Synthesis of Spirooxindoles from N-Arylamide Derivatives via Oxidative C(sp2)-C(sp3) Bond Formation Mediated by PhI(OMe)2 Generated in Situ

Article abstract of DOI:10.1021/acs.orglett.8b03741

A class of novel spirooxindole compounds (2) were readily synthesized, in a metal-free environment, from N-arylamide derivatives (1) via intramolecular oxidative cyclization. Direct oxidative C(sp²)-C(sp³) bond formation was realized with the least-studied PhI(OMe)₂ as an oxidant, formed in situ from the reaction between PhIO and MeOH.

Full text of DOI:10.1021/acs.orglett.8b03741

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Spirooxindoles from N‑Arylamide Derivatives via
Oxidative C(sp2)−C(sp3) Bond Formation Mediated by PhI(OMe)2
Generated in Situ
Xiaohua Zhen,† Xintong Wan,† Wei Zhang,† Qiao Li,† 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, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A class of novel spirooxindole compounds (2) were readily
synthesized, in a metal-free environment, from N-arylamide derivatives (1)
via intramolecular oxidative cyclization. Direct oxidative C(sp2)−C(sp3)
bond formation was realized with the least-studied PhI(OMe)2 as an
oxidant, formed in situ from the reaction between PhIO and MeOH.
he past several decades have witnessed rapid develop-
Tment of hypervalent iodine chemistry, with many
hypervalent iodine (iodine(III), iodine(V)) reagents being
developed and applied in various synthetic transformations.1
Among them, those where the I atom bears two carboxylate
substituents, in addition to the aryl group, e.g., phenyliodine-
(III) bis(trifluoroacetate) (PIFA), phenyliodine(III) diacetate
(PIDA), and their derivatives, have been extensively studied.2
Besides, iodosobenzene (PhIO), Koser’s reagent, aryliododium
salts, and PhIX2 (X = F, Cl, Br, N3) types of hypervalent
iodine(III) reagents3−6 have also been extensively investigated,
with their particular favorable reaction systems being
identified. On-going research in the field of hypervalent iodine
oxidants including utilizing Togni’s reagent,7 Stang’s reagent,8
Figure 1. Representative hypervalent iodine(III) reagents.
and iminoiodanes (Figure 1).9 Searching for such new
nonmetal oxidants and establishing new, efficient applications
are, obviously, highly desirable activities.
Carbon−carbon bond-forming reactions play a very
important role in organic synthesis.13 Hypervalent iodine
reagents have also been vastly applied to the construction of
C(sp2)−C(sp2)14 and C(sp2)−C(sp)11 bonds under metal-free
conditions. However, a literature survey indicated that
hypervalent iodine(III)-mediated C(sp2)−C(sp3)12 bond-
forming reactions are the least-exploited. In 2001, Kita and
co-workers12a reported that α-(aryl)alkyl-β-dicarbonyl sub-
strates A could undergo PIFA-mediated C(sp2)−C(sp3) bond
formation, leading to the synthesis of spirooxindole com-
pounds B (Scheme 1a). In our previous work,12b we applied
PIFA in a cascade annulation reaction of 1,3-diketone C,
enabling the dual oxidative C(sp2)−C(sp3) bond formations to
It was reported by Hill10 in 1982 that PhIO could be
converted to phenyliodine(III) dimethoxide (PhI(OMe)2)
upon treatment with MeOH, likely via solvolysis. However,
virtually no further report was found in the literature involving
PhI(OMe)2 nor the PhIO−MeOH system since then. As a
hypervalent reagent, PhI(OMe)2 demonstrates the potential to
enable certain organic transformations playing the role of an
oxidant. As a continuation of our research interest in
discovering new reactions for constructing novel organic
compounds mediated by hypervalent iodine reagent-
s,11a−c,12a−c we set out to explore such possibilities in
PhI(OMe)2. We assume that the reinvestigation on PhI-
(OMe)2 should be desirable because this “forgotten” hyper-
valent reagent may realize some transformations that might not
be readily achieved by existing hypervalent iodine reagents.
