G Model
CCLET 5523 No. of Pages 4
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X. Yuan et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
summarized in Table 1. The results revealed that HFIP was the
optimal solvent for this reaction (Table 1, entries 9–12), other
commonly used solvents such as CH3CN (acetonitrile), IPA
(isopropanol), THF (tetrahydrofuran), CH2Cl2 (dichloromethane),
etc., failed to give the corresponding product (Table 1, entries 1–8).
To our delight, even at 25 ꢁC, HFIP could promote the reaction
efficiently, affording compound 3a in 85% yield (Table 1, entry 9),
indicating the effectiveness of HFIP. Increase of the temperature
could improve the reactivity, giving compound 3a with increased
yields and decreased reaction time. These results above highlight
the importance of the temperature for the reactivity. For example,
when the reaction was performed at 75 ꢁC, compound 3a was
obtained in 94% yield (Table 1, entry 11), further increase of the
temperature failed to improve the yield of the reaction, compound
3a was generated in 92% yield when the reaction was performed at
100 ꢁC. Therefore, the optimal condition was 1a (2 mmol), 2a
(1 mmol), and HFIP (2 mL). It should be noted that no any
additional catalyst was employed in this reaction, and equivalent
amount of the starting materials were used. The reaction condition
is mild and atom-economic, thus may have potential applications
in organic synthesis.
With the optimized reaction condition in hand, we next
examined the scope of indole substrates. As shown in Scheme 1,
various indoles reacted smoothly with isatin to give the
corresponding 3,3-di(indolyl)indolin-2-ones 3a-q in good to
excellent yields (up to 98%) regardless of the position of
substituents attached to the indole ring. We also noted that for
N-unprotected indole and isatin substrates, the products were also
obtained in good yields. For example, compound 3f was formed in
98% yield. Such compounds definitely allow further modifications
on the NH group for late-state diversification, affording focused
library for biological testing. The halo atom in indole substrates
could also be utilized for diversification via the transition-metal
catalysis. However, for indole substrates containing the electron-
withdrawing group (e.g., nitro or cyano) and azaindoles, no
corresponding products were obtained under the optimal con-
ditions.
In view of the good reactivity of different indole substrates, we
next examined the scope of isatin derivatives and found that
various isatin derivatives also reacted smoothly with N-methyl-
isatin to give the title compounds 4a-j in good yields (58%–93%), of
which compound 4a was afforded in 93% yield (Scheme 2). Diverse
functional groups in isatins such as fluoro, chloro, bromo, methyl,
methoxyl and nitro were well tolerated. We found that the
electron-withdrawing group (e.g., -NO2) attached to the oxindole
ring had no remarkable effect on the reactivity, compound 4j was
formed in 78% yield. Associated with above findings, we may
conclude that the electron-density in the indole ring has a
significant effect on the reactivity, while the electron-density in
the oxindole ring has no effect on the reactivity. We speculate that
the oxindole ring of the products could be cleaved under alkaline or
acidic conditions to give the steric α,α,α-trisubstituted acetic acid
derivatives, which are difficult to access through traditional
synthetic methods.
Fig. 1. Representative natural products (A and B) and drug candidates (C)
containing the bis-indole (highlighted in blue) and oxindole (highlighted in red)
ring, respectively.
extensively used green solvent in organic synthesis due to its
unique properties such as strong H-bond donating (HBD) ability
[35–38]. We previously reported that HFIP could promote C(sp2)-H
heteroarylation [35] and nucleophilic addition reactions [36] that
enabled efficient synthesis of biaryls and nonnatural α-arylated
amino esters, respectively. Herein, we report the first HFIP-
promoted catalyst-free efficient synthesis of biologically important
3,3-di(indolyl)indolin-2-ones from indoles and isatins.
Initially, N-methylindole (1a, 2 mmol) and isatin (2a, 1 mmol)
were chosen as model substrates to optimize the reaction
conditions. Several solvents were examined, and the data are
Table 1
Optimization of the reaction condition.a
Entry
Solvent
Temp. (oC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CH3CN
IPA
THF
CH2Cl2
CHCl3
DMF
DMSO
Acetone
HFIP
25
25
25
25
25
25
25
25
25
50
75
100
12
12
12
12
12
12
12
12
12
3
0
0
0
0
0
0
0
0
85
83
94
92
Finally, we proposed a plausible reaction mechanism for the
synthesis of compound 3a (Scheme 3). Because of the strong H-
bond donating ability of HFIP, the carbonyl group of isatin is
activated by HFIP, followed by addition of N-methylindole, giving
the unstable intermediate A. Isomerization of A gives the 3-
indolyl-3-hydroxyl oxindole B, which is then activated by HFIP to
give the intermediate C. Further nucleophilic addition of indole to
9
10
11
12
HFIP
HFIP
HFIP
C forms the intermediate D, which is then subjected to
1
1
isomerization, forming compound 3a. It is anticipated that the
biologically important 3-indolyl-3-hydroxyl oxindole could be
formed if one equivalent of indole is used in this reaction. The
reaction mechanism may explain the observed effects of the
a
Reaction conditions: 1a (2 mmol), 2a (1 mmol), solvent (2 mL).
Isolated yield.
b
Please cite this article in press as: X. Yuan, et al., HFIP-promoted catalyst-free cascade reactions for the synthesis of biologically relevant 3,3-di
Yuan, Xiaohan
