Fluorinated β-diketo phosphorus ylides: Their cyclocondensation with amidines affording 4-trifluoromethyl- And 4-perfluoroalkyl-substituted pyrimidines

Article abstract of DOI:10.3987/COM-14-13075

A study is presented for the syntheses of a series of 4-trifluoromethyl- and 4-perfluoroalkyl-substituted pyrimidines from the reaction of trifluoromethyl or perfluoroalkyl β-diketo phosphorus ylides (Ph₃P=C(COR_F)COR) with amidine hydrochloride.

Full text of DOI:10.3987/COM-14-13075

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HETEROCYCLES, Vol. 89, No. 10, 2014
HETEROCYCLES, Vol. 89, No. 10, 2014, pp. 2334 - 2345. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 23rd August, 2014, Accepted, 24th September, 2014, Published online. 26th September, 2014
DOI: 10.3987/COM-14-13075
FLUORINATED -DIKETO PHOSPHORUS YLIDES: THEIR
CYCLOCONDENSATION WITH AMIDINES AFFORDING
4-TRIFLUOROMETHYL- AND 4-PERFLUOROALKYL-SUBSTITUTED
PYRIMIDINES
Ryosuke Saijo, Genki Watanabe, Ken-ichi Kurihara, and Masami Kawase*
Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho,
Matsuyama, Ehime 790-8578, Japan; E-mail: kawase@cc.matsuyama-u.ac.jp
Abstract – A study is presented for the syntheses of a series of 4-trifluoromethyl-
and 4-perfluoroalkyl-substituted pyrimidines from the reaction of trifluoromethyl
or perfluoroalkyl -diketo phosphorus ylides (Ph3P=C(CORF)COR) with amidine
hydrochloride.
INTRODUCTION
The pyrimidine ring has been known as an important framework in a large number of compounds having
pharmaceutical and agricultural applications.1 The heterocyclic core of pyrimidines is in general readily
accessible via a [3+3] fragment approach of amidines and substrates containing 1,3-dielectrophilic centers,
but methods are mostly related to the synthesis of nonfluorinated pyrimidines.1 Introduction of a
trifluoromethyl group and higher homologue CnF2n+1 substituents into a heterocycle frequently results in
compounds, which display more potent activity than the parent, probably due to the lipophilicity of the
perfluoroalkyl substituents.2 Thus, it would be very important to develop new efficient methodologies
CF3
N
CF3
N
CF3
N
CF3
N
O
CF3
N
Me
O
O
CO2Et
N
N
N
O
N
N
O
Ar
N
N
N
n-BuO
N
H
O
O
S
OH
H
H
O
SO2Me
Cruzain inhibitor4a
COX-2 inhibitor4b
Antiprolif erative
Fluacrypyrim4e
Human A-FABP
inhibitor4c
Inhibitor of AP-1 and
NF-B mediated
expression4d
Figure 1. Examples of biologically active 4-trifluoromethylpyrimidines

HETEROCYCLES, Vol. 89, No. 10, 2014
2335
for the preparation of fluorinated pyrimidines, which would be strongly expected to present new
bioactivities or functions (Figure 1).3
General methods for the preparation of these compounds involve the reactions of amidines with
trifluoromethylated precursors such as 1-trifluoromethylated 1,3-diketones,4a -unsaturated
trifluoromethyl ketones,4b enamino(trifluoromethyl)ketones,4c -trifluoroacetylpropanenitriles,4d and
-methoxyvinyl trifluoromethyl ketones.4e These 1,3-dielectrophiles are important precursors to the
trifluoromethylated pyrimidines, however, the availability of diversity substituted 1,3-diketones is limited.
Because pyrimidines are electron-deficient and generally low reactive in electrophilic substitution, the
trifluoromethylation afforded a trace amount of certain trifluoromethylated products.5 Till now, there
have been limited methodologies for the preparation of trifluoromethylated pyrimidines.6
One of the most attractive methods for the construction of these heterocyles is based on the use of easily
available fluorine-containing building blocks.2
Fluorinated -diketo phosphorus ylides (1),
-acyl--perfluoroacylmethylenetriphenylphosphorane, have been so far scarcely studied,7 despite the
fact that the ylides (1) should also be of interest as a novel synthone for CF3-heterocycles due to the ready
accessibility and the easy-to-handle compounds. Thus, the reactions of Ph3P=C(COCF3)COPh (1a) and
the related compounds with lithium reagents lead to the formation of fluorinated -unsaturated
ketones.7a Pyrolysis of 1a gives acetylenic ketones.7b
Owing to the increasing importance of trifluoromethyl-containing heterocycles in biology, pharmacology,
and industrial applications,2d we decided to investigate their reactions of the ylides (1) with amidines in
order to develop new syntheses of trifluoromethylated and perfluoroalkylated pyrimidines.
