Sequential elimination-reduction reactions promoted by samarium diiodide: Synthesis of 2,3-dideuterioesters or -amides

Article abstract of DOI:10.1002/1521-3765(20011001)7:19<4266::AID-CHEM4266>3.0.CO;2-8

A facile and general sequential elimination/reduction process promoted by samarium diiodide provides an efficient method for synthesizing saturated esters or amides 3 from readily available starting materials. The reaction involves a β-elimination of the starting 2-halo-3-hydroxyesters or -amides 1 and subsequent 1,4-reduction of the obtained α,β-unsaturated esters or amides in the presence of H₂O. When D₂O is used instead of H₂O, 2,3-dideuterioesters or -amides 4 are isolated. A mechanism is proposed to account for this synthesis.

Full text of DOI:10.1002/1521-3765(20011001)7:19<4266::AID-CHEM4266>3.0.CO;2-8

FULL PAPER
Sequential Elimination ± Reduction Reactions Promoted by Samarium
Diiodide: Synthesis of 2,3-Dideuterioesters or -amides
Jose M. ConcelloÂn* and Humberto Rodríguez-Solla[a]
Abstract: A facile and general sequential elimination/reduction process promoted
by samarium diiodide provides an efficient method for synthesizing saturated esters
Keywords: deuterium ´ elimination ´
reduction ´ samarium ´ sequential
reactions
or amides 3 from readily available starting materials. The reaction involves a b-
elimination of the starting 2-halo-3-hydroxyesters or -amides 1 and subsequent 1,4-
reduction of the obtained a,b-unsaturated esters or amides in the presence of H2O.
When D2O is used instead of H2O, 2,3-dideuterioesters or -amides 4 are isolated. A
mechanism is proposed to account for this synthesis.
this reason, the development of an effective general method
for the synthesis of 2,3-dideuterioesters or -amides would
seem to be a valuable goal.
Introduction
Sequential reactions are of enormous potential because
considerably less time, effort, and material are required to
obtain organic compounds with respect to more traditional
multi-step procedures. One reagent that exhibits excellent
properties for sequential organic reactions is samarium
diiodide.[1]
We recently described the first general methodology for the
promotion of b-elimination reactions using SmI2. We reported
a highly stereoselective synthesis of (Z)-vinyl halides from O-
acetylated 1,1-dihaloalkan-2-ols,[2] as well as a novel prepara-
tion of a,b-unsaturated esters[3] or amides[4] with total or very
high selectivity by treatment of the readily available 2-halo-3-
hydroxyesters or -amides, respectively, with samarium diio-
dide.
On the other hand, selective conjugated reduction of a,b-
unsaturated carboxylic acid derivatives is a useful reaction in
organic chemistry and has been achieved by using several
methodologies.[5] However, the conjugated reduction of a,b-
unsaturated esters or amides with deuterium instead of
hydrogen has been scarcely reported. To the best of our
knowledge, only two alternative methodologies to the ex-
pensive catalytic addition of D2 to a,b-unsaturated esters[6]
have been described, specifically, the use of enzymes in D2O,[7]
and treatment with CD3OD or D2O in the presence of
metals.[8] Similarly, in the case of deuteration of a,b-unsatu-
rated amides, only two examples have hitherto been de-
scribed,[9] both of which involved catalytic addition of D2. For
With regard to the synthetic application of samarium
diiodide in organic synthesis, three papers have been pub-
lished concerning its use in the conjugated reduction of a,b-
unsaturated esters or amides. In two of these methodologies,
additives such as N,N-dimethylacetamide (DMA)[10] or hexa-
methyl phosphoramide (HMPA)[11] were required to facilitate
the reduction; in the third case, the reduction was carried out
in the presence of methanol as a proton source.[12] However, to
the best of our knowledge, the simplest 1,4-reduction of
conjugated carboxylic acid derivatives by using SmI2 and H2O
or D2O has not been described.[13]
In the present contribution, we describe a novel means of
obtaining saturated esters or amides 3 by an efficient
sequential process. Thus, a b-elimination reaction of 2-halo-
3-hydroxyesters or -amides 1 promoted by SmI2, followed by a
1,4-reduction of the obtained a,b-unsaturated esters or
amides with H2O in the presence of SmI2, has been found to
afford the corresponding saturated esters or amides. In view
of the utility of isotopically labeled compounds in establishing
the mechanisms of organic reactions and of the biosynthesis of
many natural compounds,[14] we have also applied this
methodology to obtain 2,3-dideuterioesters or -amides 4 by
using D2O instead of H2O.
Results and Discussion
Synthesis of saturated esters and amides: The 2-halo-3-
hydroxyesters or -amides 1 used as starting compounds were
easily prepared by reactions of the corresponding lithium
enolates of a-haloesters or -amides (generated by treatment
of a-haloesters or a-chloroamides 2 with LDA at 788C)
with aldehydes at 788C (Scheme 1).
Â
[a] Dr. J. M. Concellon, H. Rodríguez-Solla
Â
Â
Departamento de Química Organica e Inorganica
Facultad de Química, Universidad de Oviedo
33071 Oviedo (Spain)
Fax : (‡34)98-510-34-46
E-mail: jmcg@sauron.quimica.uniovi.es
4266
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0719-4266 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 19

4266±4271
room temperature, and then with D2O (2 mL) for 30 min,
afforded the corresponding 2,3-dideuterioesters 4a ± e or
amides 4i ± m, respectively, in high yields (Scheme 3). The
yields obtained in the syntheses of 2,3-dideuterated com-
pounds 4 are shown in Table 2. When the conjugated
reduction was incomplete at room temperature, this step
was carried out under reflux and an additional three
equivalents of SmI2 were added (Table 2).[15]
Scheme 1. Synthesis of the starting compounds 1.
With the requisite substrates in hand, preliminary studies
were performed to determine the optimum reaction condi-
tions for preparing saturated esters. Reaction of 2-halo-3-
hydroxyesters with a solution of SmI2 (5 equivalents) in THF
for 30 min at room temperature afforded the corresponding
a,b-unsaturated esters, which were treated with H2O (2 mL)
at the same temperature to give, after stirring for 30 min, the
corresponding saturated esters 3e ± g in high yield as a result
of a conjugated reduction (Scheme 2).
Scheme 3. Synthesis of 2,3-dideuterioesters or -amides 4.
The position of deuteration was established by 1H and
13C NMR spectroscopy of compounds 4, while the complete
deuterium incorporation (>99%) was verified by mass
spectrometry.[16] These 2,3-dideuterio compounds were iso-
1
lated as mixtures of stereoisomers (roughly 1:1 by H NMR
spectroscopy and GC-MS).
Scheme 2. Synthesis of the saturated compounds 3.
This proposed methodology for obtaining saturated esters
or amides 3 and 2,3-dideuterioesters or -amides 4 is general:
R1 and R2 can be varied widely. Thus, aliphatic (linear,
branched, or cyclic), unsaturated, or aromatic aldehydes may
be used to introduce different R1 groups; R2 may also be
varied using different a-chloroesters or -amides to prepare the
starting compounds 1 (Scheme 1). The synthesis of 2,3-
dideuterioesters was also found to tolerate the presence of
To prepare the saturated amides 3l and 3m, a longer
reaction time (120 min) was necessary to achieve the required
elimination due to the somewhat lower reactivity of the
starting 2-chloro-3-hydroxyamides as compared to the es-
ters.[4] The results obtained for the synthesis of saturated
esters and amides are summarized in Table 1.
