2
(PIP) as the directing group to realize the copper-mediated C−H
thiolation of (hetero)arenes with disulfides14a and S8.14b Assisted
by 2-aminalkylbenzimidazole (MBIP) as directing group, Song
reported copper-mediated C−H thiolation of arenes and olefins.15
Recently, Ackermann developed a copper-catalyzed highly
regioselective C−H thiolation of indoles (C2 position) and
indolines (C7 position).16 Very recently, our group disclosed a
Cu-mediated room-temperature C−H thiolation of arenes by
using ethylene sulfide as the thiolation reagent.17
7). The yield of thiolation could be improved to 57 % by
o
increasing the temperature to 110 C (entry 8-10). When the
reaction was carried out under N2 atmosphere, 65% yield of
desired product could be obtained (entry 12). Unexpectedly, all
the raw materials were decomposed and no desired product could
be observed under O2 conditions (entry 11). When we increased
loading of copper catalyst to 2 equiv., the yield could be
improved to 76% (entry 13-15). Prolonged reaction time could
slightly improve the yield with higher di- to mono-thiolation ratio
(Entry 16-19).
Despite those undisputable advances, strongly coordinating
directing groups are often required in the reaction. Copper
catalyzed or mediated C–H thiolation via weakly coordinating
directing group is rare, possibly due to relatively low catalytic
activity and the irreversible coordination of copper catalyst with
sulfur compounds.18 In 2016, Ackermann and coworkers
achieved copper mediated C−H thiolation and chalcogenation of
1,2,3-triazoles via weak O-assistance (Scheme 1C).19 Previously,
our group reported copper mediated ortho-hydroxylation and
With the optimal conditions in hand, we proceeded to explore the
substrate scope of benzamide derivatives. As shown in Table 2,
our protocol appeared to be very general with respect to the
substituents in benzamide 1 (1a-1r). Electron-rich OMe, Ph-
substituted arenes gave the corresponding products in 72% and
68% yields respectively (3c, 3d). Electron-deficient arenes
bearing halogen, cyano, trifluoromethyl, ester, sulfonyl and nitryl
group could be thiolated smoothly under the standard conditions,
obtaining the corresponding products in moderated to good yields
(3e-3o). When the ortho-position was substituted by fluorine,
methyl and trifluoromethyl, the yields decreased to 35-67%,
possibly due to the steric hindrance (3p-3r). 1-
Naphthylbenzamide afforded mono-thiolation product 3s in 68%
yields (3s). Compared to 3, 5-dimethoxyl benzamide, 3, 5-
difluoro benzamide gave higher selectivity of di-thiolation
product perhaps due to the small size of the fluorine atom (3t,
3u). To our delight, this protocol could be compatible with
heterocycles including thiophene, pyrrole, imidazole and indole
derivatives, furnishing the desired thiolated products in moderate
to good yields (3v, 3w, 3x, 3aa). Substrates containing strongly
coordinated pyridine and quinoline could also be thiolated in
good yields (3y, 3z, 3ab, 3ac).
amination of arenes by utilizing
a weakly coordinating
monodentate directing group (Scheme 1D).20 In this work, we
reported a copper-mediated C−H thiolation of (hetero)arenes by
weakly coordinating directing group.
