First synthesis of 3-aryl-4-unsubstituted-6-CF3-pyridin-2-ones via aryl migration reaction in the presence of PhI(OAc)2/NaOH

Article abstract of DOI:10.1039/c0cc01815e

3-Aryl-4-unsubstituted-6-CF₃-pyridin-2-ones have been efficiently synthesized from readily available 4-aryl-3-carbamoyl-6-CF ₃-pyridin-2(1H)-ones by treatment with PhI(OAc)₂ in the presence of NaOH.

Full text of DOI:10.1039/c0cc01815e

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First synthesis of 3-aryl-4-unsubstituted-6-CF3-pyridin-2-ones via aryl
migration reaction in the presence of PhI(OAc)2/NaOHw
Hai Yi,a Liping Song,*ab Wei Wang,a Jianning Liu,a Shizheng Zhu,b Hongmei Dengc and
Min Shaoc
Received 10th June 2010, Accepted 22nd July 2010
DOI: 10.1039/c0cc01815e
3-Aryl-4-unsubstituted-6-CF3-pyridin-2-ones have been efficiently
synthesized from readily available 4-aryl-3-carbamoyl-6-CF3-
pyridin-2(1H)-ones by treatment with PhI(OAc)2 in the presence
of NaOH.
Table 1 Optimization of this one-pot reactiona
Multicomponent reactions (MCRs) belong to the most efficient
methods for the preparation of heterocyclic compounds.1,2 In
recent years, MCRs in which multiple bond-forming events
occur in one synthetic step have become an important industrial
process for preparing products containing complex structure
and their libraries.3
Entry
Base/equiv.
Solvent/mL
Yield of 4ab (%)
1
2
3
4
5
6
7
8
9
AcONH4/30
Pyridine/0.25
Et3N/0.25
Piperidine/0.10
Piperidine/0.25
Piperidine/0.50
Piperidine/0.25
Piperidine/0.25
Piperidine/0.25
EtOH/15
EtOH/15
EtOH/15
EtOH/15
EtOH/15
EtOH/15
CH3OH/15
CH3CN/15
CH2Cl2/30
Trace
Trace
Trace
65
79
79
69
44
Trace
It is well known that the introduction of fluorine to organic
molecules often results in dramatic modification of their physical,
chemical and biological properties.4–6 Particularly, the trifluoro-
methyl group is a key structural unit in many fluorinated
compounds of biological and pharmaceutical significance. As a
result, fluorine-containing heterocycles are now widely recognized
as important organic molecules showing interesting biological
activities with potential for applications in the medicinal and
agricultural fields.7,8 For example, 6-(trifluoromethyl)pyridin-2-
one is an adaptable intermediate of potential use in the preparation
of pharmaceutical and agrochemical products.9,10 It is not there-
fore surprising that the synthesis of trifluoromethyl heterocyclic
compounds has drawn much attention in recent days.11
a
Reaction conditions: 1a (1.5 mmol), 2 (1.5 mmol), 3a (1.5 mmol),
b
refluxing. Isolated yield.
to a series of novel 3-aryl-4-unsubstituted-6-trifluoromethyl-
pyridin-2(1H)-ones by treatment with the combination of
iodobenzene diacetate and sodium hydroxide.
Initial studies were performed using benzaldehyde 1a, cyano-
acetamide 2 and ethyl 4,4,4-trifluoro-3-oxobutanoate 3a as
model substrates (Table 1). Different bases were first briefly
examined and it was found that piperidine was the best
catalyst for this one-pot, three-component reaction (Table 1,
entries 1–4). After further examination of the catalyst loading
and solvents (Table 1, entries 4–9), the best result was obtained
by using 25 mol% of piperidine as catalyst and EtOH as the
solvent (Table 1, entry 5).
