Radical addition to ynol ethers - A convenient procedure for the stereoselective preparation of α-iodo enol ethers in neutral conditions

Article abstract of DOI:10.1139/V08-094

α-Iodo enol ethers, precursors of acyl anion equivalents, are not easily prepared. Herein we report that addition of activated iodoalkanes to ynol ethers under mild and neutral radical reaction conditions leads to α-iodo enol ethers in moderate to excellent yields with high stereoselectivity. The reaction can be carried out in various solvents at different temperatures. The methodology allows the preparation of β-alkylated and β,β- dialkylated α-iodo enol ethers. Reduction of the carbon-iodine bond of these species leads to the corresponding enol ethers with good yields.

Full text of DOI:10.1139/V08-094

970
Radical addition to ynol ethers — A convenient
procedure for the stereoselective preparation of
␣-iodo enol ethers in neutral conditions
Fanny Longpré, Natalia Rusu, Maxime Larouche, Rana Hanna, and Benoit Daoust
Abstract: α-Iodo enol ethers, precursors of acyl anion equivalents, are not easily prepared. Herein we report that addi-
tion of activated iodoalkanes to ynol ethers under mild and neutral radical reaction conditions leads to α-iodo enol
ethers in moderate to excellent yields with high stereoselectivity. The reaction can be carried out in various solvents at
different temperatures. The methodology allows the preparation of β-alkylated and β,β-dialkylated α-iodo enol ethers.
Reduction of the carbon-iodine bond of these species leads to the corresponding enol ethers with good yields.
Key words: ynol ethers, enol ethers, radical addition, stereoselective.
Résumé : Les α-iodoéthers d’énol, des précurseurs d’équivalents d’anions acyles, sont difficiles à préparer. Cet article
présente nos résultats de notre étude sur l’addition d’iodoalcanes activés sur des éthers d’ynol. Cette réaction, qui
conduit à des α-iodoéthers d’énol avec des rendements allant de bons à excellents, s’effectue en milieu neutre et dans
des conditions réactionnelles très douces. De plus, cette réaction est très stéréosélective. La réaction peut être effectuée
dans différents solvants, à différentes températures. Cette méthodologie permet de préparer des α-iodoéthers d’énol β-
alkylés et β,β-dialkylés. La réduction du lien carbone-iode de ces composés permet d’isoler des éthers d’énol avec de
bons rendements.
Mots-clés : éthers d’ynol, éthers d’énol, addition radicalaire, stéréosélectif.
[Traduit par la Rédaction] Longpré et al. 975
Introduction
tion conditions emerges as an important and challenging
synthetic endeavor.
α-Halo enol ethers are interesting precursors of substi-
tuted enol ethers and are also umpolungs for acyl groups (1).
Transmetallation of the α-halo enol ether halogen atom pro-
duces α-alkoxy vinyl anions that have shown versatile appli-
cations in organic synthesis (2, 3). These halogenated
species were also used in cross-coupling reactions (4). How-
ever, very few methods exist for preparing these useful α-
halo enol ethers (2, 5). Most of them require the use of
strong bases or the intermediacy of α-alkoxy vinylstannane
compounds. Recently, Yu and Jin developed a more conve-
nient method using in situ produced hydrohalic acids (2).
These then react with ynol ethers to produce α-halo enol
ethers with good to excellent yields. Unfortunately, this
method requires acidic reaction conditions that are known to
be deleterious to a number of α-halo enol ethers (1). Also,
only mono β-alkylated α-halo enol ethers can be prepared by
this method. As a consequence, the development of a new
methodology for the preparation of β-alkylated and β,β-
dialkylated α-halo enol ethers under neutral and mild reac-
Results and discussion
Our strategy for the preparation of α-iodo enol ethers is
outlined in Scheme 1. We hypothesized that intermediate
electrophilic radical 2 formed by homolytic cleavage of io-
dinated active methylene 1 (Z = CO2Et, CN, CONH2) would
add to the electron-rich β-carbon of 3 to give trans radical
adduct 4. The anti attack leading to trans radical 4 should be
favored for stereoelectronic reasons (6). The use of iodides,
which are efficient halogen-atom transfer agents, should
ensure rapid trapping of vinyl radical 4 before its inter-
conversion leading to E-isomer 5 with stereoselection (7).
