Formation of Phenyliodonio-Substituted Spirofurooxindole Trifluoroacetates from N-Substituted 3-Oxopentanediamides via Phenyliodine Bis(trifluoroacetate)-Mediated Oxidative Cascade Reactions

Article abstract of DOI:10.1002/adsc.201700075

The reaction of N-substituted 3-oxopentanediamides with phenyliodine bis(trifluoroacetate) (PIFA) was found to give a novel class of phenyliodonio-substituted spirofurooxindole trifluoroacetates under metal-free conditions. The reaction is postulated to proceed via a cascade process involving an oxidative C—O bond formation, an oxidative C—C bond formation and a final iodination step. (Figure presented.).

Full text of DOI:10.1002/adsc.201700075

Title: Formation of Spirooxindoles Iodonium from N-Substituted 3-
Oxopentanediamides via Phenyliodine Bis(trifluoroacetate)-
Mediated Oxidative Cascade Reactions
Authors: Yunfei Du, Bei Hu, Yang Cao, Bobo Zhang, and Daisy Zhang-
Negrerie
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700075
Link to VoR: http://dx.doi.org/10.1002/adsc.201700075

Advanced Synthesis & Catalysis
10.1002/adsc.201700075
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Formation of Spirooxindoles Iodonium from N-Substituted 3-
Oxopentanediamides via Phenyliodine Bis(trifluoroacetate)-
Mediated Oxidative Cascade Reactions
†
†
†
†
,†,‡
Bei Hu, Yang Cao, Bobo Zhang, Daisy Zhang-Negrerie, and Yunfei Du*
†
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and
Technology, Tianjin University, Tianjin 300072, People’s Republic of China.
‡
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China.
Fax: +86-22-27404031; Tel: +86-22-27404031; e-mail: 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. The reaction of N-substituted 3-
oxopentanediamides
with
phenyliodine
bis(trifluoroacetate) (PIFA) was found to give a novel
class of spirooxindole iodonium compounds under
metal-free conditions. The reaction is postulated to
undergo a cascade process involving an oxidative C-O
bond formation, an oxidative C-C bond formation and
a final iodination step.
Keywords: hypervalent iodine(III) reagent; cascade
3
2
2
reaction; C(sp )–C(sp ) bond formation; C(sp )–O bond
formation; spirooxindoles iodonium
Cascade reactions,[1] during which several bonds are
formed in one pot without reagents added or
intermediates isolated, are powerful approaches in
organic synthesis. Numerous cascade reactions have
been discovered for the formation of polycyclic
heterocycles, a class of compounds known playing
Scheme 1. Oxidative Cascade Reactions Mediated by
Hypervalent Iodine Reagent
or N–S[11] is formed during the oxidative coupling
step. Not many cascade reactions have been reported,
[2]
key roles in various interesting biological activities.
[12,4k,l]
and even less in forming polyheterocycles
or
However, literature survey shows that the majority of
the existing methods rely on the transition-metal-
mediated C–H functionalization, arguably the most
commonly adopted and applicable strategy
nowadays.[ Due to the issue of heavy metal residue,
there is a need for the development of the transition-
metal-free method as an alternative method for
construction of the polycyclic heterocyclic skeletons.
Hypervalent iodine reagents, a class of non-metal
oxidants, have been widely used in the construction
of various heterocyclic compounds in the past decade
[13]
spiroheterocycls.
PIFA-mediated intramolecular cascade oxidative C–
bond formations which converted ,N
diphenylmalonamides to spirooxindoles (Scheme
In 2012, our group reported
C
N
1
3
-
3]
[13a]
1a).
Later our study found that diverse
spirofurooxindole derivatives could be formed from
ethyl 3-oxopentanioate monoamide derivatives by
chiral aryl iodine-mediated cascade C−O and C–C
[13c]
oxidative bond formations (Scheme 1b).
Inspired
by the results of this work, we envisaged a parallel
reaction of the amide version of ethyl 3-
oxopentanioate monoamide where the ester
substituent was replaced with an N-aryl amide moiety.
[
4a-g]
due to their ready availability, high reactivity,
and
mild toxicity.[
4h-l]
In most of these reactions, a single
[5]
[6]
[7]
[8]
[9]
[10]
bond of C–N, C–O, C–C, C–S, N–N, N–O,
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700075
We prepared compound 1a (N
1
,N
5
-dimethyl-3-oxo-
Table 2. Synthesis of Spirooxindoles iodonium via
PIFA-Mediated Oxidative Cascade Reaction.
a
N ,N
1 5
-diphenylpentanediamid) and had it subjected to
the conditions used for the construction of
spirofurooxindoles. To our delightful surprise, 1
equivalent of 1a with 2.2 equivalents of PIFA in
