Reformatsky reactions with SmI2 in catalytic amount

Article abstract of DOI:10.1016/j.tetlet.2005.01.079

A substoichiometric protocol for Reformatsky-type addition of α-haloesters, α-haloketones, α-halonitriles, and α-halophosphonates to carbonyl compounds has been developed. β-Hydroxyesters and β-hydroxynitriles were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2005.01.079

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1909–1911
Reformatsky reactions with SmI2 in catalytic amount
Fulvia Orsini* and Elvira Maria Lucci
Dipartimento di Chimica Organica e Industriale, University of Milano, Via Venezian, 21-20133 Milano, Italy
Received 2 August 2004; revised 12 January 2005; accepted 18 January 2005
Abstract—A substoichiometric protocol for Reformatsky-type addition of a-haloesters, a-haloketones, a-halonitriles, and a-halo-
phosphonates to carbonyl compounds has been developed. b-Hydroxyesters and b-hydroxynitriles were obtained in good to
excellent yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The reaction of a-haloesters with carbonyl compounds
in the presence of metallic zinc, to give b-hydroxy esters,
represents a powerful synthetic tool for carbon–carbon
bond formation. Since its discovery by Reformatsky,
this reaction has been undergoing several improvements
and its scope and selectivity have been considerably ex-
tended. Various parameters, such as metal activation,
reaction temperature, solvent, properly designed re-
agents and educts have been extensively investigated.
In addition, besides the classical zinc method, various
other metals or metal derivatives have been tested.1 To
this concern, transition metals may offer important
advantages in terms of milder conditions, higher repro-
ducibility and stereoselectivity. A metal which has also
proved quite useful is samarium(II) (used as SmI2), par-
ticularly for the remarkable stereoselectivity exhibited in
intramolecular reactions, achieved through chelation
control of the samarium intermediate in the transition
state.2 More recently we reported SmI2-mediated reac-
tions of diethyl (a-iodomethyl)phosphonate with car-
bonyl compounds to give b-hydroxyphosphonates.3a
The same protocol was then extended to esters and lac-
tones and applied to the synthesis of a precursor of the
C-glycosyl analogue of thymidine 50-(b-L-rhamnos-
yl)diphosphate.3b
tion, the use of the convenient, commercially available
tetrahydrofuran solution of SmI2 is affected by low
reproducibility when a stoichiometric protocol is used.
To overcome these problems, we now report an SmI2/
Mg promoted Reformatsky-type reaction which allows
the use of a substoichiometric amount of Sm(II)
(10%), provided magnesium metal is present to carry
out the reduction Sm(III)/Sm(II). We have optimised a
similar protocol for Co(0)-mediated Reformatsky-type
and aldol-type reactions of a-halo esters, ketones and
phosphonates with various electrophiles.4 To our
knowledge, few systems employing co-reductants for
the catalytic use of SmI2 have been reported: for exam-
ple Zn amalgam in the annulation of ketones to c-lac-
tones and in the radical cyclisation of unsaturated
halides;5 mischmetall in Reformatsky-type reactions;6
Mg in pinacolic coupling of carbonyl compounds in
the presence of trimethylsilyl chloride.7
The results are reported in Table 1 and deserve some
comments.
The addition product was obtained in good to excellent
yield when an a-bromoester and a carbonyl compound
(aldehyde or ketone) were used. a,b-Unsaturated carbo-
nyls such as cinnamaldehyde gave the 1,2-addition prod-
uct in excellent yield. Lower yields were obtained when
an aromatic a-bromoketone or a-bromoacetonitrile
was used.
Unfortunately in these reactions, a 2.2–2.5 equiv of
samarium(II) must be used to ensure reduction of the
initially formed radical to an organosamarium; in addi-
The pinacolic coupling product was observed in appre-
ciable amounts only with benzaldehyde (10–15%
depending on the run and on the addition order of the
organic reagents to the samarium(II)).
Keywords: Catalysed Reformatsky reaction; Samarium(II) iodide.
*
Corresponding author. Tel.: +39 02 50314111; fax: +39 02
50314106; e-mail: fulvia.orsini@unimi.it
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.079

