One-Pot Sequential Multistep Transformation of α,β-Unsaturated Trifluoromethyl Ketones: Facile Synthesis of Trifluoromethylated 2-Pyridones

Article abstract of DOI:10.1055/s-0037-1612077

A one-pot transformation of α,β-unsaturated trifluoromethyl ketones with 2-(phenylsulfinyl)acetamide to give trifluoromethylated 2-pyridones is realized. The reaction proceeds under mild conditions and involves multiple steps in an expeditious and controlled sequence to provide efficient access to a broad range of trifluoromethylated 2-pyridones in moderate to high yields. Moreover, further synthetic manipulations permit the routine synthesis of a diverse array of trifluoromethylated pyridines with good efficiency.

Full text of DOI:10.1055/s-0037-1612077

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
N. Lv et al.
Letter
Synlett
One-Pot Sequential Multistep Transformation of α,β-Unsaturated
Trifluoromethyl Ketones: Facile Synthesis of Trifluoromethylated
2-Pyridones
Ning Lva
O
S
O
R2
O
Yi-Qiang Tiana
Fa-Guang Zhang*a
Jun-An Ma*a,b
Ph
NH
2One-pot reaction
NH
N
O
+
0
0
0
0-0
0
0
2-0
2
5
1-
0
4
5
6
R1
CF3
R
CF3
R
CF3
20 examples
35–96% yields
9 examples
R = Ar, alkenyl, alkynyl
a Department of Chemistry, Tianjin Key Laboratory of Molecular
Optoelectronic Sciences, and Tianjin Collaborative Innovation
Centre of Chemical Science and Engineering, Tianjin University,
Tianjin 300072, P. R. of China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. of China
zhangfg1987@tju.edu.cn
majun_an68@tju.edu.cn
Received: 16.10.2018
CF3
Accepted after revision: 21.12.2018
Published online: 23.01.2019
DOI: 10.1055/s-0037-1612077; Art ID: st-2018-k0670-l
Cl
Cl
O
F3C
Me
N
N
H
N
N
O
N
CN
NH
N
Abstract A one-pot transformation of α,β-unsaturated trifluoromethyl
ketones with 2-(phenylsulfinyl)acetamide to give trifluoromethylated 2-
pyridones is realized. The reaction proceeds under mild conditions and
involves multiple steps in an expeditious and controlled sequence to
provide efficient access to a broad range of trifluoromethylated 2-pyri-
dones in moderate to high yields. Moreover, further synthetic manipula-
tions permit the routine synthesis of a diverse array of trifluoromethyl-
ated pyridines with good efficiency.
OH
N
N
HIV NNRT inhibitor
CSF1R inhibitor
CF3
O
CF3
CF3
O
F3C
N
OEt
N
O
N
MeO
Me
H
Me
S
Key words trifluoromethyl group, pyridones, trifluoromethylpyri-
dines, one-pot synthesis, multistep reaction
NC
N
O
fungicide
insecticide
ligand
Figure 1 Trifluoromethylated 2-pyridone and 2-(trifluoromethyl)pyri-
dine moieties found in bioactive molecules and ligands
The 2-pyridone moiety is a unique type of structural
motif present in numerous biologically active natural prod-
ucts, pharmaceuticals, ligands, and biomaterials.1–4 More-
over, 2-pyridones have also been used as important build-
ing blocks for the preparation of a wide range of useful het-
arene derivatives, such as pyridines.5 On the other hand, the
introduction of trifluoromethyl group (CF3) into organic
molecules has a significant impact on their physical and
chemical properties, including their metabolic stability, sol-
ubility, and lipophilicity.6 As such, the efficient synthesis of
CF3-functionalized heterocycles has been a longstanding
goal within the organic-synthesis community.7 More im-
portantly, trifluoromethylated 2-pyridones and 2-(trifluo-
romethyl)pyridines have emerged as core units in an in-
creasing number of valuable drugs and agrochemicals (Fig-
ure 1).
