Palladium-Catalyzed 5-exo-dig Cyclization Cascade, Sequential Amination/Etherification for Stereoselective Construction of 3-Methyleneindolinones

Article abstract of DOI:10.1002/adsc.202001369

An cascade intramolecular 5-exo-dig cyclization of N-(2-iodophenyl)propiolamides and sequential amination/etherification (with N-hydroxybenzamides, phenyl hydroxycarbamate) protocol for the synthesis of amino- and phenoxy-substituted 3-methyleneindolinones using unexpensive Pd(PPh₃)₄ as catalyst has been developed. The protocol enables the assembly of structurally important oxindole cores featuring moderate functional group tolerance (particularly the halo group), affording a broad spectrum of products with diverse substituents in good to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202001369

Title: Palladium-Catalyzed 5-exo-dig Cyclization Cascade, Sequential
Amination/Etherification for Stereoselective Construction of 3-
Methyleneindolinones
Authors: Youpeng Zuo, Xinwei He, Qiang Tang, Wangcheng Hu,
Tongtong Zhou, Wenbo Hu, and Yongjia Shang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001369
Link to VoR: https://doi.org/10.1002/adsc.202001369

10.1002/adsc.202001369
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed 5-exo-dig Cyclization Cascade, Sequential
Amination/Etherification for Stereoselective Construction of 3-
Methyleneindolinones
Youpeng Zuo,a Xinwei He,a,* Qiang Tang,a Wangcheng Hu,a Tongtong Zhou,a Wenbo
Hu,a and Yongjia Shang a,*
a
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based
Materials (State Key Laboratory Cultivation Base), College of Chemistry and Materials Science, Anhui Normal
University, Wuhu 241000, P.R. China, E-mail: xinweihe@mail.ahnu.edu.cn; shyj@mail.ahnu.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. An cascade intramolecular 5-exo-dig cyclization (particularly the halo group), affording a broad spectrum of
of
N-(2-iodophenyl)propiolamides
and
sequential products with diverse substituents in good to excellent
amination/etherification (with N-hydroxybenzamides, phenyl yields.
hydroxycarbamate) protocol for the synthesis of amino- and
phenoxy-substituted
3-methyleneindolinones
using
Keywords:
Cyclization;
hydroxybenzamides
3-Methyleneindolinones;
N-(2-iodophenyl)propiolamides;
Amination;
N-
unexpensive Pd(PPh3)4 as catalyst has been developed. The
protocol enables the assembly of structurally important
oxindole cores featuring moderate functional group tolerance
aryl iodides and aryliodonium salts for the
construction of all-carbon tetrasubstituted olefin
containing oxindoles has been developed in recent
years (Scheme 1a, eq 1).[13] Sekar and Müller also
recently reported an improved procedure for the
preparation of 3-allylidene-2(3H)-benzofuranones
and 3-arylpropynylidene indolones via intramolecular
5-exo-dig of N-halophenylalkynylamides followed by
subsequent Heck and Sonogashira coupling in the
presence of palladium catalyst (Scheme 1a, eqs 2,
3).[14] In 2010, Müller and co-workers demonstrated a
consecutive three-component cyclocarbopalladation,
Sonogashira coupling, Michael addition of N-(2-
iodophenyl)propiolamides, terminal alkynes, and
amines giving 4-aminoprop-3-enylidene indolones
which displayed intense solid-state fluorescence with
large Stokes shifts (Scheme 1b).[15] Subsequently,
Müller group and Tang group synthesized a series of
3-piperazinyl propenylidene indolone merocyanines
and poly(indolone)s with good Aggregation Induced
Emission (AIE) properties through similar procedure,
respectively.[16] Indeed, palladium-catalyzed cross-
coupling reaction is a well-established strategy to
construct C-N bond for increasing molecular
complexity and functional group,[17] yet there have no
successful examples reported to-date regarding the
Introduction
The oxindole skeleton is a structural motif not only in
natural products[1] but also in several other fields such
as medicinal,[2] agricultural,[3] and dye chemistry.[4]
Especially, 3-methyleneindolinone derivatives are
among the most important structural classes of 2-
indolinones, which are present in numerous naturally
occurring substances and biologically active
compounds,[5] such as AMPK activator,[6] and to
synthesize TMC-95A[7] and anti-cancer drugs.[8]
Importantly, they are used as anticancer drugs,
especially for breast cancer, due to tamoxifen-like
activity, antirheumatic effects, etc.[9] For instance,
Alkaloids isatinone A and B, which were isolated
from ethanolic extracts of the herb Isatis costata, have
significant antifungal activity.[10] Despite their wide
importance, 3-methyleneindolinone exists as a pair of
stereoisomers (E/Z), and highly stereoselective
synthesis of (E)- and (Z)-3-methyleneindolinone
derivatives still remains to be a formidable challenge.
