Sequential ring-closing metathesis/Pd-catalyzed, Si-assisted cross-coupling reactions: General synthesis of highly substituted unsaturated alcohols and medium-sized rings containing a 1,3-cis-cis diene unit

Article abstract of DOI:10.1016/j.tet.2004.06.149

A sequential ring-closing metathesis/silicon-assisted cross-coupling protocol has been developed. Alkenyldimethylsilyl ethers of allylic, homoallylic and bis(homoallylic) alcohols undergo facile ring closure with Schrock's catalyst to afford 5-, 6-, and 7-membered cycloalkenylsiloxanes, respectively, in some cases with substituents on both alkenyl carbons. These siloxanes are highly effective coupling partners that afford styrenes and dienes (with various aryl and alkenyl halides) in high yield and specificity as well as good functional group compatibility. The siloxanes bearing a Z-iodoalkenyl tether undergo an intramolecular coupling process in the presence of [allylPdCl] ₂ which constitutes a powerful method for the construction of medium-sized rings with an internal 1,3-cis-cis diene unit. The formation of 9-, 10-, 11-, and 12-membered carbocyclic dienes is achieved in good yield. Extension to the synthesis of 9-membered ring unsaturated ethers has also been accomplished. Noteworthy features of this process include: (1) highly stereospecific intramolecular coupling, (2) flexible positioning of the revealed hydroxy group, and (3) potential extension to other medium-sized carbocycles and heterocycles. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.06.149

Tetrahedron 60 (2004) 9695–9708
Sequential ring-closing metathesis/Pd-catalyzed, Si-assisted
cross-coupling reactions: general synthesis of highly substituted
unsaturated alcohols and medium-sized rings containing a
1,3-cis–cis diene unit
*
Scott E. Denmark and Shyh-Ming Yang
Department of Chemistry, Roger Adams Laboratory, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801, USA
Received 30 April 2004; revised 8 June 2004; accepted 12 June 2004
Available online 11 September 2004
Abstract—A sequential ring-closing metathesis/silicon-assisted cross-coupling protocol has been developed. Alkenyldimethylsilyl ethers of
allylic, homoallylic and bis(homoallylic) alcohols undergo facile ring closure with Schrock’s catalyst to afford 5-, 6-, and 7-membered
cycloalkenylsiloxanes, respectively, in some cases with substituents on both alkenyl carbons. These siloxanes are highly effective coupling
partners that afford styrenes and dienes (with various aryl and alkenyl halides) in high yield and specificity as well as good functional group
compatibility. The siloxanes bearing a Z-iodoalkenyl tether undergo an intramolecular coupling process in the presence of [allylPdCl]2 which
constitutes a powerful method for the construction of medium-sized rings with an internal 1,3-cis–cis diene unit. The formation of 9-, 10-,
11-, and 12-membered carbocyclic dienes is achieved in good yield. Extension to the synthesis of 9-membered ring unsaturated ethers has
also been accomplished. Noteworthy features of this process include: (1) highly stereospecific intramolecular coupling, (2) flexible
positioning of the revealed hydroxy group, and (3) potential extension to other medium-sized carbocycles and heterocycles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
with respect to both of the addends, and (4) the broad
functional group compatibility.
The formation of carbon–carbon bonds by transition metal-
catalyzed cross-coupling reactions, has evolved into a
general and powerful synthetic method over the past three
decades.1 Among the most notable and commonly
employed procedures are the Suzuki coupling of organo-
boranes, the Stille coupling of organostannanes, and the
Negishi coupling of organozinc compounds. In recent years,
the cross-coupling reactions of organosilicon compounds
have been extensively developed and emerged as an
extremely viable alternative in view of the high chemical
stability, low toxicity, and ease of handling of the
precursors.2,3 A series of reports from these laboratories4
has demonstrated the ability of organosilicon components
(including silacyclobutanes,4a–d silanols,4e,j silyl hydrides,4f
cyclic silyl ethers,4g,k,m,nand even oligosiloxanes4h) to serve
as donors in Pd-catalyzed cross-coupling reactions. The
practical advantages of this process include: (1) the ease of
introduction of the silicon containing moiety, (2) the
mildness of reaction conditions, (3) the stereospecificity
In response to the growing interest in the palladium-
catalyzed cross-coupling reactions, a number of methods are
now available to introduce silicon-based functionality into
molecules.5 The ability to introduce the silicon donor in a
regio- and stereocontrolled fashion is a prerequisite for
stereocontrolled construction of alkenes. This feature of the
method has been demonstrated in the intramolecular
hydrosilylation/cross-coupling4g and intramolecular silyl-
formylation/cross-coupling reactions4m to efficiently and
stereoselectively prepare homoallylic alcohols. In those
studies, a temporary silicon tether was employed to set the
geometry of an exo alkylidenylsiloxane by hydrosilylation
or silylformylation. A recent report by Trost and Ball also
describes an intramolecular endo-dig hydrosilylation cata-
lyzed by a cationic ruthenium complex to afford a
cycloalkenylsiloxane which contains a geometrically
defined alkene in the ring.6 We envisioned an alternative
construction of the cycloalkenylsiloxane that would employ
ring-closing metathesis (RCM) of a vinylsilyl ether of an
unsaturated alcohol to create the cycloalkenylsiloxane in
regio- and stereo-defined form. This cyclic silane could then
participate as a coupling partner in Pd-catalyzed cross-
coupling reactions.
Keywords: Palladium; Cross-coupling; Organosilicon; RCM; Medium-
sized ring.
* Corresponding author. Tel.: C1-217-333-0066; fax: C1-217-333-3984;
e-mail: denmark@scs.uiuc.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.149

