Dual catalysis: Combination of photocatalytic aerobic oxidation and metal catalyzed alkynylation reactions-C-C bond formation using visible light

Article abstract of DOI:10.1002/chem.201200050

Shedding new light on the right combination of catalysts: A new dual catalytic system for efficient C-H functionalization was developed. The appropriate choice of two metal catalysts allows the oxidative alkynylation of tertiary amines under mild and sust

Full text of DOI:10.1002/chem.201200050

DOI: 10.1002/chem.201200050
Dual Catalysis: Combination of Photocatalytic Aerobic Oxidation and Metal
À
Catalyzed Alkynylation Reactions—C C Bond Formation Using Visible
Light
Magnus Rueping,* Renꢀ M. Koenigs, Konstantin Poscharny, David C. Fabry,
Daniele Leonori, and Carlos Vila[a]
Dedicated to Professor Dr. Dr. h.c. Lutz F. Tietze on the occasion of his 70th birthday
À
The direct formation of new C C bonds from unreactive
open up the way to many new methods that rely on a dual
catalytic photo- and metal-catalyzed transformations.
Herein we report on the first combination of light-induced
À
C H bonds is one of the major challenges in modern syn-
thetic organic chemistry. To date several examples have
been realized, yet, they are typically limited to the activa-
À
aerobic oxidation reactions and a metal-catalyzed C C
2
3
À
tion of sp carbon atoms. In general, the activation of sp C
H bonds is more challenging, as the reactions are typically
conducted by employing significant amounts of precious
bond forming reaction (Scheme 1).
metals or under harsh reaction conditions. For this reason,
3
À
only a few examples of the activation of unreactive sp C H
bonds have been realized. The oxidation of tertiary amines
is an elegant alternative to overcome the intrinsically low re-
Scheme 1. Dual metal catalysis—combining photoredox catalysis and
3
À
À
metal-catalyzed C C bond formation.
activity of sp C H bonds. Following this approach highly
reactive intermediate iminium ions can be generated that
can be intercepted by nucleophiles to yield the desired cou-
pling products.[1] In such a way, oxidative cross couplings
were realized with different metal catalysts in the past few
years. Yet, they mainly rely on the use of stoichiometric
amounts of oxidant and/or on elevated temperature for an
efficient oxidation of the tertiary amine. Recently, visible-
light photoredox catalysis[2–6] has emerged as a highly prom-
ising approach to such reaction sequences. Especially with
respect to the development of new sustainable and green
synthetic methods, the application of visible light as a renew-
able source of energy is of wide general interest in modern
organic chemistry. Based on single photoelectron transfer
reactions,[7,8] photoredox catalysts provide new reaction pro-
tocols that enable an environmentally benign approach
under mild conditions to valuable fine chemicals.[2,4,5]
In contrast to previous work on photoredox catalysis, spe-
cial hurdles need to be overcome that arise from combining
two metal catalysts. First, the appropriate choice of metal
catalyst 7 is crucial for a consecutive catalytic system, based
on a photoredox cycle A and a second metal catalytic cycle
B. Second, metal catalysts can easily undergo oxidative or
reductive degradation (Scheme 2). In particular, the metal
catalyst can be easily reduced by strongly reducing inter-
mediates that are passed in the photocatalytic cycle, which is
one of the central challenges that needs to be addressed.[10]
Thus the successful development of this dual catalytic reac-
tion is strongly reliant on the compatibility of catalysts
Continuing our efforts on dual catalytic transformations,[9]
we became interested in an efficient combination of photo-
À
redox and transition-metal catalysis for C C bond forming
reactions. This would not only be the first example of this
kind of combination of two metal catalysts, but it would also
[a] Prof. Dr. M. Rueping, Dr. R. M. Koenigs, Dipl.-Chem. K. Poscharny,
D. C. Fabry, Dr. D. Leonori, Dr. C. Vila
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-8092665
E-mail: Magnus.Rueping@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200050.
Scheme 2. The complex interplay of photoredox catalysis and metal catal-
ysis.
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Chem. Eur. J. 2012, 18, 5170 – 5174

COMMUNICATION
Table 1. Survey of different metal salts, additives, and light.
