M. Raghavender Reddy et al. / Tetrahedron Letters 57 (2016) 3622–3624
3623
O
Results and discussions
R1
H
N
SH
N
Cl
+
OMe
O
O
In order to test our hypothesis, we carried our initial experi-
ments, we investigated different reaction conditions using thio-
phenol (1a) and 1,3,5-trimethoxy benzene (3a) as model
substrates in the presence of different halogen sources including
NCS, NBS, and NIS in DCM at room temperature. It was observed
that the reaction preceded efficiently using NCS (Table 1, entries
1–4). Increasing the amount of NCS (1–1.5 equiv) gave desired pro-
duct 3a in 89% yield (Table 1, entry 4). The structure of product was
confirmed by means of 1H NMR, 13C NMR, IR and Mass spectrom-
etry analysis. When NBS or NIS was used as halogen source instead
of NCS, the reaction also proceeded to obtain 3a up to 45% yield
(Table 1, entries 9 and 10). However, the reaction failed in the
absence of NXS (Table 1, entry 7), which indicated that the use of
NXS is essential for this reaction. Further to optimize the reaction
conditions, the reaction was studied in different temperatures,
room temperature was found to be more suitable for this reaction.
Increasing or decreasing the temperature did not enhance the
yield (Table 1, entries 5 and 6). Next, we have also studied other
solvents such as DCE, Toluene, DMSO, DMF, and ethanol, but they
were less or ineffective for this reaction (Table 1, entries 8–14). It
was assumed that thiophenol forms an intermediate sulfenyl chlo-
ride (see Scheme 2), which facilitates the easy generation of
required product.
With the optimized results in hand, a series of thiophenols were
investigated for this reaction and the results are summarized in
Table 2. To our delight, various substituted thiophenols reacted
with 1,3,5 trimethoxy benzene and generated the desired products
in moderate to excellent yields. In this process thiophenols con-
taining e-withdrawing group reacted smoothly with methoxyben-
zenes to afford corresponding products in high yields, where as
e-donating activating groups containing thiophenols however
exhibited lower activity than electron deficient ones. For instance,
electron withdrawing group (nitro) corresponding products 3g, 3h,
and 3i in 96%, 90%, and 94% yields respectively, the substrate
1
O
2
OMe
2
R1
R1
S
S
Cl
A
OMe
R1
3
Cl-
+
S
HCl
H
B
OMe
Scheme 2. Plausible reaction mechanism.
Table 2
Substrate scope of the NCS promoted reaction of aryl thiophenols and methoxy-
benzenes for aryl sulfidesa
S
3
NCS
SH
+
(OMe)n
R1
DCM, rt
(OMe)n
2
R1
1
OMe
OMe
OMe
S
S
S
OMe
OMe
MeO
3a (89%)
OMe
OMe
MeO
OMe
OMe
3c (86%)
3b (80%)
OMe
S
S
S
MeO
OMe
MeO
OMe
3e (85%)
3f (90%)
S
3d (91%)
OMe
OMe
OMe
S
S
Table 1
O2N
OMe
O2N
MeO
OMe
OMe
O2N
MeO
Optimization of reaction conditionsa
OMe
3i (94%)
S
3h (90%)
3g (96%)
MeO
S
MeO
MeO
OMe
OMe
OMe
NXS
OMe
+
SH
OMe
S
S
solvent, rt
MeO
3a
MeO
MeO
OMe
2a
1a
Entry
OMe
3j (82%)
3l (80%)
3k (75%)
NXS (equiv)
Thiophenol (equiv)
Solvent
Yieldb (%)
OMe
OMe
OMe
OMe
1
2
3
4
5
6
7
8
NCS (1)
1
1
2
2
2
2
2
2
2
2
2
2
2
2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
60
67
80
89
S
S
S
NCS (1.2)
NCS (1.2)
NCS (1.5)
NCS (1.5)
NCS (1.5)
—
NCS (1.5)
NCS (1.5)
NBS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
MeO
MeO
MeO
MeO
OMe
MeO
OMe
70c
50d
NR
79
3o (87%)
3n (82%)
3m (90%)
OMe
OMe
OMe
S
S
S
9
38
45
NR
Trace
NR
65
Cl
MeO
OMe
Cl
OMe
10
11
12
13
14
OMe
OMe
OMe
3t (trace)
3p (88%)
S
3q (85%)
OMe
S
NR = no reaction.
a
F
MeO
3r (89%)
OMe
F
MeO
3s (80%)
Reaction conditions: Thiophenol 1a (2 equiv) and N-halosuccinimide (1.5 equiv)
under a nitrogen atmosphere in solvent (3–4 mL) at rt for 30 min, then 1,3,5 tri-
methoxy benzene 2a (1.0 equiv) at rt for 30 min.
b
a
Isolated yield.
Reaction temperature at 0 °C.
Reaction temperature at reflux.
Reaction conditions: Thiophenol 1 (2 equiv) and N-chlorosuccinimide (1.5 equiv)
under a nitrogen atmosphere in solvent (3–4 mL) at rt for 30 min, then substituted
methoxy benzene 2 (1.0 equiv) at rt for 30 min.
c
d