JOURNAL OF CHEMICAL RESEARCH 2014 281
Typical experimental procedure for TBHP-mediated thiolation of
tetrahydrofuran with disulfides
t-BuOOH
t-BuO /HO
t-BuO
+
OH
Disulfide 1 (0.5 mmol), TBHP (2 equiv.), Na2CO3 (0.1 equiv.) and
tetrahydrofuran 2 (1 mL) were added to a Schlenk tube. Then the tube
was stirred at 120 °C (oil bath temperature) under an argon atmosphere
for the indicated time until complete consumption of starting material
as monitored by TLC or GC-MS analysis. After the reaction was
finished, the reaction mixture was cooled to room temperature, diluted
in ethyl acetate (5 mL), and washed with brine (3×1 mL). The aqueous
phase was extracted with ethyl acetate (3×2 mL). The combined
organic layers were dried with anhydrous Na2SO4 and concentrated
under reduced pressure and the resulting residue was purified by
column chromatography on silica gel (hexane/ethyl acetate=20:1) to
afford the desired products 3a–h.
PhSSPh
1a
PhS
O
3a
O
O
A
2a
PhS
t-BuOH/H2O
PhSH
Scheme 2 Possible mechanism.
2a
O
2-(Phenylthio)tetrahydrofuran (3a):20 Light-yellow oil; 1H NMR
(500 MHz, CDCl3) δ: 7.43 (d, J=8.0 Hz, 2H), 7.15–7.24 (m, 3H), 5.57
(m, 1H), 3.93–3.98 (m, 1H), 3.87–3.91 (m, 1H), 2.28–2.32 (m, 1H),
1.87–1.97 (m, 2H), 1.79–1.83 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
135.7, 131.1, 128.8, 126.8, 87.1, 67.3, 32.6, 24.8; LRMS (EI, 70 eV) m/z
(%): 180 (M+, 100).
2-(p-Tolylthio)tetrahydrofuran (3b):21 Light-yellow oil; 1H NMR
(500 MHz, CDCl3) δ: 7.33 (d, J=8.1 Hz, 2H), 7.03 (d, J=8.1 Hz, 2H),
5.49 (m, 1H), 3.92–3.97 (m, 1H), 3.84–3.88 (m, 1H), 2.22–2.28 (m, 1H),
2.23 (s, 3H), 1.85–1.94 (m, 2H), 1.77–1.81 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ: 137.0, 131.8, 131.7, 129.6, 87.6, 67.2, 32.6, 24.8, 21.0; IR (KBr,
cm–1): 2975, 2867, 1492, 1456, 1241, 1045, 906, 806; LRMS (EI, 70 eV)
m/z (%): 194 (M+, 100).
Table 2 Thiolation between disulfides (1) and tetrahydrofuran (2)a
TBHP, Na2CO3
+
RSSR
RS
O
120 oC, 24 h
O
2c
1
3
Entry
R
Disulfide
Product
Yield/%b
1
2
3
4
5
6
7
p-MeC6H4
p-FC6H4
1b
1c
1d
1e
1f
3b
3c
3d
3e
3f
71
90
85
70
89
80
60
p-ClC6H4
p-BrC6H4
m-MeC6H4
p-CO2MeC6H4
Bn
2-(4-Fluorophenylthio)tetrahydrofuran (3c): Colourless oil; 1H NMR
(500 MHz, CDCl3) δ: 7.42 (m, 2H), 6.92 (t, J=8.6 Hz, 2H), 5.45 (m, 1H),
3.92–3.96 (m, 1H), 3.85–3.89 (m, 1H), 2.25–2.29 (m, 1H), 1.80–1.93 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 162.3 (d, J=245.4 Hz, 1C), 133.9
(d, J=8.0 Hz, 2C), 130.4 (d, J=3.4 Hz, 1C), 115.8 (d, J=21.6 Hz, 2C),
87.8, 67.2, 32.5, 24.8; LRMS (EI, 70 eV) m/z (%): 198 (M+, 100); HRMS
(ESI) for C10H12FOS (M+H)+: calcd 199.0587, found 199.0595.
1g
1h
3g
3h
aReaction conditions: 1 (0.5 mmol), 2 (1 mL), TBHP (2.0 equiv.; 70% in
water solution), and Na2CO3 (0.1 equiv.) at 120 °C for 24 h.
bIsolated yield based on disulfides 1.
1
2-(4-Chlorophenylthio)tetrahydrofuran (3d):22 Light-yellow oil; H
optimal conditions, (entries 1–6). Moreover, substituents
at different positions of the aromatic ring (para-, meta-, or
ortho-position) did not affect the efficiency. For example, p-F-
substituted diaryl disulfide 1c gave the desired product 3c in
90% yield (entry 2), whereas m-F-substituted diaryl disulfide
1f also afford product 3f in 89% yield (entry 5). Interestingly,
o-CO2Me-substituted diaryl disulfide 1g reacted with THF 2a,
TBHP and Na2CO3, providing the corresponding product 3g in
good yield (entry 6). Using aliphatic disulfide 1h, the desired
product 3h was also obtained in moderate yield (entry 7).
