Synthesis of novel 7-substituted 5,6-dihydroindol-2-ones via a Suzuki-Miyaura cross-coupling strategy

Article abstract of DOI:10.1016/j.tetlet.2007.10.093

A versatile method for the synthesis of new 7-substituted 5,6-dihydroindol-2-ones is described. The synthetic strategy proceeds through the use of the established palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of halogenated indol-2-ones and a

Full text of DOI:10.1016/j.tetlet.2007.10.093

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Tetrahedron Letters 48 (2007) 9008–9011
Synthesis of novel 7-substituted 5,6-dihydroindol-2-ones
via a Suzuki–Miyaura cross-coupling strategy
Wai Kean Goh, David StC Black and Naresh Kumar*
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
Received 20 September 2007; revised 12 October 2007; accepted 17 October 2007
Available online 22 October 2007
Abstract—A versatile method for the synthesis of new 7-substituted 5,6-dihydroindol-2-ones is described. The synthetic strategy pro-
ceeds through the use of the established palladium-catalyzed Suzuki–Miyaura cross-coupling reaction of halogenated indol-2-ones
and arylboronic acids/esters.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The indole heterocyclic system 1 is present in many nat-
urally occurring alkaloids that exhibit medicinal and
biological activity.1–3 This system has been important
in both the development of natural products chemistry
and pharmaceuticals as it is a common building block
for many complex molecular constructions.
tion as a scaffold for the development of neuroprotective
6,7
drugs in the treatment of neurodegenerative disease
and in the retrosynthesis of natural products.8
Recent syntheses have produced 2-, 3-, 4- and 6-substi-
tuted indolones with various pharmacological bene-
fits.6,9–13 However, the synthetic scope of 7-substituted
dihydroindol-2-ones with different attached aryl substit-
uents is limited with many of these compounds being
subsets of larger complex molecules. Currently there is
no general synthetic method reported in the literature
to access such a system.
O
N
N
H
H
1
2
The palladium-catalyzed Suzuki–Miyaura aryl–aryl
cross-coupling presents a viable established route to
the 7-substituted derivatives via a direct coupling of
halogenated indolones with arylboronic acids/esters.
The key advantage of this coupling strategy lies in their
high reactivity towards a vast range of easily available/
synthesizable boronic acid/ester substrates and allows
for the rapid preparation of a library of 7-substituted
indol-2-ones as building blocks for various molecular
constructions.
The great diversity of the biologically active indoles has
prompted many to focus on the synthesis and function-
alization of indoles.4 More so, the ease of the Suzuki–
Miyaura coupling reaction with various palladium cata-
lytic systems to form aryl–aryl bonds has modernized
many synthetic routes to electron-rich indoles.
A class of compounds that are yet to be researched sys-
tematically is that based on the 5,6-dihydroindol-2-one
2. Such compounds are isosteres of the indoles and share
similar structural motifs that could potentially possess
similar biological activity. In addition, they also serve
as an alternative precursor to the indoles.5 Recently,
indolone-nucleated compounds have gained much atten-
R-B(OH)2
O
O
N
N
PdCl2(PPh3)2
THF, Base
Br
R
Ph
Ph
3
4
*
Corresponding author. Tel.: +61 293854698; fax: +61 293856141;
e-mail: n.kumar@unsw.edu.au
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.093

W. K. Goh et al. / Tetrahedron Letters 48 (2007) 9008–9011
9009
O
O
i
OH
+
O
H
O
O
5
6
7
ii
iii
iv
O
O
O
7
N
OH
N
N
Br
Ph
Ph
Ph
8
9
3
Scheme 2. Reagents and conditions: (i) H3PO4 (85%), 100 ꢁC, 6 h, 40%; (ii) BnNH2, CH2Cl2, reflux, 4 h, 68%; (iii) p-TsOH, CHCl3, reflux, 2 h, 70%;
(iv) NBS, CCl4, reflux, 4 h, 63%.
Herein, we report the synthesis of novel 7-substituted
5,6-dihydroindol-2-ones 4 using a simple and efficient
one-step procedure involving the palladium-catalyzed
Suzuki–Miyaura coupling reaction (Scheme 1).
bearing the bromine substituent as C-7, with a value of d
108.5 ppm.
The Suzuki–Miyaura coupling reaction was attempted
with the 7-bromo derivative 3 under standard conditions
using PdCl2(PPh3)2 as the catalyst.16 Preliminary inves-
tigation of the non-aqueous environment showed that
THF was not a satisfactory solvent as the reaction pro-
ceeded very sluggishly and product yields were
negligible.
The reduced benzofuranone 7 provides a starting point
for the direct synthesis of indolone 9, in which a sub-
14
sequent direct lactone-lactam conversion would pro-
vide the basic reduced indolone scaffold. The reduced
benzofuranone was obtained via the phosphoric acid
catalyzed condensation and cyclization of cyclohexa-
none 5 and glyoxylic acid monohydrate 6 (Scheme 2).15
Success was achieved by using a dual-solvent system
THF/H2O (6:1) and the phase transfer catalyst Bu4NI.
Cross-coupling with boronic acid 10a gave product 4a
in good yield.
The reduced benzofuranone 7 was treated with benzyl-
amine under reflux conditions to yield the intermediate
hydroxy-dihydroindolone 8 as the only product (TLC
monitoring) in moderate yield. This strategy of direct
conversion of a benzofuranone to the dihydroindol-
2-one was previously observed in the lactone-lactam
conversion of fimbrolides to the corresponding dihydro-
pyrrol-2-ones.14
To optimize the reaction conditions, various solvents
such as toluene or dioxane, and bases such as KF
and CsF were investigated. The use of THF/H2O and
KF together was found to be the optimal conditions in
terms of ease of workup and purification of the final
products, while the product yields were relatively
consistent.
A mechanistic scheme for the formation of hydroxy-
dihydroindolone 8 incorporates formation of an amide
intermediate followed by an intramolecular cyclization
to generate the reduced indolone ring system.14
It was postulated that the use of a dual-solvent reaction
mixture ensures complete solvation of the reactants,
especially the KF base in the aqueous phase and palla-
dium in the organic phase, which catalyzed the coupling
reaction efficiently.17,18
Dehydration of the intermediate hydroxy-compound to
yield the basic indolone scaffold could be accomplished
with common dehydrating agents such as phosphorus
pentoxide or p-toluenesulfonic acid (p-TsOH). It was
found that treatment with the latter under reflux condi-
tions gave the cleanest reaction and the reduced indo-
lone 9 was obtained in good yield.
With these optimized reaction conditions, a variety of
substituted arylboronic acids/esters 10a–k were reacted
with 3 yielding a library of new 7-substituted 5,6-dihydr-
oindol-2-ones 4a–k (Table 1).19 All reported products
1
were characterized by H and 13C NMR, IR spectra,
The ensuing step involves conditioning the indolone for
reaction at the 7-position. This was only attainable
through selective halogenation due to the many reactive
sites on the indolone as seen from the treatment with
bromine that gave multiple products that were difficult
to purify and characterize. Selective halogenation by
treatment with N-bromosuccinimide (NBS) in CCl4 pro-
vided the 7-bromo indolone 3 in good yield. Selective
mass spectra and elemental analyses.
In conclusion, a general versatile synthesis of new
7-substituted 5,6-dihydroindol-2-ones 4 bearing various
functionalities has been developed. This reaction pro-
ceeds via an optimized palladium-catalyzed Suzuki–
Miyaura cross-coupling reaction starting from a halo-
genated indolone 3. This new series of 7-substituted
5,6-dihydroindol-2-ones offers access to many new
building blocks for molecular constructions. These
novel compounds are currently being evaluated for their
biological activity.
1
bromination at C-7 was evident as the H NMR exper-
iment showed only the loss of a multiplet peak at d
5.50 ppm, which corresponds to H-7 of the starting
material 9. Further 13C NMR data identified the carbon

