Substrate scope in the copper-mediated construction of bis-oxindoles via a double C-H/Ar-H coupling process

Article abstract of DOI:10.1016/j.tet.2015.02.060

Abstract The synthesis of bis-oxindoles via the copper(II)-mediated double cyclisation of linear bis-anilides is described. Cu(OAc)₂·H₂O was identified as an efficient and inexpensive catalyst for this process. In contrast to previous methods, which rely on the synthesis of the central core from existing oxindole building blocks, this new approach focusses on concurrent formation of both oxindole rings from a simple linear precursor, allowing the formation of bis-oxindoles containing a diverse range of cyclic and acyclic linkers using a single synthetic method.

Full text of DOI:10.1016/j.tet.2015.02.060

Tetrahedron 71 (2015) 7124e7136
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Substrate scope in the copper-mediated construction
of bis-oxindoles via a double CeH/AreH coupling process
*
Pauline Drouhin, Timothy E. Hurst, Adrian C. Whitwood, Richard J.K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of bis-oxindoles via the copper(II)-mediated double cyclisation of linear bis-anilides is
described. Cu(OAc)2$H2O was identified as an efficient and inexpensive catalyst for this process. In
contrast to previous methods, which rely on the synthesis of the central core from existing oxindole
building blocks, this new approach focusses on concurrent formation of both oxindole rings from
a simple linear precursor, allowing the formation of bis-oxindoles containing a diverse range of cyclic and
acyclic linkers using a single synthetic method.
Received 23 January 2015
Accepted 16 February 2015
Available online 20 February 2015
Dedicated to the memory of Alan Katritzky:
inspirational giant of heterocyclic chemistry,
collaborator, and friend
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Bis-oxindoles
Copper
CeH Functionalisation
1. Introduction
excellent control over both relative and absolute stereochemistry
can often be achieved in such systems.
The oxindole motif has long been the subject of considerable
attention due to its prevalence in natural and unnatural compounds
with varied and extensive biological activities.1 More recently, bis-
oxindoles have emerged as interesting yet synthetically challenging
targets owing to their complex polycyclic architecture. Some bi-
ologically active spirocyclic bis-oxindoles include the synthetic
anti-bacterial/anti-cancer spirooxindole-pyrrolidine 1,2 naturally
occurring anti-inflammatory geleganimine B 2,3 and cholinesterase
inhibitor 3 (Fig. 1).4 Non-spirocyclic bis-oxindole 4 has also been
shown to possess potent anti-bacterial activity against both Gram
positive and Gram negative organisms.5 Moreover, bis-oxindoles
(e.g., 5) have been used extensively as key intermediates in the
total synthesis of the cyclotryptamine6 and related7 alkaloids.
Given the demonstrated utility of bis-oxindoles, coupled with
the synthetic challenge of preparing complex polycyclic scaffolds
containing multiple stereogenic centres, it is not surprising that
a number of approaches to these intriguing heterocycles have been
reported.8 Some representative examples of bis-spirooxindoles,
containing various core ring sizes and linkers, are shown in Fig. 2.
These have been prepared by cascade reactions9 (e.g., 6, 8, and 9),
photochemical [2þ2]-cycloadditions10 (e.g., 7), and by condensa-
tion onto isatin-based imines11 (e.g., 10). It is noteworthy that
O
H
H
H
H N
N
N
O
Me
H
Me
OH
H
O
OMe
NMe
OMe
N
CN
H
O
H
O
O
N
O
N
H
H
H
H
O
HN
1
geleganimine B, 2
(anti-inflammatory)
(anti-bacterial and anti-cancer)
H
N
OMe
Boc
N
O
O
NH
O
O
N
O
O
N
N
HO
O
O
Ar
O
HN
N
NH
Boc
Ar
Ar = 2,4-Cl2C6H3, 3
(cholinesterase inhibitor)
4
5
(anti-bacterial)
(cyclotryptamine
intermediate)
* Corresponding author. Tel.: þ44 1904 322606; e-mail address: richard.taylor@
york.ac.uk (R.J.K. Taylor).
Fig. 1. Examples of valuable bis-oxindoles.
http://dx.doi.org/10.1016/j.tet.2015.02.060
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
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2. Results and discussion
2.1. Synthesis of spirocyclic bis-oxindoles
In our preliminary studies,13 we focussed on the synthesis of
spirocyclic bis-oxindoles 16aek by the copper-mediated double
cyclisation of linear bis-anilides 15aek in moderate to good yields
(Scheme 2). These results are reproduced here, and warrant only
brief comment. Optimisation studies carried out for the cyclisation
of cyclopentanone 2,5-dicarboxamide 15a showed that the pre-
ferred reaction conditions involved Cu(OAc)2$H2O (2.2 equiv) and
KOtBu (2.2 equiv) in DMF at 110 ꢀC for 15 min, delivering the de-
sired bis-spirooxindole 16a in 67% isolated yield and as a single
diastereomer. The trans-relationship of the carboxamides present
in both the linear bis-anilide 15a and bis-oxindole 16a was con-
firmed unambiguously by X-ray crystallography (Fig. 3). We also
examined the scope of this copper-mediated double cyclisation,
exemplified by the synthesis of symmetrical (16bed) and un-
Fig. 2. Examples of bis-spirooxindoles prepared by elaboration of pre-formed ox-
indoles. Bonds formed in the cyclisation process are shown in red.
However, regardless of the structural diversity of bis-oxindoles
that can be accessed via these different synthetic manifolds, the
previous approaches all rely on a single overall strategy: i.e., syn-
thesis of the central core from pre-existing oxindole building
blocks, often derived from isatin.
We have previously demonstrated the efficient synthesis of
oxindoles from linear anilides in high yield via a copper(II)-
mediated formal CeH/AreH coupling reaction,12 and sub-
sequently reported preliminary studies, which took advantage of
this method to provide access to bis-spirooxindoles with complete
control of diastereoselectivity (Scheme 1, Eq. 1).13 We now wish to
disclose full results on the copper(II)-mediated double cyclisation
of readily available linear bis-anilides, which offers a fundamentally
different approach to the synthesis of bis-oxindoles by simulta-
neous formation of both oxindole rings around an existing central
linker (Scheme 1, Eqs. 1 and 2). In this fashion, we are able to
prepare spirocyclic bis-oxindoles with full control over the size of
the core ring system, as well as bis-oxindoles connected by diverse
acyclic linkers, using a single synthetic method. In addition to de-
tailed experimental procedures, 15 previously unreported cyclisa-
tions are included in this publication.
Scheme 2. Substrate scope in the synthesis of spirocyclic bis-oxindoles. All com-
Scheme 1. Bis-anilide double cyclisation strategy for the synthesis of bis-oxindoles.
pounds were isolated as single diastereomers.

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P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
highest chemical yield of 18 was observed in toluene at 110 ꢀC
(entry 2). Of greater import, a slight bias in favour of one di-
astereomer was observed in all cases, providing encouragement for
the potential success of this approach in the synthesis of the ste-
rically more encumbered bis-spirooxindoles.
The linear bis-anilide precursor 19 containing the (S)-a-meth-
ylbenzyl chiral auxiliary on both nitrogen atoms was therefore
prepared in analogous fashion to 15a. Cyclisation of 19 under the
optimised conditions for bis-spirooxindole formation delivered 20
in 46% yield as an inseparable mixture of diastereomers in a 44:56
ratio (Scheme 3), similar to 18 above.
Fig. 3. Crystal structures of trans-cyclopentanone 2,5-dicarboxamide 15a and spi-
rocyclic bis-oxindole 16a (50% probability ellipsoids).
symmetrical (16eeg, differentiated by both ring substitution and
nitrogen protecting group) bis-oxindoles, as well as those con-
taining varying core ring sizes (16hek). Key features of this method
include the inexpensive copper salt used, the short reaction time,
broad diversity in the cyclic linker, and high diastereoselectivity
observed in the cyclisation.
Scheme 3. Cyclisation of linear bis-anilide 19.
Despite the rather disappointing diastereoselectivity imparted
by the (S)-a-methylbenzyl group, these preliminary results show
promise for future improvement through optimisation of the chiral
auxiliary and reaction conditions.
2.2. Towards a copper-mediated cyclisation approach to
enantioenriched spirocyclic bis-oxindoles
2.3. Synthesis of bis-oxindoles with an acyclic monoketone
linker
In a new aspect to this work, we wished to explore the potential
of extending the diastereoselective copper-mediated double cycli-
sation to the enantioselective synthesis of spirocyclic bis-oxindoles.
Having established the utility of the double cyclisation of linear
bis-anilides for the synthesis of spirocyclic bis-oxindoles, attention
turned to expanding the scope of this method to include substrates
containing an acyclic linker. The required cyclisationprecursors were
easily prepared in three steps from known ester 21 (Scheme 4).12a
Thus, saponification of the ester moiety in 21 followed by treat-
ment with oxalyl chloride delivered acid chloride 22, which was
sufficiently stable to allow storage at ꢁ10 ꢀC for several months
without degradation. Treatment of anilides 23aec with LDA, fol-
lowed by addition of the acid chloride 22 delivered the target linear
bis-anilides 24aec in 40e69% yield. Crucially, this stepwise strategy
provided access to unsymmetrical substrates differentiated by ring
Jones and McCarthy have reported the use of the a-methylbenzyl
group as a chiral auxiliary on nitrogen in the radical cyclisation of
N-arylacrylamides to give enantioenriched 3,3-disubstituted oxin-
doles, albeit in a moderate 39% ee after removal of the auxiliary.14 It
was anticipated that a similar approach might be successful in our
process. To test this hypothesis, model linear anilide 17 bearing an
(S)-a-methylbenzyl group was prepared in 68% yield via
Mukaiyama coupling of the requisite aniline and carboxylic acid.
The copper-mediated cyclisation of 17 was then carried out under
several different sets of conditions to examine the effect on the
diastereoselectivity of the reaction (Table 1). In the event, the
substitution (24b, R1¼Me), and at the carbonyl
a-position (24c,
R2¼Et).
Table 1
Cyclisation of 24a in the presence of Cu(OAc)2$H2O (2 equiv) and
KOtBu (2.2 equiv) in DMF at 110 ꢀC for 1 h delivered the desired
bisoxindole 25a as a mixture of diastereomers, along with signifi-
cant quantities of an oxidative cleavage by-product, namely N-
methyl 3-hydroxy-3-methyloxindole 26 (trans-25a/cis-25a/26
molar ratio¼1:3:1). Pleasingly, formation of this by-product can be
minimised by performing the reaction without base in mesitylene
at 170 ꢀC for 30 min, giving bis-oxindole 25a as a separable 40:60
mixture of trans/cis-diastereomers in 58% combined yield. The
small amount of hydroxyindole 26 formed in this reaction was
easily removed during the workup by washing with 4 M NaOH
solution. Unsymmetrical bisoxindole 25b was prepared in similar
Cyclisation of linear anilide 17
Entry Conditions
Yield (%) dr
1
2
3
Cu(OAc)2$H2O (1 equiv), KOtBu, DMF, 110 ꢀC, 1 h
Cu(OAc)2$H2O (1 equiv), toluene, 110 ꢀC, 18 h
26
76
44:56
44:56
45:55
fashion. Interestingly, changing one of the a-methyl groups to the
Cu(OAc)2$H2O (1 equiv), mesitylene, 170 ꢀC, 1.5 h 55
bulkier ethyl group (25c, R2¼Et) prompted a change in selectivity,

