Organocatalytic asymmetric vinylogous Michael addition of dicyanoolefins to imine intermediates generated in situ from arenesulfonylalkylindoles

Article abstract of DOI:10.1002/adsc.201200286

An organocatalytic asymmetric vinylogous Michael addition of dicyanoolefins to vinylogous imine intermediates generated in situ from arenesulfonylalkylindoles has been developed. This protocol provides an easy and convenient approach to C-3 alkyl-substitu

Full text of DOI:10.1002/adsc.201200286

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DOI: 10.1002/adsc.201200286
Organocatalytic Asymmetric Vinylogous Michael Addition of
Dicyanoolefins to Imine Intermediates Generated in situ from
Arenesulfonylalkylindoles
Xing-Li Zhu,a Wu-Jun He,a Liang-Liang Yu,a Chang-Wu Cai,a Zong-Le Zuo,a
Da-Bin Qin,a Quan-Zhong Liu,a and Lin-Hai Jinga,*
a
Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University,
Nanchong 637002, Peopleꢀs Republic of China
Fax : (+86)-817-256-8081; e-mail: cwnujlh@yahoo.com.cn
Received: May 5, 2012; Revised: August 9, 2012; Published online: October 30, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200286.
Abstract: An organocatalytic asymmetric vinylo-
gous Michael addition of dicyanoolefins to vinylo-
gous imine intermediates generated in situ from
arenesulfonylalkylindoles has been developed. This
protocol provides an easy and convenient approach
to C-3 alkyl-substituted indole derivatives with high
yields (up to 93%), diastereomeric ratios (up to
99:1 dr) and enantioselectivities (up to 99% ee).
The resulting adducts can be also readily converted
to pyrazolo derivatives or a-alkylation products of
ketones without any decrease of the diastereoselec-
tivities and enantioselectivities.
Scheme 1. Nucleophilic Michael addition to vinylogous
imines generated in situ from arenesulfonylalkyl-substituted
indoles 1.
limited progress has been made in their asymmetric
variants.[7] On the other hand, an asymmetric vinylo-
gous-type reaction, which enables a facile access to
chiral materials with structural diversity and complex-
ity, has gained increasing attention.[8] Recently, a,a-di-
cyanoolefins,[9] which are readily prepared by the con-
densation of the corresponding carbonyl compounds
and malononitrile, have been demonstrated as excel-
lent vinylogous nucleophiles in some asymmetric vi-
Keywords: arenesulfonylalkylindoles; asymmetric
catalysis; dicyanoolefins; organic catalysis; vinylo-
gous Michael addition
Optically active 3-substituted indole structural motifs nylogous-type reactions by Jørgensen,[10] Deng or
have been widely found in a number of naturally oc- Chen,[11] Loh,[12] and Zhou groups.[13] Inspired by
curring compounds and biologically active mole- these elegant studies, and considering that the vinylo-
cules.[1] Therefore, their asymmetric synthesis has gous Michael addition reaction is still in its infancy,[8i]
been the subject of intensive investigation.[2] The most herein we wish to demonstrate, to the best of our
common strategy to access these compounds is via the knowledge, the first highly stereoselective vinylogous
enantioselective Friedel–Crafts reaction of indole at Michael addition of dicyanoolefins to vinylogous
the 3-position.[3] However, some chiral 3-substituted imine intermediates generated in situ from arenesul-
indoles cannot be prepared by this approach due to fonylalkyl-substituted indoles under chiral organoca-
the lack of the corresponding electrophiles. In 2006, talysts.[14] The resulting Michael adducts can be fur-
an innovative solution to this structural skeleton using ther conveniently transformed to pyrazolo derivatives
arenesulfonylalkyl-substituted indoles 1 was described or the a-alkylation products of ketones without any
by Petrini and co-workers.[4] Compounds 1, generating decrease of the diastereoselectivities and enantiose-
in situ highly active vinylogous imine intermediates lectivities.
under basic conditions,[5] can react with various nucle-
ophiles to afford the corresponding 3-substituted alysts 3 for the model reaction of arenesulfonylalk-
indole derivatives (Scheme 1).[6] Nevertheless, quite
ylindole 1a and a,a-dicyanoolefin 2a in toluene under
We commenced our studies by using a series of cat-
AHCTUNGTRENNUNG
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Table 1. Optimization of reaction conditions for reaction of arenesulfonylalkyl-substituted indole 1a with a,a-dicyanoolefin
2a.[a]
Entry
Cat.
