Microwave-assisted sequential amide bond formation and intramolecular amidation: A rapid entry to functionalized oxindoles

Article abstract of DOI:10.1021/ol0473804

(Chemical Equation Presented) A general method has been developed for the synthesis of N-substituted oxindoles. The two-step process involves initial microwave-assisted amide bond formation between 2-halo-arylacetic acids and various alkylamines and anilines, followed by a palladium-catalyzed intramolecular amidation under aqueous conditions. In the case of alkylamines, the procedure can be carried out as a one-pot process without isolation of the intermediate amide.

Full text of DOI:10.1021/ol0473804

ORGANIC
LETTERS
2005
Vol. 7, No. 5
863-866
Microwave-Assisted Sequential Amide
Bond Formation and Intramolecular
Amidation: A Rapid Entry to
Functionalized Oxindoles
Rajamohan R. Poondra and Nicholas J. Turner*
School of Chemistry, UniVersity of Edinburgh, Kings Buildings, West Mains Road,
Edinburgh, EH9 3JJ, UK
n.j.turner@ed.ac.uk
Received December 21, 2004
ABSTRACT
A general method has been developed for the synthesis of N-substituted oxindoles. The two-step process involves initial microwave-assisted
amide bond formation between 2-halo-arylacetic acids and various alkylamines and anilines, followed by a palladium-catalyzed intramolecular
amidation under aqueous conditions. In the case of alkylamines, the procedure can be carried out as a one-pot process without isolation of
the intermediate amide.
The indole template is generally recognized as a privileged
structure in medicinal chemistry, and in particular, oxindoles
are important constituents of natural indole alkaloids as well
as drugs in development and also in the clinic.1 In this
context, it is important to continue to develop efficient
methods for the synthesis of this class of compounds,
especially routes based upon readily available starting
materials. Although a number of transition-metal-catalyzed2
and radical-mediated3 reactions have been reported for the
synthesis of oxindoles, there remains a need for new methods.
A conceptually different approach to the construction of
heterocycles, including oxindoles, has arisen from the work
of Buchwald, Hartwig, and others and is based upon
palladium-catalyzed intramolecular amination/amidation/
Heck reaction of appropriately substituted arenes, via C-N/
C-C bond formation.4 A recent report describes the use of
nickel rather than palladium.5
In parallel with these developments in the metal-mediated
construction of C-C and C-N bonds, there has been a
general recognition that microwave heating can accelerate a
broad range of reactions in organic synthesis, especially in
the field of metal-catalyzed cross-coupling reactions.6 Mi-
(1) (a) Akai, S.; Tsujino, T.; Akiyama, E.; Tanimoto, K.; Naka, T.; Kita,
Y. J. Org. Chem. 2004, 69, 2478. (b) Marti, C.; Carreira, E. M. Eur. J.
Org. Chem. 2003, 2209. (c) Zhang, T. Y.; Zhang, H. Tetrahedron Lett.
2002, 43, 193. (d) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo,
B. J. Org. Chem. 1991, 56, 6527.
(2) Rhodium-catalyzed reactions: (a) Hirao, K.; Morri, N.; Joh, T.;
Takahashi, S. Tetrahedron Lett. 1995, 36, 6243. (b) Brown, D. S.; Elliott,
M. C.; Moody, C. J.; Mowlem, T. J.; Marino, J. P.; Jr.; Padwa, A. J. Org.
Chem. 1994, 59, 2447. (c) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.;
Mahapatro, S. N. J. Org. Chem. 1988, 53, 1017.
(4) (a) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084. (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (c)
Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193. (d) Lee, S.;
Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (e) Ashimori, A.; Bachand,
B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477. (f)
Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.;
Poon, D. J. J. Am. Chem.. Soc. 1998, 120, 6488. (g) Shaughnessy, K. H.;
Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546.
(5) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y.
Org. Lett., 2003, 5, 2311.
(3) (a) Jones, K.; McCarthy, C. Tetrahedron Lett. 1989, 30, 2657. (b)
Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron Lett. 1988, 29,
6657.
10.1021/ol0473804 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/10/2005

