pubs.acs.

org/OrgLett Letter

Gold/Chiral Amine Relay Catalysis Enables Asymmetric Synthesis of

C2-Quaternary Indolin-3-ones
Wen-Bin Wang, Ji-Chao Lu, Hao Bai, Yan-Ming Fu, Lan-Jun Cheng, Cheng-Feng Zhu, You-Gui Li,*
and Xiang Wu*
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ABSTRACT: A mild and effective strategy for the asymmetric

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synthesis of C2-quaternary indolin-3-ones from 2-alkynyl arylazides

and ketones by gold/chiral amine relay catalysis is described. In
this reaction, 2-alkynyl arylazides undergo gold-catalyzed cycliza-
tion, nucleophilic attack, and oxidation to form intermediate 2-
phenyl-3H-indol-3-ones, followed by an L-proline-catalyzed asymmetric Mannich reaction with ketones, to afford corresponding
products in satisfactory yields with excellent enantio- and diastereoselectivities.

O ver the past two decades, the development of dual

catalysis involving the combination of organocatalysis
and transition-metal catalysis has allowed for the discovery of
construction of a library of synthetic methods for chiral
molecules.
The 2,2-disubstituted indolin-3-ones with a quaternary
novel transformations, as well as the improvement of the carbon center at the C2 position are important structural
stereocontrol, efficiency, and scope of well-known reactions units in many naturally occurring bioactive compounds, such
that are unattainable using single catalytic systems.1 In as isatisine A, austamide, and aristotelone (Figure 1A).
particular, asymmetric relay catalysis decreases overall reaction Additionally, the C2-quaternary indolin-3-one frameworks
time; avoids the additional workup of either isolable or can also serve as valuable building blocks for the preparation
unstable intermediates; prevents secondary reactions of of nonpeptidic mimetic7 and fluorescent probe.8 Therefore, an
intermediates and, thus, increases efficiency; reduces labor efficient asymmetric approach for the construction of
costs; and minimizes waste.1 More importantly, the concept of structurally diverse chiral C2-quaternary indolin-3-ones is
asymmetric organo/metal relay catalysis has already demon- highly desired. Recently, some asymmetric syntheses of C2-
strated its invaluable importance and will continue to be widely quaternary indolin-3-ones have been developed from 2-
applied in the enantioselective construction of molecular substitued-3H-indol-3-ones 19 and 2-substitued indoles 410
complexity from readily available starting materials.2,3 as substrates. Direct asymmetric Mannich-type reaction of
The field of homogeneous gold catalysis bloomed cyclic indolin-3-ones 1 with simple nucleophiles 2 could be
extensively in the early 21st century and has come to be catalyzed by proline,9a chiral phosphoric acid,9b,c solid-
recognized as a powerful tool for synthetic applications. Since supported proline,9d and chiral thiourea9e to afford corre-
the pioneering example reported by Thomas et al.,4 numerous sponding C2-quaternary products 3 (Figure 1B). Asymmetric
gold-catalyzed alkyne transformations that cannot be per- oxidative dearomative cascade reaction of indoles 4 is a
formed by other transition metals have been disclosed on the convenient strategy for the synthesis of chiral C2-quaternary
basis of the electrophilic activation of the π-systems for the indolin-3-ones 3 (Figure 1C).10 In this strategy, optical pure
construction of carbon−carbon and carbon−heteroatom proline could be combined with TEMPO oxoammonium
bonds.5 Moreover, chiral amines have been employed in salt,10a transition metal catalysis,10b photocatysis,10c and
asymmetric aminocatalysis for the activation of unsaturated electrosynthesis10d for the asymmetric catalytic transformation.
carbonyl compounds via enamine catalysis and iminium Interestingly, wheat germ lipase (enzyme catalysis) could be
catalysis. Importantly, the combination of gold and chiral also employed in this asymmetric oxidative dearomative
amine has attracted increasing attention because such catalysis cascade reaction in combination with electrosynthesis10e and
could significantly improve the efficiency and selectivity of
chemical transformations compared with gold or chiral amine Received: December 20, 2023
alone.6 However, the orthogonal relay catalysis involving gold/ Revised: February 16, 2024
chiral amine remains very limited because of the compatibility Accepted: February 23, 2024
between all catalysts and reagents, common conditions, and Published: February 28, 2024
reaction ordering.2 Consequently, developing new gold/chiral
amine orthogonal relay catalysis is still in demand for the

