6770
S. Keesara et al. / Tetrahedron Letters 55 (2014) 6769–6772
S
O
Cl
Br
S
S
O
O
N
H
N
H
S
N
N
H
N
H
N
H
N
H
H2N
NH2
N
Br
1a
1e
1c
1g
S
O
S
S
N
H
N
H
N
H
N
H
N
H
N
H
N
1b
1d
1f
Figure 1. Structures of thiourea ligands.
O
S
with sulfur.36 We also examined the simple thiourea 1g system
and found to be completely inactive (entry 10). According to Guo
and co-workers an additional substituent on nitrogen atom in
N-phenyl urea may cause steric hindrance, which we have also
observed in case of 1f ligand.37 The ligand 1d was completely
inactive in the Heck reaction, which can be explained by the
possible formation of highly stable bis-complex, wherein the
formation of strongly coordinating sulfur and nitrogen bonds with
Pd was expected.
O
1. NH4SCN
R
N
H
N
H
Cl
Acetone, 0 °C
2. amine
R1
R1
1a-d
R
R1
a = picolyl
b = ph
H
H
c = 4-bromophenyl Br
d = pyridyl
Me
Earlier, it was reported that N,N0-mono substituted acyclic N–H
featuring thiourea ligands are completely inactive in Pd catalyzed
Heck reaction.26 But in our case, we highlight that the N–H
featuring thiourea ligands (1a–c) act as good catalysts in the Heck
reaction due to the presence of the carbonyl functional group
adjacent to nitrogen atom. From the above results, it is clear that
the position of heterocyclic ring and the carbonyl functional group
on nitrogen atom in each thiourea ligand plays an important role in
the catalytic activity of Pd(OAc)2 in the Heck reaction.
Scheme 1. Synthesis of N,N0-mono substituted acyclic thiourea ligands.
Cl
S
NCS
DCM
N
H
N
H
+
N
0 ºC, RT
N
Cl
1e
NH2
Scheme 2. Synthesis of N,N0-mono substituted acyclic thiourea ligand (1e).
The Heck coupling reaction of various aryl halides and olefins
has been investigated in the presence of Pd(OAc)2/1a (1:2). The
results are summarized in Table 2.38 Deactivated and activated aryl
bromides were reacted with different aromatic olefins to give
moderate to excellent yields of the coupled products
(0.001 mol % of Pd, 2 equiv LiOHꢀH2O, DMF, 130 °C) (entries 1–7
& 10–15). Sterically hindered 2-bromoanisole and 2-bromotoluene
could also be coupled in moderate yields by increasing the catalyst
loading (0.01 mol % of Pd) (entries 16 and 17). Furthermore, aryl
iodides were also excellent substrates suitable for our reaction
conditions (entries 18–21). We have achieved high turnover
numbers (6.6 ꢁ 105 and 4.7 ꢁ 105) with electron rich aryl bromides
(entries 8 & 9) and aryl iodides (9.7 ꢁ 105 and 9.5 ꢁ 105) using as
low as 0.0001 mol % of Pd (entries 18 & 19). The above optimized
reaction conditions were less effective for the Heck reaction of aryl
chlorides (entry 22).
Encouraged by these results, further we have examined the cou-
pling reaction of aryl halides with n-butyl acrylate using Pd(OAc)2/
1a (1:2) (Table 3).39 When aryl iodides were used as substrates,
excellent yields were obtained (entries 1–5). Aryl bromides
resulted in moderate to excellent yields with n-butyl acrylate
(entries 6–9). Poor yields were observed in case of aryl chlorides
(entry 10).
Table 1
Heck reaction between 4-bromoanisole and styrenea
Ph
Br
Pd(OAc)2 / ligand
+
Ph
LiOH.H2O, DMF
MeO
MeO
Entry
Ligand
Base
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
NaOAc
K2CO3
K3PO4
LiOHꢀH2O
LiOHꢀH2O
LiOHꢀH2O
LiOHꢀH2O
LiOHꢀH2O
LiOHꢀH2O
LiOHꢀH2O
10
10
10
10
10
10
10
15
24
24
62
90
32
98
82
86
—
94
34
—
10
1g
a
Reaction conditions: 4-bromoanisole 1 mmol, styrene 2 mmol, base 2.0 mmol,
0.01 mol % of catalyst (Pd(OAc)2/ligand = 1:2) in 2 mL DMF, reaction temperature
130 °C.
b
Isolated yield.
thiourea ligand (1a) in 2 mL DMF, using a variety of bases (2 mmol)
for about 10 h (entries 1–4). Among these (entry 4), the LiOHꢀH2O
base gave the best results. In the series of thiourea ligands (1a–d)
studied, the picolyl group containing ligand 1a (entry 4) resulted in
excellent yields. When the picolyl group is replaced with the phe-
nyl group (1b &1c), the yields were slightly lower (entries 5 & 6).
No activity was observed for the ligand 1d, as the pyridine group
was directly attached to nitrogen atom (entry 7). The ligand 1e
(entry 8) gave an excellent yield, whereas 1f (commercially avail-
able) gave very low yield (entry 9). The ligand 1e is similar to
the earlier reported one, wherein we exchanged the oxygen atom
In conclusion, we have accomplished phosphine-free N,N0-mono
substituted acyclic thiourea ligands for Pd catalyzed Heck cross-
coupling reactions. Compared to the earlier reports on thiourea
ligands, ours is better for Heck reactions of deactivated aryl bro-
mides. We have achieved high turnover numbers for both aryl
iodides and aryl bromides. Since these ligands are inexpensive
and easy to prepare, the present protocol has potential application
for the synthesis of Heck products. Work is in progress in our
laboratory to extend the application of these ligands to other
palladium-catalyzed transformations.