Practical regioselective method for (E)-enol ehter

Article abstract of DOI:10.1016/S0040-4039(00)00603-1

A new practical and highly regioselective synthetic method for (E)-enol ether is reported. (E)-enol ethers (E:Z = 93:7-99:1) were prepared from the corresponding enol acetates (E:Z?3:1) in two steps by bromination and anti- elimination of α-bromodialkylac

Full text of DOI:10.1016/S0040-4039(00)00603-1

Tetrahedron Letters 41 (2000) 4579±4582
Practical regioselective synthetic method for (E)-enol ether
Hyeung-geun Park,* Dong-Hwa Kim, Mi-Sook Yoo,
Mi-kyoung Park and Sang-sup Jew*
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 13 March 2000; revised 3 April 2000; accepted 7 April 2000
Abstract
A new practical and highly regioselective synthetic method for (E)-enol ether is reported. (E)-enol ethers
(E:Z=93:7±99:1) were prepared from the corresponding enol acetates (E:Z3:1) in two steps by bromination
and anti-elimination of a-bromodialkylacetal via metal halogen exchange. # 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: (E)-enol ether; a-bromodialkylacetal; anti-elimination.
Enol ethers have been considerable synthetic intermediates in various organic reactions such as
the [2+2]-cycloaddition1 and Claisen rearrangement2 because the regioselective isomer of di-, or
trisubstituted enol ether can provide a new diastereogenic center. Generally, (Z)-enol ether
could be easily obtained via syn-addition of alkoxide to alkyne,3a partial syn-hydrogenation of
alkoxyalkynes3b or direct alkylidenation using 1,1-dibromoalkane and ester,3c but the preparation
of regioselective (E)-enol ether has been quite a challenge. Several synthetic methods for (E)-enol
ether have been introduced but they did not provide good regioselectivity or they were relatively
less practical.4 Recently, the conversion of a-bromobicyclic ketal to methylene pyran moiety was
employed in the total synthesis of natural product.5 Also Utimoto et al. reported a stereospeci®c
conversion of erythro a-iodosilylalkylacetal to (E)-enol ether via elimination.6 We have developed
a new synthetic method for (E)-enol ether by the combination of these two synthetic strategies.
Here, the practical and highly regioselective synthetic method of (E)-enol ether via anti-elimination
of a-bromodialkylacetals (2) as a key step was reported.
The synthetic strategy was shown in Scheme 1. The a-bromodialkylacetals (2) were prepared
from the corresponding enol acetates (1, ca. E:Z3:1) by the modi®ed method of Bedoukian.7a
Compound 1 was easily prepared by the treatment of acetic anhydride and potassium acetate
with corresponding aldehydes in quantitative yield.3a,7 Bromination of 1 with a carbon tetra-
chloride solution of bromine at 0ꢀC followed by the double substitution of halide and acetate by
alcohol gave 28 in high yield (Table 1). The addition of n-BuLi (1.2 equiv.) to a tetrahydrofuran
solution of 2 at ^78ꢀC gave highly regioselective (E)-enol ethers 38 (E:Z=93:7±99:1) (Table 1).
* Corresponding authors.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00603-1

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Scheme 1.
Table 1
Preparation of (E)-enol ether from enol acetate (1)
We suspect that the high selectivity was due to the relative conformational stability of 2 in the
stage of anti-elimination via a metal±halide exchange. The molecular conformational energy
minimization9 studies showed that 2a (entry 3: 0.690 kcal/mol) with the gauche conformation
between RL (large group) and H have lower energy than 2b (entry 3: 1.457 kcal/mol) with the
gauche conformation between RL and alkoxy (Scheme 2). Severe steric repulsion between the
alkoxy and RL groups makes 2b a less favorable conformation (Scheme 2). Generally, the more
bulky alkoxy group gave higher selectivity (entries 3±5). Surprisingly, trisubstituted enol ether
gave quite high selectivity (entry 9). But the cyclohexyl substrate (entry 10) did not give enol ether
product because tert-aliphatic bromide (2) would not permit metal±halogen exchange, even by
t-BuLi at ^78ꢀC. In the case of allylic enol ether (entry 6), the high selectivity could make it possible
to apply this method to the Claisen rearrangement. In conclusion, a new practical and highly
regioselective synthetic method for (E)-enol ether by the elimination of a-bromodialkylacetal
which can be easily prepared from corresponding aldehydes is reported. This synthetic method
could be connected with other useful reactions that require regioselective pure (E)-enol ether such
as the Claisen rearrangement or asymmetric dihydroxylation for chiral a-hydroxy aldehyde. The
applications of this method are currently being investigated.
General procedure for preparing (E)-enol ether 3: To a carbon tetrachloride solution of enol
acetate (10 mmol) was added a 0.5 M bromine in carbon tetrachloride in an ice-bath until the
reaction solution was slightly brown. The reaction was stirred for 0.5 h and then the excess
bromine was removed in vacuo. The residue was diluted with carbon tetrachloride and excess
corresponding alcohol (5 equiv.) was added. The reaction solution was stirred for 12 h. To the

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Scheme 2.
reaction solution was added sat. aq. NaHCO3 and carbon tetrachloride solvent was removed in
vacuo. The water layer was extracted with EtOAc (50 mLÂ3) and the combined EtOAc
solution was washed with H2O (30 mL) and brine (30 mL) and dried over anhydrous MgSO4.
After the solvent was removed in vacuo, the residue was puri®ed by column chromatography
(n-hexane:EtOAc=30:1) to give 2. To a tetrahydrofuran solution (5 mL) of 2 was added n-BuLi
(1.6 M solution in hexane, 1.2 equiv.) at ^78ꢀC. The reaction was stirred for 5 min at ^78ꢀC and
excess n-BuLi was quenched by methyl alcohol. The tetrahydrofuran solvent was removed in vacuo
and the residue was diluted with EtOAc (50 mL) and washed with H2O (10 mLÂ2), and brine
(10 mL) and dried over anhydrous MgSO4. After the solvent was removed in vacuo, the residue
was puri®ed by column chromatography (n-hexane:EtOAc=60:1) to give (E)-enol ether 3.
Acknowledgements
This research was supported by the Research Center of New Drug Development of Seoul
National University and the Research Institute of Pharmaceutical Sciences in the College of
Pharmacy of Seoul National University.
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