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S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
Ring-closing metathesis of 1,u-dienes, catalyzed by Mo or
Ru complexes, has revolutionized the way in which
carbocycles and heterocycles are constructed.7 There are
now several reports of RCM of silicon tethered allylic ethers
that employ Grubbs ruthenium alkylidene complexes 1 as
the catalyst (Fig. 1).8 Synthesis of structurally defined and
functionalized conjugated dienes via silicon-tethered enyne
metathesis with complexes 1 or 2 was also disclosed
recently.9 Moreover, asymmetric RCM of an allylsilyl ether
has attracted attention in recent years by the use of a chiral
Mo-based complex as the catalyst.10 Certain vinylsilanes
are particularly competent substrates for metathesis reac-
tions. For example, trialkoxyvinylsianes undergo cross
metathesis reactions with alkenes upon treatment with
catalyst 2.11 In addition, a 2-trialkoxysilyl-substituted 1,7-
octadiene undergoes ring closure easily to afford the
corresponding 1-trialkoxysilylcycloalkene using complex
2.5g However, RCM of sterically more demanding vinylsilyl
ethers of unsaturated alcohols requires the sterically less
sensitive molybdenum carbene complex 3, developed by
Schrock.12
Scheme 1. Sequential RCM/Pd-catalyzed, Si-assisted cross-coupling
reactions.
carbocycles.16,17 An extension to the synthesis of medium-
sized ring ethers are described as well.
2. Results
2.1. Sequential RCM/Pd-catalyzed, Si-assisted
intermolecular cross-coupling reactions
2.1.1. RCM of olefinic vinylsilyl ethers 4. To test the
feasibility of the overall transformation and to further
explore the influence of tether length (i.e., ring size) and
substituents on the RCM/cross-coupling process, vinylsilyl
Figure 1. Representative catalysts for RCM.
The main goal of the program described herein was the
development of a sequential RCM/Pd-catalyzed, Si-assisted
cross-coupling reaction. The precursor cycloalkenyl-
siloxanes should be easily available by RCM of the
vinylsilyl ether of unsaturated alcohols using Mo-complex
as catalyst. These cyclosiloxanes would, in turn, be
subjected to intermolecular cross-coupling reaction leading
to stereocontrolled preparation of highly substituted alkenyl
alcohols (Scheme 1). If the siloxane product of RCM
contains a suitably disposed electrophile, then the ensuing
intramolecular cross-coupling would afford medium-sized
rings with an internal, 1,3-cis–cis diene unit. The synthesis
of medium-sized rings,13 particularly with a conjugated
diene unit is well known to be challenging because of
unfavorable entropic and enthalpic factors.14 Indeed
palladium-catalyzed intramolecular cross-coupling,
especially the Stille coupling of organostannanes, has
been widely employed for construction of macrocycles
containing an internal diene unit.15 However, the formation
of medium-sized rings with an internal 1,3-diene unit by
intramolecular Stille coupling strategies are scarce.15b
Although significant progress had been recorded in the
intermolecular process, the intramolecular cross-coupling
reactions of organosilanes have yet to be investigated. We
report in full the successful realization of this approach for
the stereocontrolled construction of highly substituted
unsaturated alcohols as well as 9- to 12-membered
Scheme 2. Synthesis of olefinic alkenylsilyl ethers 4.

