Synthesis of 3-(diarylmethylenyl)oxindole by a palladium-catalyzed domino carbopalladation/C-H activation/C-C bond-forming process

Article abstract of DOI:10.1021/ol062022h

(Chemical Equation Presented) A highly efficient palladium-catalyzed synthesis of unsymmetrically substituted 3-(diarylmethylenyl)indolinones from readily accessible starting materials is developed. The domino reaction involves a sequence of intermolecula

Full text of DOI:10.1021/ol062022h

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4927-4930
Synthesis of
3-(Diarylmethylenyl)oxindole by a
Palladium-Catalyzed Domino
Carbopalladation/C−H Activation/C−C
Bond-Forming Process
Artur Pinto, Luc Neuville, Pascal Retailleau, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received August 16, 2006
ABSTRACT
A highly efficient palladium-catalyzed synthesis of unsymmetrically substituted 3-(diarylmethylenyl)indolinones from readily accessible starting
materials is developed. The domino reaction involves a sequence of intermolecular carbopalladation, C H activation, and C C bond formation.
A plausible mechanistic pathway for the reaction is discussed on the basis of the kinetic isotope effect [KH/KD (intermolecular) 1, KH/KD
(intramolecular) 2.7] as well as the electronic effect.
−
−
)
)
3-Alkylideneoxindoles are attractive synthetic targets because
of their significant biological activities1 as well as their
proved utilities as valuable intermediates in the elaboration
of complex naturally occurring alkaloids and drug candi-
dates.2 Whereas (3-arylidenyl)indolinone is easily accessible,3
methods allowing a rapid and reliable access to stereochemi-
cally defined unsymmetrically substituted 3-(diarylmethyl-
enyl)indolinones (1) are scarce.4-7 Furthermore, the reported
transformations required the use of 2-iodoanilides4-6 or
2-(alkynyl)phenylisocyanates7 as starting materials. We have
recently reported a synthesis of tetracyclic heterocycles by
a palladium-catalyzed domino sequence involving a key
C-H functionalization step.8 As a continuation of this
research program, we report herein a novel and efficient
synthesis of 1 that involves a palladium-catalyzed domino
intermolecular carbopalladation/C-H activation/C-C bond-
forming process (Scheme 1).9,10 Besides being conceptually
novel, this approach allows the use of anilides (2) that are
(1) Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Science 2004, 303,
1800-1805.
(2) (a) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122,
5666-5667. (b) Ma, D.; Wu, Q. Tetrahedron Lett. 2000, 41, 9089-9092.
(c) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347-6355.
(3) (a) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000,
2239-2240. (b) Couty, S.; Lie´gault, B.; Meyer, C.; Cossy, J. Org. Lett.
2004, 6, 2511-2514. (c) Teichert, A.; Jantos, K.; Harms, K.; Studer, A.
Org. Lett. 2004, 6, 3477-3480. (d) Kalinski, C.; Umkehrer, M.; Schmidt,
J.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W.; Hoffmann, S. D. Tetrahedron
Lett. 2006, 47, 4683-4686 and references therein. See also: (e) Xing, X.;
Wu, J.; Luo, J.; Dai, W.-M. Synlett 2006, 2099-2103.
(5) Pd-catalyzed Heck cyclization/Suzuki-Miyaura coupling: (a) Che-
ung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741-
3744. (b) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.; Yamashita, M.;
Ohta, S.; Takemoto, Y. J. Org. Chem. 2005, 70, 6972-6975.
(6) Pd-catalyzed Heck cyclization/Sonogashira coupling: D’Souza, D.
M.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem., Int. Ed. 2005, 44, 153-
158.
(7) Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Schu¨sseler, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2005, 44, 7718-7721.
(8) (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2003,
42, 4774-4777. (b) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem.
Soc. 2004, 126, 14475-14484.
(4) Indium-mediated cyclization/Pd-catalyzed cross-coupling: Yanada,
R.; Obika, S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004, 6, 2825-2828.
10.1021/ol062022h CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/15/2006