RESULTS AND DISCUSSION
The differently fluorinated compounds 1a-d, known compounds, were easily prepared in moderate to
good yields by the reaction of acyl ylides with perfluorinated anhydrides (Table 1).7
1a d
Table 1. Preparations of ylides ( - )
O
O
RF
R1
O
O
Et3N (4.4 equiv.)
solvent, rt
R1
Ph3P
Ph3P
RF
O
RF
O
-
(1.1 equiv.)
Br
1a-d
R1
Solvent
RF
Entry
Time (h)
Yields (%)
1
2
3
4
CF3
CF3
C2F5
C3F7
Ph
Me
Ph
Ph
THF
1
1a (81)
1b (73)
1c (46)
1d (46)
MeCN
THF
THF
24
24
24

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HETEROCYCLES, Vol. 89, No. 10, 2014
As listed in Table 2, 1a and acetamidine hydrochloride were used as the model substrates to optimize
reaction conditions including the temperature, solvents, bases, and catalysts under argon atmosphere.
Table 2. Optimization of reaction conditions
CF3
O
Me
NH
CF3
Ph
base ( equiv.), additive (0.2 equiv.)
x
N
Ph3P
HCl
NH2
1.2 eq
solvent
N
Ph
Me
O
1a
2a
Base (x equiv.) Additive
Solvent
Temp (°C) Time (h)
Yields of 2a (%)
Entry
NRa
20
23
37
47
48
58
47
14
NRa
17
18
60
61
63
49
47
58
41
56
53
51
56
62
57
43
56
67
66
62
56
69
CuBr
DMSO
DMSO
DMSO
xylene
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
AcONa (3)
DBU (3)
Cs2CO3 (3)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
80
5
5
1
1
1
1
1
5
9
1
5
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
3
CuBr
CuBr
CuBr
150
200
200
200
200
200
150
150
200
150
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
4
5
6
CuBr
CuBr
diglyme
diglyme
diglyme
DMF
ZnBr2
ZnBr2
ZnBr2
ZnBr2
-
7
8
9
DMF
diglyme
DMSO
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
-
ZnCl2
ZnI2
Zn(OAc)2
CuBr2
CuCl
CuI
Cu2O
CuOTf·PhH
Cu(OTf)2
Cu(OAc)2·H2O
MgBr2
MgI2
LiCl
TiCl4
AlCl3
CeCl3
FeCl3
Yb(OTf)3
Sc(OTf)3
BF3·OEt2
a no reaction

HETEROCYCLES, Vol. 89, No. 10, 2014
2337
At first, the effects of temperature were investigated in the presence of 3 equiv of Cs2CO3 and 0.2 equiv
of CuBr (entries 1-5). The temperature strongly influenced the yield. High temperature (200 °C) was
needed to obtain a good yield of 2a (entry 5). Various solvents such as DMSO, xylene, and diglyme
were tested (entries 3-5), the last one is the solvent of choice for the reaction (entry 5). Instead of
Cs2CO3 (entry 5), K2CO3 also gave the good result (entry 6). When the reaction was performed in the
presence of ZnBr2 instead of CuBr, 2a was obtained in a good yield (58%) (entry 7). Among various
bases such as K2CO3, AcONa, and DBU (entry 7-10), K2CO3 gave best results in the presence of ZnBr2
(entry 7). No pyrimidine was detected when organic base such as DBU was used (entry 10). The
product 2a was obtained in low yield or not at all in the absence of additives such as CuBr and ZnBr2
(entries 11 and 12). To further improve the yield, we have extensively screened various additives
(entries 13-32) in the presence of two equiv of K2CO3 and found that BF3 etherate was the best additive.
We conducted that the most efficient set of conditions employs 1.0 equiv of 1a, 1.2 equiv of acetamidine
hydrochloride, 2 equiv of K2CO3 and 0.2 equiv of BF3 etherate in diglyme at 200 °C (entry 32).
