A novel access to 4-trifluoromethyl-1,3-thiazole derivatives via an intermediate thiocarbonyl ylide

Article abstract of DOI:10.1016/j.jfluchem.2019.02.003

A Lewis acid catalyzed reaction of trifluoroacetyldiazomethane (CF₃COCHN₂) with thiourea occurs in boiling THF solution in the presence of BF₃·OEt₂ yielding 2-amino-4-trifluoromethyl-1,3-thiazole in a fair yield

Full text of DOI:10.1016/j.jfluchem.2019.02.003

Accepted Manuscript
Title: A novel access to 4-trifluoromethyl-1,3-thiazole
derivatives via an intermediate thiocarbonyl ylide
Authors: Emilia Obijalska, Magdalena Błaszczyk, Marcin K.
Kowalski, Grzegorz Mlosto n´ , Heinz Heimgartner
PII:
S0022-1139(19)30020-X
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.02.003
FLUOR 9286
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
11 January 2019
4 February 2019
4 February 2019
Please cite this article as: Obijalska E, Błaszczyk M, Kowalski MK, Mloston´
G, Heimgartner H, A novel access to 4-trifluoromethyl-1,3-thiazole derivatives
via an intermediate thiocarbonyl ylide, Journal of Fluorine Chemistry (2019),
https://doi.org/10.1016/j.jfluchem.2019.02.003
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Journal of Fluorine Chemistry,
A novel access to 4-trifluoromethyl-1,3-thiazole derivatives via an intermediate
thiocarbonyl ylide
a,
a
a
a
Emilia Obijalska *, Magdalena Błaszczyk , Marcin K. Kowalski , Grzegorz Mlostoń , Heinz
Heimgartnerb
aUniversity of Łódź, Faculty of Chemistry, Department of Organic and Applied Chemistry
Tamka 12, PL-91-403 Łódź, Poland,
b
University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich,
Switzerland
Emilia Obijalska
Department of Organic and Applied Chemistry,
Faculty of Chemistry, University of Łódź
Tamka 12, 91-403 Łódź, Poland
Tel.:
+48 42 665 50 41
Fax:
+48 42 665 51 62
e-mail:
emilkaobijalska@gmail.com
and
emilia.obijalska@uni.lodz.pl
Graphical abstract
HO
F C
N
3
F C
3
O
S
.
N
S
BF3 OEt2
+
R
N2
R
-
H O
2
F C
3
R
NH2
THF, reflux, 3.5-5 h or
PhMe, MW (500W), 2-4 min.
S
2
5-62%
Abstract
A Lewis acid catalyzed reaction of trifluoroacetyldiazomethane (CF
3
COCHN
2
) with thiourea
occurs in boiling THF solution in the presence of BF
3
.OEt
2
yielding 2-amino-4-
trifluoromethyl-1,3-thiazole in a fair yield. Analogous reactions with aromatic thioamides,
performed in the presence of a mesylchloride/triethylamine mixture as a dehydrating agent led
to the corresponding 2-aryl-4-trifluoromethyl-1,3-thiazoles. Aromatic thioamides also react
1

with CF
3
COCHN under MW irradiation, and after 2 min, the corresponding 1,3-thiazoles
2
were obtained in fair yields. The obtained fluorinated 2-amino-1,3-thiazole was used for the
reactions with selected N-alkylating and N-acylating reagents to give trifluoromethylated
analogues of commonly known pharmaceuticals with 1,3-thiazole structures (Fanetizole and
Lotifazole).
Keywords: Diazo compounds, 1,3-thiazoles, fluoroalkylated heterocycles, thioamides, boron
trifluoride, thiocarbonyl ylides
1
. Introduction
Reactions of diazo compounds 1 with thioketones 2 and other thiocarbonyl derivatives
offer an attractive synthetic approach to more complex sulfur-containing and also sulfur-free
products. They are formed in domino reactions, in which thiocarbonyl ylides 3 are the key
intermediates. Depending on the substitution pattern of the starting materials, the ‘in situ’
formed thiocarbonyl ylides can undergo diverse reactions such as 1,3- and 1,5-dipolar
electrocyclization, [3+3]-dimerization, or [3+2]-cycloaddition with a suitable dipolarophile
(Scheme 1). In addition, the trapping of the reactive intermediate with diverse nucleophiles is
also known as inter- as well as intramolecular processes [1].
2

