Hybrid Palladium Catalyst Assembled from Chiral Phosphoric Acid and Thioamide for Enantioselective β-C(sp3)?H Arylation

Article abstract of DOI:10.1002/anie.202004485

A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β-C(sp³)?H functionalization of thioamides (up to 99 percent yield, 97 percent ee). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp³)?H arylation can be achieved with high s-factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.

Full text of DOI:10.1002/anie.202004485

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Accepted Article
Title: Hybrid Palladium Catalyst Assembled from Chiral Phosphoric
Acid and Thioamide for Enantioselective β-C(sp3)‒H Arylation
Authors: Liuzhu Gong, Hua-Jie Jiang, Xiu-Mei Zhong, Zi-Ye Liu, Rui-
Long Geng, Yang-Yang Li, Yun-Dong Wu, and Xinhao Zhang
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10.1002/anie.202004485
Angewandte Chemie International Edition
COMMUNICATION
Hybrid Palladium Catalyst Assembled from Chiral Phosphoric
Acid and Thioamide for Enantioselective β-C(sp3)‒H Arylation
Hua-Jie Jiang,[a], + Xiu-Mei Zhong, [b], + Zi-Ye Liu, [b], + Rui-Long Geng,[a] Yang-Yang Li,[a] Yun-Dong
Wu,[b,c] Xinhao Zhang,[b,c], * and Liu-Zhu Gong[a], *
Abstract:
phosphoric acid (CPA) and thioamide shows a high capacity for
enabling
highly efficient and enantioselective β-C(sp3)‒H
A
hybrid palladium catalyst assembled from chiral
switched the regioselection of C‒H activation from the carbon
adjacent to the nitrogen to the acyl side of the thioamide, allowing
for the generation of chiral β-amidation products.[4d]
a
functionalization of thioamides (up to 99% yield, 97% e.e.). A kinetic
resolution of unsymmetrical thioamides via intermolecular C(sp3)‒H
arylation can be achieved in high-levels of s-factor. Mechanistic
investigations have revealed that stereocontrol is achieved by
embedding the substrate in a robust chiral cavity defined by the bulky
CPA with a neutral thioamide ligand.
Aliphatic C(sp3)‒H functionalization remains difficult due to high
C‒H bond energy (typically 90−100 kcal/mol), low acidity
(estimated pKa = 45−60), and an unreactive molecular orbital
profile.[1] It is a longstanding goal of chemists to achieve
stereochemically controlled C(sp3)‒H functionalization. During
the past decades, dozens of reactions have been developed by
using the strategy of incorporating a functional group into
substrates in either site- or stereoselective auxiliary-oriented bond
cleavage enabled by transition metal catalysis.[2] The ability of
sulfur atom to coordinate with transition metals has led to the use
of sulfur-containing functional groups as directing groups in
transition metal-catalyzed site-selective C‒H functionalization.[3-4]
As shown in Scheme 1a, Yu and coworkers reported an
enantioselective amine α-C(sp3)‒H arylation of thioamides
afforded by combining a chiral phosphoric acid (CPA) with a
palladium catalyst.[4a] We found that a hybrid palladium catalyst
containing
a
chiral Co(III)-complex anion and
a
chiral
phosphoramidite ligand is highly efficient for a similar reaction,
delivering up to 99% yields and 99% e.e.[4b] Using a chiral
phosphoramidite ligand, Glorius and coworkers established an
asymmetric Rh(I)-catalyzed amine α-arylation of 1,2,3,4-
tetrahydroquinolines bearing a tert-butyl thioamide directing
group.[4c] The Cp*Co(III)/chiral carboxylic acid catalyst system,
together with the use of dioxazolone as the amidation reagent,
Scheme 1. The regioselectivity of asymmetric C(sp3)−H functionalization
reactions of thioamides.
