Construction of Oxepino[3,2-b]indoles via [4+3] Annulation of 2-Ylideneoxindoles with Crotonate-Derived Sulfur Ylides

Article abstract of DOI:10.1002/adsc.202001580

A [4+3] annulation of 2-ylideneoxindoles with crotonate-derived sulfur ylides has been developed. A series of oxepino[3,2-b]indoles were prepared in moderate to excellent yields (62-93%) under mild conditions. Moreover, the synthetic oxepino[3,2-b] indoles can be further transformed into more complex cyclopropa[5,6]oxepino[3,2-b]indoles via a [2+1] cyclopropanation. In addition, the synthetic compounds show certain antiproliferative activity against K562 and MCF-7 cells, and its IC₅₀ values for these two kinds of tumor cells up to 5.40±0.88 μM and 18.41±0.50 μM, respectively. (Figure presented.).

Full text of DOI:10.1002/adsc.202001580

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DOI: 10.1002/adsc.202001580
Construction of Oxepino[3,2-b]indoles via [4+3] Annulation of 2-
Ylideneoxindoles with Crotonate-Derived Sulfur Ylides
Xing-Hai Fei,+a Yong-Long Zhao,+a,* Fen-Fen Yang,a Xiang Guan,a
Zong-Qin Li,c Da-Peng Wang,b Meng Zhou,a Yuan-Yong Yang,a and Bin Hea
a
State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, and Engineering Research Center
for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University,
Guiyang 550004, People’s Republic of China
E-mail: zhaoyl05@126.com; zhaoyonglong@gmc.edu.cn
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical
b
University, Guiyang, 550025, People’s Republic of China
Department of Neurology, Sichuan Mianyang 404 Hospital, Mianyang 621000, People’s Republic of China
c
+
These authors made equal contribution to this work.
Manuscript received: April 22, 2021; Revised manuscript received: April 22, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001580
b] indoles are generally lacking (Scheme 1).[3] In
Abstract: A [4+3] annulation of 2-ylideneoxin-
recently years, a few synthetic methods like NHC-
doles with crotonate-derived sulfur ylides has been
catalyzed annulation reaction of indolin-3-ones with
developed. A series of oxepino[3,2-b]indoles were
prepared in moderate to excellent yields (62-93%)
under mild conditions. Moreover, the synthetic
oxepino[3,2-b] indoles can be further transformed
into more complex cyclopropa[5,6]oxepino[3,2-b]
indoles via a [2+1] cyclopropanation. In addition,
α,β-unsaturated aldehydes (Scheme 1a),[3d] visible light
catalyzed diastereoselective oxidative CÀ N/CÀ O bond
formation tandems (Scheme 1b)[3f] and gold-catalyzed
bicyclization of diaryl alkyne (Scheme 1c)[3e] have
been developed to construct oxepino[3,2-b] indole
skeletons, however, these reported strategies usually
the synthetic compounds show certain antiprolifer-
require complex reaction system and have limited
ative activity against K562 and MCF-7 cells, and its
applications. Therefore, more efficient approaches for
IC50 values for these two kinds of tumor cells up to
the construction of oxepino[3,2-b]indole skeletons is
5.40�0.88 μM and 18.41�0.50 μM, respectively.
still highly desired.
