One-Pot, Atom and Step Economy (PASE) Assembly of Trifluoromethylated Pyrimidines from CF3-Ynones

Article abstract of DOI:10.1002/ejoc.201700727

A highly efficient synthetic method for the preparation of of 6-trifluoromethylated pyrimidines was developed. The reaction of CF₃-substituted ynones and nitrogen 1,3-bis(nucleophile)s was employed for the one-pot assembly of the pyrimidine core. The cascade route proceeded through an aza-Michael addition, intramolecular cyclization, and dehydration reaction sequence to give the target heterocycles in excellent yields (up to 97 %). When acetamidine was used as the bis(nucleophile), the unexpected addition of two equivalents of the CF₃-substituted ynone to the acetamidine was observed.

Full text of DOI:10.1002/ejoc.201700727

A Journal of
Accepted Article
Title: One-pot, atom and step economy (PASE) assembly of
trifluoromethylated pyrimidines from CF3-ynones
Authors: Alexey Romanov, Alexander Rulev, Igor Ushakov, Vasiliy
Muzalevskiy, and Valentine Nenajdenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700727
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
One-pot, atom and step economy (PASE) assembly of trifluoromethylated
pyrimidines from CF3-ynones
Alexey R. Romanov,[a] Alexander Yu. Rulev,* [a] Igor A. Ushakov,[a] Vasiliy M. Muzalevskiy,[b] and
Valentine G. Nenajdenko*[b]
[a] A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Irkutsk 664033, Russia,
E-mail: rulev@irioch.irk.ru
[b] Department of Chemistry, Lomonosov Moscow State University, 119899 Moscow, Russia,
E-mail: nenajdenko@org.chem.msu.ru
Absract: Highly efficient synthesis of 6-trifluoromethylated pyrimidines based on reaction of CF3-
ynones with nitrogen 1,3-binucleophiles was developed. One-pot assembly of pyrimidine core
proceeds by the cascade route via aza-Michael addition – intramolecular cyclization – dehydration
sequence giving the target heterocycles in excellent yields (up to 97%). When acetamidine was used as
a binucleophile, the unexpected addition of two equivalents of CF3-ynone to acetamidine was
observed.
Keywords: pyrimidines / trifluoromethylated ynones / 1,3-binucleophiles
Introduction
A development of new methods for efficient and selective construction of biologically active
molecules is one of the most important challenges of modern organic chemistry. Nowadays, a
significant attention is paying to the study effective approaches to the fluorine-bearing organic
compounds. The interest in the development of versatile methods of the synthesis of such type of
derivatives is explained by unique properties provided by the presence of fluorinated fragment in a
molecule.1 More than two hundreds of currently used drugs contain at least one fluorine atom in the
structure.2 Significant part of these drug molecules belongs to fluorinated aza-heterocycles which are
recognized as privileged pharmacophores.3 For example, 5-fluorouracyl was the first synthetic
fluorinated medicine synthesized in 1957 by Heidelberger.4 This simple and small molecule has
triggered huge impact of fluorinated molecules to our life. Remarkable progress has been achieved in
the synthesis of perfluoroalkylated aza-heterocyclic compounds using selective methods of
fluorination or perfluoroalkylation. However, the most efficient approach to the construction of such
heterocyclic systems is based on the use of fluorinated building blocks. For example, recently we have
demonstrated that fluorinated bromoenones can be used for the assembly of trifluoromethylated
piperazinones,5 bicyclic piperazines,6 morpholines, oxazepanes and other heterocycles.7
Being a structural moiety of nucleic acids and drugs, pyrimidines occupy a distinct and unique
place in bioorganic and medicinal chemistry, life-science and medicine.8 Many pyrimidine derived
1
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
drugs are used mainly as anti-cancer, antiviral, anti-HIV, antibacterial, and antifungal agents (Figure
1).9 A number of methods for their preparation has been described so far.10 The most common
approach to the non-fluorinated pyrimidines involves cyclocondensation of 1,3-dicarbonyl compounds
or their equivalents with 1,3-binucleophiles bearing N-C-N moiety such as amidines, guanidines,
ureas, and their derivatives. This procedure is known as the “principal synthesis” of pyrimidines. Until
recently, only a very limited number of methods for the synthesis of trifluoromethylated pyrimidines
based on easily accessible materials has been described.11 Previously, the preparation of mono-, di-,
and trifluoromethylated pyrimidines from fluorinated 1,3-diketones,12 enones13 and aminoenones,14 β-
alkoxyvinyl(perfluoroalkyl)ketones,15 perfluoroalkyl β-diketo phosphorus ylides,16 and propargylic
fluorides17 was also reported.
O
F3C
NH
F
F
HO
H2N
O
N
O
O
N
NH
HN
NH
O
OH
O
Fluorouracil
(anticancer)
Flucytosine
(antifungal)
Trifluridine
(antiviral)
CF3
F
O
N
O
N
H
N
CF3
N
HN
N
N
NH2
O
O
O
F
F
Carmofur
Gemigliptin
(anticancer)
(antidiabetic)
Figure 1. Examples of drugs derived from fluorinated pyrimidines.
While many sufficient methods for the pyrimidine synthesis were described, the development
of new strategies for the preparation of these heterocycles remains an attractive area of the current
chemical research. The search for new pharmaceutical drugs possessing broad spectrum of activities
stimulates the search for novel reagents for the synthesis of pyrimidine derivatives. In continuation of
our research program devoted to the synthesis of fluorinated aza-heterocycles, we decided to develop
an alternative route for the assembly of fluorinated pyrimidine core based on the CF3-ynones 1 and N-
C-N nucleophiles. To the best of our knowledge, CF3-ynones have never been used for the synthesis of
trifluoromethylated pyrimidines.
Trifluoromethyl alkynyl ketones 1 are valuable building blocks and key intermediates in the
synthesis of a wide range of fluorinated aza-heterocycles. Recently, we have shown that five- and
2
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
seven-membered nitrogen-bearing heterocyclic compounds – pyrazoles18 and diazepines19 – can be
successfully prepared from these building blocks. High polarity of the acetylenic bond and significant
difference in electrophilicity of the triple bond and the carbonyl group of ynones 1 provides high
selectivity in heterocyclic synthesis. Herein, we describe the efficient synthesis of trifluoromethylated
pyrimidines based on these bielectrophiles.
Results and Discussion
Firstly, we have examined the reaction of ynones 1a-g with amidines 2a-c (Table 1). We have found
that aryl- and alkylsubstituted acetylenic ketones 1 react well with amidine acetate or hydrochloride
2a-c in the presence of organic (alkali metal alkoxides, sodium acetate, DBU, or triethylamine) or
mineral (Na2CO3) base to give the target pyrimidines 3a-p in moderate to high yields. The reaction
proceeds in the polar solvent (alcohols, acetonitrile) under reflux and is generally complete within 2-4
hours. The assembly of trifluoromethylated pyrimidine system occurs much faster than their non-
fluorinated analogs bearing even activated triple bond (see, for example, 12). The best results were
obtained when ketones 1 were treated with benzamidine 2b (Table 1, entries 6-10).
Table 1. Synthesis pyrimidines 3 from ynones 1a-g and amidines 2a-c.
