Angewandte
Chemie
DOI: 10.1002/anie.201307778
Photooxidative Cyanation
Continuous-Flow Oxidative Cyanation of Primary and Secondary
Amines Using Singlet Oxygen**
Dmitry B. Ushakov, Kerry Gilmore, Daniel Kopetzki, D. Tyler McQuade, and
Peter H. Seeberger*
Abstract: Primary and secondary amines can be rapidly and
quantitatively oxidized to the corresponding imines by singlet
oxygen. This reactive form of oxygen was produced using
a variable-temperature continuous-flow LED-photoreactor
with a catalytic amount of tetraphenylporphyrin as the
sensitizer. a-Aminonitriles were obtained in good to excellent
yields when trimethylsilyl cyanide served as an in situ imine
trap. At 258C, primary amines were found to undergo oxidative
coupling prior to cyanide addition and yielded secondary
a-aminonitriles. Primary a-aminonitriles were synthesized
from the corresponding primary amines for the first time, by
an oxidative Strecker reaction at –50 8C. This atom-economic
and protecting-group-free pathway provides a route to racemic
amino acids, which was exemplified by the synthesis of tert-
leucine hydrochloride from neopentylamine.
et al. have reported the efficient oxidation of secondary
benzylamines to the corresponding imines by singlet oxygen
in a batch reactor in 8–14 h (Scheme 1a), which was followed
Scheme 1. Previous work by Che et al.:[10,11] a) 1O2 oxidation of benzylic
amines to imines and subsequent trapping in an Ugi-type reaction;
b) oxidative cyanation of tetrahydroisoquinoline derivatives.
I
mines are versatile and valuable building blocks for organic
synthesis, particularly because of the prevalence of nitrogen-
containing biologically active compounds.[1] Whereas they are
classically prepared by the condensation of carbonyl com-
pounds and amines, the selective oxidation of amines to
imines provides a more elegant pathway. Direct oxidation is,
however, generally limited to the use of benzylamines,
expensive stoichiometric oxidants,[2] biocatalysts,[3] or com-
plex metal catalysts.[4–6] Singlet oxygen is an attractive oxidant
because it is inexpensive and a highly atom-economic
reagent,[7,8] although it is difficult to generate and handle,
resulting in its rare use for the formation of imines.[9] Che
by stepwise Ugi-type reactions.[10] An organogold(III) com-
plex[11] with a long-lived and highly emissive triplet excited
state is also suitable for the activation of singlet oxygen.
Oxidative cyanation of tetrahydroisoquinolines with this
catalyst and using sunlight to generate singlet oxygen resulted
in a-aminonitriles in high yields and shorter reaction times
(1.5 h; Scheme 1b).
We have recently developed a variable-temperature flow
1
photoreactor for the efficient generation of O2,[7] which was
later improved to operate more efficiently using a low-energy
LED lamp (420 nm)[12] and tetraphenylporphyrin (TPP) as
the photosensitizer.[13] This set-up was key to the continuous
synthesis of the anti-malarial drug artemisinin.[13] Herein, we
report the utilization of our photooxidation module for the
highly efficient and rapid continuous aerobic oxidative
cyanation of amines, a process that is not limited to the use
[*] Dr. D. B. Ushakov, Dr. K. Gilmore, Dr. D. Kopetzki,
Prof. Dr. P. H. Seeberger
Department fꢀr Biomolekulare Systeme
Max-Planck-Institut fꢀr Kolloid- und Grenzflꢁchenforschung
Am Mꢀhlenberg 1, 14476 Potsdam (Germany)
E-mail: peter.seeberger@mpikg.mpg.de
À
of activated benzylic C H bonds and allows for the oxidative
Prof. Dr. P. H. Seeberger
Institut fꢀr Chemie und Biochemie
Freie Universitꢁt Berlin
cyanation of primary amines without oxidative coupling for
the first time.
Arnimallee 22, 14195 Berlin (Germany)
Initially, we focused on the oxidation step in the flow
system. A 0.5m solution of dibenzylamine (1) and TPP
(0.1 mol%) in dichloromethane (0.5 mLminÀ1) was mixed
with oxygen gas (5 mLminÀ1) with the help of a T-mixer, prior
Prof. Dr. D. T. McQuade
Department of Chemistry and Biochemistry
Florida State University
Tallahassee, FL 32306 (USA)
to entering
a continuous-flow photooxidation module
[**] We gratefully acknowledge financial support from the Max Planck
Society. We thank Thomas Kolrep and Fabian Klautzsch for
assistance in preparing high-resolution mass spectra. We also thank
Matthew Plutschack for fruitful discussions and David Ausserhoff
for a picture used in the graphical abstract.
(3.5 mL; Figure 1). Subsequent evaporation of the solvent
revealed clean and quantitative conversion into N-benzyli-
dene-1-phenylmethanamine (5). By-products, such as nitriles,
nitrones, amides, or carbonyl compounds, that usually accom-
pany the oxidative synthesis of imines were not observed.
Whereas the use of a medium-pressure mercury lamp gave
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 557 –561
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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