Scheme 1. Synthesis of 2-Oxindoles by a Sequence of
Carbopalladation/C-H Activation/C-C Bond Formation
Table 1. Synthesis of 3-Alkylideneoxindoles through Domino
Carbopalladation/ C-H Functionalizationa
readily synthesized from cheap and easily accessible anilines
and arylpropiolic acid.
The reaction between N-(4-methoxyphenyl)-N-methyl-3-
phenylpropiolamide (2a, R ) 4-MeO, R1 ) Me, R2 ) Ph)11
and 1-iodo-2-nitrobenzene (3a) was initially examined. After
a brief survey of reaction conditions, it was observed that
the reaction was best performed under ligandless conditions
using Pd(OAc)2 as a catalyst and NaOAc as a base. DMF
was found to be a superior solvent to ethanol and toluene.
Overall, under optimized conditions [5 mol % of Pd(OAc)2,
NaOAc, DMF, 110 °C, 3 h], reaction of 2a and 3a afforded
1a (R ) 4-OMe, Ar ) 2-nitrophenyl, R2 ) phenyl) in 82%
yield as a single stereoisomer (Figure 1). The E-configuration
Figure 1. X-ray structure of oxindole 1a.
of the tetrasubstituted double bond was deduced from NOE
studies and was unambiguously assigned by X-ray analysis.
(9) For a selected Domino process involving C-H functionalization,
see: (a) Brown, S.; Clarkson, S.; Grigg, R.; Sridharan, V. Tetrahedron Lett.
1993, 34, 157-160. (b) Brown, D.; Grigg, R.; Sridharan, V.; Tambyrajah,
V. Tetrahedron Lett. 1995, 36, 8137-8140. (c) Grigg, R.; Loganathan, V.;
Sridharan, V. Tetrahedron Lett. 1996, 37, 3399-3402. (d) Bedford, R. B.;
Cazin, C. S. J. Chem. Commun. 2002, 2310-2311. (e) Karig, G.; Moon,
M. T.; Thassana, N.; Gallagher, T. Org. Lett. 2002, 4, 3115-3118. (f)
Masselot, D.; Charmant, J. P. H.; Gallagher, T. J. Am. Chem. Soc. 2006,
128, 694-695. (g) Rahman, S. M. A.; Sonoda, M.; Itahashi, K.; Tobe, Y.
Org. Lett. 2003, 5, 3411-3414. (h) Mauleo´n, P.; Nu´n˜ez, A. A.; Alonso, I.;
Carretero, J. C. Chem.-Eur. J. 2003, 9, 1511-1520. (i) Ohno, H.;
Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44,
5103-5106. (j) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc.
2005, 127, 13148-13149. (k) Bour, C.; Suffert, J. Org. Lett. 2005, 7, 653-
656. (l) Ferraccioli, R.; Carenzi, D.; Motti, E.; Catellani, M. J. Am. Chem.
Soc. 2006, 128, 722-723. (m) Campo, M. A.; Huang, Q.; Yao, T.; Tian,
Q.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506-11507. (n) Huang,
Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc.
2004, 126, 7460-7461. (o) Zhao, J.; Campo, M.; Larock, R. C. Angew.
Chem., Int. Ed. 2005, 44, 1873-1875. (p) Zhao, J.; Larock, R. C. J. Org.
Chem. 2006, 71, 5340-5348 and references therein.
a Reaction conditions: aniline (1.0 equiv), iodoarene (1.1 equiv),
Pd(OAc)2 (5 mol %), and NaOAc (2.0 equiv), in DMF (c 0.75 M), at 110
°C. b Isolated yield. c Both E- and Z-isomers were isolated in a 2.3:1 ratio.
The regioselective syn insertion of the arylpalladium species
to the triple bond of the propiolamide can account for the
observed double bond geometry.12
The generality of this novel domino transformation was
examined by varying the electronic and steric properties of
both reactants (Table 1). With respect to anilides, it was noted
that a tertiary amide has to be used to ensure the smooth
occurrence of the annulation reaction because the reaction
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Org. Lett., Vol. 8, No. 21, 2006

