An efficient synthesis of 2-bromo-3-hydroxy esters by reaction of ketones with ethyl dibromoacetate promoted by samarium diiodide

Article abstract of DOI:10.1002/ejoc.200500940

A simple and efficient samarium diiodide mediated synthesis of 2-bromo-3-hydroxy esters 1 by the reaction of a variety of ketones 2 with ethyl dibromoacetate (3) is described. The relative configuration of the major diastereoisomer obtained was established by NOESY experiments of the corresponding α,β-epoxy esters 4 prepared from 1. Additionally, a mechanism is proposed to explain the results obtained. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500940

FULL PAPER
DOI: 10.1002/ejoc.200500940
An Efficient Synthesis of 2-Bromo-3-hydroxy Esters by Reaction of Ketones
with Ethyl Dibromoacetate Promoted by Samarium Diiodide
José M. Concellón,*[a] Carmen Concellón,[a] and Pamela Diaz[a]
Keywords: Samarium / 2-Bromo-3-hydroxy ester / Aldol reaction
A simple and efficient samarium diiodide mediated synthesis
of 2-bromo-3-hydroxy esters 1 by the reaction of a variety
of ketones 2 with ethyl dibromoacetate (3) is described. The
relative configuration of the major diastereoisomer obtained
ing α,β-epoxy esters 4 prepared from 1. Additionally, a
mechanism is proposed to explain the results obtained.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
was established by NOESY experiments of the correspond- Germany, 2006)
ketones to obtain 2-halo-3-hydroxy esters has not been pub-
lished to date.
Introduction
The highly functionalized 2-bromo-3-hydroxy esters 1 are
interesting compounds because of their synthetic applica-
tions.[1] However, unlike the syntheses of 2-chloro-3-hy-
droxy esters, the preparation of 2-bromo-3-hydroxy esters
is difficult to achieve by using classical methodologies. For
instance, the reaction of lithium or magnesium enolates
(generated with bases) derived from α-bromo esters with
carbonyl compounds yields the corresponding α,β-epoxy
ester as the major product instead of 2-bromo-3-hydroxy
esters.[2] This result is obtained because the bromine atom
is displaced by the highly nucleophilic alcoholate group
even at low temperatures (–78 °C). In particular, the epoxy
ester constitutes the major product when the reactant is a
ketone. In addition, conventional Reformatsky conditions
are generally inappropriate for the formation of α-bromo
zinc ester enolates from the corresponding dibromo esters.
To the best of our knowledge, the only example describing
an efficient Reformatsky reaction required low temperature
and a tedious process to prepare the zinc/silver-on-graphite
reagent.[3] For this reason, an efficient and simple synthesis
of 2-bromo-3-hydroxy esters at room temperature is very
desirable.
We have previously reported the highly diastereoselective
preparation of (E)-α,β-unsaturated esters by treating alde-
hydes with ethyl dibromoacetate in the presence of SmI2.[7]
In this paper, we describe a SmI2-mediated method to ob-
tain 2-bromo-3-hydroxy esters by reaction between com-
mercially available ketones and ethyl dibromoacetate.
Results and Discussion
We are interested in developing an efficient method for
the synthesis of 2-bromo-3-hydroxy esters 1 so that these
compounds can be used in other reactions. Initially, the
method chosen to prepare compounds 1 was the reaction of
the lithium enolate derived from ethyl bromo acetate with
ketones at low temperature (–85 °C). The reaction with 2-
pentanone or acetophenone afforded the corresponding ep-
oxy ester as the major product and the corresponding 2-
bromo-3-hydroxy esters 1 in very low yields. Higher yields
of compounds 1 were not obtained by using magnesium
enolates instead of lithium derivatives.
