Dehydrogenative coupling reactions catalysed by Rose Bengal using visible light irradiation

Article abstract of DOI:10.1039/c1gc15489c

Rose Bengal, an organic dye, was demonstrated to be a photoredox catalyst for dehydrogenative coupling reactions using visible light irradiation. α-Functionalised tertiary amines were obtained with good to excellent yields. Air is essential for this react

Full text of DOI:10.1039/c1gc15489c

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Dehydrogenative coupling reactions catalysed by Rose Bengal using visible
light irradiation†‡§
Yuanhang Pan, Choon Wee Kee, Li Chen and Choon-Hong Tan*
Received 2nd May 2011, Accepted 20th July 2011
DOI: 10.1039/c1gc15489c
Rose Bengal, an organic dye, was demonstrated to be a
photoredox catalyst for dehydrogenative coupling reactions
using visible light irradiation. a-Functionalised tertiary
amines were obtained with good to excellent yields. Air is
essential for this reaction and acts as the terminal oxidant.
This is an environmentally friendly C–H functionalisation
methodology that avoids the use of metal catalysts and
stoichiometric amount of peroxo-compounds.
oxidants to complete the catalytic cycle. These reactions can be
made more environmentally friendly if we can avoid the use of
transition metals and reduce or avoid the consumption of large
amount of peroxo-compounds.
Unlike photochemistry using ultraviolet irradiation,
photo-induced single electron transfer (SET) processes using
visible light are easy to perform, as there is no need for
special instrument or apparatus. Furthermore, the reaction
conditions are mild, thus attracting increasing attention
from synthetic organic chemists.3 Several single electron
transfer photoredox catalysts have been shown to work well
in numerous reactions that are irradiated by visible light.4
In photoredox chemistry, tertiary amines are often used as a
reductant to quench the excited state of the photoredox catalyst.
Making slight modification to the reaction, Stephenson et al.
reported dehydrogenative coupling reactions between cyclic
tertiary amines such as N-aryl-tetrahydroisoquinolines and
nitroalkanes, catalysed by Ir(ppy)2(dtbbpy)PF6.5 Subsequently,
Rueping et al. reported the reaction of similar cyclic tertiary
amine with ketones, catalysed using a dual catalyst system,
Ru(bpy)3Cl2 and L-proline.6 Despite these advancements, the
development of dehydrogenative coupling reactions under
metal-free conditions is still highly desirable.
The dehydrogenative coupling reactions, performed under ox-
idative conditions, are an important C–C bond formation
methodology.1 As the reactive intermediates are generated
in situ, it avoids the pre-functionalisation of the substrates.
This makes synthetic routes shorter and more atom-economical.
This reaction has been utilized to activate a-C–H bonds of
tertiary amines and ethers, benzylic and allylic C–H bonds, and
alkane C–H bonds.2 Current dehydrogenative coupling reactions
require transition metal catalyst to activate the C–H bonds
and stoichiometric amount of peroxo-compounds as terminal
Department of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore, 117543. E-mail: chmtanch@nus.edu.sg; Fax: (+65)
6779 1691; Tel: (+65) 6516 2845
Organic dyes are cheap and easier to modify compared
to metal photoredox catalysts (Fig. 1). Most recent research
on organic dyes has focused on their potential application in
dye-sensitizer solar cells.7 The potential use of organic dyes
† Representative procedure for organic dye-catalysed dehydrogenative
coupling reaction: N-aryl-tetrahydroisoquinoline 1a and nitromethane
2a : 1a (20.9 mg, 0.1 mmol, 1.0 equiv.) was added to a solution of RB
(5.0 mg, 0.005 mmol, 5 mol%) in 1.0 ml nitromethane 2a. The reaction
mixture was stirred under green LEDs irradiation at room temperature.
After 10 h, the solvent was removed in vacuo and the crude product was
directly loaded onto a short silica gel column. Flash chromatography
was performed using gradient elution with hexane/EA mixtures (40/1–
15/1 ratio). After removing solvent, product 3a (24.7 mg) was obtained
as yellow oil in 92% yield.
‡ Representative procedure for organic dye-catalysed dehydrogenative-
Mannich reaction: N-aryl-tetrahydroisoquinoline 1a (20.9 mg,
0.1 mmol, 1.0 equiv.) was added to a solution of RB (5.0 mg, 0.005
mmol, 5 mol%) in 1.0 ml acetone 4a. This was followed by pyrrolidine
(2.5 ml, 0.03 mmol, 30 mol%) and TFA (2.3 ml, 0.03 mmol, 30 mol%).
The reaction mixture was stirred under green LEDs irradiation at room
temperature. After 20 h, the solvent was removed in vacuo and the
crude product was directly loaded onto a short silica gel column. Flash
chromatography was performed using gradient elution with hexane/EA
mixtures (40/1 - 15/1 ratio). After removing solvent, product 5a (24.1
mg) was obtained as pale yellow solid in 91% yield.
§ Electronic supplementary information (ESI) available: General pro-
cedures for dehydrogenative coupling reactions, spectroscopic data,
computational details. See DOI: 10.1039/c1gc15489c
Fig. 1 Absorption wavelength of different organic dyes.9c,10
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Table 1 Dehydrogenative coupling between N-aryl-tetrahydroiso-
quinoline 1a and nitromethane 2aa
Table 2 Dehydrogenative coupling catalysed by Rose Bengal with
visible lighta
Entry
Organic dye
x
LED color
Conv. %b
Entry
1[Ar]
2[R]
t (h)
3
Yield %b
1
2
3
4
5
6
RB
5
5
5
5
5
5
5
5
Green
Green
Violet
Red
Blue
Green
—
Green
Green
Green
Green
100
40
<10
25
50
70
0
100
35
50
100
1
1a[C6H5]
2a[H]
2b[Me]
2c[Et]
2a[H]
2a[H]
10
24
72
48
15
3a
3b
3c
3d
3e
92
82
95
89
85
Rhodamine B
TPP
Methylene Blue
Fluorescein
Eosin Y
RB
RB
RB
2c
3c,d
4
1a[C6H5]
1a[C6H5]
1b[4-Br–C6H4]
1c[4-Me–C6H4]
5
a Reaction was performed using 0.1 mmol of 1 in 1.0 ml of 2. b Isolated
yield. c dr = 3 : 2 d Reaction was performed using 0.1 mmol of 1a and
1.0 mmol of 2c in 1.0 ml CH3CN as solvent, dr = 3 : 2.
7c
8d
9d
10d
11d
0.1
1
10
RB
RB
10 mol% did not result an obvious rate enhancement (Table 1,
entries 9–11). Hence 5 mol% loading of RB was chosen for the
substrate scope evaluation.
a Reaction was performed using 0.05 mmol of 1a in 0.2 ml of 2a.
b Conversion was determined by 1H NMR. c Reaction was performed
in the dark. d 0.5 ml of 2a was used. Reaction time was 10 h.
Using the established conditions, we evaluated the perfor-
mance of different N-aryl-tetrahydroisoquinolines 1a–c with
nitroalkanes 2a–c in the presence of 5 mol% RB (Table 2).
Both nitromethane (Table 2, entries 1, 4 and 5) and nitroethane
(Table 2, entry 2) provided desired coupled products with good
to excellent yields. Excellent yield was also obtained when 1-
nitropropane was coupled with cyclic amine 1a in CH3CN (Table
2, entry 3).
Tertiary amine without a benzyl group is found to give a
lower yield under the optimized conditions. Moderate yield was
observed when 3 in nitromethane was irradiated with green light
(Scheme 1). A small amount of by-product, the bis-addition
product, was observed. The lower reactivity of 3 relative to
1a does not lie in their relative ease of oxidation, as density
functional theory calculations11 indicate that the oxidation
of 3 (Eox = +1.02 V vs. NHE)15 is thermodynamically more
favourable than 1a (Eox = +1.14 V vs. NHE) by 4.5 kcal mol-1
in nitromethane. The lower reactivity is attributed to the more
unfavourable thermodynamics in the formation of the required
iminium for 3 relative to 1a (formation of iminium from 1a∑+ is
14.8 kcal mol-1 more favourable than from 3∑+).
as catalysts for organic reactions was recognized many years
before, with high power light source, which requires high energy
input and thus undesirable from an environmental point of view.8
Recently, several examples were reported on the use of organic
dyes as photoredox catalysts using visible light irradiation from
low power source.9 In 2010, our group demonstrated that
using irradiation from a 11 W household fluorescence bulb,
Rose Bengal (RB) was able to catalyse a-oxyamination of
1,3-dicarbonyl compounds and 2,2,6,6-tetramethylpiperidine-
1-oxyl (TEMPO) with excellent yields.9a Griesbeck found that
nanosized semiconductor particles and lucigenin can also be
used as catalysts in photoinduced azidohydroperoxidation of
myrtenyl hydroperoxide reaction.9b More recently, Zeitler re-
ported Eosin Y-catalysed dehalogenation and enantioselective
a-alkylation reactions, in the presence of both photoredox
catalyst and organocatalyst.9c In this manuscript, we wish to
report the use of organic dyes as photoredox catalysts in
dehydrogenative coupling reactions of tertiary amines using low
power light source.
