Cascade Formation of C3-Unsymmetric Spirooxindoles via PhI(OAc)2-Mediated Oxidative C?C/C?N Bond Formation

Article abstract of DOI:10.1002/adsc.201800314

A series of C₃-unsymmetric spirooxindoles were achieved by reaction of diphenylmalonamides with PhI(OAc)₂ (PIDA) under metal-free conditions. Control experiments suggest that the hypervalent iodine-mediated reaction undergoes a cascade process involving an oxidative C?C bond formation preceeding an oxidative C?N bond formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201800314

Title: Cascade Formation of C3-Unsymmetric Spirooxindoles via
PhI(OAc)2-Mediated Oxidative C–C/C–N Bond Formation
Authors: Jiyun Sun, Guangchen Li, Guangtao Zhang, Ying Cong,
Xuechan An, Daisy Zhang-Negrerie, and Yunfei Du
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800314
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10.1002/adsc.201800314
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cascade Formation of C3-Unsymmetric Spirooxindoles via
PhI(OAc)2-Mediated Oxidative C–C/C–N Bond Formation
Jiyun Sun,a Guangchen Li,a Guangtao Zhang,a Ying Cong,a Xuechan An,a Daisy Zhang-
Negrerie,a and Yunfei Dua,b,*
a
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and
Technology, Tianjin University, Tianjin 300072, China.
Tel: +86-22-27406121; duyunfeier@tju.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
b
Tel: +86-22-27406121; duyunfeier@tju.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract:A series of C3-unsymmetric spirooxindoles were
achieved by reaction of diphenylmalonamides with
PhI(OAc)2 (PIDA) under metal-free conditions. Control
experiments suggest that the hypervalent iodine-mediated
reaction undergoes
a cascade process involving an
oxidative C–C bond formation preceeding an oxidative C–
N bond formation.
Keywords:
spirooxindole;
PhI(OAc)2;
metal-free
conditions; cascade reaction; oxidative coupling
Compounds bearing a spirooxindole skeleton have
been found in many biologically active natural[1a-b, 2]
and pharmaceutically synthesized compounds,[1c-e]
displaying antimicrobial,[1d,2b-f] antitumor,[1c,1d,2c-d]
cytotoxic
antitubercular,[1d]
activities.[1e,2a] Representative examples include
mitraphylline (anti-inflammatory
activity),[2a]
activity toward
MCF-7
cells,[1b]
and
anti-inflammatory
voachalotine oxindole (antimalarial activity),[2b] and
alstonisine (antitumor, antiviral activity)[2c,d] shown in
Figure 1. Many synthetic methods have been
developed for the synthesis of this important class of
compounds.[1b,1d-e,2b,2d-f] Among all the methods,
cascade reactions, where multiple reactions steps can
all take place under the same reaction conditions in
one-pot, with each intermediate leading to the next
one without interfering with each other but down the
Scheme 1. Postulated I(III)-Mediated Construction of
Spirooxindole Skeleton Based on the Previously Reported
Works.
path to form the final product, proved to be the most
attractive approach[3] for building this type of
skeleton. However, majority of these cascade
reactions reported require the participation of one or
more transition metals as an indispensable catalyst.[4]
In this regard, developing novel, efficient, metal-free
approaches for synthesis of spirooxindoles is highly
desirable.
Hypervalent iodine reagents,[5] being a class of
non-metallic oxidant, have been widely used in the
construction of various heterocyclic compounds via
formation of a single C–N,[6] C–O,[6i, 6k, 7] C–C,[8] C–
S,[6k] N–N,[9] N–O,[10] or N–S[11] bond. However, their
applications in cascade reactions involving two
Figure 1. Naturally Occuring Alkaloids Bearing
Spirooxindole Skeleton.
1
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10.1002/adsc.201800314
Advanced Synthesis & Catalysis
oxidative bond-forming process for construction of
complicated heterocyclic compounds, especially the
spirocyclic compounds, under metal-free conditions
were not vastly exploited.[12]
entry 13). When PIDA dissolved in TFE was
introduced to a solution of 1a slowly, dropwise, 88%
yield of 2a was achieved (Table 1, entry 14). When
the reaction temperature was raised from room
temperature to reflux, the yield decreased to 55% due
to the formation of more unidentified byproducts
(Table 1, entry 15). On the other hand, when the
In 1990, Kikugawa and co-workers reported that
upon treatment with PhI(OCOCF3)2 (PIFA), N-
methoxy-2-phenylacetamide A was converted to N-
o
aryl-N-methoxyamide
B
via an intramolecular
temperature was lowered to 0 C, the reaction was
oxidative C–N bond formation, possibly through a
nitrenium ion intermediate (Scheme 1a).[6h] In our
previous work, we reported that the reaction of
anilides C and PIFA in trifluoroethanol (TFE)
underwent the intramolecular cascade C–C bond
formation to give spirooxindole compounds D
(Scheme 1b).[12f] Inspired by the above works, we
envisaged diphenylmalonamides 1 to undergo the
same I(III)-mediated C–N and C–C oxidative bond
formation to give spirooxindole compounds 2
(Scheme 1c).
greatly retarded and a lower yield of 76% of product
2a was achieved after 2 h (Table 1, entry 16).