Chiral β-aryl isobutyramides and their derivatives (γ-aryl
isobutanol, β-aryl esters, etc.), which can be easily accessed from
thioamides,[5] have frequently been encountered in bioactive
compounds
and
pharmaceuticals.[6]
Enantioselective
desymmetrization of butyric thioamides would be a powerful
method for the synthesis of these compounds, but has not yet
been achieved by available strategies (Scheme 1a).[4] The
formidable challenge is obviously arisen from the difficulty in the
differentiation between a small α-methyl group and an even
smaller α-hydrogen atom.[2f,7] We noticed that in previous studies
on the Pd(II)-catalyzed N-α-C(sp3)‒H activation reactions, the C–
H bond cleavage exclusively occurs at the most accessible site of
the thioamide (Scheme. 1b).[4a,4b,8] These precedent observations
imply that the site-selectivity in Pd(II)-catalyzed C(sp3)‒H
activation might be modulated and switched by tuning the steric
bulkiness of N-substituent of the thioamide. We initially carried out
density functional theory (DFT) calculations to verify this
speculation and found that an increase in steric hindrance at the
α-position of the amide nitrogen (1a-1c) led to considerably higher
activation barrier (ΔGN≠) of C‒H activation at the carbon α to the
nitrogen, via TS-N, and a comparable C‒H activation barrier at β-
[a]
[b]
H.-J. Jiang+, R.-L. Geng, Y.-Y. Li, Prof. Dr. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026, China
E-mail: gonglz@ustc.edu.cn
X.-M. Zhong+, Z.-Y. Liu+, Prof. Dr. X. Zhang, Prof. Dr. Y.-D. Wu
Lab of Computational Chemistry and Drug Design, State Key
Laboratory of Chemical Oncogenomics
Peking University Shenzhen Graduate School
Shenzhen 518055, China
E-mail: zhangxh@pkusz.edu.cn
Prof. Dr. X. Zhang, Prof. Dr. Y.-D. Wu
Shenzhen Bay Laboratory
Shenzhen, 518055, China
These authors contributed equally to this work.
[c]
+
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202004485
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COMMUNICATION
≠
position of the thioamide, via TS-S (ΔGS ). TS-S gets more
favorable than TS-N as the N-substituents become bulkier
(Scheme 1c, for details see Section 2.2 in SI). These theoretical
predictions prompted us to posit that the incorporation of a bulky
N, N-diisopropyl amine group into isobutyric thioamides might
enable the Pd(II)-catalyzed β-C(sp3)‒H functionalization to
achieve enantioselective desymmetrization (Scheme 1d).
hydrogen atom and thus, various Akiyama-Terada phosphoric
acids (CPA) were examined.[11] Both the catalytic activity and
stereoselectivity of the palladium catalysts appeared to be highly
sensitive to the 3- and 3’-substituents of CPA (Table 1, entries 1-
5). Among the CPAs evaluated, CPA1, bearing 9-anthryl
substituents at the 3- and 3’-positions, gave an excellent yield and
stereochemical outcome (91% yield and 96% e.e., Table 1, entry
1), but the others resulted in significantly attenuated
enantioselectivity (entries 2-4). Only trace amounts of the product
(3a) were observed in the presence of CPA5 with 2,4,6-
triisopropylphenyl substituents (Table 1, entry 5) and no product
was detected in the absence of the CPA, suggesting that the CPA
participates in the cleavage of the C(sp3)‒H bond, presumably via
the well-known concerted deprotonation-metalation (CMD)
mechanism (Table 1, entry 6).[12] The absence of 3 Å molecular
sieves and the addition of KHCO3 as base both led to diminished
yields (Table 1, entries 7 and 8 vs entry 1). Interestingly,
substituents in the benzoquinone oxidants led to slightly lower
enantioselectivity, but a significantly attenuated yield (Table 1,
entries 9-13). These results suggest that the benzoquinone and
the corresponding hydroquinone anion may not participate in the
enantioselectivity-determining step. In our previous study, we
demonstrated that the neutral phosphoramidite ligand can
accelerate the C(sp3)‒H bond cleavage in the palladium-
catalyzed α-arylation reactions of thioamides.[4b] We speculated
accordingly, that an unidentified neutral ligand might exist and
assist the Pd(II) catalyst to accelerate the C‒H bond cleavage.
