A simple catalytic synthesis of condensed pyridones from o-bromoarylcarboxamides involving ipso substitution via palladacycles

Article abstract of DOI:10.1021/ja0566127

A catalytic synthesis of condensed pyridones starting from o-bromoaromatic carboxamides is reported using Pd(OAc)₂/TFP as catalyst, K₂CO₃ as a base in DMF at 105 °C. Under these conditions an unprecedented reaction sequenc

Full text of DOI:10.1021/ja0566127

Published on Web 12/30/2005
A Simple Catalytic Synthesis of Condensed Pyridones from
o-Bromoarylcarboxamides Involving ipso Substitution via Palladacycles
Raffaella Ferraccioli,* Davide Carenzi, Elena Motti, and Marta Catellani*
CNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), Dipartimento di Chimica Organica e Industriale,
UniVersita` di Milano, Via C. Golgi 19, 20133 Milano, Italy, and Dipartimento di Chimica Organica e Industriale,
UniVersita` di Parma, Parco Area delle Scienze, 17/A, 43100 Parma, Italy
Received September 27, 2005; E-mail: raffaella.ferraccioli@istm.cnr.it
Scheme 1
Palladacycles are key intermediates in inter- and intramolecular
cross-coupling reactions.1 We recently described a catalytic pro-
cedure involving palladacycles,2 which has been applied to the
synthesis of condensed quinolin-4(5H)-ones shown in Scheme 1,
starting from o-substituted iodoarenes and amides of o-bromo arene-
and heteroarenecarboxylic acids.3 The reaction has been carried out
in the presence of norbornene, Pd(OAc)2/2-trifurylphosphine (TFP)
Table 1. Pd-catalyzed Synthesis of 1a
and K2CO3 in DMF.
Surprisingly, in the absence of norbornene, coupling of two
molecules of the o-bromoaromatic carboxamide followed an
unpredictable pathway, which is the subject of this preliminary
communication. Symmetrically condensed pyridones 1 were ob-
tained simply starting from 2 (X ) HCdCH, S, O, N-Me), in the
presence of Pd(OAc)2/TFP as the catalyst, K2CO3 as a base in DMF
at 105 °C (eq 1). Under these conditions, compounds 1 were isolated
in 23-86% yield (Table 1).
As shown in Table 1, the reaction readily occurs using secondary
amides with N-bonded Me, PMB, and Ph, while the primary ones
did not give the expected products (e.g., entry 6). In addition to 1a
(23%) and 1b (30%) the reactions of 2a and 2b gave compounds
3 and 4 in 34% and 20% yield, respectively (Figure 1). As we
shall see, these compounds derive from the same initial steps as
for 1a and 1b.
Scheme 2 shows a possible reaction pathway (TFP ligand is
omitted). Palladium(0) oxidatively adds to the Br-amide 2 in the
first step. At this point, we suggest that complex 5 gives rise to a
five-membered palladacycle 6,5 in which the CONHR1 group takes
part in the construction of a metallacycle. This favors further
reaction with a second molecule of 2 possibly through an oxidative
addition process involving a palladium(IV) species6 leading to C-C
bond formation in a new palladium complex 7 (Scheme 2). The
latter then undergoes intramolecular ipso aromatic substitution at
the carbon atom bearing the CONHR1 with formation of 1, amine,
and CO2.7 Accordingly the reaction of 2c (R1 ) Ph) gave aniline
(1H NMR of the crude), which was isolated as 1-(PMB)-3-
phenylurea (23% yield) after addition of an excess of PMBNCO
to the crude. To account for this result we propose that the
aminocarbonyl group is attacked by the palladium-bonded bicar-
bonate anion (formed by exchange of the Pd-Br bond with
KHCO3). This would lead to the unstable carbamic carbonic mixed
anhydride HOCOOCONHPh, which decomposes to amine and two
a Reaction conditions: 2 (0.45 mmol, 1 equiv), Pd(OAc)2 (5 mol %),
TFP (10 mol %), K2CO3 (2 equiv), DMF (10 mL) at 105 °C. Reaction
conditions were not optimized. Unless otherwise indicated, conversion of
2 was complete. b Isolated yield. c 34% yield of 3 (see Figure 1). d 20%
yield of 4 (see Figure 1). e p-Methoxybenzyl. f In parentheses the yield in
the presence of aniline (0.5 equiv).4 g No trace of 1c was observed; only
2c and dehalogenated 2c were isolated in ca. 25 and 9% yield. h 90%
conversion. i 80% conversion.
molecules of CO2.8 C-N bond-forming reductive elimination
regenerates palladium(0), and the reaction turns out to be catalytic.
To our knowledge this process is unprecedented.
The amine R1NH2 itself resulting from the ipso-substitution
process can compete, if sufficiently nucleophilic, with the inorganic
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10.1021/ja0566127 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Figure 1. Other products of reaction 1.
Scheme 2
In summary, a catalytic multistep process based on a novel
reaction sequence combining the palladacyle-catalyzed homocou-
pling of 2 with intramolecular aromatic ipso substitution leads to 1
