Direct regioselective Csp2-H trifluoromethylation of pyrimidinones and pyridinones

Article abstract of DOI:10.1016/j.tet.2016.04.048

A direct regioselective C_sp2-H trifluoromethylation of pyrimidinones and pyridinones using CF₃SO₂Na/Mn(OAc)₃ to afford 5-trifluoromethyl pyrimidinones and 3-trifluoromethyl pyridinones in moderate to good yields was described. The reaction showed that the steric hindrance due to bulky groups adjacent to the position of attack by the trifluoromethyl radical had important influence on the yield.

Full text of DOI:10.1016/j.tet.2016.04.048

Tetrahedron 72 (2016) 3250e3255
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct regioselective Csp2eH trifluoromethylation of pyrimidinones
and pyridinones
,
,
Pei-Zhi Zhang a y, Cheng-Kun Li a y, Guo-Yu Zhang a, Ling Zhang a, Yao-Jia Jiang c,
,b,
Jian-Ping Zou a
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University, 199 Renai Street, Suzhou,
Jiangsu, 215123, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai,
200032, China
c Institute of Advanced Materials (IAM), College of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, Jiangsu, 21009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct regioselective Csp2eH trifluoromethylation of pyrimidinones and pyridinones using CF3SO2Na/
Mn(OAc)3 to afford 5-trifluoromethyl pyrimidinones and 3-trifluoromethyl pyridinones in moderate to
good yields was described. The reaction showed that the steric hindrance due to bulky groups adjacent to
the position of attack by the trifluoromethyl radical had important influence on the yield.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 16 January 2016
Received in revised form 18 April 2016
Accepted 20 April 2016
Available online 22 April 2016
Keywords:
Trifluoromethylation
Radical reaction
Pyrimidinone
Pyridinone
1. Introduction
2. Results and discussion
The incorporation of trifluoromethyl group into medicinal and
agrochemical molecules have gained attention since it can dra-
matically improve their bioactivity, solubility, lipophilicity, mem-
brane permeability and stability.1e6 Several reports on
trifluoromethylation have been published in recent years including
trifluoromethylation of heteroarenes via the coupling reaction of
heteroaryl halides, amines or boronic acid derivatives with various
Initially, CF3SO2Na/Mn(OAc)3 system was applied to the tri-
fluoromethylation of different types of substrates. The results
showed that the reaction of CF3SO2Na with styrene, electron-
deficient alkenes, conjugated alkynes, thiophene, methox-
ybenzene, indole, quinoline, chromenone and flavone resulted in
a mixture of regioisomers due to these substrates possessing
multiple electron density similar sites, leading to the tri-
fluoromethylation non-selective. On the other hand, no reactions
were observed in the case of pyridine and quinone. To our delight,
when the same conditions were applied to pyrimidinone and pyr-
idinone, both of them afforded the corresponding selective tri-
fluoromethylated compounds in moderate yields (Scheme 1).
In order to get a better yield, other trifluoromethylating systems
were tested for the trifluoromethylation of 2,6-diphenyl pyr-
imidinone (1a). The results indicated that neither CF3SO2Na/TBHP
(tert-butyl hydroperoxide), CF3SO2Na/TBHP/CuCl nor TMSCF3/PIDA
(phenyl iodanediyl diacetate) could react with 1a, while the re-
action of either CF3SO2Na/AgNO3, CF3SO2Na/I2O5 or Togni’s reagent
with 1a gave a mixture of regioisomers due to trifluoromethylation
occurred both phenyl and pyrimidiyl ring (Table 1, entries 1e6).
Consequently, CF3SO2Na/Mn(OAc)3 remained the most suitable for
the trifluoromethylation of 1a. After the reaction temperature and
trifluoromethylating
reagents.1e7
The
direct
CeH
tri-
fluoromethylation of heteroaromatics has focused mainly on
electron-rich compounds, such as five-membered heteroarenes,
with some being associated with low yields and a mixture of
regioisomers.1c,7 Therefore, the direct regioselective trifluoro-
methylation of electron-deficient heteroarenes is still a challenge.
In continuation of our previous studies on trifluoromethylation,8
herein, we report a general, straightforward method for the tri-
fluoromethylation of pyrimidinones and pyridinones with
CF3SO2Na mediated by Mn(OAc)3.
