Copper(ii) chloride mediated (aza)oxindole synthesis by oxidative coupling of Csp2-H and Csp3-H centers: Substrate scope and DFT study

Article abstract of DOI:10.1039/c3ob41254g

A CuCl₂ mediated direct intramolecular oxidative coupling of Csp²-H and Csp³-H centers gives access to 3,3-disubstituted oxindoles containing aromatic, heteroaromatic and alkyl substituents as well as a heteroatom at the quaternary center in good to excellent yields. The reaction is carried out in the presence of NaOtBu and CuCl₂ in DMF at 110 °C. The key step of this reaction is the formation of an amidyl radical by one electron oxidation of amide enolate followed by an intramolecular radical cyclization reaction (homolytic aromatic substitution reaction). A detailed DFT study shows that the cyclization of the amidyl radical is the rate-limiting step in the oxindole synthesis, whereas the second single electron transfer (SET) becomes the rate-determining step in the aza-oxindole formation. Computational data are in agreement with the experimentally observed relative reactivity and regioselectivity.

Full text of DOI:10.1039/c3ob41254g

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PAPER
Copper(II) chloride mediated (aza)oxindole synthesis
by oxidative coupling of Csp2–H and Csp3–H centers:
substrate scope and DFT study†
Cite this: Org. Biomol. Chem., 2013, 11,
6734
Chandan Dey, Evgeny Larionov and E. Peter Kündig*
A CuCl2 mediated direct intramolecular oxidative coupling of Csp2–H and Csp3–H centers gives access to
3,3-disubstituted oxindoles containing aromatic, heteroaromatic and alkyl substituents as well as a hetero-
atom at the quaternary center in good to excellent yields. The reaction is carried out in the presence of
NaOtBu and CuCl2 in DMF at 110 °C. The key step of this reaction is the formation of an amidyl radical by
one electron oxidation of amide enolate followed by an intramolecular radical cyclization reaction
(homolytic aromatic substitution reaction). A detailed DFT study shows that the cyclization of the amidyl
radical is the rate-limiting step in the oxindole synthesis, whereas the second single electron transfer
(SET) becomes the rate-determining step in the aza-oxindole formation. Computational data are in
agreement with the experimentally observed relative reactivity and regioselectivity.
Received 18th June 2013,
Accepted 6th August 2013
DOI: 10.1039/c3ob41254g
www.rsc.org/obc
Introduction
Oxindoles are interesting synthetic targets for organic chemists
owing to the presence of this heterocyclic motif in many
natural products and pharmaceutically active compounds.1–8
Numerous synthetic approaches to these moieties have been
developed.1–5,9 Out of the many, one efficient and straightfor-
ward method to construct the oxindole core is the intramole-
cular homolytic aromatic substitution on the phenyl ring by
an amidyl radical. The amidyl radical can be generated by
(1) homolysis of a C–X bond (X = heteroatom such as Br,10 S,11
Se,12 O13); (2) single electron transfer to an α-halo amide
followed by halide elimination;14,15 (3) generation of an aryl
radical followed by a 1,5-hydrogen atom translocation (1,5-
HAT);16,17 (4) a one electron oxidation of an amide enolate18–26
(Scheme 1). The first three of these approaches require specifi-
cally functionalized precursors, such as the presence of an
o- or α-halogen, an α-selenium, an α-xanthate or an α-tempo
group, respectively. This work will focus on the fourth strategy
for the generation of the amidyl radicals.
In the course of our studies on asymmetric 3,3-disubstituted
oxindole synthesis via Pd(chiral N-heterocyclic carbene) cata-
lysed intramolecular α-arylation of amide,27 we discovered a
Scheme 1 Generation of amidyl radical.
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet,
1211 Geneva 4, Switzerland. E-mail: peter.kundig@unige.ch; http://www.unige.ch/
novel, efficient and highly atom-economical route to access
racemic 3,3-disubstituted oxindoles.18 This relied on the direct
oxidative coupling of aromatic Csp2–H and Csp3–H centers.
Amidyl radicals were formed by one electron oxidation
of amide enolates (NaOtBu–CuCl2). Radical addition to the
sciences/chiorg/kundig/; Fax: +41 22-379-3215; Tel: +41 22-379-6093
†Electronic supplementary information (ESI) available: Experimental details,
spectral characterisation and analytical data of reported compounds, as well as
details of the calculations and full ref. 42. See DOI: 10.1039/c3ob41254g
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conditions (entry 2). The cyclization protocol was extended to
the meta-substituted anilide substrates (1c–1e) and, as
expected, these substrates afforded two regioisomeric products
(2c–2e and 2c′–2e′) arising from the addition of the amidyl
radicals ortho or para to the substituent (entries 3–5). The reac-
tion with m-Me substituted acetanilide 1c afforded 2c and 2c′
in a 1 : 1 ratio in 99% yield (entry 3). Interestingly, electron-
rich m-OMe substituted acetanilide 1d afforded quantitatively
a 77 : 23 mixture of 2d and 2d′ (entry 4).30 The m-CF3-substi-
tuted substrate 1e reacted sluggishly (entry 5) and yielded a
mixture of 2e and 2e′ in only 48% yield with a selectivity oppo-
site to that observed for 2d/2d′. Unidentified decomposition
products were an important component in this reaction.
