An asymmetric hetero-claisen approach to 3-alkyl-3-aryloxindoles

Article abstract of DOI:10.1021/ol901441t

The reaction of a chiral N-phenylnitrone derived from Garner's aldehyde with alkylarylketenes generates 3-alkyl-3-aryloxindoles directly in excellent yields and with good to excellent levels of enantioselectivity (up to 90% ee).

Full text of DOI:10.1021/ol901441t

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3858-3861
An Asymmetric Hetero-Claisen
Approach to 3-Alkyl-3-aryloxindoles
Nicolas Duguet, Alexandra M. Z. Slawin, and Andrew D. Smith*
EaStCHEM, School of Chemistry, UniVersity of St Andrews, North Haugh,
St Andrews, KY16 9ST, U.K.
ads10@st-andrews.ac.uk
Received June 25, 2009
ABSTRACT
The reaction of a chiral N-phenylnitrone derived from Garner’s aldehyde with alkylarylketenes generates 3-alkyl-3-aryloxindoles directly in
excellent yields and with good to excellent levels of enantioselectivity (up to 90% ee).
3,3-Difunctionalized oxindoles are widely recognized as
valuable synthetic intermediates, forming the core of numer-
ous natural products and medicinal targets.1 As a representa-
tive subclass, 3-alkyl-3-aryloxindoles are readily derivatized
to the central motif of a range of hexahydropyrroloindole
alkaloids that display an array of biological activities and
present significant challenges for asymmetric total synthesis.2
A number of strategies for the synthesis of the 3-alkyl-3-
aryloxindole motif in both racemic and enantiomerically
enriched form have been developed in recent years, including
Pd-catalyzed asymmetric intramolecular Heck cyclization,3
Pd-mediated asymmetric allylation,4 Pd-catalyzed arylation5
and alkylation,6 direct C-H/Ar-H coupling methods,7 and
oxidative rearrangements,8 among a host of others.9
The [3,3]-sigmatropic rearrangement of O-allyl indolyl
ethers is an elegant alternative process to prepare 3-substi-
tuted oxindoles.10 Classically, the Brunner oxindole synthe-
(4) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308.
(5) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546. (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(c) Arao, T.; Sato, K.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006,
54, 1576. (d) Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006,
54, 1743. (e) Ku¨ndig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G.
Angew. Chem., Int. Ed. 2007, 46, 8484. (f) Luan, X.; Mariz, R.; Robert,
C.; Gatti, M.; Blumentritt, S.; Linden, A.; Dorta, R. Org. Lett. 2008, 10,
5569.
(6) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084. For a related amination approach to 3,3-oxindoles, see: Wasa, M.;
Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(7) Jia, Y.-X.; Ku¨ndig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636.
Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249.
(1) For examples, see: Galliford, C. V.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 8748. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org.
Chem. 1993, 58, 6949. Ashimori, A.; Bachand, B.; Calter, M. A.; Govek,
S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
Overman, L. E.; Poon, D. J. Angew. Chem., Int. Ed. 1997, 36, 518.
(2) For a review, see: Steven, A.; Overman, L. E. Angew. Chem., Int.
Ed. 2007, 46, 5488. For pharmacological activity of 3-alkyl-3-aryloxindoles,
see: Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M. C.; Wolfe,
J. F. J. Am. Chem. Soc. 1985, 107, 435.
(8) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett. 2008,
10, 4009.
(9) For select examples, see: (a) He, R.; Ding, C.; Maruoka, K. Angew.
Chem., Int. Ed. 2009, 48, 4599. (b) Liang, J.; Chen, J.; Du, F.; Zeng, X.;
Li, L.; Zhang, H. Org. Lett. 2009, 11, 2820. (c) Munusamy, R.; Dhathath-
reyan, K. S.; Balasubramanian, K. K.; Venkatachalam, C. S. J. Chem. Soc.,
Perkin Trans 2 2001, 1154. Fu and Vedejs have elegantly shown that
heterocyclic compounds can promote catalytic asymmetric O- to C-carboxyl
group transfer of indolyl carbonates: (d) Hills, I. D.; Fu, G. C. Angew. Chem.,
Int. Ed. 2003, 42, 3921. (e) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf,
J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925. (f) Duffey,
T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14.
(3) Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.;
Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003,
125, 6261.
10.1021/ol901441t CCC: $40.75
Published on Web 07/31/2009
 2009 American Chemical Society

