Photocatalytic Barbier reaction-visible-light induced allylation and benzylation of aldehydes and ketones

Article abstract of DOI:10.1039/C8SC02038H

We report a photocatalytic version of the Barbier type reaction using readily available allyl or benzyl bromides and aromatic aldehydes or ketones as starting materials to generate allylic or benzylic alcohols. The reaction proceeds at room temperature under visible light irradiation with the organic dye 3,7-di(4-biphenyl)1-naphthalene-10-phenoxazine as a photocatalyst and DIPEA as sacrificial electron donor. The proposed cross-coupling mechanism of a ketyl- and an allyl or benzyl radical is supported by spectroscopic investigations and cyclic voltammetry measurements.

Full text of DOI:10.1039/C8SC02038H

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DOI: 10.1039/C8SC02038H
Journal Name
ARTICLE
Photocatalytic Barbier Reaction – Visible-Light induced Allylation
and Benzylation of Aldehydes and Ketones
Anna Lucia Berger, Karsten Donabauer and Burkhard König*
Received 00th January 20xx,
Accepted 00th January 20xx
We report a photocatalytic version of the Barbier type reaction using readily available allyl or benzyl bromides and aromatic
aldehydes or ketones as starting materials to generate allylic or benzylic alcohols. The reaction proceeds at room
temperature under visible light irradiation with the organic dye 3,7-di(4-biphenyl)1-naphthalene-10-phenoxazine as a
photocatalyst and DIPEA as sacrificial electron donor. The proposed cross-coupling mechanism of a ketyl- and an allyl or
benzyl radical is supported by spectroscopic investigations and cyclic voltammetry measurements.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
that can recombine to give the desired product (Scheme 1b).[12]
Although first reported over a century ago, Barbier-type
reactions are still important tools for carbon–carbon bond
formations in organic synthesis today.[1] In the classical Barbier
reaction a metal, e.g. zinc[2] or magnesium[3] is able to insert in
the carbon–halide bond of a reactive organic halide to form a
Photocatalytic reductions of aromatic aldehydes to the
corresponding alcohols have been known since a report by Pac
et al. in 1983[13] and in 1990 the formation of diols as
homocoupling products of ketyl radical anions has been
observed.[14]
nucleophilic organometallic intermediate
4 which can undergo
a reaction with various electrophiles, like aldehydes or ketones
to form the corresponding secondary or tertiary alcohols as
products (Scheme 1a). One of the main application of Barbier
reactions is the synthesis of allylic or benzylic alcohols from an
aldehyde or ketone and allyl or benzyl bromide using a metal as
reductant.[4] Over the years, Barbier-type reactions have been
developed further, and today they are known for many
different substrates[5] and with various metals e.g. tin[6]
,
indium,[7] praseodymium[8] or manganese.[9] While these
methods offer a wide variety of reaction conditions, they all are
overall two-electron processes which is why they require the
use of a stoichiometric amount of metal as a reductant. Using a
photoredox catalyst to access an organic electron source
instead of a metal would represent an interesting and more
environmentally benign alternative. However, photoredox
catalyzed two-electron processes are scarce, as photocatalytic
reactions usually proceed via radical intermediates that are
generated by a photoinduced single electron transfer (SET).[10]
To generate carbanion synthons with similar reactivity as the
nucleophilic organometallic intermediate in classical Barbier-
type reactions, two consecutive SETs would be required to
generate a radical first followed by another reduction to the
corresponding carbanion.[11] Due to the high reactivity of most
radicals and their low concentration in photocatalytic reactions
this process is rather unlikely. Another strategy to enable
photocatalytic two-electron processes would be a reductive
radical-radical cross coupling where one electron is transferred
to each starting material, generating two radical intermediates
Scheme 1 – a) Classical and b) photocatalytic version of the
Barbier-type reaction; c and d) other photocatalytic reactions
with ketyl radicals.
After having been used only rarely in photoredox catalysis for
many years, there has been an increasing number of reports
about photocatalytic reductions of aldehydes and ketones
Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31,
93053 Regensburg, Germany, E-mail: Burkhard.Koenig@chemie.uni-regensburg.de;
Fax: (+49)-941-943-1717; Tel: (+49)-941-943-4575
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information available should be included here]. See DOI: 10.1039/x0xx00000x
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recently. Ketyl radicals have often been used for radical-radical
coupling reactions,[12, 15] e.g. in the work of Rueping and co-
workers about a photoredox-catalyzed reductive dimerization
of aldehydes and ketones (Scheme 1c)[15b] or in the reductive
arylation of carbonyl derivatives by Xia et al. in 2017.[12] Apart
from radical-radical coupling reactions, it is also possible to use
ketyl radicals for cyclization reactions[16] or to trap them
intermolecularly with alkenes.[17] In the work of Chen and co-
workers, hydroxymethyl radicals derived from the
photocatalytic reduction of aldehydes or ketones are added to
allyl sulfones (Scheme 1d) to form the corresponding
homoallylic alcohols as products.[17a] While this is an elegant
method for the photocatalytic allylation of aldehydes and
ketones, it is only possible for allyl sulfones with electron
withdrawing CO2Et-groups. A photochemical method for the
allylation and benzylation of ketones and 1,2-diketones using
organotrifluoroborate has been reported in 2009 by Nishigaichi
et. al.[18] We developed a method for the direct photocatalytic
synthesis of allylic and benzylic alcohols from ketones or
aldehydes and allyl or benzyl bromides with an organic
photocatalyst via a reductive radical-radical cross coupling.