Next, the scope of the procedure with respect to other substrates was studied (Table 3). Under these
conditions, product 2b was obtained in 98% yield by treating 1a with benzamidine (entry 2). The
reaction with O-methylisourea afforded 2-methoxy- (2eA) and 2-hydroxypyrimidine (2eB) in low yields,
respectively (entry 5). 4-Pentafluoroethyl- (2g) and 4-heptafluoro-n-propylpyrimidine (2h) were
obtained in high yields, respectively (entries 7 and 8).
Table 3. Reactions with various amidines
RF
O
K2CO3 (2.0 equiv.)
BF3·OEt2 (0.2 equiv.)
R2
NH
RF
R1
N
Ph3P
HCl
diglyme, 200 °C
NH2
R2
N
R1
O
2a-h
1a-d
Entry
1
RF
R1
R2
Time (h)
Yields of 2 (%)
2a (69)
1
2
3
4
5a
6
7
8
a
a
a
a
a
b
c
Me
Ph
H
NH2
OMe
Ph
1
1
1
1
1
6
1
1
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C3F7
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
2b
(98)
2c (51)
2d (56)
2eA (21) b
2f
(84)
Ph
Ph
2g (91)
2h (83)
d
a Methylisourea was used as a H2SO4 salt .
b Plus 2eB (R2=OH, 18% yield)

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HETEROCYCLES, Vol. 89, No. 10, 2014
These reaction conditions are also suitable for cyclocondensation of 1a with cyclic amidines such as
2-aminobenzimidazole, 3-amino-1,2,4-triazole, and 3-aminopyrazole (Scheme 1). The reaction of 1a
with 2-aminobenzimidazole gave 4-phenyl-2-(trifluoromethyl)pyrimido[1,2-a]benzimidazole (3) in 66%
yield. The compound 3 has been previously prepared as one of the two regioisomers from the reaction
between 1,1,1-trifluoro-4-methoxy-4-phenylbut-3-en-2-one and 2-aminobenzimidazole.8
The reaction of 1a with 3-amino-1,2,4-triazole gave a mixture of 4a and 4b (2:3) in 56% yield, in which
the authentic 4b was prepared by the condensation of 4-ethoxy-1,1,1-trifluoro-4-phenylbut-3-en-2-one
and 3-amino-1,2,4-triazole.9
The reaction of 1a with 3-aminopyrazole gave a mixture of 5a and 5b (1:1) in 75% yield. The authentic
5a was alternatively prepared by the condensation of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (6) and
3-aminopyrazole.10
CF3
N
CF3
N
CF3
CF3
N
CF3
N
N
N
N
N
N
N
N
Ph
Ph
N
Ph
Ph
N
Ph
N
N
N
N
5a
4a
4b
5b
3
Scheme 1
6
Table 4. Reactions of 1-phenyl-4,4,4-trifluorobutan-1,3-dione ( ) with acetamidine
CF3
O
O
Me
NH
K2CO3 (2 equiv.), additive
diglyme
N
HCl
Ph
CF3
NH2
Me
N
Ph
6
2a
Acetamidine
HCl (equiv.)
Entry
Base (equiv.) Additive (equiv.)
Solvent
Temp (°C) Time (h)
Yields of 2a
NRa
NRa
NRa
NRa
3.2
2.3
1.0
1.0
1.2
1.2
NaOMe (1.0)
KOH (1.1)
-
MeOH
MeOH
DMF
1
2
3
4
5
80
30
22
24
12
1
-
80
NaOAc (1.0)
K2CO3 (2.0)
K2CO3 (2.0)
-
80
-
EtOH
100
200
BF3·OEt2 (0.2)
diglyme
a no reaction
Finally, we examined the reactions of 6 with acetamidine. Because reactions of 6 and amidines such as
guanidine derivatives, S-methylisothiourea, and 5-aminopyrazoles have been reported to afford the
corresponding trifluoromethylpyrimidines.4a However, the reactions with other amidines such as

HETEROCYCLES, Vol. 89, No. 10, 2014
2339
acetamidine and benzamidine were not reported. According to our observations, no reaction occurred
when acetamidine was heated under several reaction conditions with 6 (Table 4, entries 1-4). The
product 2a was obtained in only 3.2% yield (entry 5), when the reaction was performed under the same
conditions with 1a (Table 3, entry 1). In contrast, our results with 1a indicate the clear advantage of
using 1 (Table 3).
1
All the pyrimidines prepared were characterized by 13C and H NMR spectroscopy and mass
spectrometry. Products 2a,11 2b,4b 2d,11 2eA,12 2eB,13 2h,14 3,8 4b,9 and 5a10 have been described and
characterized previously, while compounds 2c, 2eB, 2f,15 2g, 4a, and 5b have not been characterized, or
are unknown compounds.
