Intramolecular Pd-mediated processes of amino-tethered aryl halides and ketones: Insight into the ketone α-arylation and carbonyl-addition dichotomy. A new class of four-membered azapalladacycles

Article abstract of DOI:10.1021/ja029114w

An exploration of the scope and limitations of Pd(O)-catalyzed intramolecular coupling reactions of amino-tethered aryl halides and ketones has been conducted. Two different and competitive reaction pathways starting from ω-(2-haloanilino) alkanones, enolate arylation and addition to the carbonyl group, have been observed, while ω-(2-halobenzylamino) alkanones exclusively underwent the enolate arylation process. The dichotomy between ketone α-arylation and carbonyl-addition in the reactions of ω-(2-haloanilino) alkanones has been rationalized by the intermediacy of unprecedented four-membered azapalladacycles, from which X-ray data and chemical behavior are reported.

Full text of DOI:10.1021/ja029114w

Published on Web 01/18/2003
Intramolecular Pd-Mediated Processes of Amino-Tethered
Aryl Halides and Ketones: Insight into the Ketone r-Arylation
and Carbonyl-Addition Dichotomy. A New Class of
Four-Membered Azapalladacycles
Daniel Sole´,*,† Llu´ıs Vallverdu´,† Xavier Solans,‡ Merce` Font-Bard´ıa,‡ and
Josep Bonjoch†
Contribution from the Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, UniVersitat de
Barcelona, AV. Joan XXIII s/n, 08028-Barcelona, and Departament de Cristal.lografia,
Mineralogia i Dipo`sits Minerals, UniVersitat de Barcelona, Mart´ı i Franque`s s/n,
08028-Barcelona, Spain
Received October 28, 2002 ; E-mail: dsole@farmacia.far.ub.es
Abstract: An exploration of the scope and limitations of Pd(0)-catalyzed intramolecular coupling reactions
of amino-tethered aryl halides and ketones has been conducted. Two different and competitive reaction
pathways starting from ω-(2-haloanilino) alkanones, enolate arylation and addition to the carbonyl group,
have been observed, while ω-(2-halobenzylamino) alkanones exclusively underwent the enolate arylation
process. The dichotomy between ketone R-arylation and carbonyl-addition in the reactions of ω-(2-
haloanilino) alkanones has been rationalized by the intermediacy of unprecedented four-membered
azapalladacycles, from which X-ray data and chemical behavior are reported.
Introduction
has been extensively studied and is now recognized to be a
useful methodology for the synthesis of R-aryl carbonyl
A growing interest in the application of transition metal
promoted processes to the synthesis of heterocyclic systems has
been seen in recent years.1 Besides its synthetic application,
transition metal chemistry involving heteroatom-containing
compounds is of interest from the mechanistic point of view
due to its unique characteristics stemming from the heteroatom
present in the substrates.2
compounds, the intramolecular processes have received less
attention. The first examples of this latter type of cyclization
reaction were reported by Ciufolini in 1988, who described the
intramolecular arylation of soft enolates catalyzed by zerovalent
palladium complexes.9 Later on, coinciding with the develop-
ment of the intermolecular processes, Muratake reported the
As part of our ongoing program on the synthesis of natural
products, we recently reported the palladium-catalyzed intramo-
lecular coupling of vinyl halides and ketone enolates as a
suitable methodology for the synthesis of nitrogen heterocycles.3
Continuing our research on this palladium chemistry, we decided
to extend the carbocyclization process to the intramolecular
coupling of amino tethered aryl halides and ketones (eq 1).
(2) For some examples in which the coordination of N with the metal controls
or modifies the course of transition metal promoted processes, see: (a)
Oestreich, M.; Dennison, P. R.; Kodanko, J. J.; Overman, L. E. Angew.
Chem., Int. Ed. 2001, 40, 1439-1442. (b) Mauleo´n, P.; Alonso, I.;
Carretero, J. C. Angew. Chem., Int. Ed. 2001, 40, 1291-1293. (c) Olofsson,
K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66, 544-
549. (d) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado, A. J.
Am. Chem. Soc. 1994, 116, 12133-12134.
(3) Sole´, D.; Peidro´, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225-2228.
(4) For reactions starting from ketones, see: (a) Palucki, M.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 11108-11109. (b) Hamann, B. C.; Hartwig,
J. F. J. Am. Chem. Soc. 1997, 119, 12382-12383. (c) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473-1478. (d) Fox, J. M.;
Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
1360-1370. (e) Terao, Y.; Kametani, Y.; Wakui, H.; Satoh, T.; Miura,
M.; Nomura, M. Tetrahedron 2001, 57, 5967-5974. (f) Mutter, R.;
Campbell, I. B.; Martin de la Nava, E. M.; Merritt, A. T.; Wills, M. J.
Org. Chem. 2001, 66, 3284-3290. (g) Hamada, T.; Chieffi, A.; Ahman,
J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (h)
Ehrentraut, A.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2002, 344, 209-
217. (i) Churruca, F.; SanMartin, R.; Tellitu, I.; Dom´ınguez, E. Org. Lett.
2002, 4, 1591-1594. (j) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org.
Lett. 2002, 4, 4053-4056.
