Visible light photoredox-catalyzed multicomponent reactions

Article abstract of DOI:10.1021/ol400317v

Oxidative three-component reactions for the direct synthesis of α-amino amides and imides from tertiary amines have been developed. These reactions involve the functionalization of C(sp³)-H bonds adjacent to nitrogen atoms via mild aerobic oxid

Full text of DOI:10.1021/ol400317v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Visible Light Photoredox-Catalyzed
Multicomponent Reactions
Magnus Rueping* and Carlos Vila
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany
magnus.rueping@rwth-aachen.de
Received February 3, 2013
ABSTRACT
Oxidative three-component reactions for the direct synthesis of R-amino amides and imides from tertiary amines have been developed. These
reactions involve the functionalization of C(sp3)ꢀH bonds adjacent to nitrogen atoms via mild aerobic oxidation using visible light photoredox
catalysis. The protocols are applicable to a wide range of amines and isocyanides, as well as water and carboxylic acids, providing straightforward
access to a variety of highly functionalized R-amino amides and imides.
The Ugi multicomponent reaction1 has been intensively
studied over the past decades and has found wide applica-
tion in the synthesis of R-amino amides which are im-
portant in organic synthesis. One of the main benefits of
this procedure is the possibility to prepare large compound
libraries through one-pot multicomponent reactions.
R-Amino amides are found in a wide range of natural
products and pharmaceuticals2 and have been used as in-
termediates for the synthesis of different heterocycles.3 In
terms of step and atom economy and with regard to green
and mild methodologies to access R-amino amides, the
development of Ugi-type reactions represents an important
field. While the typical Ugi reaction involves the reaction
of an imine, generated in situ from an aldehyde and a
primary amine, with an isocyanide and a carboxylic acid,
it was Zhu4a and Che4b who developed an elegant oxidative
multicomponent reaction using secondary amines in which
the imine is formed via a dehydrogenative pathway.
Furthermore, Ye5 and co-workers reported the oxida-
tive Ugi-type reaction with tertiary amines by applying
copper catalysis in combination with TBHP as oxidant to
activate C(sp3)ꢀH bonds adjacent to nitrogen.
Recently, visible-light-mediated photoredox catalysis6
has become very attractive in organic synthesis and catalysis.
Typically, readily available and easy to handle catalysts are
applied in combination with visible light to conduct a variety
of organic transformations.7
Scheme 1. Photoredox-Catalyzed Oxidative Ugi-Type
Multicomponent Reactions
(1) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
1959, 71, 386. (b) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
(c) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8. (d) Domling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168. (e) Domling, A. Chem. Rev.
2006, 106, 17.
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Chem. 2002, 9, 2085.
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2004, 126, 14475. (b) Erb, W.; Neuville, L.; Zhu, J. P. J. Org. Chem. 2009,
74, 3109.
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In this regard, the oxidative CꢀH functionalization of
C(sp3)ꢀH bonds adjacent to nitrogen atoms using photo-
catalysis has attracted attention.8ꢀ10 Given our interest in
visible-light-mediated processes, we envisioned the possi-
bility of synthesizing R-amino amides starting from ter-
tiary amines and employing a visible light photoredox
catalysis protocol (Scheme 1).
r
10.1021/ol400317v
XXXX American Chemical Society

Herein, we present an oxidative photoredox-catalyzed
three-component reaction employing tertiary amines, iso-
cyanides, and carboxylic acids or water.
Initially, the reaction between N,N-dimethylaniline (3a),
p-toluenesulfonylmethyl isocyanide (4a), and H2O was
chosen as a model reaction for the optimization of the
multicomponent reaction (Table 1). To our delight, by
using an iridium [1a](PF6) photoredox catalyst in CH3CN,
we were able to isolate the desired R-amino amide 5a in
53% yield (Table 1, entry 1). Next, westudied the reactivity
in different solvents (Table 1, entries 1ꢀ5), and we ob-
served that protic (MeOH) and apolar (toluene) solvents
gave poor yields and required longer reaction times. In
order to improve the yield of the product, we tested dif-
ferent photoredox catalysts (Table 1, entries 1, 6ꢀ8).