R1
HN
O
O
O
R2
NH
R2
H2N
R1
RF
R1
NH
Ph3P
O
Ph3P
Ph3P
NH
RF
Ph3P=O
N
R2
O
H
RF
-O
BF3
7
1
HO R1
N
O
R1
base
H
R1
NH
N
H2O
R2
RF
N
R2
RF
N
R2
RF
N
H
9
8
2
Scheme 2
Being two electrophilic centers in 1,3-positions, trifluoromethyl -diketo phosphorus ylides (1) can be
undergo cyclization reactions with 1,3-binucleophilic agents of amidines to pyrimidines 2. There have
been reports that these unsymmetrical 1,3-diketones react with water, alcohols, ethanethiol, pyrrolidine
and hydrazines to give the adducts at the COCF3 carbonyl.16 It is therefore likely that the reaction
proceeds via addition of amidines to the COCF3 carbonyl activated by the Lewis acidic BF3, as shown in
Scheme 2. The intermediate oxaphophetane 7 undergoes elimination of triphenylphosphine oxide to
give 8. Subsequent intramolecular cyclization of 7 affords dihydropyrimidine 9. One molecule of
water is then eliminated to give the aromatic pyrimidines 2.
In conclusion, we examined the scope and limitation of the cyclocondensation of fluorinated -diketo
phosphorus ylides 1 with amidines. The reaction was applicable to a wide range of amidines possessing
various substituents to give 2,6-disubstituted 4-trifluoromethylpyrimidines in good yields. Moreover,

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HETEROCYCLES, Vol. 89, No. 10, 2014
the method appears to be useful and convenient for construction of 4-perfluoroalkylpyrimidines in terms
of the ready accessibility of the starting materials, cheap reagents, and operational simplicity.
EXPERIMENTAL
All melting points were determined using a Yanagimoto hot-stage melting point apparatus and are
uncorrected.
tetramethylsilane (Me4Si) as an internal reference. 13C-NMR spectra were obtained on a Bruker
1H-NMR spectra were measured on Bruker AVANCE500 spectrometer with
1
13
AVANCE500 spectrometer (at 126 MHz). Both H- and C-NMR spectral data are reported in parts
per million () relative to Me4Si. 31P-NMR spectra were obtained on a Bruker AVANCE500
spectrometer (at 202 MHz) and were reported relative to external standard 85% aqueous phosphoric acid.
Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 spectrometer. Low- and high-resolution
MS were obtained with a JEOL JMS-GC mate II spectrometer with a direct inlet system at 70 eV and a
Bruker micrOTOF-Q mass spectrometer with methanol as the solvent. Elemental analyses were carried
out on a Yanaco CHN Corder MT-5 at the Integrated Center for Science, Ehime University. Standard
work-up means that the organic layers were finally dried over Na2SO4, filtered, and concentrated in vacuo
below 45 °C using a rotary evaporator.
General procedure for the preparation of -acyl--perfluoroacylmethylenetriphenylphosphoranes
(1): These compounds were prepared by employing the reported method17 with slight modifications.
To a suspension of a phosphonium salt (11.0 mmol) in THF (25 mL) was added triethylamine (48.4
mmol) at 0 °C, and the mixture was stirred for 30 min. To the mixture was added dropwise
perfluorinated anhydride (12.1 mmol), and the whole was stirred at rt for indicated time in Table 1. The
precipitate was filtered off, washed with cold THF (x 3), and the filtrate was evaporated. The residue
was triturated with water, and the insoluble material was collected by filtration, washed with water, and
dried in vacuo to give the product 1.
4,4,4-Trifluoro-1-phenyl-2-(triphenylphosphoranylidene)butane-1,3-dione (1a). Yellow crystals,
81% yield. mp 179–181 °C (MeOH) (mp18 182–183 °C). IR (KBr): 3063, 2357, 1643, 1577, 1561,
1440, 1264, 1200, 1169, 1131, 1108, 886, 750, 688, 507 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.36 (t,
J = 7.5 Hz, 2H, ArH), 7.47 (td, J = 7.8, 3.2 Hz, 7H, ArH), 7.57 (t, J = 7.4 Hz, 3H, ArH), 7.66 (d, J = 12.9
Hz, 3H, ArH), 7.68 (d, J = 13.0 Hz, 3H, ArH), 7.83 (d, J = 8.1 Hz, 2H, ArH) ppm. 31P NMR (202 MHz,
CDCl3) δ = 20.93 ppm. MS (EI) m/z: 476 (M+, 26), 129 (100).
