Palladium-catalyzed direct C(sp3)-H arylation of indole-3-ones with aryl halides: A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones

Article abstract of DOI:10.1039/c8ra04807j

A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones via palladium-catalyzed direct C(sp³)-H arylation of indole-3-ones with aryl halides has been developed. Various 2-monoarylated indole-3-ones were readily obtained with yields up to 95%. As a class of important nucleophilic intermediates, 2-monoarylated indole-3-ones can be used for the construction of C2-quaternary indolin-3-one skeletons.

Full text of DOI:10.1039/c8ra04807j

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Palladium-catalyzed direct C(sp3)–H arylation of
indole-3-ones with aryl halides: a novel and
efficient method for the synthesis of nucleophilic
2-monoarylated indole-3-ones†
Cite this: RSC Adv., 2018, 8, 25292
a
*
Yong-Long Zhao,
Yong-Qin Tang,a Xing-Hai Fei,a Tao Xiao,a Ya-Dong Lu,a
Xiao-Zhong Fu,a Bin He,a Meng Zhou,a Chun Li,a Peng-Fei Xu
b
*
a
*
and Yuan-Yong Yang
A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones via
palladium-catalyzed direct C(sp3)–H arylation of indole-3-ones with aryl halides has been developed.
Various 2-monoarylated indole-3-ones were readily obtained with yields up to 95%. As a class of
important nucleophilic intermediates, 2-monoarylated indole-3-ones can be used for the construction
of C2-quaternary indolin-3-one skeletons.
Received 5th June 2018
Accepted 9th July 2018
DOI: 10.1039/c8ra04807j
rsc.li/rsc-advances
2,2-Disubstituted indole-3-ones (trivially known as pseudo- Although some useful methods were developed via Baeyer–Vil-
indoxyl) are privileged core heterocyclic structural motifs that liger oxidation of C-3 phenyl substituted indole derivatives (A
occur in a great number of biologically active natural products. and B) and direct arylation of indolin-3-one 1a with aryllead
(Fig. 1, (ꢀ)Isatisine A,1a–c Aristotelone,1e Fluorocarpamine1d).1 triacetate, it should be noted that the application of these
In addition, they can be used as a key synthetic intermediate in methods is restricted by the limited number of available
the synthesis of many natural products (Fig. 1, Hinckdentine substrates and the low yields (Scheme 1b).5 In 2015, a method
A,2a–c Lapidilectine B2d,e and (ꢀ)-Trigonoliimine C2f–j).2 Owing to for the potassium tert-butoxide mediated direct C2-arylation of
its interesting structure and biological activity, the pseudo- indolin-3-ones 1 was reported by Liu et al., however, diary-
indoxyl scaffold has attracted extensive attention from both liodonium salts were required as the arylating agents and lower
synthetic and medicinal chemists. Numerous elegant synthetic yields (up to 70%) were obtained.3d In addition, the “Selective
protocols have been developed for the construction of the 2,2- Problem” arose due to the use of unsymmetric diaryliodonium
disubstituted indole-3-one scaffold.2c,3,4 Recently, nucleophilic salts as the arylating agents and the mixtures of two C2-
indole-3-ones have been demonstrated to be very reliable
building blocks for the enantioselective or racemic construction
of C2-quaternary indolin-3-one skeletons.3d,4 Among these
signicant advances, one of the key substrates was nucleophilic
2-monoarylated indole-3-ones (Scheme 1a).3d,4a
So far, much of the effort has been focused on the synthesis
of C2-quaternary indolin-3-one skeletons,2c,3,4 however, the
routes for the synthesis of nucleophilic 2-monoarylated indole-
3-ones have been challenging and are rare (Scheme 1a).3d,4a,5
aState Key Laboratory of Functions and Applications of Medicinal Plants, School of
Pharmacy, Engineering Research Center for the Development and Application of
Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University,
Guiyang 550004, P. R. China. E-mail: zhaoyl05@lzu.edu.cn; 2211452786@qq.com;
1156320953@qq.com; 643904784@qq.com; 1536408086@qq.com; 2660860532@
qq.com; binhe@gmc.edu.cn; qingfeng476281051@163.com; 1784193313@qq.com;
312854015@qq.com
bState Key Laboratory of Applied Organic Chemistry, College of Chemistry & Chemical
Engineering, Lanzhou University, Lanzhou 730000, P. R. China. E-mail: xupf@lzu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra04807j
Fig. 1 Natural products containing the C2-quaternary indolin-3-ones
fragment and representative natural products that were synthesized
with using 2,2-disubstituted indole-3-one as the key intermediate.