Compounds containing the 3-alkyl-3-heteroaryloxindole
structural motif exhibit important biological activities such as
preventing sodium channel mediated diseases.31,32 We have
extended the CuCl2-mediated oxidative coupling protocol to
the synthesis of 3-methyl-3-pyridyl oxindole derivatives. The
data in Table 1 show that the oxindoles containing o-, m-, and
p-pyridyl groups as well as the quinoline group at the quater-
nary center (2f–2i) were obtained in excellent yields (entries
6–9). However, the amide substrates containing an α-furyl (1o)
or α-thiophenyl (1p) group did not cyclize under the reaction
conditions. Instead decomposition of the starting materials
was observed (Fig. 1).
Oxindoles bearing heteroatoms at the quaternary center are
very useful compounds in the pharmaceutical field.33–35 Syn-
thesis of 3-alkoxy-3-phenyloxindole and 3-amino-3-phenyloxin-
doles will be presented in this section. Reaction with the
α-methoxy amide 1j resulted in the formation of 3-methoxy-3-
phenyloxindole 2j, albeit in modest yield (entry 10).18 Exten-
sion of the synthesis protocol to 3-phenyl-3-aminooxindoles
was probed next. Substrate 1k did not afford the corresponding
oxindole (entry 11). Changing the oxidant (CuCl2, Cu(OAc)2,
Cu(OTf)2), base (NaOtBu, KOtBu), and conditions (tempera-
ture, time, and microwave irradiation (170 °C)) also did not
help. The reluctance of the amidyl radical derived from 1k to
react with the phenyl ring may be due to the ‘capto-dative
stabilization’ of the radical as it is α- to the electron-withdraw-
ing amide group as well as α- to the electron-donating amine
substituent. This mutual reinforcement of the two substituent
Scheme 2 Oxindole and aza-oxindole synthesis by oxidative coupling.
phenyl ring, oxidation and aromatisation afforded oxindoles in
fair to excellent yields (Scheme 2).18 Subsequently, Taylor,19–23
Yu,24 and Bisai25,26 reported similar intramolecular oxidative
coupling reactions using Cu(OAc)2, Ag2O, I2 or DDQ as
oxidants.
The CuCl2-mediated oxidative coupling protocol was
extended to the synthesis of 3,3-disubstituted aza-oxindoles.28
The key step of this transformation is a Minisci reaction, the
intramolecular radical cyclization on a pyridine ring. This
method was applied to a range of o-, m-, and p-pyridyl amides
to obtain aza-oxindoles in good to excellent yields (Scheme 2).
In the course of these studies, we also found a new route to
aza-oxindoles that proceeded via a base promoted Truce–
Smiles rearrangement.29
Here we report an extension of the substrate scope in the
radical coupling reaction (Scheme 1, path 4). Notably we show
that the reaction can be scaled up and that it can be used to
prepare oxindoles with OR, NR2, pyridyl, and quinoline substi-
tuents at C(3). In the second part we show the results of a
detailed DFT study to better understand the mechanism of the
oxidative coupling reactions with a focus on the reactivity and
regioselectivity of the process.
Results and discussion
Substrate scope
The requisite amide substrates were prepared by one of the effects is diminished in substrate 1l and indeed it afforded the
following methods (see ESI† for detailed procedures):
(a) amide coupling between acids and amines (1a–e, 1g)
oxindole 2l in 61% yield (entry 12). Two other 3-aminooxin-
doles 2m and 2n were obtained in moderate yields (entries
(b) by nucleophilic substitution reaction of carbamoyl 13–14), whereas the α-phthalimidyl amide 1q did not cyclize
chloride with pyridyl carbanions followed by α-methylations under the reaction conditions, and instead resulted in its
(1f, 1h, 1i)
(c) by nucleophilic substitution reaction of α-chloroacetani-
lide with amides (or amines) (1k–n).
decomposition.
Computational study
The intramolecular oxidative cyclization was carried out In order to probe the mechanism of oxidative coupling and in
using the cyclization conditions developed previously.18
particular to delineate the copper species undergoing single
Entry 1 of Table 1 shows that the reaction with substrate 1a electron transfer (SET) as well as to identify the rate-limiting
can readily be scaled up to 26 mmol without serious loss of step(s), we have carried out a detailed computational study.
yield compared to the previously reported reaction on the Another focus was to rationalize the reactivity differences for
1 mmol scale (83% vs 93%18) (Table 1, entry 1).23 3-Allyl-3-phe- oxindole vs. azaoxindole synthesis and to explain the regio-
nyloxindole 2b was obtained in 45% yield under the standard selectivity observed (vide infra).
