Cooperative heterogeneous organocatalysis and homogeneous metal catalysis for the one-pot regioselective synthesis of 2-pyridones

Article abstract of DOI:10.1002/adsc.201200367

A direct, one-pot and regioselective access to N-alkyl- and N-aryl-substituted 2-pyridones is described from readily available β-keto amides and either primary or secondary propargylic alcohols. This approach involves the combination of two different cooperative homogeneous and heterogeneous catalytic systems based on a transition metal oxide and a supported organocatalyst, respectively. Copyright

Full text of DOI:10.1002/adsc.201200367

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DOI: 10.1002/adsc.201200367
Cooperative Heterogeneous Organocatalysis and Homogeneous
Metal Catalysis for the One-Pot Regioselective Synthesis of
2-Pyridones
Christophe Allais,a Olivier Baslꢀ,a Jean-Marie Grassot,a Maxime Fontaine,a
Stꢀphane Anguille,a Jean Rodriguez,a,* and Thierry Constantieuxa,*
a
Aix-Marseille Universitꢀ, UMR CNRS 7313 iSm2, Campus Saint Jꢀrꢁme, service 531, 13397 Marseille, France
Fax : (+33)-(0)491-289-187; phone: (+33)-(0)491-282-874; e-mail: jean.rodriguez@univ-amu.fr or
thierry.constantieux@univ-amu.fr
Received: April 26, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200367.
Abstract: A direct, one-pot and regioselective
access to N-alkyl- and N-aryl-substituted 2-pyri-
dones is described from readily available b-keto
amides and either primary or secondary propargylic
alcohols. This approach involves the combination of
two different cooperative homogeneous and hetero-
geneous catalytic systems based on a transition
metal oxide and a supported organocatalyst, respec-
tively.
The 2-pyridone core is an important structural
motif found in numerous biologically active natural
products with potent pharmacological and agrochemi-
cal activities.[5] In addition, heterocycles containing
this scaffold are also of widespread interest as syn-
thetic intermediates for the construction of alkaloid
derivatives,[6] or as intermolecular connectors between
building blocks in material science.[7] Consequently,
the synthesis of substituted 2-pyridones has long been
an area of intense investigation resulting in the devel-
opment of a wide range of synthetic methods.[8] Two
main synthetic approaches have been favoured, in-
volving either the modification of the pre-constructed
heterocyclic ring by pyridinium salt chemistry[9] and
N-alkylation[10] and arylation,[11] or through the con-
struction of the heterocyclic skeleton by condensation
Keywords: cooperative catalysis; b-keto amides; or-
ganocatalysis; propargylic alcohols; 2-pyridones
In current organic chemistry, transition metal cataly- of acyclic systems.[12] Among the latter methods, tran-
sis[1] and more recently studied organocatalysis[2] have sition metal-catalyzed cyclization procedures[13,14] and
been established as highly performing activation approaches involving a conjugate addition as the key
modes for numerous chemical reactions. Since a few step[15] have received significant recent attention.
years, with the aim to disclose more efficient method- However, general drawbacks such as lack of generali-
ologies to access complex molecules synthesis, combi- ty, harsh reaction conditions, multistep procedures or
nations of two different catalytic systems have been formation of by-products are frequently associated
explored, enabling unprecedented transformations with some of these methodologies. Therefore, the de-
not currently possible by the use of one of the two
systems separately. Among the different strategies,[3]
the potentiality of combinations of organocatalysis
with transition metal catalysis has been particularly
visited.[4] In this context, we would like to report on
the combination of two different cooperative homo-
geneous and heterogeneous catalytic systems based
on a transition metal oxide and a basic supported or-
ganocatalyst, respectively, promoting a new user-
friendly domino sequence for the regioselective syn-
thesis of 2-pyridones 3 from b-keto amides 1 and
propargylic alcohols 4 [Scheme 1, Eq. (2)].
Scheme 1. Domino synthesis of 2-pyridones 3 from b-keto
amides 1.
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Christophe Allais et al.
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manganese dioxide triggering the domino cyclodehy-
dration to give 3a in 66% yield.