* Corresponding author. E-mail address: jpzou@suda.edu.cn (J.-P. Zou).
y
Equal contribution to this paper.
http://dx.doi.org/10.1016/j.tet.2016.04.048
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

P.-Z. Zhang et al. / Tetrahedron 72 (2016) 3250e3255
3251
Table 2
Reactions of pyrimidinones (1) with CF3SO2Na (2)a
Scheme 1. Exploration of trifluoromethylation of different types of substrates.
ratio of 1a/CF3SO2Na/Mn(OAc)3 were screened, the optimal re-
action conditions were determined to be 2,6-diphenyl pyr-
imidinone 1a (0.1 mmol), CF3SO2Na (0.3 mmol) and Mn(OAc)3
(0.3 mmol) in HOAc (4 mL) at 25 ꢀC for 12 h to give 2,6-diphenyl-3-
trifluoromethyl pyrimidinone (3a) in 60% yield (Table 1, entry 8).
With the optimized reaction conditions at hand, the scope of
pyrimidin-4(3H)-ones (1) was then investigated (Table 2). In gen-
eral, the reaction tolerated both aryl and alkyl substitutions at 2-
and 6-positions to give regioselective 5-trifluoromethylation
products in moderate to good yields. The reactions involving 2,6-
diarypyrimidin-4(3H)-ones were conducted, and the desired
products were obtained in moderate yields (Table 2, 3ae3e).
a
Unless the otherwise noted, reactions were performed using 1a (0.50
mmol), 2a (1.50 mmol) and Mn(OAc)3 (1.50 mmol) in HOAc (10 mL)
at 25 oC for 12 h in air;
b Isolated yield.
Furthermore, the reactions of 2-methyl-6-arylpyrimidin-4(3H)-
ones also gave the corresponding products 3fe3h in moderate yields.
It is noteworthy that reactions involving 2,6-dialkylpyrimidin-4(3H)-
ones afforded the products 3je3k in good yields. It indicated that
the small groups adjacent to the position of attack by the tri-
fluoromethyl radical favored to the reaction. The low yield of 3i was
an exception due to the oxidation of the 2-methyl-6-(3-
bromophenyl) pyrimidin-4(3H)-one (1i) thereby forming 3-
bromobenzoic acid as a by-product.
Table 1
Optimization of the reaction conditionsa
Moving further, the same reaction conditions were applied to
pyridin-2(1H)-ones
4 thereby obtaining 3-trifluoromethylated
pyridin-2(1H)-ones 5 in moderate to good yields as shown in
Table 3. Remarkably, no 5-trifluoromethylated pyridinones or
phenyl-trifluoromethylated products were observed.
Entry
Reagent
1a:Oxidant
Temp (ꢀ C)
Yield (%)b
Also, it was observed that different aromatic substituents at the
4 and 6-positions of pyridinones had no significant effect on the
yield of product. When phenyl group at position 6 of 2,6-
diarylpyridinone was substituted by a methyl group, moderate
yield of trifluoromethylated product was isolated (Table 3, 5i and
5j). It is worthy to note that less sterically hindered pyridinones,
such as the unsubstituted 5h, or ester substituted 5k and 5l gave
the products in good to excellent yields (Table 3).
In order to understand the mechanism of this reaction, some
control experiments have been done, and the results in Scheme 2
showed that the reaction of 2,6-diphenyl pyrimidinone (1a) with
CF3SO2Na (2) can be inhibited by radical scavenger like TEMPO and
1,1-diphenylethene.
Based on the results above, a possible mechanism is proposed
for the reaction of pyrimidinones (1) or pyridinones (4) with
CF3SO2Na (2) mediated by Mn(OAc)3 (Scheme 3). Trifluoromethyl
radical A derived from 2 selectively adds to the 5-position of 1 or 3-
position of 4 to form intermediate radical B, which is oxidized by
Mn(OAc)3 to carbocation C. Subsequent deprotonation of C gave the
products 3 and 5, respectively.
1
2
3
4
5
6
7
8
TBHP
1:3
1:3
1:3
1:3
1:3
1:3
1:1
1:3
1:4
1:5
1:3
1:3
1:3
25
25
50
50
50
50
25
25
25
25
50
60
80
N.R.c,d
N.R.c,e
N.R.c,f
Mixture
Mixture
TBHP/CuCl
TMSCF3/PIDA
AgNO3
g
d
I2O5
h
Togni’s reagent
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mixture
26
60
53
46
55
43
30
9
10
11
12
13
a
Unless the otherwise noted, reactions were performed using 1a (0.20 mmol), 2a
(0.60 mmol) and oxidant in HOAc (4 mL) for 12 h under open-flask atmosphere.
b
Isolated yield.