We first examined the radical addition of ethyl iodoacetate
(1a) to ethoxyacetylene (3a ; R = ethyl, R′ = H), the only
commercially available ynol ether. In CH2Cl2 at room tem-
perature (Table 1, entry 1), completion of the reaction was
observed within 15 min using Et3BO2 as radical initiator. We
were very happy to isolate 97% of the expected adduct 5a
with complete stereoselectivity. Indeed, only the E-isomer
could be observed in NMR spectra and GCMS chromato-
graphs (E/Z > 99:1). This result not only supports our hy-
pothesis about the ability of ynol ethers to accept
electrophilic radicals but also confirms the slow inter-
conversion of vinyl radical 4 (see Scheme 1). We were very
pleased to observe that low temperature (–78 °C) had no im-
portant effect on the reaction efficiency (entry 2, 90% yield).
We then tested an ynol ether possessing a more sterically de-
Received 8 March 2008. Accepted 6 May 2008. Published on
the NRC Research Press Web site at canjchem.nrc.ca on
27 August 2008.
F. Longpré, N. Rusu, M. Larouche, R. Hanna, and
B. Daoust.1 Département de Chimie-Biologie, Université du
Québec à Trois-Rivières, 3351 Boulevard des Forges, C.P.
500, Trois-Rivières, QC G9A 5H7, Canada.
1Corresponding author (e-mail: Benoit.Daoust@uqtr.ca).
Can. J. Chem. 86: 970–975 (2008)
doi:10.1139/V08-094
© 2008 NRC Canada

Longpré et al.
971
Scheme 1.
tion to occur. We then decided to prepare a series of substi-
tuted menthoxyethyne (R = menthyl) possessing groups with
increasing bulkiness at the β-position. First, 1-
′′
menthoxypropyne 3d (R = menthyl, R = Me) was tested (8).
The radical reaction between 3d and ethyl iodoacetate
occured with yields comparable to those obtained with 3b
(entries 6 and 7, 72% and 70% yield). Again, complete
stereocontrol of the double bond was observed. We then de-
cided to install groups possessing secondary carbon at the β-
position. Isopropyl was our first choice. We examined the
′′
possibility of producing compound 3e (R = menthyl, R = i-
Pr) by reacting menthoxyethyne 3b with triisopropylborane
(10) using Greene’s protocol (8). Unfortunately, we were
not able to isolate the desired product. Though TLC revealed
the presence of a new compound with an Rf characteristic of
ynol ethers, compound 3e, if ever produced, seemed to be
very unstable and degradation was observed before any
characterization could be performed. We also tried to pre-
pare compound 3f (R = menthyl, R′ = s-Bu) according to
Greene’s protocol (8). In that case, the desired compound 3f
could be obtained and isolated, though it showed a very high
propensity to decomposition. We submitted this freshly pro-
duced ynol ether to our radical reaction conditions. Unfortu-
nately, compound 3f decomposed before any addition
reaction could occur. Hoping that highly encumbered triple
bonds would be easier to handle, we tried to prepare very
crowded ynol ethers 3g (R = Et, R′ = Si-t-BuMe3) and 3h
(R = Et, R′ = Si-t-BuPh3) (11). Fortunately, these compounds
were chemically stable and could thus be isolated and puri-
fied. However, radical addition of these two ynol ethers with
ethyl iodoacetate did not produce the desired adducts 5g–5h
(entries 8 and 9, 0% yield in both cases). Only the starting
materials were recovered.
Table 1. Addition of ethyl iodoacetate (1a) to ynol ethers 3a–3d,
3g, and 3h in CH2Cl2.
