Arylation of N-Methyl-2-oxindole with Arylboronic Acids in Water Catalyzed by Palladium(II) Pincer Complexes with a Low Catalyst Loading

Article abstract of DOI:10.1002/cctc.201601411

Two new Pd^II ONO pincer complexes were utilized efficiently as homogeneous catalysts for the site-selective C3-arylation of N-methyl-2-oxindole with arylboronic acids at room temperature in aqueous media to yield a series of 3-aryl-N-methyl-2-oxindoles. This catalytic reaction progressed well with a low catalyst loading (0.01 mol %) under open-flask conditions. Notably, a column-chromatography-free method for the quantitative preparation of C3-arylated N-methyl-2-oxindoles is reported. The catalyst showed good compatibility with wide range of substrates with recyclability in up to five consecutive runs without an appreciable loss of yield.

Full text of DOI:10.1002/cctc.201601411

Accepted Article
Title: Arylation of N-methyl-2-oxindole with arylboronic acids in water
catalyzed by Pd(II) pincer complexes with low catalyst loading
Authors: Vignesh Arumugam, Werner Kaminsky, and Dharmaraj
Nallasamy
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Arylation of N-methyl-2-oxindole with arylboronic acids in water
catalyzed by Pd(II) pincer complexes with low catalyst loading
Arumugam Vignesh,[a] Werner Kaminsky[b] and Nallasamy Dharmaraj*[a]
Abstract: A couple of new Pd(II) ONO pincer complexes were
efficiently utilized as homogeneous catalysts for the site-selective
C3-arylation of N-methyl-2-oxindole with arylboronic acids at room-
temperature to yield a series of 3-aryl-N-methyl-2-oxindoles in
aqueous media. This catalytic reaction progressed well with low
catalyst loading (0.01 mol %) under open-flask conditions. Of note, a
column chromatography free methodology for C3-aryalated N-
methyl-2-oxindoles in quantitative yield is reported. The catalyst
showed good compatibility with wide range of substrates with
recyclability up to five consecutive runs without appreciable loss of
yield.
arylation of oxindole using palladium as catalyst in combination with
electron rich phosphine ligand. Later, S. L. Buchwald et al.,
published a chemo-selective C-3 arylation of oxindole catalyzed by
Pd-dialkylbiarylphosphine-based catalyst system.[13a] Highly enantio-
selective, Pd-catalyzed intermolecular coupling of oxindoles with aryl
and vinyl bromides facilitated by a biaryl monophosphine ligand was
documented by S. L. Buchwald et al. [13b] Further, the same research
group has proclaimed palladium-catalyzed α-arylation/alkylation of
[13c]
oxindole by continuous-flow synthesis method.
Besides, aryl
halides were the most commonly utilized coupling partners for direct
α-arylation of oxindoles promoted by transition-metal catalysts.[9,13]
However, these strategies required the use of high catalyst
loadings, elevated temperature, long reaction times and inert
atmosphere. Specifically, use of arylboronic acids as coupling
Search for novel and efficient synthetic methodologies
towards rapid functionalization of indoles has triggered great deal of
interest among synthetic organic and medicinal chemists.[1] Indoles
are the target molecules for several research activities owing to their
presence in a number of active pharmaceutical ingredients[2] and
also in material science.[3] C−C Bond formation via carbon−hydrogen
(C−H) bond activation receives top priority to construct new
molecular architects.[4] A regio-selective, direct C−H functionalization
methodology for arylation of indole scaffolds is favored over the
conventional coupling reaction (e.g., Suzuki coupling).[5] This C−H
bond activation protocol avoids the pre-functionalization of indole
derivatives and thus offers a proficient synthetic route to construct
arylated indoles.[6] Palladium-catalyzed α-arylation to create a new
C−C bond at the α-position of a carbonyl group is an important
methodology for the synthesis of several natural products and
biologically active organic compounds.[7] Pd-Catalyzed α-arylation of
carbonyl and related compounds was achieved with an array of
nucleophiles such as ketones,[8a] aldehydes,[8b] esters,[8c]
malonates,[8d] nitriles,[8e] silyl enol ethers[8f] and amides.[8g] However,
owing to the high pKa of the amide enolates, arylation of such
substrates is more challenging and hence required the use of a
strong base.[9]
[9,13]
partners with N-methyl-2-oxindole remains unexplored so far.
Owing to the inherent merits of boronic acids such as less toxicity,
stability to ambient conditions including humidity and the facile
removal of boron containing side products, aromatic boranes are
widely utilized in such coupling reactions. [14] Based on these facts,
we decided to carry out arylation of N-methyl-2-oxindole with
arylboronic acids as the coupling partner.