N.R. means no reaction.
Solvent: CH2Cl2/H2O (3: 1).
Solvent: CH2Cl2/MeOH/H2O (3: 3: 1).
c
d
e
f
The mixture of 1a (0.10 mmol), KF (0.4 mmol), TMSCF3 (0.4 mmol), PhI(OAc)2
(0.30 mmol) in EtOAc (1 mL) at 50 ꢀC for 12 h.
g
Solvent: NMP.
Solvent: EtOAc.
h

3252
P.-Z. Zhang et al. / Tetrahedron 72 (2016) 3250e3255
Table 3
Reactions of pyridinones (4) with CF3SO2Na (2)a
Scheme 3. Proposed mechanism for the trifluoromethylation.
3. Conclusion
In conclusion,
a direct and efficient protocol for tri-
fluoromethylation of pyrimidinones and pyridinones was de-
veloped using CF3SO2Na/Mn(OAc)3 as reagent. The reaction
proceeded under mild conditions in air to afford selectively 5-
trifluoromethyl pyrimidinones and 3-trifluoromethyl pyridinones
in moderate to good yield. This protocol provides a straightforward,
effective and cheap method of synthesizing 5-trifluoromethyl
pyrimidinones and 3-trifluoromethyl pyridinones.
a Unless the otherwise noted, reactions were performed using 4 (0.50
mmol), 2 (1.50 mmol) and Mn(OAc)3 (1.50 mmol) in HOAc (10 mL) at
25 oC for 12 h in air;
4. Experimental section
4.1. General
b Isolated yield.
1H NMR (400 MHz or 300 MHz), 13C NMR (150 or 100 MHz) and
19F NMR (282 or 376 MHz) spectra were determined with CDCl3 or
DMSO-d6 as solvent and tetramethylsilane (TMS) as internal stan-
dard. Chemical shifts were reported in parts per million (ppm) from
internal TMS (d); all coupling constants (J values) were reported in
hertz (Hz). High-resolution mass spectra were recorded on a TOF
machine (CI and ESI). Column chromatography was performed with
300e400 mesh silica gel using flash column techniques. All of the
reagents were used directly as commercially available unless oth-
erwise noted.
4.2. General procedure for the preparation of 5-
trifluoromethyl pyrimidinones (3) and 3-trifluoromethyl
pyridinones (5)
Scheme 2. Radical trap experiments.
4.2.1. Typical procedure for the preparation of 2,6-diphenyl-5-
trifluoromethyl pyrimidinone (3a). To a solution of 2,6-diphenyl
pyrimidinone (1a) (0.16 g, 0.5 mmol) and sodium tri-
fluoromethanesulfinate 2 (0.258 g, 1.5 mmol) in acetic acid (10 mL),
was added manganese triacetate hydrate (0.402 g, 1.5 mmol) in
batches. The mixture was stirred at 25 ꢀC in air for 12 h. After the
completion of the reaction, water (20 mL) was added to the reaction
mixture, extracted with ethyl acetate (15 mLꢁ3). The combined
organic fractions were dried over anhydrous Na2SO4, and concen-
trated under vacuum to give the crude product, which was purified
by flash column chromatography (silica gel, petroleum ether/ethyl
acetate¼2:1) to give 2,6-diphenyl-5-trifluoromethyl pyrimidinone
(3a).
As depicted in Scheme 3, the regioselectivity of tri-
fluoromethylation of pyrimidinones 1 or pyridinones 4 may be
dependent on the combination of compatible substrate, radical
initiator and oxidant. In the above reaction, trifluoromethyl radical
A initiated by Mn(OAc)3 favors to attack the position adjacent to the
C]O group to form radical B. This is due to the presence of the
carbonyl group which makes the adjacent carbon more reactive.
Then, B was rapidly oxidized to carbocation C by a second molecule
of Mn(OAc)3, thus avoiding other competitive reactions. The final
deprotonation of C took place readily. Furthermore, comparing the
yields of 6-arylpyrimidinones such as 3g or 4-arylpyridinones (5i)
with their less sterically hindered analogues (3j, 3k and 5h, 5k, 5l),
the latter were obtained in good yields. It is obvious that the sub-
stituent R1 (Scheme 3) offered no stabilization for the radical B, so
the less bulky substituents at 6-position of pyrimidinones or 4-
position of pyridinones facilitated the trifluoromethyl radical at-
tack, leading to the high yield of products.