Taking into account the low nucleophilicity of the samar-
ium alcoholates (with respect to magnesium or lithium), we
demonstrated an alternative method to prepare the target
products 1 by using the samarium enolate derived from
ethyl bromoacetate. Thus, reaction of several ketones
(1 equiv.) 2 with ethyl dibromoacetate (1.2 equiv.) (3) in the
presence of a solution of SmI2 (4 equiv.) in THF at room
temperature afforded 2-bromo-3-hydroxy esters 1 in high
yield (Scheme 1). The reaction seems to be general, as
shown by the data reported in Table 1: linear, branched,
and cyclic aliphatic and aromatic ketones can be used as
starting materials. It is worth mentioning that these reac-
tions can be performed on easily enolizable ketones
(Table 1, entry 5), unlike other previously reported reac-
Since its introduction into organic synthesis by Kagan
in 1977,[4] samarium diiodide has become among the most
important reagents to carry out transformation reactions
performed under reducing conditions.[5] In particular, sa-
marium diiodide has previously been used to promote the
Reformatsky reaction starting from 2-halo esters and car-
bonyl compounds.[6] However, to the best of our knowledge,
the SmI2-promoted reaction of 2,2-dihalo esters with
[a] Departamento de Química Orgánica e Inorgánica, Universidad
de Oviedo,
Julián Clavería, 8, 33071, Oviedo, Spain
Fax: +34 98 510 34 46
E-mail: jmcg@uniovi.es
Eur. J. Org. Chem. 2006, 2197–2200
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. M. Concellón, C. Concellón, P. Diaz
FULL PAPER
tions of anionic reagents, such as phosphorus ylides.[8] tive configuration of the other compounds 1 prepared was
Moreover, unlike other SmI2-promoted Reformatsky reac- assigned by analogy.
tions previously described, byproducts such as ethyl 3-
The observed results can be explained (Scheme 3) by as-
oxobutanoate or their bromo derivatives generated by a di- suming the initial metalation of the C–Br bond of dibro-
merization reaction of the reactant ethyl dibromoacetate moacetate by two consecutive single electron transfers from
were not detected.[6a]
SmI2. The ketone 2 undergoes an addition reaction of the
generated samarium bromoenolate intermediate 5 to afford
the corresponding alcoholate 6, which, after hydrolysis,
gives the final 2-bromo-3-hydroxy esters 1. Although we do
not have direct evidence for the existence of the samarium
bromoenolate intermediate 5, a radical mechanism can be
rejected considering that no differences were observed in
the course or the result of the reaction when compound 1b
was synthesized either in the dark or in the presence of
AIBN.
Scheme 1.
Table 1. Synthesis of 2-bromo-3-hydroxy esters 1.
Entry
1[a] R1
R2
de [%][b]
Yield [%][c]
1
2
3
4
5
6
7
8
1a Ph
1b Me
1c Et
1d Ph
1e PhCH2
1f C5H11
1g CH3CH(CH3)CH2
1h -(CH2)5-
Et
Et
Et
Me
Me
Me
Me
34
18
–
22
42
10
14
–
85
90
93
50
91
87
82
78
[a] All reactions were carried out by using 4 equiv. of SmI2 in a
reaction time of 2h. [b] Determined on crude reaction products by
1H and 13C NMR spectroscopy (300 and 75 MHz) and GC-MS.
[c] Isolated yields based on starting ketone 2 after column
chromatography.
Scheme 3.
The solution of SmI2 in THF was rapidly obtained
(10 min) by the reaction of diiodomethane with samarium
powder in the presence of sonic waves.[9]
The 2-bromo-3-hydroxy esters 1 were isolated as a mix-
ture of diastereoisomers (see Table 1), and the diastereoiso-
meric ratio was established by using 1H NMR spectrometry
(300 MHz). To determine the relative configuration of the
major diastereoisomer, compounds 1a and 1d were trans-
formed into the corresponding α,β-epoxy esters 4a and 4d
by treatment with potassium hexamethyldisilazide at –78 °C
overnight (Scheme 2). In the case of epoxide 4a, the major
diastereoisomer can be isolated in pure form by column
chromatography (hexanes/EtOAc, 20:1).