© 2024 American Chemical Society https://doi.org/10.1021/acs.orglett.3c04285

1792 Org. Lett. 2024, 26, 1792−1796
Organic Letters pubs.acs.org/OrgLett Letter

Table 1. . Optimization of the Reaction Conditionsa

yield ee
entry [Au] solvent oxidant (%)b (%)c
1 t-BuXPhosAuNTf2 acetone DDQ 44 4
2d t-BuXPhosAuNTf2 acetone DDQ 8
3 t-BuXPhosAuNTf2 acetone 1,4-benzoquinone 70 80
4 t-BuXPhosAuNTf2 acetone 1,4- 75 79
naphthoquinone
5 t-BuXPhosAuNTf2 acetone chloranil 14 63
6 t-BuXPhosAuNTf2 acetone dichlone 40 79
7 t-BuXPhosAuNTf2 acetone menadione 80 81
8 t-BuXPhosAuNTf2 toluene menadione 90 75
9 t-BuXPhosAuNTf2 EtOH menadione 91 85
10 t-BuXPhosAuNTf2 CH3CN menadione 85 90
11 t-BuXPhosAuNTf2 DCM menadione 89 91
12 JohnPhosAuNTf2 DCM menadione 82 39
13 PhX-PhosAuNTf2 DCM menadione 62 43
14 BINAPAuNTf2 DCM menadione 38 91
15 t-BuXPhosAuBF4 DCM menadione 91 95
16 t-BuXPhosAuSbF6 DCM menadione 90 99
a
Figure 1. Selected natural products containing C2-quaternary indolin- Unless stated otherwise, the reaction was carried out with 5a (0.1
3-ones and strategies for the enantioselective synthesis of C2- mmol, 1 equiv), 2a (0.8 mmol, 8 equiv), H2O (1 equiv), and oxidant
quaternary indolin-3-ones. (0.4 mmol, 4 equiv) in the presence of 10 mol % (0.01 mmol, 0.10
equiv) of gold complexes. The resulting solution was stirred at room
temperature in solvent (1.5 mL) for 72 h. bYield of the isolated
products. cDetermined by chiral phase HPLC analysis. dWithout L-
photocatysis.10f 2-Alkynyl arylazides 5 are easily available proline.
substrates that could be converted to C2-quaternary indole-3-
ones 3 via palladium-catalyzed one-pot transformation (Figure
1D).11 Actually, in the presence of palladium catalyst and synthesis of the target product 3a with outstanding yield
sulfonic acid, 2-substituted-3H-indol-3-ones 1 could be formed (90%) and excellent enantioselectivity (99% ee).
first and subsequently undergo Mannich reaction. Unfortu- With the optimal reaction conditions in hand, the substrate
nately, only racemic products were obtained in this palladium- scope of the reaction was next investigated. As shown in
catalyzed one-pot transformation.11,12 Therefore, herein, we Scheme 1, this relay catalysis reaction displayed a wide
report the gold/chiral amine relay catalysis to enable the direct tolerance for various functional groups on a broad spectrum of
transformation from 2-alkynyl arylazides to chiral C2- 2-(alkynyl)phenyl azides 5. Electron-donating (MeO-, Me-, t-
quaternary indole-3-ones in the presence of oxidants (Figure Bu-) or electron-withdrawing substituents (F-, Cl-, Br-, CF3-,
1E). CN-) on the scaffold were all suitable for the reaction. It is
We commenced our investigation by choosing 1-azido-2- noteworthy that electron-donating groups significantly im-
(phenylethynyl)benzene 5a and acetone 2a as model proved the yields and greatly reduced the reaction times (3b−
substrates to optimize the reaction conditions with acetone f). However, electron-withdrawing groups led to longer
serving both as a substrate and as a reaction solvent (Table 1). reaction times and lower yields (3g−m), probably because it
Initially, in the presence of t-BuXPhosAuNTf2 (10 mol %), L- is more difficult to form 3H-indol-3-one intermediates.
proline, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), Substrate 5n with two methoxy groups provided the target
and H2O at rt for 72 h, the desired product 3a was obtained product 3n in moderate yield and excellent enantioselectivity.
in 44% yield and 4% ee (Table 1, entry 1). Interestingly, when In addition, esters 5o and 5p derived from L-menthol and
the reaction was conducted without chiral proline, the product estrone were subjected to the standard conditions to furnish
could be obtained in 8% yield (entry 2). It means that the gold 3o and 3p in good yields with excellent diastereoselectivities.
complex could also catalyze the Mannich reaction, which Naphthyl and thienyl-substituted substrates 5q−s also
should be prohibited through the condition optimization [for provided corresponding products with excellent enantioselec-
details, see the Supporting Information (SI)]. The screening of tivities, albeit in moderate yields. Substrates 5t−v with alkyl
oxidants showed that menadione afforded the best yield and groups could also be successfully employed in the reaction,
enantioselectivity (entries 1−7). Then, the amount of acetone which resulted in products 3t−v with slightly lower yields but
was reduced to 8 equiv, and several solvents were tested moderate to excellent enantioselectivities. Notably, alkyl-
(entries 8−11). Notably, DCM provided excellent yield and group-substituted chiral C2-quaternary indole-3-ones have
enantioselectivity for the target product 3a. Subsequently, rarely been synthesized in a direct enantioselective catalytic
ligands of the gold catalyst were screened, and no satisfactory manner, which further demonstrated the compatibility and
results were achieved (entries 12−14). Fortunately, anion superiority of the gold/chiral amine relay catalysis.10a,b The
screening (entries 15 and 16) revealed that SbF6− enabled the corresponding products 3w−f′ were produced in high yields
1793 https://doi.org/10.1021/acs.orglett.3c04285
Org. Lett. 2024, 26, 1792−1796
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 1. Scope of 2-(Alkynyl)phenyl Azides 5b−f′a

a
All reactions were carried out with 5 (0.1 mmol, 1 equiv), 2a (0.8 mmol, 8 equiv), menadione (0.4 mmol, 4 equiv), t-BuXPhosAuSbF6 (10 mol
%), L-proline (0.01 mmol, 10 mol %), and H2O (0.1 mmol, 1 equiv) in DCM (1.5 mL).

(up to 88%) and excellent enantioselectivities (up to 99% ee) Scheme 2. Scope of Ketones 2b−ja
whether they had electron-donating (Me-, MeO-) or electron-
withdrawing groups (F-, Cl-, CF3-, and -CO2Me). Unfortu-
nately, when the methyl group was located on the 5-position of
substrate 5d′, only a 45% yield was obtained, probably because
of the steric effect. Two groups of substituted substrates with
different electronic effects were also shown to be well-suited
for the reaction, which yielded corresponding products 3e′ and
3f′ with excellent yields and enantioselectivities.
Encouraged by the above results of 2-(alkynyl)phenyl azides
and acetone, we also investigated different ketones 2b−j as
substrates on this tandem reaction (Scheme 2). Acyclic 2-
pentanone and 1-cyclohexylpropan-2-one reacted well with 1-
azido-2-(phenylethynyl)benzene to afford the corresponding
products 3ab and 3ac in satisfactory yields and with excellent
enantioselectivities and regioselectivities. Cyclohexanone was
also suitable for this reaction and gave products 3ad in a yield
of 56% with excellent stereoselectivities (>20:1 dr, 97% ee).
Besides cyclohexanone, 4-methylcyclohexanone, 4-tert-butylcy-
clohexanone, N-Boc-4-oxopiperidine, tetrahydro-4H-pyran-4-
one, and tetrahydro-4H-thiopyran-4-one also gave the desired
a
products in moderate yields with excellent dr and ee values All reactions were carried out with 5a (0.1 mmol 1 equiv), 2 (0.8
(3ae−ai). However, the reaction between cyclopentanone and mmol, 8 equiv), menadione (0.4 mmol, 4 equiv), t-BuXPhosAuSbF6
5a gave the desired product 3aj in 67% yield with 8:1 dr and (10 mol %), L-proline (0.01 mmol, 10 mol %), and H2O (0.1 mmol, 1
equiv) in DCM (1.5 mL).
84% ee. The absolute configurations of all products were
determined by comparison with chiral HPLC analysis reported
previously. in a lower but moderate yield of 56% with 96% ee. To verify
To assess the efficiency of the method, a gram-scale the potential reaction mechanism, control experiments were
experiment was conducted (eq 1). The reaction proceeded performed. To elucidate the origin of the oxygen at position 3
under the standard conditions and afforded desired product 3a of product 3a, isotope labeling experiments were conducted
1794 https://doi.org/10.1021/acs.orglett.3c04285
Org. Lett. 2024, 26, 1792−1796
Organic Letters pubs.acs.org/OrgLett Letter