Table 1. Optimization of Reaction Conditions.a)
Entry Oxidant Solvent Temp. (oC) Yield (%)b)
1
2
3
4
5
6
7
8
PIFA
PIDA
PhIO
PIFA
PIFA
PIFA
PIDA
PIDA
PhIO
PhIO
HTIB
HTIB
PIDA
PIDA
PIDA
PIDA
CH3CN
CH3CN
CH3CN
DCE
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
TFE
TFE
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
reflux
0
30
0c)
0c)
trace
45
35
63
50
9
trace
trace
75
46
82
88
55
76
10
11
12
13d)
14e)
15
16f)
Figure 2. X-ray Crystal Structure of 2a.
N1-Methoxy-N2-methyl-N2,2-diphenylmalonamide
1a was selected as the model substrate to test the
feasibility of the proposed reaction. To our delight,
reaction of 1a (1 equiv) with PIFA (2.1 equiv) in
acetonitrile (CH3CN) proceeded very quickly (10
min) and the reaction conveniently afforded 30%
yield of the desirable spirooxindole compound 2a
after 10 min (Table 1, entry 1). The structure of the
spirooxindole 2a was later confirmed unambiguously
through X-ray crystallographic analysis (Figure 2).[13]
With the exciting result as the starting point, we set
out to search for the optimal reaction conditions for
this method. Switching PIFA to other iodine(III)
oxidants, including PhI(OAc)2 (PIDA) and PhI=O,
failed to afford the desired product under the same
conditions (Table 1, entries 2-3). Several other
solvents including 1,2-dichloroethane (DCE), TFE,
hexafluoroisopropanol (HFIP) were put to test (Table
1, entries 4-6). Results showed TFE to be the most
appropriate solvent with the desired product formed
in the highest yield (45%) (Table 1, entry 5). To
reduce the formation of byproducts, the reactions
were carried out with the milder oxidants, i.e. PIDA,
PhIO and HTIB, in TFE and HFIP (Table 1, entries
7-12). The combination of PIDA as oxidant and TFE
as solvent led to a significant increase in the yield of
the desired product (Table 1, entries 7). Diluting the
concentration of 1a from 0.1 M to 0.025 M further
significantly increased the yield to 82% (Table 1,
TFE
a) Reactions conditions: 1a (0.5 mmol), oxidant (2.1 equiv),
in solvent (c = 0.1 M) for 10 min unless otherwise stated. b)
c)
d)
Isolated yield.
No desired product detected.
The
concentration of 1a was 0.025 M. e) PIDA dissolved in TFE
(10 mL) was added dropwise to a solution of 1a in TFE
(10 mL). f) The reaction time was elongated to 2 h.
Under optimized reaction conditions (Table 1,
entry 14), we furthered our investigation in the
aspects of the scope and limitations of this newly
developed cascade annulation reaction. A variety of
diphenylmalonamides 1a-t were studied under the
optimized conditions (Table 2). Yield data show that
the method worked well with substrates bearing an
ethyl, isopropyl, n-butyl, cyclopropylmethyl as well
as a phenyl R group on the N-atom of the anilide
moiety (Table 2, 2b-f). Concerning the Ar1 ring, our
results showed that substrates bearing the anilide
carrying an electron-donating group (Me, MeO) at
the para position of the phenyl ring afforded the
expected spirooxindoles 2g and 2h in 80% and 55%
yield, respectively, while bi-substituted the case of an
3,5-dimethylphenyl group substituted on the anilide
ring gave a significantly lower yield (41%) as the
steric effects hindered the conversion (Table 2, 2i).
The reaction of the substrates bearing electron-
withdrawing groups (CO2Me, NO2, Cl, I,) at the para
2
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10.1002/adsc.201800314
Advanced Synthesis & Catalysis
position of the aniline ring gave the desired products
2j-m in 53-81% yield in each case. For the reaction
of substrate bearing 3-bromo substituent, two
isomeric products, namely, 4-bromo-1'-methoxy-1-
methyl-3,3'-spirobi[indoline]-2,2'-dione (2n) and 6-
bromo-1'-methoxy-1-methyl-3,3'-spirobi[indoline]-
2,2'-dione (2n') were formed in 39% and 28% yield,
respectively. Unfortunately, the reaction of the
substrates bearing 3-methoxycarbonyl group or 3-
methoxyl group on the Ar1 ring did not give the
desired spirocyclized products, as the reaction
afforded some unidentified complex byproducts even
at the lower temperature or with the concentration of
the oxidant and the substrates being further diluted.
investigate the regioselectivity of the reaction by
using the substrate with a 3-methoxycarbonyl
substituent on the Ar2 ring was unsuccessful as the
reaction afforded the complex byproducts and the
desired spirooxindole product was not obtained at all.