Over the past decades, crotonate-derived sulfur
ylides have been widely used as C1, C2 and C3
synthons in various cascade annulation reactions and
Keywords: 2-ylideneoxindoles; sulfur ylides; [4+3]
annulation; oxepino[3,2-b]indoles
has shown great potential in the synthesis of structur-
ally diverse carbo- and heterocyclic skeletons.[2c,4] In
particular, the formal [4+3] annulation involving
Indoles with a fused seven-membered ring at the C2- crotonate-derived sulfur ylides has provided a powerful
and C3-positions are prevalent in a wide range of tool to construct highly functionalized seven-mem-
natural products and biologically active molecules.[1–3] bered heterocycles.[4c,f,j] For example, by using above
Because of its importance in structure and biological similar [4+3] cascade annulation strategies, the syn-
activity, these indole-fused seven-membered ring skel- thesis of thieno[3,2-b]oxepines,[4f] benzofuro[3,2-b]
etons has drawn tremendous interest from both azepine[4c] and azepino[2,3-b]indole[4j] skeletons have
synthetic and medicinal chemists.[1,2] So far, although been realized in recent years by Meng’s, Huang’s and
various synthetic methods have been developed for the Li’s group, respectively. Despite these significant
construction of these indole-fused seven-membered advances, it should be noted that the development of
ring skeletons,[1a,g,2,3] most of these established methods new cyclization domino reactions of crotonate-derived
mainly focus on cyclohepta[b]indole skeletons[1a,2a–b] sulfur ylides with new substrates and its applications in
and indole-fused seven-membered nitrogen-hetero- the synthesis of important polycyclic skeletons remains
cycle skeletons,[1g,2c–k] but the research on oxepino[3,2- to be developed. Based on our investigation of sulfur
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ylide mediated cyclization domino reactions[2c,4] and
indolin-3-one chemistry,[5] herein, we envisaged that
the oxepino[3,2-b]indole skeletons 3 could be easily
created via a base promoted [4+3] annulation reaction
of crotonate-derived sulfur ylides 2 with 2-ylideneox-
indoles 1 (Scheme 1d).
Initially, we chose pure (Z)-2-ylideneoxindole 1a
and crotonate-derived sulfur ylide 2 as model sub-
strates in the presence of Et3N (1.5 equiv.) in MeCN at
°
25 C (Table 1, entry 1). To our delight, the desired [4
+3] annulation product 3a was obtained in 30% yield.
To improve the yield and try to obtain other
unprecedented annulation products,[4c,f,o] various organ-
ic and inorganic bases such as DABCO, K2CO3,
K3PO4, NaOH, tÀ BuOK and Cs2CO3 were also tested
(Table 1, entry 1–7), and Cs2CO3 was founded to be
the optimal choice (Table 1, entry 7). Interestingly,
except for [4+3] annulation product 3a, no other
annulation products were produced under the above-
tested reaction conditions. Next, we evaluated the
effect of solvents on this [4+3] cascade annulation
Scheme 1. Synthetic methods of oxepino[3,2-b]indoles.
Table 1. Optimization of reaction conditions.[a]
Entry
base (equiv.)
solvent
time (min)[e]
yield (%)[b]
1
2
3
4
5
6
7
8
Et3N (1.5)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
CHCl3
toluene
acetone
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
20
20
120
20
20
240
20
60
120
8
300
20
90
8
20
40
300
60
40
30
49
45
49
42
32
55
72
76
85
11
73
61
29
77
74
51
61
72
DABCO (1.5)
K2CO3 (1.5)
K3PO4(1.5)
NaOH (1.5)
tÀ BuOK (1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.0)
Cs2CO3(0.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
Cs2CO3(1.5)
9
10
11
12
13[g]
14[h]
15
16
17[f]
18[c]
19[d]
[a] Reactions were performed with 0.10 mmol of 1a, 0.15 mmol of 2, Cs2CO3 (1.50 equiv.) in 1.0 mL of the solvent for 8 min,
°
reaction performed at 25 C.
[b] The yields were isolated yields.
[c] (E)-1a, 0.10 mmol.
[d] (Z/E)-1a, 0.10 mmol, Z:E=1:1.
[e] Reaction time was determined by TLC.
[f] 0.11 mmol of 2 was used.
[g]
°
Reaction performed at 0 C.
[h]
°
Reaction performed at 50 C.
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reaction by screening solvents such as CH2Cl2, THF,
CHCl3, toluene, acetone and MeCN (Table 1, entry 7–
12). Among the screened solvents, CHCl3 was found to
be the best solvent and the desired product 3a was
obtained in 85% yield after only 8 minutes reaction
time (Table 1, entry 10). Encouraged by these results,
we then examined the effects of reaction temperatures
(Table 1, entry 10, and 13–14) and the loading amounts
of the Cs2CO3 and sulfur ylide 2 (Table 1, entry 10,
and 15–17). Accordingly, the experimental results
indicated that Cs2CO3 (1.5 equiv.), crotonate-derived
sulfur ylide 2 (1.5 equiv.) and the solvent CHCl3 at
Table 2. Substrate scope of the [4+3] cascade annulation
reaction.[a]
°
25 C are the optimal conditions for this annulation
reaction (Table 1, entry 10). Under the optimal reaction
conditions, we also examined the effects of Z or E
configuration of 2-ylideneoxindole 1a for this annula-
tion reaction, the results showed that longer reaction
time are needed and the yield of desired product 3a
are decreased when we used (E)-1a or (Z/E)-1a as a
substrate (Table 1, entry 10 and 18–19). Therefore, we
used pure (Z)-2-ylideneoxindoles 1 as the substrates in
the later studies (Table 1, entry 10).