1 and 7. In addition, the efficiency of this dual catalytic
transformation is strongly dependent on the interplay of
both catalytic cycles; in particular, reaction rates need to be
adapted, which is obligatory for an efficient trapping of the
highly reactive iminium ion, as it can readily undergo an un-
wanted side reaction, leading to the formation of amide 5,[2]
which in turn results in diminished yield of the desired reac-
tion product 4. The formation of the amine radical cation
2a, the iminium ion 3, and the reoxidation of the photocata-
lyst by oxygen are well known.[11] It has been suggested that
Entry[a] Light source
cat/metal salt/additive
Time[b] Yield [%][c]
1
2
3
4
5
6
7
8
Blue LED
Blue LED
Blue LED
5 W lamp
5 W lamp
5 W lamp
5 W lamp
5 W lamp
5 W lamp
5 W lamp
5 W lamp
1a/AgO2CCF3
1a/AgOBz
1a/AgOBz + CSA
1a/AgOBz + CSA
1b/AgOBz + CSA
24
24
72
24
16
16
16
16
36
36
36
decomp
–
[d]
32
50
74
33
63
88
C
the formation of 3 is caused through a hydrogen (H ) ab-
1a/Cu
ACHTUNGTRENNUNG
straction of the amine radical cation 2a by the superoxide
anion formed in the regeneration of the photoredox catalyst.
Mechanistically two other reaction pathways appear to be
plausible. These differ in the order in which the deprotona-
tion and the electron transfer occur: On one hand the 1,2-
hydrogen transfer forms C-radical 2b, which then provides
the iminium ion 3 as a result of deprotonation by the terti-
ary amine or superoxide radical anion, followed by electron
1b/CuACHTNUGTRENNUNG
1b/
1b/
ACHTUNGTRENNUNG
9[c]
10
11
A
–
–
–
[d]
[d]
A
[d]
[a] Reaction conditions: 0.1 mmol 2a, 1 mol% photocatalyst, 10 mol%
metal salt/additive, 2 mL CH2Cl2, 5 equiv 6a. [b] Yield after purification.
[c] In the absence of oxygen. [d] No reaction.
II
II
C
transfer to Ru , Ru *, or HOO . On the other hand depro-
tonation may form the neutral C-radical 2c, which, for ex-
ample, can react with olefins or, as described here, can pro-
vide 3 by electron transfer. The iminium ion 3 formed in
situ can then be transformed in the second catalytic cycle B,
via a metal-catalyzed 1,2-addition reaction into the amine.
Bearing this in mind, we decided to develop a suitable dual
catalytic system for an oxidative alkynylation reaction,[12–16]
which comprises the advantages that it does not necessitate
the use of ligands for the stabilization of the metal catalyst
and thus circumvents problems that might occur due to
redox reactions of the metal catalyst. Additionally, the appli-
cation of different metal salts offers an operationally simple
control of the second catalytic cycle, as the nature of the
counterion has a direct influence on both reaction rates k3
and k4 of this catalytic cycle.
action rate, we decided to switch the light source to a less in-
tense 5 W fluorescent bulb; however, only moderate conver-
sions were observed. Therefore, we changed to the more
potent photoredox catalyst [RuACHTUGNRTNE(GUNN bpy)2ACHTUNRGTEG(NNNU dtbbpy)]ACHTNUGTERN(NUGN PF6)2 (1b).
Under these reaction conditions we were able to isolate the
oxidative alkynylation product in 74% yield (Table 1,
entry 5).
After having for the first time established the general con-
ditions for the dual catalytic oxidative alkynylation, we ex-
amined different metal salts, as these could have a direct
impact on the reaction rate of the second catalytic cycle (k3
and k4). In further studies, different copper salts were exam-
ined; these studies proved that the alkynylation reaction
proceeds smoothly, regardless of whether CuI or CuII salts
were applied. The best yield (88%) was obtained by using
the (MeCN)4CuIPF6 complex. In further optimization stud-
ies of this new dual catalytic transformation, the influence
of solvent was investigated. The results showed that the
transformation can be carried out most efficiently using di-
chloromethane or ethyl acetate as solvent, whereas all other
solvents proved to be detrimental for a high efficiency.