The palladium-catalyzed coupling reaction of aryl halides and
enolates has been widely investigated in the past few years.
However, while the intermolecular version4-8 of this reaction
(5) For reactions starting from aldehydes, see: Terao, Y.; Fukuoka, Y.; Satoh,
T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002, 43, 101-104.
(6) For reactions starting from esters, see: (a) Moradi, W. A.; Buchwald, S.
L. J. Am. Chem. Soc. 2001, 123, 7996-8002. (b) Lee, S.; Beare, N. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410-8411. (c) Jorgensen,
M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 12557-12565.
† Laboratori de Qu´ımica Orga`nica, Universitat de Barcelona.
‡ Departament de Cristal.lografia, Universitat de Barcelona.
(1) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A Guide for
the Synthetic Chemist; Pergamon: Amsterdam, 2000.
(7) For reactions starting from amides, see: Shaughnessy, K. H.; Hamann, B.
C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546-6553.
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J. AM. CHEM. SOC. 2003, 125, 1587-1594
1587

A R T I C L E S
Sole´ et al.
intramolecular R-arylation of ketones,10,11 and Hartwig described
the synthesis of oxindoles7,12 by means of the Pd-catalyzed
R-arylation of amides.13,14 Finally, very recently, Buchwald has
reported the intramolecular R-arylation of R-amino acid esters.15
Table 1. Pd(0)-Catalyzed Cyclization of 2-Haloanilino Ketones 1a,
1b, 3, and 5
In this paper, we present a full account of the scope and
limitations of the palladium-mediated intramolecular coupling
of aryl halides and ketone enolates as a methodology for the
synthesis of nitrogen heterocycles as well as the discovery of a
new class of four-membered azapalladacycles, the formation
of which allows the behavior of ω-(2-haloanilino) alkanones
in their Pd(0)-catalyzed reactions to be understood.
entry
substrate
methoda
product (yield)b
Results and Discussion
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
3
3
3
5
5
A
B
2 (84%)
2 (68%)
2 (76%)
2 (67%)
2 (60%)
2 (78%)
Our initial studies were focused on developing an optimum
set of reaction conditions for the palladium-catalyzed intramo-
lecular coupling of amino tethered aryl halides and ketone
enolates. The reactions of 2-haloanilines 1a, 1b, 3, and 5 were
chosen as the model systems to optimize the annulation process
because their cyclization would afford a synthetic entry to the
hexahydro-2,6-methano-1-benzazocine framework (Table 1).16
This is a bridged ring system present in some natural products
such as aspernomine17 and strychnochromine18 and is closely
related to the 2-azabicyclo[3.3.1]nonane framework successfully
prepared in our earlier work.3 The most representative results
of the studies carried out with the aforementioned models are
summarized in Table 1. Thus, in the presence of 0.2 equiv of
Pd(PPh3)4 and 3 equiv of KOt-Bu in refluxing THF (entry 1),
aryl iodide 1a underwent the desired cyclization reaction to give
ketone 2 in good yield. The annulation reaction could also be
carried out by using Cs2CO3 (entry 2) or K3PO4 (entry 3) as
the base, but in these cases higher temperatures and long reaction
times were required. No significant effect was observed in the
cyclization reaction when the halide was changed from iodide
to bromide (compare entries 1-3 with entries 4-6, respec-
tively). In contrast, varying the substituent at the nitrogen atom
had a marked effect on the cyclization. Thus, when KOt-Bu
was used as the base, acetamide 3 gave a complex reaction
mixture, and no cyclization product was obtained (entry 7),19
C
Ac
B
Cd
A
B
4 (33%)e
4 (38%)e
6 (48%)
6 (92%)
6 (35%)
C
10
11
12
A
Bf
C
5
a Method A: Pd(PPh3)4 (0.2 equiv), KOt-Bu (3 equiv), THF, reflux, 3.5
h. Method B: PdCl2(PPh3)2 (0.2 equiv), Cs2CO3 (3 equiv), THF, 100-110
°C, sealed tube, 24 h. Method C: Pd(PPh3)4 (0.2 equiv), K3PO4 (3 equiv),
THF, 100-110 °C, sealed tube, 24 h. b Yield refers to pure isolated products.
c Pd(PPh3)4 (0.1 equiv). d 48 h. e 4-(N-Acetyl-N-phenylamino)cyclohexanone
(∼5%) was also isolated. f PdCl2(PPh3)2 (0.3 equiv), 48 h.
Chart 1. Type I: 2-Haloanilino Alkanones
(8) For reactions starting from methylene active carbonyl compounds,8a
nitroalkanes,8b and nitriles,8c see: (a) Beare, N. A.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 541-555. Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.;
Wife, R. Tetrahedron Lett. 2002, 43, 2539-2542. Aramend´ıa, M. A.; Borau,
V.; Jime´nez, C.; Marinas, J. M.; Ruiz, J. R.; Urbano, F. J. Tetrahedron
Lett. 2002, 43, 2847-2849. Kondo, Y.; Inamoto, K.; Uchiyama, M.;
Sakamoto, T. Chem. Commun. 2001, 2704-2705. See also ref 4c. (b) Vogl,
E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106-111. (c) Culkin, D.