1,1,1-Trifluoro-3-(triphenylphosphoranylidene)pentane-2,4-dione (1b).18 The solvent was MeCN
instead of THF. Pale yellow crystals, 73% yield. mp 138–140 °C (CHCl3/hexane). IR (KBr): 3465,
3058, 2921, 2363, 1580, 1561, 1484, 1441, 1273, 1192, 1178, 1133, 1106, 942, 755, 748, 688, 512 cm-1.
1H NMR (500 MHz, CDCl3) δ = 2.34 (s, 3H, CH3), 7.47 (td, J = 7.9, 3.2 Hz, 6H, ArH), 7.56 (tq, J = 7.5,

HETEROCYCLES, Vol. 89, No. 10, 2014
2341
2.0 Hz, 3H, ArH), 7.64 (dd, J = 13.0, 1.4 Hz, 3H, ArH), 7.65 (d, J = 13.0 Hz, 3H, ArH) ppm. 13C NMR
3
5
1
(126 MHz, CDCl3) δ = 30.2 (dq, JC-P = 5.5 Hz, JC-F = 4.5 Hz, CH3), 85.4 (d, JC-P = 106.8 Hz, C=P),
117.7 (qd, 1JC-F = 290.6 Hz, 3JC-P = 15.9 Hz, CF3), 124.8 (d, 1JC-P = 93.1 Hz, Ar), 128.9 (d, 2JC-P = 12.7 Hz,
Ar), 132.2 (d, 4JC-P = 2.8 Hz, Ar), 133.1 (d, 3JC-P = 10.0 Hz, Ar), 174.6 (qd, 2JC-F = 34.0 Hz, 2JC-P = 8.8 Hz,
2
COCF3), 194.2 (d, JC-P = 4.2 Hz, COCH3) ppm. 31P NMR (202 MHz, CDCl3) δ = 19.83 ppm. MS
(EI) m/z: 414 (M+, 43), 345 (100).
4,4,5,5,5-Pentafluoro-1-phenyl-2-(triphenylphosphoranylidene)pentane-1,3-dione (1c).19
Yellow
crystals, 46% yield. mp 171–173 °C (MeOH). IR (KBr): 3070, 1640, 1556, 1439, 1325, 1251, 1216,
1169, 1108, 1018, 881, 778, 748, 728, 716, 691, 518 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.36 (t, J =
7.8 Hz, 2H, ArH), 7.46 (td, J = 7.9, 3.2 Hz, 7H, ArH), 7.57 (td, J = 7.5, 1.9 Hz, 3H, ArH), 7.64 (dd, J =
13.0, 1.3 Hz, 3H, ArH), 7.65 (d, J = 13.2 Hz, 3H, ArH), 7.87 (dd, J = 8.3, 1.4 Hz, 2H, ArH) ppm. 13C
NMR (126 MHz, CDCl3) δ = 81.3 (d, 1JC-P = 99.2 Hz, C=P), 108.7 (tqd, 1JC-F = 269.1 Hz, 2JC-F = 36.7 Hz,
1
2
1
3JC-P = 12.6 Hz, CF2), 118.8 (qt, JC-F = 289.3 Hz, JC-F = 35.7 Hz, CF3), 123.8 (d, JC-P = 92.6 Hz, Ar),
128.1, 129.0 (d, 2JC-P = 12.7 Hz, Ar), 129.3, 132.0, 132.6 (d, 4JC-P = 3.7 Hz, Ar), 133.6 (d, 3JC-P = 10.3 Hz,
3
5
2
2
Ar), 142.2 (dt, JC-P = 5.5 Hz, JC-F = 2.8 Hz, Ar), 174.5 (td, JC-F = 24.6 Hz, JC-P = 5.3 Hz, COCF3),
192.1 (d, 2JC-P = 7.3 Hz, COPh) ppm. 31P NMR (202 MHz, CDCl3) δ = 21.08 ppm. MS (ESI) m/z: 527
[M+H]+. Anal. Calcd for C29H20F5O2P: C, 66.16; H, 3.83. Found: C, 65.99; H, 3.60; N, 0.17.
