Pd-catalyzed regiodivergent synthesis of diverse oxindoles enabled by the versatile heck reaction of carbamoyl chlorides

Article abstract of DOI:10.1021/acs.orglett.0c01197

We report herein a miscellaneous oxindole synthesis bearing an all-carbon quaternary center, enabled by Pd-catalyzed intramolecular cyclization followed by multiple intermolecular Heck reactions of both easily accessible alkene-tethered carbamoyl chlorides and olefins. This protocol obviates the use of prefunctionalized olefinic reagents, exhibits excellent functional group tolerance, and features fascinating reactive versatility.

Full text of DOI:10.1021/acs.orglett.0c01197

pubs.acs.org/OrgLett
Letter
Pd-Catalyzed Regiodivergent Synthesis of Diverse Oxindoles
Enabled by the Versatile Heck Reaction of Carbamoyl Chlorides
Xianqing Wu, Zaiquan Tang, Chengxi Zhang, Chenchen Wang, Licheng Wu, Jingping Qu,*
and Yifeng Chen*
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ABSTRACT: We report herein a miscellaneous oxindole synthesis
bearing an all-carbon quaternary center, enabled by Pd-catalyzed
intramolecular cyclization followed by multiple intermolecular Heck
reactions of both easily accessible alkene-tethered carbamoyl
chlorides and olefins. This protocol obviates the use of prefunction-
alized olefinic reagents, exhibits excellent functional group tolerance,
and features fascinating reactive versatility.
he oxindole skeleton, especially a 3,3-disubstituted one, as
a representative nitrogen-containing heterocyclic com-
Scheme 1. Development for Domino Cyclization/Heck
Reaction of Carbamoyl Chloride
T
pound prevails in cores of numerous complex molecules and
exhibits a variety of great bioactivities found in natural products
and pharmaceuticals.1−4 Transition metal-catalyzed dicarbo-
functionalization of N-arylacrylamides is a powerful synthetic
tool for the rapid construction of oxindole skeletons.5−8 Among
these studies, the reaction with an alkenylative reagent is of
particularly great interest because of its ability to be further
functionalized.8 However, most the olefinic coupling partners
are either alkenyl metallic reagents or vinyl bromides, which are
much less available or unstable, thus requiring multiple
synthetic steps or tedious manipulations to facilitate this
cascade reaction (Scheme 1a). The leverage of alkene without
any prefunctionalization enables the domino Heck reaction to
become an appealing approach for the assembly of molecular
complexity from simple feedstocks with high atom econo-
my.9−11 Recently, the Glorius group developed a photoinduced
Pd-catalyzed aryl bromide-tethered olefin dicarbofunctionaliza-
tion with reactive styrene and acrylamides as coupling partners,
enabling the expeditious synthesis of heterocyclic compounds.
Because the reaction proceeded via the open-shell intermediate,
the scope of olefins restricts the tri- and tetrasubstituted alkenes
to stabilize the radical intermediate, and only two oxindoles
with an olefinic substituent were accessible (Scheme 1a).12
Carbamoyl chloride, a stable and easily accessible feedstock
derived from widespread secondary amine, is a good precursor
for the expedient access to oxindole derivatives. Pioneering
work by Grigg13 and Takemoto,14 carbopalladation-initiated
cyclization of alkene-tethered carbamoyl chlorides, has emerged
as an efficient approach to constructing oxindoles bearing all-
carbon quaternary centers. Other elegant works involving
Received: April 3, 2020
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© XXXX American Chemical Society
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Letter
different termination reactions such as iodization,15 boryla-
tion,16 carbene insertion,17a alkynylation,17b and acylation18
have also been reported by Tong and co-workers, Lautens and
co-workers, Zhu and co-workers, and Wang and co-workers,
respectively. Despite the advances, more useful reaction
patterns still need to be continuously developed. Herein, we
report a Pd-catalyzed two-sequence Heck-type reaction from
carbamoyl chlorides and alkene feedstocks via intramolecular
cyclization followed by intermolecular Heck reaction, allowing
for the rapid assembly of a 3,3-disubstituted oxindole-bearing
quaternary carbon center with broad functional group
tolerance, which could serve as an advancement of the
cyclization of N-(2-halophenyl)acrylamide and circumvent
the use of prefunctionalized alkenyl organometallics or alkenyl
halides (Scheme 1b, i). Moreover, the sequential Heck−1,4-Pd
migration−Heck pattern was successfully applied to provide the
hindered 3-arylated, all-carbon substituted oxindole synthesis
when an aryl group was prefunctionalized on the tethered
alkene moiety (Scheme 1b, ii).7a,19 Additionally, the relay Heck
sequence could be selectively incorporated with alkenols as the
coupling component to introduce the aldehyde functionality at
the remote site (Scheme 1b, iii).20
the reaction (entry 7), probably due to the insufficient ratio of
ligand to catalyst. The nickel catalyst possessed no reactivity
(entry 8).21
With the optimal conditions in hands, we sought to
investigate the generality of the domino cyclization/intermo-
lecular Heck reaction. As depicted in Scheme 2, diverse N-
Scheme 2. Substrate Scope of Sequential Cyclization
a
Intermolecular Heck Reaction
Initial attempts with our proposed protocol were carried out
with model substrate carbamoyl chloride 1a and ethyl acrylate
2a. As outlined in Table 1, the reaction proceeded smoothly to
a
Table 1. Optimization of Reaction Condition
entry
deviation from above
3a (%)
b
1
2
3
4
5
6
7
8
none
84 (79)
54
2.0 equiv of K3PO4, without DIPEA
without K3PO4
without ligand or K3PO4
TMP instead of DIPEA
Cy2NMe instead of DIPEA
PdCl(allyl)IPr
53
31
63
63
12
0
Ni(cod)2 instead of Pd(dba)2
a
Standard conditions: 1a (1.0 equiv), 2a (2.0 equiv), Pd(dba)2 (5
mol %), IPr·HCl (10 mol %), K3PO4 (20 mol %), DIPEA (2.0 equiv),
b
Tol (0.1 M), 110 °C, 20 h. Isolated yield.
