Stereochemistry of the cyclization of alkoxy-substituted 5-hexenyllithiums: Effect of solvent and lithium iodide on diastereoselectivity

Article abstract of DOI:10.1016/j.tet.2005.01.042

The stereochemistry of the cyclization of 4-methoxy-5-hexenyllithium, 4-(methoxymethoxy)-5-hexenyllithium, 4-tert-butoxy-5-hexenyllithium, and 3-methoxy-5-hexenyllithium, each of which was generated from the corresponding iodide by low-temperature lithium-iodine exchange, has been studied in a variety of solvent systems. The results of these studies demonstrate that the stereochemical outcome of the cyclizations of alkoxy-substituted 5-hexenyllithiums may be profoundly affected by the medium in which the ring closures are conducted. The etiology of these often dramatic solvent effects is attributed to the ability of certain lithiophilic ligands to competitively complex the lithium iodide salt that is present as a co-product from the exchange reaction used to prepare the organolithiums.

Full text of DOI:10.1016/j.tet.2005.01.042

Tetrahedron 61 (2005) 3183–3194
Stereochemistry of the cyclization of alkoxy-substituted
5-hexenyllithiums: effect of solvent and lithium iodide
on diastereoselectivity
†
*
William F. Bailey and Xinglong Jiang
Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA
Received 18 September 2004; revised 5 November 2004; accepted 6 January 2005
Abstract—The stereochemistry of the cyclization of 4-methoxy-5-hexenyllithium, 4-(methoxymethoxy)-5-hexenyllithium, 4-tert-butoxy-5-
hexenyllithium, and 3-methoxy-5-hexenyllithium, each of which was generated from the corresponding iodide by low-temperature lithium–
iodine exchange, has been studied in a variety of solvent systems. The results of these studies demonstrate that the stereochemical outcome of
the cyclizations of alkoxy-substituted 5-hexenyllithiums may be profoundly affected by the medium in which the ring closures are conducted.
The etiology of these often dramatic solvent effects is attributed to the ability of certain lithiophilic ligands to competitively complex the
lithium iodide salt that is present as a co-product from the exchange reaction used to prepare the organolithiums.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
is capable of intramolecular coordination to the lithium
atom of the substrate.5,6 In this connection, some time ago
we reported the initial results of an investigation of the
cyclization of 4-methoxy-5-hexenyllithium (1), which was
generated from the corresponding iodide (2) by low-
temperature lithium–iodine exchange.7 Quite unexpectedly,
the stereochemical outcome of the cyclization of this
prototypical alkoxy-substituted 5-hexenyllithium was
found to be dramatically dependent on the solvent system
in which the isomerization was conducted. For example, as
illustrated below, the ring closure of 1 is highly trans-
selective (viz., trans/cis ratio z20/1) in an ether–hydro-
carbon medium but it is cis-selective (viz., cis/trans ratio
z4/1) when conducted in the presence of TMEDA.7
Control experiments confirmed that these product ratios
reflect the stereoselectivities of kinetically controlled
cyclizations. At the time these observations were reported,
it was tentatively suggested that lithiophilic Lewis base
additives, such as TMEDA and THF, affect the stereo-
chemistry of the cyclization of 1 by sequestration of the LiI
generated in the course of the exchange reaction used to
prepare 1.7 Herein, we report the results of a more
detailed study of the effect of solvent on the stereochemical
course of ring closure of alkoxy-substituted 5-hexenyl-
lithiums. As detailed below, the stereochemistry of the
cyclization of such 5-hexenyllithiums is highly solvent
dependent and the etiology of these solvent effects appears
to be related to the presence of LiI in the reaction medium
(Scheme 2).
The cyclization of unsaturated organolithiums provides a
regiospecific and highly stereoselective route to
functionalized carbocyclic1 and heterocyclic ring systems.2
The diastereoselectivity that characterizes the 5-exo ring
closure of substituted 5-hexenyllithiums is a consequence of
a chair-like transition state, shown below, in which the
lithium atom is intramolecularly coordinated with the
remote p-bond and a substituent preferentially occupies a
pseudoequatorial position.3 It might be noted that the
ground state of 5-hexenyllithium is also essentially that of a
cyclohexane chair (Scheme 1).4
Scheme 1.
One might anticipate that the stereochemistry of the
cyclization of a 5-hexenyllithium bearing a heteroatomic
substituent may be more involved if the heteroatomic group
Keywords: Organolithiums; Cyclization; Stereochemistry.
* Corresponding author. Tel.: C1 860 486 2163; fax: C1 860 486 2981;
e-mail: william.bailey@uconn.edu
† Present address: Novartis Pharmaceuticals Corp., Process Research and
Development, East Hanover, NJ 07936, USA.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.042

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W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
Scheme 2.
lithiums bearing heteroatomic groups at the C(2) position:
prior work had demonstrated that such species would
undergo rapid b-elimination to give 1,5-hexadiene.9 Simi-
larly, placement of a heteroatomic substituent at C(5) was
avoided; ring-closure of such species would invariably lead
to expulsion of the heteroatomic group with formation of
methylenecyclopentene.9
The 5-hexenyllithiums were generated, as described below,
from the corresponding iodides by low-temperature
lithium–iodine exchange.10 The preparation of 6-iodo-3-
methoxy-1-hexene (2)7 has been previously reported; the
remaining iodides were prepared as illustrated in Scheme 3
using standard synthetic routes detailed in Section 4.
Authentic samples of the trans- and cis-isomers of the
products expected from the cyclization of the substituted
5-hexenyllithiums (1, 5–7) were prepared in a similar
fashion from pure trans-2-methylcyclopentanol,11,7 pure
cis-2-methylcyclopentanol,12,7 or a mixture of trans- and
cis-3-methylcyclopentanol.
Figure 1. Substituted 5-hexenyllithiums.
2. Results and discussion
A representative set of 5-hexenyllithiums, depicted in
Figure 1,8 bearing an ethereal oxygen substituent at the
C(3) or C(4) position were selected for this exploratory
investigation. No effort was made to prepare 5-hexenyl-
Scheme 3.

W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
3185
Scheme 4.
2.1. 4-Methoxy-5-hexenyllithium
(Scheme 4) by allowing solutions of the organolithium,
generated from 2 in diethyl ether, n-pentane–diethyl ether
mixtures, or pure n-pentane, to warm and stand (normally at
0 8C) for 1 h before quench with an excess of deoxygenated
MeOH. The ability to generate 1 from 2 in n-pentane
deserves comment: pure n-pentane is not recommended as a
generally useful solvent for the lithium–iodine exchange
reaction; indeed, no exchange is observed when simple
alkyl iodides are treated with t-BuLi at low temperature in
pure hydrocarbon solution.10 Typically, the exchange
reaction is conducted in a solvent system containing an
ether in which the t-BuLi reagent is predominantly
dimeric.10 Apparently, the CH3O group in 2 (and in the
other alkoxy-substituted substrates discussed below) serves
to disaggregate the t-BuLi allowing a normal exchange in
hydrocarbon solution.