Table 1. Optimization of the desymmetrization of isobutyric thioamide 2a.[a]
entry
1
conditions
yield (%)[b]
e.e. (%)[c]
CPA1
90 (91[d]
64
)
96
13
60
23
-
2
CPA2
3
CPA3
84
4
CPA4
60
5
CPA5
trace
N.R.
6
without CPA
-
7
without 3Å M.S.
with 2.0 equiv. KHCO3
2.0 equiv. 2,5-DMBQ
2.0 equiv. 2,6-DMBQ
2.0 equiv. thymoquinone
2.0 equiv. 2,5-DPBQ
2.0 equiv. 2,5-DTBQ
82(83[d]
51
)
97
86
92
91
90
92
-
8
9
49
10
11
12
13
60
36
49
N.R.
[a] Standard conditions: thioamide 2a (0.1 mmol, 1.0 equiv.), PhB(OH)2 (0.2
mmol, 2.0 equiv.), Pd2(dba)3 (0.005 mmol, 5 mol%), CPA (0.012 mmol, 12
t
mol%) 1,4-BQ (0.2 mmol, 2.0 equiv.), AmylOH (1.0 mL), 3 Å M.S. (50 mg),
60 °C, 12 h, then quenched with 60 μL pyridine. [b] Determined by 1H NMR
analysis of the crude products using trimethyl 1,3,5-benzenetricarboxylate as
the internal standard. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] Yield of the isolated product. 2,5-DMBQ = 2,5-dimethyl-1,4-
benzoquinone. 2,6-DMBQ = 2,6-dimethyl-1,4-benzoquinone. 2,5-DPBQ =
2,5-diphenyl-1,4-benzoquinone.
benzoquinone.
2,5-DTBQ
=
2,5-di-tert-butyl-1,4-
The validation of the theoretical prediction commenced with the
palladium-catalyzed asymmetric β-C(sp3)‒H arylation reaction
between N, N-diisopropyl isobutyric thioamide (2a) and
phenylboronic acid in the presence of catalytic amounts of sodium
salts of anionic chiral CoIII complexes in combination with chiral
phosphoramidite ligands, which was convinced to be highly
efficient catalyst system for the enantioselective amine α-arylation
of thioamides.[4b] However, only trace amounts of the desired
product (3a) were detected (for details see Table S1 in SI). Next,
we evaluated the chiral phosphoric acids (CPA), which have been
proven to function as anionic ligands capable of inducing
significant stereochemical outcomes in palladium catalyzed C‒H
functionalizations.[4a,9-10] The flexibly tunable steric environment
by varying the 3- and 3’-substituents allows the CPA to
discriminate the subtle difference between the methyl and a
Scheme 2. Scope of coupling partners with isobutyric thioamides (2a). Standard
conditions: thioamide 2a (0.1 mmol, 1.0 equiv.), ArB(OH)2 (0.2 mmol, 2.0 equiv.),
Pd2(dba)3 (0.005 mmol, 5 mol%), CPA1 (0.012 mmol, 12 mol%), 1,4-BQ (0.2
t
mmol, 2.0 equiv.), AmylOH (1.0 mL), 3 Å M.S. (50 mg), 60 °C, 12 h, then
quenched with 60 μL pyridine. The values beneath each structure indicate the
yields of isolated products. Enantiomeric excesses were determined by HPLC
analysis on a chiral stationary phase. [a] Compound 3s was obtained from the
reaction with MeB(OH)2 (1.0 mmol, 10.0 equiv.) at 100 oC, 24 h.
