Reductive Umpolung of Carbonyl Derivatives with Visible-Light Photoredox Catalysis: Direct Access to Vicinal Diamines and Amino Alcohols via α-Amino Radicals and Ketyl Radicals

Article abstract of DOI:10.1002/anie.201511235

Visible-light-mediated photoredox-catalyzed aldimine-aniline and aldehyde-aniline couplings have been realized. The reductive single electron transfer (SET) umpolung of various carbonyl derivatives enabled the generation of intermediary ketyl and α-amino radical anions, which were utilized for the synthesis of unsymmetrically substituted 1,2-diamines and amino alcohols. Anilines can be coupled with aldimines or aldehydes in a visible-light-mediated photoredox-catalyzed process. Reductive single electron transfer (SET) umpolung of the carbonyl derivatives leads to the generation of intermediary ketyl and α-amino radical anions, which were used for the synthesis of unsymmetrically substituted 1,2-diamines and amino alcohols.

Full text of DOI:10.1002/anie.201511235

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201511235
German Edition: DOI: 10.1002/ange.201511235
Photoredox Catalysis
Reductive Umpolung of Carbonyl Derivatives with Visible-Light
Photoredox Catalysis: Direct Access to Vicinal Diamines and Amino
Alcohols via a-Amino Radicals and Ketyl Radicals
Eleonora Fava, Anthony Millet, Masaki Nakajima, Sebastian Loescher, and Magnus Rueping*
Abstract: Visible-light-mediated photoredox-catalyzed aldi-
mine–aniline and aldehyde–aniline couplings have been real-
ized. The reductive single electron transfer (SET) umpolung of
various carbonyl derivatives enabled the generation of inter-
mediary ketyl and a-amino radical anions, which were utilized
for the synthesis of unsymmetrically substituted 1,2-diamines
and amino alcohols.
a complementary approach to the well-established SET
oxidation of amines that are difficult to access by the latter
pathway.[7]
As a continuation of our work, we wondered whether
a-amino radical anions I, generated under catalytic photo-
redox conditions, would be able to undergo radical recombi-
nation with a second radical species II, which would be
generated by SET oxidation of tertiary amines. Provided that
the previously described dimerization of a-amino radical
anions I and neutral a-amino radicals II can be suppressed,
this strategy will enable the straightforward synthesis of
unsymmetric 1,2-diamines,[8] a common motif found in many
natural products with valuable biological properties that are
difficult to synthesize otherwise (Scheme 1).
I
n the field of photochemistry, significant progress has been
achieved over the past decades.[1] In particular, visible-light-
mediated photoredox catalysis, which uses its ability to induce
single electron transfer (SET) processes in organic molecules
in a similar manner to conventional radical chemistry, has
attracted increasing attention.[2] The circumvention of unsta-
ble radical initiators, simple practical implementation, and
mild reaction conditions are undoubtedly attractive features.
The strategic advantage of this concept lies in the chemical
ambivalence of the catalyst, demonstrated by its flexibility to
switch between oxidative, reductive, and energy-transfer
processes according to the reaction conditions. Different
reactive intermediates have been generated based on this
strategy and successfully employed in carbon–carbon and
carbon–heteroatom bond-forming reactions.
Recent advances in this field include the functionalization
of carbonyl derivatives by reductive SET umpolung.[3,4] Our
group recently reported the photoredox-catalyzed formation
of ketyl radical intermediates by means of a proton-coupled
electron transfer (PCET), which enabled the reductive
dimerization of aldehydes, ketones, and aldimines.[5] The
targeted use of persistent secondary a-amino radical anions
derived from imines has also been described by the groups of
MacMillan and Ooi.[6] The generation of such secondary
a-amino radical anions through SET umpolung constitutes
Scheme 1. Top: Complementary strategies for the generation of secon-
dary a-amino radicals. Bottom: Proposed photoredox catalytic cycle for
the synthesis of 1,2-diamines. PC=photocatalysis.
[*] Dr. E. Fava, Dr. A. Millet, Dr. M. Nakajima, B. Sc. S. Loescher,
Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
E-mail: Magnus.Rueping@rwth-aachen.de
On the basis of the SET umpolung concept, we herein
report a general method for the synthesis of vicinal diamines
from easily accessible starting materials. Our initial inves-
tigations focused on the reaction between aldimine 1a and
N,N-dimethyl-4-methylaniline (2a) in combination with iri-
dium polypyridyl complexes as the catalysts. Searching for
suitable reaction conditions, we identified photocatalyst 3a in
dimethylacetamide (DMA) in combination with Li2CO3 as
a crucial additive to be suitable for our transformation (see
the Supporting Information for details; see Table S4 for
solvent and additive effects).
Prof. Dr. M. Rueping
King Abdullah University of Science and Technology (KAUST)
KAUST Catalysis Center (KCC)