Results and Discussion
View Article Online
For the optimization of the reaction coDnOdIi:ti1o0n.1s0,39w/Ce8uSCse02d03th8He
readily available substrates benzaldehyde (1a) and allyl
bromide (2a) as starting materials. Initial experiments have
shown that we could obtain 22% of the desired product 3a
when the reaction was performed in dry DMF with 4CzIPN (A)
as a photocatalyst and DIPEA as sacrificial electron donor (Table
1, entry 1).
By using 3,7-di(4-biphenyl) 1-naphthalene-10-phenoxazine (B)
as a photocatalyst[19] the yield could be increased to 38% (Table
1 – entry 2) and by changing the irradiation wavelength from
455 to 400 nm and the solvent from DMF to DMA a yield of 54%
could be obtained (Table 1 – entry 3). With the iridium-based
photocatalyst C only 21% of 3a was formed (Table 1 – entry 4).
By adding 1.5 equivalents of LiBF4 to the reaction mixture the
formation of the diol homocoupling product of 1a could be
suppressed, which further increased the yield to 64% (Table 1 –
entry 5).[15a] Reducing the reaction time from 18 to 2 hours only
slightly decreased the yield (Table 1 – entry 6).
Table 1 – Optimization of the reaction conditions.[a]
PC (mol%,
DIPEA
(eq.)
Additive
(eq.)
t
Yield 3a
[%][b]
Yield 5a
[%][c]
Yield 8a
[%][d]
Entry
Solvent
hν, [nm])
[h]
DMF
(dry)
DMF
(dry)
DMA
A (5, 455)
B (5, 455)
6
6
–
–
18
18
22
38
15
8
31
17
1
2
B (5, 400)
C (2, 455)
B (5, 400)
B (5, 400)
B (5, 400)
B (5, dark)
– (400)
6
6
6
6
–
6
6
6
6
–
18
18
18
2
54
21
64
59
0
14
19
13
12
0
23
43
23
28
0
3
4
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
–
LiBF4 (1.5)
LiBF4 (1.5)
LiBF4 (1.5)
LiBF4 (1.5)
LiBF4 (1.5)
LiBF4 (1.5)
LiBF4 (1.5)
5
6
18
18
15
4
7
0
0
0
8
46
3
3
15
6
9
– (400)
2
10
11
– (455)
15
0
0
0
[a] The reactions were performed using 1 eq. (0.2 mmol) 1a and 2 eq. (0.4 mmol) 2a in 2 mL degassed
[b]
solvent under nitrogen, yields were determined by GC analysis with 1-naphthol as an internal
[c]
standard, yields were determined by crude NMR with 1,3,5-trimethoxybenzene as an internal
standard, [d]yields were determined by GC analysis with 1-naphthol as an internal standard.
2 | J. Name., 2012, 00, 1-3
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While light and DIPEA are necessary for product formation remaining starting material was observed (3b
ARTICLE
3c,V3iefw, 3Arhtic)lewOhnilcinhe
,
DOI: 10.1039/C8SC02038H
(Table 1 – entries 7 and 8), the reaction also works in moderate indicates an incomplete reaction. While the homocoupling of
2
yields without photocatalyst at 400 nm (46%, Table 1 – entry 9). did not have any influence on the yield in most cases, it seems
However, the presence of the photocatalyst significantly to have significant effect when benzyl bromide (2c) was used.
accelerates the reaction as we already obtain complete This can be seen in the case of 3c, where 66% of the
conversion after 3 hours with 5 mol% of B, while only traces of homocoupling product 8a was formed.
3a were formed after the same time without photocatalyst
(Table 1 – entry 10). When the reaction was performed at Table 2 – Scope of the reaction.[a]
455 nm without
B no product formation could be observed
(Table 1 – entry 11). As shown in Table 1, varying amounts of
the homocoupling products 5a and 8a are formed under all
tested reaction conditions. Due to the use of an excess of allyl
bromide (2a), the generation of 8a has little influence on the
yield of the reaction. In contrast, the formation of the diol
homocoupling product 5a decreases the yield of the desired
product significantly, as two equivalents of the stoichiometric
reagent 1a are required to form one equivalent of 5a
.
