Palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole to diastereoselectively access spirooxindoles

Article abstract of DOI:10.1039/c8ob02859a

A novel palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole with α,β-unsaturated nitroalkenes is reported. A series of spirooxindole derivatives were synthesized in high yields and good to excellent diastereoselectivities. This developed protocol offers a new and efficient pathway for the assembly of spirooxindoles.

Full text of DOI:10.1039/c8ob02859a

Organic &
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Palladium-catalysed ring-opening [3 + 2]-
annulation of spirovinylcyclopropyl oxindole to
diastereoselectively access spirooxindoles†
Cite this: Org. Biomol. Chem., 2019,
17, 103
Jun-An Xiao, a,b Xiu-Liang Cheng,a Yu-Chun Li,a Yi-Miao He, a,b Jin-Lian Li,a
c
Zhi-Ping Liu,a,b Peng-Ju Xia,c Wei Su*a,b and Hua Yang
*
Received 16th November 2018,
Accepted 28th November 2018
A novel palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole with
α,β-unsaturated nitroalkenes is reported. A series of spirooxindole derivatives were synthesized in high
yields and good to excellent diastereoselectivities. This developed protocol offers a new and efficient
pathway for the assembly of spirooxindoles.
DOI: 10.1039/c8ob02859a
rsc.li/obc
possess interesting biological activities such as antitumor,
antibiotic and antiparasitic activities.10 For example, citrina-
Introduction
Donor–acceptor cyclopropane (DAC) has attracted significant dine B, isolated from Penicillium citrinum N059 by Kobayashi,
attention recently, due to its versatile reactivities and high displays cytotoxicity against murine leukemia L1210 cells.11
efficiency in the construction of cyclic compounds.1 In Marcfortine A is a fungal metabolite of Penicillium roqueforti
general, ring-opening [3 + n]-cycloadditions/annulations are showing potent antiparasitic activity.12 Noticing the existence
the major work modes, which usually involve the generation of of a spiro(cyclopentyl-3-oxindole) scaffold in these bioactive
highly reactive dipoles promoted by a Lewis acid,2 protic acid,3 compounds, we envisaged that ring-opening of spirovinylcyclo-
Lewis base4 and palladium(0) catalyst.5 Among all the DACs, propane oxindole (SVCP) might offer an efficient approach to
vinylcyclopropanes (VCPs) have attracted special attention due access these spirooxindole structures. Unfortunately, this strat-
to their unparalleled reactivities in the context of the ring- egy has been rarely applied to construct spirooxindoles.13
opening strategy (Scheme 1).6 In particular, VCPs can be used Herein we describe a practical protocol via a palladium-cata-
to access multicyclic or spirocyclic derivatives with the aid of a
palladium(0) complex or Lewis acid.6a,b Several elegant protocols
have been established for the formation of spirocyclic com-
pounds via the ring-opening [3 + 2]-annulation of VCPs with dipo-
larophiles.6c,7 Despite these encouraging advances in the syn-
thetic utilization of VCPs, the exploitation of a new VCP-based
methodology is still extremely attractive to meet the demand in
the diversity and complexity of ring systems and allow for the
facile construction of a wide range of cyclic scaffolds.8
Spirooxindoles are important core skeletons in biologically
active alkaloids and relevant natural products (Scheme 2).9
Compounds bearing spirooxindole units have proven to
Scheme 1 Construction of spirocyclic scaffolds via [3
+ 2]-cyclo-
addition/annulation of vinyl cyclopropanes.
aCollege of Chemistry and Materials Science, Guangxi Teachers Education University,
Nanning 530001, P. R. China
bGuangxi Key Laboratory of Natural Polymer Chemistry and Physics,
Guangxi Teachers Education University, Nanning, 530001, P. R. China.
E-mail: suwmail@163.com
cCollege of Chemistry and Chemical Engineering, Central South University,
Changsha 410083, P. R. China. E-mail: hyangchem@csu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1857257 and
1857258. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c8ob02859a
Scheme 2 Representative natural products bearing spirooxindole motifs.
