UV-Light-Irradiated Trifluoromethylation of Diheteroaryl Disulfides with CF3SO2Na

Article abstract of DOI:10.1002/ejoc.201801565

A simple protocol for the UV light irradiated preparation of heteroaryl trifluoromethyl thioethers from disulfides and inexpensive, environmentally sodium triflinate (CF₃SO₂Na) has been developed. The features of simple and clean rea

Full text of DOI:10.1002/ejoc.201801565

A Journal of
Accepted Article
Title: UV light irradiated trifluoromethylation of diheteroaryl disulfides
with CF3SO2Na
Authors: Bao-Qian Cao, Yi-Feng Qiu, Xi Zhang, Zheng-He Zhu, Zheng-
Jun Quan, and Xi-Cun Wang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801565
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801565
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10.1002/ejoc.201801565
European Journal of Organic Chemistry
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UV light irradiated trifluoromethylation of diheteroaryl disulfides
with CF3SO2Na
Bao-Qian Cao,[a,b] [‡] Yi-Feng Qiu,[a,b] [‡] Xi Zhang, [a,b] Zheng-He Zhu, [a,b] Zheng-Jun Quan, *, [a,b] and Xi-
Cun Wang*,[a,b]
Dedication ((optional))
Abstract: A simple protocol for the UV light irradiated preparation of
heteroaryl trifluoromethyl thioethers from disulfides and inexpensive,
environmentally sodium triflinate (CF3SO2Na) is been developed.
The features of simple and clean reaction conditions, in moderate to
good yields, and broad substrate scope render this new approach
synthetically attractive for the preparation of potentially
pharmaceutically active compounds.
used their hypervalent iodine(III)–CF3 reagent to perform the
trifluoromethylation of sulphydryl compounds (Scheme 1b).9
After that, Shibata described the reductive trifluoromethylation of
homocystine
and
cystine
to
provide
corresponding
trifluoromethyl thioethers through the CF3I/Na/Liq.NH3 system
(Scheme 1c).10 Still, the exploration of safety, operationally
simple, and environmentally friendly (metal and oxidant free)
synthetic methods with high efficiency on trifluoromethylation of
sulfur-containing precursors is fueled by strong and increasing
aspiration.
Introduction
Organofluorine has achieved considerable development during
last decades, specifically in pharmaceutical research, pesticide
chemistry, and material science.1,2 Thus, the exploration for
efficient strategies on the introduction of fluoroalkyl groups into
organic compounds has become the present research focus.3,4
Among such numerous fascinating fluorine-containing groups,
the trifluoromethyl group (CF3) and trifluoromethylthio group
(SCF3) have attracted much attention for desirable properties in
biological and pharmacological activities.5
Disulfide has the advantages of being inexpensive, easy to
prepare, and stable in air, which could provide two S-containing
moieties via a facile S-S bond cleavage under mild conditions. 6
In recent years, our group has been working on the study of
dipyrimidyl disulfide, and we have found that compounds
containing pyrimidine structure have certain biological activity. In
addition, the trifluoromethylation of sulfur-containing precursors
has caused great interest among chemists.7 Nevertheless, these
methods suffer from various unavoidable drawbacks, such as
tedious operations, harsh conditions, toxic metal catalysts, poor
selectivity and functional group compatibility. Stimulated by
advancing aspiration on new routes to introduce the
trifluoromethyl group into sulfur-containing precursors, adequate
advancements have been achieved in the development of
various new reagents. In 2004, Dolbier and other researchers
developed the addition of CF3 anion, generated from the
reduction of CF3I by tetrakis-(dimethylamino)ethylene (TDAE),
onto disulfides (Scheme 1a).8 In 2007, Togni and co-workers
Scheme 1. Strategies for trifluoromethylation of sulfur-containing precursors
and our new anticipation.
As a stable and cheap trifluoromethylation reagent, sodium
triflinate (Langlois reagent) is widely used in the field of organic
fluorine chemistry.11 In 2016, the Li group reported a simple and
clean
strategy
for
direct
trifluoromethylation
of
arenes/heteroarenes under ultraviolet/visible light irradiation.12
By taking into consideration of our current interests in the
transformation of sulfur-containing organic compounds,13 as well
as the continued anticipation of new approaches to skeletons of
pharmaceutical molecule, we designed a UV light irradiated
trifluoromethylation of disulfides with CF3SO2Na (Scheme 1d).
The conversion has relatively good functional group compatibility,
and the disulfide has fully utilized while constructing two S-CF3
bonds. Inexpensive and commercially available CF3SO2Na
provided CF3 source without external photocatalyst, generating
the corresponding products in moderate to good yields under
mild conditions. Notably, the trifluoromethylthio group in the
products would lead to a great promotion of membrane
permeability and absorption rate in bioavailability for its high
lipophilicity, electronegativity, and metabolic stability.14 This
[a]
Bao-Qian Cao, Yi-Feng Qiu, Xi Zhang, Zheng-He Zhu, Prof. Dr.