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With the optimized reaction conditions in hand, the scope of the
reaction was investigated with various coupling partners. Both
electronically rich and deficient aryl boronic acids smoothly
underwent the desymmetric C‒H arylation and gave the coupling
products in high yields and excellent enantioselectivities ranging
from 86% to 97% e.e. (Scheme 2). A variety of functionalities,
such as vinyl (3d), nitro (3h), ester (3i), trifluoromethyl (3j) and
carbonitrile (3k) were compatible with the reaction conditions. The
electronic feature of the substituent on the benzene ring of the
aryl boronic acids did not exert considerable influence on the
reaction performance as shown in the cases involving para-
substituted phenyl boronic acids, all of which provided high yields
and excellent levels of enantioselectivity (3a-3k). In addition, both
meta- and ortho-methylphenyl boronic acids underwent a clean
reaction, delivering the arylation products in high yields and with
greater enantioselectivities than the para-methylphenyl boronic
desymmetrization reaction, the kinetic resolution requires the
recognition of different enantiomers in a racemic mixture.[2f]
Although kinetic resolution has been established in C(sp2)–H
activation,[14] only a few examples can be found in C(sp3)–H
substrates,[9f,15] particularly even fewer in intermolecular C(sp3)–
H activation.[16] However, the use of identical conditions in the
kinetic
resolution
of
N,N-diisopropyl-2-methyl-3-phenyl-
propanethioamide (3a) failed to give satisfactory results (for
details see Table S2 in SI). Re-evaluation of CPAs identified
CPA6 to be a more stereoselective co-catalyst, enabling the
reaction giving the desired diarylation products with high levels of
enantioselectivity (4a, 92% e.e. and 4b, 82% e.e.), accompanied
with the recovered 3a in 62% e.e. and 86% e.e. respectively
(Scheme 3). The kinetic resolution of a structurally diverse range
of thioamides proceeded well, giving the corresponding products
with high enantioselectivity. The oxidative coupling reaction
between rac-3f and phenylboronic acid led to the diarylation
product 4b’, the enantiomer of 4b, in 88% e.e. More significantly,
primary alkyl-substituted substrates could be resolved with high
s-factor values (4c-4g, for details see Table S3 in SI). CPA6 can
even differentiate an ethyl group from the methyl group as shown
in the thioamide rac-3s with high enantioselectivites of both the
starting material and the corresponding product (s-factor = 37).
The cyclopentyl-substituted thioamide (3x) also reacted smoothly,
giving high enantioselectivity for the product and 66% e.e. for the
recovered 3x.
acid (3l and 3m vs 3b). However,
a much diminished
enantioselectivity was observed for meta-fluorophenyl boronic
acid in comparison with the para-substituted isomer (3n vs 3e).
Disubstituted aryl and 2-naphthyl boronic acids were excellent
substrates, leading to chiral coupling products with high yields and
enantioselectivities (3o-3r), but the oxidative coupling reaction
with a methyl boronic acid gave 3s in only 18% yield and a
relatively lower enantioselectivity. The absolute configuration of
3g was assigned by single-crystal X-ray crystallography (See SI
for details).
Scheme 4. Scale-up reaction and synthetic applications.
To elucidate the practicality of this transformation, a twenty-fold
scale oxidative C‒H coupling reaction between 2a and 4-
chlorophenylboronic acid was successfully carried out to afford
(S)-3f in 92% yield and with 95% e.e. (Scheme 4a). Diversification
of the β-arylation product to incorporate other important functional
groups was achieved through simple chemical modifications. The
product (S)-3f (95% ee) was readily converted into an amide (5)
with 94% e.e. by treatment with m-CPBA.[17] Methylation and
subsequent reduction of (S)-3f provided an aldehyde, which was
then treated with NaBH4 to furnish the chiral alcohol 6 with 94%
e.e.[5] The chiral alcohol 6 can be easily converted into a S1P
agonist using known methods (Scheme 4b).[6d]
Scheme 3. Kinetic resolution of unsymmetrical thioamides. Standard
conditions: thioamide 3 (0.1 mmol, 1.0 equiv.), ArB(OH)2 (0.1 mmol, 1.0 equiv.),
Pd2(dba)3 (0.005 mmol, 5 mol%), CPA6 (0.012 mmol, 12 mol%), 1,4-BQ (0.1
mmol, 1.0 equiv.), tAmylOH (1.0 mL), 3 Å M.S. (50 mg), 60 °C, 12 h, then
quenched by 60 μL pyridine. The values beneath each structure indicate the
yields of isolated product. [a] 2.0 equiv. ArB(OH)2 and 2.0 equiv. BQ were used.
