Regio- and enantioselective synthesis of N-allylindoles by iridium-catalyzed allylic amination/transition-metal-catalyzed cyclization reactions

Article abstract of DOI:10.1002/chem.201400026

Regio- and enantioselective synthesis of N-allylindoles was realized through an iridium-catalyzed asymmetric allylic amination reaction with 2-alkynylanilines and subsequent transition-metal-catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir-catalysis were treated with catalytic amount of NaAuCl₄×2 H₂O or PdCl₂ providing various substituted N-allylindoles in excellent yields and enantioselectivities. Regio- and enantioselective synthesis of N-allylindoles was realized through an iridium-catalyzed asymmetric allylic amination reaction with 2-alkynylanilines and subsequent transition-metal- catalyzed cyclization reactions (see scheme). The highly enantioenriched allylic amines prepared from Ir catalysis were treated with catalytic amount of NaAuCl₄×2 H₂O or PdCl₂ providing various substituted N-allylindoles in excellent yields and enantioselectivities (dbcot=dibenzo[a,e]cyclooctatetraene).

Full text of DOI:10.1002/chem.201400026

DOI: 10.1002/chem.201400026
Communication
&
Synthetic Methods
Regio- and Enantioselective Synthesis of N-Allylindoles by
Iridium-Catalyzed Allylic Amination/Transition-Metal-Catalyzed
Cyclization Reactions
Ke-Yin Ye, Li-Xin Dai, and Shu-Li You*[a]
5,6-dicyano-1,4-benzoquinone; DDQ) is needed to oxidize the
Abstract: Regio- and enantioselective synthesis of N-allyl-
indoles was realized through an iridium-catalyzed asym-
metric allylic amination reaction with 2-alkynylanilines and
subsequent transition-metal-catalyzed cyclization reac-
tions. The highly enantioenriched allylic amines prepared
from Ir-catalysis were treated with catalytic amount of
NaAuCl4·2H2O or PdCl2 providing various substituted N-al-
lylindoles in excellent yields and enantioselectivities.
corresponding indoline to indole. Therefore, it is extremely de-
sirable to develop a catalytic asymmetric protocol to access
optically active N-alkylated indoles with broad substrate scope
in an atom-economical pathway.
As part of our ongoing programs towards Ir-catalyzed allylic
substitution reactions,[8] we envisaged that N-allylindoles could
be accessed through an Ir-catalyzed allylic amination reac-
tion[9,10] with ortho-alkynylanilines and subsequent transition-
metal-catalyzed cyclization reactions[11] (Scheme 1C). This strat-
egy merits from modular synthesis of enantioenriched N-ally-
lindoles by incorporating diverse substituents that are not
easily accessed either from indoles or indolines with the exist-
ing methods. Notably, Bandini and coworkers recently reported
an elegant enantioselective gold-catalyzed cascade sequence
to access substituted oxazino-indoles from ortho-alkynylaniline
diols[12]. Herein, we report an efficient synthesis of enantioen-
Enantioenriched N-alkylated indole is a privileged structural
motif embedded in a large number of natural and unnatural
compounds.[1] However, among various catalytic asymmetric
functionalizations of indole,[2] N-alkylation[3] of indole has been
less developed compared with the well-established asymmetric
reactions at the indolyl C3[4] (or
C2[5]) position due to the high
nucleophilicity of the C3 position
and the weak acidity of the NH
group of indoles. By introducing
an electron-withdrawing group
(EWG) on the indole core, the
proton on the nitrogen atom be-
comes more acidic thus making
the NH prone to alkylation.[6]
This strategy has been success-
fully utilized by Hartwig[6b] and
Trost[6e] with Ir and Pd catalysis,
respectively (Scheme 1A). Anoth-
er approach towards chiral
N-allylindoles is the stepwise
N-alkylation of indoline and
subsequent oxidation sequence
(Scheme 1B).[7] Despite its good
compatibility of electronically
Scheme 1. Methods for the synthesis of enantioenriched N-allylindoles.
diverse substrates, an excess
amount of oxidant (2,3-dichloro-
riched N-allylindoles by the sequential iridium-catalyzed asym-
metric allylic amination and transition-metal-catalyzed cycliza-
tion reactions.
[a] K.-Y. Ye, Prof. L.-X. Dai, Prof. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P. R. China)
E-mail: slyou@sioc.ac.cn
We began our studies on the Ir-catalyzed allylic amination
reaction by utilizing 2-(phenylethynyl)aniline (1a) and cinnamyl
methyl carbonate (2a) as the model substrates. The results are
summarized in Table 1. In the presence of 2 mol% of [Ir-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400026.
