Deuteration of α,β-acetylenic esters, amides, or carboxylic acids without using deuterium gas: Synthesis of 2,2,3,3-tetradeuterioesters, amides, or acids

Article abstract of DOI:10.1016/j.tetlet.2004.01.051

An easy, simple, rapid, and nonhazardous deuteration of the C-C triple bond of α,β-acetylenic esters, amides, or acids by means of samarium diiodide in the presence of D₂O, provides an efficient method for synthesizing 2,2,3,3-tetradeuterioesters, amides, or carboxylic acids, respectively. When H₂O is used instead of D₂O, saturated carboxylic esters, amides, or acids were isolated. A mechanism to explain these reduction reactions has been proposed.

Full text of DOI:10.1016/j.tetlet.2004.01.051

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2129–2131
Deuteration of a,b-acetylenic esters, amides, or carboxylic acids
without using deuterium gas: synthesis of 2,2,3,3-
tetradeuterioesters, amides, or acids
*
Jos ꢀe M. Concell oꢀ n, Humberto Rodr ꢀı guez-Solla and Carmen Concell oꢀ n
Departamento de Qu ꢀı mica Org ꢀa nica e Inorg ꢀa nica, Facultad de Qu ꢀı mica, Universidad de Oviedo,
Juli ꢀa n Claver ꢀı a, 8, 33071 Oviedo, Spain
Received 15 December 2003; revised 8 January 2004; accepted 13 January 2004
Abstract—An easy, simple, rapid, and nonhazardous deuteration of the C–C triple bond of a; b-acetylenic esters, amides, or acids by
means of samarium diiodide in the presence of D
amides, or carboxylic acids, respectively. When H O is used instead of D
2
O, provides an efficient method for synthesizing 2,2,3,3-tetradeuterioesters,
O, saturated carboxylic esters, amides, or acids were
2
2
isolated. A mechanism to explain these reduction reactions has been proposed.
Ó 2004 Elsevier Ltd. All rights reserved.
Isotopically labeled compounds are very useful to
establish the mechanism of organic reactions and the
biosynthesis of many natural compounds. However,
by using the nonhazardous SmI
of significant value.
2 2
/D O system would be
1
there is only a methodology describing the conjugated
reduction, employing a deuterium source, of a,b-acetyl-
enic acid derivatives. Specifically, a,b-acetylenic esters
have been deuterated by using methanol-D and mag-
With regard to the synthetic application of samarium
4
diiodide in organic synthesis, only two papers have
been published concerning its use in selective reduction
of alkynes. In the first, cis- or trans-olefins are obtained
by using different alcohols or acetic acid as proton
2
nesium, and the same methodology has been used to
prepare 2,2,3,3-tetradeuterioacids in two steps (deuter-
5
donors in the presence of transition metal catalysts. In
the second phenylacetylene and diphenylacetylene are
reduced to ethylbenzene and dibenzyl, respectively, it is
3
ation of a,b-acetylenic esters and further hydrolysis).
This methodology is hazardous due to generation of D
2
gas and when methyl a,b-acetylenic esters are not used,
transesterification reaction takes place and a mixture of
different esters can be isolated.
2
necessary for H O and pentamethylethylene triamine to
be present for these reactions to occur.
6
3
Previously we described a practical methodology for the
synthesis of various deuterated compounds such as 2,3-
Although catalytic deuteration may be possible to use,
to the best of our knowledge, no reduction of a,b-acet-
ylenic esters, amides, or acids with deuterium gas have
been described. This lack of examples may be due to the
7
dideuterioesters or amides, (E)-a,d-dideuterio-b,c-
unsaturated esters, and 2,3-dideuterioacids.
8
9
fact that D gas is hazardous, its availability may be
2
In the present contribution we describe a novel and
rapid method to obtain 2,2,3,3-tetradeuterioesters,
amides, or carboxylic acids by an efficient, simple,
and nonhazardous reduction of the C–C triple bond of
a,b-acetylenic esters, amides, or carboxylic acids, the
affected by regulations, and, in general, methodologies
involving the use of gas are tedious or must be per-
formed under pressure. For all these reasons, the
development of a simple alternative method for the
synthesis of 2,2,3,3-tetradeuterioesters, amides, or acids
reaction being promoted by SmI
2
in the presence of
D O. This reduction can be also carried out by using
2
H O instead of D O, obtaining the corresponding
2 2
saturated esters, amides, or carboxylic acids 2. A
mechanism to explain these reduction reactions has been
proposed.
Keywords: Deuterium; Reductions; Samarium diiodide.
*
Corresponding author. Tel.: +34-985-103457; fax: +34-985-103446;
e-mail: jmcg@sauron.quimica.uniovi.es
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.051