X
X
O
Base
N
N
. Y
+
H2N
NH
CF3
R
CF3
R
1a-g
2a-c
3a-o
1: R = Ph (a), 4-t-BuC H (b), 4-ClC H (c), 4-MeOC H (d), n-Hex (e),
MeO
(f), 4-BrC6H4 (g)
6
4
6
4
6
4
2: X = H, Y = AcOH (a); X = Ph, Y = HCl (b); X = Me, Y = HCl (c)
Initial reagents
Entry
1
Product
Conditions
Yield, %[a]
84
1
2
N
N
1a
2a
3a
t-BuOK, t-BuOH, 5 h
Ph
CF3
N
N
2
3
1b
1c
2a
2a
3b
3c
t-BuOK, t-BuOH, 5 h
t-BuOK, t-BuOH, 5 h
73
83
4-t- BuC6H4
CF3
N
N
4-ClC6H4
CF3
N
N
4
1d
2a
3d
t-BuOK, t-BuOH, 5 h
83
4- MeOC6H4
CF3
3
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
N
N
5
6
1e
1a
2a
2b
3e
3f
t-BuOK, t-BuOH, 5 h
53
80
n-Hex
Ph
CF3
Ph
EtONa, EtOH, 4 h
N
N
CF3
Ph
7
8
1b
1c
2b
2b
3g
3h
EtONa, EtOH, 4 h
EtONa, EtOH, 4 h
93
83
N
N
4-t- BuC6H4
CF3
Ph
N
N
N
N
4-ClC6H4
CF3
CF3
Ph
9
1d
2b
3i
EtONa, EtOH, 4 h
EtONa, EtOH, 4 h
79
97
N
4- MeOC6H4
Ph
10
1f
2b
2c
3j
N
MeONpht
CF3
11
12
13
1a
3k
EtONa, EtOH, 4 h
Na2CO3, MeCN, 4 h
AcONa, t-BuOH, 4 h
48[b]
17
N
N
37[c]
Ph
CF3
N
N
14
1b
1c
2c
2c
3l
Et3N, t-BuOH, 3 h
57[b]
4-t- BuC6H4
CF3
15
16
3m
DBU, t-BuOH, 4 h
Et3N, t-BuOH, 4 h
18[c]
45[b]
N
N
17
18
MeONa, t-BuOH, 4 h
t-BuOK, t-BuOH, 4 h
54 (63[c])
4-ClC6H4
CF3
65[c]
19
20
1d
1e
2c
2c
3n
3o
MeONa, MeOH, 4 h
Et3N, t-BuOH, 2 h
90
N
N
44[b]
4- MeOC6H4
CF3
21
22
Na2CO3, MeCN, 3 h
MeONa, t-BuOH, 4 h
31
N
N
61[c]
n-Hex
CF3
23
1g
2c
3p
Na2CO3, MeCN, 4 h
49[b]
N
N
4-BrC6H4
CF3
[a]
[b]
Isolated yield;
Pyrimidines 4 were also isolated in the yield of 8 (entry 11), 20 (entry 14), 4%
(entry 16), 16% (entry 20), and 15% (23); [c] According to 19F NMR.
However, when the reaction with acetamidine hydrochloride 2c was studied, the expected
pyrimidines 3 were isolated in only moderate yield (Table 1, entries 11-23). All attempts to improve
the yields of target heterocycles by varying the base or solvent failed. The nature of the base which
was used for generation of acetamidine from its salt strongly influenced the pyrimidine yields. As a
4
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
rule, when the reactions were performed in the presence of alkoxides, the target heterocycles were
obtained in good yields. In contrast, the reaction was less efficient when DBU was used as a base. It
was found that major byproducts formed during the reaction are compounds 4 derived from
participation in the reaction of two molecules of ynone 1 with one molecule of acetamidine. Even in
the case of low basic Na2CO3 or Et3N pyrimidines 3k-n,p were isolated in moderate yields together
with adducts 4a-e in yield up to 20% (Scheme 1, Table 1, entries 11, 14, 16, 20, 23). Such type of
transformations has never been described for acetamidine in the literature.20
HO
CF3
O
R
N
N
Base
N
N
. HCl
NH
+
H2N
CF3
+
R
CF3
R
R
CF3
1a-d,g
2c
3k-n,p
4a-e
4: R = Ph (a), 4-t-BuC6H4 (b), 4-ClC6H4 (c), 4-MeOC6H4 (d), 4-BrC6H4 (e)
Scheme 1. Reaction of ynones 1 with acetamidine 2.
Trying to find the conditions for selective formation of both pyrimidine derivatives and to
explain the mechanism of formation of adduct 4, we assumed that pyrimidine 4 is the result of direct
addition of 2-methylpyrimidine 3 as CH-acid to the second equivalent of ynone 1. To proof this
sequence of transformations, we examined the reaction of pyrimidine 3k with one equivalent of the
19
ketone 1c under the same conditions (Et3N, MeCN, reflux, 4h). According to F NMR spectrum of
reaction mixture, the transformation of pyrimidine 3k into corresponding adduct 4 did not occur: only
the signals of initial heterocycle 3k and ketone 1a, and some unidentified products were observed. The
same result was obtained when the reaction was performed under UV irradiation (no signal of the
expected adduct 4 was observed in the 19F NMR spectrum after irradiation of the reaction mixture at a
slightly elevated temperature for 6 hours) or in a superbasic medium (stirring of reaction mixture at
room temperature in the system DMSO/KOH). Therefore, we proposed an alternative reaction
pathway including a participation of methyl group of acetamidine as nucleophilic center. Most
probably the formation of adduct 4 occurs due to imine-enamine equilibrium for intermediate A
formed after Michael addition. For example, sequence 1 → A → A’ → B → 4 can explain formation
of products 4 (Scheme 2). The postulated intermediates should be quite reactive species formed in
minor amounts. Our attempts to determine their structure were unsuccessful. Only low intensity
signals (19F NMR) of unidentified derivatives were registered during the reaction monitoring.
5
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
CF3
HO
Ar
NH
N
N
NH
O
Ar
N
N
CF3
Ar
CF3
Ar
O
3
A
CF3
2c
4
CF3
Ar
1
CF3 NH2
NH2
HO
1
N
O
N
O
CF3
Ar
CF3
Ar
Ar
A'
B
Scheme 2. Possible mechanism of formation of adduct 4.
Next, we used other N-C-N binucleophiles for the assembly of pyrimidine core. We have found
that the condensation of ketones 1a-e with guanidine carbonate 2d or hydrochloride 2e under the same
conditions afforded 2-aminopyrimidines 3q-u in good yields (Scheme 3). This type of pyrimidines is
especially important due to the fact that these heterocycles demonstrated a wide range of biological
activity such as anti-inflammatory, analgesic, antitubercular, adenosine receptor antagonists, and
protein kinases inhibitors.21
Finally, the reaction of CF3-ynones 1 with isothiourea derivatives 2e,f was studied (Scheme 3).
When ketones 1a,e were treated with ethyl isothiouronium salt 2e in the presence of sodium acetate,
the target 2-ethylsulfanyl pyrimidines 3v,w were obtained in good yields. Their benzylsulfanyl analogs
3x,y were prepared by a similar procedure. Sulfanyl group is an important leaving group in pyrimidine
chemistry because such derivatives can be used in reaction with some nucleophiles to construct 2-
substituted pyrimidines. This fragment can be also oxidized to sulfones moiety to form even better
nucleofuge.