under mild conditions. They belong to the class of 6-phenanthri-
dinones and their heterocyclic analogues, which show promising
biological activity.13 We believe that the present work opens up
the access to important classes of compounds through one-pot
procedures much simpler than the conventional ones.3,13
Acknowledgment. We thank Consiglio Nazionale delle Ricerche
(CNR) and Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica (PRIN Project 200303977774).
Supporting Information Available: Experimental procedures and
characterization for compounds 1-4 and hydrogenolysis product from
7c. This material is available free of charge via the Internet at http://
pubs.acs.org.
Scheme 3
base for the attack on the aminocarbonyl group leading to 1 and
the symmetrically substituted urea 9 (Scheme 3).9
References
Since a possible alternative to the pathway shown in Scheme 3
could involve elimination of R1NCO, followed by the reaction with
a molecule of R1NH2, we performed the reaction of 2c (R1 ) PMB)
(2 equiv) in the presence of aniline (1 equiv) to eventually trap the
isocyanate. Under these conditions, no trace of the expected urea
PhNH-CO-NHPMB was observed, whereas 9 was isolated in 50%
yield.10
The absence of the mixed urea in this experiment also suggests
that a scarcely nucleophilic amine such as aniline, is less prone to
react with the CONHR1 group. In fact, we were not able to get
any evidence for N,N-diphenylurea formation in the reaction of 2c
(R1 ) Ph).
(1) For reviews of the role of palladacycles in catalytic transformations, see:
(a) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004, 689,
4055. (b) Dyker, G. In Handbook of Organopalladium Chemistry for
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(4) The reason for the better performance in the presence of aniline, possibly
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the bicarbonate anion, is under investigation.
(5) C-N palladacycles are transient intermediates in intramolecular Pd-
catalyzed N-arylation of amides: Yang, B. H.; Buchwald, S. L. Org. Lett.
1999, 1, 35 and references therein. A stable complex of platinum(II) has
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Further support to the proposed reaction course comes from the
following observations: (a) bis-amides corresponding to hydrogenoly-
sis of complex 7 were found as byproducts (ca. 10%) in reactions
of 2c and 2d. They turned out to be stable under basic conditions
in the absence of palladium (Cs2CO3, DMF, 105 °C), suggesting
that the presence of the metal is needed for ipso substitution accord-
ing to the mechanism of Scheme 2; (b) we prepared the hydrogenoly-
sis product of complex 7a (R1 ) Ph) and caused it to react with
PdCl2(MeCN)2 to form 1a (R1 ) Ph) via the palladium chloride
complex corresponding to 7a (R1 ) Me) (Scheme 2). A small but
significant amount of 1a was obtained (ca. 5% yield after 2 h at
105 °C) with palladium black separation and almost complete re-
covery of the starting compound; (c) the formation of compound
3, which is the main product in the reaction of 2a (R1 ) Me) (Figure
1, Table 1), implies the intermediacy of 7a to give palladacycle 10
(Scheme 4).1b,11 The latter will allow the reaction of another mol-
ecule of 2a to form 11 and finally 3 through ipso substitution, which
is preferred to attack on one of the two aromatic C-H available.11a
A different pathway leads to product 4 (Figure 1), the formation
of which must be interpreted as deriving from further attack of 2b
to the thienopyridone 1b.7,12
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(8) Belforte, A.; Belli Dell’Amico, D.; Calderazzo, F. Chem. Ber. 1988, 121,
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(9) Urea 9 was detected (1H NMR analysis) in the crude of the reaction of 2c
(R1 ) PMB).
(10) The reaction of 2c (R1 ) PMB) (2 equiv) in the presence of PhNCO (1
equiv) leads to a 1/1 mixture of PhNH-CO-NHPMB and 9 which
quantitatively accounts for the amine eliminated in the course of the
reaction.
(11) For intramolecular C-H aromatic bond activation, see: (a) Dyker, G.
Angew. Chem., Int. Ed. 1992, 31, 1023. (b) Dyker, G. Angew. Chem., Int.
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T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951.
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Gronowitz, S.; Timari, G. J. Heterocycl. Chem. 1990, 27, 1501. (c)
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Noteworthy, the selectivity of the reactions with benzocondensed
o-bromo-heterocyclic amides 2c-e increased, C-H activating
arylation being not feasible (entries 3-8).
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