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COMMUNICATION
Journal Name
4
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may be generated via reversible protonation by t-BuOK and t-
BuOD. These conclusions were further supported by the model
reaction with 0.2 equivalent of added t-BuOD, which gave the
alkylation product 3a contained deuterium at both α- and β-
positions (Scheme 6c).
(72% D)
H/D
(a)
(>99% D)
S
Ni(OAc)2 (2 mol%)
(15% D)
D/H
D
D
S
S
Et
P(t-Bu)3 (4 mol%)
N
Et
Et
+
+
+
+
56%
+
OH
N
N
t-BuOK (1.0 equiv)
H/D Et
(5% D)
Et
Et
1,4-dioxane, 80 °C, 12 h
1a-D2
(1.0 equiv)
2a
2a
2a
(2.0 equiv)
2a
3a-D
,
0.8 equiv recovered
63% yield
3a
3a-D1 3a-D2
10%,
34%,
(71% D)
H/D
5
(b)
(>99% D)
(93% D)
S
Ni(OAc)2 (2 mol%)
D
D
S
D
D
Et
P(t-Bu)3 (4 mol%)
N
Et
N
OH
OH
t-BuOK (1.0 equiv)
H/D Et
(5% D)
Et
1,4-dioxane, 80 °C, 12 h
1a-D2
(2.0 equiv)
(1.0 equiv)
3a-D
,
67% yield
3a-D1 3a-D2
56%
1a-D
0.4 equiv recovered
3a
11%,
33%,
(10% D)
H/D
(c)
S
Ni(OAc)2 (2 mol%)
S
Et
P(t-Bu)3 (4 mol%)
N
Et
N
OH
t-BuOK (1.0 equiv)
t-BuOD (0.2 equiv)
H/D Et
(17% D)
Et
6
7
1,4-dioxane, 80 °C, 12 h
1a
(1.0 equiv)
(1.5 equiv)
3a-D
, 75% yield
Scheme 6. The deuterium labeling experiments
8
(a) Hans Reich's Collection. Bordwell pKa Table
In summary, we have developed a nickel-catalyzed α-
alkylation of thioamides, unactivated acetamides and t-butyl
esters with primary alcohols. Notably, this method enables C-
selective monoalkylation of both primary acetamides and
tertiary thioacetamide with alcohols for the first time. The
simple Ni(OAc)2/P(t-Bu)3 is also applicable to other amides and
t-butyl esters.
PY and BT thank the National Natural Science Foundation of
China (21602126, 91753111, 21675103, and 21804081), the
Key Research and Development Program of Shandong
Province (2018YFJH0502), the Higher Educational Science and
Technology Program of Shandong Province (J18KA077) for
financial support. JSZ acknowledges financial supports from
Peking University Shenzhen Graduate School and Shenzhen
Bay Laboratory Institute of Chemical Biology.
9
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Conflicts of interest
There are no conflicts to declare.
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17 Example of N-alkylation of amide (high temperature is
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Notes and references
1
F. A. Carey and R. J. Sundberg, in Advanced Organic
Chemistry Part B: Reactions and Synthesis, Springer, New
York, USA, 5th ed., 2007, pp. 1-62.
2
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3
For selective reviews on C−C bond formation via hydrogen
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4 | J. Name., 2012, 00, 1-3
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