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Table 1 Scope of oxindole synthesis via intramolecular oxidative radical couplinga
Entry
1
Substrate
Product
Time (h)
5.5
Yieldb (%)
93 (83)c
2
3
24
5
45
99d [2c/2c′ 50/50]
4
5
98d [2d/2d′ 77/23]
5
9
48d,e [2e/2e′ 34/66]
6
7
8
18
18
18
82
88
88
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Table 1 (Contd.)
Entry
9
Substrate
Product
Time (h)
18
Yieldb (%)
89
10
11
5
38f
24
n.r.g,h
12
13
12
12
61
33
14
12
30
a 1.0 mmol scale for 1a18 and 0.2–0.5 mmol scale for 1b–n in DMF (0.05 M). b Isolated yield. c 26.0 mmol scale
for 1a in DMF (0.1 M). d Isolated combined yield of two regioisomeric products. e 2e was obtained together with
an inseparable, unidentified impurity. f Ref. 18. g No reaction; a small amount of unidentified complex mixture
obtained together with recovered starting material. h Different oxidants (CuCl2, Cu(OAc)2, Cu(OTf)2), bases
(NaOtBu, KOtBu), and microwave irradiation (170 °C) were screened.
Scheme 3 Reaction free energies (in DMF) for the formation of Cu tert-butox-
ide complexes.
Fig. 1 Unsuitable substrates.
First, we studied the copper species present in the reaction Cu(II) species in DMF solution. This is in accordance with the
mixture (Scheme 3). The computational data show that substi- literature data.36
tution of chloride for tert-butoxide in CuCl2 lowers the free
Different pathways for the reduction half-reaction of the
energy by 161 kJ mol−1. Cu(OtBu)2 is indeed the most stable SET step were considered next (Scheme 4). CuCl2 is a better
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reduction of Cu(OtBu)2 with the formation of neutral CuOtBu
and NaOtBu (eqn (2): ΔGSET = −307 kJ mol−1). Reduction of
Cu(OtBu) to copper (0) is much less favourable (eqn (5): ΔGSET
= −233 kJ mol−1).
The mechanism of copper(II) mediated cyclization was then
calculated (Fig. 2). Due to the complexity of the system, par-
ticularly the ability of Cu to coordinate to the amide oxygen,
several scenarios with Cu(I) and Cu(II) coordinated to the sub-
strate oxygen were considered (see ESI† for details). However,
Scheme 4 Possible pathways for the reduction half-reaction of the SET step the most favourable pathway proceeds via intermediates with
(in DMF).
non-bound oxygen and this is discussed in detail (Fig. 2).
The first step, deprotonation of the amide (1a) by NaOtBu
to give intermediate 3a, is slightly endergonic: ΔGrxn = 15.5 kJ
oxidant than Cu(OtBu)2, but if the free energies of ligand mol−1. The SET to amide enolate 4a to form the radical 5a pro-
exchange (from Scheme 3) are taken into account, Cu(OtBu)2 ceeds intermolecularly with almost no energy gain: ΔGrxn
=
turns out to be the best oxidant under the reaction conditions. −0.5 kJ mol−1. The key step, cyclisation of radical 5a, proceeds
The most energetically favourable pathway is through the via the transition state TS5a–6a to give a radical intermediate
Fig. 2 Free energy reaction profile (ΔG298 in DMF, kJ mol−1) for the copper(II) mediated oxindole synthesis.
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Table 2 Spin densities on selected carbon atoms
Atom
5a
TS5a–6a
6a
C1
C2
C3
C4
C5
C6
C7
0.713
0.206
0.221
0.205
0.000
0.002
0.001
0.453
0.094
0.099
0.096
0.279
0.314
0.221
0.030
0.002
0.002
0.004
0.437
0.542
0.330
Scheme 5 Copper(II) mediated (aza)-oxindole synthesis.
the sake of comparison, we carried out the synthesis of 2a in
toluene. The product was isolated in 88% yield, but after a
much longer reaction time than with the aza-substrates 1r–t
(Scheme 5). The substrates 1r and 1s are slightly more reactive
than 3-aminopyridine derivative 1t.