4.3. Characterization
4.3.1. 2,6-Diphenyl-5-(trifluoromethyl)pyrimidin-4(3H)-one
(3a). White powder, 60% yield (95 mg), mp 258e260 ꢀC. 1H NMR

P.-Z. Zhang et al. / Tetrahedron 72 (2016) 3250e3255
3253
(DMSO-d6, 400 MHz):
d
13.54 (s, 1H), 8.16 (d, J¼7.5 Hz, 2H), 7.65 (t,
6.96 (d, J¼8.3 Hz, 2H), 3.86 (s, 3H), 2.58 (s, 3H). 13C NMR (CDCl3,
J¼7.3 Hz, 1H), 7.48e7.60 (m, 7H). 13C NMR (DMSO-d6, 101 MHz):
75 MHz): d 166.4, 162.6, 161.5, 160.0, 130.4, 129.9, 123.1 (q,
d
165.3, 160.7, 158.8, 138.7, 133.2, 131.8, 130.2, 129.2, 129.0, 128.60,
J¼273.8 Hz), 113.6, 111.4, 55.4, 22.0. 19F NMR (CDCl3, 376 MHz):
128.58, 128.4, 123.9 (q, J¼272.8 Hz), 110.8 (q, J¼27.8 Hz). 19F NMR
d
ꢂ56.2 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for C13H11F3N2O2
(DMSO-d6, 376 MHz):
d
ꢂ56.3 (CF3). HRMS (CI-TOF) m/z: Mþ Anal.
284.0773, found 284.0766.
Calcd for C17H11F3N2O 316.0823, found 316.0827.
4.3.9. 6-(3-Bromophenyl)-2-methyl-5-(trifluoromethyl)pyrimidin-
4(3H)-one (3i). White powder, 35% yield (58 mg), mp 203e205 ꢀC.
4.3.2. 2-Phenyl-6-(p-tolyl)-5-(trifluoromethyl)pyrimidin-4(3H)-one
(3b). White powder, 61% yield (101 mg), mp 269e271 ꢀC. 1H NMR
1H NMR (CDCl3, 400 MHz):
d 13.28 (s, 1H), 7.55e7.71 (m, 2H), 7.39
(DMSO-d6, 400 MHz):
d
13.49 (s, 1H), 8.15 (d, J¼6.6 Hz, 2H),
(d, J¼7.7 Hz, 1H), 7.32 (t, J¼7.8 Hz, 1H), 2.60 (s, 3H). 13C NMR (CDCl3,
7.39e7.69 (m, 5H), 7.30 (d, J¼7.0 Hz, 2H), 2.38 (s, 3H). 13C NMR
101 MHz): d 165.2,160.8,139.5,135.2,133.1,131.0,129.6,126.8,122.6
(DMSO-d6, 75 MHz):
d
165.2, 160.8, 158.4, 140.1, 135.8, 133.1, 131.8,
(q, J¼273.7 Hz), 122.2, 22.0. 19F NMR (CDCl3, 376 MHz):
d
ꢂ56.6
129.2, 128.94, 128.90, 128.7, 124.0 (q, J¼272.9 Hz), 110.5 (q,
(CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for C12H8F3N2OBr
J¼30.8 Hz), 21.4. 19F NMR (CDCl3, 282 MHz):
d
ꢂ56.6 (CF3). HRMS
333.9752, found 333.9754.
(EI-TOF) m/z: Mþ Anal. Calcd for C18H13F3N2O 330.0980, found
330.0987.
4.3.10. 2,6-Dimethyl-5-(trifluoromethyl)pyrimidin-4(3H)-one
(3j). White powder, 75% yield (72 mg), mp 130e131 ꢀC. 1H NMR
4.3.3. 6-(4-Methoxyphenyl)-2-phenyl-5-(trifluoromethyl)pyrimidin-
4(3H)-one (3c). White solid, 63% yield (109 mg), mp
(DMSO-d6, 400 MHz):
d
12.95 (s, 1H), 2.36 (q, J¼2.9 Hz, 3H), 2.30 (s,
3H). 13C NMR (DMSO-d6, 101 MHz):
d 165.2, 161.8, 159.5, 124.6 (q,
272.3e274.5 ꢀC. 1H NMR (DMSO-d6, 400 MHz):
d
13.45 (s, 1H), 8.20
J¼272.9 Hz), 110.6 (q, J¼29.3 Hz), 23.3, 21.6. 19F NMR (DMSO-d6,
(d, J¼7.5 Hz, 2H), 7.75e7.52 (m, 5H), 7.09 (d, J¼8.3 Hz, 2H), 3.87 (s,
3H). 13C NMR (DMSO-d6, 101 MHz): 164.4, 160.8, 158.2, 134.6, 132.6,
130.3, 129.4, 128.8, 128.7, 128.5, 128.4, 123.5 (q, J¼272.5 Hz), 55.3.