Recently, N-arylpropiolamides have received
significant attention in the formation of oxindole
skeleton owing to their easy availability, cost
effectiveness, and versatility in the synthesis of a
wide variety of nitrogen based heterocycles.[11] In this
regard, considerable efforts have been devoted to
development of efficient protocols for the
stereoselective synthesis of highly substituted 3-
methyleneindolinones.[12] For example, palladium-
catalyzed cascade intramolecular 5-exo-dig/Suzuki
coupling of N-arylpropiolamides with arylboronic,
synthesis
of
hetero-substituted
3-
methyleneindolinone derivatives. In connection with
our recent interests in N-hydroxybenzamides as
amination substrates,[18] We herein report
a
palladium-catalyzed cascade reaction between N-(2-
iodophenyl)propiolamides and N-hydroxybenzamides,
phenyl hydroxycarbamate (Scheme 1c). This process
1
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10.1002/adsc.202001369
Advanced Synthesis & Catalysis
proceeds via the intramolecular 5-exo-dig cyclization
of N-(2-iodophenyl)propiolamides in the presence of
Pd(PPh3)4 and then continues the direct
(Table 1, entries 24, 26, 28). Conclusively, 5 mol%
Pd(PPh3)4 and 2 equiv of Cs2CO3 in acetonitrile at
reflux gave the best output with (Z)-stereoselectivity.
amination/etherification
for
stereoselective
Table 1. Optimization of the Reaction Conditions.a T
construction of amino- and phenoxy-substituted 3-
methyleneindolinones.
entry
catalyst
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
PdCl2
base
NaOAc toluene
solvent temp./°C yield/%b
1c
1
100
68
92
64
35
37
57
84
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
reflux
reflux
reflux
reflux
reflux
reflux
2
3
4
5
6
PdBr2
Pd(PPh3)2Cl2 Cs2CO3
Pd2(dba)3
Cs2CO3
7
Cs2CO3
MeCN
reflux
0
-
8
9
10
11
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Na2CO3
K2CO3
Ag2CO3 MeCN
CsOAc
AgOAc
NaOAc
Cs2CO3 MeNO2
Cs2CO3
Cs2CO3
Cs2CO3 toluene
Cs2CO3
MeCN
MeCN
reflux
reflux
reflux
reflux
reflux
reflux
90
reflux
reflux
90
57
54
39
72
59
64
34
27
trace
64
51
trace
trace
53
MeCN
MeCN
MeCN
12
13
14
15
16
17
18
19
20
21
22
DCE
THF
Scheme 1. Pd-catalyzed cascade 5-exo-dig/coupling
reaction of N-(2-iodophenyl)propiolamides.
PhCl
DMF
90
90
90
50
Cs2CO3
Cs2CO3 DMSO
Cs2CO3
Cs2CO3
Results and Discussion
MeCN
MeCN
We commenced our investigation using N-(2-
iodophenyl)-N-methyl-3-phenylpropiolamide 1a with
N-hydroxybenzamide 2a in the presence of 5 mol%
Pd(PPh3)4 and Cs2CO3 as a base in acetonitrile at
reflux for 18 h. To our delight, the reaction resulted
in the formation of 5-exo-dig cyclized/aminated
product 3aa as the major product in 92% yield.
Unfortunately, substituting Pd(PPh3)4 with other
palladium catalysts, including Pd(OAc)2, PdCl2, 28
PdBr2, Pd(PPh3)2Cl2, and Pd2(dba)3, could not
improve the yield at all (Table 1, entries 2-6). It is
worth noting that no reaction occurred in the absence
of a catalyst (Table 1, entry 7), suggesting the crucial
role of the Pd-catalyst. Further screening of different
bases suggested that Cs2CO3 gave the highest yield
(Table 1, entries 13). A brief screening of solvents
confirmed that acetonitrile gives the highest yields,
whereas nitromethane, 1,2-dichloroehtane (1,2-DCE),
tetrahydrofuran (THF), toluene, chlorobenzene,
dimethylformamide (DMF), and dimethylsulfoxide
(DMSO) were failed miserably to give the desired
product (Table 1, entries 14-20). A lower reaction
temperature (50 °C or 70 °C) gave only a moderate
yield (53% and 68% respectively, Table 1, entries 21,
22). Similarly, decreasing the catalyst/base loading
and reaction time reduced the reaction yields (Table 1,
entries 23, 25, 27), while increasing the catalyst/base
loading and reaction time could not improve the yield
70
68
23c
24d
25e
26f
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
reflux
reflux
reflux
reflux
reflux
reflux
48
82
68
86
57
92
g
27
h
aReaction
condition:
N-(2-iodophenyl)-N-methyl-3-
phenylpropiolamide 1a (0.25 mmol), N-hydroxybenzamide
2a (0.25 mmol), solvent (3 mL), and catalyst (5.0 mol%)
b
for 18 h. Ioslated yields. c2.5 mol% of catalyst was used.