N2
S
+
R1
R2
R3
R4
Ar
Ar
R3
1
2
S
R1
R2
R3
R4
Ar
Ar
R1
R4
-N2
1
2
R , R = H
S
-[S]
S
R2
3
4
R , R = Ar
5
4
7
R1
R3
[
3+3]-CA
1,3-EC
R2
S
R4
3
5
A=B
3+2]-CA
R = COR
3
1
,5-EC
[
R5
A B
R5 XH
X = O, S, NR
R1
R2
R3
R4
O
R1
S
R4
R2
S
8
6
XR5 R3
R1
R2
S
R4
6
Scheme 1. Generation and typical reactions of the in situ generated thiocarbonyl ylides 3.
Thiocarbonyl ylides 3 can be generated either via initial [3+2]-cycloaddition of a diazo
and a thiocarbonyl compound, followed by N
2
elimination, or by the initial metal-catalyzed
[
1c,2] or microwave-assisted decomposition of the diazo compound 1 [3] and subsequent
addition of the carbene formed thereby onto the sulfur atom of 2.
The most reactive thiocarbonyl compounds are thioketones and thioesters. In contrast,
thioamides are less reactive dipolarophiles and do not react with diazo compounds via the
[
3+2]-cycloaddition pathway. On the other hand, the most reactive diazo 1,3-dipoles are
diazomethane (CH ) and its alkyl and aryl derivatives; the presence of an electron
withdrawing carbonyl group in α-position substantially reduces their 1,3-dipolar reactivity
1d,2].
2
N
2
[
Among the five-membered aromatic sulfur heterocycles, 1,3-thiazoles are of great
importance as biologically active compounds with a wide range of pharmaceutical
applications [4]. One of the most important building blocks is 2-amino-1,3-thiazole, which is
used for the preparation of diverse derivatives functionalized at the amino group [5]. For
example, in a very recent publication, a multicomponent reaction for the synthesis of highly
substituted 2-amino-1,3-thiazoles was reported [5c].
3

It is well documented that the introduction of a fluoroalkyl group modifies not only the
physico-chemical properties of the organic compound but also contributes to the amplification
of its biological activity [6]. In general, fluoroalkylated 1,3-thiazoles are rarely described, but
2
-amino-4-trifluoromethyl-1,3-thiazole has already been reported [7], and it is recommended
as a versatile synthon for the preparation of highly functionalized derivatives. The described
syntheses are based on heterocyclization reactions starting with thiourea and 1,1,1-trifluoro-3-
haloacetone [7a–c] or 1-phenylsulfonyl-1-trifluoromethyloxirane [7d,e].
The goal of the presented study was the elaboration of a new method for the synthesis
of some 2-substituted 4-trifluoromethyl-1,3-thiazole derivatives, including the 2-amino
representative, via a ‘thiocarbonyl ylide approach’.
2
. Results and discussion
In analogy to other acyldiazomethanes, 1-diazo-3,3,3-trifluoropropanone (10) was
prepared according to the Arndt–Eistert method from trifluoroacetic acid anhydride (TFAA)
and diazomethane (CH ) [8]. The test reactions aimed at the preparation of 2-amino- and 2-
2
N
2
phenyl-4-trifluoromethyl-1,3-thiazoles 12a and 12b were carried out using the fluorinated α-
diazoketone 10 and thiourea (11a) or thiobenzamide (11b), respectively. The reactions were
performed in boiling, anhydrous tetrahydrofuran (THF) solution, in the presence of boron
trifluoride etherate (BF .
the reaction was complete, and in the case of thiourea (11a), only one product was obtained in
5% yield. Based on spectroscopic data, its structure was elucidated as 2-amino-4-
OEt ) as a strong Lewis acid. Under these conditions, after 3.5–5 h
3
2
3
trifluoromethyl-1,3-thiazole (12a, Scheme 2). On the other hand, the experiment with
thiobenzamide (11b) led to a mixture of two products identified as the expected 1,3-thiazole
1
2b and its hydrated precursor 13.
F C
3
N
R = NH2
NH2
S
O
S
BF3 . OEt2
THF, reflux
1
2a (62%)
N2
+
F C
3
R
NH2
OH
S
F C
3
-N2
F C
3
N
N
10
11a R = NH2
1b R = Ph
+
1
R = Ph
Ph
Ph
S
12b (38%)
13 (25%)
4