afford the desired oxindole product 3a in 84% GC yield with 5
mol % Pd(dba)2 as the catalyst, 10 mol % IPr·HCl as the
supporting ligand, and 2.0 equiv of DIPEA as the organic base,
and an additional 0.2 equiv of inorganic base K3PO4 was
necessary to liberate the free carbene ligand to give 3a in 79%
isolated yield (entry 1). The product yield dropped dramatically
to 54% when DIPEA was replaced with K3PO4 (entry 2).
Substoichiometric K3PO4 was also essential for high catalytic
efficiency; the yield decreased to 53% with the omission of the
K3PO4 (entry 3). The reaction could also proceeded under
ligand free conditions, albeit with 31% recovery of 3a and 40%
recovery of 1a (entry 4), indicating the necessity of the IPr
ligand. The lower efficiency of the reaction could be observed
by using other common organic bases such as TMP and
Cy2NMe (entries 5 and 6, respectively). Meanwhile, the NHC-
coordinated precatalyst PdCl(allyl)IPr, which was expected to
furnish a better result, conversely caused a detrimental effect in
a
Standard conditions: 1 (1.0 equiv), 2 (2.0 equiv), Pd(dba)2 (5 mol
%), IPr·HCl (10 mol %), K3PO4 (20 mol %), DIPEA (2.0 equiv), Tol
(0.1 M), 110 °C, 11−57 h.
protecting groups such as Me, Bn, PMB, and Ph are well
tolerated in this reaction (3a−3d, respectively). Substituents on
the pendant alkene were also examined. Bulky alkylated groups,
including isopropyl and CH2OTBS-substituted olefins, could
also participate in the reaction, affording the corresponding
products in 51−79% isolated yield (3e−3g). Fascinatingly,
halide substituent groups such as Cl and Br groups on the
B
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aromatic ring were accommodated with para-, meta-, and ortho-
substituted carbamoyl chlorides, which could be utilized for
further derivatization to form more functionalized oxindole
scaffolds (3i−3k, respectively).22 Meanwhile, both electron-
donating and -withdrawing groups on the aromatic ring did not
interfere with the formation of a productive alkene-tethered
oxindole skeleton, generating the corresponding products in
excellent yields (3h, 3l, and 3m). Carbamoyl chloride with a
pendant alkylate alkene was also applicable in this trans-
formation, delivering functional γ-lactam 3n in a moderate
yield. In addition, the scope of the olefins was also evaluated in
this reaction. Both tert-butyl acrylate and methyl acrylate
proceeded quite smoothly under the standard conditions,
affording the desired product in a good isolated yield (3o and
3p, respectively). Likewise, acrylonitrile (3q; E/Z = 3/1),
acrylamide (3r), and vinyl ketones (3s and 3t) were also
investigated in this reaction, delivering moderate to good yields
of the desired products. Styrene including bromide could also
be tolerated, giving 3u in a 42% isolated yield.
manner, providing the arylated oxindoles 4 in excellent yields
(Scheme 3). We began to explore the reaction of the phenyl-
substituted starting material, with which the desired product 4a
was obtained in 91% isolated yield. Then the substrate scope of
both the electrophiles and the olefins was investigated.
Gratifyingly, carbamoyl chlorides bearing halogens such as F,
Cl, and Br could be subjected to the standard conditions,
delivering moderate to excellent yields of the products (4c−4e,
respectively). Notably, the fluorine group ortho to the double
bond provided the product without interfering with the
insertion efficiency. Meanwhile, effects of the substituents on
alkene were also examined. Both electron-donating and
electron-withdrawing groups on the aromatic rings such as
the phenyl group (4f), the methoxyl group (4g), and the
trifluoromethyl group (4h) were tolerated without restricting
the 1,4-Pd shift proficiency in this reaction. The heterocyclic
thiophene-substituted alkene could also proceed via 1,4-Pd
migration to provide 4i, with a slight decrease in the yield.