6
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
X
X
O
Base
N
N
. Y
+
H2N
NH
CF3
Solvent
R
CF3
R
1a-e
2d-g
3q-y
1: R = Ph (a), 4-t-BuC6H4 (b), 4-ClC6H4 (c), 4-MeOC6H4 (d), n-Hex (e)
2: X = NH2, Y = 0.5 H2CO3 (d); X = NH2, Y = Cl (e);
X = SEt, Y = HBr (f); X = SBn, Y = HCl (g)
NH2
NH2
NH2
N
N
N
N
N
N
CF3
CF3
Ph
CF3
Cl
t-Bu
3q, 82% (A)
3s, 64% (B)
3r, 73% (A)
NH2
SEt
SEt
NH2
N
N
N
N
N
N
N
N
CF3
Hex
CF3
Ph
CF3
Hex
CF3
MeO
3w, 73% (C)
3v, 77% (C)
3u, 62% (A)
3t, 71% (B)
SBn
SBn
N
N
N
N
CF3
CF3
MeO
Cl
3y, 70% (D)
3x, 66% (D)
Conditions: A: t-BuOH; B: MeONa/MeOH; C: AcONa/t-BuOH; D: Et3N/t-BuOH
Scheme 3. Synthesis of functionalized pyrimidines 3q-y from ynones 1a-e
and guanidines 2d,e or isothiourea derivatives 2f,g.
The reactions of CF3-ynones with guanidine and isothiourea derivatives proceed more quickly
(3-5 times faster) than the similar reaction with non-fluorinated ynones. It should be noted that the
product structure depends strongly on reaction conditions. Thus, when ketone 1d was treated with
guanidine hydrochloride 2e in the presence of equimolar amounts of sodium methoxide in methanol,
the target pyrimidine 3t was formed in good yield (Scheme 3, conditions B). However, when the same
reaction was performed with EtONa obtained from ethanol containing little amount of water, only 4-
methoxyphenylacetylene 5 was isolated in good yield. The similar cleavage of acetylenic ketones
under the action of nitrogen nucleophiles was recently reported.22
In conclusion, the developed one-pot procedure can be regarded as an efficient alternative
method for the synthesis of trifluoromethylated pyrimidines. One-pot, atom and step economy
(PASE)23 combination in the proposed protocol, easy accessibility of starting
7
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
trifluoromethyl(alkynyl)ketones as well as good and high yields of target heterocycles are the main
advantages of this route to functionalized pyrimidines.
Experimental part
1
13
19
15
General Remarks H (400.1 MHz), C (100.6 MHz) F (376.5 MHz), and N (40.6 MHz) NMR
spectra were recorded on Bruker AVANCE 400 MHz spectrometer. Chemical shifts (δ) are given in
1
ppm; the coupling constants (J) are given in Hertz. The concerted application of H-1H 2D
homonuclear experiments NOESY and COSY as well as 1H-13C 2D heteronuclear experiments HMBC
and HSQC were used for the distinction of the carbon and proton resonances. The IR spectra were
recorded with a Bruker Vertex 70 FT-IR spectrometer and with a portable Varian 3100 diamond
ATR/FT-IR spectrometer. The GC/MS analyses were performed with a Shimadzu GCMS-QP5050A
instrument (EI, 70 eV). HRMS spectra were measured at Orbitrap Elite instrument. The silica gel used
for column chromatography was 230-400 Mesh. All reagents were of reagent grade and were used as
such or distilled prior to use. All the solvents were dried according to standard procedures and freshly
distilled prior to use. Ynones 1 were prepared as reported previously.18
General procedure for synthesis of pyrimidines 3.
A mixture of the appropriate base (0.75 mmol, Et3N, DBU, AcONa, t-BuOK, EtONa, or MeONa; see
main text) and binucleophile salt 2 (0.75 mmol) in the appropriate solvent (2 mL, t-BuOH, EtOH,
MeOH, or MeCN; see main text) was stirred at r.t. for 0.5-2 h to generate the free binucleophile (in
case of guanidinium carbonate 2d no base was used). Next, ynone 1 (0.5 mmol) was added and the
reaction mixture was refluxed for 2-4 h (TLC control). After being cooled the mixture was
concentrated in vacuo, the residue was purified by column chromatography on silica gel or aluminium
oxide (3s,t) using appropriate mixtures of hexane and CH2Cl2 (3:1-2:1, 3a-3e, 3v, 3w), CHCl3 (3f-3p,
3s,t, 3x,y), or mixture of CH2Cl2 and MeOH (100:1, 3q, 3r, 3u).
4-(Trifluoromethyl)-6-phenylpyrimidine 3a. Pale yellow solid, mp 48-49 °C (lit.:16 31-33 °C), yield
1
94 mg (84%). Rf 0.24 (Hexane/CH2Cl2, 1:1) (UV). H NMR (CDCl3): 7.49-7.57 (m, 3H, Ar), 7.99 (s,
13
1H, C5H), 8.10-8.13 (m, 2H, Ar), 9.35 (s, 1H, C2H). C NMR (CDCl3): 112.5 (q, J = 1.9 Hz, C5),
120.6 (q, J = 275.0 Hz, CF3), 127.3, 129.2, 132.1, 135.2 (Ar), 156.1 (q, J = 36.1 Hz, C-CF3), 159.3
+
(C2), 166.4 (C6). 19F NMR (CDCl3): -71.1. HRMS (ESI): calcd for C11H8F3N2 : [M + H]+ 225.0634;
found 225.0635. The NMR data are in agreement with those in the literature.16
4-(4-tert-Butylphenyl)-6-(trifluoromethyl)pyrimidine 3b. Pale yellow solid, mp 89-90 °C, yield 102
mg (73%). Rf 0.28 (Hexane/CH2Cl2, 1:1) (UV). 1H NMR (CDCl3): 1.37 (s, 9H, t-Bu), 7.56 (d, J = 8.6
8
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
13
Hz, 2H, Ar), 8.00 (s, 1H, C5H), 8.08 (d, J = 8.6 Hz, 2H, Ar), 9.35 (s, 1H, C2H). C NMR (CDCl3):
31.1 (C(CH3)3), 35.0 (C(CH3)3), 112.2 (q, J = 2.6 Hz, C5), 120.7 (q, J = 275.0 Hz, CF3), 126.3, 127.2,
132.5, 155.89 (Ar), 155.94 (q, J = 35.8 Hz, C-CF3), 159.4 (C2), 166.4 (C6). 19F NMR (CDCl3): -71.2.
+
HRMS (ESI): calcd for C15H16F3N2 : [M + H]+ 281.126; found 281.1261.
4-(4-Chlorophenyl)-6-(trifluoromethyl)pyrimidine 3c. Pale yellow solid, mp 59-60 °C, yield 107
1
mg (83%). Rf 0.25 (Hexane/CH2Cl2, 1:1) (UV). H NMR (CDCl3): 7.49 (d, J = 8.6 Hz, 2H, Ar), 7.98
(s, 1H, C5H), 8.08 (d, J = 8.6 Hz, 2H, Ar), 9.36 (s, 1H, C2H). 13C NMR (CDCl3): 112.2 (q, J = 2.6 Hz,
C5), 120.6 (q, J = 275.3 Hz, CF3), 128.6, 129.5, 133.7, 138.6 (Ar), 156.3 (q, J = 36.1 Hz, C-CF3),
19
+
159.4 (C2), 165.2 (C6). F NMR (CDCl3): -71.1. HRMS (ESI): calcd for C11H7ClF3N2 : [M + H]+
259.0250 (35Cl), 261.0220 (37Cl); found 259.0244 (35Cl), 261.0214 (37Cl).
