Copper-catalyzed three component C[sbnd]S/C[sbnd]N coupling for the synthesis of trifluorothioacetamides

Article abstract of DOI:10.1016/j.jfluchem.2020.109640

A copper-catalyzed three component C[sbnd]S/C[sbnd]N coupling reaction of imines with sulfur and CFC-113a was developed. The reaction involves amination and C[dbnd]S double bond formation of CFC-113a, leading to biologically important trifluorothioacetamides. The method features efficient construction of trifluorothioacetyl moiety from cheap sulfur and CFC-113a, and safe disposal for environmentally persistent Freon

Full text of DOI:10.1016/j.jfluchem.2020.109640

Journal of Fluorine Chemistry 239 (2020) 109640
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
– –
Copper-catalyzed three component C S/C N coupling for the synthesis
of trifluorothioacetamides
,c,
Bo-Lun Hua, Yi-Kang Songa, Guoqiang Zhangb, Zengwen Yaob, Xing-Guo Zhanga
*
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325035, China
b Huafon Group Company Limited, Wenzhou, 325200, China
c Guangxi Key Laboratory of Calcium Carbonate Resources Comprehensive Utilization, Hezhou University, Hezhou, 542899, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
– –
A copper-catalyzed three component C S/C N coupling reaction of imines with sulfur and CFC-113a was
–
Copper-catalyzed
developed. The reaction involves amination and C S double bond formation of CFC-113a, leading to biologi-
–
– –
S/C N coupling
C
cally important trifluorothioacetamides. The method features efficient construction of trifluorothioacetyl moiety
from cheap sulfur and CFC-113a, and safe disposal for environmentally persistent Freon
Trifluorothioacetamides
CFC-113a
1. Introduction
chlorofluorocarbons (CFCs) presents a major challenge, and Montreal
Protocol was achieved to phase out CFCs and other substances which
Thioamides are essential structural motifs found in a variety of bio-
logically active molecules [1], natural products (closthioamide) [2] and
pharmaceuticals [3], with remarkable biological and medicinal prop-
erties, including antibacterial, and inhibitor properties [1–3]. Further-
more, many thioamides derivatives have demonstrated wide
applications in diverse areas of science (fluorescence probes, supra
molecular scaffolds, metal-ions sensors) [4], as well as building blocks in
organic synthesis [5]. Consequently, considerable efforts have been
devoted to the development of efficient methods for the preparation of
thioamides and their derivatives [6]. However, the synthesis of tri-
fluorothioacetamides is rarely reported [[7]] although the incorporation
of CF3 group into organic molecules often enhances their biological
activity and has become a powerful strategy in drug design [8]. For
example, some trifluorothioacetamide-containing peptides were re-
ported as general tight-binding sirtuin probes [9], and some tri-
fluorothioacetamides were used in antipsychotic disease drugs and
pesticides [10]. Up to now, only two examples were applied to their
synthesis, including the thionation of trifluoroacetamides with Law-
esson’s reagent (Scheme 1, eq. 1) [7a] and the nucleophilic addition of
isothiocyanates with TMSCF3 (eq. 2) [7b] Therefore, the development of
efficient and practical strategy for the synthesis of tri-
fluorothioacetamides, particularly from new sulfur and CF3 source, re-
mains highly desirable.
destroy stratospheric ozone [11]. Therefore, many efforts have been
directed to the safe disposal of these compounds [12]. However, CFCs
could also be considered as raw materials for various useful chemicals,
and their transformation can provide an opportunity for their use. For
example, trifluorotrichloroethane (CFC-113a), one of the most inex-
pensive and abundant industrial raw material, is commonly used for the
preparation of various trifluoromethylated compounds (such as tri-
fluoroacetic acid) [13]. In general, CFC-113a is a fluorine-containing C2
synthon which could be regarded as an ideal CF3 group source for tri-
fluoromethylated molecules. Herein, we wish to report
a
–
copper-catalyzed three component C–S/C N coupling reaction of im-
ines with CFC-113a and elemental sulfur, which represents a novel
method for the practical synthesis of trifluorothioacetamides (eq. 3).
2. Results and discussion
2.1. Screening of optimal reaction conditions
We began investigation by examining the reaction of N, 1-diphenyl-
methanimine 1a with S8 and CFC-113a to screen the optimal reaction
conditions, and the results are summarized in Table 1. Initially, the re-
action was carried out in the presence of 10 mol % of CuI, 20 mol % of
1,10-phen, 2.0 equiv of K3PO4 in 1,4-dioxane at 120 ◦C, the product 2a
was isolated in 30 % yield (entry 1). Subsequently, a variety of copper
In environment field, the presence of large amounts of
* Corresponding author at: College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325035, China.