6a. This step has an activation barrier of ΔGact = 75.5 kJ mol−1
We have calculated the key intermediates and transition
and is rate-determining (Fig. 2). The radical 6a is slightly more state for the azaoxindole synthesis in toluene (Fig. 3). Switch-
stable (8.7 kJ mol−1) than 5a. This is due to the compensation ing the solvent from DMF to toluene does not change the rate-
of two effects which operate in opposite directions: broken aro- limiting step (cyclisation of radical 5a) in oxindole formation.
maticity and delocalisation of the unpaired spin through the However, the activation barrier is higher in toluene, reflecting
system of conjugated double bonds in 6a. In order to shed a lower reactivity of 1a in this solvent compared to DMF. In
light on the nature of the radical species involved in the cycli- contrast to the cyclisation of 1a, intermediates 7r–t have
sation step, we have compared the spin densities (from Mulli- higher free energy than transition states TS5–6 for the reaction
ken population analysis) on selected carbon atoms (Table 2). of aza-substrates 1r–t. The second SET is therefore rate-deter-
An unpaired spin in radical 5a is mostly located on C1 with mining for the cyclisation of 1r–t. This switch of the rate-limit-
some delocalisation on ortho- and para-carbons (C2, C3, C4) of ing step is by virtue of two factors: the lower activation energy
the phenyl group. In contrast, in the cyclised intermediate 6a of the cyclisation step and the higher energy of the second SET
the spin is more delocalised in the benzene ring (on atoms C5, for aza-substrates 1r–t. The former is due to the stabilisation
C6, C7) with the highest density on C6. The transition state of radical 6 in the pyridine ring, whereas the latter is a conse-
TS5a–6a can be considered as late since the total spin density quence of the destabilisation of cation 7. For meta-substituted
on atoms C5–C7 is higher than that on C1. A comparison of substrate 1t, the cations 7t′ and 7t″ are more destabilised
the lengths of the formed C–C bond in 5a, TS5a–6a and 6a is because of the positive charge on the nitrogen atom in one of the
also in favour of a late TS (Fig. 2).
resonance structures of 7t′/7t″. On the whole, the stability of
The second SET to 6a gives a cationic intermediate 7a, cations 7 decreases in the order 7a > 7r > 7s > 7t′. This order
which is 50.9 kJ mol−1 higher in energy than the radical 6a. It correlates well with the N–C(vO) distance, which increases
was shown that the activation free energies for SET estimated from 7a to 7t′ (Fig. 4).
using Marcus theory are often very close to the reaction ener-
For substrates 1r and 1s, the energy of the second SET (73.0
gies for the formation of the intermediates.37 The activation and 70.9 kJ mol−1, respectively) is lower than the activation
barrier of the second SET can therefore be roughly estimated energy for the cyclisation of radical 5a (78.3 kJ mol−1). This is
as ΔGact ≈ 51 kJ mol−1. Deprotonation of 7a to give the in agreement with experiment, where 1a is less reactive than
aromatic product 2a is associated with a large energy gain: 1r and 1s under the reaction conditions (Scheme 5). Substrate
ΔGrxn = −218.6 kJ mol−1
.
1t gives a mixture of regioisomeric products 2t′ and 2t″ in a
In summary, the cyclization of radical 5a is the rate-limiting 84 : 16 ratio. The pathway leading to the formation of the
step in the copper mediated oxindole synthesis. The second minor product 2t″ has a consistently higher activation energy
SET has a lower activation barrier but it can become higher of cyclisation as well as energy of the second SET than for
when the cation 7a is destabilized by electron-withdrawing the formation of product 2t′ (Fig. 3). This is due to the greater
substituents. This can be the case for the CF3-substituted stability of the C-centered radical 6t′ compared to the radical
substrate 1e, which is less reactive than amides 1c and 1d with 6t″, which is N-centered (the highest spin density in 6a is on
electron-donating substituents (see Table 1). This then leads C6, vide infra). The differences in activation free energies of
us to the question of rationalizing reactivity differences in oxi- the cyclisation steps between two regioisomeric pathways can
ndole vs. azaoxindole synthesis as well as explaining the be used to estimate the ratio of products (Scheme 6). The com-
observed regioselectivity with substrate 1t (Scheme 5).
putationally predicted regioselectivity (90 : 10 in toluene and
The optimized conditions for the azaoxindole synthesis use 77 : 23 in the gas phase) is in excellent agreement with the
toluene as a solvent (rather than DMF as for oxindoles). For experimental results (84 : 16).
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Fig. 3 Comparison of free energy reaction profiles (ΔG298 in toluene, kJ mol−1) for the copper(II) mediated (aza)oxindole formation.
Scheme 6 Regioselectivity in copper(II) mediated cyclization of 1t: comparison
with experiment.
disubstituted oxindoles by the direct intramolecular CuCl2
mediated oxidative coupling of aromatic Csp2–H and Csp3–H
centers. This method has been successfully applied to a wide
range of substrates leading to oxindoles with aromatic, hetero-
aromatic, heteroatom and allyl substituents in the 3-position.
In addition, the applicability of the CuCl2 mediated oxindole
synthesis protocol in the larger scale process was also demon-
strated. The DFT study shows that Cu(OtBu)2 is formed under
Fig. 4 Structures of intermediates 7 for the copper(II) mediated azaoxindole
formation.