Thuwal, 23955-6900 (Saudi Arabia)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201511235.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited and is not used for commercial purposes.
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Scheme 2. Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Li2CO3
(20 mol%), 3a (1 mol%), degassed DMA (0.6 mL), room temperature,
irradiation with blue LEDs (11 W, 450 nm), 72 h. Yields of isolated
products are given. dtbbpy=4,4’-di-tert-butyl-2,2’-bipyridine, ppy=
2-phenylpyridine.
With the optimized reaction conditions in hand, we then
examined the substrate scope and limitations of our radical–
radical coupling reaction (Scheme 2). Regarding the N sub-
stitution of imines 1a–h, both electron-poor and electron-rich
(hetero)aromatic substrates with different substitution pat-
terns were well-tolerated. Interestingly, even the reaction of
ortho-substituted imine 1c provided the corresponding prod-
uct in nearly quantitative yield.
Next, we examined the imine scope with respect to
variation of the aldehyde-derived R substituent. In all cases,
good or excellent reactivity was observed in the presence of
both electron-withdrawing and -donating groups on the aryl
ring (Scheme 3). In particular, satisfactory reactivity was
achieved with fluorine-containing aldimines (1o–q) and
heterocyclic (1s and 1t) and polycyclic imines (1u). Remark-
ably, our method is applicable to phenyliminoacetate 1v, thus
providing access to amino acid derivative 4v.
The scope was then extended by testing various anilines
(Scheme 4), which could be coupled with our standard
substrate 1a in moderate to good yields. To our delight,
N-methyldiphenylamine (2k) was converted into the corre-
sponding product 5j in 74% yield. Reduced yields were
observed for substrates with electron-donating groups in the
para position (5a and 5c) or a bromine substituent (5h).
Intending to couple two secondary a-amino radical frag-
ments, we next turned our attention to secondary anilines. Not
surprisingly, our initial model substrate N-methylaniline
turned out to be unreactive. However, the introduction of
electrofugal groups, such as trimethylsilyl or carboxylic acid
moieties, on the methylene moiety allowed us to obtain the
desired products in satisfactory yields (Scheme 5). This
approach was first developed by the groups of Mariano[9]
Scheme 3. Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Li2CO3
(20 mol%), 3a (1 mol%), degassed DMA (0.6 mL), room temperature,
irradiation with blue LEDs (11 W, 450 nm), 72 h. Yields of isolated
products are given.
and Pandey[10] for UV-mediated photochemistry in an
attempt to suppress the formation of N-alkylation byproducts
and was later applied to visible-light photoredox catalysis by
the groups of Reiser and Nishibayashi.[11]
Encouraged by the promising results for the imine–aniline
coupling, we took this idea further and tested carbonyl
compounds as potential acceptor substrates (Scheme 6).[12]
Surprisingly, whereas cyclic and aryl ketones were found to be
generally inactive under these reaction conditions, benzalde-
hyde 7a successfully provided the desired product 8a in good
yield. To the best of our knowledge, this reaction represents
a rare example of a direct intermolecular ketyl radical
coupling in the field of photoredox chemistry.[3c] Additional
re-optimization revealed the beneficial effect of catalytic
amounts of benzoic acid, which allowed us to carry out the
amino alcohol synthesis at a catalyst loading of only 0.5 mol%
and in significantly shorter reaction times (6 h). It should be
noted that our reaction conditions are compatible with
common functional groups, such as fluorine, chlorine, ester,
ether, and acetamide moieties, as well as heterocycles.
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Scheme 4. Reaction conditions: 1a (0.3 mmol), 2 (0.9 mmol), Li2CO3
(20 mol%), 3a (1 mol%), degassed DMA (0.6 mL), room temperature,
irradiation with blue LEDs (11 W, 450 nm), 72 h. Yields of isolated
products are given.
Scheme 6. Reaction conditions: 7 (0.5 mmol), 2a (1.5 mmol),
PhCO2H (20 mol%), 3a (0.5 mol%), degassed DMA (1 mL), room
temperature, irradiation with blue LEDs (11 W, 450 nm), 6–24 h. Yields
of isolated products are given.
Acknowledgments
The research leading to these results has received funding
from the European Research Council under the European
Union’s Seventh Framework Programme (FP/2007-2013)/
ERC Grant Agreement No. 617044 (SunCatChem).
Keywords: amino alcohols · diamines · photocatalysis ·
redox chemistry · umpolung
Scheme 5. Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), Li2CO3
(20 mol%), 3a (1 mol%), degassed DMA (0.6 mL), room temperature,
irradiation with blue LEDs (11 W, 450 nm), 24 h. Yields of isolated
products are given.
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6776–6779
Angew. Chem. 2016, 128, 6888–6891
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Received: December 3, 2015
Revised: February 7, 2016
Published online: May 2, 2016
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