■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its Supporting Information.
*
sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.3c04285.
Experimental procedures and spectral data (PDF)

■ AUTHOR INFORMATION
Corresponding Authors
You-Gui Li − School of Chemistry and Chemical Engineering,
(eq 2). When H218O was used in the model reaction, the 18O- Hefei University of Technology, Hefei 230009, China;
labeled product 3a was detected by HRMS analysis, which Email: liyg@hfut.edu.cn
indicated that the oxygen atom of the carbonyl group Xiang Wu − School of Chemistry and Chemical Engineering,
originated from water. When the starting substrate 5a was Hefei University of Technology, Hefei 230009, China;
subjected to the reaction in the absence of 2a and L-proline orcid.org/0000-0001-5428-9063; Email: wuxiang@
under standard conditions, the intermediate VI was produced hfut.edu.cn
and confirmed by HRMS analysis, which is a pivotal
Authors
intermediate undergoing a Mannich reaction to afford the
product 3a (eq 3).8 Wen-Bin Wang − School of Chemistry and Chemical
On the basis of the above experimental results and previous Engineering, Hefei University of Technology, Hefei 230009,
research, we preliminarily proposed a mechanism for the China
current Au/proline relay-catalyzed formation of C2-quaternary Ji-Chao Lu − School of Chemistry and Chemical Engineering,
indolin-3-ones, as illustrated in Scheme 3. This process Hefei University of Technology, Hefei 230009, China
Hao Bai − School of Chemistry and Chemical Engineering,
Scheme 3. Proposed Mechanism Hefei University of Technology, Hefei 230009, China
Yan-Ming Fu − School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009,
China; orcid.org/0000-0001-8296-3166
Lan-Jun Cheng − School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009,
China
Cheng-Feng Zhu − School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009,
China; orcid.org/0000-0002-9676-6750
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.3c04285

Notes
involves the activation of the 2-alkynyl arylazide substrate
through coordination with the Au catalyst, which leads to the The authors declare no competing financial interest.
formation of the Au-coordinated intermediate I that undergoes
cyclization to give compound II. After the releasing of N2, α-
amino gold carbene complex III is formed and subsequently
■ ACKNOWLEDGMENTS
We are grateful for financial support from Anhui Province Key
trapped by water to provide complex IV. Then, the proton Research and Development Program (202104e11020007). We
demetalation step of IV generates intermediate V. In the thank the support of Postdoctoral Scientific Research Station
presence of the oxidant, the crucial intermediate 2-phenyl-3H- of Materials Science and Engineering at Hefei University of
indol-3-one VI is formed. Imine intermediate VI interacts with Technology.
enamine VII generated from proline and acetone to form a
nine-membered transition state VIII,10a−c which undergoes
Mannich reaction and affords the desired product 3a.
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