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Scheme 1 Reported approaches toward the synthesis of C2-quaternary indolin-3-one skeletons and palladium-catalyzed direct C(sp3)–H
arylation reaction of indole-3-ones with aryl halides.
arylation products were produced (Scheme 1c).3d Therefore, 1, entry 2, 6 and 7). Next, Pd(OAc)2, Pd(TFA)2, PdCl2 and
more efficient methods for the synthesis of nucleophilic 2- Pd(dba)2 were also tested for this a-arylation reaction using
monoarylated indole-3-ones are highly desired.
K2CO3 as the base in the presence of Xphos ligand L3 (Table 1,
Palladium-catalyzed a-arylation of carbonyl and related entry 3, 8, 9 and 10), and Pd(dba)2 was found to be the optimal
compounds has served as a powerful tool for the quick choice (Table 1, entry 3). Finally, various bases such as K2CO3,
t
t
construction of C–C bonds.6 Although palladium-catalyzed C-3 KHMDS, BuOK, BuONa, CsCO3, K3PO4 and AcONa were also
arylation of 2-oxindole has been reported by Willis et al.,6c tested (Table 1, entry 3, 12, 13, 14, 15 and 16), and K2CO3 was
palladium-catalyzed direct C(sp3)–H arylation of indole-3-ones found to be the most promising base (Table 1, entry 3). We then
with aryl halides remains unexplored.3d With our ongoing tested the effect of high boiling-point solvents on this a-aryla-
interest in the study of palladium-catalyzed coupling reac- tion process, some common solvents such as THF, toluene and
tions6d,7 and indolin-3-one chemistry,4d,e we developed an effi- dioxane were used, and THF was found to be the optimal choice
cient procedure for this transformation for the synthesis of (Table 1, entry 3). Finally, we examined the effect of different
nucleophilic 2-monoarylated indole-3-ones 3 (Scheme 1c).
concentrations and reaction time on this a-arylation process,
1-Acetylindolin-3-one 1a and bromobenzene 2a were used as and found this process could be nished in 14 hours in the
the model substrate for the initial study and the results are presence of the Pd(dba)2 (2 mol%) and Xphos ligand L3
summarized in Table 1. It was found that 1-acetylindolin-3-one (3 mol%) under 2.0 ml THF. Accordingly, Pd(dba)2 (2 mol%),
1a and bromobenzene 2a reacted in the presence of the Brett- Xphos ligand L3 (3 mol%) and K2CO3 (1.1 equiv.) with THF as
phos ligand L1 (3 mol%), K2CO3 (1.1 equiv.) and Pd(dba)2 the solvent under an high pure nitrogen atmosphere at 70 ꢁC are
(2 mol%) in THF under an high pure nitrogen atmosphere at the optimal conditions for this a-arylation reaction of indole-3-
70 ꢁC to furnish the desired product 3a with a low yield (Table 1, ones with aryl halides.
entry 1). Various ligands was then screened and Xphos ligand L3
With the reaction conditions optimized, we next investigated
was found to be the best ligand for this a-arylation reaction the substrate scopes of indole-3-ones 1 and aryl halides 2 (Table
(Table 1, entry 3). For ligands L4 and L5, no desired product was 2). In most cases, the reactions afforded the corresponding 2-
obtained (Table 1, entries 4 and 5). For ligands L2, L6 and L7, monoarylated indole-3-one products 3a–f with moderate to
desired product 3a was obtained albeit with lower yields (Table excellent yields (19–95%). First, we examined the reactions of 1-
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Table 1 Optimization of Reaction Conditionsa
Entry
Cat. [Pd]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(OAc)2
PdCl2
Pd(TFA)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
L1
L2
L3
L4
L5
L6
L7
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KHMDS
tBuOK
CsCO3
K3PO4
AcONa
tBuONa
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Dioxane
Toluene
THF
THF
THF
THF
<10
26
87
NRc
NRc
<10
<10
<10
<10
24
9
10
11
12
13
14
15
16
17
18i
19f
20g
21h
22j
<10
d
—
<10
32
NRc
d
—
53
24
80
73
66
84
a
Reactions performed on a 0.25 mmol scale using 1a (1.0 equiv.) and 2a (1.1 equiv.) in 2.0 ml of the solvent for 14 h, reaction performed at 70 ꢁC
b
c
d
f
under an high pure nitrogen atmosphere. Isolated yield. NR ¼ no reaction. Decomposition observed based on TLC. 1.0 ml THF was used
g
h
i
as the solvent. 3.0 ml THF was used as the solvent. Reaction time ¼ 10 h. Reaction performed at 100–110 ꢁC and 1.0 ml solvent was used.