19F NMR (CDCl3, 376 MHz): ꢂ56.5 (CF3). HRMS (CI-TOF) m/z:
(MþH)þ Anal. Calcd for C18H13F3N2O2 347.1007, found 347.1003.
376 MHz):
C7H7F3N2O 192.0510, found 192.0508.
d
ꢂ56.3 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for
4.3.11. 6-Ethyl-2-methyl-5-(trifluoromethyl)pyrimidin-4(3H)-one
(3k). White solid, 73% yield (75 mg), mp 163e165 ꢀC. 1H NMR
(DMSO-d6, 400 MHz):
d 12.95 (s, 1H), 2.67e2.57 (m, 2H), 2.32 (s,
4.3.4. 6-(4-Bromophenyl)-2-phenyl-5-(trifluoromethyl)pyrimidin-
4(3H)-one (3d). White powder, 66% yield (130 mg), mp
3H), 1.15 (t, J¼7.5 Hz, 3H). 13C NMR (DMSO-d6, 101 MHz):
d 167.4,
162.1, 159.7, 124.6 (q, J¼273.1 Hz), 110.0 (q, J¼29.1 Hz), 29.4, 21.7,
251e253 ꢀC. 1H NMR (DMSO-d6, 400 MHz):
d
13.57 (s, 1H), 8.15 (d,
13.5. 19F NMR (DMSO-d6, 376 MHz):
d
ꢂ56.1 (CF3). HRMS (CI-TOF)
J¼7.0 Hz, 2H), 7.72 (d, J¼7.7 Hz, 2H), 7.68e7.40 (m, 5H). 13C NMR
m/z: (MþH)þ Anal. Calcd for C8H9F3N2O 207.0745, found 207.0743.
(DMSO-d6, 101 MHz):
d 164.1, 160.9, 159.0, 137.9, 133.2, 131.8, 131.5,
130.7, 129.2, 129.0, 123.9 (q, J¼273.0 Hz), 123.8. 19F NMR (CDCl3,
4.3.12. 6-Phenyl-4-(p-tolyl)-3-(trifluoromethyl)pyridin-2(1H)-one
(5a). White powder, 55% yield (91 mg), mp 223e224 ꢀC. 1H NMR
376 MHz):
d
ꢂ56.6 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for
C
17H10F3N2O 395.9908, found 395.9912.
(DMSO-d6, 400 MHz):
d
12.55 (s, 1H), 7.84 (d, J¼5.4 Hz, 2H), 7.66 (s,
1H), 7.15e7.62 (m, 6H), 6.46 (s, 1H), 2.37 (s, 3H). 13C NMR (CDCl3,
4.3.5. 6-(3-Methoxyphenyl)-2-phenyl-5-(trifluoromethyl)pyrimidin-
4(3H)-one (3e). White powder, 55% yield (95 mg), mp 226e228 ꢀC.
101 MHz): d 165.4,143.3,141.8, 141.0, 137.3,136.0,134.1, 133.9, 132.8,
132.4, 129.0 (q, J¼273.5 Hz), 26.0 19F NMR (CDCl3, 376 MHz):
1H NMR (DMSO-d6, 400 MHz):
d
13.55 (s, 1H), 8.16 (d, J¼7.4 Hz, 2H),
d
ꢂ56.6 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for C19H14F3NO
7.65 (t, J¼7.0 Hz, 1H), 7.56 (t, J¼7.3 Hz, 2H), 7.41 (t, J¼7.6 Hz, 1H),
329.1027, found 329.1024.
7.07e7.14 (m, 3H), 3.81 (s, 3H). 13C NMR (DMSO-d6, 101 MHz):
d
169.9, 165.4, 163.9, 144.7, 137.9, 136.5, 134.4, 133.9, 133.7, 128.6 (q,
4.3.13. 4-(2-Methoxyphenyl)-6-phenyl-3-(trifluoromethyl)pyridin-
2(1H)-one (5b). White powder, 58% yield (100 mg), mp
J¼273.1 Hz), 125.0, 124.9, 120.2, 118.9, 60.4. 19F NMR (CDCl3,
376 MHz):
C
d
ꢂ56.6 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for
194e196 ꢀC. 1H NMR (CDCl3, 400 MHz):
d 12.94 (s, 1H), 7.90 (s, 2H),
18H13F3N2O2 346.0929, found 346.0925.