Conclusion
In conclusion, we have presented a simple and general
methodology for the samarium diiodide promoted prepara-
tion of 2-bromo-3-hydroxy esters 1 by reaction of commer-
cially available ketones 2 with ethyl dibromoacetate (3) at
room temperature. Determination of the relative configura-
tions of the major diastereoisomer of 2-bromo-3-hydroxy
esters 1 was performed by NOESY experiments after trans-
formation of 1 into the corresponding α,β-epoxy esters 4.
A mechanism to explain this transformation has been pro-
posed.
Experimental Section
Scheme 2.
General Remarks: Reactions requiring an inert atmosphere were
conducted under dry nitrogen, and the glassware was oven-dried
(120 °C). THF was distilled from sodium/benzophenone ketyl im-
mediately prior to use. All reagents were purchased in the highest
quality available and were used without further purification. Sa-
marium diiodide was prepared by reaction of CH2I2 with samarium
powder in the presence of sonic waves.[7] Flash column chromatog-
raphy was carried out on silica gel 230–400 mesh. Compounds were
visualized on analytical thin layer chromatograms (TLC) by UV
light (254 nm). 1H NMR spectra were recorded at 300 MHz. 13C
NMR spectra and DEPT experiments were determined at 75 MHz.
The relative configuration of epoxides 4a and 4d was es-
tablished by NOESY experiments. A cis relative configura-
tion for the major diastereoisomer was determined in both
cases on the basis of the observation of NOE interactions
between the CH2 (4a) or CH3 (4d) groups and the α-hydro-
gen atom in the major diastereoisomer and between the Ph
groups and the α-hydrogen atom in the minor diastereoiso-
mer. Consequently, having determined the cis configuration
of compounds 4a and 4d, we established the relative config-
uration of compounds 1a and 1d as 2R*,3S*.[10] The rela- Chemical shifts are given in ppm relative to tetramethylsilane
2198
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2197–2200

Reaction of Ketones with Ethyl Dibromoacetate Promoted by Samarium Diiodide
FULL PAPER
(TMS), which is used as an internal standard, and coupling con-
74.2 (C), 61.9 (CH2), 52.3 (CH), 27.5 (CH2), 27.4 (CH2), 13.6
stants (J) are reported in Hz. The diastereomeric excesses were ob-
(CH3), 7.8 (CH3), 7.2 (CH3) ppm. MS (70 eV, EI): m/z (%) = 252
1
tained by using H and 13C NMR spectroscopy as well as GC-MS
[M+, Ͻ1], 223 (66), 87 (100), 57 (97). IR (neat): ν = 3516, 1722,
˜
analysis of the crude products. GC-MS and HRMS were per-
formed at 70 eV or by using FAB conditions. When HRMS could
not be measured on the basis of the molecular ion, the HRMS of
a significant fragment is given. Only the most important IR absorp-
tions (in cm–1) and the molecular ions and/or base peaks in MS
are given.
1156 cm–1; Rf = 0.6 (hexanes/EtOAc 3:1); C9H17BrO3 (253.13):
calcd. C 42.70, H 6.77; found C 42.75, H 6.90.
Ethyl 2-Bromo-3-hydroxy-3-phenylbutanoate (1d): Yield: 50%,
72 mg. Data from a mixture of diastereoisomers in a ratio of 61:39.
1H NMR (300 MHz, CDCl3): δ = 7.59–7.28 (m, 10 H), 4.67 (s, 1
H, minor isomer), 4.55 (s, 1 H, major isomer), 4.40 (q, J = 7.1 Hz,
2 H, major isomer), 3.98 (q, J = 7.1 Hz, 2 H, minor isomer), 2.63
(s, 2 H), 1.78 (s, 3 H, major isomer), 1.67 (s, 3 H, minor isomer),
1.27 (t, J = 7.1 Hz, 3 H, major isomer), 0.98 (t, J = 7.1 Hz, 3 H,
minor isomer) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9 (C,
major isomer), 169.4 (C, minor isomer), 142.9 (C, major isomer),
142.7 (C, minor isomer), 132.9 (CH), 128.4 (CH), 128.2 (CH), 128.1
(CH), 128.0 (2×CH), 127.5 (CH), 127.4 (CH), 124.9 (2×CH), 74.1
(C, minor isomer), 73.8 (C, major isomer), 62.1 (CH2, major iso-
mer), 61.8 (CH2, minor isomer), 55.0 (CH, major isomer), 53.0
(CH, minor isomer), 28.2 (CH3, minor isomer), 26.6 (CH3, major
isomer), 13.6 (CH3, major isomer), 13.3 (CH3, minor isomer) ppm.
