Intramolecular Pd(0)-catalyzed reactions of β-(2-iodoanilino) carboxamides: Enolate arylation and nucleophilic substitution at the carboxamide group

Article abstract of DOI:10.1021/jo8020715

(Chemical Equation Presented) Two different reaction pathways, the enolate arylation and the acylation of the aryl halide, can be promoted by a Pd(0) catalyst starting from β-(2-iodoanilino) carboxamides. The intramolecular acylation of β-(2-iodoanilino) carboxamides reported here is the first example of a nucleophilic attack of a σ-arylpalladium species at the carboxamide group, a framework that is usually inert toward organopalladium reagents.

Full text of DOI:10.1021/jo8020715

Intramolecular Pd(0)-Catalyzed Reactions of ꢀ-(2-Iodoanilino)
Carboxamides: Enolate Arylation and Nucleophilic Substitution at
the Carboxamide Group
Daniel Sole´* and Olga Serrano
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, and Institut de Biomedicina (IBUB),
UniVersitat de Barcelona, 08028 Barcelona, Spain
dsole@ub.edu
ReceiVed September 18, 2008
Two different reaction pathways, the enolate arylation and the acylation of the aryl halide, can be promoted
by a Pd(0) catalyst starting from ꢀ-(2-iodoanilino) carboxamides. The intramolecular acylation of ꢀ-(2-
iodoanilino) carboxamides reported here is the first example of a nucleophilic attack of a σ-arylpalladium
species at the carboxamide group, a framework that is usually inert toward organopalladium reagents.
Introduction
versions of these reactions14-18 have found growing application
in the synthesis of complex natural products.9,10,19-29
Parallel with the progress in this field, there also has been
growing interest in the direct addition of the aryl- and vinyl
palladium species to electrophilic carbon-heteroatom multiple
bonds. So far, the intramolecular attack of these relatively low
nucleophilic species on the carbonyl group of aldehydes,30
ketones,31 and esters32 and on the imino,33 cyano,34 and
isocyanate35 groups has been described.
During the past decades, there has been continuous interest
in developing reliable Pd-catalyzed coupling reactions to form
carbon-carbon bonds.1 Among the different cross-coupling
processes, the Pd-catalyzed arylation2-8 and alkenylation9-13
of enolate-type nucleophiles are emerging as extremely powerful
tools in organic synthesis. In particular, the intramolecular
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10.1021/jo8020715 CCC: $40.75 2008 American Chemical Society
Published on Web 11/12/2008

Pd(0)-Catalyzed Reactions of ꢀ-(2-Iodoanilino) Carboxamides
SCHEME 1
Although both the reaction at the R position and the
nucleophilic attack on the carbon-heteroatom multiple bond
probably involve similar σ-C-bonded palladium(II) intermedi-
ates, these two reaction pathways seem to operate quite
independently of each other, and almost no competition between
the two processes has been reported.36 In fact, such competition
has been observed only in the Pd-catalyzed intramolecular
coupling of aryl halides with aldehydes17,37 and in reactions
starting from ꢀ-(2-haloanilino) ketones.14c,31c
In this context, we have reported recently that starting from
ꢀ-(2-iodoanilino) esters either the enolate arylation18b or the
nucleophilic substitution at the alkoxycarbonyl group32 catalyzed
(15) Intramolecular R arylation of amides: (a) Shaughnessy, K. H.; Hamann,
B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546–6553. (b) Lee, S.; Hartwig,
J. F. J. Org. Chem. 2001, 66, 3402–3415. (c) Freund, R.; Mederski, W. W. K. R.
HelV. Chim. Acta 2000, 83, 1247–1255. (d) Kim, G.; Kim, J. H.; Lee, K. Y. J.
Org. Chem. 2006, 71, 2185–2187. (e) Arao, T. K.; Kondo, K.; Aoyama, T.
Tetrahedron Lett. 2006, 47, 1417–1420. (f) Satyanarayana, G.; Maier, M. E.
Tetrahedron 2008, 64, 356–363. (g) Marsden, S. P.; Watson, E. L.; Raw, S. A.