j
Reaction time ¼ 18 h.
acetylindolin-3-one 1a with various substituted aryl halides 2. 1H-indole, 2-bromofuran and 2-bromothiophene are failed (3r–
Bromobenzene, chlorobenzene and iodobenzene were all t). The variation on the indolin-3-one scaffold could also be
effective substrates for the synthesis of 3a and bromobenzene tolerated in this a-arylation process and the desired products
was the best substrate for the a-arylation of indole-3-one 1a. The 3n–p were afforded with 32–91% yields. Furthermore, when 5-
structural variation of aryl bromides 2 could be well tolerated in bromo- and chloro-substituted of indole-3-ones were used,
this reaction irrespective of the electronic nature or the posi- corresponding products 3o and 3p were also obtained.
tions of the substituents on the aromatic ring. Compared with
To investigate the potential utility of this strategy, the large-
the electron-withdrawing aryl bromides (3g–h), the electron- scale synthesis of 3a was also performed under the optimized
donating aryl bromides (3b) gave higher yields. Generally conditions. The reaction proceeded smoothly to afford the
speaking, the steric effect of aryl bromides decreased the yields corresponding 2-monoarylated indole-3-one 3a product albeit
of products (3c–d vs. 3b) and 3e was obtained in only 26% yield. with the actual yield decreased to 72% (Scheme 2). In addition,
When both bromo- and chloro-substituents were present in the the 2-monoarylated indole-3-one 3 could be used as a kind of
arenes, selective reactions at the bromo positions were always key nucleophilic substrate for the chiral or achiral synthesis of
observed (3i–j, 3q). It is noteworthy that this a-arylation process C2-quaternary indolin-3-one skeletons.3d,4a
could also be successfully extended to others complex aryl
As shown in Scheme 3, a possible reaction mechanism for
bromides and corresponding desired products 3k–m were ob- this palladium-catalyzed a-arylation of indole-3-ones was
tained with 41–72% yields, however, the examples for 5-bromo- proposed based on the reported mechanisms of the similar
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Table 2 Substrate scope of palladium-catalyzed direct C(sp3)–H arylation of indole-3-ones with aryl halidesa
a
Unless otherwise specied, all reactions were carried out with using 1 (0.25 mmol, 1.0 equiv.) and 2 (1.1 equiv.) in 2.0 mL of the THF for 14 h at
70 ꢁC under an high pure nitrogen atmosphere and all the yields were isolated yield. b Reaction performed at 110 ꢁC and 1.0 ml PhMe was used as
the solvent. c Pd(dba)2 (10 mol%) and Xphos (10 mol%) was used. Aryl bromides (2.0 equiv.) and K2CO3 (2.0 equiv.) was used.
d
palladium-catalyzed a-arylation of carbonyl and related its isomerism intermediate 60. Finally, anionic palladium
compounds with aryl halides.6 The oxidative addition of intermediate 7 is formed by above isomerism intermediate 60 in
a palladium complex into the C–X bond of aryl halides rst the presence of a base,6e,f which then undergoes a reductive
occurs and the palladium complex intermediate 4 is formed. At elimination to form the desired 2-monoarylated indole-3-one 3,
the same time the enolate intermediate 5 is also produced by at the same time restores the original palladium catalyst and
indole-3-one 1 in the presence of a base, which reacts with completes the catalytic cycle.
intermediate 4 to get the arylpalladium enolate complex 6 and
In conclusion, we have developed an efficient method for
the synthesis of 2-monoarylated indole-3-ones via palladium-
catalyzed direct C(sp3)–H arylation of indole-3-ones with aryl
halides. The nucleophilic 2-monoarylated indole-3-ones were
obtained in moderate to good yields (up to 95%). The products
could be used as building blocks for the enantioselective or
racemic synthesis of C2-quaternary indolin-3-one skeletons.
Further investigation and application of the nucleophilic 2-
monoarylated indole-3-one derivatives are ongoing in our
laboratories.
Scheme 2 The large-scale synthesis of the product 3a.
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Scheme 3 A proposed mechanism for the palladium-catalyzed direct C(sp3)–H arylation of indole-3-ones with aryl halides.
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Conflicts of interest
There are no conicts of interest to declare.
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We are grateful for nancial support from the National Natural
Science Foundation of China (grants. 21502030, 81660348,
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