Synthesis of the N-substituted pyridin-1(2H)-one framework by ligand-assisted Pd-catalyzed reactions

Article abstract of DOI:10.1002/ejoc.201201151

An efficient Pd-catalyzed method for the synthesis of N-substituted pyridin-1(2H)-ones was developed. The corresponding derivatives, which can be found in numerous biologically active compounds, were obtained in good to excellent yields. A possible mechanism for this reaction is discussed. An efficient ligand-assisted palladium-catalyzed approach for the straightforward synthesis of the pyridin-2(1H)-one framework was developed. This method provides one of the easiest pathways to access this class of valuable compounds from easily available starting materials (2-chloropyridines). A possible mechanism for this reaction is discussed. Copyright

Full text of DOI:10.1002/ejoc.201201151

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201151
Synthesis of the N-Substituted Pyridin-1(2H)-one Framework by
Ligand-Assisted Pd-Catalyzed Reactions
Kang Zhou,[a] Ping Wen,[a] Wenlin Chen,[a] Chaowei Ma,[b] and Guosheng Huang*[a]
Keywords: Nitrogen heterocycles / Palladium / Reactions mechanisms / Synthetic methods
An efficient Pd-catalyzed method for the synthesis of N-sub-
active compounds, were obtained in good to excellent yields.
stituted pyridin-1(2H)-ones was developed. The correspond- A possible mechanism for this reaction is discussed.
ing derivatives, which can be found in numerous biologically
Introduction
The pyridin-2(1H)-one motif is one of the more impor-
tant heterocyclic frameworks because of its prevalence in
building the core structures of numerous biologically active
natural products and drugs. Owing to their increasing use
in the treatment of malaria, asthma, and epilepsy, much
attention has been paid to pyridin-1(2H)-ones as building
Figure 1. Bioactive pyridin-2(1H)-one derivatives.
blocks for synthesizing potassium channel activators and
there remains a great demand for developing simple and
antitumor agents, such as, elfamycin, mappicine, campto-
efficient synthetic methods for the formation of the N-sub-
stituted pyridin-1(2H)-one moiety.
thecin, and camptothecin derivatives[1] (Figure 1). They also
form the basic structural elements of a number of impor-
tant metabolites.[2] In addition, functionalized pyridones
are very important in pharmaceutical chemistry and the ag-
rochemical industry,[3] and their analogues are widely used
as versatile intermediates in the synthesis of a variety of
aza-heterocycles, such as, pyridine, piperidine, quinolizid-
ine, and indolizidine alkaloids.[4,5] Considering the impor-
tance of compounds with these structural units, the devel-
opment of an efficient approach for the synthesis of pyr-
idin-1(2H)-ones is therefore desirable.
However, the development of synthetic strategies contin-
ues to be extensively investigated because more improve-
ments are still needed, particularly concerning the synthesis
of the N-substituted pyridin-1(2H)-one framework. Al-
though many of the reported methods are effective, the re-
actions are incompatible with sensitive functionalities or
need harsh reaction conditions, and in some cases, the start-
ing materials are not readily available[6] (Figure 2). Herein,
[a] State Key Laboratory of Applied Organic Chemistry, Lanzhou
University,
Figure 2. Synthesis protocol for the preparation of the pyridin-
1(2H)-one framework.
Lanzhou 730000, China
Fax: +86-931-8912582
E-mail: hgs@lzu.edu.cn
Homepage: http://chem.lzu.edu.cn/
[b] Xinjiang Polytechnic College Urumqi,
Xinjiang 830091, China
Interestingly, we recently discovered a novel ligand-as-
sisted Pd-catalyzed efficient divergent route to systems
based on the pyridin-2(1H)-one framework by starting from
commercially available 2-chloropyridines. Herein, we report
our preliminary results on this topic.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201151.
448
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Eur. J. Org. Chem. 2013, 448–452

