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J. M. Concello´n, M. Huerta / Tetrahedron Letters 43 (2002) 4943–4946
dideuterioesters
diastereoisomers since the incorporation of deuterium
generates two stereogenic centres.
3
were isolated as mixture of
presence of in situ generated SmI2, afforded the corre-
sponding 2,3-dideuterioesters 3. We understand this
synthesis to be the first example of a sequenced process
using metallic samarium.
This sequenced process is both convenient and efficient,
and taking into account that D2O is the cheapest
deuteration reagent available for obtaining organic
compounds isotopically labeled with deuterium, the
described methodology can be chosen to prepare 2,3-
dideuterioesters.
So, the treatment of 2-halo-3-hydroxyesters 1 in THF
at 0°C with a mixture of diiodomethane (5 equiv.) and
samarium metal (5 equiv.) for 2 h, allowing the reaction
mixture at room temperature, and further reaction with
D2O (2 mL) for 30 min at room temperature, afforded
the corresponding 2,3-dideuterioesters 3 in high yield.
This transformation took place through an efficient
sequenced elimination/reduction process without the
isolation of 2 (Scheme 1).
In a typical procedure, a solution of 2-halo-3-hydroxy-
ester 1 (0.4 mmol) in THF (4 mL) and diiodomethane
(2 mmol, 0.16 mL) were successively added to a suspen-
sion of samarium powder (2 mmol, 0.344 g) in THF (24
mL) at 0°C. The reaction mixture was warmed to room
temperature and stirred for 2 h and then D2O (2 mL)
was added at the same temperature. After stirring for
30 min, the reaction mixture was quenched with 0.1 M
aqueous HCl (5 mL). Usual workup provided crude
2,3-dideuterioesters 3, which were purified by column
flash chromatography over silica gel (hexane:ethyl ace-
tate, 5:1) provided pure compounds 3.
The starting compounds 1 were easily prepared by
reaction of the corresponding lithium enolates of a-
haloesters (generated by treatment of a-haloesters with
LDA at −85°C) with aldehydes at −78°C.
The reaction time for this sequential process promoted
by Sm/CH2I2 was shorter (2.5 h) than using preformed
SmI2 (3 h to generate SmI2+1 h of reaction with SmI2).3
Table 1 summarizes the results. The yields of the
obtained 2,3-dideuterioesters 3 by using Sm/CH2I2 are
higher than by using preformed SmI2.3 R1, R2, and R3
can be varied widely: R1 can be aliphatic (linear,
branched, or cyclic), unsaturated, or aromatic groups,
while R2 can be aliphatic and aromatic. Moreover, the
sequenced reaction was unaffected by the presence of
bulky groups R3 on the carboxyl ester (Table 1, entry
4).
When the reaction was carried out by using H2O
instead of D2O, saturated esters 4 were obtained and no
important differences were observed (Table 1, entry 7).
3-Deuterioesters 5 can be prepared by the successive
treatment of the obtained 2,3-dideuterioesters 3 with
LDA and H2O (Scheme 2). Thus, the reaction of 3e
with LDA and further hydrolysis afforded the corre-
sponding 3-deuterioester 5e in 91% yield.
1
The position of deuteration was established by H and
The transformation of the starting compounds 1 into
3-hydroxyesters 6 can be achieved by modifying the
proposed methodology. Treatment of 1f with Sm/
CH2I2/MeOH gave the corresponding 3-hydroxyester 6f
13C NMR spectrometry of the 2,3-dideuterioesters 3,
while complete deuterium incorporation (>99%) was
determined by mass spectroscopy.15 The obtained 2,3-
Table 1. Synthesis of 2,3-dideuterioesters 3 or saturated esters 4
Entry
Producta
R1
R2
R3
X
Yieldb
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
C7H15
Cyclohexyl
PhCH(Me)
Me2CꢀCH(CH2)2CH(Me)CH2
p-MeO-C6H4
Ph
Ph
Me
Me
C4H9
Ph
Me
Et
Et
Et
iPr
Et
Et
Et
Cl
Cl
Br
Cl
Cl
Br
Br
95
87
80
98
99
60
65
C4H9
C4H9
4fc
a All products were fully characterized by spectroscopic methods (IR, NMR and MS).
b Isolated yield after column chromatography based on compound 1.
c In this case, H2O was added instead of D2O, obtaining the saturated ester 4f, without deuterium.
D
D
CO2Et
Me
CO2Et
1. LDA, -78ºC, 30 min
Me
2. H2O
D
MeO
MeO
5e
3e
Scheme 2.
Concellón, José M