d10 mol% of catalyst was used. e1.0 equivalent of base was
f
g
used. 4.0 equivalent of base was used. reaction time for
12 h. hreaction time for 24 h.
With the optimal reaction conditions in hand, we
investigated the substrate scope concerning various
N-(2-iodophenyl)propiolamides 1 firstly. We were
pleased to find that a wide range of N-(2-
iodophenyl)propiolamides 1 could readily react with
N-hydroxybenzamide 2a to afford the corresponding
products 3aa-3oa in 77-95% yields (Table 2). In
detail, electron-donating substituents (e.g. –Me and –
OMe) and moderate electron-withdrawing groups
2
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10.1002/adsc.202001369
Advanced Synthesis & Catalysis
(e.g. –F, –Cl, and –Br) present at the para-, meta-,
and ortho-position of aniline yielded the
corresponding (Z)-3-(arylaminomethylene)indolin-2-
ones 3aa-3ja in good to excellent yields (84-95%).
Interestingly, the reaction of the alkynyl moiety
bearing an alkyl groups (e.g. –Me and –Et) also
reacted to give the desired products 3ka and 3la in
77% and 78% yields, respectively. Meanwhile, the
effect of various N-protecting groups, including ethyl,
allyl and benzyl, on N-(2-iodophenyl)propiolamides 1
was also investigated, delightfully, all of the
protected substrates reacted efficiently under the
standard reaction conditions to give the respective
products 3ma, 3na, and 3oa in 94%, 91%, and 89%
yields, respectively.
transformation, affording the corresponding products
3am-3ar in 68%-87% yields. However, the reaction
of the alkyl-substituted N-hydroxyformamide was
found to be inferior (Scheme 3, compound 3as).
Additionally, the Z-stereoconformation of compound
3ae was confirmed by X-ray analysis.
Table 3. Substrate scope of N-hydroxybenzamides.a,b
Table
2.
Substrate
scope
of
N-(2-
iodophenyl)propiolamides.a,b
a
Reaction conditions: N-(2-iodophenyl)-N-methyl-3-
phenylpropiolamide
1a
(0.25
mmol),
N-
hydroxybenzamides 2 (0.25 mmol), Pd(PPh3)4 (5 mmol%),
Cs2CO3 (2.0 equiv) and MeCN (3 mL) under reflux for 18
h. b Isolated yield.
a
Reaction conditions: N-(2-iodophenyl)propiolamides 1
(0.25 mmol), N-hydroxybenzamide 2a (0.25 mmol),
Pd(PPh3)4 (5 mmol%), Cs2CO3 (2.0 equiv) and MeCN (3
mL) under reflux for 18 h. b Isolated yield.
Furthermore, to verify whether this transformation
is suitable for other class of N-hydroxyformamide,
Subsequently, a variety of N-hydroxybenzamides 2
was investigated to extend substrate diversity 2
(Table 3). It was found that a wide range of N-
hydroxybenzamides bearing different substituents on
the benzene ring could be smoothly processed to
afford the desired products 3ab-3al in 85%-95%
yields. The reaction efficiency was less affected by
the variations of the electronic properties (e.g. –Me, –
OMe, –tBu, and halo) or the position of substituents
(para-, meta-, and ortho-) on the benzene ring,
indicating that the transformation exhibits good
tolerance of functional groups and steric hindrance.
Interestingly, the electron-deficient substrates
containing a strong electron-withdrawing group like –
CF3 also reacted to give the desired products 3ah in
we
extended
this
protocol
to
phenyl
hydroxycarbamate 4 under the standard conditions
(Table 4). Surprisingly, an exclusively E-
stereoisomer product was isolated with the absolute
configuration of the isolated product were also
confirmed by X-ray crystallographic analysis
(compound 5f). As further demonstration of the
substrate scope of this transformation showed that the
reaction of substrate
4
with various N-(2-
iodophenyl)propiolamides 1 under the standard
conditions smoothly furnished the corresponding
products 5a-5i in 76%-94% yields. Of note,
substituted aromatic rings of different electronic
properties were readily tolerated as well as N-
protected groups.
