Visible-light photoredox catalyzed oxidative Strecker reaction

Article abstract of DOI:10.1039/c1cc15643h

An aerobic photocatalytic oxidative cyanation of tertiary amines providing valuable α-aminonitriles in good to excellent yields was developed. Mild reaction conditions and low catalyst loading are attractive features of the protocol. The Royal Society of

Full text of DOI:10.1039/c1cc15643h

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Visible-light photoredox catalyzed oxidative Strecker reactionw
´
Magnus Rueping,* Shaoqun Zhu and Rene M. Koenigs
Received 12th September 2011, Accepted 11th October 2011
DOI: 10.1039/c1cc15643h
An aerobic photocatalytic oxidative cyanation of tertiary amines
providing valuable a-aminonitriles in good to excellent yields
was developed. Mild reaction conditions and low catalyst loading
are attractive features of the protocol.
valuable a-aminonitriles using readily available KCN as cheap
CNꢀ source.
We initiated our studies on the cyanation reaction by
examining the photochemical oxidation of N-phenyl tetra-
hydroisoquinoline 1a in the presence of KCN and acetic acid.
To our delight, we could isolate the desired a-aminonitrile in very
high yield (90%) using only 1 mol% of the [Ir(ppy)2bpy]PF6
(ppy = 2-phenyl-pyridine, bpy = 2,20-bipyridine) photocatalyst
(Table 1, entry 1). Acetic acid proved to be crucial in this
transformation. This can be attributed to the liberation of
HCN in the presence of AcOH, as otherwise only little CNꢀ is
present in solution. Thus, AcOH acts as a co-catalyst in this
process.10
a-Aminonitriles are an important class of versatile intermediates
for a wide range of natural products and pharmaceuticals
since the nitrile function can be readily hydrolyzed to produce
a-amino acids.1 Nucleophilic additions to a-aminonitriles
provide access to valuable a-amino aldehydes, ketones and
b-amino alcohols. Alternatively, nitriles can be easily hydro-
genated to yield useful 1,2-diamines. Therefore, it is not
surprising that great efforts have been devoted to the development
of new methods for the construction of a-aminonitriles.
Among the different approaches available for the preparation
of these structural motives, the catalytic oxidative cyanation of
sp3 C–H bonds adjacent to nitrogen atoms represents one of
the most straightforward and convenient methods for the
synthesis of a-aminonitriles.2–5 Previous efforts showed that
treatment of tertiary amines with different metal catalysts in
the presence of stoichiometric amounts of oxidants allows the
generation of highly reactive iminium ion intermediates that
can be intercepted with HCN to yield the corresponding
a-cyanation products.2,3 In a similar manner, non-catalytic
metal-free methods using stoichiometric amounts of tropylium
ions4a or hypervalent iodine4b or electrochemical methods5 can
be applied for the oxidative cyanation reaction.
To validate this hypothesis, the reaction was carried out
without acid, yet only trace amounts of the desired reaction
product were observed (Table 1, entry 2). TMSCN and
CH2(CN)2 were also reported as efficient sources of CNꢀ in
metal catalyzed oxidative cyanation reaction.12 To our great
delight, the corresponding cyanation product was also
obtained with good yield using TMSCN or CH2(CN)2
(Table 1, entries 3 and 4, 83% and 65% respectively), which
can be attributed to the liberation of HCN from TMSCN or
CH2(CN)2 in the presence of water.
As solvent has a great influence on aerobic photochemical
cross dehydrogenative coupling reactions, different solvents
were investigated (Table 1, entries 1, 5–9). Whereas, apolar
Table 1 Influence of CNꢀ source and solvent
The use of visible light in synthetic organic chemistry has
recently attracted significant interest as visible light is a
ubiquitous, renewable and clean source of energy.6–9 Among
the different photosensitizers that have been applied in the
development of new synthetic methods under irradiation with
visible light, inorganic ruthenium and iridium based poly-
pyridyl complexes play a pivotal role, as they possess well-
known photochemical properties and can readily be tuned by
the choice of the right ligands.6 Based on the work on
photochemical oxidation of tertiary amines,8,9 we decided to
investigate an aerobic photochemical oxidative cyanation
reaction that would allow an operationally simple access to
Entrya CNꢀ source Additive Solvent
Timeb/h Yieldc (%)
1
2
3
4
5
6
7
8
9
KCN
KCN
TMSCN
CH2(CN)2
KCN
KCN
KCN
KCN
KCN
AcOH
—
—
MeCN
MeCN
MeCN
MeCN
THF
MeOH
DMF
Toluene 32
AcOH 24
20
32
18
36
16
28
16
94
Trace
83
65
90
86
—
AcOH
AcOH
AcOH
AcOH
AcOH
90
72
68
a
Reaction conditions: 0.1 mmol 1a, 1 mol% 3a, 1 mL solvent, CNꢀ
source (1.2 equiv.) and additive (5.0 equiv. or none), 5 W fluorescent
RWTH Aachen University, Institute of Organic Chemistry,
Landoltweg 1, D-52074 Aachen, Germany.
E-mail: magnus.rueping@rwth-aachen.de; Fax: +49 241 8092665
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc15643h
b
bulb. Refers to the time until all starting material is consumed.
c
Yield of the isolated product.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12709–12711 12709

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Table 2 Scope of the photoredox catalyzed oxidative cyanation
reaction
Table 3 Evaluation of different N,N-dialkylaniline derivatives in the
oxidative cyanation
Entrya
R1
2
Timeb/h
Yieldc (%)
Entrya
5
Ar
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
Phenyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
20
12
12
12
32
48
48
36
72
72
48
12
97
97
77
84
76
82
79
86
76
81
88
51
1
2
5a
5b
5c
5d
5e
Phenyl
H
H
Me
Pr
Ph
H
H
Me
Pr
Me
82
70
74
78
84
4-Me-phenyl
4-Et-phenyl
4-MeO-phenyl
4-F-phenyl
4-Br-phenyl
4-Biphenyl
3-MeO-phenyl
2-Me-phenyl
2,4-Me2-phenyl
2-Naphthyl
Allyl
3-Me-phenyl
Phenyl
Phenyl
3b
4b
5b
Phenyl
a
Reaction conditions: 0.1 mmol 4a–e, 1 mol% 3b, 1 mL MeCN,
1.2 equiv. of KCN, 5 equiv. of AcOH, 5 W fluorescent bulb, 12–96 h.
b
9
Reaction performed under an oxygen atmosphere; yield determined
1
by H NMR.
10
11
12
2j
2k
2l
From a mechanistic point of view, the formation of the
amine cation radical intermediate, the iminium ion intermediate
and the reoxidation of the photoredox catalyst by molecular
oxygen are well-known.9 Yet, in the recent literature on the
photoredox catalyzed oxidative functionalization of tertiary
amines, the mechanism of the formation of the iminium ion
intermediate C (Scheme 1) was often assumed to take place by
hydrogen atom (Hꢁ) abstraction from the amine cation radical
a
Reaction conditions: 0.1 mmol 1a–l, 1 mol% photocatalyst 3b, 1 mL
MeCN, 1.2 equiv. of KCN, 5.0 equiv. of AcOH, 5 W fluorescent bulb.
b
c
Refers to the time until all starting material is consumed. Yield of
the isolated product.
and protic solvents gave poor results and required prolonged
reaction time (Table 1, entries 6, 8 and 9), polar and aprotic
solvents (THF, DMF and MeCN; Table 1, entries 1, 5 and 7)
gave excellent yields, of which MeCN proved to be the best (94%).
To further improve this oxidative cyanation reaction, we
tested a series of Ir(III) and Ru(II) photoredox catalysts. In
general, all iridium and ruthenium based photocatalysts gave
the desired a-aminonitrile in good to excellent yields.11 In view
of both best reaction yield and shortest reaction time, catalyst
3b ([Ir(tbp-py)2(bpy)]PF6; tbp-py = 2-(4-tBu-phenyl)-pyridine)
was selected to further investigate the substrate scope of this
oxidative cyanation reaction. Initially, a variety of different N-aryl
tetrahydroisoquinolines were subjected to the optimal reaction
conditions (Table 2).
A by the superoxide anion (O2 ꢀ) that is formed upon
ꢁ
reoxidation of the photoredox catalyst.
In contrast to the recent literature we now suggest that the
iminium ion is generated on a different, ionic pathway. From a
mechanistic perspective, two different pathways which differ in
the order of deprotonation and single electron transfer are
possible (Scheme 1). On the one hand, the amine radical A can
undergo a [1,2]-hydrogen shift, furnishing the carbon centred
radical B, which can now be easily deprotonated by a base
(tertiary amine or superoxide anion radical O2 ꢀ), yielding the
ꢁ
desired iminium ion C after electron transfer to Ir(III), Ir(III)*
or HOOꢁ. On the other hand, the deprotonation may initially
take place, providing carbon centred neutral radical D, which
can then undergo electron transfer to give the iminium ion C.
Conclusively, both discussed pathways provide a mechanistic
rationale for the generation of the desired iminium ion inter-
mediate, while the hydrogen atom (Hꢁ) abstraction by the
superoxide anion is probably not taking place.
In general, the corresponding cyanation products 2a–l were
obtained in good to excellent yields. Substrates bearing electron-
withdrawing substituents and meta- and ortho-substituted N-aryl
groups could be subjected to this oxidative cyanation reaction
only under prolonged reaction times. To our delight, the N-allyl
substituted tetrahydroisoquinoline could also be efficiently
applied under the present reaction conditions.
In summary, we have developed the first efficient aerobic,
photocatalytic oxidative cyanation of tertiary amines employing
cheap and readily available KCN as CNꢀ source that yields
valuable a-aminonitriles under mild reaction conditions and
To further investigate the substrate scope, we decided to
subject different acyclic tertiary amines 4a–e to the photoredox-
catalyzed oxidative cyanation reaction. The oxidation of aniline
derivatives using metal based photoredox catalysts is scarce
and only few examples have been realized to date. However,
under the present reaction conditions different dialkyl anilines
could be efficiently subjected to the photochemical oxidation
reaction, yielding the valuable a-aminonitriles 5a–e in high
yields (Table 3).
We could show that the photochemical oxidation is not only
applicable to cyclic benzylic amines, but also linear aliphatic
tertiary amines can be readily oxidized to the reactive iminium
ion. In the presence of both a benzyl- and an ethyl-group, we
could observe the selective oxidation of the benzyl group and
the corresponding amino nitrile 5e was obtained in 84% yield.
Scheme 1 Mechanism of iminium ion formation.
c
12710 Chem. Commun., 2011, 47, 12709–12711
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with low catalyst loadings.12 In addition, we could present that
photoredox catalyzed oxidation reactions can be applied for
the functionalization of acyclic aniline derivatives. Further-
more, an alternative pathway for the generation of the iminium
ion intermediate was proposed. The generation of the carbon
centred neutral radical intermediate suggested thereby can be
further explored to design radical-type processes.
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8 Selected articles on photochemical oxidations of tertiary amines
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H. W. Sprintschnik, H. Abruna, T. J. Meyer and D. G. Whitten,
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10 For examples of Brønsted acid catalyzed Strecker reactions from
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Chem., Int. Ed., 2006, 45, 2617–2619; (b) M. Rueping, E. Sugiono
and S. A. Moreth, Adv. Synth. Catal., 2007, 349, 759–764; For the
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S.-Q. Zhu gratefully acknowledges the CSC (Chinese Scholarship
Council) for a fellowship.
Notes and references
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6 Selected recent review articles on photoredox catalysis:
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(b) P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 1360–1363;
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11 See ESIw.
12 During the preparation of this manuscript an initial study (4 examples)
on the photocatalytic cyanation of tetrahydroisoquinolines with
malononitrile as cyanide source has appeared: D. P. Hari and
B. Konig, Org. Lett., 2011, 13, 3852–3855.
7 Selected articles on the use of visible-light photoredox catalysis for
organic transformation: (a) M. A. Ischay, M. E. Anzovino,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12709–12711 12711