Ru(II)-Catalyzed Oxidative Olefination of Benzamides: Switchable Aza-Michael and Aza-Wacker Reaction for Synthesis of Isoindolinones

Article abstract of DOI:10.1021/acs.orglett.0c01237

Selective tandem oxidative C-H olefination-aza-Michael/aza-Wacker reaction of N-arylbenzamides is achieved by fine-tuning between base and additive to access valuable 3-oxoisoindolinyls and 3-oxoisoindolinylidenes, respectively. Careful optimization and c

Full text of DOI:10.1021/acs.orglett.0c01237

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Letter
Ru(II)-Catalyzed Oxidative Olefination of Benzamides: Switchable
Aza-Michael and Aza-Wacker Reaction for Synthesis of
Isoindolinones
Manoj Kumar,† Shalini Verma,† and Akhilesh K. Verma*
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ABSTRACT: Selective tandem oxidative C−H olefination−aza-
Michael/aza-Wacker reaction of N-arylbenzamides is achieved by
fine-tuning between base and additive to access valuable 3-
oxoisoindolinyls and 3-oxoisoindolinylidenes, respectively. Careful
optimization and control experiments provides a guiding principle
in the design of a proposed catalytic cycle. The copper−iminium
complex acting as a precursor for the binding of Ru catalyst was
isolated and confirmed by X-ray diffraction. The versatility of this
catalytic system has been demonstrated by the synthesis of
biologically relevant molecules.
soindoline represents an important structural motif owing
Ito its fascinating biological and physiological properties.
The isoindoline core has been found to serve as a key
precursor for the synthesis of valuable drug molecules and
complex natural products.1 Considering the enormous
potential of isoindolines, immense effort toward the develop-
ment of new synthetic strategies for their synthesis is not
surprising.2 In the ensuing years, auxiliary-assisted transition-
metal-catalyzed C−H olefination followed by oxidative
annulation has been executed successfully in this area.
Although extensive studies have been done on ortho-C−H
olefination of unactivated arenes to access alkenylated3 and
alkylated4 arenes, only a modest success has been achieved for
the tandem oxidative annulation of alkenylated arenes to
synthesize isoindolines. In this regard, most of the established
methods rely on use of expensive metal-based catalytic
system.5 In particular, the precious Rh catalyst gains
considerable attention due to its high catalytic activity in C−
H functionalization.6 Despite having impressive advances, the
use of expensive rhodium metal necessitates the development
of an efficient strategy utilizing relatively inexpensive, yet
sustainable, catalyst. Recently, the use of ruthenium catalyst in
C−H activation has spurred considerable interest in a plethora
of organic transformations.7 In particular, the use of Ru(II)
species for C−H olefination of unactivated arenes is currently
under development.8 In 2015, Jeganmohan et al. reported the
only Ru catalyzed synthesis of isoindolines by cyclization of N-
alkylbenzamides with allylic alcohols.9a Subsequently, Acker-
mann et al. introduced bidentate 8-aminoquinoline and tosyl
auxiliaries for Co- and Ru-catalyzed oxidative C−H alkenyla-
tion.9b,c More recently, Zhang et al. developed a multi-
component synthesis of isoindolinones by Rh(III) relay
catalysis.6e The reaction does not require the prepreparation
of amide substrate and demonstrates the use of N-pyridin-2-yl
benzamide as an effective directing group.
To date, we are unaware of any precedent on Ru-catalyzed
tandem oxidative C−H olefination/aza-Michael and aza-
Wacker reaction of N-arylbenzamides with α,β-unsaturated
esters to access isoindolinones (Scheme 1). Owing to the easy
accessibility and preparation of α,β-unsaturated esters, they
have been widely used as coupling partners for oxidative C−H
alkenylation3a−c and alkylation;4a,b however, only a limited
number of studies have appeared in literature on their use for
isoindoline synthesis.6a,b,8 Employing α,β-unsaturated esters as
coupling partners provides the synthesized motifs, leading to
their easy modification to access synthetically useful mole-
cules.10 Further, the choice of directing group is also crucial to
induce reactivity and selectivity in reaction. The small
difference in directing group can lead to change in reaction
pathway. In most of the reported Ru-catalyzed reactions, use of
directing groups is limited to N-alkylamides,8,9a while N-
aromatic amides are shown to be less favorable due to steric
interactions.8c In contrast, the present work makes effective use
of N-pyridylamides as directing group to synthesize N-
pyridylisoindolines which are documented to show potent
antitumor activity and DNA binding features.11 Inspired by the
Received: April 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01237
© XXXX American Chemical Society
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A

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Scheme 1. Synthesis of 3-Oxoisoindolinones
Scheme 3. Synthesis of Substituted 3-
a
Oxoisoindolinylidenes
a
Scheme 2. Synthesis of Substituted 3-Oxoisoindolinyls
a
Reactions were performed using 0.5 mmol of 1, 3.0 equiv of 2,
[{RuCl2(p-cymene)}2] (5.0 mol %), AgSbF6 (20 mol %), and
Cu(OAc)2·H2O (2.0 equiv) in 2 mL of DCE under N2 at 120 °C for
b
C
10 h. Isolated yield. Recovered starting material.
