Trifluoroethoxy group as a leaving group for regioselective sequential substitution reactions of 5-trifluoromethylpyrimidine derivative with heteroatom nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2015.07.016

Highly regioselective substitution reaction of 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (TFEFP) with aniline derivatives smoothly proceeded firstly at the 2-postion. For the subsequent nucleophilic substitution at the 4-position with alkoxides, trifluoroethoxy group at the 4-position serves as a practically efficient leaving group.

Full text of DOI:10.1016/j.jfluchem.2015.07.016

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Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Trifluoroethoxy group as a leaving group for regioselective sequential
substitution reactions of 5-trifluoromethylpyrimidine derivative with
heteroatom nucleophiles
*
Takumi Kagawa , Daiki Shigehiro, Kosuke Kawada
Research Laboratory, TOSOH F-TECH, Inc., 4988 Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Highly regioselective substitution reaction of 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimi-
dine (TFEFP) with aniline derivatives smoothly proceeded firstly at the 2-postion. For the subsequent
nucleophilic substitution at the 4-position with alkoxides, trifluoroethoxy group at the 4-position serves
as a practically efficient leaving group.
Received 28 April 2015
Received in revised form 10 July 2015
Accepted 11 July 2015
Available online xxx
ß 2015 Elsevier B.V. All rights reserved.
Keywords:
Trifluoromethyl
Pyrimidine
2,2,2-Trifluoroethoxy
Regioselective
1. Introduction
regioselectivity in favor of substitution at the 2-position
[4,11,12,18]. On the other hand, many reports are indicating that
5-Trifluoromethylpyrimidine is often used as the key raw
material in the development of pharmaceutical products [1–10].
Many of these pharmaceutical products have different substitu-
ents at the 2- and the 4-positions on the pyrimidine ring. For the
sequential substitution reactions of 5-trifluoromethylpyrimidine
derivatives, 2,4-dichloro-5-trifluoromethylpyrimidine (CFP) has
been used as a readily available and reactive starting material.
However, contrary to a variety of 5-substituted 2,4-dichloropyr-
imidines, in the case of CFP as a starting material, the regioselec-
tivity in the nucleophilic substitution reactions is generally low. It
should be noted that lack of regioselectivity in CFP is an
exceptional substituent effect of trifluoromethyl group in the
nucleophilic substitution of 2,4-dichloropyrimidine derivatives as
summarized in Scheme 1.
Several examples for non-selective reactions of CFP with
alkylamines or anilines (typically in the presence of Et3N as a
base in CH3CN, EtOH or n-BuOH) [2,11–16] and with pyrazole
(K2CO3 as a base in CH3CON(CH3)2) [17] giving rise to an almost 1:1
mixture of 2-amino and 4-amino products can be shown from the
literature survey. It was also reported that the use of Lewis acids
such as ZnCl2 as an additive works nicely to improve the
similar nucleophilic substitution reactions of 2,4-dichloropyrimi-
dine having a variety of substituent at the 5-position typically such
as F, Cl, Br, I, CH3, CH3O, CN with amines and alcohols proceeded
selectively at the 4-position.
Together with the electronically negative nature of trifluor-
omethyl group, its steric bulkiness as compared with that of other
groups (F, Cl, Br, I, CH3, CH3O, CN) would be a major factor for the
lack of selectivity in CFP by blocking an approach of a negatively
charged nucleophile to the sterically hindered 4-position rather
than to the 2-position [12,19–21]. Additive effect of Lewis acid on
improvement of the selectivity at the 2-position in CFP can be
partly explained by the steric bulkiness of trifluoromethyl group at
the 5-position, which would work as steric hindrance toward an
approach of Lewis acid nearby, and thus as a result Lewis acid
would coordinate to N-1 or N-3 in CFP to enhance the reactivity of
C-2.
On the basis of these reported results and from our extensive
study we concluded that CFP is not an ideal intermediate to realize
a complete regioselectivity with a variety of nucleophiles. For
example, under the optimized conditions using lithium methoxide
(THF, 20 8C, 16 h) we obtained 2-methoxy-4-chloro isomer and
2-chloro-4-methoxy isomer in a ratio of 87.5:11.9 (%) along with
the formation of 2,4-dimethoxy derivative in 0.5%, respectively
(Scheme 2). With other alkoxides much lower regioselectivities
were the results. Although the major product, 2-methoxy-4-chloro
*
Corresponding author.
E-mail address: kagawa@f-techinc.co.jp (T. Kagawa).
http://dx.doi.org/10.1016/j.jfluchem.2015.07.016
0022-1139/ß 2015 Elsevier B.V. All rights reserved.
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Scheme 1. Reaction of CFP with lithium methoxide.
Cl
Cl
N
OMe
N
OMe
N
CF3
CF3
CF3
CF3
N
MeOLi
N
N
N
THF, 20 oC, 16.5 h
Cl
N
MeO
Cl
MeO
96% Conv. 2-OMe : 4-OMe : 2,4-(OMe)2 = 87.5 : 11.9 : 0.5
CFP
Scheme 2. Reaction of CFP with lithium methoxide.
isomer can be used to introduce the second nucleophile such as
aromatic amines or another lithium alkoxide into the 4-position
obtaining 2-methoxy-4-substituted 5-trifluoromethylpyrimidine
derivatives, the methoxy group at the 2-position in the products
does not work well as a leaving group (Scheme 3).
This fact indicates that the low reactivity of the methoxy group
in the final step brings about the limitation in the use of 2-
methoxy-4-chloro isomer and search for more appropriate leaving
group, which is maybe less reactive than chlorine atom but more
reactive than methoxy group is needed.
In this paper, we would like to report a highly efficient utility of
2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine
(TFEFP) 1 for the regioselective sequential substitutions at the 2-
and 4-positions with heteroatom nucleophiles. The requisite
starting material TFEFP 1 can be readily prepared by the reaction
of CFP with 2,2,2-trifluoroethoxylithium in 80% yield after the
purification by distillation (Scheme 4).
lower. For example, reaction of TFEFP 1 with aniline required a
certain Brønsted acid catalyst or the use of metal anilide form to
activate aniline itself. Among the Brønsted acid catalysts examined,
the results on using bis(phenylsulfonyl)imide BPSI and bis(trifluor-
omethanesulfonyl)imide (Tf2NH) TFSI, are summarized in Table 1.
Similar to aniline itself, aniline derivatives having electron-
donating group such as 4-toluidine, 2-toluidine and 4-anisidine
gave the desired regioselectively substituted products 3a–d in high
yields, although in the case of sterically hindered 2-toluidine long
reaction time was required (Runs 2–6). On the other hand, anilines
having electron-withdrawing group such as 4-cyano, 4-fluoro and
4-nitro derivatives retarded the progress of the reaction giving rise
to the product in low yield even with low conversion (Runs 7–9).