Other olefinic partners, including styrene and acrylonitrile,
could be employed in this reaction efficiently to furnish
intermolecular Heck products 4j and 4k in 92% (E/Z = 5/1)
and 81% yields, respectively.
To our delight, when the substitution group on the alkene
moiety of the starting material 1′ was switched to the aromatic
groups, the reaction proceeded in the sequential carbamoyla-
tion−migratory insertion−1,4-Pd migration−Heck reaction
It would be challenging to incorporate the alcohol as the
coupling partner, because the alcoholic functionality could not
only serve as the transmetalation group with the palladium
intermediate but also participate in the transesterification step
with carbamoyl chloride. Attempts to interrogate various
alkenols as the Heck reaction component also succeeded in
providing the aldehyde-substituted oxindole product 5
(Scheme 4). The reaction proceeded in a carbamoylation−
Scheme 3. Substrate Scope of Sequential Cyclization/1,4-Pd
a
Shift/Heck Reaction
Scheme 4. Substrate Scope of Sequential Cyclization/1,4-Pd
a
Shift/Intermolecular Relay Heck Reaction
a
a
Standard conditions: 1′ (1.0 equiv), 2 (2.0 equiv), Pd(dba)2 (5 mol
Standard conditions: 1′ (1.0 equiv), 2 (2.0 equiv), Pd(dba)2 (5 mol
%), IPr·HCl (10 mol %), K3PO4 (20 mol %), DIPEA (2.0 equiv), Tol
(0.1 M), 110 °C, 12−21 h.
%), IPr·HCl (10 mol %), K3PO4 (20 mol %), DIPEA (2.0 equiv),
Tol/DCE (2/1, 0.1 M), 110 °C, 15−24 h.
C
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Scheme 5. Plausible Mechanism
migratory insertion of alkene−1,4-Pd shift−relay Heck manner.
In this transformation, allyl alcohol could proceed smoothly,
providing 5a in 67% isolated yield. In addition, the length of the
chain between the alcohol and alkene minimally affects the
efficiency of the relay Heck reaction. Excellent yields could be
obtained with an increased chain length (5b and 5c). Next, the
electronic effect on the phenyl group linked to the alkene was
also evaluated. Electron-withdrawing group CF3 accelerated the
reaction, while electron-donating substituent OMe provided a
slightly decreased yield of the desired product (5d and 5e).
Synthetically versatile substituents on the oxindole backbones
such as F, Cl, and Br groups were examined in this
transformation. All of these groups could be employed to give
the desired products in moderate to good yields (5f−5h,
respectively); the fluorine group vicinal to the tethered alkene
might affect the first insertion step, while the modest yield of 5f
is likely due to disfavored steric hindrance.
proceed through different pathways depending on the nature of
the ingredient to afford 3,3-disubstituted oxindoles bearing an
all-carbon quaternary center alkene and aldehyde functional
group. This tranformation is distinguished by its multiple
reactivities and broad functional group tolerance, which might
establish a complementary approach to the synthesis of some
useful pharmaceutical scaffolds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01197.
Detailed experimental procedures, characterization data,
and copies of NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1b−1n, 1′b, 1′f−1′h, 3a−3u, 4a−4k, 5a−
5h, and 6−11 (ZIP)
On the basis of the experimental results, we propose the
following reaction pathways (Scheme 5). First, oxidative
addition of carbamoyl chloride to Pd(0) formed A, which
subsequently proceeded via the intramolecular migratory
insertion into the tethered alkene to generate alkylpalladium
species B. When the R group on B was an alkyl substituent, the
existence of another olefinic counterpart led to the sequential
intermolecular migratory insertion, followed by the β-H
elimination to provide the oxindole product 3, and the reactive
Pd(0) intermediate was regenerated via the reductive
elimination step (circle I). Moreover, when the R group on
intermediate B was an aromatic ring, the reaction proceeded via
path II. Intramolecular C−H activation of alkylpalladium with a
phenyl group on an alkene resulted in a 1,4-Pd migration to
afford intermediate C, which then could be trapped by alkene
via intermolecular Heck reaction to furnish product 4.
Alternatively, when alkenols were used as the olefin counterpart
to participate in this reaction, intermediate E was originally
formed from species D, which then proceeded via the fast
reinsertion of the Pd−H reactive intermediate to initiate the
final relay Heck process. Aldehyde 5 was obtained to finish the
whole domino process.
AUTHOR INFORMATION
Corresponding Authors
■
Jingping Qu − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry and
Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology and
Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China; orcid.org/0000-0002-7576-
0798; Email: qujp@dlut.edu.cn
Yifeng Chen − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry and
Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology and
Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China; orcid.org/0000-0003-3239-
6209; Email: yifengchen@ecust.edu.cn
Authors
In summary, we have developed an efficient and intriguing
protocol for the construction of various useful oxindole
scaffolds via a Pd-catalyzed cascade intramolecular cyclization
and versatile intermolecular Heck reaction of easily accessible
carbamoyl chlorides with simple alkenes. The reaction can
Xianqing Wu − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
D
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Letter
(2) Monde, K.; Sasaki, K.; Shirata, A.; Takasugi, M. Brassicanal C and
Two Dioxindoles from Cabbage. Phytochemistry 1991, 30, 2915.
