The first enantioselective halo aldol reaction of ethyl propiolate and aldehydes

Article abstract of DOI:10.1002/ejoc.200400230

The first enantioselective halo aldol reaction of ethyl propiolate with aldehydes has been established by using Jacobsen's chiral cyclohexylsalen ligand. The reaction was conducted at -20 °C in dichloromethane with Et ₂AlI as the source of halo

Full text of DOI:10.1002/ejoc.200400230

FULL PAPER
The First Enantioselective Halo Aldol Reaction of Ethyl Propiolate and
Aldehydes
Dianjun Chen,[a] Cody Timmons,[a] Junying Liu,[a] Allan Headley,[a] and Guigen Li*[a]
Keywords: Aldol reactions / MoritaϪBaylisϪHillman esters / Chiral salen / Enantioselectivity
The first enantioselective halo aldol reaction of ethyl propiol-
ate with aldehydes has been established by using Jacobsen’s
chiral cyclohexylsalen ligand. The reaction was conducted at
−20 °C in dichloromethane with Et2AlI as the source of hal-
ogen and Lewis acid promoter. Excellent geometric selectiv-
ity (only the Z isomer) has been achieved for all 14 examples
examined. The reaction works well with aromatic aldehydes;
it also works with aliphatic aldehydes and α,β-unsaturated
aldehydes, albeit with diminished yields and ee. This method
provides the first enantioselective synthesis of β-iodo
Morita−Baylis−Hillman (MBH) esters.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
suffered as a result of the extra steps for the chiral auxiliary
coupling/cleavage. In this paper, we would like to report
that β-halo MoritaϪBaylisϪHillman (MBH) esters can be
enantiomerically synthesized by reacting allenoate with al-
dehydes in the presence of Jacobsen’s chiral salen ligand.[9]
This method indeed presents the first enantioselective syn-
thesis of β-iodo MBH esters as represented by Scheme 1.
The asymmetric aldol reaction is among the most im-
portant carbonϪcarbon bond formation reaction in or-
ganic chemistry.[1Ϫ3] However, the halo aldol reaction and
its asymmetric versions have not been well explored thus
far. Recently, we and others reported several halo aldol re-
actions and the corresponding asymmetric versions.[4,5]
These reactions led to versatile building blocks that can be
functionalized with an array of functional groups, and
therefore, can serve as important precursors to a variety of
chemically and biologically important compounds. One of
our previous asymmetric halo aldol processes deals with the
reaction of α,β-unsaturated ketones with aldehydes in the
presence of N-C3F7CO oxazaborolidine catalyst[2,4a] in
which the fluorinated protecting group was found to play a
crucial role in controlling enantiomeric and geometric selec-
tivities. This asymmetric reaction provided the first enantio-
selective approach to β-halo MoritaϪBaylisϪHillman
Scheme 1
[6,7]
(MBH)
ketones.
In our next study we tried to establish an asymmetric
approach to β-halo MoritaϪBaylisϪHillman (MBH) esters
which are more useful than their ketone counterparts in
organic synthesis. Our initial attempts at using allenoates to
replace allenolates for the asymmetric reaction under simi-
lar catalytic conditions[4a] resulted in very limited success.
Essentially, the N-C3F7CO oxazaborolidine catalyst did not
result in any enantioselectivity. Later, a chiral auxiliary-con-
trolled asymmetric strategy with (1R,2S,5R)-menthol was
Results and Discussion
Benzaldehyde was used as the electrophile to react with
β-iodoallenoate for the model reaction study. Since MgI2
has been successfully utilized in the racemic and chiral
auxiliary-directed halo aldol reaction of allenoates with al-
dehydes and since it is also very easy to handle,[10] it was
first tested as both a halogen source and a Lewis acid acti-
vator for the present system. Unfortunately, when two com-
mon chiral ligands (A and B, Figure 1) were coordinated to
MgI2, the desired product was not observed.