Base
Solvent
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3i
3i
3i
3i
3i
3i
3i
3i
3i
3i
3i
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Na3PO4
Cs2CO3
Na2CO3
LiOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
mesitylene
DCM
82
85
87
82
83
92
88
90
93
93
92
82
90
51
82
93
98
85
90
88
83
87
89
67:33
63:37
82:18
78:22
99:1
99:1
99:1
77:23
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
50:50
99:1
45
26
À36
À23
29
À63
46
51
80
77
57
46
42
47
17
<5
51
50
65
40
7
<5
<5
9
10
11
12
13[e]
14[f]
15
16[e]
17
18
19
20
21
22
23
KOH
KF/Al2O3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
87:13
66:34
76:24
79:21
75:25
chloroform
dioxane
THF
3i
3i
[a]
Unless otherwise noted, all reactions were carried out with 1a (0.11 mmol), 2a (0.1 mmol), catalyst (0.02 mmol) and base
(0.11 mmol) in solvent (2.0 mL) at 308C for 16 h.
Isolated yield.
Determined by HPLC analysis.
Determined by HPLC analysis on a chiral stationary phase.
Reaction time 2 h.
[b]
[c]
[d]
[e]
[f]
Reaction time 72 h.
K2CO3 conditions. As summarized in Table 1, all (DHQ)2PHAL 3d as catalyst (Table 1, entry 4). Sur-
tested catalysts could smoothly afford the desired prisingly, excellent diastereoselectivity was observed
product 4a in high yields with various dr and ee. Natu- when (DHQD)2PHAL 3e was used as catalyst, al-
ral Cinchona alkaloids quinine 3a, cinchonidine 3b though with no improvement in enantioselectivity
and cinchonine 3c only gave poor diastereo- and (Table 1, entry 5). 9-Thiourea-Cinchona alkaloids 3f
enantioselectivities albeit with good yields (Table 1, and 3g afforded the products with slightly increased
entries 1–3). No enhancement in stereoselectivity was ee and excellent dr values (Table 1, entries 6 and 7).
achieved when the reaction was carried out using However, catalyst 3h gave poor results (Table 1,
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Organocatalytic Asymmetric Vinylogous Michael Addition of Dicyanoolefins to Imine Intermediates
Table 2. Asymmetric vinylogous Michael addition of dicyanoolefins to arenesulfonylalkyl-substituted indoles.[a]
Entry
1
2
4
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2d
2d
2d
2e
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
–
–
4n
4o
4p
4q
4r
4s
4t
93
82
86
69
78
61
65
68
93
60
67
91
62
–
99:1
89:11
87:13
69:31
92:8
93:7
90:10
99:1
80:20
99:1
80:20
86:14
99:1
–
80
91
90
95
96
>99
86
76
98
À90
95
97
71
–
5
6
7[e]
8
9
10[f]
11
12
13
14[g]
15[g]
16
17
18
19
20
21[f]
22
23
1j
1k
1l
1m
1n
1o
1d
1e
1f
1l
1d
1e
1f
1l
–
–
–
77
74
61
82
67
65
67
74
95:5
58:42
60:40
52:48
58:42
81:19
93:7
80:20
94
93
86
94
81
À82
71
96
4u
[a]
Unless otherwise noted, all reactions were carried out with 1 (0.11 mmol), 2 (0.1 mmol), 3i (0.02 mmol) and K2CO3
(0.11 mmol) in toluene (2.0 mL) at 308C for 16 h.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
1
Determined by H NMR spectroscopy of the crude mixture.
Enantiomeric ratios were measured using chiral stationary phase HPLC.
Reaction time 72 h.
Catalyst 3f was used instead of 3i and gave the opposite enantiomer.
Reaction time 48 h.
[g]
entry 8). Then our attention turned to another type of ties were observed with the use of K3PO4, Na3PO4,
thiourea catalyst bearing a chiral diaminocyclohexane Cs2CO3 and Na2CO3 (Table 1, entries 11–14). LiOH
skeleton. To our delight, Takemotoꢀs catalyst 3i pro- and KOH gave much more inferior results and even
vided the highest ee value and excellent diastereose- racemates, respectively (Table 1, entries 15 and 16).
lectivity (Table 1, entry 9).[15] Subsequently, a variety Only a 1:1 dr was obtained when KF/Al2O3 was ap-
of bases was investigated. Moderate enantioselectivi- plied (Table 1, entry 17). The influence of other sol-
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vents was also examined and much more inferior ste-
reoselectivities were observed compared with toluene
(Table 1, entries 18–23).