of the secondary anilide 2b (R1 ) H) afforded the corre-
sponding oxindole 1b in less than 10% yield, most probably
for conformational reasons. The N-benzylated anilides 2f
participated in the reaction without the occurrence of
competitive C-H functionalization of the benzyl group that
would otherwise produce an isoquinolinone derivative. The
N-SEM protecting group is tolerated under these reaction
conditions providing 1c in 93% yield that is readily converted
to oxindole 1b with a free NH function. When N-(3-
methoxyphenyl)-N-methyl propiolamide 2h was employed,
the 6-methoxy-3-alkylideneoxindole was obtained at the
expense of the 4-methoxy isomer (entry 13). Interestingly,
electron-poor N-(4-nitrophenyl)-N-methyl anilide participated
well in this reaction with 3a to afford oxindole 1n (entry
14). Interestingly, in this case, both E- and Z-isomers were
isolated in a ratio of 2.3:1.13 As far as aryl iodide (3) was
concerned, the electron-poor aryl iodide tended to give better
results than the electron-neutral or electron-rich counterpart.
Reaction of 4-iodo-chlorobenzene 3e with 2a is chemose-
lective leading to a chlorinated compound (1g) that could in
principle be further functionalized by way of transition-metal-
catalyzed reaction of aryl chloride.14
Scheme 2. Proposed Reaction Mechanism
A possible reaction scenario that accounts for the formation
of oxindole 1 is shown in Scheme 2. Oxidative addition of
aryl iodide to palladium(0) would give the arylpalladium-
(II) species (4) that would subsequently coordinate to the
triple bond of propiolamide. The syn carbopalladation would
then take place to afford vinylpalladium intermediate 6. The
high regioselectivity observed in this carbopalladation process
is somehow unexpected because it is well-known that the
regioselectivity of such a reaction is insensitive to electronic
effects and is predominantly affected by steric factors.12,15
We reasoned that the observed selectivity is inherent to the
propiolamide structure and results from the combination of
coordination power and steric influence of the amide group.
Similar high regioselectivity is seen in Lu’s domino carbo-
palladation/intramolecular Heck reaction/anion capture se-
quence.16
Two benzenoid C-H’s, those of ring A and ring B in
intermediate 6, are available for activation. Activation of the
ring B C-H followed by vinyl to aryl migration of palladium
and cyclization according to Larock17 would produce a
fluorene derivative (9) via an intermediate (8). However, this
sequence did not take place even in the case of the reaction
between 2a and 3-(N-methyl-N-acetyl)iodobenzene 3g wherein
ring A and ring B (R3 ) m-acetamido) in the intermediate
(6) have a very similar electronic and steric environment.
The C-H activation of ring A occurred instead to provide a
six-membered palladacycle 7. Reductive elimination would
then lead to the formation of 1 with the concomitant
regeneration of Pd(0).
To probe the reaction mechanism, we set out to examine
the kinetic isotope effect of this reaction. Toward this end,
(10) For reviews on C-H activation, see: (a) Ryabov, A. D. Chem. ReV.
1990, 90, 403-424. (b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698-
1712. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633-639. (d) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211-
241. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731-
1770. (f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826-834. (g)
Li, C.-J. Acc. Chem. Res. 2002, 35, 533-538. (h) Catellani, M. Synlett
2003, 298-313. (i) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253-1264.
Scheme 3. Synthesis of Deuterated Anilides
(11) 2a is synthesized by DCC-mediated coupling of N-methyl-N-(4-
methoxyphenyl)amine with phenylpropiolic acid. 2e, 2g, and 2h are similarly
prepared. 2c and 2f are synthesized by alkylation of the corresponding
secondary amides with BnBr and SEMCl, respectively. 2i is synthesized
by acylation of N-methyl-N-(4-nitrophenyl)amine with phenylpropiolyl
chloride. See also refs 4-6.
(12) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309. (b)
Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920.
(13) The structure of the Z-isomer was determined by X-ray analysis
(cf. Supporting Information). However, we do not know at the present stage
of development if the Z-isomer was produced during the reaction sequence
or by isomerization of the E-isomer. A control experiment indicated that
E-1n is partially isomerized to Z-1n in a CDCl3 solution at room temperature
and vice versa.
(14) For a review, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176-4211.
(15) For a leading reference, see: Zhou, C.; Larock, R. C. J. Org. Chem.
2005, 70, 3765-3777 and references therein.
Org. Lett., Vol. 8, No. 21, 2006
4929