4,4,5,5,6,6,6-Heptafluoro-1-phenyl-2-(triphenylphosphoranylidene)hexane-1,3-dione (1d). Yellow
crystals, 46% yield. mp 147–149 °C (MeOH) (mp7b 143 °C). IR (KBr): 3085, 3066, 1652, 1577, 1557,
1439, 1335, 1259, 1223, 1208, 1111, 928, 885, 752, 716, 693, 517 cm-1. 1H NMR (500 MHz, CDCl3) δ
= 7.35 (t, J = 7.9 Hz, 2H, ArH), 7.45 (td, J = 7.9, 3.0 Hz, 7H, ArH),7.56 (td, J = 7.6, 1.9 Hz, 3H, ArH),
7.63 (dd, J = 13.0, 1.4 Hz, 3H, ArH), 7.65 (d, J = 12.9 Hz, 3H, ArH), 7.86 (dd, J = 8.5, 1.5 Hz, 2H, ArH)
ppm. 31P NMR (202 MHz, CDCl3) δ = 20.88 ppm. MS (EI) m/z: 576 (M+, 22), 407 (100).
General Procedure for Reaction of Fluorinated -diketo phosphorus ylides with various amidines
(2): To a stirred suspension of 1 (0.5 mmol), amidine (0.6 mmol), and K2CO3 (158 mg, 1.0 mmol) in
diglyme (2.5 mL) was added BF3·OEt2 (13 L, 0.1 mmol), and the mixture was heated at 200 °C for 1 h.
After cooling to rt, and work up with 5% aq NaOH (30 mL), the mixture was extracted with AcOEt (30
mL x 3). The combined organic layers were washed with brine, dried over anhyd Na2SO4, and
evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 18:1 to
2:1) to give 2.
2-Methyl-6-phenyl-4-(trifluoromethyl)pyrimidine (2a).11 Yellow oil, 82 mg, 69% yield. IR (neat):
3067, 1594, 1554, 1388, 1260, 1142, 879, 832, 765, 716, 693, 641, 450 cm-1. 1H NMR (500 MHz,
CDCl3) δ = 2.89 (s, 3H, CH3), 7.52–7.58 (m, 3H, ArH), 7.83 (s, 1H, H-5), 8.14 (dd, J = 7.8, 2.0 Hz, 2H,
ArH) ppm. MS (EI) m/z: 238 (M+, 100).

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2,6-Diphenyl-4-(trifluoromethyl)pyrimidine (2b). White crystals, 147 mg, 98% yield. mp 77–79 °C
(MeOH/H2O) (mp4b 83–84 °C). IR (KBr): 3067, 2972, 2927, 1591, 1460, 1380, 1286, 1166, 1028, 874,
848, 831, 778, 757, 715, 658, 633 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.53–7.59 (m, 6H, ArH), 7.90
(s, 1H, H-5), 8.27–8.28 (m, 2H, ArH), 8.63–8.65 (m, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3) δ =
109.9 (q, 3JC-F = 2.8 Hz, C-5), 120.9 (q, 1JC-F = 275.8 Hz, CF3), 127.5, 128.7, 128.7, 129.2, 131.6, 131.9,
136.0, 136.6, 156.8 (q, 2JC-F = 35.8 Hz, C-4), 165.4, 166.5 ppm. MS (EI) m/z: 300 (M+, 100).
6-Phenyl-4-(trifluoromethyl)pyrimidine (2c). Yellow crystals, 57 mg, 51% yield. mp 31–33 °C
(hexane). IR (KBr): 3077, 1598, 1393, 1305, 1263, 1200, 1172, 1143, 1062, 890, 766, 694, 634 cm-1.
1H NMR (500 MHz, CDCl3) δ = 7.53–7.60 (m, 3H, ArH), 8.03 (s, 1H, H-5), 8.16 (dd, J = 7.6, 1.6 Hz, 2H,
ArH), 9.39 (s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3) δ = 112.5 (q, 3JC-F = 2.6 Hz, C-5), 120.7 (q,
2
1JC-F = 275.7 Hz, CF3), 127.4, 129.3, 132.1, 135.4 156.2 (q, JC-F = 35.8 Hz, C-4), 159.4, 166.5 ppm.
MS (EI) m/z: 224 (M+, 13), 128 (100). HRMS (ESI) for C11H8F3N2 [M+H]+: Calcd, 225.0634. Found,
225.0630.