Org. Lett. 2008, 10, 2905–2908. (h) Hillgren, J. M.; Marsden, S. P. J. Org.
Chem. 2008, 73, 6459–6461.
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M. A.; Browne, M. E. Tetrahedron Lett. 1987, 28, 171–174. (b) Ciufolini, M. A.;
Qi, H.-B.; Browne, M. E. J. Org. Chem. 1988, 53, 4149–4151.
(17) Intramolecular R arylation of aldehydes and nitro derivatives: Muratake,
H.; Nakkai, H. Tetrahedron Lett. 1999, 40, 2355–2358.
(18) Intramolecular R arylation of esters: (a) Gaertzen, O.; Buchwald, S. L.
J. Org. Chem. 2002, 67, 465–475. (b) Sole´, D.; Serrano, O. J. Org. Chem. 2008,
73, 2476–2479.
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by Pd(0) could be selectively promoted by changing the reaction
conditions only slightly (Scheme 1). The acylation reaction
shown in Scheme 1 constitutes the first example of palladium-
catalyzed substitution at the alkoxycarbonyl group by an aryl
halide.38 The intermediacy of a four-membered azapallada-
cycle,39 which strongly modifies the interaction of the metal
center with the carbonyl group,31c was invoked to explain the
otherwise unexpected attack of the σ-arylpalladium species at
the less electrophilic ester carbonyl.
Continuing our research on this aspect of palladium chemistry,
we were interested to see whether changing the ester to an amide
moiety could modify the course of the palladium-catalyzed
reactions on this type of substrate. We expected that the higher
pKas of the amides would make the R arylation a more
challenging task, while the less electrophilic character of the
amide carbonyl could avoid the direct nucleophilic attack of
the σ-arylpalladium species.
(27) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D.
J. Am. Chem. Soc. 2008, 130, 5368–5377.
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3618–3621.
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4757.
Herein, we report that starting from ꢀ-(2-iodoanilino) car-
boxamides the two alternative pathways, involving either the
enolate arylation or the nucleophilic substitution at the amide
group, can be promoted by a Pd(0) catalyst. This has allowed
us to develop new synthetic entries to both indole-3-carboxa-
mides40 and dihydroquinolin-4-ones,41 which constitute impor-
tant classes of compounds in medicinal chemistry.
(30) (a) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579–
4583. (b) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999,
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4345. (d) Vicente, J.; Abad, J.-A.; Lo´pez-Pela´ez, B.; Mart´ınez-Viviente, E.
Organometallics 2002, 21, 58–67. (e) Yang, M.; Zhang, X.; Lu, X. Org. Lett.
2007, 9, 5131–5133.
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121, 3545–3546. (b) Quan, L. G.; Lamrani, M.; Yamamoto, Y. J. Am. Chem.
Soc. 2000, 122, 4827–4828. (c) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia,
M.; Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1578–1594. (d) Liu, G.; Lu, X.
J. Am. Chem. Soc. 2006, 128, 16504–16505. (e) Song, J.; Shen, Q.; Xu, F.; Lu,
X. Org. Lett. 2007, 9, 2947–2950. (f) Liu, G.; Lu, X. AdV. Synth. Catal. 2007,
349, 2247–2252. See also refs 14c and 30c,d.
(32) Sole´, D.; Serrano, O. Angew. Chem., Int. Ed. 2007, 46, 7270–7272.
(33) (a) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 5662–5663. (b) Ohno, H.; Aso, A.; Kadoh, Y.; Fujii, N.; Tanaka, T. Angew.
Chem., Int. Ed. 2007, 46, 6325–6328.
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1994, 2629–2630. (b) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc.
1999, 121, 3238–3239. (c) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem.
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(g) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551–3558. See also ref
30c.
Results and Discussion
We commenced our investigation by studying the R arylation
of amides 1a-d, 2, and 3, which were synthesized from the
(37) The formation of the carbonyl arylation products was explained in this
case by means of the insertion of the σ-arylpalladium species into the formyl
C-H bond. However, the alternative mechanism involving the addition of the
σ-arylpalladium species to the CdO bond of the aldehyde, followed by ꢀ-hydride
elimination from the resulting palladium(II) alkoxide, also could be possible.