Zheng-Jun Quan, and Prof. Dr. Xi-Cun Wang
College of Chemistry and Chemical Engineering
Northwest Normal University, Lanzhou, 730070, People’s Republic
of China
E-mail: wangxicun@nwnu.edu.cn
quanzhengjun@hotmail.com
[b]
Gansu International Scientific and Technological Cooperation Base
of Water-Retention Chemical Functional Materials, Lanzhou,
730070, People’s Republic of China.
[‡]
B.-Q. C. and Y.-F.Q. contributed equally.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801565
European Journal of Organic Chemistry
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synthetic strategy may provide potential application of
pharmaceutical synthesis in industrial production.
Results and Discussion
1,2-Di(pyrimidin-2-yl) disulfides (1a) was selected as the model
substrate for the optimization of reaction conditions (Table 1).
The initial attempt was conducted in CH3CN under the irradiation
of 365 nm UV light (300 W) under air at room temperature for 4
h, which gave the desired trifluoromethylation product 3a in 30%
isolated yield (Table 1, entry 1). A short survey on solvents
revealed that acetone performed best for this reaction (entries 2-
6). Changing the loadings of 2a to 8 equivalents improved the
yield of product 3a to 85% (entries 7-9). The investigation on the
light sources indicated that 100 W UV (365 nm) was the most
effective light source with 86% yield of product 3a obtained
(entries 10-11). The subsequent control experiments verified
that the light source made significant influences on this
transformation since no reaction occurred in darkness. (entry 12).
Prolonging the reaction time to 6 h gave a slight improvement of
the yield to 88% (entry 13). After the above detailed
investigations, the optimized reaction conditions were settled as
the use of 1a in the presence of CF3SO2Na 2a (8 equivalents) in
acetone at room temperature for 6 h.
Table 1. Optimization of Reaction Conditions[a]
Scheme 2. Substrate scope of 1,2-di(pyrimidin-2-yl) disulfides.
wide range of disulfides could be tolerated under the optimal
reaction conditions, generating the corresponding trifluoromethyl
thioethers products in moderate to good yields (50%–89%). As
for the 1,2-di(pyrimidin-2-yl) disulfides part (Scheme 2), both
electron-rich (Me and OMe) and -deficient (F, Cl and Br) groups
at the para-position and meta-position of the aromatic ring gave
good yields of the corresponding trifluoromethylation products
(3b–3j). The substituents at the ortho-position such as Me and F
afforded the corresponding products 3k, 3m in 81%−86% yields,
except for OMe, with a slight decrease (3l). Poly-substituted
disulfides could also give moderate yields under the standard
reaction conditions (3n, 3o). When the disulfides possess a
multiple-ring group or heterocyclic-group at the C4 position, such
as 2-thiopheny, 2-piperonyl, α/β-naphthyl group, the desired
products 3p-3s could be obtained in 53%-70% yield,
respectively. Subsequently, the effect of substituent at the C5
position was also investigated. Products with substituent groups
on R2 could be converted into the corresponding products in
moderated to good yields (3t, 3u and 3v). The substituent of i-Pr
at the C6 position also afforded the desired product 3w in
satisfactory yield. Unfortunately, diphenyl disulfide 1x failed to
give the corresponding trifluoromethyl thioethers product in this
condition. It gives a complex mixture and the raw materials
disappeared. We believed this may due to PhS• redical has a
redox potential out of range from the redox potential of the
Langlois' reagent.
Entry
1
Solvent
CH3CN
1,4-dioxane
acetone
DCE
Light source
300 W UV
300 W UV
300 W UV
300 W UV
300 W UV
300 W UV
300 W UV
300 W UV
300 W UV
100 W UV
300 W UV
-
Yield (%)[b]
30
40
68
45
62
trace
76
85
83
86
72
0
2
3
4
5
DMSO
6
EtOH
7[c]
8[d]
9[e]
10
11[f]
12
13[g]
14[h]
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
100 W UV
100 W UV
88
85
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.4 mmol), solvent (2.0 mL) at
room temperature under 365 nm UV light (300 W) irradiation under air for 4 h.
[b] Isolated yields. [c] 6 equiv of 2a were added. [d] 8 equiv of 2a were added.
[e] 10 equiv of 2a were added. [f] This reaction was conducted under 254 nm
UV light irradiation. [g] This reaction was conducted for 6 h. [h] This reaction
was conducted for 8 h.
With the optimized reaction conditions in hand, as depicted in
Scheme 2, different kinds of disulfides, including 1,2-
di(pyrimidin-2-yl) disulfides and quinoline-2-disulfides were then
synthesized to investigate the substrate scope. To our delight, a
Subsequently, the reactions of
a variety of substituted
quinoline-2-disulfides derivatives with CF3SO2Na (2a) were also
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10.1002/ejoc.201801565
European Journal of Organic Chemistry
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investigated under the optimized reaction conditions. As shown
in Scheme 3, a series of functional groups on the quinoline rings
were tolerated, leading to the desired products in good to
excellent yields(5a-5e).
In order to probe the mechanism, some necessary inhibition
experiments were performed (Scheme 4). When 5 equivalents of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated
hydroxytoluene (BHT) were added into the reaction system, only
trace or 28% yield of product 3a was detected, respectively
[Scheme 4, eqn (1) and (2)], suggesting that the •CF3 radical
was likely involved as the reactive species in the transformation.
