Visible light-mediated oxidative decarboxylation of arylacetic acids into benzyl radicals: Addition to electron-deficient alkenes by using photoredox catalysts

Article abstract of DOI:10.1039/c3cc44438d

Reactions of arylacetic acids bearing an amino group at the para-position in the benzene ring with alkenes in the presence of a catalytic amount of transition metal polypyridyl complexes as photocatalysts under visible light illumination proceed smoothly to give the corresponding benzylated products via oxidative decarboxylation in good to high yields.

Full text of DOI:10.1039/c3cc44438d

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Visible light-mediated oxidative decarboxylation of
arylacetic acids into benzyl radicals: addition to
electron-deficient alkenes by using photoredox
catalysts†
Cite this: Chem. Commun., 2013,
49, 7854
Received 13th June 2013,
Accepted 4th July 2013
DOI: 10.1039/c3cc44438d
Yoshihiro Miyake,*z Kazunari Nakajima and Yoshiaki Nishibayashi*
www.rsc.org/chemcomm
Reactions of arylacetic acids bearing an amino group at the para-position
in the benzene ring with alkenes in the presence of a catalytic amount of
transition metal polypyridyl complexes as photocatalysts under visible
light illumination proceed smoothly to give the corresponding benzyl-
ated products via oxidative decarboxylation in good to high yields.
Oxidative decarboxylation of carboxylic acids is one of the funda-
mental and important processes in nature. The mechanism of
decarboxylation has been extensively studied in biochemistry.1 In
Scheme 1 Oxidative decarboxylation of carboxylic acids bearing an amino group.
organic chemistry, decarboxylation under electrochemical and of the aminoarylacetic acids to electron-deficient alkenes.
photochemical conditions provides a useful approach to the for- Preliminary results are described herein.
mation of alkyl radicals, therefore the decarboxylative dimerization
At first, we investigated the reaction of 4-(N,N-dimethylamino)-
has been found to occur via alkyl radicals as reaction intermedi- phenylacetic acid (1a) with ethyl (E)-2-cyano-3-phenylpropenoate (2a)
ates.2,3 The selective bond cleavage at the b-position with respect to under various conditions (Table 1). When a solution of 1a with 1.1
the radical cation center triggered by photoinduced electron transfer equiv. of 2a in the presence of [4a][BF4] (1 mol%) in acetonitrile (MeCN)
is expected to be one of the most useful methods for the decarboxy- was illuminated with a white LED (14 W) at 25 1C for 18 h, ethyl
lative formation of alkyl radicals from carboxylic acids.4 Especially, it 2-cyano-4-(4-(N,N-dimethylamino)phenyl)-3-phenylbutanoate (3a) was
is well known that a single electron oxidation of a-amino acids gives obtained in 85% yield (Table 1, entry 1). The reaction using [4b][BF4]
a-aminoalkyl radicals via decarboxylation, and synthetic use of the as a photocatalyst also proceeded smoothly to give 3a in a similar yield
a-aminoalkyl radicals has been reported (Scheme 1a).5,6 In contrast, (Table 1, entry 2), while the yield of 3a slightly decreased with the use of
synthetic utilization of the aminoarylacetic acids, which are the [4c][BF4] or [Ru(bpy)3][BF4]2 as a photocatalyst (Table 1, entries 3 and 4).
