2-Trifluoromethyl-1,3-diazabutadienes as useful intermediates for the construction of 2-trifluoromethylpyrimidine derivatives

Article abstract of DOI:10.1055/s-0037-1610444

A methodology to prepare 2-trifluoromethylpyrimidines has been developed on the basis of a cyclization reaction of 2-trifluoromethyl-1,3-diazabutadienes. These 2-trifluoromethyl-1,3-diazabutadienes were prepared by the condensation of trifluoroacetamidine and amide acetals or with chloromethaniminium salt derived from N, N-dimethylbenzamide with phosphorus oxychloride. The cycloaddition reactions of these 2-trifluoromethyl-1,3-diazabutadienes with DMAD and phenylacetyl chloride provided 2-trifluoromethylpyrimidine derivatives in regular to moderate overall yield.

Full text of DOI:10.1055/s-0037-1610444

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
I. Medina-Mercado et al.
Paper
Synthesis
2-Trifluoromethyl-1,3-diazabutadienes as Useful Intermediates
for the Construction of 2-Trifluoromethylpyrimidine Derivatives
Ignacio Medina-Mercadoa
Ivann Zaragoza-Galiciaa
R
Me
X
N
N
R1
Me
X = OMe, Cl
F3C
NH2
Horacio F. Olivob
0
0
0
0
0-
0
0
2
8-
0
8
2
5-
2
8
5
R = H, Boc
Moisés Romero-Ortega*a
a Departamento de Química Orgánica, Facultad de Química,
Universidad Autónoma del Estado de México, Toluca, C.P.
50180, México
mromeroo@uaemex.mx
b Medicinal and Natural Products Chemistry, The University of
Iowa, Iowa City, IA 52242, USA
CO2Me
O
1)
Ph
Cl
CO2Me
CO2Me
Et3N
–10 °C to r.t.
R1
N
CO2Me
r.t.
Ph
Cl
R
N
N
R1
N
F3C
N
R1
F3C
2) POCl3
F3C
N
N(CH3)2
toluene
reflux
R1 = H, Me, Et, Ph
22–64% overall
R
1 = Me, 40% overal
Received: 04.05.2018
Accepted after revision: 02.06.2018
Published online: 16.07.2018
H
HO
H
N
H
O
N
Me
DOI: 10.1055/s-0037-1610444; Art ID: ss-2018-m0308-op
F3C
Abstract A methodology to prepare 2-trifluoromethylpyrimidines has
been developed on the basis of a cyclization reaction of 2-trifluoro-
methyl-1,3-diazabutadienes. These 2-trifluoromethyl-1,3-diazabuta-
dienes were prepared by the condensation of trifluoroacetamidine and
amide acetals or with chloromethaniminium salt derived from N,N-di-
methylbenzamide with phosphorus oxychloride. The cycloaddition re-
actions of these 2-trifluoromethyl-1,3-diazabutadienes with DMAD and
phenylacetyl chloride provided 2-trifluoromethylpyrimidine derivatives
in regular to moderate overall yield.
CF3
CF3
)-mefloquine
(
)-fluoxetine
(
CF3
N
F
F
N
NO2
N
N
F3C
N
NH2
O
F
NO2
sitagliptin
Key words trifluoroacetamidine, cycloaddition reaction, 1,3-diazabu-
benfluralin
tadienes, 2-trifluoromethylpyrimidines, trifluoromethyl group
Figure 1 Examples of trifluoromethylated drugs
It is well known that fluorination or perfluorination of
organic molecules causes a significant change in their phys-
icochemical properties. For this reason it is important to
devise efficient methods for the synthesis of organofluorine
compounds to obtain derivatives with pharmaceutical
properties.1 In fact, about 25% of drugs and at least 30% of
all agrochemicals that are in the market contain at least one
fluorine atom, and several of them have important biologi-
cal activities due to the presence of this element.2
In this context, a trifluoromethyl group attached to aro-
matic systems is one of the most important units used for
the design of new molecules with specific biological activi-
ty.3 Some examples of arenes and heterocyclic rings with
biological properties that contain the trifluoromethyl
group in the structure include the antidepressant fluoxe-
tine (Prozac®), (±)-mefloquine (Larim®; used to treat ma-
laria), antidiabetic sitagliptin (Januvia®), and a herbicide
benfluralin (Balan®) (Figure 1). For this reason, the devel-
opment of new synthetic routes for the introduction of tri-
fluoromethyl groups in heterocyclic systems including aro-
matic rings has become a major challenge within the area
of synthetic organic chemistry and medicinal chemistry.
There are several strategies for introducing the trifluo-
romethyl group in a range of heterocyclic systems, for ex-
ample, from prefunctionalized organic substrates such as
heteroaryl halides, heteroaryl amines or heteroaryl boronic
acids using different trifluoromethylating agents.4–7 How-
ever, few reports for the synthesis of trifluoromethylpyrim-
idine derivatives can be found in the literature. The majori-
ty of these synthetic methods involve condensation reac-
tions with building blocks that contain the trifluoromethyl
group in their chemical structure.8–17
Early studies on the [4+2]-cycloaddition reactions of
azadienes with different dienophiles established the great
potential of the approach for the synthesis of six-mem-
bered heterocycles that contain nitrogen.18 Specifically, 1,3-
diaza-1,3-butadienes have been used as key intermediates
for the synthesis of various heterocyclic systems.19 Unfortu-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
I. Medina-Mercado et al.
Paper
Synthesis
nately, most of these 1,3-diazadienes are substituted with
an alkyl or aryl group at position N-1, and it is thus not pos-
sible to obtain aromatic compounds.20–24
In previous reports we have described that trichloroac-
etamidine can be condensed either with amide acetals25 or
with chloromethaniminium salts, also known as Vilsmeier–
Haack reagents.26,27 It was thought that trifluoroacetami-
dine 1 might react with these electrophilic agents in an
analogous manner. This supposition proved to be correct
when 1 was treated with a slight excess of N,N-dimethylfor-
mamide dimethylacetal (1.2 equiv) in tetrahydrofuran solu-
tion at room temperature for 16 hours, which led to the for-
mation of 2-trifluoromethyl-1,3-diazabutadiene 2a in 95%
yield in crude form (Scheme 2). Unfortunately, 2-trifluoro-
methyldiazadiene 2a was obtained as a mixture together
with the 4-dimethylaminotrifluoroacetamide 3 (possibly
formed by the partial hydrolysis of 2a) in ca. 1:1 ratio. The
corresponding 2-trifluoromethyldiazapentadiene 2b was
prepared in the same manner from 1 using N,N-dimethy-
lacetamide dimethylacetal in 96% yield as practically the
only product. The 4-phenyl-2-trifluoromethyldiazabutadi-
ene 2c was prepared in 80% yield from the condensation of
1 with the respective chloromethaniminium salt (Vilsmei-
er–Haack reagent) derived from the reaction of N,N-di-
methylbenzamide and phosphorus(V) oxychloride, accord-
ing to our previously reported methodology.26 Unfortunately,
2c was isolated as a mixture with N,N-dimethylbenzamide.
As part of an ongoing study on the cycloaddition reac-
tion of 1,3-diazadienes, our group previously reported
some strategies for the preparation of NH-2-trichlorometh-
yl-1,3-diaza-1,3-butadienes and showed their utility for the
construction of pyrimidine25,26 and quinazoline27 deriva-
tives by cycloaddition reactions mainly with electron-defi-
cient acetylenes or benzyne. Herein, we now describe the
synthesis of trifluoroacetamidine 1 (Scheme 1) and its pre-
liminary study as a suitable building block for the synthesis
of 2-trifluoromethyl-1,3-diazabutadienes, and the use of
the latter as intermediates, particularly in cycloaddition re-
actions for the construction of 2-trifluoromethylpyrimi-
dines.
H
H
N
N
NH3
CF3CN
–78 °C
NH2
NH2
F3C
F3C
Anti
Syn
1
Scheme 1 Synthesis of trifluoroacetamidine 1
OMe
NMe2
OMe
THF, 16 h, r.t.
Trifluoroacetamidine 1 was described first by Husted28
in 1954 and it was synthesized in 87% yield from trifluoro-
acetonitrile and ammonia.29 Unfortunately, it has not been
characterized because it is typically used in its crude form
for the synthesis of other types of compounds.29–31 In this
paper, we present its synthesis, spectroscopic characteriza-
tion, and some of its uses in the preparation of 2-trifluoro-
methyl-1,3-diazadienes.
H
N
R
F3C
NH
F3C
NH2
R
N
1
NMe2
Cl
NMe2
2) DIPEA
CH2Cl2
1)
2a R = H (95%)
2b R = Me (96%)
Ph
OPOCl2
F3C
O
F3C
NH
Ph
Our study began with the synthesis and characteriza-
tion of 1, which was prepared from trifluoroacetonitrile
and ammonia at –78 °C (Scheme 1). The excess of ammonia
was removed from the reaction mixture followed by further
vaporization under vacuum of the volatile residues. Com-
pound 1 does not survive silica gel column chromatogra-
phy; therefore, no attempt was made to obtain pure trifluo-
roacetamidine and the usual yield in crude form was simi-
H
O
N
+
N
Ph
NMe2
NMe2
NMe2
3
2c (80%)
Scheme 2 Synthesis of 2-trifluoromethyl diazadienes 2a–c
In our previous work, we observed that when the 1,3-
diazabutadienes with the trichloromethyl group in position
2 are exposed to conditions of dilution at room temperature
for long periods of time, they tend to degrade to trichloro-
acetonitrile and their respective N,N-dimethylamidine.25
We found that the 2-trifluoromethyldiazabutadienes 2a
and 2b were decomposed in CH2Cl2 solution at room tem-
perature in less than 3 hours. An attempt to obtain the 2-
trifluoromethyldiazadiene 2a in pure form by silica gel col-
umn chromatography failed, and produced the 4-(dime-
thylamino)trifluoroacetamide 3 as the only isolable prod-
uct in low yield together with very polar decomposition
products, possibly as a consequence (amongst other things)
of a fragmentation of 2a to N,N-dimethylformamidine and
trifluoroacetonitrile or hydrolysis by the presence of water.
1
lar to that reported in the literature. Although the H and
13C NMR spectra correspond to the structure of 1, the 19F
spectrum shows two signals at –74.56 and –75.31 ppm,
which indicates the presence of syn- and anti-isomers of
trifluoroacetamidine.
Trifluoroacetamidine 1 was obtained as an oil with
ammonia odor and is relatively stable at low temperatures
(–5 °C). In its solution form, in CH2Cl2 and CHCl3 at room
temperature for 24 hours, the decomposition to trifluoro-
acetonitrile and ammonia accelerates, and in the presence
of a trace amount of water its hydrolysis to trifluoroacet-
amide occurs easily.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
I. Medina-Mercado et al.
Paper
Synthesis
In startling contrast to 2a and 2b, 4-phenyl-2-(trifluoro-
methyl)diazadiene 2c exhibited good stability when it was
purified by silica gel column chromatography and it could
be isolated and characterized by NMR spectroscopy.
OMe
NMe2
OMe
R
Boc
Boc
NH2
H
F3C
N
N
N
Boc2O/DMAP
THF, 20 h, r.t.
(1.2–2.7 equiv)
R
N
F3C
F3C
NH2
THF, Δ
30 min to 1.5 h
Focusing on the study to evaluate the cycloaddition pro-
cess of 1,3-diazadienes to prepare heterocyclic systems, we
decided to use the 2-trifluoromethyl-1,3-diazadienes 2a–c
without purification. Like 2-trichloromethyldiazabuta-
dienes, which are well behaved in cycloaddition reactions
towards DMAD, the 2-trifluoromethyldiazadiene 2a react-
ed efficiently when it was treated with 2.0 equivalents of
DMAD at room temperature in CH2Cl2 solution (Scheme 3).
After 3 hours, the respective 2-trifluoromethylpyrimidine
4a was obtained in 37% overall yield (from trifluoroacet-
amidine 1) accompanied by the dimethylamine-acetylene
adduct 5. In an analogous manner, 2-trifluoromethyldi-
azapentadiene 2b under the same conditions gave pyrimi-
dine 4b in 64% overall yield. In the same way, 4c could be
obtained from 2c in 22% overall yield.
6
NMe2
1
(62%)
2d R = H (88%)
2e R = Me (92%)
2f R = Et (72%)
Scheme 4 Synthesis of N-Boc-2-trifluoromethyl-1,3-diazadienes 2d–f
treated with DIPEA (3.0 equiv) at 0 °C in CH2Cl2 solution,
followed by subsequent addition of DMAD (2.0 equiv) at
room temperature. Under these conditions only the 2-tri-
fluoromethylpyrimidines 4b and 4d could be obtained from
7e and 7f in 50% and 30% yield, respectively. In startling
contrast, when the same reaction was carried out using 7d,
no cyclization product could be obtained and only the N,N-
dimethylaminotrifluoroacetamide 3 was obtained. This re-
sult is consistent with the rapid hydrolysis reaction that 2-
trifluoromethyldiazadiene 2 suffers when the substituent
at C-4 is hydrogen.
R
CO2Me
CO2Me
MeO2C
Me2N
H
DMAD (2.0 equiv)
CH2Cl2, 3 h, r.t.
N
2a–c
+
CO2Me
F3C
4a R = H
N
Boc
5
F3C
N
F3C
(37%)
NH2
TFA (10 equiv)
7d R = H
7e R = Me
7f R = Et
MeCOO
4b R = Me (64%)
4c R = Ph (22%)
R
R
N
N
CH2Cl2, Δ
NMe2
N(CH3)2
Scheme 3 Cycloaddition reaction of 2a–c with DMAD
2d–f
1) DIPEA (3.0 equiv) 2) DMAD (2.0 equiv)
CH2Cl2, 0 °C
N-tert-Butoxycarbonylamidines are synthetic equiva-
lents of N-unsubstituted amidines. In an effort to improve
yields of the 2-trifluoromethyldiazabutadienes 2, we pro-
posed the protection of position 1 with the tert-butoxycar-
bonyl group (Boc). To this end, N-Boc-trifluoroacetamidine
6 was prepared by the reaction of 1 with di-tert-butylpyro-
carbonate in the presence of 4-(N,N-dimethylamino)pyri-
dine (DMAP) and was obtained in 62% yield after flash col-
umn chromatography purification (Scheme 4). This N-Boc-
amidine 6 shows greater stability than its predecessor 1
and reacts efficiently with amide dimethylacetals in reflux-
ing THF solution, to give N-Boc-2-trifluoromethyl diaza-
dienes 2d–f in good yields. However, heating in refluxing
toluene solution of diazadienes 2d–f with an excess of
DMAD, did not lead to the formation of the respective 2-tri-
fluoromethylpyrimidines and only the starting materials
were observed after 16 hours, possibly because of the elec-
tron-withdrawing effect of the Boc group.