Enantiomeric ratios were determined by HPLC analysis on a chiral stationary
phase. C=e.e.s/(e.e.s+e.e.p), s=ꢀln[(1−C) (1−e.e.s)]/ln[(1−C)(1+e.e.s)].
To understand the successful role of Pd in combination with
CPA in the reaction, both mass spectrometry analysis and DFT
calculations were conducted. We designed a stoichiometric
stepwise reaction and monitored the reaction process by
With the success in the enantioselective desymmetrization of
isobutyric thioamides, we investigated the kinetic resolution of
unsymmetrical
thioamides.[13]
Compared
with
the
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electrospray ionization mass spectrometry (ESI-MS, for details
see Section 2.1 in SI).[18] The experiments suggest that CPA is
able to facilitate the C‒H activation to generate the palladation
intermediates. In the C‒H activation step, two thioamides (2a)
coordinate to the palladium, one undergoing β-C‒H activation and
the other acting as a neutral ligand at the beginning of reaction.
Accompanying with the reaction undergoing, the product 3a
grows and gradually replaces the substrate 2a to be the neutral
ligand (Figure S43).
(JCYJ20170412150343516) and the Shenzhen San-Ming Project
(SZSM201809085).
Keywords: palladium catalysis • chiral phosphoric acid • C(sp3)–
H arylation• thioamides
[1]
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[2]
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Scheme 5. Stereocontrol model rationalizing the origin of the enantioselectivity.
Based on the intermediates identified by HRMS, we calculated
diastereomers of the transition states to elucidate the origin of the
enantioselectivity (Scheme 5 and Section 2.2 in SI). These
studies reveal that TS1A_S, which yields the (S)-product, is 2.4
kcal/mol lower in energy than TS1A_R, which yields the (R)-
product. The origin of the preference can be found by measuring
the corresponding dihedral angle, α1 (highlighted in green in
Scheme 5). A larger angle (α1 = - 65.9°) found in TS1A_S reveals
the structure to engage in a staggered transition state (Scheme
5a). In contrast, the corresponding dihedral angle of TS1A_R, α2
is - 33.7°, which leads to an unfavorable structure with stronger
torsional strain (Scheme 5b). We also considered the transition
state, which is assisted by a molecule of product (3a) instead of
substrate (2a) as the neutral ligand (Figure S48 in SI). The similar
results imply that the chirality of thioamide 3a does not affect
much on the selectivity. Further examination of structures of these
transition states shows that the substrate adjusts its structure to
fit the shape of the catalyst, and consequently, the excellent
stereocontrol is achieved here presumably by embedding the
substrate in a chiral robust cavity defined by the bulky CPA and
the neutral ligand (2a or 3a). In this scenario, it is not surprising
that the e.e. value appears to be sensitive to the nature of the
CPA (Figure S49 in SI).
[3]
Selected examples of sulfur-directed C−H functionalization: a) X.-S.
Zhang, Q.-L. Zhu, Y.-F. Zhang, Y.-B. Li, Z.-J. Shi, Chem. Eur. J. 2013,
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Sullivan, D. J. Dixon, J. Seayad, Angew. Chem. Int. Ed. 2017, 56, 16550;
Angew. Chem. 2017, 129, 16777; d) Z.-J. Cai, C.-X. Liu, Q. Gu, S.-L.
