Stereoselective oxindole synthesis by palladium-catalyzed cyclization reaction of 2-(alkynyl)aryl isocyanates with amides

Article abstract of DOI:10.1021/ol900759f

A new cyclization reaction occurred on treatment of 2-(alkynyl)aryl isocyanates with amides in the presence of a palladium(0)/diphosphine catalyst to stereoselectively form 3-(amidoalkylidene)oxindoles. A carbon-nitrogen bond as well as a carbon-carbon bo

Full text of DOI:10.1021/ol900759f

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2141-2143
Stereoselective Oxindole Synthesis by
Palladium-Catalyzed Cyclization
Reaction of 2-(Alkynyl)aryl Isocyanates
with Amides
Tomoya Miura, Takeharu Toyoshima, Yusuke Takahashi, and
Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received April 8, 2009
ABSTRACT
A new cyclization reaction occurred on treatment of 2-(alkynyl)aryl isocyanates with amides in the presence of a palladium(0)/diphosphine
catalyst to stereoselectively form 3-(amidoalkylidene)oxindoles. A carbon-nitrogen bond as well as a carbon-carbon bond were simultaneously
introduced onto the alkyne moiety to construct an oxindole skeleton with stereoselective placement of the amino substituent cis to the
carbonyl group.
Transition metal-catalyzed C-N bond-forming reactions
have been the subject of intense research1 because of the
importance of nitrogen-containing compounds. Oxindoles are
often found in bioactive molecules as the key substructure,2
which has driven increased interest in exploring new methods
for their preparation. In particular, 3-(aminoalkylidene)ox-
indoles are of significant pharmaceutical value,3 and there-
fore, methods to prepare them in a stereodefined way are in
high demand. We report herein a palladium-catalyzed
cyclization reaction of 2-(alkynyl)aryl isocyanates4 with
primary and secondary amides, which produces 3-(ami-
doalkylidene)oxindoles.5 The reaction allows for the inter-
molecular C-N bond introduction onto the alkyne moiety
cis to the developing carbonyl group in a stereoselective
fashion.
(1) Reviews: (a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F. Eds.; Wiley-
VCH: Weinheim, 2004. (b) Hartwig, J. F. Synlett 2006, 1283. (c) Wolfe,
J. P. Eur. J. Org. Chem. 2007, 571. (d) Severin, R.; Doye, S. Chem. Soc.
ReV. 2007, 36, 1407.
(4) For the synthesis of 3-alkylideneoxindoles by the palladium-catalyzed
reaction of 2-(alkynyl)aryl isocyanates, see: Kamijo, S.; Sasaki, Y.;
Kanazawa, C.; Schu¨sseler, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005,
44, 7718.
(2) Reviews: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748.
(5) For recent example of the synthesis of 3-alkylideneoxindoles with
transition-metal catalysis other than reference,4 see: (a) Yanada, R.; Obika,
S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta, S.; Takemoto, Y. J.
Org. Chem. 2005, 70, 6972. (b) Cheung, W. S.; Patch, R. J.; Player, M. R.
J. Org. Chem. 2005, 70, 3741. (c) Shintani, R.; Yamagami, T.; Hayashi, T.
Org. Lett. 2006, 8, 4799. (d) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem.,
Int. Ed. 2007, 46, 3291. (e) Tang, S.; Yu, Q.-F.; Peng, P.; Li, J.-H.; Zhong,
P.; Tang, R.-Y. Org. Lett. 2007, 9, 3413. (f) Tang, S.; Peng, P.; Pi, S.-F.;
Liang, Y.; Wang, N.-X.; Li, J.-H. Org. Lett. 2008, 10, 1179. (g) Tang, S.;
Peng, P.; Wang, Z.-Q.; Tang, B.-X.; Deng, C.-L.; Li, J.-H.; Zhong, P.; Wang,
N.-X. Org. Lett. 2008, 10, 1875. (h) Wasa, M.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 14058.
(3) (a) Eberwein, D. J.; Harrington, L.; Griffin, R.; Tadepalli, S.; Knick,
V.; Phillips, K.; Dickerson, S.; Davis, S. Proc. Am. Assoc. Cancer Res 2002,
43, 1611. (b) Davis, S. T.; Dickerson, S. H.; Harris, P. A.; Hunter, R. N.;
Kuyper, L. F.; Luzzio, M. J.; Veal, J. M.; Walker, D. H. (Glaxo Wellcome
Inc.) US6387919 B1, May 14, 2002. (c) Hauf, S.; Cole, R. W.; LaTerra,
S.; Zimmer, C.; Schnapp, G.; Walter, R.; Heckel, A.; van Meel, J.; Rieder,
C. L.; Peters, J. M. J. Cell Biol. 2003, 161, 281. (d) Heckel, A.; Roth,
G. J.; Kley, J.; Hoerer, S.; Uphues, I. (Boehringer Ingelheim Int.).
WO2005087727 A1, September 22, 2006.
10.1021/ol900759f CCC: $40.75
Published on Web 04/21/2009
 2009 American Chemical Society

