Synthesis of substituted oxindoles from α-chloroacetanilides via palladium-catalyzed C - H functionalization

Article abstract of DOI:10.1021/ja037546g

A novel method for the synthesis of oxindoles is described. In the presence of catalytic palladium acetate and 2-(di-tert-butylphosphino)biphenyl, α-chloroacetanilides are converted to oxindoles in good to excellent yields with high functional group compatibility using triethylamine as a stoichiometric base. The cyclization is highly regioselective, obviating the need for prefunctionalized arenes. Plausible mechanistic pathways for the reaction are discussed. Copyright

Full text of DOI:10.1021/ja037546g

Published on Web 09/13/2003
Synthesis of Substituted Oxindoles from r-Chloroacetanilides via
Palladium-Catalyzed C-H Functionalization
Edward J. Hennessy and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received July 25, 2003; E-mail: sbuchwal@mit.edu
Table 1. Palladium-Catalyzed Synthesis of Oxindoles
The oxindole ring is a prominent structural motif found in
numerous natural products and pharmaceutically active compounds.1
The importance of this heterocyclic system notwithstanding, existing
methods for oxindole synthesis are limited in their scope and
generality. Among the techniques commonly used in synthesis are
derivatization of other heterocycles (e.g. Wolf-Kishner reduction
of the corresponding isatin, oxidation of the corresponding indole2),
cyclization of o-aminophenylacetic acid derivatives,2 and radical
cyclization reactions.3 The intramolecular Heck reaction can be used
to generate oxindoles,4 and asymmetric cyclizations have found
widespread use in synthesis. Alternatively, the intramolecular
arylation of amides5 or amide enolates1,6 has been employed to
access oxindoles. Unfortunately, all of the aforementioned methods
inherently require a specifically functionalized precursor (e.g., the
presence of an ortho-halogen, an amino group, a preexisting ring
system). Thus, a nontrivial synthetic sequence may be required to
prepare the appropriate precursors. A classical approach to the
oxindole system that circumvents the need for such functionalization
is the Friedel-Crafts cyclization onto R-halo7 or R-hydroxy8
acetanilides. While it is a modular technique in that the reactive
functional group is transferred away from the aromatic nucleus,
the strongly acidic conditions and high temperatures required for
such reactions limit the range of functional groups that are tolerated.9
In this communication, we report on the development of a novel
variant of the Friedel-Crafts procedure using palladium-catalyzed
C-H functionalization,10 obviating the need for harsh reaction
conditions. Specifically, the combination of catalytic amounts of
palladium acetate, 2-(di-tert-butylphosphino)biphenyl (1) as a
ligand, and triethylamine as base, R-chloroacetanilides can be
smoothly converted to oxindoles in high yields with high levels of
regioselectivity. The requisite substrates are easily prepared by the
condensation of the corresponding aniline with the inexpensive
chloroacetyl chloride.11 Among the phosphine ligands examined,
only 1 is highly effective for this transformation. Even structurally
similar phosphines commonly used in cross-coupling reactions
provided considerably lower amounts of oxindole in the time
reactions employing 1 proceeded to nearly complete conversion.
As shown in Table 1, a variety of substituted oxindoles can be
obtained in high yields. Substrates that can result in two distinct
products cyclize with high regioselectivity. Apparently, steric
interactions direct the ring substituents to the 6-position, rather than
the 4-position, of the oxindole. Even electron-deficient aromatic
nuclei are reactive, allowing for the synthesis of oxindoles that may
be difficult to obtain using classical Friedel-Crafts methodology.
Importantly, functional groups incompatible with strong Lewis acids
(-OMe, -CF3, -TMS) are well tolerated, as is typical of reactions
catalyzed by late transition metals. This method is also compatible
with electron-rich aryl chlorides, allowing for palladium-catalyzed
coupling reactions to occur after the oxindole cyclization re-
action.12 In addition, aryl-TBS ethers, which are prone to cleavage
a Isolated yield (average of two runs; estimated to be >95% pure by 1H
NMR and combustion analysis). PMB ) p-methoxybenzyl, TBS ) tert-
butyldimethylsilyl, TMS ) trimethylsilyl, DPM ) diphenylmethyl. b 15:1
regioselectivity. c 14:1 regioselectivity. d >20:1 regioselectivity. e Reaction
conducted at 100 °C for 19 h.
in the presence of palladium salts,13 are stable under the reaction
conditions.
Despite the efficiency of the cyclization reaction, the substrate
scope is limited to N-alkyl or N-aryl chloroacetanilides. As of yet,
we have been unable to cyclize N-H or N-acyl (amide, carbamate)
substrates. In addition, 2,5-disubstituted chloroacetanilides are
essentially unreactive under these and more forcing conditions,
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J. AM. CHEM. SOC. 2003, 125, 12084-12085
10.1021/ja037546g CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Observed Kinetic Isotope Effects
In conclusion, we have developed a reliable and operationally
simple protocol to regioselectively synthesize substituted oxindoles.
The high levels of functional group tolerance without the need for
ortho-halogenation should make this an attractive synthetic alterna-
tive to currently used methods. Future work will concentrate on
expanding the substrate scope to include R-substituted halo-
acetanilides (forming 3-substituted oxindoles) as well as gaining a
firmer mechanistic understanding of the process.
possibly due to combined steric interactions in the cyclization
transition state.
Acknowledgment. We thank the NIH (GM46059) for funding.