A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330-9331.
(9) Ciufolini, M. A.; Qi, H.-B.; Browne, M. E. J. Org. Chem. 1988, 53, 4149-
4151.
(10) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581-7582.
(11) For the Pd-catalyzed intramolecular coupling of aryl halides and aldehyde
enolates, see: Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355-
2358.
(12) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415.
(13) (a) Freund, R.; Mederski, W. W. K. R. HelV. Chim. Acta 2000, 83, 1247-
1255. (b) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193-195.
(c) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363-1365.
(14) For the extension of the R-arylation of amides to the synthesis of δ-lactams,
see: Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631-633.
(15) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465-475.
(16) Sole´, D.; Vallverdu´, L.; Bonjoch, J. AdV. Synth. Catal. 2001, 343, 439-
442.
while carbamate 5 afforded tricyclic ketone 6 as the only isolable
product, although in moderate yield (entry 10). The Pd-catalyzed
cyclization of amide 3 could be accomplished by using Cs2-
CO3 (entry 8) or K3PO4 (entry 9) as the base, although in
moderate yield and isolating small amounts of the dehalogenated
amide.20 On the other hand, under the same reaction conditions
(entries 11 and 12), carbamate 5 afforded ketone 6 as the only
isolable product.
Once we had developed a set of reaction conditions for the
intramolecular coupling, we planned to extend the carbocy-
clization process to the construction of other nitrogen hetero-
cycles by varying the relative position of the 2-haloaryl moiety
and the ketone carbonyl group. Two types of amino-tethered
2-haloaryl alkanones were chosen for this study (Charts 1 and
(17) Staub, G. M.; Gloer, J. B.; Dowd, P. F.; Wicklow, D. T. J. Am. Chem.
Soc. 1992, 114, 1015-1017.
(18) Quetin-Leclercq, J.; Angenot, L.; Dupont, L.; Dideberg, O.; Warin, R.;
Delaude, C.; Coune, C. Tetrahedron Lett. 1991, 32, 4295-4298.
(19) The failure of the cyclization of acetanilide 3 under these reaction conditions
might be attributed to the acid hydrogens of the acetamido group. In fact,
the Pd-catalyzed intramolecular R-arylation of 2-haloacetanilides using
NaOt-Bu as the base has been reported; see refs 7 and 12.
(20) The formation of hydrodehalogenation byproducts has been reported; see
for example refs 7, 10, and 14.
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Pd-Mediated Ketone Arylation Processes
A R T I C L E S
Chart 2. Type II: 2-Halobenzylamino Alkanones
11a. During the course of these studies, we found that when
using K2CO3 as the base instead of Cs2CO3, alcohol 12 was
obtained in similar yield, whereas with Et3N, no reaction took
place, and the starting material was recovered. On the other
hand, it should be noted that purification of alcohol 12 was
hampered by the formation of considerable amounts of γ-bu-
tyrolactone when using THF as the solvent in the reaction (vide
infra). Interestingly, addition of Et3N (2 equiv) to the otherwise
standard cyclization conditions resulted in very clean reactions
by avoiding the formation of γ-butyrolactone. Finally, it was
also found that the use of toluene as the solvent instead of THF,
in combination with Et3N, slightly increased the yield of the
addition reaction (entry 3).
Bromide 11b was less efficient in the addition to the carbonyl
group than iodide 11a, and in the same reaction conditions it
afforded N-benzyl-2-bromoaniline as the main product, resulting
from the retro-Michael fragmentation of the starting material
(entry 4).
2), 2-haloanilino alkanones (type I) and 2-halobenzylamino
alkanones (type II). In both cases, γ-amino-, â-amino-, and
R-amino ketones were studied.
The palladium-catalyzed intramolecular addition to the
carbonyl proceeded smoothly from other â-(2-iodoanilino)
ketones to give the corresponding alcohols in moderate to
good yields (entries 5-15). The use of THF as the solvent
instead of toluene always gave inferior results, and in some cases
it resulted in the formation of considerable amounts of the retro-
Michael decomposition compounds (entry 7 vs 8, and 12 vs
13).
We began by studying the intramolecular coupling of the (2-
haloanilino) alkanone derivatives (type I, Table 2),21 which was
attempted under reaction conditions similar to those we suc-
cessfully used for the synthesis of 2,6-methano-1-benzazocines
(methods A, B, and C, Table 1). However, when the above
compounds were submitted to the reaction conditions of method
A, no cyclization products were obtained, and only compounds
arising from hydrodehalogenation and degradation of the amino
ketone moiety were isolated.22 On the other hand, we found
that using the reaction conditions of method B led to two
different and competitive cyclization pathways, enolate arylation
and the addition to the carbonyl group, depending on the
structure of the starting amino ketone. As can be seen from the
results summarized in Table 2, Pd-catalyzed intramolecular
coupling of γ-(2-iodoanilino) ketone 7 in the presence of PdCl2-
(PPh3)2 and Cs2CO3 in THF at 110 °C (entry 1) took place
exclusively at the R-position to give quinolines 8 and 9, although
in low yield, together with the hydrodehalogenated compound
10. The alcohol 9 is formed by oxidation of 8 under the
cyclization conditions; in fact, longer reaction times (72 h)
resulted in the formation of alcohol 9 as the major reaction
product. The lower yield in the cyclization reaction of γ-anilino
ketone 7 when compared with 1a could be interpreted on
conformational grounds. Thus, the higher conformational free-
dom of the open chain γ-anilino ketone 7 might thwart the
coordination of the enolate with the σ-arylpalladium moiety,
allowing competing reactions (e.g., reduction) to occur exten-
sively.
