Metal-Free Trifluoromethylthiolation of Arylazo Sulfones

Article abstract of DOI:10.1021/acs.joc.0c02669

A visible-light-driven protocol for the synthesis of aryl trifluoromethyl thioethers under photocatalyst- and metal-free conditions has been pursued. The procedure exploits the peculiar properties of arylazo sulfones (having electron-rich or electron-poor substituents on the (hetero)aromatic ring) as photochemical precursors of aryl radicals and S-trifluoromethyl arylsulfonothioates as easy-to-handle trifluoromethylthiolating agents.

Full text of DOI:10.1021/acs.joc.0c02669

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Metal-Free Trifluoromethylthiolation of Arylazo Sulfones
Ankun Li,⊥ Yuxuan Li,⊥ Junjie Liu, Jingqi Chen, Kui Lu, Di Qiu, Maurizio Fagnoni, Stefano Protti,*
and Xia Zhao*
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ABSTRACT: A visible-light-driven protocol for the synthesis of
aryl trifluoromethyl thioethers under photocatalyst- and metal-free
conditions has been pursued. The procedure exploits the peculiar
properties of arylazo sulfones (having electron-rich or electron-
poor substituents on the (hetero)aromatic ring) as photochemical
precursors of aryl radicals and S-trifluoromethyl arylsulfonothioates
as easy-to-handle trifluoromethylthiolating agents.
Scheme 1
he formation of an Ar−SCF3 bond is important in life
T
sciences for the synthesis of bioactive molecules. In fact
the SCF3 group, when present in an aromatic compound,
strongly affected its physicochemical properties, mostly its
lipophilicity. The latter is a key parameter in drug design since
the bioavailability of the drug is enhanced when lipophilicity
increases.1 In this case, a combined effect of the presence of
fluorine atoms2 with heteroatoms imparts a good lipophilicity
as witnessed by the high values of the Hansch parameters (πR
= 1.44).3 Some drugs, such as the antiprotozoal agent
Toltrazuril and the stimulant amphetamine Tiflorex, contain
the Ar−SCF3 moiety. Accordingly, a more reliable synthetic
procedure in the forging of the Ar−S bond could increase a
wider application of trifluoromethylthiolated aromatics in
medicinal chemistry. In the last years, several synthetic
protocols for the introduction of a SCF3 group in a
(hetero)aromatic core have been developed.4 An interesting
approach is the direct trifluoromethylthiolation of (hetero)-
arenes, but only certain electron-rich derivatives led to the
desired product in a clean fashion, avoiding the concomitant
formation of undesired regioisomers (Scheme 1a).5 Thus,
several approaches have been developed by replacing an
aromatic substituent with a SCF3 group making use of a metal
catalyst (e.g., Cu,6 Ni,7 Pd,8 and Ag9). The reaction is, in most
cases, an ipso-substitution that starts from aryl diazonium
salts,6a,d,h aryl halides,6c,7a,c,d,9 aryl boronic acids,6b−g aryltri-
fluoroborates,6e di(hetero)aryl-λ3-iodanes,6f aryl sulfonates,7b
and arylmercaptodifluoroacetic acids (Scheme 1b).8a Metal-
free alternatives, however, are limited to the alkylation of aryl
sulfides by using CF3I under basic conditions10 (Scheme 1c)
except the trifluoromethylation of diaryl sulfides with
trifluoromethyltriisopropylsilane (TIPSCF3)11 and the radical
trifluoromethylthiolation of arenediazonium salts with
Me4NSCF3.12 In recent years, a handful of examples were
reported where photochemistry was applied for the synthesis
of ArSCF3 thanks to the easy photogeneration of aryl radicals
Received: November 9, 2020
https://dx.doi.org/10.1021/acs.joc.0c02669
© XXXX American Chemical Society
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from aryl diazonium salts and ensuing reaction with a S-
trifluoromethyl arylsulfonothioate13a,b or 1,2-bis-
(trifluoromethyl)disulfane (CF3S)2 (Scheme 1d).13c Unfortu-
nately, the latter approach requires the presence of a
photocatalyst (PC) and a sensitive aryl radical precursor
complicated by the special caution required on the use and
storage of arenediazonium salts.14
We then envisioned that a straightforward route to Ar−SCF3
could involve again aryl radicals but was generated by visible-
light irradiation of arylazo sulfones (ArN2SO2Me, Scheme 1e).
Such derivatives exhibit a wavelength selective behavior15 and
release an aryl radical upon visible-light irradiation16 by
cleavage of the N−S bond followed by nitrogen loss of the
resulting aryl diazenyl radical.17 The thus generated aryl
radicals were recently applied for the forging of various Ar−C
and Ar−heteroatom bonds.18 In view of these premises, we
planned to use such sulfones for the easy arylation of a SCF3-
containing derivative to form the desired Ar−SCF3. As the
trifluoromethylthiolating agent, we exclude the use of (CF3S)2
due to its difficult handling,13c focusing our attention on S-
trifluoromethyl arylsulfonothioates.
when doubling the concentration of the reactants, 3a was
isolated in 63% yield (entry 10), and this yield slightly
decreased by using a 0.5 M amount of 1a (entry 11). Notably,
increasing the loading of the trifluoromethylthiolating agent 2a
from 2.0 equiv to 4.0 equiv improved the yield up to 75%
(entry 12). The formation of 3a was completely inhibited in
the absence of light (entry 13). Dedicated on−off experiments
confirmed that the reaction did not proceed in the dark (see
Figure S1).
The conditions described in entry 12 have been thus
adopted to investigate the scope of the synthetic protocol.
Compound 3a was also synthesized on a gram scale and
isolated in 45% yield (see Table 2). We then investigated the
a
Table 2. Trifluoromethylthiolation of Arylazo Sulfones
Preliminary experiments were carried out on compound 1a,
and the obtained results are summarized in Table 1. Irradiation
a
Table 1. Optimization of the Reaction Conditions
2
light source
(LED)
yield
(%)
entry
1a (conc)
(equiv)
solvent
1
2
3
4
5
6
7
8
1a, 0.125 M
1a, 0.125 M
1a, 0.125 M
1′a, 0.125 M
1a, 0.125 M
1a, 0.125 M
1a, 0.125 M
1a, 0.125 M
1a, 0.125 M
1a, 0.25 M
1a, 0.5 M
2a (2)
2a (2)
2a (2)
2a (2)
2b (2)
2c (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (4)
2a (2)
DCE
DCE
DCE
DCE
DCE
DCE
toluene
DMF
MeCN
DCE
DCE
DCE
DCE
21 W green
9 W blue
21
39
53
49
49
52
20
19
<5%
63
60
75
trace
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
21 W blue
b
9
10
11
12
a
1a, 0.25 M
1a, 0.25 M
A solution of 1a−x in DCE in the presence of 2a (4 equiv) irradiated
b
c
13
for 36 h by means of a 21 W Blue Light LED. Reaction carried out
on 10 mmol 1a, 48 h irradiation (gram scale = 1.15 g). 2 equiv of 2a
employed. Quinoline (30% yield) was observed as the byproduct via
GC−MS analyses. Benzothiazole (24% yield) was observed as the
byproduct via GC−MS analyses.
c
a
b
Reaction time = 12−36 h. Biphenyl was observed as the main
d
c
product; In the dark.
e
of 1a (0.125 M, in 1,2-dichloroethane, DCE) in the presence
of two equivalents of S-(trifluoromethyl) 4-difluorobenzene-
sulfonothioate (2a) by means of a 21 W green LED afforded
the arylated compound 3a in low yields (21%, entry 1).