(38) Reaction of arylpalladium complexes with acetic anhydride: Cacchi, S.;
Fabrizi, G.; Gavazza, F.; Goggiamani, A. Org. Lett. 2003, 5, 289–291.
(39) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J.
Organometallics 2004, 23, 1438–1447.
(40) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996. (b) Joule,
J. A. In Science of Synthesis; George Thieme Verlag: Stuttgart, 2000; Vol. 10.
(c) Kazuhiro, H. Kawassaki, T. Nat. Prod. Rep. 2007, 24, 843, and previous
reviews in this series.
(35) Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Schu¨sseler, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2005, 44, 7718–7721.
(36) It should be noted that in the majority of the examples in which the
nucleophilic attack takes place the formation of the R-arylation products is
prevented either by the substitution pattern of the substrate or by the size of the
ring to be formed.
(41) (a) Daruwala, A. B.; Gearien, J. E.; Dunn, W. J., III; Benoit, P. S.;
Bauer, L. J. Med. Chem. 1974, 17, 819–824. (b) Nishijima, K.; Shinkawa, T.;
Yamashita, Y.; Sato, N.; Nishida, H.; Kato, K.; Onuki, Y.; Mizota, M.; Ohmoto,
K.; Miyano, S. Eur. J. Med. Chem. 1998, 33, 267–277.
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Sole´ and Serrano
TABLE 1. Pd(0)-Catalyzed r Arylation of ꢀ-(2-Iodoanilino) Carboxamidesa
a Reaction conditions: 5 mol % of Pd(PPh3)4, phenol (2.75 equiv), and KO-t-Bu (2.25 equiv) in THF at reflux. b Unless otherwise indicated, yields
d
refer to pure products isolated by flash chromatography. c Indoline 8b suffered partial air oxidation to indole 9b during 13C NMR experiments. 1H
f
NMR analysis of the crude reaction mixture gave indoline 8c as the only reaction product. e At 20 mol % of Pd(PPh3)4. Stereochemistry is based on H
1
g
h
and 13C NMR. See ref 18b. 1H NMR analysis of the crude reaction mixture gave a 1:1.3 mixture of 15b and 16b. 1H NMR analysis of the crude
i
reaction mixture gave a 1:1.4 mixture of 15c and 16c. 1H NMR analysis of the crude reaction mixture gave a 1:2:1 mixture of 19a, 19b, and 20.
j N-Methyl-p-toluidine also was isolated (10%). k At 10 mol % of Pd(PPh3)4. l The hydrodehalogenation compound also was detected in the reaction
mixture, although it could not be isolated.
9374 J. Org. Chem. Vol. 73, No. 23, 2008

Pd(0)-Catalyzed Reactions of ꢀ-(2-Iodoanilino) Carboxamides
SCHEME 2
SCHEME 3
corresponding esters by reaction with the dimethylaluminum
chloride dimethylamine complex.42 The most representative
results are summarized in Table 1.
(Table 1, entry 7). It should be noted that on standing in a
chloroform solution indoline 15a quantitatively oxidized to
indole 16a.
We were pleased to find that the conditions we have
previously employed in the Pd(0)-catalyzed intramolecular
arylation of amino-tethered esters, using 5 mol % of Pd(PPh3)4
and 2.25 equiv of PhOK in refluxing THF,18b allowed iodoa-
niline 1a to undergo the R arylation to give indoline 8a in 68%
yield (Table 1, entry 1). Under the same reaction conditions,
iodoanilines 1b-d, bearing electron-donating or electron-
withdrawing groups at the arene ring, afforded reaction mixtures
in which the corresponding indolines 8b-d were also the only
detected products (Table 1, entries 2-4). While indolines 8b43
and 8d could be isolated and characterized, indoline 8c oxidized
spontaneously during the purification process to give indole 9c.44
The use of K3PO4 as the base in the presence of a catalytic
quantity of phenol in DMF, which also allowed the Pd(0)-
catalyzed cyclization in the ester series,18b was found to be less
effective for the present R-arylation reaction. For example,
treatment of 1b under these reaction conditions resulted in the
formation of significant amounts of the reduction product 10b
together with indoline 8b and indole 9b (Scheme 2). The use
of a stronger base such as LiO-t-Bu was completely ineffective
in promoting the cyclization and led to the formation of complex
reaction mixtures.
