A convenient synthesis of (E)-α,β-unsaturated esters with total stereoselectivity promoted by catalytic samarium diiodide

Article abstract of DOI:10.1055/s-0030-1259089

Synthesis of (E)-α,β-unsaturated esters in high yields and with total stereoselectivity is achieved from α-halo-β-hydroxy esters promoted by catalytic amounts of SmI₂. The starting compounds were easily prepared from α-halo esters and aldehydes as a mixture of stereoisomers. A mechanism is proposed to explain this samarium(II)-promoted catalytic β-elimination reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259089

262
LETTER
A Convenient Synthesis of (E)-a,b-Unsaturated Esters with Total
Stereoselectivity Promoted by Catalytic Samarium Diiodide
Synthesis
o
of
(
E
)-
a
,
b
-U
s
nsaturate
d
é
E
sters
w
ith
T
ota
M
l
Stereoselectivity . Concellón,* Humberto Rodríguez-Solla,* Carmen Concellón, Ainhoa Díaz-Pardo, Ricardo Llavona
Dpto. Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain
Fax +34(985)102971; E-mail: hrsolla@uniovi.es
Received 25 October 2010
enolates of a-halo esters (generated by treatment of a-halo
esters 1 with LDA at –85 ºC) with aldehydes 2 at the same
temperature (Scheme 1).8
Abstract: Synthesis of (E)-a,b-unsaturated esters in high yields
and with total stereoselectivity is achieved from a-halo-b-hydroxy
esters promoted by catalytic amounts of SmI2. The starting com-
pounds were easily prepared from a-halo esters and aldehydes as a
mixture of stereoisomers. A mechanism is proposed to explain this
samarium(II)-promoted catalytic b-elimination reaction.
O
OH
O
R2
1) LDA
OR3
R1
OR3
2) R1CHO (2)
Key words: a,b-unsaturated esters, catalytic reactions, elimina-
tions, samarium
Hal R2
Hal
3) H3O+
1
3
Scheme 1 Synthesis of a-halo-b-hydroxy esters 3
Samarium diiodide has become an important reagent in
synthetic organic chemistry because of its versatility in
electron-transfer reactions. In the last years, samarium di-
iodide has been applied to a multitude of organic transfor-
mations, which generally proceed with high selectivities.1
Initial attempts were carried out on compound 3a. We
tested several conditions varying the amounts of SmI2
(20%, 10%, 5%, 2.5% of the 2.0 equiv required for the
stoichiometric reaction and 2 drops) and reaction times.
The best results were obtained when 20% of a SmI2 solu-
tion was employed in the presence of a mixture of Mg/
TMSCl during 18 hours (Table 1, entry 1). With this pre-
ceding result in hand, our following efforts were directed
towards the generalization of this process.
A major drawback of SmI2 has been its cost since it has
been generally employed in stoichiometric amount. For
this reason, methods to carry out transformations using
this salt in catalytic amounts would be desirable. Several
systems for the regeneration of Sm(II) from Sm(III) have
been reported. So, the use of catalytic amounts of samari-
um diiodide in Reformatsky-type reactions,2 Barbier-type
processes,3 pinacol couplings,4 dimerization of aromatic
esters5 and p-coupling reactions has been published.6
Thus, when a mixture of six equivalents of magnesium
turnings activated with six equivalents of TMSCl, 0.4
equivalent of SmI2 and one equivalent of the correspond-
ing a-chloro-b-hydroxy ester 3a–c was stirred at room
temperature for 18 hours, (E)-a,b-unsaturated esters 4a–c
were obtained, after hydrolysis in high yields and as a sole
stereoisomer.15 These results are summarized in Table 1.
Samarium diiodide has been widely employed to promote
b-elimination reactions with high or total stereoselectivi-
ty.7 In this field, we have previously reported the SmI2-
promoted stereoselective synthesis of (E)-a,b-unsaturated
esters,8 amides,9 ketones,10 or nitroalkenes,11 (Z)-vinyl ha-
lides,12 (Z)-vinyl allylsilanes,13 and (Z)-b,g-unsaturated
nitriles.14 In all these cases, the 1,2-elimination reaction
was initiated by the metalation of a carbon–halogen bond
using stoichiometric amounts of samarium diiodide.