The effect of the amine protecting group in the addition
reaction was also examined in these series. Acetanilide 13
exclusively gave alcohol 14 (entry 5), whereas carbamate 15
afforded alcohol 16 in 44% yield, and 3-acetylindole 17 in 29%
yield (entry 6), the latter resulting from the oxidation, under
the reaction conditions, of the 3-acetylindoline initially formed
by intramolecular arylation of the ketone enolate. Thus, changing
the substituent at the nitrogen atom from alkyl to methoxycar-
bonyl had a marked effect on the cyclization and resulted in
the formation of significant amounts of the product from
R-arylation of the ketone. The same behavior was observed in
carbamate 26, which afforded a mixture of alcohols 27-cis and
27-trans, and ketone 28, the latter resulting from the arylation
of the enolate (entries 14 and 15). A noteworthy exception was
the Pd(0)-catalyzed cyclization of carbamate 20 that exclusively
afforded alcohol 21, although in low yield (entries 9 and 10).
The cyclization reactions of â-(2-iodoanilino) ketones 24 and
26 merit some additional comments. Thus, while Pd(0)-catalyzed
intramolecular addition to the carbonyl in 24 took place
stereoselectively to give alcohol 25-cis as the major isomer (cis/
trans ratio 3.5:1), the reaction of 26 took place with the inverse
selectivity to give alcohol 27 as a 1:2 mixture of the cis and
trans isomers. On the other hand, no significant effect was
observed in either the stereoselectivity (cis/trans) or the
chemoselectivity (R-arylation/carbonyl addition) of the reaction
of 26 after changing the solvent from THF to toluene (compare
entries 14 and 15).
In contrast, under the same reaction conditions, â-(2-
haloanilino) ketone 11a exclusively afforded alcohol 12 in 40%
yield, as a result of the addition process to the ketone carbonyl
group (entry 2, Table 2). The unexpected outcome23,24 led us
to study the Pd-catalyzed cyclization of â-(2-haloanilino) ketone
(21) For a preliminary account of part of our studies with ω-(2-haloanilino)
alkanones, see: Sole´, D.; Vallverdu´, L.; Peidro´, E.; Bonjoch, J. Chem.
Commun. 2001, 1888-1889.
(22) For example, under reaction conditions of method A, â-anilino ketones
11a and 18, and R-anilino ketones 29 and 32, afforded N-benzylaniline as
the only isolable product.
(23) The intramolecular addition of aryl palladium halides to ketones is an
uncommon transformation that has not been described until very recently,
see: Quan, L. G.; Lamrani, M.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 4827-4828.
(24) For the intramolecular addition of vinyl palladium intermediates to
ketones,24a,b aldehydes,24b,c and nitriles,24d see: (a) Quan, L. G.; Gevorgyan,
V.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 3545-3546. (b) Vicente,
J.; Abad, J.-A.; Lo´pez-Pela´ez, B.; Mart´ınez-Viviente, E. Organometallics
2002, 21, 58-67. (c) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem.
1993, 58, 4579-4583. Gevorgyan, V.; Quan, L. G.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 4089-4092. (d) Larock, R. C.; Tian, Q.;
Pletnev, A. A. J. Am. Chem. Soc. 1999, 121, 3238-3239.
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A R T I C L E S
Sole´ et al.
Table 2. Pd(0)-Catalyzed Cyclization of 2-Haloanilino Ketonesa
a Reaction run with 0.2 equiv of PdCl2(PPh3)2 and 3 equiv of Cs2CO3 in a sealed tube at 100-110 °C for 48 h. b (equiv). c Yield refers to pure isolated
products. d 24 h. e N-Benzyl-2-bromoaniline (46%) was also isolated. f 65 h. g N-Benzyl-2-iodoaniline (34%) was also isolated. h N-Methyl-2-iodoaniline
(30%) was also isolated. i Cis/trans ratio. j After the cyclization reaction, the crude mixture was treated with TFA.
The intramolecular addition to the carbonyl was also the
reaction pathway observed in the palladium-catalyzed cyclization
of R-(2-iodoanilino) ketones 29 and 32, which exclusively
afforded alcohols 30 and 33 (Figure 1), respectively, as was
confirmed by careful analysis of the crude reaction mixtures.
Figure 1.
These alcohols could not be characterized due to their instability
and were converted to the corresponding indoles 31 and 34 by
treatment with TFA25 (entries 16-19).
The use of K3PO4 as the base (method C) in the palladium-
catalyzed reaction of type I compounds resulted in the same
reaction pathway obtained when using Cs2CO3, but always gave
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Pd-Mediated Ketone Arylation Processes
A R T I C L E S
Table 3. Pd(0)-Catalyzed Cyclization of 2-Halobenzylamino
latter result could be understood considering that as the
cyclization giving the bridged system proceeds more slowly than
the formation of fused compounds, the use of the less reactive
bromide prevents an extensive occurrence of competing reac-
tions (i.e., reduction).