With the optimal reaction conditions established,
we next investigated the substrate scope of this Cs2CO3
promoted [4+3] annulation reaction of crotonate-
derived sulfur ylides 2 with (Z)-2-ylideneoxindoles 1
(Table 2). Generally, the desired annulation products
3a–z and 3aa–3ac were obtained in 62–93% yields
and the structure of 3b was unambiguously confirmed
by single-crystal X-ray crystallography (Table 2).[6]
Although some substrates (such as 1ad–1aj) failed in
synthesis (see the ESI), this substrate scope of this
reaction is rather broad. For the substituents of
aromatic ring R2, both electron-withdrawing or elec-
tron-donating groups (1a–o) at the different positions
could be well tolerated in this [4+3] annulation
reaction and the corresponding products 3a–o were
[a] Unless otherwise specified, all reactions were carried out
with 1 (0.10 mmol, 1.0 equiv.), 2 (1.5 equiv.) and Cs2CO3
°
(1.5 equiv.) in 1.0 mL of the CHCl3 for 8 min at 25 C; the
yields were isolated yields.
[b] Reaction time was 2 h.
obtained at 66–93% yields. Although slightly lower been also applied to this [4+3] annulation reaction,
yields for products 3g–h and higher yield for product which gave the desired products 3y–z with good
3e were obtained, but the results of 3a–o revealed that results (81–87% yields).
this [4+3] annulation reaction was not obvious regular
To further investigate the potential application of
affected by steric hindrance and electronic effects of this base promoted [4+3] cascade annulation strategy,
substituents at the aromatic ring R2. In addition, the the large-scale synthesis of oxepino[3,2-b] indole 3d
(Z)-2-ylideneoxindoles (1p–s) bearing substituents and the further [2+1] cyclopropanation of the prod-
such as 2-naphthyl, isopropyl and other heterocycles ucts 3 were also performed (Scheme 2). Firstly, the
could also be well tolerated to yield corresponding gram scale reaction of (Z)-2-ylideneoxindole 1d with
products 3p–s albeit with 62% yield was obtained for crotonate-derived sulfur ylides 2 was conducted under
isopropyl substituted product 3q. Next, we further the optimized conditions and the corresponding prod-
investigated the effect of different R1 substitutions of uct 3d was obtained with 72% yield (Scheme 2a). To
indolin-3-ones 1 on this annulation reaction, and the our delight, annulation products 3 could easily react
results showed that the presence of a halide (1t–v and with (CH3)3SOI via a NaH promoted [2+1] cyclo-
1aa–1ab), electron-withdrawing (1t) or electron- propanation reaction to afford the cyclopropanation
donating (1w–x) groups on the aromatic ring of products 4a–h and 4–2i in 61–88% yields (dr>20:1)
indole-3-ones 1 could be also tolerated in this reaction and the relative configuration and structure of 4b was
and the desired products 3t–x and 3aa–3ab were unambiguously confirmed by single-crystal X-ray
afforded with moderate yields (65–86%). Finally, N- crystallography (Scheme 2b).[6] To our surprise, the
tosyl or acetyl substituted indole-3-ones 1y or 1z have deacetylated product 4–2i could be obtained with 79%
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Scheme 3. The explaination of high diastereoselective [2+1]
cyclopropanation reaction and relative configuration of cyclo-
propanation products 4.
