Transition-metal-free synthesis of oxindoles by potassium tert-butoxide-promoted intramolecular α-arylation

Article abstract of DOI:10.1021/ol301704z

Potassium tert-butoxide-mediated intramolecular α-arylations of fluoro- and chloro-substituted anilides provide oxindoles in DMF at 80 °C. In this manner, diversely substituted products have been obtained in moderate to high yields.

Full text of DOI:10.1021/ol301704z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Transition-Metal-Free Synthesis of
Oxindoles by Potassium tert-Butoxide-
Promoted Intramolecular r-Arylation
Astrid Beyer, Julien Buendia, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received June 21, 2012
ABSTRACT
Potassium tert-butoxide-mediated intramolecular r-arylations of fluoro- and chloro-substituted anilides provide oxindoles in DMF at 80 °C. In this
manner, diversely substituted products have been obtained in moderate to high yields.
Oxindoles represent an important heterocyclic scaffold
that can be found in many natural products.1 Several of
them show significant bioactivities.2 In the past decades, a
wide range of synthetic methods have been developed,
giving access to oxindoles with a variety of functionalities.
In particular, palladium-catalyzed cyclization reactions,
including MizorokiÀHeck couplings,3 arylations,4 and
alkylations5 were shown to be useful. Metal-catalyzed ox-
indole syntheses by direct Csp2ÀH/Csp3ÀH couplings have
also been reported.6 A few other methods are known,7 and
most of them require the presence of a palladium complex in
combination with a suitable ligand.8 Recently, transition-
metal-free processes for the formation of CÀC, CÀN,
CÀO, and CÀS bonds have gained importance.9 Our
interest has been focused on base-promoted aryla-
tion reactions,10 and in particular, on intramolecular
(1) For reviews on total syntheses of oxindole natural products, see:
(a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b) Trost,
B. M.; Brennan, M. K. Synthesis 2009, 3003. For a review on transition-
metal-mediated routes to 3,3-disubstituted oxindoles, see: (c) Klein, J. E.
M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 34, 6821. For a review
on 3-alkenyloxindoles, see: (d) Millemaggi, A.; Taylor, R. J. K. Eur. J.
Org. Chem. 2010, 4527.
(2) For a review on pyrrolidinylspirooxindoles, see: Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(3) Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.;
Overman, L. E.; Pfeifer, L. A.; Weis, M. M. J. Am. Chem. Soc. 2003, 125,
6261 and references cited therein.
(7) For an aryl radical cylization, see: (a) Beckwith, A. L. J.; Storey,
J. M. D. J. Chem. Soc., Chem. Commun. 1995, 977. (b) Khan, T. A.;
Tripoli, R.; Crawford, J. J.; Martin, C. G.; Murphy, J. A. Org. Lett.
2003, 16, 2971. (c) Lidong, C.; Chaozhong, L. Chin. J. Chem. 2010, 28,
1640. For a PhI(OAc)2/I2-promoted cyclization, see: (d) Wei, H.-L.;
Piou, T.; Dufour, J.; Neuville, L.; Zhu, J. Org. Lett. 2011, 13, 2244. For
the synthesis of nitrooxindoles by vicarious nucleophilic substitution
(VNS), see: (e) Makosza, M.; Paszewski, M. Synthesis 2002, 2203.
(f) Makosza, M. Pure Appl. Chem. 1997, 69, 559.
(8) For some selected asymmetric examples, see: (a) Franckevicius,
V.; Cuthbertson, J. D.; Pickworth, M.; Pugh, D. S.; Taylor, R. J. K. Org.
Lett. 2011, 13, 4264. (b) Liu, L.; Ishida, N.; Ashida, S.; Murakami, M.
Org. Lett. 2011, 13, 1666. (c) Luan, X.; Wu, L.; Drinkel, E.; Mariz, R.;
Gatti, M.; Dorta, R. Org. Lett. 2010, 12, 1912. (d) Jia, Y.-X.; Katajev,
(4) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F.