Conclusions
In summary, we have demonstrated the utility of an efficient the reaction conditions and acts as an oxidant for the SET
and atom economic protocol for the synthesis of 3,3- steps. The cyclization of radical 5a is the rate-limiting step in
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the copper mediated oxindole synthesis. However, the second general procedure (0.1 M concentration in DMF). Purified by
SET becomes the rate-determining step for the cyclisation of chromatography (pentane–Et2O = 2 : 1), 5.1 g (83% yield), oil.
aza-analogues 1r–t. Computational results are in line with 1H NMR (500 MHz, CDCl3): δ 7.36–7.30 (m, 5H), 7.26 (tt, J =
experimental data on the relative reactivity and regioselectivity, 6.7, 1.5 Hz, 1H), 7.22 (dd, J = 7.5, 0.7 Hz, 1H), 7.12 (td, J = 7.5,
corroborating thus the proposed mechanistic model.
1.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 3.26 (s, 3H), 1.82 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 179.5, 143.3, 140.9, 134.9, 128.6,
128.2, 127.3, 126.7, 124.3, 122.8, 108.4, 52.2, 26.5, 23.8. IR
(neat, cm−1): 3054, 2970, 2933, 1708, 1610, 1491, 1469, 1371,
1342, 1258, 1099, 1023, 748, 729, 694. HRMS (ESI): calcd for
C16H16N1O ([M + H]+): 238.1226, found: 238.1222. Anal. calcd
for C16H15NO: C, 80.98; H, 6.37; N, 5.90, found: C, 80.74;
H, 6.20; N, 5.74.
Experimental section
The experimental procedure and characterisation of the oxi-
ndole products are described here. For the synthesis and
characterisation of the precursor amides see ESI.†
1,3,4-Trimethyl-3-phenylindolin-2-one (2c) + 1,3,6-trimethyl-
3-phenylindolin-2-one (2c′). The reaction was carried out start-
ing with 1c (0.4 mmol) according to the general procedure.
Purified by chromatography (pentane–Et2O = 2 : 1), 100 mg
(99% combined yield), (2c/2c′ = 50/50), oil. 1H NMR (300 MHz,
CDCl3): δ 7.36–7.21 (m, 11H), 7.11 (d, J = 7.6 Hz, 1H), 6.95 (d, J
= 7.5 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H),
6.79 (brs, 1H), 3.26 (s, 3H), 3.25 (s, 3H), 2.46 (s, 3H), 2.06 (s,
3H), 1.89 (s, 3H), 1.81 (s, 3H).
General information
Toluene, THF, and CH2Cl2 were dried by filtration on Al2O3
drying columns (Solvtek® system). Triethylamine was dried
over CaH2 and distilled under nitrogen. DMF (Acros) was dried
over activated 4 Å molecular sieves. NaOtBu and KOtBu were
sublimed and stored in a glove box. All reactions were carried
out under nitrogen in glassware dried by heating under
vacuum. Weighing of CuCl2, NaOtBu, and KOtBu was per-
formed in the glove box. Proton (1H) and carbon (13C{H}) NMR
spectra were recorded using Bruker AMX-400 or AMX-500 FT
spectrometers with an internal deuterium lock. Chemical
shifts are quoted in parts per million (ppm) downfield of
tetramethylsilane. Coupling constants J are quoted in Hz.
Infrared spectra were recorded using a Perkin-Elmer Spec-
trum One spectrophotometer with a diamond ATR Golden
Gate sampler. Electron impact (EI) mass spectra were
obtained using Varian CH-4 or SM-1 instruments operating at
40–70 eV. Electrospray ionization (ESI) HRMS measurements
were obtained using a VG analytical 7070E instrument.
Analytical thin layer chromatography (TLC) was performed on
13C NMR (75 MHz, CDCl3): δ 179.8, 179.4, 143.7, 143.4,
141.1, 139.6, 138.3, 134.9, 132.6, 132.0, 128.7, 128.6, 128.2,
127.24, 127.21, 126.71, 126.65, 125.2, 124.0, 123.3, 109.3,
106.0, 52.5, 52.0, 26.7, 26.5, 23.9, 21.9, 20.8, 18.3. IR (neat,
cm−1): 3042, 3025, 2966, 2928, 1709, 1613, 1600, 1467, 1369,
1047, 1026, 910, 773, 726, 695, 590. HRMS (ESI): calcd for
C17H18NO ([M + H]+): 252.1382, found: 252.1384.
