Enantioselective synthesis of N-allylindoles via palladium-catalyzed allylic amination/oxidation of indolines

Article abstract of DOI:10.1039/c4ra00701h

A highly efficient synthesis of N-allylindoles was realized via palladium-catalyzed asymmetric allylic amination/oxidation sequential reaction of indolines. The N-alkylated indole derivatives were obtained with up to 91% yield and 97% ee.

Full text of DOI:10.1039/c4ra00701h

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Enantioselective synthesis of N-allylindoles via
palladium-catalyzed allylic amination/oxidation of
indolines†
Cite this: RSC Adv., 2014, 4, 10875
Received 6th January 2014
Accepted 5th February 2014
*
Qiang Zhao, Chun-Xiang Zhuo and Shu-Li You
DOI: 10.1039/c4ra00701h
www.rsc.org/advances
A highly efficient synthesis of N-allylindoles was realized via palla- compounds.10,11 Therefore, in this paper, we would like to report
dium-catalyzed asymmetric allylic amination/oxidation sequential our results on Pd-catalyzed allylic amination of indolines/
reaction of indolines. The N-alkylated indole derivatives were obtained oxidation sequence, providing an efficient synthesis of enan-
with up to 91% yield and 97% ee.
tioenriched 1,3-diarylallyl indoles (eqn (2), Scheme 1).
At the outset, indoline 1a and (E)-1,3-diphenylallyl acetate 2a
were chosen as the model substrates, and the results are
summarized in Table 1. In the presence of 5 mol% of [Pd(C3H5)-
Cl]2, 11 mol% of the Phox ligand L1, and 2.0 equiv. of Na2CO3,
the reaction of 1a with 2a in THF for 12 h gave the (E)-1,3-
diphenylallyl indoline 3aa in 99% yield and 95% ee (entry 1,
Table 1). The effects of chiral ligands were examined next.
Ligands L2 and L4–L7 were found to be suitable ligands to
afford 3aa in moderate to good yields with moderate ee (entries
2 & 4–7, Table 1). However, the reaction with ligand L3 pro-
ceeded in low yield with moderate ee (entry 3, Table 1).
In addition, various bases such as Li2CO3, Cs2CO3, K3PO4,
KOAc, DBU, Et3N, NaOAc and DABCO were also tested (entries
8–15, Table 1). The examination of bases led to the discovery of
Na2CO3 as the optimal base. Meanwhile screening of various
solvents (entries 16–20, Table 1) led to the identication of THF
as the best solvent. Aer systematic optimization studies, the
Chiral indole moieties are embedded extensively in numerous
biologically active natural products and pharmaceuticals, therefore
the enantioselective functionalization of indoles is now becoming
one of the most important research areas.1 In this regard, enor-
mous efforts have been made towards the synthesis of various
functionalized chiral indole scaffolds in the past two decades.2 For
the most studied Friedel–Cras reaction, it is well developed for
the C-3 alkylation of indole because C-3 is the innately most
reactive site of the indole core.3 Recently, the enantioselective C-2
alkylation of indoles was also realized.4 While the methods for the
asymmetric synthesis of 3-substituted and 2-substituted indoles
are well established, the development of catalytically enantiose-
lective synthesis of N-substituted indoles is relatively slow.5
Transition-metal-catalyzed allylic substitution reaction is
one of the most powerful method for the construction of C–C
and C–X bonds.6,7 During our efforts towards the asymmetric
functionalization of indoles,8 recently, we reported the asym-
metric synthesis of N-allylindoles via the iridium-catalyzed
allylic alkylation/oxidation of indolines (eqn (1), Scheme 1).9
The method provided highly enantioenriched N-allylindoles
bearing a terminal alkene, which could be utilized in the
enantioselective synthesis of one diastereomer of natural
product yuremamine. This two-step strategy has not been
explored for other transition-metal-catalysis except for iridium.
In addition, the substituted N-allylindoles are also popular
structural motifs in natural alkaloids and biologically active
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China.
E-mail: slyou@sioc.ac.cn
† Electronic supplementary information (ESI) available. CCDC 979724. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra00701h
Scheme 1 One-pot synthesis of substituted N-allylindoles via Pd-
catalyzed allylic alkylation of indolines/oxidation sequence.
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Table 1 Optimization of the reaction conditionsa