R
DMAD, toluene
CO2Me
N
Δ
F3C
N
CO2Me
4a R = H
4b R = Me (50%)
4d R = Et (30%)
nd
Scheme 5 Cycloaddition reaction of 1,3-diaza-1,3-butadienes with
DMAD
Recently, we reported that trichloromethyl analogues
1,3-diazadienes, react with different acyl chlorides, fol-
lowed by chlorination reaction with an excess of POCl3 to
produce 2-trichloromethylchloropyrimidines. We decided
to exemplify this type of strategy using phenylacetyl chlo-
ride and diazadiene 2e. Once the Boc group in 2e was re-
moved with TFA, Et3N was added to generate the free diaza-
diene 2b followed by addition of phenylacetyl chloride, giv-
ing a mixture of the 2-trifluoromethyl-4-pyrimidone 8 and
O-acylpyrimidine 9 (Scheme 6). Finally, treatment of this
mixture of 8 and 9 with POCl3 in refluxing toluene solution,
afforded only 2-trifluoromethyl-4-chloropyrimidine 10 in
40% overall yield from 6.
Given that the Boc group deactivates diazadienes 2e–d
in the cycloaddition process with DMAD, we explored re-
moval of the Boc group with trifluoroacetic acid (TFA) in re-
fluxing CH2Cl2 solution before the cycloaddition reaction
(Scheme 5). The 2-trifluoromethyldiazadienium trifluoro-
acetates 7d–f were obtained as oils. The salts 7d–f were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
I. Medina-Mercado et al.
Paper
Synthesis
2-Trifluoromethyl-1,3-diazabutadienes 2a,b; General Procedure
Me
Boc
Me
Under nitrogen atmosphere, the amide acetal (1.2 equiv) was added
to a solution of trifluoroacetamidine 1 (1.0 equiv) in anhydrous THF
(5.0 mL). The reaction mixture was stirred at r.t. for 16 h, then the re-
mains of solvent and the amide acetal were evaporated under vacu-
um to obtain the product as an oil. These 1,3-diazadienes were used
in crude form for the following reactions.
Ph
O
F3C
N
Ph
O
N
1) TFA, CH2Cl2
N
+
N
Me
2) PhCH2COCl
Et3N, 0 °C
F3C
N
F3C
N
H
Ph
NMe2
O
8
9
2e
POCl3
(10 equiv)
toluene
Δ, 12 h
2-Trifluoromethyl-4-N,N-dimethylamino-1,3-diazabutadiene (2a)
According to the general procedure using 1 (0.2655 g, 2.3 mmol) and
N,N-dimethylformamide dimethylacetal (0.36 mL, 2.7 mmol), 2a (191
mg, 95% yield) was obtained as a yellow oil.
Me
N
Ph
Cl
N
2-Trifluoromethyl-4-N,N-dimethylamino-1,3-diazapentadiene
F3C
(2b)
10 (40%)
According to the general procedure using 1 (143 mg, 1.23 mmol) and
N,N-dimethylacetamide dimethylacetal (0.25 mL, 1.53 mmol), 2b
(0.2241 g, 96% yield) was obtained as a red oil.
Scheme 6 Cycloaddition reaction of 2e with phenylacetyl chloride
In summary, 2-trifluoromethyl-1,3-diazabutadienes
were prepared from trifluoroacetamidine using amide ac-
etals or by Vilsmeier–Haack reagent. 2-Trifluoromethyl-1,3-
diazabutadienes in free from reacted with electron-defi-
cient acetylenes or with acyl chlorides to form 2-trifluoro-
methylpyrimidine derivatives in moderate global yields.
Further investigations, including the extension of this
methodology to other substrates are continuing in our labo-
ratory.
N-((Dimethylamino)methylene)-2,2,2-trifluoroacetamide (3)
This product was obtained after flash column chromatography (silica
gel, hexanes–EtOAc 1:1) from crude 2a as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 8.59 (s, 1 H), 3.25 (s, 3 H), 3.21 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 168.43 (q, J = 35.7 Hz), 162.49, 116.87
(q, J = 287.0 Hz), 41.99, 35.96.
19F NMR (282 MHz, CDCl3): δ = –76.52.
MS: m/z (%) = 169 (23) [M+ + H], 121 (18), 101 (100), 68 (48), 50 (60).
2-Trifluoromethyl-4-N,N-dimethylamino-4-phenyl-1,3-diazabuta-
diene (2c)
Reagents were purchased from Aldrich and used without further pu-
rification. Solvents such as THF and CH2Cl2 were previously dried ac-
cording to standard laboratory methods. N,N-Dimethylpropionamide
dimethylacetal32 was prepared according to a published procedure.