As shown in Scheme 2, a possible mechanism was
proposed.9,10 Initially, TBHP is readily split into a butoxy
radical and a hydroxy radical. Hydrogen abstract of THF (2a)
by a butoxy radical or a hydroxy radical takes place to form
radical intermediate A, followed by reaction with PhSSPh (1a)
affording product 3a and the PhS⋅radical. Finally, the R2S⋅ free
radical intermediate reacts with THF (2a) leading to radical
intermediate A and PhSH. The role of bases is suggested to be
the promotion of the hydrogen abstraction from THF (2a).
In summary, we have developed a simple protocol for the
construction of C–S bonds by TBHP-mediated C–H oxidative
cross-coupling of tetrahydrofuran with disulfides, promoted
by catalytic amounts of Na2CO3. In the presence of TBHP and
Na2CO3, various tetrahydrofuran-containing sulfides were
obtained in moderate to high yield.
NMR (500 MHz, CDCl3) δ: 7.36 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.2 Hz,
2H), 5.52 (m, 1H), 3.87–3.96 (m, 2H), 2.28–2.31 (m, 1H), 1.79–1.96 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 134.2, 132.9, 132.4, 128.9, 87.2,
67.3, 32.6, 24.8; LRMS (EI, 70 eV) m/z (%): 216 (35Cl M+ +2, 35), 214
(35Cl M+, 100).
2-(4-Bromophenylthio)tetrahydrofuran (3e): Light-yellow oil; 1H
NMR (500 MHz, CDCl3) δ 7.33 (d, J=8.7 Hz, 2H), 7.29 (t, J=8.7 Hz,
2H), 5.53 (m, 1H), 3.87–3.96 (m, 2H), 2.27–2.31 (m, 1H), 1.79–1.95 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 134.9, 132.6, 131.8, 120.9, 87.1,
67.3, 32.6, 24.8; LRMS (EI, 70 eV) m/z (%): 260 (M+ +2, 10), 258 (M+,
10), 71 (100); HRMS (ESI) for C10H1279BrOS (M+H)+: calcd 258.9787,
found 258.9797.
2–(3–Fluorophenylthio)tetrahydrofuran (3f): Light-yellow oil; 1H
NMR (500 MHz, CDCl3) δ 7.16–7.19 (m, 3H), 6.81–6.85 (m, 1H), 5.60
(m, 1H), 3.90–3.96 (m, 2H), 2.28–2.34 (m, 1H), 1.81–1.95 (m, 3H);
13C NMR (125 MHz, CDCl3) δ 162.7 (d, J=246.4 Hz, 1C), 138.2 (d,
J=8.0 Hz, 1C), 129.9 (d, J=8.4 Hz, 1C), 125.9 (d, J=3.0 Hz, 1C), 117.2
(d, J=22.7 Hz, 1C), 113.5 (d, J=21.1 Hz, 1C), 86.8, 67.3, 32.6, 24.8;
LRMS (EI, 70 eV) m/z (%): 198 (M+, 100); HRMS (ESI) for C10H12FOS
(M+H)+: calcd 199.0587, found 199.0593.
Methyl 2-(tetrahydrofuran-2-ylthio)benzoate (3g): Light-yellow
1
oil; H NMR (500 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.78 (d,
J=7.8 Hz, 1H), 7.37 (t, J=8.5 Hz, 1H), 7.11 (t, J=8.5 Hz, 1H), 5.67 (m,
1H), 3.90–3.94 (m, 2H), 3.82 (s, 3H), 2.32–2.37 (m, 1H), 1.97–2.02 (m,
2H), 1.81–1.85 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 166.9, 140.9,
132.3, 130.8, 128.3, 128.1, 124.6, 84.5, 67.5, 52.0, 32.3, 25.0; LRMS
(EI, 70 eV) m/z (%): 238 (M+, 9), 71 (100); HRMS (ESI) for C12H15O3S
(M+H)+: calcd 239.0736, found 339.0743.
Experimental
2-(Benzylthio)tetrahydrofuran (3h):23 Light-yellow oil; 1H NMR
(500 MHz, CDCl3) δ 7.22–7.28 (m, 4H), 7.14–7.18 (m, 1H), 5.14 (m,
1H), 3.84–3.91 (m, 2H), 3.81 (d, J=13.2 Hz, 1H), 3.67 (t, J=13.2 Hz,
1H), 2.08–2.14 (m, 1H), 1.91–1.94 (m, 1H), 1.70–1.78 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 138.6, 128.9, 128.4, 126.8, 83.0, 66.7, 35.0, 32.0,
24.8; LRMS (EI, 70 eV) m/z (%): 194 (M+, 100).
NMR spectroscopy was performed on a Bruker advanced spectrometer
operating at 500 MHz (1H NMR) and 125 MHz (13C NMR). TMS
(tetramethylsilane) was used as an internal standard and CDCl3 was
used as the solvent. Mass spectrometric analysis was performed on
GC-MS analysis (SHIMADZU GCMS-QP2010) and ESI-Q-TOF
(Bruker MicroQTOF-II).