Oxindole synthesis by direct C-H, Ar-H coupling

Article abstract of DOI:10.1039/b903516h

A novel copper(ii)-mediated route for the conversion of anilides into 3,3-disubstituted-oxindoles is described which proceeds via a formal C-H, Ar-H coupling process.

Full text of DOI:10.1039/b903516h

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Oxindole synthesis by direct C–H, Ar–H couplingw
Alexis Perry and Richard J. K. Taylor*
Received (in Cambridge, UK) 18th February 2009, Accepted 6th April 2009
First published as an Advance Article on the web 22nd April 2009
DOI: 10.1039/b903516h
A novel copper(II)-mediated route for the conversion of anilides
into 3,3-disubstituted-oxindoles is described which proceeds via a
formal C–H, Ar–H coupling process.
on the corresponding esters 1 (EWG = CO2Et) and are thus
complementary to the Jia and Kundig study.10
¨
Initial experiments, summarised in Table 1, were carried out
using the readily available anilide 1a11 and potassium
tert-butoxide as base. If possible, we wanted an inexpensive
cyclisation procedure and therefore started with catalytic
Pd(OAc)2 (without additional ligands) along with a stoichio-
metric co-oxidant12 (entries i–iii). The use of Pd(OAc)2–
p-benzoquinone gave no oxindole 4a but we were encouraged
to observe a low yield of 4a13 when using Pd(OAc)2 with
Oxindoles are versatile synthetic building blocks and also form
the cornerstone of a range of natural products and related
compounds of biological and medicinal importance.1 There
are many synthetic routes to oxindoles1,2 with ortho-halogenated
anilides being commonly-used precursors, particularly in
palladium-mediated cyclisation processes.3 However, the
preparation of these halogenated cyclisation precursors
generally requires a tedious synthetic route including ortho-/
para-isomer separation. In addition, many recent palladium-
catalysed procedures require expensive or designer ligands.3
As part of a programme to develop efficient and practical
tandem and/or telescoped procedures to prepare heterocyclic
systems,4 we have recently become interested in indole
synthesis.5 Whilst speculating on improved synthetic routes
to substituted oxindoles, the sequence outlined in Scheme 1
was considered. It was proposed that treatment of a simple
anilide 1 with base and catalytic Pd(II) should generate a
palladated intermediate such as 2 (or its enolate equivalent).6
Next, C–H activation was envisaged generating the cyclo-
palladated intermediate 3. Reductive elimination would
produce oxindole 4 and Pd(0) which, on oxidation, would
AgOAc as
a
co-oxidant.12 However, the use of
Pd(OAc)2–Cu(OAc)2 gave the first substantial yield of
oxindole 4a and so this combination was studied in more
detail (entries iv–vi). The biggest improvement came when the
solvent was changed from THF to DMF; further optimisation
of the reaction temperature led to a reduction in the time for
full conversion (to 1 h) as shown in entry vi. However, rather
unexpectedly, an increase in the catalyst loading had no impact
on the yield of the reaction (compare entries iii and iv) and this
aroused suspicion concerning the requirement for Pd(II) in the
cyclisation process. A control reaction using stoichiometric
Pd(OAc)2 was therefore performed (entry vii) which confirmed
this supposition—in the absence of Cu(II) only 5% of oxindole
4a was formed.
Further optimisation produced the preferred cyclisation
conditions which employ Cu(OAc)2ÁH2O (1.0 eq.) and KOtBu
(1.1 eq.) in DMF at 110 1C for 1 h (entry viii). A range of other
metal salts were investigated (e.g. Mn(OAc)3 or CuI) but the
only competitive result (entry ix) was obtained using copper(II)
chloride.10
regenerate the Pd(II) catalyst.7 Alternatively, anilide
1
could undergo Ar–H bond activation first,8 but such a route
would still produce the same oxindole product 4.
The route shown in Scheme 1 would utilise readily available
starting materials 1 and rapidly generate highly substituted
oxindole products 4. Given the recent interest in C–H
activation processes,7–9 we were therefore encouraged to move
from the realms of hypothesis to practical investigations.
During these investigations, a publication appeared by Jia
The result shown in Table 1, entry viii, is remarkable—a
direct C–H, Ar–H coupling has been effected on a readily
available starting anilide 1a generating the disubstituted
oxindole product 4a rapidly (1 h) in quantitative yield by
using Cu(OAc)2ÁH2O, a cheap (od1 per 10 g), air-stable
oxidant (and, as shown later, without the need for inert or
dry conditions).
and Kundig10 which described a similar approach to 3-aryl-
¨
oxindoles utilising anilides 1 (EWG = Ph or Ar). We are
therefore disclosing our preliminary studies which concentrated
Following the optimisation studies, we looked at the
generality of this new route to substituted oxindoles
(Scheme 2). However, the first experiment on anilide 1b under
the optimised conditions gave a complex mixture of products
(oxindole 4b is reported14 to be unstable), indicating that this
Department of Chemistry, University of York, Heslington, York,
UK YO10 5DD. E-mail: rjkt1@york.ac.uk
w Electronic supplementary information (ESI) available: Analytical
data for novel compounds. See DOI: 10.1039/b903516h
Scheme 1 Proposed oxindole synthesis via direct Pd(II)-catalysed intramolecular arylation of anilides.