Generally, C-arylated indoles demonstrate great potential
in pharmaceuticals;[10] especially anticancer drugs.[10c,d] Among them,
C-3 arylated indoles were tested and proved as for the treatment of
uterine fibroids.[11] In spite of the numerous synthetic protocols
known for C-3 arylation of indoles,[12] only few of them dealt with that
of N-methyl-2-oxindoles.[9,13] Michael C. Wills group reported[9] the α-
Scheme 1. Reported and present protocol for the C-3 arylation of N-
methyl-2-oxindole.
[a]
Inorganic & Nanomaterials Research Laboratory,
Department of Chemistry, Bharathiar University, Coimbatore 641
046, India. E-mail: dharmaraj@buc.edu.in; Home page:
http://ndharmaraj.wixsite.com/inrl Fax: +91 4222422387; Tel: +91
4222428316
In our quest towards designing new palladium complexes
as homogeneous catalysts for cross coupling reactions, [15] herein we
present the synthesis and structural characterization of two new
palladium(II) complexes incorporating an ONO pincer type ligand for
the C3-arylation of N-methyl-2-oxindole with arylboronic acids. The
highlight of the present methodology merits attention as it doesn’t
require high catalyst loading, elevated temperatures, external
oxidants, additives, phase transfer reagents and stringent reaction
[b] Department of Chemistry, University of Washington, Seattle,
Washington 98195, USA
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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conditions. To the best of our insight, this is the first report on the
utility of pincer type palladium(II) complexes 1 and 2 as catalysts for
the arylation of N-methyl-2-oxindole.
Complexes 1 and 2 were obtained by the reaction of
[PdCl2(PPh3)2] with substituted aroyl hydrazones (H2L1–H2L2) via
metal introduction route as outlined in Scheme 2 (vide infra). The
ONO donor atoms present in the chosen hydrazones are suitable to
form pincer type palladium complexes.
Figure 1. ORTEP diagram of complex 1 with thermal ellipsoids at
the 50% probability level.
Scheme 2. Synthetic route of ligands and their palladium(II)
complexes.
Single-crystal XRD studies of complexes 1 and 2 revealed
that the pincer type ligands (H2L1– H2L2) were chelated to the
palladium ion in a binegative tridentate manner. The naphtholate
oxygen, azomethine nitrogen and the deprotonated imidol oxygen
atoms and formed respectively a five membered and six membered
chelate rings with the palladium ion, while the fourth coordination site
was occupied by a triphenylphosphine molecule. The geometry
around the Pd(II) center in complexes 1 and 2 is described as
distorted square-planar. ORTEP representations of complexes 1and
2 are shown in Figure 1 and 2. The observed bond lengths and bond
angles are in good agreement with reported data on related
palladium(II) complexes. [16] Details on the data collection, structure
refinements, bond angles, bond lengths were gathered in Tables
S1– S3 in Supporting Information.
Figure 2. ORTEP diagram of complex 2 with thermal ellipsoids at
the 50% probability level.
After having realized fruitful results in the model reaction
discussed above, we explored the generality of our novel catalytic
system towards a range of arylboronic acids. To our delight,
arylboronic acids bearing both electron-rich and electron- deficient
groups afforded the desired products 5a–5r in good yields as shown
in Table 2. Arylboronic acids with methyl and methoxy groups at the
ortho-position gave the respective C3-arylated products 5b and 5e in
88% and 87% yields. Further, boronic acids having electron-
donating groups such as -CH3, CH3O-, (CH3)3–C-, –N(CH3)2 and -OH
were well tolerated to afford the respective products in significant
quantities Table 2, compounds 5c, 5f, 5i, and 5n). It is worth to
mention here that the boronic acids substituted with moderately
deactiving chloro, bromo, acetyl and formyl functionalities also nicely
underwent α-arylation reaction that might be of significant use for
further synthetic transformations (Table 2, compounds 5l, 5m, 5o,
5p, and 5q). Reaction of N-methy-2-oxoindole with disubstituted
arylboronic acids (2,6-dimethoxy and 2,3-dimethyl phenylboronic
acids) proceeded smoothly and furnished the desired products with
excellent site-selectivity (Table 2, compounds 5d & 5g). In addition,
biphenyl and naphthyl boronic acids also yielded 3-arylated indole
derivatives in 73 and 70% isolated yields. Succesfully, phenylboronic
acids possessing a strong deactivating –CF3 group at the para
position also well tolerated and yielded the expected product in 66%.