The arylation reaction also was used successfully for the
preparation of 2,3-disubstituted indolines (Table 1, entry 5).
However, amide 3 failed to give the R-arylation reaction and
afforded the reduction compound 14 together with small
amounts of dihydroquinolone 13, the latter resulting from the
nucleophilic substitution at the carboxamide group (Table 1,
entry 6). In this case, the slowness of the reaction at the more
hindered R-methine position allowed competitive processes such
as reduction or an attack on the carbonyl group to occur.
The palladium-catalyzed R arylation was extended to the
Weinreb amides 4a-c, 5, and 6. Weinreb amides are important
carbonyl equivalents that have found many applications in the
synthesis of carbonyl compounds.45 However, there are few
examples of the use of ꢀ-amino Weinreb amides.46
Similar results were obtained from iodoanilines 4b and 4c,
which also afforded mixtures of the corresponding indolines
and indoles. In these cases, however, the oxidation was
completed during the purification process and only the indoles
16b and 16c were isolated (Table 1, entries 8 and 9, respective).
Once again, the use of K3PO4 as the base in the presence of
a catalytic quantity of phenol in DMF was less effective for
the arylation reaction. Thus, for example, under these reaction
conditions, 4a afforded a nearly equimolecular mixture of indole
17 and the reduction product 18a. Interestingly, the Weinreb
amide moiety remained unchanged in both products (Scheme
3).
The Pd-catalyzed R arylation of amide 5 afforded a mixture
of indolines 19a and 19b and indole 20 (∼1:2:1), but after flash
chromatography only 19a (18%) and 20 (58%) were isolated
because indoline 19b quantitatively oxidized to indole 20 (Table
1, entry 10). The attempt at R arylation of Weinreb amide 6
resulted in the formation of a complex reaction mixture (Table
1, entry 11). After column chromatography, the main products
could be identified, although not all of them were completely
characterized. Thus, the three main fractions consisted of an
unseparated mixture of the R arylation product 21 and the
hydrodehalogenation compound 22; hexahydroacridinone 23,
which resulted from the substitution at the carboxamide group;
and N-methyl-p-toluidine. As with the simple amides, the R
arylation at the more-hindered R-methine position of a Weinreb
amide was troublesome.
Finally, it is noteworthy that the R arylation also could be
extended to the secondary amide 7, which under the
optimized reaction conditions afforded indoline 15a in an
acceptable yield (Table 1, entry 12). The alternative pathway
involving lactamization by formation of the C-N bond47 was
not observed.
At this point, we turned our attention to the unexpected
formation of minor amounts of dihydroquinolones 13 and
23, resulting from the nucleophilic substitution at the
carboxamide group, in the attempts at R arylation of amides
3 and 6 (vide supra). The lower electrophilic character of
the amide carbonyl group surprisingly did not avoid the
nucleophilic attack.
Treatment of amide 4a under the optimized reaction condi-
tions afforded a mixture of indoline 15a and indole 16a, resulting
from the R arylation and demethoxylation of the Weinreb amide
To our delight, when amide 3 was treated with Pd(PPh3)4 in
the presence of K3PO4 as the base in toluene, the formal
nucleophilic substitution at the carboxamide group became the
main reaction, with dihydroquinolone 13 being obtained in 40%
yield (Table 2, entry 1). Similar behavior was observed starting
from amides 1a,b and 2, which afforded the corresponding
dihydroquinolones in low to moderate yields together with the
hydrodehalogenated anilines (Table 2, entries 2-4). As expected
from the less electrophilic character of the amide carbonyl group,
the Pd(0)-catalyzed intramolecular acylation reactions starting
from amides afforded lower yields than those obtained in the
reactions of the corresponding esters.48 Interestingly, when
(42) Hughes, D. L.; Bergan, J. J.; Amato, J. S.; Bhupathy, M.; Leazer, J. L.;
McNamara, J. M.; Sidler, D. R.; Reider, P. J.; Grabowski, J. J. J. Org. Chem.