Entry Substrate Temp.a
Product Yieldb (%) E/Z ratioc,d
1
2
3
4
5
6
7
8
9
3a
3a
3b
3b
3c
3d
3d
3g
3h
RT
–78 °C
RT
–78 °C
RT
RT
–78 °C
RT
RT
5a
5a
5b
5b
5c
5d
5d
5g
5h
97
90
75
70
0
72
70
0
> 99:1
> 99:1
> 99:1
> 99:1
–
> 99:1
> 99:1
–
Other solvents were then assessed (Table 2) for the reac-
tion involving ethyl iodoacetate (1a) and ynol ether 3b. In
benzene (entry 1), the reaction took place with a slightly
better yield (80%) compared to CH2Cl2 (Table 1, entry 3). In
hexanes, acetone, and DMSO (Table 2, entries 2, 3, and 4),
the yields were slightly lower (51%–65%). Reaction did not
occur in THF (entry 5, 0% yield).
0
–
It is of note that when volatile solvents were used (for ex-
ample, CH2Cl2 or hexanes), no aqueous work-up was re-
quired, thus reducing the risk of hydrolysis of iodo vinyl
ethers 5. The adducts 5 must be isolated by carefully evapo-
rating the solvent and Et3B with a nitrogen gas flow. Indeed,
we observed that rotary evaporation dramatically accelerated
decomposition of these highly functionalized adducts.
Table 3 summarizes results of radical addition of two
other iodinated active methylenes towards ynol ether 3d in
CH2Cl2. Entries 1, 2, and 3 reveal that iodoacetonitrile added
to ynol ether 3d at different temperatures (RT, 0 °C and
–78 °C) with poorer yields (49%–57%) than ethyl
iodoacetate (1a). Here again, only one isomer of the double
bond was observed. Iodoacetamide (entries 4, 5, and 6)
added to ynol ether 3d with modest yields (18%–30%) but
with high stereoselection. We also tried the addition of two
other α-iodo carbonyl compounds, namely diethyl
iodomalonate and 1-iodopropan-2-one. Unfortunately, both
iodinated compounds failed to react with ynol ethers 3a and
3b. Brominated activated methylenes BrCH2CO2Et,
BrCH2CN, and BrCH(CO2Et)2 were also reacted with ynol
Note: Reaction time: 2 h in all cases except for entry 1 (15 min).
aRT = room temperature.
bIsolated yield based on 3.
1
cThe E-isomer was easily detected by H and 13C NMR, TLC,
and GCMS ; we could not detect the presence of any of the Z-
isomers with these methods.
dThe geometries of the double bond of 5a and 5b were deter-
mined by the characteristic coupling constants of their reduced
counterparts 6a and 6b (see Table 4). The geometry of the double
bond of 5d was determined by NOESY spectra of the reduced
counterpart 6d.
manding group attached to the oxygen atom:
menthoxyethyne 3b (R = menthyl, R′ = H) (8). As one can
see from entries 3 and 4, the reaction with 3b proceeds with
good yields (75% and 70%) and complete stereoselectivity
at RT and at –78 °C. When we tried an ynol ether with even
more sterically demanding adamantyl group (3c ; R =
adamantyl, R′ = H) (9), no desired adduct was observed (en-
try 5); only the starting material was recovered.
These results suggest that the menthyl group might be the
steric limit on the oxygen side of the ynol ether for our reac-
© 2008 NRC Canada

972
Can. J. Chem. Vol. 86, 2008
Table 2. Addition of ethyl iodoacetate 1a to ynol ethers 3b in
different solvents at room temperature.
Table 4. Formation of di- and trisubstituted enol ethers 6a, 6b,
and 6d from deiodination of 5a, 5b, and 5d.
Reaction
time (h)
Yielda of
5b (%)
Entry
Solvent
E/Z ratio
1
2
3
4
5
Benzene
Hexanes
DMSO
Acetone
THF
2
2
1
1
1
80
65
51
60
0
> 99:1
> 99:1
> 99:1
> 99:1
—
Reducing
agent
Yielda
(%)
E/Z
Entry
Substrate
Product
ratiob
1
2
3
5a
5a
5b
Bu3SnHc
6a
6a
6b
96%
70%
15%
> 99:1
> 99:1
> 99:1
t-BuLid
aIsolated yield based on 3b.