We embarked our investigation by screening a number of
organic dyes for photocatalytic activities, using the reaction
between N-aryl-tetrahydroisoquinolines 1a and nitromethane
2a (Table 1).5 Different Light Emitting Diode (LED, 0.5–5W)
colours were used to match the absorption wavelength of the
different dyes used. For example, green light was used when
Rose Bengal (Ered = +1.04 V vs. NHE, for the triplet excited state
of RB)14 was investigated. Amongst the dyes tested, RB showed
the best reactivity, catalysing a complete conversion after 20 h
with 5 mol% catalyst (Table 1, entry 1). Eosin Y provided a
good conversion of approximately 70% while other dyes gave
low conversions, as determined with 1H NMR (Table 1, entries
2–6). Visible light from the LED was essential for the reaction
to proceed. No conversion was observed when the reaction was
conducted in the dark (Table 1, entry 7). When the volume of
nitromethane was increased, decreasing the concentration of the
catalyst and cyclic amine, the reaction rate was increased and the
reaction was completed in 10 h. Decreasing the RB loading to
0.1 or 1 mol% led to lower conversion while increasing RB to
Scheme
1 Dehydrogenative coupling between 4-methyl N,N-
dimethylaniline and nitromethane.
The ability to harness solar energy for chemical reaction
is of paramount importance to photochemistry,12 therefore
we performed our dehydrogenative coupling reaction between
N-aryl tetrahydroisoquinoline 1a and nitromethane 2a with
sunlight. A faster reaction was observed and 87% yield of 3a
was isolated after 3 h (Scheme 2).
The dehydrogenative-Mannich reaction occurs between a
tertiary amine and a ketone. This methodology is potentially
more useful than the ‘classical’ Mannich reaction as the reactive
iminium intermediate was generated in situ, compared to the
requirement for an extra step to prepare the imine as in Mannich
reaction.6,13 RB was once again shown to be a good catalyst
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Table 3 Dehydrogenative-Mannich reaction catalysed by Rose Bengal
under visible lighta
Entry
1[Ar]
4[R]
t (h)
5
Yield %b
1
2
3
4
5
1a[C6H5]
4a [Me]
4a [Me]
4a [Me]
4a [Me]
4b [Et]
20
48
15
20
20
5a
5b
5c
5d
5e
91
95
87
99
80
1b[4-Br–C6H4]
1c[4-Me–C6H4]
1d[4-OMe–C6H4]
1a[C6H5]
Fig.
coupling.
2
Proposed mechanism for RB-catalysed dehydrogenative
a Reaction was performed using 0.1 mmol of 1 in 1.0 ml of 4. b Isolated
yield.
the RB radical anion back to the ground state RB by dioxygen.
The tertiary amine radical cation donates one hydrogen atom
to the dioxygen radical anion and results in the formation of
an iminium, which could be trapped by nucleophiles under mild
conditions, to release the final product. Hydroperoxide anion is
also generated in the same process.
Scheme 2 Dehydrogenative coupling reaction under ambient sunlight.
Preliminary assessment of the role of dioxygen by performing
a control reaction in a glovebox (O2 at 0.1 ppm) indicated that it
is not essential for the reaction to occur, however in the absence
of dioxygen, a much lower yield was obtained relative to reaction
performed in open air, which is consistent with the observation
by Stephenson et al.5
In conclusion, we have developed an environmentally friendly,
metal-free dehydrogenative coupling reaction catalysed by an
organic dye, Rose Bengal under visible light irradiation. Both
nitroalkanes and ketones can be used as nucleophiles and gave
excellent yields under very mild conditions. Organic dye, which
is environmentally benign, cheaper, readily available and easy to
modify, was demonstrated to be a viable alternative inorganic
photoredox catalyst. We are currently carrying out mechanistic
studies to understand this reaction and will be reported in due
course.
for the dehydrogenative-Mannich reaction between N-aryl-
tetrahydroisoquinolines 1a–d and acetone (Table 3, entries 1–4).
Pyrrolidine/TFA was used to generate the enamine nucleophiles
from acetone. When butanone was subjected to the dual catalysts
system, good yield and excellent regioselectivity was obtained
(Table 3, entry 5). Cyclohexanone is typically a poor donor for
dehydrogenative coupling reactions and gave low yield under
standard condition. But by simply changing pyrrolidine/TFA
to L-proline and the solvent to CH3CN, 66% yield of the
desired product with 9 : 1 dr could be obtained (Scheme 3). As
the enamine catalysis has been well developed for asymmetric
organocatalysis, several catalysts including L-proline and deriva-
tives were tested. The highest ee value of 15% was achieved for
reaction between N-aryl-tetrahydroisoquinoline 1d to acetone
4a (Scheme 4).
Acknowledgements
This work was supported by ARF grants (R-143-000-461-112)
and a scholarship (to Y. Pan and L. Chen) and a President
Graduate Fellowship (to C. W. Kee) from the National Univer-
sity of Singapore. We thank the computer centre for generously
providing free CPU time.
Scheme 3 L-Proline and Rose Bengal co-catalysed dehydrogenative-
Mannich reaction.
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