(3) Miah, S.; Moody, C. J.; Richards, I. C.; Slawin, A. M. Z. Synthesis
of the Marine Dibromooxoindoline Convolutamydine C. J. Chem. Soc.,
Perkin Trans. 1 1997, 1, 2405.
Engineering, East China University of Science & Technology,
Shanghai 200237, China
Zaiquan Tang − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China
Chengxi Zhang − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China
Chenchen Wang − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China
Licheng Wu − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry and
Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China
(4) (a) Richmond, E.; Ling, K. B.; Duguet, N.; Manton, L. B.; C
̧
elebi-
̈
Olcu
̧
̈
m, N.; Lam, Y.-H.; Alsancak, S.; Slawin, A. M. Z.; Houk, K. N.;
Smith, A. D. An Asymmetric Pericyclic Cascade Approach to 3-Alkyl-
3-aryloxindoles: Generality, Applications and Mechanistic Investiga-
tions. Org. Biomol. Chem. 2015, 13, 1807. (b) Guo, J.; Dong, S.; Zhang,
Y.; Kuang, Y.; Liu, X.; Lin, L.; Feng, X. Chiral Scandium(III)-
Catalyzed Enantioselective a-Arylation of N-Unprotected 3-Substi-
tuted Oxindoles with Diaryliodonium Salts. Angew. Chem., Int. Ed.
2013, 52, 10245. (c) Khoury, K.; Popowicz, G. M.; Holak, T. A.;
̈
Domling, A. The p53-MDM2/MDMX Axis−A Chemotype Perspec-
tive. MedChemComm 2011, 2, 246.
(5) For selected reviews and examples of a radical manner, see: (a) Li,
C.-C.; Yang, S.-D. Various Difunctionalizations of Acrylamide: An
Efficient Approach to Synthesize Oxindoles. Org. Biomol. Chem. 2016,
14, 4365. (b) Song, R.-J.; Liu, Y.; Xie, Y.-X.; Li, J.-H. Difunctionaliza-
tion of Acrylamides through C−H Oxidative Radical Coupling: New
Approaches to Oxindoles. Synthesis 2015, 47, 1195. (c) Chen, J.-R.;
Yu, X.-Y.; Xiao, W.-J. Tandem Radical Cyclization of N-Arylacryla-
mides: An Emerging Platform for the Construction of 3,3-
Disubstituted Oxindoles. Synthesis 2015, 47, 604. (d) Li, Z.; Zhang,
Y.; Zhang, L.; Liu, Z.-Q. Free-Radical Cascade Alkylarylation of
Alkenes with Simple Alkanes: Highly Efficient Access to Oxindoles via
Selective (sp3)C-H and (sp2)C-H Bond Functionalization. Org. Lett.
2014, 16, 382. (e) Fan, J.-H.; Wei, W.-T.; Zhou, M.-B.; Song, R.-J.; Li,
J.-H. Palladium-Catalyzed Oxidative Difunctionalization of Alkenes
with α-Carbonyl Alkyl Bromides Initiated through a Heck-type
Insertion: A Route to Indolin-2-ones. Angew. Chem., Int. Ed. 2014,
53, 6650. (f) Kong, W.; Casimiro, M.; Merino, E.; Nevado, C. Copper-
Catalyzed One-Pot Trifluoromethylation/Aryl Migration/Desulfony-
lation and C(sp2)-N Bond Formation of Conjugated Tosyl Amides. J.
Am. Chem. Soc. 2013, 135, 14480.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01197
(6) For selective examples of a cationic cyclization process, see:
(a) Li, C.-C.; Yang, S.-D. Oxidant-Free Rhodium(I)-Catalyzed
Difunctionalization of Acrylamide: An Efficient Approach To
Synthesize Oxindoles. Org. Lett. 2015, 17, 2142. (b) Zhou, B.; Hou,
W.; Yang, Y.; Feng, H.; Li, Y. Copper(I)-Catalyzed Aryl or Vinyl
Addition to Electron-Deficient Alkenes Cascaded by Cationic
Cyclization. Org. Lett. 2014, 16, 1322. (c) Shi, L.; Wang, Y.; Yang,
H.; Fu, H. Copper-Catalyzed bis-Arylations of Alkenes Leading to
Oxindole Derivatives. Org. Biomol. Chem. 2014, 12, 4070. (d) Mu, X.;
Wu, T.; Wang, H.-Y.; Guo, Y.-L.; Liu, G. Palladium-Catalyzed
Oxidative Aryltrifluoromethylation of Activated Alkenes at Room
Temperature. J. Am. Chem. Soc. 2012, 134, 878. (e) Wu, T.; Mu, X.;
Liu, G. Palladium-Catalyzed Oxidative Arylalkylation of Activated
Alkenes: Dual C-H Bond Cleavage of an Arene and Acetonitrile.