E-mail address: zxg@wzu.edu.cn (X.-G. Zhang).
https://doi.org/10.1016/j.jfluchem.2020.109640
Received 16 July 2020; Received in revised form 9 September 2020; Accepted 14 September 2020
Available online 22 September 2020
0022-1139/© 2020 Elsevier B.V. All rights reserved.

B.-L. Hu et al.
Journal of Fluorine Chemistry 239 (2020) 109640
yields were found for methoxycarbonyl and trifluoromethyl (2n, 71 %
and 2o, 68 %). Gratifyingly, N-naphthalen-1-yl phenylmethanimines
underwent the reaction smoothly to provide product 2p in 67 % yield.
During the test of N-alkyl imines, we were pleased to find that N-phe-
nylethyl thioamide 2q was isolated as sole product, albeit in moderate
yield (45 %). The similar results were also observed for N-cyclopentyl
thioamide 2r (31 %). The practicality of this procedure was further
applied to tetrahydroisoquinolines, which were easily oxidized to 3,4-
dihydroisoquinolines bearing imine moiety in the presence of CuCl
and O2 [14]. We were delighted to found that they were also suitable
substrates for this reaction. 1,2,3,4-Tetrahydroisoquinoline, for
instance, was conducted under standard conditions to afford desired
product 2 s in 78 % yield. Moreover, the structure of product 2 s was
confirmed by X-ray crystallography (Fig. 1). Finally, 6,7-dimethoxy and
7-bromo-substituted tetrahydroisoquinolines were also transformed to
the corresponding thioamides 2t and 2u in 79 % and 60 % yields
(Table 2).
Scheme 1. Synthetic Methods for Trifluorothioacetamides.
Table 1
Screening of optimal reaction conditionsa.
In order to further understand the mechanism of this reaction, we
conducted a series of control experiments (Scheme 2). When aniline was
used in the reaction instead of imine under standard conditions, only
trifluoroacetamide 3 was isolated in 27 % yield and the desired product
2a could not be detected (eq. 4). Moreover, the reaction of 3 with sulfur
did not work under standard reaction conditions (eq. 5). These results
demonstrated that the product 2a might not be produced through the
hydrolysis of imine or the thiolation transformation of carbonyl into
thiocarbonyl. The compound 3 was isolated in 35 % yield when sub-
strate 2a was treated with 0.1 ml H2O under standard reaction condi-
tions (eq. 6), indicating that water could promote the hydrolysis of
product 2 to form trifluoroacetamide. Furthermore, the reaction of
substrate 1 s was conducted with 0.1 ml H128O under standard reaction
conditions (eq. 7). A mixture of the product 18O-2s and 16O-2s was
isolated in 65 % yield with a 52:48 ratio and was confirmed by HRMS,
which suggested that a hydrolysis process occurred in the three
component C–S/C-N coupling reaction.
Entry
[Cu]
Base
Solvent
Yield(%)b
1
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
KOAc
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
30
25
45
35
30
NR
20
23
Trace
40
35
25
62
55
2
CuBr
CuCl
CuTc
CuCl2
–
3
4
5
6
7
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
8
MeCN
9
DCE
10
11
12
13c
14d
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
t-BuOK
K3PO4
K3PO4
a
Reaction conditions: 1a (0.2 mmol), S8 (0.2 mmol), Cl3CCF3 (4.0 mmol),
catalyst (10 mol %), 1.10-phen (20 mol %) and base (0.4 mmol) in solvent
(2 mL) at 120 ◦C under air atmosphere for 4 h.
b
c
Isolated yield.
2.3. Possible mechanism
100 mg anhydrous MgSO4.
d
100 mg 4 Å MS.
On the basis of the obtained results and related precedents [6d], a
possible mechanism is proposed as outlined in Scheme 3. In the presence
of CuCl and base, CF3CCl3 is decomposed to yield carbine :CClCF3 under
high temperature [15], which is combined with sulfur to produce tri-
fluorothioacetyl chloride A (confirmed by 19F NMR) [16]. The coordi-
nation of imine 1a with CuCl affords complex B [17], which undergo an
oxidative addition with trifluorothioacetyl chloride A to provide Cu (III)
complex C [18]. The following reductive elimination gives intermediate
D. However, the path of direct nucleophilic substitution of 1a with A to
generate D can not be ruled out. Finally, the hydrolysis of imine ion D
affords product 2a, benzaldehyde and hydrogen proton, which undergo
neutralization with base to regenerate water.
catalysts were tested, including CuBr, CuCl, CuTc, CuCl2 (entries 2–5).