ˆ
other C C double bonds (Table 2, entry 4), and proved to be
unaffected by the presence of bulky groups R3 on the carbonyl
ester (Table 2, entry 4).
Table 1. Synthesis of saturated esters and amides 3.
Entry
Compounds 1
Products 3
R2
1
Hal
3
R1
pMeO-C6H4 Me
C7H15
Ph
Y
Yield [%][a]
It is noteworthy that D2O is the cheapest deuteration
reagent available for obtaining organic compounds isotopi-
cally labeled with deuterium.
1
2
3
4
5
6
1e
1 f
1g
1l
Cl
Cl
Br
Cl
Cl
3e
3 f
3g
3l
OEt 84
OEt 68
H
C4H9 OEt 60
H
Me
H
The synthesis of 2,3-dideuterioesters can also be carried out
starting from the corresponding a,b-unsaturated esters or
amides. Thus, successive treatment of methyl cinnamate with
SmI2 (2.5 equivalents) for 30 min at room temperature, and
then with D2O (2 mL) for 30 min afforded methyl 2,3-
dideuterio-3-phenylpropanoate (4h) in 69% yield. In the
case of cinnamamide, the corresponding saturated amide 3n
(73% yield) was obtained by using H2O as a proton source
under the same reaction conditions. However, when D2O was
used, a roughly 3:1 mixture of 2,3-dideuterio-3-phenylpropan-
amide and 3-phenylpropanamide was obtained as a conse-
quence of competitive hydrolysis arising from H/D exchange
of the NH2 protons (see proposed mechanism). Accordingly,
when the cinnamamide was pre-treated with D2O, 2,3-
dideuterio-3-phenylpropanamide (4n) was isolated as the
sole product. In accordance with the literature,[17] no 1,4-
reduction was observed[18] for a,b-unsaturated amides incor-
Ph
NEt2 96
NEt2 69
NH2 73
1m
3m Ph
3n[b] Ph
[a] Isolated yield after column chromatography based on compound 1
consumed. [b] See discussion of results.
Synthesis of 2,3-dideuterioesters and -amides: No significant
differences were observed in the reaction when D2O was used
instead of H2O. Thus, the successive treatment of 2-halo-3-
hydroxyesters or -amides 1 with a solution of SmI2 (5 equiv-
alents) in THF, for 30 min (esters) or 120 min (amides) at
Â
Â
Abstract in Spanish: La reaccion secuencial de eliminacion ±
Â
Â
reduccion de 2-halogeno-3-hidroxiesteres o amidas, promovida
Â
por diyoduro de samario, conduce a esteres o amidas saturadas
ˆ
porating a tetrasubstituted C C bond.
Â
en presencia de H2O. Cuando la reaccion se lleva a cabo en
The described methodology can be used to obtain 2,3-
dideuterated, 2- or 3-monodeuterated, and non-deuterated
esters or amides. Thus, starting from ethyl 2-chloro-3-
hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate, the cor-
responding 2,3-dideuterated ester 4e or saturated ester 3e
presencia de D2O, se aislan los correspondientes 2,3-dideute-
Â
Â
Â
rioesteres o amidas. El metodo que se describe, es simple, facil,
Â
general y los compuestos de partida son facilmente accesibles.
Se propone un mecanismo para explicar este proceso.
Chem. Eur. J. 2001, 7, No. 19
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0719-4267 $ 17.50+.50/0
4267

Â
J. M. Concellon and H. Rodríguez-Solla
FULL PAPER
Table 2. Synthesis of 2,3-dideuterioesters and -amides 4.
Entry
Compounds 1
Hal
Products 4
1
4
R1
R2
Y
Yield [%][a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
Cl
Cl
Br
Cl
Cl
4a
4b
4c
4d
4e
4h[c]
4i
4j
4k
4l
C7H15
Me
Me
C6H13
Ph
Me
H
H
H
H
H
OEt
OEt
OEt
OiPr
OEt
OMe
NEt2
NEt2
NEt2
NEt2
NEt2
NH2
68
60
96
69
84
69
67
77
65
85
57
73
cyclohexyl[b]
PhCH(Me)
ˆ
Me2C CH(CH2)2CH(Me)CH2
pMeO-C6H4
Ph
1i
1j
1k
1l
1m
Cl
Cl
Cl
Cl
Cl
cyclohexyl[b]
C7H15
PhCH(Me)
Ph
Ph
Ph
10
11
12
4m
Me
H
4n[c]
[a] Isolated yield after column chromatography based on compound 1 consumed. [b] When D2O was added (second step), a further three equivalents of SmI2
were also added and the reaction was allowed to proceed under reflux. [c] See discussion of results.
of the obtained a,b-unsaturated esters or amides is initiated
by oxidative addition of the reagent to generate the enolate
radical 10,[21] which, after a second electron transfer from SmI2
and hydrolysis with H2O or D2O, affords the corresponding
compound 3 or 4 (Scheme 5).
Conclusion
The SmI2-promoted elimination/reduction sequence (in the
presence of H2O) provides an efficient method for synthesiz-
ing saturated esters or amides. The reaction involves b-
elimination from 2-chloro-3-hydroxyesters or -amides and
subsequent 1,4-reduction of the obtained a,b-unsaturated
esters or amides. When D2O is used instead of H2O, 2,3-
dideuterioesters or -amides are isolated. The present method
is easy, simple, and general, and the starting compounds are
readily available. Moreover, the cheap deuterium source D2O
is used to obtain the isotopically labeled esters and amides. A
mechanism has been proposed to account for this synthesis.
(without deuterium) were obtained by using D2O or H2O,
respectively. Reaction of 4e with LDA and further hydrolysis
afforded the corresponding 3-deuterioester 5e, while the
successive treatment of 3e with LDA and D2O gave the
2-deuterioester 6e.
The starting compounds 2 may be converted to 2-deuterio-
3-hydroxyesters 7[16] by a modification of the proposed
methodology. Thus, treatment of 1b and 1e with a solution
of samarium diiodide in THF/D2O gave the corresponding
monodeuterated 3-hydroxyesters 7b and 7e in 66 and 72%
yield, respectively (Scheme 4), this transformation being
difficult to achieve through other methodologies.[19] Indeed,
compounds 7 are difficult to prepare by other synthetic
routes.[20]
Experimental Section
General: Reactions requiring an inert atmosphere were conducted under
dry nitrogen in oven-dried (1208C) glassware. THF was distilled from
sodium/benzophenone immediately prior to use. All reagents were
purchased from Aldrich or Merck and were used without further
purification. Samarium diiodide was prepared by the reaction of CH2I2
with samarium powder.[22] 2-Chloroamides 2 were prepared by reacting
amines with the appropriate 2-chloro acid chlorides, which, in turn, were
obtained according to a literature procedure from the corresponding
carboxylic acids.[23] Silica gel for flash chromatography was purchased from
Merck (230 ± 400 mesh); compounds were visualized on analytical thin-
layer chromatograms (TLC) by exposure to UV light (254 nm). All NMR
spectra were recorded at room temperature. 1H NMR spectra were
recorded at 200 or 300 MHz. 13C NMR spectra were accumulated and
DEPT experiments were carried out at 50 or 75 MHz. Chemical shifts are
given in ppm relative to tetramethylsilane (TMS), which was used as an
internal standard; coupling constants (J) are reported in hertz (Hz). GC-
MS (HP 5973) and HRMS (Finnigan MAT 95) were measured at 70 eV.
Only the most important IR absorptions (in cm 1) and the molecular ions
and/or base peaks in the mass spectra are listed.
Scheme 4. Synthesis of 2-deuterio-3-hydroxyesters 7.