Previous investigation has shown that 4-hydroxy-3-phenyl-
pyridin-2(1H)-ones are a sort of anti-mycobacterial medicament.12
However, fluorinated 3-aryl-4-unsubstituted pyridin-2-ones,
despite their potential interest as building blocks in organic
synthesis for the construction of more complex trifluoro-
methylated heterocycles, have not received much attention,
probably owing to the lack of general methods for the synthesis
of these compounds. To the best of our knowledge, there is no
report on the preparation of 3-aryl-4-unsubstituted pyridin-2-
ones. In this communication, we report a convenient one-pot
synthesis of a variety of 4-aryl-3-carbamoyl-6-trifluoromethyl-
pyridin-2(1H)-ones, which can undergo aryl-migration leading
With the optimal reaction conditions in hand, we next
examined the scope and limitations of this one-pot, three-
component reaction. A variety of aromatic aldehydes with
electron-withdrawing or electron-donating groups were
employed as the reaction substrates and the reactions afforded
the corresponding products in moderate to good yields
(Table 2). In general, the presence of substituents on aromatic
aldehydes appeared to have only a slight influence on the
reactivity in most cases (Table 2, entries 1–11). The reaction
of para-nitrobenzaldehyde 1d proceeds smoothly at room
temperature to afford the corresponding product 4d in 64%
yield (Table 1, entry 4). The reactions of 1l and 1m need to be
carried out at room temperature with prolonged reaction time to
give the corresponding products 4l and 4m in 27% and 33%
yields, respectively (Table 2 entries 12–13), and these reactions
produce some unidentified products at higher temperature. A
similar result can be obtained when the non-fluorinated aceto-
acetic ester is employed as starting material (Table 2, entry 14).
a Department of Chemistry, School of Science, Shanghai University,
99 Shangda Road, Shanghai 200444, P. R. China.
E-mail: lpsong@shu.edu.cn; Fax: +86-21-66132797;
Tel: +86-21-66134846
b Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Science, 354 Fenglin Road,
Shanghai 200032, P. R. China
c Instrumental Analysis and Research Center, Shanghai University,
99 Shangda Road, Shanghai 200444, P. R. China
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 779094. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc01815e
c
This journal is The Royal Society of Chemistry 2010
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Table 2 One-pot synthesis of product 4a
Table 3 The effect of different amounts of sodium hydroxide on the
yield of product 6aa
Entry
Ar
R
Time/h
Yield of 4b (%)
1
2
C6H5
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
2
5
2
16
5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
79
74
73
64
76
79
77
82
79
89
93
27
33
63
Products %b
p-ClC6H4
p-BrC6H4
p-O2NC6H4
p-NCC6H4
p-CH3OC6H4
p-CH3C6H4
p-HOC6H4
m-ClC6H4
o-ClC6H4
o-CH3OC6H4
o-O2NC6H4
Furan-2-yl-
C6H5
3
4c
5
5
6a
Entry
Base/equiv.
Solvent/mL Temp./1C
1
2
3
4
5
6
7
8
—
—
EtOH/12
EtOH/12
EtOH/12
EtOH/12
EtOH/12
EtOH/12
EtOH/12
EtOH/12
CH3OH/12
CH3OH/12
25
78
25
78
25
78
25
78
25
64.5
87
89
—
—
—
—
—
—
—
—
—
—
40
47
65
83
47
40
35
77
6
7
8
9
10
11
12c
13c
14
8
3
NaOH/1.2
NaOH/1.2
NaOH/2.5
NaOH/2.5
NaOH/10
NaOH/10
KOH/2.5
KOH/2.5
16.5
2.5
16.5
2
72
24
2
9
10
a
a
Reaction conditions: 1 (1.5 mmol), 2 (1.5 mmol), 3a or 3b (1.5 mmol),
b
piperidine (0.25 eq.), EtOH (15.0 mL), refluxing. Isolated yield.
Reaction conditions: 4a (1.0 mmol), PhI(OAc)2 (1.5 mmol), solvent
b
(12.0 mL). Isolated yield.
c
Reaction at room temperature.
compound 5, generated from the reaction of isocyanate
derivatives with solvent ethanol, was obtained in good to
excellent yields regardless of the reaction temperature
(Table 3, entries 1–2). Interestingly, when the above reaction
was carried out under the same conditions in the presence of
sodium hydroxide, product 6a, derived from elimination of
isocyanic acid and aryl rearrangement, was obtained.