Angew. Chem., Int. Ed. 2011, 50, 12578. (f) Jaegli, S.; Dufour, J.; Wei,
H.-L.; Piou, T.; Duan, X.-H.; Vors, J.-P.; Neuville, L.; Zhu, J.
Palladium-Catalyzed Carbo-Heterofunctionalization of Alkenes for the
Synthesis of Oxindoles and Spirooxindoles. Org. Lett. 2010, 12, 4498.
(7) For selective examples of intramolecular Heck cyclization of N-
(2-halophenyl)acrylamide, see: (a) Ping, Y.; Li, Y.; Zhu, J.; Kong, W.
Construction of Quaternary Stereocenters by Palladium-Catalyzed
Carbopalladation-Initiated Cascade Reactions. Angew. Chem., Int. Ed.
2019, 58, 1562. (b) Ma, T.; Chen, Y.; Li, Y.; Ping, Y.; Kong, W. Nickel-
Catalyzed Enantioselective Reductive Aryl Fluoroalkenylation of
Alkenes. ACS Catal. 2019, 9, 9127. (c) Xu, S.; Wang, K.; Kong, W.
Ni-Catalyzed Reductive Arylacylation of Alkenes toward Carbon-
ylContaining Oxindoles. Org. Lett. 2019, 21, 7498. (d) Li, Y.; Wang,
K.; Ping, Y.; Wang, Y.; Kong, W. Nickel-Catalyzed Domino Heck
Cyclization/Suzuki Coupling for the Synthesis of 3,3-Disubstituted
Oxindoles. Org. Lett. 2018, 20, 921. (e) Wang, K.; Ding, Z.; Zhou, Z.;
Kong, W. Ni-Catalyzed Enantioselective Reductive Diarylation of
Activated Alkenes by Domino Cyclization/Cross-Coupling. J. Am.
Chem. Soc. 2018, 140, 12364. (f) Rodríguez, J. F.; Marchese, A. D.;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21421004 and 21702060), the Shanghai
Municipal Science and Technology Major Project (Grant
2018SHZDZX03), the Program of Introducing Talents of
Discipline to Universities (B16017), and the Fundamental
Research Funds for the Central Universities. The authors thank
the Research Center of Analysis and Test of East China
University of Science and Technology for the help on NMR
analysis.
REFERENCES
■
(1) For selective reviews and examples, see: (a) Singh, G. S.; Desta, Z.
Y. Isatins As Privileged Molecules in Design and Synthesis of Spiro
Fused Cyclic Frameworks. Chem. Rev. 2012, 112, 6104. (b) Galliford,
C. V.; Scheidt, K. A. Pyrrolidinyl-Spirooxindole Natural Products as
Inspirations for the Development of Potential Therapeutic Agents.
Angew. Chem., Int. Ed. 2007, 46, 8748. (c) Trost, B. M.; Brennan, M. K.
Asymmetric Syntheses of Oxindole and Indole Spirocyclic Alkaloid
Natural Products. Synthesis 2009, 18, 3003. (d) Huters, A. D.;
Styduhar, E. D.; Garg, N. K. Total Syntheses of the Elusive
Welwitindolinones with Bicyclo[4.3.1] Cores. Angew. Chem., Int. Ed.
2012, 51, 3758. (e) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.;
Hirota, H.; Ohta, T.; Williams, R. M.; Tsukamoto, S. Notoamides A−
D: Prenylated Indole Alkloids Isolated from a Marine-Derived Fungus,
Aspergillus sp. Angew. Chem., Int. Ed. 2007, 46, 2254.
E
https://dx.doi.org/10.1021/acs.orglett.0c01197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Lautens, M. Palladium-Catalyzed Synthesis of Dihydrobenzoindolones
via C-H Bond Activation and Alkyne Insertion. Org. Lett. 2018, 20,
4367. (g) Yen, A.; Lautens, M. Nickel-Catalyzed Intramolecular
Arylcyanation for the Synthesis of 3,3-Disubstituted Oxindoles. Org.
molecular Heck-Type Reaction of Chloroformamides. Chem. Pharm.
Bull. 2008, 56, 1567. (d) Tsukano, C.; Okuno, M.; Takemoto, Y.
Palladium-Catalyzed Amidation by Chemoselective C(sp3)-H Activa-
tion: Concise Route to Oxindoles Using a Carbamoyl Chloride
Precursor. Angew. Chem., Int. Ed. 2012, 51, 2763. (e) Yasui, Y.;
Kakinokihara, I.; Takeda, H.; Takemoto, Y. Preparation of α,β-
Unsaturated Lactams through Intramolecular Electrophilic Carba-
moylation of Alkenes. Synthesis 2009, 2009, 3989.
(15) Chen, C.; Hu, J.; Su, J.; Tong, X. Synthesis of Substituted γ-
Lactam via Pd(0)-Catalyzed Cyclization of Alkene-Tethered Carba-
moyl Chloride. Tetrahedron Lett. 2014, 55, 3229.