When the same conditions were employed for the synthe-
sis of aromatic or conjugated a,b-unsaturated esters, no
Table 1 Synthesis of (E)-a,b-Unsaturated Esters 4a–c
O
OH
O
SmI2 (20%)
R1
OR3
R1
OR3
As part of our program concerned with the development
of new b-elimination reactions mediated by SmI2, we
wish to report herein a new and easy access to (E)-a,b-un-
saturated esters, by treatment of a-halo-b-hydroxy esters,
with catalytic amounts of SmI2. Also, a mechanism is pro-
posed to explain this samarium(II)-promoted catalytic b-
elimination reaction.
Mg, TMSCl, THF
Cl R2
R2
4a–c
3a–c
Entry
4a
R1
R2
R3
Yield (%)b
1
2
3
4a
4b
4c
n-C7H15
n-C7H15
Cy
H
Me
Et
65
69
89
Me
Me
The starting materials 1 were easily prepared as a diaste-
reoisomeric mixture (roughly 1:1) by reaction of lithium
Et
a All compounds were obtained in stereoisomerically pure form (E/Z
>98:2) determined by GC–MS, and/or 300 MHz 1H NMR analysis of
the crude reaction products 4a–c.
SYNLETT 2011, No. 2, pp 0262–0264
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1259089; Art ID: G29410ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1
b Isolated yield of pure compounds 4a–c after column chromatogra-
phy based on compounds 3a–c.

LETTER
Synthesis of (E)-a,b-Unsaturated Esters with Total Stereoselectivity
263
reaction took place and a mixture of the starting materials C double bond in compound 4a was assigned on the basis
with products proceeding from the metalation and further of the magnitude of 1H NMR coupling constant between
hydrolysis (b-hydroxy esters) were isolated instead. It had the olefinic protons, and by comparison of its NMR spec-
been previously published that ZnCl2 was employed as a trum with that described in the literature for the same un-
Lewis acid for SmI2-promoted reactions.16 We attempted saturated ester.19 The relative configuration of compounds
the use of Mg/I2/ZnCl2 on substrates 3d–i. Thus, treatment 4b–i was assigned by NOESY experiments for compound
of a-halo-b-hydroxy esters 3d–i with six equivalents of 4h, and/or by comparison of their NMR spectra (4b–g and
Mg, six equivalents of ZnCl2 and a crystal of molecular io- 4i) with those previously described in the literature for the
dine at room temperature for 18 hours afforded aromatic same unsaturated esters.20
(Table 2, entries 1–4) or conjugated (Table 2, entry 5) (E)-
The principle of the catalytic redox process with samari-
um is outlined in Scheme 2. The synthesis of a,b-unsatur-
a,b-unsaturated esters 4d–i with total stereoselectivity.17
ated esters 4 might be explained assuming a chelation-
Table 2 Synthesis of (E)-a,b-Unsaturated Esters 4d–i
control model. In this sense, after metalation of the C–Hal
O
OH
O
bond of compounds 3 with the samarium(II) halide, a six-
membered-ring intermediate (depicted as I or II in
Scheme 2) is generated through chelation of the highly
oxophilic SmIII center with the hydroxy group.21
SmI2 (20%), ZnCl2
Mg, I2, THF
R1
OR3
R1
OR3
Hal R2
R2
3d–i
4d–i
Entry 4a
R1
R2
R3
Hal
Yield
O
(%)b
R1
OR3
1
2
3
4
5
6
4d
4e
4f
Ph
n-Pr
H
Et
Me
Et
Et
Et
Et
Br
Cl
Cl
Cl
Cl
Cl
72
R2
Mg, TMSCl
or Mg, I2
2 SmX3
(X = Cl, I)
4-ClC6H4
4-MeOC6H4
4-O2NC6H4
cyclohexen-1-yl
Bn
22
4
Me
Me
Me
Me
60
MgII
4g
4h
4i
66
57
TMSCl
or ZnCl2
64
a All compounds were obtained in stereoisomerically pure form (E/Z
>98:2) determined by GC–MS, and/or 300 MHz 1H NMR analysis of
the crude reaction products 4d–i.
SmIII
2 SmX2
H
O
O
b Isolated yield of pure compounds 4d–i after column chromatogra-
phy based on compounds 3d–i.
R1
OR3
R2
OH
R1
Hal R2
O
5
Literature data indicates that increasing substitution
around the double bond usually results in diminishing ste-
reoselectivity. This samarium-based methodology differs
from the others in that no Z-isomer was detected in the
crude samples. Analyses of Tables 1 and 2 reveal that the
synthesis of unsaturated esters is general, allowing the use
of linear, cyclic or aromatic a-halo-b-hydroxy esters 1.
Moreover, in contrast to other previously described syn-
theses of a,b-unsaturated esters, this preparation can be
carried out by using starting material with readily enoliz-
able protons18 (Table 2, entry 6). Finally, it is noteworthy
that other functionalities are compatible with this transfor-
mation, such as ethers, chlorine, nitro groups and C–C
double bonds (Table 2, entries 1–5). Moreover, no differ-
ences were observed on the reaction outcome when this
process was carried out on bromo or chloro derivatives as
starting materials (Table 2, entries 1 and 2–6).
OR3
H
O
3
H
O
R1
R1
R2
O
O
SmIII
OR3
H
R2 R3O
SmIII
H
I
II
Scheme 2 Mechanistic proposal for the conversion of 3 into 4
Once the compound 4 is generated, samarium(III) species
are then reduced with magnesium to produce more samar-
ium(II) that is again involved in the catalytic cycle to pro-
mote the above-mentioned b-elimination reaction.
Trimethylsilyl chloride played a double role. On one
hand, it was added to activate the magnesium turnings; on
the other hand it was used to release the samarium(III)
atom from intermediates being regenerated to samari-
um(II) by the activated magnesium. In the case of aromat-
ic compounds 3d–i, zinc dichloride was required to
provide free samarium(III) and magnesium turnings were
activated by the presence of molecular iodine.
The E/Z ratio for compounds 4 was determined by GC–
MS analysis and/or examination of the 1H NMR spectrum
(300 MHz) of the crude reactions. The E stereoisomer was
isolated as a single isomer and no Z-isomer was detected
in the crude product. The relative configuration of the C–
Synlett 2011, No. 2, 262–264 © Thieme Stuttgart · New York

264
J. M. Concellón et al.
LETTER
(12) Concellón, J. M.; Bernad, P. L.; Pérez-Andrés, J. A. Angew.
Chem. Int. Ed. 1999, 38, 2384.
(13) (a) Concellón, J. M.; Bernad, P. L.; Bardales, E. Org. Lett.
2001, 3, 937. (b) Concellón, J. M.; Rodríguez-Solla, H.;
Simal, C.; Gómez, C. Synlett 2007, 75.
In order to explain the E-stereoselectivity, we propose a
half-chair transition state model I in which the bulkier
group R1 is pseudoequatorial. As depicted in the C2–C3
Newman projection of II, R1 and R2 have a cis relation-
ship leading to the E-stereoisomers upon elimination. In
addition, thermodynamic control of the elimination would
afford the E-isomer.22
(14) Concellón, J. M.; Rodríguez-Solla, H.; Simal, C.; Santos, D.;
Paz, N. R. Org. Lett. 2008, 10, 4549.
