Efficient C(sp3alkyl)-SCF3 bond formations via copper-mediated trifluoromethylthiolation of alkyl halides

Article abstract of DOI:10.1039/c4ob00403e

A general and convenient copper-mediated trifluoromethylthiolation of primary and secondary alkyl halides was described. Variation of the solvent, additives and time allowed optimization of the reaction. A wide range of alkyl halides were explored to give a set of alkyl trifluoromethyl thioethers in moderate to excellent yields. A variety of functional groups, including ethers, thioether, esters, nitriles, amides, and ketal groups, were well tolerated in the electrophilic partner. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00403e

Organic &
Biomolecular Chemistry
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Efficient C(sp3alkyl)–SCF3 bond formations via
copper-mediated trifluoromethylthiolation of
alkyl halides†
Cite this: Org. Biomol. Chem., 2014,
12, 5500
Quanfu Lin,a Li Chen,a Yangjie Huang,a Mingguang Rong,a Yaofeng Yuana and
Zhiqiang Weng*a,b
A general and convenient copper-mediated trifluoromethylthiolation of primary and secondary alkyl
halides was described. Variation of the solvent, additives and time allowed optimization of the reaction. A
wide range of alkyl halides were explored to give a set of alkyl trifluoromethyl thioethers in moderate to
excellent yields. A variety of functional groups, including ethers, thioether, esters, nitriles, amides, and
ketal groups, were well tolerated in the electrophilic partner.
Received 21st February 2014,
Accepted 12th May 2014
DOI: 10.1039/c4ob00403e
www.rsc.org/obc
reagents. For instance, Billard and co-workers have developed
the electrophilic trifluoromethylthiolation of alkenes and orga-
Introduction
Over the past several decades, organic molecules that contain nometallic nucleophiles with trifluoromethanesulfanylamides
a trifluoromethylthio group (–SCF3) have been an important as reagents.34–36 Lu, Shen and co-workers recently reported the
class of compounds, due to their remarkable stability, electro- electrophilic α-trifluoromethylthiolation of β-ketoesters using
negativity, and lipophilicity properties.1,2 These have found an electrophilic hypervalent iodine reagent.37 More recently,
potential applications in a variety of areas, including pharma- Rueping and co-workers have demonstrated a highly enantio-
ceutical and agrochemical, as well as in advanced materials selective trifluoromethylthiolation of β-ketoesters with N-tri-
industries.3–5 Consequently, there has been an immense effort fluoromethylthiophthalimide as the electrophilic SCF3
to develop novel methods and reagents to access this class of source.38 The successful implementation of these strategies
compounds.6,7
has greatly expanded the utility of these transformations.
Alkyl trifluoromethyl sulfides have been involved in numer-
Aryl trifluoromethyl thioethers (ArSCF3) have typically been
prepared by nucleophilic,8–11 electrophilic,12–14 or radical15–20 ous synthetic applications, mainly devoted to the synthesis of
trifluoromethylation of sulfur substrates with a trifluoromethyl- bioactive molecules. Examples include trifluoromethylthio-
ation reagent or nucleophilic reaction of trifluoromethyl- acetic acid and its derivatives, which serve as useful intermedi-
thiolate
with
aryl
halides.21–26
Metal-mediated ates in the synthesis of the cephalosporin antibiotic
trifluoromethylthiolation has been developed as an attractive cefazaflur.39,40 From a preparative point of view, nucleophilic
route for the formation of C(sp2aryl)–SCF3 bonds under mild trifluoromethylthiolation with a large pool of readily available
reaction conditions. The catalytic systems reported by the alkyl halides, particularly with secondary alkyl halides, would
groups of Buchwald,27 Qing,28 Vicic,29,30 Daugulis,31 Shibata32 be an attractive alternative for the generation of C(sp3alkyl)–
and Rueping33 illustrate the major importance of these SCF3 bonds. One of the greatest challenges associated with
transformations.
using alkyl halides is to achieve high selectivity for trifluoro-
However, compared with these well-established procedures, methylthiolation with suppressed β-hydride elimination.41
relatively limited methods are currently available for the con- Thus, efficient and selective methods to access this class of
struction of C(sp3alkyl)–SCF3 bonds, which mainly rely on the compounds are actively being sought.9,11,16,18,19,42–44
strategy of employing electrophilic trifluoromethylthiolation
Recently, we invented a copper reagent (bpy)Cu(SCF3) 1 for
the nucleophilic trifluoromethylthiolation of aryl halides,45
benzyl bromides46 and allylic bromides.47 These reactions pro-
vided a novel and convenient synthetic route for preparing
new trifluoromethylthiolated derivatives. Herein, we report an
efficient and general preparation of alkyl trifluoromethyl sul-
fides by means of copper-mediated trifluoromethylthiolation
of alkyl halides.
aDepartment of Chemistry, Fuzhou University, Fuzhou 350108, China.
E-mail: zweng@fzu.edu.cn; Fax: +86 594 22866121; Tel: +86 594 22866121
bState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
†Electronic supplementary information (ESI) available: Copies of 1H, 13C,
19F NMR of synthesized products. See DOI: 10.1039/c4ob00403e
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However, when AgF and Bu4NF were used, product 3a was
formed with a lower yield (Table 1, entries 10 and 11). Further
Results and discussion
Our initial experiment with 1-bromooctane (2a) and (bpy)Cu- screening of the reaction conditions revealed that the reaction
(SCF3) (1),45 by using CH3CN as the solvent at 110 °C for 15 h time has a profound impact on the reaction rate and
provided 62% of trifluoromethylthiolated product 3a (Table 1, efficiency. Shortening the time to 8 h led to a reduced yield
entry 1). It is worthwhile to note that no β-hydride elimination (48%; Table 1, entry 12). Consequently, the optimized reaction
by-products were observed in this reaction. Taking into conditions were determined as the combination of (bpy)Cu-
account these preliminary results, we then examined the influ- (SCF3) 1 (1.2 equiv.), alkyl bromide (1.0 equiv.), KF (2.0 equiv.)
ence of the solvent, additive and reaction time on the in CH3CN at 110 °C with a reaction time of 15 h.
efficiency of our model reaction. Studies on the effect of the
The scope of this copper-mediated trifluoromethylthiola-
solvent revealed that CH3CN was the solvent of choice (Table 1, tion was further examined by using various alkyl halides under
entry 1). This finding is consistent with our previous work on the optimized conditions (Table 2). Importantly, a variety of
the trifluoromethylthiolation of aryl halides.45 When dimethyl- functional groups such as ethers, thioether, esters, nitriles,
formamide (DMF), dimethyl sulfoxide (DMSO), toluene, THF amides, and ketal were well tolerated under the reaction
and CH2Cl2 were employed, the transformation was dramati- conditions.
cally retarded (Table 1, entries 2–6).
