A Synthesis of Spirooxindole-Isoindolinones Through Ugi Reaction Followed by Copper-Catalyzed Tandem C?N/C?C Coupling Process

Article abstract of DOI:10.1002/adsc.202100889

A synthesis of spiroindolinone-isoindolinone skeletons is presented. The protocol is through a Ugi four-component reaction followed by highly efficient and mild copper-catalyzed intramolecular tandem C?N/C?C coupling process. Control experiments demonstra

Full text of DOI:10.1002/adsc.202100889

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100889
Very Important Publication
A Synthesis of Spirooxindole-Isoindolinones Through Ugi
Reaction Followed by Copper-Catalyzed Tandem CÀ N/CÀ C
Coupling Process
Xianqiang Zhong,a Jianghao Luo,a Wei Zhou,a,* and Qian Caia,*
a
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of
Chinese Ministry of Education, College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632,
People’s Republic of China
E-mail: weizhou88@jnu.edu.cn; caiqian@jnu.edu.cn
Manuscript received: July 16, 2021; Revised manuscript received: August 23, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100889
Abstract: A synthesis of spiroindolinone-isoindolinone skeletons is presented. The protocol is through a Ugi
four-component reaction followed by highly efficient and mild copper-catalyzed intramolecular tandem CÀ N/
CÀ C coupling process. Control experiments demonstrated that the formation of CÀ C bond is a copper
catalyzed coupling process rather than base promoted nucleophilic aromatic substitution pathway which
proposed in Prof. Van der Eycken’s palladium catalyst system previously.
Keywords: Spirooxindole-isoindolinones; Copper catalyzed; Post-Ugi Reaction; CÀ N Coupling; CÀ C Coupling
Introduction
rearrangement,[3] Heck reaction,[4] intramolecular Man-
nich reaction,[5] ring expansion,[6] and 1,3-dipolar
Spirooxindole structures have been extensively found cycloaddition.[7] Despite these great progresses, search-
as key skeletons in many natural products and pharm- ing and establishing improved route from commercial
aceuticals, and exhibited a wide range of bioactivities, available starting materials are still highly desirable.
including antitumor, antivirus, and antiinflammation
Over the past few decades, multicomponent reac-
(Figure 1).[1] Due to their importance, many elegant tions (MCRs) have extensively been employed as
methodologies have been developed for the synthesis highly efficient synthetic strategies for the access of
of spirooxindole structures,[2] such as oxidative multifunctional molecular architectures under mild
reaction conditions. Among these multicomponent
transformations,[8] isocyanides involved Ugi four-com-
ponent reactions (Ugi-4CR)[9] and the post functionali-
zation of Ugi adducts[10,11] have been widely employed
as highly efficient synthetic strategies for the access of
multifunctional molecular architectures under mild
reaction conditions. In 2014, Van der Eycken and co-
workers furnished the first palladium catalyzed post-
Ugi cascade cyclizations for the construction of
spiroindolinone-isoindolinones (Scheme 1a).[12] How-
ever, high reaction temperature was required since the
CÀ C bond formation step is a base promoted nucleo-
philic aromatic substitution process rather than palla-
dium catalyzed CÀ C coupling.
During our continuous efforts in the development
of copper catalyzed coupling and tandem reactions,[13]
Figure 1. Bioactive compounds containing spirooxindole-fused
heterocycles.
we became intrigued by the possibility of synthesis of
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Table 1. Optimization of Reaction Conditions.[a]
Entry
X
L
Base
Solvent
Yield[b](%)
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuONa
NaH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMSO
Dioxane
Toluene
THF
DMSO
DMSO
DMSO
DMSO
DMSO
32
40
28
17
46
42
78
37
26
30
51
41
38
65
34
Scheme 1. Post-Ugi cascade cyclization towards spiroindoli-
none-isoindolinone framework.
spirooxindole-isoindolinones through Ugi reaction fol-
lowed by copper-catalyzed tandem CÀ N/CÀ C coupling
process. We envisaged that the copper catalyst system
might be different from palladium and participate in
both CÀ N and CÀ C bond formation steps, accordingly
higher reaction temperature could be prevented (Sche-
me 1b). Herein, we wish to report a mild copper-
catalyzed post-Ugi cascade cyclizations towards spi-
roindolinone-isoindolinone frameworks.
