Synthesis of (Z)-α-chloro-α,β-unsaturated esters with complete stereoselectivity promoted by samarium diiodide

Article abstract of DOI:10.1016/j.tetlet.2004.04.101

Stereoselective β-elimination in α,α-dichloro-β- hydroxyesters 2 was achieved by using samarium diiodide, yielding (Z)-α-chloro-α,β-unsaturated esters 1. The starting compounds 2 were easily prepared by reaction of the lithium enolate of ethyl dichloroacetate with different aldehydes at -78°C. A mechanism to explain this process is proposed.

Full text of DOI:10.1016/j.tetlet.2004.04.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4665–4667
Synthesis of (Z)-a-chloro-a,b-unsaturated esters with complete
stereoselectivity promoted by samarium diiodideq
*
ꢀ
Jose M. Concellon, Monica Huerta and Ricardo Llavona
ꢀ
ꢀ
Departamento de Quꢀımica Orgꢀanica e Inorgꢀanica, Facultad de Quꢀımica, Universidad de Oviedo, E-33071 Oviedo, Spain
Received 17 March 2004; revised 31 March 2004; accepted 20 April 2004
Abstract—Stereoselective b-elimination in a,a-dichloro-b-hydroxyesters 2 was achieved by using samarium diiodide, yielding (Z)-a-
chloro-a,b-unsaturated esters 1. The starting compounds 2 were easily prepared by reaction of the lithium enolate of ethyl di-
chloroacetate with different aldehydes at )78 °C. Amechanism to explain this process is proposed.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Now, we are interested in the use of a-chloro-a,b-
unsaturated esters in organic synthesis. For this reason
our objective in this work is to describe the synthesis
of (Z)-a-chloro-a,b-unsaturated esters 1 through a b-
elimination reaction of a,a-dichloro-b-hydroxyester
promoted by the nontoxic14 SmI2.15 This preparation
takes place with complete stereoselectivity.
a-Chloro-a,b-unsaturated esters (a-chloroacrylates) are
useful building blocks in organic synthesis1 and are
attractive starting materials to obtain natural products
or pharmaceuticals.2
a-Chloro-a,b-unsaturated esters are most often pre-
pared by dehydrohalogenation,3 rearrangements,4 alk-
oxycarbonylation,5 thermal eliminations6 or Wittig–
Horner condensations7 and Peterson-type reactions.8
However, most of these syntheses are limited by their
poor stereoselectivity, low yields or involve multi-step
transformations. While this paper was being prepared, a
synthesis of a-chloro-a,b-unsaturated esters with com-
plete stereoselectivity,9 which suffers from the use of
toxic CrCl2, was described.
2. Results and discussion
The starting a,a-dichloro-b-hydroxyesters 2 were easily
prepared by reaction of the lithium enolate derived from
methyl dichloroacetate (generated by treatment of
methyl dichloroacetate 3 with LDAat )78 °C) with
various aldehydes 4 at )78 °C16 (Scheme 1 and Table 1).
Recently, we have described the first general method to
promote b-elimination reactions by using SmI2 with
complete or high stereoselectivity. Thus, we reported the
synthesis of (Z)-vinyl halides,10 (E)-a,b-unsaturated
esters11 or amides12 and (Z)-vinylsilanes,13 with total or
high stereoselectivity.
With the requisite starting compounds in hand, the
initial studies were performed to determine the optimum
reaction conditions to prepare unsaturated esters. The
best results were obtained by treatment of a,a-dichloro-
b-hydroxy esters 2 with a solution of SmI2 (2.5 equiv) in
THF following the conditions shown in Table 1. The
Cl
OH
O
LDA
OR2
R1CHO
Keywords: Alkenes; Stereoselection; Eliminations; Samarium;
a-Chloro-a,b-unsaturated esters.
+
R1
OR2
Cl
-78 ºC
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.04.101
* Corresponding author. Tel.: +34-985103457; fax: +34-985103446;
e-mail: jmcg@fq.uniovi.es
Cl Cl
O
3
4
2
Scheme 1. Synthesis of starting materials 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.101