Except for the case of 4-fluoro derivative (Run 8), regioselectivities
were excellent, although high temperature, long reaction time and
substrate limitation are the issues to be solved from the view point
of practically useful level.
2.2. Reaction of TFEFP 1 with aniline derivatives 2 promoted by base
2. Results and discussion
As mentioned above, in the presence of acid catalysts reactions
of TFEFP 1 with aniline derivatives proceeded at the 2-position
regioselectively, but under the harsh conditions. To enhance the
nucleophilicity of anilines, metal anilide forms were examined.
Typical examples examined are summarized in Table 2.
2.1. Reaction of TFEFP 1 with aniline derivatives 2 in the presence of
Brønsted acid catalyst
As expected, compared to 2,4-dichloro derivative (CFP), reactivi-
ty of TFEFP 1 in the nucleophilic substitution reaction is somewhat
Scheme 3. Derivation of 4-chloro-2-methoxy-5-(trifluoromethyl)pyrimidine.
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Scheme 4. Preparation of TFEFP 1.
Table 1
Reaction of TFEFP 1 with aniline derivatives 2 in the presence of Brønsted acid catalyst.
.
Runa
2 R
Catalyst (10 mol%)
Solvent
Temp. (8C)
Time (h)
Conv. (%)b
Yield (%)b
Select. (%)c
3
4
1
2
3
4
5
6
7
8
9
H
TsOH
BPSId
BPSId
TFSIe
BPSId
BPSId
BPSId
TFSIe
TFSIe
Toluene
Cumene
Cumene
Cumene
Cumene
Cumene
Cumene
Cumene
Cumene
110
150
150
150
150
150
150
150
150
120
16
95
99
3a
3a
3b
3b
3c
3d
3e
3f
80
59
83
80
88
90
27
24
53
0
0
0
0
0
1
0
4
0
100
100
100
100
100
99
H
4-Me
4-Me
2-Me
4-MeO
4-CN
4-F
16
99
16
96
62
92
16
>99
73
112
112
112
100
86
64
4-NO2
59
3g
100
a
TFEFP 1 (0.50 g, 1.45 mmol), aniline 2 (1.3 equiv), acid catalyst (10 mol%), solvent (10 ml, 0.145 M).
b
c
Determined by 19F NMR of the reaction mixture with C6F6 as an internal standard.
In all cases, 2,4-disubstituted product 5 could not be observed. Selectivity shows the ratio (%) of 3 vs 3 + 4.
BPSI: bis(phenylsulfonyl)imide.
d
e
TFSI: bis(trifluoromethylsulfonyl)imide.
Table 2
Reaction of TFEFP 1 with aniline derivatives 2 promoted by base.
.
Runa
2 R
Base
Temp. (8C)
Time (h)
Conv. (%)b
Yield (%)b
Select. (%)c
3
4
1
2
3
4
5
6
7
8
H
n-BuLid
À80 8C ꢀ rt
À80 8C ꢀ rt
À80 8C ꢀ rt
rt
16
16
16
8
100
67
94
99
97
76
96
98
3a
3a
3a
3a
3b
3e
3f
0
45
93
99
90
63
95
92
0
2
1
0
0
1
0
0
–
96
e
f
H
n-BuLi/ZnCl2
n-BuLi/ZnCl2
Et2Zng
Et2Zng
H
99
H
100
100
98
4-Me
4-CN
4-F
À80 8C ꢀ rt
À80 8C ꢀ rt
À80 8C ꢀ rt
À80 8C ꢀ rt
16
16
16
24
f
n-BuLi/ZnCl2
Et2Zng
Et2Zng
100
100
4-(MeOCO)
3h
a
TFEFP 1 (0.50 g, 1.45 mmol), solvent (10 ml, 0.145 M).
Determined by 19F NMR of the reaction mixture with C6F6 as an internal standard.
b
c
d
e
f
In all cases, 2,4-disubstituted product 5 could not be observed. Selectivity shows the ratio (%) of 3 vs 3 + 4.
n-BuLi (1.0 equiv).
n-BuLi (1.0 equiv)/ZnCl2 (1.0 equiv).
n-BuLi (1.0 equiv)/ZnCl2 (2.2 equiv).
Et2Zn (2.2 equiv).
g
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Scheme 5. Reaction of TFEFP 1 with N-methylaniline.
Reaction of TFEFP 1 with lithium anilide generated in situ by
treating aniline with n-BuLi (1.0 equiv, 1.6 M hexane solution) in
THF at low temperature (dry-ice/acetone bath) resulted in a
complex mixture after stirring at room temperature for 16 h (Run
1). We found that addition of ZnCl2 to lithium anilide is effective for
the substitution reaction, in particular on using 2.2 equimolar
amount of ZnCl2 relative to lithium anilide reaction proceeded
smoothly at room temperature to give the desired product 3a in
high yield (93%) after 16 h (Runs 2 and 3). Furthermore, the use of
Et2Zn provided an excellent result to obtain the 2-anilinopyr-
imidine 3a as a sole product (Run 4). Although under the acid
catalyzed conditions aniline derivatives having electron-with-
drawing group gave poor results (see Table 1), Et2Zn worked very
nicely not only with 4-methyl derivative but also 4-fluoro and 4-
methoxycarbonyl derivatives (Runs 5, 7, 8). In all cases examined
disubstitution reactions at the 2- and 4-positions leading to the
products 5 were not observed.
It should be noted that the efficiency of Et2Zn was also found in
the reaction with N-methylaniline. As shown in Scheme 5, under
the acid catalyzed conditions (10 mol% TFSI) not only the
conversion (62%, after 112 h at 150 8C), but also the regioselectivity
(yield: 3i 41% vs 4i 8%) was far from a practical level. On the other
hand, on using Et2Zn (1.2 equiv) reaction proceeded completely in
THF at 60 8C for 24 h to give the desired product 3i in 95% yield,
while 4i in less than 1% yield (Scheme 5).
compared to chlorine in CFP, trifluoroethoxy group in TFEFP 1
served as an effective leaving group to achieve highly regioselec-
tive substitution reaction. As shown in Table 3, reaction of TFEFP 1
with lithium methoxide (1.0 equiv) in THF at room temperature for
21 h gave the 2-methoxy derivative 7a in 84% yield along with the
formation of 4-methoxy isomer 8a in 2% yield and 2,4-dimethoxy
product 9a was not detected (Run 1). In this case, selectivity for the
2-position was as high as 98%, while that in the case of the
dichloride CFP was found to be 87% as shown in Scheme 1. Likewise,
lithium phenylmethoxide,
a primary alkoxide, gave the 2-
substituted product 7b in 87% yield with excellent regioselectivity
(Run 2). Secondary and tertiary alkoxides gave the corresponding
products 7c–e in somewhat lower yields, but keeping the high
regioselectivities (Runs 3–5). It should be noted that again,
regioselectivity in the reaction of 5-bromo- and 5-iodo-2,4-
dichloropyrimidine with alkoxide is different from that of
trifluoromethyl derivative CFP. That is, these nucleophilic substi-
tution reactions were reported to proceed at the 4-position similar
to the cases of nitrogen nucleophiles [2].
