Asymmetric decarboxylative allylation of oxindoles

Article abstract of DOI:10.1021/ol201613a

An asymmetric decarboxylative palladium-catalyzed allylation of alkyl- and aryl-substituted oxindoles has been developed, enabling the installation of an all-carbon quaternary chiral center at the oxindole 3-position in excellent yields and good to excell

Full text of DOI:10.1021/ol201613a

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4264–4267
Asymmetric Decarboxylative
Allylation of Oxindoles
ꢀ
Vilius Franckevicius, James D. Cuthbertson, Mark Pickworth,
David S. Pugh, and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
richard.taylor@york.ac.uk
Received June 15, 2011
ABSTRACT
An asymmetric decarboxylative palladium-catalyzed allylation of alkyl- and aryl-substituted oxindoles has been developed, enabling the
installation of an all-carbon quaternary chiral center at the oxindole 3-position in excellent yields and good to excellent enantioselectivity. An
intriguing substrate-dependent reversal in stereoselectivity has been observed, whereby the size of the substituent determines the facial
selectivity in the allylation step.
The oxindole structural motif is present in a large class of
both bioactive naturally occurring alkaloids and synthetic
analogs of medicinal value.1 Bioactive oxindoles fre-
quently contain a quaternary stereogenic center at the
3-position,2 and a variety of catalytic asymmetric methods
for constructing the tetra-substituted carbon center by
means of metal- and organo-catalysis have been developed
overtheyears.3 Following theoriginalreportbyTrostetal.
of a catalytic asymmetric allylic alkylation4 of ketone
enolates,5 methods for the installation of a quaternary
carbon center in the 3-position of oxindoles by way of
either palladium6 or molybdenum7 catalysis have been
reported. However, no one method is applicable to both
alkyl- and aryl-substituted oxindoles. In addition, either
the use of stoichiometric amounts of base for enolate
generation or elevated temperature is required for the
reaction to proceed efficiently.
In order to establish reaction conditions which would
not necessitate the use of a base and be suitable for a
broader range of oxindole substrates, we aimed to exploit
the utility of the TsujiÀTrost decarboxylative allyl group
transfer process as a stereoselective entry to 3,3-disubsti-
tuted oxindoles.8 Although the decarboxylative palla-
dium-mediated allyl transfer processes with enolates as
nucleophiles have now matured into a robust asymmetric
transformation,9 with major contributions from the
groups of Tunge,10 Trost,11 and Stoltz,12 among others,13
an asymmetric variant for the installation of a quaternary
center at the oxindole 3-position has not been reported to
(1) For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (b) Millemaggi, A.; Taylor, R. J. K. Eur.
J. Org. Chem. 2010, 4527.
(2) For reviews concerning synthesis of substituted oxindoles, see: (a)
Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
5969. (b) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347, 1473. (c)
Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149. (d) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (e)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (f) Christoffers,
J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (g) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(3) For a review of asymmetric catalytic oxindole syntheses, see:
Zhou, F.; Liu, Y. L.; Zhou, J. A. Adv. Synth. Catal. 2010, 352, 1381.
(4) For general reviews in the area, see: (a) Hartwig, J. F.; Stanley,
L. M. Acc. Chem. Res. 2010, 43, 1461. (b) Trost, B. M.; Fandrick, D. R.
Aldrichimica Acta 2007, 40, 59. (c) Miyabe, H.; Takemoto, Y. Synlett
2005, 1641. (d) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (e) Belda, O.;
Moberg, C. Acc. Chem. Res. 2004, 37, 159. (f) Trost, B. M. Chem. Pharm.
Bull. 2002, 50, 1. (g) Hayashi, T. J. Organomet. Chem. 1999, 576, 195. (h)
Helmchen, G. J. Organomet. Chem. 1999, 576, 203.
(7) (a) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (b)
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548. (c) Trost,
B. M.; Zhang, Y. Chem.;Eur. J. 2011, 17, 2916.
(8) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199. (b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24,
1793. (c) Tsuji, J.; Minami, I.; Shimizu, I. Chem. Lett. 1983, 1325. (d)
Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. For reviews, see: (e)
Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (f) Pan, Y.;
Tan, C.-H. Synthesis 2011, 2044.
(5) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
(6) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005,
44, 308. (b) Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc.
2011, 133, 7328. (c) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc.
2010, 132, 15534.
r
10.1021/ol201613a
Published on Web 07/21/2011
2011 American Chemical Society