The scope of the reaction was investigated using the optimized
reaction conditions (Table 2). Apart from allyl bromide (2a) the
reaction also worked in moderate to good yields with 3-bromo
cyclohexene (2b), benzyl bromide (2c) (1-bromoethyl)benzene
(2d). When 3,3-dimethylallyl bromide (2e) was used, a mixture
of product 3n-a and 3n-b was obtained, with 3n-a being the
main product. Using alkyl or phenyl bromides did not lead to
any product formation, probably because the radicals formed
upon reduction and debromination are too unstable to undergo
the coupling reaction. Aromatic aldehydes containing ester
groups (3e, 3f), or aliphatic aldehydes (3g) were also tolerated
in the reaction with moderate yields. Notably, the reaction
selectively takes place at the carbonyl group in benzylic
position, while other carbonyl groups in the molecule remain
unchanged. Apart from benzaldehydes which gave moderate
yields (3a
naphthaldehyde
thiophenecarboxaldehyde (3h). Good yields were obtained
when benzophenone was used (3k 3n) and 1,2-diketones (3r
-
3g) the reaction also works well with 1- and 2-
(
3i 3j and with the heterocyclic 2-
,
)
-
-
3u) are also viable substrates. Using a non-symmetric diketone
with an electron rich and an electron poor arene gave a mixture
of product 3t-a and 3t-b with only a slight preference of the less
electron rich position (3t-a). Product 3u shows an important
advantage over the classical Barbier reaction, as the reaction
selectively takes place at the sterically more hindered ketone
next to the aromatic system. Halogen substituted substrates
[a] The reactions were performed using 1 eq. (0.2 mmol)
(0.4 mmol) in 2 mL degassed DMA under nitrogen, all yields are of
1 and 2 eq.
(3o, 3p, 3s, 3t) and substrates containing a methoxy group (3v)
2
[b]
were also tolerated. Alkyl aldehydes and ketones did not yield
any product as they have significantly lower reduction
the isolated products, a 1:1 mixture of the syn- and anti-product
[c]
was obtained, yields of the side products were determined by
potentials and can therefore not be reduced by
B
crude NMR with 1,3,5-trimethoxybenzene as an internal standard.
(E1/2red(benzophenone 1e) = –1.83 V vs SCE,[20] compared to
E1/2red(cyclohexanone 2m) = –2.79 V vs SCE[15a]). Additionally, an
aromatic system in α-position to the carbonyl group seems to
be required, probably due to the enhanced stability of the ketyl
radical.
As moderate yields are obtained in many cases, the side
products of the reaction were determined for selected
examples (3a
, 3b, 3c, 3f, 3h, 3i). The diol homocoupling
products were observed in all examples. In some cases,
5
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Control reactions have shown that under the reaction
conditions the homocoupling products of benzaldehyde (5a
and allyl or benzyl bromide ( ) could be observed (Scheme 2a).
This confirms that the ketyl- (1a•–) as well as the allyl- (2a•) or
benzyl radical (2c•) are present in the reaction mixture and lead
to product formation via a radical-radical cross-coupling
reaction. Notably, the homocoupling products of 2a and 2c are
formed also without photocatalyst just by irradiating a mixture
View Article Online
2000000
1600000
1200000
800000
400000
0
DOI: 10.1039/C8SC02038H
)
PC (30 µM)
c(1a) = 0.7 mM
c(1a) = 1.3 mM
c(1a) = 2.0 mM
c(1a) = 3.2 mM
c(1a) = 4.8 mM
c(1a) = 6.3 mM
c(1a) = 9.1 mM
c(1a) = 11.8 mM
c(1a) = 16.7 mM
c(1a) = 25 mM
c(1a) = 40 mM
c(1a) = 50 mM
c(1a) = 100 mM
8
of the bromide
2 and DIPEA with 400 nm while the
photocatalyst is required for the formation of the diol 5a from
benzaldehyde. However, DIPEA and 400 nm light are both
crucial for the formation of allyl radicals, as irradiating only 2a
at 400 nm as well as stirring a mixture of 2a and DIPEA in the
dark or at 455 nm did not lead to the formation of
homocoupling product 8a. It was also possible to trap the allyl
radical, which was formed upon irradiation with 1,1-
450
475
500
525
550
λ / nm
2000000
1600000
1200000
800000
400000
0
diphenylethylene (9) yielding product 10 (Scheme 2b).
PC (30 µM)
c(2a) = 0.7 mM
c(2a) = 1.3 mM
c(2a) = 2.0 mM
c(2a) = 3.2 mM
c(2a) = 4.8 mM
c(2a) = 6.3 mM
c(2a) = 9.1 mM
c(2a) = 11.8 mM
c(2a) = 16.7 mM
c(2a) = 25 mM
c(2a) = 40 mM
c(2a) = 50 mM
c(2a) = 100 mM
450
475
500
525
550
λ / nm
Figure
1
–
Fluorescence quenching experiments of
photocatalyst
B
upon addition of benzaldehyde (1a) and allyl
bromide (2a).
