Intramolecular regioselective addition of radicals and carbanions to ynol ethers. A strategy for the synthesis of exocyclic enol ethers

Article abstract of DOI:10.1016/j.tet.2010.11.024

The scope and limitations of radical and anionic cyclization reactions involving halo ynol ethers have been investigated. 5-exo and 6-exo radical cyclizations of 6-iodo and 7-iodo ynol ethers proceeded well when the oxygen of the ynol ether was bearing an ethyl group. Exocyclic iodoenol ethers resulting from these cyclizations were highly unstable and decomposed rapidly. Li-I exchange of iodo ynol ethers proceeded smoothly at -78 °C. 6-Alkoxy-5-hexynyllithiums underwent regiospecific 5-exo-dig anionic cyclization to produce five-membered rings bearing an exocyclic enol ether moiety. The cyclized vinyllithium intermediate was successfully trapped with electrophiles to afford functionalized cycloalkoxyalkylidene derivatives in modest to good yields. 7-Alkoxy-6-heptynyllithiums did not cyclize via a 6-exo anionic process.

Full text of DOI:10.1016/j.tet.2010.11.024

Tetrahedron 67 (2011) 92e99
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular regioselective addition of radicals and carbanions to ynol ethers.
A strategy for the synthesis of exocyclic enol ethers
*
Rana Hanna, Benoit Daoust
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
ꢁ
ꢀ
Departement de Chimie-Biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada G9A 5H7
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2010
Received in revised form 3 November 2010
Accepted 3 November 2010
Available online 11 November 2010
The scope and limitations of radical and anionic cyclization reactions involving halo ynol ethers have
been investigated. 5-exo and 6-exo radical cyclizations of 6-iodo and 7-iodo ynol ethers proceeded well
when the oxygen of the ynol ether was bearing an ethyl group. Exocyclic iodoenol ethers resulting from
these cyclizations were highly unstable and decomposed rapidly. LieI exchange of iodo ynol ethers
proceeded smoothly at ꢀ78 ꢁC. 6-Alkoxy-5-hexynyllithiums underwent regiospecific 5-exo-dig anionic
cyclization to produce five-membered rings bearing an exocyclic enol ether moiety. The cyclized vinyl-
lithium intermediate was successfully trapped with electrophiles to afford functionalized cyclo-
alkoxyalkylidene derivatives in modest to good yields. 7-Alkoxy-6-heptynyllithiums did not cyclize via
a 6-exo anionic process.
Keywords:
Ynol ethers
Enol ethers
Radical cyclization
Anionic cyclization
Alkyllithiums
Vinyllithiums
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
radical formation is easier with iodoalkanes than it is with bro-
moalkanes9 and (ii) alkylmetals are formed more cleanly starting
Formation of carbocycles is one of the most important en-
deavors in organic chemistry. A simple approach to this synthetic
problem is the intramolecular addition of a reactive center to a CC
multiple bond acceptor. Additions to alkynes are especially in-
teresting since they generally lead to exocyclic unsaturated com-
pounds. Radical1,2 and anionic3e5 additions to alkynes have been
studied. Some of these cyclization reactions were performed on
functionalized alkynes,4,5 but very few on alkoxylated alkynes (ynol
ethers).6-8 In our ongoing research program dedicated to the de-
velopment of functionalized ynol ethers,9,10 we decided to explore
the scarcely studied addition of radical and anionic reactive centers
to ynol ethers.
from iodinated compounds than brominated ones.3
1. nBuLi, THF
OR
I
2.
I
OR
n
HMPA
I
r.t.(20 h) 40 °C(2 h)
n
1 (R = Et, menthyl))
a (R = Et, n=1) (75% yield)
2
2b (R = Menthyl, n=1) (90% yield)
2c (R = Et, n=2) (89% yield)
2d (R = Menthyl, n=2) (75% yield)
Scheme 1.
Models 2a and 2c were prepared by alkylating the deprotonated
ethoxyethyne (1 (R¼Et), commercially available) with 1,4-diido-
butane or 1,5-diiodopentane, in the presence of HMPA. Yields were,
respectively, 75 and 89%. In the absence of HMPA, yields dropped to
less than 10%.
Models 2b and 2d were first prepared using a two-step sequence.
First, ynol ether 1 (R¼menthyl) was prepared from menthol, using
Greene’s protocol (KH and TCE then BuLi and H2O).11 It was then
transformed to the desired iodinated compounds using the pro-
cedure described in the previous paragraph, with comparable yields
(90 and 75%, respectively). Compounds 2b and 2d could also be
2. Results and discussion
2.1. Preparation of models
Models with different R groups and different carbon saturated
chains were prepared (compounds 2aed, see Scheme 1). Our
strategy consisted in preparing 6- and 7-iodo ynol ethers, and not
bromoynol ethers. This choice was made since it is known that (i)
* Corresponding author. Tel.: þ819 376 5011; fax: þ819 376 5084; e-mail
synthesized from menthol without isolation of b-unsubstituted ynol
address: Benoit.Daoust@uqtr.ca (B. Daoust).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.024

R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
93
Table 1
ether 1 (R¼menthyl) (KH and TCE then BuLi and diiodoalkane). With
a,b
Intramolecular radical addition of 2a in CH2Cl2
this procedure, 2b was prepared with 90% yield and 2d was prepared
with 45% yield. It should be noted that menthylated ynol ethers 2b
and 2d are stable at ꢀ5 ꢁC for more than a week. Ethylated ynol
ethers 2a and 2c are stable at ꢀ5 ꢁC for only a few days.
Entry
Bu3SnH added
(total equiv)c
Reaction
time (h)
Temp
(ꢁC)
Yieldsd (%)
5a
6a
1
2
3
4
5
6
7
0
0
0
1.2
1.2
2
24
24
4
0.25
6
23
23
40
9
10
0e
0
0
0
0
0
2.2. Radical cyclization
23
0e
ꢀ78
ꢀ78
ꢀ78
40
85
45
Scheme 2 illustrates the expected radical cyclization mechanism
for models 2aed. Upon treatment with Et3B initiator, compound 2
should produce alkyl radical 3. Cyclization would lead to vinyl
radical 4. In the absence of an H-transfer agent, abstraction of io-
dine from the starting material should form iodoenol ether 5 (path
a). In the presence of an H-transfer agent (e.g., Bu3SnH), path b,
leading to 6, is also possible. Also possible is a transfer of H to
radical 3 prior to cyclization leading to 7.
6
6
0
30
4
a
Concentration of 2a: 0.05 M.
b
The radical initiator, Et3B 1.0 M/hexanes, was added every 15 min (100
the first 2 h (except for entry 2 where it was added for the first 4 h).
mL) for
c
Bu3SnH (0.3 equiv) was added every hour until the amount of equivalents was
reached.
d
e
Yields obtained by 1H NMR (internal standard: diphenylmethane).
Product degradation.
I
OR
but Et3B was then added every 15 min for the first 4 h. The yield did
not improve significantly (10%, entry 2). In both reactions, the
remaining material was a mixture of decomposition products and
unreacted 2a. When heated at reflux (entry 3), the starting product
did not survive the reaction conditions.
OR
I
n
+
3a-d
n
2a (R = Et, n=1)
2b (R = Menthyl, n=1)
2c (R = Et, n=2)
5a-d
In view of these unsatisfying results, it was decided to use
a hydride transfer agent, Bu3SnH. It was hoped that Bu3SnH would
improve the intramolecular addition by generating a more efficient
radical chain or by acting as a better radical initiator. The product
generally expected from a tin hydride radical chain reaction is the
hydrogenated compound (here, compound 6a, see Scheme 1). This
is explained by that fact that reaction of the alkyl radical with tin
hydride is generally faster than abstraction of iodide from the
starting material (kH is generally >kI, see Scheme 1). However, the
case is different with cyclized vinyl radicals. Curran demonstrated
that for these radicals kI is at least three times faster than kH.1 In our
case, it is most probable that alkoxylated vinyl radicals will behave
the same way, thus favoring the production of 5a over 6a.
2d (R = Menthyl, n=2)
2a-d
Et3B
path a
(-I
)
OR
OR
5-exo cyclization (n=1)
or 6-exo cyclization (n=2)
n
n
4a-d
To avoid reduction of radical 3a to 7a (see Scheme 1) prior to its
cyclization to 4a, small quantities of Bu3SnH (0.3 equiv) were added
every hour (entry 4). In these conditions, at room temperature,
compound 2a reacted very rapidly and led to a complex mixture of
products. At ꢀ78 ꢁC (entry 5), a 40% conversion of iodinated car-
bocycle 5a was observed. Reduced cyclized compound 6a could not
be detected. By adding a total of 2 equiv of Bu3SnH, the conversion
went up to 85% (entry 6). Adding 4 equiv of Bu3SnH (entry 7) finally
led to the reduced product with 30% yield. Still, 45% of the iodinated
compound was obtained. Adding more Bu3SnH led to more con-
version to 6a (observed in the 1H NMR of the crude reaction mix-
ture), however, because of tin compounds this precluded the
recording of any NMR conversion yield or isolation of any expected
products.
3a-d
path b
Bu3SnH
Bu3SnH
or RH (solvent)
H
OR
+
Bu3Sn
n
OR
H
6a-d
n
As observed by Curran with other vinyl radicals,1 it must be
concluded that in the present case, kI is larger than kH. This radical
cyclization is therefore very exothermic and most probably irre-
versible (another reason why any thermodynamically favored six-
membered ring products were not observed). Volatility might also
contribute to the very small amount of 6a observed. Indeed, com-
pound 6a seemed to be more volatile than 5a, as suggested when
entry 7, Table 1, was allowed to have a very long evaporation time
(1 h instead of the regular 5 min evaporation). In that case, the yield
of 6a fell to 5% while the yield of 5a decreased only to 40%.
Other solvents were also assessed (Table 2) for the cyclization of
compound 2a in the presence of Bu3SnH. In benzene (entry 1) at
room temperature, the reaction took place with a lower conversion
(50%) than in CH2Cl2 at ꢀ78 ꢁC (Table 1, entry 6). In hexanes and in
acetone (entries 2e5), the reaction was much slower and led to
lower conversions (0e21%). Reaction did not occur in THF (entries 6
7a-d
Bu3SnI + 3a-d
2a-d
Scheme 2.
Since the best solvent for intermolecular addition of carbon-
centered radicals to ynol ethers9,10 is known to be dichloromethane,
this solvent was chosen to begin the present investigation.
2.2.1. Compound 2a. The radical reaction was performed by adding
radical initiator Et3B to a 0.05 M CH2Cl2 solution of 2a at room
temperature. The results are presented in Table 1. Low concentra-
tion (0.05 M) of ynol ether 2a was used to favor intramolecular
processes over intermolecular processes. In entry 1, 0.3 equiv of
Et3B was added every 15 min for 2 h. After 24 h, a modest 9% yield of
the desired compound was observed. The experiment was repeated

94
R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
Table 2
Compound 5b was also unstable and decomposed rapidly when in
Intramolecular radical addition of 2a in different solventsa,b,c
contact with air. Dissolved in deoxygenated acetone-d6, the product
was stable long enough to record a 1H NMR and thus confirm its
structure (no 13C NMR could be recorded).
Entry
Solvent
Reaction
time (h)
Temp (ꢁC)
Yieldsd (%)
5a
6a
1
2
3
4
5
6
7
Benzene
Hexanes
Hexanes
Acetone
Acetone
THF
24
6
24
6
24
6
24
23
ꢀ78
23
50
5
18
0
21
0
0
0
0
0
0
0
0
0
2.2.3. Compound 2c. Intramolecular radical addition of compound
2c was also investigated. Here, the 6-exo cyclization should be fa-
vored over the 7-endo process. Since this 6-exo cyclization is known
to be slower than 5-exo, lower conversions than those observed for
compound 2a were expected. Results of this cyclization are gath-
ered in Table 4.
ꢀ78
23
ꢀ78
23
THF
a
Concentration of 2a: 0.05 M.
b
The radical initiator, Et3B 1.0 M/hexanes, was added every 15 min (100
the first 2 h.
mL) for
Table 4
a,b
Intramolecular radical addition of 2c in CH2Cl2
c
Bu3SnH (0.3 equiv) was added every hour until a total of 2 equiv was reached.
d
Yields obtained by 1H NMR (internal standard: diphenylmethane).
Entry
Bu3SnHc
(total equiv)
Reaction
time (h)
Temp
(ꢁC)
Product
Yieldsd
(%)
1
2
3
4
0
2
2
2
24
6
24
6
23
23
23
ꢀ78
5c
5c
5c
5c
0
5
50
78
and 7, 0% conversion). A lot of decomposition products were ob-
served in reactions performed at room temperature.
The desired compound 5a was unstable. It decomposed rapidly
when in contact with air. Dissolved in deoxygenated acetone-d6,
the product was just stable enough to record a 1H NMR and thus
confirm its structure (no 13C NMR could be recorded). The structure
of 5a was also confirmed indirectly: rapidly after its formation
(without purification), compound 5a was treated with BuLi (see
a
Concentration of 2c: 0.05 M.
b
The radical initiator, Et3B 1.0 M/hexanes, was added every 15 min (100
the first 2 h.
mL) for
c
Bu3SnH (0.3 equiv) was added every hour until the amount of equivalents was
reached.
d
Yields obtained by 1H NMR (internal standard: diphenylmethane).
anionic cyclization, below) and suffered
a trans-metallation.