Bu3SnHc
4
5
6
5b
5b
5d
t-BuLid
n-BuLie
t-BuLid
6b
6b
6d
69%
16%
72%
> 99:1
> 99:1
> 99:1
Table 3. Addition of iodinated active methylenes 1b and 1c to
ynol ether 3d in CH2Cl2.
aIsolated yields.
bThe geometries of the double bond of 6a–6b were determined
by their characteristic coupling constants. The geometry of the
double bond of 6d was determined by NOESY spectra.
cBu3SnH 1.2 eq., benzene, 1–3 h, RT.
dt-BuLi 1.2 eq, THF, –78 °C, 0.5 h.
en-BuLi 1.2 eq., THF, –78 °C, 0.5 h.
Iodinated
compound
Entry
Temp.a
Product
Yield
E/Z ratiob
Conclusion
1
2
3
4
5
6
RT
1b
1b
1b
1c
1c
1c
5i
5i
5i
5j
5j
5j
57
51
49
30
25
18
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
0 °C
–78 °C
RT
0 °C
–78 °C
In conclusion, we demonstrated, for the first time, that ac-
tivated methylenes add to ynol ethers in neutral radical con-
ditions. The yields obtained vary from moderate to excellent.
The diastereoselectivity of the addition is very high in all
cases. The possibility of avoiding the aqueous work-up rep-
resents a great advantage over existing methods for prepar-
ing hydrolysis-sensitive α-iodo enol ethers. The latter are
interesting precursors of substituted enol ethers and are acyl
anion equivalents. This method is one of the very few that
allowed the stereo-controlled formation of α-iodo β,β-
disubstituted enol ether (12). We are now working on the
radical addition of activated iodoalkanes to silyl ynol ethers.
This should allow us to prepare stereocontrolled β,β-
disubstituted silyl enol ethers, enolate equivalents, known to
be difficult to prepare (13).
Note: Reaction time of 2 h in all cases.
aRT = room temperature
bThe geometry of double bonds of 5i and 5j were determined
by NOESY spectra.
ethers 3a and 3b. In all cases, only the starting materials
were recovered.
The radical nature of this new methodology was con-
firmed using
a radical scavenger. Addition of tert-
butylphenylnitrone to a mixture of 1a and 3a followed by
Et3B addition gave ~ 0% yield of the desired adduct.
To demonstrate the usefulness of α-iodo enol ethers, we
performed C–I bond reductions of adducts 5a, 5b, and 5d
(Table 4). Di and trisubstituted cis enol ethers were obtained
with modest to excellent yields (15%–96%) using tributyltin
hydride, n-BuLi or t-BuLi as reducing agents. The desired
compounds 6a, 6b, and 6d were all isolated with complete
stereoretention. A one-pot procedure involving radical addi-
tion of ethyl iodoacetate 1a to ynol ether 3d followed by
Bu3SnH reduction without isolation of the intermediate iodo
enol ether 5d did not lead to the desired reduced compound
6d (0% yield).
Experimental2
All reactions requiring anhydrous conditions were con-
ducted under positive nitrogen atmosphere in oven-dried
glassware and the reaction flasks were fitted with rubber
septa for the introduction of substrates and reagents via stan-
dard syringe techniques. All solvents were distilled prior to
use, except for anhydrous tetrahydrofuran (THF) that was
used as received from Sigma-Aldrich (SureSeal). n-
Butyllithium (1.6 mol/L solution in hexanes) and tert-
butyllithium (1.7 mol/L solution in pentane) were purchased
from Sigma-Aldrich and titrated prior to use (diphenylacetic
2 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 3776. For more
information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
© 2008 NRC Canada

Longpré et al.