(15) General Procedure for the Synthesis of Aliphatic (E)-a,b-
Unsaturated Esters 4a–c: A solution of the requisite a-
halo-b-hydroxy ester 3a–c (0.2 mmol) in THF (2.5 mL) was
added dropwise at r.t. and vigorous stirring to a mixture of
SmI2 (0.1 M in THF, 0.8 mL) and activated magnesium (1.2
mmol) with TMSCl (1.2 mmol) in THF (2.5 mL). After
stirring at the same temperature for 18 h, the excess of SmI2
was removed by bubbling a stream of air through the
solution. An aqueous solution of 0.1 N HCl (10 mL) was
then added and the aqueous phase was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
dried over anhyd Na2SO4, filtered and concentrated in
vacuo. Flash column chromatography on silica gel (hexane–
EtOAc, 5:1) provided pure compounds 4a–c.
In conclusion, an efficient, general and very cheap meth-
odology has been developed to synthesize a,b-unsaturated
esters with total E stereoselectivity from easily available
a-halo-b-hydroxy esters, with catalytic amounts of SmI2.
Attempts to carry out other processes by using catalytic
samarium diiodide, are currently under investigation
within our laboratory.
Acknowledgment
We thank the Ministerio de Ciencia e Innovación (MICINN
CTQ2007-61132) and the Principado de Asturias (FICYT IB08-
028) for financial support. C.C. thanks MICINN for a Juan de la
Cierva contract.
(16) Kunishima, M.; Nakata, D.; Sakuma, T.; Kono, K.; Sato, S.;
Tani, S. Chem. Pharm. Bull. 2001, 49, 97.
(17) General Procedure for the Synthesis of Aromatic (E)-a,b-
Unsaturated Esters 4d–i: A solution of the requisite a-
halo-b-hydroxy ester 3d–i (0.2 mmol) in THF (2.5 mL) was
added dropwise at r.t. and vigorous stirring to a mixture of
SmI2 (0.1 M in THF, 0.8 mL) and activated magnesium (1.2
mmol) with iodine and zinc dichloride (1.2 mmol) in THF
(2.5 mL). After stirring at the same temperature for 18 h, the
excess of SmI2 was removed by bubbling a stream of air
through the solution. An aqueous solution of 0.1 N HCl (10
mL) was then added. The aqueous phase was filtered
through a pad of celite® and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over anhyd
Na2SO4, filtered and concentrated in vacuo. Flash column
chromatography on silica gel (hexane–EtOAc, 5:1) provided
pure compounds 4d–i.
(18) Wittig reactions carried out with enolizable carbonyl
compounds can generate alkenes in very low yield:
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(19) Spectroscopic data of compound 4a has been described in:
Concellón, J. M.; Pérez-Andrés, J.; Rodríguez-Solla, H.
Angew. Chem. Int. Ed. 2000, 39, 2773.
References and Notes
(1) For reviews concerning the synthetic applications of SmI2,
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(20) Spectroscopic data of compounds 4b–g and 4i have been
described in the following references: (a) For compounds
4b, 4c and 4f see, ref. 19. (b) For compound 4d, see: Wolan,
A. Tetrahedron 2009, 65, 7429. (c) For compound 4e, see:
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(21) Other six-membered ring transition state models have been
proposed to explain the selectivity in other reactions of
SmI2: (a) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am.
Chem. Soc. 1987, 109, 453. (b) Urban, D.; Skrydstrup, T.;
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(e) See also refs 1j and 8–13.
(22) This model assumes that the transformation of
diastereoisomeric mixture of 3 leads only to the stereoisomer
of appropriate conformation for coordination of the
samarium(III) center by the hydroxy group.
(6) Corey, E. J.; Zheng, G. Z. Tetrahedron 1997, 12, 2045.
(7) To see a review about b-elimination reactions promoted by
SmI2, see ref. 1j.
(8) Concellón, J. M.; Pérez-Andrés, J. A.; Rodríguez-Solla, H.
Angew. Chem. Int. Ed. 2000, 39, 2773.
(9) Concellón, J. M.; Pérez-Andrés, J. A.; Rodríguez-Solla, H.
Chem. Eur. J. 2001, 7, 3062.
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1931.
(11) Concellón, J. M.; Bernad, P. L.; Rodríguez-Solla, H.;
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Synlett 2011, No. 2, 262–264 © Thieme Stuttgart · New York

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