Scheme 2 One-pot synthesis of substituted N-allylindoles.
Table 2 The reaction substrate scope
Entry 1, R1
2, R2
4, Yielda (%) eeb (%)
1
2
3
4
5
6
7
8
1a, R1 ¼ H
2a, R2 ¼ Ph
2a, R2 ¼ Ph
2a, R2 ¼ Ph
2a, R2 ¼ Ph
2a, R2 ¼ Ph
4aa, 80
4ba, 81
4ca, 53
4da, 72
4ea, 77
4fa, 72
4ga, 82
4ha, 75
4ia, 73
95
96
96
97
95
61
93
97
96
97
39
Entry Ligand Solvent Base
t/h Conv.b (%) Yieldc (%) eed (%)
1b, R1 ¼ 2-Me
1c, R1 ¼ 2-Ph
1d, R1 ¼ 3-Me
1e, R1 ¼ 4-Me
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
Na2CO3 12 100
Na2CO3 12 100
Na2CO3 12 90
Na2CO3 12 96
Na2CO3 12 72
Na2CO3 12 72
Na2CO3 12 100
Li2CO3 33 73
Cs2CO3 33 89
K3PO4 15 100
KOAc
DBU
Et3N
NaOAc 21 60
DABCO 21 20
Na2CO3 23 100
99
94
28
90
70
71
97
71
73
96
90
60
92
60
—
93
75
94
93
—
95
47
50
43
14
47
86
69
86
75
67
95
77
58
30
86
91
71
83
62
1f, R1 ¼ 5-OMe 2a, R2 ¼ Ph
1g, R1 ¼ 7-Me
1h, R1 ¼ 5-Cl
1i, R1 ¼ 6-Br
1a, R1 ¼ H
2a, R2 ¼ Ph
2a, R2 ¼ Ph
2a, R2 ¼ Ph
9
10
11
2b, R2 ¼ 4-ClC6H4 4ab, 91
1a, R1 ¼ H
2c, R2 ¼ Me
4ac, 48
9
a
Isolated yield of 4. b Determined by HPLC analysis.
10
11
12
13
14
15
16
17
18
19
20
15 100
15 100
21 99
enantiopure 4aa. The reaction of C-2 methyl substituted indo-
line 1b gave product 4ba in 81% yield and 96% ee (entry 2, Table
2). Notably, when indoline 1c bearing a phenyl group at the C-2
position, the reaction could also react smoothly, providing
product 4ca in 53% yield and 96% ee (entry 3, Table 2). The
substrates bearing either an electron-donating group (3-Me, 4-
Me, 5-OMe, 7-Me) or an electron-withdrawing group (5-Cl, 6-Br)
on the indoline core all reacted and gave the corresponding
Dioxane Na2CO3 23 100
Toluene Na2CO3 23 100
Et2O
Na2CO3 23 100
CH3CN Na2CO3 23 83
a
Reaction conditions: 0.24 mmol of 1a, 0.2 mmol of 2a, 0.4 mmol of
b
base in solvent (2.0 mL) at room temperature. Determined by 1H
c
NMR of the crude reaction mixture. Isolated yield of 3aa. indole products in moderate to good yields with excellent ee
d
Determined by HPLC analysis.
(72–82% yields, 93–97% ee, entries 4–9, Table 2). When the
electrophile was switched to (E)-1,3-di(para-chlorophenyl)-
allylic acetate 2b, the reaction occurred smoothly to afford
best reaction conditions are the following: 1a and 2a in THF indole product 4ab in excellent yield and ee (91% yield, 97% ee,
with 5 mol% of [Pd(C3H5)Cl]2, 11 mol% L1, and 2.0 equiv. of entry 10, Table 2). However, when (E)-1,3-dimethylallyl acetate
Na2CO3 at room temperature. This process produces (E)-1,3- 2c was utilized, the reaction took place with only moderate yield
diphenylallyl indoline 3aa in 99% yield and 95% ee (entry 1, and ee (48% yield, 39% ee, entry 11, Table 2).
Table 1). Next, we investigated the one-pot allylic amination of
The kinetic resolution reaction of C-2 methyl substituted
indolines/oxidation sequence. To our great delight, with DDQ indoline 1b has also been carried out. To our disappointment,
as an efficient oxidant, the oxidation reaction of 3aa to 4aa went under the optimized reaction conditions, indoline 1b was
smoothly in 10 min at room temperature without loss of the recovered in 31% yield with only 4% ee (Scheme 3).
optical purity, affording (E)-1,3-diphenylallyl indole 4aa in 80%
yield and 95% ee (Scheme 2).
In summary, we have developed a highly efficient synthesis
of enantio-enriched N-1,3-diarylallyl indoles via palladium-
Under the above optimized reaction conditions, various catalyzed enantioselective allylic amination of indolines/oxida-
substituted indolines and allylic acetates were explored to tion sequence. The N-alkylated indole derivatives were obtained
examine the generality of the process. The results are summa- with up to 91% yield and 97% ee. Further studies on the
rized in Table 2. The stereochemistry of the products was substrate scope and applications of the enantioenriched N-
assigned as S based on an X-ray crystallographic analysis of allylindoles are currently underway in our laboratory.
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Scheme 3 The kinetic resolution reaction with substrate 1b.
Acknowledgements
We thank the National Basic Research Program of China (973
Program 2010CB833300) and the National Natural Science
Foundation of China (21025209, 21121062, 21332009) for
generous nancial support.
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