ARTICLES
Received 11 June 2017; accepted 6 September 2017;
published online 6 November 2017
a
H
N
PhLi (4.5 equiv.)
Ether, –78 °C to r.t., 2 h
H
N
H
N
H
N
References
( )-8, trace
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7
H
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PhLi (7.5 equiv.)
OH
Ph
H
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+
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3 equiv.
Ether, –78 °C to r.t., 2 h
( )-8, trace
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7
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b
(i) n-BuLi (1 equiv.), –78 °C, 10 min
(ii) PhLi (1.5 equiv.), –78 °C to r.t., 2 h
O
+
N
H
H
H
N
H
Ph
Ph
Ether (solvent)
1.2 equiv.
( )-8, 54%
PhLi (2.5 equiv.)
N
O
+
N
H
Ph
Ph
Ether, –78 °C to r.t., 2 h
H
1.2 equiv.
( )-8, 58%
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O
+
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Ph
Ether, –78 °C to r.t., 2 h
N
H
N
H
n-Bu
1.2 equiv.
H
( )-35, 32%
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Figure 2 | Control studies and simplification of the set-up conditions.
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employing phenyl lithium as the base in the first step. Simply adding
an excess of phenyl lithium to a mixture of pyrrolidine and benzo-
phenone led to the formation of 8 in a nearly identical yield to that
observed before. This experiment establishes, rather unexpectedly,
that the rates of both pyrrolidine deprotonation and hydride trans-
fer vastly exceed the rate of the potentially competing addition of
phenyl lithium to benzophenone, a known process38. We also eval-
uated this simplified reaction set-up in the α-n-butylation of azacy-
clotridecane. Although the yield of 35 was substantially lower than
that in the stepwise process (32 versus 64%), this result is quite
remarkable as it indicates that the reduction of benzophenone by
the intermediate lithium amide can compete with the known
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In conclusion, we have developed an operationally convenient
method for the α-C–H bond functionalization of cyclic N–H
amines. This approach complements existing methodology, is pro-
tecting-group free and is uniquely effective in the stereospecific
functionalization of cyclic amines with pre-existing substituents.
In contrast to the vast majority of current approaches for amine
C–H functionalization, no transition metals are required in
this process.
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Data availability. Crystallographic data for the structure reported in
this Article have been deposited at the Cambridge Crystallographic
Data Centre, under deposition number CCDC 1535260 (( )-45).
Copies of the data can be obtained free of charge via www.ccdc.
of this study, including experimental procedures and compound
characterization, are available within the Article and its
Supplementary Information, or from the corresponding author
upon reasonable request.
27. Payne, P. R., Garcia, P., Eisenberger, P., Yim, J. C. H. & Schafer, L. L. Tantalum
catalyzed hydroaminoalkylation for the synthesis of α- and β-substituted
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4
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