Angewandte Chemie International Edition
10.1002/anie.201706293
COMMUNICATION
An outline for a plausible copper-catalyzed amination mechanism
is shown in Figure 4. The reaction of CuX and amine in the presence
the success of this reaction is to generate copper amide intermediate
(18), which react with α-bromoamide (1). Although β-H elimination
of a base could give copper amide (18 where L might be PPh
3
). The
3
from α-bromoamide was problematic, the presence of PPh inhibited
resulting 18 could react with 1 to generate 3 via oxidative addition
followed by a reductive elimination process. The overall reaction
mechanism is unclear, but we conducted some control experiments
to support our postulated mechanism (Figure 5). At first, we checked
the reactivity of 1a and stoichiometric amounts of Cu salt. As the
result, the reaction gave no product and 1a was recovered
the undesired side reaction. Furthermore, the reaction of α-
bromoamide and a chiral amine nucleophile generated a chiral
quaternary carbon center at the α-position.
Acknowledgements
We warmly thank the program to YU project for formation of the
core research center (TN), the Ube foundation, Grant-in-Aid for
Challenging Exploratory Research Grant No:16K13995 (TN), and
Grant-in-Aid for Scientific Research (B) Grant No:16H04120 (YS).
completely (Figure 5I). K
reaction. The reaction of Cu salt and H
of K PO gave the corresponding copper amide (18′) in 26% yield
but 18′ was not obtained without K PO (Figure 5II). The resulting
copper amide (18′) reacted with 1a to produce 3a (39%) and β-H
elimination product 19 (37%) in the presence of K PO and PPh . In
the absence of K PO , the yields of both 3a and 19 increased. When
increasing amounts of PPh were used, 94% yield of 3a was obtained
3
PO
4
played an important role in this
2
Nt-Bu (2a) in the presence
3
4
3
4
Keywords: copper • amination • alkylation • amide
3
4
3
3
4
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6
[
3
(
Figure 5IV). Those control experiments could support our proposed
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Figure 4. Proposed mechanism.
[
[
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I) The reaction of stoichiometric copper salt with 1a
O
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CuBr(SMe )(1 equiv)
2
[
[
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NHPh
No reaction
Br
6
K3PO4 (0 or 1.2 equiv)
a (1 equiv)
1
4
II) The reaction of Copper and NH2tBu
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CuBr(SMe2) + H2NtBu + K3PO4
[Cu(NH Bu)]8
toluene
5 C, 23h
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1
equiv
50 equiv 18 equiv
o
18': 26 %
2
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III) The reaction of Cu(NHtBu) with 1a
1
O
1
a
PPh3 (X equiv)
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O
+
NHPh
+
N
H
NHPh
toluene
rt, 23 h
1
8'
3a
19
(
1 equiv)
X=0a :19%
X=1 :39%
19%
37%
0%
1
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a
With K3PO4 (1 equiv)
[
[
[
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1
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K PO (1.2 equiv)
3
4
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1
a
+
3a: 99%
NH2
toluene
rt, 23 h
2
a (3 equiv)
Figure 5. Control experiments [a]
[
a]
1
All yields were determined by H NMR analysis.
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In conclusion, we have established the synthesis of sterically
congested α-amino acid derivatives at room temperature. The key to
[
C. Fu, Angew. Chem., Int. Ed. 2013, 52, 5129-5133.
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