Mechanism: The synthesis of 3 and 4 may be rationalized by
assuming that the metalation of the halogen of 1 with SmI2
generates the enolate intermediate 8. In the absence of a
proton/deuteron source (H2O or D2O), 8 undergoes elimi-
nation to afford (E)-a,b-unsaturated esters or amides 9 with
total or high selectivity.[3, 4] When the metalation is carried out
in the presence of D2O, the corresponding 2-deuterio-3-
hydroxyester 7 is isolated. The SmI2-promoted 1,4-reduction
The preparation and characterization of the following compounds are
described in reference [4]: 2-chloro-N,N-diethyl-3-hydroxydecanamide
(1j),
2-chloro-N,N-diethyl-3-hydroxy-4-phenylpentanamide
(1k),
4268
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0719-4268 $ 17.50+.50/0 Chem. Eur. J. 2001, 7, No. 19

Sequential Reactions
4266±4271
(CH2), 22.3 (CH2), 22.2 (CH2), 18.7 (CH3), 14.0
(CH3), 13.8 (CH3), 13.7 (CH3); IR (neat): nÄ ˆ
3490, 1729 cm 1; Rf ˆ 0.2 (hexane/AcOEt, 5:1)
Isopropyl
2-chloro-3-hydroxy-5,9-dimethyl-2-
phenyldec-8-enoate (1d): 1H NMR (200 MHz,
CDCl3): d ˆ 7.57 ± 7.33 (m, 10H), 5.15 ± 5.02 (m,
4H), 4.65 ± 4.42 (brm, 2H), 2.2 ± 1.0 (m, 38H),
0.96 ± 0.76 (m, 8H); 13C NMR (50 MHz, CDCl3):
d ˆ 169.8 (C), 169.4 (C), 136.2 (C), 135.9 (C),
130.2 (C), 128.0 (CH), 127.9 (CH), 127.8 (CH),
127.4 (CH), 127.1 (CH), 126.0 (CH), 125.9 (CH),
124.5 (CH), 124.4 (CH), 74.2 (CH), 74.0 (CH),
70.1 (CH), 70.0 (CH), 58.7 (C), 38.9 (CH2), 38.7
(CH2), 37.6 (CH2), 37.5 (CH2), 29.0 (CH), 28.3
(CH), 25.3 (CH3), 25.1 (CH2), 24.9 (CH2), 25.3
(CH3), 20.9 (CH3), 20.8 (CH3), 20.7 (CH3), 20.2
(CH3), 20.1 (CH3), 18.5 (CH3), 18.4 (CH3), 17.2
(CH3); IR (neat): nÄ ˆ 3525, 1747 cm 1; Rf ˆ 0.3
(hexane/AcOEt, 10:1).
Ethyl 2-chloro-3-hydroxy-3-(4-methoxyphenyl)-
2-methyl-propanoate (1e): 1H NMR (200 MHz,
CDCl3): d ˆ 7.37 ± 7.28 (m, 4H), 6.89 ± 6.83 (m,
4H), 5.17 (s, 1H), 5.15 (s, 1H), 4.27 (q, J ˆ
7.18 Hz, 2H), 4.26 (q, J ˆ 7.18 Hz, 2H), 3.78 (s,
3H), 3.73 (s, 3H), 3.29 (m, 2H), 1.64 (s, 3H), 1.57
(s, 3H), 1.30 (t, J ˆ 7.18 Hz, 6H); 13C NMR
(50 MHz, CDCl3): d ˆ 170.7 (C), 170.3 (C), 129.6
(C), 129.2 (CH), 129.1 (CH), 128.8 (CH), 114.0
(CH), 113.0 (CH), 112.7 (CH), 76.9 (CH), 73.4
(C), 69.6 (C), 62.2 (CH2), 62.1 (CH2), 55.0 (CH3),
54.9 (CH3), 22.5 (CH3), 21.3 (CH3), 13.6 (CH3);
IR (neat): nÄ ˆ 3490, 1737 cm 1; Rf ˆ 0.3 (hexane/
AcOEt, 5:1).
Scheme 5. Mechanism of the sequential elimination/reduction reaction.
Methyl
2-chloro-3-hydroxydecanoate
(1 f):
1H NMR (300 MHz, CDCl3): d ˆ 4.29 (d, J ˆ
3.93 Hz, 1H), 4.12 (d, J ˆ 6.98 Hz, 1H), 4.02 ± 3.81 (m, 2H), 3.74 (s, 6H),
3.11 ± 3.01 (brs, 1H), 2.91 ± 2.81 (brs, 1H), 1.66 ± 1.00 (m, 24H), 0.82 (t, J ˆ
6.32 Hz, 6H); 13C NMR (75 MHz, CDCl3): d ˆ 169.2 (C), 169.0 (C), 72.4
(CH), 71.8 (CH), 61.8 (CH), 59.4 (CH), 53.0 (CH3), 52.8 (CH3), 33.4 (CH2),
32.6 (CH2), 31.6 (CH2), 31.5 (CH2), 29.1 (CH2), 28.9 (CH2), 25.3 (CH2), 25.0
(CH2), 22.4 (CH2), 13.8 (CH3); IR (neat): nÄ ˆ 3452, 1754 cm 1; Rf ˆ 0.3, 0.2
(two diastereoisomers) (hexane/AcOEt, 5:1).
Ethyl 2-bromo-2-butyl-3-hydroxy-3-phenylpropanoate (1g): 1H NMR
(300 MHz, CDCl3): d ˆ 7.46 ± 7.28 (m, 10H), 5.09 (m, 2H), 4.28 (q, J ˆ
7.18 Hz, 4H), 3.19 (brs, 2H), 2.19 ± 1.75 (m, 12H), 1.28 (t, J ˆ 7.18 Hz,
6H), 0.88 (t, J ˆ 6.93 Hz, 6H); 13C NMR (75 MHz, CDCl3): d ˆ 169.9 (C),
169.3 (C), 138.2 (C), 137.7 (C), 128.0 (CH), 127.8 (CH), 127.6 (CH), 123.3
(CH), 78.2 (CH), 77.5 (CH), 62.2 (CH2), 62.0 (CH2), 37.6 (CH2), 36.9 (CH2),
28.1 (CH2), 27.8 (CH2), 22.3 (CH2), 22.2 (CH2), 13.6 (CH3), 13.5 (CH3); IR
(neat): nÄ ˆ 3505, 1725 cm 1; Rf ˆ 0.2 (hexane/AcOEt, 5:1).
2-chloro-N,N-diethyl-3-hydroxy-3-phenylpropanamide (1l), and 2-chloro-
N,N-diethyl-3-hydroxy-2-methyl-3-phenylpropanamide (1m).
Synthesis of 2-halo-3-hydroxyesters or -amides (1):[24] Lithium diisopropyl-
amide [prepared from MeLi (6.4 mL of a 1.5m solution in diethyl ether,
10 mmol) and diisopropylamine (1.4 mL, 10 mmol) in THF (50 mL) at 08C]
was added dropwise to a stirred solution of the appropriate 2-haloester 2
(9 mmol) in dry THF (4 mL) at 858C. After stirring for 10 min, a solution
of the appropriate aldehyde (4.5 mmol) in dry THF (4.5 mL) was added
dropwise at 788C. The reaction mixture was stirred for 1 h and then
quenched by the addition of saturated aqueous NH4Cl solution (5 mL).
Standard workup provided crude 2-halo-3-hydroxyesters 1, which were
purified by flash column chromatography on silica gel (hexane/ethyl
acetate, 10:1) to provide the pure compounds.