973
acid end-point in dry THF). Tributyltin hydride,
ethoxyacetylene (40% in hexanes), and triethylborane
(1 mol/L in hexane) were also purchased from Sigma-
Aldrich and used as received. Flash chromatography was
performed on triethylamine pretreated Merck silica gel 60
(0.040–0.063 mm) using compressed air pressure. Analytical
thin-layer chromatography (TLC) was carried out on
precoated (0.25 mm) Merck silica gel F 54 plates previously
General procedure for radical addition of iodoalkanes
to ynol ethers
In a 10 mL round-bottomed flask, 0.28 mmol of ynol
ether and 1.5 equiv. of the appropriate iodoalkane were dis-
solved in 2 mL of freshly distilled solvent at the desired
temperature. Triethylborane (1.0 mol/L in hexane) was
added (100 µL) to initiate the radical chain process.
Triethylborane (100 µL) was then added every 15 min until
no starting material was detectable by TLC. The solvent was
removed by a gentle flow of dry nitrogen gas. The crude
product was rapidly purified by flash chromatography using
100% hexanes to 10% acetone–hexanes (the contact time
with the silica gel must be less than 15 min to avoid decom-
position).
α-Iodo enol ethers 5a, 5b, 5d, 5i, and 5j were not fully
characterized because of their instability. HRMS could not
be recorded. In most cases, recording 13C NMR spectra was
not possible. When using diluted solutions in the NMR tube,
the long acquisition time led to decomposition before 13C
spectra could be recorded. Concentrating the solution (to re-
duce the time required to obtain the 13C NMR) accelerated
decomposition, thus precluding the recording of the spectra.
However, the stable reduced parents of 5a, 5b, and 5d, the
enol ethers 6a, 6b, and 6d, were fully characterized.
The geometry of double bonds was determined by
NOESY spectra for compounds 5d, 5i, 5j, and 6d. For the
reduced compounds 6a and 6b, the geometry of the double
bonds was determined with the help of the characteristic cis-
isomer coupling constants.
1
treated with triethylamine. H NMR spectra were recorded
on a Varian 200 MHz NMR spectrometer using CDCl3 (δ =
7.26 ppm) or CD3COCD3 (δ = 2.09 ppm) as the reference.
13C NMR were recorded at 50.3 MHz using CDCl3 (δ =
77.1 ppm), CD3COCD3 (δ = 30.6 ppm), or C6D6 (δ =
128.6 ppm) as the reference. NMR data are reported as fol-
lows: chemical shift in ppm, multiplicity (d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad, dd = doublet
of doublets, dt = doublet of triplets, td = triplet of doublets),
number of protons, and coupling constants in Hertz. IR
spectra were recorded on
a
Nicolet Impact 420
spectrophotometer. Gas chromatography – mass spectra
(GC–MS) were recorded on an Agilent model 6890N. High-
resolution mass spectra (HRMS) were recorded on a ZAB-
2F model VG apparatus.
Preparation of starting materials
The preparation and characterization of menthoxyethyne
(3b), 1-menthoxypropyne (3d), and 1-menthoxy-3-
methylpentyne (3f) have been reported previously (8).
Compounds 3c (9) and 3g (11) have also been prepared and
characterized previously (9). Ethoxyacetylene (3a) is com-
mercially available.
(E)-Ethyl 4-ethoxy-4-iodobut-3-enoate (5a)
Yellow oil. IR (cm–1): 3018, 2952, 2915, 1731, 1629,
1454. 1H NMR (CD3COCD3) δ: 1.22 (m, 6H), 2.80 (m, 1H),
3.12 (d, 1H, J = 7.0 Hz), 3.77 (q, 2H, J = 7.4 Hz), 4.09 (q,
2H, J = 7.0 Hz), 5.53 (t, 1H, J = 7.2Hz). MS: 157 (M+ – I),
129, 101, 99, 83, 73, 55.