Under a nitrogen atmosphere, phosphorus oxychloride (0.13 mL, 1.39
mmol, 1.0 equiv) was added dropwise at r.t. to a solution of N,N-di-
methylbenzamide (210 mg, 1.41 mmol, 1.0 equiv) in anhydrous
CH2Cl2 (4.0 mL) and the solution was heated at 40 °C for 5 h. After this
time the mixture was diluted with anhydrous CH2Cl2 (5.0 mL) and a
solution of trifluoroacetamidine 1 (166 mg, 1.49 mmol, 1.05 equiv) in
anhydrous THF (2.0 mL) was added dropwise at 0 °C and the mixture
was stirred overnight at r.t. Finally, DIPEA (0.54 mL, 3.1 mmol, 2.2
equiv) was added dropwise at 0 °C and the reaction mixture was
washed with saturated NaCl solution (20.0 mL), the product was ex-
tracted with CH2Cl2 (3 × 15.0 mL), and the organic phase was dried
over Na2SO4 and concentrated under vacuum. Compound 2c was pu-
rified by flash column chromatography (silica gel, hexanes–EtOAc
1:1).
The reactions were followed by thin-layer chromatography (TLC) us-
ing silica gel 60 aluminum plates, coated with fluorescent indicator F-
254 from Merck, which were visualized under UV light (254 nm).
Compounds were purified by column chromatography using silica gel
60 Merck 0.04 to 0.063 (230–400 mesh ASTM). Melting points report-
ed were obtained with a Mel-Temp II apparatus, and are uncorrected.
1H, 13C, and 19F NMR spectra were recorded with Bruker Avance 300
and Varian 500 NMR Systems, in CDCl3 with TMS as the internal stan-
dard; chemical shifts are reported in ppm. Mass spectra were record-
ed with a Shimadzu GCMS-QP2010 plus (EI, 70 eV).
Yield: 274 mg (80%); brown oil.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.34 (m, 3 H), 7.25–7.19 (m, 2 H),
3.24 (s, 3 H), 2.94 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.52, 164.36 (q, J = 35.6 Hz), 132.56,
130.54, 128.78, 127.42, 116.83 (q, J = 288.3 Hz), 40.50, 38.99.
Trifluoroacetamidine (1)
In a 100 mL round flask equipped with a dry-ice/acetone cooled con-
denser and immersed in a dry-ice/acetone bath, ammonia and triflu-
oroacetonitrile were condensed. The reaction was stirred at –78 °C for
1 h and the cold bath was removed. The excess of ammonia was evap-
orated at r.t. and the remains of ammonia were removed under vacu-
um to give the product as a colorless oil.
19F NMR (282 MHz, CDCl3): δ = –75.82.
1H NMR (300 MHz, CDCl3): δ = 5.98 (br s).
N-tert-Butoxycarbonyltrifluoroacetamidine (6)
13C NMR (125 MHz, CDCl3): δ = 154.67 (dd, J = 69.6, 34.8 Hz), 117.12
(q, J = 281.0 Hz).
19F NMR (282 MHz, CDCl3): δ = –74.56, –75.31.
Under a nitrogen atmosphere, a solution of di-tert-butylpyrocarbon-
ate (4.88 g, 22.36 mmol, 1.02 equiv) in anhydrous THF (10.0 mL) was
added dropwise at r.t. to a solution of trifluoroacetamidine 1 (2.46 g,
22 mmol, 1.0 equiv) and DMAP (5 mol%, catalytic amount) in anhy-
drous THF (10.0 mL). The reaction mixture was stirred for 20 h. After
this time, the reaction mixture was washed with saturated NH4Cl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
I. Medina-Mercado et al.
Paper
Synthesis
solution (30.0 mL) and extracted with EtOAc (3 × 20.0 mL). The organ-
ic phase was dried over Na2SO4 and the solvent was evaporated under
vacuum. The product was purified by flash column chromatography
(silica gel, hexanes–EtOAc 8:2) to give 6.
19F NMR (282 MHz, CDCl3): δ = –70.34.
MS: m/z (%) = 264 (5) [M+], 233 (92), 206 (39), 175 (86), 148 (90), 51
(100).
Yield: 2.9 g (62%); colorless oil.
Dimethyl 6-Methyl-2-trifluoromethylpyrimidine-4,5-dicarboxyl-
ate (4b)
1-tert-Butoxycarbonyl-2-trifluoromethyl-1,3-diazabutadienes
2d–f; General Procedure
By following the general procedure using 2b (220 mg, 1.24 mmol) and
DMAD (0.3 mL, 2.44 mmol), 4b was obtained and purified by column
chromatography (silica gel, hexanes–EtOAc 9:1).
Under a nitrogen atmosphere, the amide acetal (1.2–2.7 equiv) was
added to a solution of N-tert-butoxycarbonyltrifluoroacetamidine 6
(1.0 equiv) in anhydrous THF (5.0 mL). The solution was heated at re-
flux (30–90 min), then the remains of solvent and the amide acetal
were evaporated under vacuum to obtain the product as an oil. These
compounds were used in crude form for the following reactions.
Yield: 280 mg (64%); white solid; mp 69–70 °C (CH2Cl2–hexanes).
1H NMR (300 MHz, CDCl3): δ = 4.04 (s, 3 H), 4.02 (s, 3 H), 2.76 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.23, 165.29, 163.48, 156.34 (q, J =
37.8 Hz), 153.92, 128.19, 118.92 (q, J = 276.1 Hz), 53.89, 53.52, 22.74.
19F NMR (282 MHz, CDCl3): δ = –70.42.