4-Methoxy-1,3-dimethyl-3-phenylindolin-2-one (2d) + 6-methoxy-
1,3-dimethyl-3-phenylindolin-2-one (2d′). The reaction was
carried out starting with 1d (0.4 mmol) according to the
general procedure. Purified by chromatography (cyclohexane–
EtOAc = 3 : 2), 104 mg (98% combined yield), (2d/2d′ = 77/23),
1
Merck precoated plastic-backed TLC plates (silica gel 60 F254
)
oil. H NMR (300 MHz, CDCl3): δ 7.37–7.23 (m, 6.5H), 7.12 (d,
and visualized using a UV lamp (254 nm) and potassium per-
manganate. Flash chromatography (FC) was performed using
silica gel 60 (23–400 mesh). Technical grade solvents were
employed. Melting points were determined using a Büchi 510
apparatus.
J = 8.2 Hz, 0.7H), 6.70 (d, J = 8.4 Hz, 1.1H), 6.65 (d, J = 2.3 Hz,
0.6H), 6.61 (d, J = 7.7 Hz, 1.1H), 6.54 (d, J = 2.2 Hz, 0.3H), 3.88
(s, 0.9H), 3.75 (s, 3.0H), 3.24 (s, 0.9H), 3.23 (s, 3.1H), 1.89 (s,
3.4H), 1.80 (s, 0.9H). 13C NMR (75 MHz, CDCl3): δ 180.1, 179.8,
160.3, 156.1, 144.7, 144.6, 141.3, 140.1, 129.6, 128.6, 128.5,
128.3, 127.2, 127.1, 126.73, 126.70, 120.2, 106.7, 106.4, 101.7,
96.4, 55.7, 55.5, 52.3, 51.8, 26.8, 26.6, 24.1, 21.2. IR (neat,
General procedure for the oxidative coupling reaction
In a dry Schlenk tube amide (0.40 mmol, 1.0 equiv.), CuCl2 cm−1): 2965, 2936, 1709, 1604, 1471, 1368, 1339, 1311, 1260,
(0.88 mmol, 2.2 equiv.), and NaOtBu (2.00 mmol, 5.0 equiv.) 1064, 1027, 774, 726, 694, 578. HRMS (ESI): calcd for
were combined. DMF (8 mL) was introduced to the Schlenk C17H18NO2 ([M + H]+): 268.1332, found: 268.1331.
tube by a syringe under a N2 atmosphere. The resulting
1,3-Dimethyl-3-phenyl-4-(trifluoromethyl)indolin-2-one (2e).
mixture was stirred at 110 °C until completion of the reaction The reaction was carried out starting with 1e (0.4 mmol)
(monitored by TLC). After cooling to r.t., the mixture was fil- according to the general procedure. Purified by chromato-
tered through a short pad of celite. The filtrate was washed graphy (cyclohexane–EtOAc = 3 : 2), 20 mg (16% yield), oil.
with brine (20 mL) and extracted with EtOAc (3 × 30 mL). 1H NMR (500 MHz, CDCl3): δ 7.52 (t, J = 7.8 Hz, 1H), 7.38 (d,
The combined organic phase was washed two times with J = 7.8 Hz, 1H), 7.30–7.25 (m, 4H), 7.16 (d, J = 7.8 Hz, 1H),
brine (2 × 20 mL) and dried over anhydrous Na2SO4. The 7.10–7.08 (m, 1H), 3.29 (s, 3H), 1.94 (s, 3H). 13C NMR
solvent was evaporated and the product was purified by flash (125 MHz, CDCl3): 179.0, 145.2, 140.0, 132.5, 129.1, 129.0,
3
chromatography.
128.6, 127.4, 126.2, 120.7 (q, JC,F = 5.0 Hz), 111.6, 53.4, 27.0,
Compounds 2b,38 2e′39 and 2j18 are literature known.
21.2. IR (neat, cm−1): 3062, 2933, 1720, 1624, 1458, 1167, 1128,
1,3-Dimethyl-3-phenylindolin-2-one (2a). The reaction was 1059, 700. HRMS (ESI): calcd for C17H15F3NO ([M + H]+):
carried out starting with 1a (26.0 mmol) according to the 306.1100, found: 306.1097.
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1,3-Dimethyl-3-(pyridin-2-yl)indolin-2-one (2f). The reaction (cyclohexane–EtOAc–Et3N = 1 : 1 : 0.05), 37 mg (61% yield),
was carried out starting with 1f (0.5 mmol) according to the oil.
