Palladium-catalyzed dehydrogenative C-H cyclization for isoindolinone synthesis

Article abstract of DOI:10.1039/d1ra04661f

In this paper Pd-catalyzed intramolecular dehydrogenative C(sp³)-H amidation for the synthesis of isoindolinones is described. This method features the use of a Pd/C catalyst and the addition of a stoichiometric amount of oxidant is not necessary. A mechanistic study suggested the possible formation of H₂gas during the reaction.

Full text of DOI:10.1039/d1ra04661f

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Palladium-catalyzed dehydrogenative C–H
cyclization for isoindolinone synthesis†
Cite this: RSC Adv., 2021, 11, 26988
*
*
Kaho Ueta, Saki Tanaka, Tetsutaro Kimachi and Kiyofumi Inamoto
Masahiro Abe,
In this paper Pd-catalyzed intramolecular dehydrogenative C(sp3)–H amidation for the synthesis of
isoindolinones is described. This method features the use of a Pd/C catalyst and the addition of
a stoichiometric amount of oxidant is not necessary. A mechanistic study suggested the possible
formation of H2 gas during the reaction.
Received 16th June 2021
Accepted 29th July 2021
DOI: 10.1039/d1ra04661f
rsc.li/rsc-advances
The isoindolinone scaffold occurs frequently in numerous oxidant should be crucial for the successful construction of the
biologically active compounds ranging from designed medic- isoindolinone ring.
inal agents to natural products, thus constituting an extremely
Herein, we describe a catalytic system that enables cycliza-
important class of heterocycles.1,2 Although a number of tion of 2-benzyl-N-mesylbenzamides leading to isoindolinone
synthetic methods exist for the preparation of isoindolinones,3 derivatives, in which benzylic C(sp3)–H functionalization in the
the development of more general, versatile, and efficient presence of a palladium catalyst smoothly occurs. It is partic-
procedures to construct the isoindolinone framework is still an ularly noteworthy to mention that any stoichiometric oxidants
ongoing, intensive research area.
are not necessary for our isoindolinone synthesis. The key to
Among a variety of synthetic strategies for isoindolinones, success is the use of Pd/C as a catalyst. In this dehydrogenative
methods that make use of transition metal-catalyzed C–H process, an only detectable by-product was H2, which should
functionalization represent a remarkable approach.4 In this also be an appealing feature of the process.
research area, catalytic oxidative annulation of N-substituted
Based on our fruitful results of the heterocycles synthesis via
benzamides and appropriate coupling partners (e.g. alkenes, transition metal-catalyzed C–H cyclization,5 our investigation
alkynes, isocyanides, diazo compounds) has been extensively began by examining the conversion of N-tosyl-protected ben-
studied, most of which employ transition metals such as rho- zamide 1a to the corresponding isoindolinone 2a. During the
dium,4d,g,h,n,o ruthenium,4l cobalt,4a,i,j,k and palladium.4b,m These screening studies utilizing a range of transition metal catalysts
precedents oen require the use of stoichiometric oxidants or as well as various oxidants, it was found that 2a did produce
prefunctionalized coupling partners to make the process even in the absence of an oxidant when Pd/C was used as
catalytic.
On the other hand, an approach that involves intramolecular
a catalyst. Indeed, the use of 10 mol% of Pd/C along with
C–H cyclization of benzamide derivatives exploiting a transition
metal catalyst could provide another efficient, facile, and direct
access to isoindolinones, although less attention has been paid
to such a process (Scheme 1). Kondo et al. previously reported
C(sp3)–H aminative cyclization of 2-methyl-N-arylbenzamides in
the presence of a copper catalyst along with a stoichiometric
amount of di-tert-butyl peroxide as an oxidant, which resulted in
the formation of 3-unsubstituted isoindolinones (Scheme 1a).4c
Bedford's group also developed a copper-based catalytic system
composed of 20 mol% of Cu(OTf)2 and 2 equiv. of PhI(OAc)2
that successfully effected the intramolecular benzylic C–H sul-
famidation of 2-benzyl-N-tosylbenzamides for the synthesis of
isoindolinones (Scheme 1b).4f In both cases, the choice of an
School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University,
11-68, 9-Bancho, Koshien, Nishinomiya, Hyogo 663-8179, Japan. E-mail: abe_111@
mukogawa-u.ac.jp; inamoto@mukogawa-u.ac.jp
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral/analytical data. See DOI: 10.1039/d1ra04661f
Scheme 1 C–H cyclization strategies for isoindolinone synthesis.
26988 | RSC Adv., 2021, 11, 26988–26991
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Table 2 Optimization of reaction parametersa
20 mol% of KOAc enabled the desired cyclization process,
providing 2a in 42% yield (Table 1). Intrigued by this unex-
pected oxidant-free process, the effect of the protecting group
on the nitrogen atom of an amide moiety was briey evaluated.
We are pleased to nd that the reaction of 1f possessing a mesyl
group (–Ms) efficiently occurred and the isoindolinone 2f was
obtained in fairly good yield (75%).6
Settled in –Ms for the protecting group, further examination
of the reaction parameters was performed employing 1f (Table
2). Use of Na2HPO4 gave a slightly better result (entry 2), while