Moving to blue light (entries 2 and 3) resulted in an
improvement of the efficiency of the process, and a 53% yield
was reached with a 21W blue LED lamp. The use of a different
arylazo sulfone (1a′, entry 4) as well as the adoption of either
electron-rich (2b) or difluorinated (2c) benzenesulfono-
thioates (entries 5 and 6) did not afford better results, while,
among the different media tested (entries 7−9), DCE
furnished the most satisfactory performance. Hydrodeaminated
biphenyl can be competitively formed as the main product by
changing the reaction medium (e.g., MeCN). Gratifyingly,
scope of the protocol, as shown in Table 2. The desired
trifluoromethylthiolated products have been isolated in
discrete to satisfactory yields, and the process showed a good
tolerance to both electron-donating and electron-withdrawing
substituents present on the aromatic ring, including (thio)-
alkoxy groups (see products 3c−e, 3p), halogens (3i,n), and
carbonyls (3k−m). In some cases, good results were obtained
in the presence of only 2 equiv of 2a (as in the synthesis of 3f
and 3l). The process was found to be also suitable to prepare
naphthyl derivative 3q, whereas heteroaryl trifluoromethyl
thioethers (3r−x) were mainly obtained in a lower yield. In the
B
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(ion trap) or Bruker Solarix XR FTMS (Q-TOF) mass instrument. All
arylazo sulfones were prepared from the corresponding arenediazo-
nium tetrafluoroborates according to literature procedures.18e−g The
light-promoted reactions were carried out by using a standard blue
LED lamp with 20 one-light-emitting diodes (12−28 V, 21 W, 465−
470 nm). The distance from the light source to the irradiation vessel
was 3 cm.
Typical Procedure for the Preparation of Arenediazonium
Tetrafluoroborates. Method A. In a 100 mL round-bottom flask,
the aromatic amine (20 mmol) was dissolved in a mixture of H2O (10
mL) and HBF4 (48% aq, 6 mL). After the mixture was stirred for 15
min, a solution of NaNO2 (1.5 g, 1.1 equiv, in 4 mL of H2O) was
added dropwise at 0 °C (in an ice bath). The mixture was stirred for
another 30 min at 0 °C. Then, the arenediazonium tetrafluoroborate
was removed by filtration and washed with diethyl ether (2 × 10 mL).
The crude product was dried in vacuo for 20 min and was then
directly used without further purification.
latter cases, the hydrodeamination product (see the case of 3u
and 3x) was detected as the main byproduct (up to 30% yield).
A tentative mechanism is shown in Scheme 2. Sulfones 1a−x
possess a weak nπ band between 400 and 500 nm (ε ca. 500
Scheme 2. Proposed Mechanism for the
Thiotrifluoromethylation of Arylazo Sulfones
Method B. In a 100 mL round-bottom flask, the aromatic amine
(20 mmol) was dissolved in a mixture of ethanol (8 mL) and HBF4
(48% aq, 6 mL). Subsequently, tert-butyl nitrite (4.7 mL, 2.0 equiv)
was added dropwise to the solution at 0 °C. The reaction mixture was
stirred for 30 min at 0 °C, and anhydrous diethyl ether (20 mL) was
added to precipitate the corresponding arenediazonium tetrafluor-
oborate. The solid was filtered off and washed with diethyl ether (2 ×
10 mL). The product was then dried in vacuo for 20 min and used
without further purification.
Typical Procedure for the Preparation for Arylazo Sulfones. In a
100 mL round-bottom flask, the suspension of the freshly prepared
arenediazonium tetrafluoroborate (20 mmol) in CH2Cl2 (20 mL) was
stirred at 0 °C; then sodium methanesulfinate (2.24 g, 1.1 equiv) was
added to the reaction system in one portion. The temperature was
risen to rt; the mixture was stirred overnight and then filtered, and the
obtained solution evaporated. The crude product was thus purified by
dissolution in CH2Cl2 and precipitation by adding cold petroleum
ether. The obtained arylazo sulfones were filtered and dried in vacuo
for 30 min.
M−1) sufficient to allow the absorption in the visible region
(465−470 nm blue LEDs have been used as inexpensive light
source).16 A direct photolysis of 2a is safely excluded since its
absorption at the wavelength used is negligible (see Figure S2).
The labile S−N bond underwent a smooth photocleavage
(path a) liberating the desired aryl radical Ar• that, as
previously described,13a,b gave a substitution reaction with 2a
(path b) to form derivatives 3a−x along with the stable 4-
fluorophenylsulfonyl radical. Hydrogen atom abstraction of Ar•
from the solvent to form the hydrodeaminated product Ar−H
(path c) is the main competitive path.18c The intermediacy of
an aryl radical has been further confirmed by the formation of
adduct 4k that was isolated in 30% yield when the reaction of
1k with 2a was carried out in the presence of TEMPO (4
equiv, path d).
In summary, we proposed a radical trifluoromethylthiolation
reaction for the formation of aryl−SCF3 bonds via simple
visible-light activation of bench-stable arylazo sulfones under
both metal-free and (photo)catalyst-free conditions. The
process employed S-(trifluoromethyl) 4-difluorobenzenesulfo-
nothioate as the trifluoromethylthiolating agent and was found
suitable for the preparation of both electron-rich and electron-
poor SCF3-substituted aromatics in discrete to satisfactory
yields. In analogy with other metal-free12 or photocatalyze-
d13a−c trifluoromethylthiolation protocols, a low efficiency in
the synthesis of heteroaryl trifluoromethyl thioethers was
observed, with the only exception of benzofuran 3r.