P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
7127
2.4. Synthesis of bis-oxindoles with diketone linkers
With the synthesis of bis-oxindoles separated by a one-carbon
ketone linker established via this copper-mediated double cycli-
sation, we next sought to extend the scope to incorporate linkers of
varying chain lengths. The required linear substrates were easily
prepared via reaction of diacid chlorides 27 with 2.4 equiv of the
enolate derived from anilides 23 (Scheme 5). This flexible approach
provided rapid access to cyclisation precursors containing a diverse
array of central linkers incorporating various aliphatic chains
(28aed), an adamantane (28e) and aromatic rings (28fej). In most
cases an inseparable 50:50 mixture of dl/meso-diastereomers was
obtained, which is inconsequential for the subsequent cyclisation.
The exception was malonate-derived substrate 28a, where the di-
astereomers were separable by column chromatography, giving
meso-28a and dl-28a in 32% and 27% yields, respectively. The rel-
ative stereochemistry in meso-28a and dl-28a was assigned based
on the characteristic signals for the gem-dimethyl group in the 1H
NMR spectrum (2ꢂ3H singlets at dH 1.42 and 1.23 for meso-28a,
1ꢂ6H singlet at dH 1.21 for dl-28a). In addition, the structure of dl-
28a was confirmed by X-ray crystallography (Fig. 5).
Scheme 4. Synthesis of bis-oxindoles with an acyclic monoketone linker. a2 equiv of
Cu(OAc)2$H2O was used with a reaction time of 3 h.
with trans-25c isolated as the major product. The relative stereo-
chemistries in trans-25a, trans-25c and cis-25c were all confirmed
by X-ray crystallography (Fig. 4).
The moderate diastereoselectivities observed in the synthesis of
bis-oxindoles 25aec containing a flexible acyclic linker highlights
the key role played by the more rigid cyclic core in spirocyclic bis-
oxindoles 16aek, which serves to more efficiently relay stereo-
chemical information during the cyclisation, leading to the com-
plete diastereoselectivity observed in the latter case.
O
O
Me
Me
Me Me
MeN
NMe
O
O
meso-29a
Fig. 5. Crystal structures of dl-28a, dl-29a, meso-29a, dl-29j and meso-29j (50%
probability ellipsoids).
As expected, cyclisation of meso-28a occurred smoothly on
heating in the presence of Cu(OAc)2$H2O (1 equiv) in mesitylene,
giving a separable 44:56 mixture of meso-29a and dl-29a in
a combined 55% yield (Scheme 6). The same result was obtained
Fig. 4. Crystal structures of trans-25a, trans-25c and cis-25c (50% probability
ellipsoids).

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P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
Scheme 5. Synthesis of bis-oxindole linear precursors. With the exception of 28a, all compounds were isolated as an inseparable 50:50 mixture of dl/meso-diastereomers.
when dl-28a was used as the substrate. Once again, the structures
of meso-29a and dl-29a were confirmed by the characteristic 1H
NMR signals for the gem-dimethyl group, as well as by X-ray
crystallography (Fig. 5). Variation in the aliphatic linker chain
length was also tolerated, delivering bis-oxindoles 29bed as mix-
tures of diastereomers. Replacement of the gem-dimethyl groups in
29b with methylene groups (29c, R¼H) results in a significant re-
duction in yield, highlighting the preference for substitution at the
incorporating an aromatic linker derived from the well-known rho-
dium ligand
a0 0-tetramethyl-1,3-benzenedipropionic acid
a,a, ,a
(H2esp),15 could be also prepared in similar fashion. It is noteworthy
that substitution on the aromatic ring with both electron-donating
(29g, R1¼OMe) and electron-withdrawing groups (29h, R1¼CF3), or
replacement of the oxindole C-3/C-30 methyl groups with an aro-
matic ring (29i, R2¼Ph) all resulted in successful cyclisation reactions.
Aromatic-linked bis-oxindoles meso-29j and dl-29j proved separable
by column chromatography. However, determination of the relative
stereochemistry proved difficult by NMR spectroscopy alone, ne-
cessitating their characterisation by X-ray crystallography (Fig. 5).
carbonyl a-positions to avoid decomposition.
More complex linkers were also well tolerated, exemplified by the
synthesis of adamantane 29e in 70% yield. Bis-oxindoles 29fei,
Scheme 6. Synthesis of bis-oxindoles with diketone linkers. With the exception of 29a and 29j, all compounds were isolated as an inseparable 50:50 mixture of dl/meso-
diastereomers.

P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
7129
complete diastereoselectivity observed in the synthesis of spi-
rocyclic bis-oxindoles containing various core ring sizes. Further-
more, we are able to prepare bis-oxindoles connected by diverse
acyclic linkers using this single synthetic method.
This simple double cyclisation represents a fundamentally dif-
ferent approach to the synthesis of bis-oxindoles by simultaneous
formation of both oxindole rings around an existing central linker.
We anticipate that this method should find ready application in the
synthesis of complex bis-oxindoles, efforts towards which are un-
derway in our laboratory.
4. Experimental
4.1. General information
Except where stated, all reagents were purchased from com-
mercial sources and used without further purification. Anhydrous
solvents (CH2Cl2, toluene, DMF) were obtained from an Innovative
Technologies solvent purification system. Anhydrous THF was ob-
tained by distillation over sodium benzophenone ketyl immediately
before use. NMR spectra were recorded on a JEOL spectrometer
operating at 400 MHz (1H) and 100 MHz (13C). All spectral data were
Scheme 7. Synthesis of ester-containing linear precursors. All compounds were iso-
lated as an inseparable 50:50 mixture of dl/meso-diastereomers.
acquired at 295 K. Chemical shifts (d) are quoted in parts per million
(ppm). The residual solvent peak, dH 7.26 (CHCl3) and dC 77.0 (CDCl3)
was used as a reference. Coupling constants (J) are reported in hertz
(Hz) to the nearest 0.1 Hz. The multiplicity abbreviations used are: s
singlet, d doublet, t triplet, q quartet, m multiplet, br broad. Signal
assignment was achieved by analysis of DEPT, COSY, NOESY, HMBC
and HSQC experiments where required. Infrared (IR) spectra were
recorded neat on a PerkineElmer Spectrum Two FTIR-ATR spec-
trometer. Mass-spectra (low- and high-resolution) were obtained
using electrospray ionisation (ESI) on a Micro-TOF spectrometer.
Melting points were recorded in capillary tubes on a Gallenkamp
apparatus and are uncorrected. Thin layer chromatography was
carried out on silica gel 60F254 pre-coated aluminium foil sheets
and were visualised using UV light (254 nm) and stained with either
basic aq potassium permanganate, ethanolic p-anisaldehyde or
ammonium molybdate as appropriate. Flash column chromatog-
raphy was carried out using slurry packed silica gel (SiO2), 35e75
2.5. Synthesis of ester-containing bis-oxindoles
In a final new aspect to this work, we wished to explore the
effect of moving the required electron-withdrawing group from the
linker into the C-3 position of the oxindole. The required linear
precursors 31aec were rapidly prepared from anilide 30 by
deprotonation with NaH followed by introduction of the requisite
dibromide (Scheme 7).
In the event, cyclisation of 31aec under the optimised conditions
deliveredbis-oxindolescontainingaliphatic(32a), olefinic(32b)and
aromatic (32c) linkers in good to excellent yield (Scheme 8).
ꢀ
Dm particle size, 60 A pore size, under a light positive pressure,
eluting with the specified solvent system.
4.2. General procedure 1 for the formation of spirocyclic bis-
oxindoles 16aek
To a stirred solution of the bis-anilide 15 (1 equiv) in DMF
(0.02e0.06 M) were added Cu(OAc)2$H2O (2 equiv) and KOtBu
(2.2 equiv). The reaction mixture was stirred at 110 ꢀC for 15 min
under an atmosphere of air and allowed to cool to room tempera-
ture. An aq solution of 10% NH4OH (2ꢂ5 mL) was added and the
aqueous phase was extracted with EtOAc (2ꢂ5 mL). The combined
organic phases were washed with water (4ꢂ5 mL), and brine
(5 mL), dried (MgSO4), filtered and concentrated in vacuo. The 1H
NMR spectrum of the crude reaction mixture showed only the
trans-diastereoisomer present. The residue was purified by column
chromatography (SiO2, hexane/EtOAc) to give the title compound 16.
4.2.1. (trans)-1,100-Dimethyl-1,100,2,200-tetrahydrodispiro[indole-3,10-
cyclopentane-30,300-indole]-2,20,200-trione (16a). Bis-anilide 15a
(27.4 mg, 0.078 mmol), Cu(OAc)2$H2O (32.2 mg, 0.161 mmol) and
KOtBu (18.8 mg, 0.168 mmol) in DMF (3 mL) were subjected to
general procedure 1. The residue was purified by column chroma-
tography (SiO2, hexane/EtOAc, 4:1) to give the title compound 16a
(18.2 mg, 67%) as a colourless solid, mp 184e186 ꢀC; Rf 0.42 (hex-
ane/EtOAc, 1:1); nmax (ATR, cmꢁ1) 1751, 1704, 1612, 1493, 1471, 1370,
1347, 1266, 1070, 885, 752; dH (400 MHz, CDCl3) 7.43 (2H, dd, J¼7.6,
Scheme 8. Synthesis of ester-containing bis-oxindoles. All compounds were isolated
as an inseparable 50:50 mixture of dl/meso-diastereomers.
3. Conclusions
In conclusion, we have developed a concise synthesis of bis-
oxindoles from linear bis-anilides via a copper(II)-mediated for-
mal CeH/AreH coupling process. Highlights of this method include
the inexpensive copper salt used, the short reaction times and the