reported a cycloaddition reaction between methyl (2Z)-2-
bromo-4,4,4-trifluorobut-2-enoate and 2-tosylacetamides
in the presence of potassium tert-butoxide to give a series
of 4-(trifluoromethyl)-2-pyridones in moderate to good
yields [Scheme 1(a)].9 Li’s group recently developed a copper-
catalyzed [3 + 3] annulation of oxime acetates with trifluo-
romethylated acrylate that delivered a range of 4-(trifluoro-
methyl)-2-pyridones with good efficiency and selectivity
[Scheme 1(b)].10 Despite these remarkable advances, exist-
ing drawbacks such as cryogenic reaction temperatures, the
use of transition metals or sensitive bases, and a limited
substrate scope are continuing challenges to be overcome.
In particular, a general and efficient approach for the con-
struction of 6-(trifluoromethyl)-2-pyridones is surprisingly
unprecedented.11 In this regard, we anticipated that the em-
ployment of α,β-unsaturated trifluoromethyl ketones as
key building blocks to react with appropriate nucleophilic
partners might offer convenient access to 6-(trifluoromethyl)-
2-pyridones. Here, we report our investigations on the
In this context, although the preparation of trifluoro-
methylated 2-pyridones has been described in several sem-
inal studies,8 implementing efficient and practical
approaches to access these appealing compounds remains a
significant challenge. Notably, Zhang and co-workers
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
N. Lv et al.
Letter
Synlett
development of a one-pot protocol to generate CF3-func-
tionalized 2-pyridones under mild conditions [Scheme
1(c)]. Moreover, the wide synthetic utility of this method
was further demonstrated by routine syntheses of a diverse
array of CF3-functionalized pyridines.
Table 1 Optimization of the Reaction Conditionsa
O
S
O
O
Ph
Ph
NH2
CF3
base, additive
solvent, rt, 4 h
1
+
AcOH
temperature, 10 h
NH
O
Ph
CF3
3a
2a
a) Zhang and Lu's work: 4-CF3-2-pyridones
O
R2
O
Entry
Base
DIPEA
Additive
Solvent
Temp (°C) Yieldb (%)
NHR2
N
Br
tBuOK
R1
MeO
+
THF, -78 °C
1
2
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
DCE
82
82
82
82
82
82
82
82
82
82
65
82
82
82
82
45
3
F3C
OH
O
CF3
R1
DABCO
DMAP
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
O
b) Li's work: 4-CF3-2-pyridones
3
25
80
38
76
81
66
58
47
23
45
60
nrf
10
O
NOAc
NH
CuCl, NaOAc
4
+
DMSO, 100 °C
Me
F3C
OMe
R
F3C
R
5c
c) our work: 6-CF3-2-pyridones and 2-CF3-pyridines
6d
7e
O
R2
O
F3C
R
NH
DBU, LiCl
then AcOH, Δ
N
+
8
O
S
O
R1
CF3
R
CF3
9
KCl
LiI
Ph
NH2
10
11e
12e
13e
14e
15e
Scheme 1 Synthesis of trifluoromethylated 2-pyridones from various
CF3-containing building blocks
LiCl
LiCl
LiCl
LiCl
LiCl
Inspired by the elegant work of the Fukuyama group,12
we chose 2-(phenylsulfinyl)acetamide (1) as the nucleo-
philic partner to react with the α,β-unsaturated trifluoro-
methyl ketone 2a (Table 1). At the outset, we screened a se-
ries of organic bases (DIPEA, DABCO, DMAP, and DBU) for
their ability to facilitate the 1,4-addition step (Table 1, en-
tries 1–4), and DBU turned out to be the best promoter.
In contrast to the previous study (in which the reaction
was conducted at 50 °C), this process proceeded smoothly
at room temperature, presumably due to the strongly elec-
tron-withdrawing nature of the trifluoromethyl group.