As illustrated in Scheme 4, 4-methoxy-5-hexenyllithium (1)
was generated by treatment of iodide 2 with 1.75 molar
equiv of t-BuLi, rather than the full 2 molar equiv of the
reagent typically employed for the exchange.10 As we have
previously noted, it is necessary to use less than an optim0al
quantity of t-BuLi in order to minimize the fairly rapid S N
addition of excess t-BuLi to 1 (and other 5-hexenyllithiums
such as 5 and 6 that bear a leaving group at the allylic
position) leading to consumption of 1 and formation of 2,2-
dimethyl-4-octene.7 Unfortunately, when less than 2 equiv
of t-BuLi is used, a quantity of tert-butyl iodide cogenerated in
the exchange remainsinthe reactionmixture and this serves as
a proton source leading to inadvertent quench of 1 to give
3-methoxy-1-hexene. As a result, the yield of 1 from the
reactionof2with1.75 equivoft-BuLiislessthanquantitative.
The proportions of trans- and cis-(2-methoxycyclopentyl)-
methyllithium formed upon kinetically controlled ring
Be that as it may, the ring closure of 1 was investigated
Table 1. Cyclization (Scheme 4) of 4-methoxy-5-hexenyllithium (1)a
Entry
Solvent system
Temp, 8C
Products, % yieldb
12
3C4
trans (3)/cis (4)c
d
1
2
3
4
5
6
7
8
n-C5H12
0
0
0
0
0
60.8
78.1
31.0
25.1e
12.1
49.0
14.6
36.0
22.2
18.3g
5.9
39.1
21.9
69.0
63.7
88.1
47.8
85.4
65.4
74.5
73.6
94.1
88.0
60.0
2.9
3.1
4.3
4.6
7.7
19.8
8.2
11.1
0.25
0.34
0.18
0.43
8.5
n-C5H12–Et2O 49:1 by vol
19:1 by vol
9:1 by vol
3:2 by vol
3:2 by vol
K20
0
1:1 by vol
Et2O
0
0
20
18
0
9
TMEDAf
10
11
12
13
TMEDAf
TMEDAh
1,4-dioxanei
n-C5H12–Et2O 3:2 by vol C LiIj
12.2
!1k
0
a 4-Methoxy-5-hexenyllithium (1) was generated at K78 8C by addition of 1.75 equiv of t-BuLi to a solution of iodide 2 in either n-pentane–diethyl ether, pure
diethyl ether, or pure n-pentane. Where indicated, TMEDA or 1,4-dioxane was added at K78 8C, the cooling bath was then removed, and the mixture was
allowed to stand at the specified temperature for 1 h before the addition of an excess of oxygen-free methanol.
b Yields were determined by capillary GC using n-heptane as internal standard and correction for detector response.
c Ratio of trans- (3) and cis-1-methoxy-2-methylcyclopentane (4).
d Following the exchange, the mixture was filtered at K78 8C through a short column packed with dry, basic alumina and then allowed to warm and stand at
0 8C for 1 h; analysis of the aqueous phase for iodide following quench of the reaction mixture revealed that 5% of the original amount of LiI remained in the
reaction mixture.
e Product mixture contained 8% of 2,2-dimethyl-4-octene.
f
TMEDA (1.75 molar equiv) was added to a solution of 1 in n-C5H12–Et2O (3:2 by vol) and the mixture was allowed to warm and stand at the specified
temperature for 1 h.
g Product mixture contained 4% of 2,2-dimethyl-4-octene.
h TMEDA (1.75 molar equiv) was added to a solution of 1 in n-C5H12–Et2O (3:2 by vol) at K78 8C, the mixture was filtered through a short column packed
with dry, basic alumina and then allowed to warm and stand at C18 8C for 1 h; analysis of the aqueous phase for iodide following quench of the reaction
mixture revealed that 7% of the original amount of LiI remained in the reaction mixture.
i
1,4-Dioxane (3.0 molar equiv) was added to a solution of 1 in n-C5H12–Et2O (3:2 by vol) at K78 8C, the mixture was allowed to warm and stand at 0 8C for
1 h.
LiI (4.0 molar equiv; generated by treatment tert-butyl iodide with t-BuLi at K78 8C), was added to the reaction mixture at K78 8C and the reaction mixture
was then allowed to warm and stand at 0 8C for 1 h.
j
k Product mixture contained 40% of 2,2-dimethyl-4-octene.

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W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
closure of 1 were assayed as trans- and cis-1-methoxy-2-
methylcyclopentane (3 and 4, respectively) by capillary GC
using n-heptane as internal standard. The effect of TMEDA
and 1,4-dioxane on the stereochemistry of the cyclization of
1 was investigated in a separate series of experiments in
which these additives were added at K78 8C to solutions of
1 prior to warming of the organolithium. The results of these
experiments are summarized in Table 1.
impediment. If this rationale is correct, addition of excess
LiI to the reaction medium should result in a more trans-
selective cyclization. Conversely, removal of LiI from the
reaction mixture would favor cyclization via A (Scheme 5)
and lead to higher proportion of the cis-product. The results
of the experiments summarized in Table 1 are fully
consistent with these expectations.
Addition of 4.0 molar equiv of LiI (generated by adding
t-BuLi to tert-butyl iodide at K78 8C) to a solution of 1 in
n-pentane–diethyl ether (3:2 by vol) followed by warming
the reaction mixture to 0 8C afforded more trans-1-
methoxy-2-methylcyclopentane (trans (3)/cis (4)Z8.5)
than the reaction conducted under identical conditions but
in the absence of added LiI (trans (3)/cis (4)Z7.7; Table 1,
cf. entries 5 and 13). Removal of lithium iodide from the
reaction mixture proved to be a more difficult proposition.
The data presented in Table 1, along with those presented in
our initial report,7 demonstrate that the stereochemistry of
the cyclization of 1 depends rather strongly on the medium.
The ring closure is trans-selective in n-pentane, in pentane–
diethyl ether mixtures, and in pure diethyl ether (Table 1,
entries 1–8); as noted previously,7 this trans-selectivity can
be substantial at lower temperatures (Table 1, entry 6).
Significantly, the trans-selectivity increases monotonically
as the proportion of diethyl ether in the solvent increases: at
0 8C, the trans (3)/cis (4) ratio, which is 2.9 in pure pentane
(Table 1, entry 1), increases to 11.1 in pure ether (Table 1,
entry 8). The presence of 1.75 molar equiv of TMEDA or
3.0molarequivof1,4-dioxane inareactionmixture composed
primarily of n-pentane–diethyl ether (3:2 by vol) renders the
cyclization cis-selective (Table 1, entries 9–12). These results
are perhaps best discussed with reference to the two
stereochemically distinct modes of ring closure possible for
chair-like conformations of 1 (Scheme 5, RZCH3).
Various Lewis bases, such as TMEDA and 1,4-dioxane,
form stable complexes with lithium halides.14,15 Indeed,
addition of TMEDA at K78 8C to solutions of 1 generated
by lithium–iodine exchange in n-pentane–diethyl ether
affords a precipitate. Thus, filtration of the reaction mixture
at a low temperature (to minimize cyclization during the
filtration) should serve to remove at least a portion of the LiI
as the TMEDA complex and lead to a higher proportion of
cis-isomer in the product mixture. As shown by the results
summarized in Table 1 removal of the TMEDA–LiI
precipitate by filtration through a pad of meticulously dry,
basic alumina leads to an increase in the amount of cis-
product (Table 1, entry 11; trans (3)/cis (4)Z0.18) relative
to the outcome of a similar experiment conducted without
filtration (Table 1, trans (3)/cis (4)Z0.34). It should be
noted that the precipitate recovered by filtration of the
TMEDA-containing reaction mixtures had a melting point
(mpZ242–243 8C) identical to that reported by White for
the [(TMEDA)LiI]2 complex (lit.15 mpZ242–245 8C). That
such filtration was effective for removal of LiI was
confirmed by analysis of the aqueous phase for iodide
following quench of reaction mixtures. The Volhard
method16 was used to quantitate the amount of iodide
remaining after filtration: an excess standard aqueous silver
nitrate solution was added to the aqueous layer and the
excess silver nitrate was titrated with standard sodium
thiocyanate using iron (III) as an indicator. This analysis
demonstrated that filtration of the reaction mixture to which
1.75 equiv of TMEDA had been added (Table 1, entry 11)
served to remove 93% of the LiI.
