Catalytic Asymmetric Nucleophilic Addition of 3-Vinyl Indoles to Imines

Article abstract of DOI:10.1021/acs.orglett.6b01880

The 3-vinyl indole is used as a nucleophile to react with aromatic and aliphatic imines. Chiral 3-substituted indoles bearing multiple functional groups are produced with up to 99% yield, a 98:2 E/Z ratio, and 97% ee. A possible mechanism is proposed to explain the observed stereoselectivities. This strategy provides an efficient way for the preparation of novel chiral 3-substituted indoles.

Full text of DOI:10.1021/acs.orglett.6b01880

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Nucleophilic Addition of 3‑Vinyl Indoles to
Imines
Jia-Hui Xue, Ming Shi, Feng Yu, Xiao-Yun Li, Wen Ren, Li-Na Fu, and Qi-Xiang Guo*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China
S
* Supporting Information
ABSTRACT: The 3-vinyl indole is used as a nucleophile to
react with aromatic and aliphatic imines. Chiral 3-substituted
indoles bearing multiple functional groups are produced with
up to 99% yield, a 98:2 E/Z ratio, and 97% ee. A possible
mechanism is proposed to explain the observed stereo-
selectivities. This strategy provides an efficient way for the
preparation of novel chiral 3-substituted indoles.
ndole is one of the most widely distributed heterocycles in
nature. Substituted indole units not only appear extensively
involved strategies for the synthesis of structurally diverse chiral
I
3-substituted indoles. As a part of our continuous research
effort,5 we attempted to discover 3-functional indoles other
than 3-indolylmethanol, while aiming to find new reaction
models and subsequently enrich the synthetic methodologies
for chiral 3-substituted indoles.
in biologically active natural and unnatural compounds1 but
also have been referred to as “privileged structures” in a large
number of drugs.2 Chiral indoles bearing various substituents at
the 3-position are the most popular researched indoles because
of their wide range of biological activities. There are two
approaches toward the synthesis of optically active 3-
substituted indoles. One approach is the use of enantioselective
Friedel−Crafts-type reactions of indoles with various electro-
philes (Figure 1a, (i)).3 The other approach is the use of 3-
3-Vinyl indole is one of the most important 3-functional
indoles, and its derivatives are sophisticated building blocks in
the asymmetric synthesis of substituted indoles. Summarily, 3-
vinyl indoles have already been successfully used as dienes,6
dienophiles,7 and electrophiles8 in asymmetric catalysis. We
noticed that the 3-vinyl indole has been reported as a good
nucleophile in the formylation,9a,b trifluoromethylation,9c
alkylation,9d and conjugated addition9e reactions, leading to
the corresponding achiral or racemic 3-subsituted indoles
(Figure 1a, (iii−iv)). We envisioned that this nucleophilic
property could be used in catalytic asymmetric synthesis for
encounters between prochiral electrophiles and 3-vinyl indole,
consequently producing a series of new chiral 3-substituted
indoles bearing multiple functional groups (Figure 1b). If so, a
new application of 3-vinyl indole in catalytic asymmetric
synthesis would be achieved. However, there are two challenges
in this strategy: the 2-position of 3-vinyl indole can easily
participate in the reaction, which will lower the efficiency of
preparing chiral 3-substituted indoles, and both of the enantio-
and cis/trans- selectivities of the target products need to be
improved simultaneously. The benefits and aforementioned
challenges stimulated our interest in working on this strategy.
We chose the phenyl substituted 3-vinyl indole 1a and N-Boc
aminal10 2a as reactants, and the well-known group of chiral
phosphoric acids11 as catalysts to validate our hypothesis. We
hoped the phenyl of 1a could prevent the potential cyclization
reaction. If so, this transformation will give a concise way
leading to the indolyl substituted allylic amines. Many
compounds bearing 3-indolyl allylic amine skeletons have
Figure 1. (a) Representative approaches leading to 3-substituted
indoles; (b) hypothetical pathway (E = Electrophile, Nu =
Nucleophile).
functional indoles, such as 3-indolylmethanols, as reactants for
the synthesis of chiral 3-substituted indoles (Figure 1a, (ii);4
with this approach, many chiral 3-substituted indoles that are
difficult to synthesize from indoles can be easily prepared.
However, in this respect, 3-indolylmethanols have been the
only well-used candidates and are limited in their ability to act
as electrophiles because of their molecular structure properties.
Therefore, it is valuable to develop new 3-functional indole-
Received: June 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01880
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
been reported with good biological activities, such as 5-HT2A
receptors, selective serotonin reuptake inhibitors, and 5-HT1A
antagonists.12 As expected, in the promotion of 10 mol %
phosphoric acid (R)-3a, the desired product 4a was obtained in
moderate yield; however, there was no enantioselective
discrimination observed (Table 1, entry 1). Then, the chiral
and the E/Z ratio and enantioselectivity were still maintained at
a high level (Table 1, entry 16).
With the optimal reaction conditions in hand, we then
examined the substrate scope of this three-component reaction.