The unfunctionalized alkyl bromides 2a and 2b reacted
We next examined the additive effect of this newly designed with (bpy)Cu(SCF3) (1) to give the trifluoromethylthiolated pro-
trifluoromethylthiolation. During the course of our work on ducts 3a and 3b in excellent yields (90% and 96%, respectively;
the trifluoromethylthiolation/selenolation of α-halo-α,β-unsatu- Table 2, entries 1 and 2). Alkyl bromides bearing an arene unit
rated carbonyl compounds, we found that the addition of CsF (2c and 2d) smoothly afforded the corresponding products 3c
as a additive was beneficial in terms of yield of the desired pro- and 3d in 90% and 95% yields, respectively (Table 2, entries 3
ducts.48 Therefore, we examined several fluorides to accelerate and 4). The alkyl bromides 2e possessing a methoxy substitu-
the subsequent reactions. Indeed, a significant increase in the ent at the para position of the aromatic ring reacted with 1 to
yield of trifluoromethylthiolated product 3a was observed give product 3e in 98% yield (Table 2, entry 5). However, lower
when KF (1.0 equiv.) was employed as an additive (71%; yields were observed for electrophiles containing electron-poor
Table 1, entry 7). Additionally, increasing the amount of KF to para-NO2-substituted aromatic rings, as found in the reaction
2.0 equiv. accelerated the reaction to give 3a in 91% yield with 2f, which led to 3f in 34% isolated yield and 1-nitro-4-
(Table 1, entry 8). It was subsequently found that the reaction vinylbenzene as major side products (Table 2, entry 6). The
using CsF afforded the product in comparable yield (Table 1, alkyl bromides 2g–2i carrying ether and thioether substituents
entry 9). Although the reasons for the improved yield from the furnished high yields of the corresponding products 3g–3i (98,
addition of an excess amount of alkaline fluoride salts are 96 and 89%, respectively; Table 2, entries 7–9). However, in the
unclear, the presence of these fluorides accelerates the rate of case of 2-(2-bromoethoxy)tetrahydro-2H-pyran 2j, product 3j
reaction probably by facilitating the formation of active inter- was obtained in a moderate yield of 42% along with some un-
mediate.48 There are numerous cited examples of improving identified by-products (Table 2, entry 10), which could be a
chemical processes by using CsF or KF as additive.49–52 result of the inherent instability of this compound. In
addition, alkyl bromide 2k having a nitrile substituent reacted
with 1 to afford the corresponding product 3k in 99% yield
(Table 2, entry 11). Interestingly, the presence of sensitive ester
groups in the alkyl moiety (2l and 2m) did not affect the
Table 1 Optimization of the trifluoromethylthiolation of 1-bromo-
octanea
process, and the corresponding products 3l and 3m were iso-
lated in excellent yields (98 and 99%, respectively; Table 2,
entries 12 and 13). Likewise, an alkyl bromide 2n bearing a
ketal group also allowed the formation of the desired product
3n in 70% yield (Table 2, entry 14). Furthermore, 2-(3-bromo-
propyl)isoindoline-1,3-dione 2o also reacted to afford the
product 3o in 99% yield (Table 2, entry 15).
Entry Additive (equiv.) Solvent
T (°C) Time (h) Yieldb (%)
1
2
3
—
—
—
CH3CN
DMF
DMSO
110
110
110
15
15
15
15
15
15
15
15
15
15
15
8
62
9
12
1
The substrate scope of the reaction was also extended to
include unactivated alkyl electrophiles. The secondary alkyl
iodides 2p and 2q proceeded smoothly to form the products
3p and 3q in 86 and 63% yield, respectively (Table 2, entries 16
and 17). Furthermore, heterocycle-containing secondary alkyl
bromide 2r could be converted to 3r, albeit in modest yield
after an extended reaction time (Table 2, entry 18). However,
this method has its limitations. The reactions of cyclic second-
ary bromide 2s and alkyl chloride 2c′ failed to produce the tar-
geted compounds 3s and 3c, respectively (Table 2, entries 19
4
5
—
—
Toluene 110
THF
90
40
3
6
7
8
9
10
11
12
—
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1<
71
91
81
45
46
48
KF (1.0)
KF (2.0)
CsF (2.0)
AgF (2.0)
Bu4NF (2.0)
KF (2.0)
110
110
110
110
110
110
a Reaction conditions: 1 (0.060 mmol), 2a (0.050 mmol), solvent
(1.0 mL), under N2 atmosphere. b The yield was determined by
19F NMR spectroscopy with PhOCF3 as internal standard.
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Table 2 Substrate scope of trifluoromethylthiolation of alkyl halidesa
Table 2 (Contd.)
Entry Alkyl halide
21
Product
Yield (%)
48
Entry Alkyl halide
1
Product
Yield (%)
90
12b
32
2
3
96
90
22
23
4
5
95
98
24
25
11b
13b
6
34
a Reaction conditions: 1 (0.30 mmol), alkyl halide 2 (0.25 mmol),
KF (0.50 mmol, 2 equiv.), 15 h, N2, 110 °C. Yields shown are of isolated
products. b The yield was determined by 19F NMR spectroscopy with
PhOCF3 as internal standard.