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Table 1 Cyclisation studies to prepare oxindole 4aa
%Isolated yield
(%conv.)b
Entry
Catalyst (eq.)
Oxidant (eq.)
Solvent
Temp/1C
Time/h
i
ii
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (1.0)
—
p-BQc (2.0)
THF
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
65
65
65
65
110
110
110
110
110
18
18
18
18
18
1
18
1
1
NRc
(35)
(40)
(40)
98
AgOAc (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
—
iii
iv
v
vi
vii
viii
ix
98d
(5)
Cu(OAc)2 ÁH2O (1.0)
98ef
(60)e
—
CuCl2 (1.0)
a
Standard conditions: to a solution (0.05 M) of the ester 1a (B0.1 mmol) were successively added KOtBu (2.2 eq., unless otherwise stated),
catalyst and oxidant. Conversion is the approximate yield determined by 1H-NMR spectroscopy. p-BQ = p-benzoquinone; NR = no
b
c
d
e
f
discernible reaction. 80% yield at 65 1C for 1 h. Using 1.1 eq. base. Yields diminished when less than 1 eq. of Cu(II) was employed, even when
oxygen was used as a re-oxidant; no reaction was observed in the absence of KOtBu.
method cannot be employed to generate monosubstituted
oxindoles directly. Fortunately, further studies indicated that
a range of disubstituted oxindoles 4c–e can be prepared
efficiently using the Cu(II) procedure and that the method is
compatible with several electron withdrawing groups, as well
as with both alkyl and aryl substituents.15
established that the corresponding nitrile 1f and phosphonate
1g also underwent the alkylation–cyclisation sequence
efficiently giving oxindoles 4d and 4e, respectively.
We briefly explored the preparation of 3-monoalkylated
oxindoles. Initial studies indicated that direct Cu(II)-mediated
C–H, Ar–H coupling of simple unactivated amides was not
facile. However, anilide 1b underwent a telescoped, one-pot
methylation–cyclisation–decarboxyalkylation sequence to give
In preparing the a-methyl-anilide 1a by methylation of 1b,
we observed rapid (o5 min) and quantitative room-temperature
alkylation using stoichiometric base and iodomethane. Given
the efficiency of this reaction, it seemed plausible that the
alkylation and oxidative cyclisation steps might be combined
into a single telescoped procedure. Gratifyingly, treatment of
anilide 1b with KOtBu and then methyl iodide, followed by
addition of a further equivalent of KOtBu and Cu(OAc)2ÁH2O
to effect cyclisation, gave oxindole 4a in an excellent yield
(Table 2, entry i). It should also be noted that when this
reaction was carried out in ‘‘laboratory’’ DMF (not dried or
degassed) without protection from the atmosphere, little loss
in yield was observed (80%), indicating the robustness of these
procedures.
3-methyl-oxindole
(Scheme 3).
5 in 69% unoptimised, overall yield
Finally, we considered the mechanism of these copper(II)-
mediated cyclisation processes. A review of the literature,16
taken with the deuterium labelling studies recently reported by
Jia and Kundig,10 indicated that a radical mechanism was
¨
likely, wherein Cu(II) generated a b-dicarbonyl-flanked radical
which underwent intramolecular homolytic aromatic substitu-
tion. This postulate was tested as shown in Scheme 4.
Anilide 1h was subjected to the standard cyclisation condi-
tions (KOtBu, Cu(OAc)2ÁH2O, DMF, 110 1C). However, none
of the corresponding oxindole could be detected, the only
isolable product (65%) being the dienyl anilide 1i. Cyclo-
propanes have long been employed as radical probes,17 and
thus it is likely that radical 6 is generated from the respective
enolate by Cu(II); in this example, cyclopropane scission would
give radical 7 which would undergo Hꢁ abstraction (or oxidise
The scope of this telescoped sequence was briefly examined
as shown in Table 2, entries ii–v. Thus, using anilide 1b, it was
shown that alkylation–cyclisation could also be successfully
carried out to produce the benzyl- and allyl-substituted
oxindoles 4f and 4g, respectively. In a similar manner, it was
Scheme 2 Synthesis of differentially substituted oxindoles by Cu(II)-mediated cyclisation of anilides.
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Table 2 Alkylation–cyclisation studies to prepare oxindoles 4a
to produce 3-methyl-oxindole. We are currently extending
the scope of the Cu(II)-cyclisation procedure as well as
investigating catalytic and asymmetric variants.
We thank the EPSRC for funding (A.P.; EP/029841/1).
Notes and references
1 Review: C. Marti and E. Carreira, Eur. J. Org. Chem., 2003, 2209.
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J. Wu, Synlett, 2008, 2716; Y. Yasui, H. Kamisaki and
Y. Takemoto, Org. Lett., 2008, 10, 3303; A. Pinto, L. Neuville
and J. Zhu, Angew. Chem., Int. Ed., 2007, 46, 3291.