2130
J. M. Concell ꢀo n et al. / Tetrahedron Letters 45 (2004) 2129–2131
Table 1. Synthesis of 2,2,3,3-tetradeuterioesters, amides and acids
X ¼ D)
(
a
Entry
2
R
Y
Yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Ph
OEt
OEt
OEt
NEt
84
83
90
81
86
91
71
75
79
C
C
5
6
H
H
11
13
Ph
2
Scheme 1. Synthesis of 2,2,3,3-tetradeuterioesters and amides (X=D).
C
C
5
6
H
H
11
NMe
NMe
OH
2
13
2
2g
2h
2i
Ph
Our first attempts involved the preparation of 2,2,3,3-
tetradeuterioesters or amides. Thus, a solution of the
starting acetylenic esters or amides (1 equiv) in THF and
C
C
5
6
H
H
11
OH
OH
13
a
10
Isolated yield after column chromatography based on compound 1.
D
2
O was stirred with a solution of SmI
2
(6 equiv) in
THF for 30 min at room temperature, affording after
acidification with HCl 0.1 M the corresponding 2,2,3,3-
tetradeuterioesters or amides 2 in high yield (Scheme 1).
NMR spectrometry of products 2a–i, and was found to
1
13
be >95%. Moreover, H, C NMR of compounds 2c,f,i,
have been compared with the corresponding nondeu-
terated products.
We also carried out the direct reduction of acetylenic
acids. In this case, a pre-treatment of the corresponding
2
acetylenic carboxylic acid with D O for 1 h at room
2 2
When H O was used instead of D O, no important
differences were observed in the reduction reaction and
saturated ester amide or acids were also prepared (Table
temperature was performed. The reaction of the O–D
acetylenic carboxylic acids with D O for 30 min and
2
2
with a solution of SmI (6 equiv) in THF at room tem-
perature afforded the corresponding 2,2,3,3-tetradeute-
riocarboxylic acid (Scheme 2).
2).
It is noteworthy that D O is the most widely available
2
deuteration reagent for obtaining organic compounds
isotopically labeled with deuterium.
When the acetylenic carboxylic acids were not pre-
treated with D O, no complete deuterium incorporation
2
takes place, affording a mixture of carboxylic acids
bearing different number of deuterium atoms.
Synthesis of labeled compounds 2 may be explained by
11
assuming that the SmI
tiated by a single electron transfer from SmI
2
-promoted reduction of 1 is ini-
to generate
2
1
2
13
The starting acetylenic esters (Y ¼ OEt), amides
the anion radical 3, which is hydrolyzed by the protic
medium (X ¼ D, H), affording the corresponding alkene
14
(
Y ¼ NEt
2
, NMe
2
), or acids (Y ¼ OH) 1 were easily
prepared by reaction of the corresponding lithium
acetylides (generated by treatment of alkynes with BuLi
at )78 °C) with ethyl chloroformiate, diethylcarbamyl-
chloride, or dimethylcarbamylchloride at )30 °C, and
16
radical 4. After a second electron transfer from SmI
the radical generated the anion 5, this being hydrolyzed
by D O to afford the corresponding a,b-unsaturated
2
2
17
carboxylic compound 6. After other successive elec-
tron-transfer and proton-transfer steps the correspond-
ing tetradeuterated ester, amide, or acid 2 is obtained.
When the acetylenic acids were not pre-treated with
15
solid CO at )78 °C, respectively.
2
The reduction described, seems to be general and ali-
phatic or aromatic acetylenic carboxylic acids and their
derivatives can be reduced. Deuterated esters, amides,
and acids were obtained in similar, high, or very high
yields (Table 1).
2
D O, a competitive hydrolysis of 3 and/or 5 produced by
the acid proton of the carboxylic group and D O,
2
affording a mixture of carboxylic acids with differing
numbers of deuterium atoms (Scheme 3).
1
The position of deuteration was established by H and
C NMR spectrometry of compounds 2. The complete
In conclusion, a SmI
enic esters, amides, or acids, in the presence of D
provides an easy, rapid, nonhazardous, and efficient
method for synthesizing aromatic or aliphatic 2,2,3,3-
tetradeuterioesters, amides, or acids in high, or very high
2
-promoted reduction of a,b-acetyl-
O,
13
2
1
13
deuterium incorporation was determined by H,
C
2 2
yields. When H O was used instead of D O, saturated
carboxylic acids and derivatives were isolated. A
mechanism to explain these syntheses has been pro-
posed. The application of samarium diiodide-based C–C
Table 2. Synthesis of saturated esters, amides, and acids (X ¼ H)
a
Entry
2
R
Y
Yield (%)
1
2
3
2j
C
C
C
6
H
13
H
13
H
13
OEt
NMe
OH
87
87
80
2k
2l
6
6
2
a
Scheme 2. Synthesis of 2,2,3,3-tetradeuterioacids (X ¼ D).
Isolated yield after column chromatography based on compound 1.

