3
2.
3.
(a) Seebach, D.; Beck, A. K.; Bossler, H. G.; Gerber, C.; Ko, S.
Table 3. Ir-Catalyzed -Alkylation of Various Tertiary and
Secondary Acetamides with 2aa
Y.; Murtiashaw, C. W.; Naef, R.; Shoda, S.-I.; Thaler, A.; Krieger,
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O
O
0.5 mol % 1b
1.2 equiv KOtBu
R
R
+ H2O
N
Ph
N
Ph
2a
OH
+
PhMe
80 oC, 12 h
R'
R'
For reviews, see: (a) Fujita, K.-i.; Yamaguchi, R. Synlett 2005, 4,
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3, 2 equiv
5
O
O
N
O
Ph
Ph
Ph
N
Ph
Ph
N
O
5b, 84%
5c, 89%
5d, 92%
O
O
H
O
H
H
H
N
Ph
N
Ph
N
Et
tBu
5e, 76%
5f, 78%
5g, 75%
O
O
O
N
H
H
N
Ph
N
Ph
5h, 82%
5i, 72%
5j, 79%
OMe
a Reaction conditions: 1b (0.5 mol %), 2 (1 mmol), 3a (2 mmol), and KOtBu
(1.2 mmol) in 1.0 mL of PhMe at 80 oC for 12 h. Yields shown are of isolated
products.
4.
For examples, see: (a) Gunanathan, C.; Milstein, D. Angew. Chem.
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The studies of the scope of amides revealed that the method
was not limited to reactions of N, N-dimethylacetamide 3a. As
shown in Table 3, a wide range of tertiary and secondary
acetamides underwent alkylation with primary alcohols using 0.5
mol % of Ir at 80 oC. The tertiary amides, such as N, N-
diethylacetamide, N-acetylpiperidine, and 4-acetylmorpholine,
were alkylated with benzyl alcohol 2a to form the corresponding
products in 84-92% yields. Furthermore, the reactions of N-alkyl-
or N-aryl-substituted secondary acetamides afforded the -
alkylation products in 72-82% yields (5e-5j). It is noteworthy
that the classic -alkylations of secondary amides using alkyl
halides in the presence of a superbase often result in the
formation of undesired N-alkylation.1 In contrast, this Ir-
catalyzed method is highly selective for C-alkylation relative to
N-alkylation. However, the catalyst system is not effective for
alkylation of unactivated amides that bearing substituents at -
5.
positions.
For
example,
the
reaction
of
N,N-
dimethylpropionamide with benzyl alcohol under the standard
catalytic conditions did not give the alkylation product.
In summary, we have disclosed that the NCP-Ir pincer catalyst
is highly active for -alkylation of unactivated secondary and
tertiary acetamides with low-toxic alcohols as the alkylating
agents. Featuring low catalyst loadings, relatively mild reaction
conditions, high conversion and selectivity, and wide functional
group tolerance, the Ir-catalyzed -alkylation of amides is an
attractive process for construction of C–C bonds.
6.
Acknowledgments
We acknowledge the financial support from the National
Natural Science Foundation of China (No. 21422209, 21432011,
and 21421091), the Science and Technology Commission of
Shanghai Municipality (13JC1406900), and the CAS/SAFEA
International Partnership Program for Creative Research Teams.
References and notes
1.
Challis, B. C.; Challis, J. In The Chemistry of Amides; Zabicky, J.,
7.
Ed.; John Wiley & Sons: London, 1970; pp 731-857.