0.00003
0.00002
0.00001
0.00000
-0.00001
-0.00002
Benzaldehyde
Benzaldehyde + DIPEA + LiBF4 (1:6:1.5)
Scheme 1 – Control reactions for radical-radical cross
coupling.
Stern-Volmer fluorescence quenching experiments of
photocatalyst
B show that the excited state of B is quenched
efficiently by benzaldehyde 1a, but not by allyl bromide (2a) or
DIPEA (Figure 1). These results are in accord with the prior
observations, as they show that radical 1a•– is generated by a
reduction of 1a
-0.00003
-2.0
SET from
B
to 1a while the allyl radical (2a•) is formed without
-1.5
-1.0
-0.5
0.0
0.5
1.0
Potential / V vs. Fc/Fc+
photocatalyst. According to cyclic voltammetry, benzaldehyde
Figure 2 – Cyclic voltammograms of benzaldehyde (1a, black)
and a mixture of 1a (1 eq.), DIPEA (6 eq.) and LiBF4 (1.5 eq.)
(red); the peak that corresponds to the reduction of 1a is
shifted to lower potentials upon addition of DIPEA and LiBF4.
has a reduction potential of –2.0 V vs. SCE in DMF and should
therefore not be in the range of photocatalyst
B
(E0* = –1.80 V
19c]
vs. SCE).[19b,
However, it is known that the potential of
aldehydes and ketones can be lowered by activating the
carbonyl group with Lewis acids[15d] or with the oxidized form
of the tertiary amine (DIPEA•+).[15b] Indeed, CV-measurements
show, that the signal for the reduction of 1a is clearly shifted to
lower potentials upon addition of DIPEA and LiBF4 (Figure 2).
This effect could only be observed when both additives were
present in the reaction mixture, which explains the role of LiBF4
in the reaction.
Although the mixture of allyl bromide and DIPEA has no
detectable absorbance at 400 nm, there seems to be a weak
interaction between 2a and DIPEA leading to the absorption of
small amounts of light and initiating an electron transfer from
the amine to 2a. After a few minutes of irradiation, the
absorption spectrum of the reaction mixture changes and an
absorbance band with λmax, abs= 413 nm arises, therefore
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enabling the efficient absorbance of 400 nm light and speeding
up the reaction (Figure 3).
Conclusion
View Article Online
DOI: 10.1039/C8SC02038H
To gain further insight, the quantum yield of the reaction was
measured. While the determined value of φ = 7.6 % is rather
high for photocatalytic reactions, it is in accordance with the
fast reaction times.
In summary, we have developed a photocatalytic version of the
Barbier-type reaction, which generates allylic or benzylic
alcohols from aldehydes or ketones and allyl- or benzyl
bromides under mild conditions via a radical-radical cross-
coupling. Instead of using stoichiometric amounts of zerovalent
metal as a reductant to generate an organometallic carbanion
synthon, we use an organic photocatalyst, a tertiary amine and
visible light to reduce both substrates to the corresponding
radicals. The cross-coupling of these radicals leads to the
desired product and enables a photocatalytic two electron
process.
2.0
DIPEA + Allyl bromide
10 min at 400 nm
20 min at 400 nm
30 min at 400 nm
1.5
1.0
0.5
0.0
Conflicts of interest
There are no conflicts to declare.
300
400
500
600
λ / nm
Acknowledgements
Figure 3 – UV/Vis absorption spectra of allyl bromide (2a, 1 eq.)
and DIPEA (3 eq.) in DMA before irradiation and after 10, 20 and
30 minutes of 400 nm irradiation.
This work was supported by the German Science Foundation
(DFG, GRK 1626). We thank Dr Rudolf Vasold for GS-MS
measurements and Regina Hoheisel for cyclic voltammetry
measurements.
Based on these mechanistic investigations and recent literature
reports,[15, 21] we propose the reaction mechanism depicted in
Scheme 4. Photocatalyst
B is excited upon irradiation with
400 nm light and benzaldehyde (1a) can be reduced to the ketyl
radical 1a•– by a SET from the excited photocatalyst B*. DIPEA
Notes and references
1
2
P. Barbier, C. R. Acad. Sci. 1899, 128, 110-111.
acts as
a sacrificial electron donor to regenerate the
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B.
Irradiation of allyl bromide and DIPEA initiates an electron
transfer, which after the cleavage of Br-, leads to the formation
[21]
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and the transient allyl radical 2a• recombine in a radical-
[22]
3
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DOI: 10.1039/C8SC02038H