7
8
9
98
96
89
and 20) under the standard reaction conditions. Nevertheless,
the cyclic secondary iodides 2t, 2s′, 2u and 2v could be trans-
ferred through this procedure although reduced yields of the
corresponding products 3t, 3s, 3u and 3v were produced (48,
12, 32 and 11%, respectively; Table 2, entries 21–24). Similarly,
the reaction has been extended to tertiary alkyl iodide 2w
which gave a relatively low yield of the desired product 3w
(13%; Table 2, entry 25).
10
42
11
12
99
98
To demonstrate the practical utility, the trifluoromethylthio-
lation of 2o was carried out on a 0.5-g scale (Scheme 1). As a
result, the product 3o was isolated in 99% yield (0.538 g).
To further illustrate the synthetic potential of these alkyl tri-
fluoromethyl thioethers, the subsequent oxidation was per-
formed. As shown in Table 3, the trifluoromethylthiolated
compound 3 underwent smooth oxidation with H2O2 in acetic
acid to give the corresponding alkyl trifluoromethanesulfones
4 in good yields.
13
14
15
99
70
99
In an attempt to examine whether any radical intermediates
are generated during trifluoromethylthiolation, a series of
experiments were carried out under the optimized conditions.
16
86
The addition of
a radical scavenger, cyclohexa-1,4-diene
17
18
63
37
(CHD), to the reaction of 1 with 2g did not suppress this trans-
formation (Scheme 2). The trifluoromethylthiolated product 3g
was formed in similar yield both in the absence (98%; Table 2,
19
20
Trace
Trace
Scheme 1 Scalability of the trifluoromethylthiolation of 2o.
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formed the desired product 12 in 79% yield (19F NMR). Given
the good reactivity of alkyl tosylates, the mechanism of the
present trifluoromethylthiolation might involve an SN2-type
substitution with 1.
Table 3 Synthesis of alkyl trifluoromethyl sulfones
Conclusions
In conclusion, an efficient method for the preparation of alkyl
trifluoromethyl thioethers via the copper-mediated trifluoro-
methylthiolation of primary and secondary alkyl halides has
been developed. The reactions proceeded smoothly with yields
up to 99% and demonstrated good compatibility with a wide
range of functional groups, e.g., ethers, thioether, esters,
nitriles, amides, and ketal, etc.
Experimental
General remarks
Scheme 2 Radical scavenger experiments.
1H NMR, 19F NMR and 13C NMR spectra were recorded using a
entry 7) and presence of 1.0 equiv. of the radical scavenger 400 Hz spectrometer. 1H NMR and 13C NMR chemical shifts
(95%; 19F NMR yield).
were reported in parts per million (ppm) downfield from tetra-
Subsequently, the intermediacy of alkyl radical was probed methylsilane and 19F NMR chemical shifts were determined
by reactions with a radical clock, such as (bromomethyl)cyclo- relative to CFCl3 as the external standard and low field is posi-
propane 5 and 6-bromo-1-hexene 8. The rates of radical ring- tive. Coupling constants (J) are reported in hertz (Hz). The
opening of 5 and the cyclization of 8 are known to be 1.3 × 108 residual solvent peak was used as an internal reference:
and 1.0 × 105 s−1, respectively.53 The reaction of 1 with 5 or 8 1H NMR (chloroform δ 7.26) and 13C NMR (chloroform δ 77.0).
was conducted in CD3CN solvent at 110 °C for 15
h
The following abbreviations were used to explain the multipli-
(Scheme 3). These reactions formed the products 6 and 9 from cities: s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
C(sp3alkyl)–SCF3 coupling in 79 and 80% yields (19F NMR), tiplet, br = broad. HRMS data were obtained at the Shanghai
respectively. No ring-opened product 7 or cyclized product 10 Institute of Organic Chemistry. Alkyl bromides 2i and 2r, alkyl
were detected. These results indicate that radicals are not pro- iodide 2p and 2r,54 2t,55 2q,56 2u–v,56 and (bpy)Cu(SCF3) (1),45
duced in this trifluoromethylthiolation.
were prepared according to the published procedures. Other
Additionally, trifluoromethylthiolation with alkyl tosylates reagents were received from commercial sources. Solvents were
was also examined (Scheme 4). Reaction of 1 with 1 equiv. of freshly dried and degassed according to published pro-
hexyl p-toluenesulfonate 11 for 15 h at 110 °C in CH3CN cedures57 prior to use. Column chromatography purifications
were performed by flash chromatography using silica gel 60.
General procedure for trifluoromethylthiolation of alkyl
bromide with [(bpy)Cu(SCF3)] (1)
[(bpy)Cu(SCF3)] (1) (96 mg, 0.30 mmol, 1.2 equiv.), alkyl
bromide 2 (0.25 mmol), KF (29 mg, 0.50 mmol, 2 equiv.), and
CH3CN (1.0 mL) were added to a reaction tube equipped with
a magnetic stirrer bar. The tube was sealed and the solution
was placed into a preheated 110 °C oil bath for 15 h. The tube
was removed from the oil bath and allowed to cool. The reac-
tion mixture was then filtered through Celite to remove metal
salts. Water (10.0 mL) was added to the mixture at 0 °C. The
resulting mixture was extracted with diethyl ether (3 × 6.0 mL),
and the combined organic layers were dried over magnesium
sulfate. The solvent was removed by rotary evaporation in an
ice bath and the resulting product was purified by column
chromatography on silica gel with n-pentane.
Scheme 3 Radical clock experiments.
Scheme 4 Reaction of 1 with alkyl tosylates.
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General procedure for synthesis of alkyl trifluoromethyl
sulfones
IR (KBr) ν 3005, 2956, 2936, 2837, 1612, 1585, 1514, 1466,
1320, 1250, 1112, 1037, 822, 756, 699 cm−1. GC-MS m/z 236
(M+), 135 (M+ − SCF3 100%). HRMS (EI) calcd for C10H11F3OS:
A 30% (w/w) aqueous solution of H2O2 (0.21 mL, 2 mmol) was 236.0483; Found: 236.0487.
added dropwise to a solution of 3 (0.50 mmol) in acetic acid
(4-Nitrophenethyl)(trifluoromethyl)sulfane (3f). Obtained
(5 mL) at room temperature. The mixture was stirred at as a pale yellow oil in 34% yield (22 mg). Rf (n-pentane): 0.25.