9
10
11
12
13
14
15
NaOH
Cs2CO3
K2CO3
[a] 1a (0.2 mmol, 1.0 equiv.), 2a (0.2 mmol, 1.0 equiv.), 3a
(0.24 mmol, 1.2 equiv.), 4a (0.2 mmol, 1.0 equiv.), CuI
(0.02 mmol, 10 mol%), ligand (0.04 mmol, 20 mol%), base
(0.6 mmol, 3.0 equiv.), solvent (2 mL), 4 h.
Results and Discussion
Initially, 2-iodobenzaldehyde 1a, 2-iodobenzoic acid
2a, methylamine 3a and tert-butyl isocyanide 4a were
chosen as model substrates to explore the reaction
condition. The 4-components reaction went smoothly
[b] Isolated yield.
in MeOH at room temperature. Our efforts were were also tested and worked well in the reactions and
focused on the challenging copper-catalyzed tandem afforded the corresponding products in good yields
CÀ N/CÀ C coupling process. As shown in table 1, (5v–5x).
Ligands screening revealed that 1,10-phnanthroline
As similar as Prof. Van der Eycken’s palladium
(L5) showed better result (Table 1, entry 5) by compar- catalyst,[12] the attempt to expand isoindolinone to
ing with other ligands (L1–L4, Table 1, entries 1–4) to isoquinolinone ring by using 2-iodophenylacetic acid
promote the cascade reaction in MeCN at room as substrate was unsuccessful and no product was
temperature. (Table 1, entry 5). To our delight, better observed under standard conditions (Scheme 3).
outcome was obtained by using DMSO as solvent and
Further substrate scope exploration demonstrated
the desired product 5a was delivered in 78% yield that the present catalyst system is also suitable for 2-
(Table 1, entry 7). Other bases, such as tBuONa, NaH, bromobenzaldehydes and 2-bromobenzoic acids
°
NaOH, Cs2CO3, K2CO3 were further screened and all (Scheme 4). Under higher reaction temperature (50 C),
delivered inferior results (Table 1, entries 11–15).
the copper-catalyzed tandem CÀ N/CÀ C coupling-g
Under the optimal reaction conditions (Table 1, process went smoothly and the desired products were
entry 7), the substrate scope were further investigated afforded in good yield.
and the results were shown in Scheme 2. Different
Asymmetric reactions were also tried by using a
substituents on the phenyl ring of 2-iodobenzic acid or chiral oxazoline ligand (L6) and the preliminary results
2-iodobenzaldehydes were well tolerated and the revealed that the chiral spiroindolinone-isoindolinones
desired products 5b–5t were delivered in good yields. could be produced in 20–37% yields with good
For a reaction with ortho-substiuted 3-methyl-2- enantioselectivities (Scheme 5).
iodobenzaldehyde(1u), higher reaction temperature
To demonstrate the potential synthetic utility of the
°
(70 C) was required and the desired product 5u was current protocol, a gram-scale reaction was conducted
obtained in moderate yield. Other amines or isocyides (Scheme 6). Under the standard reaction system, the
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Scheme 4. Copper-catalyzed post-Ugi cascade cyclizations of
2-bromobenzaldehydes and 2-bromobenzoic acids.
Scheme 5. Copper-catalyzed asymmetric post-Ugi cascade cyc-
lization.
Scheme 2. Substrate scope. Reaction conditions: 1 (0.2 mmol),
2
(0.2 mmol), 3 (0.24 mmol, 1.2 equiv.), 4 (0.2 mmol,
1.0 equiv.) in MeOH (5 mL) for 12 h; CuI (0.02 mmol,
10 mol%), 1,10-phenanthroline (0.04 mmol, 20 mol%), tBuOLi
a
(0.6 mmol, 3.0 equiv.), DMSO (2 mL), 4 h, isolated yield. The
°
reaction temperature is 70 C.