Synthesis of N-Substituted Pyridin-1(2H)-ones
loading of the ligand was increased to 30 mol-% (Table 1,
entry 12). The replacement of PivOH by AcOH reduced the
yield slightly (Table 1, entry 13). The reaction failed com-
pletely in the absence of a Pd catalyst (Table 1, entry 14).
Other palladium species, including PdCl2 and Pd2(dba)3,
were substantially less effective (Table 1, entries 15 and 16).
With the optimized conditions in hand, we investigated
the scope of this method among a variety of allyl com-
pounds, including acrylic esters, acrylonitrile, acrylic
amides, diacrylate, and acrylic acid. The results are summa-
rized in Table 2. In general, the corresponding products
were obtained in good to excellent yields (80–98%). It was
a surprise to find that when using diacrylate as the sub-
strate, only monosubstituted product 3ag was obtained.
Unfortunately, vinyl acetate was not suitable for this reac-
tion system, and a low yield was observed when acrylic acid
was used.
Results and Discussion
Initially, 2,3-dichloro-5-(trifluoromethyl)pyridine (1a)
and butyl acrylate (2a) were chosen as model substrates for
surveying the reaction parameters (Table 1). These two
partners were treated in DMF at 130 °C for 20 h in the
presence of PivOH as the additive, Pd(OAc)2 as a catalyst,
and AgOAc (3 equiv.) as the chloride scavenger and base.
To our pleasure, desired product 3aa was obtained in 37%
yield (Table 1, entry 1). Then, we wondered whether the
oxygen was from the trace amount of H2O. Unfortunately,
little product was detected by replacing PivOH with H2O
(Table 1, entry 2). When the reaction was performed under
an oxygen atmosphere without PivOH, only a trace amount
of the desired product was obtained (Table 1, entry 3).
These experiments indicated that the oxygen was from
PivOH rather than from the trace amount of H2O or oxy-
gen in the air. No reaction took place without AgOAc in
this system (Table 1, entry 4).
Table 2. Scope of the synthesis of N-substituted pyridin-1(2H)-
ones: Substituents on the acrylic ester.[a]
Table 1. Screening of reaction conditions.[a]
Entry
Catalyst
Addition (equiv.)
Yield [%][b]
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
PivOH (2.0)
H2O (2.0)
O2
37
Ͻ5
trace
0
78
81
72
53
48
89
82
96
80
0
4[c]
5[d]
6[e]
7[f]
8[g]
9[h]
10
11
12[i]
13
14
15
16
PivOH (2.0)
PivOH (2.0)
PivOH (2.0)
PivOH (2.0)
PivOH (2.0)
PivOH (2.0)
PivOH (2.5)
PivOH (3.0)
PivOH (2.5)
AcOH (2.5)
PivOH (2.5)
PivOH (2.5)
PivOH (2.5)
PdCl2
Pd2(dba)3
82
67
[a] Reaction conditions: Pyridine (0.5 mmol), butyl acrylate
(2.0 mmol), Pd(OAc)2 (10 mol-%), 1,10-phen (30 mol-%), AgOAc
(3.0 equiv.), and additive (2.5 equiv.) in DMF (0.8 mL) at 130 °C
for 20 h. Isolated yields are given.
[a] Reaction conditions: Pyridine (0.5 mmol), butyl acrylate
(2.0 mmol), Pd(OAc)2 (10 mol-%), AgOAc (3.0 equiv.), and addi-
tive (2.5 equiv.) in DMF (0.8 mL) at 130 °C for 20 h. [b] Isolated
yield of the product. [c] AgOAc was not added. [d] The ligand 2,2-
bipy (15 mol-%) was used. [e] The ligand 1,10-phen (15 mol-%) was
used. [f] Dimethylacetamide (DMAc) was used as the solvent.
[g] N-Methyl-2-pyrrolidone (NMP) was used as the solvent. [h] Xyl-
ene was used as the solvent. [i] The ligand 1,10-phen (30 mol-%)
was used.
To further explore the generality and scope of this practi-
cal approach, a variety of 2-chloropyridine derivatives were
investigated, and the results are summarized in Table 3. It
appears that the position and the electronic properties of
the substituents on the pyridine rings have some effect on
Notably, the ligands played a critical role in the reaction the reactions. The results showed that 5-substituted pyr-
efficiency. The use of 1,10-phenanthroline turned out to be idines containing electron-deficient groups had a higher
the best ligand choice, and the yield could be improved ob- efficiency (typically 83–98%) than 3-substituted pyridines
viously (Table 1, entry 6). When the solvent was switched to (typically 51–92%). Sterically hindered 3-substituted pyr-
DMA, NMP, or xylene, the yield of 3aa decreased (Table 1, idines do not work well in this transformation.
entries 7–9). Subsequently, we were pleased to find that the
Only a trace amount of the desired product, or even no
use of 2.5 equiv. of PivOH furnished an excellent isolated product, was observed (product 4jc) when the reaction was
yield of the product (Table 1, entry 10). It is noteworthy performed with an electron-deficient group at the 4-posi-
that satisfactory isolated yields were obtained when the tion of the pyridine, and this further showed the electronic
Eur. J. Org. Chem. 2013, 448–452
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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449