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J. M. Concellꢀon et al. / Tetrahedron Letters 45 (2004) 4665–4667
Table 1. Synthesis of starting compounds 2 and a-chloro-a,b-unsaturated esters 1
Entry
Producta
R1
R2
% Yield of 2b
t (h)c
% Yield of 1d;e
% Def
1
2
a
b
c
d
e
f
i-Pr
n-C4H9
Me
Me
Me
Ph
87
60
72
60
72
73
87
86
89
93
12
4
73
79
62
83
76
92
68
85
75
87
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
3
Cyclohexyl
Cyclohexyl
12
1
4
5
Cyclohexyl
n-C7H19
i-Pr
i-Pr
Me
i-Pr
Me
Me
1
6
1
7
g
h
i
CH3CH(Ph)
CH3CH(Ph)
(E)-(C6H5)CH@CH
(CH3)2C@CH(CH2)2CH(CH3)CH2
4
8
1
9
10
12
12
j
a All compounds 1 were fully characterized by elemental analysis and spectroscopic methods (IR, 1H, 13C, and HMRS).
b Isolated yield after column chromatography based on compound 3.
c Reaction time to transform 2 into 1.
d All reactions were carried out by using 2.5 equiv of SmI2 at room temperature.
e Isolated yield after column chromatography based on compound 2.
f Diastereoisomeric excess (de) determined by GC–MS and 300 MHz 1H and 13C NMR analysis of the crude products 1.
the elimination reaction was unaffected by the presence
of bulky (R2 ¼ i-Pr) substituents on oxygen (Table 1,
entries 5, 6 and 8).18
OH
O
O
SmI2
R1
OR2
R1
OR2
Cl Cl
Cl
2
1
The stereoselectivity of the reaction was determined on
the crude reaction products by GC–MS and by 1H
NMR spectroscopy (300 MHz), and only a single ste-
reoisomer was observed.
Scheme 2. Synthesis of (Z)-a-chloro-a,b-unsaturated esters 1.
corresponding a-chloro-a,b-unsaturated esters 1,17 were
isolated, with total stereoselectivity and in good yield by
using these reaction conditions (Scheme 2).
The Z stereochemistry in the double bond C@C of a,b-
unsaturated esters 1 was established by NOESY exper-
iments (compounds 1e, 1f and 1h). NOE effects were
observed between the olefinic proton and the methylic
hydrogens of the alcoholic group (i-Pr), showing a cis
relationship between Hb and COOR2 group.
The results obtained from subjecting a range of a,a-di-
chloro-b-hydroxyesters 2 to SmI2 are summarized in
Table 1 and illustrate the generality of the method.
Thus, R1 can be varied and the reaction can be carried
out with aliphatic linear, branched, cyclic or unsaturated
a,a-dichloro-b-hydroxy esters 2 (Table 1). In addition,
The b-elimination reaction and the observed configura-
tion of the C@C bond in products 1 may be explained by
OH
O
R1
OR2
I2Sm Cl
OH
O
O
R1
OR2
R1
OR2
I2
Sm
Cl Cl
Cl
H
O
O
2
1
R1
OR2
Cl
5
R1
Cl
O
Cl
O
O
O
I2
H
Sm
R1
SmI2
OR3
OR2
H
H
I
II
Scheme 3. Proposed mechanism.