7.50 (s, 3H), 7.40 (t, J¼7.5 Hz, 1H), 7.20 (d, J¼7.3 Hz, 1H), 7.04 (t,
J¼7.2 Hz, 1H), 9.97 (d, J¼8.3 Hz, 1H), 6.45 (s, 1H), 3.81 (s, 3H). 13
C
4.3.6. 2-Methyl-6-phenyl-5-(trifluoromethyl)pyrimidin-4(3H)-one
(3f). White powder, 63% yield (80 mg), mp 194e196 ꢀC. 1H NMR
NMR (CDCl3, 101 MHz): d 155.6, 152.8, 148.3, 131.9, 131.0, 130.0,
129.3, 129.2, 128.3, 127.9, 127.1, 123.5 (q, J¼273.7 Hz), 120.3, 110.7,
(DMSO-d6, 400 MHz):
d
13.21 (s, 1H), 7.49e7.43 (m, 3H), 7.42e7.38
165.3, 162.0,
108.2, 107.4 (q, J¼24.9 Hz), 55.5. 19F NMR (DMSO-d6, 376 MHz):
(m, 2H), 2.37 (s, 3H). 13C NMR (DMSO-d6, 101 MHz):
d
d
ꢂ55.1 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for C19H14F3NO2
159.8,138.6,129.9,128.3,128.26, 128.25, 123.8 (q, J¼272.9 Hz), 110.6
345.0977, found 345.0973.
(q, J¼29.4 Hz), 21.9. 19F NMR (CDCl3, 376 MHz):
ꢂ56.6 (CF3). HRMS
d
(EI-TOF) m/z: Mþ Anal. Calcd for C12H9F3N2O 254.0667, found
4.3.14. 4-(4-Bromophenyl)-6-phenyl-3-(trifluoromethyl)pyridin-
2(1H)-one (5c). White powder, 64% yield (126 mg), mp
254.0674.
255e256 ꢀC. 1H NMR (DMSO-d6, 400 MHz):
d 12.62 (s, 1H), 7.85 (d,
4.3.7. 2-Methyl-6-(p-tolyl)-5-(trifluoromethyl)pyrimidin-4(3H)-one
(3g). White powder, 57% yield (76 mg), mp 218e219 ꢀC. 1H NMR
J¼6.6 Hz, 2H), 7.67 (d, J¼8.1 Hz, 2H), 7.50e7.52 (m, 3H), 7.34 (d,
J¼8.1 Hz, 2H), 6.50 (s, 1H). 13C NMR (DMSO-d6, 101 MHz):
d 160.6,
(DMSO-d6, 400 MHz):
d
13.15 (s, 1H), 7.31 (d, J¼8.1 Hz, 2H), 7.26 (d,
154.5, 152.2, 138.2, 131.6, 131.3, 129.9, 129.3, 128.0, 124.2 (q,
J¼8.1 Hz, 2H), 2.36 (s, 6H). 13C NMR (DMSO-d6, 101 MHz):
d
165.2,
J¼273.3 Hz), 122.5. 19F NMR (DMSO-d6, 376 MHz):
d
ꢂ55.1 (CF3).
161.8, 160.1, 139.8, 135.7, 128.9, 128.45, 128.43, 124.0 (q, J¼272.9 Hz),
HRMS (CI-TOF) m/z: Mþ Anal. Calcd for C18H11F3NO 392.9976, found
110.3 (q, J¼30.9 Hz), 21.9, 21.4. 19F NMR (CDCl3, 376 MHz):
d
ꢂ56.6
392.9970.
(CF3). HRMS (EI-TOF) m/z: Mþ Anal. Calcd for C13H11F3N2O
268.0823, found 268.0828.
4.3.15. 4-Phenyl-6-(4-methoxyphenyl)-3-(trifluoromethyl)pyridin-
2(1H)-one (5d). White solid, 54% yield (93 mg), mp 243e245 ꢀC. 1H
4.3.8. 6-(4-Methoxyphenyl)-2-methyl-5-(trifluoromethyl)pyrimidin-
4(3H)-one (3h). White powder, 64% yield (91 mg), mp 173e174 ꢀC.