sis11 generates 3-substituted oxindoles from acyclic reaction
precursors, though elevated reaction temperatures are re-
quired to promote this transformation. A number of related
3-oxa-4-aza-[3,3] sigmatropic rearrangements have been
developed that require the formation of a metal enolate or
forcing reaction conditions to promote the rearrangement and
generate racemic oxindoles.12 An alternative hetero-Claisen-
type process,13 first investigated by Staudinger,14 and
subsequently by Lippman15 and Taylor,16 employs the
reaction of phenylnitrone with 2 equiv of diphenylketene,
generating 3,3-diphenyloxindole after methanolysis. Only
limited use of this transformation has been made despite its
potential synthetic versatility,17 and to the best of our
knowledge, no examples of this process using unsymmetrical
disubstituted ketenes or asymmetric versions of this reaction
have been demonstrated. Herein, we detail the development
of an efficient, metal-free, asymmetric variant of this reaction
that generates 3-alkyl-3-aryloxindoles with high enantiopurity
(up to 90% ee) (Figure 1).
Figure 1. Proposed synthesis of 3-alkyl-3-aryloxindoles (Xc )
stereodirecting group).
Figure 2. Synthesis of (()-3-alkyl-3-aryloxindoles.
Initial studies focused upon the demonstration of this
process in the racemic series. In an optimized procedure,
treatment of nitrone 1 with methylphenylketene gave (()-
3-methyl-3-phenyloxindole 5 and 4-bromobenzaldehyde
directly after workup, furnishing (()-5 in 85% isolated yield.
This reaction proved general, tolerating a range of C(2)-aryl
and C(2)-alkyl substituents within the ketene component,
generating (()-oxindoles 6-12 in excellent isolated yield
(83-90%). A range of N-aryl nitrones are also tolerated, with
4- or 2-substituted N-aryl nitrones 2-4 giving the (()-5- or
(()-7-substituted oxindoles 13-15, respectively, in excellent
yield (87-93%) (Figure 2).
With an efficient synthetic protocol developed to generate
(()-3-alkyl-3-aryloxindoles, the ability of a chiral nitrone
to induce asymmetry in this transformation was investigated.
Treatment of Garner’s aldehyde18 with phenylhydroxylamine
and MgSO4 gave (R,Z)-N-phenylnitrone 16 as a bench stable
crystalline solid as a single diastereoisomer in 87% yield.
The (Z)-configuration within 16 was confirmed by single-
crystal X-ray diffraction (Scheme 1).19
Treatment of nitrone 16 with methylphenylketene (1 equiv)
followed by aqueous workup afforded oxindole (S)-5 in 85%
yield and 87% ee20 and recovered Garner’s aldehyde in 80%
(10) For representative examples, see: Kawasaki, T.; Shinada, M.;
Kamimura, D.; Ohzuno, M.; Ogawa, A. Chem. Commun. 2006, 420.
Kawasaki, T.; Ogawa, A.; Terashima, R.; Saheki, T.; Ban, N.; Sekiguchi,
H.; Sakaguchi, K-E. M. J. Org. Chem. 2005, 70, 2957. Kawasaki, T.;
Terashima, R.; Sakaguchi, K.; Sekiguchi, H.; Sakamoto, M. Tetrahedron
Lett.1996,42,7525. ForarecentcatalyticasymmetricMeerwein-Eschenmoser
Claisen rearrangement, see: Linton, E. C.; Kozlowski, M. C. J. Am. Chem.
Soc. 2008, 130, 16162.
(13) For a review of related hetero [3,3]-sigmatropic rearrangements,
see: Blechert, S. Synthesis 1989, 71.
(14) Staudinger, H.; Miescher, K. HelV. Chim. Acta 1919, 2, 554.
(15) Hassall, C. H.; Lippmann, A. E. J. Chem. Soc. 1953, 1059.
(16) Hafiz, M.; Taylor, G. A. J. Chem. Soc., Perkin Trans. 1 1980, 1700.
Stokes, D. P.; Taylor, G. A. J. Chem. Soc. C 1971, 2334. Pratt, R. N.;
Stokes, D. P.; Taylor, G. A. J. Chem. Soc. C. 1968, 1653.
(11) Brunner, K. Monatsh. Chem. 1896, 17, 479. Endler, A. S.; Beeker,
E. I. Org. Synth. 1957, 37, 60. Wolff, J.; Taddei, M. Tetrahedron 1996, 42,
4267.
(17) For examples of related reactions that generate achiral oxindoles,
see: Takaoka, K.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1999, 40, 3017.
Baker, A. D.; Wong, D.; Lo, S.; Bloch, M.; Horozoglu, G.; Goldman, G. L.;
Engel, R.; Liotta, D. C. Tetrahedron Lett. 1978, 19, 215. Calder, I. C.;
Williams, P. J. J. Chem Soc., Chem. Commun. 1972, 891.
(12) For representative examples, see: Coates, R. M.; Said, I. M. J. Am.
Chem. Soc. 1977, 99, 2355. Blechert, S. Tetrahedron Lett. 1984, 25, 1547.
Uchida, T.; Endo, Y.; Hizatate, S.; Shudo, K. Chem. Pharm. Bull. 1994,
42, 419. Endo, Y.; Uchida, T.; Hizatate, S.; Shudo, K. Synthesis 1994, 1096.
Almeida, P. S.; Prabhakar, S.; Lobo, A. M.; Marcelo-Curto, M. J.
Tetrahedron Lett. 1991, 32, 2671. Lobo, A. M.; Prabhakar, S. Pure Appl.
Chem. 1997, 69, 547. Santos, P. F.; Almeida, P. S.; Lobo, A. M.; Prabhakar,
S. Heterocycles 2001, 55, 1029. Mao, Z.; Baldwin, S. W. Org. Lett. 2004,
6, 2425.
(18) Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18. Garner, P.;
Ramakanth, S. J. Org. Chem. 1986, 51, 2609.
(19) Crystallographic data for compound 16 has been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 737167. These data can be obtained free of charge from
www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 11, No. 17, 2009
3859