85%
yield.
Encouragingly,
disubstituted,
N-
trisubstituted
N-hydroxybenzamides,
Table
4.
Synthesis
of
3-
hydroxylnaphthamides and N-hydroxythiophene-3-
(phenoxy(phenyl)methylene)indolin-2-ones using phenyl
hydroxycarbamate.a,b
carboxamide were also compatible with this
3
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10.1002/adsc.202001369
Advanced Synthesis & Catalysis
the C3-selective functionalization of the oxindole
framework.
a
Reaction conditions: N-(2-iodophenyl)propiolamides 1
(0.25 mmol), phenyl hydroxycarbamate 4 (0.25 mmol),
Pd(PPh3)4 (5 mmol%), Cs2CO3 (2.0 equiv) and MeCN (3
mL) under reflux for 18 h. b Isolated yield.
In addition, the effect of halogen substituent (e.g.
fluoro,
chloro,
and
bromo)
of
N-(2-
iodophenyl)propiolamide 1 on the fate of the reaction
was investigated (Scheme 2a). The reaction of fluoro-
substituted substrate was unsuccessful in this
transformation, whereas the reaction of chloro- and
bromo-substituted substrate gave a poor yield of the
desired product. Simultaneously, the effect of
substitution on phenyl hydroxycarbamate, such as
Scheme 2. Further Studies.
To further probe the mechanisms for this
transformation, some control experiments were
designed and investigated (Scheme 3). When aniline
and isocyanatobenzene were employed under
standard conditions, respectively. The same product
was obtained in 85% yield using isocyanatobenzene
as substrate (Scheme 3b) while no reaction occurred
using aniline (Scheme 3a). In addition, O-benzoyl-
substituted substrate 11 also could generate the
corresponding product 3aa in 72% yield (Scheme 3c).
These results implied isocyanatobenzene is a possible
intermediate. Compared to aromatic alkyne
substituents, only a trace amount of the desired
product 3aa was produced (detected by TLC) when
N-(2-iodophenyl)-N-methylpropiolamide used as
substrate under the standard conditions (Scheme 3d).
Moreover, N-(2-iodophenyl)-N-methylcinnamamide,
generated the intramolecular annulation product 15 in
45% yield, could not undergo the cascade
intramolecular 5-exo-dig/amination process (Scheme
3e). For the etherification, phenol was employed as a
substrate to react with N-(2-iodo-5-methylphenyl)-N-
methyl-3-phenylpropiolamide 1g under the same
condition, and the desired product 5e was observed in
86% yield (Scheme 3f). These facts demonstrated
phenyl
ethoxycarbamate
6
and
phenyl
(allyloxy)carbamate 7, was also examined (Scheme
2b). Gratifyingly, the O-substituted phenyl
hydroxycarbamate 6 and 7 reacted smoothly with N-
(2-iodophenyl)propiolamides
1g
without
compromising the optimized reaction conditions to
afford their corresponding product 5e in 86% and
83% yield, respectively. Moreover, the scalability of
the reaction was investigated with the large-scale (10
mmol) reaction of N-(2-iodophenyl)-N-methyl-3-
phenylpropiolamide 1a with N-hydroxybenzamide 2a
under the optimized reaction conditions that gave the
corresponding product 3aa in 90% yield without any
significant loss in the optimized reaction yields
(Scheme
2c).
Notably,
further
synthetic
transformations of the obtained products were also
explored. The synthesized product 3ag readily
undergoes the Suzuki coupling reaction to yield the
corresponding product 9 in 76% yield (Scheme 2d),
illustrating that compounds containing halgen
substituents could be further functionalized by a C-C
coupling reaction for further π-expansion of the 3-
alkylideneoxindole skeleton. To our delight, the
treatment of 3-alkylideneoxindole 3aa with
iodomethane in the presence of sodium hydride led to
the corresponding product 10 of 3-methylation
(Scheme 2e), thus providing a synthetic approach for
that
N-hydroxybenzamide
would
generate
isocyanatobenzene as the key intermediate via proton
migration and Lossen rearrangement process in the
presence of Cs2CO3 as base.[19]
4
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10.1002/adsc.202001369
Advanced Synthesis & Catalysis
Scheme 4. Proposed Mechanism.
Conclusion
In conclusion, we have established a versatile
protocol for the synthesis of structurally diverse 3-
methyleneindolinones
cascade reaction of readily available N-(2-
iodophenyl)propiolamides with N-
through
Pd(0)-catalyzed
hydroxybenzamides and phenyl hydroxycarbamate.