J. Org. Chem. 1998, 63, 6546. For asymmetric arylations, see: (b) Lee, S.;
€
Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (c) Kundig, E. P.; Seidel, T. M.;
Jia, Y.-X.; Bernardinelli, G. Angew. Chem., Int. Ed. 2007, 46, 8484. For a
recent example, see: (d) Wu, L.; Falivene, L.; Drinkel, E.; Grant, S.; Linden,
A.; Cavallo, L.; Dorta, R. Angew. Chem., Int. Ed. 2012, 51, 2870.
(5) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084.
€
D.; Bernardinelli, G.; Seidel, T. M.; Kundig, E. P. Chem.;Eur. J. 2010,
16, 6300. (e) Ackermann, L.; Vicente, R.; Hofmann, N. Org. Lett. 2009,
€
€
11, 4274. (f) Wurtz, S.; Lohre, C.; Frohlich, R.; Bergander, K.; Glorius,
F. J. Am. Chem. Soc. 2009, 131, 8344.
(6) For a Pd-catalyzed CÀH ArÀH coupling, see: (a) Jia, Y.-K.;
(9) For a review on transition-metal-free coupling reactions of aryl
halides, see: (a) Shirakawa, E.; Hayashi, R. Chem. Lett. 2012, 41, 130. For
an overview of tert-butoxide mediated reactions, see: (b) Yanigasawa, S.;
Itami, K. ChemCatChem 2011, 3, 827. (c) Wang, Y. Synlett 2011, 2901.
€
Kundig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636. For Cu-promoted
CÀH ArÀH couplings, see: (b) Perry, A.; Taylor, R. J. K. Chem.
Commun. 2009, 3249.
r
10.1021/ol301704z
XXXX American Chemical Society

To further optimize the reaction parameters, the base
quantity, reaction time, and temperature were varied.
Lowering the temperature led to a decrease in conversion
and, thus, tolower yields of oxindole 2a(entries 13 and 14).
Byusinglessbasethe yield of2acouldbe slightly increased,
and the best result was obtained with 1.5 equiv of KO-t-Bu
(83%, entry 16). A similar yield was obtained when the
reaction time was shortened from 24 to 16 h (entry 18).
Table 1. Optimization of the Reaction Conditions
entry
base (equiv)
solvent temp (°C) time (h) yielda (%)
1
2
KOH (3.0)
DMSO
DMSO
dioxane
toluene
DMA
80
80
80
80
80
80
80
80
80
80
80
80
60
40
80
80
80
80
80
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
16
14
traces
23
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KOH (3.0)
Table 2. Screening of Halo- and N-Substituents
3
s.m.
s.m.
65
4
5
6
MeCN
DMF
s.m.
78
7
8
DMF
s.m.
47
9
NaO-t-Bu (3.0) DMF
LiO-t-Bu (3.0) DMF
entry
substrate
X
R
product
yield of 2a (%)
10
11
12
13
14
15
16
17
18
19
s.m.
s.m.
s.m.
70
1
2
3
4
5
6
1b
1c
1d
1e
1f
Cl
Br
I
Me
Me
Me
H
2a
2a
2a
2b
2c
2d
76b
55
44c
NaOEt (3.0)
LiOH (3.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
KO-t-Bu (3.0)
KO-t-Bu (3.0)
KO-t-Bu (2.0)
KO-t-Bu (1.5)
KO-t-Bu (1.2)
KO-t-Bu (1.5)
KO-t-Bu (1.5)
F
59
F
Ts
82
1g
F
Bn
83
80
a After column chromatography. b Use of 1.5 equiv of KOt-Bu; 16 h
reaction time. c Use of 3.0 equiv of KO-t-Bu at 100 °C.
82
78
a After column chromatography; s.m. = starting material.
Using the chloro, bromo, and iodo analogues of 1a also
yielded oxindole 2a (Table 2, entries 1À3). Hence, a com-
parable yield (76%) was obtained when chloro-substituted
anilide 1b was applied. In the reactions of the bromo- and
iodo-substituted anilides1cand 1d, loweryieldsof2a(55%
and 44%, respectively) were observed. No conversion
occurred in the attempt to cyclize NH-amide 1e (entry 4).