Scheme 1. Preparation and Molecular Representation of the
Single-Crystal X-Ray Structure of Nitrone 16
Figure 3. Asymmetric oxindole synthesis: generality.
A mechanistic proposal for this reaction is outlined in
Figure 4. Nucleophilic addition of nitrone 16 to the ketene,
yield. The absolute configuration within 5 was assigned by
N-methylation to give the known N-methyloxindole 17 and
comparison of its specific rotation with the literature21
(Scheme 2).
Scheme 2. Asymmetric Oxindole Formation
The generality of this asymmetric process was next probed
through treatment of nitrone 16 with a series of alky-
larylketenes. A range of C(2)-aryl groups incorporating
electron-donating and -withdrawing substituents, plus C(2)-
alkyl substituents within the ketene component, are tolerated,
generating the corresponding (S)-3-alkyl-3-aryloxindoles22
in excellent isolated yield (78-91%) and 78-90% ee.
Garner’s aldehyde was recovered in 78-87% yield in each
case (Figure 3).23
Figure 4. Mechanistic proposal for asymmetric oxindole synthesis.
preferentially anti- to the C(2)-aryl substituent,24 will gener-
ate the corresponding enolate 21. Subsequent asymmetric
[3,3]-sigmatropic rearrangement proceeds under the control
3860
Org. Lett., Vol. 11, No. 17, 2009