1-tert-Butoxycarbonyl-2-trifluoromethyl-4-N,N-dimethylamino-
1,3-diazabutadiene (2d)
MS: m/z (%) = 278 (4) [M+], 219 (35), 190 (100), 161 (36), 110 (33).
By following the general procedure using 6 (210 mg, 1.01 mmol), N,N-
dimethylformamide dimethylacetal (0.17 mL, 1.2 mmol, 1.2 equiv) in
30 min, 2d was obtained.
Dimethyl 6-Phenyl-2-trifluoromethylpyrimidine-4,5-dicarboxyl-
ate (4c)
By following the general procedure using 2c and DMAD (0.34 mL,
2.76 mmol), 4c was obtained and purified by column chromatogra-
phy (silica gel, hexanes–EtOAc 9:1).
Yield: 203 mg (88%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.12 (s, 1 H), 3.13 (s, 3 H), 3.09 (s, 3 H),
1.51 (s, 9 H).
19F NMR (282 MHz, CDCl3): δ = –70.32.
Yield: 100 mg (22%); white solid; mp 120–122 °C (CH2Cl2–hexanes).
1H NMR (300 MHz, CDCl3): δ = 7.80–7.77 (m, 2 H), 7.61–7.50 (m, 3 H),
4.06 (s, 3 H), 3.87 (s, 3 H).
1-tert-Butoxycabonyl-2-trifluoromethyl-4-N,N-dimethylamino-
1,3-diazapentadiene (2e)
13C NMR (75 MHz, CDCl3): δ = 166.39, 165.46, 162.99, 156.07 (q, J =
37.9 Hz), 154.44, 134.68, 131.29, 128.57, 128.41, 126.96, 118.57 (q, J =
276.2 Hz), 53.55, 53.02.
19F NMR (282 MHz, CDCl3): δ = –70.28.
MS: m/z (%) = 340 (86) [M+], 325 (100), 309 (85), 224 (91), 127 (88).
By following the general procedure using 6 (240 mg, 1.17 mmol), N,N-
dimethylacetamide dimethylacetal (0.28 mL, 1.72 mmol, 1.5 equiv) in
1 h, 2e was obtained.
Yield: 300 mg (92%); yellow oil.
Dimethyl 6-Ethyl-2-trifluoromethylpyrimidine-4,5-dicarboxylate
(4d)
1-tert-Butoxycabonyl-2-trifluoromethyl-4-N,N-dimethylamino-
1,3-diazahexadiene (2f)
Under a nitrogen atmosphere, a solution of 1,3-diazabutadiene 2f
(130 mg, 0.44 mmol) and TFA (0.35 mL, 4.54 mmol, 10.0 equiv) in an-
hydrous CH2Cl2 (4.0 mL) was heated at reflux for 3 h and stirred for 15
h at r.t. After this time, the excess of TFA and solvent were removed
under vacuum to obtain the 1,3-diazadienium trifluoroacetate as a
brown oil. Subsequently, the oil was dissolved in anhydrous CH2Cl2
(1.0 mL), DIPEA (0.24 mL, 1.37 mmol, 3.0 equiv) and DMAD (0.11 mL,
0.89 mmol, 2.0 equiv) were added dropwise at 0 °C and the mixture
reaction was stirred at r.t. for 3 h. After this time, the mixture was
washed with saturated NH4Cl solution (20.0 mL) and extracted with
CH2Cl2 (3 × 15.0 mL). The organic phase was dried over Na2SO4 and
the solvent was evaporated under vacuum. The product was purified
by column chromatography (silica gel, hexanes–EtOAc 8:2) to give 4d.
By following the general procedure using 6 (134 mg, 0.634 mmol),
N,N-dimethylpropionamide dimethylacetal (253 mg. 1.72 mmol, 2.7
equiv) in 1.5 h, 2f was obtained.
Yield: 130 mg (72%); yellow oil.
2-Trifluoromethylpyrimidines 4a–c; General Procedure
Under a nitrogen atmosphere, DMAD (2.0 equiv) was added dropwise
to a solution of 1,3-diazabutadiene 2 in anhydrous CH2Cl2 (5.0 mL) at
r.t., then the reaction was stirred for 3 h. After this time, the mixture
was washed with saturated NH4Cl solution (20.0 mL) and extracted
with CH2Cl2 (3 × 15.0 mL). The organic phase was dried over Na2SO4
and the solvent was evaporated under vacuum. The product was puri-
fied by column chromatography.
Yield: 55.6 mg (30%); white solid; mp 48–49 °C (CH2Cl2–hexanes).
1H NMR (300 MHz, CDCl3): δ = 4.03 (s, 3 H), 4.01 (s, 3 H), 2.99 (q, 2 H,
J = 7.5 Hz), 1.37 (t, 3 H, J = 7.5 Hz).
Dimethyl 2-Trifluoromethylpyrimidine-4,5-dicarboxylate (4a)
13C NMR (75 MHz, CDCl3): δ = 173.52, 165.47, 163.55, 156.59 (q, J =
37.8 Hz), 153.68, 128.05, 119.04 (q, J = 276.1 Hz), 53.91, 53.51, 29.19,
12.42.