6-Phenyl-4-(trifluoromethyl)pyrimidin-2-amine (2d). White crystals, 67 mg, 56% yield. mp
128–129 °C (MeOH/H2O) (mp11 130–132 °C). IR (KBr): 3495, 3320, 3210, 1636, 1598, 1556, 1458,
1386, 1263, 1242, 1193, 1180, 1126, 997, 835, 773, 688, 648, 435 cm-1. 1H NMR (500 MHz, CDCl3) δ
= 5.35 (br s, 2H, NH2), 7.35 (s, 1H, H-5), 7.48–7.53 (m, 3H, ArH), 8.04 (dd, J = 7.9, 1.8 Hz, 2H, ArH)
ppm. 13C NMR (126 MHz, CDCl3) δ = 102.9 (q, 3JC-F = 2.9 Hz, C-5), 120.8 (q, 1JC-F = 275.7 Hz, CF3),
2
127.3, 129.0, 131.5, 136.2, 157.2 (q, JC-F = 35.3 Hz, C-4), 163.5, 168.2 ppm. MS (EI) m/z: 239 (M+,
100).
2-Methoxy-6-phenyl-4-(trifluoromethyl)pyrimidine (2eA). Yellow crystals, 27 mg, 21% yield. mp
39–40 °C (hexane) (mp12 47–48 °C). IR (KBr): 3003, 2962, 2928, 1601, 1551, 1480, 1396, 1362, 1258,
1196, 1148, 1042, 913, 869, 779, 698 cm-1. 1H NMR (500 MHz, CDCl3) δ = 4.16 (s, 3H, OCH3),
7.51–7.59 (m, 3H, ArH), 7.68 (s, 1H, H-5), 8.15 (dd, J = 8.0, 1.7 Hz, 2H, ArH) ppm. MS (EI) m/z: 254
(M+, 100).
2-Hydroxy-6-phenyl-4-(trifluoromethyl)pyrimidine (2eB). White crystals, 22 mg, 18% yield. mp
230–232 °C (CHCl3/hexane) (mp13 233–235 °C). IR (KBr): 3504, 3149, 3077, 2972, 1661, 1613, 1578,
1561, 1397, 1265, 1200, 1149, 1107, 1005, 773, 689 cm-1. 1H NMR (500 MHz, DMSO-d6) δ =
7.49–7.58 (m, 3H, ArH), 7.73 (br s, 1H, H-5), 8.13 (d, J = 7.5 Hz, 2H, ArH), 12.8 (br s, 1H, OH) ppm.
13C NMR (126 MHz, DMSO-d6) δ = 103.1, 120.4 (q, 1JC-F = 276.2 Hz, CF3), 127.6, 129.0, 132.2, 133.9,
157.9, 163.7, 167.3 ppm. MS (EI) m/z: 240 (M+, 100).
6-Methyl-2-phenyl-4-(trifluoromethyl)pyrmidine (2f).15 Yellow crystals, 100 mg, 84% yield. mp
54–56 °C (hexane). IR (KBr): 3042, 1597, 1401, 1375, 1243, 1186, 1143, 859, 763, 714, 968, 554 cm-1.
1H NMR (500 MHz, CDCl3) δ = 2.70 (s, 3H, CH3), 7.36 (s, 1H, H-5), 7.48–7.52 (m, 3H, ArH), 8.50–8.52

HETEROCYCLES, Vol. 89, No. 10, 2014
2343
3
1
(m, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3) δ = 24.7, 113.9 (q, JC-F = 2.5 Hz), 120.8 (q, JC-F
=
2
275.6 Hz, CF3), 128.6, 131.4, 136.5, 155.7 (q, JC-F = 35.5 Hz), 165.1, 170.1 ppm. MS (ESI) m/z: 239
[M+H]+. Anal. Calcd for C12H9F3N2: C, 60.51; H, 3.81; N, 11.76. Found: C, 60.62; H, 4.11; N, 11.56.
2,6-Diphenyl-4-(pentafluoroethyl)pyrimidine (2g). White crystals, 159 mg, 91% yield. mp
81–82 °C (MeOH). IR (KBr): 3076, 1587, 1575, 1545, 1384, 1371, 1332, 1212, 1198, 1164, 1152, 1009,
757, 735, 692 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.52–7.56 (m, 6H, ArH), 7.91 (s, 1H, H-5),
8.24–8.26 (m, 2H, ArH), 8.61–8.63 (m, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3) δ = 110.8 (tq,
1JC-F = 255.7 Hz, 2JC-F = 38.2 Hz, CF2), 111.3 (t, 3JC-F = 3.9 Hz, C-5), 118.8 (qt, 1JC-F = 287.3 Hz, 2JC-F
=
2
36.4 Hz, CF3), 127.5, 128.7, 128.8, 129.2, 131.6, 131.9, 136.0, 136.6, 156.8 (t, JC-F = 26.0 Hz, C-4),
165.1, 166.3 ppm. MS (ESI) m/z: 373 [M+Na]+. Anal. Calcd for C18H11F5N2: C, 61.72; H, 3.17; N,
