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10.1002/anie.201713031
Angewandte Chemie International Edition
COMMUNICATION
A Catalyst-Free Flow Amination of Functional Organolithium
Reagents
Heejin Kim, Yuya Yonekura, Jun-ichi Yoshida*
Abstract: We report an electrophilic amination of functional
organolithium intermediates with well-designed aminating reagents
under mild conditions using flow microreactors. The aminating
reagents were explored and optimized to achieve an efficient C–N
bond formation without using any catalyst. The electrophilic amination
reactions of functionalized aryllithiums were successfully conducted
under mild conditions within 1 min using flow microreactors. The
aminating reagent was also prepared by the flow method. Based on
stopped-flow NMR analysis, the reaction time for the preparation of
the aminating reagent was quickly optimized without any necessity of
work-up. Integrated one-flow synthesis consisting of generation of an
aryllithium, the preparation of an aminating reagent, and their reaction
was successfully achieved to give desired amine product within 5 min
of total reaction time.
described in the concept of flash chemistry,[19] the controllability
of rapid reactions is one of the most unique and powerful
advantages of flow chemistry.[20] Using flow microreactors, the
reaction time can be precisely adjusted to milliseconds or less, so
that reactions can proceed or stop in accordance with synthetic
purpose.[21]
Herein, we report a design, preparation, and synthetic use of
aminating reagents for a flow amination of functionalized
organolithiums under mild conditions (Scheme 1). Various in-situ
generated organolithiums could be reacted with optimized
aminating reagents in flow for C–N bond formation without using
any catalyst. In particular, the amination of unstable
organolithiums was achieved under mild conditions in a short time
by using flow microreactors.
A synthetic methodology for the formation of carbon–nitrogen
bond has become an important subject of considerable attentions
in organic synthesis.[1] With an advancement of transition-metal-
catalyzed coupling reactions, Ullman–Goldberg amination,[2]
Buchwald–Hartwig amination,[3] and Chan–Lam coupling
reactions[4] have been developed as highly reliable means of
carrying out the C–N bond formation as a nucleophilic amination.
Recently, C–H amination reactions based on electrochemical[5]
and photoredox methods[6] have also been reported.
Electrophilic amination of carbanions (typically, organometallic
compounds)[7] serves as an alternative tool, which is based on the
umpolung strategy.[8] Many electrophilic aminating reagents have
been developed for the electrophilic amination of organometallic
compounds such as organo-magnesiums,[9] organozincs,[10]
organocoppers,[11] and organoaluminums.[12] These compounds,
however, are often prepared by the metal exchange from
corresponding organolithiums. Therefore, the direct use of
organolithiums would serve as more efficient synthetic way from
a viewpoint of atom[13] and step economy.[14] Though the direct
amination of organolithiums[15,16] has also been studied from the
beginning of organolithium chemistry, it still remains an ongoing
challenge. The direct amination of organolithiums has suffered
from low yields, formations of by-products, and limited scopes,
due to an instability and low selectivity of organolithiums.[7a,7d]
The field of flow chemistry which is often based on
microfluidics has rapidly been growing up in last two decades.[17]
To keep up with recent demands on safe and environmentally
benign chemical methods,[18] continuous flow technology has
come into the spotlight with its high potential as well as previously
reported numerous merits on chemical synthesis. As well
Scheme 1. Concept of this work: electrophilic amination of functionalized
organolithiums using flow microreactors
We began our investigation by carrying out the reaction of
phenyllithium with a common electrophilic aminating reagent, O-
benzoyl-N,N-diethylhydroxylamine (1a)[7] in a flask (Table 1, entry
1). At −78 °C, PhLi was reacted with 1a for 20 min. The desired
N,N-diethylaniline (2a) was not obtained at all, but major products
were benzophenone (68%) and triphenylmethanol (20%), due to
unwanted nucleophilic attacks to a carbonyl moiety of the
aminating reagent. Thus, our interests in the amination of
organolithiums was piqued by the direct nucleophilic attack of the
potential leaving group on the nitrogen atom. We prepared
various candidate reagents bearing sterically hindered leaving
groups (entries 2–6).
Table 1. Electrophilic amination of PhLi with various amine reagents in a
flask.
[*]
Dr. H. Kim, Y. Yonekura, Prof. Dr. J. -i. Yoshida
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Entry
Aminating reagent
Yield [%][a]
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.
Kim, Heejin