Scheme 5.
Formation of the cis-isomer (4) requires that the allylic
CH3O group occupy a pseudoaxial position and intra-
molecular coordination of the lithium atom with the
proximal oxygen might be expected to stabilize such an
arrangement (Scheme 5, A). The trans-isomer arises from
cyclization of a species bearing a pseudoequatorial CH3O
group (Scheme 5, B). It is well known that organolithiums
co-associate with lithium halides and it is likely, given the
method used to prepare 1, that it exists as an aggregate
containing the co-generated LiI.13 We have previously
noted that intraaggregate coordination of the 4-OCH3 group
with LiI may disrupt the intramolecular Li–O coordination
depicted in structure A (Scheme 5) and have suggested that
Lewis base additives, such as TMEDA and 1,4-dioxane,
affect the stereochemistry of the cyclization of 1 by
sequestering the LiI generated in the exchange reaction.7
In short, LiI acts as an impediment to cis-selective
cyclization; preferential formation of a complex between
LiI and a Lewis base may simply serve to remove this
Although lithium iodide has a reasonable solubility in
diethyl ether, it is essentially insoluble in n-pentane. Thus,
an increase in the pentane–ether solvent ratio should lead to
a decrease in the trans/cis product ratio because the lithium
iodide will be less soluble in such a solvent system. These
expectations were confirmed by a series of experiments,
noted above and summarized in Table 1 (entries 1–8); the
trans (3)/cis (4) product ratio decreased from a high of 11.1
in pure diethyl ether (Table 1, entry 8) to a low of 2.9 in pure
n-pentane (Table 1, entry 1). The low solubility of lithium
iodide in n-pentane at K78 8C allowed removal of the
lithium iodide by filtration of the reaction mixture (Table 1,
entry 1) prior to warming to 0 8C. Quantitative analysis of
the aqueous phase following quench of the reaction mixture

W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
3187
Scheme 6.
revealed that 95% of the lithium iodide had been removed
by the filtration.
Inspection of Table 2 reveals that the cyclization of 5 is less
trans-selective in a given solvent system than is cyclization
of 4-methoxy-5-hexenyllithium (1). A model similar to that
proposed to account for the stereochemistry of the
cyclization of 1 may be constructed to account for these
observations (Scheme 5, RZCH2OCH3). The presence of
two potential sites for intramolecular coordination of the Li
atom with the acetal oxygens of the MOM group in the axial
conformation of 5 (Scheme 5, A) may well provide
additional stabilization relative to the analogous confor-
mation of 1 and lead to a higher proportion of cis-product
than is observed in the cyclization of the 4-methoxy analog.
In accord with the results noted above for the 4-methoxy
system, sequestration of LiI by addition of a complexing
agent such as TMEDA (Table 2, entry 5) or 1,4-dioxane
(Table 2, entry 6) results in a cis-selective cyclization of 5.
The experiments outlined above and summarized in Table 1
seem to support the hypothesis that Lewis base additives
remove lithium iodide from the reaction medium. The cis-
selectivity observed for cyclizations conducted in the
presence of TMEDA and 1,4-dioxane is probably a result
of both the sequestering of LiI by the Lewis base as well as
stabilization of the transition state leading to the cis-isomer
(Scheme 5, A).
2.2. 4-(Methoxymethoxy)-5-hexenyllithium
It was of interest to see if additional oxygen atoms in an
ether group at the allylic position of 5-hexenyllithium would
affect the stereochemistry of the cyclization. To this end, the
cyclization of 4-(methoxymethoxy)-5-hexenyllithium (5)
was investigated (Scheme 6). Treatment of iodide 9 with
1.75 equiv of t-BuLi in n-pentane–diethyl ether (3:2 by
volume) at K78 8C, following the same procedure as that
used to prepare 1, afforded 5; addition of deoxygenated
MeOH to the cold reaction mixture gave a quantitative yield
of 3-methoxymethoxy-1-hexene (15). When warmed to an
appropriate temperature, 5 cyclizes to deliver trans- (13)
and cis-1-(methoxymethoxy)-2-methylcyclopentane (14)
after quench of the reaction mixture. The stereochemistry
of the cyclization of 5 was investigated under a variety of
experimental conditions. The results of these studies are
summarized in Table 2. As was the case for the cyclization
of 1, the stereochemical outcome of isomerization of
4-(methoxymethoxy)-5-hexenyllithium (5) depends upon
the solvent system.
2.3. 4-tert-Butoxy-5-hexenyllithium
4-tert-Butoxy-5-hexenyllithium 6 was chosen for study in
order to investigate the influence of a bulky ether group at
C(4) on the stereochemistry of the cyclization. The
organolithium was generated (Scheme 7) from iodide 10
and 1.75 equiv of t-BuLi. When allowed to warm and stand
at an appropriate temperature, 6 undergoes cyclization to
give trans- (16) and cis-1-tert-butoxy-2-methylcyclo-
pentane (17) after quench of the reaction mixture with
MeOH. Here again, as demonstrated by the data sum-
marized in Table 3, the stereochemical outcome of the ring
closure is solvent dependent.
A remarkable and quite surprising feature of the cyclization
of 6 is its extraordinary diastereoselectivity: the cis-isomer
(17) is the major product of the ring-closure under all
Table 2. Cyclization (Scheme 6) of 4-(methoxymethoxy)-5-hexenyllithium (5)a
Entry
Solvent system
Temp, 8C
Products, % yieldb
15
13C14
trans (13)/cis (14)c
1
2
3
4
5
6
n-C5H12
20
22
K30
20
23
42.9
18.3
82.7
21.0
19.9
26.3
57.1
81.6
17.3
78.1
80.0
70.2
1.5
2.1
4.1
1.9
0.20
0.60
n-C5H12–Et2O 3:2 by vol
3:2 by vol
Et2O
TMEDAd
1,4-dioxanee
23
a 4-(Methoxymethoxy)-5-hexenyllithium (5) was generated at K78 8C by addition of 1.75 equiv of t-BuLi to a solution of iodide 9 in either n-pentane–diethyl
ether, pure diethyl ether, or pure n-pentane. Where indicated, TMEDA or 1,4-dioxane was added at K78 8C, the cooling bath was then removed, and the
mixture was allowed to stand at the specified temperature for 1 h before the addition of an excess of oxygen-free methanol.
b Yields were determined by capillary GC using n-heptane as internal standard and correction for detector response.
c Ratio of trans- (13) and cis-1-(methoxymethoxy)-2-methylcyclopentane (14).
d TMEDA (1.75 molar equiv) was added to a solution of 5 in n-C5H12–Et2O (3:2 by vol) and the mixture was allowed to warm and stand at 23 8C for 1 h.
e 1,4-Dioxane (3.0 molar equiv) was added to a solution of 5 in n-C5H12–Et2O (3:2 by vol) at K78 8C, the mixture was allowed to warm and stand at 23 8C for 1 h.