utilized
for
the
synthesis
of
chiral
β-iodo
MoritaϪBaylisϪHillman esters.[8] However, this method
[a]
Department of Chemistry and Biochemistry, Texas Tech
Et2AlI was then used for the formation of chiral com-
plexes with a variety of enantiomerically pure protic li-
University,
Lubbock, TX 79409-1061, USA
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400230
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The First Enantioselective Halo Aldol Reaction of Ethyl Propiolate and Aldehydes
FULL PAPER
solubility of the reaction species in toluene at low tempera-
ture since some solids were observed during the reaction
process. As indicated in Table 1, the optimal reaction tem-
perature is Ϫ20 °C; lowering the temperature to Ϫ40 °C
did not lead to better enantioselectivity. Furthermore, there
were no products detected at Ϫ78 °C in either CH2Cl2 or
toluene.
Table 1. Solvent and temperature effects on aromatic aldehyde-
based reactions
Entry R
Solvent Temperature (°C) Yield (%)[a] ee %[b]
1
2
3
4
5
6
7
8
Ph
THF
Et2O
Ϫ20
Ϫ20
no reaction
no reaction
no reaction
62
65
71
66
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3CN Ϫ20
toluene Ϫ20
toluene Ϫ40
CH2Cl2 Ϫ20
CH2Cl2 Ϫ40
CH2Cl2 Ϫ78
40
64
63
64
no reaction
9
4-BnOϪC6H4 toluene Ϫ20
4-BnOϪC6H4 CH2Cl2 Ϫ20
50
62
35
57
47
49
43
76
10
11
12
1-Naph
1-Naph
toluene Ϫ20
CH2Cl2 Ϫ20
[a]
[b]
Figure 1. Chiral ligands for halo aldol reaction
The yields after purification by column chromatography.
All
enantiomer excesses were determined by chiral HPLC using chiral
OD-H or AD columns with isopropyl alcohol and hexane as the
mobile phase.
gands, such as vicinal diols, binaphthol and Jacobsen’s salen
ligand (Figure 1). It was found the ligands C and D did give
the desired MBH esters; however, enantiomeric excesses
were poor (less than 13% ee). To our satisfaction, when Ja-
cobsen’s chiral cyclohexylsalen ligand E was utilized, an en-
antiomerically enriched product was generated to give ee of
63% and a chemical yield of 71% (Scheme 2).
Interestingly, the manner in which the reactants were
loaded was found to be very important with regard to both
enantioselectivity and yields, as can be seen from Table 2.
Firstly, Et2AlI should be added to the solution of salen li-
gand over a period of 30 minutes with a syringe pump; the
resulting solution should then be stirred at room tempera-
ture for about 1 hour. Secondly, the in situ pre-prepared
metal complex should be slowly transferred to the mixture
of ethyl propiolate and aldehyde.
Based on the optimization results, the reaction was car-
ried out in CH2Cl2 solution at Ϫ20 °C, with the slow ad-
dition of Et2AlI. In addition, ethyl propiolate was loaded
in two portions (as described in Exp. Sect.) which further
improves the yields. The results are shown in Table 3.
A noteworthy aspect of the optimized conditions is the
complete E/Z selectivity as revealed by proton NMR spec-
troscopy. Only Z isomers were observed in all examples;
Scheme 2
The reaction conditions were optimized by varying the this is better than the results obtained from our previous
solvents, temperatures and reactant loading sequences. The asymmetric synthesis of MBH ketones.[4a] The E/Z configu-
reaction did not proceed in THF, Et2O, or CH3CN (Entry ration was revealed by ROSEY NMR spectroscopic experi-
1Ϫ3, Table 1); only CH2Cl2 and toluene proved to be effec- ments, as mentioned in our previous papers.[8,10] The abso-
tive for this reaction, and CH2Cl2 was superior in most lute configuration of the major enantiomeric isomer was
cases. In the case of benzaldehyde, the two solvents gave determined by chemical correlation. Product 1 (Entry 1,
similar yields and enantioselectivities (Entry 4Ϫ7, Table 1). Table 3) was transformed to methyl-α-methoxyphenyl acet-
However, for other substrates, such as 4-benzoxybenzal- ate, its 1H NMR and chiral HPLC data were compared
dehyde and 1-naphthaldehyde, the reaction gave lower with an authentic sample. The determination of the abso-
yields and enantiomeric excesses in toluene (Entries 9Ϫ12, lute configuration is done by chemical correlation as dem-
Table 1) than in CH2Cl2. This is probably due to the low onstrated in Scheme 3.
Eur. J. Org. Chem. 2004, 3330Ϫ3335
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D. Chen, C. Timmons, J. Liu, A. Headley, G. Li
FULL PAPER
Table 2. Effect of experimental conditions on the benzaldehyde-based reaction
Entry
Solvent
Addition of Et2AlI
Temperature (°C)
Yield (%)[a]
ee %[b]
1
2
3
4
toluene
toluene
CH2Cl2
CH2Cl2
slow addition
dropwise
slow addition
dropwise
Ϫ40
Ϫ40
Ϫ20
Ϫ20
65
20
71
40
64
39
63
25
[a]
[b]
The yields after purification by column chromatography. Enantiomer excesses were determined by chiral HPLC using a chiral OD-
H column with isopropyl alcohol and hexane as the mobile phase.
Table 3. Results of asymmetric halo aldol reactions with aromatic aldehydes
[a]
In all cases, only Z isomers were observed from crude 1H NMR spectroscopic analysis. Enantiomeric excesses were determined by
[b]
chiral HPLC using chiral OD-H or AD columns with isopropyl alcohol and hexane as the mobile phase. The yields after purification
by column chromatography. Yields in parentheses were calculated based on recovered starting materials. HPLC determination of its
[c]
mesyl-protected derivative.
As can be seen from Table 3, the reaction worked well for aromatic aldehydes that have electron-donating groups
a wide range of aromatic aldehydes. Almost all aromatic required longer reaction times than benzaldehyde (Entries
aldehydes gave similar enantioselectivities; 1-naphth- 5 and 6, Table 3). It is worth noting that for the tri-
aldehyde gave the highest ee of 76% (Entry 3, Table 3). The fluorotolualdehyde-derived product (Entry 10, Table 3) it
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Eur. J. Org. Chem. 2004, 3330Ϫ3335

The First Enantioselective Halo Aldol Reaction of Ethyl Propiolate and Aldehydes
FULL PAPER
yields and enantiomeric excesses were all lower than those
of their aromatic counterparts. Further study of this new
asymmetric reaction will be continued in our laboratories.
The Z-geometry preference of the product is illustrated in
Scheme 4; the Z isomer is formed as a kinetically controlled
product, which results from the less hindered chair-like
transition state.
Scheme 3. Reaction conditions: a) MeI, Ag2O, MeCN, reflux for
4 h; b) NaOH, MeOH/H2O, room temperature; c) H5IO6, RuCl2,
CCl4/MeCN/H2O (v/v, 1:1:2); d) MeOH, TMSCl
Conclusion
was extremely difficult to determine the ee value by HPLC.
This determination was achieved by converting it into its
The first enantioselective halo aldol reaction of ethyl pro-
mesyl-(methylsulfonyl-)protected derivative and by using a piolate with aldehydes has been developed by using Jacob-
chiral AD column with hexane/isopropyl alcohol (v/v, 20:1) sen’s chiral salen ligand. This method serves as the first en-
as the mobile phase. It should be noted that other protect- antioselective synthesis of β-iodo MoritaϪBaylisϪHillman
ing groups, such as methyl, benzyl, tosyl groups, among (MBH) esters. The reaction showed broad substrate scope
others, were not useful for this determination.
and gave modest to good enantioselectivities and chemical
So far, only four aliphatic aldehydes were subjected to yields. The absolute structure has been unambiguously de-
the present reaction (Table 4). Unfortunately, the chemical termined by chemical correlation using 1H NMR spec-
Table 4. Results of asymmetric halo aldol reactions with aliphatic aldehydes
[a]
Enantiomer excesses were determined by chiral HPLC using chiral OD-H or AD columns with isopropyl alcohol and hexane as the
[b]
mobile phase.