Characterization Data for the Arylazo Sulfones 1a−t. 1-
([1,1′-Biphenyl]-4-yl)-2-(methylsulfonyl)diazene (1a).18d Yellow
1
solid (3.6 g, 69%). Mp (dec): 107−109 °C. H NMR (400 MHz,
CDCl3): δ 8.03 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.68−
7.66 (m, 2H), 7.52−7.48 (m, 2H), 7.46−7.42 (m, 1H), 3.24 (s, 3H).
1-([1,1′-Biphenyl]-4-yl)-2-((4-nitrophenyl)sulfonyl)diazene (1a′).
1
Yellow solid (4.0 g, 54%). Mp (dec): 100−101 °C. H NMR (400
MHz, CDCl3): δ 8.45 (d, J = 8.88 Hz, 2H), 8.19 (d, J = 8.92 Hz, 2H),
7.89 (d, J = 8.64 Hz, 2H), 7.75 (d, J = 8.68 Hz, 2H), 7.64−7.62 (m,
2H), 7.51−7.41 (m, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ
151.3, 148.7, 147.9, 139.4, 138.9, 131.8, 129.1, 129.0, 128.2, 127.3,
125.5, 124.1. IR (neat, υ cm−1): 3413, 1616, 1526, 1352, 1149, 1074,
952, 858, 620, 517. The compound was found to decompose upon
HRMS analysis.
4-(4-((Methylsulfonyl)diazenyl)phenyl)morpholine (1b). Orange
1
solid (2.1 g, 39%). Mp (dec): 139−140 °C. H NMR (400 MHz,
CDCl3): δ 7.86 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 3.86 (t, J
= 4.8 Hz, 4H), 3.46 (t, J = 5.1 Hz, 4H), 3.14 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 155.7, 140.9, 127.8, 113.1, 66.3, 46.8, 35.0. IR
(neat, υ cm−1): 3413, 1607, 1379, 1318, 1234, 1141, 1067, 619, 533.
HRMS (ESI) m/z: [M + H]+ calcd for C11H16N3O3S, 270.0907;
found, 270.0904.
1-(Methylsulfonyl)-2-(4-phenoxyphenyl)diazene (1c). Brown
1
solid (4.4 g, 80%). Mp (dec): 110−111 °C. H NMR (400 MHz,
CDCl3): δ 7.94 (d, J = 9.0 Hz, 2H), 7.47−7.43 (m, 2H), 7.27 (t, J =
7.4 Hz, 1H), 7.13−7.01 (m, 4H), 3.20 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 164.3, 154.5, 144.0, 130.2, 127.1, 125.4, 120.6,
117.7, 34.8. IR (neat, υ cm−1): 3413, 1615, 1486, 1338, 1243, 1137,
949, 853, 773, 617, 502. HRMS (ESI) m/z: [M + H]+ calcd for
C13H13N2O3S, 277.0641; found, 277.0641.
EXPERIMENTAL SECTION
■
General Remarks. All solvents were distilled prior to use. For
chromatography, 200−300 mesh silica gel (Qingdao, China) was
1
employed. H, 13C, and 19F NMR spectra were recorded at 400, 100
(Benzyloxy)phenyl)-2-(methylsulfonyl)diazene (1d). Pale yellow
1
and 375 MHz with a Bruker ARX 400 spectrometer. Chemical shifts
are reported in ppm using tetramethylsilane as an internal standard.
HRMS was performed on an Thermo Scientific LTQ Orbitrap XL
solid (3.0 g, 52%). Mp (dec): 150−151 °C. H NMR (400 MHz,
CDCl3): δ 7.95 (d, J = 9.8 Hz, 2H), 7.45−7.36 (m, 5H), 7.11 (d, J =
9.1 Hz, 2H), 5.19 (s, 2H), 3.19 (s, 3H). 13C{1H} NMR (100 MHz,
C
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CDCl3): δ 164.8, 143.3, 135.5, 128.8, 128.5, 127.5, 127.3, 115.7, 70.7,
34.9. IR (neat, υ cm−1): 3413, 1614, 1485, 1338, 1137, 949, 852, 617,
502. HRMS (ESI) m/z: [M + H]+calcd for C14H15N2O3S, 291.0795;
found, 291.0798.
Ethyl 5-((Methylsulfonyl)diazenyl)benzofuran-2-carboxylate
(1r).18e Yellow solid (4.6 g, 78%). Mp (dec): 117−118 °C. 1H
NMR (400 MHz, CDCl3): δ 8.35 (d, J = 2.0 Hz, 1H), 8.05 (dd, J =
2.0, 9.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 0.8 Hz, 1H),
4.47 (q, J = 7.1 Hz, 2H), 3.24 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).
2-Methyl-5-((methylsulfonyl)diazenyl)benzo[d]thiazole (1s).18e
1-(Methylsulfonyl)-2-(4-(methylthio)phenyl)diazene (1e). Yellow
1
solid (2.9 g, 63%). Mp (dec): 130−132 °C. H NMR (400 MHz,
1
Brown solid (3.9 g, 77%). Mp (dec): 123−124 °C. H NMR (400
CDCl3): δ 7.87 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H) 3.20 (s,
3H), 2.58 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 150.0,
145.8, 125.4, 124.9, 34.8, 14.7. IR (neat, υ cm−1): 3413, 1614, 1486,
1337, 1137, 949, 617, 502. HRMS (ESI) m/z: [M + H]+ calcd for
C8H11N2O2S2, 231.0257; found, 231.0256.
MHz, CDCl3): δ 8.50 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H),
7.92 (dd, J = 1.9, 8.6 Hz, 1H), 3.25 (s, 3H), 2.89 (s, 3H).
Methyl 5-((Methylsulfonyl)diazenyl)nicotinate (1t).18e Yellow
1
solid (4.1 g, 85%). Mp (dec): 103−105 °C. H NMR (400 MHz,
1-(4-(tert-Butyl)phenyl)-2-(methylsulfonyl)diazene (1f).18d Yel-
CDCl3): δ 9.46 (d, J = 1.9 Hz, 1H), 9.38 (d, J = 2.3 Hz, 1H), 8.73 (t, J
= 2.1 Hz, 1H), 4.02 (s, 3H), 3.29 (s, 3H).
1
low solid (2.6 g, 55%). Mp (dec): 78−80 °C. H NMR (400 MHz,
7-((Methylsulfonyl)diazenyl)quinoline (1u). Red solid (3.1 g,
66%). Mp (dec): 140−142 °C. 1H NMR (400 MHz, CDCl3): δ
9.06 (dd, J = 1.5, 4.2 Hz, 1H), 8.79 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H),
7.99−7.92 (m, 2H), 7.59−7.56 (m, 1H), 3.31 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 152.1, 149.0, 148.1, 136.0, 133.7, 132.0, 129.8,
123.8, 116.2, 34.8. IR (neat, υ cm−1): 3440, 3045, 3020, 1500, 1463,
1328, 1151, 946, 867, 772, 746, 616, 566, 443. HRMS (ESI) m/z: [M
+ Na]+ calcd for C10H9N3O2SNa, 258.0308; found, 258.0308.