Scheme 2. Reaction of diazo compound 10 with thiourea (11a) and thiobenzamide (11b) in
the presence of BF leading to 1,3-thiazoles 12.
.OEt
3
2
Based on these results, the reaction with 11b was repeated and the crude reaction
mixture was treated with phosphorus pentoxide (P or mesyl chloride
MsCl)/triethylamine (TEA) in order to dehydrate the initially formed product 13. Under these
2
5
O )
(
conditions only compound 12b was obtained in up to 48% yield (Scheme 3). Further
optimization of the reaction conditions showed that 1,2-dimethoxyethane (DME) can be used
as an alternative solvent and a comparable result was obtained with 11b as in THF solution.
The replacement of BF .
DCE) led again to mixtures of 12b and 13; the ratio of both products in the case of Cu(OTf)
was established to ca. 1:8 (total yield was 54%).
OEt
by other Lewis acids such as Cu(OTf) in 1,2-dichloroethane
3
2
2
(
2
Scheme 3. Yields of 4-trifluoromethyl-1,3-thiazoles 12 prepared under different conditions
(aMethod A: (a) BF .
OEt
, THF, reflux; (b) P
O
5
dehydration; Method B: (a) BF
b
.OEt
, PhMe, MW (500W)).
, THF,
3
3
2
3
3
c
.OEt
reflux; (b) MsCl/TEA dehydration; Method C: BF
3
3
5

The obtained results prompted us to check if corresponding carbonyl compounds, i.e.
thiourea and benzamide, can be used in the reaction with 10 to give 1,3-oxazole derivatives.
However, the experiments performed under the optimized conditions were unsuccessful.
Using the optimized conditions (THF, BF
3
.OEt
, reflux; MsCl/TEA), reactions of 10
2
with 4-methoxy- and 4-nitrothiobenzamide (11c,d) were performed and the desired 1,3-
thiazoles 12c and 12d were obtained in 32% and 27% yield, respectively (Scheme 3).
Analogously, the reaction with 4-chlorothiobenzamide (11e) and P
2e in 26%. Unexpectedly, applying the same procedure for the reaction with thioacetamide
afforded the expected 1,3-thiazole 12f only in traces.
2
5
O dehydration yielded
1
In a recent publication, reactions of hetaryl thioketones with less reactive -
diazoketones under microwave (MW) irradiation, leading to diverse products, have been
reported [3]. In all cases, thiocarbonyl ylides were proposed as reactive intermediates.
Prompted by these results, we decided to examine reactions of 10 with aromatic thioamides in
a microwave reactor. To our delight, the test reaction with thiobenzamide (11b) performed in
toluene in the presence of BF
3
.OEt
afforded after 2 min irradiation 1,3-thiazole 12b in 52%
2
yield. Similar results were obtained with 11c–e, leading to the corresponding products 12c–e
in acceptable yields (Scheme 3). Unfortunately, the analogous syntheses of 2-amino- and 2-
methyl-4-trifluoromethyl-1,3-thiazoles 12a and 12f under MW-irradiation were unsuccessful.
In the second part of this study, 2-amino-1,3-thiazole 12a was converted into 2-N-
functionalized derivatives by treatment with some electrophilic agents such as 1-bromo-2-
phenylethane (14) and 2,2,2-trichloroethyl chloroformate (16), respectively. The
corresponding products 15 and 17 were obtained in good yields, and in each case a
trifluoromethylated analogue of an already known 1,3-thiazole-derived drug (Fanetizole and
Lotifazole, respectively) [9] is represented (Scheme 4).
O
F C
3
Br
F C
3
F3C
Ph
Ph
Cl
O
CCl3
O
CCl3
N
N
N
14
16
O
N
NH2
N
S
Cs CO ,
DMF, reflux
S
DMAP, TEA, DCM, rt
S
H
2
3
H
15
12a
17
Scheme 4. N-Alkylations of 2-amino-1,3-thiazole 12a leading to fluorinated analogues of
already known bioactive compounds.
6

The mechanism of the reaction leading to 4-trifluoromethylated 1,3-thiazoles 12
requires a comment. Taking into account that thioamides, and especially thiourea, are known
as very poor dipolarophiles, and fluorinated diazoketones belong to the less reactive 1,3-
dipoles, a typical [3+2]-cycloaddition of 10 and 11 can be excluded as the initial step of the
described reaction. Addition of BF
0, which is converted into a reactive species corresponding to an electrophilic carbene-type
intermediate. The latter attacks the S-atom of the thioamide to give a thiocarbonyl ylide 18
Scheme 5), very likely complexed with BF . This complexation may hinder the typical 1,5-
dipolar electrocyclization of α-oxo thiocarbonyl ylides leading to 1,3-oxathiols 6 (Scheme 1).
Instead, the activated carbonyl group is attacked by the NH group to form the 1,3-thiazole
3
.OEt
2
, acting as a strong Lewis acid, leads to activation of
1
(
3
2
skeleton in the intermediate 19. The observed formation of product 13 occurs via 1,4-proton
migration. A competitive pathway via dehydration of 19 leads to 1,3-thiazole 12, which can
also be formed via elimination of H
2
O from compound 13.
O
H
CF3
S
HO
F C
BF3
F3B
3
NH
O
S
N2
+
H
R
F C
3
R
NH2 -N2
S
R
NH2
10
11
18
19
1,4-H-shift
-
H O
2
F C
3
HO
F C
N
3
N
R
-H O
2
R
S
S
12
13
Scheme 5. Mechanistic explanation of the formation of 1,3-thiazoles 12 from diazo
compound 10 and thioamides 11 via the intermediate thiocarbonyl ylide 18.
3
. Conclusions
The presented study shows a new methodology for the synthesis of 2-amino- and 2-
aryl-4-trifluoromethyl-1,3-thiazoles via in situ-formed thiocarbonyl ylides. The reaction
7

occurs in the presence of boron trifluoride etherate (BF
3
.OEt
) as a strong Lewis acid, which
2
activates the diazo compound and, very likely, prevents the expected 1,5-dipolar
electrocyclization of the transient thiocarbonyl ylide leading to a 1,3-oxathiole. Instead, the
intramolecular nucleophilic attack of the NH
in the formation of the 1,3-thiazole. 2-Aryl-4-trifluoromethyl-1,3-thiazoles were also prepared
from aromatic thioamides and CF COCHN under MW irradiation for 2 min. Furthermore,
2
group onto the activated carbonyl group results
3
2
the obtained trifluoromethylated 2-amino-1,3-thiazole was used as an attractive building block
for the preparation of fluorinated analogues of some 1,3-thiazole-based pharmaceuticals.
4
. Experimental
4
.1. General information
Solvents and chemicals were purchased and used as received without further
purification. Tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), diethyl ether (Et O) and
2
toluene (PhMe) were distilled over sodium/benzophenone(violet-coloured solution prior to
use). Trifluoroacetic acid anhydride (TFAA), 2-(bromoethyl)benzene and 2,2,2-
trichloroethylchloroformate were purchased from FluoroChem; sodium nitrite (NaNO
thiourea were purchased from Avantor; thioamides 11a–e, boron trifluoride etherate
BF ), and triethylamine (TEA) were purchased from Sigma-Aldrich (Merck). Obtained
.OEt
2
) and
(
3
2
products were purified by standard column chromatography on silica gel (230–400 mesh,
Merck) or FLASH column chromatography using Grace Reveleris X2 apparatus with UV–Vis
and ELSD detection (commercially available 12 g or 24 g SiO
solvent flow rate 25–28 ml/min). Petroleum ether with increasing amounts of ethyl acetate
AcOEt) was used as eluent. Unless stated otherwise, yields refer to analytically pure samples.
2
columns, pressure 20–25 psi,
(
1
13
NMR spectra were recorded with Bruker Avance III 600 MHz ( H NMR [600MHz]; C
1
9
NMR [151 MHz]; F NMR [565 MHz]) instrument. Chemical shifts are reported in ppm
1
13
relative to solvent residual peaks ( H NMR: δ = 7.26 ppm [CHCl
3
]; C NMR: δ = 77.0 ppm
[
CDCl ]). For detailed peak assignments 2D (HMQC) spectra were measured. IR spectra were
3
measured with a FTIR NEXUS spectrometer (as KBr pellets). MS spectra were recorded on
Varian 500 MS LS IonTrap spectrometer. Melting points were determined in capillaries with
a Stuart SMP30 apparatus. Reactions under microwave conditions were carried out in CEM-
Discover SP reactor.
8

4
.2. Synthesis of the 4-trifluoromethyl-1,3-thiazoles 12a-f
Methods A and B: Reactions under thermal conditions - general procedure
Thiourea (11a) or an appropriate thioamide 11b–f (1.0 mmol) was dissolved in
anhydrous THF (1.0 ml), then BF
3
.OEt
2
(2.0 mmol, 0.25 ml) and 3-diazo-1,1,1-
trifluoropropan-2-one (10, 1.2 mmol, 166 mg) were added. The solution was heated under
reflux for 3.5–5 h (TLC control). After completion, the reaction was quenched with water and
the product was extracted with dichloromethane (DCM) (4 x 15 mL). The combined organic
layers were dried over anhydrous Na
2
SO , and the solvent was removed ‘in vacuo’. Obtained
4
compounds were separated and purified by standard column chromatography (SiO
petroleum ether with increasing amounts (up to 80%) of AcOEt.
2
, eluent:
Method A: Dehydration of mixtures containing compounds of type 13 - reactions with P
2
5
O -
general procedure
The reaction mixture obtained with 11b–f was dissolved in 0.5 mL DCM and then
diluted with toluene (10 mL). Then, phosphorus pentoxide (P ) was added and the reaction
mixture was heated under reflux. After 1 h, the mixture was neutralized with saturated,
aqueous NaHCO solution and extracted with DCM (4 x 15 mL), the combined organic
phases were dried over anhydrous Na SO , the drying agent was filtered off, and the solvents
were evaporated at reduced pressure. Obtained products were purified by standard column
2
O
5
3
2
4
chromatography (SiO
AcOEt.
2
, eluent: petroleum ether with increasing amounts (up to 30%) of
Method B: Dehydration of mixtures containing compounds of type 13 - reactions with mesyl
chloride (MsCl) and triethylamine (TEA) - general procedure
The reaction mixture obtained with 11b–f was dissolved in anhydrous DCM (25 mL),
mesyl chloride (MsCl, 1.2 equiv., 1.2 mmol, 138 mg) and triethylamine (TEA, 2.5 equiv, 2.5
mmol, 252 mg) were added while dissolved in DCM (~ 1 mL) and the reaction mixture was
heated at reflux for 1 h. Then, the mixture was neutralized with saturated, aqueous NaHCO
3
solution and extracted with DCM (4 x 15 mL), and the combined organic layers were dried
over anhydrous Na
2
SO
4
. The drying agent was removed by filtration and the solvent was
9

evaporated ‘in vacuo’. The obtained crude products were purified by column chromatography
SiO , eluent: petroleum ether with increasing amounts (up to 30%) of AcOEt.
(
2
Method C: Reactions under MW irradiation - general procedure
An appropriate thioamide 11b–f (1.0 mmol) was dissolved in anhydrous toluene (5
mL), then BF .
OEt (2.0 mmol, 0.25 ml) and 10 (1.2 mmol, 166 mg) was added. The solution
3
2
was placed in a microwave reactor and heated to 150 °C. After 2‒4 min irradiation, the
reaction was quenched with water and the product was extracted with DCM (4 x 15 mL). The
combined organic layers were dried over anhydrous Na
2
SO , and the solvent was removed ‘in
4
vacuo’. Obtained compounds were separated and purified by column chromatography (SiO ,
2
eluent: petroleum ether with increasing amounts (up to 30%) of AcOEt.
4
.2.1. 4-(Trifluoromethyl)-1,3-thiazol-2-amine (12a)
Yield: Method A: 104 mg (62%). Colourless crystals, mp 65–67 °C (PE/DCM; [9]:
1
6
8‒69.5 ºC). H NMR (CDCl
3
, 600 MHz):  = 5.55 (s, 2H, NH ), 6.95 (s, 1H, CHthiazole).
2
1
3
C-NMR:  = 110.2 (q, JC,F = 4.5 Hz, CHthiazole), 120.2 (q, 1JC,F = 268.5 Hz, CF
3
3
), 140.4
q, 2JC,F = 37.5 Hz, CCF
CF
055vs (CF
), 169.1 (C(2) thiazole). F NMR (CDCl
19
, 565 MHz):  = –65.21
(
(
3
3
3
). IR (KBr):  3287w, 3123br.w (NH), 1668w, 1627m, 1533m, 13736m, 1231s, 1172–
–
1
+
1
3
), 922s, 836m cm . ESI-(+)-MS: m/z 169 (100, [M+H] ); ESI-(–)-MS: m/z 167
–
(
100, [M–H] ). EA calcd. for C
4
H
3
F
3
2
N S (229.22): C 52.40, H 2.64, N 6.11; found: C 52.27,
H 2.41, N 6.26.
4
.2.2. 2-Phenyl-4-(trifluoromethyl)-1,3-thiazole (12b)
Yield: Method A: 110 mg (48%); Method B: 103 mg (45%); Method C:119 mg
1
(
52%). Colourless crystals, mp 48–49 °C (PE). H NMR (CDCl
3
, 600 MHz):  = 7.45–7.50
, 151 MHz): 
1
3
(
m, 3H, Ph), 7.73 (s, 1H, CHthiazole), 7.97–7.99 (m, 2H, Ph). C NMR (CDCl
3
=
120.5 (q, 3JC,F = 3.0 Hz, CHthiazole), 120.8 (q, 1JC,F = 268.5 Hz, CF
5CH, Ph), 132.8(1C, Ph), 146.0 (q, 2JC,F = 36.0 Hz, CCF
CDCl , 565 MHz):  = –64.01 (CF
230m, 1118–1083s (CF ), 984m, 903m, 732m cm . ESI-(+)-MS: m/z 230 (100, [M+H] ).
EA calcd. for C10 NS (168.14): C 28.57, H 1.80, N 16.66; found: C 28.86, H 1.96, N
6.92.
3
), 127.2, 129.4, 131.3
19
(
(
3
), 170.8 (C(2) thiazole). F NMR
3
3
). IR (KBr):  3144w, 1630w, 1465m, 1440m, 1366m,
–1
+
1
3
H
F
6 3
1
10