8.00. Found: C, 61.83; H, 3.18; N, 7.87.
2,6-Diphenyl-4-(heptafluoropropyl)pyrmidine (2h). White crystals, 166 mg, 83% yield. mp
66–67 °C (MeOH) (mp14 85–86 °C). IR (KBr): 3067, 2980, 1589, 1574, 1547, 1374, 1342, 1230, 1207,
1196, 1185, 1114, 929, 735, 687 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.53–7.59 (m, 6H, ArH), 7.91 (s,
1H, H-5), 8.27–8.29 (m, 2H, ArH), 8.62–8.64 (m, 2H, ArH) ppm. MS (EI) m/z: 400 (M+, 68), 128
(100).
4-Phenyl-2-(trifluoromethyl)pyrimido[1,2-a]benzimidazole (3). Yellow crystals, 103 mg, 66% yield.
mp 190–192 °C (MeOH/H2O) (mp8 188 °C). IR (KBr): 3077, 3049, 3033, 1532, 1493, 1452, 1443,
1401, 1261, 1189, 1177, 1144, 1110, 1091, 831, 769, 740, 707, 702 cm-1. 1H NMR (500 MHz, CDCl3) δ
= 6.79 (d, J = 8.6 Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.14 (t, J = 7.5 Hz, 1H, ArH), 7.55 (t, J = 7,5 Hz, 1H,
ArH), 7.63 (d, J = 7.2 Hz, 2H, ArH), 7.70 (t, J = 7.8 Hz, 2H, ArH), 7.76 (t, J = 7.4 Hz, 1H, ArH), 8.07 (d,
3
J = 8.3 Hz, 1H, ArH) ppm. 13C NMR (126 MHz, CDCl3) δ = 103.4 (q, JC-F = 1.6 Hz, C-3), 115.1,
1
120.4 (q, JC-F = 276.6 Hz, CF3), 121.1, 122.6, 127.0, 128.1, 129.7, 131.5, 131.8, 145.7, 149.8, 151.7 (q,
2JC-F = 36.9 Hz), 151.9 ppm. MS (EI) m/z: 313 (M+, 100).
Mixture of 7-Phenyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (4a) and 5-Phenyl-
7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (4b). Pale yellow crystals, 296 mg, 56% yield
(from 2.0 mmol scale of 1a, 4a:4b = 2:3). mp 135–139 °C (4b: mp9 143–146 °C). IR (KBr): 3080,
1547, 1455, 1400, 1295, 1265, 1218, 1183, 1146, 987, 852, 771, 698, 625 cm-1. 1H NMR (500 MHz,
CDCl3) 4a: δ = 7.57 (s, 1H, H-6), 7.64–7.70 (m, 3H, ArH), 8.18 (dd, J = 8.0, 1.6 Hz, 2H, ArH), 8.72 (s,
1H, H-2) ppm. 4b: δ = 7.57–7.63 (m, 3H, ArH), 7.90 (s, 1H, H-6), 8.25 (dd, J = 7.8, 1.9 Hz, 2H, ArH),
8.64 (s, 1H, H-2) ppm. MS (EI) m/z: 264 (M+, 16.8), 83 (100).
Mixture of 7-Phenyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (5a) and 5-Phenyl-
7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (5b). Yellow crystals, 99 mg, 75% yield (5a:5b = 1:1).
mp 58–62 °C (5a: mp10 100 °C). IR (KBr): 3133, 3104, 3063, 1633, 1558, 1397, 1344, 1337, 1286,

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1277, 1261, 1230, 1195, 1162, 1141, 861, 770, 691, 624 cm-1. 1H NMR (500 MHz, CDCl3) 5a: δ = 6.98
(d, J = 2.4 Hz, 1H, H-3), 7.22 (s, 1H, H-6), 7.59–7.63 (m, 3H, ArH), 8.10–8.12 (m, 2H, ArH), 8.31 (d, J =
2.3 Hz, 1H, H-2) ppm. 5b: δ = 6.86 (d, J = 2.5 Hz, 1H, H-3), 7.50–7.53 (m, 3H, ArH), 7.60 (s, 1H, H-6),
8.08–8.10 (m, 2H, ArH), 8.25 (d, J = 2.4 Hz, 1H, H-2) ppm. MS (EI) m/z: 263 (M+, 100).
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