Organic Letters
Letter
a
2
Table 1. Optimization Studies
Scheme 2. Palladium-Catalyzed C(sp )−H Silylation of
a
Benzylamines
entry
1
oxidant
base
solvent
yield of 2a (%)
none
K CO
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DCE
2
10
9
3
b
2
AgCO3
AgO
K CO
2
3
3
3
3
3
3
3
3
3
3
4
K CO
2
AgOAc
K S O
K CO
2
84
3
b
5
K CO
2
2
2
8
6
7
8
9
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
K CO
2
39
83
4
K CO
2
toluene
K CO
2
DMF
K CO
2
NMP
0
10
11
12
13
14
15
16
K CO
2
tert-amyl-OH
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
0
none
80
72
77
79
67
0
Na CO
2
3
KHCO3
K HPO
2
4
K PO
3
4
c
K CO
2
3
a
Reaction conditions: 1a (0.1 mmol), Si Me (0.3 mmol), Pd(OAc)
2
2
6
(
1
5 mmol %), oxidant (0.3 mmol), base (0.2 mmol), solvent (1.5 mL),
30 °C, 18 h. Oxidant (0.2 mmol). No palladium catalyst. Yield was
b c
based on GC using tridecane as the internal standard.
Extensive screening of oxidants, bases, and solvents showed that
the use of AgOAc as oxidant, K CO as base, and 1,4-dioxane as
2
3
a
solvent provided 2a in 84% yield (Table 1, entry 4). Poor yields
were obtained with other oxidants (entries 2, 3, and 5). The
solvent effect showed that 1,4-dioxane was the optimal solvent.
Protic and aprotic polar solvents such as tert-amyl-OH, DMF,
and NMP inhibited the reaction. The solvent toluene gave a
slightly decreased yield of silylated product, whereas use of DCE
as solvent drastically decreased the yield (entries 6−10). It is
noteworthy that silylation in toluene gave a yield similar to that
obtained with 1,4-dioxane (entry 7). Further optimization
showed that K CO increased the yield of the product. Without
Reaction conditions: 1 (0.2 mmol), Si Me (0.6 mmol), Pd(OAc) (5
2 6 2
mol %), AgOAc (0.6 mmol), K CO (0.4 mmol), 1,4-dioxane (3 mL),
1
mL). Toluene (3 mL).
2
3
b
c
30 °C, 24 h, isolated yields. Pd(OAc) (10 mol %). Toluene (1
2
d
Reaction of the substrates 1-naphthalenemethylamine and 2-
thiophenemethylamine also proceeded well, providing silylation
products (2q,r) in moderate to good yield. Notably, the
challenging 2s was also obtained in moderate yield with the
same reaction conditions. Other silylation reagents such as
phenyldimethylsilane gave silylation products in moderate yield
(2t).
More importantly, germanylation of benzylamine derivatives
also proceeded well under the optimized reaction conditions
(Scheme 3), giving the germanylated product substituted (3a−
d) at the γ-position of the benzylamines in moderate to good
yield.
To gain a deep understanding of C−H silylation assisted by
the oxalyl amide directing group, we treated oxalyl amide
protected phenylethylamine 4 with hexamethyldisilane under the
standard reaction conditions. Unexpectedly, products silylated at
the δ-position of phenylethylamine and monosilylation products
were obtained in moderate yield (Scheme 4). Substituents such
as methoxyl, 3,4-dimethoxyl, nitro, F, and Br were tolerated (5d−
h). In addition, reaction of the α-methyl substituent of the
substrate phenyethylamine (5b) proceeded well to give the
silylated product in moderate yield. Further exploration showed
that heterocycloamines such as thiophene-2-ethylamine (5i) also
gave the corresponding product silylated at the δ-position of the
amine.
2
3
base or upon replacement of K CO with other inorganic base,
2
3
the yield of silylated products decreased (entries 11−15).
Control experiments confirmed that no reaction happened
without use of palladium catalyst, implicating the crucial role of
Pd(OAc) for the transformation (Table 1, entry 16).
2
We surveyed the substrate scope of the silylation reaction by
using a variety of benzylamines and disilanes under the optimized
reaction conditions. As shown in Scheme 2, all of the reactions
proceeded well and gave the corresponding silylation products in
moderate to good yields and with excellent γ-regioselectivity and
selectivity for monosilylated products. Functional groups such as
Me, MeO, F, Cl, Br, and CF were tolerated. Substituents bearing
3
electron-donating groups and electron-withdrawing groups at
the ortho position gave silylation products in high yields (2a,b,h−
k). In addition, different substituents at the ortho, meta, or para
positions of the benzylamines were tolerated. Generally, the
ortho-substituted benzylamines gave a higher silylation yield than
did meta- or para-substituted substrates. The silylation product of
Br-substituted benzylamine under standard conditions at 58%
yield and disilylation product at 27% yield (2j,j′) were obtained.
The α-substituted benzylamine derivatives (2n−p) also gave the
corresponding silylation products in moderate to high yield.
2
On the basis of the Pd-catalyzed C(sp )−H silylation, we
3
turned our attention to the more challenging C(sp )−H bond.
B
Org. Lett. XXXX, XXX, XXX−XXX