‘‘phenylogue’’ of the a-amino acids, has been quite limited6a,7,8 in In sharp contrast, when 9,10-dicyanoanthracene (DCA) was used in
spite of the utility of the generated benzyl radicals bearing an amino place of [4a][BF4], no formation of 3a was observed at all (Table 1,
group in organic synthesis (Scheme 1b).9
entry 5). Use of dimethyl sulfoxide (DMSO) as a solvent in place of
Recently we have succeeded in the utilization of a-aminoalkyl MeCN afforded 3a in 81% yield (Table 1, entry 6). When other polar
radicals via fragmentation of radical cations10 by a single electron solvents such as N,N-dimethylformamide (DMF) and methanol were
oxidation of amines mediated by photocatalysts.11–13 We have used, 3a was obtained in lower yields (Table 1, entries 7 and 8). Using
envisaged that a single electron transfer using photocatalysts is ethyl 4-(N,N-dimethylamino)phenylacetate (5a) under similar conditions
suitable for oxidation of aminoarylacetic acids to trigger decarbox- did not afford 3a at all (Table 1, entry 9). Separately, we confirmed that
ylation resulting in the corresponding benzyl radicals (Scheme 1b). no formation of 3a was observed in the absence of visible light or a
In fact, we have found radical addition reactions via decarboxylation photocatalyst. In the previously reported oxidative decarboxylation,2,3,7
the homo-coupling of benzyl radicals easily occurred to give the
corresponding bibenzyl (6), while no formation of 6 was observed in
all cases presented in Table 1. This result indicates that a visible light-
mediated electron transfer using photocatalysts is favorable for addition
of benzyl radicals derived from phenylacetic acids to alkenes.
Next, we investigated reactions of a variety of arylacetic acids (1)
with 2a (Table 2). The reaction of phenylacetic acid bearing an
N,N-diethylamino moiety at the para-position of the benzene ring
Institute of Engineering Innovation, School of Engineering, The University of Tokyo,
Yayoi, Bunkyo-ku, Tokyo, 113-8656, Japan. E-mail: ynishiba@sogo.t.u-tokyo.ac.jp;
Fax: +81 3-5841-1175; Tel: +81 3-5841-1175
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data for all new compounds. See DOI: 10.1039/c3cc44438d
‡ Current address: Department of Applied Chemistry, Graduate School of Engi-
neering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.
E-mail: miyake@apchem.nagoya-u.ac.jp
c
7854 Chem. Commun., 2013, 49, 7854--7856
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Table 1 Photochemical reactions of 4-(N,N-dimethylamino)phenylacetic acid
(1a) with ethyl (E)-2-cyano-3-phenylpropenoate (2a)a
Table 3 Photochemical reactions of arylacetic acids (1d or 1g) with alkenes (2)a
Entry
Photocatalyst
Solvent
Yield of 3ab (%)
Arylacetic
Entry acid (1)
Yield of
Alkene (2)
3b (%)
1
2
3
4
5
6
7
8
9c
[4a][BF4]
[4b][BF4]
[4c][BF4]
[Ru(bpy)3][BF4]2
DCA
[4a][BF4]
[4a][BF4]
[4a][BF4]
[4a][BF4]
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
85
84
70
68
0
81
76
57
0
1
2
3
4
5
6
7
1d
1d
1d
1d
1d
1d
1d
1d
1g
1g
R3 = 4-MeOC6H4, E1 = CN, E2 = CO2Et (2b) 74 (3i)
R3 = 4-MeC6H4, E1 = CN, E2 = CO2Et (2c)
R3 = 4-PhC6H4, E1 = CN, E2 = CO2Et (2d)
R3 = 4-ClC6H4, E1 = CN, E2 = CO2Et (2e)
93 (3j)
66 (3k)
52 (3l)
R3 = PhCH2CH2, E1 = CN, E2 = CO2Et (2f) 80 (3m)
i
R3 = Pr, E1 = CN, E2 = CO2Et (2g)
51 (3n)
70 (3o)
16 (3p)
90 (3q)
R3 = Ph, E1 = E2 = CN (2h)
MeOH
MeCN
8
R3 = Ph, E1 = E2 = CO2Et (2i)
9c
10c
R3 = 4-MeC6H4, E1 = CN, E2 = CO2Et (2c)
R3 = PhCH2CH2, E1 = CN, E2 = CO2Et (2f) 51 (3r)
a
All reactions of 1 (0.25 mmol) with 2a (0.275 mmol) were carried out in
the presence of [4a][BF4] (0.0025 mmol) in MeCN (2.5 mL) under 14 W
b
c
white LED illumination at 25 1C for 18 h. Isolated yield. DMSO was
used in place of MeCN.