Scheme 4. Synthesis of Biologically Active Molecules
further screening, we found that reaction 1a with 2a in the
presence of [{RuCl2(p-cymene)}2] (5.0 mol %), AgSbF6 (20
mol %), and Cu(OAc)2·H2O (2.0 equiv) in DCE under N2
atmosphere at 120 °C for 10 h gave the product 4a exclusively
in 68% yield. As the product 3a was supposed to be formed by
tandem aza-Michael, we hypothesized that the addition of base
could enhance the formation of 3a. Pleasingly, addition of
NaOAc (2.0 equiv) instead of AgSbF6 under O2 atmosphere
delivers the product 3a in 72% yield. With promising
conditions, the scope of the reaction was evaluated for the
synthesis of 3-oxoisoindolinyls (Scheme 2). Various sub-
stituted benzamides were subjected to react with methyl
acrylate 2a under optimal reaction conditions (Table S5, entry
3). The reaction of substrates 1b−d bearing electron-releasing
substituents such as −Me, −tBu, and −OMe at the 4-position
afforded the desired products 3b−d in 58−76% yields.
It is worthwhile to note that substrate 1e bearing −Me at the
3-position provided exclusively mono-olefinated products 3e in
75% yield. Likewise, 3,4-OMe-containing substrate 1f delivered
the product 3f in comparable yield. Further, substrates 1g−j
bearing strong electron-withdrawing −NO2, −CHO, and
halogens, such as −F and −Br at the 4-position, were reacted
smoothly to afford the corresponding products 3g−j in 52−
a
Reactions were performed using 0.5 mmol of 1, 3.0 equiv of 2,
[{RuCl2(p-cymene)}2] (5.0 mol %), NaOAc (2.0 equiv), and
Cu(OAc)2.H2O (2.0 equiv) in 2 mL of DCE under O2 at 120 °C
b
C
for 6 h. Isolated yield. Recovered starting material.
elegant contribution of momentous isoindolines in pharma-
ceuticals and our continuous efforts12 in developing efficient
methodologies for the synthesis of diversified heterocycles, we
herein report the selective synthesis of valuable 3-oxoisoindo-
linyls and 3-oxoisoindolinylidenes by tandem oxidative C−H
olefination/aza-Michael and aza-Wacker reaction of amides
(Scheme 1). A plausible reaction cycle is provided, strongly
supported by performed series of control experiments and
characterization of reaction intermediates by mass spectrom-
etry and X-ray diffraction.