Ketonesa
Both â-amino ketone 42 and R-amino ketone 45 failed to
afford the cyclization products. These results could be under-
stood considering that the enolization to the R-methine position
generates a more hindered enolate, which would react more
slowly in the cyclization reaction, allowing degradation pro-
cesses to occur. It should be noted, however, that R-arylation
of carbamate 26 took place at the R-methine position to afford
28, although in moderate yield (entries 14 and 15, Table 2).
Both the formation of a five-membered ring and the lower
tendency of carbamates to give the retro-Michael fragmentation
could facilitate the cyclization reaction in this case. Finally, the
use of K3PO4 as the base for the Pd(0)-catalyzed cyclization of
type II compounds afforded only products of R-arylation, but,
once again, yields were very low, and it was impossible to drive
reactions to completion.
At this point, we turned our attention to the “anomalous”
behavior of type I compounds, which in some cases intriguingly
changed the reaction pathway from R-arylation to addition to
the carbonyl group. Although both the intramolecular enolate
arylation10 and the addition of aryl halides to ketones23 catalyzed
by Pd(0) have been previously reported in the carbocyclic series,
these two reactions seem to operate quite independently of each
other, and no competition between the two processes has been
described.29,30 Considering the similarity of the reaction condi-
tions and the structural analogy, it is interesting to compare the
results obtained by Muratake in the carbocyclic series10 and
those obtained in this work from type I compounds (Scheme
1). This comparison suggests the origin of the change in the
reaction pathway lies in the nitrogen atom, and, as a hypothesis,
we considered that this change could be caused by the ability
of the nitrogen to chelate the palladium atom.
a Reaction run with 0.2 equiv of PdCl2(PPh3)2, 3 equiv of Cs2CO3, and
3 equiv of Et3N in a sealed tube at 100-110 °C for 24 h. b Yield refers to
pure isolated products. c 4-(N,N-Dibenzylamino)cyclohexanone (∼10%) was
also isolated. d 48 h. e 63 h. f 4-Acetyl-2-benzyl-2H-isoquinolin-1-one (41)28
was also isolated (∼5%).
inferior results. Thus, for example, after 3 days under the
reaction conditions of method C, γ-(2-haloanilino) ketone 7
afforded a 3:1:1 mixture of the starting material, R-arylation
compound, and the reduction product. On the other hand, under
the same reaction conditions, â-(2-haloanilino) ketone 11a
afforded alcohol 12 in 15% yield.
At this point, we extended the studies on the palladium-
catalyzed intramolecular coupling to the 2-halobenzylamino
alkanones (type II compounds, Table 3). Once again, no
cyclization compound could be obtained when KOt-Bu was used
as the base. Interestingly, when the Pd-catalyzed reactions of
type II compounds were run using Cs2CO3 as the base, a
behavior different from that of type I compounds was observed.
Thus, under these reaction conditions, either γ- or â- and R-(2-
halobenzylamino) ketones afforded the R-arylation compound
as the only cyclization product, and the addition to the carbonyl
was never observed. As shown in Table 3, the formation of
seven-, six-, and five-membered rings was accomplished in
moderate to high yields.26 It is noteworthy that R-(2-haloben-
zylamino) ketones 43a and 43b directly afforded isoindole 44,
as a result of the oxidation, under the reaction conditions, of
the R-arylation product initially formed.27 Generally, aryl
bromides gave worse results than iodides, an exception being
the formation of the bridged azatricyclic ketone 36 (entries 1
and 2), in which the iodide gave a lower yield and afforded a
significant amount of the hydrodehalogenation product. This
Hoping to gain more insight into the above Pd(0)-catalyzed
carbocyclizations, we attempted the isolation of the σ-aryl
palladium complexes, the purported intermediates in these
reaction, to study their chemical behavior. Gratifyingly, γ-(2-
iodoanilino) ketone 7 reacted with Pd(PPh3)4 (1:1 molar ratio)
in benzene (room temperature, 72 h) to give a mixture of the
four-membered palladacycles 46 and 47, which were isolated
by flash chromatography in 56 and 15% yield, respectively
(Scheme 2). A shorter reaction time afforded a mixture in which
a third compound was observed together with small amounts
of palladacycles 46 and 47. The NMR data suggested that it
(28) It is interesting to note that on standing in solution isoquinoline 40 partially
oxidizes to isoquinolone 41.
(29) Muratake had observed some competition between the enolate arylation
and the carbonyl arylation in Pd(0)-catalyzed reactions of aldehydes.11 The
formation of the carbonyl arylation compounds was explained by means
of the insertion of σ-arylpalladium species into the formyl C-H bond, a
reaction that is not possible from ketones.
(25) Wender, P. A.; White, A. W. Tetrahedron 1983, 39, 3767-3776.
(26) Especially interesting is the preparation of the novel benzazepine 38, whose
use in the synthesis of Crinane-type alkaloids is now being studied.
(27) Aromatization of existing rings is an important means of synthesis of
isoindoles, see: Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2, pp 119-206.