4-(Trifluoromethyl)-6-(4-methoxyphenyl)pyrimidine 3d. Pale yellow solid, mp 58-60 °C, yield 106
mg (83%). Rf 0.29 (Hexane/CH2Cl2, 1:1) (UV). 1H NMR (CDCl3): 3.86 (s, 3H, OCH3), 7.00 (d, J = 8.9
13
Hz, 2H, Ar), 7.91 (s, 1H, C5H), 8.09 (d, J = 8.9 Hz, 2H, Ar), 9.27 (s, 1H, C2H). C NMR (CDCl3):
55.4 (OCH3), 111.5 (q, J = 1.8 Hz, C5), 114.5, 120.7 (q, J = 275.0 Hz, CF3), 127.6, 129.1, 155.7 (q, J =
19
35.8 Hz, C-CF3), 159.2 (C2), 162.9, 165.8 (C6). F NMR (CDCl3): -71.2. HRMS (ESI): calcd for
C12H10F3N2O+: [M + H]+ 255.074; found 255.0741.
4-(Trifluoromethyl)-6-hexylpyrimidine 3e. Pale yellow oil, yield 61 mg (53%). Rf 0.5 (CH2Cl2)
(UV). 1H NMR (CDCl3): 0.85-0.89 (m, 3H, CH3, Hex), 1.23-1.38, (m, 6H, (CH2)3, Hex), 1.71-1.79 (m,
2H, CH2, Hex), 2.86 (t, J = 7.8 Hz, 3H, C7H2), 7.49 (s, 1H, C5H), 9.24 (s, 1H, C2H). 13C NMR
(CDCl3): 14.0, 22.5, 28.6, 28.9, 31.5, 38.1, 116.0 (q, J = 1.8 Hz, C5), 120.6 (q, J = 275.3 Hz, CF3),
19
155.2 (q, J = 36.5 Hz, C-CF3), 158.9 (C2), 174.1 (C6). F NMR (CDCl3): -71.2. HRMS (ESI): calcd
+
for C11H16F3N2 : [M + H]+ 233.126; found 233.1260.
2,4-Diphenyl-6-trifluoromethylpyrimidine 3f
White solid, mp 84-86 °C (lit.:16 77-79 °C), yield 120 mg (80%). 1H NMR (CDCl3): 7.48-7.60 (m, 6H,
13
Ph), 7.86 (s, 1H, C5H), 8.20-8.28 (m, 2H, Ph), 8.59-8.68 (m, 2H, Ph). C NMR (CDCl3): 110.0 (C5),
121.0 (q, J = 275.3 Hz, CF3), 127.5, 128.7, 128.8, 129.2, 131.6, 131.9, 136.0, 136.6 (Ph), 156.8 (q, J =
15
35.6 Hz, C6), 165.4 (C4), 166.5 (C2). 19F NMR (CDCl3): -70.3. N NMR (CDCl3): -96.1 (N3), -110.9
(N1). IR (KBr, cm–1): ν 1140, 1184 (C-F), 1550 (C2=N-C4=C5), 1587 (C6=N). MS (EI) m/z (relative
intensity, %): 300 (100, M+), 197 (18), 128 (80), 104 (37), 103 (33), 102 (18), 101 (10), 77 (31), 76
(18), 51 (18). HRMS (ESI): calcd for C17H11F3N2H+: [M + H]+ 301.0947; found 301.0948. The NMR
data are in agreement with those in the literature.16
9
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4-(4-tert-Butylphenyl)-2-phenyl-6-trifluoromethylpyrimidine 3g
Pale yellow solid, mp 59-61 °C, yield 165 mg (93%). 1H NMR (CDCl3): 1.41 (s, 9H, CH3, t-Bu), 7.52-
7.57 (m, 3H, Ph), 7.59 (d, J = 8.2 Hz, 2H, Ar), 7.86 (s, 1H, C5H), 8.20 (d, J = 8.2 Hz, 2H, Ar), 8.63-
8.69 (m, 2H, Ph). 13C NMR (CDCl3): 31.3 (C(CH3)3), 35.2 (C(CH3)3), 109.8 (C5), 121.2 (q, J = 275.3
Hz, CF3), 126.3, 127.4, 133.3, 155.7 (Ar), 128.8, 128.9, 131.6, 136.8 (Ph), 156.7 (q, J = 35.5 Hz, C6),
165.4 (C4), 166.5 (C2). 19F NMR (CDCl3): -70.3. IR (film, cm–1): ν 1152, 1179 (C-F), 1544 (C2=N-
C4=C5), 1582 (C6=N). MS (EI) m/z (relative intensity, %): 356 (48, M+), 342 (43), 341 (100), 313 (29),
171 (19), 157 (46), 128 (13), 122 (12), 115 (10), 103 (11), 77 (10). Calcd for C21H19F3N2: C 70.77; H
5.37; N 7.86. Found: C 70.91; H 5.44; N 7.95.
4-(4-Chlorophenyl)-2-phenyl-6-trifluoromethylpyrimidine 3h
Pale yellow solid, mp 128-130 °C, yield 138 mg (83%). 1H NMR (CDCl3): 7.45-7.57 (m, 5H, Ph, Ar),
7.81 (s, 1H, C5H), 8.17 (d, J = 8.2 Hz, 2H, Ar), 8.54-8.63 (m, 2H, Ph). 13C NMR (CDCl3): 109.8 (C5),
121.0 (q, J = 275.3 Hz, CF3), 128.9 (3 C), 129.6, 134.5, 136.5, 138.4 (Ph, Ar), 157.1 (q, J = 35.6 Hz,
15
C6), 165.4 (C4), 165.6 (C2). 19F NMR (CDCl3): -70.3. N NMR (CDCl3): -96.1 (N3), -109.4 (N1). IR
(KBr, cm–1): ν 1148, 1179 (C-F), 1543 (C2=N-C4=C5), 1584 (C6=N). MS (EI) m/z (relative intensity,
%): 336 (34, M++2), 335 (20, M++1), 334 (100, M+), 230 (14), 164 (15), 162 (55), 139 (11), 127 (15),
126 (12), 104 (35), 103 (27), 77 (12), 76 (13), 75 (12), 51 (13). Calcd for C17H10ClF3N2: C 61.00; H
3.01; N 8.37. Found: C 60.89; H 2.87; N 8.43.