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P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
1.2 Hz, CH), 7.31 (2H, td, J¼7.6, 1.2 Hz, CH), 7.10 (2H, td, J¼7.6, 1.2 Hz,
CH), 6.84 (2H, d, J¼7.6 Hz, CH), 3.21 (6H, s, CH3), 3.15e3.10 (2H, m,
CH2), 2.78e2.72 (2H, m, CH2); dC (100 MHz, CDCl3) 208.0 (C), 175.0
(C), 144.4 (C), 129.8 (C), 129.1 (CH), 124.3 (CH), 123.6 (CH), 108.4
(CH), 63.7 (C), 32.4 (CH2), 26.6 (CH3); HRMS (ESI): MNaþ, found
369.1213. [C21H18N2NaO3]þ requires 369.1210. CCDC 1004040
contains the supplementary crystallographic data for this com-
pound. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
purified by column chromatography (SiO2, hexane/EtOAc, 4:1 to 1:1)
to give the title compound 16e (19.0 mg, 37%) as a colourless solid, mp
176e178 ꢀC;Rf 0.48(hexane/EtOAc, 3:2);nmax (ATR,cmꢁ1)2940,1749,
1691, 1601, 1496, 1465, 1433, 1349, 1310, 1287, 1216, 1172, 1067, 1040,
1022, 845; dH (400 MHz, CDCl3) 7.23e7.22 (1H, m, CH), 7.12e7.09 (2H,
m, CH), 6.84 (1H, dd, J¼8.4, 2.5 Hz, CH), 6.74 (1H, d, J¼8.4 Hz, CH), 6.72
(1H, d, J¼7.9 Hz, CH), 3.80 (3H, s, CH3), 3.19 (3H, s, CH3), 3.18 (3H, s,
CH3), 3.16e3.06 (2H, m, CH2), 2.77e2.68 (2H, m, CH2), 2.34 (3H, s,
CH3); dC (100 MHz, CDCl3) 208.1 (C), 174.8 (C), 174.7 (C), 156.6 (C),
142.0 (C), 137.7 (C), 133.1 (C), 130.8 (C), 129.5 (C), 129.3 (CH), 124.9
(CH), 113.9 (CH), 111.1 (CH), 108.7 (CH), 108.0 (CH), 63.9 (C), 63.7 (C),
55.9 (CH3), 32.4 (CH2), 32.3 (CH2), 26.5 (CH3), 26.4 (CH3), 21.1 (CH3);
HRMS (ESI): MHþ, found 391.1655. [C23H23N2O4]þ requires 391.1652.
4.2.2. (trans)-1,100-Dibenzyl-1,100,2,200-tetrahydrodispiro[indole-3,10-
cyclopentane-30,300-indole]-2,20,200-trione (16b). Bis-anilide 15b
(14.7 mg, 0.029 mmol), Cu(OAc)2$H2O (11.6 mg, 0.058 mmol) and
KOtBu (7.22 mg, 0.064 mmol) in DMF (1.5 mL) were subjected to
general procedure 1. The residue was purified by column chroma-
tography (SiO2, hexane/EtOAc, 4:1) to give the title compound 16b
(8.2 mg, 57%) as a pale yellow solid, mp 115e117 ꢀC; Rf 0.50 (hexane/
EtOAc, 2:1); nmax (ATR, cmꢁ1) 1740, 1703, 1612, 1488, 1467, 1455,
1359, 1311, 1178, 873, 752, 734; dH (400 MHz, CDCl3) 7.48 (2H, dd,
J¼7.6, 1.0 Hz, CH), 7.34e7.30 (4H, m, CH), 7.30e7.27 (6H, m, CH), 7.19
(2H, td, J¼7.6, 1.0 Hz, CH), 7.07 (2H, td, J¼7.6, 1.0 Hz, CH), 6.70 (2H, d,
J¼7.6 Hz, CH), 5.02 (2H, d, J¼15.9 Hz, CH2), 4.83 (2H, d, J¼15.9 Hz,
CH2), 3.26e3.15 (2H, m, CH2), 2.93e2.81 (2H, m, CH2); dC (100 MHz,
CDCl3) 208.0 (C), 175.2 (C), 143.5 (C), 135.3 (C), 129.8 (C), 129.1 (CH),
129.0 (CH), 127.8 (CH), 127.1 (CH), 124.4 (CH), 123.7 (CH), 109.5 (CH),
63.8 (C), 43.9 (CH2), 32.5 (CH2); HRMS (ESI): MNaþ, found 521.1825.
[C33H26N2NaO3]þ requires 521.1836.
4.2.6. (trans)-1-Benzyl-100-methyl-di-1,100,2,200-tetrahydrodispiro[in-
dole-3,10-cyclopentane-30,300-indole]-2,20,200-trione (16f). Bis-anilide
15f (0.107 g, 0.250 mmol), Cu(OAc)2$H2O (0.100 g, 0.500 mmol),
and KOtBu (62.0 mg, 0.550 mmol) in DMF (4 mL) were subjected to
general procedure 1. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc, 9:1 to 4:1) to give the title
compound 16f (29.1 mg, 28%) as a colourless solid, mp 92e94 ꢀC; Rf
0.53 (hexane/EtOAc, 3:2); nmax (ATR, cmꢁ1) 2934, 1752, 1697, 1610,
1488, 1466, 1345, 1309, 1253, 1176, 1079, 1030; dH (400 MHz, CDCl3)
7.47 (1H, dd, J¼7.4, 0.7 Hz, CH), 7.46 (1H, dd, J¼7.4, 0.7 Hz, CH),
7.36e7.23 (6H, m, CH), 7.19 (1H, td, J¼7.8, 1.2 Hz, CH), 7.12 (1H, td,
J¼7.6, 0.8 Hz, CH), 7.07 (1H, td, J¼7.6, 0.8 Hz, CH), 6.86 (1H, d,
J¼7.7 Hz, CH), 6.70 (1H, d, J¼7.7 Hz, CH), 4.99 (1H, d, J¼15.9 Hz, CH2),
4.85 (1H, d, J¼15.9 Hz, CH2), 3.23 (3H, s, CH3), 3.20e3.12 (2H, m,
CH2), 2.87e2.77 (2H, m, CH2); dC (100 MHz, CDCl3) 207.9 (C), 175.2
(C), 174.8 (C), 144.3 (C), 143.4 (C), 135.2 (C), 129.7 (C), 129.6 (C), 129.0
(CH), 128.90 (CH), 128.86 (CH), 127.6 (CH), 127.0 (CH), 124.3 (CH),
124.2 (CH), 123.52 (CH), 123.49 (CH), 109.3 (CH), 108.3 (CH), 63.65
(C), 63.61 (C), 43.8 (CH2), 32.4 (CH2), 32.3 (CH2), 26.5 (CH3); HRMS
(ESI): MNaþ, found 445.1516. [C27H22N2NaO3]þ requires 445.1523.
4.2.3. (trans)-1,100,5,500-Tetramethyl-1,100,2,200-tetrahydrodispiro[in-
dole-3,10-cyclopentane-30,300-indole]-2,20,200-trione (16c). Bis-anilide
15c (39.8 mg, 0.105 mmol), Cu(OAc)2$H2O (43.7 mg, 0.219 mmol)
and KOtBu (25.8 mg, 0.230 mmol) in DMF (4 mL) were subjected to
general procedure 1. The residue was purified by column chroma-
tography (SiO2, hexane/EtOAc, 4:1) to give the title compound 16c
(26.2 mg, 67%) as a colourless solid, mp 197e199 ꢀC; Rf 0.60 (hex-
ane/EtOAc,1:2); nmax (ATR, cmꢁ1) 1751, 1701, 1624,1602, 1499, 1349,
1271,1069, 918, 811; dH (400 MHz, CDCl3) 7.24 (2H, dd, J¼1.3, 0.6 Hz,
CH), 7.10 (2H, ddd, J¼7.9, 1.3, 0.6 Hz, CH), 6.72 (2H, d, J¼7.9 Hz, CH),
3.19 (6H, s, CH3), 3.17e3.04 (2H, m, CH2), 2.77e2.64 (2H, m, CH2),
2.33 (6H, s, CH3); dC (100 MHz, CDCl3) 208.4 (C), 175.0 (C), 142.1 (C),
133.3 (C), 129.8 (C), 129.3 (CH), 125.1 (CH), 108.1 (CH), 63.8 (C), 32.5
(CH2), 26.6 (CH3), 21.2 (CH3); HRMS (ESI): MNaþ, found 397.1506.
[C23H22N2NaO3]þ requires 397.1523.
4.2.7. (trans)-100-Benzyl-1,5-dimethyl-1,100,2,200-tetrahydrodispiro[in-
dole-3,10-cyclopentane-30,300-indole]-2,20,200-trione (16g). Bis-anilide
15g (0.116 g, 0.263 mmol), Cu(OAc)2$H2O (0.105 g, 0.526 mmol),
and KOtBu (65.0 mg, 0.579 mmol) in DMF (8 mL) were subjected to
general procedure 1. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc, 1:4 to 1:1) to give the title
compound 16g (37.8 mg, 33%) as a colourless solid, mp 102e104 ꢀC;
Rf 0.51 (hexane/EtOAc, 3:2); nmax (ATR, cmꢁ1) 2942, 1753, 1701,
1605, 1498, 1466, 1348, 1310, 1253, 1175, 1080, 1059, 1030; dH
(400 MHz, CDCl3) 7.51 (1H, dd, J¼7.3, 0.6 Hz, CH), 7.34e7.29 (4H, m,
CH), 7.27e7.23 (2H, m, CH), 7.19 (1H, td, J¼7.7, 1.3 Hz, CH), 7.14e7.11
(1H, m, CH), 7.07 (1H, td, J¼7.7, 0.9 Hz, CH), 6.74 (1H, d, J¼7.9 Hz,
CH), 6.68 (1H, d, J¼7.7 Hz, CH), 5.00 (1H, d, J¼16.0 Hz, CH2), 4.85
(1H, d, J¼16.0 Hz, CH2), 3.25e3.09 (2H, m, CH2), 3.20 (3H, s, CH3),
2.86e2.74 (2H, m, CH2), 2.35 (3H, s, CH3); dC (100 MHz, CDCl3) 208.1
(C), 175.3 (C), 174.7 (C), 143.4 (C), 141.9 (C), 135.1 (C), 133.2 (C), 129.8
(C), 129.5 (C), 129.3 (CH), 128.8 (CH), 127.6 (CH), 126.9 (CH), 124.8
(CH),124.3 (CH),123.5 (CH),109.3 (CH),108.0 (CH), 63.7 (C), 63.6 (C),
43.7 (CH2), 32.4 (CH2), 32.3 (CH2), 26.4 (CH3), 21.1 (CH3); HRMS
(ESI): MNaþ, found 459.1662. [C28H24N2NaO3]þ requires 459.1679.
4.2.4. (trans)-5,500-Dimethoxy-1,100-dimethyl-1,100,2,200-tetrahy-
drodispiro[indole-3,10-cyclopentane-30,300-indole]-2,20,200-trione
(16d). Bis-anilide 15d (41.7 mg, 0.102 mmol), Cu(OAc)2$H2O (41.1 mg,
0.206 mmol) and KOtBu (25.6 mg, 0.228 mmol) in DMF (4 mL) were
subjected to general procedure 1. The residue was purified by column
chromatography (SiO2, hexane/EtOAc, 4:1 to hexane/EtOAc, 2:1) to
give the title compound 16d (18.3 mg, 44%) as a colourless solid, mp
180e182 ꢀC; Rf 0.46 (hexane/EtOAc,1:2); nmax (ATR, cmꢁ1) 1749,1701,
1600,1497,1469,1435,1354,1288,1039, 811; dH (400 MHz, CDCl3) 7.07
(2H, d, J¼2.6 Hz, CH), 6.83 (2H, dd, J¼8.4, 2.6 Hz, CH), 6.74 (2H, d,
J¼8.4 Hz, CH), 3.79 (6H, s, CH3), 3.18 (6H, s, CH3), 3.15e3.03 (2H, m,
CH2), 2.79e2.67 (2H, m, CH2); dC (100 MHz, CDCl3) 207.9 (C), 174.7 (C),
156.7 (C),137.9 (C),130.8 (C),114.1 (CH),111.1 (CH),108.8 (CH), 64.1 (C),
56.0 (CH3), 32.5 (CH2), 26.6 (CH3); HRMS (ESI): MNaþ, found 429.1433.
[C23H22N2NaO5]þ requires 429.1421.
4.2.8. (trans)-1,100-Dimethyl-1,100,2,200-tetrahydrodispiro[indole-3,10-
cyclohexane-30,300-indole]-2,20,200-trione
(16h). Bis-anilide
15h
(33.3 mg, 0.091 mmol), Cu(OAc)2$H2O (37.4 mg, 0.187 mmol) and
KOtBu (22.7 mg, 0.202 mmol) in DMF (3 mL) were subjected to
general procedure 1. The residue was purified by column chroma-
tography (SiO2, hexane/EtOAc, 4:1) to give the title compound 16h
(14.2 mg, 43%) as a colourless solid, mp 210e212 ꢀC; Rf 0.64 (hexane/
EtOAc,1:4); nmax (ATR, cmꢁ1) 1705,1688,1610,1494,1471,1372,1348,
1266, 1105, 753; dH (400 MHz, CDCl3) 7.57 (2H, dd, J¼7.4, 1.2 Hz, CH),
7.28 (2H, dd, J¼7.4, 1.2 Hz, CH), 7.07 (2H, td, J¼7.4, 1.2 Hz, CH), 6.79(2H,
4.2.5. (trans)-5-Methoxy-1,100,500-trimethyl-1,100,2,200-tetrahy-
drodispiro[indole-3,10-cyclopentane-30,300-indole-2,20,200-trione
(16e). Bis-anilide 15e (51.0 mg, 0.130 mmol), Cu(OAc)2$H2O
(52.0 mg, 0.260 mmol), and KOtBu (32.0 mg, 0.286 mmol) in DMF
(4 mL) were subjected to general procedure 1. The crude product was