80–90 °C for 5–7 h. The resulting solution was cooled to room 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 7.41 (d,
temperature, and poured into water (5 mL) and then extracted J = 8.4 Hz, 2H), 3.24–3.11 (m, 4H). 19F NMR (376 MHz, CDCl3)
with diethyl ether (3 × 10 mL). The combined organic layers δ −40.9 (s). 13C NMR (101 MHz, CDCl3) δ 147.1 (s), 146.2 (s),
were washed with water (3 × 10 mL), saturated aqueous 130.9 (q, J = 308.1 Hz), 129.5 (s), 124.0 (s), 35.72 (s), 30.5 (q, J =
NaHCO3 (2 × 10 mL) and water again (2 × 10 mL), then dried 2.2 Hz). IR (KBr) ν 3081, 2946, 2855, 1606, 1520, 1348, 1111,
over MgSO4 and concentrated under vacuum at room tempera- 855, 746, 695 cm−1. GC-MS m/z 251 (M+), 150 (M+ − SCF3
ture. The crude product was purified by column chromato- 100%). HRMS (EI) calcd for C9H8F3NO2S: 251.0228; Found:
graphy on silica gel, eluting with (n-pentane–diethyl ether).
251.0230.
Octyl(trifluoromethyl)sulfane.20 (3a). Obtained as a pale
(4-Phenoxybutyl)(trifluoromethyl)sulfane (3g). Obtained as
1
yellow oil in 90% yield (68 mg). Rf (n-pentane): 0.91. H NMR a pale yellow oil in 98% yield (61 mg). Rf (n-pentane): 0.67.
(400 MHz, CDCl3) δ 2.90 (t, J = 7.4 Hz, 2H), 1.83–1.63 (m, 2H), 1H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 7.7 Hz, 2H), 7.00 (t, J =
1.49–1.22 (m, 10H), 0.91 (t, J = 6.6 Hz, 3H). 19F NMR (376 MHz, 7.4 Hz, 1H), 6.94 (d, J = 7.4 Hz, 2H), 4.03 (t, J = 4.4 Hz, 2H),
CDCl3) δ −41.3 (s). 13C NMR (101 MHz, CDCl3) δ 131.2 (q, J = 3.00 (t, J = 7.7 Hz, 2H), 2.01–1.91 (m, 4H). 19F NMR (376 MHz,
305.1 Hz), 31.7 (s), 29.9 (s), 29.4 (s), 29.0 (s), 28.9 (s), 28.5 (s), CDCl3) δ −41.1 (s). 13C NMR (101 MHz, CDCl3) δ 158.9 (s),
22.6 (s), 14.0 (s). IR (KBr): ν 2929, 2858, 1458, 1152, 1118, 131.2 (q, J = 305.8 Hz), 129.5 (s), 120.8 (s), 114.5 (s), 66.9 (s),
756 cm−1. GC-MS m/z 214 (M+), 145 (M+ − CF3 100%).
29.7 (q, J = 2.1 Hz), 28.1 (s), 26.4 (s). IR (KBr) ν 3041, 2948,
Dodecyl(trifluoromethyl)sulfane.12 (3b). Obtained as a pale 2873, 1600, 1587, 1497, 1245, 1117, 754, 691 cm−1. GC-MS m/z
yellow oil in 96% yield (65 mg). Rf (n-pentane): 0.89. H NMR 249 (M+), 148 (M+ − SCF3 100%). HRMS (EI) calcd for
1
(400 MHz, CDCl3) δ 2.90 (t, J = 7.4 Hz, 2H), 1.82–1.64 (m, 2H), C11H13F3OS: 250.0639; Found: 250.0641.
1.52–1.14 (m, 18H), 0.91 (t, J = 6.6 Hz, 3H). 19F NMR (376 MHz,
(3-(Benzyloxy)propyl)(trifluoromethyl)sulfane (3h). Obtained
CDCl3) δ −41.3 (s). 13C NMR (101 MHz, CDCl3) δ 131.2 (q, J = as a pale yellow oil in 96% yield (60 mg). Rf (n-pentane): 0.62.
305.7 Hz), 31.9 (s), 29.9 (q, J = 2.0 Hz), 29.6 (s), 29.5 (s), 29.4 1H NMR (400 MHz, CDCl3) δ 7.43–7.31 (m, 5H), 4.54 (s, 2H),
(s), 29.3 (s), 28.9 (s), 28.5 (s), 22.7 (s), 14.1 (s). IR (KBr) ν 2926, 3.61 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.06–1.99 (m,
2855, 1466, 1159, 1118, 756 cm−1. GC-MS m/z 270 (M+), 269 2H). 19F NMR (376 MHz, CDCl3) δ −41.2 (s). 13C NMR
(M+ − SCF3 100%).
(101 MHz, CDCl3) δ 138.2 (s), 131.2 (q, J = 305.9 Hz), 128.4 (s),
127.7 (s), 127.6 (s), 73.1 (s), 67.8 (s), 29. 8 (s), 26.9 (q, J =
Phenethyl(trifluoromethyl)sulfane.58 (3c). Obtained as
a
pale yellow oil in 90% yield (50 mg). Rf (n-pentane): 0.92. 2.2 Hz). IR (KBr) ν 3032, 2861, 1455, 1114, 912, 741, 697 cm−1
.
1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 7.4 Hz, 2H), 7.34–7.27 GC-MS m/z 249 (M+), 148 (M+ − SCF3 100%). HRMS (EI) calcd
(m, 1H), 7.25 (d, J = 7.4 Hz, 2H), 3.18 (t, J = 7.7 Hz, 2H), 3.04 (t, for C11H13F3OS: 250.0639; Found: 250.0638.
J = 7.7 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ −41.0 (s).
p-Tolyl(3-((trifluoromethyl)thio)propyl)sulfane (3i). Obtained
13C NMR (101 MHz, CDCl3) δ 139.0 (s), 131.2 (q, J = 306.0 Hz), as a pale yellow oil in 89% yield (39 mg). Rf (n-pentane): 0.56.
128.7 (s), 128.5 (s), 126.9 (s), 36.0 (s), 31.2 (q, J = 1.9 Hz). 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.2 Hz, 2H), 7.15 (d,
IR (KBr) ν 3031, 2929, 1497, 1455, 1112, 757, 712, 697 cm−1
GC-MS m/z 205 (M+), 104 (M+ − SCF3 100%).
.
J = 7.2 Hz, 2H), 3.06–2.99 (m, 4H), 2.36 (s, 3H), 2.13–1.81 (m,
2H). 19F NMR (376 MHz, CDCl3) δ −41.0 (s). 13C NMR
(3-Phenylpropyl)(trifluoromethyl)sulfane.59 (3d). Obtained (101 MHz, CDCl3) δ 136.8 (s), 131.6 (s), 131.0 (q, J = 306.6 Hz),
as a pale yellow oil in 95% yield (52 mg). Rf (n-pentane): 0.86. 130.8 (s), 129.8 (s), 33.1 (s), 28.8 (s), 28.5 (q, J = 2.0 Hz),
1H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 7.3 Hz, 2H), 7.29–7.23 21.0 (s). IR (KBr) ν 3021, 2924, 2860, 1493, 1456, 1419, 1115,
(m, 3H), 2.93 (t, J = 7.3 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 805, 756 cm−1. GC-MS m/z 265 (M+), 164 (M+ − SCF3 100%).
2.19–1.95 (m, 2H). 19F NMR (376 MHz, CDCl3) δ −41.0 (s). HRMS (EI) calcd for C11H13F3S2: 266.0411; Found: 266.0410.
13C NMR (101 MHz, CDCl3) δ 140.5 (s), 131.2 (q, J = 305.8 Hz),
2-(2-((Trifluoromethyl)thio)ethoxy)tetrahydro-2H-pyran (3j).
128.6 (s), 128.5 (s), 126.3 (s), 34.4 (s), 31.0 (s), 29.2 (q, J = 2.0 Obtained as a pale yellow oil in 42% yield (28 mg). Rf
Hz). IR (KBr) ν 3029, 2931, 1497, 1455, 1114, 744, 699 cm−1
GC-MS m/z 220 (M+), 119 (M+ − SCF3 100%).
.
(n-pentane): 0.65. 1H NMR (400 MHz, CDCl3) δ 4.66 (t, J =
3.2 Hz, 1H), 4.04–3.82 (m, 2H), 3.75–3.50 (m, 2H), 3.13 (t, J =
(4-Methoxyphenethyl)(trifluoromethyl)sulfane (3e). Obtained 6.4 Hz, 2H), 1.90–1.68 (m, 2H), 1.64–1.52 (m, 4H). 19F NMR
as a pale yellow oil in 98% yield (65 mg). Rf (n-pentane): 0.78. (376 MHz, CDCl3) δ −41.3 (s). 13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.5 Hz, 2H), 6.89 (d, δ 131.1 (q, J = 305.9 Hz), 98.9 (s), 65.9 (s), 62.2 (s), 30.4 (s), 29.8
J = 8.5 Hz, 2H), 3.82 (s, 3H), 3.12 (t, J = 7.7 Hz, 2H), 2.96 (t, J = (q, J = 2.1 Hz), 25.3 (s), 19.2 (s). IR (KBr) ν 2946, 2874, 1201,
7.7 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ −41.0 (s). 13C NMR 1116, 1081, 1032 cm−1. GC-MS m/z 230 (M+), 129 (M+ − SCF3
(101 MHz, CDCl3) δ 158.5 (s), 131.2 (q, J = 305.8 Hz), 131.0 (s), 100%). HRMS (EI) [M+ − H] calcd for C8H12F3O2S: 229.0510;
129.6 (s), 114.1 (s), 55.3 (s), 35.1 (s), 31.6 (q, J = 1.8 Hz). Found: 229.0512.
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7-((Trifluoromethyl)thio)heptanenitrile (3k). Obtained as a 306.3 Hz), 128.6 (s), 128.4 (s), 126.2 (s), 40.6 (q, J = 1.4 Hz),
pale yellow oil in 99% yield (68 mg). Rf (n-pentane): 0.71. 38.5 (s), 32.8 (s), 22.5 (s). IR (KBr) ν 3029, 2929, 2861, 1496,
1H NMR (400 MHz, CDCl3) δ 2.91 (t, J = 7.2 Hz, 2H), 2.37 (t, J = 1455, 1382, 1116, 747, 699 cm−1. GC-MS m/z 234 (M+), 133 (M+
7.2 Hz, 2H), 1.78–1.66 (m, 4H), 1.58–1.41 (m, 4H). 19F NMR − SCF3 100%). HRMS (EI) calcd for C11H13F3S: 234.0690;
(376 MHz, CDCl3) δ −41.2 (s). 13C NMR (101 MHz, CDCl3) Found: 234.0693.
δ 131.1 (q, J = 305.7 Hz), 119.5 (s), 29.7 (q, J = 2.1 Hz), 29.1 (s),
Nonan-5-yl(trifluoromethyl)sulfane (3q). Obtained as a pale
1
28.0 (s), 27.6 (s), 25.2 (s), 17.1(s). IR (KBr) ν 2941, 2863, 2246, yellow oil in 63% yield (36 mg). Rf (n-pentane): 0.84. H NMR
1464, 1427, 1116, 755 cm−1. GC-MS m/z 211 (M+), 110 (400 MHz, CDCl3) δ 3.31–2.83 (m, 1H), 1.78–1.59 (m, 4H),
(M+ − SCF3 100%). HRMS (EI) calcd for C8H12F3NS: 211.0643; 1.50–1.29 (m, 8H), 0.94 (t, J = 7.1 Hz, 6H). 19F NMR (376 MHz,
Found: 211.0638.