(16) Whyte, A.; Burton, K. I.; Zhang, J.; Lautens, M. Enantioselective
Intramolecular Copper-Catalyzed Borylacylation. Angew. Chem., Int.
Ed. 2018, 57, 13927.
(17) (a) Sun, W.; Chen, C.; Qi, Y.; Zhao, J.; Bao, Y.; Zhu, B.
Palladium-Catalyzed Cascade Reactions of Alkene-Tethered Carba-
moyl Chlorides with N-tosyl Hydrazones: Synthesis of Alkenefunc-
tionalized Oxindoles. Org. Biomol. Chem. 2019, 17, 8358. (b) Sun, W.;
Shi, X.; Chen, C.; Zhu, Y.-P.; Liu, Z.; Zhu, B. Palladium-Catalyzed
Cascade Cyclization/Alkynylation of AlkeneTethered Carbamoyl
Chlorides with Terminal Alkynes: Synthesis of Alkyne-Functionalized
Oxindoles. Asian J. Org. Chem. 2020, 9, 575.
́
Lett. 2018, 20, 4323. (h) Franzoni, I.; Yoon, H.; García-Lopez, J.-A.;
Poblador-Bahamonde, A. I.; Lautens, M. Exploring the Mechanism of
the Pd-Catalyzed Spirocyclization Reaction: a Combined DFT and
Experimental Study. Chem. Sci. 2018, 9, 1496. (i) Kong, W.; Wang, Q.;
Zhu, J. Water as a Hydride Source in Palladium-Catalyzed
Enantioselective Reductive Heck Reactions. Angew. Chem., Int. Ed.
2017, 56, 3987. (j) Vachhani, D. D.; Butani, H. H.; Sharma, N.; Bhoya,
U. C.; Shah, A. K.; Van der Eycken, E. V. Domino Heck/Borylation
Sequence towards Indolinone-3-methyl Boronic Esters: Trapping of
the σ-Alkylpalladium Intermediate with Boron. Chem. Commun. 2015,
51, 14862. (k) Liu, X.; Ma, X.; Huang, Y.; Gu, Z. Pd-Catalyzed Heck-
Type Cascade Reactions with N-Tosyl Hydrazones: An Efficient Way
to Alkenes via in Situ Generated Alkylpalladium. Org. Lett. 2013, 15,
4814.
(8) For selected reviews and examples, see: (a) Cherney, A. H.;
Kadunce, N. T.; Reisman, S. E. Enantioselective and Enantiospecific
Transition-Metal-Catalyzed Cross-Coupling Reactions of Organo-
metallic Reagents To Construct C-C Bonds. Chem. Rev. 2015, 115,
9587. (b) Fretwell, P.; Grigg, R.; Sansano, J. M.; Sridharan, V.;
Sukirthalingam, S.; Wilson, D.; Redpath, J. Palladium Catalysed
Tandem Cyclisation−Anion Capture Processes. Part 4: Organotin
(IV) Transfer Agents. Tetrahedron 2000, 56, 7525. (c) Packer, G.;
Lepre, K.; Kankanala, J.; Sridharan, V. Bimetallic (Cu/Pd) Catalytic
Cascade Reactions to 3,3-Disubstituted Oxindole Analogues. RSC Adv.
2014, 4, 3457. (d) Seashore-Ludlow, B.; Somfai, P. Domino
Carbopalladation-Cross-Coupling for the Synthesis of 3,3-Disubsti-
tuted Oxindoles. Org. Lett. 2012, 14, 3858. (e) Li, Y.; Ding, Z.; Lei, A.;
Kong, W. Ni-Catalyzed Enantioselective Reductive Aryl-Alkenylation
of Alkenes: Application to the Synthesis of (+)-Physovenine and
(+)-Physostigmine. Org. Chem. Front. 2019, 6, 3305.
(18) Fan, P.; Lan, Y.; Zhang, C.; Wang, C. Nickel/Photo-Cocatalyzed
Asymmetric Acyl-Carbamoylation of Alkenes. J. Am. Chem. Soc. 2020,
142, 2180.
(19) For selected reviews and examples of the 1,4-Pd shift, see:
(a) Rahim, A.; Feng, J.; Gu, Z. 1,4-Migration of Transition Metals in
Organic Synthesis. Chin. J. Chem. 2019, 37, 929. (b) Shi, F.; Larock, R.
C. Remote C−H Activation via Through-Space Palladium and
Rhodium Migrations. Top. Curr. Chem. 2009, 292, 123. (c) Ma, S.;
Gu, Z. 1,4-Migration of Rhodium and Palladium in Catalytic
Organometallic Reactions. Angew. Chem., Int. Ed. 2005, 44, 7512.