the SEAr mechanism for the C-H activation step.19 Accord-
ing to these observations and in light of the recent compu-
tational studies, we think that proton abstraction via either
σ-H bond metathesis (14) or formation of an agostic C-H
intermediate (15) followed by H-transfer to palladium bond
acetate provided the best explanation for the C-H activation
mechanism.20 Figure 2 shows a possible C-H activation
Scheme 4. Electronic Effect on the Domino Process
the deuterated anilides 2e-D1 and 2e-D5 were synthesized
(Scheme 3). Ortho lithiation of N-Boc aniline 10 followed
by quenching with CD3OD afforded the deuterated derivative
11 in 98% yield with 90% deuterium incorporation according
Figure 2. Possible C-H activation mechanism.
1
to the H NMR spectrum. A three-step sequence involving
N-methylation, removal of N-Boc function, and DCC-
mediated amide formation provided 2e-D1 in excellent overall
yield. 2e-D5 was synthesized from the commercially available
D7-aniline (13) in two steps involving: (a) DCC-mediated
coupling with phenylpropiolic acid and (b) N-methylation.
A competitive experiment of 2e and its pentadeuterated
derivative (2e-D5) provided an intermolecular KH/KD value
of 1. This result indicated that the C-H functionalization
(from intermediate 6 to product) is not the rate-determining
step of this domino process. On the other hand, an intramo-
lecular isotope effect of 2.8 was obtained18 in the cyclization
of 2e-D1 indicating that the mechanism of C-H activation
is incompatible with the SEAr mechanism.
mechanism.
In summary, we have disclosed a novel synthesis of
3-(diarylmethylenyl)indolinones (1) by developing a pal-
ladium-catalyzed domino carbopalladation/C-H function-
alization process. Experimental data revealed that the C-H
activation is not the rate-determining step and that it
proceeded most probably through a proton abstraction
mechanism.
Acknowledgment. We thank CNRS and this institute for
financial support. A.P. thanks the Ministe`re de l′Enseigne-
ment Supe´rieur et de la Recherche for a doctoral fellowship.
We also designed an intramolecular competition experi-
ment using anilide 2j as a substrate and found that electronic
effects influenced only weakly the regioselectivity of the
C-H functionalization step (Scheme 4). Actually, the
cyclization occurred preferentially at the electron-poor
benzene ring (1o/1p ) 1.5:1) that is again incompatible with
Supporting Information Available: General experimen-
tal procedure, product characterization for 1a-p and deter-
mination of the kinetic isotope effects and X-ray analyses
of E-1a and Z-1n. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL062022H
(16) (a) Xie, X.; Lu, X. Tetrahedron Lett. 1999, 40, 8415-8418. (b)
Xu, W.; Lu, X. J. Org. Chem. 2006, 71, 3854-3858. See also: (c) Hay, L.
A.; Koenig, T. M.; Ginah, F. O.; Copp, J. D.; Mitchell, D. J. Org. Chem.
1998, 63, 5050-5058.
(17) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 701-704.
(18) (a) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084-12085. (b) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J.
Am. Chem. Soc. 2006, 128, 581-590 and references cited therein.
(19) Mart´ın-Matute, B.; Mateo, C.; Ca´rdenas, D. J.; Echavarren, A. M.
Chem.-Eur. J. 2001, 7, 2341-2348.
(20) (a) Mota, A. J.; Dedieu, A.; Bour, C.; Suffert, J. J. Am. Chem. Soc
2005, 127, 7171-7172. (b) Davies, D. L.; Donald, S. M. A.; Macgregor,
S. A. J. Am. Chem. Soc. 2005, 127, 13754-13755. (c) Garcia-Cuadrado,
D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc.
2006, 128, 1066-1067.
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