MS (70 eV, EI): m/z (%) = 286 [M+, Ͻ1], 271 (5), 121 (100), 105
(62), 91 (7). HRMS (70 eV): calcd. for C12H15BrO3 [M+] 286.0205,
General Procedure for the Synthesis of Compounds 1: A THF solu-
tion (20 mL) of SmI2 (2 mmol) was added to a stirred solution
of ethyl dibromoacetate (0.6 mmol) and the corresponding ketone
(0.5 mmol) in THF (2 mL) under nitrogen. The reaction was stirred
at room temperature for two hours before it was quenched with
aqueous HCl (1 ). The organic material was extracted with dichlo-
romethane, the combined extracts were dried with Na2SO4, and
the solvent was removed under reduced pressure. Purification by
chromatography on silica gel (hexanes: EtOAc 5:1) provided pure
compounds 1.
Ethyl 2-Bromo-3-hydroxy-3-phenylpentanoate (1a): Yield: 85%,
128 mg. Data from a mixture of diastereoisomers in a ratio of
67:33. 1H NMR (300 MHz, CDCl3): δ = 7.33–7.26 (m, 10 H), 4.70
(s, 1 H, minor isomer), 4.55 (s, 1 H, major isomer), 4.24 (q, J =
7.2 Hz, 2 H, major isomer), 3.98 (q, J = 7.1 Hz, 2 H, minor iso-
mer), 3.80 (s, 2 H), 2.32–1.71 (m, 4 H), 1.33 (t, J = 7.1 Hz, 3 H,
major isomer), 0.96 (t, J = 7.2 Hz, 3 H, minor isomer), 0.76 (t, J
= 7.3 Hz, 3 H, major isomer), 0.70 (t, J = 7.3 Hz, 3 H, minor
found 286.0192. IR (neat): ν = 3500, 1720, 763.5 cm–1; R = 0.6
˜
f
(hexanes/EtOAc 3:1); C12H15BrO3 (287.15): calcd. C 50.19, H 5.27;
found C 50.15, H 5.19.
Ethyl 2-Bromo-3-hydroxy-3-methyl-4-phenylbutanoate (1e): Yield:
91%, 137 mg. Data from a mixture of diastereoisomers in a ratio
isomer) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.2 (C, major of 71:29. H NMR (300 MHz, CDCl3): δ = 7.31 (s, 10 H), 4.24 (q,
1
isomer), 170.0 (C, minor isomer), 141.1 (C, major isomer), 140.7
(C, minor isomer), 128.2 (2×CH, major isomer), 128.0 (2×CH,
minor isomer), 127.5 (CH, minor isomer), 127.2 (CH, major iso-
mer), 125.8 (2×CH, minor isomer), 125.4 (2×CH, major isomer),
76.7 (C, major isomer), 76.4 (C, minor isomer), 62.3 (CH2, major
isomer), 61.9 (CH2, minor isomer), 54.3 (CH, major isomer), 53.0
J = 7.1 Hz, 4 H), 4.18 (s, 1 H, major isomer), 4.17 (s, 1 H, minor
isomer), 3.34 (s, 1 H, major isomer), 3.20 (s, 1 H, minor isomer),
3.10–2.90 (m, 4 H), 1.42 (s, 3 H, minor isomer), 1.32 (s, 3 H, major
isomer), 1.29 (t, J = 7.0 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.6 (2×C), 136.0 (C), 135.8 (C), 130.3 (4×CH),
128.2 (4×CH), 126.8 (2×CH), 73.3 (C, minor isomer), 72.4 (C,
(CH, minor isomer), 32.9 (CH2, minor isomer), 31.9 (CH2, major major isomer), 62.1 (2×CH2), 53.6 (CH, major isomer), 51.2 (CH,
isomer), 13.8 (CH3, major isomer), 13.4 (CH3, minor isomer), 8.3
(CH3, major isomer), 7.1 (CH3, minor isomer) ppm. MS (70 eV,
EI): m/z (%) = 271 [M+ – C2H5, 27], 135 (100), 105 (71), 77 (12).