By following the general procedure using 2a (190 mg, 1.14 mmol) and
DMAD (0.28 mL, 2.29 mmol), 4a was obtained and purified by col-
umn chromatography (silica gel, hexanes–EtOAc 9:1).
19F NMR (282 MHz, CDCl3): δ = –70.37.
MS: m/z (%) = 292 (35) [M+], 260 (73), 232 (25), 202 (56), 174 (100),
Yield: 110 mg (37%); white solid; mp 79–80 °C (CH2Cl2–hexanes).
1H NMR (300 MHz, CDCl3): δ = 9.43 (s, 1 H), 4.06 (s, 3 H), 4.03 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 163.90, 162.34, 160.10, 159.58, 158.42
(q, J = 38.3 Hz), 123.61, 118.83 (q, J = 276.2 Hz), 53.73, 53.65.
59 (57).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
I. Medina-Mercado et al.
Paper
Synthesis
Cycloaddition Reaction of 1,3-Diazabutadienium Trifluoroacetate
7e with Phenylacetyl Chloride
Funding Information
The Consejo Nacional de Ciencia y Tecnologia is gratefully acknowl-
edged for providing a M.Sc. fellowship to Ignacio Medina (CONACyT
581817 and grant S-26659).
Under a nitrogen atmosphere, Et3N (0.68 mL, 4.87 mmol, 6.0 equiv)
and phenylacetyl chloride (0.21 mL, 1.59 mmol, 2.0 equiv) were add-
ed dropwise at 0 °C to a solution of 1,3-diazabutadienium trifluoroac-
etate (generated from 220 mg of 2e) in anhydrous CH2Cl2 (5.0 mL).
The reaction was stirred at r.t. for 2 h. After this time, two products
were observed by TLC analysis (8 and 9) and the mixture reaction was
washed with saturated NH4Cl solution (10.0 mL) and the product was
extracted with CH2Cl2 (3 × 15.0 mL). The organic phase was dried over
Na2SO4 and the solvent was evaporated under vacuum. The product
was purified by column chromatography (silica gel, using hexanes–
EtOAc 9:1).
C
o
nsoe
j
N
a
ocin
a
l
de
Ceinaci
y
Te
c
n
o
lga
i
C(
O
N
A
C
y
T
5
8
1
8
1
7
C)
o
nsoe
j
N
a
ocin
a
l
de
Ceinaci
y
Te
c
n
o
lga
i
S(-2
6
6
5
9)
Acknowledgment
The authors wish to thank María de las Nieves Zavala Segovia, M Sc.
(CCIQS UNAM-UAEM) for obtaining NMR spectra and M. Sc. Lizbeth
Triana Cruz for obtaining mass spectra.
Supporting Information
6-Methyl-5-phenyl-2-trifluoromethylpyrimidin-4(3H)-one (8)
Supporting information for this article is available online at
Yield: 55.6 mg (28%); white solid; mp 177–179 °C (CH2Cl2–hexanes).
1H NMR (300 MHz, CDCl3): δ = 7.47–7.41 (m, 3 H), 7.32–7.26 (m, 2 H),
https://doi.org/10.1055/s-0037-1610444.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.34, 163.83, 147.83 (q, J = 38.3 Hz),
131.88, 129.55, 128.59, 128.53, 126.21, 117.94 (q, J = 276.4 Hz), 22.74.
19F NMR (282 MHz, CDCl3): δ = –70.75.
References
(1) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(2) (a) Harsanyi, A.; Sandford, G. Green Chem. 2015, 17, 2081.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (c) Hagmann, W. K. J. Med. Chem. 2008,
51, 4359. (d) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(e) Salas, P. F.; Herrmann, C.; Orvig, C. Chem. Rev. 2013, 113,
3450.
MS: m/z (%) = 254 (97) [M+], 253 (100), 233 (45), 89 (45).
6-Methyl-5-phenyl-2-trifluoromethylpyrimidin-4-yl-2-phenylac-
etate (9)
Yield: 46 mg (20%); white solid; mp 137–140 °C (CH2Cl2–hexanes).
(3) Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem.
2010, 131, 951.
(4) Alonso, C.; Martínez De Marigorta, E.; Rubiales, G.; Palacios, F.
Chem. Rev. 2015, 115, 1847.
(5) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013,
52, 8214.
(6) Zhu, W.; Wang, J.; Wang, S.; Gu, Z.; Aceña, J. L.; Izawa, K.; Liu, H.;
Soloshonok, V. A. J. Fluorine Chem. 2014, 167, 37.
(7) Ma, J. A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975.
(8) Barone, J. A.; Peters, E.; Tieckelmann, H. J. Org. Chem. 1959, 24,
198.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.35 (m, 3 H), 7.23–7.21 (m, 3 H),
7.14–7.11 (m, 2 H), 6.94–6.93 (m, 2 H), 3.60 (s, 2 H), 2.47 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.12, 167.16, 162.58, 154.21 (q, J =
37.5 Hz), 131.08, 130.26, 128.64, 128.43, 128.22, 128.07, 127.97,
127.86, 126.58, 118.35 (q, J = 275.7 Hz), 39.90, 22.10.