As mentioned in Section 1 regioselectivity in the nucleophilic
substitution of CFP is generally low due to mainly steric effect of
bulky trifluoromethyl group at the 5-position blocking an
approach of nucleophiles on C-4 position.
2.4. Preparation of 4-alkoxy derivatives from 2-anilino-4-
trifluoroethoxy derivatives 3
2.3. Reaction of TFEFP 1 with lithium alkoxides
We developed a regioselective amination reaction of TFEFP 1 at
the 2-position under mild conditions by using ZnEt2 (see Table 2).
Further nucleophilic substitution of the trifluoroethoxy group at
Next we studied the regioselective introduction of alkoxy
functionality into TFEFP 1. It turned out immediately that
Table 3
Reaction of TFEFP 1 with lithium alkoxides.
.
Runa
6 ROLi
Time (h)
Conv.b (%)
Yield (%)b
7
Select. (%)c
8
1
2
3
4
5
MeOLi
21
4
99
99
84
94
82
7a
7b
7c
7d
7e
84
87
67
58
53
2
1
2
2
1
98
99
97
97
98
PhCH2OLi
i-PrOLi
2
c-C6H11OLi
tert-BuOLi
2
19
a
TFEFP 1 (0.50 g, 1.45 mmol), ROLi 6 (1.0 equiv) prepared from ROH and n-BuLi at 0 8C, THF (10 ml, 0.145 M).
Determined by 19F NMR of the reaction mixture with C6F6 as an internal standard.
b
c
In all cases, 2,4-disubstituted product 9 could not be observed. Selectivity shows the ratio (%) of 7 vs 7 + 8.
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Table 4
Preparation of 4-alkoxy derivatives from 2-anilino-4-trifluoroethoxy derivatives 3.
.
Runa
3
R
R’OM
Time (h)
Conv. (%)b
10
Yield (%)b
1
3b
3b
3b
3b
3b
3b
3a
3c
3d
3e
3f
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
H
PHCH2OLi
PhCH2ONa
PhCH2OK
MeOK
20
22
22
22
16
41
17
16
16
17
17
8
58
93
67
10
65
96
44
63
30
90
10b-1
10b-1
10b-1
10b-2
10b-3
10b-3
10a
6
47
66
48
5
2
3
4
5
i-PrOLi
6C
7
i-PrOLi
14
70
39
55
24
67
PhCH2OK
PhCH2OK
PhCH2OK
MeOK
8
2-Me
4-MeO
4-CN
4-F
10c
9
10d
10
11
10e
PhCH2OK
10f
a
The reaction of 3 (0.342 mmol) with R’OM (1.2 equiv) which were prepared from R’OH with corresponding 1.0 M metal salt of hexamethyldisilazane (1.2 equiv) solution in
THF at 0 8C, were performed in the corresponding solvent (2 ml, 0.145 M)
b
Determined by 19F NMR with hexafluorobenzene as an internal standard.
the 4-positon was conducted using 3b and alkoxide form of benzyl
alcohol as model reactions (Table 4). Reactivity of lithium and
sodium alkoxides were not enough, while potassium alkoxide
showed a reasonable reactivity to afford the desired product 10b-1
in 66% yield after stirring in THF at 65 8C for 22 h (Run 3 vs Runs 1,
2). Similarly, with potassium benzylalkoxide (primary alkoxide)
moderate yields of the desired products 10a–f were obtained (Runs
7–11). On the other hand, with potassium isopropoxide (secondary
alkoxide) reactivity of the trifluoroethoxy group at the 4-positon of
3b was not high enough to give the substitution product 10b-3 in
poor yield (Runs 5, 6; 5% in THF, 14% in THF–DMSO). In these cases,
addition of polar solvent (DMSO) accelerate the reaction (higher
conversion), but the product selectivity lowered.
4.2. Preparation of 2,4-bis(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine (TFEFP) 1
To a solution of 2,2,2-trifluoroethanol (5.99 g, 59.9 mmol) in THF
(85 ml), n-BuLi (1.6 M in hexane, 34.5 ml, 55.2 mmol) was added at
À2 8C and the mixture was held at the same temperature for 30 min.
After
2,4-dicholoro-5-(trifluoromethyl)pyrimidine
(5.00 g,
23.0 mmol) was added to the mixture at À20 8C, the whole was
then heated at 40 8C for 24 h. After the reaction was completed, the
reaction mixture was quenched with saturated NH4Cl (30 ml), and
concentrated under reduced pressure to remove most of THF. The
residue was extracted with CH2Cl2 (30 ml  3 times). The collected
organic layers were dried over Na2SO4 and then concentrated under
reduced pressure to obtain crude TFEFP 1. Purification of the crude 1
by distillation (bp = 118 8C/49 Torr.) gave pure TFEFP 1 as a colorless
oil (6.35 g, 18.5 mmol, 80%).
3. Conclusion
We found that TFEFP 1 can be used as a useful synthetic
intermediate for the sequential introduction of different sub-
stituents at the 2-position and the 4-position of 5-trifluoromethyl-
pyrimidine. That is, diethylzinc promoted reaction of TFEFP 1 with
aniline derivatives proceeded regioselectively at the 2-position in
high yields under mild reaction conditions. Further substitution
reactions at the 4-position could be achieved by using potassium
alkoxide of primary alcohols.