CDCl3) δ −39.1 (s). 13C NMR (101 MHz, CDCl3) δ 131.4 (q, J =
Ethyl 6-((trifluoromethyl)thio)hexanoate (3l). Obtained as a 305.8 Hz), 46.7 (q, J = 1.2 Hz), 34.8 (s), 28.5 (s), 22.4 (s),
pale yellow oil in 98% yield (28 mg). Rf (n-pentane): 0.74. 13.9 (s). IR (KBr) ν 2960, 2932, 1466, 1112 cm−1. GC-MS m/z
1H NMR (400 MHz, CDCl3) δ 4.15 (q, J = 7.2 Hz, 2H), 2.90 (t, J = 228 (M+), 159 (M+ − CF3 100%). HRMS (EI) calcd for
7.2 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 1.77–1.64 (m, 4H), C10H19F3S: 228.1160; Found: 228.1164.
1.53–1.40 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz,
4-Methyl-7-(3-(trifluoromethylthio)butoxy)-2H-chromen-2-one
CDCl3) δ −41.2 (s). 13C NMR (101 MHz, CDCl3) δ 173.4 (s), (3r). Obtained as a colourless oil in 37% yield (35 mg).
1
131.1 (q, J = 305.7 Hz), 60.3 (s), 34.0 (s), 29.6 (q, J = 2.2 Hz), Rf (n-pentane): 0.72. H NMR (400 MHz, CDCl3) δ 7.53 (d, J =
29.1 (s), 27.9 (s), 24.3 (s), 14.2 (s). IR (KBr) ν 2939, 2863, 1734, 1301, 8.8 Hz, 1H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 6.84 (d, J = 2.4 Hz,
1115, 1032 cm−1. GC-MS m/z 244 (M+), 143 (M+ − SCF3 100%). 1H), 6.17 (s, 1H), 4.25–4.13 (m, 2H), 3.62 (dq, J = 13.6, 6.7 Hz,
HRMS (EI) calcd for C9H15F3O2S: 244.0745; Found: 244.0747.
1H), 2.43 (s, 3H), 2.25–2.01 (m, 2H), 1.56 (d, J = 6.9 Hz, 3H).
5-((Trifluoromethyl)thio)pentyl acetate (3m). Obtained as a 19F NMR (376 MHz, CDCl3) δ −39.0 (s). 13C NMR (101 MHz,
pale yellow oil in 99% yield (68 mg). Rf (n-pentane): 0.74. CDCl3) δ 161.6 (s), 161.3 (s), 155.2 (s), 152.6 (s), 131.0 (q, J =
1H NMR (400 MHz, CDCl3) δ 4.08 (t, J = 6.5 Hz, 2H), 2.90 (t, J = 306.4 Hz), 125.6 (s), 113.8 (s), 112.5 (s), 112.2 (s), 101.5 (s), 65.2
7.4 Hz, 2H), 2.06 (s, 3H), 1.82–1.59 (m, 4H), 1.57–1.38 (m, 2H). (s), 37.9 (q, J = 1.6 Hz), 36.0 (s), 22.7 (s), 18.7 (s). IR (KBr)
19F NMR (376 MHz, CDCl3) δ −41.3 (s). 13C NMR (101 MHz, ν 3029, 2929, 2861, 1496, 1455, 1382, 1116, 747, 699 cm−1
.
CDCl3) δ 171.0 (s), 131.1 (q, J = 305.7 Hz), 64.0 (s), 29.6 (q, J = GC-MS m/z 332 (M+), 233 (M+ − SCF3 100%). HRMS (EI) calcd
1.9 Hz), 29.1 (s), 28.0 (s), 24.9 (s), 20.8 (d, J = 1.2 Hz). IR (KBr) for C15H15F3O3S: 332.0694; Found: 332.0691.
ν 2943, 2866, 1741, 1367, 1238, 1117, 1044 cm−1. GC-MS m/z
Cyclohexyl(trifluoromethyl)sulfane.36
(3s). 12%
230 (M+), 129 (M+ − SCF3 100%). HRMS (EI) [M+ + H] calcd for (19F NMR). This volatile compound was identified by 19F NMR
C8H14F3O2S: 231.0667; Found: 231.0663.
spectra and GC-MS of reaction mixtures. 19F NMR (376 MHz,
2-(2-((Trifluoromethyl)thio)ethyl)-1,3-dioxolane (3n). Obtained CH3CN) δ −38.9 (s). GC-MS m/z 184 (M+), 83 (M+ − SCF3 100%).
yield
as a colorless oil in 70% yield (39 mg). Rf (n-pentane): 0.62.
(2,3-Dihydro-1H-inden-2-yl)(trifluoromethyl)sulfane (3t).
1H NMR (400 MHz, CDCl3) δ 5.00 (t, J = 4.1 Hz, 1H), 4.04–3.96 Obtained as a pale yellow oil in 48% yield (26 mg). Rf (n-pentane):
1
(m, 2H), 3.94–3.87 (m, 2H), 3.02 (t, J = 4.1 Hz, 2H), 2.16–2.06 0.91. H NMR (400 MHz, CDCl3) δ 7.27–7.19 (m, 4H), 4.10 (p,
(m, 2H). 19F NMR (376 MHz, CDCl3) δ −41.7 (s). 13C NMR J = 7.6 Hz, 1H), 3.46 (dd, J = 16.1, 7.7 Hz, 2H), 3.09 (dd, J = 16.0,
(101 MHz, CDCl3) δ 131.1 (q, J = 305.9 Hz), 102.4 (s), 65.1 (s), 7.5 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ −40.4 (s). 13C NMR
33.7 (s), 23.9 (q, J = 2.3 Hz). IR (KBr) ν 2889, 2359, 1115, 913, (101 MHz, CDCl3) δ 140.6 (s), 131.0 (q, J = 306.3 Hz), 127.1 (s),
742 cm−1. GC-MS m/z 200 (M+), 99 (M+ − SCF3 100%). HRMS 124.3 (s), 42.3 (q, J = 1.7 Hz), 40.6 (d, J = 0.8 Hz). IR (KBr)
(EI) [M+ − H] calcd for C6H8F3O2S: 201.0197; Found: 201.0202. ν 3212, 2926, 2853, 1715, 1683, 1539, 1116, 743 cm−1. GC-MS
2-(3-((Trifluoromethyl)thio)propyl)isoindoline-1,3-dione (3o). m/z 217 (M+ − H), 116 (M+ − SCF3 100%). HRMS (EI) calcd for
Obtained as a white solid in 99% yield (72 mg). Mp: 48–50 °C. C10H9F3S: 218.0377; Found: 218.0375.