We are also grateful to Pfizer, Merck, and Bristol-Myers Squibb
for unrestricted support.
To probe the mechanism of this transformation, we have
conducted experiments with isotopically labeled substrates (Scheme
1). No kinetic isotope effect was observed in the competitive
reaction of N-methyl chloroacetanilide and the corresponding
pentadeuterated substrate. However, an intramolecular primary
isotope effect of 4 is seen in the cyclization of the ortho-
monodeuterated substrate.14
Supporting Information Available: Experimental procedures,
characterization data for all unknown compounds, and spectral data
for isotope effect determination (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Scheme 2. Possible Mechanistic Pathways for Cyclization
References
(1) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M. C.; Wolfe, J.
F. J. Am. Chem. Soc. 1985, 107, 435 and references therein.
(2) Sundberg, R. J. Indoles; Academic Press: London, 1996; pp 17, 152-
154.
(3) (a) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A.
Tetrahedron Lett. 1995, 36, 949. (b) Jones, K.; Wilkinson, J.; Ewin, R.
Tetrahedron Lett. 1994, 35, 7673. (c) Jones, K.; McCarthy, C. Tetrahedron
Lett. 1989, 30, 2657. (d) Bowman, W. R.; Heaney, H.; Jordan, B. J.
Tetrahedron Lett. 1988, 29, 6657.
(4) (a) Donde, Y.; Overman, L. E. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley: New York, 2000; Chapter 8G and references
therein. (b) Mori, M.; Ban, Y. Tetrahedron Lett. 1979, 20, 1133. (c) Mori,
M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1807.
(5) Kametani, T.; Ohsawa, T.; Ihara, M. Heterocycles 1980, 14, 277.
(6) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (b) Shaughnessy,
K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546.
(7) Beckett, A. H.; Daisley, R. W.; Walker, J. Tetrahedron 1968, 24, 6093
and references therein.
(8) Ben-Ishai, D.; Peled, N.; Sataty, I. Tetrahedron Lett. 1980, 21, 569.
(9) This reaction has been conducted photochemically as well, although yields
are generally moderate. See: Hamada, T.; Okuno, Y.; Ohmori, M.; Nishi,
T.; Yonemitsu, O. Chem. Pharm. Bull. 1981, 29, 128.
(10) For recent reviews on C-H activation, see: (a) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. ReV. 2002, 102, 1731. (b) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1698.
(11) See Supporting Information.
(12) Higher catalyst loadings are required to achieve complete conversion for
these substrates, likely due to nonproductive, competitive oxidative
addition at the aryl chloride. Thus, bromide or iodide substituents on the
aromatic ring are presumably not compatible with our current protocol.
(13) (a) Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918. (b) Wilson,
N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153.
(14) This is similar to isotope effects previously observed in aromatic
palladation reactions; for example, see: (a) Boele, M. D. K.; van
Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.;
On the basis of these findings, we suggest several plausible
reaction mechanisms (Scheme 2). The process is most likely
initiated by oxidative addition of the R-chloro amide to Pd(0),
resulting in a Pd(II) enolate.15 The observed isotope effects suggest,
somewhat surprisingly, that this bimolecular step is slow relative
to subsequent intramolecular processes and is rate determining
overall.16 The formation of the carbon-carbon bond may proceed
by an electrophilic aromatic substitution to give a six-membered
palladacycle,17 which undergoes reductive elimination to afford the
product oxindole and regenerate the active Pd(0) species. Alterna-
tively, carbopalladation of the aromatic ring followed by anti-
elimination of HPdCl (or isomerization and syn-â-hydride elimi-
nation) would afford the same product,18 and it is possible that both
mechanisms are operative under the reaction conditions. The
observed intramolecular isotope effect implies that either palladation
process would be reversible and rapid relative to C-H bond
cleavage. A third mechanistic possibility consistent with this
observation is a true “C-H activation,” which may proceed via
σ-bond metathesis or through the intermediacy of a π,η1 interac-
tion19 (whereby the palladium enolate acts as a π-acid to the nearby
arene, sufficiently weakening the C-H bond that is eventually
broken).
van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586 (kH/kD
3). (b) Shue, R. S. J. Am. Chem. Soc. 1971, 93, 7116 (kH/kD ) 5).
)
(15) (a) Albe´niz, A. C.; Catalina, N. M.; Espinet, P.; Redo´n, R. Organometallics
1999, 18, 5571. (b) Veya, P.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C.
Organometallics 1993, 12, 4899.
(16) Another possibility is that rotation about the carbonyl C-N bond of the
palladium enolate into a reactive conformation is slow relative to the
palladation event. For an analogous situation, see: Cohen, T.; McMullen,
C. H.; Smith, K. J. Am. Chem. Soc. 1968, 90, 6866. We are grateful to a
reviewer for making this suggestion.
(17) Echavarren, A. M.; Go´mez-Lor, B.; Gonza´lez, J. J.; de Frutos, OÄ . Synlett
2003, 58 and references therein.
(18) This mechanistic dichotomy has been discussed previously. See (a) Sezen,
B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274. (b) Glover, B.; Harvey,
K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5,
301. (c) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa,
M.; Ihara, M. Org. Lett. 2002, 4, 4293. (d) Hughes, C. C.; Trauner, D.
Angew. Chem., Int. Ed. 2002, 41, 1569.
(19) (a) Ca´mpora, J.; Gutie´rrez-Puebla, E.; Lo´pez, J. A.; Monge, A.; Palma,
P.; del R´ıo, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40, 3641. (b)
Ca´mpora, J.; Lo´pez, J. A.; Palma, P.; Valerga, P.; Spillner, E.; Carmona,
E. Angew. Chem., Int. Ed. 1999, 38, 147.
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