4-(4-Methoxyphenyl)-2-phenyl-6-trifluoromethylpyrimidine 3i
1
Yellowish solid, mp 119-120 °C (lit.:13 120-121 °C), yield 131 mg (79%). H NMR (CDCl3): 3.87 (s,
3H, CH3), 7.02 (d, J = 8.8 Hz, 2H, Ar), 7.48-7.56 (m, 3H, Ph), 7.76 (s, 1H, C5H), 8.19 (d, J = 8.8 Hz,
13
2H, Ar), 8.57-8.63 (m, 2H, Ph). C NMR (CDCl3): 55.6 (CH3), 109.1 (C5), 121.2 (q, J = 275.2 Hz,
CF3), 114.6, 128.5, 128.8, 128.9, 129.3, 131.6, 136.9, 163.0 (Ph, Ar), 156.5 (q, J = 35.3 Hz, C6), 165.3
(C4), 165.9 (C2). 19F NMR (CDCl3): -70.3. IR (KBr, cm–1): ν 1143, 1182 (C-F), 1545 (C2=N-C4=C5),
1587 (C6=N). MS (EI) m/z (relative intensity, %): 330 (100, M+), 227 (21), 165 (12), 158 (68), 133
(11), 132 (20), 103 (22), 77 (15). HRMS (ESI): calcd for C18H13F3N2OH+: [M + H]+ 331.1053; found
331.1054. The NMR data are in agreement with those in the literature.16
4-(4-Methoxynaphtalen-1-yl)-2-phenyl-6-trifluoromethylpyrimidine 3j
Yellowish solid, mp 149-151 °C, yield 185 mg (97%). 1H NMR (CDCl3): 4.08 (s, 3H, CH3), 6.93 (d, J
= 8.1 Hz, 2H, Ar), 7.48-7.65 (m, 5H, Ar, Ph), 7.73-7.80 (m, 1H, Ar), 7.76 (s, 1H, C5H), 8.35-8.47 (m,
10
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13
2H, Ar), 8.58-8.68 (m, 2H, Ph). C NMR (CDCl3): 55.9 (CH3), 103.5 (C5), 121.2 (q, J = 275.3 Hz,
CF3), 114.7, 122.8, 124.8, 126.0, 126.2, 127.7, 128.1, 128.9, 128.9, 130.0, 131.7, 136.8, 157.8 (Ph,
Ar), 156.3 (q, J = 35.3 Hz, C6), 165.2 (C4), 169.4 (C2). 19F NMR (CDCl3): -70.2. IR (KBr, cm–1): ν
1147, 1177 (C-F), 1540 (C2=N-C4=C5), 1571 (C6=N). MS (EI) m/z (relative intensity, %): 380 (100,
M+), 379 (81), 365 (25), 364 (26), 312 (15), 311 (65), 296 (21), 180 (21), 164 (12), 138 (12), 77 (10).
Calcd for C22H15F3N2O: C 69.47; H 3.97; N 7.36. Found: C 69.32; H 3.96; N 6.97.
2-Methyl-4-phenyl-6-trifluoromethylpyrimidine 3k
1
Yellow oil, yield 115 mg (48%). H NMR (CDCl3): 2.85 (s, 3H, CH3), 7.45-7.55, 8.05-8.15 (m, 5H,
Ph), 7.78 (s, 1H, C5H). 13C NMR (CDCl3): 26.2 (CH3), 109.6 (C5), 120.9 (q, J = 275.2 Hz, CF3), 127.5,
129.3, 131.9, 135.9 (Ph), 156.3 (q, J = 35.3 Hz, C6), 166.6 (C4), 169.7 (C2). 19F NMR (CDCl3): -69.8.
15N NMR (CDCl3): -87.5, -104.5. IR (KBr, cm–1): ν 1142, 1174 (C-F), 1554 (C2=N-C4=C5), 1577 (Ph),
1595 (C6=N). MS (EI) m/z (relative intensity, %): 238 (100, M+), 197 (38), 177 (15), 128 (72), 102
(21). Calcd for C12H9F3N2: C 60.51; H 3.81; N 11.76. Found: C 60.17; H 3.83; N 11.46. The NMR
data are in agreement with those in the literature.16
2-Methyl-4-(4-tert-butylphenyl)-6-trifluoromethylpyrimidine 3l
1
Pale yellow solid, mp 73-75 °C, yield 84 mg (57%). H NMR (CDCl3): 1.35 (s, 9H, CH3, t-Bu), 2.85
13
(s, 3H, CH3), 7.53 (d, J = 8.5 Hz, 2H, Ar), 7.78 (s, 1H, C5H), 8.04 (d, J = 8.5 Hz, 2H, Ar). C NMR
(CDCl3): 26.4 (CH3), 31.3 (C(CH3)3), 35.2 (C(CH3)3), 109.4 (C5), 121.0 (q, J = 275.1 Hz, CF3), 126.3,
127.4, 133.2, 155.7 (Ar), 156.3 (q, J = 35.2 Hz, C6), 166.7 (C4), 169.7 (C2). 19F NMR (CDCl3): -70.3.
IR (film, cm–1): ν 1150, 1199 (C-F), 1549 (C2=N-C4=C5), 1590 (C6=N). MS (EI) m/z (relative
intensity, %): 294 (14, M+), 280 (18), 279 (100), 251 (22), 91 (11). HRMS (ESI): calcd for
C16H17F3N2H+: [M + H]+ 295.1417; found 295.1418.
4-(4-Chlorophenyl)-2-methyl-6-trifluoromethylpyrimidine 3m
Pale yellow solid, mp 50-51 °C, yield 111 mg (41%). 1H NMR (CDCl3): 2.85 (s, 3H, CH3), 7.48 (d, J
13
= 8.2 Hz, 2H, Ar), 7.77 (s, 1H, C5H), 8.07 (d, J = 8.2 Hz, 2H, Ar). C NMR (CDCl3): 26.3 (CH3),
109.4 (C5), 120.9 (q, J = 275.3 Hz, CF3), 128.9, 129.6, 134.3, 138.4 (Ar), 156.6 (q, J = 35.4 Hz, C6),
165.4 (C4), 169.9 (C2). 19F NMR (CDCl3): -70.3. IR (KBr, cm–1): ν 1151, 1201 (C-F), 1551 (C2=N-
C4=C5), 1590 (C6=N). MS (EI) m/z (relative intensity, %): 274 (31, M++2), 272 (100, M+), 233 (12),
231 (37), 211 (16), 164 (21), 162 (66), 138 (10), 136 (28), 127 (17), 126 (16), 75 (24), 66 (28), 50 (12).
HRMS (ESI): calcd for C12H8ClF3N2H+: [M + H]+ 273.0401 (35Cl), 275.0372 (37Cl); found 273.0403
(35Cl), 275.0368 (37Cl).
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European Journal of Organic Chemistry
4-(4-Methoxyphenyl)-2-methyl-6-trifluoromethylpyrimidine 3n
1
Pale yellow solid, mp 79-81 °C, yield 121 mg (90%). H NMR (CDCl3): 2.81 (s, 3H, CH3), 3.86 (s,
13
3H, OCH3), 6.99 (d, J = 7.4 Hz, 2H, Ar), 7.71 (s, 1H, C5H), 8.08 (d, J = 7.4 Hz, 2H, Ar). C NMR
(CDCl3): 26.3 (CH3), 55.6 (OCH3), 108.7 (C5), 121.0 (q, J = 274.8 Hz, CF3), 114.6, 128.3, 129.2,
162.9 (Ar), 156.0 (q, J = 34.9 Hz, C6), 166.0 (C4), 169.5 (C2). 19F NMR (CDCl3): -70.4. IR (KBr, cm–
1): ν 1135, 1179 (C-F), 1549 (C2=N-C4=C5), 1591 (C6=N). MS (EI) m/z (relative intensity, %): 268
(100, M+), 227 (15), 225 (14), 158 (26), 132 (22), 66 (14), 63 (11). HRMS (ESI): calcd for
C13H11F3N2OH+: [M + H]+ 269.0896; found 269.0901.