Ethoxyethynyl(1,1-dimethylethyl)diphenylsilane (3h)
The preparation of the title compound was carried out
according to the procedure described by Pericas and co-
workers for the synthesis of similar compounds (10b). Under
inert atmosphere, n-BuLi (3 mL, 1.50 mol/L in n-hexane,
(E)-Ethyl 4-iodo-4-menthoxybut-3-enoate (5b)
Yellow oil. IR (cm–1): 3017, 2960, 2922, 1735, 1633,
4.60 mmol) was added dropwise to
a solution of
1
ethoxyacetylene (40% in hexanes, 1 mL, 4.18 mmol) in an-
hydrous THF (2.9 mL) at 0 °C over a period of 10 min. The
mixture was stirred for 1.5 h and hexamethylphosphoric
triamide (0.81 mL) was added. After 10 min, tert-
butyldiphenylsilyl chloride (1.17 mL, 4.51 mmol) was
added. The cooling bath was removed and the mixture was
stirred overnight at room temperature. The reaction mixture
was poured on a mixture of ice (3 g) and n-hexane (6 mL).
The organic layer was separated, and the aqueous layer was
extracted twice with n-hexane (4 mL). The combined or-
ganic layers were washed with brine (4 mL), dried over
MgSO4, and concentrated in vacuo. The crude product was
chromatographed through silica gel (pretreated with 1% v/v
of triethylamine) eluting with hexane to give 90% yield of
3h as a colorless oil.
1451. H NMR (CD3COCD3) δ: 0.80–2.20 (m, 21H), 3.12
(d, 2H, J = 7.4 Hz), 3.67 (td, 1H, J = 5.5 and 10.9 Hz), 4.11
(q, 2H, J = 7.0 Hz), 5.54 (td, 1H, J = 1.6 and 7.0 Hz). MS:
267 (M+ – I), 139, 123, 95, 83, 69, 55.
(E)-Ethyl 4-iodo-4-menthoxy-3-methylbut-3-enoate (5d)
Yellow oil. IR (cm–1): 2955, 2921, 2868, 1734, 1636,
1
1457, 1180. H NMR (CD3COCD3) δ: 0.80–2.20 (m, 24H),
3.11 (d, 1H, J = 15.6 Hz), 3.37 (d, 1H, J = 15.6 Hz), 3.66
(td, 1H, J = 4.3 and 10.9 Hz), 4.13 (q, 2H, J = 7.0 Hz). 13C
NMR (CD3COCD3) δ: 13.9, 16.2, 20.3, 21.8, 23.4, 23.7,
25.6, 31.5, 34.3, 37.1, 39.6, 47.1, 60.3, 82.1, 116.6, 120.5,
170.1. MS: 281 (M+ – I), 270, 142, 83, 69, 55.
IR (cm–1): 3065, 3048, 2959, 2929, 2891, 2857, 2174,
(E)-Ethyl 4-iodo-4-menthoxy-3-methylbut-3-enenitrile
(5i)
1
1427, 1103. H NMR (CDCl3) δ: 8.09 (m, 4H), 7.58 (m,
Yellow oil. IR (cm–1): 2953, 2917, 2865, 2246, 1636,
6H), 4.38 (q, 2H, J = 7.0 Hz), 1.60 (t, 3H, J = 7.0 Hz), 1.36
(s, 9H). 13C NMR (CDCl3) δ: 14.7, 19.0, 27.6, 33.0, 75.6,
113.0, 128.0, 129.6, 135.0, 136.0. HRMS calcd. for
C20H24SiO (+NH4): 326.1940; found : 326.1931
1
1454. H NMR (CDCl3) δ: 0.80–2.2 (m, 21H), 3.36–3.57
(m, 2H), 3.75 (td, 1H, J = 4.7 and 10.5 Hz). 13C NMR
(CD3COCD3) δ: 16.1, 19.7, 20.3, 21.7, 22.5, 23.4, 25.6,
© 2008 NRC Canada

974
Can. J. Chem. Vol. 86, 2008
31.6, 34.2, 39.7, 47.0, 82.9, 116.1, 116.8. MS: 234 (M+ – I),
139, 97, 83, 69, 55.