After optimizing the reaction conditions, we examined the
substrate scope of this photooxidative alkynylation reaction
(Table 2). In general, a variety of different aromatic alkynes
could be efficiently added to the photochemically generated
reactive iminium ion intermediates. Only the p-tBu-phenyl-
substituted alkyne could not be added efficiently using the
CuI metal catalyst; in this case only the decomposition of
the starting material was observed. However, we were able
to demonstrate, that in this case a silver salt can be efficient-
ly used as a substitute for the CuI catalyst (Table 2, entry 3).
This underlines the potential of this newly developed modu-
lar dual catalytic system: Both catalysts can be easily substi-
tuted to rapidly determine the perfect catalyst combination
to obtain high yields for each individual combination of sub-
strates. Besides different aromatic substituted alkynes, we
employed different aliphatic and functionalized terminal al-
We initiated our investigations on the oxidative alkynyla-
tion reaction by examining the oxidation of N-phenyl-tetra-
hydroisoquinoline (2a) in the presence of photoredox cata-
lyst [RuACHTUNGTRENNUNG(bpy)3]ACHTUNGTRENNUNG
(PF6)2, (1a),[10] phenylacetylene (6a), and dif-
ferent silver salts (Table 1). However, the use of blue LEDs
as light source and AgO2CCF3 as metal catalyst resulted
only in the formation of a silver mirror and decomposition
of the tertiary amine. Interestingly, silver benzoate proved
to be more robust under the present reaction conditions, as
no silver mirror was observed after a reaction time of a few
days, yet, no conversion of 2a to the desired product was
observed. We therefore investigated under otherwise identi-
cal reaction conditions a ternary catalyst mixture, consisting
of the photoredox catalyst, a photochemically inert silver
salt, and camphor sulfonic acid, which was intended to act
as a phase-transfer catalyst of Ag+ ions. Following this pro-
cedure, low concentrations of Ag+ ions can be obtained, re-
sulting in diminished photodegradation of the metal catalyst.
Employing this ternary catalyst mixture, we could indeed
isolate the desired alkynylation product for the first time in
32% yield (Table 1, entry 3). To adapt the rate of the pri-
mary photocatalytic cycle to the second metal-catalyzed re-
Chem. Eur. J. 2012, 18, 5170 – 5174
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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M. Rueping et al.
Table 2. Scope of the photooxidation–alkynylation reaction.
Table 3. Extension of the substrate scope to N-alkyl tetrahydroquino-
lines.
Entry[a] H4-iQ/
Alkyne
R1/R2/R3
Product Yield
[%][b]
Entry[a] H4-iQ/Alkyne R1/R2/R3
Product Yield [%][b]
1
2
2a/6a
2a/6b
2a/6c
2a/6d
2a/6e
H/Ph/Ph
H/Ph/pTol
H/Ph/pACTHNGUTRENNU(G tBu)Ph
H/Ph/pPentylPh
H/Ph/6MeO-2-
9
88
71
77
95
67
1
2
3
4
5
6
7
8
2h/6a
2h/6b
2h/6c
2i/6a
2i/6b
2i/6c
2i/6l
H/Me/Ph
H/Me/pTol
H/Me/pACTHNUTRGENUG(N tBu)Ph
H/tBu/Ph
H/tBu/pTol
H/tBu/pACTHNUTRGNEUG(N tBu)Ph
H/tBu/cyclohexenyl 33
OMe/Me/Ph 34
27
28
29
30
31
32
67
73
67
57
64
53
57
43
10
11
12
13
3[c]
4
5
AHCTUNGTRENNG(UN Naphthyl)
6
7
8
9
10
11
12
13
14
15
16
17
18
2a/6 f
2a/6g
2a/6h
2a/6i
2a/6j
2a/6k
2b/6a
2c/6a
2d/6a
2e/6a
2 f/6a
2g/6a
2b/6d
H/Ph/Cyclopropyl
H/Ph/Cyclohexyl
H/Ph/Bu
H/Ph/tBu
H/Ph/CO2Et
H/Ph/TPS
14
15
16
17
18
19
20
21
22
23
24
25
26
62
50
59
51
56
84
67
65
68
73
85
70
56
2j/6a
[a] Reaction conditions: 0.1 mmol 2, 1 mol% 1b, 10 mol%
(MeCN)4CuPF6, 5 equiv 6, 2 mL CH2Cl2, 5 W fluorescent bulb, reaction
time 16–36 h. [b] Yield after purification.