This stimulating preliminary result with a propargyl-
ic alcohol prompted us to optimize the dual catalytic
system. The test reaction involved b-keto amide 1a, 3-
phenylprop-2-ynol (4a) in refluxing THF for 12 h, in
the presence of 10 mol% of P-BEMP and different
oxidizing catalysts (Table 1). We first studied various
oxidants in stoichiometric amounts (entries 1–4). In
this series, RuO2·xH2O proved to be the most effi-
cient with a 75% NMR yield for the desired 2-pyri-
done (entry 3). Motivated to make this methodology
even more ecocompatible, we investigated the use of
this optimal oxidant in a catalytic amount under an
atmosphere of dioxygen (entries 5 and 6). To our de-
light, only 10 mol% of RuO2·xH2O were necessary to
get an excellent 95% NMR yield for 3a while only
5% were formed under an argon atmosphere. Other
Scheme 2. Preliminary experiments.
velopment of general methods to access diversely sub- oxidative species such as Cu2O or Fe2O3 were also
stituted N-alkyl- and N-aryl-2-pyridones from simple tested but without any success (entries 7 and 8). Inter-
substrates under mild conditions is still on demand.
estingly enough, the use of anhydrous RuO2 lowered
In connection with our studies on new eco-compati- the yield drastically, highlighting the indispensable
ble multiple bond-forming transformations[16] from but not yet elucidated role of water in this oxidation
1,3-dicarbonyls[17] initiated by organocatalyzed Mi- (entry 9). Finally, we clearly demonstrated the crucial
chael additions,[18] we anticipated that the reaction of cooperative action of both catalysts, since either no
b-keto amides[19] 1 with propargylic aldehydes or ke- reaction or degradation of substrates were observed
tones 2 would lead to the 2-pyridone core 3 via a de- when either P-BEMP or RuO2·xH2O was omitted
hydrative heterocyclization. This formal [3+3]cyclo- (entries 10 and 11, respectively).
addition constitutes a conceptually new metal-free
With these optimal conditions in hand, we then sur-
À
À
C H/N H bond functionalizations producing water veyed the scope of this new formal [3+3]heteroannu-
as only by-product, and involving ynals or ynones as lation by varying both the b-keto amide 1[23] and the
1,3-dielectrophiles [Scheme 1, Eq. (1)]. This approach primary propargylic alcohol 4 (Scheme 3). Pleasingly,
may also be interpreted as a complement to the Bohl- we were able to generate a wide variety of diversely
mann–Rahtz reaction[20] which, to the best of our substituted 2-pyridones with different patterns and
knowledge,[21] has never been explored in view of the
direct synthesis of 2-pyridone derivatives.
To achieve this goal, and to overcome the limited
commercial availability and the potential unstability
of propargylic carbonyls 2, we propose the direct use
of more easily accessible propargylic alcohol precur-
sors under oxidative conditions [Scheme 1, Eq. (2)].
Our approach takes advantages of both activation
modes while maximizing the compatibility of the two
different catalysts, and constitutes an efficient ad-
vancement in the field of cooperative action of metal-
lic catalysis and organocatalysis.
As illustrated in Scheme 2, two preliminary experi-
ments confirmed our hypothesis concerning the possi-
bility of easy access to 2-pyridones from b-keto
amides. In one experiment, the reaction between sub-
strate 1a and phenyl propargylaldehyde (2a) in the
presence of a catalytic amount of a phosphazene-sup-
ported organocatalyst (P-BEMP),[22] afforded the ex-
pected product 3a with an excellent isolated yield. In
the other experiment, we also demonstrated that the
cheaper corresponding propargylic alcohol 4a may
also be used, via in situ oxidation by an excess of
Table 1. Optimization of the dual catalytic system.
Entry Oxidant
Equiv. Ar/O2 NMR yield[b] of 3a [%]
1
2
3
4
5
6
7
8
MnO2
IBX
RuO2·xH2O 1.5
RuCl3·xH2O 1.5
RuO2·xH2O 0.1
RuO2·xH2O 0.1
Cu2O
Fe2O3
RuO2
–
1.5
1.5
Ar
Ar
Ar
Ar
O2
Ar
O2
O2
O2
O2
O2
36
5
75
0
95
5
0
0
0.1
0.1
0.1
–
9
6
10
no reaction
degradation
11[a]
RuO2·xH2O 0.1
[a]
Reaction conducted in the absence of P-BEMP.
Based on 1a using an internal standard.
[b]
2
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Cooperative Heterogeneous Organocatalysis and Homogeneous Metal Catalysis
Scheme 4. Extension of the methodology to secondary prop-
argylic alcohols.