(30) A careful analysis of the haloaryl ketones studied by Yamamoto23 reveals
that the substitution pattern of the majority prevents the R-arylation reaction
from taking place.
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A R T I C L E S
Sole´ et al.
Scheme 1
Figure 2. ORTEP drawing for 46.
Scheme 2. Synthesis of Palladacycles 46 and 48, and Their
Cyclization Reactions
Figure 3. ORTEP drawing for 48.
from the transient bis(triphenylphosphane)palladium complexes
initially generated when using Pd(PPh3)4.32,33
could be the corresponding trans-bis(triphenylphosphane)-
palladium complex.31 Unfortunately, this compound could not
be isolated and characterized, because on standing in solution
it turned into palladacycles 46 and 47. Palladacycle 46 was also
obtained, in 84% yield, by using Pd2(dba)3 and PPh3 (0.55:1
molar ratio) instead of Pd(PPh3)4, the hydroxopalladium complex
47 not being detected under these reaction conditions.
The structures proposed for palladacycles 46 and 48 on
spectroscopic grounds have been unambiguously confirmed by
X-ray crystallography (Figures 2 and 3).34 The four-membered
metallacycle of 48 is planar (largest deviation to mean plane
0.004(4) Å in the C bonded to the Pd atom). The dihedral angle
between this ring and the adjacent phenyl ring is 1.4(2)°. The
electronic coupling due to the planarity of the Pd(C6H4)N moiety
in 48 produces the shortening of the Pd-C(Ar) bond length
(1.989(3) Å, average value for the shortest Pd-C in CCDC
database 2.07(2) Å,35 range 2.022-2.102 Å) and decreases the
N-Pd-C bond angle (65.91(13)°, average value 67.8(7)°, range
66.33-70.76°). The steric hindrance produced by this geometric
Similar reactions were observed starting from γ-(2-iodo-
anilino) ketone 1a, which on treatment with Pd2(dba)3 and PPh3
afforded the four-membered palladacycle 48 in 65% yield. The
use of Pd(PPh3)4 as the zerovalent palladium complex resulted
in the formation of considerable amounts of hydroxopalladium
complex 49, together with palladacycle 48. The isolation of the
hydroxopalladium complexes 47 and 49 only when Pd(PPh3)4
was used as the zerovalent palladium source, and the fact that
palladacycle 46 was recovered unchanged after several days at
room temperature in different solvents (benzene, THF, ...),
suggested that these hydroxopalladium species were formed
(32) These reactions were carried out without precautions against the presence
of moisture. So, as long reactions times are required, adventitious water
could account for the formation of the hydroxopalladium(II) complexes.
For the formation of hydroxopalladium complexes, see: (a) Getty, A. D.;
Goldberg, K. I. Organometallics 2001, 20, 2545-2551. (b) Matos, K.;
Soderquist, J. A. J. Org. Chem. 1998, 63, 461-470.
(33) It is interesting to note that the N atom could play an important role in the
formation of these hydroxopalladium complexes because they have not been
observed during the preparation of the bis(triphenylphosphane)palladium
complexes of the non-nitrogen-containing haloaryl ketones. So, the hy-
drolysis reaction could occur by deprotonation by the amino group of the
more acidic coordinated water. For a related process, see: Albe´niz, A. C.;
Espinet, P.; Manrique, R.; Pe´rez-Mateo, A. Angew. Chem., Int. Ed. 2002,
41, 2363-2366.
(31) The 31P NMR spectrum of this bis(triphenylphosphane)palladium complex
shows a singlet at δ 19.5. On the other hand, the 1H NMR spectrum of this
compound shows a singlet at δ 4.46, corresponding to the nondiastereotopic
NCH2Ar protons, and all of the protons of the palladated aromatic ring are
between δ 6 and 7. These NMR data are very different from those recorded
for the azapalladacycles 46 and 47 (see the Supporting Information).
(34) Detailed crystallographic and spectroscopic data of 46 and 48 are provided
in the Supporting Information.
(35) Allen, F. H.; Kennard, O. Chem. Des. Autom. News 1993, 8, 31-37.
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Pd-Mediated Ketone Arylation Processes
A R T I C L E S
shortening produces the lengthening of the Pd-N bond length
(2.228(3) Å, average value 2.03(2) Å, range 2.006-2.084 Å),
the Pd-C-C bond angle (99.5(3)°, average value 89(2)°, range
86.5-92.6°), and the N-C-C bond angle (109.6(3)°, average
value 105.5(17)°, range 101.9-108.4°).
azapalladacycles is required, we attempted the isolation of the
σ-arylpalladium complexes from 2-iodobenzylamines 37a and
43a, and from the non-nitrogen-containing compounds 50-53.
2-Iodobenzylamines 37a and 43a reacted with either Pd2-
(dba)3 and PPh3 or Pd(PPh3)4 in benzene at room temperature
(3-4 days) to give the five-membered azapalladacycles 54 and
55,38 respectively, as the only isolable products (eq 2). The
intermediacy of these azapalladacycles in the Pd-catalyzed
intramolecular R-arylation of γ-(2-iodobenzylamino) ketones
37a and 43a was also confirmed. Thus, for example, treatment
of 54 with Cs2CO3 (3 equiv) in THF at 110 °C in a sealed tube
for 21 h afforded 38 in quantitative yield. Interestingly, the
R-arylation reaction from azapalladacycle 55 took place even
in the absence of Cs2CO3. Thus, when palladacycle 55 was
heated in THF at 100 °C in a sealed tube, no addition to the
carbonyl was observed, and instead isoindole 44 was obtained
in 70% yield.