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Table 1. Optimization of the Reaction Conditionsa
€
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(8) Reviews including the photochemical oxidations of tertiary
amines: (a) Pandey, G. Synlett 1992, 546. (b) Renaud, P.; Giraud, L.
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entry
catalyst (mol %)
solvent
light source
yield (%)b
1
[1a]PF6 (1)
[1a]PF6 (1)
[1a]PF6 (1)
[1a]PF6 (1)
[1a]PF6 (1)
[1b]PF6 (1)
[2a](PF6)2 (1)
[2b](PF6)2 (1)
[1a]PF6 (1)
[1a]PF6 (1)
[1a]PF6 (1)
[1a]PF6 (2)
[1a]PF6 (1)
[1a]PF6 (2)
[1a]PF6 (1)
CH3CN
CH2Cl2
toluene
THF
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
green LEDs
11 W lamp
blue LEDs
blue LEDs
blue LEDs
blue LEDs
53
42
27
46
24
52
44
45
52
58
41
66
75
62
55
2
(9) Selected examples: (a) Condie, A. G.; Gonzalez-Gomez, J. C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464. (b) Xie, Z.;
Wang, C.; deKrafft, K. E.; Lin, W. J. Am. Chem. Soc. 2011, 133, 2056. (c)
Xuan, J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.; Xiao, W.-J. Chem.
Commun. 2011, 47, 8337. (d) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.;
Rong, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171.
(e) Rueping, M.; Vila, C.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C.
Chem. Commun. 2011, 47, 2360. (f) Wang, C.; Xie, Z.; deKrafft, K. E.;
Lin, W. J. Am. Chem. Soc. 2011, 133, 13445. (g) Rueping, M.; Zhu, S.;
3c
4c
5c
MeOH
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
7c
8c
9d
10e
11
12
13
14
15f
16g
€
Koenigs, R. M. Chem. Commun. 2011, 47, 8679. (h) Hari, D. P.; Konig,
B. Org. Lett. 2011, 13, 3852. (i) Rueping, M.; Zhu, S.; Koenigs, R. M.
Chem. Commun. 2011, 47, 12709. (j) Pan, Y.; Wang, S.; Kee, C. W.;
Dubuisson, E.; Yang, Y.; Loh, K. P.; Tan, C.-H. Green Chem. 2011, 13,
3341. (k) Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011,
47, 9615. (l) Maity, S.; Zhu, M.; Shinabery, R.; Zheng, N. Angew. Chem.,
Int. Ed. 2012, 5, 222. (m) Freeman, D. B.; Furst, L.; Condie, A. G.;
Stephenson, C. R. J. Org. Lett. 2012, 14, 94. (n) Liu, Q.; Li, Y.-N.;
Zhang, H.-H.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Chem.;Eur. J. 2012,
18, 620. (o) Courant, T.; Masson, G. Chem.;Eur. J. 2012, 18, 423. (p)
Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-H. Green Chem. 2011, 13, 2682.
a Reactions were performed with N,N-dimethylaniline 3a (0.15 mmol),
4a (0.15 mmol), H2O (10 equiv), and catalyst in 1 mL of solvent for 2 days
at room temperature. b Yield after column chromatography. c The reac-
tion time was 3 days. d 1.5 equiv of 3a was used. e 1.5 equiv of 4a was used.
f 2.0 equiv of 3a was used. g Traces of product were observed after 4 days.
€
(q) Mohlmann, L.; Baar, M.; Riess, J.; Antonietti, M.; Wang, X.;
Blechert, S. Adv. Synth. Catal. 2012, 354, 1909. (r) Rueping, M.;
Koenigs, R. M.; Poscharny, K.; Fabry, D. C.; Leonori, D.; Vila, C.
Chem.;Eur. J. 2012, 18, 5170. (s) Rueping, M.; Zoller, J.; Fabry, D. C.;
Poscharny, K.; Koenigs, R. M.; Weirich, T. E.; Mayer, J. Chem.;Eur. J.