of the remote stereodirecting group to generate, after
aromatization, the imino acid 23 that undergoes facile
hydrolysis and cyclization upon workup to generate the
enantioenriched 3-alkyl-3-aryloxindole 24 and Garner’s
aldehyde.25
Scheme 3. Synthetic Utility of Asymmetric Oxindole Synthesis
To exemplify the experimental simplicity of this protocol,
and its potential utility in synthesis, its application to the
rapid construction of the 3-phenyl-hexahydropyrroloindole
skeleton from simple starting materials was undertaken.
Allylphenylketene 26 was prepared in situ by dehydrohalo-
genation of 2-phenylpent-4-enoyl chloride 25 and treated
with nitrone 16 at -78 °C, generating (S)-3-allyl-3-pheny-
loxindole 27 in 93% yield and 80% ee,26 with recrystalli-
zation giving (S)-27 in >99% ee. N-Methylation gave 28 in
93% yield and >99% ee, with ozonolysis, in situ treatment
with methylamine, and subsequent LiAlH4 reduction giving
29 in 63% yield over three steps (Scheme 3).27
In conclusion, we have developed a simple synthetic
procedure for the asymmetric synthesis of 3-alkyl-3-arylox-
(20) As shown by HPLC analysis with reference to an authentic racemic
sample, see Supporting Information for full details.
5e
20
23
(21) [R]D -81.2 (c ) 1.1, CH2Cl2), 87% ee; lit. [R]D -86.0 (c )
1.00, CH2Cl2), 94% ee; see Supporting Information for full details.
(22) The absolute configurations within 6, 8-10, and 18-20 were
assigned by analogy to that proven for 5. All ee values were measured by
HPLC analysis with reference to authentic racemic samples; see Supporting
Information for full details.
indoles (up to 90% ee). Further applications of this meth-
odology in natural product synthesis, studies directed toward
understanding how the remote stereocenter controls the facial
selectivity of this transformation, and the development of
catalytic asymmetric variants are currently underway within
this laboratory.
(23) The specific rotation of recovered Garner’s aldehyde {[R]D20 -75.4
20
(c ) 1.00, CHCl3)} was equivalent {[R]D -76.3 (c ) 0.89, CHCl3)} to
that used to prepare nitrone 16, consistent with no racemization of the
stereodirecting fragment during the rearrangement.
(24) For theoretical studies concerning the selectivity of nucleophilic
additions to ketenes, see: Cannizzaro, C. E.; Houk, K. N. J. Am. Chem.
Soc. 2004, 126, 10992.
Acknowledgment. The authors would like to thank the
Royal Society for a University Research Fellowship (ADS),
The Leverhulme Trust (ND) for funding, and the EPSRC
mass spectrometry facility.
(25) Assuming a concerted [3,3]-sigmatropic rearrangement, we cannot
currently distinguish between potential chair- and boat-type transition states
that would both lead to the correct absolute configuration of the oxindole
product and would have the opposite configuration at the stereocenter within
22 that is lost upon rearomatization. Using this framework, it is also not
clear how the remote stereocenter influences the facial selectivity of this
reaction; this is the focus of current investigations.
Supporting Information Available: Experimental pro-
cedures plus spectroscopic and HPLC data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL901441T
(27) The enantiopurity of 29 could not be assigned unambiguously by
HPLC analysis but was assigned as >99% ee on the assumption that no
racemization had taken place in the conversion from 28. The absolute
configuration within 29 was assigned by comparison of its specific rotation
(26) The absolute (S)-configuration of 27 was assigned both by analogy
to that proven for 5 and unambiguously through its conversion to (S)-1-
benzyl-3-(2-hydroxyethyl)-3-phenylindolin-2-one via N-benzylation, ozo-
nolysis, and NaBH4 reduction and comparison of the HPLC retention times
with that of the literature (see Overman et al.; ref 3); see Supporting
Information for full details.
20
with the literature (see Maruoka et al., ref 9a); [R]D +114.2 (c ) 1.06,
CHCl3); lit.9a [R]D +111.63 (c ) 0.62, CHCl3), 90% ee; see Supporting
23
Information for full details.
Org. Lett., Vol. 11, No. 17, 2009
3861