008, 47, 4882; Angew.
Chem. 2008, 120, 4960.
[10] K.-J. Xiao, D. W. Lin, M. Miura, R.-Y. Zhu, W. Gong, M. Wasa, J.-Q.
Yu. J. Am. Chem. Soc. 2014, 136, 8138.
[11] For reviews of the synthesis of enantiopure cyclobutane derivatives,
see: a) E. Lee-Ruff, G. Mladenova. Chem. Rev. 2003, 103, 1449; b) F.
Secci, A. Frongia, P. P. Piras. Molecules 2013, 18, 15541.
[3] a) M. Wasa, K. M. Engle, D. W. Lin, E. J. Yoo, J.-Q. Yu. 2011, 133,
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137, 2042; c) G. Chen, W. Gong, Z. Zhuang, M. S. Andra, Y.-Q. Chen,
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[12] For selected examples of Pd-catalyzed enantioselective C–H
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[13] M. H. Shaw, N. G. McCreanor, W. G. Whittingham, J. F. Bower. J.
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[4] For selected Pd(0)-catalyzed intramolecular enantioselective C–H
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4
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10.1002/anie.201813055
Angewandte Chemie International Edition
C–H Activation
L. Hu, P.-X. Shen, Q. Shao, K. Hong,
J. X., Qiao, J.-Q. Yu* __________
Page – Page
Pd(II)-Catalyzed Enantioselective
C(sp3)–H Activation/Cross-Coupling
Reactions of Free Carboxylic Acids
Pd(II)-catalyzed enantioselective C(sp3)−H cross-coupling of free carboxylic
acids with organoborons has been realized using either mono-protected
amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM)
ligands. A diverse range of aryl- and vinyl-boron reagents can be used as
coupling partners to provide chiral carboxylic acids. This reaction provides an
alternative
approach
to
the
enantioselective
synthesis
of
cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-
chiral tertiary and quaternary stereocenters. The utility of this reaction was
further demonstrated by converting the carboxylic acid into cyclopropyl amine
without loss of optical activity.
5
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10.1002/anie.201813055
Angewandte Chemie International Edition
6
This article is protected by copyright. All rights reserved.