Of note, during the entirity of reactions carried out with a arylboronic
To test the ability of the complexes
1 and 2 as
homogeneous catalysts for C-C bond formation, we began our
investigation by employing N-methyl-2-oxindole (3a) and
phenylboronic acid (4a) as model substrates. As expected, the
reaction was successful and gave the desired product 5a in
presence of complex 2 as catalyst in EtOH at room-temperature.
With this result in hand, we worked out to find the optimum reaction
conditions. In this connection, we tested the reaction using several
inorganic and organic bases, among those KOH was found to be the
most effective base. Nevertheless, the desired product 5a was not at
all obtained in the absence of base. Similarly, screening of several
solvents as reaction medium revealed that H2O proved to be the
best one and thus gave the product 5a in 82 % yield. Further, up on
using the palladium complex 1 as a catalyst for the reaction, the
isolated yield of 5a was increased to 90 % (Table 1, entry 21). In
addition, the catalytic potential of complexes 1 and 2 were compared
with Pd salts like [PdCl2] and [PdCl2(PPh3)2]. Herein, only less yield
of the expected product was realized. (Table 1, entries 22 & 23) .
Overall, an excellent output from the present study was obtained by
involving N-methyl-2-oxindole (4 mmol), arylboronic acid (4 mmol),
KOH (5 mmol), H2O (5 mL) and complex 1 as catalyst (0.01 mol %)
at room-temperature.
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10.1002/cctc.201601411
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acids, formation of any homo-coupled or other by-products was
never observed.
Table 2. Scope of arylboronic acids under optimized reaction
conditions.a
Table 1. Optimization of the reaction conditions.a
a
= Reaction conditions: N-methyl-2-oxindole (4 mmol), arylboronic
To extend the present methodology for large scale
production, we investigated the gram scale synthesis of 1-methyl-3-
phenyl-1,3-dihydro-indol-2-one (5a) as a representative example
wherein 85 % yield was realised. Reusability of the selected catalyst
1 was assessed under parallel reaction conditions. The first cycle
afforded 90% of the corresponding coupled product followed by 88%
in the next run. However, third and fourth cycles gave 81% and 76%
of the coupled product. In the fifth cycle, only 68% of the product
was realized (Figure 3).
acid (4 mmol) KOH (5 mmol), H2O and catalyst (0.01 mol %) stirred
at room-temperature for 5-8 h in an open-flask. TON = Turnover
number = ratio of moles of product formed to moles of catalyst used.
b = Isolated yield.
With an aim to get some significant insights into the
mechanism of the titled reaction, the following controlled
experiments were carried out. At first, a trial reaction conducted
without the palladium catalyst was completely unsuccessful with total
recovery of the substrates intact. This fact demonstrated that the
presence of the palladium catalyst is inevitable to effect the expected
reaction. Next, we focused our attention to know whether any
catalyst poisoning occurred during the catalysis by adding mercury
to the reaction medium, wherein no influence was noticed and thus
proved the active catalyst is likely to be a homogeneous species and
not metallic palladium nanoparticles.
Figure 3. Recyclability of catalyst 1.
Based on the controlled experiments and literature
reports,[15,17] a plausible mechanism to explain the catalytic process
was proposed in Scheme 3. Initially, an active species, Pd(0)L (I) was
Transmetalation of intermediate II with phenylboronic acid
gave intermediate III which on further reductive elimination afforded
the coupled product,[17b] 3-phenyl-2-oxindole with the regeneration of
the active species Pd(0)L (I). At the end of the cycle, the catalyst
Pd(II)L was regenerated by the oxidation of intermediate I by O2.[17 c,d]
The same reaction performed under nitrogen atmosphere also
afforded the expected product.
formed
through a two-electron reduction of the palladium(II)
complex by transmetalation of arylboronic acids[17a] followed by an
oxidative addition of deprotonated N-methyl-2-oxindole in the enol
form to Pd(0)L to form intermediate II.
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In this communication, we report a novel as well as green
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arylboronic acids catalyzed by palladium(II) complex in aqueous
media under open-flask conditions at room-temperature. From the
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Acknowledgements
Mr. A. Vignesh thanks the University Grants Commission (UGC),
New Delhi, India. for the award of Senior Research Fellowship (SRF)
under UGC-BSR RFSMS.
Bhuvanesh,
N.
Dharmaraj,
J.
Org.
Chem.
2016,
Keywords: Nitrogen heterocycles • C-H activation • Arylboronic
acid • Pd(II) complex • Open-flask condition
DOI: 10.1021/acs.joc.6b02277.
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A. Vignesh, W. Kaminsky and N.
Dharmaraj*
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Arylation of N-methyl-2-oxindole with
arylboronic acids in water catalyzed
by Pd(II) pincer complexes with low
catalyst loading
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