Based on the above results and previous reports,12,15
a
plausible mechanism is outlined in Scheme 5. Two potential
paths may achieve this result. As shown in path a, acetone is
excited by ultraviolet light irradiation to generate the excited
species A, which is reduced by CF3SO2Na and generate the
•CF3 radical B with concomitant release of one equivalent of SO2
and sodium radical anion C. In the reaction end, two sodium
radical anions C can couple to form a salt sodium 2,3-
dimethylbutane-2,3-bis(olate).16 Subsequently, the addition of
disulfides 1 and the •CF3 radical afforded the final product 3 with
concomitant release of one equivalent of thiyl radicals D, which
could also be generated by the hemolytic cleavage of S-S bond
(path b), then coupled with a •CF3 radical to give the final
product 3.
Conclusions
In summary, we have developed a UV light irradiation
promoted trifluoromethylation of disulfides. In this reaction, a
series of trifluoromethyl thioethers products including
pyrimidinyl-2-trifluoromethyl
thioethers
and
quinoline-2-
trifluoromethyl thioethers were synthesized smoothly. This
transformation process proved to involve a •CF3 radical pathway
which avoided the addition of external photocatalyst and could
be easily operated under an air atmosphere. In addition, the
synthetic utility of our developed reaction system has been
demonstrated by its applicability to synthetically useful
heteroaromatic disulfides.
Scheme 3. Substrate scope of quinoline-2-disulfides.
Experimental Section
Typical Procedure for the Synthesis of 3a: Under an
atmosphere of air, diethyl 2,2'-disulfanediylbis(6-methyl-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate) 1a (0.1 mmol, 0.0546 g), NaSO2CF3
2a (8 equivalent 0.8 mmol, 0.1248 g) were added to a tube. Acetone (2.0
mL) was added by dropper and the mixture was stirred for 6 h at rt. 100
W UV light and the reaction was monitored by TLC analysis. The residue
was purified by column chromatography on silica gel (ethyl acetate/
petroleum ether = 1:20) to give the corresponding product 3a. All of the
products were synthesized according to above described procedure.
Scheme 4. Control experiments.
Ethyl
4-methyl-6-phenyl-2-((trifluoromethyl)thio)pyrimidine-5-
carboxylate (3a). Colourless oil (60.2 mg, 88%); 1H NMR (600 MHz,
CDCl3) δ = 7.68–7.65 (m, 2H), 7.51–7.43 (m, 3H), 4.20 (q, J = 7.2 Hz,
2H), 2.59 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
= 167.28, 166.68, 165.10 (q, JC-F = 3.15 Hz, C-SCF3), 164.08, 136.53,
130.68, 128.59, 128.47, 128.20 (q, JC-F = 306.3 Hz, SCF3), 123.30, 62.08,
22.51, 13.58. 19F NMR (376 MHz, CDCl3) δ = -41.09. HRMS (ESI) m/z:
Calcd for C15H13F3N2O2S: 343.0723 [M+H]+, Found: 343.0728.
Ethyl
4-methyl-6-(p-tolyl)-2-((trifluoromethyl)thio)pyrimidine-5-
carboxylate (3b). Colourless oil (57.6 mg, 81%); 1H NMR (600 MHz,
CDCl3) δ = 7.60–7.58 (m, 2H), 7.27–7.24 (m, 2H), 4.24 (q, J = 7.2 Hz,
2H), 2.57 (s, 3H), 2.40 (s, 3H), 1.14 (t, J = 7.8 Hz, 3H). 13C NMR (150
MHz, CDCl3) δ = 167.50, 166.45, 164.95 (q, JC-F = 3.0 Hz, C-SCF3),
163.88, 141.24, 133.62, 129.34, 128.49, 128.22 (q, JC-F = 306.4 Hz,
Scheme 5. Proposed reaction mechanism.
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10.1002/ejoc.201801565
European Journal of Organic Chemistry
FULL PAPER
SCF3), 123.05, 62.06, 22.47, 21.39, 13.66. 19F NMR (376 MHz, CDCl3) δ
= -41.10. HRMS (ESI) m/z: Calcd for C16H15F3N2O2S: 357.0879 [M+H]+,
Found: 357.0883.
-109.46–-114.65 (m). HRMS (ESI) m/z: Calcd for C15H12F4N2O2S:
361.0628 [M+H]+, Found: 361.0627.