4-Hexyl-2-methyl-6-trifluoromethylpyrimidine 3o
Yellow oil, yield 115 mg (31%). 1H NMR (CDCl3): 0.75-0.92 (m, 3H, CH3, Hex), 1.20-1.40, 1.65-1.78
(m, 8H, (CH2)4, Hex), 2.76 (s, 3H, C7H3), 2.77-2.83 (m, 2H, CH2), 7.26 (s, 1H, C5H). 13C NMR
(CDCl3): 14.2, 22.7, 26.2, 29.0, 29.2, 31.7, 38.5 (Hex, C7H3), 112.7 (C5), 120.9 (q, J = 275.1 Hz, CF3),
155.6 (q, J = 35.3 Hz, C6), 169.2 (C4), 174.1 (C2). 19F NMR (CDCl3): -70.0. 15N NMR (CDCl3): -81.1,
-106.1. IR (film, cm–1): 1152, 1181 (C-F), 1563 (C2=N-C4=C5), 1596 (C6=N). MS (EI) m/z (relative
intensity, %): 246 (2, M+), 203 (15), 189 (26), 176 (100). Calcd for C12H17F3N2: C 58.52; H 6.96; N
11.37. Found: C 58.53; H 6.87; N 11.10.
4-(4-Bromophenyl)-2-methyl-6-trifluoromethylpyrimidine 3p
Pale yellow solid, mp 49-51 °C, yield 78 mg (49%). 1H NMR (CDCl3): 2.85 (s, 3H, CH3), 7.65 (d, J =
8.5 Hz, 2H, Ar), 7.77 (s, 1H, C5H), 8.00 (d, J = 8.5 Hz, 2H, Ar). 13C NMR (CDCl3): 26.3 (CH3), 109.4
(C5), 120.9 (q, J = 275.3 Hz, CF3), 126.9, 129.1, 132.6, 134.9 (Ar), 156.7 (q, J = 35.5 Hz, C6), 165.5
(C4), 169.9 (C2). 19F NMR (CDCl3): -70.3. IR (KBr, cm–1): ν 1147 (C-F), 1549 (C2=N-C4=C5), 1588
(C6=N). MS (EI) m/z (relative intensity, %): 318 (98, M++1), 317 (17, M+), 316 (100, M+-1), 277 (25),
275 (25), 208 (38), 206 (40), 182 (12), 180 (13), 127 (34), 101 (10), 76 (11), 75 (19), 66 (17), 50 (12).
Calcd for C12H8BrF3N2: C 45.45; H 2.54; N 8.83. Found: C 45.82; H 2.41; N 8.89.
2-Amino-4-phenyl-6-trifluoromethylpyrimidine 3q. Pale yellow solid, mp 124-125 °C (lit.:16 128-
129 °C), yield 98 mg (82%). Rf 0.30 (CH2Cl2) (UV). 1H NMR (CDCl3): 5.90 (br.s., 2H, NH2), 7.31 (s,
1H, C5H), 7.46-7.54 (m, 3H, Ar), 8.00-8.03 (m, 2H, Ar). 13C NMR (CDCl3): 102.8 (q, J = 3.0 Hz, C5),
120.7 (q, J = 275.3 Hz, CF3), 127.2, 128.9, 131.5, 136.1 (Ar), 157.1 (q, J = 35.4 Hz, C6), 163.5 (C4),
168.2 (C2). 19F NMR (CDCl3): -71.8. The NMR data are in agreement with those in the literature.16
2-Amino-4-(4-tert-butylphenyl)-6-trifluoromethylpyrimidine 3r. Pale yellow solid, mp 134-136 °C,
1
yield 107 mg (73%). Rf 0.32 (CH2Cl2) (UV). H NMR (CDCl3): 1.36 (s, 9H, t-Bu), 5.96 (br.s., 2H,
12
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NH2), 7.30 (s, 1H, C5H), 7.51 (d, J = 8.4 Hz, 2H, Ar), 7.95 (d, J = 8.4 Hz, 2H, Ar). 13C NMR (CDCl3):
31.1 (C(CH3)3), 34.9 (C(CH3)3), 102.6 (q, J = 2.6 Hz, C5), 120.8 (q, J = 275.0 Hz, CF3), 125.9, 127.0,
133.3, 155.1 (Ar), 156.9 (q, J = 34.6 Hz, C6), 163.5 (C4), 168.1 (C2). 19F NMR (CDCl3): -71.7. HRMS
+
(ESI): calcd for C15H17F3N3 : [M + H]+ 296.1369; found 296.1369.
2-Amino-4-(4-chlorophenyl)-6-trifluoromethylpyrimidine 3s
1
Pale yellow solid, mp 192-194 °C (lit.:24 202-203 °C), yield 88 mg (64%). H NMR (DMSO-d6): 7.39
13
(br.s., 2H, NH2), 7.54 (s, 1H, C5H), 7.58 (d, J = 8.3 Hz, 2H, Ar), 8.20 (d, J = 8.3 Hz, 2H, Ar). C
NMR (DMSO-d6): 100.8 (C5), 120.8 (q, J = 275.4 Hz, CF3), 128.9, 129.0, 134.7, 136.3 (Ar), 156.2 (q,
J = 34.2 Hz, C6), 163.8 (C4), 165.7 (C2). 19F NMR (DMSO-d6): -69.5. IR (KBr, cm–1): ν 1137, 1184
(C-F), 1551 (C2=N-C4=C5), 1591 (C6=N). MS (EI) m/z (relative intensity, %): 275 (30, M++2), 274
(29, M++1), 273 (100, M+), 272 (58, M+-1), 252 (16), 162 (21), 136 (16), 127 (16), 126 (12), 75 (27),
51 (12), 50 (15). HRMS (ESI): calcd for C12H10F3N3OH+: [M + H]+ 274.0354 (35Cl), 276.0324 (37Cl);
found 274.0356 (35Cl), 276.0320 (37Cl). The NMR data are in agreement with those in the literature.24
2-Amino-4-(4-methoxyphenyl)-6-trifluoromethylpyrimidine 3t
1
Pale yellow solid, mp 184-187 °C (lit.:24 193-194 °C), yield 95 mg (71%). H NMR (DMSO-d6): 3.83
(s, 3H, OCH3), 7.05 (d, J = 8.6 Hz, 2H, Ar), 7.25 (br.s., 2H, NH2), 7.44 (s, 1H, C5H), 8.15 (d, J = 8.6
Hz, 2H, Ar). 13C NMR (DMSO-d6): 55.3 (OCH3), 100.0 (C5), 121.0 (q, J = 275.3 Hz, CF3), 114.2,
128.1, 128.9, 162.0 (Ar), 155.8 (q, J = 33.9 Hz, C6), 163.8 (C4), 166.4 (C2). 19F NMR (DMSO-d6): -
69.6. 15N NMR (DMSO-d6): -132.9 (N3), -150.7 (N1), -293.6 (NH2). IR (KBr, cm–1): ν 1137, 1188 (C-
F), 1553 (C2=N-C4=C5), 1594 (C6=N). MS (EI) m/z (relative intensity, %): 269 (100, M+), 268 (38),
254 (10), 206 (13). HRMS (ESI): calcd for C12H10F3N3OH+: [M + H]+ 270.0849; found 270.0851. The
NMR data are in agreement with those in the literature.24
2-Amino-4-hexyl-6-trifluoromethylpyrimidine 3u. Pale yellow oil, yield 76 mg (62%). Rf 0.35
(CH2Cl2) (UV). 1H NMR (CDCl3): 0.83-0.90 (m, 3H, CH3), 1.24-1.37 (m, 6H, (CH2)3, Hex), 1.62-1.70
(m, 2H, CH2), 1.62-1.70 (m, 2H, CH2), 2.62 (t, J = 7.8 Hz, 2H, CH2-Het), 5.69 (br.s., 2H, NH2), 6.76
(s, 1H, C5H). 13C NMR (CDCl3): 14.0, 22.5, 28.5, 28.9, 31.5, 38.1, 105.7 (q, J = 2.6 Hz, C5), 120.6 (q,
J = 275.3 Hz, CF3), 156.2 (q, J = 35.0 Hz, C6), 163.1 (C4), 175.4 (C2). 19F NMR (CDCl3): -71.8.