Subsequently, acetic acid was added to the reaction system
to trigger further reaction steps, leading to the formation of
4-phenyl-6-(trifluoromethyl)pyridin-2(1H)-one (3a) in a
one-pot manner. To our great delight, in the presence of
DBU and lithium chloride in acetonitrile, the desired prod-
uct 3a was obtained in 80% isolated yield (Table 1, entry 4).
Encouraged by this result, we examined the effects of vary-
ing the amounts of DBU, LiCl, and AcOH (entries 5–7), re-
vealing that the amount of AcOH could be dramatically re-
duced by half (entry 7). Remarkably, the reaction still pro-
ceeded in the absence of LiCl, giving 3a in comparable yield
(entry 8). The use of KCl or LiI also proved feasible, giving 3a
in practical yields (entries 9 and 10). Note that these results
are again surprisingly different from those of a previous
study,13 highlighting the unique reactivity of trifluorometh-
ylated compounds in comparison to their nonfluorinated
counterparts. In addition, the effects of the reaction tem-
perature and a series of solvents were also probed, but no
improvement was observed (entries 11–15). Taken togeth-
er, the optimal reaction conditions were established as
THF
EtOAc
a Reaction conditions: 1 (0.4 mmol, 2.0 equiv), 2a (0.2 mmol, 1.0 equiv),
base (0.6 mmol, 3.0 equiv), additive (0.6 mmol, 3.0 equiv), solvent (3 mL),
stirring, r.t., 4 h; then, AcOH (2 mmol, 10 equiv), indicated temperature,
10 h (unless otherwise noted).
b Yield of the isolated product.
c DBU (2.0 equiv) was employed.
d LiCl (2.0 equiv) was employed.
e AcOH (5.0 equiv) was employed.
f nr = no reaction.
follows: α,β-unsaturated trifluoromethyl ketone 2a was
treated with 2-(phenylsulfinyl)acetamide 1 in the presence
of DBU and LiCl in MeCN at room temperature for four
hours, then acetic acid was added and the mixture was re-
fluxed for ten hours to give the desired trifluoromethylated
pyridone 3a in a one-pot operation (entry 7).
With the optimized reaction conditions in hand,14 we
set out to investigate the substrate scope with a range of
α,β-unsaturated trifluoromethyl ketones (Scheme 2). The
one-pot protocol proved to be pleasingly effective for sub-
strates bearing electron-donating groups on the phenyl
ring, as exemplified by the formation of products 3b–f in
high yields. Importantly, substitution patterns such as
ortho, para, and meta had little influence on the reaction
performance (products 3b–d). To our delight, halogens, the
trifluoromethyl group, and polyfluorinated substrates were
also compatible with this reaction, permitting the genera-
tion of the corresponding 2-pyridones 3g–k in practical
yields. Moreover, trifluoromethyl ketones containing other
types of aromatic ring, including 2-naphthyl, 1-naphthyl, 9-
anthryl, 2-thienyl, and 2-furyl, also smoothly participated
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
N. Lv et al.
Letter
Synlett
in this transformation, giving the corresponding products
3l–p in yields as high as 96% (3o). Remarkably, the broad
scope of this reaction is further demonstrated by its the
tolerance of (2-phenylethenyl)- and (2-phenylethynyl)-
derived trifluoromethyl ketones under identical reaction
conditions (products 3q and 3r). However, when alkyl-
derived substrates were subjected to this reaction protocol,
no formation of the target 2-pyridone was observed.
was treated with 2-(phenylsulfinyl)acetamide (1) under the
same one-pot reaction conditions (Scheme 3). Pleasingly,
the corresponding 4-(trifluoromethyl)-2-pyridone 5 was
obtained in 47% yield, highlighting the practicability of the
current method.