The effect of different amounts of sodium hydroxide and
reaction temperature on the reaction efficiency and yield was then
screened (Table 3, entries 3–8). The best result was obtained by
using 2.5 equiv. of NaOH in refluxing EtOH (Table 3, entry 6).
Another inorganic base, potassium hydroxide, was investigated
and it was found to be inferior compared to sodium hydroxide in
terms of product yields (Table 3, entries 9, 10).
Scheme 1 Plausible mechanism for formation of 4.
Investigations of the reaction scope revealed that various
substituents could be utilized in this protocol. Both electron-
withdrawing and electron-donating substituents on the aromatic
ring were well tolerated and have no considerable influence on
the reaction yields. However, the steric effect was noticeable.
The presence of ortho-substituted groups has obviously influenced
the rate and efficiency of the reaction. The substrates with
ortho-substituted groups resulted in lower yields and needed
longer reaction time compared to those with para- or meta-
substituted groups due to the effect of steric hindrance in
aryl groups migration. Note that when the non-fluorinated
analogue was used as substrate, similar results were obtained
and the corresponding non-fluorinated product was isolated in
89% yield (Table 4, entry 9).
It is well known that cyclic CF3-compounds easily form
hemi-ketal, hemi-aminal or even hemi-amidal due to the strong
electron-withdrawing properties of the CF3 group.13,14 How-
ever, in our case, we exclusively obtained a series of compounds
4 in which CF3 groups are bonded to sp2 carbon atoms, without
formation of the hemi-amidal.
From the results described above, a preliminary proposed
reaction pathway is outlined in Scheme 1. Firstly, intermediate
A was formed via initial Knoevenagel condensation reaction
followed by Michael addition reaction catalyzed by piperidine,
which then underwent intramolecular cyclization reaction to
afford the intermediate B. Due to the instability of the corres-
ponding hemiamidal intermediate B under the present reaction
conditions, intermediate B could be further transformed into
more stable products 4 by losing one molecular water, followed
by the hydrolysis of the cyano group.
The structure of compound 6a was further confirmed by
single crystal X-ray analysis to support our speculation on
structures of these products (Fig. 1).w
To demonstrate the principal possibility of the application of
products 4 in organic synthesis, the above products were treated
with iodobenzene diacetate either in the presence or in the
absence of sodium hydroxide.15 We observed that the base
played an important role in this reaction. When 4a reacted with
iodobenzene diacetate in the absence of sodium hydroxide,
Combining the above results and theoretical analysis, we
propose a plausible mechanism for formation of compounds 5
and 6 (Scheme 2). Initially, compound 4 was converted into
intermediate C via Hofmann rearrangement reaction by treat-
ment of compound 3 with iodobenzene diacetate. In the
absence of sodium hydroxide, the intermediate C reacted with
c
6942 Chem. Commun., 2010, 46, 6941–6943
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Table 4 Reaction results of transformation of 4 to 6a
Municipal Education Commission (No. J50102), and Key
Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry.
Notes and references
Yield of
6b (%)
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Entry
Ar
R
Time/h
1
2
3
4
5
6
7
8
9c
C6H5
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
2
2
1
1
1
1
7
8
9
83
82
75
73
78
74
11
43
89
p-ClC6H4
p-BrC6H4
p-CH3OC6H4
p-CH3C6H4
m-ClC6H4
o-ClC6H4
o-CH3OC6H4
C6H5
a
Reaction conditions: 4 (1.0 mmol), PhI(OAc)2 (1.5 mmol), NaOH
b
(2.5 mmol), EtOH (12.0 mL). Isolated yield. Non-fluorinated
substrate was used.
c
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5
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PhI(OAc)2/NaOH via aryl rearrangement reactions. The
synthesised 6-trifluoromethyl/methyl-pyridin-2(1H)-ones 5 and
6 can be used as essential building blocks for construction of
trifluoromethylated heterocycles.
We are grateful for financial support from the National Natural
Science Foundation of China (NNSFC) (Nos. 20672072,
20772080), Leading Academic Discipline Project of Shanghai
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6941–6943 6943