Rf (n-pentane): 0.35. 1H NMR (400 MHz, CDCl3) δ 7.88–7.81
Cycloheptyl(trifluoromethyl)sulfane (3u). Obtained as a
(m, 2 H), 7.76–7.69 (m, 2H), 3.82 (t, J = 7.0 Hz, 2H), 2.92 (t, J = pale yellow oil in 32% yield (16 mg). Rf (n-pentane): 0.91.
7.0 Hz, 2H), 2.10 (p, J = 7.0 Hz, 2H). 19F NMR (376 MHz, 1H NMR (400 MHz, CDCl3) δ 3.45–3.51 (m, 1H), 2.19–2.03 (m,
CDCl3) δ −41.2 (s). 13C NMR (101 MHz, CDCl3) δ 168.2 (d, J = 2H), 1.83–1.65 (m, 4H), 1.65–1.48 (m, 6H). 19F NMR (376 MHz,
0.8 Hz), 134.1 (s), 132.0 (s), 131.0 (q, J = 306.1 Hz), 123.3 (d, J = CDCl3) δ −39.6 (s). 13C NMR (101 MHz, CDCl3) δ 131.2 (q, J =
1.1 Hz), 36.5 (s), 28.9 (s), 27.3 (q, J = 2.2 Hz). IR (KBr) ν 3469, 306.1 Hz), 45.9 (q, J = 1.2 Hz), 35.5 (s), 28.0 (s), 25.4 (s).
3063, 2943, 1772, 1716, 1615, 1583, 1395, 1117, 1016, 756, IR (KBr) ν 2930, 2857, 1460, 1125 cm−1. GC-MS m/z 198 (M+),
719 cm−1. GC-MS m/z 289 (M+), 188 (M+ − SCF3 100%). HRMS 129 (M+ − CF3 100%). HRMS (EI) calcd for C8H13F3S: 198.0690;
(EI) calcd for C12H10F3NO2S: 289.0384; Found: 289.0382.
(4-Phenylbutan-2-yl)(trifluoromethyl)sulfane (3p). Obtained
Found: 198.0691.
Cyclooctyl(trifluoromethyl)sulfane (3v). 11% yield (19F
as a pale yellow oil in 86% yield (50 mg). Rf (n-pentane): 0.65. NMR). This compound was identified by 19F NMR spectra and
1H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 7.3 Hz, 2H), 7.26–7.19 GC-MS of reaction mixtures. 19F NMR (376 MHz, CH3CN)
(m, 3H), 3.39–3.25 (m, 1H), 2.86–2.71 (m, 2H), 2.07–1.85 (m, δ −39.1 (s). GC-MS m/z 212 (M+), 143 (M+ − SCF3 100%).
2H), 1.49 (d, J = 6.9 Hz, 3H). 19F NMR (376 MHz, CDCl3)
tert-Butyl(trifluoromethyl)sulfane.36
(3w). 13%
yield
δ −38.9 (s). 13C NMR (101 MHz, CDCl3) δ 140.9 (s), 131.2 (q, J = (19F NMR). This volatile compound was identified by 19F NMR
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spectra of reaction mixtures. 19F NMR (376 MHz, CH3CN) δ The filtrate was analyzed by 19F NMR and GC-MS. The yield of
−36.2 (s).
the (4-phenoxybutyl)(trifluoromethyl)sulfane 3g was calculated
1-((Trifluoromethyl)sulfonyl)octane.60 (4a). Obtained as a to be 95%.
colorless oil in 88% yield (54 mg). Rf (n-pentane–diethyl ether
1
Procedure for the reaction of 1 with (bromomethyl)
cyclopropane 5
= 3 : 1): 0.87. H NMR (400 MHz, CDCl3) δ 3.28–3.18 (m, 2H),
1.96 (dt, J = 15.7, 7.9 Hz, 2H), 1.56–1.45 (m, 2H), 1.42–1.22 (m,
8H), 0.91 (t, J = 6.8 Hz, 3H). 19F NMR (376 MHz, CDCl3)
δ −78.2 (s). 13C NMR (101 MHz, CDCl3) δ 119.5 (q, J = 327.2
Hz), 49.6 (q, J = 1.0 Hz), 31.6 (s), 28.8 (s), 28.4 (s), 22.6 (s), 20.6
(s), 14.1 (s). IR (KBr) ν 3086, 3032, 2931, 1647, 1112, 963, 749,
693 cm−1. GC-MS m/z 246 (M+), 113 (M+ − SO2CF3 100%).
1 (19.2 mg, 0.060 mmol), 5 (6.8 mg, 0.050 mmol), KF (5.8 mg,
0.10 mmol), and 0.6 mL CD3CN were added to an NMR tube
containing a septum-lined screw cap. The tube was sealed and
1
an initial H NMR spectrum was acquired. The reaction solu-
tion was then placed into a pre-heated 110 °C oil bath for 15 h.
The tube was removed from the oil bath and cooled to rt, and
(3-((Trifluoromethyl)sulfonyl)propyl)benzene.61
Obtained as pale yellow oil in 80% yield (50 mg).
(4d).
1
a
a final H NMR spectrum was also acquired. 10 µL (trifluoro-
Rf (n-pentane–diethyl ether = 3 : 1): 0.77. 1H NMR (400 MHz,
CDCl3) δ 7.42–7.15 (m, 5H), 3.28–3.13 (m, 2H), 2.86 (t, J = 7.3
Hz, 2H), 2.37–2.24 (m, 2H). 19F NMR (376 MHz, CDCl3) δ −78.1
(s). 13C NMR (101 MHz, CDCl3) δ 138.8 (s), 128.9 (s), 128.4 (s),
126.9 (s), 119. 5 (q, J = 327.1 Hz), 48.8 (s), 34.0 (s), 22.3 (s).