N-Tosylanilide 1f decomposed upon treatment with KO-t-
Bu in DMF under the given reaction conditions (entry 5),14
and N-benzyl derivative 1g remained uncyclized because
of the formation of a rather stable anion formed by a
competing deprotonation at the benzyl group (enty 6).
Thus, none of those starting materials (1eÀg) led to the
N-arylations for the synthesis of benzimidazol-2-ones11
and N-substituted phenoxazines.12 In this context, we now
developed a transition-metal-free protocol for the intra-
molecular cyclization of anilides to generate substituted
oxindoles. It takes place in the presence of simple KO-t-Bu
in DMF at 80 °C and is applicable to a wide range of
functionalized substrates.
Fluoro-substituted anilide 1a was chosen as model sub-
strate for the initially attempted intramolecular R-aryla-
tion using the superbasic medium KOH/DMSO (Table 1,
entry 1).13 However, to our disappointment, only traces of
the cyclized product were formed. Most of the starting
material could be recovered after 24 h at 80 °C. When the
base was changed to KO-t-Bu, the desired oxindole 2a was
obtained in 23% yield (entry 2). Encouraged by this result,
various base/solvent combinations were screened (entries
3À12), and it was found that KO-t-Bu in DMF gave the
best result. After a reaction time of 24 h at 80 °C, oxindole 2a
was obtained in 78% yield (entry 7). Among the other
solvents tested, only DMA gave a comparable result
(entry 5). All other solvents proved to be ineffective, and
in most cases, no conversion of the starting material was
observed (entries 3, 4, and 6).
corresponding products (2bÀd).
To extend the substrate scope of the cyclization reaction,
various anilides were synthesized15 and submitted to the
KO-t-Bu/DMF system. The results of this study are shown
in Table 3. Varying the R-substituent from ethyl to methyl
and phenyl led to full substrate conversions providing
products 2e and 2f in high yields (entries 1 and 2). When
anilide 1k having only a single phenyl substituent in the
R-position was applied, the use of less base (0.9 equiv)
increased the yield and the corresponding product 2g was
obtained in 61% (entry 4). R-Heteroatom-substituted
anilides 1l and 1m gave oxindoles 2h and 2i in moderate
yields of 35 and 29%, respectively. In addition, substrates
with various aryl substituents were tested, and in most
cases, high yields of the corresponding oxindoles were
achieved (entries 7À18). In general, anilides with both
ꢀ
(10) (a) Yuan, Y.; Thome, I.; Kim, S. H.; Chen, D.; Beyer, A.;
Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth. Catal.
ꢀ
2010, 352, 2892. For a related study, see: (b) Cano, R.; Ramon, D. J.;
Yus, M. J. Org. Chem. 2011, 76, 654.
(11) Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett. 2011, 13,
2876.
(14) The formation of N-(2-fluorophenyl)-4-methylbenzenesulfona-
mide was observed.
(15) For more details on the synthesis of starting materials, see the
Supporting Information.
ꢀ
(12) Thome, I.; Bolm, C. Org. Lett. 2012, 14, 1892.
(13) KOH in DMSO is known as a “super base” and has proven to be
effective in arylation reactions, as shown in ref 10.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Scope of the Intramolecular R-Arylation for the Synthesis of Oxindoles
a After column chromatography. b Use of 1.5 equiv of KO-t-Bu; 16 h reaction time. c Use of 0.9 equiv of KO-t-Bu; 24 h reaction time. d Use of 1.2
equiv of KO-t-Bu; 16 h reaction time. e Use of 1.5 equiv of KO-t-Bu; 24 h reaction time. f Use of 2.0 equiv of KO-t-Bu; 20 h reaction time.