H/pTol/Ph
H/pEt/Ph
H/pClPh/Ph
H/oTol/Ph
H/2-Naphthyl/Ph
MeO/Ph/Ph
H/pTol/pPentylPh
are essential for the successful realization of this dual cata-
lytic transformation, as many side reactions need to be cir-
cumvented. For instance, strongly reducing intermediates of
the photoredox catalyst are passed throughout the photoca-
[a] Reaction conditions: 0.1 mmol 2,
(MeCN)4CuPF6, 5 equiv 6, 2 mL CH2Cl2, 5 W fluorescent bulb, reaction
time 16–36 h. [b] Yield after purification. [c] 10 mol% Ag(O2CCF3).
1
mol% 1b, 10 mol%
talytic cycle (e.g. [RuACHTNUTGRNEUNG
(bpy)3]+), which can easily degrade the
metal catalyst. In addition, the intermediate iminium ion
can be degraded by oxidation to the undesired amide. We
also demonstrated that a dual catalytic system can be realiz-
ed in the oxidative alkynylation reaction. It features a highly
modular catalytic system and mild reaction conditions. Re-
actions can be carried out using visible light as a source of
energy for the oxidation of various tertiary amines, yielding
valuable propargylic amines in good to excellent yields.
Moreover, we were able to demonstrate for the first time
that besides N-aryl amines also alkyl amines, namely glycin-
AHCTUNGTRENNUNG
kynes, which could be added to the photochemically gener-
ated iminium ions. However, yields are lower than the yield
of aromatic alkynes. Use of triphenylsilylacetylene gave an
excellent yield of 84% of the desired product (Table 2,
entry 11).
Apart from different alkynes we also investigated the in-
fluence of the substituents attached to the isoquinoline. A
variety of different N-arylated isoquinolines and different
isoquinoline cores were subjected to the general reaction
conditions and the desired alkynylation products were ob-
tained in good isolated yields.
Besides the variation of aromatic amines, we were inter-
ested in a further expansion of the substrate scope to non-
aromatic amines. To date the photochemical synthesis of
imines with visible light was almost exclusively carried out
with substrates that yielded N-aryl imines.[4] We therefore
decided to investigate the photochemical oxidation of differ-
ent glycine derivatives, which can be oxidized with photore-
dox catalyst 1b to the corresponding iminium ions, yielding
propargylamines upon alkynylation. Different glycine
esters,[17] tetrahydroisoquinoline backbones and alkynes
were investigated, yielding the desired propargylic amines in
good yields (Table 3).[18,19]
In summary, we herein describe the first dual catalytic
system that consists of a photoredox catalyst and a metal
catalyst. Besides the perfect interplay of both catalytic
cycles the choice of reaction parameters, and notably the
light source, the photoredox catalyst, and the metal catalyst
yl esters, can be subjected to this photoredox-catalyzed func-
3
À
tionalization of sp C H bonds. The high modularity of the
catalytic system allows an easy adaption of this concept to
other substrates. The realization of this concept is an impor-
tant advancement in the area of both dual catalytic as well
as photoredox catalytic transformations. Current investiga-
tions are focussed on extending the repertoire of dual
metal-catalyzed transformations with visible light.
Acknowledgements
The authors acknowledge Evonik Degussa for financial support, the
Fonds der chemischen Industrie for a scholarship to R.M.K., and Euro-
pean Research Council for a starting grant (BIMOC).
Keywords: alkynylation · C–C coupling · C–H activation ·
oxidation · photocatalysis
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Dual Catalysis
COMMUNICATION
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porting Information).
Chem. Eur. J. 2012, 18, 5170 – 5174
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[16] During the refereeing process a similar reaction was been reported:
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[17] Glycine esters 2h–i were synthesized following a similar procedure
to the one described in reference [4i].
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[18] The use of amino acids could lead to diasteroselective reactions.
[19] Chiral Cu-bisoxazoline catalysts complexes provided the products
with moderate enantiomeric excess.
Received: May 9, 2011
Revised: January 5, 2012
Published online: March 16, 2012
5174
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Chem. Eur. J. 2012, 18, 5170 – 5174