HRMS (70 eV): calcd. for C13H17BrO3 [M+ – C2H5] 270.9970;
minor isomer), 45.3 (CH2, minor isomer), 44.8 (CH2, major iso-
mer), 24.1 (CH3, minor isomer), 23.8 (CH3, major isomer), 13.7
(2×CH3) ppm. MS (70 eV, EI): m/z (%) = 300 [M+, Ͻ1], 209 (69),
91 (100), 65(19), 43 (53). IR (neat): ν = 3516, 1724 cm–1; R = 0.6
˜
f
found 270.9973. IR (neat): ν = 3491, 1713 cm–1; R = 0.6 (hexanes/
(hexanes/EtOAc 3:1). C13H17BrO3 (301.18): calcd. C 51.84, H 5.69;
found C 51.95, H 5.72.
˜
f
EtOAc 3:1); C13H17BrO3 (301.18): calcd. C 51.84, H 5.69; found C
51.72, H 5.60.
Ethyl 2-Bromo-3-hydroxy-3-methyloctanate (1f): Yield: 87%,
Ethyl 2-Bromo-3-hydroxy-3-methylpentanoate (1b): Yield: 90%,
108 mg. Data from a mixture of diastereoisomers in a ratio of
59:41. 1H NMR (300 MHz, CDCl3): δ = 4.28–4.21 (m, 6 H), 1.73–
1.57 (m, 4 H), 1.33–1.27 (m, 12 H), 0.96 (t, J = 7.6 Hz, 3 H, major
isomer), 0.91 (t, J = 7.4 Hz, 3 H, minor isomer) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.5 (C, major isomer), 169.4 (C, minor
isomer), 72.7 (C, major isomer), 72.1 (C, minor isomer), 61.8
(2×CH2), 53.9 (CH, minor isomer), 53.1 (CH, major isomer), 31.7
(CH2, major isomer), 31.5 (CH2, minor isomer), 22.8 (CH3, major
isomer), 22.7 (CH3, minor isomer), 13.5 (2×CH3), 7.8 (CH3, major
isomer), 7.5 (CH3, minor isomer) ppm. MS (70 eV, EI): m/z (%) =
122 mg. Data from a mixture of diastereoisomers in a ratio of
45:55. H NMR (300 MHz, CDCl3): δ = 4.22 (q, J = 7.1 Hz, 2 H,
1
major isomer), 4.21 (q, J = 7.2 Hz, 2 H, minor isomer), 4.21 (s, 1
H, minor isomer), 4.20 (s, 1 H, major isomer), 3.08 (s, 2 H), 1.62–
1.53 (m, 16 H), 1.31 (s, 3 H, minor isomer), 1.30 (s, 3 H, major
isomer), 1.27 (t, J = 7.1 Hz, 6 H), 0.84 (t, J = 6.8 Hz, 3 H, minor
isomer), 0.82 (t, J = 6.9 Hz, 3 H, major isomer) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.8 (C, major isomer), 169.6 (C, minor
isomer), 72.7 (C, major isomer), 72.2 (C, minor isomer), 62.0
(2×CH2), 54.4 (CH, minor isomer), 53.5 (CH, major isomer), 39.3
(CH2, major isomer), 39.1 (CH2, minor isomer), 32.0 (CH2, major
154 [M+ – C2H4, Ͻ 1], 120 (6), 106 (52), 91 (100). HRMS (70 eV): isomer), 31.9 (CH2, minor isomer), 23.7 (CH2, major isomer), 23.6
calcd. for C8H15BrO3 [M+ – C2H4] 209.9892; found 209.9922. IR (CH2, minor isomer), 23.4 (CH2, minor isomer), 22.4 (CH2, major
(neat): ν = 3511, 1726 cm–1; R = 0.5 (hexanes/EtOAc 3:1); isomer), 13.8 (2×CH3), 13.7 (4×CH3) ppm. MS (70 eV, EI):
˜
f
C8H15BrO3 (239.11): calcd. C 40.19, H 6.32; found C 40.27, H 6.28.