This highly efficient and stereoselectivity strategy
constructs two new chemical bonds and one new
five-membered
intramolecular
ring
5-exo-dig
through
sequential
and
Scheme 3. Control experiments.
annulation
amination/etherification process. A wide range of
novel 3-alkylideneoxindoles were obtained with good
functional group tolerance to show the broadness of
the reaction. Moreover, gram-scale synthesis and
easily transformation through cross-coupling and
methylation showed the practical utility of this
protocol.
Driven by the above experimental results and
literature precedents,[20,21]
a
plausible reaction
pathway was proposed as shown in Scheme 4.
Initially, the oxidative addition of N-(2-
iodophenyl)propiolamides 1 by the ligated Pd(0)
species that subsequently coordinate with the triple
bond of propiolamide generates arylpalladium species
A, which undergoes cascade metathetic displacement
of iodide by carbonate and intramolecular 5-exo-dig
Experimental Section
annulation to form intermediate
B (via syn-
General procedure for the synthesis of amino-
substituted 3-methyleneindolinones 3. The mixture of
alkynamide 1 (0.25 mmol), N-hydroxyamide 2 (0.25
mmol), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv.) and
MeCN (3 mL) were successively added to a Schlenk
reaction tube. The reaction mixture was stirred vigorously
at reflux in oil bath with stirring 18 hours. After the
reaction mixture was cooled to room temperature,
extracted with CH2Cl2 (3 × 10 mL), and washed with brine.
The organic layers were combined, dried over Na2SO4,
filtered, and then evaporated under vacuum. The residue
was purified using flash column chromatography with a
silica gel (200-300 mesh), using ethyl acetate and
petroleum ether as the elution solvent to give desired
product 3.
carbopalladation and subsequent E,Z-equilibration).
Then intermediate
isocyanatobenzene
B
could be trapped by
derived from N-
hydroxybenzamides 2 to give intermediate C, which
provides intermediate D by amination of vinyl
palladium species. Finally, the reductive elimination
and decarboxylation of intermediate D furnishes the
intermediate 3′ and regenerates Pd(0), which
continues to participate in the next cycle. The
compound 3′ quickly converts to the final compound
3 with an intramolecular hydrogen bond to make the
(Z)-stereoisomer more stable via base-catalyzed
isomerization of vinylogous amide. On the other hand,
the intermediate would prior to react with highly
active phenol derived from phenyl hydroxycarbamate
4 to furnish the corresponding product 5 through the
etherification of intermediate E.
General procedure for the synthesis of phenoxy-
substituted 3-methyleneindolinones 5. The mixture of
alkynamide 1 (0.25 mmol), phenyl hydroxycarbamate 4
(0.25 mmol), Pd(PPh3)4 (5 mol%), Cs2CO3 (2.0 equiv.) and
MeCN (3 mL) were successively added to a Schlenk
reaction tube. The reaction mixture was stirred vigorously
at reflux in oil bath with stirring 18 hours. After the
reaction mixture was cooled to room temperature,
extracted with CH2Cl2 (3 × 10 mL), and washed with brine.
The organic layers were combined, dried over Na2SO4,
filtered, and then evaporated under vacuum. The residue
5
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10.1002/adsc.202001369
Advanced Synthesis & Catalysis
was purified using flash column chromatography with a
silica gel (200-300 mesh), using ethyl acetate and
petroleum ether as the elution solvent to give desired
product 5.
[7] a) S. Lin, S. J. Danishefsky, Angew. Chem., Int. Ed.
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X-Ray Diffraction Studies of 3ae and 5f
Crystallographic data for the structures reported in this
paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-2035849 for 3ae and CCDC-2035853 for 5f
and cif file details are provided in the Supporting
Information. Copies of the data are available free of charge
[8] R. Romagnoli, P. G. Baraldi, F. Prencipe, P. Oliva, S.
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Acknowledgements
The work was partially supported by the National Natural
Science Foundation of China (No. 21772001), the Anhui
Provincial Natural Science Foundation (No. 1808085MB41),
and Cultivation Project for University Outstanding Talents of
[10] I. Fatima, I. Ahmad, I. Anis, A. Malik, N. Afza,
Anhui Province (2019)
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Advanced Synthesis & Catalysis
FULL PAPER
Palladium-Catalyzed
5-exo-dig
Cyclization
Cascade, Sequential Amination/Etherification for
Stereoselective
Methyleneindolinones
Construction
of
3-
Adv. Synth. Catal. 2020, 362, Page – Page
Youpeng Zuo, Xinwei He,* Qiang Tang,
Wangcheng Hu, Tongtong Zhou, Wenbo Hu, and
Yongjia Shang*
8
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