NMR (CDCl3, 400 MHz):
7.52e7.44 (m, 3H), 7.35e7.40 (m, 2H), 7.03 (d, J¼8.9 Hz, 2H), 6.44 (s,
1H), 3.90 (s, 3H). 13C NMR (CDCl3, 101 MHz):
166.1, 164.9, 160.0,
d
12.58 (s, 1H), 7.86 (d, J¼8.9 Hz, 2H),
1H NMR (CDCl3, 400 MHz):
d
13.30 (s, 1H), 7.50 (d, J¼8.2 Hz, 2H),
d

3254
P.-Z. Zhang et al. / Tetrahedron 72 (2016) 3250e3255
154.1, 143.5, 133.8, 132.8, 131.8, 130.0, 128.6 (q, J¼273.5 Hz), 119.0,
19.2, 13.8. 19F NMR (CDCl3, 376 MHz):
d
ꢂ61.1 (CF3). HRMS (CI-TOF)
111.0 (q, J¼30.2 Hz), 60.2. 19F NMR (DMSO-d6, 376 MHz):
d
ꢂ56.2
m/z: Mþ Anal. Calcd for C7H6F3NO 249.0613, found 249.0612.
(CF3). HRMS (CI-TOF) m/z: (MþH)þ Anal. Calcd for C19H14F3NO2
346.1055, found 346.1038.
4.3.23. Propyl-6-methyl-2-oxo-3-(trifluoromethyl)-1,2-
dihydropyridine-4-carboxylate (5l). White powder, 84% yield
4.3.16. 6-(4-Bromophenyl)-4-phenyl-3-(trifluoromethyl)pyridin-
2(1H)-one (5e). White powder, 62% yield (122 mg), mp
(110 mg), mp 178e179 ꢀC. 1H NMR (CDCl3, 400 MHz):
d 13.45 (s,
1H), 6.09 (s, 1H), 4.27 (t, J¼6.7 Hz, 2H), 2.43 (s, 3H), 1.82e1.69 (m,
268e269 ꢀC. 1H NMR (DMSO-d6, 400 MHz):
d
12.64 (s, 1H), 7.87 (d,
J¼5.1 Hz, 3H), 7.75e7.64 (m, 2H), 7.52e7.54 (m, 3H), 7.29e7.44 (m,
2H), 6.52 (s, 1H). 13C NMR (DMSO-d6, 101 MHz):
160.6, 154.5,
2H), 1.00 (t, J¼7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz):
d 166.1, 161.8,
151.8, 146.8 (q, J¼2.5 Hz), 122.5 (q, J¼272.6 Hz), 112.4 (q, J¼31.3 Hz),
d
103.9, 68.3, 21.6, 19.1, 10.2. 19F NMR (CDCl3, 376 MHz):
d
ꢂ61.1 (CF3).
138.2, 131.6, 131.3, 129.9, 129.4, 128.0, 124.2 (q, J¼273.3 Hz), 122.5.
HRMS (CI-TOF) m/z: Mþ Anal. Calcd for C7H6F3NO 249.0613, found
19F NMR (CDCl3, 282 MHz):
Anal. Calcd for C18H11F3NO 392.9976, found 392.9974.
d
ꢂ56.6 (CF3). HRMS (CI-TOF) m/z: Mþ
249.0612.
Acknowledgements
4.3.17. 4-(4-Methoxyphenyl)-6-(4-bromophenyl)-3-(trifluoromethyl)
pyridin-2(1H)-one (5f). White powder, 57% yield (121 mg), mp
J.-P.Z. specially thank the National Natural Science Foundation of
China (Nos. 20772088, 21172163, 21472133), the Priority Academic
Program Development of Jiangsu Higher Education Institutions &
State and Local Joint Engineering Laboratory for Novel Functional
Polymeric Materials for their financial support.
252e255 ꢀC. 1H NMR (DMSO-d6, 400 MHz):
d 12.59 (s, 1H), 7.85 (d,
J¼8.4 Hz, 2H), 7.74 (d, J¼8.6 Hz, 2H), 7.36 (d, J¼8.7 Hz, 2H), 7.06 (d,
J¼8.8 Hz, 2H), 6.59 (s, 1H), 3.84 (s, 3H). 13C NMR (DMSO-d6,
101 MHz):
d 160.3, 159.6, 155.0, 133.4, 131.8, 130.6, 130.2, 129.6,
128.9, 124.8 (q, J¼69.7 Hz), 124.4, 122.4, 113.6, 108.4 (q, J¼28.0 Hz),
55.2. 19F NMR (CDCl3, 376 MHz):
d
ꢂ56.6 (CF3). HRMS (CI-TOF) m/z:
Supplementary data
Mþ Anal. Calcd for C19H13BrF3NO2 423.0082, found 423.0093.