Received: November 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03741
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Organic Letters
Letter
Scheme 1. Oxidative C(sp2)−C(sp3) Bond Formation
Reactions
Table 1. Optimization of the PhIO/MeOH-Mediated
a
Cyclization Reaction Conditions
b
oxidant
(equiv)
temperature
time
(h)
yield
entry
solvent
(°C)
(%)
1
2
3
4
5
6
7
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIDA (1.5)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (3.0)
PhIO (2.0)
PhIO (1.5)
PhIO (1.5)
PhIO (1.5)
TFE
TFE
65
rt
reflux
reflux
reflux
65
reflux
reflux
65
65
65
65
65
65
reflux
65
65
rt
reflux
reflux
reflux
reflux
2
3
5
3
3
3
3
3
4
5
3
3
4
3
3
3
3
24
3
3
5
5
40
30
NR
43
41
35
DCM
MeOH
MeOH
MeCN
MeOH
MeOH
MeCN
toluene
DMF
DCE
THF
TFE
HFIP
i-PrOH
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
c
56
81
8
9
trace
NR
NR
NR
10
18
15
20
35
trace
55
30
28
51
10
11
12
13
14
15
16
17
18
19
20
afford spirooxindole D (Scheme 1b). In this work, we report a
convenient synthesis of spirooxindoles 2 from N-arylamide
derivatives 1 via oxidative C(sp2)−C(sp3) bond formation
mediated by PhI(OMe)2 generated in situ (Scheme 1c).
Substrate 1a was used as model substrate to test the reaction
of converting N-methyl-2-oxo-N-phenyltetrahydrofuran-3-car-
boxamide (and derivatives) to the hitherto undocumented
spiroheterocycle 2a via iodine(III)-mediated oxidative C-
(sp2)−C(sp3) bond formation. Much to our delight, treating
1a with PIFA in TFE under Kita’s conditions12a or those
developed in a previous report,12b we were able to obtain the
desired product, albeit the yield was low. However, when the
reaction was performed at 65 °C, 2a was afforded in 40% yield.
The solvent including TFE, DCM, MeCN, and MeOH (Table
1, entries 1−4) were also tested, the result of which showed
that MeOH was the most suitable solvent for the reaction.
With an attempt to further improve the yield, we introduced
NaHCO3 (Table 1, entry 5) to the reaction to neutralize the
generated TFA. However, no improvement in yield was
attained. Conjecturing that the lower yield might be due to the
side reactions caused by the presence of the powerful oxidant
of PIFA, we continued our studies by switching to less-potent
hypervalent iodine(III) oxidants. To our satisfaction, when
PIDA was applied, the yield was improved to 56% (Table 1,
entry 7), and with PhIO, 2a was afforded in a gratifying yield of
81% (Table 1, entry 8). Further studies with PhIO as the
oxidant showed that the dosage had to be at least 3 equiv to
ensure complete consumption of the substrates, and the
reaction was very sluggish at room temperature (Table 1, entry
18) and the reaction at 65 °C (the reflux temperature of
MeOH) provided the best yield. Solvent-screening studies
showed that all nonalcohol solvents, e.g., MeCN, toluene,
DMF, DCE, THF (Table 1, entries 9−13), impeded the
transformation, while all alcohol solvents, including EtOH,
isopropanol, TFE, and HFIP (Table 1, entries 14−17) all
facilitate the reaction, although to a lesser level than MeOH.
We also introduced Lewis acids including BF3·Et2O and FeCl3
d
21
e
22
a
Reaction conditions: 1a (1.0 mmol), PhIO (3.0 mmol), MeOH (5
mL), stirred at reflux (65 °C) for between 2 and 24 h. Abbreviations
used: TFE, tetrafluoroethylene; DCM, dichloromethane; MeCN,
acetonitrile; MeOH, methyl alcohol; DMF, dimethylformamide;
THF, tetrahydrofuran; HFIP, hexafluoro-2-propanol; i-PrOH, iso-
propyl alcohol; EtOH, ethyl alcohol; rt, room temperature. Isolated
yield. NaHCO3 (3.2 mmol) was added. BF3·Et2O (10% mmol) was
added. FeCl3 (10% mmol) was added.
b
c
d
e
to promote the reaction. However, we were disappointed to
find that no improvement could be achieved in each case
(Table 1, entries 21 and 22). On the basis of the fact that the
reaction does not occur in nonalcoholic reaction, we
postulated that the effective oxidant might not be the original
PhIO, but the PhI(OMe)2 species, generated in situ from
PhIO and MeOH. A reaction was then performed, by
following Hill’s method,10 between PhIO and MeOH. As
expected, PhI(OMe)2 was obtained as a white crystalline after
crystallization in n-hexane at −22 °C and was finely
characterized by nuclear magnetic resonance (1H NMR, 13C
NMR) and high-resolution mass spectroscopy (HRMS)
analysis (see the Supporting Information for details).
However, PhI(OMe)2 was found to be unstable at room
temperature and was gradually decomposed back to PhIO and
MeOH.10 This might account for the fact that at least 3 equiv
of PhIO was required to realize a full conversion of the
reaction. When substrate 1a was treated with pure PhI(OMe)2
in DCE, the desired product was obtained in 60% yield
(Scheme 2). This result indicates that PhI(OMe)2 might be
involved in the reaction as the intermediate of oxidant. What
we had observed was a two-step process in a one-pot reaction.