P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
7131
d,J¼7.4Hz,CH), 3.17(6H, s, CH3), 2.50(6H,s, CH2);dC (100MHz,CDCl3)
203.2 (C), 175.8 (C), 143.9 (C), 132.9 (C), 128.7 (CH), 124.4 (CH), 123.4
(CH), 108.3 (CH), 62.3 (C), 33.5 (CH2), 26.6 (CH3), 17.1 (CH2); HRMS
(ESI): MNaþ, found 383.1370. [C22H20N2NaO3]þ requires 383.1366.
(17.7 mg, 0.089 mmol). The reaction mixture was stirred at 110 ꢀC
for 18 h under an atmosphere of air and allowed to cool to room
temperature. The copper salt was removed by addition of an aq soln
of NH4OH (5 mL). The aqueous phase was extracted with EtOAc
(2ꢂ5 mL). The combined organic extracts were washed with water
(5 mL), and brine (5 mL), dried (MgSO4), filtered and concentrated
in vacuo. The crude product was purified by column chromatogra-
phy (SiO2, hexane/EtOAc, 9:1) to give the title compound 18 (44:56,
21.0 mg, 76%) as a yellow oil; Rf 0.23 (hexane/EtOAc, 6:1); nmax (ATR,
cmꢁ1) 2982, 2936, 1741, 1714, 1607, 1484, 1467, 1350, 1237, 1190,
1112, 1019, 752, 698; dH (400 MHz, CDCl3) 7.41e7.37 (1H, m, CH),
7.35e7.26 (4H, m, CH), 7.23 (0.45H, d, J¼7.4 Hz, CH), 7.22 (0.55H, d,
J¼7.4 Hz, CH), 7.08e7.01 (1H, m, CH), 6.96 (0.45H, td, J¼7.6, 1.0 Hz,
CH), 6.96 (0.55H, td, J¼7.6, 1.0 Hz, CH), 6.49 (0.45H, d, J¼7.6 Hz, CH),
6.45 (0.55H, d, J¼7.6 Hz, CH), 5.92 (0.55H, q, J¼7.2 Hz, CH), 5.83
(0.45H, q, J¼7.2 Hz, CH), 4.24e4.13 (1.1H, m, CH2), 4.12e4.02 (0.9H,
m, CH2), 1.85 (1.35H, d, J¼7.2 Hz, CH3), 1.82 (1.65H, d, J¼7.2 Hz, CH3),
1.72 (1.35H, s, CH3), 1.71 (1.65H, s, CH3), 1.20 (1.65H, t, J¼7.1 Hz, CH3),
1.15 (1.35H, t, J¼7.1 Hz, CH3); dC (100 MHz, CDCl3) 175.5 and 175.4
(C), 171.4 and 170.0 (C), 141.7 and 141.5 (C), 139.1 and 139.0 (C), 130.6
and 130.5 (C), 128.8 and 128.7 (CH), 128.56 and 128.55 (CH), 127.54
and 127.45 (CH), 126.7 and 126.6 (CH), 123.01 and 122.97 (CH),
122.52 and 122.50 (CH), 111.4 and 111.1 (CH), 62.1 and 62.0 (CH2),
55.01 and 54.99 (C), 49.5 and 48.8 (CH), 20.0 and 19.7 (CH3), 16.2
and 16.1 (CH3), 13.94 and 13.92 (CH3); HRMS (ESI): MNaþ, found
346.1406. [C20H21NNaO3]þ requires 346.1414.
4.2.9. 5-tert-Butyl-(trans)-1,100-dimethyl-1,100,2,200-tetrahydrodispiro
[indole-3,10-cyclohexane-30,300-indole]-2,20,200-trione (16i). Bis-ani-
lide 15i (45.4 mg, 0.108 mmol), Cu(OAc)2$H2O (43.8 mg,
0.219 mmol) and KOtBu (25.6 mg, 0.228 mmol) in DMF (4.5 mL)
were subjected to general procedure 1. The residue was purified by
column chromatography (SiO2, hexane/EtOAc, 4:1) to give the title
compound 16i (24.1 mg, 54%) as a colourless solid, mp 152e154 ꢀC;
Rf 0.48 (hexane/EtOAc, 1:2); nmax (ATR, cmꢁ1) 1707, 1690, 1651, 1610,
1494, 1470, 1371, 1346, 1263, 753; dH (400 MHz, CDCl3) 7.86 (1H, dd,
J¼7.6, 1.2 Hz, CH), 7.34 (1H, dd, J¼7.6, 1.2 Hz, CH), 7.28 (1H, dd, J¼7.6,
1.2 Hz, CH), 7.28 (1H, dd, J¼7.6,1.2 Hz, CH), 7.08 (1H, td, J¼7.6,1.2 Hz,
CH), 7.07 (1H, td, J¼7.6, 1.2 Hz, CH), 6.81 (1H, d, J¼7.6 Hz, CH), 6.78
(1H, d, J¼7.6 Hz, CH), 3.19 (3H, s, CH3), 3.14 (3H, s, CH3), 3.05e2.95
(1H, m, CH), 2.48 (1H, t, J¼13.1 Hz, CH2), 2.34 (2H, d, J¼8.8 Hz, CH2),
2.19 (1H, d, J¼14.9 Hz, CH2), 0.96 (9H, s, CH3); dC (100 MHz, CDCl3)
203.9 (C), 176.4 (C), 175.5 (C), 143.9 (C), 143.8 (C), 133.9 (C), 132.7 (C),
128.8 (CH),128.6 (CH),124.7 (CH),124.0 (CH),123.5 (CH),123.3 (CH),
108.4 (CH), 108.2 (CH), 63.3 (C), 61.9 (C), 37.5 (CH), 35.8 (CH2), 35.6
(CH2), 32.6 (C), 27.3 (CH3), 26.7 (CH3), 26.5 (CH3); HRMS (ESI):
MNaþ, found 439.2011. [C26H28N2NaO3]þ requires 439.1992.
4.2.10. (trans)-1,100-Dimethyl-1,100,2,200-tetrahydrodispiro[indole-3,10-
cycloheptane-30,300-indole]-2,20,200-trione
(16j). Bis-anilide
15j
4.3.2. 1,100-Bis[(1S)-1-phenylethyl]-1,100,2,200-tetrahydrodispiro[in-
dole-3,10-cyclopentane-30,300-indole]-2,20,200-trione (20). To a stirred
solution of bis-anilide 19 (35.9 mg, 0.068 mmol) in DMF (2 mL) was
added Cu(OAc)2$H2O (27.7 mg, 0.139 mmol) and KOtBu (16.7 mg,
0.149 mmol). The reaction mixture was stirred at 110 ꢀC for 15 min
under an atmosphere of air and allowed to cool to room tempera-
ture. An aq solution of 10% NH4OH (2ꢂ5 mL) was added and the
aqueous phase was extracted with EtOAc (2ꢂ5 mL). The combined
organic phases were washed with water (4ꢂ5 mL), and brine
(5 mL), dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, hexane/
EtOAc, 8:1) to give the title compound 20 (44:56, 16.4 mg, 46%) as
a colourless solid, mp 66e68 ꢀC; Rf 0.31 (hexane/EtOAc, 4:1); nmax
(ATR, cmꢁ1) 2981, 1755, 1700, 1608, 1484, 1466, 1348, 1310, 1254,
1052, 850, 752, 697; dH (400 MHz, CDCl3) 7.50e7.45 (2H, m, CH),
7.36e7.26 (10H, m, CH), 7.10e7.00 (4H, m, CH), 6.51 (1.1H, d,
J¼7.1 Hz, CH), 6.44 (0.9H, dd, J¼7.1, 0.7 Hz, CH), 5.78 (2H, pent,
J¼7.1 Hz, CH), 3.26e3.16 (2H, m, CH2), 2.94e2.83 (2H, m, CH2), 1.84
(3H, d, J¼7.2 Hz, CH3), 1.84 (3H, d, J¼7.2 Hz, CH3); dC (100 MHz,
CDCl3) 208.1 and 208.0 (C), 175.2 and 175.1 (C), 142.5 and 142.4 (C),
139.0 and 138.6 (C), 130.2 and 130.1 (C), 128.8 (CH),128.6 (CH),127.6
and 127.5 (CH), 126.6 (CH), 124.4 and 124.3 (CH), 123.24 and 123.19
(CH),111.2 and 111.0 (CH), 63.8 and 63.6 (C), 49.6 and 49.2 (CH), 32.7
and 32.3 (CH2), 16.5 and 16.3 (CH3); HRMS (ESI): MNaþ, found
549.2162. [C35H30N2NaO3]þ requires 549.2149.
(24.5 mg, 0.065 mmol), Cu(OAc)2$H2O (27.5 mg, 0.138 mmol) and
KOtBu (16.4 mg, 0.146 mmol) in DMF (2.5 mL) were subjected to
general procedure 1. The residue was purified by column chroma-
tography (SiO2, hexane/EtOAc, 4:1) to give the title compound 16j
(18.8 mg, 77%) as a colourless solid, mp 196e198 ꢀC; Rf 0.69 (hexane/
EtOAc,1:2); nmax (ATR, cmꢁ1) 1701,1682,1608,1493,1470,1373,1347,
1260, 1126, 1079, 947, 753, 729; dH (400 MHz, CDCl3) 7.36 (2H, d,
J¼7.6 Hz, CH), 7.23 (2H, td, J¼7.6,1.2 Hz, CH), 7.02 (2H, td, J¼7.6,1.2 Hz,
CH), 6.76 (2H, d, J¼7.6 Hz, CH), 3.20 (6H, s, CH3), 2.85 (2H, br s, CH2),
2.43 (2H, br t, J¼9.0 Hz, CH2), 2.07e1.94 (4H, m, CH2); dC (100 MHz,
CDCl3) 174.9 (C), 142.8 (C), 132.0 (C), 128.5 (CH), 125.3 (CH), 122.9
(CH), 108.2 (CH), 67.9 (C), 33.9 (CH2), 26.5 (CH3), 24.2 (CH2); HRMS
(ESI): MNaþ, found 397.1510. [C23H22N2NaO3]þ requires 397.1523.
4.2.11. (trans)-1,100-Dimethyl-1,100,2,200,70,90-hexahydro-50H-dispiro
[indole-3,60-benzo[7]annulene-80,300-indole]2,200,70-trione (16k). Bis-
anilide 15k (31.1 mg, 0.073 mmol), Cu(OAc)2$H2O (30.2 mg,
0.151 mmol) and KOtBu (19.1 mg, 0.170 mmol) in DMF (2 mL) were
subjected to general procedure 1. The residue was purified by col-
umn chromatography (SiO2, hexane/EtOAc, 4:1) to give the title
compound 16k (14.3 mg, 46%) as a yellow solid, mp 214e216 ꢀC; Rf
0.50 (hexane/EtOAc, 1:1); nmax (ATR, cmꢁ1) 1710, 1678, 1609, 1493,
1471, 1370, 1347, 1261, 1077, 1023, 910, 798, 752; dH (400 MHz,
CDCl3) 7.33 (2H, dd, J¼5.4, 3.3 Hz, CH), 7.26 (2H, td, J¼7.6, 1.2 Hz,
CH), 7.16 (2H, dd, J¼5.4, 3.3 Hz, CH), 7.04 (2H, d, J¼7.6 Hz, CH), 6.98
(2H, td, J¼7.6, 1.2 Hz, CH), 6.81 (2H, d, J¼7.6 Hz, CH), 3.65 (2H, d,
J¼14.7 Hz, CH2), 3.46 (2H, d, J¼14.7 Hz, CH2), 3.17 (6H, s, CH3); dC
(100 MHz, CDCl3) 205.2 (C), 174.9 (C), 143.9 (C), 135.9 (C), 132.5 (C),
130.8 (CH), 128.8 (CH), 127.7 (CH), 125.0 (CH), 123.1 (CH), 108.3 (CH),
65.7 (C), 38.0 (CH2), 26.5 (CH3); HRMS (ESI): MNaþ, found 445.1527.
[C27H22N2NaO3]þ requires 445.1523.
4.4. General procedure 2 for the synthesis of monoketone
linked bis-oxindoles 25aec
To a stirred solution of bis-anilide 24 (1 equiv) in mesitylene
(0.03e0.1 M) was added Cu(OAc)2$H2O (1 equiv). The reaction
mixture was stirred for 30 min at 170 ꢀC (Drysyn heating block)
under an atmosphere of air. Mesitylene was removed in vacuo. The
resulting residue was diluted with EtOAc (5 mL) and washed twice
with a 10% aq solution of NH4OH (2ꢂ5 mL) and 4 M solution of
NaOH (3ꢂ5 mL). The 1H NMR spectrum of the crude reaction
showed a mixture of diastereoisomers present. Purification by
column chromatography (SiO2, hexane/EtOAc) gave the title com-
pound 25.
4.3. Synthesis of bis-oxindoles 18 and 20 bearing chiral
auxiliaries
4.3.1. Ethyl 3-methyl-2-oxo-1-[(1S)-1-phenylethyl]-2,3-dihydro-1H-
indole-3-carboxylate (18). To
a stirred solution of anilide 17
(27.7 mg, 0.085 mmol) in toluene (2 mL) was added Cu(OAc)2$H2O

7132
P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
4.4.1. dl-3-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-indole-3-carbonyl)-
1,3-dimethyl-2,3-dihydro-1H-indol-2-one (dl-25a) and meso-3-(1,3-
dimethyl-2-oxo-2,3-dihydro-1H-indole-3-carbonyl)-1,3-dimethyl-
2,3-dihydro-1H-indol-2-one (meso-25a). Bis-anilide 24a (35.7 mg,
0.101 mmol), and Cu(OAc)2$H2O (21.0 mg, 0.105 mmol) in mesity-
lene (3.5 mL) were submitted to general procedure 2. The 1H NMR
diastereoisomers in a ratio of 60:40 trans-25c/cis-25c. Purification
by column chromatography (SiO2, hexane/EtOAc, 4:1 to hexane/
EtOAc, 1:1) gave first trans-25c (20.8 mg, 41%) as a colourless solid,
mp 200e202 ꢀC; Rf 0.42 (hexane/EtOAc, 1:1); nmax (ATR, cmꢁ1
)
1724, 1701, 1609, 1489, 1461, 1369, 1346, 1259, 1160, 1101, 765; dH
(400 MHz, CDCl3) 7.11e7.05 (3H, m, CH), 7.03 (1H, dd, J¼7.6, 1.2 Hz,
CH), 7.01e6.93 (2H, m, CH), 6.29 (2H, d, J¼7.6 Hz, CH), 2.80 (3H, s,
CH3), 2.79 (3H, s, CH3), 2.21 (1H, dq, J¼14.8, 7.4 Hz, CH2), 2.10 (1H,
dq, J¼14.8, 7.4 Hz, CH2), 1.47 (3H, s, CH3), 0.42 (3H, t, J¼7.4 Hz, CH3);
dC (100 MHz, CDCl3) 196.1 (C), 174.2 (C), 173.2 (C), 144.9 (C), 144.0
(C), 129.0 (CH), 128.9 (CH), 127.9 (C), 126.0 (CH), 125.4 (C), 125.2
(CH), 122.1 (CH), 121.9 (CH), 107.9 (CH), 107.7 (CH), 67.2 (C), 62.3 (C),
29.1 (CH2), 26.4 (CH3), 26.2 (CH3), 22.8 (CH3), 7.8 (CH3); HRMS (ESI):
MNaþ, found 385.1525. [C22H22N2NaO3]þ requires 385.1523. CCDC
1016758 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
spectrum of the crude reaction showed
a mixture of di-
astereoisomers in a ratio of 40:60 dl-25a/meso-25a. Purification by
column chromatography (SiO2, hexane/EtOAc, 4:1) gave first dl-25a
(9.6 mg, 27%) as a white solid, mp 262e264 ꢀC; Rf 0.42 (hexane/
EtOAc, 1:1); nmax (ATR, cmꢁ1) 2932, 1728, 1706, 1611, 1492, 1469,
1446, 1374, 1345, 1120, 1028, 988, 768, 752; dH (400 MHz, CDCl3)
7.10 (2H, td, J¼7.6, 1.1 Hz, CH), 7.06 (2H, dd, J¼7.6, 1.1 Hz, CH), 6.98
(2H, td, J¼7.6, 1.1 Hz, CH), 6.31 (2H, d, J¼7.6 Hz, CH), 2.78 (6H, s,
CH3), 1.48 (6H, s, CH3); dC (100 MHz, CDCl3) 196.3 (C), 174.1 (C), 144.1
(C), 129.0 (CH), 127.8 (C), 125.5 (CH), 122.2 (CH), 107.9 (CH), 62.1 (C),
26.3 (CH3), 22.7 (CH3); HRMS (ESI): MNaþ, found 371.1350.
[C21H20N2NaO3]þ requires 371.1366. CCDC 1004039 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The diastereoisomer cis-25c (13 mg, 26%) was then isolated by
column chromatography (SiO2, hexane/EtOAc, 1:1) as a colourless
solid, mp 155e157 ꢀC; Rf 0.23 (hexane/EtOAc, 1:1); nmax (ATR, cmꢁ1
)
The diastereoisomer meso-25a (10.9 mg, 31%) was then isolated
by column chromatography (SiO2, hexane/EtOAc, 4:1) as a white
1727, 1712, 1611, 1493, 1470, 1372, 1347, 1259, 1161, 1102, 755; dH
(400 MHz, CDCl3) 7.20 (1H, td, J¼7.6, 1.2 Hz, CH), 7.19 (1H, td, J¼7.6,
1.2 Hz, CH), 6.78 (1H, td, J¼7.6, 1.2 Hz, CH), 6.73 (1H, td, J¼7.6, 1.2 Hz,
CH), 6.65 (1H, d, J¼7.6 Hz, CH), 6.60 (1H, d, J¼7.6 Hz, CH), 6.57 (1H,
dd, J¼7.6, 1.2 Hz, CH), 6.48 (1H, dd, J¼7.6, 1.2 Hz, CH), 2.94 (3H, s,
CH3), 2.85 (3H, s, CH3), 2.18 (1H, dq, J¼14.8, 7.4 Hz, CH2), 2.09 (1H,
dq, J¼14.8, 7.4 Hz, CH2), 1.48 (3H, s, CH3), 0.47 (3H, t, J¼7.4 Hz, CH3);
dC (100 MHz, CDCl3) 197.7 (C), 174.2 (C), 173.3 (C), 145.0 (C), 144.6
(C), 129.12 (CH), 129.10 (CH), 128.6 (C), 126.6 (C), 124.3 (CH), 123.7
(CH), 122.2 (CH), 108.4 (CH), 108.1 (CH), 66.2 (C), 61.6 (C), 29.6 (CH2),
26.5 (CH3), 26.2 (CH3), 22.9 (CH3), 7.7 (CH3); HRMS (ESI): MNaþ,
found 385.1518. [C22H22N2NaO3]þ requires 385.1523. CCDC
1004041 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
solid, mp 170e172 ꢀC; Rf 0.25 (hexane/EtOAc, 1:1); nmax (ATR, cmꢁ1
)
1731, 1717, 1608, 1490, 1468, 1374, 1344, 1120, 1032, 761, 542; dH
(400 MHz, CDCl3) 7.20 (2H, td, J¼7.6, 1.2 Hz, CH), 6.76 (2H, td, J¼7.6,
1.2 Hz, CH), 6.63 (2H, d, J¼7.6 Hz, CH), 6.55 (2H, dd, J¼7.6, 1.2 Hz,
CH), 2.91 (6H, s, CH3), 1.50 (6H, s, CH3); dC (100 MHz, CDCl3) 197.9
(C), 174.2 (C), 144.4 (C), 129.1 (CH), 128.6 (C), 123.9 (CH), 122.3 (CH),
108.3 (CH), 61.3 (C), 26.4 (CH3), 22.9 (CH3); HRMS (ESI): MNaþ,
found 371.1372. [C21H20N2NaO3]þ requires 371.1366.
4.4.2. trans/cis-3-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-3-
carbonyl)1,3,5-trimethyl-2,3-dihydro-1H-indol-2-one
(trans/cis-
25b). Bis-anilide 24b (89.0 mg, 0.243 mmol), and Cu(OAc)2$H2O
(97.0 mg, 0.486 mmol) in mesitylene (2.4 mL) were submitted to
general procedure 2, with a reaction time of 3 h. The crude product
was purified by column chromatography (SiO2, hexane/EtOAc, 9:1
to 4:1) to give trans/cis-25b (38.5:61.5, 36.2 mg, 41%) as a colourless
solid, mp 143e145 ꢀC; Rf 0.20 (hexane/EtOAc, 3:2); nmax (ATR, cmꢁ1
)
4.5. General procedure 3 for the formation of diketone linked
bis-oxindoles 29aej
2929, 1714, 1694, 1604, 1502, 1490, 1468, 1445, 1421, 1368, 1342,
1257, 1185, 1146, 1118, 1027; dH (400 MHz, CDCl3) 7.22 (0.615H, td,
J¼7.8, 1.1 Hz, CH), 7.19 (0.385H, td, J¼7.8, 1.1 Hz, CH), 7.00e6.96 (1H,
m, CH), 6.84 (0.615H, td, J¼7.5, 0.8 Hz, CH), 6.75 (0.385H, td, J¼7.5,
0.8 Hz, CH), 6.71 (0.615H, dd, J¼7.4, 0.8 Hz, CH), 6.62 (0.385H, d,
J¼7.8 Hz, CH), 6.58 (0.615H, d, J¼7.8 Hz, CH), 6.54 (1H, d, J¼7.9 Hz,
CH), 6.51 (0.385H, d, J¼7.9 Hz, CH), 6.34 (0.385H, s, CH), 6.17 (0.615H,
s, CH), 2.96 (1.85H, s, CH3), 2.90 (1.15H, s, CH3), 2.87 (1.15H, s, CH3),
2.81 (1.85H, s, CH3), 2.12 (1.15H, s, CH3), 2.05 (1.85H, s, CH3), 1.50
(1.85H, s, CH3), 1.49 (1.15H, s, CH3), 1.48 (1.15H, s, CH3), 1.47 (1.85H, s,
CH3); dC (100 MHz, CDCl3) 197.9 (C), 174.3 and 174.09 (C), 174.06 and
173.9 (C), 144.3 and 144.1 (C), 142.2 and 142.0 (C), 131.63 and 131.58
(C),129.4 and 129.3 (CH),129.0 and 128.9 (CH),128.8 and 128.51 (C),
128.48 and 128.2 (C), 124.9 and 124.7 (CH), 123.7 and 123.6 (CH),
122.22 and 122.19 (CH), 108.2 and 108.1 (CH), 107.8 and 107.7 (CH),
61.4 and 61.2 (C), 61.1 and 61.0 (C), 26.5 and 26.34 (CH3), 26.29 and
26.2 (CH3), 22.73 and 22.71 (2ꢂCH3), 20.91 and 20.87 (CH3); HRMS
(ESI): MNaþ, found 385.1514. [C22H22N2NaO3]þ requires 385.1523.
A solution of bis-anilide 28 (1 equiv) and Cu(OAc)2$H2O
(1 equiv) in mesitylene (0.1 M) was heated at 165 ꢀC for 2 h under
an atmosphere of air, then cooled to room temperature. Saturated
NH4Cl (15 mL) was added and the aqueous phase extracted with
EtOAc (3ꢂ15 mL). The combined organics were washed with 10%
NH4OH (15 mL), 4 M NaOH (3ꢂ15 mL), and saturated brine (15 mL),
dried over MgSO4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc) to give the title compound 29.
4.5.1. meso-1,3-Bis(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-
2,2-dimethylpropane-1,3-dione (meso-29a) and dl-1,3-bis(1,3-
dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-2,2-dimethylpropane-
1,3-dione (dl-29a)
4.5.1.1. From dl-N,N0-2,4,4,6-hexamethyl-3,5-dioxo-N,N0-diphe-
nylheptanedicarboxamide (dl-28a). Bis-anilide dl-28a (0.180 g,
0.426 mmol) and Cu(OAc)2$H2O (85.0 mg, 0.426 mmol) in mesi-
tylene (4.3 mL) were subjected to general procedure 3. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc, 9:1 to 4:1) to give meso-29a (47.6 mg, 27%) as a colourless
4.4.3. trans-3-(3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-indole-3-
carbonyl)-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (trans-25c) and
cis-3-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-indole-3-carbonyl)-
1,3-dimethyl-2,3-dihydro-1H-indol-2-one (cis-25c). Bis-anilide 24c
(51.3 mg, 0.140 mmol) and Cu(OAc)2$H2O (28.0 mg, 0.140 mmol) in
mesitylene (4 mL) were subjected to general procedure 2. The 1H
NMR spectrum of the crude reaction showed a mixture of
solid, mp 159e161 ꢀC; Rf 0.50 (hexane/EtOAc, 3:2); nmax (ATR, cmꢁ1
)
2936, 1721, 1705, 1694, 1667, 1607, 1492, 1470, 1445, 1366, 1343,
1256, 1121, 1099, 1082, 1027, 990; dH (400 MHz, CDCl3) 7.40 (2H, dd,
J¼7.5, 0.8 Hz, CH), 7.34 (2H, td, J¼7.8, 1.1 Hz, CH), 7.06 (2H, td, J¼7.5,

P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
7133
0.8 Hz, CH), 6.88 (2H, d, J¼7.8 Hz, CH), 3.25 (6H, s, CH3), 1.57 (6H, s,
CH3), 0.98 (3H, s, CH3), 0.94 (3H, s, CH3); dC (100 MHz, CDCl3) 203.4
(C), 175.6 (C), 142.9 (C), 130.2 (C), 128.9 (CH), 124.8 (CH), 122.9 (CH),
108.3 (CH), 64.5 (C), 60.4 (C), 26.6 (CH3), 24.3 (CH3), 23.4 (CH3), 22.7
(CH3); HRMS (ESI): MHþ, found 419.1972. [C25H27N2O4]þ requires
419.1965. CCDC 1013389 contains the supplementary crystallo-
graphic data for this compound. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
The diastereoisomer dl-29a (53.7 mg, 30%) was then isolated as
a colourless solid, mp 128e130 ꢀC; Rf 0.40 (hexane/EtOAc, 3:2); nmax
(ATR, cmꢁ1) 2930, 1697, 1657, 1609, 1492, 1470, 1447, 1372, 1346,
1260, 1117, 1094, 1028, 976; dH (400 MHz, CDCl3) 7.33 (2H, td, J¼7.7,
1.2 Hz, CH), 7.29 (2H, dd, J¼7.5, 0.7 Hz, CH), 7.10 (2H, td, J¼7.6,
0.9 Hz, CH), 6.85 (2H, d, J¼7.7 Hz, CH), 3.24 (6H, s, CH3), 1.57 (6H, s,
CH3), 0.89 (6H, s, CH3); dC (100 MHz, CDCl3) 204.0 (C), 175.8 (C),
142.8 (C), 129.7 (C), 128.9 (CH), 124.4 (CH), 123.1 (CH), 108.3 (CH),
64.5 (C), 60.5 (C), 26.5 (CH3), 23.8 (CH3), 21.2 (CH3); HRMS (ESI):
MHþ, found 419.1975. [C25H27N2O4]þ requires 419.1965. CCDC
1013390 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
123.134 and 123.129 (CH), 108.52 and 108.51 (CH), 61.6 (C), 37.8 and
37.7 (CH2), 26.5 (CH3), 22.4 and 22.3 (CH2), 19.0 and 18.9 (CH3);
HRMS (ESI): MNaþ, found 455.1931. [C26H28N2NaO4]þ requires
455.1941.
4.5.4. dl/meso-1,8-Bis(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)-2,2,7,7-tetramethyloctane-1,8-dione (dl/meso-29d). Bis-anilide
dl/meso-28d (0.250 g, 0.480 mmol) and Cu(OAc)2$H2O (96.0 mg,
0.480 mmol) in mesitylene (4.8 mL) were subjected to general
procedure 3. The crude product was purified by column chro-
matography (SiO2, hexane/EtOAc, 9:1 to 4:1) to give the title
compound dl/meso-29d (50:50, 0.164 g, 66%) as a colourless solid,
mp 109e111 ꢀC; Rf 0.25 (hexane/EtOAc, 3:1); nmax (ATR, cmꢁ1
)
2938, 1718, 1687, 1609, 1493, 1467, 1449, 1374, 1342, 1261, 1119,
1101, 1030, 981; dH (400 MHz, CDCl3) 7.31 (2H, tdd, J¼7.1, 2.0,
1.2 Hz, CH), 7.04e7.00 (4H, m, CH), 6.86 (2H, d, J¼7.7 Hz, CH),
3.252 (3H, s, CH3), 3.247 (3H, s, CH3), 1.49 (6H, s, CH3), 1.42e1.32
(2H, m, CH2), 1.27e1.19 (2H, m, CH2), 0.93e0.77 (4H, m, CH2),
0.88 (3H, s, CH3), 0.87 (3H, s, CH3), 0.79 (6H, s, CH3); dC
(100 MHz, CDCl3) 208.0 and 207.9 (C), 176.2 (C), 143.3 (C), 129.8
(C), 128.8 (CH), 123.273 and 123.269 (CH), 122.8 (CH), 108.5 (CH),
60.8 (C), 49.7 (C), 40.89 and 40.86 (CH2), 26.4 (CH3), 24.91 and
24.87 (CH2), 24.5 and 24.38 (CH3), 24.36 and 24.28 (CH3), 23.4
(CH3); HRMS (ESI): MNaþ, found 539.2859. [C32H40N2NaO4]þ re-
quires 539.2880.
4.5.1.2. From meso-N,N0-2,4,4,6-hexamethyl-3,5-dioxo-N,N0-di-
phenylheptanedicarboxamide (meso-28a). Bis-anilide meso-28a
(0.148 g, 0.350 mmol) and Cu(OAc)2$H2O (70.0 mg, 0.350 mmol) in
mesitylene (3.5 mL) were subjected to general procedure 3. The
crude product was purified by column chromatography (SiO2,
hexane/EtOAc, 9:1 to 4:1) to give meso-29a (35.4 mg, 24%) as a col-
ourless solid, followed by dl-29a (45.2 mg, 31%) as a colourless solid.
4.5.5. dl/meso-3-[3-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-3-
carbonyl)adamantane-1-carbonyl]-1,3-dimethyl-2,3-dihydro-1H-in-
dol-2-one (dl/meso-29e). Bis-anilide dl/meso-28e (0.206 g,
0.400 mmol) and Cu(OAc)2$H2O (80.0 mg, 0.400 mmol) in mesi-
tylene (4 mL) were subjected to general procedure 3. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc, 9:1 to 4:1) to give the title compound dl/meso-29e (0.143 g,
70%) as a colourless solid, mp 173e174.5 ꢀC; Rf 0.34 (hexane/EtOAc,
1:3); nmax (ATR, cmꢁ1) 2930, 1707, 1685, 1608, 1491, 1470, 1447,
1372, 1342, 1258, 1171, 1119, 1099, 1043, 1022; dH (400 MHz, CDCl3)
7.34 (2H, tt, J¼7.7, 1.5 Hz, CH), 7.07e6.99 (2H, m, CH), 6.94 (1H, dd,
J¼7.0, 0.6 Hz, CH), 6.91e6.88 (2H, m, CH), 6.82 (1H, d, J¼7.3 Hz,
CH), 3.29 (3H, s, CH3), 3.27 (3H, s, CH3), 1.80e1.76 (1H, m, CH),
1.74e1.68 (1H, m, CH), 1.64e1.52 (3H, m, CH2), 1.46e1.43 (3H, m,
CH2), 1.45 (3H, s, CH3), 1.44 (3H, s, CH3), 1.38e1.30 (5H, m, CH2),
1.27e1.23 (1H, m, CH2); dC (100 MHz, CDCl3) 206.7 and 206.6 (C),
176.1 and 176.0 (C), 143.6 and 143.4 (C), 129.71 and 129.66 (C),
129.0 and 128.9 (CH), 123.1 (CH), 122.97 and 122.95 (CH), 108.8
and 108.7 (CH), 60.58 and 60.55 (C), 49.1 and 48.9 (C), 39.2 and
39.1 (CH2), 37.52 and 37.47 (CH2), 36.9 (CH2), 36.6 (CH2), 34.99 and
34.98 (CH2), 27.84, 27.82 and 27.80 (CH), 26.6 and 26.5 (CH3), 23.13
and 23.05 (CH3); HRMS (ESI): MNaþ, found 533.2421.
[C32H34N2NaO4]þ requires 533.2411.
4.5.2. dl/meso-1,6-Bis(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)-2,2,5,5-tetramethylhexane-1,6-dione (dl/meso-29b). Bis-anilide
dl/meso-28b (0.215 g, 0.436 mmol) and Cu(OAc)2$H2O (87.0 mg,
0.436 mmol) in mesitylene (4.4 mL) were subjected to general
procedure 3. The crude product was purified by column chroma-
tography (SiO2, hexane/EtOAc, 1:9 to 1:4) to give the title compound
dl/meso-29b (50:50, 0.136 g, 64%) as a colourless solid, mp
182e184 ꢀC; Rf 0.57 (hexane/EtOAc, 3:2); nmax (ATR, cmꢁ1) 2972,
1706, 1688, 1608, 1491, 1471, 1373, 1346, 1259, 1118, 1098, 1029, 983;
dH (400 MHz, CDCl3) 7.34e7.29 (2H, m, CH), 7.05e7.02 (4H, m, CH),
6.88 (2H, d, J¼7.9 Hz, CH), 3.27 (6H, s, CH3), 1.50 (6H, s, CH3),
1.31e1.25 (2H, m, CH2), 1.09e0.99 (2H, m, CH2), 0.90 (3H, s, CH3),
0.89 (3H, s, CH3), 0.77 (3H, s, CH3), 0.76 (3H, s, CH3); dC (100 MHz,
CDCl3) 207.66 and 207.65 (C), 176.3 and 176.2 (C), 143.4 (C), 129.8
and 129.7 (C), 128.9 (CH), 123.50 and 123.46 (CH), 122.80 and
122.78 (CH), 108.6 (CH), 60.8 (C), 49.5 and 49.4 (C), 35.7 and 35.5
(CH2), 26.5 (CH3), 24.3 (CH3), 24.0 (CH3), 23.44 and 23.43 (CH3), 23.4
(CH3); HRMS (ESI): MHþ, found 489.2746. [C30H37N2O4]þ requires
489.2748.
4.5.6. dl/meso-3-[2-({3-[3-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-in-
dol-3-yl)-2,2-dimethyl-3-oxopropyl]phenyl}methyl)-2-
4.5.3. dl/meso-1,6-Bis(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)hexane-1,6-dione (dl/meso-29c). Bis-anilide dl/meso-28c (0.218 g,
0.500 mmol) and Cu(OAc)2$H2O (0.100 g, 0.500 mmol) in mesity-
lene (5 mL) were subjected to general procedure 3. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc, 9:1 to 4:1) to give the title compound dl/meso-29c (50:50,
52.9 mg, 25%) as a colourless solid, mp 120e122 ꢀC; Rf 0.19 (hexane/
EtOAc, 3:2); nmax (ATR, cmꢁ1) 2937, 1719, 1689, 1608, 1491, 1475,
1374, 1348, 1258, 1160, 1119, 1099, 1061, 1035, 985; dH (400 MHz,
CDCl3) 7.34e7.28 (2H, m, CH), 7.08e7.02 (4H, m, CH), 6.89 (2H, d,
J¼8.0 Hz, CH), 3.263 (3H, s, CH3), 3.259 (3H, s, CH3), 2.28e2.21 (2H,
m, CH2), 1.97e1.89 (2H, m, CH2), 1.51 (3H, s, CH3), 1.50 (3H, s, CH3),
1.24e1.16 (4H, m, CH2); dC (100 MHz, CDCl3) 202.8 and 202.7 (C),
175.9 (C), 143.6 (C), 129.3 (C), 129.0 (CH), 123.33 and 123.31 (CH),
methylpropanoyl]-1,3-dimethyl-2,3-dihydro-1H-indol-2-one
(dl/
meso-29f). Bis-anilide dl/meso-28f (0.145 g, 0.255 mmol) and
Cu(OAc)2$H2O (51.0 mg, 0.255 mmol) in mesitylene (2.6 mL) were
subjected to general procedure 3. The crude product was purified
by column chromatography (SiO2, hexane/EtOAc, 9:1 to 4:1) to give
the title compound dl/meso-29f (50:50, 93.2 mg, 65%) as a colourless
oil, Rf 0.60 (hexane/EtOAc, 3:2); nmax (ATR, cmꢁ1) 2972, 2930, 1710,
1690, 1608, 1491, 1467, 1447, 1372, 1341, 1257, 1118, 1097, 1030, 984;
dH (400 MHz, CDCl3) 7.27 (2H, tt, J¼7.8, 1.3 Hz, CH), 7.06 (1H, td,
J¼7.6, 3.3 Hz, CH), 6.90e6.83 (6H, m, CH), 6.69e6.63 (3H, m, CH),
3.27 (6H, s, CH3), 2.89 (1H, d, J¼13.2 Hz, CH2), 2.88 (1H, d, J¼13.2 Hz,
CH2), 2.56 (1H, d, J¼13.2 Hz, CH2), 2.55 (1H, d, J¼13.2 Hz, CH2), 1.53
(3H, s, CH3), 1.52 (3H, s, CH3), 0.94 (3H, s, CH3), 0.93 (3H, s, CH3), 0.74
(3H, s, CH3), 0.72 (3H, s, CH3); dC (100 MHz, CDCl3) 207.38 and