We previously described the palladium-catalyzed cycliza-
tion of 2-(alkynyl)aryl isocyanates with organoboron re-
agents.6 In this reaction, an oxapalladacyclic intermediate
formed by oxidative cyclization undergoes transmetalation
with an organoboron species, converting a palladium-oxygen
bond into a palladium-carbon bond. It was then envisaged
that the use of protic nitrogen nucleophiles in place of organo-
borons would result in the generation of a palladium-nitrogen
bond through ligand substitution, leading to the introduction
of a carbon-nitrogen linkage. Thus, 2-(1-hexynyl)phenyl
isocyanate (1a, 1.0 equiv) was treated with trifluoroacetamide
(2a, 1.1 equiv) in the presence of Pd2(dba)3·CHCl3/dppf (1
mol %; dppf ) 1,1′-bis(diphenylphosphino)ferrocene) in
toluene (0.05 M) at 100 °C. The reaction reached completion
in 3 h, and an extractive workup followed by precipitation
from CH2Cl2/hexane afforded the 3-(amidoalkylidene)oxin-
dole 3aa in 83% yield as a single stereoisomer (Z/E ) >20:
1,7 eq 1).
promote ligand substitution by amide 2a and thus, the
additional usage of an external base is dispensed with for
generation of the palladium(II) amide species C.9 Finally,
reductive elimination from C affords the product 3aa,
regenerating the palladium(0) catalyst.
As shown in Table 1, primary and secondary alkyl groups
were suitable for the substituent at the alkyne terminus
Table 1. Pd(0)-Catalyzed Cyclization Reaction of 1 with
Trifluoroacetamide (2a)a
We propose that the reaction proceeds through the pathway
outlined in Scheme 1. Initially, both alkynyl and isocyanato
Scheme 1. Proposed Reaction Pathway
a Conditions: 1 (0.2 mmol), 2a (0.22 mmol), Pd2(dba)3·CHCl3 (2 µmol,
1 mol %), and dppf (4 µmol, 2 mol %) in toluene (4 mL) at 100 °C for 3 h
under Ar. b Isolated yield (stereoisomer ratio ) >20:1). c 2a (0.6 mmol, 3
equiv) was used for 13 h.
(entries 1-3). Even the bulky tert-butyl group permitted the
reaction, albeit under more forcing conditions, to give the
product 3ea in 56% yield (entry 4). Substrates possessing a
wide range of aryl and heteroaryl groups successfully
participated in the cyclization reaction (entries 5-10). Vinyl-
substituted substrate 1l was also converted to the product
3la in good yield (entry 11).10 Functional groups including
halide, ether, ester, and nitrile were tolerated on the aryl
group of 1 (entries 12-17). Interestingly, even the bromo
group of 1m remained intact.
groups of 1a coordinate to a palladium(0) center prompting
oxidative cyclization to form oxapalladacyclic intermediate
B.8 The palladium(II) oxide moiety then acts as a base to
(6) (a) Miura, T.; Toyoshima, T.; Takahashi, Y.; Murakami, M. Org.
Lett. 2008, 10, 4887. See also: (b) Miura, T.; Takahashi, Y.; Murakami,
M. Org. Lett. 2007, 9, 5075. (c) Miura, T.; Takahashi, Y.; Murakami, M.
Org. Lett. 2008, 10, 1743.
(7) The stereochemistry of the exocyclic double bond was assigned by
a difference NOE study.
(8) A result supportive for the presumed oxapalladacycle was obtained
by a 1H NMR study; when 1a was treated with a stoichiometric amount of
Pd2dba3·CHCl3 and dppf in THF-d8 at 80 °C for 2 h, the signal (-CH2C3H7)
shifted downfield from 2.45 to 2.76 ppm. However, an attempt to isolate it
as solids has been unsuccessful so far.
(9) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 4206.
(10) The substrates with R1 ) H and SiMe3 gave a complex mix-
ture.
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Org. Lett., Vol. 11, No. 10, 2009