O
S
O
O
Ph
NH2
NH
1
DBU, LiCl
AcOH
O
+
F3C
Ph
5, 47% yield
MeCN, rt, 4 h
82 °C, 10 h
O
S
O
O
F3C
Ph
1
4
Ph
R
NH2
NH
DBU, LiCl
AcOH
Scheme 3 Synthesis of a 4-trifluoromethyl-2-pyridone
+
O
MeCN, rt, 4 h
82 °C, 10 h
2
R
CF3
3
CF3
To demonstrate the synthetic utility of our newly devel-
oped protocol, we next investigated further synthetic trans-
formations of the 2-pyridone products. First, a gram-scale
preparation of the 6-trifluoromethyl-2-pyridone 3a was
performed, and resulted in a slightly higher yield (85%),
thereby providing additional proof of the robustness of this
reaction. Subsequent O-triflation provided 4-phenyl-6-(tri-
fluoromethyl)pyridin-2-yl triflate (6a) in excellent yield
(Scheme 4),15 thereby providing a range of opportunities for
the generation of diverse CF3-containing pyridines. For ex-
ample, palladium-catalyzed detriflation proceeded smooth-
ly to give 4-phenyl-2-(trifluoromethyl)pyridine (6b) in 82%
yield.16 Furthermore, the triflate 6a is also compatible with
classic cross-coupling methodologies, as exemplified by the
formation of 6c and 6d in satisfactory yields through Suzuki
coupling and iron-catalyzed sp2–sp3 coupling, respective-
ly.17 Moreover, the SNAr reaction of 6a with cyclohexyl-
amine readily gave the biologically valuable compound 6e
in high yield.18 Importantly, 2-(trifluoromethyl)isonicotinic
acid (6h) was smoothly synthesized in good overall yield in
three steps from the 4-furyl-2-pyridone 3p (Scheme 4,
middle). Finally, 4-phenyl-6-(trifluoromethyl)pyridin-2-
amine (6i) was obtained in excellent yield by employing
commercially available 2-chloroacetamide as an amine
source (Scheme 4, bottom).19 Note that CF3-containing pyri-
dines are core units found in many pharmaceutical targets
and agrochemicals.5a,20 Smith’s group recently reported an
elegant isothiourea-mediated one-pot synthesis of 4-trifluo-
romethylated pyridines from trifluoromethyl α,β-unsatu-
rated ketimines.21 Our synthetic protocol permits the rou-
tine synthesis of a diverse array of 2-trifluoromethyl-func-
tionalized pyridines with good efficiency, thereby paving a
way to further investigations in the synthesis of related
functional molecules and their biological study.
O
O
O
NH
Me
NH
NH
Me
CF3
CF3
CF3
3a, 81%
3b, 80%
3c, 87%
O
O
O
NH
NH
NH
Me
CF3
CF3
CF3
MeO
Me
Me
3e, 90%
3f, 82%
3d, 79%
O
O
O
NH
NH
NH
CF3
CF3
CF3
Br
F
Cl
3i, 62%
3g, 65%
3h, 55%
O
O
O
NH
NH
F
F
NH
CF3
CF3
CF3
F3C
F
3j, 52%
3k, 65%
3l, 60%
O
O
O
NH
NH
NH
CF3
S
CF3
CF3
3m, 86%
3n, 35%
3o, 96%
O
O
O
NH
NH
NH
CF3
CF3
CF3
O
To elucidate the mechanistic pathway of our multistep
transformation, control experiments were carefully per-
formed. As shown in Scheme 5(a), when the reaction was
interrupted before the addition of acetic acid, the cyclized
product I-2a was isolated in 93% yield. This solid result re-
veals that DBU is probably not only responsible for the 1,4-
addition step, but also plays a critical role in promoting the
3r, 40%
3p, 94%
3q, 73%
Scheme 2 Substrate scope for the synthesis of 6-(trifluoromethyl)-2-
pyridones
These encouraging results prompted us to explore the
preparation of 4-(trifluoromethyl)-2-pyridones by means
of this approach. To this end, the β-trifluoroethyl enone 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