Ethyl
4-(3-chlorophenyl)-6-methyl-2-
Ethyl
4-(4-methoxyphenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3i). Colourless oil
(67.0 mg, 89%); H NMR (600 MHz, CDCl3) δ = 7.65 (t, J = 1.8 Hz, 1H),
1
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3c). Colourless oil
(56.6 mg, 76%); 1H NMR (600 MHz, CDCl3) δ = 7.71–7.65 (m, 2H), 6.98–
6.93 (m, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 2.55 (s, 3H), 1.17 (t, J
= 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ = 167.72, 166.33, 164.81 (q,
JC-F = 3.15 Hz, C-SCF3), 163.13, 161.90, 130.32, 128.25 (q, JC-F = 306.0
Hz, SCF3), 128.70, 122.58, 114.08, 62.07, 55.37, 22.44, 13.75. 19F NMR
7.56–7.53 (m, 1H), 7.47–7.45 (m, 1H), 7.38 (t, J = 7.8 Hz, 1H), 4.25 (q, J
= 7.2 Hz, 2H), 2.59 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ = 167.05, 166.83, 165.31 (q, J = 2.9 Hz, C-SCF3), 162.51,
138.16, 134.67, 130.68, 129.89, 128.55, 128.10 (q, J = 306.5 Hz, SCF3),
126.65, 123.35, 62.28, 22.56, 13.63. 19F NMR (376 MHz, CDCl3) δ ppm =
-41.12. HRMS (ESI) m/z: Calcd for C15H12ClF3N2O2S: 377.0333 [M+H]+,
Found: 377.0335.
(376 MHz, CDCl3)
C16H15F3N2O3S: 373.0828 [M+H]+, Found: 373.0823.IR
δ = -41.09. HRMS (ESI) m/z: Calcd for
Ethyl 4-(4-fluorophenyl)-6-methyl-2-((trifluoromethyl)thio)pyrimidine-
5-carboxylate (3d). Colourless oil (56.2 mg, 78%); 1H NMR (600 MHz,
CDCl3) δ = 7.71–7.67 (m, 2H), 7.16–7.12 (m, 2H), 4.24 (q, J = 7.2 Hz,
2H), 2.58 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
= 167.21, 166.79, 165.18, 165.12 (q, J = 3.0 Hz, C-SCF3), 163.51,
162.73, 132.60 (d, J = 3.2 Hz), 130.71 (d, J = 8.7 Hz), 128.15 (q, J =
306.5 Hz, SCF3), 123.08, 62.18, 22.48, 13.65.19F NMR (376 MHz, CDCl3)
Ethyl
4-(3-bromophenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3j). Colourless oil
(71.2 mg, 85%); 1H NMR (600 MHz, CDCl3) δ ppm = 7.80 (t, J = 1.8 Hz,
1H), 7.63–7.58 (m, 2H), 7.32 (t, J = 7.8 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H),
2.59 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ ppm
= 167.06, 166.82, 165.31 (q, JC-F = 2.9 Hz, C-SCF3), 162.40, 138.38,
133.60, 131.41, 130.13, 128.09 (q, JC-F =306.5 Hz, SCF3), 127.11,
127.07, 123.34, 122.62, 62.31, 22.58, 13.68. 19F NMR (376 MHz, CDCl3)
δ ppm = -41.12. HRMS (ESI) m/z: Calcd for C15H12BrF3N2O2S: 420.9828
[M+H]+, Found: 420.9829.
δ
=
-41.14, -109.43–-109.51 (m). HRMS (ESI) m/z: Calcd for
C15H12F4N2O2S: 361.0628 [M+H]+, Found: 361.0630.
Ethyl
4-(4-chlorophenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3e). Colourless oil
(57.2 mg, 76%); 1H NMR (600 MHz, CDCl3) δ = 7.63–7.61 (m, 2H), 7.44–
7.41 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 1.14 (t, J = 7.2 Hz,
Ethyl
4-methyl-6-(o-tolyl)-2-((trifluoromethyl)thio)pyrimidine-5-
carboxylate (3k). Colourless oil (57.7 mg, 81%); 1H NMR (600 MHz,
CDCl3) δ ppm = 7.48 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz,
1H), 7.29 (d, J = 7.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.40
(s, 3H), 1.10 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ ppm =
167.33, 166.57, 165.01 (q, J = 3 Hz, C-SCF3), 164.25, 138.37, 136.45,
131.46, 129.07, 128.49,128.20 (q, J = 306.5 Hz, SCF3), 125.59, 123.34,
62.04, 22.51, 21.37, 13.60. 19F NMR (376 MHz, CDCl3) δ ppm = -41.09.
HRMS (ESI) m/z: Calcd for C16H15F3N2O2S: 357.0879 [M+H]+, Found:
357.0873.
3H). 13C NMR (150 MHz, CDCl3) δ = 167.09, 166.90, 165.24 (q, JC-F
=
3.0 Hz, C-SCF3), 162.70, 137.20, 134.90, 129.87, 129.12 (q, JC-F =306.3
Hz, SCF3), 128.92, 123.12, 62.25, 22.54, 13.68. 19F NMR (376 MHz,
CDCl3) δ = -41.14. HRMS (ESI) m/z: Calcd for C15H12ClF3N2O2S:
377.0333 [M+H]+, Found: 377.0335.
