Dual catalysis: Combining photoredox and Lewis base catalysis for direct Mannich reactions

Article abstract of DOI:10.1039/c0cc04539j

A dual catalytic system combining photoredox and Lewis base catalysis has been developed. By the appropriate choice of light source and catalyst, the photoredox cycle can be optimally modulated to match the base catalyzed reaction cycle to provide the cor

Full text of DOI:10.1039/c0cc04539j

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Dual catalysis: combining photoredox and Lewis base catalysis for direct
Mannich reactionsw
´
Magnus Rueping,* Carlos Vila, Rene M. Koenigs, Konstantin Poscharny and David C. Fabry
Received 21st October 2010, Accepted 22nd November 2010
DOI: 10.1039/c0cc04539j
A dual catalytic system combining photoredox and Lewis base
catalysis has been developed. By the appropriate choice of light
source and catalyst, the photoredox cycle can be optimally
modulated to match the base catalyzed reaction cycle to provide
the corresponding products under mild reaction conditions.
Recently, visible light, being a ubiquitous source of energy,
attracted again the attention of synthetic organic chemists.1
Although photochemical reactions have been utilized in
organic chemistry, traditional photochemistry suffers from
the drawback of often being dependent on high-energy UV
radiation.2 Furthermore, the photochemistry of many organic
compounds is unknown and therefore many obstacles need to
be overcome.
Scheme 1 Competitive pathways in the photooxidation of tertiary
amines.
the iminium ion intermediate is of crucial importance to get a
highly efficient catalytic system.
The oxidation of tertiary amines to highly reactive iminium
ions is a much studied area of research.6a,10 For example, the
oxidation of N-aryl-tetrahydroisoquinolines using catalytic
amounts of VO(acac)2 and tBuOOH as terminal oxidant has
been reported by Klussmann and coworkers.10h The
intermediate isoquinolinium ion can be intercepted by the
enamine nucleophile derived from a variety of different
ketones. Similar work has been reported by Stephenson and
coworkers using photoredox catalysis for the same class of
substrates. In this case the more nucleophilic nitromethane was
added in an aza-Henry reaction to capture the highly reactive
isoquinolinium ion intermediate.6a
However, the photochemistry of inorganic poly-bipyridine
complexes is well-understood.3 Irradiation of these complexes
with visible light generates a long-living, photoexcited state
that exhibits stronger oxidation and reduction potential
compared to the corresponding ground-state.3,4
Recently, the application of visible light photoredox catalysis
has emerged as a growing field in organic chemistry,1a,b,e,fin
particular for applications using combinations of metal- and
organocatalysts.5 The first applications were realized using the
well-known [Ru(bpy)3]2+ or [Ir(ppy)2(bpy)]+ (bpy = 2,20-
bipyridine, ppy = 2-phenylpyridine) complexes as photoredox
catalysts (Fig. 1).6–8
We became interested in the addition of ketones to
photocatalytically generated iminium ions applying a Lewis
base catalyzed Mannich-type addition.
The photocatalytic oxidation of C–H bonds adjacent to
nitrogen atoms has given valuable, highly reactive iminium
ion intermediates that can be used for further functionalization.9
In this process oxygen is necessary for catalyst reoxidation
and to obtain high turnovers. It also represents a major
obstacle in that it can react with the highly reactive iminium
ion intermediates to result in the corresponding amides
(Scheme 1). Thus the interplay between the photoredox
catalytic cycle and the effective addition of the nucleophile to
Therefore, we started to examine the addition of acetone to
N-phenyl-tetrahydroisoquinoline. To our delight the
photoredox catalyzed Mannich addition to the iminium ion
formed from 3a proceeded using [1](PF6)2 as photoredox
catalyst. However, the reaction proved to be sluggish since
the side reaction to the oxidized isoquinoline could not be
prevented. This indicated that the nucleophilic attack of
acetone needed to be accelerated. This was achieved by the
addition of 20 mol% of L-proline giving an 87% yield and
significantly less by-products (Table 1, entry 2). Notably, using
L-proline we obtained, in addition to the high yield, 8% ee,
which demonstrates that L-proline accelerates the Mannich
reaction.
In order to maximize the yields we tested different
photocatalysts in the dual catalytic process.
Interestingly, when using the chloride complex of 1 the
reaction was again sluggish (54% yield, Table 1, entry 3).
Applying the more reactive iridium complex [2]PF6 provided
the product in only 61% yield due to side reactions (Table 1,
entry 4).4b,6a,j Furthermore, various solvents were evaluated in
this photooxidation-Mannich reaction. In DMF or THF the
starting material was rapidly consumed. However, the fast
formation of the iminium ion intermediate is a drawback, since
Fig. 1 Ruthenium and iridium polypyridyl complexes.