Org. Biomol. Chem., 2019, 17, 103–107 | 103
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lysed ring-opening [3 + 2] annulation of SVCP for the diastereo- (Table 1, entry 4). The replacement of Pd(OAc)2 with Pd2(dba)3
selective synthesis of spirooxindole derivatives under mild led to a slightly decreased yield (81%), but with unchanged dr
conditions. This novel protocol would offer alternative path- (Table 1, entry 5). Subsequently, solvents were also extensively
ways stereoselectively accessing spirocyclic systems.
examined (entries 6–11) and toluene was proven to be the
most suitable solvent for this transformation in terms of yield
and diastereoselectivity. It is worth noting that the protonic
solvent was found to have a dramatic impact on the efficiency
of the annulation reaction (Table 1, entry 9). Presumably,
methanol has an effect on the catalytic activity of the palla-
dium catalyst and thus leads to the spirooxindole 3a in a poor
yield and diastereoselectivity. Finally, the ratio of spirocyclo-
propane 1a and nitroalkenes 2a was also modulated and the
yield of 3a was slightly eroded when the amount of nitro-
alkenes 2a was decreased from 2.0 equiv. to 1.0 equiv.
(entries 12–14).
Results and discussion
We initiated our studies by testing a model reaction of spiro-
vinylcyclopropane oxindole 1a and β-nitrostyrene 2a catalysed
by Pd(OAc)2 and S-BINAP. It is noteworthy that 1a was syn-
thesized from N-benzyl-2-oxindole and 1,4-dibromobut-2-ene
in a moderate yield with >20 : 1 dr. Unfortunately, only 41% of
diastereomer 1a′ was isolated and the desired annulation
product 3a was unable to be accessed (Scheme 3).
In order to establish a viable protocol for this strategy, a
variety of Pd(II) salts and ligands were tested in this annulation
process (as shown in Table 1). Interestingly, using 10 mol% of
Pd(PPh3)4 as the catalyst in toluene afforded the corresponding
product 3a in 44% yield with 74 : 26 dr (Table 1, entry 1). Next,
various ligands were also evaluated by using Pd(OAc)2 as the
catalyst. Lower yields of 3a were obtained in the presence of
1,3-bis(diphenylphosphino)propane (DPPP) or PPh3 (Table 1,
entries 2 and 3). Pleasingly, the employment of xantphos gave
the desired product 3a in 89% yield and 86 : 14 dr within 12 h
With the optimal reaction conditions established, we next
investigated the substrate scope of the title reaction by employ-
ing
a
series of spirovinylcyclopropyl oxindoles and
α,β-unsaturated nitroalkenes. Firstly, different N-substituted
spirocyclopropanes 1 were evaluated. As expected from our
optimization efforts, N-protected spirocyclopropanes 1a–1d
gave moderate to excellent yields (56%–89%) and good dr
(83 : 17–88 : 12) (PG = Me, Bn, Allyl and Boc). However, the reac-
tion of unsubstituted spirocyclopropane 1e and nitroalkenes
2a afforded 67% yield but with a significantly decreased dia-
stereomeric ratio (51 : 49). Subsequently, various substituted
spirocyclopropanes 1g–1l were examined. In general, high to
good yields (64%–84%) and moderate to excellent drs
(57 : 43–95 : 5) were achieved with the substitution at the C5,
C6 or C7 position on the oxindole moiety. It is worth noting
that the diastereoselectivity obviously dropped upon increasing
the steric hindrance of the substituting group (1g–1i). The
introduction of an electron-donating group onto the oxindole
Scheme 3 Preliminary study of the designed strategy.
Table 1 Optimization of reaction conditionsa
Entry
Cat.
Ligand
Solvent
Time (h)
Yieldb (%)
drc (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
DPPP
PPh3
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
DCE
THF
MeOH
DMSO
24
24
24
12
12
12
12
12
12
12
12
12
12
24
44
31
27
89
81
67
90
80
16
83
77
88
85
77
74 : 26
86 : 14
75 : 25
86 : 14
86 : 14
72 : 28
71 : 29
58 : 42
52 : 48
75 : 25
61 : 39
85 : 15
82 : 18
82 : 18
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
9
10
11
12d
13e
14f
MeCN
Toluene
Toluene
Toluene
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Pd salts (5 mol%), ligand (10 mol%), solvent (2.0 mL), rt, 12–24 h. b Isolated yield.
c Determined by 1H NMR, based on the isolated product. d The ratio of 1a : 2a = 1 : 1.5. e The ratio of 1a : 2a = 1 : 1.2. f The ratio of 1a : 2a = 1 : 1.
