Enantioselective intramolecular Aza-Michael additions of indoles catalyzed by chiral phosphoric acids

Article abstract of DOI:10.1002/anie.201003919

Two ways to win: The title reaction has been realized using chiral phosphoric acid catalysts to provide the heterocyclic products in excellent yields and with high eevalues. The polycyclic indoles were also constructed using an olefin cross-metathesis/int

Full text of DOI:10.1002/anie.201003919

Communications
DOI: 10.1002/anie.201003919
Asymmetric Catalysis
Enantioselective Intramolecular Aza-Michael Additions of Indoles
Catalyzed by Chiral Phosphoric Acids**
Quan Cai, Chao Zheng, and Shu-Li You*
Chiral indole frameworks are widely distributed throughout
natural products and pharmaceuticals.[1] In this scenario,
enormous efforts have been devoted to the development of
efficient syntheses of enantioenriched indole derivatives.[2] It
has been well documented that the C3-position of an indole is
the most reactive of the three reactive positions (N1, C2, C3).
Therefore, considerable attention has been paid to the
asymmetric C3 alkylation of indole.[3] Recently, the enantio-
selective C2 alkylation of indole was realized through an
asymmetric Pictet–Spengler reaction,[4] alkylation of 2-indolyl
trifluoroborate salts,[5] and Friedel–Crafts alkylation of 4,7-
dihydroindoles.[6] However, the enantioselective N alkylation
of an indole has rarely been explored,[7] despite the fact that
the products are privileged structural motifs in natural
alkaloids and biologically active compounds.[8]
indole could increase the nucleophilicity of the indolyl
nitrogen atom. However, this approach would have to avoid
the C3 alkylation of the 3-substituted indoles to produce the
indolenines, a strategy that has been demonstrated by several
groups that employed transition-metal catalysis or organo-
catalysis.[9] For the initial investigation, the indolenine prod-
uct was obtained from the tetrahydrocarbazole and enone in
the presence of chiral phosphoric acid; the N-alkylation
product was not observed [Eq. (3)]. Interestingly, when the
Upon introduction of an electron-withdrawing group
(EWG) on the indole core, the proton on the nitrogen atom
becomes more acidic, therefore making the N position prone
to alkylation under basic reaction conditions [Eq. (1), E =
intramolecular reaction was tested, the N-alkylation product
was obtained chemoselectively [Eq. (4)], providing facile
electrophile]. In taking advantage of this strategy, several
groups have successfully realized the enantioselective N al-
kylation of indoles.[7] However, in most of the reported
catalytic systems, indoles without electron-withdrawing
groups were not tolerated, the only exception being in the
work by Chen et al.[7c]
As part of our ongoing program on the asymmetric
Friedel–Crafts alkylation of indoles,[2e] we recently explored
the N alkylation of indoles by using chiral phosphoric acid
catalysts [Eq. (2)]. We envisaged that installation of an
electron-donating group (EDG) at the C3-position of the
access to enantioenriched polycyclic indoles.[10] Herein we
communicate our study on the chiral phosphoric acid
catalyzed asymmetric, intramolecular Friedel–Crafts-type
aza-Michael reaction of indoles and the preliminary mecha-
nistic investigation.
We first studied the cyclization of a,b-unsaturated ketone
4a with various chiral phosphoric acids (entries 1–7, Table 1).
To our delight, the aza-Michael addition product was
obtained with promising chemoselectivity and enantioselec-
tivity. Chiral phosphoric acid 1g bearing triphenylsilyl groups
proved to be the optimal catalyst, affording product 5a in
96% yield and 89% ee (entry 7, Table 1). Additional screen-
ing of solvents (entries 7–9, Table 1) revealed that toluene
was the best. When 4 ꢀ molecular sieves (M.S.) were used as
[*] Q. Cai, C. Zheng, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-5492-5087
E-mail: slyou@mail.sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
[**] We thank the National Natural Science Foundation of China
(20732006, 20821002), the National Basic Research Program of
China (973 Program 2010CB833300), and the Chinese Academy of
Sciences for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003919.