(d) Rocaboy, R.; Anastasiou, I.; Baudoin, O. Redox-Neutral Coupling
between Two C(sp3)-H Bonds Enabled by 1,4-Palladium Shift for the
Synthesis of Fused Heterocycles. Angew. Chem., Int. Ed. 2019, 58,
14625. (e) Pan, J.; Su, M.; Buchwald, S. L. Palladium(0)-Catalyzed
Intermolecular Amination of Unactivated Csp3-H Bonds. Angew.
Chem., Int. Ed. 2011, 50, 8647. (f) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. Catalysts for Suzuki-Miyaura
Coupling Processes: Scope and Studies of the Effect of Ligand
Structure. J. Am. Chem. Soc. 2005, 127, 4685. (g) Hu, T.-J.; Li, M.-Y.;
Zhao, Q.; Feng, C.-G.; Lin, G.-Q. Highly Stereoselective Synthesis of
1,3-Dienes through an Aryl to Vinyl 1,4-Palladium Migration/Heck
Sequence. Angew. Chem., Int. Ed. 2018, 57, 5871. (h) Campo, M. A.;
Zhang, H.; Yao, T.; Ibdah, A.; McCulla, R. D.; Huang, Q.; Zhao, J.;
Jenks, W. S.; Larock, R. C. Aryl to Aryl Palladium Migration in the
Heck and Suzuki Coupling of o-Halobiaryls. J. Am. Chem. Soc. 2007,
129, 6298. (i) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R.
C. Pd-Catalyzed Alkyl to Aryl Migration and Cyclization: An Efficient
Synthesis of Fused Polycycles via Multiple C-H Activation. J. Am.
Chem. Soc. 2004, 126, 7460. (j) Campo, M. A.; Huang, Q.; Yao, T.;
Tian, Q.; Larock, R. C. 1,4-Palladium Migration via C-H Activation,
Followed by Arylation: Synthesis of Fused Polycycles. J. Am. Chem.
Soc. 2003, 125, 11506. (k) Campo, M. A.; Larock, R. C. Novel 1,4-
Palladium Migration in Organopalladium Intermediates Derived from
o-Iodobiaryls. J. Am. Chem. Soc. 2002, 124, 14326. (l) Karig, G.; Moon,
M.-T.; Thasana, N.; Gallagher, T. C-H Activation and Palladium
Migration within Biaryls under Heck Reaction Conditions. Org. Lett.
2002, 4, 3115. (m) Lu, Z.; Cui, Y.; Jia, Y. Palladium-Catalyzed Domino
Heck/C−H Activation/Intermolecular Direct Arylation Reactions.
Synthesis 2011, 2011, 2595. (n) Lu, Z.; Hu, C.; Guo, J.; Li, J.; Cui, Y.;
Jia, Y. Water-Controlled Regioselectivity of Pd-Catalyzed Domino
Reaction Involving a C-H Activation Process: Rapid Synthesis of
Diverse Carbo- and Heterocyclic Skeletons. Org. Lett. 2010, 12, 480.
(9) (a) Heck, R. F. Palladium-Catalyzed Reactions of Organic
Halides with Olefins. Acc. Chem. Res. 1979, 12, 146. (b) Beletskaya, I.
P.; Cheprakov, A. V. The Heck Reaction as a Sharpening Stone of
̈
Palladium Catalysis. Chem. Rev. 2000, 100, 3009. (c) Brase, S.; de
Meijere, A. Cross-Coupling of Organic Halides with Alkenes: The Heck
Reaction; Wiley-VCH Verlag GmbH & Co., KGaA, 2004; pp 217.
(d) Oestreich, M., Ed. The Mizoroki−Heck Reaction; Wiley: New York,
2009.
(10) Szlosek-Pinaud, M.; Diaz, P.; Martinez, J.; Lamaty, F. Efficient
Synthetic Approach to Heterocycles Possessing the 3,3-Disubstituted-
2,3-dihydrobenzofuran Skeleton via Diverse Palladium-Catalyzed
Tandem Reactions. Tetrahedron 2007, 63, 3340.
(11) Ju, B.; Chen, S.; Kong, W. Pd-Catalyzed Enantioselective
Double Heck Reaction. Org. Lett. 2019, 21, 9343.
(12) Koy, M.; Bellotti, P.; Katzenburg, F.; Daniliuc, C. G.; Glorius, F.
Synthesis of All-Carbon Quaternary Centers by Palladium-Catalyzed
Olefin Dicarbofunctionalization. Angew. Chem., Int. Ed. 2020, 59, 2375.
(13) (a) Fielding, M. R.; Grigg, R.; Urch, C. J. Novel Synthesis of
Oxindoles from Carbamoyl Chlorides via Palladium Catalyzed
Cyclisation−Anion Capture. Chem. Commun. 2000, 2239.
(b) Anwar, U.; Fielding, M. R.; Grigg, R.; Sridharan, V.; Urch, C. J.
Palladium Catalysed Tandem Cyclisation−Anion Capture Processes.
Part 8 [1]: In situ and Preformed Organostannanes. Carbamyl
Chlorides and Other Starter Species. J. Organomet. Chem. 2006, 691,
1476.