N. Lv et al.
Letter
Synlett
O
S
O
OTf
O
N
CF3
a)
b)
O
S
O
HCOOH, Pd(OAc)2
Tf2O, DIPEA
CH2Cl2
Ph
NH2
CF3
N
NH
Ph
NH
1
DBU, LiCl
MeCN, rt
dppp, Et3N, DMF
CF3
O
OH
Ph
Ph
CF3
Ph
Ph
6a, 93% yield
3a
CF3
6b, 82% yield
Ph
2a
I-2a, 93% yield, 3:1 dr
OMe
O
O
O
S
Ph
DBU, LiCl
MeCN, rt
Ph
NH2
CF3
NH
OH
1
n-Hex
N
O
NH
then AcOH
82 °C, 1 h
Ph
N
N
CF3
I-3a, 37% yield
Ph
2a
F3C
Ph
CF3
CF3
6d, 75% yield
Ph
O
S
O
c)
6e, 87% yield
6c, 90% yield
O
NH2
Ph
NH2
CF3
DBU
DBU
1
O
O
OTf
CF3
O
S
1,4-addition
cyclization
HCOOH, Pd(OAc)2
dppp, Et3N, DMF
NH
Tf2O, DIPEA
CH2Cl2, rt
N
Ph
R
O
R
I-1
2
CF3
CF3
O
S
O
O
O
O
O
3p
6f, 60% yield
AcOH
AcOH
Ph
NH
NH
NH
N
N
dehydration
R
OH
OH
sulfoxide
NaIO4, RuCl3•xH2O
elimination
R
R
CF3
CF3
CF3
I-2
CF
3 CCl4, CH3CN, H2O, rt
I-3
HOOC
CF3
3
O 6g, 80% yield
6h, 89% yield
Scheme 5 Control experiments and proposed process
O
NH2
N
NH
CONH2, NaI, K2CO3
DMF, 100 °C
ClCH2
Ph
CF3
Ph
CF3
3a
6i, 95% yield
Funding Information
Scheme 4 Transformation of 6-(trifluoromethyl)-2-pyridones into
various CF3-functionalized pyridines
This work was supported financially by the National Natural Science
Foundation of China (No. 21472137, 21532008, and 21772142) and
the National Basic Research Program of China (973 Program:
2014CB745100).
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
4
7
2
1
3
7)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
7
7
2
1
4
2)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(
21532008
)
cyclization process. Moreover, when the reaction was
stopped one hour after the addition of acetic acid, the inter-
mediate I-3a was obtained and fully characterized [Scheme
5(b)].22 This experiment suggests that the sulfoxide elimi-
nation occurs before the dehydration event. Based on these
results, a proposed process is outlined in Scheme 5(c). Ini-
tially, 2-(phenylsulfinyl)acetamide 1 and the α,β-unsaturat-
ed trifluoromethyl ketone 2 undergo 1,4-addition in the
presence of DBU; this is followed by a cyclization step to
give intermediate I-2. Subsequently, sulfoxide elimination
proceeds when acetic acid is added to the reaction
sequence, generating intermediate I-3. At this stage, the de-
hydration is likely to occur expeditiously to provide the
final product.
In conclusion, we have developed an efficient and prac-
tical transformation of α,β-unsaturated trifluoromethyl
ketones with 2-(phenylsulfinyl)acetamide in a one-pot
manner. This protocol permits the facile preparation of a
broad range of CF3-functionalized 2-pyridones and a
diverse array of CF3-functionalized pyridines in pleasing
yields under mild conditions. Considering the high biologi-
cal importance of CF3-containing 2-pyridones and pyri-
dines, this method holds the promise of finding applica-
tions in syntheses of potential pharmaceuticals and agro-
chemicals.
Acknowledgment
We thank Baili Li (TJU) for assistance in performing IR spectroscopic
analyses.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612077.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
(1) For reviews, see: (a) Chu, D. T. W. Med. Res. Rev. 1999, 19, 497.