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moiety would slightly decrease the yield and increase the the presence of Pd(PPh3)4. Surprisingly, over half of spirocyclo-
diastereoselectivity (1j). In contrast to C5 and C6 substituted propane 1a was epimerized to its diastereomer 1a′ within
spirocyclopropanes (1h and 1k), the substrate bearing a chloro 30 minutes, and an equilibrium was achieved after 6 hours
group at the C7 position afforded a good yield (67%) and an with a 39 : 61 diastereomeric ratio (Scheme 4, eqn (1)).
excellent diastereoselectivity (91 : 9 dr). Next, various Interestingly, cyclopropane 1a′ was successfully employed in
α,β-unsaturated nitroalkenes 2a–2l were also investigated. the title reaction and the desired spirooxindole 3a was
Pleasingly, para-substituted nitroalkenes 2a–2d gave good obtained in 78% yield with 85 : 15 dr, which are paralleled
yields (80%–87%) and drs (81 : 11–94 : 6) (Table 2, 3m–3p). It with the results by utilizing 1a as the substrate (Scheme 4,
was found that the introduction of a strong electron-donating eqn (2)). These unexpected results suggest that spirocyclo-
group onto the phenyl group in nitroalkene 2, no matter on propane could be epimerized to the thermodynamically stable
the para-position or the meta-position, would decrease the diastereomer upon the promotion by a palladium complex via
yield and diastereoselectivity (Table 2, 3q–3r). Interestingly, the intramolecular cyclization, which would hardly impact the
ortho-substituted nitroalkenes gave the corresponding product annulation process.
3s in good dr but the yield was remarkably decreased.
Next, in order to better help us understand the mechanistic
Presumably, the difference in reactivity might be majorly due pathway, three independent control experiments were per-
to the steric effect induced by the ortho-substituent. Besides, formed. Firstly, spirocyclopropane 4 without a terminal alkene
other aromatic substituted α,β-unsaturated nitroalkenes were moiety attached was tested. Unfortunately, the desired spiroox-
also well tolerated (3t–3v), except for (1E)-2-phenylethenyl indole was unable to be obtained (Scheme 5, eqn (a)). In con-
nitroalkene (3w). Additionally, other dipolarophiles, such as trast, spirocyclopropane 5 bearing an internal alkene moiety
cinnamonitrile, ethyl cinnamate, 2-cyclohexen-1-one, N-tosyl-3- gave spirooxindole 6 in 92% yield with good diastereo-
nitroindole, 2-nitrobenzofuran and alkyne derivatives, were selectivity (84 : 16 dr, Scheme 5, eqn (b)). Finally, nonaromatic
tested under the standard conditions, but essentially no nitroalkene 7 was also examined in this annulation reaction,
reaction was observed. Consequently, it can be concluded that but a complex reaction was observed (Scheme 5, eqn (c)).
the above-mentioned dipolarophiles demonstrate relatively
lower reactivity toward [3 + 2]-annulation of SVCP than
nitroalkene 2. Finally, the chemical structure and relative con-
figuration of spirooxindole 3l were unambiguously confirmed
by X-ray crystal structure analysis (CCDC 1857258†).
At this stage, we were curious about the effect of the conver-
sion from 1a and 1a′ on the [3 + 2]-annulation process. As a
result, a series of monitoring experiments were carried out in
Table 2 Substrate scope of the [3 + 2]-annulation reactiona
Scheme 4 Monitoring experiments and comparison experiments of
SVCP.
a Reaction conditions:
1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2
(5 mol%), xantphos (10 mol%), toluene (2.0 mL), rt, 12 h. b 1b′ was
used.
Scheme 5 Control experiments.
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(2018KY0364), the“BAGUI Scholar” Program of Guangxi
Province of China and Central South University.
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Scheme 6 Plausible mechanism for the ring-opening [3
annulation.
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Presumably, the nonaromatic nitroalkene might be unstable
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Conclusions
In summary, we have developed
a
diastereoselective
palladium-catalysed ring-opening [3 + 2] annulation reaction
for the construction of spirooxindole scaffolds in high yields
and good diastereomeric ratios. The developed protocol
features broad substrate scope, mild reaction conditions and
high efficiency. This work broadens the application of spiro-
vinylcyclopropane derivatives as versatile useful building
blocks in the assembly of valuable spirocyclic systems. Further
investigation on asymmetric catalytic annulation of spirovinyl-
cyclopropanes is currently being pursued in our laboratory.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (21761006 and
21861008), the Guangxi Natural Science Foundation
(2018GXNSFBA138037), the Basic Ability Improvement Project
for Young Teachers in Guangxi Colleges and Universities
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