Addition of alkyl radicals, generated from carboxylic acids via photochemical decarboxylation, to glyoxylic oxime ether: a mild and efficient route to α-substituted α-aminoesters

Article abstract of DOI:10.1016/j.tetlet.2010.02.112

Radical addition to a glyoxylic oxime ether was accomplished under mild conditions using an alkyl radical generated from a free carboxylic acid via photochemical decarboxylation. The photoreaction provided an efficient route to α-substituted α-aminoesters from carboxylic acids and oxime ether.

Full text of DOI:10.1016/j.tetlet.2010.02.112

Tetrahedron Letters 51 (2010) 2332–2334
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Tetrahedron Letters
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Addition of alkyl radicals, generated from carboxylic acids via
photochemical decarboxylation, to glyoxylic oxime ether: a mild
and efficient route to
a-substituted
a-aminoesters
a
a
a
a
Yasuharu Yoshimi a, , Kosuke Kobayashi , Hayato Kamakura , Keisuke Nishikawa , Yoshiki Haga ,
*
Kousuke Maeda a, Toshio Morita a, Tatsuya Itou b, Yutaka Okada b, Minoru Hatanaka c,
*
a Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
b Department of Applied Chemistry, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu 525-8577, Japan
c Department of Medicinal and Organic Chemistry, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Radical addition to a glyoxylic oxime ether was accomplished under mild conditions using an alkyl rad-
ical generated from a free carboxylic acid via photochemical decarboxylation. The photoreaction pro-
Received 3 February 2010
Revised 16 February 2010
Accepted 22 February 2010
Available online 24 February 2010
vided an efficient route to
a
-substituted
a
-aminoesters from carboxylic acids and oxime ether.
Ó 2010 Elsevier Ltd. All rights reserved.
Radical addition to glyoxylic oximes is attracting increased
-amino
increasing the reactivity of the oxime ether and as a radical source
is attracting interest because of its ready availability and less tox-
icity as compared to Lewis acid and alkyl iodides.
attention as a synthetic method for the preparation of
a
acid derivatives.1 In this method, Lewis acids such as Et3B, In,
and Zn are used to increase the reactivity of oximes by the coordi-
nation of the C@N bond and radical generation from an alkyl io-
dide. However, less toxic and mild reaction conditions are still
desired from an environmental point of view.
Initially, decarboxylative addition of carboxylic acid 1 to gly-
oxylic oxime ether 2 (Bn = benzyl) was examined, as shown in Ta-
ble 1. Excitation of an aqueous acetonitrile solution (CH3CN/
H2O = 9:1) containing phenanthrene (Phen, 20 mM), 1,4-dicyano-
benzene (DCB, 20 mM), cyclohexanoic acid 1a (20 mM), and 2
(20 mM) with a 100-W high-pressure mercury lamp through a Pyr-
ex filter (>300 nm) under an argon atmosphere for 6 h at room
temperature afforded 3a in 45% yield along with the recovery of
Phen and DCB (>90%) (entry 1 in Table 1). In contrast to previous
results obtained with alkenes,3c the addition of 1 equiv of NaOH
to this solution prevented the photoreaction, and the formation
of 3 was not observed at all. In addition, the use of the sodium salt
of 1a instead of 1a did not provide the adduct 3a. These results
We have recently reported that the decarboxylation of free ali-
phatic carboxylic acids is effected by the photogenerated cation
radical in a redox-photosensitized reaction2 system, and inter-
and intra-molecular additions of electron-deficient alkenes pro-
ceed via the generated radical (Scheme 1).3 The finding provides
an efficient generation method of alkyl radicals from free aliphatic
carboxylic acids under mild conditions, and led us to investigate
radical addition to a glyoxylic oxime ether by using the photoreac-
tion. The use of a carboxylic acid both as a Brønsted acid for
*
Phen
DCB
Phen; phenanthrene
ν
h
DCB; 1,4-dicyanobenzene
Phen
Phen
DCB
-CO2
O
C
O
C
- H+
+ H+
+
X
X
X
X
R
R
O
R
OH
R
R
R
Scheme 1. Radical addition to alkene via photochemical decarboxylation of free carboxylic acids.
* Corresponding authors. Tel.: +81 776 27 8633; fax: +81 776 27 8747 (Y.Y.).
E-mail address: yyoshimi@u-fukui.ac.jp (Y. Yoshimi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.112

Y. Yoshimi et al. / Tetrahedron Letters 51 (2010) 2332–2334
2333
Table 1
R
hν
Radical addition to glyoxylic oxime ether 2 from carboxylic acids 1 via photochemical
decarboxylationa
O
C
Phen (20 mM)
DCB (20 mM)
+
R
OH
CO2CH3
4 (20 mM)
hν
BocN
R
CH3CN/H2O=9:1
Phen(20mM)
DCB(20mM)
O
C
1a, e (20 mM)
+
R
OH
CO2CH3
BnON
CN
BnOHN
CO2CH3
CH3CN/H2O=9:1
5a, e
1 (20 mM)
2 (20 mM)
3
Scheme 2. Photoreaction of 1 with 4.
Entry
Carboxylic acid 1
Yield of 3 (%)
CO2H
11); however, the addition of Brønsted acids such as HClO4 and
TsOH or Lewis acids such as Sc(OSO2CF3)3 decreased the yield of
3, since these acids prevented the deprotonation of 1. Also, the
higher concentration of 1 (>60 mM) decreased the yield of 3. When
the solution was irradiated in the absence of Phen or DCB, photo-
chemical decarboxylation of 1 did not occur. Thus, the photoreac-
tion required Phen to act as a photosensitizer and DCB to act as an
electron-acceptor; oxime ether 2 acted as neither a photosensitizer
nor an electron-acceptor.4 The use of other carboxylic acids such as
primary alkyl carboxylic acid 1b, tertiary alkyl carboxylic acid 1c,
and protected gulonic acid 1d instead of 1a also yielded the corre-
sponding adducts 3b–3d in moderate yields (entries 3–7). It is
1
45
1a;
2b
3
1a
55
38
1b:CH3(CH2)4CO2H
4
37
46
1c;
CO2H
5b
1c
O
O
O
6
32
40
1d;
noteworthy that the photoreaction provided the novel
a-amino
CO2H
O
acid derivative 3d having a sugar skeleton with a slight diastere-
oselectivity (3:2) under mild conditions (entries 6 and 7). On the
other hand, cyanoacetic acid, which produces an electron-poor
radical via photochemical decarboxylation, did not result in the
O
7b
1d
BocHN
CO2H
CO2H
formation of adducts. When amino acids such as N-Boc-
1e, N-Boc- -phenylalanine 1f, and N-Boc- -proline 1g (Boc = t-
butoxycarbonyl) were subjected to photoreaction, ,b-amino acid
derivatives 3e–g were also obtained in moderate yields as a diaste-
reoisomer mixture (entries 8–12). Thus, a variety of unique -ami-
L-valine
8
55
70
1e;
L
L
9b
1e
a
BocHN
Ph
a
1f;
10
57
65
no acid derivatives could be directly prepared from carboxylic acid
1 and oxime ether 2.
11b
1f
Next, we examined photodecarboxylative addition of N-Boc gly-
oxylic imine 4 (Scheme 2). Photoreaction of 1a or 1e with 4 under
the same conditions provided 4-alkyl-1-cyanobenzene 5a,e (30,
27%) via a substitution of DCB, respectively.3b No formation of
the adduct with 4 indicates that the lower basicity of 4 than that
of 2 prevented the formation of the iminium cation of 4, and the
generated radical via the photochemical decarboxylation could
not add to 4.
Boc
N
12
45
CO2H
1g;
a
The photoreaction was carried out with Phen (0.8 mmol), DCB (0.8 mmol), 1
(0.8 mmol), and 2 (0.8 mmol) in aqueous CH3CN solution (CH3CN, 36 mL; H2O,
4 mL) using a 100-W high-pressure mercury lamp under argon atmosphere for 6 h.
The photoreaction was carried out with Phen (0.8 mmol), DCB (0.8 mmol), 1
(1.6 mmol), and 2 (0.8 mmol) in aqueous CH3CN solution (CH3CN, 36 mL; H2O,
b
Scheme 3 shows a plausible mechanism for this photoreaction.
First, protonation of 2 by 1 led to the formation of iminium cation 6
and a carboxylate ion. Decarboxylation of the carboxylate ion with
the photogenerated cation radical of Phen produced the radical 7.
The addition of the radical 7 to 6 produced the cation radical 8.
Subsequently, electron transfer between 8 and the anion radical
of DCB produced the adduct 3.
4 mL) using a 100-W high-pressure mercury lamp under argon atmosphere for 6 h.
indicate that the formation of iminium cation through the proton-
ation of 2 by carboxylic acid 1 was essential for the successful com-
pletion of the reaction. An increase in the concentration of 1
(40 mM) slightly increased the yield of 3 (entries 2, 5, 7, 9, and
*
Phen
Phen; phenanthrene
DCB; 1,4-dicyanobenzene
DCB
hν
Phen
R
Phen
DCB
BnOHN
CO2CH3
- CO2
O
O
C
3
R
R
7
R
C
1
OH
R
O
BnOHN
CO2CH3
+
+
8
CO2CH3
BnON
CO2CH3
BnOHN
2
6
Scheme 3. Plausible mechanism for the photoreaction.

2334
Y. Yoshimi et al. / Tetrahedron Letters 51 (2010) 2332–2334
In conclusion, we found that carboxylic acid 1 served both as a
References and notes
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the protonation of 2. The photoreaction proceeded smoothly under
very mild conditions without any metal catalysts and allowed the
direct preparation of a-substituted a-amino acid derivatives start-
ing from 1 and 2. Further investigation of the diastereoselectivity
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Acknowledgment
This work was supported by Mitsubishi Gas Chemical Company
Award in Synthetic Organic Chemistry, Japan.
Supplementary data
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Supplementary data (general procedure for photoreaction and
characterization data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.02.112.