9010
W. K. Goh et al. / Tetrahedron Letters 48 (2007) 9008–9011
Table 1. Reactions of 7-bromo dihydroindol-2-one with various
boronic acids/esters via Suzuki–Miyaura cross-couplinga
Acknowledgements
We thank the University of New South Wales and the
Australian Research Council for their financial support.
PdCl2(PPh3)2
O
O
+
R-B(OH)2
N
N
THF:H2O
KF, Bu4NI
Br
R
Ph
Ph
References and notes
3
10
4
Entry 10
Coupling partner R
Product 4 Yieldb (%)
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4a
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F
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4b
67
CF3
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10c
10d
4c
4d
67
91
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CN
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10e
10f
4e
4f
75
67
OCF3
OMe
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7
8
10g
10h
4g
4h
68
80
NO2
S
Me
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19. Representative procedure for the synthesis of 4k: Bromo-
9
10i
4i
4j
52
64
N
Me
O
O
O B
10
10jc
indolone
3
(0.66 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-
O
dioxaborolan-2-yl)-1H-indole (0.98 mmol), bis(triphenyl-
phosphine)palladium(II) dichloride (0.04 mmol) and
tetrabutylammonium iodide (0.14 mmol) were suspended
in tetrahydrofuran (20 mL). A solution of potassium
fluoride in H2O (2.0 M, 3 mL) was added and the mixture
refluxed for 20 h. The solvent was evaporated and the
residue extracted with dichloromethane. The organic
phase was separated, dried (Na2SO4) and the solvent
evaporated in vacuo. Purification of the residue by
chromatography on silica gel with ethyl acetate/dichloro-
methane (1:9, v:v) as the eluent gave 4k (0.15 g, 68%) as a
white solid, m.p. 208–212 ꢁC. 1H NMR (300 MHz): d
1.85–1.93 (m, 2 H, CH2), 2.56 (t, J = 6.0 Hz, 2H, CH2),
2.67–2.72 (m, 2H, CH2), 4.50 (s, 2H, NCH2), 5.93 (s, 1H,
O
11
10kc
4k
68
B
O
N
H
a Reactions were carried out using a mixture of indolone 3, boronic
acid/ester 10 (1.5 equiv), KF (4 equiv), 5 mol % PdCl2(PPh3)2,
5 mol % Bu4NI, THF/H2O (6:1) under refluxing conditions for 24 h.
b Isolated yields.
c Commercially available pinacol esters were used instead of the cor-
responding acid.

W. K. Goh et al. / Tetrahedron Letters 48 (2007) 9008–9011
9011
CH), 6.37–6.40 (m, 3H, Haryl), 6.80–6.83 (m, 1H, Haryl),
6.96–7.07 (m, 3H, Haryl), 7.20–7.24 (m, 3H, Haryl), 8.63 (br
s, 1H, NH). 13C NMR (75 MHz): d 23.1 (CH2), 24.7
(CH2), 34.2 (CH2), 44.4 (CH2Ph), 102.7 (CHaryl), 110.5
(CHaryl), 114.3 (CH), 120.9 (CHaryl), 122.5 (CHaryl), 125.0
(CHaryl), 126.21 (CHaryl), 126.26 (2 · CHaryl), 127.4 (C),
127.6 (2 · CHaryl), 128.9 (C), 130.0 (C), 134.4 (C), 135.3
(C), 137.8 (C), 150.1 (C), 172.2 (C=O). IR (Nujol, m,
cmÀ1): 3204, 1661, 1454, 1377, 1361, 1366, 1319, 711. UV
(CH3OH): kmax 328.5 nm (e 11470 cmÀ1 MÀ1), 289.5 nm (e
14240 cmÀ1 MÀ1). HRMS (ESI): m/z 363.1487 (M+Na+,
C23H20N2ONa requires 363.1468).