Scheme 3. Scope of the reaction.
with high to excellent isolated yields up to 98%. The
products were recovered by simple filtration through
a short pad of silica and evaporation. Both aromatic
(3a–h) and aliphatic (3i–l) substitutents may be regio-
selectively introduced at the 4 position of the hetero-
cycle. Of particular interest is the direct access to
either N-aryl- or N-alkyl-substituted 2-pyridones (3f, Figure 1. X-ray analyses of compounds 3a and 3p.
i), usually obtained by metal-catalyzed coupling reac-
tions from the parent NH pyridone.[10,11,24]
We then turned our attention to the use of secon- cohol used. The regioselectivity of this reaction has
dary propargylic alcohols, with the aim to generate in been demonstrated by determination of the structure
situ more challenging conjugated ynones that would of the products, that has been confirmed in the case
allow introduction of a supplementary substituent on of products 3a and 3p by X-ray analysis (Figure 1).[26]
position 6 of the 2-pyridone core. As expected, the To rationalize these results, we suggest the mechanism
oxidation of secondary alcohols[25] revealed to be depicted in Scheme 5. Clearly, the cocktail
more demanding and required the use of toluene and RuO2·xH2O/P-BEMP is crucial to trigger the domino
30 mol% of RuO2·xH2O in an open flask for 72 h. sequence (Table 1, entries 10 and 11), allowing both
Gratifyingly, this optimized set of parameters allowed the in situ oxidation of the propargylic alcohol and
us to access tetrasubstituted 2-pyridones 3m–q in the formation of the transient amido enolate to gener-
a
single operation, with good isolated yields ate the intermediate II via an intermolecular Michael
(Scheme 4).
addition.[27] At this stage, reversible thermodynamical-
All the polysubstituted 2-pyridones prepared ac- ly controlled proton transfers will siphon the reaction
cording to this new methodology have been isolated by the selective cyclodehydration of diastereomer
as a single regioisomer regardless the class of the al- IIIa.
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Christophe Allais et al.
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mosphere overnight. The mixture was filtered on a short
pad of celite and thoroughly rinsed with ethyl acetate. Sol-
vent was removed under reduced pressure and the corre-
sponding pyridone was obtained with excellent chemical
purity in most cases. An analytical sample was obtained by
flash chromatography over silica gel.
Synthesis of N-arylated-6-substituted-2-pyridones: A solu-
tion of b-keto amide (0.22 mmol, 1 equiv.), secondary prop-
argylic alcohol (0.24 mmol, 1.1 equiv.), RuO2·xH2O
(30 mol%), P-BEMP (10 mol%) in toluene (4 mL) was
heated 72 h at 808C under air atmosphere (open flask). The
mixture was filtered on a short pad of celite and thoroughly
rinsed with ethyl acetate. Solvent was removed under re-
duced pressure and the corresponding pyridone was ob-
tained with excellent chemical purity in most cases. Analyti-
cal sample was obtained by flash chromatography over silica
gel.
Acknowledgements
This work was supported by the French Research Ministry,
CNRS (UMR 7313 iSm2 and RDR2 research network), Aix-
Marseille Universitꢀ and the Agence Nationale de la Recher-
che (ANR-07-CP2D-06). Dr. M. Giorgi is gratefully ac-
knowledged for X-ray analysis.
Scheme 5. Suggested mechanism.
In conclusion, we have developed an efficient
direct one-pot catalytic access to N-alkyl- and N-aryl-
substituted 2-pyridones from easily accessible acyclic
starting materials. The crucial cooperative action of
two different heterogeneous and homogeneous cata-
lysts enabled this unprecedented formal [3+3]cyclo-
dehydration approach not possible by use of the tran-
sition metal complex or the organocatalyst alone. This
simple user-friendly method accommodates a large
scope of substrates, allowing highly regioselective
access to polysubstituted products with high to excel-
lent yields in a single step.
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6 Cooperative Heterogeneous Organocatalysis and
Homogeneous Metal Catalysis for the One-Pot
Regioselective Synthesis of 2-Pyridones
Adv. Synth. Catal. 2012, 354, 1 – 6
Christophe Allais, Olivier Baslꢀ, Jean-Marie Grassot,
Maxime Fontaine, Stꢀphane Anguille, Jean Rodriguez,*
Thierry Constantieux*
6
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