1H NMR (400 MHz, CDCl3):
J = 4.9 Hz, 2H), 4.85 (q, J = 4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
= 167.07, 165.00, 158.38 (q, J = 4.7 Hz), 122.99 (q, J = 275.8 Hz),
122.74 (q, J = 275.6 Hz), 122.28 (q, J = 269.4 Hz), 108.5 (q,
J = 34.7 Hz), 64.39 (q, J = 36.7 Hz), 63.39 (q, J = 37.2 Hz); 19F NMR
d = 8.60 (d, J = 0.8 Hz, 1H), 4.91 (q,
d
(376 MHz, CDCl3):
d
= À63.80, À74.82 (t, J = 7.5 Hz), À74.89 (t,
J = 7.5 Hz); EIMS (m/z) 344 (45, M+), 325 (58), 275 (100), 246 (93),
163 (90), 83 (95); Anal Calcd. for C9H5F9N2O2: C, 31.41; H, 1.46; N,
8.14. Found: C, 31.32; H, 1.46; N, 8.16.
4. Experimental
4.3. General procedure for the preparation of 3 in the presence of acid
4.1. General
catalyst
2,4-Dichloro-5-(trifluoromethyl)pyrimidine used in this study
is a commercial product of Tosoh F-tech. All other chemicals and
solvents were purchased commercially and used without further
purification.
The 1H, 19F, and 13C NMR spectra were recorded on BRUKER
AVANCE 400 spectrometer. 1H NMR spectra were obtained using
chloroform-d as the solvent with tetramethylsilane as an internal
standard. 19F NMR spectra were recorded in chloroform-d using
C6F6 as an internal standard unless otherwise noted. Mass spectra
(EIMS) were obtained with SHIMADZU GC-MS-QP2010 PLUS
spectrometer.
A solution of TFEFP 1 (500 mg, 1.45 mmol), aniline derivative 2
(1.3 equiv.) and acid catalyst (10 mol%) in toluene or cumene
(10 ml) was heated at 110 8C or 150 8C for 16–120 h. The reaction
mixture was cooled to room temperature and passed through a
short silica–gel column (eluent: CH2Cl2) to give crude 3 after
evaporation of solvent under reduced pressure. At this stage, the
conversion of TFEFP 1, yield of 3 and the selectivity of 3 were
determined by 19F NMR of the crude 3 using C6F6 as an internal
standard. After purification of crude 3 by thin layer chromatogra-
phy on silica–gel (hexane/AcOEt = 8/2), pure 3 was obtained as a
solid.
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4.3.1. 2-Phenylamino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3a
4.3.6. 2-(4-Fluorophenyl)amino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3f
Pale yellow solid (66% isolated yield: Run 1 in Table 1); 1H NMR
Colorless solid (15% isolated yield: Run 8 in Table 1); 1H NMR
(400 MHz, CDCl3):
7.38 (t, J = 8.0 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H), 4.83 (q, J = 8.1 Hz, 2H);
13C NMR (100 MHz, CDCl3):
= 165.34, 161.10, 157.61 (q,
d
= 8.46 (d, J = 0.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H),
(400 MHz, CDCl3):
7.25 (brs, 1H), 7.08 (dd, J = 9.4, 8.2 Hz, 2H), 4.81 (q, J = 8.1 Hz, 2H);
13C NMR (100 MHz, CDCl3):
= 165.39, 161.25, 159.85 (d,
d = 8.45 (d, J = 0.4 Hz, 1H), 7.60–7.40 (m, 2H),
d
d
J = 4.6 Hz), 137.94, 129.30, 124.67, 123.18 (q, J = 268.4 Hz),
123.00 (q, J = 275.9 Hz), 120.98, 102.96 (q, J = 32.8 Hz), 62.60 (q,
J = 242.9 Hz), 157.71 (q, J = 4.7 Hz), 133.88 (d, J = 3.0 Hz), 123.18
(d, J = 7.0 Hz), 123.02(q, J = 268.0 Hz), 122.97 (q, J = 275.9 Hz),
116.04 (d, J = 23.0 Hz), 103.07 (q, J = 33.4 Hz), 62.53 (q, J = 36.8 Hz);
J = 36.8 Hz); 19F NMR (376 MHz, CDCl3):
d
= À63.10, À74.90 (t,
J = 8.1 Hz); EIMS (m/z)337 (58, M+), 336 (100), 318 (8), 296(12), 195
(16), 180 (34), 77(52); AnalCalcd. for C13H9F6N3O:C, 46.30; H, 2.69;
N, 12.46. Found: C, 46.21; H, 2.69; N, 12.45.
19F NMR (376 MHz, CDCl3):
d
= À63.19, À74.94 (t, J = 7.5 Hz),
À118.89; EIMS (m/z) 355 (87, M+), 354 (100), 336 (15), 314 (15),
286 (6), 178 (10), 95 (25); Anal Calcd. for C13H8F7N3O: C, 43.96; H,
2.27; N, 11.83. Found: C, 43.85; H, 2.27; N, 11.80.
4.3.2. 2-(4-Methylphenyl)amino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3b
4.3.7. 2-(4-Nitrophenyl)amino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3 g
Colorless solid (71% isolated yield: Run 3 in Table 1); 1H NMR
(400 MHz, CDCl3):
2H), 7.19 (d, J = 8.0 Hz, 2H), 4.81 (q, J = 8.1 Hz, 2H), 2.35 (s, 3H); 13
NMR (100 MHz, CDCl3): = 165.31, 161.25, 157.72 (q, J = 4.6 Hz),
d
= 8.43 (s, 1H), 7.80 (brs, 1H), 7.38 (d, J = 7.6 Hz,
Yellow solid (43% isolated yield: Run 9 in Table 1); 1H NMR
C
(400 MHz, CDCl3):
J = 9.2 Hz, 2H), 7.55 (brs, 1H), 4.88 (q, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6): = 165.97, 161.85, 159.28 (q, J = 4.4 Hz),
d = 8.58 (s, 1H), 8.28 (d, J = 9.2 Hz, 2H), 7.79 (d,
d
135.25, 134.53, 129.83, 123.12 (q, J = 269.1 Hz), 123.03 (q,
J = 275.9 Hz), 121.24, 102.69 (q, J = 39.0 Hz), 61.98 (q,
d
146.85, 143.19, 124.89 (q, J = 275.8 Hz), 122.36, 120.76, 120.51 (q,
J = 268.2 Hz), 103.54 (q, J = 35.1 Hz), 63.99 (q, J = 35.2 Hz); 19F NMR
J = 36.8 Hz), 21.07; 19F NMR (376 MHz, CDCl3):
d
= À63.07,
À74.92 (t, J = 7.5 Hz); EIMS (m/z) 351 (70, M+), 350 (100), 332
(5), 282 (2), 267 (5); Anal Calcd. for C14H11F6N3O: C, 47.87; H, 3.16;
N, 11.96. Found: C, 47.83; H, 3.16; N, 11.94.