2012, 18, 3478. (t) Cai, S.; Zhao, X.; Wang, X.; Liu, Q.; Li, Z.; Wang,
D. Z. Angew. Chem., Int. Ed. 2012, 51, 8050. (u) Tucker, J. W.; Zhang,
Y.; Jamison, T. F.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2012, 51,
4144. (v) Neumann, M.; Zeitler, C. Org. Lett. 2012, 14, 2658. (w)
In general, the iridium catalysts showed better reactivity
compared to ruthenium catalysts. Subsequently, we exam-
ined different light sources and catalyst loadings as well as
substrate ratios. The best result was obtained with catalyst
€
Cherevatskaya, M.; Neumann, M.; Fuldner, S.; Harlander, C.;
€
€
Kummel, S.; Dankesreiter, S.; Pfitzner, A.; Zeitler, K.; Konig, B. Angew.
Chem., Int. Ed. 2012, 51, 4062. (x) Zhao, G.; Yang, C.; Guo, L.; Sun, H.;
Chen, C.; Xia, W. Chem. Commun. 2012, 48, 2337. (y) Zhu, S.; Rueping,
M. Chem. Commun. 2012, 48, 11960. (z) DiRocco, D. A.; Rovis, T.
J. Am. Chem. Soc. 2012, 134, 8094.
(10) (a) Maity, S.; Theng, N. Synlett 2012, 23, 1851. (b) Shi, L.; Xia,
W. Chem. Soc. Rev. 2012, 41, 7687.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Substrate Scope for the Multicomponent Reactiona
Scheme 2. Substrate Scope for Multicomponent Reactiona
entry
3
R1
R2
4
R3
5
yield (%)b
1
3a
H
Me 4a CH2Ts
Me 4a CH2Ts
Me 4a CH2Ts
5a
5b
5c
5d
5e
5f
75
65
70
65
60
65
52
48
47
45
45
72
2c
3
3b 4-Me
3c 3-Me
4c
5
3d 3,5-Me2 Me 4a CH2Ts
3e 4-Cl
3f 4-Br
3g 3-Br
Me 4a CH2Ts
Me 4a CH2Ts
Me 4a CH2Ts
6
7
5g
5h
5i
8
3h
3a
3a
3a
3a
H
H
H
H
H
Et
4a CH2Ts
9
Me 4b Bu
10
11
12c
Me 4c cyclohexyl
5j
Me 4d CH2CO2Me 5k
Me 4e CH2Ph 5l
a Reactions were performed with amine 3 (0.15 mmol), isocyanide 4
(0.225 mmol), H2O (10 equiv), and [1a]PF6 (1 mol %) in 1 mL of CH3CN
for 2 days at room temperature. b Yield after column chromatography.
c 2.0 equiv of 3 was used.
Table 3. Optimization of the Reaction Conditionsa
entry
additive
light source
yield (%)b
1
11 W lamp
blue LEDs
11 W lamp
11 W lamp
11 W lamp
11 W lamp
blue LEDs
blue LEDs
41
32
34
40
48
55
60
63
2
3
100 mg Na2SO4
˚
4
100 mg 4 A
˚
5
100 mg 3 A
6c
7c
8c,d
150 mg 3 A
˚
˚
150 mg 3 A
˚
150 mg 3 A
a Reactions were performed with N,N-dimethylaniline 3a (0.15 mmol),
4a (0.15 mmol), 6a (0.15 mmol), and [1a]PF6 (1 mol %) in 1 mL of
CH3CN for 2 days at room temperature. b Yield after column chromatog-
raphy. c 2.0equivof3a, 1.0equivof4a, and1.5equivof6a wereused. d Dry
CH3CN was used as solvent.
a Reactions were performed with amine 3 (0.3 mmol), isocyanide 4
˚
(0.15 mmol), acid 6 (0.225 mmol), 150 mg 3 A, and [1a]PF6 (1 mol %) in
1 mL of CH3CN at room temperature.