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(dbcot)Cl]2 (dbcot=dibenzo[a,e]cyclooctatetraene), introduced
by Helmchen and coworkers[13] in Ir-catalyzed allylic substitu-
tion reactions, together with Alexakis ligand L3[14] exhibited ex-
cellent reactivity and selectivities (77% yield, branched/linear
>97:3, 99% ee, entry 2, Table 1). With the Ir-catalyst generated
in situ from 2 mol% of [Ir(dbcot)Cl]2 and 4 mol% of L3 in THF
at 508C, examination of bases disclosed that all tested ones af-
forded excellent regioselectivity and enantioselectivity (en-
tries 2–9, Table 1). Et3N was found as the best base in terms of
yield, regioselectivity and enantioselectivity (98% yield,
branched/linear >97:3, 96% ee, entry 9, Table 1). Notably, ex-
cellent enantioselectivity could also be obtained in the reac-
tion without external base, but the yield was dramatically de-
creased (entry 10, Table 1). Various solvents (CH2Cl2, Et2O, tolu-
ene, dioxane, and MeCN) were compatible and CH2Cl2 was
found to be the best one (97% yield, branched/linear 97:3,
98% ee, entry 11, Table 1). Finally, among several readily avail-
able chiral phosphoramidites tested, L3 was found to be the
optimal one (entries 11, 16–19, Table 1).
Table 1. Optimization of the reaction conditions.[a]
Entry Ligand Solvent
Base
Yield [%][b] 3aa/4aa[c] ee [%][d]
1[e]
2
3
4
5
6
7
8
L1
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L1
L2
L4
L5
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
Et2O
K3PO4
K3PO4
Cs2CO3
Li2CO3
NaOEt
22
77
78
62
75
95:5
>97:3
97:3
92:8
97:3
>97:3
>97:3
97:3
97:3
94:6
94
99
97
95
98
95
96
96
96
94
98
98
98
91
98
92
94
60
87
DABCO 29
DBU
DIEA
Et3N
–
Et3N
Et3N
40
79
98
77
97
97
83
88
96
23
20
82
62
9
10
With the optimal conditions of Ir-catalyzed allylic amination
reaction, we next investigated the transition-metal-catalyzed
cyclization reaction. When NaAuCl4·2H2O[15] was used, the de-
sired N-allylindole was obtained exclusively and no N-allyl
group migration occurred.[16] Further attempts to perform the
amination and subsequent cyclization reactions in one-pot
proved to be successful. Therefore, the regio- and enantiose-
lective synthesis of N-allylindoles by Ir-catalyzed allylic amina-
tion/Au-catalyzed cylization reactions was realized as the fol-
lowing: upon the completion of the Ir-catalyzed enantioselec-
tive allylic amination reaction, the solvents were evaporated in
vacuo and then NaAuCl4·2H2O and EtOH were added.
11
12
13
14
15
16
17
18
19
>97:3
96:4
96:4
toluene Et3N
dioxane Et3N
97:3
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
Et3N
Et3N
Et3N
Et3N
>97:3
>97:3
>97:3
91:9
87:13
[a] Reaction conditions: [Ir(dbcot)Cl]2/L/1a/2a/base=0.02:0.04:1.0:1.1:1.1,
0.1m of 1a at 508C. Catalyst was prepared through n-PrNH2 activation.
[b] Isolated yield of 3aa and 4aa. [c] Determined by 1H NMR analysis of
the crude reaction mixture. [d] Determined by HPLC analysis. [e] [Ir-
(cod)Cl]2 was used instead of [Ir(dbcot)Cl]2.
Under these above conditions, the substrate scope of N-ally-
lindoles by Ir/Au catalysis was explored. The results are sum-
marized in Table 2. With respect to allylic precursors, aryl and
alkyl substituted allylic methyl carbonates were well tolerated
providing N-allylindoles in good yields (67–95%) and enantio-
selectivities (92–98% ee, entries 1–8, Table 2). Various o-substi-
tuted alkynylanilines with aryl, heteroaryl, alkyl substituents on
the alkynyl moiety also afforded good results (entries 9–13,
Table 2). For alkynylaniline bearing 1-c-hexenyl substituent, ex-
cellent ee was also maintained albeit with a moderate yield
and decreased regioselectivity (entry 14, Table 2). It is worth to
mention that the TMS group on the alkynyl moiety can be effi-
ciently removed during the Au-catalyzed cyclization reaction
step[17] providing the N-allylindole with an H atom at the indol-
yl C2 position (entry 15, Table 2). Substrates bearing substitu-
ents (4-Me, 4-Cl) on the aromatic ring of anilines also per-
formed well leading to the corresponding N-allylindoles in ex-
cellent yields, regio- and enantioselectivities (entries 16 and 17,
Table 2).
Figure 1. Chiral phosphoramidite ligands used in this work.
The above Ir/Au catalysis provides the enantioenriched 2-
substituted N-allylindoles by a one-pot procedure. Next, we
turned our attention to develop a straightforward sequence to
access the enantioenriched N-allylindoles bearing the varia-
tions at both the indolyl C3 and C2 positions. Though the
access to C3 substituted indoles from the cyclization of o-alky-
nylanilines has been well studied,[18] the synthesis of C3 func-
(cod)Cl]2, 4 mol% of L1 (Figure 1) and 110 mol% of K3PO4, the
reaction in THF at 508C afforded the amination products in
low yield, but with excellent selectivities (22% yield, branched/
linear 95:5, 94% ee, entry 1, Table 1). To our delight, [Ir-
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Table 2. Ir-catalyzed allylic amination and subsequent Au-catalyzed cycli-
zation reactions.[a]
Table 3. Ir-catalyzed allylic amination and subsequent Pd-catalyzed cycli-
zation/Heck reactions.[a]
Entry
Product
Yield [%][b]
5/6[c]
ee [%][d]
Entry
Product
Yield [%][b]
8/9[c]
ee [%][d]
1
2
3
4
5
6
7
8
5aa: R1 =Ph
85
95
94
76
94
95
86
67
>97:3
>97:3
>97:3
>97:3
>97:3
95:5
97
98
96
96
96
96
93
92
5ab: R1 =4-MeC6H4
5ac: R1 =4-BrC6H4
5ad: R1 =4-ClC6H4
5ae: R1 =3-CF3C6H4
5af: R1 =3-ClC6H4
5ag: R1 =Et
97:3
>97:3
5ah: R1 =cPr
1
2
3
4
8aa: R1 =Ph
72
65
65
57
>97:3 96
8ab: R1 =4-MeC6H4
8ac: R1 =4-BrC6H4
8ad: R1 =Me
>97:3 97
>97:3 97
>97:3 90
9
10
11
12
13
14
15[e]
5ba: R2 =4-MeOC6H4
5ca: R2 =4-BrC6H4
5da: R2 =4-ClC6H4
5ea: R2 =2-thienyl
5 fa: R2 =CH2CH2Ph
5ga: R2 =1-c-hexenyl
5ha: R2 =H
94
81
92
84
92
44
74
94:6
94:6
97:3
96:4
95:5
98
96
99
98
98
98
95
90:10
>97:3
5
6
7
8ae: R2 =4-BrC6H4
8af: R2 =2-thienyl
8ag: R2 =CH2CH2Ph
65
60
43
>97:3 97
96:4 96
95:5 97
16
17
5ia: R3 =5-Me
5ja: R3 =5-Cl
82
92
94:6
96:4
98
97
[a] Reaction conditions: 1) [Ir(dbcot)Cl]2/L3/1/2/Et3N=0.02:0.04:1.0:1.1:1.1,
0.1m of 1 in CH2Cl2 at reflux. Catalyst was prepared through n-PrNH2 acti-
vation. 2) NaAuCl4·2H2O/1=0.05:1.0, 0.1m in EtOH at 508C. [b] Isolated
8
9
8ah: R3 =5-Me
8ai: R3 =5-Cl
69
47
94:6 98
96:4 92
1
yield of 5 and 6. [c] Determined by H NMR analysis of the crude reaction
mixture. [d] Determined by HPLC analysis. [e] R2 =TMS in the correspond-
ing o-alkynylaniline.
tionalized enantioenriched N-allylindoles remains rare. The
enantioenriched N-allyl ortho-alkynylanilines were found to be
good substrates in a cascade nucleopalladation/Heck reac-
tion.[19] Upon the completion of the Ir-catalyzed enantioselec-
tive allylic amination reaction, the amination products ob-
tained by short silica gel column chromatography were then
subjected to a cascade nucleopalladation/Heck reaction in the
presence of PdCl2/KI/acrylates in DMF at 808C. Various N-allyl-
indoles bearing an acrylate group at the indolyl C3 position
were obtained in moderate to good yields with excellent
regio- and enantioselectivities (Table 3). The reaction condi-
tions were found to be compatible for all the substituted allyl
carbonates and acrylates tested in our hands.
10
11
8aj: R4 =Me
8ak: R4 =Et
71
72
>97:3 96
>97:3 98
[a] Reaction conditions: 1) [Ir(dbcot)Cl]2/L3/1/2/Et3N=0.02:0.04:1.0:1.1:1.1,
0.1m of 1 in CH2Cl2 at reflux. Catalyst was prepared through n-PrNH2 acti-
vation. 2) PdCl2/KI/1/7=0.05:0.5:1.0:6.0, 0.1m in DMF at 808C. [b] Isolated
yield of 8 and 9. [c] Determined by 1H NMR analysis of the crude reaction
mixture. [d] Determined by HPLC analysis.