J. M. Concellꢀon et al. / Tetrahedron Letters 45 (2004) 4665–4667
4667
Bodalski, R.; Wieczorek, M.; Bujacz, G. Tetrahedron
1995, 51, 1721–1740.
^
8. Tellier, F.; Sauvetre, R. Tetrahedron Lett. 1993, 34, 5433–
5436.
9. Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.;
Falck, J. R. J. Am. Chem. Soc. 2003, 125, 3218–
3219.
assuming a chelation-control model (Scheme 3). Thus, a
two-step reduction of the C–Cl bond in 2 promoted by
SmI2, affords the enolate intermediate 5, in which the
chelation of SmIII centre with both oxygen atoms pro-
duces a six-membered ring.19 Tentatively we propose a
transition state model I with the R1 in the equatorial
orientation. As depicted in II (C2–C3 Newman projec-
tion of I), R1 and Cl show a cis relationship. Conse-
quently, elimination20 from I affords (Z)-a-chloro-a,b-
unsaturated esters 1. No formation of a-chloro-b-
hydroxy ester was observed, indicating that the elimi-
nation reaction of intermediate 5 is more rapid than its
hydrolysis by the proton of the hydroxyl group.
ꢀ
ꢀ
ꢀ
10. Concellon, J. M.; Bernad, P. L.; Perez-Andres, J. A.
Angew. Chem. 1999, 111, 2528–2530; Angew. Chem., Int.
Ed. Engl. 1999, 38, 2384–2386.
ꢀ
11. (a) Starting from a-chloro-b-hydroxyesters: Concellon, J.
ꢀ
ꢀ
ꢀ
M.; Perez-Andres, J. A.; Rodrıguez-Solla, H. Angew.
Chem., Int. Ed. Engl. 2000, 39, 2773–2775; (b) From a,b-
ꢀ
epoxyesters: Concellon, J. M.; Bardales, E. Org. Lett.
2002, 4, 189–191.
ꢀ
ꢀ
ꢀ
ꢀ
12. Concellon, J. M.; Perez-Andres, J. A.; Rodrıguez-Solla, H.
In conclusion, we present a simple and general method
for the preparation of (Z)-a-chloro-a,b-unsaturated
esters 1 with high stereoselectivity from the easily
available a,a-dichloro-b-hydroxyesters 2, with the
reaction being promoted by samarium diiodide. A
mechanism has been proposed to explain this reaction.
Chem. Eur. J. 2001, 7, 3062–3068.
ꢀ
13. Concellon, J. M.; Bernad, P. L.; Bardales, E. Org. Lett.
2001, 3, 937–939.
14. Unlike many of their main group and transition metal
counterparts, inorganic lanthanide compounds are gener-
ally classified as nontoxic when introduced orally. In fact,
samarium chloride and ytterbium chloride exhibit similar
toxicity to that of sodium chloride (LD50 of >2000–
6700 mg/Kg in mice versus 4000 mg/Kg for NaCl). (a)
Haley, T. J. J. Pharm. Sci. 1965, 54, 663–670; (b) Bruce, D.
W.; Hietbrink, B. E.; DuBois, K. P. Toxicol. Appl.
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Acknowledgements
ꢀ
We thank Ministerio de Educacion, Cultura (PB97-
1278) for financial support. J.M.C. thanks Carmen
^
Rhone-Poulenc, Paris, 1986.
15. Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim.
1977, 1, 5–7.
ꢀ
Fernandez-Florez for her time. M.H. thanks to Minis-
terio de Educacion, Cultura y Deporte for a predoctoral
ꢀ
ꢀ
16. General procedure for the synthesis of compound 2: To a
)78 °C stirred solution of lithium diisopropylamide [pre-
pared from MeLi (7.3 mL) of 1.5 M solution in diethyl
ether (11 mmol), and diisopropylamine (1.04 mL,
11 mmol) in THF (30 mL) at 0 °C] was added dropwise
the corresponding a,b-dichloroester 3 (10 mmol). After
stirring for 10 min, a solution of the corresponding
aldehyde (12 mmol) in dry THF (10 mL) was added
dropwise at )78 °C and the mixture was stirred for 2 h.
Then, the reaction mixture was quenched with a saturated
aqueous solution of NH4Cl (20 mL). Usual workup
provided crude a,a-dichloro-b-hydroxyesters 2. Purifica-
tion by flash column chromatography on silica gel
(hexane/AcOEt) provided pure compounds 2.
17. General procedure for the synthesis of compounds 1: A
solution of SmI2 (1.0 mmol) in THF (12 mL) was added,
under a nitrogen atmosphere, to a stirred solution of the
corresponding a,a-dichloroester 2 (0.4 mmol) in THF
(2 mL) at room temperature and for the time specified in
Table 1 (the reaction times were established by TLC).
Then, the reaction was quenched with aqueous HCl
(20 mL of 0.1 M solution). Usual workup afforded crude
a-chloro-a,b-unsaturated esters 1, which were purified by
column flash chromatography over silica gel (20:1, hexane/
AcOEt).
fellowship. Our thanks to Scott J. S. Hartman for his
revision of the English.
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