3188
W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
Scheme 7.
Table 3. Cyclization (Scheme 7) of 4-tert-butoxy-5-hexenyllithium (6)a
Entry
Solvent system
Temp, 8C
Products, % yieldb
16C17
18
cis (17)/trans (16)c
1
2
3
4
5
6
n-C5H12
20
26
0
K10
0
K10
40.0
40.0
28.3
30.5
28.1
28.5
60.0
60.0
71.7
69.5
71.8
71.5
1.5
3.4
3.5
2.3
20.8
23.8
n-C5H12–Et2O 3:2 by vol
3:2 by vol
3:2 by vol
TMEDAd
TMEDAd
a 4-tert-Butoxy-5-hexenyllithium (6) was generated at K78 8C by addition of 1.75 equiv of t-BuLi to a solution of iodide 10 in either n-pentane–diethyl ether
or pure n-pentane. Where indicated, TMEDA was added at K78 8C, the cooling bath was then removed, and the mixture was allowed to stand at the specified
temperature for 1 h before the addition of an excess of oxygen-free methanol.
b Yields were determined by capillary GC using n-heptane as internal standard and correction for detector response.
c Ratio of cis- (17) and trans-1-tert-butoxy-2-methylcyclopentane (16).
d TMEDA (1.75 molar equiv) was added to a solution of 6 in n-C5H12–Et2O (3:2 by vol) and the mixture was allowed to warm and stand at the specified
temperature for 1 h.
conditions investigated (Table 3). Such highly cis-selective
cyclization of a simple, monosubstituted 5-hexenyllithium
is, to our knowledge, unprecedented.1 Addition of 1.75
molar equiv of TMEDA serves to significantly enhance the
cis-preference (Table 3, cf. entries 3 and 5; 4 and 6). The
effect of TMEDA on the stereochemistry of the cyclization
of 6 is all the more dramatic when one compares the
modestly cis-selective isomerization of 4-methoxy-5-
hexenyllithium (1) at K20 8C in the presence of TMEDA
(cis/transZ4.0)7 with the almost exclusive production of
cis-1-tert-butoxy-2-methylcyclopentane (17) when the
cyclization of 6 is conducted at K10 8C in the presence of
TMEDA (Table 3, entry 6; cis (17)/trans (16)Z23.8).
simple solution to this apparent dilemma, which is
consistent with the results presented above, would posit
that intermolecular co-association between the alkoxy-
substituted 5-hexenyllithium and the LiI present in the
reaction medium is inherently less important for the large
tert-butoxy group in 6 than it is for the smaller methoxy or
MOM groups in 1 and 5, respectively. In short, the sterically
demanding tert-butyl group in 6 may well inhibit inter-
molecular association of the organolithium with LiI while
having little effect on the entropically favorable intra-
molecular Li–O interaction that stabilizes the pseudoaxial
conformation of 6.
For comparison purposes, the radical-mediated cyclization
of 10 was investigated in benzene solution at 80 8C
(Scheme 8). As expected,17 but in striking contrast to the
cis-selective cyclization of 6, ring-closure of the radical
derived from iodide 10 gave trans-1-tert-butoxy-2-methyl-
cyclopentane (16) as the major product (trans (16)/cis
(17)Z8.1).
If one assumes that 6 cyclizes via the chair-like transition
state adopted by the parent 5-hexenyllithium, the formation
of a preponderance of cis-1-tert-butoxy-2-methylcyclo-
pentane (17) requires that the tert-butoxy group preferen-
tially adopt a pseudoaxial position in the activated complex
leading to ring closure. Given that the ground state of
5-hexenyllithium is also essentially chair-like, these results
suggest that intramolecular coordination of the Li atom at
C(1) with the pseudoaxial tert-butoxy group at C(4) in the
ground state of 6 (Scheme 5, RZC(CH3)3) provides
sufficient stabilization of this arrangement to more than
compensate for the steric interactions that customarily
dictate a pseudoequatorial orientation of the substituent.
The obvious difficulty is this: why is the cyclization of 6,
with a bulky 4-tert-butoxy group, so much more cis-
selective than are ring closures of seemingly analogous
4-methoxy- (1) and 4-MOM-5-hexenyllithium (5)? A
Scheme 8.

W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
3189
Scheme 9.
2.4. 3-Methoxy-5-hexenyllithium
of a cis-rich mixture of cis- (20) and trans-1-methoxy-3-
methylcyclopentane (19) was obtained (Table 4, entry 1).
High yields of cyclized product (19C20) were obtained
only when the isomerization of 7 was conducted in the
presence of TMEDA. These cyclizations invariably gave a
cis-rich product mixture (Table 4) but the addition of
TMEDA does not substantially alter the isomeric compo-
sition of the product mixture (Table 4, cf. entries 1 and 2).
Intramolecular coordination of lithium with a proximate
oxygen is thought to be particularly effective when it can
occur via a five-membered ring.5 To explore how such
coordination might affect the stereochemistry of the
cyclization of a substituted 5-hexenyllithium, the behavior
of 3-methoxy-5-hexenyllithium (7) was studied. Organo-
lithium 7 was generated (Scheme 9) from iodide 11 in
diethyl ether, n-pentane–diethyl ether mixtures, or pure
n-pentane solution at K78 8C. It should be noted that a full
2.2 molar equiv of t-BuLi was used to produce 7; the
nettlesome S0N reaction that plagues the exchange reaction
with substrates bearing an allylic leaving group is not a
concern in this case.