+
HRMS (ESI): calcd for C11H17F3N3 : [M + H]+ 248.1369; found 248.1371.
2-Ethylsulfanyl-4-phenyl-6-trifluoromethylpyrimidine 3v. Pale yellow solid, mp 51-52 °C, yield
1
109 mg (77%). H NMR (CDCl3): 1.47 (t, J = 7.3 Hz, CH3), 3.26 (q, J = 7.3 Hz, CH2), 7.48-7.56 (m,
3H, Ar), 7.62 (s, 1H, C5H), 8.09-8.11 (m, 2H, Ar). 13C NMR (CDCl3): 14.2, 25.6, 107.2 (q, J = 2.6 Hz,
13
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C5), 120.5 (q, J = 275.7 Hz, CF3), 127.3, 129.0, 132.0, 135.3 (Ar), 156.3 (q, J = 35.8 Hz, C6), 166.2
(C4), 174.0 (C2). 19F NMR (CDCl3): -71.4. 15N NMR (CDCl3): -100.7, -115.4. HRMS (ESI): calcd for
C13H12F3N2S+: [M + H]+ 285.0668; found 285.0672.
2-Ethylsulfanyl-4-hexyl-6-trifluoromethylpyrimidine 3w. Pale yellow oil, yield 107 mg (73%). Rf
0.35 (CH2Cl2) (UV). 1H NMR (CDCl3): 0.84-0.89 (m, 3H, CH3, Hex), 1.25-1.40 (m, 9H, (CH2)3, Hex,
SCH2CH3), 1.68-1.75 (m, 2H, CH2), 2.75 (t, J = 7.8 Hz, 2H, CH2-Het), 3.16 (q, J = 7.3 Hz, CH2), 7.07
13
(s, 1H, C5H). C NMR (CDCl3): 14.0, 14.2, 22.4, 25.4, 28.4, 28.9, 31.5, 38.0, 110.7 (q, J = 2.6 Hz,
19
C5), 120.5 (q, J = 275.3 Hz, CF3), 155.4 (q, J = 36.1 Hz, C6), 173.5 (C4), 174.0 (C2). F NMR
(CDCl3): -71.5. HRMS (ESI): calcd for C13H20F3N2S+: [M + H]+ 293.1294; found 293.1299.
2-Benzylsulfanyl-4-(4-chlorophenyl)-6-trifluoromethylpyrimidine 3x
1
Pale yellow solid, mp 89-92 °C, yield 84 mg (66%). H NMR (CDCl3): 4.41 (s, 2H, CH2), 7.10-7.29
13
(m, 3H, Ph), 7.37-7.44 (m, 4H, Ph, Ar), 7.52 (s, 1H, C5H), 7.95 (d, J = 8.7 Hz, 2H, Ar). C NMR
(CDCl3): 35.8 (CH2), 107.6 (C5), 120.7 (q, J = 275.6 Hz, CF3), 127.5, 128.7, 128.9, 129.3, 129.6,
133.8, 137.3, 138.7 (Ph, Ar), 156.6 (q, J = 36.0 Hz, C6), 165.4 (C4), 173.9 (C2). 19F NMR (CDCl3): -
70.4. IR (KBr, cm–1): ν 1152, 1191 (C-F), 1532 (C2=N-C4=C5), 1586 (C6=N). MS (EI) m/z (relative
intensity, %): 382 (10, M++2), 380 (28, M+), 349 (11), 347 (36), 91 (100), 65 (26). HRMS (ESI): calcd
for C18H12ClF3N2SH+: [M + H]+ 381.0435 (35Cl), 383.0406 (37Cl); found 381.0439 (35Cl), 383.0405
(37Cl).
2-Benzylsulfanyl-4-(4-methoxyphenyl)-6-trifluoromethylpyrimidine 3y
1
Yellow solid, mp 92-94 °C, yield 131 mg (70%). H NMR (CDCl3): 3.85 (s, 3H, CH3), 4.47 (s, 2H,
CH2), 6.97 (d, J = 8.7 Hz, 2H, Ar), 7.15-7.35 (m, 3H, Ph), 7.43-7.51 (m, 2H, Ph), 7.53 (s, 1H, C5H),
13
8.04 (d, J = 8.7 Hz, 2H, Ar). C NMR (CDCl3): 35.7 (CH2), 55.6 (CH3), 106.9 (C5), 120.8 (q, J =
275.4 Hz, CF3), 127.4, 127.8, 128.7, 129.3, 129.4, 137.6, 163.1 (Ph, Ar), 156.1 (q, J = 35.7 Hz, C6),
19
166.0 (C4), 173.3 (C2). F NMR (CDCl3): -70.5. 15N NMR (CDCl3): -100.7 (N3), -115.4 (N1). IR
(KBr, cm–1): ν 1137, 1177 (C-F), 1532 (C2=N-C4=C5), 1579 (C6=N). MS (EI) m/z (relative intensity,
%): 376 (51, M+), 344 (12), 343 (54), 299 (12), 298 (13), 254 (12), 92 (12), 91 (100), 65 (28). HRMS
(ESI): calcd for C19H15F3N2OSH+: [M + H]+ 377.0930; found 377.0933.
1,1,1-trifluoro-4-phenyl-2-{[4-phenyl-6-(trifluoromethyl)pyrimidin-2-yl]methyl}but-3-yn-2-ol 4a
Pale yellow oil, yield 17 mg (8%). 1H NMR (CDCl3): 3.77 (s, 2H, CH2), 6.63 (b.s., 1H, OH), 7.17-7.64
13
(m, 8H, Ph), 7.98 (s, 1H, C5H), 8.07-8.13 (m, 2H, Ph). C NMR (CDCl3): 43.4 (CH2), 71.5 (q, J =
14
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European Journal of Organic Chemistry
32.6 Hz, C(OH)), 83.7 (C≡CPh), 87.2 (C≡CPh), 111.5 (q, J = 2.7 Hz, C5), 120.5 (q, J = 275.3 Hz,
C6CF3), 123.6 (q, J = 284.1 Hz, C(OH)CF3), 121.3, 127.8, 128.4, 129.3, 129.7, 132.1, 132.9, 134.8
(Ph), 156.5 (q, J = 36.2 Hz, C6), 167.0 (C4), 167.4 (C2). 19F NMR (CDCl3): -70.0, -81.2. IR (film, cm–
1): ν 1155, 1181 (C-F), 1551 (C2=N-C4=C5), 1597 (C6=N), 2239 (C≡C), 3343 (OH). MS (EI) m/z
(relative intensity, %): 436 (27, M+), 435 (100), 417 (12), 365 (11), 349 (25), 129 (23). Calcd for
C22H14F6N2O: C 60.56; H 3.23; N 6.42. Found: C 60.78; H 3.54; N 6.22.