The yields after purification by column chromatography. Yields in parentheses were calculated based on recovered
[c]
starting materials. All reactions were performed within 48 h.
Scheme 4
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D. Chen, C. Timmons, J. Liu, A. Headley, G. Li
FULL PAPER
1243, 1175 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.30Ϫ7.48 (m,
5 H), 7.22Ϫ7.27 (m, 3 H), 6.93Ϫ6.97 (m, 2 H), 5.50 (d, J ϭ 4.5 Hz,
1 H), 5.06 (s, 2 H), 4.19 (q, J ϭ 7.0 Hz, 2 H), 2.70 (d, J ϭ 5.5 Hz,
1 H), 1.22 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 165.9, 158.7, 145.3, 136.7, 132.5, 128.6, 128.0, 127.9, 127.5,
114.9, 86.1, 75.7, 70.0, 61.4, 14.0 ppm.
troscopy and chiral HPLC. Excellent E/Z selectivity has
been achieved for all examples examined.
Experimental Section
Typical Reaction Procedure: In a dry vial, under inert gas protec-
tion, a solution of Et2AlI (1  in toluene, 0.41 mL, 0.41 mmol) was
added slowly to a CH2Cl2 solution (2 mL) of (R,R)-Salen (0.22 g,
0.40 mmol) with a syringe pump over a period of 30 min. The re-
sulting solution was stirred at room temperature for 1 hour before
it was transferred slowly with a syringe pump (ഠ 5 h) to a CH2Cl2
solution (1.5 mL) of ethyl propiolate (0.035 mL, 0.35 mmol) and
benzaldehyde (0.03 mL, 0.30 mmol) at Ϫ20 °C. The reaction mix-
ture was stirred at Ϫ20 °C for 12 h before another portion of ethyl
propiolate (0.025 mL, 0.25 mmol) was added dropwise into the re-
action system. The reaction proceeded for another 20 h at Ϫ20 °C,
after which it was quenched with 1  aqueous HCl solution (5 mL).
The two phases were separated, and the aqueous phase was ex-
tracted with EtOAc (3 ϫ 15 mL). The combined organic phase was
washed with brine and dried with anhydrous sodium sulfate. Purifi-
cation by flash chromatography (EtOAc/hexane, v/v, 1:5) provided
the pure product.
Ethyl 2-[Hydroxy(4-methoxyphenyl)methyl]-3-iodoacrylate (6): Iso-
lated as a colorless oil (60 mg, 55% yield). IR (deposited from
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3468, 2981, 1718, 1512, 1251,
1179, 1031 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.21Ϫ7.28 (m,
3 H), 6.84Ϫ6.90 (m, 2 H), 5.50 (d, J ϭ 5.5 Hz, 1 H), 4.20 (q, J ϭ
7.0 Hz, 2 H), 3.80 (s, 3 H), 2.73 (d, J ϭ 5.0 Hz, 1 H), 1.23 (t, J ϭ
7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 165.9, 159.5,
145.4, 132.2, 127.9, 114.0, 86.0, 75.7, 61.4, 55.3, 14.0 ppm.
Ethyl 2-[(4-Fluorophenyl)hydroxymethyl]-3-iodoacrylate (7): Iso-
lated as a colorless oil (68 mg, 65% yield). IR (deposited from
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3449, 2926, 1710, 1509, 1225,
1190 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.27Ϫ7.34 (m, 3 H),
7.01Ϫ7.07 (m, 2 H), 5.53 (d, J ϭ 5.0 Hz, 1 H), 4.20 (q, J ϭ 7.0 Hz,
2 H), 2.87 (d, J ϭ 5.5 Hz, 1 H), 1.23 (t, J ϭ 7.0 Hz, 3 H) ppm. 13
C
NMR (125 MHz, CDCl3): δ ϭ 165.8, 163.5, 161.6, 144.9, 135.9,
128.4, 128.3, 115.6, 115.5, 86.9, 75.6, 61.5, 14.0 ppm.