Deuterium-labeled compounds are widely used as internal
standards in mass spectrometry or to elucidate the reaction
mechanistic hypothesis.[20] The current method allows the
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directly in the same tube. The reaction mixture was stirred at 508C
for 3 h. After the reaction was complete (monitored by TLC), the
crude reaction mixture was filtrated through Celite and washed
with EtOAc. The solvents were removed under reduced pressure.
Then the residue was purified by silica gel column chromatography
to afford the products (eluent: petroleum ether/EtOAc=100:1).
facile deuterium incorporation at the specific positions of
enantioenriched N-allylindoles. By using EtOD/D2O as the co-
solvents in the gold-catalyzed cyclization reactions, enantioen-
riched N-allylindoles bearing high deuterium incorporations at
the indolyl C3 position (D-5aa, [Eq. 1]) or both the indolyl C2
and C3 positions (D-5ha, [Eq. 2]) were obtained, respectively. It
is very attractive to use the inexpensive and safe-to-handle
EtOD/D2O as the deuterium source of D-labeled highly enan-
tioenriched N-allylindoles.
General procedure for the synthesis of 2,3-disubstituted
N-allyl indoles by Ir-catalyzed allylic amination reaction/
Pd-catalyzed cyclization and Heck reactions
In summary, we have developed an efficient synthesis of
enantioenriched substituted N-allylindoles by Ir-catalyzed
asymmetric allylic amination reaction and subsequent transi-
Ir-catalyzed allylic amination reaction was carried out following the
procedure described above. After the reaction was complete
(monitored by TLC), the solvents
were removed under reduced
pressure. Then the residue was pu-
rified by silica gel column chroma-
tography to afford the amination
product. To a flask containing the
amination product, PdCl2 (1.8 mg,
0.01 mmol, 5 mol%), KI (16.6 mg,
0.1 mmol,
50 mol%),
acrylate
(1.2 mmol, 6.0 equiv) and DMF
(2.0 mL) were added. The reaction
mixture was stirred at 808C. After
the reaction was complete (moni-
tored by TLC), the crude reaction
mixture was filtrated through
celite and washed with EtOAc. The
reaction mixture was washed twice
with H2O and then with brine. The
organic phase was separated,
dried over anhydrous Na2SO4, fil-
trated, and concentrated under re-
duced pressure. Then the residue
was purified by silica gel column
chromatography to afford the products (eluent: petroleum ether/
EtOAc=50:1).
tion-metal-catalyzed cyclization reactions. The current synthesis
of enantioenriched N-allylindoles has several notable features:
1) broad substrate scope with high yields and ee; 2) modular
synthesis of various substituted N-allylindole bearing diverse
substituents; 3) compatible with one-pot procedure and cas-
cade reaction.
Acknowledgements
We thank the National Basic Research Program of China (973
Program 2010CB833300) and the National Natural Science
Foundation of China (21025209, 2112106, 21332009) for gener-
ous financial support.
Experimental Section
General procedure for one-pot synthesis of N-allylindoles by
Ir-catalyzed allylic amination reaction and subsequent Au-
catalyzed cyclization reactions
Keywords: allylic substitution · N-allylindole · asymmetric
catalysis · enantioselectivity · iridium
A flame-dried Schlenk tube was cooled to room temperature and
filled with argon. To this flask were added [Ir(dbcot)Cl]2 (3.5 mg,
0.004 mmol, 2 mol%), phosphoramidite ligand L3 (4.8 mg,
0.008 mmol, 4 mol%), THF (0.5 mL) and n-propylamine (0.5 mL).
The reaction mixture was heated at 508C for 0.5 h, and the color
of the solution was changed from orange to light yellow. Then the
reaction mixture was cooled to room temperature, and the sol-
vents were removed in vacuo. To the same flask, ortho-alkynylani-
line derivative 1 (0.20 mmol), allylic carbonate 2 (0.22 mmol), Et3N
(22.2 mg, 0.22 mmol) and THF (2 mL) were added. The reaction
mixture was stirred at reflux for 24 h. After the reaction was com-
plete (monitored by TLC), the solvents were evaporated in vacuo,
NaAuCl4·2H2O (4.0 mg, 5 mol%) and EtOH (2 mL) were then added
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Received: January 4, 2014
Published online on February 20, 2014
Chem. Eur. J. 2014, 20, 3040 – 3044
www.chemeurj.org
3044
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