Ethyl
4-methyl-6-(m-tolyl)-2-((trifluoromethyl)thio)pyrimidine-5-
carboxylate (3f). Colourless oil (48.4 mg, 68%); 1H NMR (600 MHz,
CDCl3) δ = 7.49–7.43 (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.32–7.29 (m, 1H),
4.21 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 1.10 (t, J = 7.2 Hz,
Ethyl
4-(2-methoxyphenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3l). Colourless oil
(49.2 mg, 66%); 1H NMR (600 MHz, CDCl3) δ ppm = 7.53 (dd, J = 7.8,
1.8 Hz, 1H), 7.44–7.40 (m, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.4
Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 2.66 (s, 3H), 0.99 (t, J =
7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ ppm = 167.02, 166.13, 165.23
(q, JC-F = 3.2 Hz, C-SCF3), 163.74, 156.38, 131.62, 130.96, 128.19 (q, JC-
F =306.5 Hz, SCF3), 126.61, 124.06, 121.04, 110.18, 61.20, 55.02, 23.34,
13.52. 19F NMR (376 MHz, CDCl3) δ ppm = -41.13. HRMS (ESI) m/z:
Calcd for C16H15F3N2O3S: 373.0828 [M+H]+, Found: 373.0829.
3H). 13C NMR (150 MHz, CDCl3) δ = 167.34, 166.56, 165.02 (q, JC-F
=
3.2 Hz, C-SCF3), 164.25, 138.37, 136.45, 131.46, 128.99 (q, JC-F = 243.0
Hz, SCF3), 129.07, 128.49, 125.59, 123.33, 62.03, 22.52, 21.37, 13.6.
19F NMR (376 MHz, CDCl3) δ = -41.09. HRMS (ESI) m/z: Calcd for
C16H15F3N2O2S: 357.0879 [M+H]+, Found: 357.0875.
Ethyl
4-(3-methoxyphenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3g). Colourless oil
1
(54.4 mg, 73%); H NMR (600 MHz, CDCl3) δ = 7.34 (t, J = 7.8 Hz, 1H),
7.26 (t, J = 1.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 2.4, 1.8 Hz,
1H), 4.23 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.58 (s, 3H), 1.12 (t, J = 7.2
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ = 167.26, 166.63, 165.03 (q, JC-F
= 3.0 Hz, C-SCF3), 163.76, 159.77, 137.73, 129.61, 128.20 (q, JC-F
=306.3 Hz, SCF3), 123.39, 120.72, 116.91, 113.59, 62.12, 55.29, 22.47,
13.62. 19F NMR (376 MHz, CDCl3) δ = -41.13. HRMS (ESI) m/z: Calcd
for C16H15F3N2O3S: 373.0828 [M+H]+, Found: 373.0830.
Ethyl 4-(2-fluorophenyl)-6-methyl-2-((trifluoromethyl)thio)pyrimidine-
5-carboxylate (3m). Colourless oil (61.9 mg, 86%); H NMR (600 MHz,
1
CDCl3) δ ppm = 7.63–7.59 (m, 1H), 7.48–7.43 (m, 1H), 7.29–7.25 (m,
1H), 7.12–7.08 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.06 (t, J =
7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ ppm = 167.83, 165.80,165.57
(q, J = 3.0 Hz, C-SCF3), 161.12, 160.59, 158.94, 132.15 (d, J = 8.4 Hz),
132.19 (d, J = 2.7), 128.08 (q, J = 306.3 Hz, SCF3), 125.19 (d, J = 14.0
Hz), 124.57 (d, J = 3.5 Hz), 115.43 (d, J = 21.6 Hz), 61.78, 23.43, 13.48.
19F NMR (376 MHz, CDCl3) δ ppm = -41.15, -114.71–-117.62 (m). HRMS
(ESI) m/z: Calcd for C15H12F4N2O2S: 361.0628 [M+H]+, Found: 361.0625.
Ethyl 4-(3-fluorophenyl)-6-methyl-2-((trifluoromethyl)thio)pyrimidine-
5-carboxylate (3h). Colourless oil (49.0 mg, 68%); 1H NMR (600 MHz,
CDCl3) δ = 7.46–7.39 (m, 3H), 7.21–7.17 (m, 1H), 4.24 (q, J = 7.2 Hz,
2H), 2.59 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
= 166.95 (d, J = 13.7 Hz), 165.27 (q, J = 3.2 Hz, C-SCF3), 163.49, 162.56,
161.85, 138.55 (d, J = 7.7 Hz,), 130.22 (d, J = 8.1 Hz), 128.11 (q, J =
306.3 Hz), 124.18 (d, J = 3 Hz), 123.36, 117.65 (d, J = 21 Hz), 115.62 (d,
J = 23.3 Hz), 62.24, 22.51, 13.57. 19F NMR (376 MHz, CDCl3) δ = -41.13,
Ethyl4-(3,4-dimethoxyphenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3n). White solid (40.0
mg, 50%); m.p.: 89-91°C. 1H NMR (600 MHz, CDCl3) δ ppm = 7.38 (d, J
= 1.8 Hz, 1H), 7.27 (dd, J = 7.2, 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H),
4.27 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 2.54 (s, 3H), 1.18 (t, J
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801565
European Journal of Organic Chemistry
FULL PAPER
= 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ = 167.80, 166.31, 164.77 (q,
JC-F = 3.0 Hz, C-SCF3), 162.90, 151.52, 149.12, 128.84, 128.28 (q, JC-F
=306.3 Hz, SCF3), 122.68, 121.84, 111.64, 110.73, 62.13, 55.99, 55.83,
22.39, 13.79. 19F NMR (376 MHz, CDCl3) δ = -41.13. HRMS (ESI) m/z:
Calcd for C17H17F3N2O4S: 403.0934 [M+H]+, Found: 403.0938.