The formation of palladium complexes 46 and 48 is note-
worthy. Contrary to what might be expected, these four-
membered azapalladacycles are robust compounds that can be
purified by flash chromatography without decomposition (see
the Supporting Information). On the other hand, although
nitrogen-containing palladacycles are a widely investigated class
of organopalladium compounds, the most common are those
with five- or six-membered rings,36 and, to the best of our
knowledge, these are the first reported examples of four-
membered azapalladacycles fused with an aromatic ring.
Moreover, the formation of these palladacycles contrasts with
the results recently reported by Vicente et al.,37 who have
prepared several trans-bis(triarylphosphane)(2-aminophenyl)-
iodopalladium complexes by oxidative addition of o-iodoaniline
to “Pd(dba)2” in the presence of arylphosphines. The two types
of iodoanilines differ in that our compounds bear two alkyl
groups at the nitrogen. The subsequent steric hindrance, forcing
the nitrogen substituents out of the plane and directing the
nonbonding electron-pair toward the palladium, together with
an increase in the basicity of the N atom could facilitate the
coordination of the amino group with the palladium atom to
afford the otherwise unfavorable four-membered palladacycle.
The intermediacy of azapalladacycles 46 and 48 in the Pd-
catalyzed intramolecular R-arylation of γ-(iodoanilino) ketones
7 and 1a was confirmed by treating these Pd-complexes with
bases to promote the carbocyclization reaction (Scheme 2). Thus,
for example, treatment of 48 with Cs2CO3 in THF at 110 °C in
a sealed tube for 24 h afforded 2 (75%) together with small
amounts of the hydrodehalogenation compound. On the other
hand, when azapalladacycle 46 was treated with Ag2CO3, which
increases the electrophilicity of the palladium center by removal
of the iodide ligand while simultaneously bringing about the
enolization of the ketone, the cyclization compound 8 was
obtained as the only reaction product in nearly quantitative yield.
Interestingly, when both â-(anilino) ketone 11a and R-
(anilino) ketones 29 and 32 were treated with equimolecular
amounts of zerovalent palladium sources to obtain the corre-
sponding azapalladacycles, a reaction behavior different from
that of γ-(anilino) ketones 1a and 7 was observed. Thus, the
reaction of 11a, 29, and 32 with either Pd2(dba)3 and PPh3 or
Pd(PPh3)4 in benzene at room temperature afforded alcohols
12, 30, and 33, respectively, in quantitative yields, the four-
membered azapalladacycles not being isolated. It is worth noting
that azapalladacycle 46 did not undergo the intramolecular
addition to the carbonyl group, neither when submitted to high
temperatures in the absence of a base nor when treated with
Tl(TfO) to remove the iodo ligand and facilitate the coordination
of the carbonyl group.
On the other hand, iodoaryl ketones 50-53 reacted with Pd-
(PPh3)4 (1:1 molar ratio) in benzene (room temperature, 3-4
days) to give the trans-bis(triphenylphosphane)aryliodopalladium
complexes 56-5938 (eqs 3 and 4).39 These σ-aryl palladium
complexes are stable solids that, although they decomposed
thermally in solution, in no case afforded the alcohols resulting
from the intramolecular addition to the carbonyl group.
The above results confirm that the formation of the four-
membered azapalladacycles is the origin of the addition to the
ketone carbonyl group process in the aniline series. Because
the Lewis acidity of the Pd atom must be very similar in both
R-amino ketone compounds, the only significant difference
between five-membered azapalladacycle 55 and the transient
four-membered azapalladacycle from iodoaniline 29 is the size
of the chelate ring. So, although we have been unable to obtain
To confirm that bringing the carbonyl and iodoaryl groups
closer together, which was achieved when changing from γ- to
â- and R-anilino ketones, is not enough to promote the addition
to the carbonyl and that the formation of the four-membered
(38) The moderate yield in the preparation of palladium complexes 55 and 59
(see the Supporting Information) is due to the difficulty of separating these
complexes from PPh3 and dba.
(39) Palladium complexes 56 and 58 were also obtained, in similar yields, by
using Pd2(dba)3 and PPh3 (0.55:2 molar ratio) instead of Pd(PPh3)4.
(36) For a recent review: Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg.
Chem. 2001, 1917-1927.
(37) Vicente, J.; Abad, J.-A.; Frankland, A. D.; Ram´ırez de Arellano, M. C.
Chem.-Eur. J. 1999, 5, 3066-3075.
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A R T I C L E S
Sole´ et al.
new five- or six-membered ring is formed. On the contrary, it
would be difficult when n ) 3 (γ-anilino ketones),42 and as a
consequence the corresponding four-membered azapallada-
cycles (i.e., 46) would be stable compounds which undergo
the expected R-arylation reaction43 in the presence of Cs2CO3.