19F NMR (282 MHz, CDCl3): δ = –70.27.
MS: m/z (%) = 254 (56), 253 (57), 136 (100), 92 (69), 65 (65).
4-Chloro-6-methyl-5-phenyl-2-trifluoromethylpyrimidine (10)
POCl3 (2.0 mL, 21.8 mmol, 10.0 equiv) was added to the crude mix-
ture of 8 and 9 in toluene (5.0 mL) and the mixture was heated at re-
flux for 12 h. After this time, the solvent and residual POCl3 were
evaporated under vacuum and the residue was washed with saturat-
ed NaHCO3 solution (30.0 mL), and the product was extracted with
CH2Cl2 (5 × 10 mL). The organic phase was dried over Na2SO4 and the
solvent was removed under vacuum. The product was purified by col-
umn chromatography (silica gel, hexanes–EtOAc 9:1) to give 10.
(9) Inoue, S.; Saggiomo, A. J.; Nodiff, E. A. J. Org. Chem. 1961, 26,
4504.
(10) Kawase, M.; Hirabayashi, M.; Salto, S.; Yamamoto, K. Tetrahe-
dron Lett. 1999, 40, 2541.
(11) Soufyane, M.; Mirand, C.; Lévy, J. Tetrahedron Lett. 1993, 34,
7737.
(12) Mirand, C.; Soufyane, M.; van den Broek, S.; Khamliche, L. Het-
erocycles 1999, 51, 2445.
(13) Berber, H.; Soufyane, M.; Mirand, C.; Schmidt, S.; Aubertin, A. M.
Tetrahedron 2001, 57, 7369.
Yield: 0.1196 g (40% from 6); white solid; mp 73–74 °C (CH2Cl2–hex-
anes).
(14) Berber, H.; Soufyane, M.; Santillana-Hayat, M.; Mirand, C. Tetra-
hedron Lett. 2002, 43, 9233.
(15) Ondi, L.; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem. 2004, 3714.
(16) Takahashi, M.; Akiyama, K.; Suzuki, T.; Inoue, H. J. Heterocycl.
Chem. 2008, 45, 601.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.52 (m, 3 H), 7.26–7.24 (m, 2 H),
2.45 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 168.86, 160.94, 154.38 (q, J = 37.9 Hz),
135.60, 133.08, 128.95, 128.82, 128.25, 118.65 (q, J = 275.9 Hz), 23.29.
19F NMR (282 MHz, CDCl3): δ = –70.35.
(17) Sukach, V. A.; Tkachuk, V. M.; Rusanov, E. B.; Röschenthaler, G.
V.; Vovk, M. V. Tetrahedron 2012, 68, 8408.
MS: m/z (%) = 274 (32) [M++2], 272 (100) [M+], 140 (54), 115 (52), 69
(18) Boger, D. L. Tetrahedron 1983, 39, 2869.
(19) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002,
58, 379.
(66).
(20) Matsuda, I.; Yamamoto, S.; Ishii, Y. J. Chem. Soc., Perkin Trans. 1
1976, 1528.
(21) Mazumdar, S. N.; Mukherjee, S.; Sharma, A. K.; Sengupta, D.;
Mahajan, M. P. Tetrahedron 1994, 50, 7579.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
I. Medina-Mercado et al.
Paper
Synthesis
(22) Barluenga, J.; Tomás, M.; Ballesteros, A.; López, L. A. Tetrahedron
Lett. 1989, 30, 4573.
(27) Lechuga-Eduardo, H.; Olivo, H. F.; Romero-Ortega, M. Eur. J. Org.
Chem. 2014, 5910.
(23) Sain, B.; Singh, S. P.; Sandhu, J. S. Tetrahedron 1992, 48, 4567.
(24) Abbiati, G.; Cirrincione de Carvalho, A.; Rossi, E. Tetrahedron
2003, 59, 7397.
(25) Guzmán, A.; Romero, M.; Talamás, F. X.; Villena, R.; Greenhouse,
R.; Muchowski, J. M. J. Org. Chem. 1996, 61, 2470.
(26) Seballos-Resendiz, A.; Lechuga-Eduardo, H.; Barroso-Flores, J.;
Martinez-Otero, D.; Romero-Ortega, M. Synthesis 2016, 48,
2205.
(28) Husted, D. U.S. Patent 2 676 985, 1954.
(29) Reilly, W. L.; Brown, H. C. J. Am. Chem. Soc. 1956, 78, 6032.
(30) Barone, J. A.; Peters, E.; Tieckelmann, H. J. Org. Chem. 1959, 24,
198.
(31) Moss, R. A.; Guo, W.; Denney, D. Z.; Houk, K. N.; Rondanlb, N. G.
J. Am. Chem. Soc. 1981, 103, 6164.
(32) Bredereck, H.; Effenberger, H.; Beyerlin, F. Chem. Ber. 1964, 97,
3081.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G