During our investigation (for detailed information, see the
Supporting Information) using N-(4-methylpyridin-2-yl)-
benzamide 1a with methyl acrylate 2a as model substrate, we
initially observed formation of two products, 3a and 4a. On
B
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Scheme 5. Control Experiments
66% yields. The reaction is marginally affected by the presence
of halogens such as −Br and −Cl at the 3-position of substrate
1k and 1l, providing the products 3k and 3l in 60% and 62%
yields, respectively. Substrate 1m having −Me at the 2-position
also participated in the reaction and provided the desired
product 3m in 18% yield only. The reason might be the steric
hindrance created by the methyl group, as the less sterically
hindered substrate 1n having −F at the 2-position affords the
product 3n in 40% yield. Notably, the tolerance of nitro,
aldehyde, and halogen substituents facilitates the additional
modification of the products. Additionally, heteroaromatic
substrate 1o participates well in the reaction to give the desired
product 3o in 87% yield. Probenecid, medicinally relevant
molecule derived benzamide 1p, successfully provided the
desired product 3p, albeit in moderate yield. Next, the scope of
acrylates as a coupling partner was examined. The reaction of
68−74% yields. This method is not limited to the use of simple
acrylates; natural product containing acrylates 2h−l were also
found to be viable, as demonstrated by the successful synthesis
of corresponding compounds 3w−aa in good yields. This also
shows that steric bulk at the ester group can be tolerated in
these reactions. According to the optimal reaction conditions
(Table S4, entry 2), switching the catalytic conditions to the
Ru/AgSbF6 system led to the formation of 3-oxoisoindoliny-
lidenes via aza-Wacker cyclization. Intrigued by the result, we
proceeded to examine the scope of the reaction using
differently substituted benzamides (Scheme 3). Electron-rich
substrate 1c containing −tBu at the 4-position gave the
products 4b in 70% yield. Electron-deficient substrates bearing
a free −CHO group (1h) and −F (1i) at the 4-position were
also compatible providing the desired product 4c and 4d in
60% and 66% yields, respectively. 3,4-OMe substituted
substrate 1f furnished the product 4e selectively in 61%
yield. Importantly, substrates 1e, 1q, and 1k containing −Me,
−NO2, and −Br at the 3-position were compatible, providing
the corresponding products 4f−h in 58−78% yields. The
t
substrate 1b with butyl acrylate 2b and acrylonitrile 2c
delivers the products 3q and 3r in 57% and 87% yields,
n
respectively. Likewise, ethyl, butyl, cyclohexyl, and benzyl
acrylates 2d−g with substrate 1a gave the compounds 3s−v in
C
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Scheme 6. Plausible Mechanistic Pathway
substrate 1n substituted with −F at the 2-position also reacted
well to give the desired product 4i, albeit in slightly lower yield.
Moreover, substrate 1o bearing a thiophene core also
underwent the reaction to give the product 4j in 77% yield.
Next, to test the viability of acrylate as coupling partner,
substrate 1a was reacted with benzyl acrylate 2g and the
reaction proceeded smoothly to give the desired product 4k in
synthetically useful yield. Interestingly, menthol and fenchol
derived acrylate 2i and 2k were also found to be compatible,
providing the desired product 4l and 4m in 67% and 44%
yields, respectively.
To probe the applicability of the protocol, the reaction of 1a
was conducted on a gram scale, providing 70% yield (900 mg)
of the desired product 3a (Scheme 2). Further, the antisedative
molecule 5a11b and GABA receptor 5b11a were synthesized
efficiently under the standard protocol, which compares
favorably with the previously reported protocols (Scheme 4).
In order to realize a plausible mechanistic pathway, some
aspects of the reaction mechanism were investigated. Initially,
the intermediate I2 was isolated and further treated with 1.0
equiv of RuCl2(p-cymene) to yield 3a (Scheme 5a). The
reaction of 1m gives only 18% yield of 3m (Scheme 5b) while
that of 1s gave the product 6 in 38% yield (Scheme 5c),
thereby providing the evidence for the formation of 1m-I2.
This is further supported by the 40% yield of 3n in the case of
less sterically hindered fluoro-containing substrate 1n (Scheme
2).
bond activation (Scheme 5e).13 Addition of 10.0 equiv of D2O
to the reaction of 1a with 2a yields the product 3a-D3 (Scheme
5f). Incorporation of D at the α- and β-positions of the
carbonyl group of 3a-D3 strongly supports the formation of 3a
via alkenylation followed by aza-Michael reaction.14 The
reaction of 7 with 2a did not afford the desired product
(Scheme 5g); however, reaction of 8 successfully affords the
desired product (Scheme 5h), which clearly indicates that the
reaction proceeds via ortho-C−H alkenylation instead of N−H
alkenylation. Moreover, reaction of 8 with NaOAc successfully
yields 3a in comparable yield in the presence as well as in the
absence of O2 (Scheme 5h). The comparable yield of 3a in all
conditions (Scheme 5h) concludes that Ru and O2 are
required only up to the formation of alkenylated species 8 and
further proceed by aza-Michael reaction. In order to conclude
the role of O2, 3.0 equiv of TEMPO was added to reaction
mixture (Scheme 5i). Under these conditions, 3a was obtained
in 14% yield along with 26% yield of 4a, which indicates the
involvement of O2 in the reaction via a free-radical pathway for
formation of 3a. The decrease in yield of 3a and studies on
aerobic oxidation of Ru transfer hydrogenation catalysts
provides the evidence of Ru−hydroperoxo intermediacy.15
Subsequently, reactions were performed using reaction
condition B to analyze the catalytic cycle for the formation
of product 4a. The intermolecular competition between 1c and
1i delivered 50% yield of 4b and 54% yield of 4d (Scheme 5j).