1990, 55, 6252–6259.
(43) It should be noted that indoline 8b suffered partial air oxidation to indole
9b during 13C NMR experiments.
(44) Chou, S.-S. P.; Yuan, T.-M. Synthesis 1991, 171–172.
(45) See for a review: Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15–40.
(46) See for an example: Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.;
Li, D.; Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70,
2184–2190.
(47) (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37. (b) Kitamura,
Y.; Hashimoto, A.; Yoshikawa, S.; Odaira, J.-I.; Furuta, T.; Kan, T.; Tanaka, K.
Synlett 2006, 115–117.
(48) For example, the acylation reaction from the ester analog of amide 1b
afforded dihydroquinolone 24b in 65% yield, and the acylation from the ester
analog of 3 gave 13 in 49% yield. See ref 32.
J. Org. Chem. Vol. 73, No. 23, 2008 9375

Sole´ and Serrano
TABLE 2. Pd(0)-Catalyzed Intramolecular Acylation from
ꢀ-(2-Iodoanilino) Carboxamides
amide 6, hexahydroacridinone 23 was obtained in 41% yield
(Table 2, entry 9).
The acylation reaction of amide 26, lacking hydrogen atoms
R to the carbonyl group, afforded dihydroquinolone 27 in
excellent yield (Table 2, entry 10).
Finally, secondary amide 7 failed to produce acylation when
submitted to the usual reaction conditions and afforded the
hydrodehalogenation compound as the main product.
The effectiveness of PhOK in the Pd(0)-catalyzed R-arylation
reaction of ꢀ-(2-iodoanilino) carboxamides is somewhat surpris-
ing because the pKa of phenol is considerably lower than that
of the amides.49 Especially interesting is the R arylation of amide
7, which has the more acidic N-H bond.
Possible mechanisms for these Pd(0)-catalyzed R arylations
are shown in Scheme 4. The oxidative addition of the aryl iodide
to Pd(0) followed by ligand exchange would give the arylpal-
ladium phenoxide complex A. A related four-membered aza-
palladacycle in which the iodo ligand has been replaced by TfO-
has been previously reported.50 The formation of this transient
intermediate would not only stabilize the arylpalladium moiety,
preventing the nucleophilic attack at the carbonyl (vide infra),
but also assist the enolization reaction. Thus, the intramolecular
reaction of the phenoxide ligand51 with the coordinated car-
boxamide group would facilitate the deprotonation with con-
comitant formation of an O-bonded Pd(II) enolate B. Reductive
elimination from this Pd(II) complex52 would produce indoline
8a and the regeneration of the reactive Pd(0) species.
On the other hand, for secondary amide 7, the deprotonation
of the more acidic N-H bond of A (R:H) would afford an
O-bonded Pd(II) amidate C. In the basic reaction conditions,
this amidate would be in equilibrium with the O-bonded Pd(II)
enolate D,53 which by reductive elimination would give rise to
indoline 15a.
Two possibilities can be considered to account for the
observed R arylation/demethoxylation of Weinreb amides. A
sequence of reactions involving the initial demethoxylation of
the Weinreb amide was dismissed as inconsistent with the
experimental evidence. Thus, for example, Weinreb amide 4a
was recovered unchanged when treated with KO-t-Bu/phenol
in the absence of a Pd catalyst,54 and moreover both the R
arylation compound 21 and the hydrodehalogenation compound
22, which were formed when 6 was treated with KO-t-Bu/
phenol/Pd(PPh3)4, maintained the Weinreb amide moiety.
However, the alternative sequence, which involves demethox-
ylation of the indoline resulting from the R-arylation reaction
of the Weinreb amide, could explain the experimental results
a
Reaction conditions: 20 mol % of Pd(PPh3)4, K3PO4 (3 equiv), and
Et3N (10 equiv) in toluene at 110 °C in a sealed tube for 72 h. b Yields
refer to pure products isolated by flash chromatography.
c N-Methyl-p-toluidine also was isolated, although not quantified. d After
48 h. e Not quantified. f Stereochemistry is based on 1H and 13C NMR.
(49) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(50) Sole´, D.; D´ıaz, S.; Solans, X.; Font-Bardia, M. Organometallics 2006,
25, 1995–2001.
