Synthesis of (E)-α,β-unsaturated esters with total diastereoselectivity by using chromium dichloride

Article abstract of DOI:10.1016/j.tetlet.2004.02.011

Synthesis of di- and trisubstituted (E)-α,β-unsaturated esters is easily achieved by using chromium dichloride through an elimination reaction of a diastereoisomeric mixture of α-halo-β-hydroxy esters. The starting materials were easily prepared by the aldol reaction of lithium enolates of α-chloroesters with aldehydes. A mechanism to explain this elimination process is proposed.

Full text of DOI:10.1016/j.tetlet.2004.02.011

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2977–2979
Synthesis of (E)-a,b-unsaturated esters with total
diastereoselectivity by using chromium dichloride
*
ꢀ
Jose M. Concellon, Humberto Rodrıguez-Solla and Carmen Mejica
ꢀ
ꢀ
ꢀ
Departamento de Quꢀımica Orgꢀanica e Inorgꢀanica, Facultad de Quꢀımica, Universidad de Oviedo, Juliꢀan Claverꢀıa, 8,
33071 Oviedo, Spain
Received 20 November 2003; revised 30 January 2004; accepted 4 February 2004
Abstract—Synthesis of di- and trisubstituted ðEÞ-a,b-unsaturated esters is easily achieved by using chromium dichloride through an
elimination reaction of a diastereoisomeric mixture of a-halo-b-hydroxy esters. The starting materials were easily prepared by the
aldol reaction of lithium enolates of a-chloroesters with aldehydes. A mechanism to explain this elimination process is proposed.
Ó 2004 Elsevier Ltd. All rights reserved.
The continuing demand for ever more efficacious and
stereoselective synthetic methodology has stimulated
broad interest in the formation of carbon–carbon dou-
ble bonds.1 Consequently, the diastereoselective syn-
thesis of a,b-unsaturated esters has been extensively
developed due to the synthetic applications of these
compounds.2
Recently, we described a diastereoselective synthesis of
ðEÞ-a,b-unsaturated esters by the reaction of a-halo-b-
hydroxy esters with samarium diiodide.20 In this case,
when attempts were carried out in order to obtain
c-amino-a,b-unsaturated esters (from c-amino-a-halo-b-
hydroxy esters), the methodology was unsuccessful. For
this reason, we continued our investigations into diaste-
reoselective b-elimination reactions as a means to find
alternatives to SmI2 to promote 1,2 elimination reactions.
Herein, we report preliminary results of a new method-
ology to obtain a,b-unsaturated esters 2 with total dia-
stereoselectivity by treatment of easily available a-halo-b-
hydroxy esters 1 with chromium dichloride. A mechanism
to explain this b-elimination process is also proposed.
Synthesis of a,b-unsaturated esters is generally achieved
by C@C bond formation by Wittig,3 Horner–Emmons,4
Heck5 or Peterson6 reactions. Other useful approaches
employ the Cope rearrangement,7 utilise acetylenic
compounds8 or using a-mercaptoester derivatives.9
However, most of these methodologies, give a mixture
of diastereoisomers and poor yields can be obtained.
In other cases, poor generality is a major limitation.
In addition, preparations of a,b-unsaturated esters in
which the C@C bond is trisubstituted are scarce.10
Our first attempts were carried out using a-chloro-b-
hydroxy esters and a,b-epoxy esters in order to deter-
mine suitable starting materials. Thus, treatment of a
solution of ethyl 2-chloro-3-hydroxy-2-methyldecanoate
1d in THF with CrCl2 at reflux over 4 h afforded ethyl
2-methyldecan-2-enoate 2d, after hydrolysis, with total
diastereoselectivity (de >98%) and 64% yield. The same
treatment of 2,3-epoxy-2-methyldecanoate 3d, gave 2d
with slightly lower diastereoselection (de 95%) and yield
(51%). Based on these results, the preparation of a,b-
unsaturated esters was performed from compounds 1.
The treatment of different a-halo-b-hydroxy esters 1
with CrCl2 (3 equiv) at room temperature afforded ðEÞ-
a,b-unsaturated esters with total diastereoselectivity
(Scheme 1).21 Table 1 summarises the results obtained.
The aforementioned limitations have led to the use of
chromium dichloride to promote b-elimination reac-
tions. So, the synthesis of unsaturated compounds such
as alkenes,11 vinyl chlorides12 or iodides,13 1,1-bis(tri-
methylsilyl)alkenes,14 trialkylvinylstannanes or silanes,15
1-alkenyl sulfides,16 alkenylboronic esters17 and 2-halo-
alk-2-en-1-ols18 have been described by using CrCl2. To
the best of our knowledge, chromium dichloride has not
been applied to obtain a,b-unsaturated esters.19
Keywords: Chromium; Eliminations; Esters.
* Corresponding author. Tel.: +34-985103457; fax: +34-985103446;
e-mail: jmcg@sauron.quimica.uniovi.es
The starting materials 1 were easily prepared by reaction
of the corresponding lithium enolates of a-halo esters 4
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.011