(376 MHz, CDCl3):
d
= À62.24, À73.55 (t, J = 7.5 Hz); EIMS (m/z)
382 (72, M+), 381 (100), 366 (5), 352 (26), 335 (32), 253 (21), 225
(11); Anal Calcd. for C13H8F6N4O3: C, 40.85; H, 2.11; N,
14.66. Found: C, 40.81; H, 2.11; N, 14.61.
4.3.3. 2-(2-Methylphenyl)amino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3c
4.4. Reaction of TFEFP 1 with lithium anilide
Colorless solid (78% isolated yield: Run 5 in Table 1); 1H NMR
(400 MHz, CDCl3):
7.63 (d, J = 7.6 Hz, 1H), 7.30–7.20 (m, 2H), 7.20–7.10 (m, 1H), 4.72
(q, J = 8.1 Hz, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
= 8.38 (d, J = 0.4 Hz, 1H), 8.00–7.20 (brs, 1H),
To asolutionof aniline (176 mg,1.89 mmol) inTHF (10 ml), n-BuLi
(1.6 M solution in hexane, 1.18 ml, 1.89 mol) was added at À78 8C,
and the mixture was held at the same temperature for 30 min. And
then TFEFP 1 (500 mg, 1.45 mmol) was added to the solution and the
whole was stirred at room temperature. After the consumption of
TFEFP 1 (reaction time: 16 h), the reaction mixture was quenched
with saturated NH4Cl (30 ml), and concentrated under reduced
pressure to remove most of THF. The residue was extracted with
CH2Cl2 (30 ml  3 times). The collected organic layers were dried
over Na2SO4, concentrated under reduced pressure. The residue was
analyzed by 19F NMR, but the target product 3a was not detected.
d
= 165.39 (d, J = 0.9 Hz), 161.92, 157.77 (q, J = 4.6 Hz), 135.91,
131.43, 130.99, 126.78, 126.07, 124.40, 123.16 (q, J = 268.2 Hz),
123.02 (q, J = 275.8 Hz), 102.58 (q, J = 34.4 Hz), 62.33 (q,
J = 36.8 Hz), 18.06; 19F NMR (376 MHz, CDCl3):
d
= À62.99,
À74.93 (t, J = 9.4 Hz); EIMS (m/z) 351 (66, M+), 350 (21), 336
(100), 296 (7), 268 (45), 248 (22), 131 (30); Anal Calcd. for
C
14H11F6N3O: C, 47.87; H, 3.16; N, 11.96. Found: C, 47.72; H, 3.15;
N, 11.95.
4.3.4. 2-(4-Methoxylphenyl)amino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3d
4.5. General procedure for the preparation of 3 using ZnCl2 and
lithium anilide
Colorless solid (83% isolated yield: Run 6 in Table 1); 1H NMR
(400 MHz, CDCl3):
J = 9.2 Hz, 2H), 4.78 (q, J = 8.3 Hz, 2H), 3.82 (s, 3H); 13C NMR
(100 MHz, CDCl3): = 165.33, 161.53, 157.66 (q, J = 4.4 Hz,),
157.07, 130.77, 123.43, 123.15 (q, J = 268.1 Hz), 123.03 (q,
J = 276.0 Hz), 114.46, 102.43 (q, J = 31.0 Hz), 62.42 (q,
d
= 8.39 (s, 1H), 7.37 (d, J = 7.6 Hz, 2H), 6.92 (d,
To a solution of aniline derivative (1.45 mmol or 3.19 mmol) in
THF (10 ml), n-BuLi (1.6 M solution in hexane, 0.91 ml or 1.99 ml,
1.45 mmol or 3.19 mmol) was added at À80 8C, and the mixture was
held for 30 min. After ZnCl2 (0.5 M in THF, 2.90 ml or 6.38 ml,
1.45 mmol or 3.19 mmol) was added to the lithium anilide solution
at À80 8C, the mixture was held for 1 h to generate the zinc salt of
aniline derivative. To the zinc anilide solution, TFEFP 1 (500 mg,
1.45 mmol) was added and the mixture held at À80 8C for 1 h, then
at room temperature for 16 h. After the reaction was completed, the
reaction mixture was quenched with saturated NH4Cl (30 ml), and
concentrated under reduced pressure to remove most of THF. The
residue was extracted with CH2Cl2 (30 ml  3 times). The collected
organic layers were dried over Na2SO4 and then concentrated under
reduced pressure to obtain crude 3. At this stage, conversion of
d
J = 36.8 Hz), 55.67; 19F NMR (376 MHz, CDCl3):
d
= À62.97,
À74.90 (t, J = 7.7 Hz); EIMS (m/z) 367 (100, M+), 352 (90), 324
(11), 283 (1), 241 (7), 221 (12); Anal Calcd. for C14H11F6N3O2: C,
45.79; H, 3.02; N, 11.44. Found: C, 45.71; H, 3.01; N, 11.42.
4.3.5. 2-(4-Cyanophenyl)amino-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 3e
Colorless solid (18% isolated yield: Run 3 in Table 1); 1H NMR
(400 MHz, CDCl3):
J = 8.4 Hz, 2H), 7.45 (brs, 1H), 4.87 (q, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): = 165.37, 160.23, 157.75 (q, J = 4.7 Hz), 142.24,
d = 8.55 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.67 (d,
TFEFP 1, yield of 3 and the selectivity of 3 were determined by 19
NMR of the crude 3 using C6F6 as an internal standard.
F
d
133.54, 122.84 (q, J = 276.0 Hz), 122.70 (q, J = 267.2 Hz), 118.70,
106.82, 140.79 (q, J = 267.2 Hz), 62.85 (q, J = 37.0 Hz); 19F NMR
4.6. General procedure for the preparation of 3 in the presence of
(376 MHz, CDCl3):
d
= À63.45, À74.84 (t, J = 7.5 Hz); EIMS (m/z)
Et2Zn
362 (58, M+), 361 (100), 343 (9), 321 (11), 294 (5), 279 (6), 259 (11),
116 (11), 102 (26); Anal Calcd. for C14H11F6N3O: C, 46.42; H, 2.23;
N, 15.47. Found: C, 46.39; H, 2.22; N, 15.45.
To a solution of aniline derivative (3.19 mmol) in THF (10 ml),
Et2Zn (1.0 M solution in THF, 3.19 ml, 3.19 mmol) was added at
Please cite this article in press as: T. Kagawa, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.07.016

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7
À80 8C or room temperature, and the mixture was stirred for
30 min. After TFEFP 1 (500 mg, 1.45 mmol) was added, the
reaction mixture was stirred at room temperature for 8–24 h.
