A Tandem Oxidative Annulation Strategy for the Synthesis of Tetracyclic 3-Spirooxindole Benzofuranones

Article abstract of DOI:10.1021/acs.orglett.7b01374

A simple and efficient method was developed for the construction of the medicinally important tetracyclic 3-spirooxindole benzofuranones. In this highly atom- and step-economical one-pot protocol, one quaternary carbon center, two new cycles, and four new

Full text of DOI:10.1021/acs.orglett.7b01374

Letter
pubs.acs.org/OrgLett
A Tandem Oxidative Annulation Strategy for the Synthesis of
Tetracyclic 3‑Spirooxindole Benzofuranones
Chunxia Zhang,† Min Liu,† Mingruo Ding, Hao Xie, and Fengzhi Zhang*
College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang
University of Technology, Hangzhou, 310014, P. R. China
S
* Supporting Information
ABSTRACT: A simple and efficient method was developed for the
construction of the medicinally important tetracyclic 3-spirooxindole
benzofuranones. In this highly atom- and step-economical one-pot
protocol, one quaternary carbon center, two new cycles, and four new
bonds (C−C/C−O/C−N) were formed under simple ligand-free copper-
catalyzed conditions through a novel tandem oxidative annulation strategy.
he polycyclic 3-spirooxindole cores are privileged motifs
in bioactive molecules, pharmaceuticals, and natural
the construction of these privileged heterocyclic systems.7
Previously reported methods for the construction of the
tricyclic 3-spirooxindole lactones 6 mainly employ the
functionalized indoles or oxindoles as the starting materials
(Scheme 1, eq 1), for example, (i) the intramolecular
lactonization of 3-hydroxyoxindole esters 7,8 (ii) the intra-
molecular oxidative lactonization of 3-indolepropionic acids,9
(iii) N-heterocyclic carbene (NHC) catalyzed annulations of
T
products.1 For example, 3-spirooxindole lactones 12 and 23
(Figure 1) have shown potential anticancer and cytotoxic
Scheme 1. Synthetic Strategies for the 3-Spirooxindole
Lactone Synthesis
Figure 1. Representative examples of bioactive polycyclic spiroox-
indole derivatives.
activities, respectively. 3-Spirooxindole ether 3 was reported to
be a CB2 agonist and could be a potential drug candidate for
reducing neuropathic and bone pains.4 The tetracyclic 3-
spirooxindole benzoether 4 (Funapide) is a novel analgesic
under development by Xenon Pharmaceuticals in partnership
with Teva Pharmaceutical Industries for the treatment of a
variety of chronic pain conditions.5 Tryptoquivaline 5 are a
group of indole alkaloids that belong to tremorgenic
mycotoxins which are capable of eliciting intermittent or
sustained tremors in vertebrate animals by acting on the central
nervous system.6
Due to the polycyclic 3-spirooxindole core’s appealing
structures and significant biological activities, there has been
an intense interest in the development of efficient strategies for
Received: May 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01374
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Letter
isatins/3-hydroxyoxindoles 8 with enals or propionic acids,10
(iv) and Michael/cyclization of 3-hydroxyoxindoles.11 Recently
with linear aniline derivatives as starting materials, Du and co-
workers reported a chiral aryliodine-mediated enantioselective
synthesis of 3-spirofurooxindoles via cascade oxidative C−O
and C−C bond formation.12 Despite these reports, methods for
the construction of the tetracyclic 3-spirooxindole lactones are
limited. To the best of our knowledge there is only one
example of the synthesis of tetracyclic 3-spirooxindole
benzofuranone 10 through benzannulation of spirooxindole
butenolides 9 with benzynes, which was limited by the
availability of suitable dienes and aryne precursors (Scheme
1, eq 2).13 Therefore, more general and efficient synthetic
methodology is still required for the synthesis of tetracyclic 3-
spirooxindole benzofuranones. During our investigation of Pd/
Cu catalyzed intramolecular decarboxylative amination reaction
with benzoic acid derivatives 11 as the starting materials, we
accidentally detected the formation of a trace amount of
tetracyclic 3-spirooxindole benzofuranones 12. Despite the
challenge to inhibit the amide formation and decarboxylative
related side reactions etc.,14 we envisioned that the 3-
spirooxindole benzofuranone 12 could be prepared through
aerobic oxidation of readily available benzoic acid derivatives
11, intramolecular cyclization of the possible intermediate
diketone I, and ring distortion of the spiro[indoline-2,1′-
isobenzofuran]-3,3′-dione II (Scheme 1, eq 3), which would
provide a highly atom- and step-economical one-pot protocol
for the synthesis of this fairly complex and valuable heterocyclic
system.
to another Cu(I) catalyst such as CuCN, CuBr, or CuI, the
reactions gave better yields (Table 1, entries 2−4). The yield
could be improved to 65% by using CuBr2 as the catalyst
(Table 1, entry 5). By conducting the reaction under an air
atmosphere the yield was decreased to 53% (Table 1, entry 6).