m/z (%) = 280 [M+, Ͻ1], 209 (81), 115 (100), 55 (80), 43 (97). IR
(neat): ν = 3517, 1725, 1146 cm–1; R = 0.5 (hexanes/EtOAc 3:1);
˜
f
Ethyl 2-Bromo-3-ethyl-3-hydroxypentonoate (1c): Yield: 93%,
C11H12BrO3 (281.19): calcd. C 46.99, H 7.53; found C 47.08, H
7.47.
1
118 mg. H NMR (300 MHz, CDCl3): δ = 4.29 (q, J = 7.1 Hz, 2
H), 4.31 (s, 1 H), 3.29 (s, 1 H), 1.82–1.70 (m, 2 H), 1.66–1.58 (m,
2 H), 1.34 (t, J = 7.1 Hz, 3 H), 0.97 (t, J = 7.5 Hz, 3 H), 0.87 (t, J Ethyl 2-Bromo-3-hydroxy-3,5-dimethylhexanoate (1g): Yield: 82%,
= 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0 (C), 110 mg. Data from a mixture of diastereoisomers in a ratio of
Eur. J. Org. Chem. 2006, 2197–2200
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2199

J. M. Concellón, C. Concellón, P. Diaz
FULL PAPER
57:43. H NMR (300 MHz, CDCl3): δ = 4.23 (q, J = 7.1 Hz, 2 H,
minor isomer), 4.24 (q, J = 7.1 Hz, 2 H, major isomer), 4.24 (s, 1
H, major isomer), 4.19 (s, 1 H, minor isomer), 2.95 (s, 2 H), 1.87–
1.76 (m, 2 H), 1.59–1.48 (m, 4 H), 1.38 (s, 3 H, major isomer), 1.32
(s, 3 H, minor isomer), 1.27 (t, J = 7.1 Hz, 6 H), 0.98 (d, J = 6.6 Hz,
1
minor isomer), 3.94–3.82 (m, 2 H, major isomer), 3.64 (s, 1 H,
major isomer), 3.43 (s, 1 H, minor isomer), 1.75 (s, 3 H, minor
isomer), 1.71 (s, 3 H, major isomer), 1.30 (t, J = 7.1 Hz, 3 H, minor
isomer), 0.87 (t, J = 7.1 Hz, 3 H, major isomer) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.4 (C, minor isomer), 166.9 (C, major
6 H), 0.95 (d, J = 6.7 Hz, 3 H, major isomer), 0.92 (d, J = 6.7 Hz, isomer), 139.9 (C, minor isomer), 137.0 (C, major isomer), 128.3
3 H, minor isomer) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9
(C, minor isomer), 169.5 (C, major isomer), 73.2 (C, minor isomer),
72.7 (C, major isomer), 62.0 (2×CH2), 55.7 (CH, major isomer),
54.1 (CH, minor isomer), 47.2 (CH2, minor isomer), 46.9 (CH2,
major isomer), 24.7 (CH3, minor isomer), 24.6 (CH3, major iso-
mer), 24.4 (2×CH), 23.9 (CH3, major isomer), 23.8 (CH3, minor
isomer), 13.8 (4×CH3) ppm. MS (70 eV, EI): m/z (%) = 252 [M+,
(2×CH, minor isomer), 127.9 (CH, minor isomer), 127.8 (2×CH,
major isomer), 126.7 (CH, major isomer), 126.1 (2×CH, major
isomer), 125.0 (2×CH, minor isomer), 63.4 (CH, major isomer),
61.3 (CH, minor isomer), 60.7 (CH2, major isomer), 60.4 (CH2,
minor isomer), 26.4 (CH3, minor isomer), 24.4 (CH3, major iso-
mer), 14.0 (CH3, minor isomer), 13.5 (CH3, major isomer) ppm.
