A strategy for generating alkyl radicals from aliphatic esters and lactones via sequential hydrolysis and photoinduced decarboxylation

Article abstract of DOI:10.1016/j.tetlet.2015.02.020

Sequential hydrolysis and photoinduced decarboxylation of methyl aliphatic esters lead to efficient generation of alkyl radicals under mild conditions. The generated alkyl radicals react with a variety of reagents to produce addition, reduction, and substitution products. In addition, the new tin and halogen free process for alkyl radical generation is applicable to a variety of aliphatic esters including those of dipeptides, steroids, saccharides, and lactones.

Full text of DOI:10.1016/j.tetlet.2015.02.020

Accepted Manuscript
A strategy for generating alkyl radicals from aliphatic esters and lactones via
sequential hydrolysis and photoinduced decarboxylation
Hikaru Saito, Takayuki Kanetake, Kazuyuki Osaka, Kousuke Maeda, Toshio
Morita, Yasuharu Yoshimi
PII:
S0040-4039(15)00279-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.020
TETL 45888
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 January 2015
29 January 2015
6 February 2015
Please cite this article as: Saito, H., Kanetake, T., Osaka, K., Maeda, K., Morita, T., Yoshimi, Y., A strategy for
generating alkyl radicals from aliphatic esters and lactones via sequential hydrolysis and photoinduced
decarboxylation, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.020
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Graphical Abstract
A strategy for generating alkyl radicals from aliphatic Leave this area blank for abstract info.
esters and lactones via sequential hydrolysis and
photoinduced decarboxylation
Hikaru Saito, Takayuki Kanetake, Kazuyuki Osaka, Kousuke Maeda, Toshio Morita, Yasuharu Yoshimi*
O
ν
h
R
R Y
R
O
C
OR'
Phen, DCB
Base
Additive
O
OH
OH
aq. CH3CN
OH
HO
Y
HO
Alkyl radicals
Phen =
Y = H, CH2CH2CN,
CH2CH2CO2t-Bu,
C6H4CN
NC
CN
DCB =

1
Tetrahedron Letters
journal homepage: www.els evier.com
A strategy for generating alkyl radicals from aliphatic esters and lactones via
sequential hydrolysis and photoinduced decarboxylation
Hikaru Saito, Takayuki Kanetake, Kazuyuki Osaka, Kousuke Maeda, Toshio Morita, Yasuharu Yoshimi*
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Sequential hydrolysis and photoinduced decarboxylation of methyl aliphatic esters leads to
efficient generation of alkyl radicals under mild conditions. The generated alkyl radicals react
with a variety of reagents to produce addition, reduction, and substitution products. In addition,
the new tin and halogen free process for alkyl radical generation is applicable to a variety of
aliphatic esters including those of dipeptides, steroids, saccharides, and lactones.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Generating alkyl radical
Aliphatic ester and lactone
Hydrolysis
Photoinduced decarboxylation
Radical reaction
Radical reactions have become versatile and powerful tools in
synthetic organic chemistry.1 In these processes, alkyl radicals
are usually generated by the reaction of organic halide (RX
where X = Br or I) with AIBN as a radical initiator and Bu3SnH
as the halogen and/or hydrogen transfer agent (Scheme 1).
However, the utility of this method is limited by the toxicity of
the substrates and reagents, along with difficulties associated
with the removal of tin containing byproducts (Bu3SnX). As a
result, several recent efforts have been carried out to develop new
tin2 and halogen free3 approaches for generating alkyl radicals.
of Phen to 1,4-dicyanobenzene (DCB) (Scheme 2).4 In the
reaction, SET occurs from the carboxylate ion to the cation
radical of Phen to form carboxy radicals that rapidly lose CO2 to
produce alkyl radicals. The formed alkyl radicals react with a
variety of reagents such as an electron deficient alkenes,4c,d,g,I,j
oxime ethers,4e thiols4a,f and the radical anion of DCB4b to
provide the respective addition, reduction, and substitution
products in high yields. Although similar photoinduced
decarboxylative radical reactions of carboxylic acids by using
phthalimides,5 cyanoarenes,6 TiO2,7 Ir8 and the Fukuzumi9
catalyst have been widely explored, a related decarboxylative
process starting with aliphatic esters has only been probed in a
T raditional Method
AIBN, Bu3SnH
limited number of cases.10 Thus,
a generic method for
R
R
X
Radical reactions
decarboxylative radical reactions from aliphatic ester under mild
conditions is still in demand.
X = Br, I
Alkyl radicals
ν
h
Sensitizer
T his Work
*
Electron-acceptor
Base
O
Phen
DCB
DCB
ν
h
Radical reactions
R
R
C
OR'
Phen;
DCB;
Alkyl radicals
Phen
- e-
NC
OH
CN
Scheme 1. Generating alkyl radicals.
Phen
Recently, we described an interesting decarboxylation reaction
of aliphatic carboxylic acids that produces alkyl radicals, which
is promoted by the radical cation of phenanthrene (Phen)
produced via single electron transfer (SET) from the excited state
O
C
O
C
O
- H+
- CO2
R
O
R
C
R
O
R
R-Y
Y = H, D, CH2CH2CN,
CH(CO2CH3)NHOBn,
C6H4CN.....
Corresponding author. Tel.: +81-776-27-8633; fax: +81-776-27-
8747; e-mail: yyoshimi@u-fukui.ac.jp. (Y. Yoshimi)
Scheme 2. Decarboxylative radical reactions of aliphatic carboxylic
acids by photogenerated radical cation of Phen.

2
Tetrahedron
In the effort described below, we investigated a route for
The results indicate that control of the hydrolysis conditions
(concentration of base and temperature) and ester substituent is
required in order to ensure efficient radical generation from the
starting ester. This feature enables regioselective reactions of
unsymmetric diesters. An example of this phenomenon is found
in the sequential reaction of N-Boc Glu(Ot-Bu)OCH3 (1e), which
selectively produces adduct 3b (Scheme 4) arising by radical
formation at the methyl α-aminocarboxylate center. In addition,
the varying rates of ester hydrolysis also enable the use of
unsaturated esters as radical traps. For example, reaction of t-
butyl acrylate 2b with methyl ester 1a exclusively forms γ-amino
acid ester 3c (Scheme 4).
photoinduced decarboxylative radical reactions using aliphatic
esters as substrates, which are readily hydrolyzed under basic
conditions. The new process for the alkyl radical generation,
which utilizes sequential ester hydrolysis and photoinduced
decarboxylation, does not require toxic and expensive
organostannanes and alkyl halides. Moreover, in these reactions
the ester moiety is directly converted under mild conditions into a
variety of groups such as alkyl, hydrogen, and aryl.
Initial exploratory studies were carried out using the
decarboxylative radical addition between N-Boc L-valine methyl
ester 1a and acrylonitrile 2a.4c,d,g,I,j Prior to irradiation, an
aqueous CH3CN solution (CH3CN/H2O = 9:1) containing 1a (10
mM), 2a (10 mM), Phen (10 mM), DCB (10 mM) and NaOH (50
mM) in a Pyrex vessel (15 x 180 mm) was heated at 40oC for 2 h
under an argon atmosphere. Irradiation of the resulting solution
using a 100 W high-pressure mercury lamp for 3 h at room
temperature led to formation of the adduct 3a as a racemic
mixture in 71% yield (Entry 1, Table 1). Prolonged irradiation (6
h) led to a slightly increased yield of 3a (74%) and complete
consumption of the hydrolyzed ester (Entry 2). A similar yield of
3a was obtained when the original solution containing the ester
was not preheated but rather directly irradiated for 6 h at 40 oC
(Entry 3). Use of KOH and LiOH instead of NaOH led to slightly
lower yields of 3a, presumed consequences of the low basicity of
KOH and low solubility of LiOH (Entries 4 and 5).
Table 2. Effects of sensitizer and electron acceptor in the catalytic
system on the efficiency of photoreaction of 1a and 2a.
Heating at 40 oC for 2 h, and h
Sensitizer
ν
Electron-acceptor
NaOH (50 mM)
2a
(10 mM)
1a
(10 mM)
+
3a
CH3CN/H2O = 9:1
Entry
Sensitizer
Electron-
acceptor
Irrad. time/h
Yield of
3a/%a
1
2
3
4
5
Phen (10 mM)
BP (10 mM)
Phen (2 mM)
Phen (2 mM)
BP (2 mM)
DCN (10 mM)
DCN (10 mM)
DCB (2 mM)
DCN (2 mM)
DCN (2 mM)
6
64
65
70
60
62
6
10
10
10
aIsolated yield.
Table 1. Hydrolysis and photoinduced decarboxylative radical
reaction of ester 1a with acrylonitrile (2a).a
Heating at 40 oC for 2 h, and h , 6 h
ν
ν
Phen (10 mM), DCB (10 mM)
NaOH (50 mM)
h
Phen (10 mM), DCB (10 mM)
Base (50 mM)
OR
2a
(10 mM)
+
3a
BocHN
O
OCH3
CH3CN/H2O = 9:1
CN
+
BocHN
BocHN
CN
CH3CN/H2O = 9:1
1b-d (10 mM)
1b: R = Bn
1c
: R = Et
O
3a
2a
(10 mM)
72%
60%
trace
1a (10 mM)
Entry
Base
Irrad. time/h
Yield of 3a/%b
1d: R = t-Bu
1
2
NaOH
NaOH
NaOH
KOH
3
6
6
3
3
71
74
67
65
55
Scheme 3. Effect of ester substituent on the photoreaction of 1 with
2a.
3c
4
5
LiOH
O
Ot-Bu
O
Ot-Bu
Heating at 40 oC for 2 h, and h , 6 h
ν
aAqueous acetonitrile solutions containing 1a (10 mM), 2a (10 mM), Phen (10 mM),
DCB (10 mM), and base (50 mM) under an Ar atmosphere were heated at 40 oC for 2 h,
and then photoreactions were carried out. bIsolated yield. cWithout preheating,
photoreaction was carried out at 40 oC for 6 h.
Phen (10 mM), DCB (10 mM)
NaOH (50 mM)
OCH3
2a
(10 mM)
+
BocHN
CH3CN/H2O = 9:1
BocHN
CN
O
3b
1e (10 mM)
60%
The effects of sensitizer and electron acceptor employed in the
photocatalytic system4i on the efficiencies of the photoinduced
decarboxylative radical reaction between 1a and 2a were
explored next (Table 2). Biphenyl (BP) and 1,4-
dicyanonaphthalene (DCN) in place of Phen and DCB also serve
as SET sensitizers the photoreaction step of the conversion of 1a
and 2a to 3a (Entries 1,2). In addition, photoreactions of 1a using
catalytic amounts of Phen (2 mM) and DCB (2 mM) or BP (2
mM) and DCN (2 mM) over longer irradiation times (10 h) also
take place to produce 3a in yields that are similar to those when
10 mM of these substances are used (Entries 3-5).
Heating at 40 oC for 2 h, and h , 6 h
ν
Phen (10 mM), DCB (10 mM)
NaOH (50 mM)
+
1a
(10 mM)
CO2t-Bu
CH3CN/H2O = 9:1
BocHN
CO2t-Bu
2b
(10 mM)
3c
55%
Scheme 4. Selective photoinduced decarboxylation of esters.
In an effort aimed at elucidating the substrate scope of the new
process, reactions of methyl esters of a peptide, steroid,
saccharide and substituted arenes (1f-1j) with 2a were carried out
using the preheating protocol (Table 3). In reactions of the
dipeptide methyl ester 1f and phenoxyacetic acid methyl ester 1g,
modestly high yields of the corresponding adduct 3d and 3e were
generated (Entries 1,2). Reactions of the methyl esters 1h-1j,
each containing a free OH group and a complex structure, also
occur to form of 3f-3h, respectively, but in lower yields (Entries
3-5).
In the next phase of the study, the effect of the ester
substituent on the efficiency of the process was investigated
(Scheme 3). When benzyl ester 1b and acrylonitrile 2a were
subjected to the sequential reaction involving preheating at 40oC
for 2 h followed by irradiation for 6 h, adduct 3a was generated
in a 72% yield. In reaction of ethyl ester 1c, the yield of 3a is
slightly lower (60%) and 1c is recovered in a 15% yield. Finally,
in contrast to those of 1b and 1c, sequential reaction of t-butyl
ester 1d does not occur and the starting ester is almost recovered.

3
Table 3. Photoinduced decarboxylative radical addition of 1f-1j to
2a.
In order to expand the scope of the new method, an
investigation was carried out to explore the corresponding
reaction of a lactone (Table 5). Lactones do not undergo
hydrolysis under the conditions described above. However, ring
opening hydrolysis of lactone 6 (10 mM) does take place upon
treatment with KOH (50 mM) in CH3CN/H2O = 9:1 at reflux for
2 h. Addition of Phen, DCB, and additives such as 2a and R-SH
to the resulting solution followed by irradiation under an argon
atmosphere at room temperature gives rise to production of the
respective addition, reduction, and substitution products 7-9
(Entries 1-3).
Heating at 40 oC for 2 h, and h , 6 h
ν
Phen (10 mM), DCB (10 mM)
NaOH (50 mM)
R
R
CO2CH3
1f j
2a
(10 mM)
+
CN
CH3CN/H2O = 9:1
-
(10 mM)
3d h
-
Entry
1
Substrate 1
Yield of 3/%a
O
H
N
1f:
3d: 70
BocHN
OCH3
O
O
O
Table 5. Photoinduced decarboxylative radical reactions of lactone 6.
ν
O
h
OCH3
OCH3
2
3
4
1g:
1h:
3e: 71
3f: 49
3g: 29
O
Phen (10 mM)
DCB (10 mM)
OH
Reflux for 2 h
KOH (50 mM)
O
OH
+ Additive
HO
Y
CH3CN/H2O = 9:1
7 (Y = CH2CH2CN)
8 (Y = H)
9 (Y = C6H4CN)
OH
6
(10 mM)
Additive
O
OH
H
H
Entry
Irrad. time/h
Y
Yield of 7-
9/%a
OCH3
1i:
1
2
2a (10 mM)
R-SH (30 mM)
none
6
10
6
CH2CH2CN
H
C6H4CN
7: 64
8: 65
9: 70c
H
H
3b
HO
H
aIsolated yield. bConcetration of 6 is 30 mM. cYield based on DCB.
O
O
O
In conclusion, the study described above led to the
development of a new general method for the generation of
interesting alkyl radical that involves sequential ester hydrolysis
and SET promoted photodecarboxylation of esters and lactones
(Scheme 5). This process can be used as part of radical addition,
reduction, and substitution reactions. By selection of proper ester
hydrolysis conditions, selective generation of alkyl radicals can
be carried out. Further investigations of the applicability of this
methodology to the modification of naturally occurring esters and
polyesters are underway.
O
5
1j:
3h: 26
O
O
H3CO
aIsolated yield.
A study was carried out to determine if the new radical
process could be used to promote reduction7a,f and substitution7b
reactions of N-Boc amino acid methyl esters (Table 4). We
observed that reaction of ester 1a (10 mM) in the presence of t-
dodecanethiol (R-SH, 30 mM) as a hydrogen atom source under
similar sequential heating and irradiation conditions leads to
formation of reduction product 4a (Entry 1).11 Treatment of N-
Boc phenylalanine and methionine methyl esters, 1k and 1l,
under these conditions leads to formation of the respective
reduction products 4b and 4c (Entries 2-3). Finally, reaction of
1a conducted in the absence of a thiol and alkene leads to
production of the cyanoarene adduct 5 (65%), formed by addition
of the intermediate alkyl radical to the radical anion of DCB
followed by loss of cyanide (Entry 4).4b
ν
h
Phen
DCB
O
C
O
Additive
Base
R Y
R
R C OR'
R
O
aq. CH3CN
Alkyl radicals
Scheme 5. Generating alkyl radicals from esters via sequential
hydrolysis and photoinduced decarboxylation.
References and notes
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Carbon-Carbon Bonds; Pergamon: Oxford, 1986. (b) Neumann,
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substitution of 1a, 1k, and 1l.
Heating at 40 oC for 2 h, and h
ν
R
Phen (10 mM), DCB (10 mM)
NaOH (50 mM)
OCH3
+ Additive
R
BocHN
O
CH3CN/H2O = 9:1
BocHN
Y
1a k l
, , (10 mM)
4
5
(Y = H)
(Y = C6H4CN)
1k: R = CH2Ph
1l
: R = CH2CH2SCH3
2.
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Entry
Substrate
1
Additive
Y
Irrad.
time/h
10
Yield of 4
or 5/%a
4a: 52
1
2
1a
1k
1l
R-SH (30 mM)
R-SH (30 mM)
R-SH (30 mM)
H
H
H
10
10
4b: 69
4c: 76
5: 65c
3
4b
none
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6
1a
aIsolated yield. bConcetration of 1a is 30 mM. cYield based on DCB.
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4a.
Supplementary Material
Experimental details including procedures, characterization,
and spectra data.