7134
P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
207.37 (C), 176.3 (C), 143.09 and 143.08 (C), 136.7 (C), 133.62 and
133.59 (CH), 129.54 and 129.52 (C), 128.88 and 128.85 (CH), 128.63
and 128.62 (CH), 127.1 (CH), 123.02 and 122.98 (CH), 122.79 and
122.78 (CH), 108.4 (CH), 60.9 (C), 50.60 and 50.57 (C), 45.77 and
45.76 (CH2), 26.4 (CH3), 24.9 and 24.8 (CH3), 23.4 (CH3), 22.6 and
22.5 (CH3); HRMS (ESI): MNaþ, found 587.2876. [C36H40N2NaO4]þ
requires 587.2880.
the title compound dl/meso-29i (50:50, 0.131 g, 63%) as a colourless
solid, mp 105e107 ꢀC; Rf 0.28 (hexane/EtOAc, 3:1); nmax (ATR, cmꢁ1
)
2970, 1709, 1693, 1608, 1490, 1469, 1446, 1368, 1341, 1253, 1129,
1076, 1055, 1022; dH (400 MHz, CDCl3) 7.34 (1H, td, J¼7.7, 1.2 Hz,
CH), 7.33 (1H, td, J¼7.7, 1.2 Hz, CH), 7.29e7.26 (6H, m, CH), 7.20e7.16
(4H, m, CH), 7.07 (0.5H, d, J¼7.4 Hz, CH), 7.03 (0.5H, d, J¼7.4 Hz, CH),
6.96 (1H, td, J¼7.6, 0.6 Hz, CH), 6.93 (1H, td, J¼7.6, 0.6 Hz, CH),
6.91e6.81 (6H, m, CH), 6.68e6.66 (1H, m, CH), 3.192 (3H, s, CH3),
3.188 (3H, s, CH3), 2.92 (1H, d, J¼12.9 Hz, CH2), 2.90 (1H, d,
J¼12.9 Hz, CH2), 2.75 (1H, d, J¼12.9 Hz, CH2), 2.71 (1H, d, J¼12.9 Hz,
CH2), 1.13 (3H, s, CH3), 1.12 (3H, s, CH3), 0.82 (3H, s, CH3), 0.80 (3H, s,
CH3); dC (100 MHz, CDCl3) 207.3 and 207.2 (C), 174.6 (C), 143.97 and
143.95 (C), 138.0 (C), 136.72 and 136.69 (C), 133.8 and 133.7 (CH),
129.5 and 129.4 (CH), 129.2 and 129.1 (CH), 128.5 (CH), 128.1 (CH),
127.8 (CH), 127.13 and 127.11 (CH), 126.00 and 125.99 (CH), 125.5
and 125.4 (C), 122.8 and 122.7 (CH), 108.63 and 108.61 (CH), 70.40
and 70.39 (C), 51.24 and 51.17 (C), 45.5 and 45.3 (CH2), 26.66 and
26.65 (CH3), 24.9 and 24.5 (CH3), 22.5 and 22.2 (CH3); HRMS (ESI):
MNaþ, found 711.3170. [C46H44N2NaO4]þ requires 711.3193.
4.5.7. dl/meso-5-Methoxy-3-[2-({3-[3-(5-methoxy-1,3-dimethyl-2-
oxo-2,3-dihydro-1H-indol-3-yl)-2,2-dimethyl-3-oxopropyl]phenyl}
methyl)-2-methylpropanoyl]-1,3-dimethyl-2,3-dihydro-1H-indol-2-
one (dl/meso-29g). Bis-anilide dl/meso-28g (0.305 g, 0.485 mmol)
and Cu(OAc)2$H2O (97.0 mg, 0.485 mmol) in mesitylene (4.9 mL)
were subjected to general procedure 3. The crude product was
purified by column chromatography (SiO2, hexane/EtOAc, 9:1 to
4:1) to give the title compound dl/meso-29g (50:50, 0.223 g, 74%) as
a colourless solid, mp 60e62 ꢀC; Rf 0.09 (hexane/EtOAc, 3:1); nmax
(ATR, cmꢁ1) 2970, 2931, 1703, 1689, 1598, 1497, 1469, 1433, 1369,
1348, 1288, 1235, 1202, 1173, 1106, 1036, 985; dH (400 MHz, CDCl3)
7.04 (1H, td, J¼7.7, 3.4 Hz, CH), 6.85e6.82 (2H, m, CH), 6.76 (2H, dt,
J¼8.6, 1.8 Hz, CH), 6.72 (2H, d, J¼8.6 Hz, CH), 6.65 (0.5H, s, CH), 6.64
(0.5H, s, CH), 6.40 (1H, d, J¼2.4 Hz, CH), 6.37 (1H, d, J¼2.4 Hz, CH),
3.68 (3H, s, CH3), 3.67 (3H, s, CH3), 3.22 (6H, s, CH3), 2.82 (2H, d,
J¼12.7 Hz, CH2), 2.58 (2H, d, J¼12.7 Hz, CH2), 1.49 (6H, s, CH3), 0.88
(3H, s, CH3), 0.87 (3H, s, CH3), 0.75 (3H, s, CH3), 0.72 (3H, s, CH3); dC
(100 MHz, CDCl3) 207.6 and 207.5 (C), 176.01 and 176.00 (C), 156.1
(C), 136.64 and 136.63 (C), 136.56 and 136.55 (C), 133.53 and 133.52
(CH), 130.90 and 130.87 (C), 128.92 and 128.89 (CH), 126.99 and
126.96 (CH), 113.0 (CH), 110.4 and 110.3 (CH), 108.8 (CH), 61.22 and
61.21 (C), 55.6 (CH3), 50.59 and 50.56 (C), 45.53 and 45.52 (CH2),
26.5 (CH3), 24.4 and 24.2 (CH3), 23.6 (CH3), 23.0 and 22.8 (CH3);
HRMS (ESI): MNaþ, found 647.3106. [C38H44N2NaO6]þ requires
647.3092.
4.5.10. meso-3-(2-{4-[2-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-
3-yl)propan-2-yl]phenyl}propan-2-yl)-1,3-dimethyl-2,3-dihydro-1H-
indol-2-one (meso-29j) and dl-3-(2-{4-[2-(1,3-dimethyl-2-oxo-2,3-
dihydro-1H-indol-3-yl)propan-2-yl]phenyl}propan-2-yl)-1,3-
dimethyl-2,3-dihydro-1H-indol-2-one (dl-29j). Bis-anilide dl/meso-
28j (0.189 g, 0.350 mmol) and Cu(OAc)2$H2O (70.0 mg, 0.350 mmol)
in mesitylene (3.5 mL) were subjected to general procedure 3. The
crude product was purified by column chromatography (SiO2,
hexane/EtOAc, 1:9 to 1:4) to give the title compound meso-29j
(49.7 mg, 27%) as a colourless solid, mp 213e214 ꢀC; Rf 0.34 (hex-
ane/EtOAc, 3:1); nmax (ATR, cmꢁ1) 2979, 1691, 1606, 1490, 1471,
1450, 1374, 1343, 1251, 1118, 1095, 1033, 999; dH (400 MHz, CDCl3)
7.12 (2H, td, J¼7.6, 1.2 Hz, CH), 6.98 (2H, dd, J¼7.3, 0.9 Hz, CH), 6.89
(2H, td, J¼7.5, 0.7 Hz, CH), 6.43 (4H, s, CH), 6.37 (2H, d, J¼7.7 Hz, CH),
2.66 (6H, s, CH3), 1.53 (6H, s, CH3), 1.48 (6H, s, CH3), 1.36 (6H, s, CH3);
dC (100 MHz, CDCl3) 206.9 (C), 175.7 (C), 142.4 (C), 139.1 (C), 130.3
(C), 128.4 (CH), 126.7 (CH), 123.2 (CH), 122.5 (CH), 107.9 (CH), 60.7
(C), 53.2 (C), 29.2 (CH3), 25.9 (CH3), 24.1 (CH3), 24.0 (CH3); HRMS
(ESI): MNaþ, found 559.2565. [C34H36N2NaO4]þ requires 559.2567.
CCDC 1031379 contains the supplementary crystallographic data
for this compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
The diastereoisomer dl-29j (53.1 mg, 28%) was then isolated as
a colourless solid, mp 195e196 ꢀC; Rf 0.22 (hexane/EtOAc, 3:1); nmax
(ATR, cmꢁ1) 2978, 1704, 1692, 1609, 1493, 1471, 1449, 1373, 1343,
1256, 1121, 1032, 997; dH (400 MHz, CDCl3) 7.08 (2H, td, J¼7.6,
1.2 Hz, CH), 6.93 (2H, dd, J¼7.4, 0.6 Hz, CH), 6.83 (2H, td, J¼7.4,
0.6 Hz, CH), 6.43 (4H, s, CH), 6.34 (2H, d, J¼7.7 Hz, CH), 2.68 (6H, s,
CH3), 1.62 (6H, s, CH3), 1.47 (6H, s, CH3), 1.30 (6H, s, CH3); dC
(100 MHz, CDCl3) 206.9 (C), 175.8 (C), 142.3 (C), 139.2 (C), 130.1 (C),
128.3 (CH), 126.7 (CH), 123.2 (CH), 122.4 (CH), 107.9 (CH), 60.6 (C),
53.3 (C), 29.1 (CH3), 25.9 (CH3), 24.2 (CH3), 23.8 (CH3); HRMS (ESI):
MNaþ, found 559.2566. [C34H36N2NaO4]þ requires 559.2567. CCDC
1031380 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
4.5.8. dl/meso-5-(Trifluoromethyl)-3-[2-({3-[3-(5-(trifluoromethyl)-
1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-2,2-dimethyl-3-
oxopropyl]phenyl}methyl)-2-methylpropanoyl]-1,3-dimethyl-2,3-
dihydro-1H-indol-2-one (dl/meso-29h). Bis-anilide dl/meso-28h
(0.211 g, 0.300 mmol) and Cu(OAc)2$H2O (60.0 mg, 0.300 mmol) in
mesitylene (3 mL) were subjected to general procedure 3. The
crude product was purified by column chromatography (SiO2,
hexane/EtOAc, 9:1 to 4:1) to give the title compound dl/meso-29h
(50:50, 0.106 g, 50%) as a colourless solid, mp 68e70 ꢀC; Rf 0.12
(hexane/EtOAc, 3:1); nmax (ATR, cmꢁ1) 2971, 1717, 1694, 1620, 1503,
1471, 1452, 1372, 1343, 1324, 1288, 1254, 1215, 1157, 1115, 1067, 1025,
984; dH (400 MHz, CDCl3) 7.54 (2H, d, J¼8.2 Hz, CH), 7.05e7.01 (2H,
m, CH), 6.98 (1H, s, CH), 6.91 (2H, d, J¼8.2 Hz, CH), 6.83e6.80 (2H,
m, CH), 6.64e6.62 (1H, m, CH), 3.294 (3H, s, CH3), 3.292 (3H, s, CH3),
2.88 (2H, d, J¼13.2 Hz, CH2), 2.55 (1H, d, J¼13.2 Hz, CH2), 2.54 (1H, d,
J¼13.2 Hz, CH2), 1.55 (3H, s, CH3), 1.54 (3H, s, CH3), 0.92 (3H, s, CH3),
0.91 (3H, s, CH3), 0.73 (3H, s, CH3), 0.72 (3H, s, CH3); dC (100 MHz,
CDCl3) 206.6 (C), 176.4 (C), 146.0 (C), 136.46 and 136.45 (C), 133.32
and 132.29 (CH), 130.22 and 130.18 (C), 128.9 (CH), 127.32 and
127.31 (CH), 126.6 (q, J¼4.0 Hz, CH), 125.2 (q, J¼32.1 Hz, C), 123.9 (q,
J¼272 Hz, C), 120.11 and 120.07 (q, J¼3.7 Hz, CH), 108.3 (CH), 60.6
(C), 50.9 and 50.8 (C), 45.64 and 45.58 (CH2), 26.7 (CH3), 24.9 and
24.6 (CH3), 23.7 (CH3), 22.8 and 22.6 (CH3); HRMS (ESI): MNaþ,
found 723.2620. [C38H38F6N2NaO4]þ requires 723.2628.
4.5.9. dl/meso-3-[2-({3-[3-(2,2-Dimethyl-3-(1-methyl)-2-oxo-3-
phenyl-2,3-dihydro-1H-indol-3-yl)-3-oxopropyl]phenyl}methyl)-2-
methylpropanoyl]-1-methyl-3-phenyl-2,3-dihydro-1H-indol-2-one
(dl/meso-29i). Bis-anilide dl/meso-28i (0.208 g, 0.300 mmol) and
Cu(OAc)2$H2O (60.0 mg, 0.300 mmol) in mesitylene (3 mL) were
subjected to general procedure 3. The crude product was purified
by column chromatography (SiO2, hexane/EtOAc, 9:1 to 4:1) to give
4.6. General procedure 4 for the formation of di-ester-con-
taining bis-oxindoles 32aec
To a stirred solution of bis-anilide 31 (1 equiv) in mesitylene
(0.04e0.06 M) was added Cu(OAc)2$H2O (1 equiv). The reaction
mixture was stirred for 30 min to 2 h at 170 ꢀC under an atmo-
sphere of air and allowed to cool to room temperature. Mesitylene