IR (neat): ν = 2983, 1752, 1729, 1201 cm–1; R = 0.5 (hexanes/
˜
f
Ͻ1], 209 (48), 101 (99), 43 (100). IR (neat): ν = 3518, 1724,
EtOAc 3:1); C12H14O3 (206.24): calcd. C 69.88, H 6.84; found C
70.01, H 6.76.
˜
1144 cm–1; Rf = 0.5 (hexanes/EtOAc 3:1); C10H19BrO3 (267.16):
calcd. C 44.96, H 7.17; found C 45.02, H 7.26.
Ethyl 2-Bromo-2-(1-hydroxycyclohexyl)acetate (1h): Yield: 78%,
103 mg. H NMR (300 MHz, CDCl3): δ = 4.24 (q, J = 7.1 Hz, 2
Acknowledgments
1
H), 4.21 (s, 1 H), 3.15 (s, 1 H), 1.66–1.48 (m, 10 H), 1.32 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.5 (C), 70.7
(C), 61.7 (CH2), 54.5 (CH), 34.5 (CH2), 34.2 (CH2), 25.0 (CH2),
21.5 (CH2), 21.0 (CH2), 13.6 (CH3) ppm. MS (70 eV, EI): m/z (%)
= 264 [M+, 1], 131 (37), 97 (89), 69 (100). HRMS (70 eV): calcd.
We thank Ministerio de Ciencia y Tecnología (CTQ2004–1191/
BQU) for financial support, Dra. Cecilia Gómez (Universidad de
Alicante) for spectrometric mass determination and Dr. Vicente del
Amo for his revision of the English. C. C. thanks Ministerio de
Ciencia y Tecnología for a predoctoral grant and J. M. C. thanks
Carmen Fernández-Flórez for her time.
for C10H17BrO3 [M+] 264.0361; found 264.0296. IR (neat): ν =
˜
3516, 1723, 118 cm–1; Rf = 0.5 (hexanes/EtOAc 3:1). C10H17BrO3
(265.14): calcd. C 45.30, H 6.46;. found C 45.40, H 6.51.
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[3] A. Füstner, J. Organomet. Chem. 1987, 336, C33–36.
[4] J.-L. Namy, P. Girard, H. B. Kagan, New J. Chem. 1977, 1, 5–
7.
General Procedure for the Synthesis of Compounds 4: To a –78 °C
stirred solution of the corresponding compound 1 (1 mmol) in dry
THF (2 mL) was added dropwise potassium hexamethyldisilazide
(6.5 mL of 0.5  solution in toluene, 2 mmol). After stirring over-
night, the resulting solution was quenched with aqueous saturated
solution of NH4Cl (10 mL). The organic material was extracted
with dichloromethane, the combined extracts were dried with
Na2SO4, and the solvent was removed under reduced pressure. Pu-
rification by chromatography on silica gel (hexanes/EtOAc 20:1)
provided pure compounds 4.
[5] Reviews of synthetic applications of SmI2: a) J. A. Soderquist,
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ganic Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon
Press, Oxford, UK, 1991, vol. 1, pp. 251–282; d) G. A. Mo-
lander in Organic Reactions (Ed.: L. A. Paquette), John Wiley
and Sons, New York, 1994, vol. 46, pp. 211–367; e) G. A. Mo-
lander, C. R. Harris, Chem. Rev. 1996, 96, 307–338; f) G. A.