First, various aromatic aldehydes were introduced into this
transformation. The electron properties and position of the
substituents on the phenyl ring could affect the reaction
outcomes. For example, the 4-electron-withdrawing group
substituted benzaldehydes were excellent reaction partners in
this reaction, producing the corresponding products in high
yield and with excellent E/Z ratios and enantioselectivities
(Table 2, entries 2−4). In comparison, the enantioselectivity
a
Table 1. Optimization of Reaction Conditions
a
Table 2. Substrate Scope with Respect to Aldehydes
b
c
c
entry
3
solvent
t (h)
y (%)
E/Z
ee (%)
b
c
d
1
3a
3b
3c
3d
3e
3f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CCl4
47
10
6
68
80
75
<5
70
65
55
62
10
48
50
83
83
83
70
84
−
93:7
0
entry
4
R1
C6H5
t (h)
y (%)
E/Z
ee (%)
2
66
54
−
10
21
92
86
5
1
2
3
4a
4b
4c
4d
4e
4f
41
36
28
36
48
40
46
51
29
52
20
20
37
7.5
64
84
92
81
76
80
82
74
63
70
62
87
92
79
91
67
97:3
95:5
94:6
93:7
95:5
92:8
97:3
98:2
96:4
95:5
92
92
91
92
78
93
94
94
97
96
88
83
94
96
83
3
90:10
4-ClC6H4
4-FC6H4
4
24
40
42
97
24
70
70
17
12
10
10
60
50
−
5
86:14
64:36
92:8
96:4
99:1
97:3
98:2
97:3
94:6
97:3
97:3
e
4
4-NO2C6H4
4-MeC6H4
3-MeC6H4
3-MeOC6H4
3-FC6H4
6
5
7
3g
3b
3b
3b
3b
3b
3b
3b
3b
3b
6
8
7
4g
4h
4i
9
Et2O
8
10
11
12
PhCH3
CHCl3
DCE
81
84
81
82
92
92
92
9
3-ClC6H4
3-BrC6H4
2-ClC6H4
2-FC6H4
10
11
12
13
14
15
4j
4k
4l
89:11
94:6
d
13
DCE
e
14
DCE
4m
4n
4o
2-naphthyl
c-hexyl
98:2
ef
,
15
16 ,
DCE
93:7
fg
DCE
97:3
n-butyl
85:15
a
b
1a (0.06 mmol), 2a (0.05 mmol), 4 Å MS (50 mg). Isolated yield.
Determined by HPLC. 5 Å MS as additive. 3 Å MS as additive. 1a
(0.075 mmol), PhCHO (0.05 mmol), BocNH2 (0.125 mmol). 1a
(0.15 mmol), PhCHO (0.1 mmol), BocNH2 (0.25 mmol), 3 Å MS
(100 mg).
a
b
1a (0.15 mmol), 2 (0.1 mmol), BocNH2 (0.25 mmol). Isolated
c
d
e
f
c
d
e
yield. Determined by 1H NMR. Determined by chiral HPLC. 3g as
g
catalyst.
achieved with 4-Me benzaldehyde was lower (Table 2, entry 5).
The 3-substituted benzaldehydes having electron-rich and
-deficient functional groups generated the desired products
with excellent results (Table 2, entries 6−10), while the o-
substituted benzaldehydes decreased the enantioselectivities
slightly (Table 2, entries 11−12). Subsequently, aliphatic
aldehydes were used as acceptors in this transformation as
well. We found that cyclohexanecarbaldehyde and pentanal
were also suitable reactants, giving the corresponding products
in good yields with high E/Z ratios and enantioselectivities
(Table 2, entries 14−15).
Next, the substrates of 3-vinyl indoles were investigated. The
results are listed in Table 3. First, 3-vinyl indoles bearing
various substituents on the indole ring were involved in this
reaction. We found that both the electron-rich and -deficient
indole substituted 3-vinyl indoles produced the corresponding
products in excellent results (Table 3, entries 1−4). Then,
various 3-vinyl indoles bearing substituted phenyls were
examined. The o-substituents slightly increased the reaction
outcomes. For example, the 2-F phenyl-substituted 3-vinyl
indoles generated the product 5e in excellent yield with a high
E/Z ratio and enantioselectivity (Table 3, entry 5). Either an
electron-rich or -deficient substituent was introduced in the 3-
position of the phenyl ring of 3-vinyl indole, and the desired
phosphoric acid catalyst 3b bearing 9-anthryl was introduced in
this reaction, and the product 4a was generated in 80% yield
with 66% ee (Table 1, entry 2). These results indicated that the
bulky substituent on the 3,3′-position of catalysts 3 could
possibly enhance the enantioselectivity. Then, catalysts 3c−g
were examined in this reaction (Table 1, entries 3−7). The
catalyst 3b was the most suitable for this transformation in
terms of both yield and enantioselectivity. Accordingly, we
further optimized the reaction conditions. The solvent
screening indicated that the 1, 2-dichloroethane (DCE) was
the best solvent choice in terms of yield, E/Z ratio, and
enantioselectivity (Table 1, entry 12). We found that the
additives could affect the reaction outcomes. Specifically, the
additive 3 Å MS greatly improved the stereoselectivities (Table
1, entry 14). After optimizing the two-component reaction
conditions, we attempted to conduct this reaction in a three-
component manner because the aminal 2a could be formed
under acidic conditions. Notably, our experiment was
successful, and the product 4a was obtained in excellent E/Z
ratio and enantioselectivity, albeit the yield decreased slightly
(Table 1, entry 15). Then, we further optimized the three-
component reaction conditions. When we increased the
reactants’ concentrations, the yield of 4a enhanced to 84%,
B
DOI: 10.1021/acs.orglett.6b01880
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
existed a linear effect between the ee values of the catalyst and
products (see the Supporting Information). Based on these
results, we speculated that, in the transition state (TS I), one
catalyst molecule activated the 3-vinyl indole and imine via the
formation of hydrogen bonds simultaneously, and the phenyls
of 3-vinyl indole and imine were located at the opposite
position of the 3,3′-substituents of catalyst 3b to avoid the
steric influence. Then, the 3-vinyl indole attacked the imine at
the Si-face, producing the intermediate II (int.-II). The final
product 4a was generated via isomerization, and the catalyst 3b
was released (Figure 2b).