60.1, 80.8, 106.2, 142.0, 171.2. MS: 268, 138, 123, 97, 83,
69, 55. HRMS calcd. for C16H28O3 : 268.2038; found:
268.2028
(E)-Ethyl 4-iodo-4-menthoxy-3-methylbut-3-enamide (5j)
Yellow oil. IR (KBr, cm–1): 3433, 3187, 2962, 2867, 1662,
(Z)-Ethyl 4-menthoxy-3-methylbut-3-enoate (6d)
Yellow oil. IR (cm–1): 3005, 2956, 2868, 1740, 1456,
1
1461, 1386, 1126. H NMR (CDCl3) δ: 0.80–2.20 ppm (m,
1
1364, 1253, 1178, 1136, 1038. H NMR (CDCl3) δ: 0.80–
21H), 3.05–3.26 (m (apparent q), 2H), 3.73 (td, 1H, J = 4.5
2.20 (m, 24H), 3.05–4.20 (m, 5H), 6.04 (m, 1H). 13C NMR δ
(C6D6) δ: 14.0, 16.1, 18.0, 20.5, 22.0, 24.1, 26.0, 31.2, 34.0,
34.8, 41.3, 48.0, 60.0, 81.0, 107.0, 141.2, 171.0. MS: 219,
202, 173, 145, 127, 101. HRMS calcd. for C17H30O3:
282.2195; found: 282.2193
and 10.9 Hz), 6.20–6.40 (br, 1H), 6.60–6.80 (br, 1H).
General procedure for tributyltin hydride reduction of
␣-iodoenol ethers
In a 10 mL round-bottomed flask, 0.250 mmol of freshly
prepared α-iodoenol ether was dissolved in 1.5 mL of ben-
zene along with 0.300 mmol (87 mg, 80 µL) of tributyltin
hydride (1.2 eq.). Triethylborane (1.0 mol/L in hexane) was
added (100 µL) to initiate the radical chain process.
Triethylborane (100 µL) was then added every 15 min until
no starting material was detectable by TLC (1–3 h). A satu-
rated aqueous solution of NaHCO3 was poured into the reac-
tion mixture. After the aqueous layer was extracted with
Et2O (3×), the organic layers were combined, washed with
brine, dried (MgSO4), filtered through a pad of silica-KF,
and concentrated. The crude product was purified by flash
chromatography using 100% hexanes to 10% acetone–hex-
anes.
Acknowledgement
Acknowledgments are made to the Natural Sciences and
Engineering Research Council of Canada (NSERC) for fi-
nancial support. We are thankful to Stéphane Dugrenier and
Aurélie Becquet for performing preliminary experiments.
References
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3. J.D. White and H. Smits. Org. Lett. 7, 235 (2005).
4. For examples of cross coupling reactions involving α-halo
enol ethers: (a) R.W. Friesen, R.W. Loo, and C.F. Sturino.
Can. J. Chem. 72, 1262 (1994); (b) R.W. Friesen and R.W.
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and I.P. Beletskaya. Russ. J. Org. Chem. 35, 1273 (1999).
5. For preparation of α-halo enol ethers using strong bases: (a) E.
Boyd, M.R. Hallett, R.V.H. Jones, J.E. Painter, P. Patel, P.
Quayle, and A.J. Waring. Tetrahedron Lett. 47, 8337 (2006);
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65, 68 (1987); (c) S.F. Martin. Pure Appl. Chem. 75, 63
(2003). For preparation of α-halo enol ethers via stannyl inter-
mediates: (d) J.S. Potuzak, S.B. Moilane, and D.S. Tan. J. Am.
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Chem. Ber. 126, 2493 (1993).
General procedure for n-butyllithium and tert-
butyllithium reduction of ␣-iodoenol ethers
In a 10 mL round-bottomed flask, 0.250 mmol of freshly
prepared α-iodoenol ether was dissolved in 5 mL of anhy-
drous THF. The reaction mixture was cooled to –78 °C and
0.300 mmol (1.2 eq.) of freshly titrated BuLi was added
dropwise. After 30 min (when TLC confirms that the reac-
tion was completed), 1 mL of distilled water was added
dropwise. The cooling bath was removed and the reaction
mixture was stirred for another 10 min. A saturated aqueous
solution of NaHCO3 was poured into the reaction mixture.