These results showed that electron-donating (-Me and
-OMe) substituent has a favorable impact relative to
the electron-withdrawing (-Br and –NO2) substituent
on Ar2 for this transformation. Substrate 1s, bearing a
methyl substituent on both Ar1 and Ar2, was also
converted to the desired product in 60% yield (Table
2, 2s). From 1t, which bears an electron-donating (-
Me) and an electron-withdrawing (-F) group on Ar2
and Ar1 respectively, the desired product was
obtained in 68% yield (Table 2, 2t).
Table 2. PIDA-Mediated Oxidative Cascade Synthesis of
Spirooxindoles.a)
Scheme 2. Gram-Scale Preparation.
To study the practical application of this novel
method, the gram-scale reaction was carried out and
the desired spirooxindole 2a was obtained in 84%
yield (Scheme 2).
Scheme 3. Control Experiments.
To understand the reaction mechanism, we
designed the control experiments to capture the
intermediates that could be characterized (Scheme 3).
We found that when 0.5 equivalent of PIDA
dissolved in 10 mL of TFE were used, substrate 1a
was converted into intermediate F and 2a in 9% and
16% yield, respectively, with the recovery of 1a in 62%
yield. Further treating the isolated intermediate F
with 1.0 equivalent of PIDA afforded 2a in 90% yield.
These results indicated that the C–C bond forming
product was primarily formed, proceeding that of the
C–N bond.
a) Conditions: 1 (0.5 mmol), PIDA (1.05 mmol) in TFE (20
mL) at rt for 10 min. b) Isolated yield.
We also investigated the electronic nature of the
Ar2 ring. Substrates substituting with donating groups
(Me and OMe) at the para position of the Ar2 ring
afforded the expected spirooxindole 2o and 2p in
81% and 60% yield, respectively, while an electron-
withdrawing group (Br) substituted substrate gave a
lower yield (64%) (Table 2, 2q). When the substrate
bearing 3-nitro substituent on the Ar2 ring was
applied, two isomeric products 2r and 2r' were
isolated in a ratio of 3:1. However, attempt to
On the basis of the control experiments and the
previous reports,[15-16]
a
plausible mechanistic
pathway for this oxidative cascade process was
proposed (Scheme 4). Initially, the oxygen atom in
the N-methyl amide moiety nucleophically probably
attack the iodine center of the hypervalent iodine
reagent resulting in intermediate G, with the release
of an acetate anion. The intermediate G might be the
more favorable intermediate due to the extra stability
3
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10.1002/adsc.201800314
Advanced Synthesis & Catalysis
The organic phase was combined, washed with brine, and
dried over anhydrous Na2SO4. The solvent was removed
and the residue was purified by flash column
chromatography on silica gel (EtOAc/petroleum Ether) to
afford the spirooxindoles 2a-t.
from the extended conjugation, although the carbonyl
oxygen of the N-methoxy amide is also capable of
acting as a nucleophile for the nucleophilic attack.
Intermediate G could then lose the acidic α-proton to
afford enamine H, which possibly went through an
intramolecular cyclization to form intermediate imine
salt I. An oxindole F was probably formed after the
loss of a proton of I. Then the second round of
nucleophilic attack, leading by the nitrogen atom on
the N-methoxy amide moiety instead, at the iodine
center of PIDA could furnish intermediate J, which
might lead to intermediate K/L after losing the
acetate ion and iodobenzene. Further intramolecular
electrophilic aromatic substitution may afford the
final product of spirooxindole 2.[17]
Acknowledgements
We acknowledge the National Natural Science Foundation of
China (No. 21472136) and Tianjin Research Program of
Application
Foundation
and
Advanced
Technology
(15JCZDJC32900) for financial support.
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General Procedure for Preparation of Spirooxindoles
2a-s
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4
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10.1002/adsc.201800314
Advanced Synthesis & Catalysis
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via
www.ccdc.cam.ac.uk/data_request/cif.
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10.1002/adsc.201800314
Advanced Synthesis & Catalysis
COMMUNICATION
Cascade
Formation
via
of
C3-Unsymmetric
Spirooxindoles
PhI(OAc)2-Mediated
Oxidative C–C/C–N Bond Formation
Adv. Synth. Catal. Year, Volume, Page – Page
Jiyun Sun,a Guangchen Li,a Ying Cong,a Guangtao
Zhang,a Xuechan An,a Daisy Zhang-Negrerie,a and
Yunfei Dua,b,*
6
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