4
.2.3. 4,5-Dihydro-2-phenyl-4-(trifluoromethyl)-1,3-thiazol-4-ol (13)
Yield: Method A: 61 mg (25%). Colourless crystals, mp 129–131 °C (PE/DCM). H
NMR (CDCl , 600 MHz):  = 7.43–7.46 (m, 2H, Ph), 7.54–7.56 (m, 1H, Ph), 7.87–7.86 (m,
H, Ph). C NMR (CDCl , 151 MHz):  = 38.1 (CH ),
), 105.8 (q, 2JC,F = 30.0 Hz, CCF
23.5 (q, 1JC,F = 283.5 Hz, CF
), 128.9, 129.0, 133.0 (5CH, Ph), 131.9 (1C, Ph), 177.6 (C(2)
, 565 MHz):  = 82.63 (CF ). IR (KBr): ν 3107br.m (OH), 2799w,
600m, 1564m, 1493w, 1450w, 1322m, 1253s, 1179vs (CF ), 1060m, 1010s, 1000m, 955w
cm . ESI-(+)-MS: m/z 248 (100, [M+H] ). EA calcd. for C10 NOS (247.24): C 48.58, H
1
3
1
3
2
1
3
2
3
3
1
9
thiazole). F NMR (CDCl
3
3
1
3
–
1
+
H
F
8 3
3
.26, N 5.67; found: C 48.52, H 3.09, N 5.66.
4
.2.4. 2-(4-Methoxyphenyl)-4-(trifluoromethyl-1,3-thiazole (12c)
Yield: Method A: 104 mg (40%);Method B: 83mg (32%);Method C:80mg (31%).
1
Pale-yellow crystals, mp 50–51 °C (PE/DCM). H NMR (CDCl
3
, 600 MHz):  = 3.87 (s, 3H,
1
3
Me), 6.95–6.97 (m, 2 arom. H), 7.65 (s, 1H, CH thiazole), 7.90–7.92 (m, 2 arom. H). C
3
NMR (CDCl
3
, 151 MHz):  = 55.4 (Me), 114.4, 128.4 (4 arom. CH), 119.2 (q, JC-F = 7.0 Hz,
CH thiazole), 120.5 (q, 1JC,F = 268.7 Hz, CF
), 125.5, 161.9 (2 arom. C), 145.4 (q, 2JC,F = 37.5
) 170.3 (C(2) thiazole). F NMR (CDCl , 565 MHz):  = –64.04 (CF ). IR (KBr): ν
128w, 2941w, 2893w, 1577s, 1534m, 1522m, 1462vs, 1438s, 1417s, 1362s, 1181–1156vs
3
1
9
Hz, CCF
3
3
3
3
–
1
+
(
CF
3
), 1127vs, 1079vs, 1024vs, 983s, 907vs cm . ESI-(+)-MS: m/z 260 (100, [M+H] ). EA
NOS (259.25): C 50.96, H 3.11, N 5.40; found: C 50.94, H 2.94, N 5.51.
calcd. for C11
H F
8 3
4
.2.5. 2-(4-Nitrophenyl)-4-(trifluoromethyl-1,3-thiazole (12d)
Yield: Method B: 74 mg (27%); Method C: 88 mg (32%). Orange crystals, mp 131–
1
1
2
2
1
5
1
33 °C (PE/DCM). H NMR (CDCl
3
, 600 MHz):  = 7.89 (s, 1H, CH thiazole), 8.16–8.18 (m,
1
3
1
arom. H), 8.32–8.34 (m, 2 arom. H). C NMR (CDCl , 151 MHz):  = 120.6 (q, JC,F =
3
68.5 Hz, CF
3
), 122.6 (q, 3JC,F = 3.0 Hz, CH thiazole), 124.9, 128.0 (4 arom. CH), 138.2,
49.6 (2 arom. C), 147.1 (q, 2JC,F = 39.0 Hz, CCF
65 MHz):  = –64.03 (CF
235vs, 1182vs (CF ), 1136vs, 991s, 904m cm . ESI-(+)-MS: m/z 274 (100, [M] ). EA calcd.
S (274.22): C 43.80, H 1.84, N 10.22; found: C 43.71, H 1.83, N 10.50.
), 167.8 (C(2) thiazole). F NMR (CDCl
19
,
3
3
3
). IR (KBr): ν 3104m, 1598m, 1521vs, 1456m, 1406w, 1320vs,
–
1
+
3
for C10
H
5
F
3
N
2
O
2
4
.2.6. 2-(4-Chlorophenyl)-4-(trifluoromethyl-1,3-thiazole (12e)
11