crowave heating can dramatically reduce reaction times,
increase product purity and yields, and allow precise control
of reaction parameters, all of which are crucial factors to
consider when developing reaction protocols for both routine
synthetic transformations and parallel synthesis. Herein, we
present an efficient approach to substituted oxindoles using
microwave-assisted amide bond formation followed by
palladium-catalyzed intramolecular amidation reaction as
shown in Scheme 1.
Figure 1. Ligands screened for intramolecular amidation.
Scheme 1. Synthesis of Substituted Oxindoles
to introduction of the reagents for the second step. For
anilines it was necessary to work-up the reaction by
extraction into chloroform, followed by an aqueous wash
and evaporation of the organic layer to give a crude product
that was used directly for the next step.
The intramolecular amidation reactions were generally
complete within 30 min, and with only a few exceptions
(entries 14, 15, 19, and 22) the yields for the two steps were
excellent, typically greater than 80%. Scheme 2 shows the
potential further application of the derived oxindoles in which
the product 12 from entry 22 was subjected to a microwave-
assisted palladium-catalyzed bis-amination reaction with
3-fluoroaniline to give the new N-substituted oxindole 13
in 65% yield.
A number of features of the procedure described above
deserve comment: (i) the intramolecular amidation reaction
proceeds well under partially aqueous conditions, in the case
of alkylamines, and is subject to substantial acceleration in
rate when conducted with microwave heating; (ii) good yields
were obtained without the use of phase-transfer reagents,
which have been used previously for intramolecular amina-
Our approach was inspired by previous studies by Buch-
wald et al., who reported the palladium-catalyzed intra-
molecular amination and amidation of aryl bromides for the
synthesis of five-, six-, and seven-membered rings.7 They
described the synthesis of N-substituted oxindoles, from the
corresponding 2-bromo-N-substituted phenylacetamides, us-
ing palladium acetate and various phosphine ligands in high
yields and with reaction times of 24-36 h. We envisaged
an alternative approach involving initial generation of the
amide by microwave-assisted coupling of a 2-haloarylacetic
acid 1 with an amine 2, followed by palladium-catalyzed
intramolecular amidation to yield 3. Since the initial amide-
forming reaction generates a molar equivalent of water, it
was essential to identify conditions in the second step that
were tolerant of water.
Heating a mixture of 2-bromophenylacetic acid 4 and
benzylamine 5 under solvent-free MW conditions led to rapid
(ca. 30 min) formation of the corresponding amide in good
to excellent yield.8 To identify optimal conditions for the
palladium-catalyzed intramolecular amidation reaction to give
6, we screened a range of different phosphine ligands 7-11
(Figure 1) for activity using various combinations of pal-
ladium source/solvent/base (Table 1). In general, the best
results were obtained using either ligand 10 or 11 (6 mol
%) in the presence sodium hydroxide or cesium carbonate
(2.0 equiv).
These optimized conditions were then applied to the
synthesis of a range of substituted oxindoles as shown in
Table 2. In the case of the alkylamines, the palladium-
catalyzed intramolecular amidation step was carried out
without prior isolation of the intermediate amide. The
reaction mixture was simply purged with nitrogen gas prior
Table 1. Optimization of Reaction Conditionsa
entry
conditions
yieldb (%)
1
2
3
Pd(PPh3)4, NaOt-Bu, toluene
Pd(PPh3)4, K2CO3, dioxane
POPd,c K2CO3, toluene
nd
10
15
nd
58
55
60
78
65
82
nd
92
89
95
4
5
6
Pd(OAc)2, 7, NaOt-Bu, toluene
Pd(OAc)2, 8, Cs2CO3, toluene
Pd(dba)3, 8, K2CO3, tolune
7
Pd(OAc)2, 9, H2O/toluene
8
9
Pd(OAc)2, 10, Cs2CO3, toluene
Pd(dba)3, 10, Cs2CO3, toluene
Pd(OAc)2, 10, NaOH, H2O/toluene
Pd(OAc)2, 10, NaOH, H2O/DME
Pd(OAc)2, 11, Cs2CO3, toluene
Pd2(dba)3, 11, Cs2CO3, toluene
Pd(OAc)2, 11, NaOH, H2O/toluene
10
11
12
13
14
(6) (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250 and
references therein. (b) Mavandadi, F.; Lidstrom, P. Curr. Top. Med. Chem.
2004, 4, 773. (c) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res.
2002, 35, 717. (d) Wathey, B.; Tierney, J.; Lidstrom, P.; Westman, J. Drug
DiscoVery Today 2002, 7, 373.
(7) (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (b) Wolfe,
J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525.
(8) Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002, 58, 2155.
a Reaction was conducted with 3 mol % catalyst, 6 mol % ligand, 1.0
equiv of 2-bromophenyl acetic acid, and 2.0 equiv of base for 30 min at
100 °C on a 1.0 mmol scale of acid. b Isolated yields. c POPd: PdCl2[(t-
Bu)2P(OH)]2, purchased from Combiphos Catalysts, Inc.
864
Org. Lett., Vol. 7, No. 5, 2005

Table 2. Microwave-Assisted Synthesis of Substituted Oxindolesa
a Reagents and conditions: acid (1.0 mmol), amine/aniline (1.0 mmol), MW 300W, 150 °C, 30 min then, Pd(OAc)2 (3 mol %), ligand 11 (6 mol %),
NaOH (2.0 equiv) H2O/toluene (2 mL 1:1), microwave 75 W, 100 °C, 30 min. b Isolated yield based on amide. c Isolated amide (1.0 mmol), Cs2CO3 (1.5
equiv), toluene (2 mL), microwave 200 W, 100 °C, 30 min.
tion reactions;9 (iii) the intramolecular amidation reaction
can be carried out using aryl chlorides in addition to aryl
bromides, thereby greatly extending the range of substrates
that can be used; (iv) anilines can be used, in addition to
alkylamines, extending the range of N-substituted oxindoles
that can be prepared.
Org. Lett., Vol. 7, No. 5, 2005
865

Scheme 2. Palladium-Catalyzed Intermolecular Amination
In conclusion, we have developed an efficient route to a
Acknowledgment. We are grateful to CEM Corporation,
range of N-substituted oxindoles using sequential microwave-
assisted amide synthesis and intramolecular amidation reac-
tions. The approach is particularly efficient when using
alkylamines since there is no need to isolate the intermediate
amide.
UK, for provision of a Discover microwave synthesizer.
Supporting Information Available: Experimental details
and spectral data for all transformations and compounds
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2002,
67, 6479.
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Org. Lett., Vol. 7, No. 5, 2005