We found that CuCl provided the best results and a 45 % yield was
obtained (entry 3), while the reaction did not work in the absence of
copper catalyst (entry 6). Then, various solvents were screened, DMF,
MeCN and DCE were found to be inferior to dioxane (entries 7–9). A
range of bases were investigated, K2CO3, KOAc and t-BuOK were all
found to afford lower yields (entry 10–12). To further improve reaction
yield, anhydrous MgSO4 and 4 Å MS were added into the reaction (en-
tries 13–14), we found that anhydrous MgSO4 provided the best results
and a 62 % yield was obtained (entry 13).
2.2. Substrate scope of trifluorothioacetamides
With the optimized reaction conditions in hand, we next examined
the substrate scope of the imines. Firstly, the substitute effect of a variety
of electron-donating aryl group was investigated, and good functional
group tolerance was observed. For example, N-4-tolyl and 2-tolyl phe-
nylmethanimines gave target product 2b and 2c in 55 % and 50 %
yields, respectively. 4-tert-Bu, 4-Ph, 4-PhO, 4-MeO and 4-MeS
substituted imines afforded product 2d–2h in 45 %–70 % yields. Halo-
genated phenyl was also compatible to produce halide N-phenyl
trifluorothio-acetamides, which could provide potential handles for
further modification. Iodide product 2i and bromide product 2j were
isolated in 55 % and 62 % yields, respectively. Chloride and fluoride
thioamides 2k–2m were also obtained in 59 %–62 % yields. Subse-
quently, strong electron-withdrawing group was examined and good
Fig. 1. X-ray crystal structure of compound 2 s.
2

B.-L. Hu et al.
Journal of Fluorine Chemistry 239 (2020) 109640
Table 2
Substrate scope of trifluorothioacetamides.
Scheme 3. Possible mechanism.
3. Conclusion
In summary, we have discovered copper-catalyzed three component
C–S/C-N coupling reaction of imines with sulfur and CF3CCl3. A variety
of imines including N-aryl or alkyl phenylmethanimines and tetrahy-
droisoquinolines underwent the coupling reaction successfully to afford
the corresponding trifluorothioacetamides in moderate to good yields.
The use of inexpensive sulfur and CFC-113a as trifluorothioacetyl group
source is a significant practical advantage. The present reaction can be
used for the synthesis of trifluoromethylated molecules from cheap
commerce-available materials, and it also provided a new safe disposal
method for environmentally persistent Freon.
4. Experimental section
4.1. General information
Chemicals were either purchased or purified by standard techniques.
1H NMR, 13C NMR and 19F NMR spectra were measured on 500 or
400 MHz spectrometer (400 MHz for 1H, 125 MHz for 13C, 470 MHz for
19F), using CDCl3 as the solvent with trimethylsilane (TMS) as an in-
ternal standard at room temperature. Chemical shifts are given in δ
relative to TMS, the coupling constants J are given in hertz. High reso-
lution mass spectra were recorded on an ESI-Q-TOF mass spectrometry.
All reactions under air atmosphere were conducted using standard
Schlenk techniques. Melting points were measured on WRS-1B melting
point apparatus. Infrared data was measured by Bruker Vector-55.
Column chromatography was performed using EM Silica gel 60
(300–400 mesh).
aReaction conditions: 1 (0.2 mmol), S8 (0.2 mmol), Cl3CCF3 (4.0 mmol), CuCl
(10 mol %), 1.10-phen (20 mol %), anhydrous MgSO4 (100 mg) and K3PO4
(0.4 mmol) in 1,4-dioxane (2 mL) at 120 ◦C under air atmosphere for 4 h., iso-
lated yields.
bFor 12 h.
4.2. General procedure for the synthesis of trifulorothioamides
To a flame-dried Schlenk tube with a magnetic stirring bar was
charged with S8 (51.2 mg, 0.2 mmol), Cl3CCF3 (749.6 mg; 4.0 mmol),
CuCl (1.98 mg; 0.02 mmol), 1,10-phen (7.2 mg; 0.04 mmol), K3PO4
(51.3 mg; 0.4 mmol) and anhydrous MgSO4 (100 mg) and 1,4-dioxane
(2 mL). The reaction mixture was stirred at 120 ◦C until complete con-
sumption of the starting material as detected by TLC or GC–MS analysis.
After the reaction was complete, the mixture was poured into ethyl ac-
etate and evaporated under vacuum. The resulting crude product was
purified by flash column chromatography on silica gel using petroleum
ether/methylene chloride (10:1) as the eluent to give the pure products
2a-2 u.
2,2,2-trifluoro-N-phenylethanethioamide (2a) [7b]: Yellow oil.
(25.4 mg, 62 % yield); 1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1 H), 7.66
(d, J =8.0 Hz, 2 H), 7.36 (d, J =7.5 Hz, 2 H), 7.27 – 7.24 (m, 1 H). 13C
NMR (125 MHz, CDCl3) δ 180.4 (q, J =35.0 Hz), 136.5, 129.3, 128.1,
123.1, 117.4 (q, J =279.0 Hz). 19F NMR (470 MHz, CDCl3) δ -69.75 (s);
IR (thin film) νmax 3405, 1163, 829, 715. LRMS (EI, 70 eV) m/z (%): 205
(M+, 85), 204 (100), 184 (34), 77 (66).
Scheme 2. Control Experiments.
3

B.-L. Hu et al.
Journal of Fluorine Chemistry 239 (2020) 109640
2,2,2-trifluoro-N-(p-tolyl)ethanethioamide (2b) [19a]: Yellow solid
NMR (125 MHz, CDCl3) δ 180.5 (q, J =35.0 Hz), 135.5, 132.5, 124.6,
121.2, 117.4 (q, J = 279.0 Hz). 19F NMR (470 MHz, CDCl3) δ -69.72 (s);
IR (thin film) νmax 3425, 1175, 1061, 832, 713. LRMS (EI, 70 eV) m/z
(%): 283/285 (M+, 95), 234 (100), 157 (35), 109 (54).
1
(24.1 mg, 55 % yield), mp 54.9–55.5 ◦C; H NMR (500 MHz, CDCl3) δ
9.30 (s, 1 H), 7.62 (d, J =8.0 Hz, 2 H), 7.25 (d, J =8.0 Hz, 2 H), 2.37 (s,
3 H). 13C NMR (125 MHz, CDCl3) δ 180.2 (q, J =35.0 Hz), 138.3, 134.0,
129.9, 123.0, 117.5 (q. J = 279.0 Hz), 21.2. 19F NMR (470 MHz, CDCl3)
δ -69.72 (s); IR (thin film) νmax 3409, 2911, 1507, 1158, 823, 710. LRMS
(EI, 70 eV) m/z (%): 219 (M+, 100), 198 (30), 150 (26), 91 (88).
2,2,2-trifluoro-N-(o-tolyl)ethanethioamide (2c) [19b]: Yellow oil.
(21.9 mg, 50 % yield); 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1 H), 7.59 –
7.43 (m, 1 H), 7.24 (d, J =6.5 Hz, 3 H), 2.21 (s, 3 H). 13C NMR (125 MHz,
CDCl3) δ 182.3 (q, J =35.0 Hz), 134.7, 133.5, 131.3, 128.9, 127.0,
125.6, 117.6 (q, J = 279.0 Hz), 17.4. 19F NMR (470 MHz, CDCl3) δ
-69.59 (s); IR (thin film) νmax 3411, 2901, 1163, 818, 721. LRMS (EI,
70 eV) m/z (%): 219 (M+, 41), 204 (100), 184 (34), 166 (14).
N-(4-chlorophenyl)-2,2,2-trifluoroethanethioamide (2k) [19b]: Yellow
1
oil. (29.1 mg, 61 % yield); H NMR (500 MHz, CDCl3) δ 9.20 (s, 1 H),
7.65 (d, J =8.5 Hz, 2 H), 7.34 (d, J =8.5 Hz, 2 H). 13C NMR (125 MHz,
CDCl3) δ 179.6 (q, J =35.0 Hz), 134.0, 132.4, 128.5, 123.3, 116.3 (q,
J = 279.0 Hz). 19F NMR (470 MHz, CDCl3) δ -69.74 (s); IR (thin film)
νmax 3413, 1169, 1086, 835, 716. LRMS (EI, 70 eV) m/z (%): 239 (M+,
100), 218 (23), 144 (40), 111 (51).
N-(3-chlorophenyl)-2,2,2-trifluoroethanethioamide (2 l): Yellow oil.
(29.6 mg, 62 % yield); 1H NMR (500 MHz, CDCl3) δ 9.19 (s, 1 H), 7.81 (s,
1 H), 7.52 (d, J =8.0 Hz, 1 H), 7.32 – 7.29 (m, 1 H), 7.24 (d, J =8.0 Hz,
1 H). 13C NMR (125 MHz, CDCl3) δ 180.7 (q, J =35.0 Hz), 137.5, 135.0,
130.3, 128.2, 123.1, 121.2, 118.3 (q, J = 279.0 Hz). 19F NMR (470 MHz,
CDCl3) δ -69.77 (s); LRMS (EI, 70 eV) m/z (%): 239 (M+, 79), 238 (100),
218 (25), 170 (32), 110 (58); IR (thin film) νmax 3413, 1165, 1089, 832,
711. HRMS (ESI) Calcd for C8H6ClF3NS + ([M+H]+) 239.9856, Found:
239.9854.
N-(4-(tert-butyl)phenyl)-2,2,2-trifluoroethanethioamide (2d): Yellow
1
oil. (30.3 mg, 58 % yield); H NMR (500 MHz, CDCl3) δ 9.28 (s, 1 H),
7.70 (d, J =8.5 Hz, 2 H), 7.46 (d, J =8.5 Hz, 2 H), 1.33 (s, 9 H). 13C NMR
(125 MHz, CDCl3) δ 179.8 (q, J =35.0 Hz), 151.4, 134.0, 126.2, 122.5,
117.5 (q, J = 279.0 Hz), 34.8, 31.2. 19F NMR (470 MHz, CDCl3) δ -69.74
(s); LRMS (EI, 70 eV) m/z (%): 261 (M+, 41), 246 (100), 106 (81), 123
(25); IR (thin film) νmax 3408, 2914, 1507, 1159, 835, 712. HRMS (ESI)
Calcd for C12H15F3NS+ ([M+H]+) 262.0872, Found: 262.0865.
N-([1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethanethioamide (2e): Yellow
2,2,2-trifluoro-N-(4-fluorophenyl)ethanethioamide (2 m) [7b]: Yellow
1
oil. (26.3 mg, 59 % yield); H NMR (500 MHz, CDCl3) δ 9.34 (s, 1 H),
7.72 – 7.69 (m, 2 H), 7.15 – 7.12 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ
1
solid. (33.7 mg, 60 % yield), mp 107.5–108.2 ◦C; H NMR (500 MHz,
181.0 (q, J =35.0 Hz), 161.4 (d, J =248.0 Hz), 132.4 (d, J =3.0 Hz),
CDCl3) δ 9.26 (s, 1 H), 7.78 (d, J =8.5 Hz, 2 H), 7.58 (d, J =8.5 Hz, 2 H),
125.4 (d, J =8.5 Hz), 117.4 (q, J = 279.0 Hz), 116.3 (d, J =23.0 Hz). 19
F
7.51 (d, J =7.5 Hz, 2 H), 7.39 – 7.36 (m, 2 H), 7.31 – 7.28 (m, 1 H). 13
C
NMR (470 MHz, CDCl3) δ -69.71 (s, 3 F), -111.77 (s, 1 F); IR (thin film)
νmax 3423, 1152, 1057, 836, 711. LRMS (EI, 70 eV) m/z (%): 223 (M+,
100), 202 (30), 154 (46), 95 (56).
NMR (125 MHz, CDCl3) δ 180.0 (q, J =35.0 Hz), 141.0, 139.8, 135.7,
129.0, 127.9, 127.8, 127.1, 123.1, 117.5 (q, J =279.0 Hz). 19F NMR
(470 MHz, CDCl3) δ -69.68 (s); LRMS (EI, 70 eV) m/z (%): 281 (M+,
100), 212 (18), 185 (34), 152 (70); IR (thin film) νmax 3406, 1340, 1166,
834, 719. HRMS (ESI) Calcd for C14H11F3NS+ ([M+H]+) 282.0559,
Found: 282.0563.
methyl 4-(2,2,2-trifluoroethanethioamido)benzoate (2n): Yellow solid.
(37.3 mg, 71 % yield), mp 118.5–119.3 ◦C; 1H NMR (500 MHz, CDCl3) δ
9.80 (s, 1 H), 8.09 (d, J =8.5 Hz, 2 H), 7.95 (d, J =8.5 Hz, 2 H), 3.92 (s,
3 H). 13C NMR (125 MHz, CDCl3) δ 180.6 (q, J =35.0 Hz), 166.3, 140.7,
130.7, 129.1, 122.4, 117.2 (q, J = 279.0 Hz), 52.4. 19F NMR (470 MHz,
CDCl3) δ -69.68 (s); LRMS (EI, 70 eV) m/z (%): 263 (M+, 85), 262 (100),
248 (41), 232 (28), 137 (40); IR (thin film) νmax 3435, 2941, 1763, 1163,
835, 712. HRMS (ESI) Calcd for C10H9F3NO2S+ ([M+H]+) 264.0301,
Found: 264.0301.
2,2,2-trifluoro-N-(4-phenoxyphenyl)ethanethioamide (2f): Yellow
solid. (41.6 mg, 70 % yield), mp 46.3–47.7 ◦C ; 1H NMR (500 MHz,
CDCl3) δ 9.24 (s, 1 H), 7.61 (d, J =9.0 Hz, 2 H), 7.29 – 7.26 (m, 2 H), 7.08
– 7.05 (m, 1 H), 6.99 – 6.87 (m, 4 H). 13C NMR (125 MHz, CDCl3) δ 180.2
(q, J =35.0 Hz), 156.9, 156.3, 131.3, 130.0, 124.8, 124.2, 119.6, 118.7,
117.5 (q, J = 279.0 Hz). 19F NMR (470 MHz, CDCl3) δ -69.60 (s); LRMS
(EI, 70 eV) m/z (%): 297 (M+, 100), 264 (28), 141 (32), 77 (53); IR (thin
film) νmax 3421, 1178, 1050, 833, 709. HRMS (ESI) Calcd for
2,2,2-trifluoro-N-(4-(trifluoromethyl)phenyl)ethanethioamide
(2o)
[19b]: Yellow oil. (37.1 mg, 68 % yield); 1H NMR (500 MHz, CDCl3) δ
9.32 (s, 1 H), 7.85 (d, J =8.5 Hz, 2 H), 7.60 (d, J =8.5 Hz, 2 H). 13C NMR
(125 MHz, CDCl3) δ 180.4 (q, J =35.0 Hz), 139.4, 129.7 (q, J =33.0 Hz),
126.5 (q, J =3.8 Hz), 123.6 (q, J =271.0 Hz), 123.0, 117.2 (q,
J = 279.0 Hz). 19F NMR (470 MHz, CDCl3) δ -62.69 (s, 3 F), -69.87 (s,
3 F); IR (thin film) νmax 3445, 1480, 1155, 834, 716. LRMS (EI, 70 eV)
m/z (%): 273 (M+, 91), 272 (100), 252 (41), 204 (45), 177 (24).
2,2,2-trifluoro-N-(naphthalen-2-yl)ethanethioamide (2p): Yellow solid.
C
14H10F3NOSNa+ ([M + Na]+) 320.0327, Found: 320.0325.
2,2,2-trifluoro-N-(4-methoxyphenyl)ethanethioamide (2 g) [19b]: Yel-
low oil. (25.9 mg, 55 % yield); 1H NMR (500 MHz, CDCl3) δ 9.33 (s, 1 H),
7.63 (d, J =9.0 Hz, 2 H), 6.94 (d, J =9.0 Hz, 2 H), 3.81 (s, 3 H). 13C NMR
(125 MHz, CDCl3) δ 180.6 (q, J =35.0 Hz), 158.9, 129.4, 124.8, 117.6
(q, J = 279.0 Hz), 114.4, 55.6. 19F NMR (470 MHz, CDCl3) δ -69.61 (s);
IR (thin film) νmax 3401, 2810, 1507, 1174, 1013, 829, 713. LRMS (EI,
70 eV) m/z (%): 235 (M+, 100), 202 (30), 166 (21), 125 (22).
1
(34.2 mg, 67 % yield), mp 96.7–97.5 ◦C; H NMR (500 MHz, CDCl3) δ
9.41 (s, 1 H), 8.53 (d, J =2.0 Hz, 1 H), 7.89 (d, J =8.5 Hz, 1 H), 7.86 –
7.83 (m, 2 H), 7.61 – 7.59 (m, 1 H), 7.55 – 7.51 (m, 2 H). 13C NMR
(125 MHz, CDCl3) δ 180.2 (q, J =35.0 Hz), 133.9, 133.2, 132.4, 129.3,
128.2, 127.8, 127.1, 126.9, 121.3, 121.0, 117.5 (q, J = 279.0 Hz). 19F
NMR (470 MHz, CDCl3) δ -69.67 (s); LRMS (EI, 70 eV) m/z (%): 255 (M+,
100), 234 (23), 127 (76), 115 (38); IR (thin film) νmax 3421, 1147, 826,
706. HRMS (ESI) Calcd for C12H9F3NS+ ([M+H]+) 256.0402, Found:
256.0399.
2,2,2-trifluoro-N-(4-(methylthio)phenyl)ethanethioamide (2 h): Yellow
1
oil. (22.6 mg, 45 % yield); H NMR (500 MHz, CDCl3) δ 9.25 (s, 1 H),
7.60 (d, J =8.5 Hz, 2 H), 7.19 (d, J =8.5 Hz, 2 H), 2.41 (s, 3 H). 13C NMR
(125 MHz, CDCl3) δ 179.9 (q, J =35.0 Hz), 139.0, 133.5, 126.6, 123.4,
117.4 (q, J = 279.0 Hz), 15.6. 19F NMR (470 MHz, CDCl3) δ -69.63 (s);
LRMS (EI, 70 eV) m/z (%): 251 (M+, 100), 218 (22), 182 (15), 141 (23).
IR (thin film) νmax 3406, 2935, 1162, 835, 716. HRMS (ESI) Calcd for
C9H8F3NS2Na+ ([M+H]+) 273.9942, Found: 273.9942.