4-Methyl-7-((methylsulfonyl)diazenyl)-2H-chromen-2-one (1v).
CDCl3): δ 7.88 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 3.20 (s,
3H), 1.36 (s, 9H).
Ethyl 3-(4-((E)-(Methylsulfonyl)diazenyl)phenyl)acrylate (1g).18e
1
Yellow solid (5.5 g, 98%). Mp (dec): 98−100 °C. H NMR (400
MHz, CDCl3): δ 7.95(d, J = 8.5 Hz, 2H), 7.68−7.72 (m, 3H), 6.57
(d, J = 16.1 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.22 (s, 3H), 1.34 (t, J
= 7.1 Hz, 3H).
1-(Methylsulfonyl)-2-(4-((triisopropylsilyl)ethynyl)phenyl)-
diazene (1h).18e Yellow solid (2.7 g, 37%). Mp (dec): 63−64 °C. 1H
NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5
Hz, 2H), 3.22 (s, 3H), 1.16−1.12 (m, 21H).
1
Orange solid (2.3 g, 43%). Mp (dec): 102−104 °C. H NMR (400
MHz, CDCl3): δ 7.88−7.85 (m, 2H), 7.80 (d, J = 9.0 Hz, 1H), 6.46
(d, J = 1.3 Hz, 1H), 3.27 (s, 3H), 2.51 (d, J = 1.3 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 159.04, 153.9, 151.1, 150.2, 126.0, 125.0,
118.9, 118.0, 113.6, 35.0, 18.7. IR (neat, υ cm−1): 3440, 3045, 3006,
2920, 1715, 1624, 14110, 1340, 1259, 1158, 979, 903, 558. HRMS
(ESI) m/z: [M + H]+ calcd for C11H11N2O4S, 267.0434; found,
267.0434.
1-(4-Bromophenyl)-2-(methylsulfonyl)diazene (1i).18f Yellow
1
solid (3.2 g, 60%). Mp (dec): 131−133 °C. H NMR (400 MHz,
CDCl3): δ 7.83 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 3.22 (s,
3H).
4-((Methylsulfonyl)diazenyl)benzonitrile (1j).18h Yellow solid (3.3
1
g, 79%). Mp (dec): 114−115 °C. H NMR (400 MHz, CDCl3): δ
8.04 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 3.26 (s, 3H).
Ethyl 4-((Methylsulfonyl)diazenyl)benzoate (1k).18d Yellow solid
(3.7 g, 73%). Mp (dec): 83−84 °C. 1H NMR (400 MHz, CDCl3): δ
8.25(d, J = 8.6 Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H), 4.44 (q, J = 7.1 Hz,
2H), 3.25 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H).
9-Ethyl-3-((methylsulfonyl)diazenyl)-9H-carbazole (1w). Brown
1
solid (4.9 g, 81%). Mp (dec): 145−147 °C. H NMR (400 MHz,
CDCl3): δ 8.70 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.08
(dd, J = 1.9, 8.9 Hz, 1H), 7.58−7.54 (m, 1H), 7.48−7.45 (m, 2H),
7.37−7.33 (m, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.24 (s, 3H), 1.49 (t, J =
7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.3, 142.3,
140.9, 127.3, 123.7, 123.3, 122.2, 121.0, 120.5, 111.4, 109.6, 109.2,
38.1, 35.0, 13.8. IR (neat, υ cm−1): 3442, 3032, 2975, 1593, 1498,
1418, 1119, 958, 835, 489. HRMS (ESI) m/z: [M + H]+ calcd for
C15H16N3O2S, 302.0958; found, 302.0958.
1-(4-((Methylsulfonyl)diazenyl)phenyl)ethanone (1l).18d Yellow
1
solid (3.6 g, 80%). Mp (dec): 119−120 °C. H NMR (400 MHz,
CDCl3): δ 8.13 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 3.24 (s,
3H), 2.67 (s, 3H).
(4-((Methylsulfonyl)diazenyl)phenyl)(phenyl)methanone (1m).
1
Yellow solid (4.3 g, 75%). Mp (dec): 130 °C. H NMR (400 MHz,
5-((Methylsulfonyl)diazenyl)benzo[d]thiazole (1x). Yellow solid
(1.5 g, 31%). Mp (dec): 152−154 °C. 1H NMR (400 MHz, CDCl3):
δ 9.16 (s, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.02
(dd, J = 1.9, 8.7 Hz, 1H), 3.28 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 156.6, 153.8, 147.7, 140.7, 123.4, 122.9, 118.2, 34.9. IR
(neat, υ cm−1): 3438, 3049, 1477, 1326, 1151, 865, 823, 531. HRMS
(ESI) m/z: [M + H]+ calcd for C8H8N3O2S2, 242.0052; found,
242.0052.
CDCl3): δ 8.01 (dd, J = 8.6, 31.4 Hz, 4H), 7.81 (d, J = 7.04 Hz, 2H),
7.67−7.62 (m, 1H), 7.52 (t, J = 7.88 Hz, 2H), 3.27 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 195.1, 150.6, 142.8, 136.4, 133.2, 131.0,
130.0, 128.5, 124.2, 34.8. IR (neat, υ cm−1): 3413, 1659, 1617, 1340,
1276, 1159, 1069, 954, 861, 700. HRMS (ESI) m/z: [M + H]+ calcd
for C14H13N2O3S, 289.0638; found, 289.0641.
1-(3-Bromophenyl)-2-(methylsulfonyl)diazene (1n).18e Yellow
solid (2.5 g, 47%). Mp (dec): 95−96 °C. 1H NMR (400 MHz,
CDCl3): δ 8.06 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz,
1H), 7.47 (t, J = 8.0 Hz, 1H), 3.22 (s, 3H).