2978
J. M. Concellꢀon et al. / Tetrahedron Letters 45 (2004) 2977–2979
O
OH
O
O
OH
O
1) LDA
R2
3 CrCl2
THF
OR3
R1
OR3
OR3
R1
OR3
R1
2) R1CHO
3) H3O+
Hal R2
Hal R2
R2
Hal
1
2
4
1
Scheme 1. Synthesis of ðEÞ-a,b-unsaturated esters 2.
Scheme 2. Preparation of starting compound 1.
(generated by treatment of a-halo esters with LDA at
)78 °C) with aldehydes at )78 °C (Scheme 2 and Table
1).22
control model (Scheme 3). Thus, metallation of the
C-Hal bond (via two consecutive single electron trans-
fers) generates the enolate intermediate 5.26 Chelation of
the CrIII center with the oxygen atom of the alcohol
group produces a six-membered ring.27 Indirect proof of
this fact is the lower yield (45%) and diastereoselection
(72%) obtained when elimination was performed on the
O-acetylated form of starting compound 1a. Tenta-
tively, we surmise that the chair-like transition state
model I might be involved, with the R1 group in the
equatorial orientation. Elimination from I affords ðEÞ-
a,b-unsaturated esters.
It is noteworthy that although 1:1 mixtures of diaste-
reoisomers of 1 were used, the corresponding a,b-
unsaturated esters 2 were obtained with total diastereo-
selectivity.
The diastereoisomeric excess was determined by 1H
NMR spectroscopy (300 MHz) and GC–MS of the
crude mixtures of products 2, showing the presence of a
single diastereoisomer. The E stereochemistry in the
C@C double bond of a,b-unsaturated esters 2 was
assigned on the basis of the values of 1H NMR coupling
constants between the olefinic protons of compounds
2a–c (Table 1, entries 1–3),23 and by NOE experiments
in the case of the trisubstituted compounds 2g and 2i or
The synthesis of 2 with total diastereoselection from a
mixture of diastereoisomers of 1 can also be explained
by this mechanism. After reaction of 1 with CrCl2, the
two starting diastereoisomers 1 are transformed into
1
by comparison with the H and 13C NMR spectra of
authentic samples described in the literature (2d–e).20
This methodology for obtaining a,b-unsaturated esters
is general: R1, R2 and R3 can be widely varied. R1 can be
aliphatic (linear, branched or cyclic) or aromatic and
substitution at the C2 position could also be changed
using different esters to prepare the starting compounds
1 (Scheme 2). Interestingly, the diastereoselectivity was
unaffected by changing the carboxylic ester (compounds
2a, 2d and 2j) in contrast to the Wittig olefination
reaction.24 Although chloro and bromo hydroxy esters
(compounds 1h and 1i) can be used as the starting
material, the elimination reaction has mainly been car-
ried out with chloro esters rather than with bromo
derivatives because in this case, the starting compounds
1 were obtained in lower yields.25
CrCl2
O
HO
R1
O
HO
R1
CrCl2
OR3
1
2
OR3
R2
Cl2Cr
R2
5
H
O
R1
O
R2
OR3
CrIII
H
I
The observed C@C double bond configuration of
products 2 may be explained by assuming a chelation-
Scheme 3. Proposed mechanism.
Table 1. Synthesis of a-halo-b-hydroxy esters 1 and ðEÞ-a,b-unsaturated esters 2
1 or 2
R1
R2
R3
Hal
Yield 1 (%)a
Yield 2 (%)b
De (%)c
a
b
c
d
e
f
n-C7H15
p-Cl–C6H4
MeCH(Ph)
n-C7H15
Cyclohexyl
Ph
H
Me
Me
Me
Et
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Cl
86
85
80
78
75
85
90
55
60
76
65
68
52
64
65
60
70
65
90
70
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
H
H
Me
Me
Me
Et
Et
g
h
i
p-MeO–C6H4
Ph
Ph
Me
Et
Et
n-C6H13
n-C5H11
Me
Et
iPr
j
Cyclohexyl
a Isolated yields after column chromatography based on the starting aldehyde.
b Isolated yield after column chromatography based on compound 1.
c Determined by 1H NMR spectroscopy and GC–MS of the crude reaction products.

J. M. Concellꢀon et al. / Tetrahedron Letters 45 (2004) 2977–2979
2979
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two enolate enantiomers, which afford a single E-dia-
stereoisomer through a b-elimination reaction.
In conclusion, an easy and general methodology has
been developed to synthesise a,b-unsaturated esters with
total E-diastereoselectivity from easily available a-halo-
b-hydroxy esters, being promoted by chromium
dichloride. Attempts to carry out diastereoselective 1,2
elimination of c-amino-a-halo-b-hydroxy esters are
currently under investigation within our laboratory.
Acknowledgements
We acknowledge financial support from III Plan
ꢀ
Regional de Investigacion del Principado de Asturias
(PB-EXP01-11), and Ministerio de Ciencia y Tecnologıa
ꢀ
ꢀ
(BQU2001-3807). J.M.C. thanks Carmen Fernandez-
Florez for her time. C.M. thanks the Universidad de
ꢀ
19. While this paper was being elaborated, a synthesis of
a-chloro-a,b-unsaturated esters with total diastereoselec-
tivity using CrCl2was described Barma, D. K.; Kundu, A.;
Zhang, H.; Mioskowski, C.; Falck, J. R. J. Am. Chem.
Soc. 2003, 125, 3218–3219.
Oviedo for a predoctoral fellowship. Our thanks to
Scott J. S. Hartman for his help.
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21. General procedure for the synthesis of compound 2: To a
stirred solution of the corresponding a-halogenated-b-
hydroxy ester 1 (0.4 mmol) in dry THF (5 mL) was added
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