Molander, C. R. Harris, Tetrahedron 1998, 54, 3321–3354; g)
A. Krief, A. M. Laval, Chem. Rev. 1999, 99, 745–777; h) P. G.
Steel, J. Chem. Soc., Perkin Trans. 1 2001, 2727–2751; i) H. B.
Kagan, Tetrahedron 2003, 59, 10351–10372; j) J. M. Concellón,
H. Rodríguez-Solla, Chem. Soc. Rev. 2004, 33, 599–609.
[6] a) S. Park, I. S. Lee, Y. H. Kim, Tetrahedron Lett. 1995, 36,
1673–1674; b) E. Balaux, R. Ruel, Tetrahedron Lett. 1996, 37,
801–804; c) K. Utimoto, T. Takai, T. Matsui, S. Matsubara,
Bull. Soc., Chim. Fr. 1997, 134, 365–369.
(2S*,3S*)-Ethyl 3-Phenyl-1,2-epoxypentanoate (2S*,3S*-4a): Yield:
57%, 125 mg. 1H NMR (300 MHz, CDCl3): δ = 7.30–7.17 (m, 5
H), 3.85–3.74 (m, 2 H), 3.59 (s, 1 H), 2.13–2.01 (m, 1 H), 1.87–1.64
(m, 1 H), 0.85 (t, J = 7.5 Hz, 3 H), 0.83 (t, J = 7.7 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 167.3 (C), 135.9 (C), 127.8
(2×CH), 127.7 (CH), 126.8 (2×CH), 67.1 (C), 60.8 (CH2), 59.2
(CH), 30.5 (CH ), 13.5 (CH ), 8.5 (CH ) ppm. IR (neat): ν = 2978,
˜
2
3
3
1750, 1729, 1200 cm–1; Rf = 0.6 (hexanes/EtOAc 3:1); C13H16O3
(220.26): calcd. C 70.89, H 7.32; found C 71.02, H 7.23.
(2R*,3S*)-Ethyl 3-Phenyl-1,2-epoxypentanoate (2R*,3S*-4a): Yield:
28%, 62 mg. 1H NMR (300 MHz, CDCl3): δ = 7.30–7.17 (m, 5 H),
4.20 (c, J = 7.0 Hz), 3.37 (s, 1 H), 2.13–2.01 (m, 1 H), 1.87–1.64
(m, 1 H), 1.21 (t, J = 5.8 Hz, 3 H), 0.76 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 167.6 (C), 138.3 (C), 128.3
(2×CH), 127.7 (CH), 126.0 (2×CH), 66.4 (C), 61.4 (CH), 61.2
[7] J. M. Concellón, C. Concellón, C. Méjica, J. Org. Chem. 2005,
70, 6111–6113.
[8] B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863–927.
[9] J. M. Concellón, H. Rodríguez-Solla, E. Bardales, M. Huerta,
Eur. J. Org. Chem. 2003, 1775–1778.
[10] Stereochemical descriptors R* and S* (like/unlike) were pro-
posed by: D. Seebach, V. Prelog, Angew. Chem. 1982, 94, 696–
702.
(CH), 23.8 (CH ), 14.1 (CH ), 9.3 (CH ) ppm. IR (neat): ν = 2976,
˜
2
3
3
1756, 1728, 1199 cm–1; Rf = 0.5 (hexanes/EtOAc 3:1); C13H16O3
(220.26): calcd. C 70.89, H 7.32; found C 71.02, H 7.23.
Ethyl 3-Pheny-2,3-epoxybutanoate (4d): Yield: 90%, 186 mg. Data
from a mixture of diastereoisomers in a ratio of 61:39. 1H NMR
(300 MHz, CDCl3): δ = 7.46–7.23 (m, 10 H), 4.32–4.22 (m, 2 H,
Received: December 1, 2005
Published Online: March 6, 2006
2200
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