It is tempting to ascribe the modestly cis-selective
cyclization of 7 to ring closure via a conformation having
a pseudoequatorial 3-methoxy group (Scheme 10, C). This
picture is qualitatively similar to that advanced to account
for the cis-selective ring closures of 3-alkyl-substituted
5-hexenyllithiums.3 However, the cyclization of 7 is
considerably less stereoselective than are the seemingly
analogous 3-alkyl-substituted isomerizations3 and the
model does not account for the fact that the cyclization of
7 is much slower than are cyclizations of 3-alkyl-substituted
5-hexenyllithiums.18 Moreover, this simple rationale for the
cis-selectivity ignores the potential effects of strong
intramolecular coordination of a 3-OCH3 group with the
Li atom at C(1) via a five-membered ring. Such coordination
is depicted in Scheme 10 (structures D and E). Insofar as
5-exo ring closure of a 5-hexenyllithium requires associ-
ation of the Li atom with the olefinic p-bond, the
simultaneous intramolecular coordination of the Li atom
with both the 3-methoxy group and the olefinic moiety,
which would lead to cis-product (20), resembles a boat-like
Addition of deoxygenated MeOH to solutions of 7 at
K78 8C gives a quantitative yield of 4-methoxy-1-hexene
(21). When warmed, 7 cyclizes to deliver trans- (19) and
cis-1-methoxy-3-methylcyclopentane (20) after quench of
the reaction mixture. However, there are two interesting
features of the cyclization of 7 that were initially surprising:
(1) the streochemical course of the cyclization of 7 is much
less sensitive to the medium in which the reaction is
conducted (Table 4) than are the cyclizations of 1, 5, and
6 discussed above, and; (2) the cyclization of 7 is
unexpectedly slow in the absence of TMEDA. Indeed,
when a solution of 7 in n-pentane–diethyl ether (3:2 by vol)
was allowed to warm and stand at 23 8C for 1 h, only w27%
Table 4. Cyclization (Scheme 9) of 3-methoxy-5-hexenyllithium (7)a
Entry
Solvent system
Temp, 8C
Products, % yieldb
21
19C20
cis (20)/trans (19)c
1
2
3
4
5
6
7
8
n-C5H12–Et2O 3:2 by vol
TMEDAd
23
23
10
0
K10
K20
21
73.2
2.0
8.0
7.4
11.8
80.7
!1
21.0
26.7
98.0
92.0
92.6
88.1
19.3
99
5.3
2.6
2.3
2.3
2.1
4.0
2.2
2.4
TMEDAd
TMEDAd
TMEDAd
TMEDAd
Et2OCTMEDA
n-C5H12CTMEDA
0
79.0
a 4-Methoxy-5-hexenyllithium (7) was generated at K78 8C by addition of 2.20 equiv of t-BuLi to a solution of iodide 11 in either n-pentane–diethyl ether,
pure diethyl ether, or in pure n-pentane. Where indicated, TMEDA (2.20 molar equiv) was added at K78 8C, the cooling bath was then removed, and the
mixture was allowed to warm and stand at the specified temperature for 1 h before the addition of an excess of oxygen-free methanol.
b Yields were determined by capillary GC using n-heptane as internal standard and correction for detector response.
c Ratio of cis- (20) and trans-1-methoxy-3-methylcyclopentane (19).
d n-Pentane–diethyl ether (3:2 by vol) was used.

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W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
Scheme 10.
arrangement of atoms (Scheme 10, E). Moreover, this
scenario nicely accounts for the sluggish nature of the
isomerization of 7 since the activation energy for ring
closure via a boat-like activated complex would presumably
be higher than that for a chair-like transition state.
4. Experimental
4.1. General procedures
General spectroscopic and chromatographic procedures,
methods used for the purification of reagents and solvents,
and precautions regarding the manipulation of organo-
lithiums have been previously described.3,7,19 The concen-
tration of commercial solutions of t-BuLi in n-heptane was
determined immediately prior to use by the method of
Watson and Eastham.20
3. Conclusion
The results presented above demonstrate that the stereo-
chemical outcome of the cyclization of 4-alkoxy substituted
5-hexenyllithiums may be profoundly affected by the
medium in which the ring closures are conducted. The
cyclization of 4-methoxy- (1) and 4-(methoxymethoxy)-5-
hexenyllithium (5), each of which provides a trans-rich
mixture of products when the cyclization is conducted in
n-pentane, diethyl ether, or a pentane–ether mixture, is
rendered cis-selective in the presence of a lithiophilic Lewis
base such as TMEDA or 1,4-dioxane. The cyclization of
4-tert-butoxy-5-hexenyllithium (6), which is cis-selective
under all conditions studied, affords a exceedingly high
proportion of cis-1-tert-butoxy-2-methylcyclopentane (17)
when conducted at K10 8C in the presence of TMEDA (cis/
transZ23.8). The kinetically sluggish ring closure of
3-methoxy-5-hexenyllithium (7) is moderately cis-selective
in a variety of media.
The preparations of 6-iodo-3-methoxy-1-hexene (2),
3-methoxy-1-hexene (12), trans-1-methoxy-2-methylcyclo-
pentane (3), cis-1-methoxy-2-methylcyclopentane (4),
1-hexen-3-ol, trans-2-methylcyclopentanol, and cis-2-
methylcyclopentanol have been previously described.7
Literature procedures, incorporating some minor modifi-
cations, were followed for the preparation of 6-chloro-1-
hexen-3-ol21 and 3-[(tetrahydro-2H-pyran-2-yl)oxy]-
propanal.22
4.1.1. 6-Chloro-3-(methoxymethoxy)-1-hexene.
A
mixture of 2.00 g (14.8 mmol) of 6-chloro-1-hexen-3-ol21
and 3.0 g of phosphorus pentoxide in 87 mL of dry
chloroform and 87 mL of dry dimethoxymethane was
stirred at room temperature for 3 h. The reaction mixture
then was poured into 100 mL of cold, half-saturated,
aqueous sodium carbonate and the black oil remaining in
the flask was rinsed with the aqueous sodium carbonate. The
aqueous layer was extracted with three 60-mL portions of
diethyl ether, the ethereal layer was washed with brine,
dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (20% Et2O–hexanes, RfZ
0.77) to afford 2.40 g (91%) of the title compound as a
The etiology of these often dramatic solvent effects is
attributed to the ability of certain Lewis bases, such as
TMEDA and 1,4-dioxane, to competitively complex the
lithium iodide salt generated as a co-product from the
exchange reaction used to prepare the organolithiums.
Sequestration of the LiI salt through preferential complexa-
tion with an added ligand is thought to favor intramolecular
association of the lithium atom with a pseudoaxial 4-alkoxy
substituent leading to a cis-selective closure.
1
colorless oil: H NMR d 1.66–1.73 (m, 2H), 1.79–1.90 (m,

W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
3191
2H), 3.34 (s, 3H), 3.54 (t, JZ6.9 Hz, 2H), 3.98–4.01 (m,
1H), 4.50 and 4.67 (AB, JABZ6.7 Hz, 2H), 5.16–5.23 (m,
2H), 5.58–5.65 (m, 1H); 13C NMR d 28.5, 32.6, 44.8,
55.4, 76.5, 93.8, 117.4, 137.9; HRMS calcd for C7H13ClO
(MC–CH2O) m/z 148.0655, found m/z 148.0651.
923 cmK1. Anal. Calcd for C8H16O2: C, 66.63; H, 11.18.
Found: C, 66.34; H, 10.81.
4.1.5. cis-1-(Methoxymethoxy)-2-methylcyclopentane
(17). A mixture of 1.00 g (10.0 mmol) of cis-2-methyl-
cyclopentanol7,12 and 2.0 g of phosphorus pentoxide in
60 mL of dry chloroform and 60 mL of dry dimethoxy-
methane was stirred at room temperature for 3 h. The
reaction mixture then was poured into 50 mL of ice-cold,
half-saturated aqueous sodium carbonate and the black oil
remaining in the flask was rinsed with aqueous sodium
carbonate. The aqueous layer was extracted with 30-mL
portions of diethyl ether, the ethereal layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (10% Et2O–hexanes, RfZ
0.74) to afford 1.30 g (88%) of the title compound as a
colorless oil: 1H NMR d 0.99 (d, JZ6.6 Hz, 3H), 1.67–1.76
(m, 7H), 3.34 (s, 3H), 3.91–3.93 (m, 1H), 4.57 and 4.65
(AB, JABZ6.7 Hz, 2H); 13C NMR d 13.9, 21.8, 31.1, 31.4,
38.5, 55.1, 80.7, 95.2; IR (neat) 2954, 1457, 1368, 1147,
923 cmK1; HRMS calcd for C8H16O2 m/z 144.1150, found
m/z 144.1149.