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: Experimental
details and spectra. See DOI: 10.1039/c0cc04539j
c
2360 Chem. Commun., 2011, 47, 2360–2362
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Table 1 Survey of different photocatalysts, additives and solvents
Scheme 2 Interplay of combined photoredox-enamine catalysis.
Entrya Catalyst Additive
Solvent Timeb Yieldc
isoquinolinium ion is rapidly generated and can undergo side
reactions, whereas when the photocatalytic cycle is slowed
1d
2d
3d
4d
5e
[1](PF6)2
[1](PF6)2 L-Proline 5a (20 mol%) acetone 21
—
acetone 16
42
87
54
61
56
65
—
95
40
64
down (k1
o
k2), the intermediate is present in low
[1]Cl2
[2]PF6
L-Proline 5a (20 mol%) acetone 21
L-Proline 5a (20 mol%) acetone 21
concentrations, representing a reaction of pseudo-first order.
Thus by the appropriate choice and intensity of light as well as
the photocatalyst, reaction rate k1 can be manipulated to
obtain a highly efficient dual catalytic system.
[1](PF6)2 L-Proline 5a (10 mol%) DMF
[1](PF6)2 L-Proline 5a (10 mol%) THF
[1](PF6)2 L-Proline 5a (10 mol%) toluene
[1](PF6)2 L-Proline 5a (10 mol%) CH3CN 24
[1](PF6)2 Pyrrolidine 5b(10 mol%) CH3CN 36
16
6
6
6e
7e
8e
With the optimal conditions in hand we investigated the scope
of this combined photoredox-enamine catalysis procedure. In
general a variety of different N-aryl-tetrahydroisoquinolines can
be subjected to the photooxidation-Mannich reaction providing
the desired products in good to excellent yields (Table 3).
Generally, substrates bearing a substituent in the para-
position proved to give products in very good yields, whereas
substrates bearing substituents in the ortho-position resulted in
moderate to good yields using longer reaction times. This is
most likely due to steric reasons, since the photooxidation is
significantly slower.
9e
10e,f
[1](PF6)2 Pyrrolidine 5b/AcOH
CH3CN 36
a
Reaction conditions: substrate, 1 mol% photocatalyst, 1mL solvent,
b
5 W fluorescent bulb. Refers to the time until all starting material
c
is consumed. Yield of isolated product. 4a was used as solvent.
d
e
f
10 eq. 4a. 10 mol% 5b and 10 mol% AcOH were used.
the addition of the enamine nucleophile is significantly slower
which results only in moderate yields due to side reactions
(Table 1, entries 5 and 6). Acetonitrile proved to be the solvent
of choice for this combined photoredox enamine catalysis
(Table 1, entry 8). The reaction proceeds smoothly within
24 h without significant formation of any side product
yielding the desired Mannich product in excellent yield
(95%). However, using pyrrolidine as the Lewis base instead
of proline gave the product in poor yield (Table 1, entry 9).
Since the generation of the photoexcited state of [1](PF6)2 is
crucial for high reactivity, we examined different light sources
in the photooxidation-Mannich reaction (Table 2).
In summary we have developed a dual catalytic system for
the Mannich reaction by combining photoredox catalysis and
Lewis base catalysis. The reaction can effectively be conducted
with only 1 mol% photocatalyst loading. The perfect interplay
of both catalytic cycles is crucial for obtaining good yields, as
the highly reactive intermediates can undergo undesirable
pathways yielding complex reaction mixtures. However, we
were able to demonstrate that the photocatalytic cycle can be
adapted by carefully fine tuning the light source and the
It turned out that strong light emission, either using blue
LEDs or UV light, is counterproductive. The reactions
proceeded fast, however again the rapid formation of the
iminium ion intermediate resulted in decreased yields (42%
and 72%, respectively, Table 2, entries 4 and 3) accompanied
by the amide byproduct. The above findings can be
rationalized by the interplay of both catalytic cycles
(Scheme 2). If the rate of the photoredox catalysis is faster
than the enamine catalysis (k1 > k2), the intermediate
Table 3 Scope of the photooxidation-Mannich reaction
Entrya Amine R1/Ar
Ketone R2
Product Yieldb
Table 2 Survey of different light sources in the photooxidation-
Mannich reaction
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
H/Ph
H/Ph
H/Ph
H/pTol
H/pEt-Ph
4a
4b
4c
4a
4a
Me
Et
CH(OMe)2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6
7
8
95
47
62
64
63
78
72
83
77
61
63
47
72
59
82
9
10
11
12
13
14
15
16
17
18
19
20
H/pMeO-Ph 4a
H/pF-Ph
H/pCl-Ph
H/pBr-Ph
H/mMeO-Ph 4a
H/oTol
H/oBr-Ph
H/2-Naphthyl 4a
H/4-Biphenyl 4a
MeO/Ph
4a
4a
4a
9
Entrya
Catalyst
Light source
Timeb
Yieldc
10
11
12
13
14
15
4a
4a
1
2
3
4
[1](PF6)2
[1](PF6)2
[1](PF6)2
[1](PF6)2
Fluorescence bulb (5 W)
Fluorescence bulb (11 W)
Blue LEDs
24
14
14
14
95
70
72
42
UV lamp
3m
4a
a
a
Reaction conditions: substrate, 1 mol% [1](PF6)2, 10 eq. 4a, 1 mL
b
MeCN, reaction time as indicated. Refers to the time until all starting
Reaction conditions: substrate, 1 mol% [1](PF6)2, 10 eq. 4a–c, 1 mL
b
MeCN, 5 W fluorescent bulb, reaction time 24–48 h. Yield of isolated
c
material is consumed. Yield of isolated product.
product.
c
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