Table 3. Substrate Scope of 3-Vinyl Indoles
b
c
d
entry
5
R2/R3
t (h)
y (%)
E/Z
ee (%)
1
5a
5b
5c
5d
5e
5f
5-Me/H
6-F/H
47
47
36
47
52
33
36
52
47
40
67
52
23
12
80
75
84
85
90
88
94
78
77
78
62
88
95
98
93:7
97:3
96:4
95:5
98:2
96:4
98:2
96:4
96:4
95:5
97:3
97:3
95:5
90
91
88
87
95
89
91
89
92
89
91
91
92
83
2
3
5-Cl/H
5-Br/H
H/2-F
4
The alkenylation products were readily converted into other
indole compounds. For example, compound 4a generated
indolyl propylamine 7a through hydrogenation and depro-
tection (Scheme 1). Some compounds containing an indolyl
5
6
H/3-F
7
5g
5h
5i
H/3-Cl
H/3-Me
H/3-MeO
H/3,5-2Me
H/4-F
8
9
Scheme 1. Synthetic Application
10
11
12
13
5j
5k
5l
H/4-Cl
H/4-Me
H/4-Cl
5m
5n
e
14
90:10
a
1 (0.15 mmol), PhCHO (0.1 mmol), BocNH2 (0.25 mmol).
b
c
d
Isolated yield. Determined by 1H NMR. Determined by chiral
e
HPLC. 2-F-PhCHO instead of PhCHO.
compounds 5f−j were produced with excellent results (Table 3,
entries 6−10). Comparable results were obtained when we
used 3-vinyl indoles bearing 4-substituted phenyls as donors
(Table 3, entries 11−13). We noticed that the 4-Me phenyl-
substituted 3-vinyl indole increased the reaction rate greatly
(Table 3, entry 13) possibly because the electron-donating
property of the 4-Me group increased the nucleophilicity of 3-
vinyl indole. The absolute configuration of 5n (E, S) was
established by X-ray single-crystal analysis.13 The stereo-
chemistries of compounds 4a−o and 5a−m were assigned by
analogy with those of 5n.
The possible reaction mechanism was studied. First, the N-
Boc protected imine formed in situ under the acidic conditions
and was activated by phosphoric acid (PA*) through the
formation of a H-bond (int.-I).11 The possible transition state
was explored through a control experiment and nonlinear effect
investigation. On one hand, we found the reaction could not
proceed when we used the N-methyl 3-vinyl indole as the
donor (Figure 2a); on the other hand, we detected there
propylamine core have good biological activities.14 The single
crystal of compound 8a was then prepared and submitted to X-
ray analysis for determining the absolute configuration of the
new generated chiral center.13
In conclusion, 3-vinyl indoles were successfully used as
nucleophiles in the catalytic asymmetric synthesis of 3-
substituted indoles. The target products bearing multiple
functional groups were generated in excellent yields with high
E/Z ratios and enantioselectivities under mild reaction
conditions. A possible mechanism was proposed to explain
the stereoselectivities exhibited in these transformations.
Applications of this synthetic strategy to construct chiral 3-
substituted indoles in a broad scope are currently underway in
our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01880.
Representative experimental procedures and analytical
data for all new compounds; X-ray crystalographic data
for determination of the configuration of product (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: qxguo@swu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSFC (21272002,
21472150), the Program for New Century Excellent Talents in
Universities (NCET-12-0929), and the Open Foundation of
Figure 2. (a) Control experiment. (b) Proposed reaction mechanism.
C
DOI: 10.1021/acs.orglett.6b01880
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Northwest University.
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DOI: 10.1021/acs.orglett.6b01880
Org. Lett. XXXX, XXX, XXX−XXX