Ethyl 2-chloro-3-hydroxy-2-methyldecanoate (1a): 1H NMR (200 MHz,
CDCl3): d ˆ 4.27 (q, J ˆ 7.19 Hz, 4H), 3.98 (d, J ˆ 8.21 Hz, 2H), 2.36 (brs,
2H), 1.73 (s, 6H), 1.45 ± 1.20 (m, 30H), 0.99 ± 0.78 (d, J ˆ 7.19 Hz, 6H);
13C NMR (50 MHz, CDCl3): d ˆ 170.8 (C), 170.5 (C), 73.5 (C), 71.0 (C), 75.8
(CH), 75.5 (CH), 62.09 (CH2), 31.6 (CH2), 31.5 (CH2), 30.9 (CH2), 29.2
2-Chloro-3-cyclohexyl-N,N-diethyl-3-hydroxypropanamide (1i): 1H NMR
(200 MHz, CDCl3): d ˆ 4.97 (s, 1H), 4.30 (s, 1H), 3.51 ± 3.01 (m, 5H), 1.95
(d, J ˆ 13.05 Hz, 1H), 1.55 ± 1.46 (m, 6H), 1.21 ± 0.65 (m, 4H), 1.07 (t, J ˆ
7.18 Hz, 3H), 0.96 (t, J ˆ 7.18 Hz, 3H); 13C NMR (50 MHz, CDCl3): d ˆ
178.7 (C), 74.8 (CH), 52.3 (CH), 41.9 (CH2), 40.2 (CH2), 38.9 (CH), 28.3
(CH2), 28.0 (CH2), 25.7 (CH2), 25.3 (CH2), 25.2 (CH2), 14.0 (CH3), 11.9
(CH3); IR (neat): nÄ ˆ 3368, 1629 cm 1; Rf ˆ 0.4 (hexane/AcOEt, 3:1).
Synthesis of saturated esters and amides (3 and 4): Under nitrogen, a
solution of SmI2 (2.3 mmol) in THF (24 mL) was added dropwise to a
stirred solution of the appropriate 2-halo-3-hydroxyester or -amide 1
(0.4 mmol) in THF (4 mL) at room temperature. After stirring for 30 min
(esters) or 120 min (amides) at the same temperature, H2O or D2O (2 mL)
was added to the solution. The resulting mixture was stirred for 30 min at
this temperature, and then quenched by the addition of 0.1m aqueous HCl
(5 mL). Standard workup afforded the crude saturated esters and amides 3,
which were purified by flash column chromatography on silica gel (eluent:
hexane/AcOEt, 5:1).
(CH2), 29.1 (CH2), 29.0 (CH2), 28.9 (CH2), 26.2 (CH2), 22.4 (CH2), 22.2
1
(CH3), 22.0 (CH3), 13.8 (CH3), 13.7 (CH3); IR (neat): nÄ ˆ 3425, 1741 cm
;
Rf ˆ 0.2 (hexane/AcOEt, 10:1).
Ethyl 2-chloro-3-cyclohexyl-3-hydroxy-2-methylpropanoate (1b): 1H NMR
(300 MHz, CDCl3): d ˆ 4.22 (q, J ˆ 6.67 Hz, 4H), 3.82 ± 3.75 (m, 2H), 2.80 ±
2.35 (m, 2H), 1.95 ± 1.33 (m, 28H), 1.29 (t, J ˆ 6.67 Hz, 6H); 13C NMR
(50 MHz, CDCl3): d ˆ 170.8 (C), 170.3 (C), 78.9 (CH), 78.5 (CH), 73.2 (C),
71.7 (C), 61.7 (CH2), 61.6 (CH2), 40.5 (CH), 40.2 (CH), 30.6 (CH2), 30.3
(CH2), 28.3 (CH2), 27.9 (CH2), 26.0 (CH2), 25.7 (CH2), 25.6 (CH2), 25.5
1
(CH2), 24.6 (CH3), 21.5 (CH3), 13.4 (CH3); IR (neat): nÄ ˆ 3517, 1737 cm
;
Rf ˆ 0.3, 0.2 (two diastereoisomers) (hexane/AcOEt, 10:1).
Ethyl 2-bromo-2-hexyl-3-hydroxy-4-phenylpentanoate (1c): 1H NMR
(200 MHz, CDCl3): d ˆ 7.31 ± 7.23 (m, 10H), 4.20 ± 4.06 (m, 4H), 3.27 ±
3.09 (m, 2H), 1.52 ± 1.11 (m, 36H), 0.89 ± 0.82 (m, 6H); 13C NMR
(50 MHz, CDCl3): d ˆ 170.4 (C), 169.9 (C), 145.1 (C), 141.6 (C), 128.3
(CH), 127.7 (CH), 127.4 (CH), 126.4 (CH), 79.2 (CH), 78.1 (C), 62.3 (CH2),
60.2 (CH2), 42.7 (CH), 38.0 (CH2), 31.1 (CH2), 28.8 (CH2), 27.2 (CH2), 25.8
Ethyl 3-(4-methoxyphenyl)-2-methylpropanoate (3e): 1H NMR (300 MHz,
CDCl3): d ˆ 7.08 (d, J ˆ 8.72 Hz, 4H), 6.81 (d, J ˆ 8.72 Hz, 4H), 4.05 (q, J ˆ
7.18 Hz, 4H), 3.77 (s, 6H), 3.00 ± 2.88 (m, 2H), 2.76 ± 2.56 (m, 4H), 1.19 (t,
Chem. Eur. J. 2001, 7, No. 19
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0719-4269 $ 17.50+.50/0
4269

Â
J. M. Concellon and H. Rodríguez-Solla
FULL PAPER
J ˆ 7.18 Hz, 6H), 1.14 (d, J ˆ 6.67 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d ˆ 176.0 (C), 157.9 (C), 131.3 (C), 129.7 (CH), 113.5 (CH), 60.0 (CH2), 55.0
(CH3), 41.5 (CH), 38.7 (CH2), 16.5 (CH3), 14.0 (CH3); MS (70 eV): m/z (%):
Isopropyl 2,3-dideuterio-5,9-dimethyl-2-phenyldec-8-enoate (4d): 1H NMR
(300 MHz, CDCl3): d ˆ 7.34 ± 7.22 (m, 10H), 5.62 ± 5.58 (m, 2H), 5.12 ± 4.95
(m, 2H), 2.12 ± 1.90 (m, 8H), 1.68 (s, 6H), 1.59 (s, 6H), 1.35 ± 1.05 (m, 8H),
1.23 (d, J ˆ 6.10 Hz, 3H), 1.14 (d, J ˆ 6.11 Hz, 3H), 0.90 ± 0.84 (m, 12H);
13C NMR (75 MHz, CDCl3): d ˆ 173.5 (C), 173.4 (C), 139.5 (C), 139.4 (C),
130.9 (C), 128.3 (CH), 127.7 (CH), 126.9 (CH), 124.7 (CH), 67.6 (CH), 51.7
(t, J ˆ 19.7 Hz, CD), 36.7 (CH2), 34.5 (CH2), 34.4 (CH2), 32.1 (CH), 30.6 (t,
J ˆ 19.2 Hz, CHD), 25.6 (CH3), 25.4 (CH2), 21.7 (CH3), 21.5 (CH3), 19.3
‡
222 (80) [M] , 177 (12), 149 (18), 121 (100); HRMS calcd for C13H18O3:
222.1251; found: 222.1256; IR (neat): nÄ ˆ 3026, 2977, 2836, 1730, 1584, 1462,
1349 cm 1; Rf ˆ 0.3 (hexane/AcOEt, 10:1).
Ethyl decanoate (3 f): The 1H and 13C NMR spectra of the product obtained
were identical to those of a commercial sample.
‡
(CH3), 17.5 (CH3); MS (70 eV): m/z (%): 318 (38) [M] , 193 (3), 178 (14),
1
Ethyl 2-butyl-3-phenylpropanoate (3g): H NMR (300 MHz, CDCl3): d ˆ
137 (100); HRMS calcd for C21H30D2O2: 318.2402; found 318.2522; IR
(neat): nÄ ˆ 3084, 3060, 2927, 2860, 1727, 1375 cm 1; Rf ˆ 0.5 (hexane/AcOEt,
5:1).
7.23 ± 7.15 (m, 5H), 4.08 (q, J ˆ 7.18 Hz, 2H), 3.00 ± 2.51 (m, 3H), 1.73 ± 1.28
(m, 4H), 1.19 (t, J ˆ 7.18 Hz, 3H), 0.94 ± 0.86 (m, 5H); 13C NMR (75 MHz,
CDCl3): d ˆ 175.5 (C), 139.4 (C), 128.7 (CH), 128.1 (CH), 126.1 (CH), 59.9
(CH2), 47.5 (CH), 38.5 (CH2), 31.7 (CH2), 29.3 (CH2), 22.4 (CH2), 14.0
Ethyl
2,3-dideuterio-3-(4-methoxyphenyl)-2-methylpropanoate
(4e):
1H NMR (300 MHz, CDCl3): d ˆ 7.08 (d, J ˆ 8.48 Hz, 4H), 6.81 (d, J ˆ
8.48 Hz, 4H), 4.08 (q, J ˆ 6.97 Hz, 4H), 3.75 (s, 6H), 2.92 (s, 1H), 2.59 (s,
1H), 1.19 (t, J ˆ 6.97 Hz, 6H), 1.13 (s, 6H); 13C NMR (75 MHz, CDCl3):
d ˆ 176.1 (C), 157.9 (C), 131.2 (C), 129.7 (CH), 113.5 (CH), 60.1 (CH2), 55.0
(CH3), 41.1 (t, J ˆ 20.0 Hz, CD), 38.3 (t, J ˆ 19.2 Hz, CHD), 16.5 (CH3),
‡
(CH3), 13.8 (CH3); MS (70 eV): m/z (%): 234 (11) [M] , 189 (4), 161 (12),
91 (100); HRMS calcd for C15H22O2: 234.1619; found: 234.1617; IR (neat):
nÄ ˆ 3028, 2930, 2859, 1732 cm 1; Rf ˆ 0.5 (hexane/AcOEt, 5:1).
N,N-Diethyl-3-phenylpropanamide (3l): 1H NMR (300 MHz, CDCl3): d ˆ
7.32 ± 7.15 (m, 5H), 3.38 (q, J ˆ 7.18 Hz, 2H), 3.21 (q, J ˆ 7.18 Hz, 2H),
3.17 ± 2.94 (m, 2H), 2.65 ± 2.54 (m, 2H), 1.11 (t, J ˆ 7.18 Hz, 3H), 1.09 (t, J ˆ
7.18 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 171.0 (C), 141.4 (C), 128.2
(CH), 125.8 (CH), 41.7 (CH2), 40.0 (CH2), 34.9 (CH2), 31.5 (CH2), 14.1
‡
14.0 (CH3); MS (70 eV): m/z (%): 224 (72) [M] , 179 (12), 122 (100), 92
(35); IR (neat): nÄ ˆ 3026, 2977, 2836, 1730, 1584, 1462, 1349 cm 1; Rf ˆ 0.3
(hexane/AcOEt, 10:1).
Methyl 2,3-dideuterio-3-phenylpropanoate (4h): 1H NMR (300 MHz,
CDCl3): d ˆ 7.33 ± 7.19 (m, 5H), 3.68 (s, 3H), 2.94 (d, J ˆ 8.28 Hz, 1H),
2.63 (d, J ˆ 8.28 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 173.3 (C), 140.3
(C), 128.4 (CH), 128.2 (CH), 126.2 (CH), 51.5 (CH3), 35.2 (t, J ˆ 19.8 Hz,
‡
(CH3), 12.9 (CH3); MS (70 eV): m/z (%): 205 (100) [M] , 176 (12), 133 (4),
105 (28), 91 (44), 77 (16); HRMS calcd for C12H19NO: 205.1466; found:
205.1468; IR (neat): nÄ ˆ 3083, 3059, 3028, 2975, 1640 cm 1; Rf ˆ 0.2 (hexane/
AcOEt, 5:1).
‡
CHD), 30.5 (t, J ˆ 19.8 Hz, CHD); MS (70 eV): m/z (%): 166 (40) [M] , 135
N,N-Diethyl-2-methyl-3-phenylpropanamide (3m): 1H NMR (300 MHz,
CDCl3): d ˆ 7.26 ± 7.12 (m, 5H), 3.43 ± 3.34 (m, 1H), 3.22 ± 3.14 (m, 1H),
3.13 ± 2.93 (m, 3H), 2.89 ± 2.78 (m, 1H), 2.64 ± 2.56 (m, 1H), 1.13 (d, J ˆ
6.55 Hz, 3H), 0.99 (t, J ˆ 7.12 Hz, 3H), 0.92 (t, J ˆ 7.12 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d ˆ 174.9 (C), 140.1 (C), 128.9 (CH), 128.0 (CH), 125.9
(CH), 41.5 (CH2), 40.6 (CH2), 40.2 (CH2), 38.0 (CH), 18.1 (CH3), 14.5
(12), 107 (37), 106 (100), 92 (65); IR (neat): nÄ ˆ 3085, 3027, 2958, 1738, 1496,
1435 cm 1; Rf ˆ 0.3 (hexane/AcOEt, 10:1).
3-Cyclohexyl-2,3-dideuterio-N,N-diethylpropanamide (4i): 1H NMR
(300 MHz, CDCl3): d ˆ 3.29 (q, J ˆ 7.11 Hz, 2H), 3.23 (q, J ˆ 7.11 Hz,
2H), 2.20 (m, 1H), 1.66 ± 0.80 (m, 12H), 1.10 (t, J ˆ 7.11 Hz, 3H), 1.03 (t,
J ˆ 7.11 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 172.4 (C), 41.8 (CH2),
39.8 (CH2), 37.2 (CH), 32.9 (CH), 32.3 (t, J ˆ 19.2 Hz, CHD), 30.1 (t, J ˆ
19.2 Hz, CHD), 26.4 (CH2), 26.1 (CH2), 14.2 (CH3), 12.9 (CH3);
‡
(CH3), 12.8 (CH3); MS (70 eV): m/z (%): 219 (100) [M] , 204 (55), 119 (24),
91 (99); IR (neat): nÄ ˆ 3062, 3026, 2971, 1636, 1379 cm 1; Rf ˆ 0.3 (hexane/
AcOEt, 3:1).
‡
MS (70 eV): m/z (%): 213 (<1) [M] , 141 (<1), 130 (25), 116 (100); IR
3-Phenylpropanamide (3n): 1H NMR (300 MHz, CDCl3): d ˆ 7.35 ± 7.18
(m, 5H), 6.30 (brs, 1H), 5.83 (brs, 1H), 2.94 (t, J ˆ 7.63 Hz, 2H), 2.50 (t, J ˆ
7.63 Hz, 2H); 13C NMR (75 MHz, CDCl3): d ˆ 175.1 (C), 140.4 (C), 128.4
(CH), 128.1 (CH), 126.1 (CH), 37.2 (CH2), 31.1 (CH2); IR (neat): nÄ ˆ 3401,
3015, 2941, 1864, 1644, 1458, 1375 cm 1; elemental analysis calcd (%) for
C9H11NO: C 72.46, H 7.43, N 9.39; found: C 72.40, H 7.49, N 9.31; Rf ˆ 0.2
(hexane/AcOEt, 1:1).
(neat): nÄ ˆ 2970, 2922, 2845, 1640, 1450, 1426 cm 1; Rf ˆ 0.3 (hexane/
AcOEt, 3:1).
2,3-Dideuterio-N,N-diethyldecanamide (4j): 1H NMR (300 MHz, CDCl3):
d ˆ 3.42 ± 3.24 (m, 4H), 2.25 ± 2.23 (m, 1H), 1.61 (m, 1H), 1.35 ± 1.22 (m,
12H), 1.17 (t, J ˆ 7.18 Hz, 3H), 1.10 (t, J ˆ 7.18 Hz, 3H), 0.87 (t, J ˆ 6.46 Hz,
3H); 13C NMR (75 MHz, CDCl3): d ˆ 172.2 (C), 41.8 (CH2), 39.8 (CH2),
32.6 (t, J ˆ 19.2 Hz, CHD), 31.7 (CH2), 29.3 (CH2), 29.2 (CH2), 29.1 (CH2),
24.9 (t, J ˆ 19.2 Hz, CHD), 22.5 (CH2), 14.2 (CH3), 14.0 (CH3), 13.0 (CH3);
Ethyl 2,3-dideuterio-2-methyldecanoate (4a): 1H NMR (300 MHz, CDCl3):
d ˆ 4.13 (q, J ˆ 7.18 Hz, 2H), 1.30 ± 1.21 (m, 16H), 1.13 (s, 3H), 0.88 (t, J ˆ
6.15 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 176.9 (C), 59.9 (CH2), 39.0
(t, J ˆ 19.2 Hz, CD), 33.3 (t, J ˆ 19.2 Hz, CHD), 31.8 (CH2), 29.4 (CH2),
29.2 (CH2), 27.0 (CH2), 22.6 (CH2), 16.9 (CH3), 14.2 (CH3), 14.0 (CH3); MS
‡
MS (70 eV): m/z (%): 229 (7) [M] , 200 (<1), 130 (12), 129 (14), 116 (100);
HRMS calcd for C14H27D2NO: 229.2249; found: 229.2369; IR (neat): nÄ ˆ
2957, 2925, 2854, 1642 cm 1; Rf ˆ 0.2 (hexane/AcOEt, 1:1).
2,3-Dideuterio-N,N-diethyl-4-phenylpentanamide
(4k):
1H
NMR
‡
(70 eV): m/z (%): 216 (21) [M] , 187 (4), 171 (46), 143 (3), 117 (4); HRMS
(300 MHz, CDCl3): d ˆ 7.38 ± 7.10 (m, 5H), 3.32 (q, J ˆ 7.12 Hz, 2H), 3.10
(q, J ˆ 7.12 Hz, 2H), 2.77 ± 2.70 (m, 1H), 2.15 ± 1.83 (m, 2H), 1.28 (d, J ˆ
6.97 Hz, 3H), 1.07 (t, J ˆ 7.12 Hz, 3H), 1.01 (t, J ˆ 7.12 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d ˆ 171.9 (C), 146.6 (C), 128.2 (CH), 126.9 (CH), 125.9
(CH), 41.7 (CH2), 39.9 (CH2), 39.3 (CH), 33.0 (t, J ˆ 19.0 Hz, CHD), 30.5 (t,
J ˆ 19.5 Hz, CHD), 22.4 (CH3), 14.0 (CH3), 12.9 (CH3); MS (70 eV): m/z
calcd for C13H24D2O2: 216.1932; found: 216.2054; IR (neat): nÄ ˆ 2957, 2926,
2856, 1734, 1375 cm 1; Rf ˆ 0.5 (hexane/AcOEt, 10:1).
Ethyl 2,3-dideuterio-3-cyclohexyl-2-methylpropanoate (4b): 1H NMR
(300 MHz, CDCl3): d ˆ 4.10 (q, J ˆ 7.12 Hz, 2H), 4.09 (q, J ˆ 7.12 Hz,
2H), 2.00 ± 1.50 (m, 12H), 1.23 (t, J ˆ 7.12 Hz, 6H), 1.22 ± 1.00 (m, 8H), 1.09
(s, 6H), 0.90 ± 0.76 (m, 4H); 13C NMR (75 MHz, CDCl3): d ˆ 177.2 (C), 59.9
(CH2), 40.9 (t, J ˆ 18.9 Hz, CHD), 36.3 (t, J ˆ 20.4 Hz, CD), 35.2 (CH), 33.1
(CH2), 33.0 (CH2), 26.4 (CH2), 26.1 (CH2), 17.3 (CH3), 14.2 (CH3); MS
‡
(%): 235 (3) [M] , 163 (3), 130 (8), 116 (100); IR (neat): nÄ ˆ 1066, 3028,
1
2970, 2922, 2874, 1639, 1450, 1379 cm ;Rf ˆ 0.2 (hexane/AcOEt, 3:1).
1H
NMR
‡
2,3-Dideuterio-N,N-diethyl-3-phenylpropanamide
(4l):
(70 eV): m/z (%): 200 (5) [M] , 155 (33), 127 (11), 103 (100); HRMS calcd
(300 MHz, CDCl3): d ˆ 7.34 ± 7.19 (m, 5H), 3.38 (q, J ˆ 7.18 Hz, 2H), 3.23
(q, J ˆ 7.18 Hz, 2H), 3.00 ± 2.94 (m, 1H), 2.61 ± 2.55 (m, 1H), 1.12 (t, J ˆ
7.18 Hz, 3H), 1.11 (t, J ˆ 7.18 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ
171.0 (C), 141.2 (CH), 128.2 (CH), 125.8 (CH), 41.6 (CH2), 39.9 (CH2), 34.4
(t, J ˆ 19.7 Hz, CHD), 31.0 (t, J ˆ 19.7 Hz, CHD), 14.0 (CH3), 12.8 (CH3);
for C12H20D2O2: 200.1773; found: 200.1745; IR (neat): nÄ ˆ 2975, 2923, 2852,
1733, 1448, 1376 cm 1; Rf ˆ 0.5 (hexane/AcOEt, 10:1).
Ethyl 2,3-dideuterio-2-hexyl-4-phenylpentanoate (4c): 1H NMR
(200 MHz, CDCl3): d ˆ 7.33 ± 7.16 (m, 10H), 4.22 ± 3.99 (m, 4H), 2.76 ±
2.64 (m, 2H), 2.00 ± 1.90 (m, 2H), 1.71 ± 1.20 (m, 32H), 0.93 ± 0.84 (m,
6H); 13C NMR (50 MHz, CDCl3): d ˆ 176.4 (C), 176.0 (C), 146.7 (C), 146.4
(C), 128.5 (CH), 128.2 (CH), 126.9 (CH), 126.8 (CH), 125.9 (CH), 59.8
(CH2), 43.2 (t, J ˆ 19.2 Hz, CD), 40.4 (t, J ˆ 20.9 Hz, CHD), 38.0 (CH), 37.7
(CH), 32.9 (CH2), 32.3 (CH2), 31.5 (CH2), 29.0 (CH2), 27.0 (CH2), 22.8
(CH3), 22.4 (CH2), 21.7 (CH3), 14.2 (CH3), 14.1 (CH3), 14.0 (CH3); MS
‡
MS (70 eV): m/z (%): 207 (42) [M] , 178 (7), 149 (10), 135 (4), 107 (18), 92
(53), 77 (50); HRMS calcd for C12H17D2NO: 207.1466; found: 207.1589; IR
(neat): nÄ ˆ 3083, 3060, 3025, 2973, 2932, 1638 cm 1; Rf ˆ 0.2 (hexane/
AcOEt, 5:1).