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Table 1: Optimization of the reaction conditions for the enantioselective
Table 2: Substrate scope for the intramolecular aza-Michael reaction.[a]
aza-Michael reaction.[a]
Entry Product
t
Yield ee
[h] [%][b] [%][c]
Entry
R
Solvent T [8C] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
5a: R1 =C6H5
2
2
95
96
92
91
92
90
91
5b: R1 =4-BrC6H4
5c: R1 =4-ClC6H4
5d: R1 =4-MeC6H4
5e: R1 =4-MeOC6H4
1
2
3
4
5
6
7
8
9
4-NO2C6H4 (1a)
9-anthryl (1b)
1-naphthyl (1c)
1-pyrenyl (1d)
4-biphenyl (1e)
toluene RT
toluene RT
toluene RT
toluene RT
toluene RT
0.3 81
43
46
22
16
13
24
89
84
85
91
92
93
1.5 95
3
4
2
12
2
84
72
83
84
76
96
99
73
98
95
94
94
93
12
12
2
6
7
8
9
10
11
12
5 f: R1 =2-naphthyl
5g: R3 =ethyl
1.5 91
87
91
89
93
93
88
88
9-phenanthryl (1 f) toluene RT
2
3
3
4
3
3
91
94
96
83
85
82
SiPh3 (1g)
SiPh3 (1g)
SiPh3 (1g)
toluene RT
CH2Cl2 RT
5h: R3 =propyl
2
5i: R3 =CH2CH2COCH3
5j: R3 =CH2CH2COPh
5k: R3 =CH2CH2OH
5l: R3 =Bn
CCl4
toluene RT
toluene
RT
1
1
2
10[d] SiPh3 (1g)
11[d] SiPh3 (1g)
12[d] SiPh3 (1g)
0
toluene ꢀ20 17
[a] Reaction conditions: 10 mol% (S)-1, 0.05 molLꢀ1 of 4a. [b] Yield of
isolated product. [c] Determined by HPLC analysis using a chiral
stationary phase. [d] Used 50 mg activated 4 ꢀ M.S. (0.1 mmol 4a).
13[d]
5m
48
48
98
72
69
14[d]
15[d]
5n: R3 =Me
5o: R3 =Ph
91
93
an additive, the reaction proceeded faster and with higher
enantioselectivity (entry 10, Table 1). In general, lowering the
temperature resulted in an increased ee value but a prolonged
reaction time (entries 10–12, Table 1). Reactions at 08C led to
optimal results in terms of both enantioselectivity and
reaction time (entry 11, Table 1).
384 76
Under the optimized reaction conditions the substrate
scope of this methodology was examined. In general, several
kinds of polycyclic indoles could be synthesized in good yields
and with good ee values (Table 2). Substituted phenyl enones
bearing electron-donating or electron-withdrawing groups, as
well as 2-naphthyl enone were suitable substrates for the aza-
Michael reaction to afford 6,7,8,9-tetrahydropyrido[1,2-a]-
indoles in 91–96% yields and 87–92% ee (entries 1–6,
Table 2). Remarkably, various functionalities such as carbonyl
and hydroxy groups, as well as aromatic rings could be
tolerated in the C3 side chain (entries 7–12, Table 2) without
affecting the yields and ee values. This methodology could
also be used to construct the 2,3-dihydro-1H-pyrrolo[1,2-a]-
indole ring system, the core structure of yurenamine,[10a]
with a slightly decreased ee value (entry 13, Table 2). When
the nitrogen-linked substrates 5n–o were used, 1,2,3,4-tetra-
hydropyrazino[1,2-a]indole derivatives were obtained with
excellent ee values after a longer reaction time (entries 14 and
15, Table 2). Furthermore, the reaction was completely
inhibited by the introduction of an electron-withdrawing
group, such as an ester, at C2-position of indole (entry 16,
Table 2).
16[d]
4q
no reaction
[a] Reaction conditions: 10 mol% (S)-1g, 08C, 0.05 molLꢀ1 of 4 and
activated 4 ꢀ M.S. in toluene. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis using a chiral stationary phase. [d] The reaction
was carried out at room temperature. Boc=tert-butoxycarbonyl.