Introduction of substituents such as methoxy, methyl, phenyl, and
chloro at the para-position of the benzene ring of 2a is successful in
giving the corresponding products (3i–3l) in good to high yields
(Table 3, entries 1–4). Alkenes bearing phenylethyl and iso-propyl
groups at the b-position were applied to give 3m and 3n in 80% and
51% yields, respectively (Table 3, entries 5 and 6). The reaction of 1d
with benzylidenemalononitrile (2h) proceeded smoothly to give 3o in
70% yield (Table 3, entry 7). However, a lower yield of 3p was obtained
when diethyl benzylidenemalonate (2i) was used as a substrate
(Table 3, entry 8). The arylacetic acid bearing an amino group (1g)
was also transformed efficiently into 3q and 3r in 90% and 51%
yields (Table 3, entries 9 and 10).
a
All reactions of 1a (0.25 mmol) with 2a (0.275 mmol) were carried out
in the presence of a photocatalyst (0.0025 mmol) in solvent (2.5 mL)
b
under 14 W white LED illumination at 25 1C for 18 h. Isolated yield.
c
5a was used in place of 1a.
Table 2 Photochemical reactions of arylacetic acids (1) with 2aa
To investigate the effect of the position of an amino group, we
carried out reactions of phenylacetic acids bearing a morpholino group
at the para-, meta- and ortho-positions of the benzene ring (1d, 1d0 and
Entry
Arylacetic acid (1)
Yield of 3b (%)
1
2
3
4
5
6c
7
Ar = 4-Et2N-C6H4 (1b)
Ar = 4-PhMeN-C6H4 (1c)
Ar = 4-(N-morpholino)-C6H4 (1d)
Ar = 4-(N-pyrrolidino)-C6H4 (1e)
Ar = 4-BnHN-C6H4 (1f)
Ar = 4-H2N-C6H4 (1g)
Ar = 4-(N-morpholino)-1-naphthyl (1h)
84 (3b)
89 (3c)
96 (3d)
74 (3e)
81 (3f)
87 (3g)
61 (3h)
00
1d ) with 2a under similar conditions (Scheme 2). In sharp contrast to
00
the reaction of 1d, when 1d0 and 1d were used as substrates, no
00
formation of the corresponding products 3d0 and 3d was observed at
all. Furthermore, in order to explore the origin of this reactivity, we also
investigated fluorescence quenching studies of 4a in the presence of 1d,
a
All reactions of 1 (0.25 mmol) with 2a (0.275 mmol) were carried out in
the presence of [4a][BF4] (0.0025 mmol) in MeCN (2.5 mL) under 14 W
00
1d0 or 1d in MeCN. The rate constants for 1d and 1d0 were estimated
b
c
to be 2.86 ꢀ 108 Mꢁ1 sꢁ1 and 6.78 ꢀ 107 Mꢁ1 sꢁ1 respectively, by using
white LED illumination at 25 1C for 18 h. Isolated yield. DMSO was
used in place of MeCN.
00
the Stern–Volmer plot, while no quenching of 4a by 1d occurred at all.
From these results, it is revealed that oxidation of 1d0 certainly occurred
but sequential decarboxylation hardly proceeded. It is reported that the
unpaired electron spin density at the para-position in the benzene ring
(1b) proceeded to give 3b in 84% yield (Table 2, entry 1). Other
phenylacetic acids bearing a variety of tertiary amino groups such as
N-methyl-N-phenylamino, N-morpholino, and N-pyrrolidino moieties at
the para-position of the benzene ring were also applicable, giving the
corresponding products (3c–3e) in high yields (Table 2, entries 2–4).
Reactions of phenylacetic acids bearing secondary (1f) and primary
amino (1g) groups also took place smoothly to give 3f and 3g in 81%
and 87% yields, respectively (Table 2, entries 5 and 6). When the acetic
acid bearing a 4-(N-morpholino)-1-naphthyl (1h) group was used, 3h
was obtained in a good yield (Table 2, entry 7).
Scheme 2 Effect of the position of the amino group on reactions of 1d, 1d0,
and 1d00 with 2a.
Other reactions of 1d or 1g with a variety of alkenes (2) were
also examined by using [4a][BF4] as a photocatalyst (Table 3).
c
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now, where alkyl halides are known to be promising precursors for
generation of alkyl radicals.9 However, examples for preparation of
alkyl halides bearing amino groups in a single molecule are limited
due to undesirable reactions including N-alkylation reactions.19 We
believe that the method described here provides an alternative route
for generation of benzyl radicals bearing an amino group.
Notes and references
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Scheme 3 Plausible reaction pathway.
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of the one-electron oxidized aniline is much higher than that at the
meta-position.14 The radical character in the benzene ring of the one-
electron oxidized 1d and 1d0 is expected to have a great effect on the
desirable decarboxylation. In the case of 1d0, the radical character of
the carbon atom at the meta-position with respect to the amino group
(at the b-position with respect to the carboxyl group) of the oxidized 1d0
is too small to induce efficient decarboxylation. On the other hand,
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Stern–Volmer analysis clearly indicates that oxidation of 1d under
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This is probably because an intramolecular hydrogen bonding between
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00
the amino group and carboxylic acid in 1d inhibits the electron
transfer oxidation.15 In addition, we confirmed that no reaction of
4-methoxyphenylacetic acid (1i) under similar conditions occurred at
all. These facts clearly indicate that decarboxylation triggered by a single
electron oxidation of the amino group at the para-position is one of the
key steps to promote these transformations.
A plausible reaction pathway is shown in Scheme 3. First, a single
electron oxidation of aminoarylacetic acid (1) by an excited photo-
catalyst (*cat) and sequential decarboxylation occur to give the benzyl
radical (A) and the reduced form of the photocatalyst (catꢁ).4,8 Addition
of A to 2 results in the formation of the radical intermediate (B). Finally,
reduction of B by catꢁ and subsequent protonation proceed to give
the product (3) accompanied by regeneration of the photocatalyst (cat).
The reduction of B by the reduced form of an iridium catalyst
([Ir(ppy)2(bpy)]0) is feasible according to the literature redox poten-
tials.16,17 The quantum yield in the reaction of 1a with 2a was estimated
to be 0.21, which is less than 1 and is in the common range of
molecular transformations via photoinduced electron transfer with
transition metal polypyridyl complexes.10 This result suggests that the
contribution of a photo independent process including a radical chain
process is negligible in the present system.10 The pathway shown in
Scheme 3 is similar to that described in our previous report on the
addition of a-aminoalkyl radicals to electron-deficient alkenes.10c On
the other hand, considering the redox potential of cyanoesters 2,16 the
reaction pathway via reduction of 2 by the excited photocatalyst17 and
subsequent radical–radical coupling is also possible.10a,18
14 G. D’Aprano, E. Proynov, M. Lebœuf, M. Leclerc and D. R. Salahub,
J. Am. Chem. Soc., 1996, 118, 9736.
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´
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18 See ESI† for experimental details.
19 Examples for preparation of 4-aminobenzyl bromides: (a) G. Wang,
X. Zhang, J. Geng, K. Li, D. Ding, K.-Y. Pu, L. Cai, Y.-H. Lai and
B. Liu, Chem.–Eur. J., 2012, 18, 9705; (b) J.-P. Leclerc, J.-P. Falgueyret,
M. Girardin, J. Guay, S. Guiral, Z. Huang, C. S. Li, R. Oballa,
Y. K. Ramtohul, K. Skorey, P. Tawa, H. Wang and L. Zhang, Bioorg.
Med. Chem. Lett., 2011, 21, 6505; (c) H. Enomoto, Y. Morikawa,
Y. Miyake, F. Tsuji, M. Mizuchi, H. Suhara, K. Fujimura,
M. Horiuchi and M. Ban, Bioorg. Med. Chem. Lett., 2009, 19, 442.
In summary, we have succeeded in the visible light-mediated
synthetic utilization of benzyl radicals formed by oxidation and
subsequent decarboxylation of arylacetic acids. This reaction system
is applicable for addition of a variety of benzyl radicals bearing an
amino group at the para-position in the benzene ring to electron-
deficient alkenes. A number of transformations using alkyl radicals
from alkyl halides as reaction intermediates have been reported until
c
7856 Chem. Commun., 2013, 49, 7854--7856
This journal is The Royal Society of Chemistry 2013