B
DOI: 10.1021/acs.orglett.8b03741
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
withdrawing methoxycarbonyl substituent in the phenyl ring
was subjected to the standard conditions, the reaction afforded
the dimethoxylated product 3q as the major product, with the
desired product 2q being obtained in only 18% yield.
Furthermore, when the substrate bearing a strong electron-
withdrawing cyano group was applied, the reaction afforded
the dimethoxylated product 3r as the sole product (Scheme 4).
Disappointingly, when the substrate bearing a strong electron-
withdrawing nitro group was used, no desired cyclized or
dimethoxylated product was obtained (not shown).
Scheme 2. PhI(OMe)2-Mediated Intramolecular Oxidative
Cyclization of 1a in DCE at Low Temperature
Under the optimal conditions (Table 1, entry 7), we
explored the substrate scope with different substituents on a
series of N-arylamide derivatives by this newly established
method (Scheme 3). Results showed that the method was
Scheme 4. PhIO/MeOH-Mediated Reaction of N-Arylamide
a b
,
Derivatives Bearing Electron-Deficient Substituents
a b
,
Scheme 3. Synthesis of Spirooxindoles
a
Reaction conditions: 1 (1.0 mmol), PhIO (3.0 mmol), MeOH (5
b
mL), stirred at reflux (65 °C) for 3 h. Isolated yield.
We performed mechanistic studies on the direct N-
arylamide of 1a to elucidate the reaction mechanism in
Scheme 5, using 1a as the starting substrate. First, substrate 1a
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: 1 (1.0 mmol), PhIO (3.0 mmol), MeOH (5
b
mL), stirred at reflux (65 °C) for 3 h. Isolated yield.
is tautomarized into its enol form F, which could be
understood as stabilized by the internal hydrogen bonds.
Nucleophilic attack on the iodine center of PhI(OMe)2 by
applicable across a wide range of N-methyl-N-phenylamide
type of substrates and all the corresponding products were
obtained smoothly in good to excellent yield. Substrates
bearing electron-donating groups such as methyl and methoxyl
substituent (Scheme 3, 1b−1f) in para-, meta-, or ortho-
positions were converted to the expected spirooxindoles 2b−2f
in satisfactory yields. Notably, the reaction involving the
substrate bearing meta-methoxyl afforded two inseparable
regioisomeric products 2e and 2e′, with yields of 60% and
15%, respectively. Besides, substrates bearing electron-with-
drawing groups including chloro, bromo, and iodo substituents
also afforded the desired product 2g−2i in satisfactory yields.
For the R1 substituent, isopropyl, benzyl, and cyclohexyl
groups were all well-tolerated during the reaction. In addition,
the substrates on the N atom can also be extended to an aryl
group, as the N-arylated product 2l could be obtained in 70%
yield. Finally, the method could be extended to substrates with
the lactone moiety being replaced with a cyclopentanonyl
group, as spirooxindoles 2n−2p were all obtained in moderate
yields. However, when a substrate bearing an electron-
15
the enol of intermediate F afforded the O−I enol form F,
which could be regarded as being stabilized by the internal
hydrogen bonds. Nucleophilic attack on the iodine center of
PhI(OMe)2 by the enol of intermediate F afforded the O−I
intermediate G, which was converted to the I−C intermediate
H via 1,3-migration.16 Intramolecular cyclization then occurred
in H, furnishing the formation of the C−C bond, with the
concomitant release of phenyliodine and methoxide, affording
the iminium salt I. Finally, aromatization was realized via the
abstraction of a proton from I, giving the title product 2a.
In summary, we have discovered a novel, metal-free
synthetic method to construct a novel class of compounds of
spiroheterocyclic skeletone with the application of a “for-
gotten” PhI(OMe)2 via intramolecular oxidative C(sp2)−
C(sp3) bond formation. We hope this method may rekindle
the exploration of PhI(OMe)2 (or the PhIO/MeOH system)
as an oxidant in other novel organic transformations.
C
DOI: 10.1021/acs.orglett.8b03741
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Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03741.
■
S
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Experimental procedures, data of compounds character-
ization (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*Tel.: +86-22-27406121. E-mail: duyunfeier@tju.edu.cn.
ORCID
Yunfei Du: 0000-0002-0213-2854
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (No. 21472136), and the Tianjin Research Program of
Application Foundation and Advanced Technology (No.
15JCZDJC32900) for financial support.
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1
(15) PhI(OMe)2 was characterized by H NMR, 13C NMR, and
HRMS analysis (see the Supporting Information for details).
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E
DOI: 10.1021/acs.orglett.8b03741
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