J. M. Concell ꢀo n et al. / Tetrahedron Letters 45 (2004) 2129–2131
2131
7
8
9
. (a) Concell oꢀ n, J. M.; Rodr ꢀı guez-Solla, H. Chem. Eur. J.
2
001, 7, 4266; (b) Concell oꢀ n, J. M.; Bardales, E.; Llavona,
R. J. Org. Chem. 2003, 68, 1585.
. Concell oꢀ n, J. M.; Bernad, P. L.; Rodr ꢀı guez-Solla, H.
Angew. Chem. 2001, 113, 4015; Angew. Chem., Int. Ed.
2
001, 40, 3897.
. Concell oꢀ n, J. M.; Rodr ꢀı guez-Solla, H. Chem. Eur. J. 2002,
, 4493.
0. A solution of SmI
8
1
2
in THF was very rapidly generated by
the reaction of diiodomethane with samarium powder in
the presence of sonic waves: Concell oꢀ n, J. M.; Rodr ꢀı guez-
Solla, H.; Bardales, E.; Huerta, M. Eur. J. Org. Chem.
2003, 1775.
1. General procedure for the synthesis of 2,2,3,3-tetradeute-
rio or saturated esters, amides, or carboxylic acids (2):
1
2
Under nitrogen, a solution of SmI (6 equiv, 2.75 mmol) in
THF (29 mL) was added dropwise to a stirred solution of
the appropriate starting material 1 (1 equiv, 0.4 mmol) in
Scheme 3. Mechanistic proposal for the conversion of 1 into 2.
2
D O (2mL) and THF (2mL) at room temperature. The
reaction mixture was stirred for 30 min and then treated
with 0.1 M aqueous HCl (5 mL). Standard work-up
afforded the crude tetradeuterio esters or amides 2, which
were purified by flash column chromatography on silica
gel (hexane/ethyl acetate). When the reaction was per-
formed starting from acid carboxylic, the corresponding
triple bond partial reductions for generating olefins is
currently under investigation within our laboratory.
acid was treated with 3 mL of D
mixture was allowed to react with SmI
above. When H O was used instead of D
esters, amides, or carboxylic acids were isolated.
2
O for 1 h. Then, the
as was indicated
O, saturated
Acknowledgements
2
2
2
We acknowledge financial support from III Plan
Regional de Investigaci oꢀ n del Principado de Asturias
PB-EXP01-11) and Ministerio de Ciencia y Tecnolog ꢀı a
BQU2001-3807). J. M. C. thanks Carmen Fern ꢀa ndez-
Fl oꢀ rez for her time. C. C. thanks Ministerio de Ciencia y
Tecnolog ꢀı a for a predoctoral fellowship. Our thanks
to Scott J. S. Hartman for his revision of the
English.
12. (a) Goerger, M. M.; Hudson, B. S. J. Org. Chem. 1988, 53,
3148; (b) Koenig, B.; Pitsch, W.; Klein, M.; Vasold, R.;
Prall, M.; Schreiner, P. R. J. Org. Chem. 2001, 66, 1742.
(
(
1
3. (a) Hartke, K.; Gerber, H. D.; Roesrath, U. Tetrahedron
989, 30, 1073; (b) Piers, E.; Chong, J. M.; Keay, B. A.
Tetrahedron 1985, 26, 6265.
1
1
1
4. Barker, S. A.; Foster, A. B.; Lamb, D. C. Tetrahedron
1
962, 18, 177.
5. General procedure for the synthesis of acetylenic esters,
amides, or acids (1): Under nitrogen, a solution of BuLi
(
100 mmol) was added dropwise to a stirred solution of the
References and notes
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661.
2
2
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