Organocatalytic asymmetric Michael addition of 2-naphthols to alkylideneindolenines generated in situ from arenesulfonylalkylindoles

Article abstract of DOI:10.1016/j.tetlet.2013.05.011

An efficient enantioselective Michael addition of 2-naphthols to alkylideneindolenines generated in situ from arenesulfonylalkylindoles has been described. The protocol provides an efficient and convenient access to C-3 alkyl-substituted indole derivative

Full text of DOI:10.1016/j.tetlet.2013.05.011

Tetrahedron Letters 54 (2013) 3675–3678
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic asymmetric Michael addition of 2-naphthols
to alkylideneindolenines generated in situ from arenesulfonylalkylindoles
Liangliang Yu, Xiaohua Xie, Song Wu, Rongming Wang, Wujun He, Dabin Qin, Quanzhong Liu,
⇑
Linhai Jing
Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, Nanchong 637002, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient enantioselective Michael addition of 2-naphthols to alkylideneindolenines generated in situ
from arenesulfonylalkylindoles has been described. The protocol provides an efficient and convenient
access to C-3 alkyl-substituted indole derivatives containing phenolic hydroxyl groups with high yields
(up to 96%) and enantioselectivities (up to 98% ee) under mild conditions.
Received 17 January 2013
Revised 19 March 2013
Accepted 3 May 2013
Available online 13 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Asymmetric synthesis
Michael addition
2-Naphthol
Arenesulfonylalkylindole
The indole framework represents a privileged structure motif
frequently found in pharmaceuticals, agrochemicals, and natural
products.1 Among various indole derivatives, optically active
3-substituted indole skeletons which contain phenolic hydroxyl
groups in the substituents are important subunits in many synthetic
and naturally occurring biologically active compounds.2 However,
efficient methods for their asymmetric synthesis are rare (Scheme
1).2e,3 In 2010, Sigman and co-workers, developed the formation
of 3-substituted indoles by a palladium-catalyzed enantioselective
alkene difunctionalization reaction (Scheme 1a).2e Subsequently,
Bach and co-workers, reported the construction of 3-substituted in-
dole scaffolds through the enantioselective Friedel–Crafts reaction
of indoles with secondary ortho-hydroxybenzylic alcohols in the
presence of chiral phosphoric acids (Scheme 1b).3 Inspired by
Petrini group’s innovative solution to indole skeletons,4 herein we
wish to describe a facile and efficient enantioselective strategy for
accessing chiral 3-substituted indole derivatives including phenolic
hydroxyl groups in the substituents by Michael addition of 2-naph-
thols to alkylideneindolenines, generated in situ from arene-
sulfonylalkylindoles 1 (Scheme 1c),5–7 in the presence of chiral
organocatalysts.8
yields and ee values (Table 1, entries 1–4).9 Compared with other
three catalysts, quinidine-derived catalyst 3b provided slightly
superior result (Table 1, entry 2).10 A further study showed that
diaminocyclohexane-derived Takemoto catalyst 3e did not provide
better result (Table 1, entry 5).11 When (DHQ)2PHAL 3f was used,
almost racemic product was obtained (Table 1, entry 6). It perhaps
a) Enantioselective alkene difunctionalization
R1
R1
N
R3
N
R3
R2
OH
R2
OH
*
*
n
HO
O
n
R
R
b) Enantioselective Friedel-Crafts reaction
R1
N
R1
N
R2
R2
OH OH
R3
R
R3
OH
*
R
c) Enantioselective Michael addition (thiswork)
R1
R1
R1
At the outset of our study, arenesulfonylalkylindole 1a and 2-
naphthol 2a were chosen as model substrates for surveying the
reaction parameters, and the results are summarized in Table 1.
Cinchona alkaloid-derived thiourea catalysts 3a–d gave good
SO2Tol
Nu
R
*
Nu: 2-naphthol
base
R
R
N
H
N
H
N
1 alkylideneindolenine intermediates
⇑
Scheme 1. Methods for the asymmetric synthesis of 3-substituted indole deriva-
tives containing phenolic hydroxyl groups in the substituents.
Corresponding author. Tel./fax: +86 817 2568081.
E-mail address: cwnujlh@yahoo.com.cn (L. Jing).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.011