2,2,2-trifluoroethanol (TFE) afforded an iodonium
spirooxindole compound, 2a, in 35% yield. Although
the product was not what we had expected, it was an
iodonium compound reportedly to exhibit significant
activities against microorganisms and other potential
applications.[
4a,n,14]
Thus, we set out to investigate a
series of iodonium polyheterocycles which, to our
knowledge, had never been reported in previous
literature.
a
Table 1. Optimization of the Reaction Conditions.
b
Entry Oxidant Additive Solvent
T
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
Time / h Yield (%)
1c
2
PIFA none
PIFA none
TFE
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3
35
58
40
43
53
55
70
63
50
47
82
80
62
NR
CH
CH
3
3
3
3
3
3
CN
CN
CN
CN
CN
NO
3d
4d
5d
6d
7
3 2
PIFA BF ·Et O
PIFA TMSOTf CH
PIFA TEA
PIFA CO
3
CH
CH
CH
K
2
PIFA none
PIFA none
PIFA none
PIFA none
PIFA none
PIFA none
2
8
DCM
DMF
aAll reactions were carried out by treating substrate 1 (2
9
mmol) with PIFA (3.2 equiv) in CH
M) under air unless other state. Isolated yield.
3
NO
2
(40 mL, c = 0.05
b
1
1
1
1
0
MeOH
o
1
CH
3
NO
2
0 C
such as TEA and K
2
CO (Table 1, entries 5 and 6)
3
o
2
CH
CH
CH
3
NO
2
2
2
-10 C
4
were found to have little effect on the yield.
Screening of a series of other solvents, including
3e PIDA none
NO
NO
0 C
o
3
3
3
4e PhIO none
o
CH NO , DCM, DMF and MeOH revealed that
1
0 C
3
3
2
a
CH NO was the most suitable solvent (Table 1,
entries 7−10). Control experiment identified 0 C as
the ideal temperature for the reaction (Table 1, entries
All reactions were carried out with 1a (2 mmol) and
3
2
o
oxidant (6.4 mmol) in solvent (40 mL) unless otherwise
stated. Isolated yield. 2.2 equiv of PIFA was used. 0.2
equiv of additive was used. 1.1 equiv of TFA was added.
b
c
d
e
1
1-12). Finally, other hypervalent iodine reagents
were applied for comparison, which showed the less
potent PhI(OAc) giving a considerably lower yield
Table 1, entry 13) and iodosobenzene (PhIO), failed
Aiming to gain further insight of the newly
discovered transformation, we set out to optimize the
reaction conditions by using substrate 1a. Increasing
the dosage of the oxidant to 3.2 equivalents showed a
positive impact as the yield was improved to 58%
2
(
to afford the desired product (Table 1, entry 14).
Under the optimized conditions (Table 1, entry 11),
the scope and generality of this novel cascade
reaction was tested (Table 2). First, the electronic
nature of the phenyl ring of the amide moiety was
studied. The results showed that substrates with both
electron-donating (Me, and OMe) and electron-
(
Table 1, entry 2). Two additives, BF
3
·Et O and
2
TMSOTf were applied, but both led to slightly
decreased yield due to the formation of some
unidentified byproducts (Table 1, entries 3−4). Bases
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700075
[
17]
withdrawing (halogen) groups at the para position of
the aniline ring could be well converted to the desired
products in 60-86% yields (2b−f), although lower
yields were consistently observed for substrates
Based on the results from previous report and
our own work,
[18,13a,c]
a plausible mechanistic
pathway for this oxidative cascade process has been
proposed. As depicted in Scheme 2, the reaction
starts with a nucleophilic attack of the carbonyl
oxygen of the anilide on the hypervalent iodine center
leading to the displacement of one molecule of a
trifluoroacetate anion in PIFA. The resulting adduct
A undergoes a proton abstraction by the generated
trifluoroacetate anion, providing an iodoenolate
containing
electron-deficient
amides.
ortho-
Substituted substrates bearing a Cl group was also
well tolerable under the reaction conditions (2g). All
substrates (Br, CF and Dimethyl) at the meta-
3
position of the aniline ring were readily converted
into the corresponding desired products in good
yields (2h-j). Also, substrate 1k with methoxyl
substituents at the 3- and 4-positions of the N-aryl
moiety was converted to the product 2k, while 1l
delivered expected regioisomeric products 2l and 2l’
in an overall yield of 70%. Steric hindrance was not
found in cases 1m−p, as the corresponding
spirooxindoles iodoniums were all obtained in similar
satisfactory yields. Aiming to test the selectivity of
the transformation and improve the diversity of the
substrates, we synthesized an asymmetric amide (1q)
and carried out the reactions under the standard
conditions. Fortunately, a mixture of two isomers
were isolated in 38% and 32% yields, respectively.
1
5a,16a
intermediate B. Then 1,3-iodo-migration