general procedure. Purified by chromatography (EtOAc), 97 mg
1H NMR (400 MHz, CDCl3): δ 7.53–7.51 (m, 2H), 7.40–7.33
(82% yield), oil. 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = (m, 5H), 7.14 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H),
3.9 Hz, 1H), 7.60 (td, J = 7.8, 1.8 Hz, 1H), 7.30 (dd, J = 7.7, 1.1 3.47–3.42 (m, 1H), 3.36–3.31 (m, 1H) 3.21 (s, 3H), 2.49–2.42
Hz, 1H), 7.27–7.26 (m, 2H), 7.15 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), (m, 1H), 2.30–2.23 (m, 1H), 2.13–1.99 (m, 2H). 13C NMR
7.05 (td, J = 7.5, 0.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 3.32 (s, (100 MHz, CDCl3):
δ 175.4, 174.9, 144.7, 135.3, 129.6,
3H), 1.87 (s, 3H). 13C NMR (100 MHz, CDCl3): 179.1, 159.9, 128.9, 128.7, 128.6, 128.5, 124.7, 122.6, 108.8, 66.5, 47.1,
149.7, 143.2, 136.8, 134.8, 128.2, 124.2, 122.9, 122.2, 121.0, 31.3, 27.0, 19.2. IR (neat, cm−1): 3056, 2956, 2922, 1726, 1693,
108.4, 55.1, 26.7, 23.1. IR (neat, cm−1): 3063, 2978, 2930, 1713, 1612, 1493, 1471, 1372, 1348, 1279, 757, 733, 699, 536. HRMS
1611, 1587, 1492, 1469, 1373, 1346, 1256, 1102, 1024, 751. (ESI): calcd for C19H19N2O2 ([M + H]+): 307.1441, found:
HRMS (ESI): calcd for C15H15N2O ([M + H]+): 239.1178, found: 307.1440.
239.1173.
3-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-3-phenylindo-
1,3-Dimethyl-3-(pyridin-3-yl)indolin-2-one (2g). The reaction lin-2-one (2m). The reaction was carried out starting with 1m
was carried out starting with 1g (0.2 mmol) according to the (0.4 mmol) according to the general procedure. Purified by
general procedure. Purified by chromatography (EtOAc), 42 mg chromatography (pentane–Et2O = 1 : 1), 44 mg (33% yield),
1
(88% yield), oil. H NMR (400 MHz, CDCl3): δ 8.51 (brs, 2H), solid, m.p. = 144–146 °C. 1H NMR (500 MHz, CDCl3):
7.73 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.27–7.20 δ 7.54–7.52 (m, 2H), 7.39–7.33 (m, 5H), 7.14–7.11 (m, 1H),
(m, 2H), 7.13 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.89–6.88 (m, 1H), 3.36–3.31 (m, 1H), 3.25–3.22 (m, 1H) 3.21
3.25 (s, 3H), 1.81 (s, 3H). 13C NMR (100 MHz, CDCl3): (s, 3H), 1.96–1.91 (m, 1H), 1.86–1.82 (m, 1H), 1.19 (s, 3H), 0.99
178.6, 148.5, 148.1, 143.3, 136.7, 134.8, 133.3, 128.8, 124.3, (s, 3H). 13C NMR (125 MHz, CDCl3): δ 180.0, 174.8, 144.6,
123.6, 123.2, 108.8, 50.7, 26.7, 23.9. IR (neat, cm−1): 3037, 135.1, 129.6, 128.9, 128.62, 128.59, 124.3, 122.6, 108.8, 66.5,
2924, 1711, 1611, 1493, 1470, 1371, 1343, 1097, 1021, 713. 43.6, 40.7, 34.8, 26.9, 24.5, 23.6. IR (neat, cm−1): 3068,
HRMS (ESI): calcd for C15H15N2O ([M + H]+): 239.1178, found: 2962, 2926, 2873, 1719, 1696, 1613, 1492, 1468, 1398, 1367,
239.1178.
1342, 1275, 1257, 1127, 936, 738, 701, 621, 522, 511. HRMS
1,3-Dimethyl-3-(pyridin-4-yl)indolin-2-one (2h). The reac- (ESI): calcd for C21H23N2O2 ([M + H]+): 335.1754, found:
tion was carried out starting with 1h (0.5 mmol) according to 335.1751.
the general procedure. Purified by chromatography (EtOAc),
3-(3,3-Dimethyl-2-oxopiperidin-1-yl)-1-methyl-3-phenylindo-
104 mg (88% yield), oil. 1H NMR (400 MHz, CDCl3): δ 8.53 lin-2-one (2n). The reaction was carried out starting with 1n
(brs, 2H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.24 (d, J = 5.3 Hz, 2H), (0.4 mmol) according to the general procedure. Purified by
7.19 (dd, J = 7.3, 1.0 Hz, 1H), 7.13 (td, J = 7.5, 0.7 Hz, 1H), 6.95 chromatography (pentane–Et2O = 1 : 1), 41 mg (30% yield),
(d, J = 7.8 Hz, 1H), 3.25 (s, 3H), 1.78 (s, 3H). 13C NMR semi-solid. H NMR (500 MHz, CDCl3): δ 7.85–7.44 (brm, 1H),
1
(100 MHz, CDCl3): 178.1, 150.1, 149.8, 143.3, 133.1, 128.8, 7.37–7.30 (m, 6H), 7.10 (td, J = 7.6, 0.9 Hz, 1H), 6.86 (d, J =
124.3, 123.2, 122.0, 108.8, 51.9, 26.7, 23.5. IR (neat, cm−1): 7.8 Hz, 1H), 3.34–3.29 (m, 1H), 3.18 (s, 3H), 3.17–3.13 (m, 1H),
3051, 2978, 2930, 1708, 1611, 1595, 1492, 1470, 1373, 1347, 1.92–1.85 (m, 1H), 1.80–1.67 (m, 3H), 1.30 (s, 3H), 1.07 (s, 3H).