4.1.2. 6-Iodo-3-(methoxymethoxy)-1-hexene (9). A
solution of 3.00 g (16.8 mmol) of 6-chloro-3-(methoxy-
methoxy)-1-hexene and 5.55 g (36.9 mmol) of dried sodium
iodide in 60 mL of dry acetone was heated at gentle reflux
overnight under an atmosphere of argon. Inorganic salts
were removed by filtration, the solid was washed well with
acetone, and the combined filtrate and the washings were
concentrated at reduced pressure. The residue was taken up
in diethyl ether and the solution was washed with 5% of
aqueous sodium thiosulfate, and dried over MgSO4. The
solution was concentrated at reduced pressure and the
residue was purified by flash chromatography on silica gel
(20% Et2O–hexanes, RfZ0.37) to afford 4.00 g (88%) of the
title iodide as a colorless oil: 1H NMR d 1.60–1.69 (m, 2H),
1.86–1.94 (m, 2H), 3.18 (t, JZ6.9 Hz, 2H), 3.34 (s, 3H),
3.97–4.00 (m, 1H), 4.49 and 4.66 (AB, JABZ6.8 Hz, 2H),
5.15–5.22 (m, 2H), 5.57–5.68 (m, 1H); 13C NMR d 6.4,
29.4, 36.1, 55.5, 76.2, 93.8, 117.4, 137.9; IR (neat) 3077,
2939, 1641, 1436, 1226, 733 cmK1; HRMS calcd for
C7H13IO (MC–CH2O) m/z 240.0011, found m/z 240.0009.
4.1.6. 3-tert-Butoxy-6-chloro-1-hexene. Isobutene gas was
bubbled through a mixture of 9.20 g (68.0 mmol) of
6-chloro-1-hexen-3-ol21 and 5.00 g of Amberlyst-15w in
40 mL of dry hexane. After the reaction was complete, the
mixture was filtered, the filtrate washed with hexane, and
500 mg of anhydrous K2CO3 was added. Solvent was
removed at reduced pressure and the crude product was
purified by flash chromatography on silica gel (hexane, RfZ
0.76) to afford 11.0 g (85%) of the title compound as a
4.1.3. 3-(Methoxymethoxy)-1-hexene (15). A mixture of
1.00 g (10.0 mmol) of 1-hexen-3-ol7 and 2.0 g of phosphor-
ous pentoxide in 60 mL of dry chloroform and 60 mL of dry
dimethoxymethane was stirred at room temperature for 3 h.
The reaction mixture then was poured into 100 mL of ice-
cold, half-saturated, aqueous sodium carbonate and the
black oil remaining in the flask was rinsed with aqueous
sodium carbonate. The aqueous layer was extracted with
30-mL portions of diethyl ether, the ethereal layer was
washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by
flash chromatography on silica gel (10% Et2O–hexanes,
1
colorless oil: H NMR d 1.20 (s, 9H), 1.55–1.60 (m, 2H),
1.73–1.86 (m, 2H), 3.54 (t, JZ6.5 Hz, 2H), 3.92–3.95 (m,
1H), 4.99–5.16 (m, 2H), 5.73–5.86 (m, 1H); 13C NMR d
28.7, 28.9, 34.5, 45.2, 72.4, 74.0, 113.9, 142.3; HRMS calcd
for C6H11ClO (MC–C4H8) m/z 134.0498, found m/z
134.0497.
RfZ0.70) to afford 1.30 g (90%) of the known product:23 1
H
NMR d 0.90 (t, JZ7.1 Hz, 3H), 1.34–1.60 (m, 4H), 3.35 (s,
3H), 3.96–3.98 (m, 1H), 4.51 and 4.86 (AB, JABZ6.7 Hz,
2H), 5.13–5.20 (m, 2H), 5.58–5.71 (m, 1H); 13C NMR d
13.9, 18.6, 37.6, 55.3, 77.2, 93.7, 116.9, 138.6.
4.1.7. 3-tert-Butoxy-6-iodo-1-hexene (10). A solution of
1.00 g (5.25 mmol) of 3-tert-butoxy-6-chloro-1-hexene and
1.73 g (11.5 mmol) of dried sodium iodide in 20 mL of dry
dimethoxymethane was heated at gentle reflux overnight
under an atmosphere of argon. The mixture was cooled,
filtered by suction, and the solid was washed with DME.
The filtrate and washings were concentrated under reduced
pressure and the residue was extracted with several portions
of diethyl ether until it was white. The ethereal extract was
washed with 5% aqueous sodium thiosulfate, dried over
MgSO4, and concentrated. The crude iodide was purified by
flash chromatography on silica gel (5% Et2O–hexanes, RfZ
0.15) to afford 1.04 g (70%) of the title compound as a
4.1.4. trans-1-(methoxymethoxy)-2-methylcyclopentane
(16). A mixture of 1.00 g (10 mmol) of trans-2-methyl-
cyclopentanol7,11 and 2.0 g of phosphorus pentoxide in
60 mL of dry chloroform and 60 mL of dry dimethoxy-
methane was stirred at room temperature for 3 h. The
reaction mixture then was poured into 50 mL of ice-cold,
half-saturated aqueous sodium carbonate and the black oil
remaining in the flask was rinsed with aqueous sodium
carbonate. The aqueous layer was extracted with 30-mL
portions of diethyl ether, the ethereal layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (10% Et2O–hexanes, RfZ
0.65) to afford 1.10 g (77%) of the title compound as a
colorless oil: 1H NMR d 1.00 (d, JZ6.7 Hz, 3H), 1.68–1.77
(m, 7H), 3.32 (s, 3H), 3.82–3.84 (m, 1H), 4.54 and 4.62
(AB, JABZ6.7 Hz, 2H); 13C NMR d 19.1, 22.8, 32.2, 32.8,
39.5, 56.1, 81.6, 97.0; IR (neat) 2954, 1457, 1368, 1147,
1
colorless oil: H NMR d 1.18 (s, 9H), 1.51–1.56 (m, 2H),
1.88–1.93 (m, 2H), 3.17 (t, JZ6.6 Hz, 2H), 3.91–3.94 (m,
1H), 4.99–5.15 (m, 2H), 5.72–5.85 (m, 1H); 13C NMR d 7.1,
28.7, 29.8, 38.0, 72.0, 74.1, 113.9, 142.2; IR (neat) 3075,
2971, 1642, 1428, 1364, 1227, 730 cmK1; HRMS calcd for
C6H11IO (MC–C4H8) m/z 225.9855, found m/z 225.9850.
4.1.8. 3-tert-Butoxy-1-hexene (18). Isobutylene gas was
bubbled through a mixture of 2.00 g (20.0 mmol) of
1-hexen-3-ol7 and 2.00 g of Amberlyst-15w in 13 mL of

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W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
dry hexane. After the reaction was complete, the mixture
was filtered, the filtrate washed with hexane, and 500 mg of
anhydrous K2CO3 was added. Solvent was removed at
reduced pressure and the crude product was purified by flash
chromatography on silica gel (hexane, RfZ0.39) to afford
2.77 g (88%) of the title compound: 1H NMR d 0.88 (t, JZ
6.9 Hz, 3H), 1.17 (s, 9H), 1.18–1.40 (m, 4H), 3.87–3.89 (m,
1H), 4.95–5.12 (m, 2H), 5.74–5.86 (m, 1H); 13C NMR d
14.1, 18.9, 28.7, 39.6, 72.9, 73.8, 113.2, 143.0; IR (neat)
3076, 2970, 1641, 1463, 1365, 1197, 1019, 681 cmK1. Anal.
Calcd for C10H20O: C, 76.86; H, 12.90. Found: C, 76.46; H,
12.55.
62.5, 65.7, 65.9, 69.7, 70.3, 98.8, 99.0, 117.2, 117.3, 134.1,
134.9.
A stirred suspension of 3.50 g (146 mmol) of oil-free
sodium hydride in 60 mL of dry THF was heated to w50 8C
and a solution of 7.70 g (38.5 mmol) of the 6-[(tetrahydro-
2H-pyran-2-yl)oxy]-1-hexene-4-ol
and
3.62 mL
(58.1 mmol) of methyl iodide in 20.0 mL of dry THF was
added dropwise over a 45 min period. The resulting mixture
was heated at to w50 8C for an additional 1H, then cooled in
an ice-bath, and 10 mL of water was added. The resulting
mixture was extracted several times with diethyl ether, the
combined extracts were washed with brine, dried (MgSO4)
and concentrated to give an oil which was purified by flash
chromatography on silica gel (10% EtOAc–hexanes, RfZ
0.42) to afford 7.00 g (85%) of 4-methoxy-6-[(tetrahydro-
2H-pyran-2-yl)oxy]-1-hexene: 1H NMR d 1.47–1.81 (m,
8H), 2.24–2.28 (m, 2H), 3.31 (s, 3H), 3.34–3.39 (m, 2H),
3.77–3.84 (m, 2H), 4.54 (t, JZ5.1 Hz, 1H), 5.01–5.08 (m,
2H), 5.73–5.83 (m, 1H); 13C NMR d 19.6, 25.5, 30.7, 33.8,
37.9, 56.6, 62.2, 64.1, 77.5, 98.7, 117.7, 134.6.
4.1.9. trans-1-tert-Butoxy-2-methylcyclopentane (16).
Isobutylene gas was bubbled through a mixture of 0.50 g
(5.0 mmol) of trans-2-methylcyclopentanol7,11 and 1.00 g
of Amberlyst-15w in 8.0 mL of dry hexane. After the
reaction was complete, the mixture was filtered, the filtrate
washed with hexane, and 500 mg of anhydrous K2CO3 was
added. Solvent was removed at reduced pressure and the
crude product was purified by flash chromatography on
silica gel (hexane, RfZ0.19) to afford 0.66 g (85%) of the
1
The pH of a solution of 13.0 g (65.0 mmol) of 4-methoxy-6-
[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexene in 200 mL of
ethyl alcohol was adjusted to w3 by the dropwise addition
of 0.1 M aqueous hydrochloric acid. The resulting solution
was heated at reflux for 50 min, allowed to cool to room
temperature, and then poured into 25 mL of water and
extracted with diethyl ether. The ethereal extract was dried
(MgSO4), concentrated under reduced pressure, and the
residue was purified by flash chromatography on silica gel
(20% Et2O–hexanes, RfZ0.16) to give 8.00 g (95%) of the
title compound as a colorless oil: 1H NMR d 1.65–1.76 (m,
2H), 2.23–2.35 (m, 2H), 2.83 (br s, 1H), 3.33 (s, 3H), 3.37–
3.47 (m, 1H), 3.70 (t, JZ6.1 Hz, 2H), 5.01–5.08 (m, 2H),
5.65–5.89 (m, 1H); 13C NMR d 35.7, 37.4, 56.5, 60.5, 79.9,
117.3, 134.1; IR (neat) 3400, 3073, 2932, 1637, 1436, 1359,
1087 cmK1. Anal. Calcd for C7H14O2: C, 64.58; H, 10.84.
Found: C, 64.22; H, 10.66.
title product as a colorless oil: H NMR d 0.95 (d, JZ
6.6 Hz, 3H), 1.15 (s, 9H), 1.48–1.79 (m, 7H), 3.37–3.39 (m,
1H); 13C NMR d 17.8, 21.9, 28.7, 31.3, 34.4, 41.3, 72.7,
79.9; IR (neat) 2969, 1462, 1363, 1200, 901 cmK1. Anal.
Calcd for C10H20O: C, 76.86; H, 12.90. Found: C, 76.70; H,
12.63.
4.1.10. cis-1-tert-Butoxy-2-methylcyclopentane (17). Iso-
butylene gas was bubbled through a mixture of 1.00 g
(10.0 mmol) of cis-2-methylcyclopentanol7,12 and 2.00 g of
Amberlyst-15w in 8.0 mL of dry hexane. After the reaction
was complete, the mixture was filtered, the filtrate washed
with hexane, and 500 mg of anhydrous K2CO3 was added.
Solvent was removed at reduced pressure and the crude
product was purified by flash chromatography on silica gel
(hexane, RfZ0.60) to afford 1.35 g (87%) of the title ether
as a colorless oil: 1H NMR d 0.90 (d, JZ6.9 Hz, 3H), 1.15
(s, 9H), 1.37–1.67 (m, 7H), 3.82–3.84 (m, 1H); 13C NMR d
14.5, 21.4, 28.5, 31.6, 33.7, 38.2, 72.6, 74.8; IR (neat) 2968,
1461,1200, 1092, 1054, 900 cmK1. Anal. Calcd for
C10H20O: C, 76.86; H, 12.90. Found: C, 76.41; H, 13.09.
4.1.12. 6-Iodo-4-methoxy-1-hexene (11). Following the
general procedure of Crossland and Servis,24 3.00 g
(23.1 mmol) of 3-methoxy-5-hexene-1-ol was converted to
its mesylate. The crude mesylate was added to a solution of
8.00 g (53.3 mmol) of dry sodium iodide in 80 mL of
acetone and the mixture was stirred at room temperature
under and atmosphere of nitrogen for 10 h and then heated
at gentle reflux for 45 min. Inorganic salts were then
removed by filtration, the solid was washed well with
acetone, and the combined filtrate and washings were
concentrated by rotary evaporation. The residue was taken
up in diethyl ether and the solution was washed with 5%
aqueous sodium thiosulfate solution and dried (MgSO4).
The solution was concentrated under reduced pressure and
the residue was purified by passage through a short column
of activated alumina using pentane as the eluent to give
4.1.11. 3-Methoxy-5-hexen-1-ol. Allylmagnesium chloride
in THF (48.0 mL of a 2.0 M solution, 96 mmol) was added
dropwise at room temperature under an atmosphere of
nitrogen to a solution of 13.0 g (82.3 mmol) of 3-[(tetra-
hydro-2H-pyran-2-yl)oxy]propanal22 in 40 mL of dry THF.
The resulting mixture was heated at gentle reflux for 1H,
then cooled in an ice-bath and cautiously hydrolyzed by
dropwise addition of 10 mL of water followed by 10 mL of
saturated, aqueous K2CO3. The mixture was extracted with
three 30-mL portions of Et2O, the combined ethereal
extracts were dried (MgSO4), concentrated at reduced
pressure, and the residue was purified by flash chromato-
graphy on silica gel (20% EtOAc–hexanes, RfZ0.28) to
give 11.6 g (70%) of 6-[tetrahydro-2H-pyran-2-yl)oxy]-1-
1
5.00 g (90%) of the title iodide as an oil: H NMR d 1.89–
1.97 (m, 2H), 2.23–2.30 (m, 2H), 3.24 (t, JZ7.0 Hz, 2H),
3.36 (s, 3H), 3.28–3.34 (m, 1H), 5.03–5.11 (m, 2H), 5.68–
5.81 (m, 1H); 13C NMR d 2.7, 37.1, 37.8, 57.0, 79.8, 117.5,
133.9; IR (neat) 3062, 2975, 2921, 2823, 1637, 1436, 1354,
1092, 913 cmK1. Anal. Calcd for C7H13OI: C, 35.02; H,
5.46. Found: C, 34.76; H, 5.22.
1
hexen-4-ol: H NMR (two diastereomers) d 1.49–1.77 (m,
8H), 2.19–2.24 (m, 2H), 3.09 (br s, 1H), 3.48–3.60 (m, 2H),
3.79–3.89 (m, 3H), 4.56 (t, JZ4.2 Hz, 1H), 5.03–5.10 (m,
2H), 5.76–5.86 (m, 1H); 13C NMR (two diastereomers) d
19.3, 19.5, 25.2, 30.4, 30.6, 35.8, 35.9, 41.8, 41.8, 62.1,

W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
3193
4.1.13. 4-Methoxy-1-hexene (21). A stirred suspension of
4.3. General procedure for the cyclization of alkoxy-
substituted 5-hexenyllithiums
1.50 g (62.5 mmol) of oil-free sodium hydride in 30 mL of
dry THF was heated to w50 8C under an atmosphere of
nitrogen and a solution of 2.00 g (20.0 mmol) of 1-hexene-
4-ol25 and 2.0 mL (32 mmol) of methyl iodide in 10 mL of
dry THF was added dropwise over a 30 min period. The
resulting mixture was heated at w50 8C for an additional
1 h. The reaction mixture was then cooled in an ice bath and
hydrolyzed by addition of 10 mL of water. The resulting
solution was extracted several times with diethyl ether, the
combined extracts were dried (MgSO4), and solvent was
removed by rotary evaporation. Preparative GC on a 10-ft,
10% FFAP on Chromosorb W NAW (80/100 mesh) column
The organolithiums generated as described above were
treated in one of the following ways. (A) Quench at
K78 8C. Dry, deoxygenated MeOH or MeOD (1.0 mL) was
added to the cold reaction mixture and the cooling bath was
removed. (B) Cyclization at elevated temperatures. The
cooling bath was removed, and the solution was allowed to
warm and stand at the appropriate temperature for 1 h under
a blanket of argon before the addition of 1.0 mL of dry,
deoxygenated MeOH or MeOD. (C) Cyclization in the
presence of additives. The organolithium solution was
maintained at K78 8C under a blanket of argon and the dry,
deoxygenated additive (typically 1.75 molar equiv of
TMEDA or 3.0 equiv of 1,4-dioxane) was added by syringe.
The resulting mixture was stirred for an additional 5 min at
K78 8C, and then allowed to warm and stand at the
appropriate temperature for 1 h under a blanket of argon
prior to the addition of 1.0 mL of dry, deoxygenated MeOH
or MeOD. Reaction mixtures were washed with water, dried
(MgSO4), and analyzed by GC on a 25-m!0.20-mm HP-1
cross-linked methyl silicone fused-silica capillary column
using temperature programming (35 8C for 20 min,
30 8C/min to 250 8C) and by GC–MS on a 25-m!0.20-
mm HP-5 methyl phenyl (20%) silicone fused-silica
capillary column using temperature programming (35 8C
for 20 min, 30 8C/min to 250 8C). Reaction products were
identified by comparison of their GC retention times and
mass spectra with those of authentic samples. All yields
reported in the Tables were corrected for detector response
under the conditions of the analysis using accurately
weighed samples of pure product and standard.
1
at 100 8C afforded 2.00 g (85%) of the ether: H NMR d
0.86 (t, JZ7.4 Hz, 3H), 1.42–1.56 (m, 2H), 2.20–2.25 (m,
2H), 3.07–3.16 (m, 1H), 3.31 (s, 3H), 4.99–5.07 (m, 2H),
5.70–5.86 (m, 1H); 13C NMR d 9.3, 25.8, 37.3, 56.4, 81.6,
116.6, 135.0. Anal. Calcd for C7H14O: C, 73.63; H, 12.36.
Found: C, 73.34; H, 12.68.
4.1.14. trans-(19) and cis-1-Methoxy-3-methylcyclo-
pentane (20). A commercial (Aldrich) sample of cis- and
trans-3-methylcyclopentanol was found to consist of 40%
of the cis-isomer and 60% of the trans-isomer: the isomeric
1
composition was determined by NMR; both H and 13C
NMR of the isomers have been assigned.26 The title ethers
were prepared from this mixture. Thus, a stirred suspension
of 1.50 g (62.5 mmol) of oil-free sodium hydride in 30 mL
of dry THF was heated at w50 8C under an atmosphere of
nitrogen and a solution of 2.00 g (20.0 mmol) of the
isomeric 2-methylcyclopentanols (trans/cisZ3:2) and
2.00 mL (31.9 mmol) of methyl iodide in 15 mL of dry
THF was added dropwise over a 30 min period. The
resulting mixture was heated at w50 8C for an additional
1 h. The reaction mixture was then cooled in an ice bath and
hydrolyzed by addition of 3 mL of water. The resulting
solution was extracted several times with diethyl ether, the
combined extracts were dried (MgSO4), and solvent was
removed by rotary evaporation. Preparative GC on a 10-ft,
10% FFAP on Chromosorb W NAW (80/100 mesh) column
at 100 8C afforded 2.00 g (89%) of a mixture of the trans-
Acknowledgements
This work was supported by the Connecticut Department of
Economic Development. We are grateful to Dr. Terry
Rathman of FMC, Lithium Division, for a generous gift of
t-BuLi in pentane.
1
and cis-isomers of the ether (trans/cisZ3:2): H NMR d
0.94 (d, JZ6.7 Hz, 3H, trans isomer), 1.00 (d, JZ6.5 Hz,
3H, cis isomer), 1.03–2.10 (m, 7H), 3.22 (s, 1H), 3.73–3.79
(m, 1H); 13C NMR d 20.5, 20.8, 31.9, 32.1, 32.3, 32.6, 32.9,
40.7, 41.0, 56.1, 56.4, 83.0. Anal. Calcd for C7H14O: C,
73.63; H, 12.36. Found: C, 73.29; H, 12.40.
References and notes
1. For reviews, see: (a) Bailey, W. F.; Ovaska, T. V. In Advances
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4.2. General procedure for the preparation of 5-
hexenyllithiums by lithium–iodine exchange
The substituted 5-hexenyllithiums (1, 5, 6, and 7) were
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ether mixture containing an accurately weighed quantity of
n-heptane as internal standard was cooled under an argon
atmosphere to K78 8C (acetone-dry ice bath) and 2.20
molar equiv of t-BuLi (1.75 equiv of t-BuLi was used for the
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dropwise via syringe over a period of 5 min. The mixture
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used for subsequent reactions.
2. For a recent review, see: Mealy, M. M.; Bailey, W. F.
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¨
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3194
W. F. Bailey, X. Jiang / Tetrahedron 61 (2005) 3183–3194
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