Entry
Anilide
EWG
R
Product
Yield (%)
i
ii
iii
iv
vb
1b
1b
1b
1f
CO2Et
CO2Et
CO2Et
CN
Me
Bn
Allyl
Me
Me
4a
4f
4g
4d
4e
98
86
76
95
83
1g
P(O)(OEt)2
a
Standard conditions: to a solution (0.05 M) of the anilide in DMF
were successively added KOtBu (1.1 eq.), RX (1.0 eq.), then after
5 min, KOtBu (1.1 eq.) and Cu(OAc)2ÁH2O (1.0 eq.). Reactions were
3 K. H. Shaughnessy, B. C. Hamann and J. F. Hartwig, J. Org.
Chem., 1998, 63, 6546; S. Lee and J. F. Hartwig, J. Org. Chem.,
b
heated to 110 1C for 1 h. 2.0 eq. Cu(OAc)2ÁH2O, 110 1C for 15 h.
2001, 66, 3402; E. P. Kundig, T. M. Seidel, Y.-X. Jia and
¨
G. Bernardinelli, Angew. Chem., Int. Ed., 2007, 46, 8484;
S. P. Marsden, E. L. Watson and S. A. Raw, Org. Lett., 2008,
10, 2905; R. A. Altman, A. M. Hyde, X. Huang and
S. L. Buchwald, J. Am. Chem. Soc., 2008, 130, 9613; Y.-X. Jia,
and deprotonate) to give diene 1i. This result concurs with the
proposal that the key intermediate in the standard Cu(II)-
mediated cyclisation leading to oxindoles is a radical, such as
6, which then undergoes homolytic aromatic substitution.
In summary, we have discovered a robust, inexpensive and
efficient C–H, Ar–H coupling method for the conversion of
readily available anilides 1 into disubstituted oxindoles 4.
In addition, we have developed a telescoped alkylation–
cyclisation route to the same compounds, and a telescoped,
one-pot methylation–cyclisation–decarboxyalkylation sequence
J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Kundig,
¨
Chem. Commun., 2008, 4040; T. R. Ruck, M. A. Huffman,
M. M. Kim, M. Shevlin, W. V. Kandur and I. W. Davies, Angew.
Chem., Int. Ed., 2008, 47, 4711.
4 Y. F. Sainz, S. A. Raw and R. J. K. Taylor, J. Org. Chem., 2005,
70, 10086; R. J. K. Taylor, M. Reid, J. Foot and S. A. Raw, Acc.
Chem. Res., 2005, 38, 85; M. G. Edwards, M. N. Kenworthy,
R. Kitson, M. S. Scott and R. J. K. Taylor, Angew. Chem., Int. Ed.,
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5 J. R. Donald and R. J. K. Taylor, Synlett, 2009, 59.
6 D. A. Culkin and J. F. Hartwig, Acc. Chem. Res., 2003, 36, 234.
7 Hennessy and Buchwald devised a related arene C–H activation
route to oxindoles which commences from a-chloroacetanilides:
E. J. Hennessy and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
12084.
8 B. Li, S. Tian, Z. Fang and Z. Shi, Angew. Chem., Int. Ed., 2008,
47, 1115, and references therein.
9 Tetrahedron Symposium-in-Print, Catalytic Aromatic C–H
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10 Y.-X. Jia and E. P. Kundig, Angew. Chem., Int. Ed., 2009, 48, 1636.
¨
11 I. V. Ukrainets, P. A. Bezugly, V. L. Treskach, S. G. Taran and
Scheme 3 Telescoped methylation–cyclisation–decarboxyalkylation.
O. V. Gorokhova, Tetrahedron, 1994, 50, 10331.
12 S. Wurtz, S. Rakshit, J. J. Neumann, T. Droger and F. Glorius,
¨
¨
Angew. Chem., Int. Ed., 2008, 47, 7230, and references therein.
13 A. G. Schultz and W. K. Hagmann, J. Org. Chem., 1978, 43, 4231.
14 D. S. Brown, M. C. Elliott, C. J. Moody, T. J. Mowlem,
J. P. Marino and A. Padwa, J. Org. Chem., 1994, 59, 2447.
15 The reaction was unsuccessful using unsubstituted anilides
(Scheme 1, 1; R2 = H); however, N-methyl oxindoles can be
demethylated: see: W. G. Beyersbergen van Henegouwen,
R. M. Fieseler, F. P. J. T. Rutjes and H. Hiemstra, J. Org. Chem.,
2000, 65, 8317.
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6, 3477.
17 K. E. Liu, C. C. Johnson, M. Newcomb and S. J. Lippard, J. Am.
Chem. Soc., 1993, 115, 939.
Scheme
4 Mechanistic study: radical-mediated cyclopropane
scission.
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Chem. Commun., 2009, 3249–3251 | 3251