(51) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 15168–15169.
g N-Methyl-p-toluidine also was isolated (8%). h At 10 mol
% of
Pd(PPh3)4 and 48 h.
(52) Isolation and study of the reductive elimination reaction of arylpalladium
enolates: Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816–
5817.
(53) Related process: Altman, R. A.; Hyde, A. M.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2008, 130, 9613–9620.
(54) Moreover, no reaction was observed when N-methoxy-N-methylaceta-
mide was treated with KO-t-Bu/phenol/Pd(PPh3)4.
starting from Weinreb amides, the intramolecular acylation
reaction proceeded with better yields (compare Table 2, entries
2, 3, and 4 with 5, 6, and 8, respectively). Starting from Weinreb
9376 J. Org. Chem. Vol. 73, No. 23, 2008

Pd(0)-Catalyzed Reactions of ꢀ-(2-Iodoanilino) Carboxamides
SCHEME 4. Proposed Mechanisms for the r-Arylation Reactions
obtained in this work. In fact, treatment of indoline 19a with
KO-t-Bu/phenol in refluxing THF for 36 h resulted in the
demethoxylation reaction to give an equimolecular mixture of
indoline 19b and indole 20.
migratory insertion must be preceded by π coordination, but in
carbon-heteroatom multiple bonds the σ donation of the lone
pair of electrons on the heteroatom is the preferred mode of
interaction with the metal center. The larger negative charge
and consequent stronger coordination ability of the carbonyl
oxygen of an amide fragment57 should hinder the required σ to
π isomerization and thus prevent the carbonyl insertion.
The formal nucleophilic substitution reported here probably
proceeds through a mechanism similar to that of the Pd(0)-
catalyzed acylation by the alkoxycarbonyl group.32 The key
steps here would be (1) oxidative addition of the aryl iodide to
a Pd(0) species and (2) carbopalladation between the σ-arylpal-
ladium moiety and the carbonyl of the amide group. The
intermediacy of the four-membered azapalladacycle, which
strongly modifies the interaction of the metal center with the
carbonyl group,31c is invoked again to explain the otherwise
unexpected attack of the σ-arylpalladium species onto the barely
electrophilic amide carbonyl. Thus, the coordination of the N
atom to the palladium in the four-membered azapalladacycle
not only brings the carbonyl group nearer to the metal to
facilitate the required π coordination but also increases the
electron density on the palladium center to enable the otherwise
unfavorable carbopalladation reaction to occur. The remaining
key steps would be (3) ꢀ-amide elimination from the Pd(II)
alkoxide formed in the carbopalladation step to give the
dihydroquinolone and a Pd(II) amide complex and (4) ꢀ-hydride
elimination from the latter to regenerate the Pd(0) catalyst.
Two mechanisms can be proposed for this demethoxylation
on the basis of related reactions of Weinreb amides.55,56
A
simple E2 mechanism was an unlikely explanation of why
demethoxylation takes place after the arylation reaction only,
so it was rejected. However, a mechanism involving the
formation of an enolate, E, and its further decomposition via
unimolecular fragmentation with the loss of formaldehyde
appears more reasonable on chemical grounds, considering the
following:
(A) The facile demethoxylation of the indolines resulting from
the R-arylation reaction is consistent with the higher acidity of
the benzylic R hydrogens.
(B) Weinreb amide 21, which lacks R hydrogens, was the
R-arylation product obtained in the reaction of amide 6 (Table
1, entry 11) and was recovered unchanged after further treatment
with KO-t-Bu/phenol in refluxing THF.
(C) The isolation of Weinreb amide 19a is probably a
consequence of the steric hindrance exerted by the methyl group,
which would hinder the concerted fragmentation.
(D) The formation of indole 17 in the R-arylation reaction
of 4a when using K3PO4 as the base could be understood
considering that the low enolization promoted by such a mild
base makes the competitive oxidation the main reaction.
Returning to the acylation reaction reported in this work, we
note that it is the first example of a nucleophilic substitution at
the carboxamide group by a σ-arylpalladium species. This
reaction is quite surprising because the carboxamide group has
long been considered inert toward organopalladium reagents.