You, Angew. Chem. Int. Ed. 2018, 57, 1296; Angew. Chem. 2018, 130,
1310; e) L. Jin, J. Wang, G. Dong, Angew. Chem. Int. Ed. 2018, 57,
12352; Angew. Chem. 2018, 130, 12532; f) H. Shi, D. J. Dixon, Chem.
Sci., 2019, 10, 3733.
For examples of asymmetric sulfur-directed C(sp3)−H functionalization,
see: a) P. Jain, P. Verma, G. Xia, J.-Q. Yu, Nat. Chem. 2017, 9, 140; b)
H.-J. Jiang, X.-M. Zhong, J. Yu, Y. Zhang, X. Zhang, Y.-D. Wu, L.-Z.
Gong, Angew. Chem. Int. Ed. 2019, 58, 1803; Angew. Chem. 2019, 131,
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Angew. Chem. Int. Ed. 2018, 57, 9950; Angew. Chem. 2018, 130, 10098;
d) S. Fukagawa, Y. Kato, R. Tanaka, M. Kojima, T. Yoshino, S.
Matsunaga, Angew. Chem. Int. Ed. 2019, 58, 1153; Angew. Chem. 2019,
131, 1165. For an example of C(sp2)−H functionalization, see: f) Z.-J. Cai,
C.-X. Liu, Q. Wang, Q. Gu, S.-L. You, Nat. Commun. 2019, 10, 4168.
a) M. Iwata, R. Yazaki, I.-H. Chen, D. Sureshkumar, N. Kumagai, M.
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Lin, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2014, 53, 5327;
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[4]
[5]
[6]
In summary, a Pd-catalyzed enantioselective β-C(sp3)‒H
functionalization of thioamides has been developed using a chiral
phosphoric acid as a chiral auxiliary. The employment of a bulky
diisopropylamine auxiliary allows switching the regioselectivity
from the carbon adjacent to the nitrogen atom to the acyl side.
The MS studies and DFT analysis elucidate the role of the bulky
CPA and the assistance of thioamide ligand, which could define a
robust chiral cavity to achieve a high level of stereocontrol.
a) Z. J. Song, M. Zhao, R. Desmond, P. Devine, D. M. Tschaen, R. Tillyer,
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Kurata, K. Kusumi, K. Otsuki, R. Suzuki, M. Kurono, N. Tokuda, Y.
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S. Nakade, H. Habashita, Bioorg. Med. Chem. Lett. 2012, 22, 144.
a) Q.-F. Wu, P.-X. Shen, J. He, X.-B. Wang, F. Zhang, Q. Shao, R.-Y.
Zhu, C. Mapelli, J. X. Qiao, M. A. Poss, J.-Q. Yu, Science 2017, 355,
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Acknowledgements
[7]
[8]
We are grateful for financial support from NSFC (Grants
21831007, 21672002, 21933004), Chinese Academy of Science
(Grant
XDB20020000),
the
Shenzhen
STIC
J. E. Spangler, Y. Kobayashi, P. Verma, D.-H. Wang, J.-Q. Yu, J. Am.
Chem. Soc. 2015, 137, 11876.
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This article is protected by copyright. All rights reserved.

10.1002/anie.202004485
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hua-Jie Jiang,[a], + Xiu-Mei Zhong, [b], +
Zi-Ye Liu, [b], + Rui-Long Geng,[a] Yang-
Yang Li,[a] Yun-Dong Wu,[c] Xinhao
Zhang,[b], * and Liu-Zhu Gong[a], *
Page No. – Page No.
Hybrid Palladium Catalyst Assembled
from Chiral Phosphoric Acid and
Thioamide for Enantioselective β-
C(sp3)‒H Arylation
A Pd-catalyzed enantioselective β-C(sp3)‒H functionalization of thioamides has
been developed using a chiral phosphoric acid as a chiral auxiliary. ESI-MS studies
and DFT analysis elucidate the role of the bulky CPA and the assistance of
thioamide ligand, which could define a robust chiral cavity to achieve a high level of
stereocontrol.
This article is protected by copyright. All rights reserved.