130.60, 128.19 (q, JC-F = 306.5 Hz, SCF3), 128.57, 128.55, 123.77, 70.10,
22.43, 21.25.19F NMR (376 MHz, CDCl3) δ = -41.09. HRMS (ESI) m/z:
Calcd for C16H15F3N2O2S: 357.0879 [M+H]+, Found: 357.0877.
Methyl
4-(4-bromophenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3u). White solid (60.0
mg, 74%); m.p.:118-120 °C. 1H NMR (600 MHz, CDCl3) δ = 7.61–7.58 (m,
2H), 7.56–7.52 (m, 2H), 3.76 (s, 3H), 2.57 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ = 167.63, 167.03, 165.46 (q, JC-F = 3.0 Hz, C-SCF3), 162.75,
135.28, 131.99, 129.95, 128.09 (q, JC-F =306.3 Hz, SCF3), 125.76,
122.72, 52.92, 22.60.19F NMR (376 MHz, CDCl3) δ = -41.13. HRMS (ESI)
m/z: Calcd for C14H10BrF3N2O2S: 406.9671 [M+H]+, Found: 406.9675.
Ethyl
4-(3,4-dichlorophenyl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3o). Colourless oil
(55.8 mg, 68%); 1H NMR (400 MHz, CDCl3) δ = 7.78 (dd, J = 1.6, 0.8 Hz,
1H), 7.55–7.51 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 1.20 (t, J =
7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ = 167.17, 166.76, 165.44 (q,
JC-F = 3.3 Hz, C-SCF3), 161.35, 136.19, 135.35, 133.09, 130.69, 130.41,
127.70, 127.68, 128.05 (q, JC-F =306.5 Hz, SCF3), 123.18, 62.44, 22.60,
13.75. 19F NMR (376 MHz, CDCl3) δ = -41.14. HRMS (ESI) m/z: Calcd
for C15H11Cl2F3N2O2S: 410.9943 [M+H]+, Found: 410.9945.
Tert-butyl
4-methyl-6-phenyl-2-((trifluoromethyl)thio)pyrimidine-5-
carboxylate (3v). Colourless oil (63.6 mg, 86%); 1H NMR (600 MHz,
CDCl3) δ = 7.71–7.68 (m, 2H), 7.51–7.47 (m, 1H), 7.47–7.43 (m, 2H),
2.59 (s, 3H), 1.38 (s, 9H).13C NMR (150 MHz, CDCl3) δ = 166.21 (d, J =
11.0 Hz), 164.47 (q, J = 3.0 Hz, C-SCF3), 163.70, 136.62, 130.51, 128.69,
128.47, 128.24 (q, J = 306.3 Hz, SCF3), 124.74, 83.63, 27.64, 22.41. 19F
NMR (376 MHz, CDCl3) δ ppm = -41.09. HRMS (ESI) m/z: Calcd for
C17H17F3N2O2S: 371.1036 [M+H]+, Found: 371.1039.
Ethyl 4-methyl-6-(thiophen-2-yl)-2-((trifluoromethyl)thio)pyrimidine-
5-carboxylate (3p). Colourless oil (43.2 mg, 62%); 1H NMR (600 MHz,
CDCl3) δ = 7.93 (dd, J = 3.0, 1.2 Hz, 1H), 7.47 (dd, J = 5.4, 1.2 Hz, 1H),
7.37 (dd, J = 4.8, 3.0 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.27
(t, J = 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3) δ = 167.60, 166.19,
164.92 (q, J = 3.2 Hz, C-SCF3), 157.40, 137.74, 129.13, 128.24 (q, J =
306.3 Hz, SCF3), 127.37, 126.46, 122.16, 62.36, 22.31, 13.82. 19F NMR
Ethyl
4-isopropyl-6-(p-tolyl)-2-((trifluoromethyl)thio)pyrimidine-5-
carboxylate (3w). Colourless oil (62.2 mg, 81%); 1H NMR (600 MHz,
CDCl3) δ = 7.57 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 4.22 (q, J =
7.2 Hz, 2H), 3.19–3.12 (m, 1H), 2.40 (s, 3H), 1.30 (d, J = 6.6 Hz, 6H),
1.13 (t, J = 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3) δ = 174.25, 167.56,
165.34 (q, J = 3.2 Hz, C-SCF3), 164.12, 141.00, 133.87, 129.31, 128.40,
128.35 (q, J = 306.2 Hz, SCF3), 122.40, 62.03, 33.35, 21.55, 21.36,
13.65 19F NMR (376 MHz, CDCl3) δ = -41.09. HRMS (ESI) m/z: Calcd for
C18H19F3N2O2S: 385.1192 [M+H]+, Found: 385.1195.