4-(4-tert-Butylphenyl)-2-{[4-(4-tert-butylphenyl)-6-(trifluoromethyl)pyrimidin-2-yl]methyl}-
1,1,1-trifluorobut-3-yn-2-ol 4b
1
Yellow oil, yield 27 mg (20%). H NMR (CDCl3): 1.24 (s, 9H, CH3, t-Bu), 1.35 (s, 9H, CH3, t-Bu),
3.74 (s, 2H, CH2), 6.74 (b.s., 1H, OH), 7.19-7.25 (m, 4H, Ar), 8.07-8.13 (d, J = 8.4 Hz, 2H, Ar), 7.93
(s, 1H, C5H), 8.02 (d, J = 8.4 Hz, 2H, Ar). 19F NMR (CDCl3): -70.3, -81.5. IR (film, cm–1): ν 1183 (C-
F), 1546 (C2=N-C4=C5), 1595 (C6=N), 2237 (C≡C), 3364 (OH). MS (EI) m/z (relative intensity, %):
548 (48, M+), 547 (35), 533 (14), 531 (11), 492 (31), 491 (100), 260 (10), 259 (38), 245 (11), 161 (17),
155 (10), 115 (10), 57 (30). HRMS (ESI): calcd for C30H30F6N2OH+: [M + H]+ 549.2335; found
549.2338.
4-(4-Chlorophenyl)-2-{[4-(4-chlorophenyl)-6-(trifluoromethyl)pyrimidin-2-yl]methyl}-1,1,1-
trifluorobut-3-yn-2-ol 4c
1
Yellow oil, yield 11 mg (4%). H NMR (CDCl3): 3.79 (s, 2H, CH2), 6.41 (s, 1H, OH), 7.21-7.30 (m,
13 19
4H, Ar), 7.56 (d, J = 6.9 Hz, 2H, Ar), 7.98 (s, 1H, C5H), 8.09 (d, J = 6.9 Hz, 2H, Ar). C F NMR
(CDCl3): -70.3, -81.4. IR (film, cm–1): ν 1159, 1182 (C-F), 1548 (C2=N-C4=C5), 1594 (C6=N), 2240
(C≡C), 3370 (OH). MS (EI) m/z (relative intensity, %): 506 (18, M++2), 505 (63, M++1), 504 (28, M+),
503 (100), 419 (15), 417 (26), 272 (11), 217 (12), 165 (21), 163 (62), 137 (13), 135 (12), 101 (14), 99
(16), 75 (17). HRMS (ESI): calcd for C22H10Cl2F6N2OH+: [M – H]+ 503.0148 (35Cl), 505.0118 (37Cl);
found 503.0159 (35Cl), 505.0128 (37Cl).
1,1,1-Trifluoro-4-(4-methoxyphenyl)-2-{[4-(4-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-2-
yl]methyl}-but-3-yn-2-ol 4d
1
Yellow oil, yield 39 mg (16%). H NMR (CDCl3): 3.71 (s, 2H, CH2), 3.74 (s, 3H, CH3), 3.88 (s, 3H,
CH3), 6.73 (d, J = 8.5 Hz, 2H, Ar), 6.74 (b.s., 1H, OH), 7.02 (d, J = 8.6 Hz, 2H, Ar), 7.21 (d, J = 8.5
Hz, 2H, Ar), 7.87 (s, 1H, C5H), 8.08 (d, J = 8.6 Hz, 2H, Ar). 19F NMR (CDCl3): -70.4, -81.5. IR (film,
cm–1): ν 1181 (C-F), 1547 (C2=N-C4=C5), 1597 (C6=N), 2234 (C≡C), 3341 (OH). MS (EI) m/z
(relative intensity, %): 496 (36, M+), 495 (100), 481 (17), 409 (13), 248 (10), 159 (18). HRMS (ESI):
calcd for C24H18F6N2O3H+: [M + H]+ 497.1294; found 497.1299.
15
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10.1002/ejoc.201700727
European Journal of Organic Chemistry
4-(4-Bromophenyl)-2-{[4-(4-bromophenyl)-6-(trifluoromethyl)pyrimidin-2-yl]methyl}-1,1,1-
trifluorobut-3-yn-2-ol 4e
Light yellow oil, yield 23 mg (15%). 1H NMR (CDCl3): 3.75 (s, 2H, CH2), 6.34 (s, 1H, OH), 7.13 (d, J
= 8.3 Hz, 2H, Ar), 7.36 (d, J = 8.3 Hz, 2H, Ar), 7.68 (d, J = 8.4 Hz, 2H, Ar), 7.94 (s, 1H, C5H), 7.98
13
(d, J = 8.4 Hz, 2H, Ar). C NMR (CDCl3): 43.4 (CH2), 71.5 (q, J = 32.6 Hz, C(OH)), 84.8 (C≡CAr),
86.3 (C≡CAr), 111.2 (C5), 120.5 (q, J = 275.5 Hz, C6CF3), 123.5 (q, J = 284.4 Hz, C(OH)CF3), 120.2,
123.9, 128.1, 129.2, 131.8, 133.0, 133.5, 133.7 (Ar), 156.8 (q, J = 36.6 Hz, C6), 166.1 (C4), 167.4 (C2).
19F NMR (CDCl3): -70.3, -81.4. IR (film, cm–1): ν 1186 (C-F), 1549 (C2=N-C4=C5), 1591 (C6=N),
2239 (C≡C), 3363 (OH). MS (EI) m/z (relative intensity, %): 506 (18, M++2), 505 (63, M++1), 504
(28, M+), 503 (100), 419 (15), 417 (26), 272 (11), 217 (12), 165 (21), 163 (62), 137 (13), 135 (12), 101
(14), 99 (16), 75 (17). Calcd for C22H12Br2F6N2O: C 44.47; H 2.04. Found C 44.76; H 2.18.
1-Ethynyl-4-methtoxybenzene 5
1H NMR (CDCl3): 2.98 (s, 1H, C≡CH), 3.79 (s, 3H, CH3), 6.83 (d, J = 8.7 Hz, 2H, Ar), 7.42 (d, J = 8.7
Hz, 2H, Ar). 13C NMR (CDCl3): 55.4 (CH3), 76.0 (C≡CAr), 83.8 (C≡CAr), 114.1, 114.4, 133.8, 160.1
(Ar). The NMR data are in agreement with those in the literature.25
Acknowledgements
This work was partially supported by Russian Foundation for the Basic Research and Moscow city
Government according to the research project 15-33-70010-mol_a_mos. The spectral and analytical
data were obtained using the equipment of the Baykal analytical center for collective use SB RAS and
due to M. V. Lomonosov Moscow State University Program of Development which are also
acknowledged.
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Table-of-Contents
CF3
HO
X
X
O
HN
NH2
R
N
N
N
N
+
CF3
in a PASE
procedure!
CF3
R
R
R
CF3
25 examples
yield up to 97%
for X = Me
The use of CF3-ynones as fluorine-containing building blocks is shown to be a convenient approach to
fluorinated pyrimidines. The PASE methodology of their assembly proved to be efficient, simple, and
applicable to a variety of acetylenic ketones and 1,3-binucleophiles.
Key topic
Nitrogen heterocycles
19
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