The R-arylation reaction, which is an easy process in the
azapalladacycles when n ) 3, would be thwarted when n ) 1
and 2, as three- and four-membered rings, respectively, would
be formed.44
Finally, it should be noted that as little is known about the
mechanism of the Pd-catalyzed intramolecular addition of
arylhalides to ketones,23,24 the results obtained in this work
contribute to clarify some of the steps in the mechanism. The
catalytic cycle does not seem to demand a base but a salt (K2-
CO3 or Cs2CO3 in this work, and Na2CO3 or NaOAc in studies
by Yamamoto23) that would transmetalate the oxypalladium
intermediate into an alkoxide, which after protonolysis during
the workup would give the corresponding alcohol. Additionally,
Pd(II) obtained in the above step must undergo reduction to
Pd(0). Proof of a redox process was obtained from the isolation
of considerable amounts of γ-butyrolactone when the reaction
was carried out in THF.45
In summary, we have reported that two different structure-
depending reaction pathways can operate in the Pd-catalyzed
intramolecular coupling of amino-tethered aryl halides and
ketones, enolate arylation and addition to the carbonyl group.
The formation of unprecedented four-membered azapallada-
cycles, from which X-ray data are reported, sheds light on the
behavior of ω-(2-haloanilino) alkanones in their Pd(0)-catalyzed
reactions, which are governed by the coordination of the amino
group with the palladium atom.
Figure 4. Proposed mechanisms for the intramolecular Pd(0)-catalyzed
R-arylation and ketone carbonyl addition of 2-haloanilino ketones.
Acknowledgment. This work was supported by MCYT,
Spain (Project BQU2001-3551). Thanks are also given to the
DURSI (Catalonia) for Grant 2001SGR-00083 and a fellowship
to L.V.
experimental evidence for the formation of the four-membered
azapalladacycles from iodoanilines 11a, 29, and 32, and hence
it remains speculative, their participation as intermediates in
the carbonyl-addition reaction appears reasonable on chemical
grounds.
Supporting Information Available: Experimental procedures
for Pd(0)-catalyzed cyclization reactions and preparation of
compounds. Characterization data for all new compounds and
crystallographic data for complexes 46 and 48 (PDF and CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Moreover, the dichotomy between ketone R-arylation and
carbonyl-addition in the intramolecular Pd-catalyzed processes
from ω-(2-iodoanilino) alkanones could also be rationalized by
the intermediacy of four-membered azapalladacycles A (Figure
4). Thus, for â- and R-anilino ketones (n ) 2 and 1,
respectively), the purported four-membered azapalladacycles
undergo facile addition (even at room temperature) to the
carbonyl group. This easy addition is a consequence of the
coordination of the amino group to the palladium atom, which
brings the carbonyl nearer to the metal atom, facilitating the
formation of a transient CdO chelated intermediate,40 which
by means of a carbopalladation reaction would afford the
corresponding Pd(II) alkoxide. The formation of this CdO
chelated intermediate41 would be easy when n ) 1 or 2, as a
JA029114W
(42) The carbopalladation reaction probably requires an eclipsed arrangement
that may not be likely when n ) 3. See: Overman, L. E.; Abelman, M.
M.; Kucera, D. J.; Tran, V. D.; Ricca, D. J. Pure Appl. Chem. 1992, 64,
1813-1819.
(43) For the isolation and study of the reductive elimination reaction of aryl
palladium enolates, see: Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 5816-5817.
(44) The behavior of carbamates that afford products from both R-arylation and
addition to the ketone carbonyl group (entries 7, 8, 14, and 15 in Table 2)
could be rationalized taking into account the intermediacy of σ-arylpalla-
dium complexes with a coordinated carbonyl oxygen.12 These six-membered
palladacycles would be more stable and less prone to give the addition to
the carbonyl than the four-membered azapalladacycles, and so the R-aryl-
ation process could occur to some extent. However, σ-arylpalladium
complexes from the carbamates could not be isolated. For example,
carbamate 26 on treatment with either Pd2(dba)3 and PPh3 or Pd(PPh3)4
directly afforded alcohols 27-cis and 27-trans, although in moderate yields.
(45) When reactions were run in the presence of Et3N (entries 3-19, Table 2),
no γ-butyrolactone was obtained. It is known that tertiary amines with
R-hydrogens could be the reductants in Pd-catalyzed reactions, see: Stokker,
G. E. Tetrahedron Lett. 1987, 28, 3179-3182. Murahashi, S.-I.; Hirano,
T.; Yano, T. J. Am. Chem. Soc. 1978, 100, 348-350.
(40) The coordination ability of intramolecular ketone carbonyl groups has
already been observed: Vicente, J.; Abad, J.-A.; Mart´ınez-Viviente, E.;
Ram´ırez de Arellano, M. C.; Jones, P. G. Organometallics 2000, 19, 752-
760.
(41) We agree with the reviewer who suggests that the formation of the CdO
chelated intermediate could take place via a pentacoordinated Pd(II)
complex (not illustrated in Figure 4). For a related proposal, see: Ashimori,
A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6488-6499.
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1594 J. AM. CHEM. SOC. VOL. 125, NO. 6, 2003