Synthesis of Compound 2c. Compound 2c was obtained by
following a procedure previously reported for the synthesis of
compounds 2a,b.19 A mixture of 3,5-difluorobenzenesulfinate sodium
salt (20 mmol, 1 equiv), N-[(trifuoromethyl)thio] aniline (1 equiv),20
and paratoluenesulfonic acid (2.5 equiv) in DCE (130 mL) was
stirred at room temperature. After the completion of the reaction,
indicated by TLC, the mixture was filtered with a sand core funnel
with silica gel, washed with CH2Cl2, and dried over Na2SO4. After
concentration, the residue was purified by flash column chromatog-
raphy to obtain the final product 2c (light yellow oil, 3.8 g, 68%). 1H
NMR (400 MHz, CDCl3): δ 7.55 (dd, J = 1.92, 5.68 Hz, 2H), 7.19
(tt, J = 2.28, 8.20 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
164.1 (d, J = 11.52 Hz, 1C), 161.5 (d, J = 11.36 Hz, 1C), 147.0 (t, J =
9.46 Hz, 1C), 120.7 (q, J = 311.66 Hz, 1C), 111.3 (d, J = 29.06 Hz,
1C), 111.3 (d, J = 11.31 Hz, 1C), 110.9 (t, J = 24.89 Hz, 1C). 19F
NMR (375 MHz, CDCl3): δ −38.1 (s, 3F), −103.4 (s, 2F). The
present compound was found to decompose upon HRMS analysis.
Synthesis of Thiotrifluoromethyl Arenes (3a−x). A solution of the
chosen arylazo sulfone (1a−x, 0.25 M) in DCE was placed in a 10 mL
microwave tube, and then S-(trifluoromethyl) 4-fluorobenzenesulfo-
nothioate (2a, 1 mmol, 2.0−4.0 equiv, see Table 1) was added. The
resulting solution was irradiated under stirring at room temperature
1-(Methylsulfonyl)-2-(3,4,5-trimethoxyphenyl)diazene (1o). Pale
1
yellow solid (2.7 g, 49%). Mp (dec): 122−124 °C. H NMR (400
MHz, CDCl3): δ 7.26 (s, 2H), 4.00 (s, 3H), 3.94 (s, 6H), 3.22 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.5, 144.4, 102.5, 61.1
(d, J = 6.4 Hz), 56.3 (d, J = 5.4 Hz), 34.9. IR (neat, υ cm−1): 3413,
1614, 1486, 1338, 1137, 949, 617, 502. HRMS (ESI) m/z: [M +
H]+calcd for C10H14N2O5S, 275.0696; found, 275.0696.
1-(Benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)diazene (1p).
1
Dark green solid (0.91 g, 20%). Mp (dec): 113−114 °C. H NMR
(400 MHz, CDCl3): δ 7.69 (dd, J = 2.0, 8.2 Hz, 1H), 7.34 (d, J = 1.9,
Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.14 (s, 2H), 3.18 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 154.4, 149.5, 144.8, 129.3,
108.4, 102.8, 98.8, 34.9. IR (neat, υ cm−1): 3414, 1617, 1477, 1414,
1152, 618. HRMS (EI) m/z: [M + H]+ calcd for C8H9N2O4S,
229.0278; found, 229.0281.
1-(Methylsulfonyl)-2-(naphthalen-2-yl)diazene (1q).18e Yellow
1
solid (2.2 g, 47%). Mp (dec): 108−109 °C. H NMR (400 MHz,
CDCl3): δ 8.56 (s, 1H), 8.03−8.01 (m, 1H), 7.92−7.89 (m, 3H), 7.67
(t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 3.27 (s, 3H).
D
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Note
for 36 h by means of a 21 W blue LED, and then the reaction mixture
was concentrated under reduced pressure to evaporate the solvent.
The residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate mixture as the eluent).
Gram-Scale Preparation of 3a. 1-([1,1′-Biphenyl]-4-yl)-2-
(methylsulfonyl) diazene (1a, 10 mmol, 2.6 g) was placed in a
round-bottom flask and dissolved in DCE (100 mL) under aerated
conditions. Compound 2a (20 mmol, 2.0 equiv) was added, and the
resulting solution was irradiated under stirring for 48 h by means of a
21 W blue LED. The reaction mixture was concentrated under
reduced pressure to evaporate the solvent, and the residue was
purified by silica gel column chromatography (petroleum ether as the
eluent) to obtain [1,1′-biphenyl]-4-yl (trifluoromethyl) sulfane 3a
(1.15 g, 45%) as a white solid.
MHz, CDCl3): δ −42.3 (s, 3F). HRMS (EM) m/z: [M − e]+calcd for
C12H11F3O2S, 276.0432; found, 276.0417.
Triisopropyl((4-((trifluoromethyl)thio)phenyl)ethynyl)silane (3h).
After purification by silica gel column chromatography (PE),
compound 3h was isolated as a colorless oil (40 mg, 45%). Rf (PE)
= 0.8. 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.2 Hz, 2H), 7.51
(d, J = 8.2 Hz, 2H), 1.13 (s, 21H). 13C{1H} NMR (100 MHz,
CDCl3): δ 136.0, 134.0, 132.9, 124.4 (q, 1J(C,F) = 306.4 Hz), 126.4,
2
124.2 (q, J(C,F) = 2.1 Hz), 105.5, 94.1, 18.6, 11.3. 19F NMR (375
MHz, CDCl3): δ −42.6 (s, 3F). HRMS (EM) m/z: [M − e]+calcd for
C18H25F3SSi, 358.1398; found, 358.1385.
(4-Bromophenyl)(trifluoromethyl)sulfane (3i).13 After purification
by silica gel column chromatography (PE), compound 3i was isolated
as a colorless oil (36 mg, 56%). Rf (PE) = 0.85. 1H NMR (400 MHz,
CDCl3): δ 7.57 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H). 13C{1H}
Characterization Data for the Isolated Products (3a−x).
[1,1′-Biphenyl]-4-yl(trifluoromethyl)sulfane (3a).13 After purifica-
tion by silica gel column chromatography (PE), compound 3a was
isolated as a white solid (50 mg, 75%). Rf (PE) = 0.8. 1H NMR (400
MHz, CDCl3): δ 7.74 (d, J = 8.3 Hz, 2H), 7.66−7.60 (m, 4H), 7.49
(t, J = 7.4 Hz, 2H), 7.42 (d, J = 7.4 Hz, 1H). 13C{1H} NMR (100
1
NMR (100 MHz, CDCl3): δ 137.7 132.8 129.2 (q, J(C,F) = 306.6
Hz), 126.0, 123.4 (q, 2J(C,F) = 2.1 Hz). 19F NMR (375 MHz,
CDCl3): δ −42.7 (s, 3F).
4-((Trifluoromethyl)thio)benzonitrile (3j).13 After purification by
silica gel column chromatography (PE/EA = 100:1), compound 3j
was isolated as a white solid (27 mg, 53%). Rf (PE/EA = 50:1) = 0.35.
1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 2H), 7.72 (d, J =
8.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 136.0 132.9, 130.6
1
MHz, CDCl3): δ 143.8, 139.7, 136.7, 129.6 (q, J(C,F) = 306.4 Hz),
2
128.9, 128.1, 127.2, 123.1 (q, J(C,F) = 1.9 Hz). 19F NMR (375
MHz, CDCl3): δ −42.7 (s, 3F).
4-(4-((Trifluoromethyl)thio)phenyl)morpholine (3b).9 After puri-
fication by silica gel column chromatography (PE/EA = 30:1),
compound 3b was isolated as a white solid (39 mg, 60%). Rf (PE/EA
2
1
(q, J(C,F) = 2.1 Hz), 129.0 (q, J(C,F) = 307.0 Hz,), 117.6, 114.7.
19F NMR (375 MHz, CDCl3): δ −41.5 (s, 3F).
Methyl 4-((Trifluoromethyl)thio)benzoate (3k).13 After purifica-
tion by silica gel column chromatography (PE/EA = 50:1),
compound 3k was isolated as a yellow oil (52 mg, 83%). Rf (PE/
EA = 50:1) = 0.5. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.5 Hz,
2H), 7.71 (d, J = 8.0 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 135.5, 132.6,
1
= 20:1) = 0.3. H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.3 Hz,
2H), 6.88 (d, J = 8.3 Hz, 2H), 3.85 (t, J = 5.1 Hz, 4H), 3.23 (t, J = 5.0
Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 152.9, 137.9, 129.7
1
(q, J(C,F) = 306.3 Hz), 115.2, 112.5, 66.6, 48.0. 19F NMR (375
MHz, CDCl3): δ −44.1 (s, 3F).
(4-Phenoxyphenyl)(trifluoromethyl)sulfane (3c).13 After purifica-
tion by silica gel column chromatography (PE), compound 3c was
isolated as a white solid (39 mg, 58%). Rf (PE) = 0.55. 1H NMR (400
MHz, CDCl3): δ 7.60 (d, J = 8.7 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 2H),
7.22 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 7.00 (d, J = 8.8 Hz,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 155.6, 138.3, 129.6
(q, 1J(C,F) = 306.3 Hz), 130.0, 124.5, 120.1, 118.6, 117.3 (q, 2J(C,F)
= 2.0 Hz). 19F NMR (375 MHz, CDCl3): δ −43.5 (s, 3F).
(4-(Benzyloxy)phenyl)(trifluoromethyl)sulfane (3d).21 After puri-
fication by silica gel column chromatography (PE), compound 3d was
isolated as a white solid (37 mg, 52%). Rf (PE) = 0.6. 1H NMR (400
MHz, CDCl3): δ 7.59 (d, J = 8.8 Hz, 2H), 7.45−7.34 (m, 5H), 7.01
(d, J = 8.9 Hz, 2H), 5.09 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3):
2
1
130.8, 129.7 (q, J(C,F) = 2.0 Hz), 129.3 (q, J(C,F) = 306.5 Hz),
61.5, 14.2. 19F NMR (375 MHz, CDCl3): δ −41.9 (s, 3F).
1-(4-((Trifluoromethyl)thio)phenyl)ethanone (3l).13 After purifi-
cation by silica gel column chromatography (PE/EA = 50:1),
compound 3l was isolated as a yellow soil (36 mg, 66%). Rf (PE/
1
EA = 50:1) = 0.25. H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.4
Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 2.63 (s, 3H). 13C{1H} NMR (100
2
MHz, CDCl3): δ 197.0, 138.5, 135.7, 130.0 (q, J(C,F) = 2.0 Hz),
129.3 (q, J(C,F) = 306.6 Hz), 129.1, 26.7. 19F NMR (375 MHz,
1
CDCl3): δ −41.8 (s, 3F).
Phenyl(4-((trifluoromethyl)thio)phenyl)methanone (3m).13 After
purification by silica gel column chromatography (PE/EA = 100:1),
compound 3m was isolated as a white solid (48 mg, 68%). Rf (PE/EA
1
δ 161.0, 138.3, 136.2, 129.6 (q, J(C,F) = 306.2 Hz), 128.7, 128.2,
1
= 50:1) = 0.4. H NMR (400 MHz, CDCl3): δ 7.84−7.76 (m, 6H),
127.5, 115.8, 115.2 (q, 2J(C,F) = 2.0 Hz), 70.2. 19F NMR (375 MHz,
CDCl3): δ −43.8 (s, 3F).
7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 8.4 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 195.5, 139.5, 136.8, 135.5, 133.0, 130.6, 130.7, 129.3
(q, 1J(C,F) = 306.7 Hz), 129.1 (q, 2J(C,F) = 2.0 Hz), 128.5. 19F NMR
(375 MHz, CDCl3): δ −41.8 (s, 3F).
Methyl(4-((trifluoromethyl)thio)phenyl)sulfane (3e).13 After puri-
fication by silica gel column chromatography (PE), compound 3e was
1
isolated as a yellow oil (26 mg, 46%). Rf (PE) = 0.6. H NMR (400
(3-Bromophenyl)(trifluoromethyl)sulfane (3n).22 After purifica-
tion by silica gel column chromatography (PE), compound 3n was
isolated as a white solid (31 mg, 48%): Rf (PE) = 0.8. 1H NMR (400
MHz, CDCl3): δ 7.82 (s, 1H), 7.64−7.59(m, 2H), 7.31 (t, J = 8.0 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.7, 134.7, 134.0, 130.7,
MHz, CDCl3): δ 7.55 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H),
2.50 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 143.3, 136.6,
1
129.5 (q, J(C,F) = 306.4 Hz), 126.4, 119.7, 15.0. 19F NMR (375
MHz, CDCl3): δ −43.3 (s, 3F).
(4-(tert-Butyl)phenyl)(trifluoromethyl)sulfane (3f).13 After purifi-
cation by silica gel column chromatography (PE/EA = 100:1),
compound 3f was isolated as a colorless oil (35 mg, 60%). Rf (PE/EA
129.3 (q, 1J(C,F) = 306.5 Hz), 126.3 (q, 2J(C,F) = 2.1 Hz), 122.9. 19
NMR (375 MHz, CDCl3): δ −42.4 (s, 3F).
F
(Trifluoromethyl)(3,4,5-trimethoxyphenyl)sulfane (3o).23 After
purification by silica gel column chromatography (PE/EA = 40:1),
compound 3o was isolated as a yellow solid (30 mg, 44%). Rf (PE/EA
= 40:1) = 0.35. 1H NMR (400 MHz, CDCl3): δ 6.86 (s, 2H), 3.88(s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.4, 140.6, 129.6 (q,
1
= 50:1) = 0.6. H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz,
2H), 7.43 (d, J = 8.4 Hz, 2H), 1.33 (s, 9H). 13C{1H} NMR (100
1
MHz, CDCl3): δ 154.4, 136.1, 129.7 (q, J(C,F) = 306.0 Hz), 126.6,
120.9 (q, 2J(C,F) = 1.8 Hz), 34.9, 31.1. 19F NMR (375 MHz,
CDCl3): δ −43.0 (s, 3F).
2
1J(C,F) = 306.4 Hz), 118.5 (q, J(C,F) = 2.1 Hz), 113.7, 60.9, 56.3.
Ethyl (E)-3-(4-((Trifluoromethyl)thio)phenyl)acrylate (3g). After
purification by silica gel column chromatography (PE/EA = 50:1),
compound 3g was isolated as a white solid (22 mg, 32%). Rf (PE/EA
19F NMR (375 MHz, CDCl3): δ −43.0 (s, 3F).
5-((Trifluoromethyl)thio)benzo[d][1,3]dioxole (3p).21 After puri-
fication by silica gel column chromatography (PE), compound 3p was
isolated as a white solid (16 mg, 29%). Rf (PE) = 0.6. Mp = 113−114
°C. 1H NMR (400 MHz, CDCl3): δ 7.17 (dd, J = 1.72, 8.08 Hz, 1H),
7.09 (d, J = 1.56 Hz, 1H), 6.84 (d, J = 8.04 Hz, 1H), 6.04 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 150.3, 148.3, 131.6, 129.5 (q,
1
= 40:1) = 0.4. H NMR (400 MHz, CDCl3): δ 7.68−7.65 (m, 3H),
7.55 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 16.0 Hz, 1H), 4.28 (q, J = 7.2
Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 166.4, 142.7, 136.9, 136.5, 129.4 (q, 1J(C,F) = 306.6 Hz),
2
128.7, 126.2 (q, J(C,F) = 2.0 Hz), 120.6, 60.8, 14.3. 19F NMR (375
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Note
2
1J(C,F) = 306.3 Hz), 116.2, 116.0 (q, J(C,F) = 2.1 Hz), 109.0. 19F
1H NMR (400 MHz, CDCl3): δ 9.09 (s,1H), 8.47 (d, J = 1.6 Hz, 1H),
8.02 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 1.6, 8.4 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 155.7, 153.7, 136.7, 132.6, 131.9, 129.5
(q, 1J(C,F) = 306.4 Hz), 122.7, 122.2 (q, 2J(C,F)= 2.1 Hz). 19F NMR
(375 MHz, CDCl3): δ −42.7 (s, 3F). HRMS (ESI) m/z: [M + H]+
calcd for C8H5F3NS2, 235.9810; found, 235.9811.
NMR (375 MHz, CDCl3): δ −43.9 (s, 3F).
Naphthalen-2-yl(trifluoromethyl)sulfane (3q).10c After purifica-
tion by silica gel column chromatography (PE), compound 3q was
isolated as a white solid (27 mg, 48%). Rf (PE) = 0.9. 1H NMR (400
MHz, CDCl3): δ 8.21 (s, 1H), 7.89−7.87 (m, 3H), 7.67 (d, J = 8.5
Hz, 1H), 7.61−7.55 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
Irradiation of 1k in the Presence of TEMPO. A solution of arylazo
sulfone 1k (0.25 M) in DCE (1 mL) was placed in a 10 mL
microwave tube, and then S-(trifluoromethyl) 4-fluorobenzenesulfo-
nothioate (2a, 1 mmol, 4.0 equiv) and TEMPO (4 equiv) were
added. The resulting solution was irradiated under stirring at room
temperature for 36 h by means of a 21 W blue LED, and then the
reaction mixture was concentrated under reduced pressure to
evaporate the solvent. Purification by silica gel column chromatog-
raphy (PE/EA = 30:1), afforded ethyl 4-((2,2,6,6-tetramethylpiper-
idin-1-yl)oxy)benzoate 4k as a white solid (23 mg, 30% yield). Rf
1
137.0, 133.9, 133.4, 131.8, 129.7 (q, J(C,F) = 306.6 Hz), 129.2,
2
128.2, 127.9, 127.8, 127.0, 121.5 (q, J(C,F) = 2.3 Hz). 19F NMR
(375 MHz, CDCl3): δ −42.5 (s, 3F).
Ethyl 5-((Trifluoromethyl)thio)-2,3-dihydrobenzofuran-2-carbox-
ylate (3r). After purification by silica gel column chromatography
(PE/EA = 50:1), compound 3r was isolated as a white solid (49 mg,
1
67%). Rf (PE/EA = 50:1) = 0.4. Mp = 102−103 °C. H NMR (400
MHz, CDCl3): δ 8.03 (s, 1H), 7.73−7.70 (m, 1H), 7.64−7.62 (m,
1H), 7.53 (s, 1H), 4.46 (q, J = 7.16 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 159.0, 156.6, 147.2, 135.3,
1
(PE/EA = 30:1) = 0.4. H NMR (400 MHz, CDCl3): δ 7.93 (d, J =
1
2
9.1 Hz, 2H), 7.21 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.64−1.56 (m,
5H), 1.44−1.41 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.23 (s, 6H), 0.99
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 167.4, 166.5, 131.0,
122.4, 113.7, 60.6, 60.4, 39.7, 32.4, 20.4, 17.0, 14.4.
131.8, 129.5 (q, J(C,F) = 306.5 Hz), 128.2, 119.5 (q, J(C,F) = 2.1
Hz), 113.5, 113.2, 61.8, 14.3. 19F NMR (375 MHz, CDCl3): δ −43.3
(s, 3F). HRMS (EM) m/z: [M −e]+ calcd for C12H9F3O3S, 290.0224;
found, 290.0213.
2-Methyl-5-((trifluoromethyl)thio)benzo[d]thiazole (3s). After
purification by silica gel column chromatography (PE/EA = 20:1),
compound 3s was isolated as a white solid (19 mg, 30%). Rf (PE/EA
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02669.
■
sı
1
= 20:1) = 0.33. Mp = 87−88 °C. H NMR (400 MHz, CDCl3): δ
8.26 (d, J = 1.36 Hz, 1H), 7.87 (d, J = 8.28 Hz, 1H), 7.61 (dd, J =
1.48, 8.32 Hz, 1H), 2.86 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
1
δ 168.9, 153.9, 138.7, 131.8, 130.5, 129.6 (q, J(C,F) = 306.4 Hz),
Mechanistic studies and spectroscopic data for com-
pounds 1, 2c, and 3 (PDF)
122.1, 131.7, 20.2 (q, 1J(C,F) = 4.4 Hz). 19F NMR (375 MHz,
CDCl3): δ − 42.9 (s, 3F). HRMS (EI) m/z: [M + H]+ calcd for
C9H7F3NS2, 249.9967; found, 249.9970.
Methyl 5-((Trifluoromethyl)thio)nicotinate (3t).24 After purifica-
tion by silica gel column chromatography (PE/EA = 10:1),
compound 3t was isolated as a white solid (25 mg, 43%). Rf (PE/
EA = 5:1) = 0.5. 1H NMR (400 MHz, CDCl3): δ 9.33 (s,1H), 9.01 (s,
1H), 8.59 (s, 1H), 4.00 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
AUTHOR INFORMATION
Corresponding Authors
■
Stefano Protti − PhotoGreen Lab, Department of Chemistry,
University of Pavia, Pavia 27100, Italy; orcid.org/0000-
0002-5313-5692; Email: stefano.protti@unipv.it
Xia Zhao − Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, College of Chemistry,
Tianjin Normal University, Tianjin 300387, People’s
Republic of China; orcid.org/0000-0001-9477-5912;
Email: hxxyzhx@mail.tjnu.edu.cn
1
δ 164.4, 159.0, 152.5, 144.3, 128.9 (q, J(C,F) = 307.1 Hz), 126.9,
122.4, 52.9. 19F NMR (375 MHz, CDCl3): δ −42.0 (s, 3F).
7-((Trifluoromethyl)thio)quinoline (3u). After purification by silica
gel column chromatography (PE/EA = 30:1), compound 3u was
1
isolated as a yellow oil (17 mg, 30%). Rf (PE/EA = 10:1) = 0.3. H
NMR (400 MHz, CDCl3): δ 9.00 (d, J = 2.8 Hz, 1H), 8.48 (s, 1H),
8.21 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.5 Hz,
1H), 7.52−7.49 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.5,
Authors
1
147.8, 137.8, 136.0, 132.3, 129.5 (q, J(C,F) = 306.8 Hz), 129.0,
Ankun Li − Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, College of Chemistry,
Tianjin Normal University, Tianjin 300387, People’s
Republic of China
128.9, 125.9 (q, 2J(C,F) = 1.8 H), 122.7. 19F NMR (375 MHz,
CDCl3): δ −41.9 (s, 3F). HRMS (ESI) m/z: [M + H]+ calcd for
C10H7F3NS, 230.0246; found, 230.0246.
4-Methyl-7-((trifluoromethyl)thio)-2H-chromen-2-one (3v).25
After purification by silica gel column chromatography (PE/EA =
10:1), compound 3v was isolated as a white solid (19 mg, 29%). Rf
Yuxuan Li − Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, College of Chemistry,
Tianjin Normal University, Tianjin 300387, People’s
Republic of China; College of Biotechnology, Tianjin
University of Science & Technology, Tianjin 300457, China
Junjie Liu − Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, College of Chemistry,
Tianjin Normal University, Tianjin 300387, People’s
Republic of China; College of Biotechnology, Tianjin
University of Science & Technology, Tianjin 300457, China
Jingqi Chen − Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, College of Chemistry,
Tianjin Normal University, Tianjin 300387, People’s
Republic of China
1
(PE/EA = 10:1) = 0.2. H NMR (400 MHz, CDCl3): δ 7.66−7.64
(m,2H), 7.55 (dd, J = 1.6, 8.2 Hz, 1H), 6.38 (d, J = 1.2 Hz,1H), 2.46
(d, J = 1.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.6,
153.3, 151.3, 130.8, 129.2 (q, 1J(C,F) = 306.8 Hz), 128.3 (q, 2J(C,F)
= 2.1 Hz), 125.4, 123.9, 121.7, 116.7, 18.5. 19F NMR (375 MHz,
CDCl3): δ −41.8 (s, 3F).
9-Ethyl-3-((trifluoromethyl)thio)-9H-carbazole (3w).6d After pu-
rification by silica gel column chromatography (PE), compound 3w
1
was isolated as a colorless solid (19 mg, 25%). Rf (PE) = 0.4. H
NMR (400 MHz, CDCl3): δ 8.39 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 7.8,
Hz, 1H), 7.72 (dd, J = 1.6, 8.5 Hz, 1H), 7.55−7.51 (m, 1H), 7.45−
7.72 (m, 2H), 7.31−7.27 (m, 1H), 5.14 (q, J = 7.2 Hz, 2H), 1.46 (t, J
= 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 141.0, 140.3,
1
133.7, 129.9 (q, J(C,F) = 306.4 Hz), 129.6, 126.6, 123.9, 122.2,
Kui Lu − College of Biotechnology, Tianjin University of
Science & Technology, Tianjin 300457, China; orcid.org/
0000-0002-9685-2691
Di Qiu − Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, College of Chemistry,
120.7, 119.8, 112.5 (q, 2J(C,F) = 2.0 Hz), 109.2, 108.8, 37.7, 13.7. 19
NMR (375 MHz, CDCl3): δ −44.1 (s, 3F).
F
5-((Trifluoromethyl)thio)benzo[d]thiazole (3x). After purification
by silica gel column chromatography (PE/EA = 50:1), compound 3x
was isolated as a colorless oil (12 mg, 20%). Rf (PE/EA = 50:1) = 0.5.
F
https://dx.doi.org/10.1021/acs.joc.0c02669
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Chem. 2017, 82, 9175−9181. (c) Lu, K.; Deng, Z.; Li, M.; Li, T.;
Zhao, X. Transition Metal-Free Direct Trifluoromethylthiolation of
Indoles using Trifluoromethanesulfonyl Chloride in the Presence of
Triphenylphosphine. Org. Biomol. Chem. 2017, 15, 1254−1260.
(d) Glenadel, Q.; Alazet, S.; Billard, T. First and second generation
of trifluoromethanesulfenamide reagent: A trifluoromethylthiolating
comparison. J. Fluorine Chem. 2015, 179, 89−95. (e) Shao, X.; Xu, C.;
Lu, L.; Shen, Q. Structure-Reactivity Relationship of Trifluorometha-
nesulfenates: Discovery of an Electrophilic Trifluoromethylthiolating
Reagent. J. Org. Chem. 2015, 80, 3012−3021.
Tianjin Normal University, Tianjin 300387, People’s
Republic of China; orcid.org/0000-0001-9706-6302
Maurizio Fagnoni − PhotoGreen Lab, Department of
Chemistry, University of Pavia, Pavia 27100, Italy;
orcid.org/0000-0003-0247-7585
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02669
Author Contributions
⊥A.L. and Y.L. contributed equally to this work.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors sincerely thank the National Natural Science
Foundation of China (21572158) and the Tianjin Natural
Science Foundation (18JCQNJC76600) for financial support.
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