Ethyl 2-[(4-Chlorophenyl)hydroxymethyl]-3-iodoacrylate (8): Iso-
lated as a colorless oil (78 mg, 71% yield). IR (deposited from
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3449, 2925, 1718, 1708, 1190
cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.25Ϫ7.34 (m, 5 H), 5.50
(d, J ϭ 5.5 Hz, 1 H), 4.20 (q, J ϭ 7.0 Hz, 2 H), 3.06 (d, J ϭ 5.5 Hz,
1 H), 1.24 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 165.7, 144.6, 138.7, 134.0, 128.7, 127.9, 87.3, 75.5, 61.6,
13.9 ppm.
Ethyl 2-[Hydroxy(phenyl)methyl)-3-iodoacrylate (1): Isolated as a
colorless oil (72 mg, 71% yield). IR (deposited from CH2Cl2 solu-
1
tion on NaCl plate): ν˜ ϭ 3449, 2982, 1711, 1189 cmϪ1. H NMR
(500 MHz, CDCl3): δ ϭ 7.27Ϫ7.37 (m, 5 H), 7.24 (d, J ϭ 1.5 Hz,
1 H), 5.52 (d, J ϭ 5.5 Hz, 1 H), 4.18 (q, J ϭ 7.0 Hz, 2 H), 3.00 (d,
J ϭ 6.0 Hz, 1 H), 1.20 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 165.8, 145.1, 140.1, 128.6, 128.2, 126.5,
86.7, 76.1, 61.4, 13.9 ppm.
Ethyl 2-[(4-Bromophenyl)hydroxymethyl]-3-iodoacrylate (9): Iso-
lated as a colorless oil (91 mg, 74% yield). IR (deposited from
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3437, 2981, 1718, 1486, 1189
Ethyl 2-[Hydroxy(p-tolyl)methyl]-3-iodoacrylate(2): Isolated as a
colorless oil (78 mg, 75% yield). IR (deposited from CH2Cl2 solu-
tion on NaCl plate): ν˜ ϭ 3442, 2982, 1709, 1638, 1188 cmϪ1 1H
.
cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ 7.45Ϫ7.50 (m, 2 H),
.
NMR (500 MHz, CDCl3): δ ϭ 7.19Ϫ7.24 (m, 3 H), 7.13Ϫ7.18 (m,
2 H), 5.51 (d, J ϭ 5.5 Hz, 1 H), 4.20 (q, J ϭ 7.0 Hz, 2 H), 2.78 (d,
J ϭ 5.5 Hz, 1 H), 2.34 (s, 3 H), 1.23 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 165.9, 145.2, 138.1, 137.1, 129.3,
126.5, 86.4, 76.3, 61.4, 21.1, 13.9 ppm.
7.28Ϫ7.32 (m, 1 H), 7.18Ϫ7.24 (m, 2 H), 5.48 (d, J ϭ 5.5 Hz, 1
H), 4.20 (q, J ϭ 7.0 Hz, 2 H), 3.06 (d, J ϭ 6.0 Hz, 1 H), 1.24 (t,
J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 165.7,
144.5, 139.2, 131.7, 128.2, 122.2, 87.5, 75.6, 61.6, 13.9 ppm.
Ethyl
2-[Hydroxy(4-trifluoromethylphenyl)methyl]-3-iodoacrylate
Ethyl 2-[Hydroxy(naphthalen-1-yl)methyl]-3-iodoacrylate(3): Iso-
(10): Isolated as a colorless oil (88 mg, 73% yield). IR (deposited
from CH2Cl2 solution on NaCl plate): ν˜ ϭ 3450, 1709, 1322, 1166
lated as a colorless oil (65 mg, 57% yield). IR (deposited from
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3432, 1719, 1709, 1191 cmϪ1
.
cmϪ1 1H NMR (500 MHz, CDCl3): δ ϭ 7.61 (d, J ϭ 8.5 Hz, 2
.