After the reaction was completed, the reaction mixture was
quenched with saturated NH4Cl (30 ml), and concentrated under
reduced pressure. The residue was extracted with CH2Cl2
(30 ml  3 times). The collected organic layers were dried over
Na2SO4 and then concentrated under reduced pressure to obtain
crude 3. At this stage, conversion of TFEFP 1, yield of 3 and the
selectivity of 3 were determined by 19F NMR using C6F6 as an
internal standard.
4.7.2. 2-Benzyloxy-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 7b
White solid (75% isolated yield: Run 2 in Table 3); 1H NMR
(400 MHz, CDCl3):
5.47 (s, 2H), 4.85 (q, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
= 166.58, 166.28, 158.45 (q, J = 4.7 Hz), 135.52, 128.84, 128.73,
d = 8.58 (d, J = 0.8 Hz, 1H), 7.47–7.34 (m, 5H),
d
128.40, 122.82 (q, J = 275.2 Hz), 122.58 (q, J = 269.2 Hz), 106.49 (q,
J = 34.5 Hz), 70.60, 63.01 (q, J = 37.0 Hz); 19F NMR (376 MHz,
CDCl3):
d
= À63.71, À75.03 (t, J = 7.5 Hz); EIMS (m/z) 352 (10, M+),
351 (8), 269 (7), 246 (35), 107 (6), 91 (100), 65 (21); Anal Calcd for
C14H10F6N2O2: C, 47.74; H, 2.86; N, 7.95. Found: C, 47.62; H, 2.87;
N, 7.93.
4.6.1. 2-(4-Methoxycarbonylphenyl)amino-4-(2,2,2-
trifluoroethoxy)-5-(trifluoromethyl)pyrimidine 3h
4.7.3. 2-iso-Propoxy-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 7c
White solid (74% isolated yield: Run 8 in Table 2); 1H NMR
(400 MHz, CDCl3):
2.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.61 (brs, 1H), 4.86 (q, J = 8.0 Hz,
2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3):
= 166.74, 165.35,
d
= 8.52 (d, J = 4.0 Hz, 1H), 8.06 (dd, J = 6.8,
Colorless oil (62% isolated yield: Run 3 in Table 3); 1H NMR
(400 MHz, CDCl3):
6.3 Hz, 1H), 4.90 (q, J = 8.1 Hz, 2H), 1.42 (d, J = 6.4 Hz, 6H); 13C NMR
(100 MHz, CDCl3): = 166.52, 166.11, 158.43 (q, J = 4.7 Hz), 122.89
d = 8.55 (d, J = 0.8 Hz, 1H), 5.35 (hep, J = 6.4,
d
160.52, 157.76 (q, J = 4.6 Hz), 142.3, 121.11, 125.52, 122.90 (q,
J = 276.0 Hz), 122.82 (q, J = 268.7 Hz), 119.24, 104.2 (q, J = 34.7 Hz),
62.80 (q, J = 37.0 Hz), 52.29; 19F NMR (376 MHz, CDCl3):
À74.86 (t, J = 9.4 Hz); EIMS (m/z) 395 (36, M+), 394 (50), 364 (30),
336 (5), 253 (8), 28 (100); Anal Calcd for C15H11F6N3O3: C, 45.58; H,
2.81; N, 10.63. Found: C, 45.41; H, 2.80; N, 10.61.
d
(q, J = 275.7 Hz), 122.69 (q, J = 268.7 Hz), 105.83 (q, J = 34.0 Hz),
72.58, 62.89 (q, J = 37.0 Hz), 21.75; 19F NMR (376 MHz, CDCl3):
d
= À63.0,
d
= À63.30, À74.82 (t, J = 9.4 Hz); EIMS (m/z) 304 (2, M+), 289 (12),
263 (94), 246 (100), 243 (27), 223 (16), 193 (35), 164 (28), 136 (33),
83 (23); Anal Calcd for C10H10F6N2O2: C, 39.48; H, 3.31; N,
9.21. Found: C, 39.42; H, 3.31; N, 9.19.
4.6.2. 2-N-Methylphenylamino-4-(2,2,2-trifluoroethoxy)-5-(trifluoro
methyl)pyrimidine 3i
4.7.4. 2-cyclo-Hexyloxy-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 7d
Yellow solid (52% isolated yield: in Scheme 4 in the case of using
Et2Zn);1HNMR(400 MHz, CDCl3):
d
= 8.38(s, 1H), 7.45–7.40(m, 2H),
7.31–7.22 (m, 3H), 4.64 (brs, 2H), 3.55 (s, 3H); 13C NMR (100 MHz,
CDCl3): = 164.64, 162.50, 157.52 (q, J = 4.6 Hz), 144.31, 129.40,
Colorless oil (52% isolated yield: Run 4 in Table 3); 1H NMR
(400 MHz, CDCl3):
4.87 (q, J = 8.1 Hz, 2H), 2.07–1.27 (m, 10H); 13C NMR (100 MHz,
CDCl3): = 166.53, 166.12, 158.38 (q, J = 4.7 Hz), 122.89 (q,
d = 8.54 (d, J = 0.8 Hz, 1H), 5.12–5.02 (m, 1H),
d
127.03, 126.69, 123.52 (q, J = 267.9 Hz), 123.11 (q, J = 276.0 Hz),
10.53 (q, J = 34.1 Hz), 61.91 (q, J = 36.6 Hz), 38.97; 19F NMR
d
J = 275.7 Hz), 122.69 (q, J = 268.9 Hz), 105.79 (q, J = 34.4 Hz),
77.55, 62.90 (q, J = 37.0 Hz), 31.62, 25.49, 23.98; 19F NMR
(376 MHz, CDCl3):
d
= À62.68, À74.90; EIMS (m/z) 351 (72, M+),
350 (100), 332 (20), 268 (17), 248 (22), 106 (59), 77 (66); Anal Calcd
for C14H11F6N3O: C, 47.87; H, 3.16; N, 11.96. Found: C, 47.71; H, 3.16;
N, 11.92.
(376 MHz, CDCl3):
d
= À63.55, À74.99 (t, J = 8.1 Hz); EIMS (m/z)
263 (100), 247 (21), 246 (20), 243 (16), 223 (7), 83 (22); Anal Calcd
for C13H14F6N2O2: C, 45.52; H, 4.10; N, 8.14. Found: C, 45.31; H,
4.11; N, 8.12.
4.7. General procedure for the preparation of 7
4.7.5. 2-tert-Butoxy-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 7e
To a solution of the alcohol (1.45 mmol) in THF (10 ml), n-BuLi
(1.6 M solution in hexane, 0.91 ml, 1.45 mmol) was added at
À80 8C, and the mixture was held for 30 min. After TFEFP 1
(500 mg, 1.45 mmol) was added to the mixture, the mixture was
stirred at À80 8C for 1 h, and then at room temperature for 2–21 h.