Yield: Method B: 69 mg (26%); Method C: 145 mg (55%). Colourless crystals, mp
1
5
0–52 °C (PE/DCM). H NMR (CDCl
3
, 600 MHz):  = 7.44–7.45 (m, 2H, Ph), 7.75 (s, 1H,
1
3
1
CH thiazole), 7.91–7.92 (m, 2H, Ph). C NMR (CDCl , 151 MHz):  = 120.6 (q, JC,F =
3
2
1
5
1
68.5 Hz, CF
3
), 120.7 (q, 3JC,F = 3.0 Hz, CH thiazole), 128.3, 129.6 (4 arom. CH), 131.2,
37.4 (2 arom. C), 146.1 (q, 2JC,F = 36.0 Hz, CCF
65 MHz):  =–64.06 (CF
), 169.3 (C(2) thiazole). F NMR (CDCl
19
3
3
,
3
). IR (KBr): ν 3101w, 1597w, 1533w, 1457s, 1400m, 1250m,
–
1
+
228s, 1172–1125vs (CF
3
), 985s, 728m cm . ESI-(+)-MS: m/z 264 (100, [M+H] ), 266 (40,
ClF NS (263.66): C 45.55, H 1.91, N 5.31; found: C 45.78, H
+
[
M+H] ). EA calcd. for C10
H
5
3
2
.16, N 5.16.
4
.3. Alkylation of 2-amino-4-trifluoromethyl-1,3-thiazole (12a) – Synthesis of compound 15
2
-Amino-4-trifluoromethyl-1,3-thiazole (12a, 0.5 mmol, 84 mg) was dissolved in
anhydrous DMSO (3.0 mL), then 2-(bromoethyl)benzene (14, 1.5 mmol, 278 mg) and cesium
carbonate (2.5 mmol, 815 mg) were added. This solution was heated at 80 °C for 2 h. Then it
was extracted with DCM (4x15mL), the organic phases were combined and dried over
anhydrous Na
2
SO
4
, and the solvent was evaporated ‘in vacuo’. The obtained product was
, eluent: petroleum ether with increasing
purified by standard column chromatography (SiO
2
amounts (up to 20%) of AcOEt). It was crystallized from a mixture of hexane, heptane and DCM
by slow evaporation of the solvent.
N-Phenylethyl-4-(trifluoromethyl)-1,3-thiazol-2-amine (15). Yield: 53 mg (39%).
1
Colourless crystals, mp 120–121 °C (PE/DCM). H NMR (CDCl
3
, 600 MHz):  = 2.95–2.97
(
t, 2H, CH
.27 (m, 3H, Ph), 7.32–7.34 (m, 2H, Ph). C NMR (CDCl
CH
NH), 108.2 (q, 3JC,F = 4.5 Hz, CH thiazole), 120.4 (q, 1JC,F = 268.5 Hz, CF
29.4, 131.3 (5CH, Ph), 132.8 (1C, Ph), 141.0 (q, 2JC,F = 157.5 Hz, CCF
), 170.8 (C(2)
). IR (KBr): ν 3222w (NH), 3116w,
993w, 2918w, 2861w, 1604m, 1377m, 1235m, 1156–1121vs (CF ), 1071m, 1007w, 918w
Ph] ). EA calcd. for C12 S (272.29): C
2.93, H 4.07, N 10.29; found: C 52.85, H 3.86, N 10.38.
2
), 3.53–3.56 (q, 2H, CH
2
NH), 5.63 (brs, 1H, NH), 6.92 (s, 1H, CH thiazole), 7.22–
1
3
7
3
, 151 MHz):  = 35.3 (CH
2
), 47.3
(
2
3
), 127.2,
1
3
1
9
thiazole). F NMR (CDCl
3
, 565 MHz):  = –64.06 (CF
3
2
3
–
1
–
cm . ESI-(–)-MS: m/z 260 (100, [M–CH
2
CH
2
H F
11 3
N
2
5
12