(14) (a) Hande, S. M.; Nakajima, M.; Kamisaki, H.; Tsukano, C.;
Takemoto, Y. Flexible Strategy for Syntheses of Spirooxindoles using
PalladiumCatalyzed Carbosilylation and Sakurai-Type Cyclization.
Org. Lett. 2011, 13, 1828. (b) Kamisaki, H.; Yasui, Y.; Takemoto, Y.
Pd-Catalyzed Intramolecular Amidation of 2-(Buta-1,3-dienyl)-
phenylcarbamoyl Chloride: A Concise Synthesis of Spiro[indoline-
3,30-pyrrolidine]. Tetrahedron Lett. 2009, 50, 2589. (c) Yasui, Y.;
Takeda, H.; Takemoto, Y. Toward General Access to the
Aspidosperma-Type Terpenoid Indole Alkaloids: Synthesis of the
Key 3,3-Disubstituted Piperidones through Enantioselective Intra-
́
(o) Rene, O.; Lapointe, D.; Fagnou, K. Domino Palladium-Catalyzed
Heck-Intermolecular Direct Arylation Reactions. Org. Lett. 2009, 11,
4560.
(20) For selected reviews and examples of remote functionalization
́
́
through alkene isomerization, see: (a) Sommer, H.; Julia-Hernandez,
F
https://dx.doi.org/10.1021/acs.orglett.0c01197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
F.; Martin, R.; Marek, I. Walking Metals for Remote Functionalization.
ACS Cent. Sci. 2018, 4, 153. (b) Vasseur, A.; Bruffaerts, J.; Marek, I.
Remote Functionalization through Alkene Isomerization. Nat. Chem.
2016, 8, 209. (c) Larionov, E.; Li, H.; Mazet, C. Well-Defined
Transition Metal Hydrides in Catalytic Isomerizations. Chem.
Commun. 2014, 50, 9816. (d) Zhang, Y.; Han, B.; Zhu, S. Rapid
Access to Highly Functionalized Alkyl Boronates by NiH-Catalyzed
Remote Hydroarylation of Boron-Containing Alkenes. Angew. Chem.,
Int. Ed. 2019, 58, 13860. (e) Zhou, F.; Zhu, J.; Zhang, Y.; Zhu, S. NiH-
Catalyzed Reductive Relay Hydroalkylation: A Strategy for the Remote
C(sp3)-H Alkylation of Alkenes. Angew. Chem., Int. Ed. 2018, 57, 4058.
(f) Bruffaerts, J.; Pierrot, D.; Marek, I. Efficient and Stereodivergent
Synthesis of Unsaturated Acyclic Fragments Bearing Contiguous
Stereogenic Elements. Nat. Chem. 2018, 10, 1164. (g) Kohler, D. G.;
Gockel, S. N.; Kennemur, J. L.; Waller, P. J.; Hull, K. L. Palladium-
Catalysed Anti-Markovnikov Selective Oxidative Amination. Nat.
Chem. 2018, 10, 333. (h) Singh, S.; Bruffaerts, J.; Vasseur, A.; Marek, I.
A unique Pd-Catalysed Heck Arylation as a Remote Trigger for
Cyclopropane Selective Ring-Opening. Nat. Commun. 2017, 8, 14200.
(i) Lin, L.; Romano, C.; Mazet, C. Palladium-Catalyzed Long-Range
Deconjugative Isomerization of Highly Substituted α,β-Unsaturated
Carbonyl Compounds. J. Am. Chem. Soc. 2016, 138, 10344. (j) Mei,
T.-S.; Patel, H. H.; Sigman, M. S. Enantioselective Construction of
Remote Quaternary Stereocentres. Nature 2014, 508, 340. (k) Werner,
E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Enantioselective Heck
Arylations of Acyclic Alkenyl Alcohols Using a Redox-Relay Strategy.
Science 2012, 338, 1455. (l) Hamasaki, T.; Aoyama, Y.; Kawasaki, J.;
Kakiuchi, F.; Kochi, T. Chain Walking as a Strategy for Carbon-
Carbon Bond Formation at Unreactive Sites in Organic Synthesis:
Catalytic Cycloisomerization of Various 1,n-Dienes. J. Am. Chem. Soc.
2015, 137, 16163. (m) Kochi, T.; Hamasaki, T.; Aoyama, Y.;
Kawasaki, J.; Kakiuchi, F. Chain-Walking Strategy for Organic
Synthesis: Catalytic Cycloisomerization of 1,n-Dienes. J. Am. Chem.
Soc. 2012, 134, 16544.
(21) Lin, B.-L.; Liu, L.; Fu, Y.; Luo, S.-W.; Chen, Q.; Guo, Q.-X.
Comparing Nickel- and Palladium-Catalyzed Heck Reactions. Organo-
metallics 2004, 23, 2114.
(22) For details of derivatization of the oxindole product, see the
Supporting Information.
G
https://dx.doi.org/10.1021/acs.orglett.0c01197
Org. Lett. XXXX, XXX, XXX−XXX