Scheme 2. The large-scale synthesis of the product 3d and [2+
1] cyclopropanation of oxepino[3,2-b] indoles 3.
yield (dr>20:1) when N-acetyl substituted oxepino
[3,2-b] indole 3z was used as substrate in above [2+
1] cyclopropanation processes. In addition, a pilot
screening of inhibitory activity of the synthetic
compounds 3 and 4 against K562 and MCF-7 tumor
cell lines were also performed (see the ESI). The
results showed that the compound 3r and 4d had
certain antiproliferative activity against K562 and
MCF-7 cells (compound 3r: 72% and 85% inhibition
at 50 μM, IC50 values are 8.24�0.71 μM and 18.41�
Scheme 4. The effects of Z/E configurations and N-substituents
of 2-ylideneoxindole 1 for the base promoted [4+3] cascade
annulation reactions.
0.50 μM; compound 4d: 88% and 95% inhibition at of N-substituents, the Z-configuration substrates (1a
50 μM, IC50 values are 5.40�0.88 μM and 20.24� and 1z) showed stronger reactivity than the E-
0.10 μM).
configuration substrates (Scheme 4a-b). The experi-
The high diastereoselective results of [2+1] cyclo- mental results also showed that the electronic effect of
propanation reaction and relative configuration of N-substituents of 2-ylideneoxindoles 1 has an obvious
cyclopropanation products 4 might be explained by the influence on this [4+3] cascade annulation reactions.
conformation of [4+3] annulation products 3. As In particular, there were no [4+3] cascade annulation
shown in Scheme 3, the R2 groups and the indole reactions occurred for substrate 1ad bearing no
residues as a larger steric part in annulation products 3 electron-withdrawing substituents at the N1 position
are in the opposite side of the carbon-carbon double (Scheme 4c).
bond face. Comparing with the N-protected indole
To better understand the mechanism of this [4+3]
residues, R2 is less steric, so the [2+1] cyclopropana- cascade annulation process, we performed the deute-
tion reaction can easily occur on the side of the smaller rium-labeling experiments and control experiments as
steric hindrance R2 group and obtained the correspond- shown in Scheme 3. In the presence of 20.0 equiv-
ing cyclopropanation products 4 containing cyclo- alents of D2O and 1.0 equivalents of Cs2CO3, 100%
propane group and R2 group which are positioned on deuterium incorporation at the A-position and 79%
the same side of seven membered ring structure. Next, deuterium incorporation at the C-position was ob-
1
we also investigated the effects of Z/E configurations served in the H NMR analysis (See the ESI) of sulfur
and N-substituents of 2-ylideneoxindoles 1 for the base ylide D-2 (Scheme 3a). However, under the conditions
promoted [4+3] cascade annulation reactions of 20.0 equivalents of D2O without Cs2CO3, no
(Scheme 4). Perhaps due to the steric hindrance effect deuterated sulfur ylide 2 was observed (Scheme 3b). In
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addition, under the standard procedure, we also ylideneoxindoles (Z)-1a with crotonate-derived sulfur
performed the deuterium-labeling experiments for this ylides 2–1 and D-2 (1:1) under the standard procedure.
1
[4+3] annulation reaction of crotonate-derived sulfur According to the H NMR and HRMS analysis of
ylide 2 with (Z)-2-ylideneoxindole 1a in the presence crude reaction mixture, the determination of mixture A
of 20.0 equivalents of D2O, and 83% of D-3a was and mixture B (1: 10) revealed that this [4+3]
obtained with 87% deuterium incorporation at the A1- annulation reaction may involve an intermolecular
position and 86% deuterium incorporation at the A2- hydrogen transfer process (Scheme 5e, see the ESI).
position (Scheme 3c). The above experimental results
Based on our experimental results and previous
indicated that two kinds of carbanion allylic ylide related studies,[4c,f,g,h] a possible mechanism for this [4
resonance hybrids intermediates A or B (Scheme 6) +3] annulation reactions was also proposed
could be generated from the sulfur ylide 2 and the base (Scheme 6). Firstly, deprotonation of crotonate-derived
such as Cs2CO3 are very important for the formation of sulfur ylides 2 results in a carbanion allylic ylide
resonance hybrids intermediates A or B. More intermediate A in the presence of a base (such as
importantly, carbanion allylic ylide intermediates B Cs2CO3). Carbanion allylic ylide intermediates B is
might be the key active intermediate for this [4+3] formed by resonance of sulfur ylide intermediate A.
cascade annulation reaction according to our exper- Then, an intermolecular Michael addition involving α-
imental results of Scheme 5c. As shown in Scheme 5d, selective addition of carbanion allylic ylide intermedi-
no reaction occurred when ethyl bromocrotonate 2c ate
B
to 2-ylideneoxindoles
1
via soft-soft
and Me2S were directly used in the reaction system to interaction[4h] forms zwitterionic intermediate C. Next,
replace the corresponding sulfur ylide 2. Finally, we the intermediate C easily transforms into zwitterionic
also investigated this [4+3] annulation reaction of 2- intermediate E underwent two proton transfer proc-
esses (intermolecular proton transfer process may be
involved). Finally, an intramolecular 7-exo-tet cycliza-
tion process of intermediate E was occurred to
generate the products 3.