IR (KBr) ν 2962, 2917, 2849, 2360, 1456, 1367, 1260, 1198,
1120, 1112, 912, 799, 699 cm−1. GC-MS m/z 251 (M+), 118
(M+ − SO2CF3 100%).
methoxy)benzene was then added as an internal standard. The
reaction mixture was analyzed by 19F NMR and GC-MS. The
yield of (cyclopropylmethyl)(trifluoromethyl)sulfane 6 was cal-
culated to be 79%. Formation of but-3-enyl(trifluoromethyl)-
sulfane 7 was not detected from 1H NMR.
Procedure for the reaction of 1 with 6-bromohex-1-ene 8
1 (19.2 mg, 0.060 mmol), 8 (8.2 mg, 0.050 mmol), KF (5.8 mg,
0.10 mmol), and 0.6 mL CD3CN were added to an NMR tube
containing a septum-lined screw cap. The tube was sealed and
1-Nitro-4-(2-((trifluoromethyl)sulfonyl)ethyl)benzene
(4f).
Obtained as white solid in 80% yield (18 mg).
a
1
Mp: 134–136 °C. Rf (n-pentane–diethyl ether = 3 : 1): 0.27.
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.6 Hz, 2H), 7.46 (d,
J = 8.6 Hz, 2H), 3.55 (dd, J = 10.1, 6.1 Hz, 2H), 3.38 (dd, J = 9.9,
6.3 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ −77.8 (s). 13C NMR
(101 MHz, CDCl3) δ 143.4 (s), 129.5 (s), 124.4 (s), 119.4 (q, J =
323.2 Hz), 50.2 (q, J = 1.0 Hz), 26.7 (s). IR (KBr) ν 3083, 2993,
2933, 1521, 1353, 1211, 1108, 855, 737 cm−1. GC-MS m/z 283
an initial H NMR spectrum was acquired. The reaction solu-
tion was then placed into a pre-heated 110 °C oil bath for 15 h.
The tube was removed from the oil bath and cooled to room
1
temperature, and a final H NMR spectrum was also acquired.
10 µL (trifluoromethoxy)benzene was then added as an
internal standard. The reaction mixture was analyzed by
19F NMR and GC-MS. The yield of the hex-5-enyl(trifluoro-
methyl)-sulfane 9 was calculated to be 80%. Formation of
(cyclopentylmethyl)(trifluoromethyl)sulfane 10 was not
detected from 1H NMR.
(M+), 150 (M+
− SO2CF3 100%). HRMS (EI) calcd for
C9H8F3NO4S: 283.0126; Found: 283.0130.
Ethyl 6-((trifluoromethyl)sulfonyl)hexanoate (4l). Obtained
as a colorless oil in 78% yield (54 mg). Rf (n-pentane–diethyl
ether = 3 : 1): 0.60. 1H NMR (400 MHz, CDCl3) δ 4.15 (q, J =
7.1 Hz, 2H), 3.28–3.17 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 1.97 (dt,
J = 15.7, 7.8 Hz, 2H), 1.71 (dt, J = 14.7, 7.2 Hz, 2H), 1.61–1.51
(m, 2H), 1.27 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3)
δ −78.2 (s). 13C NMR (101 MHz, CDCl3) δ 173.1 (s), 119.5 (q, J =
327.1 Hz), 60.5 (s), 49.4 (s), 33.6 (s), 27.8 (s), 24.1 (s), 20.5 (s),
14.2 (s). IR (KBr) ν 2939, 2873, 1731, 1464, 1366, 1199, 1122,
913, 735, 614 cm−1. GC-MS m/z 276 (M+), 143 (M+ − SO2CF3
100%). HRMS (EI) calcd for C9H15F3O4S: 276.0643; Found:
276.0647.
Procedure for the reaction of 1 with hexyl p-toluenesulfonate
11
1 (19.2 mg, 0.060 mmol), 11 (12.8 mg, 0.050 mmol), KF
(5.8 mg, 0.10 mmol), and 0.6 mL CH3CN were added to a oven-
dried 5 mL test tube with Teflon screw cap. The tube was
sealed and the reaction solution was placed into a pre-heated
110 °C oil bath for 15 h. The tube was removed from the oil
bath and cooled to room temperature, and then 10 µL
(trifluoromethoxy)benzene was added as an internal standard.
The resulting mixture was filtered through a layer of Celite.
The filtrate was analyzed by 19F NMR and GC-MS. The yield of
the hexyl(trifluoromethyl)sulfane 12 was calculated to be 79%.
Procedure for the reaction of 1 with 4-phenoxybutyl bromide
2g in the presence of 1.0 equiv. CHD
1 (19.2 mg, 0.060 mmol), 2g (11.4 mg, 0.050 mmol), KF
(5.8 mg, 0.10 mmol), and 0.6 mL CH3CN were added to a oven-
dried 5 mL test tube with Teflon screw cap. CHD (2.0 mg,
Acknowledgements
0.025 mmol) was added into the mixture by syringe. The tube Financial support from National Natural Science Foundation
was sealed and the reaction solution was placed into a pre- of China (21372044), Research Fund for the Doctoral Program
heated 110 °C oil bath for 15 h. The tube was removed from of Higher Education of China (no. 20123514110003), the SRF
the oil bath and cooled to room temperature, and then 10 µL for ROCS, SEM, China (2012–1707), the Science Foundation of
(trifluoromethoxy)benzene was added as an internal standard. the Fujian Province, China (2013J01040), and Fuzhou Univer-
The resulting mixture was filtered through a layer of Celite. sity (022318, 022494) is gratefully acknowledged.
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29 C.-P. Zhang and D. A. Vicic, J. Am. Chem. Soc., 2012, 134,
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