After the reaction was completed, the reaction mixture was
quenched with saturated NH4Cl (30 ml), and concentrated under
reduced pressure. The residue was extracted with CH2Cl2
(30 ml  3 times). The collected organic layer was dried over
Na2SO4, concentrated under reduced pressure to obtain crude 7. At
this stage, conversion of TFEFP 1, yield of 7, and the selectivity of 7
were determined by 19F NMR using C6F6 as an internal standard.
Purification of crude 7 by thin layer chromatography on silica–
gel (hexane/AcOEt = 8/2) gave pure 7.
Colorless oil (43% isolated yield: Run 5 in Table 3); 1H NMR
(400 MHz, CDCl3):
d
= 8.54 (d, J = 0.8 Hz, 1H), 4.85 (q, J = 8.1 Hz,
= 166.12 (q,
2H), 1.66 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
J = 1.3 Hz), 165.96, 158.06 (q, J = 4.7 Hz), 122.91 (q, J = 275.5 Hz),
122.79 (q, J = 268.7 Hz), 105.51 (q, J = 34.5 Hz), 69.03, 62.98 (q,
J = 36.9 Hz), 28.30; 19F NMR (376 MHz, CDCl3):
(t, J = 9.4 Hz); EIMS (m/z) 303(4), 263 (91), 243 (15), 223 (8), 83 (9),
57 (100); Anal Calcd for C11H12F6N2O2: C, 41.52; H, 3.80; N,
8.80. Found: C, 41.63; H, 3.81; N, 8.78.
d
= À63.70, À74.87
4.8. General procedure for the preparation of 10
To a solution of the alcohol (0.342 mmol) in THF (2 ml), metal–
HMDS (1.0 M solution in THF, 0.40 mmol) was added at 0 8C, and
the mixture was stirred for 30 min. After 3 (0.285 mmol) was
added to the mixture, the mixture was stirred at 0 8C for 1 h and
then at 65 8C for 3 to 41 h. After the reaction was completed, the
reaction mixture was quenched with saturated NH4Cl (30 ml), and
concentrated under reduced pressure. The residue was extracted
with CH2Cl2 (30 ml  3 times). The collected organic layers were
dried over Na2SO4, and concentrated under reduced pressure to
obtain crude 10. At this stage, conversion of 3 and yield of 10 were
determined by 19F NMR using C6F6 as an internal standard.
Purification of crude 10 by thin layer chromatography on silica–
gel (hexane/AcOEt = 8/2) gave pure 10.
4.7.1. 2-Methoxy-4-(2,2,2-trifluoroethoxy)-5-
(trifluoromethyl)pyrimidine 7a
Colorless oil (79% isolated yield: Run 1 in Table 3); 1H NMR
(400 MHz, CDCl3):
d
= 8.58 (d, J = 0.8 Hz, 1H), 4.90 (q, J = 8.1 Hz,
= 166.93, 166.54,
2H), 4.08 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
158.49 (q, J = 4.7 Hz), 122.86 (q, J = 275.6 Hz), 122.63 (q,
J = 268.9 Hz), 106.25 (q, J = 34.5 Hz), 62.88 (q, J = 37.1 Hz), 55.86;
19F NMR (376 MHz, CDCl3):
d
= À63.60, À74.94 (t, J = 8.1 Hz); EIMS
(m/z) 276 (49, M+), 275 (27), 257 (24), 246 (100), 163 (37), 143 (32),
91 (27), 83 (23), 69(21); Anal Calcd for C8H6F6N2O2: C, 34.80; H,
2.19; N, 10.14. Found: C, 34.71; H, 2.19; N, 10.13.
Please cite this article in press as: T. Kagawa, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.07.016

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4.8.1. 2-Phenylamino-4-benzyloxy-5-(trifluoromethyl)pyrimidine
10a
(q, J = 4.8 Hz), 156.67, 136.07, 131.29, 128.72, 128.26, 127.51,
123.56 (q, J = 267.5 Hz), 123.10, 114.39, 103.00 (q, J = 33.0 Hz),
White solid (61% isolated yield: Run 7 in Table 4); 1H NMR
68.37, 55.74; 19F NMR (376 MHz, CDCl3):
d
= À63.04; EIMS (m/z)
(400 MHz, CDCl3):
13C NMR (100 MHz, DMSO-d6):
J = 4.2 Hz), 139.64, 136.58, 129.28, 129.19, 128.76, 128.09, 124.43
d
= 8.40 (s, 1H), 7.53–7.10 (m, 10H), 5.52 (s, 2H);
375 (65, M+), 264 (10), 213 (6), 196 (38), 121 (21), 91 (100), 65 (13);
Anal Calcd for C19H16F3N3O2: C, 60.80; H, 4.30; N, 11.23. Found: C,
61.03; H, 4.31; N, 11.23.
d
= 166.33, 161.81, 157.60 (q,
(q, J = 267.5 Hz), 123.66, 120.89, 101.14 (q, J = 33.5 Hz), 68.59; 19
F
NMR (376 MHz, CDCl3):
(3), 238 (9), 234 (6), 167 (4), 91 (100), 77 (8), 65 (21); Anal Calcd for
d
= À63.20; EIMS (m/z) 345 (11, M+), 254
4.8.7. 2-(4-Cyanophenyl)amino-4-methoxy-5-
(trifluoromethyl)pyrimidine 10e
C
18H14F3N3O: C, 62.61; H, 4.09; N, 12.17. Found: C, 62.71; H, 4.08;
White solid (19% isolated yield: Run 10 in Table 4); 1H NMR
N, 12.18.