(376 MHz, CDCl3)
δ = -41.15. HRMS (ESI) m/z: Calcd for
C13H11F3N2O2S2: 349.0287 [M+H]+, Found: 349.0286.
Ethyl
4-(benzo[d][1,3]dioxol-4-yl)-6-methyl-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3q). Colourless oil
1
(48.6 mg, 63%); H NMR (400 MHz, CDCl3) δ = 7.24–7.19 (m, 2H), 6.86
(d, J = 8.0 Hz, 1H), 6.03 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 2.55 (s, 3H),
1.21 (t, J = 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3) δ= 167.53, 166.44,
164.85 (q, J = 3.3 Hz, C-SCF3), 162.96, 150.05, 148.18, 130.36, 128.20
(q, J = 306.3 Hz, SCF3), 123.48, 122.81, 108.87, 108.35, 101.67, 62.15,
22.46, 13.78. 19F NMR (376 MHz, CDCl3) δ = -41.10. HRMS (ESI) m/z:
Calcd for C16H13F3N2O4S: 387.0621 [M+H]+, Found: 387.0625.
6-methoxy-4-phenyl-2-((trifluoromethyl)thio)quinoline (5a). Yellow
solid (57.6 mg, 86%); m.p.: 95-97 °C. 1H NMR (400 MHz, CDCl3) δ =
8.07 (d, J = 9.2 Hz, 1H), 7.59–7.49 (m, 6H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H),
7.17 (d, J = 2.8 Hz, 1H), 3.79 (s, 3H).13C NMR (150 MHz, CDCl3) δ =
158.88, 148.91, 145.74 (q, JC-F = 2.4 Hz, C-SCF3), 145.18, 137.23,
131.36, 19.64 (q, JC-F = 306.9 Hz, SCF3), 129.21, 128.85, 128.83, 127.23,
124.99 (d, JC-F = 1.8 Hz, C-CSCF3), 122.87, 103.62, 55.49. 19F NMR (376
MHz, CDCl3) δ = -39.99. HRMS (ESI) m/z: Calcd for C17H12F3NOS:
336.0664 [M+H]+, Found: 336.0666.
Ethyl
4-methyl-6-(naphthalen-2-yl)-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3r). Colourless oil
1
(54.8 mg, 70%); H NMR (600 MHz, CDCl3) δ = 8.19 (s, 1H), 7.93–7.86
(m, 3H), 7.77 (dd, J = 8.4, 1.8 Hz, 1H), 7.58–7.51 (m, 2H), 4.21 (q, J =
7.2 Hz, 2H), 2.62 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ = 167.44, 166.72, 165.13 (q, JC-F = 2.9 Hz, C-SCF3), 163.93,
133.81, 132.80, 129.02, 128.83, 128.48, 127.72, 127.65, 128.22 (q, JC-F
= 306.5 Hz, SCF3), 126.74, 125.17, 123.48, 62.15, 22.57, 13.66. 19F
NMR (376 MHz, CDCl3) δ = -41.03. HRMS (ESI) m/z: Calcd for
C19H15F3N2O2S: 393.0879 [M+H]+, Found: 393.0877.
7-chloro-4-phenyl-2-((trifluoromethyl)thio)quinoline (5b). Yellow solid
1
(54.2 mg, 80%); m.p.: 287-289 °C. H NMR (600 MHz, CDCl3) δ = 8.08
(dd, J = 9.0, 3.2 Hz, 1H), 7.86 (t, J = 2.4 Hz, 1H), 7.69 (dt, J = 9.0, 2.4 Hz,
1H), 7.58–7.54 (m, 3H), 7.52 (d, J = 3.0 Hz, 1H), 7.49–7.46 (m, 2H). 13
C
NMR (150 MHz, CDCl3) δ = 150.07 (q, JC-F = 2.4 Hz, C-SCF3), 149.56,
147.23, 136.26, 133.75, 131.36, 131.26, 139.27 (q, JC-F = 307.1 Hz,
SCF3), 129.33, 129.23, 128.96, 126.51, 124.74, 123.89 (d, JC-F = 2.1 Hz,
C-SCF3, it should be quartet, but only doublet was observed.). 19F NMR
(376 MHz, CDCl3) δ = -39.55. HRMS (ESI) m/z: Calcd for C16H9ClF3NS:
340.0169 [M+H]+, Found: 340.0166.
Ethyl
4-methyl-6-(naphthalen-1-yl)-2-
((trifluoromethyl)thio)pyrimidine-5-carboxylate (3s). Colourless oil
(41.6 mg, 53%); 1H NMR (600 MHz, CDCl3) δ = 7.94 (d, J = 8.4 Hz, 1H),
7.90–7.88 (m, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.53–7.47 (m, 3H), 7.43 (dd,
J = 6.6, 1.2 Hz, 1H), 3.81 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 0.56 (t, J = 7.2
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ = 167.31, 166.20, 165.77, 165.24
(q, J = 3 Hz, C-SCF3), 134.55, 133.46, 130.51, 130.19, 128.29, 128.13 (q,
J = 306.5 Hz, SCF3), 126.89, 126.37, 125.50, 124.99, 124.80, 61.60,
22.95, 13.07. 19F NMR (376 MHz, CDCl3) δ = -41.03. HRMS (ESI) m/z:
Calcd for C19H15F3N2O2S: 393.0879 [M+H]+, Found: 393.0881.