Scheme 6. Gram-scale reaction and synthetic transformations of
5y.
Scheme 3. Copper-catalyzed post-Ugi cascade cyclizations of
2-iodobenzaldehyde and 2-iodophenylacetic acid.
7 through Suzuki coupling and acid promoted selec-
tive CÀ N cleavage reactions respectively (Scheme 6).
To improve our understanding of this mild copper-
product 5y was achieved in 84% yield (2.1 g).
Furthermore, 5y could be easily transformed to 6 and catalyzed tandem CÀ N/CÀ C coupling process, N-(1-
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benzyl-2-oxoindolin-3-yl)-2-iodobenzamide 8 was pre- process to afford Cu(III) intermediate E rapidly.
pared and evaluated in our catalytic system Finally, spirooxindole-isoindolinones F and copper
(Scheme 7). Under standard condition, the cyclization catalyst were released from E via reductive elimina-
reaction went smoothly and the desired 5z were tion. Noteworthy, the possibility for the reverse
afforded in 71% yield. However, no product 5z was catalytic pathway, which begins with CÀ C coupling
observed in the absence of CuI catalyst. These results followed by CÀ N coupling process could not be
clearly indicated that the formation of CÀ C bond is eliminated.
through a copper catalyzed coupling process rather
than the SNAr pathway as proposed in Van der
Conclusion
Eycken’s work.[12] On the basis of previous copper
catalysed coupling reaction investigations[14] and our In summary, a highly efficient Ugi4-CR/CÀ N/CÀ C
control experiments, a plausible mechanism for this coupling process was developed for the formation of
tandem CÀ N/CÀ C coupling process is proposed in spirooxindole-isoindolinones. Asymmetric reactions
Scheme 8. The oxidative addition of copper catalyst to were also achieved with chiral oxazoline ligand and
A which was generated from deprotonation of Ugi afforded the desired chiral products in good enantiose-
adducts results in intermediate B. Cu(III) complex B lectivities, albeit in unsatisfactory yields. Further
undergo reductive elimination to deliver copper cata- studies and applications of post functionalization of
lyst and monocyclic compounds C which then partic- Ugi adducts for the synthesis of other heterocycles are
ipates second deprotonation and oxidative addition currently underway in our laboratory.
Experimental Section
General Procedure for the synthesis of spiroindolinone–isoindo-
linone: the mixture of 2-iodobenzaldehyde 1a (0.2 mmol), 2-
iodobenzoic acid 2a (0.2 mmol), methylamine 3a (0.24 mmol)
and tert-butyl isocyanide 4a (0.2 mmol) were stirred in MeOH
°
(5 mL) at 25 C for 12 hours. Afterwards, MeOH was removed
under reduced pressure and CuI (0.02 mmol, 10%), 1,10-
phenanthroline (0.04 mmol, 20%), tBuOLi (0.6 mmol,
3.0 equiv.) and DMSO (2 mL) were added under Ar. The above
mixture was stirred for another 4 hours at room temperature.
Upon completion, 25 mL EtOAc were added and the organic
phase was washed with brine, dried over Na2SO4. The solvent
was removed under reduced pressure. The crude product was
purified by flash column chromatography (ethyl acetate/petro-
leum ether=1/3) to afford product 5a as a white solid.
Scheme 7. Control experiments.
Acknowledgements
The authors are grateful to National Natural Science Foun-
dation of China (22001093, 21772066 and 21971087), Key-
Area Research and Development Program of Guangdong
Province (2020B010188001) and Guangdong Special Support
Program (2017TX04R059) for their financial support.
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Adv. Synth. Catal. 2021, 363, 1–6
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© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
A Synthesis of Spirooxindole-Isoindolinones Through Ugi
Reaction Followed by Copper-Catalyzed Tandem CÀ N/CÀ C
Coupling Process
Adv. Synth. Catal. 2021, 363, 1–6
X. Zhong, J. Luo, W. Zhou*, Q. Cai*