2,3-Dideuterio-N,N-diethyl-2-methyl-3-phenylpropanamide
(4m):
‡
(70 eV): m/z (%): 292 (12) [M] , 247 (12), 215 (4), 173 (100), 120 (59), 105
1H NMR (300 MHz, CDCl3): d ˆ 7.30 ± 7.15 (m, 10H), 3.48 ± 3.36 (m, 2H),
3.25 ± 3.13 (m, 2H), 3.05 (q, J ˆ 7.18 Hz, 4H), 2.62 (s, 2H), 1.26 (s, 3H), 1.16
(s, 3H), 1.02 (t, J ˆ 7.18 Hz, 6H), 0.93 (t, J ˆ 7.18 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d ˆ 175.0 (C), 140.6 (C), 140.1 (C), 129.0 (CH), 128.9
(95), 101 (89); HRMS calcd for C19H28D2O2: 292.2245; found: 292.2369; IR
(neat): nÄ ˆ 3084, 3062, 3027, 2928, 2857, 1729 cm 1; Rf ˆ 0.4 (hexane/AcOEt,
5:1).
4270
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0719-4270 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 19

Sequential Reactions
4266±4271
(CH), 128.1 (CH), 126.0 (CH), 125.7 (CH), 41.6 (CH2), 40.3 (CH2), 40.3 (t,
Acknowledgements
J ˆ 19.8 Hz, CHD), 37.6 (t, J ˆ 19.8 Hz, CD), 18.0 (CH3), 14.5 (CH3), 12.9
‡
(CH3); MS (70 eV): m/z (%): 221 (36) [M] , 206 (22), 121 (19), 92 (100);
Â
We thank the II Plan Regional de Investigacion del Principado de Asturias
HRMS calcd for C14H19D2NO: 221.1735; found: 221.1749; IR (neat): nÄ ˆ
Â
(PB-PGI99 ± 01) and the Ministerio de Educacion y Cultura (PB97 ± 1278)
3062, 3026, 2971, 1636, 1379 cm 1; Rf ˆ 0.3 (hexane/AcOEt, 3:1).
Â
for financial support, and Dr. Cecilia Gomez (Universidad de Alicante) for
Â
Â
obtaining the mass spectra. J.M.C. thanks Carmen Fernandez-Florez for
her time. H.R.S. thanks the Principado de Asturias for a predoctoral
fellowship.
2,3-Dideuterio-3-phenylpropanamide (4n): 1H NMR (300 MHz, CDCl3):
d ˆ 7.32 ± 7.18 (m, 5H), 5.85 (brs, 1H), 5.51 (brs, 1H), 2.93 (d, J ˆ 6.26 Hz,
1H), 2.49 (d, J ˆ 6.26 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 174.7 (C),
149.5 (C), 128.4 (CH), 128.2 (CH), 126.2 (CH), 37.0 (t, J ˆ 19.5 Hz, CHD),
30.9 (t, J ˆ 19.8 Hz, CHD); IR (neat): nÄ ˆ 3395, 3009, 2941, 1864, 1643,
1450, 1373 cm 1; Rf ˆ 0.2 (hexane/AcOEt, 1:1).
[1] For recent reviews, see: a) G. A. Molander, C. R. Harris, Chem. Rev.
1996, 96, 307 ± 338; b) G. A. Molander, C. R. Harris, Tetrahedron 1998,
54, 3321 ± 3354.
Synthesis of 2-deuterioesters and 3-deuterioesters (5e and 6e): Under
nitrogen, a solution of compound 3 or 4 (0.4 mmol) in THF (4 mL) was
added dropwise to a stirred solution of diisopropylamide (0.48 mmol) in
THF (5 mL) at 788C. After stirring for 30 min, the reaction mixture was
quenched by the addition of D2O or H2O (2 mL). Standard workup
provided the 3- or 2-deuterioesters 5e or 6e, respectively, which were
purified by flash column chromatography on silica gel (hexane/AcOEt,
5:1).
Â
Â
Â
[2] J. M. Concellon, P. L. Bernad, J. A. Perez-Andres, Angew. Chem.
1999, 111, 2528 ± 2530; Angew. Chem. Int. Ed. 1999, 2384 ± 2386.
Â
Â
Â
[3] J. M. Concellon, J. A. Perez-Andres, H. Rodríguez-Solla, Angew.
Chem. 2000, 112, 2773 ± 2775; Angew. Chem. Int. Ed. 2000, 112, 2866 ±
2868.
Â
Â
Â
[4] J. M. Concellon, J. A. Perez-Andres, H. Rodríguez-Solla, Chem. Eur.
J. 2001, 7, 3062 ± 3068.
[5] R. C. Larock, Comprehensive Organic Transformations, VCH, New
York, 1989, pp. 12 ± 17.
Ethyl 3-deuterio-3-(4-methoxyphenyl)-2-methylpropanoate (5e): 1H NMR
(300 MHz, CDCl3): d ˆ 7.08 (d, J ˆ 8.71 Hz, 4H), 6.81 (d, J ˆ 8.71 Hz, 4H),
4.09 (q, J ˆ 7.19 Hz, 4H), 3.78 (s, 6H), 2.94 ± 2.92 (m, 1H), 2.71 ± 2.58 (m,
3H), 1.20 (t, J ˆ 7.19 Hz, 6H), 1.13 (d, J ˆ 6.98 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d ˆ 176.1 (C), 158.0 (C), 131.4 (C), 129.8 (CH), 113.6 (CH), 60.1
(CH2), 55.1 (CH3), 41.5 (CH), 38.4 (t, J ˆ 19.8 Hz, CHD), 16.6 (CH3), 14.1
[6] For a review of the use of deuterium in studying the mechanism of
heterogeneous organic catalysis, see: B. S. Gudkov, Russ. Chem. Rev.
1986, 55, 259 ± 270.
[7] a) By using bakerꢁs yeast reduction: G. Fronza, C. Fuganti, P.
Grasselli, A. Mele, A. Sarra, G. Allegrone, M. Barbeni, Tetrahedron
Lett. 1993, 34, 6467 ± 6470; b) G. Fronza, C. Fuganti, M. Mendozza, R.