date. We therefore set out to prepare suitable oxindoles to
test this idea.
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Synthesis
All oxindole substrates in this study were readily acces-
sible (Scheme 1). More specifically, monoesterification of
malonic acid (1), followed by anilide formation and intro-
duction of an alkyl substituent, afforded linear intermedi-
ates of type 2. Similarly, amide bond formation from
phenylacetic acid 3 and allyloxycarbonylation generated
aryl-substituted linear precursors4. Both 2 and 4 were then
readily transformed to the cyclic oxindole core 5 by means
of the recently developed copper(II)-mediated radical
cyclization via a direct CÀH, ArÀH coupling.14
temp
yield
(%)a
ee
entry
R
solvent
(°C)
ligand
(%)b
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
THF
rt
(R)-L1
82
92
95
32
10
73
92
85
83
0
4
À6
À14
4
2
THF
rt
(R)-L2
3
THF
rt
(R)-L3
4
THF
rt
(S,S)-L4
(R,R)-L5
(R,R)-L6
(R,R)-L6
(R,R)-L6
(R,R)-L6
(R,R)-L6
(R,R)-L6
5
THF
rt
À12
46
6
THF
rt
7
DME
THF
DME
DME
toluene
rt
52
8
À40
À25
À40
À25
57
9
74
Withallyl esters5 in hand, we beganour decarboxylative
allyl transfer studies by evaluating the effect of chiral
ligands, solvents, and temperature on the reaction with
oxindoles 5a and 5h as test substrates (Table 1).
10
11
À
99
79
a Isolated yield. b Determined by chiral HPLC.
In this optimization study, the reactivity of the methyl-
substituted substrate 5a was explored first and reactions
were run in THF at room temperature for 24 h, with
Pd2(dba)3 as the source of palladium(0) in the presence
of a chiral ligand. Although Helmchen PHOX ligands of
type L115 have been shown previously to mediate decar-
boxylative allyl transfer with ketone substrates with high
enantioselectivity,12 L1 was not selective in this case,
affording an essentially racemic product, albeit in good
yield (Table 1, entry 1). The use of JOSIPHOS (L2) and
BINAP (L3) only marginally improved the enantioselec-
tivity (Table 1, entries 2 and 3). Interestingly, Trost ligands
L4 and L5 led to not only poor selectivity but also a
dramatic drop in conversion (Table 1, entries 4 and 5). In
contrast, with the commercially available anthracenyl L6
as a ligand, which had previously been successfully utilized
by Trost,6a the reactivity was restored to provide 6a in an
improved 73% yield and 46% ee (Table 1, entry 6). At this
point, a thorough solvent screen had allowed us to estab-
lish that comparable results can also be obtained with
DME as the solvent (Table 1, entry 7). Finally, a lower
reaction temperature with both THF and DME resulted in
a significant improvement in selectivity (Table 1, entries 8
and 9, 83% yield and 74% ee of 6a in DME), although
further reduction in reaction temperature in DME halted
the reaction altogether (Table 1, entry 10). Similar optimi-
zation indicated that, in the case of aryl-substituted
(9) For reviews in the area, see: (a) Weaver, J. D.; Recio, A.;
Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (b) Mohr,
J. T.; Stoltz, B. M. Chem.;Asian J. 2007, 2, 1476.
(10) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113.
(11) (a) Trost, B. M.; Xu, J. Y. J. Am. Chem. Soc. 2005, 127, 2846. (b)
Trost, B. M.; Xu, J. Y. J. Am. Chem. Soc. 2005, 127, 17180. (c) Trost,
B. M.; Xu, J. Y.; Reichle, M. J. Am. Chem. Soc. 2007, 129, 282. (d) Trost,
B. M.; Xu, J. Y.; Schmidt, T. J. Am. Chem. Soc. 2008, 130, 11852. (e)
Trost, B. M.; Xu, J. Y.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343.
(f) Trost, B. M.; Lehr, K.; Michaelis, D. J.; Xu, J. Y.; Buckl, A. K. J. Am.
Chem. Soc. 2010, 132, 8915.
(12) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044. (b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2005, 44, 6924. (c) Keith, J. A.; Behenna, D. C.;
Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.;
Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876. (d) Enquist, J. A.;
Stoltz, B. M. Nature 2008, 453, 1228. (e) Sherden, N. H.; Behenna, D. C.;
Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 6840. (f)
Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Org. Lett.
2011, 13, 825.
(13) (a) Nakamura, M.; Hajra, L.; Endo, K.; Nakamura, E. Angew.
Chem., Int. Ed. 2005, 44, 7248. (b) Kuwano, R.; Ishida, N.; Murakami,
M. Chem. Commun. 2005, 3951.
(14) (a) Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K.
Org. Lett. 2010, 12, 3446. (b) Pugh, D. S.; Klein, J. E. M. N.; Perry, A.;
Taylor, R. J. K. Synlett 2010, 934. (c) Perry, A.; Taylor, R. J. K. Chem.
Commun. 2009, 3249. (d) Jia, Y. X.; Kundig, E. P. Angew. Chem., Int. Ed.
2009, 48, 1636.
(15) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. 1998, 37, 3047.
Org. Lett., Vol. 13, No. 16, 2011
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Table 2. Investigation of Substrate Scope
a Major enantiomer drawn; see text concerning determination of absolute configuration. b A-value of the substituent at the oxindole 3-position;
source: Eliel, E. L.; Wilen, S. H. and Mander, L. N. Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994. c Isolated yield.
d Determined by chiral HPLC. e Yield based on recovered starting material. f Approximate value as baseline separation of enantiomers could not be
achieved. g A-value assumed to be larger than that for unsubstituted phenyl ring.
example 5h (Table 1, entry 11), the same catalyst and
temperature were optimal, except that toluene as the
solvent proved to be superior (79% ee of 6h).
The substrate scope of the reaction was explored next
(Table 2). Interms of N-protection, both N-Me (6a) and N-
Bn (6b) groups were compatible (Table 2, entries 1 and 2).
Crucially, methyl- and phenyl-substitution on the allyl
group was also tolerated well, affording products 6c and
6d in good to excellent yields and selectivity (Table 2,
entries 3 and 4). An acetonitrile substituent (6e) led to a
slight decrease in enantioselectivity (Table 2, entry 5),
whereas the larger isopropyl and cyclohexyl substituents
were found to provide products 6f and 6g but with the
opposite absolute stereochemical configuration (Table 2,
entries 6 and 7). Finally, a range of aryl substituents were
tested in toluene as the solvent (Table 2, entries 8À11). The
unsubstituted phenyl example as well as those with ortho-
and meta-substituents were all successful, and the desired
4266
Org. Lett., Vol. 13, No. 16, 2011