With the optimized reaction conditions in hand, we
then screened a series of arenesulfonylalkyl-substitut-
ed indoles 1 and a,a-dicyanoolefins 2 to establish the
general utility of this asymmetric transformation. As
outlined in Table 2, most arenesulfonylalkyl-substitut-
ed indoles and a,a-dicyanoolefins underwent the re-
action smoothly to afford the corresponding products
with good to excellent results. The substituent R at
the 2-position of the indole ring had a significant in-
fluence on the enantioselectivity of the reaction.[16]
For example, 2-phenyl-substituted 1e gave 96% ee,
whereas only 80% ee was obtained in the case of 2-
methyl-substituted 1a (Table 2, entry 1 vs. entry 5). A
similar phenomenon was also observed in the reaction
of 1f compared with 1c (Table 2, entry 3 vs. entry 6).
Surprisingly, for arenesulfonylalkylindoles bearing
a phenyl group with an ortho substituent, the nature
of the substituent shows an important influence on
the outcome of the reaction (Table 2, entries 8 and 9).
Sulfonylalkylindole 1m with an aliphatic substituent
could be also tolerated albeit with moderate enantio-
selectivity (Table 2, entry 13). In addition, 2-thienyl-
substituted sulfonylalkylindole 1l could be also em-
ployed and excellent enantioselectivities were at-
tained (Table 2, entries 12, 19 and 23). Notably, N-
methyl substituted 1n and N-Boc substituted 1o gave
no desired products (Table 2, entries 14 and 15). This
seems to imply the importance of a nitrogen-bound
hydrogen atom for the formation of the vinylogous
imine intermediate under basic conditions.[5a] When
catalyst 3f was used instead of 3i, an opposite enan-
tiomer was obtained (Table 2, entries 10 and 21). Fi-
nally, the non-cyclic dicyanoolefin 2e could also fur-
nish the vinylogous Michael addition product with ex-
cellent ee value (Table 2, entry 23).
Scheme 2. Synthetic transformation of Michael adducts.
The synthetic versatility of this methodology is il-
lustrated in Scheme 2. The adduct 4h was readily con-
verted to pyrazolo derivative 5 through the reaction
with hydrazine hydrate in ethanol at reflux tempera-
ture.[17] On the other hand, the product 4j was also
conveniently transformed to the a-alkylation product
of a ketone, 6, in 56% yield by a known oxidative
cleavage procedure,[10b,c,d,11h] and in both cases without
any loss of the stereoselectivities. The absolute config-
Figure 1. X-ray structure of 4a. Thermal ellipsoids are set at
30% probability. Solvent molecule and H atoms, except H-
3-N, H-2 and H-3, have been omitted for clarity.
uration of the two contiguous stereocenters of the vi- under chiral thiourea catalysis. The organocatalytic
nylogous Michael addition product 4a was unambigu- protocol provides convenient access to valuable chiral
ously assigned as (2R,3S) by X-ray diffraction analysis 3-indolyl derivatives in high yields and stereoselectivi-
(Figure 1),[18] and based on this information, the abso- ties, and the resulting adducts can be readily convert-
lute configurations of other products were assigned ed to pyrazolo derivatives or a-alkylation products of
by analogy.
ketones without any decrease of the diastereoselectiv-
In conclusion, we have developed the first highly ity and enantioselectivity. Further investigations to
stereoselective vinylogous Michael addition reaction broaden the scope of this type of transformation are
of dicyanoolefins to vinylogous imine intermediates currently underway.
generated in situ from 3-arensulfonylalkylindoles
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Organocatalytic Asymmetric Vinylogous Michael Addition of Dicyanoolefins to Imine Intermediates
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To
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1 (0.11 mmol), a,a-dicyanoolefin 2 (0.1 mmol), and Takemo-
toꢀs catalyst 3i (0.02 mmol) in toluene (2 mL) was added
K2CO3 (0.11 mmol). After being stirred at 308C for 16 h, the
reaction mixture was purified by flash chromatography on
silica gel (ethyl acetate/petroleum ether=1:20–1:10) to
afford the corresponding product 4. The diastereomeric
1
ratio was determined by H NMR analysis of the crude ma-
terial and the enantiomeric excess was determined by chiral-
phase HPLC analysis. Further experimental details can be
found in the Supporting Information.
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Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (21102117), the Education
Department of Sichuan Province (10A026), Chemical Syn-
thesis and Pollution Control Key Laboratory of Sichuan
Province (11CSPC-1-1), and China West Normal University
(10B005).
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Adv. Synth. Catal. 2012, 354, 2965 – 2970