After the aqueous layer was extracted with Et2O (3×), the
organic layers were combined, washed with brine, dried
(MgSO4), filtered, and concentrated. The crude product was
purified by flash chromatography using 100% hexanes to
10% acetone–hexanes.
(Z)-Ethyl 4-ethoxybut-3-enoate (6a)
Yellow oil. IR (cm–1): 3047, 2978, 2944, 2884, 1730,
1
1666, 1381, 1323, 1245, 1177, 1109. H NMR (CDCl3) δ:
1.22 (m, 6H), 3.11 (dd, 2H, J = 1.6 and 7.0 Hz), 3.79 (q, 2H,
J = 7.0 Hz), 4.08 (q, 2H, J = 7.0 Hz), 4.53 (q, 1H, J = 7.0
Hz), 6.06 (dt, 1H, J = 1.6 and 6.2 Hz). 13C NMR (CDCl3) δ:
14.4, 15.4, 30.0, 60.7, 68.0, 98.1, 147.0, 172.7. MS: 158,
127, 99, 85, 57. HRMS calcd. for C8H14O3: 158.0943;
found: 158.0935
7. Radical 4 is expected to interconvert very slowly since it is
known that α-oxy vinyl radicals possess a very high energy
barrier to rotation; see: (a) J.A. Kampmeier, M.S. Liu, S.
Soloway, and D.K. Wedegaertner. J. Am. Chem. Soc. 93, 3809
(1971); (b) C. Galli, A. Guarnieri, H. Koch, P. Mencarelli, and
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8. (a) A. Moyano, F. Charbonnier, and A.E. Greene. J. Org.
Chem. 52, 2919 (1987); (b) M.A. Pericas, F. Serratosa, and E.
Valenti. Tetrahedron, 43, 2311 (1987).
(Z)-Ethyl 4-menthoxybut-3-enoate (6b)
Yellow oil. IR: 3009, 2944, 1742, 1450, 1022. H NMR
1
(CDCl3) δ: 0.76 (d, 3H, J = 6.6 Hz), 0.80–2.20 (m, 21H),
3.11 (dd, 2H, J = 1.6 and 7.0 Hz), 3.39 (td, 1H, J = 4.3 and
10.9 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.51 (q, 1H, J = 7.0 Hz),
6.13 (dt, 1H, J = 1.6 and 6.3 Hz). 13C NMR (CDCl3) δ: 14.3,
16.4, 17.8, 20.5, 22.2, 23.8, 31.7, 34.2, 35.0, 41.9, 47.7,
9. H.C. Brown and U.S. Racherla. J. Org. Chem, 51, 427 (1986).
© 2008 NRC Canada

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10. (a) Y. Kita, J. Sekihachi, Y. Hayashi, Y.Z. Da, M. Yamamoto,
and S. Akai. J. Org. Chem. 55, 1108 (1990); (b) E. Valenti,
M.A. Pericas, and F. Serratosa, J. Org. Chem. 55, 395 (1990).
For other methods for preparing β,β-dialkylated α-iodo enol
ethers, see: (a) H.R. Sonawane, B.S. Nanjundiah, and M.D.
Panse. Tetrahedron Lett. 26, 3507 (1985); (b) P.J. Kropp, S.A.
McNeely, and R.D. Davis. J. Am. Chem. Soc. 105, 6907
(1983).
11. (a) J.M. Manthorpe and J.L. Gleason, J. Am. Chem. Soc. 123,
2091 (2001); (b) E. Vedejs, A.W. Kruger, N. Lee, S.T. Sakata,
M. Stec, and E. Suna. J. Am. Chem. Soc. 122, 4602 (2000);
(c) S. Hosoawa, K. Sekiguchi, M. Enemoto, and S. Kobayashi.
Tetrahedron Lett. 41, 6429 (2000); (d) N. Chatani, S. Fujii, Y.
Yamasaki, S. Murai, and N. Sonoda. J. Am. Chem. Soc. 108,
7361 (1986).
© 2008 NRC Canada