1024, 754. HRMS (ESI): calcd for C15H15N2O ([M + H]+): 13C NMR (125 MHz, CDCl3): δ 177.3, 175.3, 144.5, 135.8, 129.2,
239.1178, found: 239.1170.
129.1, 128.8, 128.6, 123.5, 122.2, 108.6, 69.3, 48.7, 39.6, 36.6,
1,3-Dimethyl-3-(quinolin-2-yl)indolin-2-one (2i). The reac- 28.4, 27.2, 26.9, 21.1. IR (neat, cm−1): 3060, 2936, 2866, 1720,
tion was carried out starting with 1i (0.2 mmol) according to 1641, 1610, 1492, 1469, 1316, 1171, 1128, 726, 695, 613, 505,
the general procedure. Purified by chromatography (cyclo- 489. HRMS (ESI): calcd for C22H25N2O2 ([M + H]+): 349.1910,
hexane–EtOAc = 1 : 1), 51 mg (89% yield), solid, m.p. = found: 349.1911.
1
131–133 °C. H NMR (500 MHz, CDCl3): δ 8.13 (d, J = 8.5 Hz,
1H), 8.01 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.70 (td,
Computational details
J = 6.9, 1.4 Hz, 1H), 7.52–7.49 (m, 1H), 7.34 (d, J = 6.8 Hz, 1H), Density functional [UB3LYP/LANL2DZ on Cu and Cl,40 6-31G-
7.31 (dd, J = 7.7, 1.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.06 (td, (d,p) on other atoms] calculations were used to examine
J = 7.6, 0.9 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 3.36 (s, 3H), important segments of the potential energy surface for the
2.01 (s, 3H). 13C NMR (125 MHz, CDCl3): 179.1, 159.2, CuCl2 mediated oxidative coupling. Single point PCM calcu-
147.9, 143.2, 136.8, 134.7, 129.9, 129.4, 128.3, 127.4, 127.3, lations in DMF and toluene of all the gas phase optimized
41
126.5, 124.6, 123.0, 119.2, 108.3, 55.8, 26.7, 23.1. IR (neat, structures yielded the solvent corrected energy Esolv
.
The
cm−1): 3059, 2995, 2938, 1701, 1609, 1600, 1492, 1470, 1443, united atom topological model with UAHF radii was used. For
1424, 1349, 1300, 1258, 1118, 1098, 1023, 813, 757, 695. the PCM calculations, the same level of theory as in the gas
HRMS (ESI): calcd for C19H17N2O ([M + H]+): 289.1335, found: phase calculations was used. Gas phase Gibbs free energy cor-
289.1333.
rections Gcorr (P = 1 atm, T = 298 K) were considered for each
1-Methyl-3-(2-oxopyrrolidin-1-yl)-3-phenylindolin-2-one (2l). species and the total Gibbs free energy G of each optimized
The reaction was carried out starting with 1l (0.2 mmol) structure was taken as G = Esolv + Gcorr. The calculations were
according to the general procedure. Purified by chromatography performed with the Gaussian09 package.42
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21 J. E. M. N. Klein, A. Perry, D. S. Pugh and R. J. K. Taylor,
Acknowledgements
Org. Lett., 2010, 12, 3446.
We thank the Swiss National Science Foundation and the Uni- 22 C. L. Moody, V. Franckevicius, P. Drouhin, J. E. M. N. Klein
versity of Geneva for financial support. We thank the SMS plat- and R. J. K. Taylor, Tetrahedron Lett., 2012, 53, 1897.
form of the University of Geneva for mass spectrometric 23 D. S. Pugh and R. J. K. Taylor, Org. Synth., 2012, 89,
measurements and Prof. Tomasz A. Wesolowski (University of
438.
Geneva) for offering us access to his computational facilities.
24 Z. S. Yu, L. J. Ma and W. Yu, Synlett, 2010, 2607.
25 S. Ghosh, S. De, B. N. Kakde, S. Bhunia, A. Adhikary and
A. Bisai, Org. Lett., 2012, 14, 5864.
26 S. Bhunia, S. Ghosh, D. Dey and A. Bisai, Org. Lett., 2013,
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Org. Biomol. Chem., 2013, 11, 6734–6743 | 6743