(b) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
(c) Hamama, W. S.; Waly, M.; El-Hawary, I.; Zoorob, H. H. Synth.
Commun. 2014, 44, 1730. (d) Vodolazhenko, M. A.; Gorobets, N.
Y. Chem. Heterocycl. Compd. 2016, 52, 894. (e) Hirano, K.; Miura,
M. Chem. Sci. 2018, 9, 22. (f) Prendergast, A. M.; McGlacken, G. P.
Eur. J. Org. Chem. 2018, 6068.
(2) For selected examples in bioactive molecules, see: (a) Xiong,
W.-N.; Yang, C.-G.; Jiang, B. Bioorg. Med. Chem. 2001, 9, 1773.
(b) Huffman, J. W.; Lu, J.; Hynd, G.; Wiley, J. L.; Martin, B. R. Bioorg.
Med. Chem. 2001, 9, 2863. (c) Surup, F.; Wagner, O.; von Frieling, J.;
Schleicher, M.; Oess, S.; Müller, P.; Grond, S. J. Org. Chem. 2007, 72,
5085. (d) Gan, C.-Y.; Low, Y.-Y.; Etoh, T.; Hayashi, M.; Komiyama,
K.; Kam, T.-S. J. Nat. Prod. 2009, 72, 2098. (e) Jessen, H. J.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
N. Lv et al.
Letter
Synlett
Gademann, K. Nat. Prod. Rep. 2010, 27, 1168. (f) Hibi, S.; Ueno,
K.; Nagato, S.; Kawano, K.; Ito, K.; Norimine, Y.; Takenaka, O.;
Hanada, T.; Yonaga, M. J. Med. Chem. 2012, 55, 10584. (g) Chen,
J.; Lu, M.-M.; Liu, B.; Chen, Z.; Li, Q.-B.; Tao, L.-J.; Hu, G.-Y.
Bioorg. Med. Chem. Lett. 2012, 22, 2300. (h) Scott, J. S.; Goldberg,
S. W.; Turnbull, A. V. J. Med. Chem. 2014, 57, 4466. (i) Neckles, C.;
Pschibul, A.; Lai, C.-T.; Hirschbeck, M.; Kuper, J.; Davoodi, S.;
Zou, J.; Liu, N.; Pan, P.; Shah, S.; Daryaee, F.; Bommineni, G. R.;
Lai, C.; Simmerling, C.; Kisker, C.; Tonge, P. J. Biochemistry 2016,
55, 2992.
(12) Fujii, M.; Nishimura, T.; Koshiba, T.; Yokoshima, S.; Fukuyama, T.
Org. Lett. 2013, 15, 232.
(13) In Fukuyama’s study, the reaction did not proceed at all in the
absence of LiCl, and the use of KCl instead of LiCl resulted in no
production of the 2-pyridone; for details, see ref. 12.
(14) 6-(Trifluoromethyl)-2-pyridones 3a–r; General Procedure
DBU (0.6 mmol, 89.7 μL) and the appropriate α,β-unsaturated
trifluoromethyl ketone 2 (0.2 mmol, 1.0 equiv) were added to a
mixture of 2-(phenylsulfinyl)acetamide (1; 0.4 mmol, 73.3 mg)
and LiCl (0.6 mmol, 25.4 mg) in MeCN (4 mL) at r.t., and the
mixture was stirred at r.t. for 4 h. When the trifluoromethyl
ketone 2 was completely consumed (TLC), AcOH (1 mmol, 57.2
μL) was added, and the resulting mixture was refluxed for 10 h,
then cooled to r.t. The reaction was then quenched with sat. aq
NaHCO3 and extracted with 10% MeOH–CHCl3 (×3). The com-
bined organic extracts were washed with brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography [silica gel,
CH2Cl2–MeOH (80:1)].