electron-withdrawing and -donating groups on the nitro-
gen-substituted aryl ring afforded satisfactory yields of
cylized products (entries 7À13). In this series, the highest
yield was obtained in a reaction of anilide 1s bearing a
trifluoromethyl group in the 4-position to the fluoro sub-
stituent. Here, the corresponding oxindole 2o was isolated
in 77% yield (entry 12). Cyclization reactions of com-
pounds with non-hydrogen substituents on the phenyl ring
in R-position to the amide carbonyl gave good to excellent
yields as well (entries 14À18). The best result was observed
in the conversion of 4-phenyl-substituted anilide 1y, which
provided oxindole 2u in 91% yield (entry 18). One excep-
tion was 4-nitro-substituted anilide 1w, which gave ox-
indole 2s in only 29% yield (entry 16).
Attempted reactions of the substrates 3aÀf (Figure 1)
revealed the limitations of the method. First, it became
apparent that the aryl substituent at the R-position of the
amide moiety was crucial. In its absence, no cyclization
occurred as seen, for example, in the attempted reaction of
cyclohexyl derivative 3a. Analogous observations were
Org. Lett., Vol. XX, No. XX, XXXX
C

made when 3bÀf were treated with KO-t-Bu in DMF. In
conditions. Instead, the starting material was almost com-
pletely recovered. Furthermore, the successful cyclization
of 1r to give 2n (Table 3, entry 11) excluded the involve-
ment of an aryne. For other substrates with different
substituents, however, alternative or even more than one
mechanism could be relevant. Thus, the possible interme-
diacy of aryl radicals (formed by electron transfer) should
also not be ruled out.17,18 Support for this mechanism
stems from a reaction with an iodo-substituted anilide 1d,
which upon treatment with KO-t-Bu (3.0 equiv) in DMF
at 40 °C provided a mixture of oxindole 2a and dehaloge-
nated starting material [N-methyl-2,N-diphenylbutana-
mide; 1 with X = H and R = Me (Table 1)]. This result
could be interpreted as evidence for the intermediacy of
radicals or arynes, and perhaps those were generally the
predominant intermediates when starting from iodo-
substituted substrates.
addition, no cyclizations occurred.
Figure 1. Unreactive substrates in the intramolecular R-aryla-
tion with KO-t-Bu in DMF.
We assume that for most substrates the reactions
follow an SN-Ar mechanism. This hypothesis is substan-
tiated by the following observations: The highest yields
were obtained with fluoro-substituted anilides, and the
leaving group activity decreases in the following order:
F > Cl > Br ≈ I.16 In the cases of the fluoro-substituted
anilides, the formation of arynes was considered unlikely
because N-(3-fluorophenyl)-N-methyl-2-phenylbutana-
mide (the 3-fluoro-substituted isomer of 1a) did not give
any oxindole 2a when treated under the standard reaction
In summary, we have developed a protocol for the
transition-metal-free synthesis of oxindoles starting from
readily available anilides. The cylization reactions are pro-
moted by KO-t-Bu and occur in DMF at 80 °C. Many
functional groups are tolerated, giving access to a wide
range of synthetically relevant heterocycles.
Acknowledgment. We thank Marta Sofia Fernandes
(RWTH Aachen University) for various synthetic contri-
butions. J.B. acknowledges support by the Alexander von
Humboldt foundation.
(16) For kinetic studies on nucleophilic aromatic substitution reac-
tions with carbanions and nitranions in DMSO, see: (a) Bordwell, F. G.;
Hughes, D. L. J. Am. Chem. Soc. 1986, 108, 5991. For a general review
on equilibrium acidities in DMSO, see: (b) Bordwell, F. G. Acc. Chem.
Res. 1988, 21, 456. For a review on nucleophilic substitutions of
compounds with nitro, fluoro and chloro groups, see: (c) Vlasov,
V. M. Russ. Chem. Rev. 2003, 72, 681.
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
1
of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) For a comment on radical and electron transfer reactions, see:
Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018.
(18) For nucleophilic substitution reactions involving electron trans-
fer, see: (a) Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413. (b) Rossi, R. A.;
~ꢀ~
Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003, 103, 71.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX