A mild deuterium exchange reaction of free carboxylic acids by photochemical decarboxylation

Article abstract of DOI:10.1039/c0cc01464h

Deuterium exchange of a carboxy group was achieved by photochemical decarboxylation of free carboxylic acids in the presence of thiol and a small amount of D₂O, and a deuterated product with excellent deuterium content was obtained; this reaction is a practical means of synthesizing regioselective deuterium-labelled compounds under mild reaction conditions.

Full text of DOI:10.1039/c0cc01464h

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A mild deuterium exchange reaction of free carboxylic acids
by photochemical decarboxylationw
Tatsuya Itou,*a Yasuharu Yoshimi,*b Keisuke Nishikawa,b Toshio Morita,b Yutaka Okada,a
Nobuyuki Ichinosec and Minoru Hatanakad
Received 18th May 2010, Accepted 1st July 2010
DOI: 10.1039/c0cc01464h
Deuterium exchange of a carboxy group was achieved by
photochemical decarboxylation of free carboxylic acids in the
presence of thiol and a small amount of D2O, and a deuterated
product with excellent deuterium content was obtained; this
reaction is a practical means of synthesizing regioselective
deuterium-labelled compounds under mild reaction conditions.
that the regioselective deuterium exchange reaction of the
carboxy group was attained through a photoreaction, the
substrates used were limited to 3-methylbenzophenone and
3-methylacetophenone.9
We report herein a new type of deuterium exchange reaction
via photochemical decarboxylation of free carboxylic acids,
effected by a redox-photosensitized reaction system to yield
the deuterated product in the presence of a deuterium source.
This method provides easy and practical access to the synthesis
of regioselective deuterated products using a slight amount of
D2O under mild reaction conditions, and can be expected to
lead to fruitful applications in synthetic and biological
investigations.
Isotope labeling is one of the most important techniques for
investigations of organic chemistry and chemical biology. In
particular, deuterium-labeled compounds are used for analyses
of molecular structure1 and investigations of reaction mechanisms.2
A number of deuterium-labeling methods have been reported
including deuterium exchange reactions catalyzed by transition
metals,3 acids,4 bases5 and microwave-enhancement,6 which
exhibited good catalytic efficiency in affording the deuterated
product. Often, however, such conventional methods of deuterium
exchange are limited to the substrate, result in products with
low deuterium content (D-content), require a large amount of
catalyst or special apparatuses, and lack regioselectivity.
Therefore, from the synthetic point of view, the development
of a more applicable deuterium exchange method which can be
performed under mild reaction conditions is desired.
Initially, we chose to study the photochemical decarboxyl-
ative deuterium exchange reaction of N-Boc-L-amino acids (1)
as summarized in Table 1. An acetonitrile–deuterium oxide
solution (CH3CN/D2O = 9 : 1) containing phenanthrene
(Phen, 10 mM), 1,4-dicyanobenzene (DCB, 10 mM), tert-
dodecanethiol (R0SH, 20 mM), and N-Boc-L-phenylalanine
(1a) (10 mM) was irradiated with a 400 W high-pressure
mercury lamp through a Pyrex filter (l > 280 nm) under an
argon atmosphere at room temperature. This resulted in the
deuterated product 2a in 87% yield as a racemic mixture. As
determined by 1H NMR, the D-content of 2a was >95%, and
there was near-quantitative recovery (>90%) of Phen, DCB
and R0SH10 (Table 1, entry 1).11 Although the photoreaction
of 1a gave 2a in high D-content (>95%) even with slight
amounts of D2O (entries 2 and 3), a solution of CH3CN/D2O =
99 : 1 was less effective (entry 4). Thus, a solution of
CH3CN/D2O = 98 : 2 was found to be optimal in terms of
isolated yield (91%) and D-content (>95%) for the photo-
reaction of 1a (entry 3). We therefore used this solvent for the
photoreactions of 1b–f. As a result, most of the N-Boc amino
acids successfully underwent decarboxylative deuteration
(entries 5–8). It is noteworthy that the photoreaction of
N-Boc-L-glutamic acid (1f), which has two carboxy groups,
selectively gave the deuterated product of the a-carboxy group
(entry 9). As expected, this selectivity resulted from the
difference in acidity between the a-carboxy group and the side
chain carboxy group.8a
Recently, we successfully demonstrated the efficient decarboxyl-
ation of free carboxylic acids to form free alkyl radicals in a
redox-photosensitized reaction7 system.8 Photochemically
generated alkyl radicals can react with a thiol to yield reduc-
tion products via hydrogen atom transfer,8a with the anion
radical of dicyanobenzene to yield alkylcyanobenzenes,8b with
electron-deficient alkenes to form C–C bonds,8c,d or with
glyoxylic oxime ether to yield a-substituted a-aminoesters.8e
During the course of examining deuterium incorporation
to elucidate its mechanisms, we noticed that the carboxy
group was selectively subjected to the deuterium exchange
reaction with a thiol to afford the corresponding deuterated
product in the presence of D2O. Although it has been reported
a Department of Applied Chemistry, College of Life Sciences,
Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu 525-8577,
Japan. E-mail: t-itou@fc.ritsumei.ac.jp; Tel: +81 77-561-2810
b Department of Applied Chemistry and Biotechnology,
Graduate School of Engineering, University of Fukui,
3-9-1 Bunkyo, Fukui 910-8507, Japan
Next, we examined the photochemical decarboxylative
deuteration of other carboxylic acids (3) derived from natural
products (Table 2). The photoreactions of a range of N-protected
peptides such as N-Boc-GlyVal-OH dipeptide (3a) and
N-Boc-GlyValVal-OH tripeptide (3b) afforded the corres-
ponding deuterated products 4a and b in good chemical yield
with high D-content (Table 2, entries 1 and 2). A uniformly
high D-content was obtained in the photoreaction of aliphatic
c Department of Chemistry and Materials Technology,
Kyoto Institute of Technology, Matsugasaki, Sakyo-ku,
Kyoto, 606-8585, Japan
d Department of Medicinal and Organic Chemistry,
School of Pharmacy,
Iwate Medical University, Yahaba, Iwate 028-3694, Japan
w Electronic supplementary information (ESI) available: Experimental
procedure and spectral data for deuterated products. See DOI:
10.1039/c0cc01464h
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Table 1 Decarboxylative deuteration of N-Boc amino acids 1a–fa
Table 2 Decarboxylative deuteration of free carboxylic acids 3a–d
Yield of 4a
(%)
D-contentb
(%)
Irradiation
Entry time/h
3
77
>95
1c
8
3a;
73
>95
2c
8
3b;
84
>95
3d
32
3c; CH3(CH2)9CO2H
Entry
1
CH3CN/D2O
Yield of 2b (%)
D-contentc (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
9 : 1
87
85
91
89
89
50
92
81
41
>95
>95
>95
57
>95
>95
>95
>95
>95
95 : 5
98 : 2
99 : 1
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
67
82
4d
12
3d;
a
b
Isolated yield based on 3. The deuterium content of the product
was determined by 1H NMR spectroscopy. The photoreactions were
c
a
The photoreactions were carried out with 0.6 mmol (10 mM) of 1,
0.6 mmol (10 mM) of Phen, 0.6 mmol (10 mM) of DCB, and 1.2 mmol
(20 mM) of R0SH using a 400 W high-pressure mercury lamp under an
carried out with 0.6 mmol (10 mM) of 3a–b, 0.6 mmol (10 mM) of
Phen, 0.6 mmol (10 mM) of DCB, and 1.2 mmol (20 mM) of R0SH
using a 400 W high-pressure mercury lamp under an argon atmosphere
b
c
d
argon atmosphere for 8 h. Isolated yield based on 1. The deuterium
1
content of the product was determined by H NMR spectroscopy.
in CH3CN/D2O = 98 : 2. The photoreaction was carried out with
0.6 mmol (10 mM) of 3c–d, 0.6 mmol (10 mM) of Phen, 0.6 mmol
(10 mM) of DCB, 1.2 mmol (20 mM) of R0SH, and 0.6 mmol (10 mM)
of NaOH using a 400 W high-pressure mercury lamp under an argon
atmosphere in CH3CN/D2O = 9 : 1.
acid (3c) (entry 3).12 In contrast, acid of sugar 3d gave a
modest D-content (82%) (entry 4).12 The reason for the
decrease in the D-content is not clear at this stage.
To demonstrate the scope of the regioselective deuterium
exchange reaction, the photoreactions of monocarboxylic acid
(5) and dicarboxylic acid (7) were examined (Scheme 1).12 It
should be emphasized that the carboxy group was entirely
substituted by deuterium atoms to afford the corresponding
deuterated products 6 and 8 in high D-content. That forma-
tion of a by-product containing a deuterium atom at the
b-position to the carboxy group did not occur indicates that
the regioselective deuterium exchange reaction of carboxy
groups can proceed in this photoreaction.
Scheme 2 illustrates a plausible mechanism for the present
reaction, which can be explained as follows. First, the photo-
chemical electron transfer (PET) between the excited Phen and
DCB would lead to a cation radical of Phen and an anion radical
of DCB (eqn (1)). This would be followed by a secondary
electron transfer from carboxylate ions to the cation radical of
Phen. These processes would afford the carboxy radical, which
is decarboxylated to form the alkyl radicals (eqn (2)).8 Sub-
sequently, the generated alkyl radicals could abstract a deuterium
atom from the R0SD formed instantly by the hydrogen–
deuterium exchange between R0SH and D2O13 (eqn (3)), to
yield the deuterated product and the thiyl radical 9 (eqn (4)).
The processes are terminated by back electron transfer (BET)
from the anion radical of DCB to the thiyl radical 9 to produce
Scheme 1 Photodecarboxylative deuteration of monocarboxylic acid
5 and dicarboxylic acid 7.
the anion 10, which undergo deuteration to recover R0SD
(eqn (5)).
In conclusion, we have demonstrated that the deuterium
exchange of the carboxy group, induced by the decarboxylation
of free carboxylic acids via a redox-photosensitized reaction
system, proceeds smoothly under mild conditions to produce
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Scheme 2 Plausible mechanism.
regioselective deuterated products with excellent D-content.
The approach offers a new methodology for labeling peptides,
enzymes and sugar chains with deuterium. Further application
of the present method is in progress with the aim of developing
an enantioselective deuterium exchange reaction.
This work was supported by Mitsubishi Gas Chemical
Company Award in Synthetic Organic Chemistry, Japan,
and the Sasagawa Scientific Research Grant from the Japan
Science Society.
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Chem. Commun., 2010, 46, 6177–6179 | 6179