Table 1 Optimization of the reaction conditionsa
SPh
2a
PhSSPh (
)
CONHArF
CONHArF
CONHArF
SPh
Cu salts, base
+
H
1b
DMSO (1 mL)
SPh
air, temp (oC), 12 h
ArF= 4-CF3(C6F4)
3b
3b'
yield (%) [mono+di]b
Entry
base (2 eq)
Cu salts (x eq)
temp (oC)
1
28 (25:3)
0
100
100
100
100
100
100
100
90
Cu(OAc)2 (1.0)
CuO (1.0)
CsOAc
CsOAc
CsOAc
/
2
3
14 (13:1)
0
CuOAc (1.0)
4
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (0)
Table 2 Scope of benzamide substratesa,b
5
16 (11:5)
33 (25:8)
48 (31:17)
34 (17:17)
57 (22:35)
55 (22:33)
ND
K3PO4
Na2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
PhSSPh (2 eq)
SPh
6
Cu(OAc)2 (2 eq)
CONHArF
or
CONHArF
H
CONHArF
or Het
CONHArF
SPh
Li2CO3 (2 eq)
7
Het
R
R
DMSO (1 mL)
N
H
SPh
2 ,110 oC, 36 h
8
ArF= 4-CF3(C6F4)
9
110
120
110
110
110
110
110
110
110
110
110
SPh
SPh
R
C2
R
CONHArF
CONHArF
CONHArF
SPh
, R = F 67%
, R = Me 62%
, R = CF3 35%
10
11c
12d
13d
14d
15d
16d,e
17d,f
18d,f
19d,g
C4
SPh
R
SPh
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
, R = H 78% (mono/di=13%:65%)
, R = Me 77% (mono/di=25%:52%)
, R = OMe 72% (mono/di= 6%:66%)
, R = Ph 68% (mono/di=14%:54%)
, R = F 75% (di)
, R = Cl 81% (di)
, R = Br 46% (di)
, R = CN 84% (di)
, R= CF3 71% (di)
, R = COOMe 51% (di)
, R = SO2Me 86% (di)
, R = NO2 61% (di)
3m
3n
3o
3p
3q
3r
, R = F 66% (mono(C2)/di = 31%:35%)
, R = Cl 81% (mono(C2)/di = 41%:40%)
, R= CF3 70% (mono(C4)/di = 56%:14%)
65 (34:31)
ND
SPh
O
CONHArF
SPh
25 (20:5)
76 (43:33)
79 (33:46)
78 (25:53)
77 (25:52)h
74 (22:52)
Cu(OAc)2 (0.3)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
F
CONHArF
SPh
CONHArF
SPh
O
F
3s
, 68%
3t
, 81%
3u
, 61%
CONHArF
SPh
SPh
SPh
S
SPh
CONHArF
PhS
N
N
CONHArF
CONHArF
N
N
a
1b
Reaction conditions: (0.1 mmol),
2a (
0.2 mmol), Cu salts, base (0.2 mmol), DMSO (1 mL), air,
3v
, 62%
3w
3x
, 38%
3y
, 71%
, 63%
12 h. b Yield was determined by 1H NMR analysis of crude reaction mixture using CH2Br2 as the
internal standard. c O2 atmosphere. d 2 atmosphere. e 24 h. f 36 h. g 48 h. h Isolated yield.
SPh
CONHArF
SPh
SPh
C5
CONHArF
SPh
C2
N
N
C
4
CONHArF
C7
PhS
CONHArF
N
We commenced our studies by selecting substrate 1b and phenyl
disulfide 2a as the model substrates. We initially treated substrate
1b with 2 equiv. of 2a, 1 equiv. of Cu(OAc)2 and 2 equiv. of
CsOAc in DMSO at 100 °C for 12 h, giving the target product in
28% with a 25/3 mono- to di-thiolation ratio (Table 1, entry 1).
Then we screened other copper catalysts, and Cu(OAc)2 gave the
best results (entry 2, 3). Base is essential in the reaction, and no
desired product could be obtained in the absence of base (entry 4-
N
N
SPh
, 68%
(mono(C7)/di=33%:35%)
(0.2 mmol), Cu(OAc)2 (0.2 mmol), Li2CO3 (2 eq), DMSO (1 mL),
3z
, 75%
3aa
, 77%
3ab
,62%
3ac
(mono(C4)/di=25%:50%)
a
1
2a
Reaction conditions: (0.1 mmol),
N2, 110 oC, 36 h. b Isolated yield.
Next, we investigated the scope of disulfides. As shown in Table
3, 1,2-diphenyl disulfide containing various substituents,
including methyl, methoxy, trifluoromethyl, fluoro, chloro, and