(400 MHz, CDCl3):
2H), 7.65 (d, J = 8.8 Hz, 2H), 4.10 (s, 3H); 13C NMR (100 MHz,
CDCl3): = 167.32, 161.49, 156.65 (q, J = 4.7 Hz), 142.76, 133.51,
123.52 (q, J = 268.3 Hz), 119.74, 119.33, 102.73 (q, J = 32.9 Hz),
100.20, 54.96; 19F NMR (376 MHz, CDCl3):
294 (53, M+), 293 (100), 259 (4), 116 (8), 102 (16), 90 (12), 75 (13);
Anal Calcd for C13H9F3N4O: C, 53.07; H, 3.08; N, 19.04. Found: C,
53.15; H, 3.09; N, 19.11.
d = 8.44 (d, J = 0.4 Hz, 1H), 7.79 (d, J = 8.8 Hz,
4.8.2. 2-(4-Methyphenyl)amino-4-benzyloxy-5-
(trifluoromethyl)pyrimidine 10b-1
d
White solid (60% isolated yield: Run 3 in Table 4); 1H NMR
d
= À63.58; EIMS (m/z)
(400 MHz, CDCl3):
2.35 (s, 3H); 13C NMR (100 MHz, CDCl3):
(q, J = 4.5 Hz), 136.00, 135.74, 133.88, 129.68, 128.73, 128.27,
127.45, 123.60 (q, J = 267.8 Hz), 121.02, 102.75 (q, J = 33.2 Hz),
68.48, 21.06; 19F NMR (376 MHz, CDCl3):
359 (27, M+), 248 (7), 238 (6), 180 (7), 91 (100), 77 (6), 65 (18); Anal
Calcd for C19H16F3N3O: C, 63.51; H, 4.49; N, 11.69. Found: C, 63.55;
H, 4.50; N, 11.72.
d
= 8.37 (s, 1H), 7.45–7.15 (m, 9H), 5.50 (s, 2H),
= 166.65, 161.44, 156.70
d
d
= À63.09; EIMS (m/z)
4.8.8. 2-(4-Fluorophenyl)amino-4-benzyloxy-5-
(trifluoromethyl)pyrimidine 10f
White solid (62% isolated yield: Run 11 in Table 4); 1H NMR
(400 MHz, CDCl3):
d
= 8.37 (s, 1H), 7.45–7.02 (m, 9H), 5.49 (s, 2H);
= 166.69, 161.46, 159.50 (d,
13C NMR (100 MHz, CDCl3):
d
4.8.3. 2-(4-Methyphenyl)amino-4-methoxy-5-
(trifluoromethyl)pyrimidine 10b-2
J = 242.0 Hz), 156.87 (q, J = 4.7 Hz), 135.92, 134.35 (d, J = 2.5 Hz),
128.76, 128.32, 127.34, 123.53 (q, J = 268.4 Hz), 122.76 (d,
J = 7.8 Hz), 115.84 (d, J = 22.5 Hz), 103.19 (q, J = 32.8 Hz), 68.50;
White solid (31% isolated yield: Run 4 in Table 4); 1H NMR
(400 MHz, CDCl3):
J = 8.0 Hz, 2H), 4.04 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3): = 167.30, 161.44, 156.34 (q, J = 4.4 Hz), 135.89, 133.73,
129.70, 123.58 (q, J = 268.0 Hz), 120.69, 102.58 (q, J = 32.9 Hz),
54.60, 21.01; 19F NMR (376 MHz, CDCl3):
d
= 8.35 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.16 (d,
19F NMR (376 MHz, CDCl3):
d
= À63.18; EIMS (m/z) 363 (20, M+),
256 (5), 252 (4), 185 (4), 91 (100), 65 (17); Anal Calcd for
C18H13F4N3O: C, 59.51; H, 3.61; N, 11.57. Found: C, 59.72; H, 3.61;
N, 11.58.
d
d
= À63.16; EIMS (m/z)
Appendix A. Supplementary data
283 (61, M+), 282 (100), 264 (5), 248 (5), 242 (5), 131 (8), 91 (19),
77 (12), 65 (9); Anal Calcd for C13H12F3N3O: C, 55.12; H, 4.27; N,
14.84. Found: C, 55.23; H, 4.28; N, 14.87.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015.07.
016.
4.8.4. 2-(4-Methyphenyl)amino-4-iso-propoxy-5-
(trifluoromethyl)pyrimidine 10b-3
White solid (12% isolated yield: Run 6 in Table 4); 1H NMR
References
(400 MHz, CDCl3):
J = 6.8 Hz, 2H), 5.41 (hep, J = 6.0 Hz), 2.30 (s, 3H), 1.39 (d, J = 6.0 Hz,
6H); 13C NMR (100 MHz, CDCl3):
= 166.60, 161.50, 165.66 (q,
J = 5.0 Hz), 136.03, 133.47, 129.67, 123.67 (q, J = 268.3 Hz), 120.46,
102.76 (q, J = 33.6 Hz), 70.86, 21.86; 19F NMR (376 MHz, CDCl3):
d = 8.27 (brs, 1H), 7.48 (d, J = 5.6 Hz, 2H), 7.12 (d,
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d
d
= À62.77; EIMS (m/z) 311 (62, M+), 268 (100), 248 (42), 234 (11),
132 (10), 106 (7), 91 (19), 77 (8); Anal Calcd for C15H16F3N3O: C,
57.87; H, 5.18; N, 13.50. Found: C, 57.68; H, 5.20; N, 13.52.
4.8.5. 2-(2-Methylphenyl)amino-4-benzyloxy-5-
(trifluoromethyl)pyrimidine 10c
White solid (33% isolated yield: Run 8 in Table 4); 1H NMR
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(400 MHz, CDCl3):
d
= 8.33 (d, J = 0.8 Hz, 1H), 7.68–7.11 (m, 9H),
= 166.71,
5.42 (s, 2H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
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4 position selective, ArNH2 and ArOH (in general scheme: Cl, CH3, CF3). 5-
CF3: only one compound (synthetic procedure: not written).
162.06, 157.01 (q, J = 4.8 Hz), 136.36, 136.01, 130.89, 130.85,
128.66, 128.23, 127.69, 126.75, 125.47, 124.03, 123.64 (q,
J = 268.2 Hz), 102.92 (q, J = 33.3 Hz), 68.40, 18.24; 19F NMR
(376 MHz, CDCl3):
d
= À63.09; EIMS (m/z) 359 (24, M+), 344
(20), 268 (20), 248 (15), 106 (10), 91 (100), 65 (16); Anal Calcd for
C
19H16F3N3O: C, 63.51; H, 4.49; N, 11.69. Found: C, 63.42; H, 4.50;
N, 11.65.
4.8.6. 2-(4-Methoxyphenyl)amino-4-benzyloxy-5-
(trifluoromethyl)pyrimidine 10d
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White solid (44% isolated yield: Run 9 in Table 4); 1H NMR
(400 MHz, CDCl3):
d
= 8.34 (s, 1H), 7.37–6.88 (m, 9H), 5.47 (s, 2H),
= 166.68, 161.77, 156.97
3.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
Please cite this article in press as: T. Kagawa, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.07.016

G Model
FLUOR-8617; No. of Pages 9
T. Kagawa et al. / Journal of Fluorine Chemistry xxx (2015) xxx–xxx
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4-NHAr 68%. (2) 2-NO2-aniline, NaH, DMF, 22 8C, 40 min, 4-NHAr 58%. 5-CH3:
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Please cite this article in press as: T. Kagawa, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.07.016