(3) For selected examples in ligands, see: (a) Wang, P.; Verma, P.;
Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.;
Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. Nature 2017, 551, 489.
(b) Zhu, R.-Y.; Li, Z.-Q.; Park, H. S.; Senanayake, C. H.; Yu, J.-Q. J. Am.
Chem. Soc. 2018, 140, 3564. (c) Pati, T. K.; Debnath, S.; Kundu, M.;
Khamrai, U.; Maiti, D. K. Org. Lett. 2018, 20, 4062.
(4) For selected examples in biomaterials, see: Matsuo, K.;
Nishikawa, Y.; Masuda, M.; Hamachi, I. Angew. Chem. Int. Ed.
2018, 57, 659.
(5) (a) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahe-
dron 1992, 48, 9111. (b) Nakao, Y.; Idei, H.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996. (c) Hill, M. D.
Chem. Eur. J. 2010, 16, 12052. (d) Bull, J. A.; Mousseau, J. J.;
Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.
(e) Allais, C.; Grassot, J. M.; Rodriguez, J.; Constantieux, T. Chem.
Rev. 2014, 114, 10829. (f) Li, C.; Kähny, M.; Breit, B. Angew.
Chem. Int. Ed. 2014, 53, 13780. (g) Zhang, X.; Yang, Z.-P.; Huang,
L.; You, S.-L. Angew. Chem. Int. Ed. 2015, 54, 1873. (h) Diesel, J.;
Finogenova, A. M.; Cramer, N. J. Am. Chem. Soc. 2018, 140, 4489.
(6) (a) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432.
(b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (d) O’Hagan, D. Chem. Soc. Rev. 2008, 37,
308. (e) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (f) Nie,
J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455.
(g) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115,
731.
(7) For selected reviews, see: (a) Zhu, S.; Song, L.; Jin, G.; Dai, B.;
Hao, J. Curr. Org. Chem. 2009, 13, 1015. (b) Tomashenko, O. A.;
Grushin, V. V. Chem. Rev. 2011, 111, 4475. (c) Barata-Vallejo, S.;
Lantaño, B.; Postigo, A. Chem. Eur. J. 2014, 20, 16806. (d) Alonso,
C.; Martínez de Marigorta, E.; Rubiales, G.; Palacios, F. Chem.
Rev. 2015, 115, 1847. (e) Li, S.; Ma, J.-A. Chem. Soc. Rev. 2015, 44,
7439. (f) Meyer, F. Chem. Commun. 2016, 52, 3077. (g) Das, P.;
Tokunaga, E.; Shibata, N. Tetrahedron Lett. 2017, 58, 4803.
(h) Feraldi-Xypolia, A.; Gomez Pardo, D.; Cossy, J. Eur. J. Org.
Chem. 2018, 3541.
(8) (a) Pitman-Dunn, S. P. J. Heterocycl. Chem. 1969, 6, 223.
(b) Kvita, V. Synthesis 1991, 883. (c) Kumar, G. S.; Kurumurthy,
C.; Rao, P. S.; Veeraswamy, B.; Rao, P. S.; Narsaiah, B. J. Hetero-
cycl. Chem. 2015, 52, 75. (d) Abdellattif, M. H.; Maghrabi, I. A.;
Areef, M. M. H.; ElDeab, H. A.; Mouneir, S. M.; Belal, A. J. Adv.
Chem. 2016, 12, 4351; DOI: 10.24297/jac.v12i4.2175.
(9) Zhang, H.-H.; Shen, W.; Lu, L. Tetrahedron Lett. 2018, 59, 1042.
(10) Bai, D.; Wang, X.; Zheng, G.; Li, X. Angew. Chem. Int. Ed. 2018, 57,
6633.
(11) There is only one report on the synthesis of 6-(trifluoromethyl)-
2-pyridones; this gives only one example, and requires two syn-
thetic steps: Yeh, P.-P.; Daniels, D. S. B.; Cordes, D. B.; Slawin, A.