products 6hÀk were obtained in excellent yields and good
to excellent enantioselectivity (quantitative yield and 95%
ee of 6i). The stereochemical configuration of 6hÀk was
found to be the same as that for the isopropyl and
cyclohexyl substituted oxindoles 6f and 6g. The absolute
configuration of seven products was determined by com-
parison of optical rotation data with literature values (see
Supporting Information for full details).7a,16
Scheme 2. Stereochemical Rationale
Speculating that the stereoselectivity of the reaction
correlates with the steric size of the oxindole substituent,
we utilized the A-values (on a cyclohexane ring) of these
substituents as an approximate descriptor of steric/electro-
nic bulk (Table 2).17 Specifically, the absolute configura-
tion of the major enantiomer of product appears to depend
on whether the oxindole substituent is small (Table 2,
entries 1À5, A-values 1.74À1.77) or large (Table 2, entries
6À11, A-values 2.2À2.8).
Taking the reasonable assumption6b that an outersphere
mechanism is in operation (the oxindole enolate is a
semistabilized anion, pKa ≈ 18.5), in the case of a small
substituent (e.g., Me, Scheme 2a), the more sterically
demanding oxindole moiety is placed under the “open
flap”,18,19 leading to the observed stereochemical outcome.
In contrast, the steric bulk of a larger substituent (e.g., i-Pr)
overrides the steric effect exerted by the oxindole moiety
and provides a product with the opposite stereochemical
configuration (Scheme 2b).20 Of course, the opposite en-
antiomers of the products could in principle be obtained by
simply employing the opposite enantiomer of the chiral
ligand.
In summary, we have developed a procedure for the
asymmetric palladium-catalyzed allylation of both alkyl-
and aryl-substituted oxindoles, installing an all-carbon
quaternary stereogenic center in excellent yields and good
to excellent enantioselectivity. We also report an unex-
pected reversal in stereoselectivity and postulate that this is
governed by the steric size of the oxindole substituent.
Accesstoenantioenrichedoxindolesopensupnewavenues
for stereoselective natural product synthesis, which is the
current focus of our work.
Acknowledgment. We thank the University of York (V.
F.) and theEPSRC (D.S.P., EP/E041302/1) for funding, as
well as the EPSRC and AstraZeneca for studentship
support (J.D.C.). Postdoctoral support from a Marie
Curie International Outgoing Fellowship (FP7) to M.P.
is gratefully acknowledged. We also thank Professor Ian
Fairlamb, University of York, for useful discussions.
Supporting Information Available. Full experimental
procedures, characterization data, copies of HPLC traces
1
and H NMR spectra, as well as a summary of optical
rotation data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) (a) Luan, X. J.; Wu, L. L.; Drinkel, E.; Mariz, R.; Gatti, M.;
Dorta, R. Org. Lett. 2010, 12, 1912. (b) Duguet, N.; Slawin, A. M. Z.;
Smith, A. D. Org. Lett. 2009, 11, 3858.
(17) A-values also reflect stereoelectronic factors involved in the
equatorial/axial substitution preference on a cyclohexane ring and are,
therefore, only a partial measure of steric bulk.
(18) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(b) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006,
39, 747.
(19) For a recent alternative stereochemical rationale, see: (a) Evans,
L. A.; Fey, N.; Harvey, J. N.; Hose, D.; Lloyd-Jones, G. C.; Murray, P.;
Orpen, A. G.; Osborne, R.; Owen-Smith, G. J. J.; Purdie, M. J. Am.
Chem. Soc. 2008, 130, 14471. (b) Butts, C. P.; Filali, E.; Lloyd-Jones,
G. C.; Norrby, P. O.; Sale, D. A.; Schramm, Y. J. Am. Chem. Soc. 2009,
131, 9945.
(20) Both methyl-substituted 6a and iso-propyl-substituted 6f have
the (S)-configuration, according to CahnÀIngoldÀPrelog priority rules.
Org. Lett., Vol. 13, No. 16, 2011
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