Palladium catalyzed C3-arylation of 4-hydroxy-2-pyridones

Article abstract of DOI:10.1039/c4cc02166e

The direct arylation of N-substituted-4-hydroxy-2-pyridones with aryl boronic acids has been achieved under palladium catalysis. The mild reaction conditions applied in this method and the use of a conventional catalytic system offer an attractive protocol for the efficient synthesis of a variety of 3-arylated products. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02166e

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Palladium catalyzed C3-arylation of
4-hydroxy-2-pyridones†
Cite this: Chem. Commun., 2014,
50, 6879
Elissavet E. Anagnostaki, Anna D. Fotiadou, Vera Demertzidou and
Alexandros L. Zografos*
Received 24th March 2014,
Accepted 8th May 2014
DOI: 10.1039/c4cc02166e
www.rsc.org/chemcomm
The direct arylation of N-substituted-4-hydroxy-2-pyridones with
aryl boronic acids has been achieved under palladium catalysis. The
mild reaction conditions applied in this method and the use of a
conventional catalytic system offer an attractive protocol for the
efficient synthesis of a variety of 3-arylated products.
The pyridone-2 heteroaromatic core is widely isolated from
natural sources covering a wide range of biological space.1 The
subclass of 4-hydroxy-2-pyridones, which appears as a compo-
nent of natural alkaloids, possesses usually diverse molecular
decoration of the main core in 3,5 and 6-positions, contributing
majorly to their biological activity.2 Despite the increasing
pharmaceutical interest in the 2-pyridone alkaloid family,
many questions, concerning their true biological potential, still
remain unanswered, hampered by the lack of efficient synthetic
methodologies in order to build their molecular complexity.
Whereas significant progress has been made in protocols for
constructing their ring systems with a diverse range of substitution
patterns,3 regioselective introduction of substituents into existing
Scheme 1 Current and existing arylation protocols for 4-hydroxy-2-
pyridones.
pyridone derivatives has not been well documented. Based on this ketone at the enolic 3-position of the pyridone ring in the presence
drawback, various synthetic approaches to modified pyridones of a chiral diphosphane and allylpalladium chloride.8 In this
using palladium-catalyzed coupling reactions have been described regard, the development of a regioselective and direct functionali-
recently, involving usually 3-, 5- or 6-alkyl or aryl functionalization zation of the 4-hydroxy-2-pyridone core would be a significantly
of their cores either by the classical Suzuki4 and Heck5 reactions or valuable synthetic method allowing for the rapid access to
through their CH-variants.6 On the other hand, cross-coupling substituted pyridone derivatives.
reactions of 4-hydroxy-2-pyridones have been developed to much
Recently, our group was engaged in the total synthesis of
less extent and their direct CH-variants are rather unexplored. In 4-hydroxy-2-pyridone alkaloids utilizing the context of a common
some scarce reported examples, the classical Suzuki arylation of synthetic scaffold.9,10 During this endeavor, we were invoked in
the 3- or 5-position of the pyridone ring has been described the direct 3-alkyl functionalization of the pyridone moiety based
(Scheme 1).7 To the best of our knowledge, the only CH-alkyl on the inherent dicarbonyl character of the heterocycle. Wishing
functionalization of the 4-hydroxy-2-pyridone ring was reported by to further expand our synthetic libraries with 3-aryl-4-hydroxy-2-
Fu¨rstner, who managed to couple enantioselectively an unsaturated pyridone derivatives 2, we sought for the development of an
efficient, direct method to achieve our goal. In general, although
the a-functionalization of activated methylene compounds with
Laboratory of Organic Chemistry, Department of Chemistry,
aryl halides in the presence of copper metal or copper salts is a
Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece.
well known protocol for more than a century,11 its initial scope
E-mail: alzograf@chem.auth.gr; Fax: +30 2310 997630; Tel: +30 2310 997870
was very narrow. Recently, significant improvements in the
scope and reaction conditions of these Hurtley-type reactions
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc02166e
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have been achieved using a combination of copper complexes
with ancillary ligands12 but still none of these reactions have
been applied in the arylation of heteroaromatics.
In this Communication, we wish to report the first direct
arylation of 4-hydroxy-2-pyridones with the aid of aryl boronic
acids under palladium acetate catalysis (Scheme 1). N-Methyl-4-
hydroxy-2-pyridone (5) was chosen as the model compound
for our survey, based on literature reports13 and on our own
laboratory experience14 which witnessed the formation of
N-aryl derivatives when unsubstituted nitrogen 4-hydroxy-2-
pyridone compounds were used in the presence of either
copper or palladium catalysts. Gratifyingly, in our first attempt,
when N-methyl derivative 5 was allowed to react with phenyl
boronic acid (6) in the presence of palladium acetate, and
potassium carbonate in DMSO at 140 1C, a mixture of the
desired 4-hydroxy-3-phenyl-2-pyridone (7), dipyridone 8 and
diphenyl was obtained in a 1 : 1 : 0.4 ratio (Table 1). Optimiza-
Scheme 2 NMR kinetic experiments.
tion of reaction conditions revealed the direct dependence of initiation and termination of the catalytic cycle (entries 8, 11
solvent polarity on mixture composition. Polar solvents (entries and 12). On the other hand, the absence of phenylboronic acid