4
.4. Acylation of 2-amino-4-trifluoromethyl-1,3-thiazole (12a) – Synthesis of compound 17
2
-Amino-4-trifluoromethyl-1,3-thiazole (12a, 0.5 mmol, 84 mg) was dissolved in
anhydrous DCM (3 mL), then 2,2,2-trichloroethyl chloroformate (16, 0.75 mmol, 159 mg),
triethylamine (TEA, 0.55 mmol, 87.5 mg) and 4-dimethylaminopyridine (DMAP, 0.05 mmol, 6
mg) were added. This solution was stirred initially at 0 °C for 45 min, then warmed to room
temperature and stirred for 12 h. Then, the reaction mixture was washed with saturated, aqueous
NaHCO
layers were collected and dried over anhydrous Na
under reduced pressure. The obtained product was purified by standard column chromatography
SiO , eluent: petroleum ether with increasing amounts (up to 20%) of AcOEt). It was
crystallized from a mixture of hexane, heptane and DCM by slow evaporation of the solvent.
3
solution and water. The product was extracted with DCM (4x10 mL). The organic
2
SO and the organic solvent was evaporated
4
(
2
2
,2,2-Trichloroethyl-N-[4-(trifluoromethyl)thiazol-2-yl]carbamate (17). Yield: 154
1
mg (90%). Colourless crystals, mp 118–120 °C (PE). H NMR (CDCl
3
, 600 MHz):  = 4.89
, 151 MHz):  =
), 115.7 (q, 3JC,F = 3.0 Hz, CH thiazole), 120.3 (q, 1JC,F = 268.5 Hz,
1
3
(
s, 2H, CH
5.4 (CH ), 94.3 (CCl
CF
), 140.3 (q, 2JC,F = 37.5 Hz, CCF
65 MHz):  = –64.58 (CF ). IR (KBr): ν 3188br.m (NH), 3076m, 2968m, 2789w, 1748vs
C=O), 1567vs, 1458m, 1374s, 1289vs, 1147–1110vs (CF
2
), 7.41 (s, 1H, CH thiazole), 8.77 (s, 1H, NH). C NMR (CDCl
3
7
2
3
19
3
3
) 151.6 (C(2) thiazole), 160.0 (C=O). F NMR (CDCl ,
3
5
3
–
1
(
(
3
), 923vs cm . ESI-(–)-MS: m/z 341
S (343.53): C 24.57, H 1.17,
–
–
100, [M–H] ), 343 (43, [M–H] ). EA calcd. for C
7
H
4
Cl
3
F
3
N
2
O
2
N 8.15; found: C 24.49, H 1.32, N 8.22.
Acknowledgements
This work is a part of the M.Sc. thesis of M. Błaszczyk, University of Łódź (2018).
Financial support by the National Science Center (Poland, Cracow) Grant PRELUDIUM–8
(project number 2014/15/N/ST5/02895)) is gratefully acknowledged.
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