1a in acetonitrile and blue LEDs (Table 1, entry 13), and
the product was isolated in 75% yield. In the absence of
light, only traces of product were obtained after prolonged
reaction time.
With the optimized conditions in hand, we explored the
scope of the reaction with different amines3, isocyanides 4,
and water (Table 2).
In general, this new visible-light-mediated catalysis proto-
col proceeded well, and the corresponding R-amino amides 5
were obtained in good yields. Different N,N-dimethyl-
anilines bearing electron-donating or electron-withdrawing
substituents at the para or meta position (Table 2, entries
2ꢀ7) proved to be good substrates for the reaction, giving
the products in good yields.
The methylgroup of the N-ethyl-N-methylaniline 3hwas
chemoselectively oxidized, and the corresponding amide
5h was obtained (Table 2, entry 8). Moreover, different
isocyanides reacted with N,N-dimethylaniline affording
the corresponding products with moderate to high yields
(Table 2, entries 8ꢀ12).
Org. Lett., Vol. XX, No. XX, XXXX
C

After examining the scope of the three-component reac-
tion with water, we turned our attention to the reaction
with carboxylic acids as this would not only lead to the
corresponding imides but also demonstrate the generality
of the newly developed photoredox catalysis procedure.
Hence, we studied the reaction of N,N-dimethylaniline,
p-toluenesulfonylmethyl isocyanide, and benzoic acid
using [1a]PF6 as photoredox catalyst under irradiation with
11 W lamp or blue LEDs (Table 3, entries 1 and 2). To our
delight, the reaction occurred, affording the R-amino imide
7a with moderate yield. Evaluation of different additives,
such as molecular sieves (Table 3, entries 3ꢀ8), had a
beneficial effect on the product formation and yield.
After having established the optimal reaction conditions
for the three-component reaction with carboxylic acids, we
examined the scope of the reaction this time using different
amines 3, isocyanides 4, and carboxylic acids 6. Again,
a series of highly diverse functionalized R-amino imides
7 were obtained (Scheme 2). Differently substituted N,N-
dimethylanilines 3 as well as aromatic carboxylic acids
6, including 4-bromo, 3-methoxy, 2-fluorobenzoic acid,
1-naphthoic acid, or 3-furancarboxylic acid, were successfully
applied in the oxidative multicomponent reaction. Further-
more, aliphatic carboxylic acids, such as 2-phenylacetic acid
or 4-pentynoic acid, reacted smoothly, and the imides were
isolated in 50 and 54% yield, respectively. Finally, the reaction
was carried out with different isocyanides, resulting in a varied
substitution pattern at the imide nitrogen.
A catalytic cycle for the present transformation is pro-
posed in Figure 1. Upon irradiation, IrIIIþ is excited to
IrIIIþ* and reductively quenched by 3 to produce IrIIþ and
radical cation 30 via SET oxidation. In the presence of
oxygen, the radical amine cation B is converted into
iminium intermediate A. The subsequent nucleophilic
attack of isocyanide 4 results in intermediate B (nitrilium
ion). This nitrilium ion is trapped by water or carboxylic
acid 6, generating intermediate C which rearranges to
give the corresponding amide 5 or imide 7, respectively.
In summary, we have developed an oxidative three-
component reaction for the synthesis of valuable R-amino
amides and imides from tertiary amines, isocyanides,
and water or carboxylic acids using visible light photoredox
Figure 1. Proposed mechanism for the photoredox-catalyzed
multicomponent reaction.
catalysis. The reaction proceeds smoothly using only
1 mol % of iridium photoredox catalyst and visible light
without the need for an additional external oxidant.
In general, the catalysis procedure tolerates various func-
tional groups and can be conducted in open reaction vessels
in the presence of air and moisture, providing a series of
differently substituted products. Further investigations of
the aerobic visible light photoredox catalysis to enable
multicomponent reactions are currently in progress and
will be reported in due course.
Acknowledgment. The authors acknowledge financial
support by RWTH Aachen University.
Supporting Information Available. Experimental pro-
cedures and full characterization (1H and 13C NMR data
and spectra, MS and IR analyses) for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX