Trifluoroacetic acid-promoted synthesis of 3-hydroxy, 3-amino and spirooxindoles from α-keto-N-anilides

Article abstract of DOI:10.1021/ol202263a

Ketoanilides containing alkyl side chains were readily cyclized to 3-hydroxy-2-oxindoles or spirooxindoles by a single or double intramolecular Friedel-Crafts reaction in the presence of trifluoroacetic acid (TFA) at room temperature or at 45 °C. α-Iminoc

Full text of DOI:10.1021/ol202263a

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5536–5539
Trifluoroacetic Acid-Promoted Synthesis
of 3-Hydroxy, 3-Amino and Spirooxindoles
from r-Keto-N-Anilides
Ioulia Gorokhovik,†,‡ Luc Neuville,*,† and Jieping Zhu*,†,‡
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198
Gif-sur-Yvette Cedex, France, and Institut of Chemical Sciences and Engineering, Ecole
ꢀ ꢀ
Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne,
Switzerland
jieping.zhu@epfl.ch; luc.neuville@icsn.cnrs-gif.fr
Received August 21, 2011
ABSTRACT
Ketoanilides containing alkyl side chains were readily cyclized to 3-hydroxy-2-oxindoles or spirooxindoles by a single or double intramolecular
FriedelꢀCrafts reaction in the presence of trifluoroacetic acid (TFA) at room temperature or at 45 °C. R-Iminocarboxamides, generated in situ from
ketoamides, cyclized similarly to 3-aminooxindoles under identical conditions.
3,3-Disubstituted oxindoles are structural subunits
found in a wide range of natural and synthetic compounds
that display interesting biological and pharmacological
properties.1 Consequently, a number of elegant synthetic
strategieshavebeendeveloped forthesynthesisofthisclass
of heterocyle.2 Recently, diversely ortho-prefunctionalized
R-ketoanilides (boronate,3 halide4) have been converted to
3-hydroxyoxindoles through metal-catalyzed cyclization
processes.
Cyclization of R-ketoamides by way of an intramolecu-
lar FriedelꢀCrafts reaction is an attractive way for the
synthesis of 3-hydroxyoxindoles.5 However, this approach
was limited essentially to the synthesis of 3-aryl con-
taining oxindoles. Indeed, competing enolization and/or
† Institut de Chimie des Substances Naturelles.
‡
ꢀ ꢀ
Ecole Polytechnique Federale de Lausanne.
(1) For recent reviews on oxindoles, see: (a) Marti, C.; Carreira, E. M.
Eur. J. Org. Chem. 2003, 12, 2209–2219. (b) Trost, B.; Brennan, M. K.
Synthesis 2009, 3003–3025. (c) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381–1407. (d) Millemaggi, A.; Taylor, R. J. K. Eur. J.
Org. Chem. 2010, 4527–4547. For a review on 3-hydroxyoxindoles, see:
(e) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20–38.
(2) Selected recent examples: (a) Zheng, K.; Yin, C.; Liu, X.-H.; Lin,
L.; Feng, X. Angew. Chem., Int. Ed. 2011, 50, 2573–2577. (b) Zhang, Z.;
Zheng, W.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 1135–1138. (c)
Lui, Z.; Gu, P.; Shi, M.; McDowell, P.; Li, G. Org. Lett. 2011, 13, 2314–
2317. (d) Badillo, J. J.; Arevalo, G. E.; Fettinger, J. C.; Franz, A. K. Org.
Lett. 2011, 13, 418–421. (e) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.;
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(f) Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang,
C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176–15178. (g) Bui, T.;
Candeias, N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2010, 132, 5574–
5575. (h) Deng, J.; Zhang; Ding, P.; Jiang, H.; Wang, W.; Li, J. Adv.
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€
(4) (a) Jia, Y.-X.; Katayev, D.; Kundig, E. P. Chem. Commun. 2010,
46, 130–132. (b) Hu, J.-X.; Wu, H.; Li, C.-Y.; Sheng, W.-J.; Jia, Y.-X.;
Gao, J.-R. Chem.;Eur. J. 2011, 5234–5237.
(5) (a) Lopatin, W.; Sheppard, C.; Owen, T. C. J. Org. Chem. 1978,
43, 4678–4679. (b) Aoyama, H.; Omote, Y.; Hasegawa, T.; Shiraishi, H.
J. Chem. Soc., Perkin I 1976, 1556–1558. For FriedelꢀCrafts conditions
using 2,2-dimethoxy arylacetanilides as precursor, see:(c) Ly, T.-M.;
Laso, N. M.; Zard, S. Z. Tetrahedron 1998, 54, 4889–4898. (d) Sai,
K. K. S.; Esteves, P. M.; da Penha, E. T.; Klumpp, D. A. J. Org. Chem.
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(6) Under super acid reaction conditions, alkyl-substituted R-ketoa-
mides produced R,β-unsaturated amides; see ref 5b.
(7) Formation of 3-methylene oxindoles from 3-hydroxy oxindoles is
well precedented, see for example: Munusamy, R.; Dhathathreyan, K.;
Balsubramanian, K. K.; Vankatachalan, C. S. J. Chem. Soc., Perkin
Trans. 2 2001, 1154–1166.
(3) Tomita, D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 6946–6948.
r
10.1021/ol202263a
Published on Web 09/29/2011
2011 American Chemical Society

dehydration of the resulting tertiary alcohol can completely
suppress the formation of 3-alkyl containing oxindoles6
or prevent the isolation of 3-hydroxy oxindoles7 when using
β-alkylated ketoamides.8
solvents (DCM/TFA or tol/TFA, v/v = 1/1), a longer
reaction time (24 h) was needed to reach completion.13 At
higher concentration (c 0.9 M), a dimerization product 6a
was produced together with 5a. However, the dimer was
formed only in a trace amount at c = 0.4 M and was not
detected at c = 0.09 M. We also noticed the formation of a
variable amount of trifluoroacetate 5b (R = CF3CO,
5ꢀ10% and up to 40% yield for some other substrates).
This product is readily hydrolyzed to 5a (R = H) upon
workup with aqueous NaOH solution before extraction.
Overall, under our optimized conditions [TFA, c 0.09M,
rt, 6 h, then aqueous NaOH (3N) at rt for 1 h], cyclization
of 4a afforded 5a in 94% yield.
In connection with our general interest in oxindole
synthesis9 and the development of strategies starting from
unfunctionalized anilides,10 we decided to evaluate the
possibility of building spirooxindoles 1 in a tandem
fashion11 by performing a double cyclization of R-ketoa-
nilides with concurrent generation of all-carbon quatern-
ary center (Nu = π-nucleophile) as depicted in Scheme 1.12
We report herein that, under acidic conditions, intramole-
cular FriedelꢀCrafts reaction of 3 takes place readily to
afford 3-alkyl(aryl)-3-hydroxy-2-oxindoles 2. With an ap-
propriately tethered nucleophile, a second cyclization oc-
curredtodirectlyprovidethe spirooxindoles1. Inaddition,
we document that 3-amino-oxindoles can be prepared
from the corresponding R-ketoamides under identical
conditions.
Scheme 2. Intramolecular Arylation of R-Ketoanilide 4a
Scheme 1. Double Cyclization Sequence for the Synthesis of
Spiro-2-oxindole
The scope of this process was next examined (Table 1).
The reaction was found to be general leading to the
expected 3-hydroxy-2-oxindoles in yields ranging from
50 to 94%. Notably and in sharp contrast to other related
literature work, diverse alkyl side-chains, such as methyl,
ethyl, isobutyl, and phenethyl, were tolerated. As expected,
aryl-substituted R-ketoamide 4h was an excellent sub-
strate, furnishing the corresponding 3-phenyl-3-hydroxy-
2-oxindole (5h) in 83% yield. A tertiary amide was man-
datoryfor the cyclization, asno oxindole was formed in the
case of 2-oxo-N-phenylbutanamide (not shown). N-Benzyl
derivative 4i afforded oxindole 5i in 58% yield, indicating
that the benzyl residue did not participate in the cyclization
reaction. Cyclization ofa tetrahydroquinoline derivative 4j
furnished tricyclic oxindole 5j in 85% yield (entry 9).
Substituted anilides bearing electron-donating groups at
the para-position (OMe, Me) cyclized smoothly to gener-
ate the expected oxindoles 5d, 5g and 5h (entries 3, 6 and 7).
The presence of a weak electron-withdrawing group
(chlorine) at the para-position of anilide was also tolerated
furnishing compound 5e in an excellent 89% yield. Gentle
heating (45 °C) and longer reaction time were however
required in this case in order to drive the reaction to
completion.
We selected N-methyl-2-oxo-N-phenylbutanamide (4a)
as a model substrate for the survey of reaction conditions
(Scheme 2). While AcOH was inefficient for promoting the
cyclization even at 45 °C, we found that the desired
cyclization proceeded readily at room temperature in the
presence of trifluoroacetic acid (TFA). In pure TFA, the
reaction was complete within 6 h, whereas in a mixture of
(8) For a recent enantioselective synthesis of 3-alkyl-3-hydroxy-
2-oxindole from ortho functionalized R-ketoanilides, see: Yin, L.; Kanai,
M.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 7620–7623.
(9) (a) Jaegli, S.; Vors, J.-P.; Neuville, L.; Zhu, J. Tetrahedron 2010,
66, 8911–8921. (b) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.;
Neuville, L.; Zhu, J. Chem.;Eur. J. 2010, 16, 5863–5867. (c) Erb,
W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74, 3109–3115. (d) Jaegli,
S.; Vors, J.-P.; Neuville, L.; Zhu, J. Synlett 2009, 2997–2999. (e) Pinto,
A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.;Eur. J. 2007, 13, 961–967.
(f) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351–
4354. 3-(Diarylmethylenyl)oxindoles: (g) Pinto, A.; Neuville, L.; Zhu, J.
Tetrahedron Lett. 2009, 50, 3602–3605. (h) Pinto, A.; Neuville, L.; Zhu,
J. Angew. Chem., Int. Ed. 2007, 46, 3291–3295. (i) Pinto, A.; Neuville, L.;
Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927–4930.
(10) (a) Wei, H.-L.; Piou, T.; Dufour, J.; Neuville, L.; Zhu, J. Org.
Lett. 2011, 13, 2244–2247. (b) Jaegli, S.; Dufour, J.; Wei, H.-L.; Piou, T.;
Duan, X.-H.; Vors, J.-P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498–
4501.
(11) For general reviews on the domino process, see: (a) Tietze, L. F.
Chem. Rev. 1996, 96, 115–136. For a monograph, see: (b) Domino
Reactions in Organic Synthesis; Tietze, L. F., Brasche, G., Gericke, K., Eds.;
Wiley-VCH: Weinheim, 2006.
Anilides containing a functionalized alkyl side chain
such as a bromoalkyl or a secondary hydroxyl group were
compatible with the reaction conditions (Scheme 3). Treat-
ment of 3-bromo-N-methyl-2-oxo-N-phenylpropanamide
(13) For the benficial effect of performing FriedelꢀCrafts processes
in concentrated or pure TFA, see: (a) Youn, S. W.; Bihn, J. H. Tetra-
hedron Lett. 2009, 50, 4598–4601. (b) Wu, Y.-C.; Liu, L.; Liu, Y.-L.;
Wang, D.; Chen, Y.-J. J. Org. Chem. 2007, 72, 9383–9386. (c) Ma, S.;
Zhang, J. Tetrahedron 2003, 59, 6273–6283.
(12) For a recent review on FriedelꢀCrafts reaction, see: Bandini,
M.; Emer, E.; Tommasi, S.; Umani-Ronchi, A. Eur. J. Org. Chem. 2006,
3527–3544.
Org. Lett., Vol. 13, No. 20, 2011
5537

4k under standard conditions, without basic aqueous
workup, afforded 3-(bromomethyl)-3-hydroxy-2-oxindole
5k in 76% yield. On the other hand, upon basic aqueous
workup, a second cyclization took place leading to spiro-
epoxyoxindole 7 in 67% yield.14 Therefore, by simply
modifying the workup procedure, we were able to obtain
two sets of heterocycles that can in principle be further
functionalized in different ways.15 Cyclization of TBS-
protected N-methyl (S)-3-hydroxy-2-oxo-N-phenyl buta-
namide16 (4l) occurred smoothly, furnishing the depro-
tected diol 5l in 80% yield. A modest but significant
diastereselectivity (dr = 3.5/1) was observed. Analysis of
SFC traces (IB column) of 5l and ent-5l, obtained by
cyclization of (S)-4l and (R)-4l, respectively, allowed us
to conclude that no epimerization occurred during the
cyclization (see Supporting Information). We have also
examined the role of the hydroxy protective group on the
diastereoselectivity of this cyclization. When (R)-4m (R =
TBDPS) was submitted to the cyclization, the deprotected
diol ent-5l was again obtained but with increased diaster-
eoselectivity (dr = 4.5/1). On the other hand, cyclization of
unprotected alcohol (R)-4o afforded ent-5l as a 2/1 mixture
of diasteromers. These results indicated that when (R)-4l
(R = TBDMS) and (R)-4m (R = TBDPS) were submitted
to our cyclization conditions, partial O-deprotection oc-
curred before cyclization and that much better diastereos-
electivity could be expected if a bulky but acid-stable
O-protective group was installed in 4o.17
Table 1. Synthesis of 3-hydroxy-2-oxindoles: substrate scope
Scheme 3. Cyclization of Functionalized R-Ketoamides
a General conditions: 4 in TFA (C = 0.09 M), rt then NaOH (3.0 M)
up to pH = 13. b Isolated yield. c At 45 °C. d Basic workup with 3.0 N
NaOH was not required.
We next turned our attention to the synthesis of
spirooxindoles through a double intramolecular
FriedelꢀCrafts reaction of R-ketoamides bearing a teth-
ered arene.18 The reactivity of compound 8a (R = H, n =
(18) Two-step synthesis of 3,30-alkyl-aryl oxindoles has been docu-
mented, see: England, D. B.; Merey, G.; Padwa, A. Org. Lett. 2007, 9,
3805–3807. N-methyl oxindoles were found to be unsuitable substrates
under their conditions, see ref 23 of this work.
(14) (a) Schulz, V.; Davoust, M.; Lemarie, M.; Lohier, J.-F.; Sopkova de
Oliveira Santos, J.; Metzner, P.; Briere, J.-F. Org. Lett. 2007, 9, 1745–1748
and references cited therein. (b) Inoue, M.; Furuyana, H.; Sakazaki, M.;
Hirama, M. Org. Lett. 2001, 3, 2863–2865.
(15) Structural diversity derived from work-up procedure, see:
~
hedron 2002, 58, 6351–6358.
(16) Optically pure 4l was prepared from D-threonine through amide
bond formation and oxidative transamination.
(17) We thank reviewers for suggesting these control experiments.
(19) The formation of 5-membered rings using FriedelꢀCrafts alky-
lation is known to be difficult: (a) Khalaf, A. A.; Roberts, R. M. J. Org.
Chem. 1969, 34, 3571–3575. The following ring formation preference,
6 > 7 and 6 > 5, has been established: (b) Johnson, W. S. Org. React.
1944, 2, 114–177. (c) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J.
Org. Chem. 2005, 70, 1316–1327.
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ꢀ
Gamez-Montano, R.; Gonzalez-Zamora, E.; Potier, P.; Zhu, J. Tetra-
5538
Org. Lett., Vol. 13, No. 20, 2011

crude iminocarboxamides in pure TFA at 45 °C for 4 h,
provided the corresponding 3-aminooxindoles 10 in yields
ranging from 59 to 90%. Neither 1,2,3,4-tetrahydroisoquino-
line-1-carboxamide 11a nor isoindoline-1-carboxamide 11b
via PictetꢀSpengler reaction were produced in the reaction.23
A 5-exo-trig cyclization mode leading to oxindoles might be
kinetically more favorable than the alternative 5-endo-trig or
6-endo-trig processes encountered in the PictetꢀSpengler
reaction. The aniline derived product 10c was found to be
stable, and the possible HofmannꢀMartius rearrangement
was not observed under our reaction conditions.24
Scheme 4. Synthesis of Spirooxindoles 1 by Double Intramole-
cular Arylation of R-Ketoanilides
Scheme 5. Synthesis of 3-Amino-2-oxindoles
2, Scheme 4) was initially evaluated and we were delighted
to isolate spirooxindole 1a in 87% yield upon exposure of
8a to TFA (0.04 M, 45 °C, 24 h). The 4-methoxy and
4-chloro-substituted anilides (8b, 8c) underwent spirocy-
clization smoothly to afford tetracyclic compounds 1b and
1c in yields of 95 and 73%, respectively. The reaction was
not limited to the formation of spiro tetrahydronaphtha-
lenes, as 5- and 7-membered carbospirocycles 1dꢀ1g were
also formed under similar conditions. The reduced yield of
spiroindene 1d can be accounted for by the competitive
dimerization/polymerization of the hydroxyoxindole inter-
mediate.19 Such a competitive pathway was markedly re-
duced when 4-substituted anilides were used leading to 1e in
62% yield. The yields of the seven-membered spirooxin-
doles 1f and 1g (64 and 69%, respectively) were quite
remarkable as a related intramolecular SEAr reaction of
3-bromoindolin-2-one produced the cyclic product in only
13% yield.20
In summary, we have demonstrated the utility of the
intramolecularFriedelꢀCrafts reaction for the synthesis of
diversely functionalized 3,30-disubstituted oxindoles and
spirooxindoles from readily accessible R-keto-N-arylace-
tamides bearing alkyl side chain residues. In TFA, R-
ketoanilides 4 cyclized readily at room temperature to
afford the 3-hydroxy-3-alkyl(aryl)-2-oxindoles 5, while
R-iminocarboxamides 9, prepared in situ from R-ketoa-
mides, cyclized under similar conditions to 3-amino-
3-alkyl-2-oxindoles 10 in good to excellent yield. From an
appropriately functionalized substrate 8, a double cycliza-
tion took place leading to spirooxindoles 1 with the creation
of an all carbon chiral quaternary center.
The 3-aminooxindoles have recently been proven to be of
interest in medicinal chemistry.21 Having established condi-
tions for the synthesis of 3-hydroxyoxindoles by the Friedelꢀ-
Crafts reaction, we reasoned that the 3-amino-2-oxindoles
could be similarly synthesized from R-iminocarboxamides
which could, in turn, be generated in situ from R-ketoamides.
The synthesis of compound 9a (R = PhCH2CH2,
Scheme 5) was easily achieved by heating phenethylamine
Acknowledgment. Financial supports from ICSN, CNRS
(France) and EPFL (Switzerland) are gratefully acknowl-
edged. I.G. thanks ICSN and EPFL for a doctoral fellowship.
with R-ketoamide 4a in toluene at reflux for 18 h.22
A
Supporting Information Available. Supporting Infor-
mation for this article, including experimental procedures,
product characterization and copies of the 1Hand13C NMR
spectra of all reported oxindoles. This material is available
free of charge via the Internet at http://pubs.acs.org.
substoichiometric amount of acid (0.5 equivalent of TFA)
was required to effectively promote the formation of com-
pounds 9b (R = Bn) and 9c (R = Ph) from the correspond-
ing amine. Evaporation of the volatile, followed by stirring the
(20) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677–680.
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(23) PictetꢀSpengler reaction of ketimines derived from R-ketoa-
mide is known, see: Bou-Hamdan, F. R.; Leighton, J. L. Angew. Chem.,
Int. Ed. 2009, 48, 2403–2406.
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