2,2,2-trifluoro-N-phenethylethanethioamide (2q): Yellow oil. (21.0 mg,
45 % yield) ; 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1 H), 7.27 – 7.25 (m,
2 H), 7.20 – 7.17 (m, 1 H), 7.13 – 7.12 (d, J =7.5 Hz, 2 H), 3.87 – 3.83
(m, 2 H), 2.94 – 2.91 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ 183.3 (q, J
=35.0 Hz), 137.3, 129.0, 128.7, 127.2, 117.3 (q, J =278.0 Hz), 46.6,
33.1. 19F NMR (470 MHz, CDCl3) δ -69.95 (s); LRMS (EI, 70 eV) m/z (%):
233 (M+, 11), 104 (100), 91 (26), 78 (11); IR (thin film) νmax 3441,
2916, 1156, 837, 717. HRMS (ESI) Calcd for C10H11F3NS+ ([M+H]+)
234.0559, Found: 234.0566.
2,2,2-trifluoro-N-(4-iodophenyl)ethanethioamide (2i) [19b]: Yellow
solid. (36.3 mg, 55 % yield), mp 81.4–82.9 ◦C; 1H NMR (500 MHz,
CDCl3) δ 9.22 (s, 1 H), 7.67 (d, J =8.5 Hz, 2 H), 7.46 (d, J =8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3) δ 180.4 (q, J =35.0 Hz), 138.4, 136.2, 124.6,
117.3 (q, J = 279.0 Hz), 92.5. 19F NMR (470 MHz, CDCl3) δ -69.68 (s); IR
(thin film) νmax 3421, 1178, 1050, 833, 709. LRMS (EI, 70 eV) m/z (%):
331 (M+, 100), 262 (14), 202 (28), 109 (35).
N-(4-bromophenyl)-2,2,2-trifluoroethanethioamide (2 j) [19b]: Yellow
solid. (35.1 mg, 62 % yield), mp 46.1–47.0 ◦C; 1H NMR (500 MHz,
N-cyclopentyl-2,2,2-trifluoroethanethioamide (2 r): Yellow oil.
CDCl3) δ 9.22 (s, 1 H), 7.59 – 7.57 (m, 2 H), 7.49 – 7.47 (m, 2 H). 13
C
(12.2 mg, 31 % yield); 1H NMR (500 MHz, CDCl3) δ 7.73 (s, 1 H), 4.59
4

B.-L. Hu et al.
Journal of Fluorine Chemistry 239 (2020) 109640
W. Loo, M.C. Bartlett, D.M. Clarke, M.R. Detty, Chalcogenopyrylium compounds as
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4683–4699;
–4.55 (m, 1 H), 2.23 – 2.02 (m, 2 H), 1.82 – 1.57 (m, 4 H), 1.52 – 1.48 (m,
2 H). 13C NMR (125 MHz, CDCl3) δ 182.3 (q, J =35.0 Hz), 117.3 (q, J
=278.0 Hz), 57.2, 31.9, 24.0. 19F NMR (470 MHz, CDCl3) δ -69.88 (s);
LRMS (EI, 70 eV) m/z (%): 197 (M+, 100), 154 (17), 130 (57), 113 (22),
67 (47); IR (thin film) νmax 3420, 2935, 1171, 829, 711. HRMS (ESI)
Calcd for C7H10F3NSNa+ ([M+H]+) 220.0378, Found: 220.0379.
2,2,2-trifluoro-N-(2-formylphenethyl)ethanethioamide (2 s): Yellow
solid. (40.7 mg, 78 % yield), mp 84.5–85.9 ◦C; 1H NMR (500 MHz,
CDCl3) δ 10.09 (s, 1 H), 9.16 (s, 1 H), 7.80 (d, J =7.5 Hz, 1 H), 7.62 –
7.59 (m, 1 H), 7.54 – 7.51 (m, 1 H), 7.38 (d, J =7.5 Hz, 1 H), 3.95 – 3.92
(m, 2 H), 3.42–3.90 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ 195.3, 183.5
(q, J =35.0 Hz), 139.7, 135.6, 134.5, 134.4, 132.2, 127.9, 117.3 (q, J
=278.0 Hz), 47.8, 30.3. 19F NMR (470 MHz, CDCl3) δ -69.86 (s); LRMS
(EI, 70 eV) m/z (%): 261 (M+, 12), 132 (100), 113 (30), 104 (75); IR
(thin film) νmax 3416, 2935, 1701, 1171, 835, 706. HRMS (ESI) Calcd for
(e) Q.-L. Wei, S.-S. Zhang, J. Gao, W.-H. Li, L.-Z. Xu, Z.-G. Yu, Synthesis and QSAR
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C
11H11F3NOS+ ([M+H]+) 262.0508, Found: 262.0507.