6-ethyl-4-(p-tolyl)-2-((trifluoromethyl)thio)quinoline (5c). Yellow solid
(53.4 mg, 77%); 1H NMR (600 MHz, CDCl3) δ = 8.08 (d, J = 8.4 Hz, 1H),
7.70 (s, 1H), 7.63 (dd, J = 9.0, 2.4 Hz, 1H), 7.50 (s, 1H), 7.42–7.39 (m,
2H), 7.36 (d, J = 7.8 Hz, 2H), 2.77 (q, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.25
(t, J = 7.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ = 149.89, 148.04 (q, JC-
Isopropyl
4-methyl-6-phenyl-2-((trifluoromethyl)thio)pyrimidine-5-
= 2.6 Hz, C-SCF3), 147.81, 144.11, 138.85, 134.23, 131.45, 129.93 (q,
F
carboxylate (3t). Colourless oil (49.2 mg, 69%); 1H NMR (600 MHz,
CDCl3) δ = 7.68–7.66 (m, 2H), 7.50–7.42 (m, 3H), 5.14–5.07 (m, 1H),
2.58 (s, 3H), 1.10 (d, J = 6.0 Hz, 6H).13C NMR (150 MHz, CDCl3) δ =
166.73, 166.42, 164.92 (q, JC-F = 3.0 Hz, C-SCF3), 163.96, 136.53,
JC-F = 108.5 Hz, SCF3), 129.63, 129.43, 129.37, 126.04, 124.02 (d, JC-F =
2.3 Hz, C-SCF3), 123.48, 29.16, 21.31, 15.45. 19F NMR (376 MHz,
CDCl3) δ = -39.77. HRMS (ESI) m/z: Calcd for C19H16F3NS: 348.1028
[M+H]+, Found: 348.1030.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801565
European Journal of Organic Chemistry
FULL PAPER
4-phenyl-2-((trifluoromethyl)thio)benzo[g]quinoline (5d). Yellow solid
(60.4 mg, 85%); m.p.: 81-83 °C. H NMR (600 MHz, CDCl3) δ = 8.01 (s,
Chen, L.-L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 12454-
12457. (c) Alazet, S.; Zimmer, L.; Billard, T. Angew. Chem. Int. Ed.
2013, 52, 10814-10817; Angew. Chem. 2013, 125, 11014–11017.
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Chem. Soc. 2005, 127, 12226-12227. (b) X.-S. Zhang, J.-Y. Jiao, X.-H.
Zhang, B.-L. Hu, and X.-G. Zhang, J. Org. Chem. 2016, 81, 5710−5716.
(c) W.-Q. Fu, T.-T. Liu, Z.-X. Fang, Y.-L. Ma, X. Zheng, W.-C. Wang, X.
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1
2H), 7.87 (dd, J = 7.8, 1.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H),
7.55–7.49 (m, 4H), 7.42–7.40 (m, 2H), 7.19–7.16 (m, 1H). 13C NMR (150
MHz, CDCl3) δ = 150.24, 150.20, 147.72 (q, JC-F = 2.3 Hz, C-SCF3),
141.53, 133.18, 132.60, 129.40, 129.21, 128.74, 128.64, 129.46 (q, JC-F
= 306.9 Hz, SCF3), 128.23, 128.19, 128.07, 127.29, 126.85 (d, JC-F = 2.0
Hz, C-SCF3, it should be quartet, but only doublet was observed.),
125.94, 123.49. 19F NMR (376 MHz, CDCl3) δ = -39.80. HRMS (ESI) m/z:
Calcd for C20H12F3NS: 356.0715 [M+H]+, Found: 356.0718.
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7.65 (s, 1H), 7.60 (dd, J = 8.4, 1.8 Hz, 1H), 7.57–7.52 (m, 3H), 7.51–7.46
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Acknowledgments
We are thankful for the financial support from the National
Natural Science Foundation of China (NSF21562036), China
Postdoctoral Science Foundation Funded Project (No.
2018M631218), Gansu Province Science Foundation for Youths
(No. 18JR3RA099).
Keywords: trifluoromethylation • disulfides • heterocycle •
ketones • radical reactions
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[17]
The
CCDC
number
of
3u
is
1855199.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801565
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Key Topic*
Bao-Qian Cao,[‡] Yi-Feng Qiu,[‡] Zheng-
Jun Quan,*, and Xi-Cun Wang*
Page No. – Page No.
UV light irradiated
A trifluoromethylation of diheteroaryl disulfides with CF3SO2Na to afford the
trifluoromethyl thioethers derivatives. The conversion has good functional group
compatibility, without external photocatalyst, generating the corresponding products
in moderate to good yields under mild conditions, and the disulfide is fully utilized
while constructing two S-CF3 bonds.
trifluoromethylation of disulfides with
CF3SO2Na
* Radical reactions Trifluoromethylation
This article is protected by copyright. All rights reserved.