Only trace amounts of product were obtained if the reaction
was carried out under a nitrogen atmosphere (Table 1, entry 7),
which demonstrated oxygen is required as a green oxidant in
this reaction. The yield could be further improved to 75% yield
under the ligand-free copper-catalyzed condition under an
oxygen atmosphere (Table 1, entry 8). Interestingly the
reaction also could be conducted under the metal-free
condition though the yield was decreased significantly (Table
1, entry 9). Next we carried out the base screening. With KOH
as the base only trace amounts of product were obtained (Table
1, entry 10). The yield was dropped to 36% with Cs2CO3 as the
base (Table 1, entry 11). The yield could be improved to 80%
with NaOMe as the base (Table 1, entry 12). By switching to
DCE as solvent, the yield decreased to 40% (Table 1, entry 13).
Finally, we found the yield could be further improved to 84%
with DMF as solvent (Table 1, entry 14).
With the optimum conditions in hand, we then prepared
various benzoic acid derivatives 13 according to the known
procedure and subjected to the reaction conditions.15 First, we
examined the substrates with substituents on the aniline ring
(Table 2). For the substrates with a simple methyl substituent,
Table 2. Substrate Scopes with Substitution Variation on the
Aniline Ring
We initiated the study of this reaction with readily available
benzoic acid derivative 13a as the starting material (Table 1).
After intensive screening of catalytic systems (see Supporting
Information), we are pleased to find the desired tetracyclic
spirooxindole benzofuranone 14a could be obtained in 44%
yield with CuCl as the catalyst (Table 1, entry 1). By switching
Table 1. Optimization of Reaction Conditions
a
b
c
entry
cat.
ligand
base
solvent
yield (%)
1
CuCl
CuCN
CuBr
CuI
Phen
Phen
Phen
Phen
Phen
Phen
Phen
−
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOH
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DCE
44
47
53
55
65
2
3
4
5
CuBr2
CuBr2
CuBr2
CuBr2
−
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
d
6
53
the yields are generally good (14b and 14c). The substrate with
a highly electron-donating group gave a much higher yield than
those with a highly electron-withdrawing group (14d and 14e).
The substrates with halogen groups such as F and Cl on the
aniline ring are effective (14f−i). By changing the protecting
group on the nitrogen to an isopropyl or a benzyl group, the
reactions gave the corresponding products in good yields
(14h−k).
e
7
trace
8
75
9
Phen
39
10
11
12
13
14
−
−
−
−
trace
36
Cs2CO3
NaOMe
NaOMe
NaOMe
80
40
−
DMF
84
Next, we examined the substrates with substituents on the
benzoic acid ring (Table 3). Generally, the substrates with
either electron-donating or -withdrawing groups are effective
and gave the corresponding products in good yields under the
optimum conditions (16a−e). Halogens such as F, Cl, and Br
a
0.2 mmol of benzoic acid 13a, 20 mol % of catalyst, 20 mol % of 1,10-
phenanthroline (phen), 2.0 equiv of base, 150 mg of 3 Å molecular
sieves, O2 atmosphere, 1.0 mL of solvent, 150 °C, 12 h. Anhydrous
solvent. Isolated yields. Air atmosphere. N2 atmosphere.
b
c
d
e
B
DOI: 10.1021/acs.orglett.7b01374
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Organic Letters
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8 h affording the only desired product 14a in 79% yield, which
shows the compounds 17 and 18 might be the intermediates of
this annulation reaction. If this reaction was conducted at 90
°C, even after 28 h, the starting materials still remained along
with the compounds 17 (10%), 18 (26%), and 14a (30%). By
treatment of compounds 17 and 18 under the optimum
conditions respectively, as we expected, both of them could be
converted into the desired 3-spirooxindole benzofuranone
product 14a completely. Furthermore, small amounts of
compound 18 were detected during the transformation of 17
to 14a, which might indicate the isochromenone 17 was
converted to 3-spirooxindole benzofuranone 14a via spiro-
[indoline-2,1′-isobenzofuran]-3,3′-diones 18 as well.
Table 3. Substrate Scopes with Substitution Variation on
Both Aromatic Rings
Based on the above experiments and previous reports,15,17
a
proposed reaction pathway for this annulation is depicted in
Scheme 3.
Scheme 3. Proposed Reaction Pathway
are tolerated under the optimum conditions, which could be
used as functional handles for further transformations. The
structure of 16c was further confirmed by X-ray analysis.16
Finally, we tested the substrates with substituents on both
aromatic rings, which also afforded the desired products in
good yields under the optimum conditions (16f−i).