Rigoni, S. Servi, G. Zuchi, Pure Appl. Chem. 1996, 68, 2065 ± 2071;
c) By using reductase: A. R. Battersby, A. L. Gutman, C. J. R. Fookes,
H. Günther, H. Simon, J. Chem. Soc. Chem. Commun. 1981, 645 ± 647.
‡
(CH3); MS (70 eV): m/z (%): 223 (45) [M] , 178 (9), 150 (15), 122 (100);
HRMS calcd for C13H17DO3: 223.1318; found: 223.1319; IR (neat): nÄ ˆ
3026, 2977, 2836, 1730, 1584, 1462, 1349 cm 1; Rf ˆ 0.3 (hexane/AcOEt,
10:1)
Â
[8] a) C. Petrier, S. Lavaitte, C. Morat, J. Org. Chem. 1990, 55, 1664 ± 1667;
Ethyl 2-deuterio-3-(4-methoxyphenyl)-2-methylpropanoate (6e): 1H NMR
(300 MHz, CDCl3): d ˆ 7.07 (d, J ˆ 8.72 Hz, 4H), 6.83 (d, J ˆ 8.72 Hz, 4H),
4.10 (q, J ˆ 7.18 Hz, 4H), 3.80 (s, 6H), 2.95 (d, J ˆ 13.72 Hz, 2H), 2.61 (d,
J ˆ 13.72 Hz, 2H), 1.21 (t, J ˆ 7.18 Hz, 6H), 1.14 (s, 6H); 13C NMR
(75 MHz, CDCl3): d ˆ 176.1 (C), 157.9 (C), 131.3 (C), 129.7 (CH), 113.5
(CH), 60.1 (CH2), 55.0 (CH3), 41.1 (t, J ˆ 20.3 Hz, CD), 38.6 (CH2), 16.5
b) T. Hudlicky, G. Sinai-Zingde, M. G. Natchus, Tetrahedron Lett.
1987, 28, 5287 ± 5290.
[9] a) M. Oba, A. Miyakawa, K. Nishiyama, J. Org. Chem. 1999, 64,
9275 ± 9278; b) G. P. Lutz, A. P. Wallin, S. T. Kerrick, P. Beak, J. Org.
Chem. 1991, 56, 4938 ± 4943.
[10] J. Inanaga, S. Sakai, Y. Handa, M. Yamaguchi, Y. Yokoyama, Chem.
Lett. 1991, 2117 ± 2118.
[11] A. Cabrera, H. Alper, Tetrahedron Lett. 1992, 33, 5007 ± 5008.
[12] a) J. L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chim. 1977, 1, 5 ± 7; b) P.
Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102, 2693 ±
2698.
[13] Only one isolated example of reduction of an a,b-unsaturated ester by
using SmI2/H2O has been reported: A. Bernardi, O. Carugo, A.
Pasquarello, A. Sidjimov, G. Poli, Tetrahedron 1991, 47, 7357 ± 7362.
[14] J. Mann, Secondary Metabolism, Oxford University Press, Oxford,
1986, p. 23.
‡
(CH3), 14.0 (CH3); MS (70 eV): m/z (%): 223 (39) [M] , 178 (8), 150 (10),
121 (100); IR (neat): nÄ ˆ 3026, 2977, 2836, 1730, 1584, 1462, 1349 cm 1; Rf ˆ
0.3 (hexane/AcOEt, 10:1).
Synthesis of 2-deuterio-3-hydroxyesters (7b and 7e): Under nitrogen, a
solution of SmI2 (1.3 mmol) in THF/D2O (2 mL) was added dropwise to a
stirred solution of the appropriate 2-halo-3-hydroxyester 1 (0.4 mmol) in
THF (4 mL) at room temperature. After stirring for 30 min at the same
temperature, the reaction was quenched by the addition of 0.1m aqueous
HCl (5 mL). Standard workup afforded the crude 2-deuterio-3-hydroxy-
esters 7, which were purified by flash column chromatography on silica gel
(hexane/AcOEt, 5:1).
[15] Difficulties associated with the conjugated reduction of compounds
bearing a cyclohexyl substituent have been documented: see ref. [10].
[16] In the mass spectra (MS and HRMS) of the deuterated compounds 4,
Ethyl
3-cyclohexyl-2-deuterio-3-hydroxy-2-methylpropanoate
(7b):
‡
1H NMR (300 MHz, CDCl3): d ˆ 4.14 (q, J ˆ 7.01 Hz, 4H), 3.59 (d, J ˆ
7.95 Hz, 1H), 3.34 (d, J ˆ 5.65 Hz, 1H), 2.64 (brs, 2H), 2.08 ± 0.79 (m, 22H),
1.25 (t, J ˆ 7.01 Hz, 6H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz,
CDCl3): d ˆ 176.6 (C), 176.4 (C), 77.6 (CH), 75.5 (CH), 60.4 (CH2), 60.3
(CH2), 41.3 (t, J ˆ 19.8 Hz, CD), 41.0 (CH), 39.9 (CH), 29.8 (CH2), 28.9
(CH2), 28.8 (CH2), 27.0 (CH2), 26.2 (CH2), 25.9 (CH2), 25.7 (CH2), 14.6
5e, 6e, and 7, the [M] peaks of the corresponding non-deuterated
compounds are either absent or very weak, indicating that these
species are present to an extent of <1%.
[17] G. A. Molander, in Organic Reactions, Vol. 46 (Eds.: L. A. Paquette),
Wiley, Chichester, 1994, p. 243.
[18] The saturated amide was not obtained from 2,3-dimethyl-4-phenyl-
but-2-enamide.
‡
(CH3), 14.0 (CH3), 9.8 (CH3); MS (70 eV): m/z (%): 215 (<1) [M] , 200
[19] The metalation of compounds 2 with Zn affords an enolate, which
undergoes a b-elimination reaction giving the corresponding a,b-
unsaturated ester (see ref. [3].
[20] The successive treatment of ethyl 3-hydroxybutanoate with lithium
diisopropylamide (LDA) and D2O gave ethyl 2-deuterio-3-hydroxy-
butanoate in very low yield.
[21] Y. Fujita, S. Fukuzumi, J. Otera, Tetrahedron Lett. 1997, 38, 2121 ±
2124.
[22] J. L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chim. 1981, 5, 479 ± 484.
[23] D. N. Harpp, L. Q. Bao, C. J. Black, J. G. Gleason, R. A. Smith, J. Org.
Chem. 1975, 40, 3420 ± 3426.
(25), 170 (8), 132 (98); IR (neat): nÄ ˆ 3495, 2970, 2922, 2864, 1728, 1450,
1376 cm 1; Rf ˆ 0.2 (hexane/AcOEt, 10:1).
Ethyl
2-deuterio-3-hydroxy-3-(4-methoxyphenyl)-2-methylpropanoate
(7e): 1H NMR (300 MHz, CDCl3): d ˆ 7.27 ± 7.20 (m, 4H), 6.87 ± 6.82 (m,
4H), 4.94 (s, 1H), 4.70 (s, 1H), 4.16 (q, J ˆ 7.12 Hz, 2H), 4.06 (q, J ˆ 7.12 Hz,
2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.06 (brs, 2H), 1.24 (t, J ˆ 7.12 Hz, 3H), 1.16
(t, J ˆ 7.12 Hz, 3H), 1.12 (s, 3H), 0.94 (s, 3H); 13C NMR (75 MHz, CDCl3):
d ˆ 175.8 (C), 175.5 (C), 159.1 (C), 158.7 (C), 133.6 (C), 127.7 (CH), 127.1
(CH), 113.6 (CH), 113.4 (CH), 75.7 (CH), 73.4 (CH), 60.5 (CH2), 60.4
(CH2), 55.0 (CH3), 46.7 (t, J ˆ 20.1 Hz, CD), 14.2 (CH3), 14.0 (CH3), 13.9
‡
(CH3), 11.1 (CH3); MS (70 eV): m/z (%): 239 (33) [M] , 220 (3), 194 (37),
[24] For the preparation of 2-chloro-3-hydroxyamides 1i ± m, see ref. [4].
137 (100); IR (neat): nÄ ˆ 3491, 3028, 3018, 2978, 1936, 1727, 1612, 1513,
1461, 1374 cm 1; Rf ˆ 0.2 (hexane/AcOEt, 10:1).
Received: April 6, 2001 [F3179]
Chem. Eur. J. 2001, 7, No. 19
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0719-4271 $ 17.50+.50/0
4271