Quenching with deoxygenated methanol afforded stable 6a. Com-
parison with spectroscopic literature data of this compound con-
firmed its structure.6
Entry 1 shows that without Bu3SnH, at room temperature, the
reaction did not take place (0% conversion; a mixture of degrada-
tion products and starting material was obtained). In the presence
of Bu3SnH, after 6 h (entry 2), only a very low yield (5%) of 5c could
be obtained (along with a little decomposition). After 24 h (entry 3),
a 50% conversion and a lot of degradation was observed. At ꢀ78 ꢁC
(entry 4), the reaction was cleaner and conversion increased to 78%.
Surprisingly, the conversion observed for this 6-exo cyclization was
similar to the one obtained for the 5-exo cyclization (Table 1 entry
6). Neither 7-endo product nor cyclized and uncyclized reduced
products (6c and 7c) were observed.
2.2.2. Compound 2b. Compound 2b was first reacted using the
experimental conditions allowing the best cyclization conversion
for iodo ynol ether 2a (see Table 1 entry 6). Entry 1 of Table 3
presents this result.
Table 3
Intramolecular radical addition of 2ba,b
The six-membered ring compound 5c is more stable than its
five-membered ring cousin 5a. It was possible to purify and isolate
5c with a 45% yield. However, once the spectral data were recorded
(few hours), the product decomposed.
Entry
Solvent
Bu3SnH addedc
(equiv)
Temp
(ꢁC)
Reaction
time (h)
Product
Yieldsd
(%)
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Benzenee
2
2
2
4
2
ꢀ78
0
23
23
80
6
8
24
24
0.5
5b
5b
5b
5b
5b
9
14
20
20
0f
2.2.4. Compound 2d. Compound 2d, when submitted to various
radical reaction conditions (2e24 h reactions, ꢀ78 ꢁCe80 ꢁC, 0 to
2 equiv of Bu3SnH), was completely refractory to cyclization. In all
cases, 0% conversion was recorded. Only a mixture of degradation
and starting materials could be observed.
a
Concentration of 2b: 0.05 M.
b
The radical initiator, Et3B 1.0 M/hexanes, was added every 15 min (100
the first 2 h.
mL) for
c
Bu3SnH (0.3 equiv) was added every hour until the amount of equivalents was
reached.
Note that in none of the above Bu3SnH experiments could any
uncyclized reduced compound 7aed be detected, though careful
TLC, GCeMS, and NMR analyses were performed. It thus seemed
that once formed, the radical isomerized to its cyclic counterpart
much more rapidly than it reacted with Bu3SnH, even for the 6-exo
radical cyclization (production of 5c).
d
e
f
Yields obtained by 1H NMR (internal standard: diphenylmethane).
(PhCO2)2 as initiator: 0.10 equiv added entirely at the beginning of the reaction.
Product degradation.
With only 9% of the desired compound, one can see that these
conditions were not optimal for compound 2b. Since the reaction
seemed to be very slow at ꢀ78 ꢁC, it was then performed at 0 ꢁC and
room temperature (entries 2 and 3). Yields were slightly better, but
still very modest (a lot of decomposition was observed at room
temperature). In order to speed up the reaction, the amount of
Bu3SnH was increased to 4 equiv (entry 4). Even after 24 h, yields
did not improved. This low reactivity prompted us to perform the
reaction in refluxing benzene (using benzoyl peroxide as initiator).
After 30 min of reflux, compound 2b had completely decomposed
(entry 5). Note that in none of these experiments could any hy-
drogenated cyclized compound 6b be detected. One can see that
the ynol ether bearing the menthyl group (2b) cyclized more slowly
than the one bearing the ethyl group (2a). Whether the effect of the
menthyl group was steric and/or electronic is difficult to establish.
2.3. Anionic cyclization
Radical cyclization showed interesting results, but failed to work
well with some models. Another drawback of this radical reaction
was the difficulty to functionalize the cyclized vinyl radical by
trapping it with an atom-transfer reagent. Even with large amounts
of Bu3SnH in the mixture, no product resulting from the hydroge-
nation of radicals could be detected.
It was then decided to assess the cyclization of our models 2aed
through an anionic pathway. Since Bailey showed that LieI ex-
change proceed smoothly with iodoalkynes,3 it was thought that
a similar metalehalogen exchange could take place for compounds

R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
95
2aed. This process should allow ynol ethers 2aed to be trans-
formed to alkyllithiums 8aed (see Scheme 3) that should be stable
the fact that intramolecular additions of organometallic reagents to
unsaturated bonds invariably form the smaller ring.3,7,8,12e14
Li
H
OR
OR
OR
BuLi
OR
MeOH
I
n
Li
n
n
n
2a (R = Et, n=1)
8a-d
9a-d
6a-d
2b (R = Menthyl, n=1)
2c (R = Et, n=2)
2d (R = Menthyl, n=2)
E
OR
E+
n
10a-d
Scheme 3.
Table 5
in solution at ꢀ78 ꢁC.3 The latter, upon warming to room temper-
ature under inert atmosphere, should isomerize to cyclized vinyl-
lithiums 9aed. Quenching with MeOH should lead to 6aed. An
important advantage of the anionic cyclization over the radical
cyclization was the possibility of functionalizing the cyclized vinyl
anion 9aed by reaction with various electrophiles (other than
MeOH) in order to produce 10aed.
Intramolecular anionic addition of 2a,ba
Entry Starting Electrophile
material (equiv)
Yieldb (%)
Product
H
1
2
2a
2a
MeOH (3)
87
OEt
6a
HO
2.3.1. Compound 2a. Before investigating any cyclization reaction,
it was needed to verify if the required LieI exchange could be
successfully performed. Treatment of a solution of 6-iodo-1-
ethoxyhexyne 2a in hexaneseethyl ether (3:2 by vol) with
2.2 equiv of n-butyllithium (n-BuLi) in hexanes at ꢀ78 ꢁC cleanly
generated the corresponding acetylenic alkyllithium 8a as dem-
onstrated by the fact that quenching the reaction mixture at ꢀ78 ꢁC
with an excess of deoxygenated methanol afforded 1-ethoxyhex-
yne 7a in 90% isolated yield. Note that this experimental procedure
slightly differs from Bailey’s protocol for LieI exchange of iodoal-
kynes. While Bailey used t-BuLi to perform LieI exchange, it was
decided here to use the more easy to handle n-BuLi. Bailey’s pro-
cedure using the more reactive t-BuLi was also tested; we obtained
the same compound 7a, with a slightly lower yield (74%). This result
convinced us to continue using the more easy to handle n-BuLi.
Knowing that ynol ether alkyllithiums can be prepared by low-
temperature lithiumeiodine exchange, the intramolecular cycliza-
tion investigation was undertaken.
i-BuCOMe (6)
70
71
OEt
10aa
HO
Ph
3
2a
PhCHO (6)
OEt
10ab
H
O
4
5
2a
2b
MeOH (3) then HClO4 71
H
MeOH (3)
90
OMenthyl
CHO
6b
The study first began by treating compound 2a with n-BuLi at
ꢀ78 ꢁC. Warming the reaction mixture to room temperature
allowed the alkyllithium intermediate 8a to cyclize and afford vinyl
anion 9a. After 2.5 h at room temperature, deoxygenated methanol
was added to quench anion 9a and led to cyclized compound 6a.
After work-up, only a very small quantity of 6a (<5%) could be
isolated, most probably due to its high volatility. Nevertheless, it
was just enough to record 1H and 13C NMR spectra. Comparison
with literature spectroscopic data6 confirmed the structure of 6a.
The experiment was then repeated, but instead of isolating the
desired compound, an NMR yield of the crude reaction mixture was
recorded and a 87% yield was observed (Table 5, entry 1). No 6-endo
cyclization product could be detected. It is clear that the kinetically
6
7
2b
DMF (6)
70
68
OMenthyl
CO2Et
10ba
2b
2b
ClCO2Et (6)
OMenthyl
H
10bb
8
MeOH (3) then HClO4 77
O
a
Alkyllithium 8a,b was generated at ꢀ78 ꢁC by the addition of 2.2 equiv of n-BuLi
favored attack at the
leading to the smaller ring system largely overcomes the ‘expected’
nucleophilic addition at the more electrophilic -carbon site. In
b-carbon of the alkoxyacetylene moiety
to a solution of 2a,b in hexanesediethyl ether (3:2 by vol), the cooling bath was
removed after 10 min, and the mixture was allowed to warm and stand at room
temperature for 2.5 h after which period the mixture was recooled to ꢀ78 ꢁC and the
required amount of equivalents of the electrophile was added.
a
addition, the exclusive formation of a five-membered ring via 5-exo
cyclization of this 6-alkoxy-5-hexynyllithiums is in agreement with
b
Isolated yields except for entry 1 (NMR yield).

96
R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
Alkyllithium propensity to preferentially add to
b
-carbon of the
NMR yield was recorded. Only 20% yield of 6c was observed
(spectral data identical to literature18e20). However, for the first
time in these reactions, a 80% yield of the dehalogenated uncyclized
product 7c was observed. Longer reaction times (4e6 h) did not
lead to better results (<20% yield of the desired 6c).
Adding lithiophilic Lewis bases to the reaction medium was then
tried. It has been demonstrated that Lewis bases can break orga-
nolithium aggregates and facilitate isomerization to cyclized
vinyllithiums.14 Two Lewis bases were tested: TMEDA and THF.
Again, no increase in the yield of the desired compound was
observed.
alkoxyacetylene moiety has also been observed in intermolecular
reactions.15 Note that this same compound cyclized, via a radical
pathway, with a very similar 85% yield (see Table 1, entry 6).
As discussed previously, an advantage of the anionic technique
of cyclization was the possibility of functionalizing the cyclized
anion by reaction with electrophiles. Instead of adding MeOH after
2.5 h at room temperature, electrophiles were added. After stirring
for 1 h, work-up and isolation led to functionalized compounds
(Table 5, entries 2 and 3).
These carbonyl reagents were selected to make sure that the
final product possessed a molecular weight high enough to avoid
any volatility problem. Yields were good in both cases (70e71%
yield).
Note that these reactions were also tested in hexanes, with no
Et2O added. Yields dropped to ∼0%. The low reactivity in hexanes
might be due to the fact that alkyllithiums are known to be highly
aggregated in hexanes, forming dimers and tetramers. Better re-
sults were obtained with ether since this solvent is known to dis-
sociate alkyllithium aggregates.
Efficient formation of exocyclic enol ether 6a led us to examine
the possibility of developing a carboxaldehyde synthesis, since
hydrolysis of 6a should lead to cyclopentane carboxaldehyde
(Table 5, entry 4). Compound 2a was treated with BuLi at ꢀ78 ꢁC,
warmed to room temperature and quenched with methanol to
afford 6a. After 2 h of stirring, 35% HClO4 was added dropwise.16,17
After work-up, a 71% yield of cyclopentane carboxaldehyde was
observed. This result demonstrates that it is possible to transform,
in one-step, 6-iodo ynol ethers to cyclopentane carboxaldehydes.
2.3.4. Compound 2d. First, formation of alkyllithium 8d was
assessed as before. Reduced uncyclized 7d was obtained with 91%
yield. Cyclization of 2d led to only 15% of the desired compound 6d
(after 2 h at room temperature and quenching with MeOH). The
major compound was uncyclized 7d (>50%). Unfortunately, after
much effort, the two compounds could not be separated. Here also,
increasing the reaction time (4e6 h) did lead to better yields. Ad-
dition of Lewis bases (TMEDA, THF) did not improve cyclization
efficiency.
In all, it must be concluded that while 5-exo anionic cyclization
to ynol ethers was efficient (yields up to 90%), its 6-exo counterpart
was quite difficult to achieve (yields lower than 20%).
Note that performing the metalehalogen exchange using Mg
instead of BuLi did not allow the desired cyclization to occur. At
ꢀ78 ꢁC, 0 ꢁC, 23 ꢁC, and at reflux in ether, all these experiments
were unsuccessful.
3. Conclusion
2.3.2. Compound 2b. Prior to intramolecular investigation, as for
compound 2a, it was imperative to make sure that LieI exchange of
compound 2b was successful before embarking on cyclization re-
actions. Treatment of a solution of 6-iodo-1-menthoxyhexyne 2b in
hexanes:ethyl ether (3:2 by vol) with 2.2 equiv of n-butyllithium
(n-BuLi) in hexane at ꢀ78 ꢁC cleanly generated the corresponding
alkyllithium 8b and produced, after addition of deoxygenated
methanol, 1-menthoxyhexyne 7b with 90% yield.
Investigation of the anionic cyclization of compound 2b was
then undertaken. Results are gathered in Table 5 (entries 5e8).
With MeOH as electrophile (entry 5), one can see that the isolated
yield was very high 90% (no problems of volatility). No 6-endo cy-
clization product could be detected. This reaction was also per-
formed in hexanes. Here also, yields dropped to ∼0%.
In this case, the starting material not being volatile (compared to
2a), it was thought that the cyclized vinyl anion could be quenched
with electrophiles allowing addition of more versatile low molec-
ular weight moieties. Reaction of cyclized anion 9b with 6 equiv of
DMF led to 70% yield of 10ba (entry 6). Chloroformate quenching of
the isomerized anion produced 68% of the functionalized cyclized
product 10bb (entry 7).
One must note that this very same compound (2b) cyclized,
under radical reaction conditions, with only 20% yield (see Table 3,
entries 3 and 4).
The radical cyclization of iodo ynol ethers has shown some syn-
thetic limitations, mainly due to the instability of the iodoenol ethers
produced. However, it was shown that 5-exo cyclization can be ef-
ficient with 6-iodo-1-ethoxyhexyne. Anionic 5-exo cyclization of
iodo ynol ethers led to exocyclic methylene compounds with yields
ranging from good to excellent. Functionalization of cyclized vinyl-
lithiums produced interesting difunctionalized exomethylenes. At-
tempts to cyclize 7-iodo-1-alkoxyheptyne in a 6-exo fashion were
not efficient.
This method represents a novel strategy for the synthesis of
functionalized five-membered ring carbocycles. In particular, it
represents a rare entry into the formation of functionalized
alkoxyalkylidenes. Via hydrolysis of the latter, this method is also
a new entry to the synthesis of cyclopentane carboxaldehydes.
4. Experimental procedures
4.1. General
All reactions requiring anhydrous conditions were conducted
under positive nitrogen atmosphere in oven-dried glassware and
the reaction flasks were fitted with rubber septa for the in-
troduction of substrates and reagents via standard syringe tech-
niques. All solvents were distilled prior to use, except for anhydrous
tetrahydrofuran (THF) that was used as received from Sigma-
eAldrich (SureSeal). Alkyllithium solutions were purchased from
SigmaeAldrich and titrated prior to use (diphenylacetic acid end-
point in dry THF). Tributyltin hydride, ethoxyacetylene (40% in
hexanes), and triethylborane (1 mol/L in hexane) were also pur-
chased from SigmaeAldrich and used as received. Flash chroma-
tography was performed on triethylamine pretreated Merck silica
gel 60 (0.040e0.063 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 treated with
triethylamine. 1H NMR were recorded on a Varian 200 MHz NMR
As for compound 6a, the possibility of transforming in situ
compound 6b to cyclopentane carboxaldehyde was tested (Table 5,
entry 8). Following the same procedure as described above, iodo
ynol ether 2b was transformed into the desired carboxaldehyde
with 77% yield.
2.3.3. Compound 2c. First, it was confirmed that LieI exchange of
2c was efficient using the above described method (BuLi ꢀ78 ꢁC
and quench with MeOH; yield of 7c¼89%). The reaction was re-
peated and the alkyllithium was allowed to warm to room tem-
perature in order for cyclization to occur. After 2.5 h, deoxygenated
MeOH was added. Since volatility was again a problem here, an

R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
97
spectrometer using CDCl3 (
as the reference. 13C NMR were recorded at 50.3 MHz using CDCl3
¼77.1 ppm) or CD3COCD3 ¼30.6 ppm) as the reference. NMR
d
¼7.26 ppm) or CD3COCD3 (
d
¼2.09 ppm)
following solution was added: 25 mmol of diiodoalkane (diiodo-
butane or diiodopentane) in 5.4 mL of THF. The cooling bath was
removed and stirred at room temperature for 24 h under nitrogen
atmosphere. The solution was then treated with 15 mL of water. The
layers were separated. The aqueous phase was extracted thrice
with hexanes. The combined organic layers were successively
washed with water and brine, and dried over anhydrous MgSO4.
Crude product was then purified with flash chromatography using
hexanes as eluent.
(d
(d
data are reported as follows: chemical shifts in parts per million,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, td¼triplet
of doublets, m¼multiplet), number of protons, and coupling con-
stants in hertz. IR spectra were recorded on a Nicolet Impact 420
spectrophotometer. Gas chromatographydlow resolution mass
spectra (GC-LRMS) were recorded on an Agilent model 6890 N.
HRMS were recorded on an Agilent HPLC model 1200 using a TOF
6210 detector.
4.3.1. 6-Iodo-1-menthoxyhexyne (2b). Yellowish oil; 90% yield; FTIR
(NaCl, nmax, cmꢀ1): 2960, 2930, 2875, 2258, 1448, 1100, 945, 895,
Products 6a,6 6c,18e20 and 7c21 are known compounds and show
identical analytic data to reported data in the literatures. Analytical
data of product 7a were identical to those of an authentic sample
(obtained from Aurora Fine Chemicals). Products 5a, 5b, and 5c
were not sufficiently stable to allow HRMS characterization.
840; 1H NMR (CDCl3,
d ppm): 0.75e1.22(m, 16H), 1.30e1.70(m, 4H),
1.92(m, 2H), 2.17(m, 2H), 3.2(t, J¼7.0 Hz, 2H), 3.85(m, 1H); 13C NMR
(CDCl3,
d ppm): 6.8, 16.6, 16.7, 20.9, 22.3, 23.5, 26.1, 30.6, 31.1, 32.8,
34.3, 37.4, 39.9, 47.0, 87.2, 88.6; HRMS: calcd for C16H27IO: 362.1107;
found: 362.1100.
4.2. General procedure for the syntheses of iodo ethoxy
alkynes
4.3.2. 7-Iodo-1-menthoxyheptyne (2d). Colorless oil; 45% yield;
FTIR (NaCl, nmax, cmꢀ1): 2976, 2932, 2867, 2263, 1451, 1383, 1113; 1H
n-BuLi (6.9 mmol, dissolved in hexanes, freshly titrated with
diphenylacetic acid) was added dropwise at ꢀ78 ꢁC under nitrogen
atmosphere to a solution containing 6.16 mmol of EtOC^CH 40% in
hexanes and 7 mL of THF. After stirring for 1 h, 13.55 mmol of HMPA
was added and the solution was stirred for another 15 min. A so-
lution of 4.93 mmol of diiodoalkane (diiodobutane or diiodo-
pentane) in 1 mL of THF was then added. The cooling bath was
removed and the solution was stirred at room temperature over-
night. The reaction mixture was then heated at 45 ꢁC for 3 h. Once
the reaction mixture had cooled to room temperature, 10 mL of
water was added. After stirring for 30 min, the organic layer was
separated. The aqueous phase was extracted twice with diethyl
ether. The organic layers were combined, washed with brine, and
dried over anhydrous MgSO4. Crude product was then purified with
flash chromatography using hexanes as eluent.
NMR (CDCl3, d ppm): 0.75e1.22(m, 16H), 1.40(m, 4H),1.50e1.95(m,
2H), 2.00e2.12(m, 4H), 3.15(t, J¼7.0 Hz, 2H), 3.70(m, 1H); 13C NMR
(CDCl3,
d ppm): 6.8, 16.6, 16.7, 20.9, 22.3, 23.5, 26.1, 28.1, 30.6, 31.1,
32.8, 34.3, 38.1, 39.9, 47.0, 87.0, 88.2; HRMS: calcd for C17H29IO:
376.1263; found: 376.1253.
4.4. General procedure for radical cyclization of iodo alkoxy
alkynes in absence of Bu3SnH
In a 25 mL round-bottomed flask, 0.42 mmol of iodo alkoxy
alkyne (2aed) was dissolved in 5.4 mL of solvent. The flask was
secured with a septum through which a needle was inserted (to let
O2 activate the Et3B initiator). At this point, depending on selected
conditions (see Tables 1e5), the reaction mixture was maintained
at room temperature or at 40 ꢁC. 0.126 mmol of Et3B (1 M in hex-
anes) was added every 15 min for the first 6 h of reaction. After the
required reaction time (see Tables 1e5), the solvent was removed in
vacuo while the flask was maintained below 5 ꢁC. The compound
was rapidly purified by flash chromatography using pentane as
eluent.
4.2.1. 6-Iodo-1-ethoxyhexyne (2a). Colorless oil; 75% yield; FTIR
(NaCl, nmax, cmꢀ1): 2974, 2933, 2878, 2248, 1443, 1388; 1H NMR
(CDCl3,
d
ppm): 1.25(t, J¼7.0 Hz, 3H), 1.45(m, 2H), 1.90(m, 2H), 2.15
(t, J¼7.0 Hz, 2H), 3.15(t, J¼7.0 Hz, 2H), 4.0(q, J¼7.0 Hz, 2H); 13C NMR
(CDCl3, d ppm): 6.9, 14.6, 16.5, 30.5, 32.7, 36.7, 74.1, 90.0; LRMS (m/z,
relative intensity): 252 (Mþ, 100); HRMS: calcd for C8H13IO:
252.0011; found: 252.0018.
4.5. General procedure for radical cyclization of iodo alkoxy
alkynes in presence of Bu3SnH
4.2.2. 7-Iodo-1-ethoxyheptyne (2c). Colorless oil; 89% yield; FTIR
(NaCl, nmax, cmꢀ1): 2963, 2944, 2868, 2264, 1456, 1380, 1232, 1032,
In a 25 mL round-bottomed flask, 0.42 mmol of iodo alkoxy
alkyne (2aed) was dissolved in 5.4 mL of solvent. The flask was
secured with a septum through which a needle was inserted (to let
O2 activate the Et3B initiator). At this point, depending on selected
conditions (see Tables 1e5), the reaction mixture was cooled to
ꢀ78 ꢁC or maintained at room temperature. Bu3SnH (0.108 mmol)
and 0.126 mmol of Et3B (1 M in hexanes) were added. Aliquots of
Bu3SnH (0.108 mmol) were added every hour for the first 4 h of
reaction. Et3B (0.126 mmol) was added every 15 min for the first 6 h
of reaction. After the required reaction time (see Tables 1e5),
diethyl ether (10e20 mL) was added. DABCO (1.26 mmol, 0.14 g;
2 equiv of DABCO per equivalent of Bu3SnH) was then added. The
reaction mixture was titrated with an iodine solution (0.1 M in
ether) until persistence of the iodine brown coloration. The solu-
tion was then poured on a 1 cm pad of SiO2 and eluted with diethyl
ether (30 mL). The solvents were removed using rotary evaporation
while the flask was maintained below 5 ꢁC. The compound was
rapidly purified by flash chromatography using pentane as eluent.
880; 1H NMR (CDCl3,
d
ppm): 1.25(t, J¼5.8 Hz, 3H), 1.48(m, 4H), 1.80
(m, 2H), 2.11(t, J¼4.6 Hz, 2H), 3.15(t, J¼7.0 Hz, 2H), 4.00(q, J¼5.8 Hz,
2H); 13C NMR (CDCl3,
d ppm): 7.2, 14.6, 17.3, 28.7, 29.9, 33.3, 37.1,
74.1, 89.8; LRMS (m/z, relative intensity): 266 (Mþ, 100); HRMS:
calcd for C9H15IO: 266.0168; found: 266.0162.
4.3. General procedure for the syntheses of iodo menthoxy
alkynes
At room temperature and under nitrogen atmosphere,
12.5 mmol of menthol in 25 mL of THF was added dropwise to
a solution containing 24.4 mmol of oil-free KH suspended in 25 mL
of THF. When hydrogen evolution had ceased, the reaction mixture
was cooled to ꢀ50 ꢁC and 12.5 mmol of TCE dissolved in 15 mL of
THF was slowly added. Once the addition was completed, the
cooling bath was removed and the solution was stirred for 1 h at
room temperature. The reaction mixture was then cooled to ꢀ78 ꢁC
and a freshly titrated solution of BuLi (30.0 mmol) was added
dropwise. After stirring for 30 min at ꢀ78 ꢁC and 30 min at ꢀ50 ꢁC,
40.5 mmol of HMPA was added. After stirring for 15 min, the
4.5.1. (Ethoxyiodomethylene)cyclopentane (5a). Yellowish oil; 85%
NMR yield, 4% isolated yield; unstable, decomposes before com-
plete characterization; FTIR (NaCl, nmax, cmꢀ1): 2975, 2868, 2928,

98
R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
1664,1455, 1384, 1109; 1H NMR (acetone-d6,
d
ppm): 0.90(t,
The reaction mixture was stirred 2.5 h at room temperature in or-
der for the cyclization to occur. The cyclized vinyllithium solution
was cooled to ꢀ78 ꢁC and an excess of electrophile (typically
6 equiv, see Table 5) was added. After the addition, the cooling bath
was removed and the reaction mixture was stirred at room tem-
perature for 4 h.
J¼7.0 Hz, 3H), 1.30(t, J¼5.8 Hz, 4H), 2.10(m, J¼5.8 Hz, 4H), 4.00(q,
J¼7.0 Hz, 2H); LRMS (m/z, relative intensity): 252 (5).
4.5.2. (Menthoxyiodomethylene)cyclopentane (5b). Yellowish oil;
20% NMR yield, 5% isolated yield; unstable, decomposes before
complete characterization; FTIR (NaCl, nmax, cmꢀ1): 2982, 2855,
2941,1661,1448,1377,1101; 1H NMR (acetone-d6,
d
ppm): 0.70e1.05
4.7.1. 1-Cyclopentylidene-1-ethoxy-2,4-dimethylpentan-2-ol
(10aa). At ꢀ78 ꢁC, the vinyllithium solution, prepared as described
above, was treated with 6 equiv of anhydrous methyl isobutyl ke-
tone. The cooling bath was removed and the solution was stirred for
2 h at room temperature. The reaction mixture was poured into
2 mL of water. The layers were separated. The aqueous layer was
extracted twice with diethyl ether. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, and evap-
orated in vacuo. The crude product was purified with flash chro-
matography using hexaneseacetone 99:1 as eluent; colorless oil;
70% yield (43 mg); FTIR (NaCl, nmax, cmꢀ1): 3350, 2932, 2853,1656,
(m, 9H), 1.20e1.40(m, 6H), 1.45e1.70(m, 5H), 1.90e2.15(m, 2H),
2.20e2.33(m, 4H), 3.68 (m, 1H); LRMS (m/z, relative intensity): 362
(5).
4.5.3. (Ethoxyiodomethylene)cyclohexane (5c). Colorless oil; 78%
NMR yield, 45% isolated yield (72 mg); slightly more stable than 5a,
13C NMR could be recorded, HRMS could not be recorded; FTIR
(NaCl, nmax, cmꢀ1): 2985, 2925, 2862, 1642,1470, 1378, 1029; 1H
NMR (acetone-d6,
d
ppm): 0.88(t, J¼7.0 Hz, 3H), 1.20e1.50(m, 6H),
2.10(t, J¼5.6 Hz, 4H), 4.00(q, J¼7.0 Hz, 2H); 13C NMR (acetone-d6,
d
ppm): 13.6, 13.9, 17.0, 22.2, 57.0, 73.8, 89.5; LRMS (m/z, relative
1456, 1384; 1H NMR (CDCl3,
(m, 7H), 1.45e1.80(m, 5H), 2.00e2.42(m, 6H), 4.01(q, J¼4.0 Hz, 2H);
13C NMR (CDCl3,
ppm): 17.8, 17.9, 19.1, 20.8, 25.9, 26.6, 27.1, 30.3,
d ppm): 0.80e1.00(m, 6H), 1.10e1.41
intensity): 266 (80).
d
4.6. General procedure for dehalogenation of iodo alkoxy
hexynes (LieI exchange assessment)
39.0, 63.4, 76.6, 117.8, 135.9; LRMS (m/z, relative intensity): 226
(Mþ, 100); HRMS: calcd for C14H26O2: 226.1933; found: 226.1934.
A 0.1 M solution of 0.27 mmol iodo ynol ether (2aed) in hex-
anes-Et2O was deoxygenated by bubbling N2 for 5 min. The mixture
was cooled to ꢀ78 ꢁC. A solution of freshly titrated n-BuLi in hex-
anes (0.57 mmol) was added dropwise. The solution was stirred for
10 more minutes at ꢀ78 ꢁC and 2e3 mL of deoxygenated methanol
was added in order to quench the uncyclized alkyllithium. The
reaction mixture was poured on 2 mL of water. The layers were
separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and evaporated in vacuo. The crude prod-
uct (7aed) was purified with flash chromatography using hexanes
as eluent.
Compound 7a was obtained in 90% yield. Analytical data of this
compound were identical to those of an authentic sample (obtained
from Aurora Fine Chemicals). Compound 7c was obtained in 89%
yield. This compound is a known compound and showed identical
analytic data to reported data in the literature.21
4.7.2. 2-Cyclopentylidene-2-ethoxy-1-phenylethanol(10ab). At ꢀ78 ꢁC,
the vinyllithium solution, prepared as described above, was treated
with 2 equiv of anhydrous benzaldehyde. The cooling bath was re-
moved and the solutionwas stirred overnight at room temperature. The
reaction mixture was poured on 2 mL of water. The layers were sepa-
rated. The aqueous layer was extracted twice with diethyl ether. The
combined organic layers were successively washed with 3ꢂ8 mL
NaHSO3 8%, water and brine, dried over anhydrous MgSO4, and evap-
orated in vacuo. The crude product was purified with flash chroma-
tography using hexaneseacetone 99.5:0.5 as eluent; colorless oil; 71%
yield (45 mg); FTIR (NaCl, nmax, cmꢀ1): 3350, 3060, 3023, 2959,
2927,2844, 1656, 1597,1491, 1464, 1384; 1H NMR (CDCl3,
0.90e1.60(m, 7H), 2.03e2.20(m, 5H), 4.02(q, J¼4.0 Hz, 2H), 5.20(s, 1H),
7.32e7.59(m, 3H), 8.00e8.12(m, 2H); 13C NMR (CDCl3,
ppm): 19.2,
d ppm):
d
20.7, 25.4, 30.1, 30.2, 64.1, 70.6, 118.9, 127.8, 128.4, 128.6, 137.1, 153.7;
HRMS: calcd for C15H20O2: 232.1463; found: 232.1463.
4.7.3. (Menthoxymethylene)cyclopentane (6b). At ꢀ78 ꢁC, the
vinyllithium solution, prepared as described above, was quenched
with 1.62 mmol of deoxygenated and anhydrous MeOH. The cool-
ing bath was removed and the solution was stirred for 30 min at
room temperature. The reaction mixture was poured into 2 mL of
water. The layers were separated. The aqueous layer was extracted
twice with diethyl ether. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, and evaporated in vacuo.
The crude product was purified with flash chromatography using
4.6.1. 1-Menthoxyhexyne (7b). Colorless oil; 90% yield; FTIR (NaCl,
nmax, cmꢀ1): 2957, 2928, 2864, 2262, 1455; 1H NMR (CDCl3,
d ppm):
3.69 (td, J¼4.7 and 10.9 Hz, 1H), 2.05e2.30 (m, 4H), 1.65 (m, 2H),
1.30e1.50 (m, 6H), 1.00e1.22 (m, 2H), 0.80e0.96 (m, 13H); 13C NMR
(CDCl3, d ppm): 13.6, 16.3, 17.0, 20.6, 21.9, 22.2, 23.3, 25.8, 31.6, 32.0,
34.1, 38.0, 39.6, 46.8, 86.8, 87.9; HRMS: calcd for C16H28O: 236.2140;
found: 236.2139.
4.6.2. 1-Menthoxyheptyne (7d). Colorless oil; 91% yield; FTIR (NaCl,
hexanes as eluent; colorless oil; 90% yield (57 mg); FTIR (NaCl, nmax
,
nmax, cmꢀ1): 2955, 2926, 2865, 2266, 1456; 1H NMR (CDCl3,
d
ppm):
cmꢀ1): 3477, 2959, 2859,1684, 1456, 1384; 1H NMR (CDCl3,
d
ppm):
3.69 (td, J¼4.3 and 10.5 Hz, 1H), 2.07e2.28 (m, 4H), 1.61e1.68 (m,
0.70e1.05(m, 9H), 1.20e1.40(m, 6H), 1.45e1.71(m, 5H), 1.90e2.10
2H), 1.01e1.50 (m, 10H), 0.80e0.96 (m, 13H); 13C NMR (CDCl3,
(m, 2H), 2.11e2.35(m, 4H), 3.32(m, 1H), 6.02 (s, 1H); 13C NMR
d
ppm): 14.0, 16.3, 17.3, 20.6, 22.0, 22.2, 23.3, 25.8, 29.6, 31.1, 31.6,
(CDCl3, d ppm): 16.2, 21.8, 23.7, 26.0, 26.5, 29.4, 31.8, 34.7, 41.8, 48.0,
34.1, 38.1, 39.6, 46.8, 86.8, 87.9; HRMS: calcd for C17H30O: 250.2297;
found: 250.2294.
54.1, 81.1, 120.2, 136.5; LRMS (m/z, relative intensity): 236 (Mþ,
100); HRMS: calcd for C16H28O: 236.2140; found: 236.2131.
4.7. General procedure for anionic cyclization of iodo alkoxy
hexynes and functionalization of the resulting vinyllithium
4.7.4. (Menthoxycarboxaldehydemethylene)cyclopentane (10ba). At
ꢀ78 ꢁC, the vinyllithium solution, prepared as described above, was
treated with 6 equiv of anhydrous DMF. The cooling bath was re-
moved and the solution was stirred for 3.5 h at room temperature.
The reaction mixture was poured into 2 mL of water. The layers
were separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and evaporated in vacuo. The crude
A 0.1 M solution of 0.27 mmol iodo ynol ether in hexaneseEt2O
was deoxygenated by bubbling N2 for 5 min. The mixture was
cooled to ꢀ78 ꢁC. A solution of freshly titrated n-BuLi in hexanes
(0.57 mmol) was added dropwise. The solution was stirred for 10
more minutes at ꢀ78 ꢁC and then the cooling bath was removed.

R. Hanna, B. Daoust / Tetrahedron 67 (2011) 92e99
99
product was purified with flash chromatography using hex-
aneseacetone 95:5 as eluent; yellowish oil; 70% yield (50 mg); FTIR
(NaCl, nmax, cmꢀ1): 2959, 2859, 2720,1720, 1675, 1456, 1390; 1H
maintained at 0 ꢁC. Comparison of NMR signals of this crude ma-
terial with the commercially available cyclopentane carbox-
aldehyde confirmed the structure of cyclopentane carboxaldehyde.
The crude mixture revealed a 71% NMR yield starting with 2a and
a 77% NMR yield starting with 2b.
NMR (CDCl3,
1.45e1.85(m, 7H), 1.90e2.01(m, 4H), 4.00(m, 1H), 9.75(s, 1H); 13C
NMR (CDCl3, ppm): 16.5, 21.4, 23.9, 26.5, 26.8, 30.1, 31.4, 36.1, 41.8,
d ppm): 0.70e1.03(m, 9H), 1.05e1.43(m, 6H),
d
48.4, 55.1, 85.4, 136.0, 148.9, 195.1; HRMS: calcd for C17H28O2:
264.2089; found: 264.2077.
4.9. NMR yields
In an NMR tube, the crude addition mixture and a known
quantity of diphenylmethane (internal standard) were dissolved in
CDCl3. The yield was obtained by comparing the integration of the
CH2 signal of diphenylmethane (3.9 ppm) with the integration of
the ethoxy CH2 signal for products 5a, 5c, 6a, and 7c (∼4.0 ppm) or
with the R2CHOalkynyl signal for compound 5b (3.3 ppm).
4.7.5. (Carboethoxymenthoxymethylene)cyclopentane
(10bb). At
ꢀ78 ꢁC, the vinyllithium solution, prepared as described above, was
treated with 6 equiv of anhydrous ClCO2Et. The cooling bath was
removed and the solution was stirred for 2.5 h at room tempera-
ture. The reaction mixture was poured on 2 mL of water. The layers
were separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and evaporated in vacuo. The crude prod-
uct was purified with flash chromatography using hex-
aneseacetone 99:1 as eluent; colorless oil; 68% yield (56 mg); FTIR
(NaCl, nmax, cmꢀ1): 2932, 2853, 1734,1656, 1456, 1384; 1H NMR
Acknowledgements
Acknowledgements is made to the Natural Sciences and Engi-
neering Council of Canada for financial support.
(CDCl3,
d ppm): 0.81e1.09(m, 9H), 1.20e1.42(m, 9H), 1.60e1.78(m,
References and notes
5H), 1.82e2.00(m, 2H), 2.11e2.20(m, 4H), 3.68(m, 1H), 4.23(q,
J¼7.0 Hz, 2H); 13C NMR (CDCl3,
d ppm): 15.1, 16.4, 21.3, 24.6, 26.1,
1. Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1989, 111, 6265.
2. Curran, D. P.; Kim, D. Tetrahedron 1991, 47, 6171.
3. Bailey, W. F.; Ovaska, T. V. J. Am. Chem. Soc. 1993, 115, 3080.
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27.3, 30.5, 31.3, 36.0, 43.2, 50.0, 55.1, 61.3, 85.4, 128.7, 141.9, 165.1;
HRMS: calcd for C19H32O3: 308.2351; found: 308.2358.
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A 0.1 M solution of 0.27 mmol iodo ynol ether (2a or 2b) in
hexanes-Et2O was deoxygenated by bubbling N2 for 5 min. The
mixture was cooled to ꢀ78 ꢁC. A solution of freshly titrated n-BuLi
in hexanes (0.57 mmol) was added dropwise. The solution was
stirred for 10 more minutes at ꢀ78 ꢁC and then the cooling bath
was removed. The reaction mixture was stirred 2 h at room tem-
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added and the reaction mixture was stirred for another 30 min at
room temperature. To this solution were added 1e2 drops of 35%
perchloric acid. The reaction mixture was stirred for 18 h at room
temperature, diluted with ether, and quenched with 5% NaHCO3.
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concentrated by rotary evaporation with a bath temperature
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