indoles.[12a] This combination of catalysts was also examined in
this intramolecular aza-Michael addition. To our delight,
when indolyl olefin 7 and the enone 2 (1.5 equiv) were heated
in toluene at 508C with (S)-1g (10 mol%) and the ruthenium
catalyst Zhan-1B (5 mol%), the desired products 5 were
obtained in excellent yields and ee values (entries 1–8,
Table 3).[13]
Interestingly, when 4p was used as the substrate, both the
N1-alkylation product 5p and the C3-alkylation product 6
were obtained [Eq. (5)]. When heated in refluxing toluene
with 10 mol% (S)-1g, compound 6 was converted into the
aza-Michael addition product 5p in 95% yield and 35% ee
The combination of mechanistically distinct organocatal-
ysis and transition-metal catalysis has enabled novel trans-
formations and often reduces labor and waste.[11] Recently, we
developed an efficient olefin cross-metathesis/intramolecular
Friedel–Crafts alkylation sequence by using a ruthenium
catalyst and a chiral phosphoric acid to construct polycyclic
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Table 3: Substrate scope for sequential catalysis.[a]
Figure 1. Optimized structures of the two most stable transition states
leading to the S and R products for 5a, respectively.
Entry R2,R3
R1
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
H, Me (7a)
H, Me (7a)
Ph (2a)
4-BrC6H4 (2b) 80 (5b) 88
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
89 (5a) 90
H, CH2CH2COCH3 (7d)
H, CH2CH2COPh (7e)
H, CH2CH2OH (7 f)
H, Bn (7g)
H, CH2CH2phthalimide (7h) 4-BrC6H4 (2b) 96 (5q) 90
6-Me, Me (7i) Ph (2a) 81 (5r) 93
92 (5i)
90
94 (5j) 90
45 (5k) 87
88 (5l) 90
[a] Reaction conditions: 10 mol% (S)-1g, 08C, 5 mol% Ru catalyst,
0.05 molLꢀ1 of 7 with 1.5 equiv 2 and activated 4 ꢀ M.S. in toluene at
508C. [b] Yield of isolated product. [c] Determined by HPLC analysis
using a chiral stationary phase.
Scheme 1. Conversion of ketone 5b into amide 8. DMAP=4-dimethyl-
aminopyridine, Ts=4-toluenesulfonyl.
combination of organocatalysis and transition-metal catalysis
makes the synthesis of these polyheterocyclic structures
highly efficient and economical. To our knowlege, this
represents the first asymmetric N-alkylation of indoles in
the absence of electron-withdrawing groups under acidic
reaction conditions. Additional studies on the reaction
mechanism are currently underway in the lab.
[Eq. (6)]. It is likely that the transformation proceeds through
a retro-Michael reaction and an aza-Michael addition to
afford product 5p. This experiment suggests that the N1 cyc-
Experimental Section
General procedure for the asymmetric olefin cross-metathesis/aza-
Michael reaction: The indolyl olefin
7 (0.2 mmol), enone 2
(0.3 mmol), and activated 4 ꢀ M.S. (100 mg) were added to toluene
(4 mL) in a dry Schlenk tube under an argon atmosphere. The
solution was heated to 508C, and then the chiral phosphoric acid
(0.02 mmol) and Ru catalyst (0.01 mmol) were added in one portion.
After the reaction was complete (monitored by TLC or 1H NMR
analysis), the solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography on silica gel (ethyl
acetate/petroleum ether= 1:50!1:100) to afford the product.
lization is thermodynamically more favorable. DFT calcula-
tions also confirm that the N1 alkylation is both thermody-
namically and kinetically favored.[14]
In addition, calculational data on the aza-Michael reac-
tion employing the depicted model system indicate that the
transition state corresponding to the S product (TS-S-a)
exhibited stronger steric repulsion between the substrate
and one SiPh3 group of the catalyst than that in TS-R-a
(Figure 1). The calculated free-energy gap between these two
transition states is 1.8 kcalmolꢀ1.[14] This prediction was in
agreement with the experimental results.[15]
Received: June 28, 2010
Revised: August 4, 2010
Published online: October 7, 2010
Notably, the enantioenriched aryl ketone product 5b
obtained here could be easily transformed into amide 8 in
good yield and without notable loss of optical purity through
the Beckmann rearrangement reaction (Scheme 1).
Keywords: asymmetric catalysis · Brønsted acids · heterocycles ·
Michael addition · synthetic methods
.
In conclusion, we have developed an enantioselective
intramolecular Friedel–Crafts-type aza-Michael addition of
an indole catalyzed by a chiral phosphoric acid and excellent
product yields and ee values were obtained. Furthermore, the
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