1 and 2) show a preference for the formation of dipyridone 8, or utilization of other coupling partners instead (e.g. phenyl
while non-polar solvents lead to the enhancement of diphenyl halides) led only to the production of the homocoupling
yields by the homocoupling of phenylboronic acid, diminishing product 8 in good yields (entry 7).
the yields of product 7 (entry 6). On the other hand, the use of
While trying to rationalize these observations an array of kinetic
water hampers completely the formation of 7, while anhydrous experiments were set up with the aid of NMR in the presence or
dioxane provided the best product to the dipyridone ratio absence of basic reaction conditions (Scheme 2). Based on these,
which increased up to 1 : 0.2 (entries 5 and 3). Unfortunately, when 4-hydroxy-2-pyridone 5 was dissolved in DMSO-d6 followed
efforts to further diminish dipyridone formation failed under by the addition of 10 mol% of palladium acetate at room
these conditions. Preliminary studies on the reaction mecha- temperature, in the presence of 1 equiv. of potassium carbonate,
nism revealed the essentiality of palladium acetate as a catalyst the formation of 3-palladium-4-hydroxy-2-pyridone complex 11 was
and the oxidative synergistic effect of copper acetate on the
Table 1 Optimization of reaction conditionsa
Oxidant
Entry (x equiv.)
Solvent/
temp. (1C)
Pd(OAc)2
(x mmol%) Base (7 : 8) of 7 (%)
Ratioe Yield
1
2
3
4
Cu(OAc)2 (3) DMSO/120
Cu(OAc)2 (3) DMF/120
Cu(OAc)2 (3) Dioxane/120
10
10
10
K2CO3 1 : 1
30
K2CO3 1 : 0.7 43
K2CO3 1 : 0.2 72
K2CO3 1 : 0.3 63
Cu(OAc)2 (3) Acetonitrile/120 10
5
Cu(OAc)2 (3) H2O/120
10
10
10
—
10
5
5
5
5
5
K2CO3
K2CO3 1 : 0.2 23
K2CO3 0 : 1
K2CO3
—
—
—
—
—
—
Traces
6
Cu(OAc)2 (3) Toluene/120
Cu(OAc)2 (3) Dioxane/120
Cu(OAc)2 (3) Dioxane/120
Cu(OAc)2 (3) Dioxane/120
Cu(OAc)2 (3) Dioxane/90
7b
8
70c
0
88
85
Traces
0
—
9
1 : 0
1 : 0
—
—
1 : 0
1 : 0.3 60
1 : 0 85
10
11
12
13
O2
Dioxane/90
AgNO3 (3) Dioxane/90
Cu(OAc)2 (2) Dioxane/90
85
14d Cu(OAc)2 (2) Dioxane/90
—
—
15
Cu(OAc)2 (2) Dioxane/90
2
a
Reaction conditions: N-methyl-4-hydroxy-2-pyridone (0.24 mmol),
phenylboronic acid (3 equiv.), Pd(OAc)2 (x mmol%), base (3 equiv.),
Cu(OAc)2 (x equiv.), solvent (2 mL) at indicated temperature for 12 h.
b
c
d
Without phenylboronic acid. Yield of compound 8. Equimolar
amount of phenylboronic acid. Ratio observed by H1-NMR.
e
Scheme 3 Postulated catalytic cycle of the reaction.
6880 | Chem. Commun., 2014, 50, 6879--6882
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observed instantly in almost 20% which raised up to 38% after (90 1C), even when the catalyst loadings have been reduced to
heating the sample to 50 1C for 3 min.
2–5% without any evidenced decrease of product yields.
In order to explore the scope and limitation of this reaction
When the same sample was allowed to stand at room
temperature for 16 hours the formation of new peaks was N-substituted-4-hydroxy-2-pyridone was reacted with several aryl
observed corresponding majorly to dipyridone compound 8, boronic acids under our optimal conditions (Table 2). In general,
along with the residual peaks of 10 and complex 11.15 When the the reaction proceeds smoothly to afford the desired product at
same experiment was set up in the absence of potassium 90 1C. Reaction of pyridone substrates with arylboronic acids
carbonate, the formation of complex 9 was diminished to possessing electron-donating substituents provided moderate to
15–20% yield and remained unaltered even when the sample good yields of coupling products. ortho-Substitution on the aryl
was heated to 70 1C for 20 min. In contrast to the previous partner does not affect the efficiency of the reaction, while highly
experiment, when the sample remained at room temperature conjugated arylboronic acids provided lower yields of products. On
for several days no other products were observed. The latter the other hand, electron-deficient aryl boronic acids (m-nitrophenyl
indicated not only the reversibility of the complex formation in boronic acid and 3,5-difluorophenyl boronic acid) failed to provide
the absence of potassium carbonate but also the synergistic useful yields of the desired coupling products (5–10%) mainly due
effect of a base in the formation of a dipyridone byproduct as to the competitive formation of dipyridone compounds.
presented in the postulated catalytic cycle of Scheme 3.
In summary, the first direct arylation of 4-hydroxy-2-pyridones
Based on these observations, the use of potassium carbonate through palladium acetate catalysis has been described. The
has been precluded from the reaction mixture. The new runs in method represents a powerful and efficient method for the rapid
dioxane solvent and various temperatures and reaction times construction of 3-arylated heterocyclic products. Although none of
showed an enhanced production of compound 7, which was the natural congeners of 4-hydroxy-2-pyridones, which are isolated
ascribed to the elimination of dipyridone 8 from the reaction until today, possess 3-aryl substitution, we believe that the ease
products (Table 1, entries 9–15). Further optimization showed and efficiency of the described methodology will enrich the library
that the reaction retains its performance at lower temperatures of synthetic 4-hydroxy-2-pyridones with novel privileged scaffolds.
This work was supported by Pharmathen S.A.
Table 2 Scope of the reaction
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6882 | Chem. Commun., 2014, 50, 6879--6882
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