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2,2,2-trifluoro-N-(2-formyl-4,5-dimethoxyphenethyl)ethanethioamide
(2 t): White solid. (50.7 mg, 79 % yield), mp 110.5–111.3 ◦C; 1H NMR
(500 MHz, CDCl3) δ 9.96 (s, 1 H), 9.27 (s, 1 H), 7.24 (s, 1 H), 6.79 (s,
1 H), 3.97 (s, 3 H), 3.95 (s, 3 H), 3.94 –3.91 (m, 2 H), 3.39 – 3.37 (m,
2 H). 13C NMR (125 MHz, CDCl3) δ 193.0, 183.5 (q, J =35.0 Hz), 154.0,
148.3, 134.7, 127.2, 117.3 (q, J =278.0 Hz), 116.6, 114.3, 56.3, 56.2,
48.0, 29.7. 19F NMR (470 MHz, CDCl3) δ -69.81 (s); LRMS (EI, 70 eV) m/
z (%): 321 (M+, 13), 192 (100), 164 (81), 149 (42); IR (thin film) νmax
3405, 2916, 2802, 1730, 1160, 828, 709. HRMS (ESI) Calcd for
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C
13H15F3NO3S+ ([M+H]+) 322.0719, Found: 322.0717.
N-(4-bromo-2-formylphenethyl)-2,2,2-trifluoroethanethioamide (2 u):
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Yellow solid. (40.7 mg, 60 % yield), mp 141.2–141.6 ◦C; 1H NMR
(500 MHz, CDCl3) δ 10.04 (s, 1 H), 8.92 (s, 1 H), 7.92 (d, J =2.0 Hz, 1 H),
7.73 – 7.71 (m, 1 H), 7.26 (d, J =8.0 Hz, 1 H), 3.94 – 3.90 (m, 2 H), 3.37
– 3.34 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ 188.2, 178.4 (q, J
=35.5 Hz), 133.2, 132.6, 132.1, 130.6, 128.5, 116.4, 112.1 (q, J = 278.0
HZ), 41.9, 24.7. 19F NMR (470 MHz, CDCl3) δ -75.06 (s); LRMS (EI,
70 eV) m/z (%): 389/341 (M+, 8), 307 (15), 210 (100), 182 (72), 113
(65); IR (thin film) νmax 3391, 2910, 1066, 1715, 1154, 830, 713. HRMS
(e) J.M. Goldberg, S. Batjargal, E.J. Petersson, Thioamides as fluorescence
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hydrogen peroxide assisted selective desulfurization of thioamide, Inorg. Chem. 51
(2012) 1634–1639.
(ESI) Calcd for
339.9613.
C
11H10BrF3NOS+ ([M+H]+) 339.9613, Found:
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ortho-methoxythiobenzamides, Org. Biomol. Chem. 2 (2004) 3039–3043;
´
(b) T.S. Jagodzinski, Thioamides as useful synthons in the synthesis of
heterocycles, Chem. Rev. 103 (2003) 197–228;
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Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
(d) S.K. Alla, P. Sadhu, T. Punniyamurthy, Organocatalytic syntheses of
–
benzoxazoles and benzothiazoles using aryl iodide and oxone via C
H
–
functionalization and C O/S bond formation, J. Org. Chem. 79 (2014)
7502–7511;
(e) P.S. Chaudhari, S.P. Pathare, K.G. Akamanchi, O-Iodoxybenzoic acid mediated
oxidative desulfurization initiated domino reactions for synthesis of azoles, J. Org.
Chem. 77 (2012) 3716–3723;
We thank the Natural Science Foundation of Guangxi Province
(2018GXNSFDA281011) and Project of Science and Technology Plan of
Zhejiang Province (2019C01095) for financial support.
(f) W.-S. Lo, W.-P. Hu, H.-P. Lo, C.-Y. Chen, C.-L. Kao, J.K. Vandavasi, J.-J. Wang,
Synthesis of sulfur-sulfur bond formation from thioamides promoted by 2,3-
dichloro-5,6-dicyanobenzoquinone, Org. Lett. 12 (2010) 5570–5572;
(g) T. Murai, F. Hori, T. Maruyama, Intramolecular cyclization of in situ generated
adducts formed between thioamide dianions and thioformamides leading to
generation of 5-amino-2-thiazolines and 5-aminothiazoles, and their fluorescence
properties, Org. Lett. 13 (2011) 1718–1721;
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
(h) L.J. Goossen, M. Blanchot, K.S.M. Salih, R. Karch, A. Rivas-Nass, Ruthenium-
catalyzed stereoselective anti-markovnikov-addition of thioamides to alkynes, Org.
Lett. 10 (2008) 4497–4499.
online version, at doi:https://doi.org/10.1016/j.jfluchem.2020.109640
.
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