In order to identify the possible reaction intermediates and
further understand this multistep annulation reaction, we
carried out the following experiments (Scheme 2). First, we
Scheme 2. . Mechanistic Studies
Under the optimum conditions the benzoic derivative 13a
might be exchangeable with the isochromenone 17. Under the
aerobic oxidation conditions the starting material 13a could be
oxidized to give the diketone 22 via a pathway reported by
Wang and Zhang through intermediates 19−21.18 The
diketone 22 could be cyclized to give the 2-spirocyclic
compound 18. Finally the desired 3-spirooxindole benzofur-
anone 14a could be obtained through ring distortion and
lactonization via intermediate 23.19 These simple reaction
conditions allow the formation of a fairly complex structure in a
single step that involves an aerobic oxidation/cyclization/
rearrangement/lactonization sequence. It is worth noting that
the 2-spirocyclic compound 18 was obtained as the final
product when Letcher and co-workers treated the 5-
methyldibenz[b,f]azocin-6,12-dione with sodium metaperio-
date in boiling 50% aqueous methanol.15 Even though the same
diketone 22 was proposed as the same intermediate, the ring
distortion did not happen and the 3-spirooxindole benzofur-
anone 14a was not obtained under their reaction conditions.
In summary, we have developed a highly atom- and step-
economical method for the synthesis of various complex and
valuable tetracyclic spirooxindole benzofuranones from readily
available benzoic acid derivatives. This multistep one-pot
protocol could be carried out under simple ligand-free
copper-catalyzed conditions with oxygen as the oxidant, in
which one quaternary carbon center, two new cycles, and four
treated the substrate 13a under the optimum conditions and
monitored the reaction every 2 h. After 2 h, small amounts of
the isochromenone intermediate 17 and spiro[indoline-2,1′-
isobenzofuran]-3,3′-diones 18 were isolated along with the
remaining starting material 13a and the desired 3-spirooxindole
benzofuranone product 14a. Within 4 h, the amounts of
compounds 17 and 18 reached the maximum. The starting
material 13a and compounds 17 and 18 then disappeared after
C
DOI: 10.1021/acs.orglett.7b01374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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new bonds were formed during this robust tandem oxidative
rearrangement reaction.
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.7b01374.
General experimental procedures, characterization de-
tails, and 1H and 13C NMR spectra of compounds (PDF)
(12) Cao, Y.; Zhang, X.; Lin, G.; Zhang-Negrerie, D.; Du, Y. Org.
Lett. 2016, 18, 5580.
(13) Zheng, C.; Yao, W.; Zhang, Y.; Ma, C. Org. Lett. 2014, 16, 5028.
(14) (a) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49,
2768. (b) Zhang, F.; Greaney, M. F. Org. Lett. 2010, 12, 4745. (c) Xie,
H.; Ding, M.; Liu, M.; Tao, H.; Zhang, F. Org. Lett. 2017, 19, 2600.
(d) Xie, H.; Yang, S.; Zhang, C.; Ding, M.; Liu, M.; Guo, J.; Zhang, F.
J. Org. Chem. 2017, 82, 5250.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangfengzhi@zjut.edu.cn.
ORCID
Fengzhi Zhang: 0000-0001-9542-6634
Author Contributions
(15) Letcher, R. M.; Kwok, N.-C.; Lo, W.-H.; Ng, K.-W. J. Chem. Soc.,
Perkin Trans. 1 1998, 1715.
†C.Z. and M.L. contributed equally.
Notes
(16) CCDC: 1539598.
́ ̌
(17) Kafka, S.; Klasek, A.; Kosmrlj, J. J. Org. Chem. 2001, 66, 6394.
(18) (a) Yu, J.-W.; Mao, S.; Wang, Y.-Q. Tetrahedron Lett. 2015, 56,
1575. (b) Wang, X.; Chen, R.-X.; Wei, Z.-F.; Zhang, C.-Y.; Tu, H.-Y.;
Zhang, A.-D. J. Org. Chem. 2016, 81, 238.
The authors declare no competing financial interest.
(19) (a) Acheson, R. M.; Booth, S. R. G. J. Chem. Soc. C 1968, 30.
(b) Cariou, K.; Ronan, B.; Mignani, S.; Fensterbank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2007, 46, 1881.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation for Distinguished
Young Scholars of Zhejiang Province (LR15H300001),
Thousand-Talent Program of Zhejiang Province, and Zhejiang
University of Technology for financial support. We would like
to thank Dr. Bencan Tang at the University of Nottingham
(Ningbo, China) for the useful discussions and Prof. Guilin
Zhuang at Zhejiang University of Technology for help with
crystal structure determination.
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D
DOI: 10.1021/acs.orglett.7b01374
Org. Lett. XXXX, XXX, XXX−XXX