A straightforward synthesis of 3aa on a gram scale was
also carried out to demonstrate the practicality of the present
method (Scheme 2). Product 3aa (2.65 g, 8.5 mmol) was
Table 3. Pd(0)-Catalyzed Cyclization Reaction of 1a with 2a
Scheme 2. Synthesis of 3aa on Gram Scale
entry
2
R3R4NH
3
yieldb (%)
1
2
3
4
5
6
7
8
2b
2c
4-CH3C6H4SO2NH2 (TsNH2)
C6H5CONH2 (BzNH2)
3ab
3ac
94
68
69c
83
98d
90
64
44
2d C6H5CH2OCONH2 (CbzNH2) 3ad
2e
2f
C6H5CH2NHCONH2
phthalimide
indolin-2-one
3ae
3af
3ag
3ah
3ai
2g
2h oxazolidin-2-one
2i aniline
a The reaction conditions are the same as those in Table 1 unless
otherwise noted. b Isolated yield (stereoisomer ratio ) >20:1). c 2d (0.6
mmol, 3 equiv) and BINAP (4 µmol, 2 mol %) as the ligand were used.
d 2f (0.6 mmol, 3 equiv) was used.
obtained starting from 2-(1-hexynyl)aniline (5, 1.73 g, 10
mmol) via the corresponding isocyanate 1a without interven-
tion of any chromatographic purification (85% yield over
two steps).
Next, hydrolysis of the trifluoroacetylamide group was
examined since 3-(free aminoalkylidene)oxindoles 4 have
been identified as potent kinase inhibitors.11 In fact, this
group could be easily removed by treatment with the mild
base K2CO3,12 as exemplified in Table 2.
3ab-ae in yields ranging from 68% to 94% (entries 1-4).
The cyclization also occurred with secondary amides such
as phthalimide (2f), indolin-2-one (2g), and oxazolidin-2-
one (2h) to afford the corresponding products in good yield
(entries 5-7). The reaction with aniline (2i) gave the product
3ai in 44% yield, together with a side product arising from
the direct addition of 2i to the isocyanato group (entry 8).
In summary, we have developed a palladium-catalyzed
amidative cyclization reaction to synthesize 3-(amidoalky-
lidene)oxindoles in a highly atom economical manner. The
overall reaction accomplishes both intramolecular C-C bond
formation and intermolecular C-N bond formation across
a carbon-carbon triple bond in a stereoselective fashion. This
unique example of cyclization will inspire the development
of transition metal-catalyzed reactions producing valuable
nitrogen-containing compounds via metallacyclic intermedi-
ates.
Table 2. Deprotection Reaction of Trifluoroacetyl Groupa
entry
3
R1
n-Bu
Ph
3-thienyl
n-Bu
R2
4
yieldb (%)
1
2
3
4
3aa
3fa
3ka
3na
H
H
H
Cl
4a
4f
4k
4n
89
85
89
90
Acknowledgment. This work was supported in part by
MEXT (Grant-in-Aids for Scientific Research on Priority
Areas “Chemistry of Concerto Catalysis” No. 20037032 and
Young Scientists (B) No. 20750078), the Mizuho Foundation
for the Promotion of Sciences, and the Uehara Memorial
Foundation. T.T. acknowledges the financial support by the
Global COE Program “Integrated Materials Science” No.
B-09.
a Conditions: 3 (0.15 mmol), K2CO3 (0.77 mmol) in MeOH/H2O (4.5/
0.1 mL) at rt for 50 min under Ar. b Isolated yield (stereoisomer ratio )
>20:1).
We studied the scope of nitrogen nucleophiles 2 for the
reaction of 1a; the results are listed in Table 3. A variety of
primary amides 2b-e including N-benzylurea worked well
to give the corresponding 3-(amidoalkylidene)oxindoles
Supporting Information Available: Experimental details
and spectra data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Burgdorf, L. T.; Bruge, D.; Greiner, H.; Kordowicz, M.; Sirrenberg,
C.; Zenke, F. (Merck Patent GmbH). WO2006131186 A1, December 14,
2006.
(12) Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1988, 53, 3108.
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