M. Z.; Smith, A. D. Org. Lett. 2014, 16, 964.
4-Phenyl-6-(trifluoromethyl)pyridin-2(1H)-one (3a)
White solid; yield: 77.5 mg (81.0%); mp 198.4–200.6 °C. 1H
NMR (400 MHz, DMSO-d6): δ = 11.83 (s, 1 H), 7.86–7.81 (m, 2
H), 7.61 (s, 1 H), 7.51 (dd, J = 5.8, 4.6 Hz, 3 H), 7.21 (s, 1 H). 19F
NMR (376 MHz, DMSO-d6): δ = –66.65 (s). 13C NMR (101 MHz,
DMSO-d6): δ = 164.9, 152.2, 144.8 (q, JC–F = 34.6 Hz), 136.2,
129.8, 129.2, 127.1, 121.5 (q, JC–F = 272.4 Hz), 110.8, 110.3.
4-(2-Tolyl)-6-(trifluoromethyl)pyridin-2(1H)-one (3b)
White solid; yield: 81.0 mg (80.0%); mp 98.7–99.9 °C. IR (neat):
1666, 1632, 1550, 1444, 1403, 1348, 1174, 1133, 965, 945, 840
1
cm–1. H NMR (400 MHz, DMSO-d6): δ = 11.85 (s, 1 H), 7.27 (d,
J = 25.6 Hz, 5 H), 6.86 (s, 1 H), 2.23 (s, 3 H). 19F NMR (377 MHz,
DMSO-d6): δ = –66.78 (s). 13C NMR (101 MHz, DMSO-d6): δ =
164.4 (s), 153.8 (s), 144.1 (q, JC–F = 33.82 Hz), 137.8 (s), 134.7 (s),
130.7 (s), 129.0 (s), 128.8 (s), 126.2 (s), 121.5 (q, JC–F = 272.33
Hz), 113.9 (s), 113.0 (s), 19.8 (s). HRMS (ESI): m/z [M + H]+ calcd
for C13H11F3NO: 254.0789; found: 254.0793.
(15) (a) Tsuchida, N.; Yamabe, S. J. Phys. Chem. A 2005, 109, 1974.
(b) Mertens, M. D.; Pietsch, M.; Schakenburg, G.; Gütschow, M.
J. Org. Chem. 2013, 78, 8966. (c) Feng, B.; Li, Y.; Li, H.; Zhang,
X.; Xie, H.; Cao, H.; Yu, L.; Xu, Q. J. Org. Chem. 2018, 83, 6769.
(16) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541. (b) Yoshida, Y.; Mohri, K.; Isobe, K.; Itoh, T.;
Yamamoto, K. J. Org. Chem. 2009, 74, 6010.
(17) (a) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11,
3954. (b) Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett.
2009, 11, 4886.
(18) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev, A. A. Synthesis
2003, 1531.
(19) Kumar, G. S.; Dev, G. J.; Kumar, N. R.; Swaroop, D. K.; Chandra, Y.
P.; Kumar, C. G.; Narsaiah, B. Chem. Pharm. Bull. 2015, 63, 584.
(20) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(b) Prachayasittikul, S.; Pingaew, R.; Worachartcheewan, A.;
Sinthupoom, N.; Prachayasittikul, V.; Ruchirawat, S.;
Prachayasittikul, V. Mini-Rev. Med. Chem. 2017, 17, 869.
(c) Burriss, A.; Edmunds, A. J. F.; Emery, D.; Hall, R. G.; Jacob, O.;
Schaetzer, J. Pest Manag. Sci. 2018, 74, 1228.
(21) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M. Z.; O’Riordan,
T. J. C.; Smith, A. D. Angew. Chem. Int. Ed. 2013, 52, 11642.
(22) The presence of a double bond at the α-position of the alcohol
cannot be ruled out at this stage.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E