occurs
in B to afford C-iodoniumenolate C. Next,
intramolecular cyclization in C via bond formation
between the carbonyl oxygen of the anilide and the
3
sp carbon connected
Scheme 2. Plausible mechanistic pathway for the
formation of 2a.
with the iodine gives D. Intermediate E is formed
from D via the abstraction of a proton. The reaction
of E with PIFA, following the same sequence of
nucleophilic attack and 1,3-iodo-migration, gives the
C−I intermediate F, which undergoes another
sequence of three steps involving a reductive
Figure 1. X-ray structure of 2e.
elimination,
intramolecular
cyclization
and
The structure of the spirooxindole moiety was
undoubtedly confirmed through the X-ray
aromatization to generate H. Being a reactive
intermediate containing an enamine moiety, H
undergoes a third iodination reaction with PIFA
leading to intermediate I. After the removal of one
molecular of CF
iodonium J in coexistence with its conjugated
iminium salt K.
In order to verify the mechanism we have proposed,
we carried out control experiments to test the
formation of intermediate D and H. When 1.0
equivalent of PIFA was used, substrate 1a was
crystallographic
dichlorofunctionalized analogue of 2a. X-ray
structural data of bond lengths: I –C (2.070
Angstrom (or 207.0 pm)), C –C (139.3 pm) and C
(132.5 pm) bonds and bond angles: N –C –C
–C20 (93.25 )
suggest double bond nature of both the C –C and
–N bonds and slightly shortened single bond of C-
analysis
of
2e,[15]
a
1
2
CO H, I is converted to the amphilic,
2
2
1
1
–
3
N
1
1
1
2
o
o
o
(
132.0 ), C
1
–C –I
2 1
(131.45 ), and C
2
–I
1
2
1
C
1
1
I while comparing to that in a classical iodonium
salt.[16,4b]
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700075
[
1] For selected examples of cascade reactions, see: a) N.
converted into intermediate E in 85% yield. However,
the treatment of the isolated E with 1.0 equivalent of
PIFA led to the formation of 2a in 45% yield, the
recovery of E in 40% yield and no formation of
intermediate H at all. Treating intermediate E with
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Scheme 3. Control Experiments for Mechanistic
Studies.
[
3] For selected examples on transition-metal-mediated
In summary, we have disclosed the synthesis of a
novel class of spirooxindoles bearing an iodonium
moiety via a PIFA-mediated cascade reaction. This
process features the oxidative coupling of an enol
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3
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4
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19]
5
[
Experimental Section
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C. D. Dey, E. Lindstedt, B. Olofsson, Org. Lett. 2015, 17,
General procedure for preparation of
spirooxindoles iodonium 2.
To a solution of substrate 1 (2 mmol) in CH
3
NO
2
(
20 mL) was slowly added PIFA (3.2 equiv) under
stirring. The resulting mixture was immersed in ice-
o
water of 0 C, and the process of the reaction was
monitored by TLC. Upon completion, the reaction
mixture was evaporated to remove the solvent and the
residue was purified by silica gel chromatography,
using a mixture of 5% MeOH/DCM to afford the
desired product 2.
4
2
554; i) E. A. Merritt, B. Olofsson, Angew. Chem., Int. Ed.
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heterocyles via C−N bond formation employing
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Angew. Chem., Int. Ed. 2012, 51, 3462; b) J. B. Huang, Y.
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Acknowledgements
We acknowledge the National Science Foundation of China
(#21472136), Tianjin Research Program of Application
Foundation and Advanced Technology (#15JCZDJC32900) and
the National Basic Research Project (#2014CB932201) for
financial support.
2
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[19] We appreciate the suggestion of further investigating
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one reviewer. Our preliminary study found that 2a could
2
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1
be converted to 1-methylisatin upon treatment with
o
Cu(OTf)
2
at 75 C. See SI for details.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201700075
COMMUNICATION
Formation of Spirooxindoles Iodonium from N-
Substituted 3-Oxopentanediamides via PIFA-
Mediated Oxidative Cascade Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
†
†
†
Bei Hu, Yang Cao, Bobo Zhang, Daisy Zhang-
†
*,†,‡
Negrerie, and Yunfei Du
6
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