1H NMR (500 MHz, CDCl3): δ ϭ 7.98Ϫ8.04 (m, 1 H), 7.80Ϫ7.90
(m, 2 H), 7.57Ϫ7.62 (m, 1 H), 7.44Ϫ7.56 (m, 3 H), 7.05 (d, J ϭ
1.5 Hz, 1 H), 6.32 (d, J ϭ 4.5 Hz, 1 H), 4.23 (q, J ϭ 7.0 Hz, 2 H),
2.85 (d, J ϭ 4.5 Hz, 1 H), 1.20 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 166.3, 145.1, 135.3, 133.8, 130.5, 129.2,
128.8, 126.6, 125.9, 125.3, 124.8, 123.4, 87.4, 72.4, 61.5, 13.9 ppm.
H), 7.47 (d, J ϭ 8.5 Hz, 2 H), 7.35 (d, J ϭ 1.0 Hz, 1 H), 5.58 (d,
J ϭ 6.0 Hz, 1 H), 4.21 (q, J ϭ 7.0 Hz, 2 H), 3.21 (d, J ϭ 6.0 Hz,
1 H), 1.23 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 165.6, 144.2, 144.1, 130.3 (q, J ϭ 33 Hz), 126.8, 125.5 (q, J ϭ
4.0 Hz), 123.9 (q, J ϭ 278 Hz) 88.1, 75.7, 61.7, 13.9 ppm.
Ethyl 3-Hydroxy-2-iodomethylene-5-phenylpent-4-enoate (11): Iso-
Ethyl 2-[Hydroxy(naphthalen-2-yl)methyl]-3-iodoacrylate (4): Iso-
lated as a colorless oil (36 mg, 35% yield). IR (deposited from
lated as a colorless oil (92 mg, 80% yield). IR (deposited from
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3449, 2981, 1718, 1190 cmϪ1
.
1
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3436, 1710, 1190 cmϪ1. H
1H NMR (500 MHz, CDCl3): δ ϭ 7.36Ϫ7.39 (m, 2 H), 7.30Ϫ7.34
(m, 3 H), 7.24Ϫ7.28 (m, 1 H), 6.67 (d, J ϭ 16 Hz, 1 H), 6.21 (dd,
J ϭ 6.5, 16 Hz, 1 H), 5.13 (dd, J ϭ 6.0, 6.0 Hz, 1 H), 4.31 (q, J ϭ
7.0 Hz, 2 H), 2.76 (d, J ϭ 5.5 Hz, 1 H), 1.34 (t, J ϭ 7.0 Hz, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 165.9, 144.6, 136.0, 132.4,
128.6, 128.1, 127.8, 126.6, 88.6, 75.0, 61.6, 14.1 ppm.
NMR (500 MHz, CDCl3): δ ϭ 7.80Ϫ7.85 (m, 4 H), 7.46Ϫ7.51 (m,
2 H), 7.39Ϫ7.43 (m, 1 H), 7.29 (d, J ϭ 1.0 Hz, 1 H), 5.70 (d, J ϭ
5.5 Hz, 1 H), 4.18 (q, J ϭ 7.0 Hz, 2 H), 3.03 (d, J ϭ 6.0 Hz, 1 H),
1.20 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ
165.9, 145.0, 137.4, 133.13, 133.12, 128.5, 128.1, 127.7, 126.4,
126.3, 125.6, 124.3, 87.2, 76.3, 61.5, 13.9 ppm.
Ethyl 2-[(4-Benzyloxyphenyl)hydroxymethyl]-3-iodoacrylate (5): Iso-
Ethyl 3-Hydroxy-2-(iodomethylene)hex-4-enoate (12): Isolated as a
lated as a colorless oil (81 mg, 62% yield). IR (deposited from colorless oil (33 mg, 37% yield). IR (deposited from CH2Cl2 solu-
1
CH2Cl2 solution on NaCl plate): ν˜ ϭ 3349, 2927, 1719, 1709, 1509, tion on NaCl plate): ν˜ ϭ 3423, 2980, 2920, 1719, 1188 cmϪ1. H
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Eur. J. Org. Chem. 2004, 3330Ϫ3335

The First Enantioselective Halo Aldol Reaction of Ethyl Propiolate and Aldehydes
FULL PAPER
Corey, R. Imwinkelried, S. Pikul, Y. B. Xiang, J. Am. Chem.