K. Zhou, P. Wen, W. Chen, C. Ma, G. Huang
SHORT COMMUNICATION
Table 3. Scope of the synthesis of N-substituted pyridin-1(2H)- very clear, we presume that the aromatic ring decreases the
ones: Substituents on the pyridines.[a]
ability of quinolin-2-ol to be converted into quinolin-2(1H)-
one. However, when 2-fluoro-3-methylpyridine was em-
ployed, the target product 4mc was obtained in 21% yield.
Unexpectedly, when 2-chloro-3-fluoropyridine and 2-
bromo-3-fluoropyridine were investigated, cross-coupling
product 4oc was the sole product. The above results indicate
that high electron density on the pyridine ring reduces the
activation in this system.
To gain some insight into the mechanism, several experi-
ments were explored to reveal the source of oxygen
(Scheme 1). Under the optimized reaction conditions, a
76% yield of deuterated product 3aa-D was obtained in the
presence of [D4]acetic acid. This led us to believe that the
oxygen atom in the products came from the hydroxy oxygen
atom of the acid. The transformation from 5-(trifluorometh-
yl)pyridin-2-yl pivalate to 5-(trifluoromethyl)pyridin-2-ol
could not be realized when AgOAc was not employed. The
above result indicated that AgOAc might be playing other
roles than just a simple base and chloride scavenger; it
might also contribute to the formation of pyridin-2-ol
[Scheme 1, Equation (2)]. Then, the reaction between butyl
acrylate and 5-(trifluoromethyl)pyridin-2-ol was tested. Re-
wardingly, the reaction furnished the desired product in
91% yield. On the basis of this result, we envisioned that 5-
(trifluoromethyl)pyridin-2-ol was a major intermediate in
this transformation. When the reaction was carried out in
the absence of PivOH, the efficiency of the reaction was
reduced dramatically, and only a 7% yield of the product
was obtained. It is reasonable to assume that PivOH played
a key role in this base-promoted reaction.
[a] Reaction conditions: Pyridine (0.5 mmol), butyl acrylate
(2.0 mmol), Pd(OAc)2 (10 mol-%), 1,10-phen (30 mol-%), AgOAc
(3.0 equiv.), and additive (2.5 equiv.) in DMF (0.8 mL) at 130 °C
for 20 h. Isolated yields are given. [b] 2-Fluoro-3-methylpyridine
was used. [c] 2-Chloro-3-methylpyridine and 2-bromo-3-methylpyr-
idine were used.
effects of the reaction. Presumably, this was the result of
the increased electron density on the pyridine ring, and the
desired products were not formed when 2-chloropyrimidine
(4lc) and 2-chloro-3-methylpyridine (4mc) were investi-
gated. It should be noted that when 2,5-dichloropyridine
Scheme 1.
A possible mechanism for this transformation is pro-
was used, only a trace amount of desired product 4nc was posed in Scheme 2. The oxidative addition of PdII to a C–
detected, owing to the weak inductive effect of chlorine. In Cl bond of pyridine provides A, and this process is assisted
addition, when 2-chloroquinoline was used as the substrate, by the ligand. Then, migratory insertion of PivOH affords
quinolin-2(1H)-one byproduct 4kЈc was obtained besides complex B, and this is followed by reductive elimination to
the target product 4kc. Though the exact reason was not furnish intermediate C with concomitant regeneration of
450
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Synthesis of N-Substituted Pyridin-1(2H)-ones
Scheme 2. A plausible mechanistic pathway.
the active PdII species for the next catalytic cycle.[7] After
this, intermediate C and AgI form complex D, which aids
in the formation of E through an ester exchange reaction,
and intermediate F is formed by enolization. Afterwards, G
is gained by Michael addition. Finally, product 3 is gener-
ated through a proton exchange reaction.
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Conclusions
In summary, we have developed an efficient ligand-as-
sisted palladium-catalyzed approach for the straightforward
synthesis of the pyridin-2(1H)-one framework. This method
provides one of the easiest pathways to access this class of
valuable compounds from easily available starting materials
(i.e., 2-chloropyridines). The scope of this reaction and its
application to the synthesis of bioactive compounds is cur-
rently under investigation in our laboratory.
Experimental Section
Typical Procedure for Synthesis of N-Substituted Pyridin-1(2H)-
ones: Pd(OAc)2 (11.2 mg, 10 mol-%), AgOAc (252 mg, 1.5 mmol),
n-butyl acrylate (256 mg, 2 mmol), 2-chloropyridine (0.5 mmol),
and PivOH (2.5 equiv.), and DMF (0.8 mL) were sequentially
added to a 10-mL glass tube with a branch vial equipped with a
magnetic stir bar. The reaction mixture was stirred at 130 °C under
1 atm of oxygen (balloon pressure) for 20 h. After cooling, the mix-
ture was diluted with CH2Cl2, filtered, and washed with CH2Cl2.
The filtrate was concentrated, and the residue was purified by flash
column chromatography to provide the desired product.
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Acknowledgments
We thank the State Key Laboratory of Applied Organic Chemistry
for financial support.
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K. Zhou, P. Wen, W. Chen, C. Ma, G. Huang
SHORT COMMUNICATION
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Received: August 23, 2012
Published Online: November 30, 2012
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