1910
F. Orsini, E. M. Lucci / Tetrahedron Letters 46 (2005) 1909–1911
Table 1. Sm(II)-catalysed Reformatsky-type reactions
Halogen compound
EWG
Electrophile
Addition product (%)
Pinacolic coupling product (%)
R
Y
R
R
R
X
EWG
R'
R'
R'
R'
YH
YH YH
''
Y = O, NR
tert-Butyl-a-bromo acetate
tert-Butyl a-bromo acetate
tert-Butyl a-bromo acetate
tert-Butyl a-bromo acetate
tert-Butyl a-bromo acetate
tert-Butyl a-bromo acetate
Benzyl a-bromo acetate
a-Bromo acetophenone
a-Bromo acetonitrile
Diethyl (a-iodomethyl) phosphonate
Diethyl (a-iodomethyl) phosphonate
Diethyl (a-iodomethyl) phosphonate
C6H5CHO
(C6H5)2CO
75a
77
10
—
—
—
60.5
—
—
—
—
—
—
—
CH3(CH2)5C(O)CH3
C6H5CH@CHCHO
C6H5CH@NCH2C6H5
2,3,5-Tri-O-benzyl-D-arabino-1,4-lactone
C6H5CHO
83
91a
24
85a,b d.r. = 2/1
90a
38
C6H5CHO
C6H5CHO
65
C6H5CHO
(CH3)3CHO
(CH3)2CHCHO
35c
33
35
a Yields determined by NMR analysis.
b A diastereoisomeric mixture was obtained.
c Diethyl methyl phosphonate was obtained (25%).
The addition to the carbon–nitrogen bond present in the
benzylimine of benzaldehyde was, in contrast, unsatis-
factory: the main product was 1,2-diphenyl-1,2-diami-
This substoichiometric protocol was also tested for the
reaction of diethyl (a-iodomethyl)phosphonate with
various aldehydes: the addition product, b-hydrox-
yphosphonate, was formed, but only in modest yields
(33–35%) and was accompanied by appreciable amounts
of diethyl methylphosphonate (20–25%). Furthermore
the reaction required, to proceed, the addition of an
equimolar amount of trimethylsilyl chloride/bromide.
noethane (meso and racemate), arising from
pinacolic coupling reaction.
a
Once optimised, the protocol was applied to the lactone
of 2,3,5-tri-O-benzyl–b-D-arabinofuranose, as model
compound for aldonolactones, useful precursors of C-
glycosides and sugar-fused b-hydroxy and b-amino
acids.8 The reaction proceeded in very good yield
(85%) and afforded the two diastereoisomeric products
in 2/1 diastereoisomeric ratio.
In a typical procedure, a solution of the carbonyl com-
pound (1 mmol) and the halo compound (1 mmol) in
tetrahydrofuran (2.0 mL) was added portion-wise at
room temperature and under vigorous stirring to a mix-
ture of samarium iodide (0.1 M solution in THF,
1.0 mL) and activated (with 1,2-dibromoethane) magne-
sium turnings (0.15 g) in THF (1.0 mL). The course of
the reaction was monitored by observing the colour of
the solution which turned blue to yellow and then back
to blue for several times during the addition of the or-
ganic reagents.9 At the end of the reaction, monitored
by thin layer chromatography (silica; eluting with n-hex-
ane/ethylacetate), the reaction mixture was filtered. The
remaining magnesium turnings were washed with tetra-
hydrofuran and reused. The organic phase was diluted
with ethyl acetate and poured into crushed ice. The
aqueous phase was extracted three times with ethyl ace-
tate (3 · 6 mL). The combined organic extracts were
dried (Na2SO4) and the solvent removed under reduced
pressure, to afford a crude material, which was purified
by column chromatography on silica gel.
To investigate whether an organomagnesium com-
pound might be involved in the carbon–carbon bond
formation, in some cases parallel experiments were
performed (tert-butyl a-bromo acetate with trans-
cinnamaldehyde or with benzaldehyde; benzyl
a-bromoacetate with cinnamaldehyde or with 2,3,5-tri-
O-benzyl-D-arabino-1,4-lactone). The bromoester and
the electrophile were added at room temperature to
two reaction flasks: one containing a substoichiometric
amount of SmI2 and magnesium in tetrahydrofuran,
the other only magnesium in tetrahydrofuran. The
amount of bromoester, electrophile, magnesium was
the same in the parallel experiments and so were the
other experimental parameters (molarity, speed of
addition of the reagents, stirring and time of reaction).
In the magnesium-only experiments, appreciable
amounts of reagents were recovered unchanged. Fur-
ther experiments evidenced that longer times and/or
heating were required for the Mg-only reactions, which
were, however, less reproducible and strongly depen-
dent on the experimental parameters, most of all mag-
nesium activation. An added advantage, when Sm(II) is
present, is the colour of the solution that continuously
changes during the addition of the organic reagents
and that allows a visualisation of the course of the
reaction.
In conclusion we have developed a new protocol for the
synthesis of b-hydroxyesters and b-hydroxynitriles via
samarium-mediated Reformatsky-type reactions, with
some advantages with respect to the corresponding stoi-
chiometric reactions: reduction of the samarium and the
solvent (tetrahydrofuran) amounts; greater reproduc-
ibility; easier monitoring of the course of the reaction
and timely visualisation of the end point, with conse-
quent minimisation of the side products. The results ob-

F. Orsini, E. M. Lucci / Tetrahedron Letters 46 (2005) 1909–1911
1911
tained in the samarium(II)-mediated reactions are com-
References and notes
parable with those obtained in the Co(0) mediated reac-
tions;4 however, samarium does not require a phosphine
to stabilise its low oxidation state, which has a double
advantage: one reagent (the phosphine) is saved and
the waste does not contain phosphine or phosphine
oxide. In addition, in the Co-mediated procedure, when
the solid triphenylphosphine is used, a chromatography
is required to purify the product from triphenylphos-
phine or triphenylphosphine oxide. Chromatography
can be avoided when the volatile trimethylphosphine is
used, but this reagent is more toxic and less easy to han-
dle. Last but not least, samarium derivatives are in gen-
eral less toxic. Glyconolactones can be used as
electrophiles, thus providing an entry to sugar-fused-b-
hydroxy acids and C-glycosides. The protocol can be
also applied to the synthesis of b-hydroxyphosphonates
but in only modest yields and in the presence of trimeth-
ylsilylchloride as an additive.
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Acknowledgements
9. The colour of the solution during the addition of the
organic reagents, however, changes more clearly in the
Co(0)-with respect to the Sm(II)-mediated reactions and, as
a consequence, the reactions are more easily monitored. To
this concern, the addition of trimethylsilyl chloride may
help, but it has no consequences on the yield of the
reactions.
`
Universita degli Studi di Milano and MIUR (Minis-
`
tero dellÕIstruzione, dellÕUniversita e della Ricerca) are
acknowledged for financial support. (FIRB: Project
code n. RBAU017KFW - COFIN 2002, Project code
n. 2002058141-007).