Organic Letters
Letter
However, the direct thiolation of an inactivated methyl C(sp3)−
H bond has yet to be established due to its thermodynamic
stability (calcd 440 kJ mol−1 for a primary C−H bond). It is
believed that the chelation-assisted transformation is facilitated
by a bidentate directing group, which leads to the site-selective
functionalization of the C(sp3)−H bonds.22 The method has
shown prime synthetic potential for exploring new types of
transformations of C(sp3)−H bonds that cannot be achieved
using conventional synthetic methods.23 In this work, we applied
the chelation-assisted method using amides as bidentate
directing groups for the direct thiolation of inactivated methyl
C(sp3)−H bonds.
Figure 2. Ineffective directing groups.
a
Scheme 2. Investigation of Aliphatic Amides Scope
To verify the proposed strategy, our initial investigation
focused on the thiolation of N-(quinolin-8-yl)pivalamide 1a (0.2
mmol) with diphenyl disulfide 2a (0.4 mmol) over Ni catalysts
(Table 1). 2,4,6-Trimethylbenzoic acid, Na2CO3, and DMF were
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: amide 1 (0.2 mmol), diphenyl disulfides 2a (0.4
mmol), NiBr2 (0.02 mmol), MesCOOH (0.04 mmol), Na2CO3 (0.4
mmol) in DMF (0.5 mL) at 160 °C for 24 h in 10 mL screw-capped
b
vials. Isolated yields; the number in the parentheses is the isolated
yield of the recovered starting amide 1.
b
entry
catalyst
ligand
base
yields (3a/3a′)
1
Ni(OAc)2
Ni(OTf)2
Ni(cod)2
Ni(acac)2
NiF2
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
PPh3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
40/5
51/20
57/17
20/0
47/18
55/10
72/8
45/0
55/0
47/23
34/0
41/8
47/7
18/0
7/0
sensitive to the structure of the amides (3ab).22 As expected, the
disulfides react with the methyl groups in the α-position of the
amide, giving both mono- and dithiolated products, with the
monothiolated product (3a) being the most favorable. The
reactions proceed exclusively at the methyl group in a highly
regioselective manner, as in the cases of 3b, 3c, and 3d. The
reactions show a predominant preference for the C(sp3)−H
bonds of the methyl groups over the methylene and benzene
groups. This fact indicates that, for the cyclometalation step, the
five-membered ring intermediate is favored over the six- or
seven-membered ring intermediates. The reaction of cyclo-
hexane carboxamide 1e results in selective monothiolation at the
methyl group. Again, in the case of 2,2′-diphenylpropionamide
1f, the reaction occurs exclusively on the methyl group, and there
is no thiolation of the benzene C−H bonds. As for the tertiary
alkyl carboxamides bearing a benzylic group (1g−1i), only
monothiolated products (3g−3i) are obtained (56%−64%
yields).
2
3
4
5
6
NiCl2
7
NiBr2
8
NiBr2
9
NiBr2
PCy3
10
11
12
13
14
15
16
17
18
19
20
NiBr2
xantphos
NiBr2
Dppbz
NiBr2
P(2-furyl)3
BINAP
NiBr2
NiBr2
Dppe
NiBr2
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
NiBr2
Cs2CO3
NaHCO3
KHCO3
NaOAc
NaOH
12/0
60/5
14/0
31/0
0
NiBr2
NiBr2
NiBr2
NiBr2
Next, the scope of the disulfides with various substituents was
examined using different amides (Scheme 3). As expected, diaryl
disulfides show high compatibility under the optimized
thiolation conditions, and the reactions tolerate a variety of
functional groups, such as methoxy, chloro, nitro, benzyl, and
even propyl groups.
a
Reaction conditions: amide (0.2 mmol), diphenyl disulfides (0.4
mmol), catalyst (0.02 mmol), ligand (0.04 mmol), base (0.4 mmol) in
solvent (0.5 mL) at 160 °C for 24 h in 10 mL screw-capped vials.
NMR yield.
b
handled under N2. After screening the catalysts, thioarylated
product 3a was obtained in 72% NMR yield over NiBr2 (entry 7).
Further optimization showed that, with variation of the ligands,
such as bidentate phosphines and bulky 2,4,6-trimethylbenzoic
acid (MesCOOH), there is a discrepancy in the catalytic activity
(entries 7−14). The efficiency of the reaction was also
significantly affected by the choice of bases (entries 15−20).
Na2CO3 and NaHCO3 result in good yields of the thiolated
products, but other bases have poor yields. In these reactions,
DMF was the solvent of choice (see Supporting Information).
Figure 2 shows the directing groups that are not effective (giving
no desired products). The results indicate the importance of
quinoline species for bidentate direction.
Encouraged by the viability of the approach for direct C−S
bond formation, we applied the system to diaryl diselenide with
an aliphatic amide, and the desired cross-coupling compound (4)
was obtained in moderate yield (eq 1).
Having successfully achieved the synthesis of highly function-
alized thioethers, we explored their conversion to carboxylic
acids, which are the building blocks for the synthesis of the
targeted key precursors. The 8-aminoquinoline group was readily
hydrolyzed in a one-step procedure using NaOH in EtOH, as
The approach was then applied to different amides under the
optimal reaction conditions (Scheme 2). The reaction was
B
Org. Lett. XXXX, XXX, XXX−XXX