NMR (500 MHz, CDCl3): δ ϭ 7.18 (d, J ϭ 1.0 Hz, 1 H), 5.74Ϫ5.83
(m, 1 H), 5.48Ϫ5.56 (m, 1 H), 4.89 (dd, J ϭ 6.0, 6.0 Hz, 1 H), 4.31
(q, J ϭ 7.0 Hz, 2 H), 2.53 (d, J ϭ 6.0 Hz, 1 H), 1.69Ϫ1.73 (m, 3
H), 1.36 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 166.1, 145.3, 129.9, 129.5, 85.3, 75.1, 61.4, 17.7, 14.1 ppm.
[2d]
Soc. 1989, 111, 5493Ϫ5495.
S. Kiooka, Y. Kaneko, K.
Kume, Tetrahedron Lett. 1992, 33, 4927Ϫ4930.
[3] [3a]
T. Bach, Angew. Chem. Int. Ed. Engl. 1994, 33, 417Ϫ419.
[3b]
[3c]
D. Enders, S. J. Ince, Synthesis 2002, 619Ϫ624.
E. J.
Corey, C. L. Cywin, T. D. Roper, Tetrahedron Lett. 1992, 33,
[3d]
6907Ϫ6910.
D. A. Evans, M. C. Kozlowski, J. A. Murray,
Ethyl 2-(1-Hydroxy-2-methylpropyl)-3-iodoacrylate (13): Isolated as
C. S. Burgey, B. T. Campos, R. J. Staples, J. Am. Chem. Soc.
a colorless oil (40 mg, 45% yield). IR (deposited from CH2Cl2 solu-
[3e]
1999, 121, 669Ϫ685.
H. Groger, E. M. Vogl, M. Shibasaki,
1
tion on NaCl plate): ν˜ ϭ 3450, 2964, 1719, 1710, 1189 cmϪ1. H
Chem. Eur. J. 1998, 4, 1137Ϫ1141.
[4] [4a]
NMR (500 MHz, CDCl3): δ ϭ 7.02 (d, J ϭ 1.0 Hz, 1 H), 4.32 (q,
J ϭ 7.0 Hz, 2 H), 4.08 (td, J ϭ 7.0, 1.0 Hz, 1 H), 2.47 (d, J ϭ
7.0 Hz, 1 H), 1.84 (o, J ϭ 6.5 Hz, 1 H), 1.36 (t, J ϭ 7.0 Hz, 3 H),
0.96 (d, J ϭ 6.5 Hz, 3 H), 0.90 (d, J ϭ 6.5 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 166.7, 146.2, 84.3, 80.9, 61.5, 32.8,
19.2, 17.5, 14.1 ppm.
G. Li, H.-X. Wei, B. S. Phelps, D. W. Purkiss, S. H. Kim,
[4b]
Org. Lett. 2001, 3, 823Ϫ826.
Timmons, M. D. Carducci, A. D. Headley, Org. Lett. 2003,
G. Li, X. Xu, D. Chen, C.
5, 329Ϫ331.
For recent racemic halo aldol reactions see: [5a] T. Kataoka, H.
[5]
Kinoshita, S. Kinoshita, T. Iwamura, S. Watanabe, Angew.
[5b]
Chem. Int. Ed. 2000, 39, 2358Ϫ2360.
H. X. Wei, T. D. Ca-
puto, D. W. Purkiss, G. Li, Tetrahedron 2000, 56, 2397Ϫ2401.
Ethyl 2-[Cyclohexyl(hydroxy)methyl]-3-iodo-acrylate (14): Isolated
[5c] S. Uehira, Z. Han, H. Shinokubo, K. Oshima, J. Org. Chem.
as a colorless oil (47 mg, 46% yield). IR (deposited from CH2Cl2
[5d]
2001, 66, 7854Ϫ7857.