3676
L. Yu et al. / Tetrahedron Letters 54 (2013) 3675–3678
Table 1
Table 2
Optimization of reaction conditionsa
Asymmetric Michael addition of 2-naphthols 2 to arenesulfonylalkylindoles 1a
HO
HO
R1
R1
SO2Tol
+ R2
OH
SO2Tol
OH Cat. 3 (10 mol%)
3b (10 mol%)
H
R
H
+
K3PO4, Toluene
30 oC, 24h
R2
Base, Solvent
30 oC, 24h
R
Ph
Ph
N
H
N
H
N
H
N
H
4a
2a
1a
4
1
2
OMe
MeO
Entry
1
R
R1
2
R2
4
Yieldb (%) eec (%)
H
H
N
N
H
N
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1c
1d
1e
1g
1j
1k
1a
1c
1d
1e
1g
1j
Ph Ph
Ph 4-F-Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
95
73
93
86
90
88
72
96
94
80
92
89
77
80
84
84
80
82
0
26
97
81
89
88
88
81
13
98
73
84
80
84
73
81
95
65
HN
HN
Ar
HN
NH
N
N
S
N
HN
S
NH
Ph 4-Br-Ph
Ph 3-F-Ph
Ph 3-Cl-Ph
Ph 3-Me-Ph
Ph 3-OMe-Ph
Ph tBu
S
Ar
Ar
3a
3b
3c
S
Ar
H
N
(DHQ)2PHAL
N
H
N
H
N
NH
9
H
Ph
N
3e
3f
NH
Ar
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Ph Ph
2b 7-OMe 4j
2b 7-OMe 4k
2b 7-OMe 4l
S
Ar = 3,5-(CF3)2C6H3
3d
Ph 4-Br-Ph
Ph 3-F-Ph
Ph 3-Cl-Ph
Ph 3-OMe-Ph
Ph 4-Cl-Ph
Ph iBu
2b 7-OMe 4m 82
Entry
Cat
Base
Solvent
Yieldb (%)
eec (%)
2b 7-OMe 4n
2b 7-OMe 4o
2b 7-OMe 4p
2c
2c
2c
2c
2c
2c
81
90
64
95
67
92
74
85
80
88
91
85
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KF/Al2O3
NaOH
KOH
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
87
90
87
84
89
78
93
90
94
87
90
92
70
89
92
88
84
82
À84
89
74
À84
77
À5
83
77
77
79
67
85
84
89
84
86
73
73
Ph Ph
7-Br
7-Br
7-Br
7-Br
7-Br
7-Br
7-Br
7-Br
4q
4r
4s
Ph 4-Br-Ph
Ph 3-F-Ph
Ph 3-Cl-Ph
Ph 3-OMe-Ph
Ph 4-Cl-Ph
4t
4u
4v
4w
4x
4y
1l
Ph 3,4-diCl-Ph 2c
2c
9
Toluene
Toluene
Toluene
1m Ph 2-Pyridyl
1a Ph Ph
10
11
12
13
14
15
16
17
18
2d 6-Br
Benzene
Xylene
a
Unless otherwise noted, all reactions were carried out with 1 (0.1 mmol), 2
(0.1 mmol), 3b (0.01 mmol), and K3PO4 (0.3 mmol) in toluene (1.0 mL) at 30 °C for
24 h.
tBu-benzene
Ethylbenzene
Mesitylene
DCM
b
Isolated yield.
Determined by HPLC analysis.
c
o-Dichlorobenzene
a
Unless otherwise noted, all reactions were carried out with 1a (0.1 mmol), 2a
1h and 1k were employed, only racemate and 13% ee were ob-
tained, respectively (Table 2, entries 8 and 16). It is noteworthy
that the substituent R at the 2-position of the indole ring has a sig-
nificant influence on the enantioselectivity of the reaction. When
1a was treated with 2a, 89% ee could be obtained (Table 2, entry
1), whereas only 26% ee was observed when 1i was used (Table
2, entry 9). Finally, the survey of several 2-naphthols reveals that
the position of R2 substituent plays an important role in the enanti-
oselectivity of the reaction. When 2c was reacted with 1a, up to
98% ee was obtained; however, only 65% ee could be observed
when 2d was employed (Table 2, entries 17 vs 25).
The absolute configuration of stereocenter of the Michael addi-
tion product 4j was unambiguously assigned as R by X-ray diffrac-
tion analysis ( Fig. 1).12 The absolute configurations of other
products were assigned by analogy.
Based on these experimental results, a plausible bifunctional
transition state was proposed. The tertiary amine of the catalyst