reactions with other bases led to lower yields (entry 3). Among
a variety of solvents tested, p-xylene was found to be the best
(entry 4). Varying the concentration of the reaction did not
enhance the process (entry 5). Performing the reaction under an
oxygen atmosphere dreadfully diminished the yield (entry 6). In
contrast, use of the degassed conditions by means of Ar
bubbling afforded the desired 2f with excellent yield (entry 7). In
addition, it was found that the yield decreased when the reac-
tion was carried out in the absence of a base (entry 8).7,8
Our new method for isoindolinone synthesis can be applied
to cyclization of a wide range of substrates (Table 3). Substitu-
ents such as an electron donating methyl or methoxy group as
well as an electron withdrawing halogen atom on the benzene
ring are well tolerated under the reaction conditions, and the
corresponding products 2j–l are successfully obtained. It is also
noteworthy that heterocycles such as thiophene and indoles are
compatible during the process (2n–q). Remarkably, benzamides
1o–q possessing an indole nucleus that can be easily oxidable
were suitable under our oxidant-free conditions.9 An attempt to
obtain 3-alkylisoindolinone 2r unfortunately failed. On the
other hand, the reaction of 1f can be easily scaled up: in this
case, 2f was obtained in 92% yield.10
Entry Variation from “standard conditions"
Yieldb,c (%)
1
None
(75)
86 (80)
2
Na2HPO4 instead of KOAc
3
NaOAc, LiOAc, K2CO3 or Cs2CO3 instead of KOAc 61–70
4
5
DMA, DMI or DMSO instead of p-xylene
0.25 M instead of 0.05 M
O2 atmosphere instead of Ar atmosphere
Degassed (bubbling with Ar)
0–28
67
4
92 (86)
72
6d
7d
8d
In the absence of KOAc
a
Reactions were run on a 0.25 mmol scale. b Yields were determined by
1H NMR using an internal standard. Isolated yields in parentheses.
c
d
Na2HPO4 was used instead of KOAc.
3 in high yield. Reduction of the carbonyl group of 2f using
LiAlH4 also successfully preceded, giving rise to isoindoline 4 in
excellent yield (97%).
Table 3 Substrate scopea,b
To further demonstrate the synthetic utility of the method
we have developed, several transformations of isoindolinone 2f
obtained were carried out (Scheme 2). Deprotection of a mesyl
group with AIBN and Bu3SnH afforded the N-free isoindolinone
Table 1 Effect of protecting groupa,b
a
b
a
b
c
Reactions were run on a 0.25 mmol scale. Isolated yields (yield
Reactions were run on a 0.25 mmol scale. Isolated yields. 1 mmol
scale.
determined by 1H NMR using an internal standard in parentheses).
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a biologically important isoindolinone nucleus. Further studies
to broaden the substrate scope of the process as well as to
improve the catalytic efficiency are vigorously underway in our
laboratory.
Conflicts of interest
The authors declare no competing nancial interest.
Scheme 2 Further transformation of isoindolinone 2f.
Acknowledgements
We gratefully acknowledge nancial support by JSPS KAKENHI
Grant Number JP19K06984.
Notes and references
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Scheme 3 Mechanistic studies.
To gain insight into the reaction mechanism of the process,
C–H cyclization of 1f in the presence of 0.5 equiv. of methyl
cinnamate (5) was performed under the optimized conditions
(Scheme 3). In addition to isoindolinone 2f, methyl 3-phenyl-
propanoate (6) was observed in 32% NMR yield, implying that
the formation of H2 gas is possibly occurring during the
reaction.11
On the basis of the nding above, a tentative reaction
pathway shown in Scheme 4 is proposed. The reaction is likely
initiated by the coordination of the nitrogen atom of an amide
moiety to give complex A. Subsequently, the insertion of Pd(0)
into the benzylic C(sp3)–H bond leading to the formation of six-
membered palladacycle B accompanied with the evolution of H2
gas and the following reductive elimination process affords the
desired isoindolinone 2.
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In summary, we have developed intramolecular Pd-catalyzed
dehydrogenative C(sp3)–H amidation for isoindolinone
synthesis. The addition of oxidants is not necessary and the Pd/
C catalyst along with a catalytic amount (20 mol%) of base is the
only reagents required for this C–H cyclization. The method
developed provides a simple, facile, and efficient access to
Scheme 4 Plausible reaction mechanism.
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7 Use of 10 mol% Cu(OAc)2 instead of 10 mol% Pd/C for the
cyclization of 1f did not afford the isoindolinone product
2f at all.
6 Liu
previously
reported
similar
catalytic
C–H
functionalization/dehydrogenative
adding any oxidants for heterocycles synthesis, see: (a)
D. Yang, Y. Zhu, N. Yang, Q. Jiang and R. Liu, Adv. Synth.
cyclization
without
8 For detailed results of the screening studies, see the ESI.†.
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Commun., 2019, 10, 4754–4764.
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X. Qi, C. Zhang, X. Ji, J. Li and R. Liu, Org. Chem. Front.,
without a signicant loss of reactivity. For details, see the
ESI.†.
11 For detailed results of the mechanistic studies, see the ESI.†.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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