In summary, we have developed a Cs2CO3 pro-
moted [4+3] cascade annulation reaction of crotonate-
derived sulfur ylides with 2-ylideneoxindoles. In the
field of the indolin-3-one chemistry, this has become
the first example of [4+3] cascade annulation reaction
involving sulfur ylides as C3 synthons. Various
oxepino[3,2-b]indoles were prepared in moderate to
excellent yields (62-93%) via this strategy. Moreover,
the synthetic oxepino[3,2-b] indoles 3 could be easily
transformed into more complex cyclopropa[5,6]
oxepino[3,2-b]indoles 4 via a [2+1] cyclopropanation
and the synthetic compounds 3 and 4 show certain
antiproliferative activity against K562 and MCF-7
cells. Further investigation and application of the
oxepino[3,2-b] indoles and cyclopropa[5,6]oxepino
[3,2-b]indoles are ongoing in our laboratories.
Scheme 5. The deuterium-labeling experiments and control
experiments for mechanism study.
Experimental Section
General procedure for the 5,6-dihydro-2H-oxepino[3,2-b]
indoles 3: To a solution of (Z)-2-ylideneoxindoles 1 (0.1 mmol)
and sulfonium salt 2 (0.15 mmol, 1.5 equiv.) in CHCl3 (1 mL)
was added Cs2CO3 (0.15 mmol, 1.5 equiv.) under stirring at
room temperature. After the required period of time (as judged
by TLC analysis). The resulting solution was concentrated and
directly purified by flash column chromatography (eluted with
petroleum ether/EtOAc=20/1 to 10/1) to afford the desired 5,6-
dihydro-2H-oxepino[3,2-b]indoles 3.
Synthetic transformations of product 3to 4: To a solution of
NaH (60% dispersion on mineral oil, 2.9 mg, 0.12 mmol) in dry
DMSO (1 mL) was added (CH3)3SOI (24.2 mg, 0.1 mmol).
After the reaction mixture was stirred at room temperature for
Scheme 6. Proposed mechanism.
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15 min, 5,6-dihydro-2H-oxepino[3,2-b]indoles 3 (0.1 mmol)
was dissolved in dry DMSO (0.5 mL) and added dropwise
slowly. Then, the above reaction mixture was stirred for the
required period of time (as judged by TLC analysis). The
reaction mixture was extracted with EtOAc (3×50 mL) and
then washed with brine. The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated in vacuo after
filtration to give crude product. The crude product was directly
purified by flash column chromatography (eluted with petro-
leum ether/EtOAc=20/1 to 10/1) to give the desired product 4.
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (grants. 22061011 and
21502030), Science and Technology Department of Guizhou
Province (QKHJC[2020]1Y031, QKHPTRC[2017]5101 and
[2019]2760), Guizhou Health Committee (gzwjkj2020-1-209),
the State Key Laboratory of Functions and Applications of
Medicinal Plants, Guizhou Medical University (No.
FAMP201904K) and the Graduate Innovation Program of
Guizhou Medical University in 2019 (GY-YJSCXJH[2019]010).
Thanks to Dr Jun Deng (Kunming Isstitute of Botany, CAS) for
the discussion to this work.
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(3b), 1989795 (4b), contains the supplementary crystallo-
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Construction of Oxepino[3,2-b]indoles via [4+3] Annulation
of 2-Ylideneoxindoles with Crotonate-Derived Sulfur Ylides
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X.-H. Fei, Y.-L. Zhao*, F.-F. Yang, X. Guan, Z.-Q. Li, D.-P.
Wang, M. Zhou, Y.-Y. Yang, B. He