interacts with hydrogen atom of phenolic hydroxyl group through
hydrogen bonding. Meanwhile, the thiourea moiety of the catalyst
serves as a Brønsted acid to activate the prochiral E-alkylidenein-
dolenine intermediate by double hydrogen bonds,7d as shown in
Scheme 2.
(0.1 mmol), catalyst 3 (0.01 mmol), and base (0.3 mmol) in solvent (1.0 mL) at 30 °C
for 24 h.
b
Isolated yield.
Determined by HPLC analysis.
c
implies the importance of the N–H of thiourea for the control of the
enantioselectivity of the reaction. To improve the enantioselectiv-
ity of the reaction, further optimization of the reaction conditions,
including bases and solvents, was carried out. However, to our dis-
appointment, no better enantioselectivities were observed (Table
1, entries 7–18).
With the optimized reaction conditions in hand, we then
screened a series of arenesulfonylalkylindoles 1 and 2-naphthols
2 to establish the general utility of this asymmetric transformation.
As listed in Table 2, both electron-withdrawing and electron-
donating substituents on the aryl ring of R1 groups could be well
tolerated (Table 2, entries 2–7, 11–15, and 18–23). The positions
of substituents on the phenyl ring of R1 groups seem to show
important influence on the enantioselectivity of the reaction. A
meta substituent seemed to be more beneficial than para substitu-
ent. For example, 3-F-substituted 1d gave 84% ee, whereas 77% ee
was obtained in the case of 4-F-substituted 1b (Table 2, entries 2 vs
4). Similar phenomena were also observed in the reactions of 1e
compared with 1j (Table 2, entries 13 vs 15 and 20 vs 22). Hetero-
cycle-substituted arenesulfonylalkylindole was also a suitable sub-
strate. For example, 2-pyridyl substituted 1m gave 91% yield and
95% ee (Table 2, entry 24). Unfortunately, when alkyl substituted
In summary, we have developed the first enantioselective
Michael addition reaction of 2-naphthols to alkylideneindolenine
intermediates generated in situ from arenesulfonylalkylindoles un-
der chiral thiourea catalysts. A series of optically active C-3 alkyl-
substituted indole derivatives containing phenolic hydroxyl groups
have been obtained. The organocatalytic protocol provides a more

L. Yu et al. / Tetrahedron Letters 54 (2013) 3675–3678
3677
Figure 1. X-ray crystal structure of adduct 4j. H atoms, except H1-N, H1-O ,and H-12, have been omitted for clarity.
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CF3
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We are grateful for the financial support from the National
Natural Science Foundation of China (21102117), the Education
Department of Sichuan Province (10ZA026), Chemical Synthesis
and Pollution Control Key Laboratory of Sichuan Province
(11CSPC-1-1), Bureau of Science & Technology and Intellectual
Property Nanchong City (12A0036), and China West Normal
University (10B005).
Supplementary data
Supplementary data (experimental procedures and character-
isation data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.011.

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