G. Li, H.-X. Wei, T. D. Caputo,
solution on NaCl plate): ν˜ ϭ 3450, 2927, 1710, 1188 cmϪ1 1H
.
[5e]
Tetrahedron Lett. 2000, 41, 1Ϫ4.
M. Shi, J.-K. Jiang, Y.-S.
NMR (500 MHz, CDCl3): δ ϭ 6.99 (d, J ϭ 1.0 Hz, 1 H), 4.33 (q,
J ϭ 7.0 Hz, 2 H), 4.08 (t, J ϭ 7.0 Hz, 1 H), 2.49 (d, J ϭ 7.0 Hz, 1
H), 1.90Ϫ1.97 (m, 1 H), 1.69Ϫ1.80 (m, 2 H), 1.64Ϫ1.68 (m, 1 H),
1.55Ϫ1.60 (m, 1 H), 1.46Ϫ1.54 (m, 1 H), 1.38 (t, J ϭ 7.0 Hz, 3 H),
1.06Ϫ1.27 (m, 3 H), 0.92Ϫ1.01 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 166.6, 145.9, 84.4, 80.4, 61.5, 42.4, 29.5,
28.2, 26.2, 26.0, 25.8, 14.1 ppm.
Feng, Org. Lett. 2000, 2, 2397Ϫ2400.
[6a] D. Basavaiah, A.J. Rao, T. Satyanarayana, Chem. Rev. 2003,
[6]
103, 811Ϫ891. [6b] E. Ciganek, Org. React. 1997, 51, 201Ϫ350.
[6c]
For a review regarding β-branched BaylisϪHillman adduct
synthesis see: G. Li, J. Hook, H.-X. Wei, in Recent Research
Developments in Organic & Bioorganic Chemistry, Transworld
Research Network, 2001, 4, 49Ϫ61.
[7] [7a]
J. S. You, J.H. Xu, J. G. Verkade, Angew. Chem. Int. Ed.
[7b]
2003, 42, 5054Ϫ5056.
Fröhlich, Organometllics 2002, 21, 4356Ϫ4368.
R. Aumann, X. L. Fu, C. Holst, R.
[7c]
S. Z. Luo,
Acknowledgments
We gratefully acknowledge the National Institutes of Health (CA,
99995-1) and the Robert A. Welch Foundation (D-1361, D-1460)
for the generous support of this work.
[7d]
P. G. Wang, J. P. Cheng, J. Org. Chem. 2004, 69, 555Ϫ558.
[7e]
Y. M. Xu, M. Shi, J. Org. Chem. 2004, 69, 417Ϫ425.
G.
W. Kabalka, B. Venkataiah, G. Dong, Tetrahedron Lett. 2003,
44, 4673Ϫ4675.
[8]
X. Xu, D. Chen, H.-X. Wei, G. Li, T. L. Xiao, D. W. Arm-
strong, Chirality 2003, 15, 139Ϫ142.
[9] [9a]
[1] [1a]
E. M. Carreira, in Comprehensive Asymmetric Catalysis
M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125,
[9b]
(Eds.: E. J. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, vol. III, pp. 997Ϫ1065. [1b]R. Mahrwald, Chem.
Rev. 1999, 99, 1095Ϫ1120.
11204Ϫ11205.
J. K. Myers, E. N. Jacobsen, J. Am. Chem.
Soc. 1999, 121, 8959Ϫ8960.
H.-X. Wei, J. J. Gao, G. Li, P. W. Pare, Tetrahedron Lett. 2002,
[10]
[2] [2a]
D. Sartor, J. Saffich, G. Helmchen, Synlett 1990, 197Ϫ198.
43, 5677Ϫ5680.
[2b] M. Takasu, H. Yamamoto, Synlett 1990, 194Ϫ196. [2c] E. J.
Received April 5, 2004
Eur. J. Org. Chem. 2004, 3330Ϫ3335
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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