Supplementary data (Experimental procedures, characteriza-
tion data, and copies of the 1H NMR, 13C NMR and 19F NMR spectra
for the products are available) associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2016.04.048.
4.3.18. 4-(4-Bromophenyl)-6-(4-bromophenyl)-3-(trifluoromethyl)
pyridin-2(1H)-one (5g). White powder, 60% yield (141 mg), mp
245e247 ꢀC. 1H NMR (CDCl3, 400 MHz):
d 12.81 (s, 1H), 7.75 (d,
J¼8.7 Hz, 2H), 7.65 (d, J¼8.7 Hz, 2H), 7.60 (d, J¼8.4 Hz, 2H), 7.21 (d,
J¼8.4 Hz, 2H), 6.42 (s, 1H). 13C NMR (DMSO-d6, 101 MHz):
d 160.1,
153.8, 149.3, 137.6, 134.9, 131.8, 131.1, 130.5, 129.6, 129.4,124.5, 123.6
(q, J¼272.7 Hz), 122.0, 108.0 (q, J¼29.5 Hz). 19F NMR (CDCl3,
References and notes
376 MHz):
d
ꢂ56.7 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for
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C
18H10Br2F3NO 470.9081, found 470.9080.
4.3.19. 6-Methyl-3-(trifluoromethyl)pyridin-2(1H)-one (5h). White
powder, 79% yield (70 mg), mp 154e155 ꢀC. 1H NMR (DMSO-d6,
400 MHz):
d
12.32 (s, 1H), 7.80 (d, J¼7.4 Hz, 1H), 6.14 (d, J¼7.2 Hz,
1H), 2.25 (s, 3H). 13C NMR (DMSO-d6, 101 MHz):
d 159.7, 152.4,
140.8,124.2 (q, J¼279.6 Hz),115.3 (q, J¼31.3 Hz),103.6,18.7. 19F NMR
(DMSO-d6, 376 MHz):
d
ꢂ63.5 (CF3). HRMS (CI-TOF) m/z: Mþ Anal.
Calcd for C7H6F3NO 177.0401, found 177.0400.
4.3.20. 4-Phenyl-6-methyl-3-(trifluoromethyl)pyridin-2(1H)-one
(5i). White solid, 68% yield (86 mg), mp 197e198 ꢀC. 1H NMR
(CDCl3, 400 MHz):
d
13.55 (s, 1H), 7.51e7.41 (m, 3H), 7.35e7.29 (m,
162.3,
2H), 6.06 (s, 1H), 2.48 (s, 3H). 13C NMR (CDCl3, 101 MHz):
d
156.3,148.2,138.2,128.1,127.6,126.58,126.56, 123.0 (q, J¼274.7 Hz),
113.21 (q, J¼28.9 Hz), 109.2, 18.5. 19F NMR (CDCl3, 376 MHz):
d
ꢂ56.4 (CF3). HRMS (CI-TOF) m/z: (MþH)þ Anal. Calcd for
C
13H10F3NO 254.0793, found 254.0791.
4.3.21. 4-(4-Chlorophenyl)-6-methyl-3-(trifluoromethyl)pyridin-
2(1H)-one (5j). White powder, 65% yield (93 mg), mp 183e185 ꢀC.
1H NMR (DMSO-d6, 400 MHz):
d
12.41 (s, 1H), 7.51 (d, J¼8.2 Hz, 2H),
7.30 (d, J¼8.2 Hz, 2H), 5.96 (s, 1H), 2.25 (s, 3H). 13C NMR (DMSO-d6,
75 MHz):
d 160.0, 154.7, 150.4, 138.0, 133.7, 129.3, 128.7, 124.2 (q,
J¼273.3 Hz), 112.5 (q, J¼30.3 Hz), 107.7, 19.0. 19F NMR (CDCl3,
376 MHz):
d
ꢂ56.6 (CF3). HRMS (CI-TOF) m/z: Mþ Anal. Calcd for
C
13H9F3NOCl 287.0325, found 287.0323.
4.3.22. Ethyl-6-methyl-2-oxo-3-(trifluoromethyl)-1,2-
dihydropyridine-4-carboxylate (5k). White powder, 82% yield
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13.45 (s,
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J¼2.6 Hz), 122.4 (q, J¼272.7 Hz), 112.5 (q, J¼31.4 Hz), 103.9, 62.8,
d

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