The reaction of 1a in the presence of 10.0 equiv of D2O led to
90% incorporation of D in 1a to give 96% of 1a-D2 (Scheme
5k), which confirms the reversibility of the C−H bond
activation step.13 The reaction of 7 did not lead to the
formation of product 4a (Scheme 5l), though the reaction of 8
successfully provides the product 4a in 74% yield (Scheme
5m) suggesting the intermediacy of 8 instead of 7.
Furthermore, reaction of 8 with AgSbF6 does not favor the
After this, reactions were conducted under reaction
conditions A to provide the catalytic cycle for the formation
of product 3a. The competition experiment between 1c and 1i
furnished the corresponding products 3c and 3i in 42% and
30% yields, respectively (Scheme 5d). Further, reaction of 1a
was conducted in the presence of 10.0 equiv of D2O, and no
incorporation of D in 1a suggests the irreversibility of C−H
D
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formation of 4a (Scheme 5m). After ortho-C−H alkenylation,
Ru thus appears to involve in the catalytic cycle. Also,
treatment of 3a under the optimized reaction conditions failed
to produce 4a (Scheme 5n), therefore ruling out the possibility
of intermediacy of 3a and suggesting an aza-Wacker pathway.
On the basis of the results of control experiments and the
literature precedents,16 a plausible catalytic cycle is proposed in
Scheme 6. At first, the coordination of 1a with Cu(OAc)2
resulted in the formation of square planar iminium complex I2
via intermediate I1′. Meanwhile, the 18e− complex of Ru was
dissociated to species (I) (under reaction conditions A) or
species (II) (under reaction conditions B)16a,c which gets
ligated to the lone pair of iminium nitrogen of I2 to give key
intermediate I3. Intermediate I3 gets dissociated to I4 in which
nitrogen atom of amide gets strongly coordinated to Ru with
the release of AcOH. The alkene 2a then coordinates to Ru in
I4 to afford I5, followed by its insertion between Ru−C bond to
give intermediate I6. β-Hydride elimination of intermediate I6
affords Ru ligated alkenylated benzamide I7. It is very
interesting to note that intermediate I7 reacts differently
under oxygen and nitrogen atmosphere to yield two different
products, 3a and 4a. In the case of oxygen atmosphere, O2 gets
inserted into Ru−H bond in I7 via single-electron transfer to
provid Ru-hydroperoxo [Ru-OOH] intermediate I8.15 Follow-
ing protonolysis, I8 gives the ortho-alkenylated product I9,
H2O2h and Ru species. The corresponding Ru species was
further oxidized to Ru(II) active species I in the presence of
Cu(OAc)2 to again take part in the catalytic cycle and the
alkenylated product I9 undergoes aza-Michael in the presence
of NaOAc to give the desired product 3a. In contrast, under N2
atmosphere, intermediate I7 affords the alkenylated product I9
in the presence of Cu(OAc)2 and regenerates the Ru species
(II).16c Subsequently, the amide group of I9 then coordinates
Ru species (II) to give intermediate I10.16a Intramolecular
coordinative insertion in I10 resulted into the formation of
intermediate I11. The intermediate I11 further undergoes β-
Hydride elimination in the presence of Cu(OAc)2 to provide
the expected product 4a and regenerate the Ru active species
(II).16a
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Akhilesh K. Verma − Department of Chemistry, University of
Delhi, Delhi 110007, India; orcid.org/0000-0001-7626-
5003; Email: averma@acbr.du.ac.in
Authors
Manoj Kumar − Department of Chemistry, University of Delhi,
Delhi 110007, India
Shalini Verma − Department of Chemistry, University of Delhi,
Delhi 110007, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01237
Author Contributions
†M.K. and S.V. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research work was supported by SERB (EEQ/2018/
000317) (M.K.) and (S.V.) are thankful to CSIR for
fellowships.
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01237.
̀
Ziccarelli, I.; Armentano, D.; Marino, N.; Giofre, S. V.; Gabriele, B.;
1
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Accession Codes
CCDC 1953284−1953285 and 1978941 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
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(10) See Scheme 4.
́
́
́
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