P. Drouhin et al. / Tetrahedron 71 (2015) 7124e7136
7135
was removed, the residue was diluted with EtOAc (5 mL), and
washed with an aq soln of NH4OH (5 mL). The aqueous phase was
extracted with EtOAc (2ꢂ5 mL). The combined organic extracts
were washed with water (5 mL), and brine (5 mL), dried (MgSO4),
filtered and concentrated in vacuo. The crude product was purified
by column chromatography (SiO2, hexane/EtOAc, 3:1) to give the
title compound 32.
J¼7.4 Hz, CH), 6.74e6.68 (2H, m, CH), 6.68e6.63 (2H, m, CH), 6.54
(1H, d, J¼7.4 Hz, CH), 6.50 (1H, d, J¼7.4 Hz, CH), 4.15 (4H, dq, J¼14.4,
7.2 Hz, CH2), 3.64 (1H, d, J¼14.2 Hz, CH2), 3.39 (1H, d, J¼14.2 Hz,
CH2), 3.33 (1H, d, J¼14.2 Hz, CH2), 3.18 (1H, d, J¼14.2 Hz, CH2), 2.93
(3H, s, CH3), 2.91 (3H, s, CH3), 1.17 (3H, t, J¼7.1 Hz, CH3), 1.15 (3H, t,
J¼7.1 Hz, CH3); dC (100 MHz, CDCl3) 173.8 and 173.7 (C), 169.3 and
169.2 (C), 144.0 and 143.4 (C), 134.1 and 133.8 (C), 129.9 and 129.7
(CH), 129.1 and 129.0 (CH), 127.4 and 127.1 (C), 126.1 and 126.0 (CH),
124.4 and 124.2 (CH), 122.4 and 122.3 (CH), 108.03 and 108.01 (CH),
62.1 and 62.0 (CH2), 61.0 and 60.9 (C), 35.94 and 35.87 (CH2), 26.2
(CH3), 14.0 (CH3); HRMS (ESI): MNaþ, found 563.2163.
[C32H32N2NaO6]þ requires 563.2153.
4.6.1. dl/meso-Ethyl 3-{4-[3-(ethoxycarbonyl)-1-methyl-2-oxo-2,3-
dihydro-1H-indol-3-yl]butyl}-1-methyl-2-oxo-2,3-dihydro-1H-in-
dole-3-carboxylate
(dl/meso-32a). Bis-anilide
dl/meso-31a
(60.1 mg, 0.121 mmol) and Cu(OAc)2$H2O (24.2 mg, 0.121 mmol) in
mesitylene (2 mL) were subjected to general procedure 4. The re-
action mixture was stirred at 170 ꢀC for 30 min. The crude product
was purified by column chromatography (SiO2, hexane/EtOAc, 3:1)
to give the title compound dl/meso-32a (50:50, 53.9 mg, 90%) as
a yellow solid, mp 145e147 ꢀC; Rf 0.35 (hexane/EtOAc, 1:2); nmax
(ATR, cmꢁ1) 1736, 1709, 1609, 1492, 1470, 1372, 1346, 1223, 1081,
1020, 750, 727; dH (400 MHz, CDCl3) 7.29 (1H, td, J¼7.4, 1.2 Hz, CH),
7.28 (1H, td, J¼7.4, 1.2 Hz, CH), 7.16 (1H, dd, J¼7.4, 1.2 Hz, CH), 7.15
(1H, dd, J¼7.4, 1.2 Hz, CH), 7.04 (1H, td, J¼7.4, 1.2 Hz, CH), 7.02 (1H,
td, J¼7.4, 1.2 Hz, CH), 6.80 (2H, t, J¼8.3 Hz, CH), 4.13e4.02 (4H, m,
CH2), 3.20 (3H, s, CH3), 3.18 (3H, s, CH3), 2.15e2.00 (4H, m, CH2), 1.12
(3H, t, J¼7.1 Hz, CH3), 1.10 (3H, t, J¼7.1 Hz, CH3), 0.99e0.73 (4H, m,
CH2); dC (100 MHz, CDCl3) 174.3 and 174.2 (C), 169.4 (C), 144.1 (C),
129.1 and 129.0 (CH), 128.1 and 128.0 (C), 123.37 and 123.36 (CH),
123.0 and 122.8 (CH), 108.3 (CH), 61.9 (CH2), 59.5 and 59.4 (C), 34.0
and 33.9 (CH2), 26.47 and 26.45 (CH3), 23.63 and 23.55 (CH2), 13.99
and 13.98 (CH3); HRMS (ESI): MNaþ, found 515.2153.
[C28H32N2NaO6]þ requires 515.2153.
Acknowledgements
We thank the University of York Wild Fund for postgraduate
support (P.D.), and the Engineering and Physical Sciences Research
Council for postdoctoral funding (T.E.H.; EP/J000124/1).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.02.060.
References and notes
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(b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
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4.6.2. dl/meso-Ethyl 3-[(2E)-4-[3-(ethoxycarbonyl)-1-methyl-2-oxo-
2,3-dihydro-1H-indol-3-yl]but-2-en-1-yl]-1-methyl-2-oxo-2,3-
dihydro-1H-indole-3-carboxylate (dl/meso-32b). Bis-anilide dl/
meso-31b (49.4 mg, 0.100 mmol), and Cu(OAc)2$H2O (20.0 mg,
0.100 mmol) in mesitylene (2 mL) were subjected to general pro-
cedure 4. The reaction mixture was stirred at 170 ꢀC for 2 h. The
residue was purified by column chromatography (SiO2, hexane/
EtOAc, 2:1) to give the title compound dl/meso-32b (50:50, 32.3 mg,
66%) as a yellow solid, mp 130e132 ꢀC; Rf 0.35 (hexane/EtOAc, 1:1);
nmax (ATR, cmꢁ1) 1736,1711,1609,1493,1470,1372,1347,1223,1086,
1021, 750, 729; dH (400 MHz, CDCl3) 7.28 (2H, td, J¼7.6, 1.1 Hz, CH),
7.14e7.09 (2H, m, CH), 7.04e6.98 (2H, m, CH), 6.79 (2H, d, J¼7.6 Hz,
CH), 5.02 (1H, dd, J¼4.4, 3.6 Hz, CH), 4.94 (1H, d, J¼3.6 Hz, CH),
4.11e4.00 (4H, m, CH2), 3.21 (3H, s, CH3), 3.14 (3H, s, CH3), 2.80 (2H,
td, J¼14.1, 3.2 Hz, CH2), 2.69e2.55 (2H, m, CH2), 1.10 (3H, t, J¼7.1 Hz,
CH3),1.09 (3H, t, J¼7.1 Hz, CH3); dC (100 MHz, CDCl3) 173.6 and 173.5
(C), 169.04 and 168.94 (C), 144.2 and 144.1 (C), 129.0 (CH), 127.9 and
127.61 (CH), 127.56 and 127.49 (C), 123.7 and 123.5 (CH), 122.8 and
122.7 (CH), 108.5 and 108.3 (CH), 61.9 and 61.8 (CH2), 59.3 and 59.1
(C), 35.64 and 35.57 (CH2), 26.6 and 26.5 (CH3), 14.0 (CH3); HRMS
(ESI): MNaþ, found 513.1997. [C28H30N2NaO6]þ requires 513.1996.
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4.6.3. dl/meso-Ethyl 3-[(2-{[(ethoxycarbonyl)-1-methyl-2-oxo-2,3-
dihydro-1H-indol-3-yl]methyl}phenyl)methyl]-1-methyl-2-oxo-2,3-
dihydro-1H-indole-3-carboxylate (dl/meso-32c). Bis-anilide dl/
meso-31c (60.2 mg, 0.111 mmol), and Cu(OAc)2$H2O (24.0 mg,
0.120 mmol) in mesitylene (3 mL) were subjected to general pro-
cedure 4. The reaction mixture was stirred at 170 ꢀC for 2 h. The
residue was purified by column chromatography (SiO2, hexane/
EtOAc, 2:1) to give the title compound dl/meso-32c (50:50, 48.3 mg,
89%) as a white solid, mp 113e115 ꢀC; Rf 0.42 (hexane/EtOAc, 1:2);
nmax (ATR, cmꢁ1) 1735, 1710, 1609, 1492, 1470, 1372, 1351, 1222,
1095, 1060, 1021, 751, 728; dH (400 MHz, CDCl3) 7.24 (1H, d,
J¼7.4 Hz, CH), 7.18 (1H, t, J¼7.4 Hz, CH), 7.14 (1H, t, J¼7.4 Hz, CH),
7.08 (1H, d, J¼7.4 Hz, CH), 6.98 (1H, t, J¼7.4 Hz, CH), 6.95 (1H, t,

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