Moreover, although different carbopalladation reactions of
carbon-heteroatom multiple bonds have been reported, these
species generally show a low propensity to undergo the insertion
process because of their coordination characteristics. The
FIGURE 1. Stabilization of Pd(II) intermediates by chelation.
The better results obtained in the acylation reactions when
using Weinreb amides are probably due to the chelation ability
of the second oxygen atom (Figure 1). Thus, the coordination
of this oxygen with the Pd center would not only facilitate the
(55) Keck, G. E.; McHardy, S. F.; Murry, J. A. Tetrahedron Lett. 1993, 34,
6215–6218.
(56) Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31, 6269–6272.
(57) For the coordination ability of the-N(R)-(CH2)n-CO-N(R)2 frame-
work in σ-arylpalladium(II) complexes, see ref 50.
J. Org. Chem. Vol. 73, No. 23, 2008 9377

Sole´ and Serrano
SCHEME 5. Proposed Mechanism for the Intramolecular
Acylation Reaction
such as enolates, as well as electrophiles such as the carbonyl
of the amide group.
Experimental Section
Representative Procedure for the Pd(0)-Catalyzed r Aryla-
tion (Table 1, Entry 1). To a solution of amide 1a (100 mg, 0.30
mmol) in THF (7 mL) were added under argon phenol (78 mg,
0.83 mmol), KO-t-Bu (0.68 mmol, 0.68 mL of 1 M solution in
tert-butyl alcohol), and Pd(PPh3)4 (17 mg, 0.015 mmol). The
solution was heated at reflux for 30 h. After being cooled at room
temperature, the mixture was diluted with CH2Cl2 and washed with
saturated aqueous NaHCO3 and 1 N aqueous NaOH. The organic
layer was dried and concentrated. The residue was purified by flash
chromatography (SiO2, CH2Cl2-MeOH 1%) to give indoline 8a (41
mg, 68%).
Representative Procedure for the Pd(0)-Catalyzed Acyla-
tion (Table 2, Entry 1). A mixture of amide 3 (75 mg, 0.21 mmol),
K3PO4 (135 mg, 0.63 mmol), Et3N (0.3 mL, 2.1 mmol), and
Pd(PPh3)4 (48 mg, 0.042 mmol) in toluene (6 mL) was stirred at
110 °C in a sealed tube for 72 h. The reaction mixture was poured
into water and extracted with Et2O. The organic extracts were
washed with brine, dried, and concentrated. The residue was purified
by flash chromatography (SiO2, from CH2Cl2 to CH2Cl2-MeOH 1%)
to give dihydroquinolin-4-one 13 (16 mg, 40%) and aniline 14 (11
mg, 22%).
formation of the carbonyl π complex required for the carbo-
palladation but also stabilize the Pd(II) alkoxide resulting from
this reaction.
Conclusions
In summary, we have reported that two different Pd(0)-
catalyzed reactions, involving either enolate arylation or the
acylation of the aryl halide, can be promoted from ꢀ-(2-
haloanilino) carboxamides by slightly changing the reaction
conditions. The Pd(0)-catalyzed acylation reaction described in
this work constitutes the first reported example of the formal
nucleophilic substitution at the carboxamide group by a
σ-arylpalladium species. Besides the potential synthetic ap-
plication of the above methodologies, this work highlights how
the presence of a strong coordinating group can modify the
reactivity of organic compounds, allowing the development of
unknown palladium-catalyzed reactions with otherwise “unre-
active” functional groups. In particular, the formation of transient
four-membered azapalladacyclic intermediates is invoked to
explain how σ-arylpalladium species can react with nucleophiles
Acknowledgment. This research was supported by Spanish
MEC-FEDER Projects CTQ2007-60573/BQU and CTQ2006-
00500/BQU and DURSI-Catalonia Grant 2005SGR-00442. D.S.
thanks the DURSI for “Distincio´ per a la promocio´ de la Recerca
Universita`ria”.
Supporting Information Available: Characterization data
for all new compounds and experimental procedures for
1
preparation of starting materials and H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO8020715
9378 J. Org. Chem. Vol. 73, No. 23, 2008