S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
Table 1. Molybdenum-catalyzed ring-closing metathesis of 4a
9697
Entry
Substrate, n
R1
R2
Catalyst, mol%
Time, h
Product
Yield,b %
1
2
3
4
4a, 0
4b, 1
4c, 1
4d, 1
4e, 1
4f, 2
H
H
H
C6H13
C6H13
H
H
H
Me
H
Me
H
7.0
5.0
8.0
7.0
—
3
1
15
12
—
12
5a
5b
5c
5d
—
5e
89
95
91
90
—
81
5
6c
7.0
a
Reactions were performed in 0.1 M concentration.
Yields of analytically pure materials.
b
c
91% conversion was observed by 1H NMR analysis.
ethers 4 were prepared (Scheme 2). Vinylsilyl ethers 4a–c
and 4f could be readily obtained in good yield (90–92%) by
the addition of organomagensium bromides (or chlorides) to
benzaldehyde followed by silylation of the resulting
alcohols with commercially available chlorodimethylvinyl-
silane. Further, treatment of 1-phenyl-3-buten-1-ol and
1-phenyl-3-methyl-3-buten-1-ol with (1-hexylvinyl)di-
methylchlorosilane (generated in situ from 2-bromo-1-
octene) gave the corresponding alkenylsilyl ethers 4d–e in
66–69% yield.
2.1.2. Pd-catalyzed intermolecular cross-coupling reac-
tions. Optimization of the Pd(0)-catalyzed coupling of
siloxane 5b with 4-iodoacetophenone employed the con-
ditions developed in these laboratories for alkenylsilanols4e
(Table 2). Thus, siloxane 5b was dissolved with a 1.0 M
solution of tetrabutylammonium fluoride (TBAF$3H2O) in
THF at room temperature, followed by the sequential
addition of 4-iodoacetophenone and 5 mol% of Pd(dba)2.
The reaction proceeded cleanly to completion in only
10 min (Table 2, entry 1). Decreasing the loading of
Pd(dba)2 (3 mol%) only marginally affected the rate of the
coupling process (entry 2). However, with a lower catalyst
loading (1.0 mol%, entry 3) or less TBAF (1.0 equiv., entry
4), the reaction did not go to completion and a significant
amount of 4-iodoacetophenone (5 and 19%, respectively)
was recovered.
Initial studies on the RCM reaction of 4b using the Grubbs
alkylidene complex 1 failed; none of the desired product,
5b, was observed by H NMR analysis. All variations in
1
conditions, including change of solvent (CH2Cl2 or
benzene) and/or temperature (rt, 45 or 80 8C) were
unsuccessful. Even the more reactive 1,3-dimesityl-4,5-
dihydroimidazol-2-ylidene-substituted ruthenium complex
2 (‘second generation’ Grubbs catalyst) failed to promote
the RCM reaction.18 Gratifyingly, substrate 4b did undergo
the RCM process by the use of the molybdenum complex 3
as the catalyst.19 After careful optimization, a near
quantitative yield of 5b was obtained with 5 mol% of 3 in
benzene (0.1 M) at ambient temperature (Table 1, entry 2).
With suitable conditions for both reactions in hand, we
turned our attention to expanding the scope of this process
with various aryl iodides. Both the nature and position of
substituents on the aromatic ring were studied under the
Table 2. Optimization of the cross-coupling reaction of 5b with
4-iodoacetophenonea
The allylic ether 4a (a five-membered ring precursor)
suffered RCM under the standard conditions (5 mol% of Mo
complex 3 in benzene, 1 h); however, only 75% conversion
could be obtained after 1 h. This problem was solved by
increasing the catalyst loading; using 7 mol% of catalyst 3,
the complete consumption of 4a was achieved within 3 h to
afford the product 5a in 89% yield (Table 1, entry 1).
However, for the preparation of a seven-membered siloxane
5e, the reaction only went to 91% completion, giving an
81% yield under these conditions (entry 6). With a mono-
substituted alkene or vinylsilane (entries 3 and 4), the RCM
process proceeded slowly compared to 4b albeit ultimately
to completion to afford 5c–d in 91 and 90%, respectively.
Unfortunately, substitution on both the alkene and vinyl-
silane (entry 5) did not lead to a successful closure (even
under harsher conditions) presumably due to the significant
increase in steric crowding.
Entry
Pd(dba)2,
mol%
TBAF,
equiv.
Time,
min
Yield,b
%
1
2
3
4
5.0
3.0
1.0
5.0
2.0
2.0
2.0
1.0
10
30
180
180
89
86
80c
65d
a
All reactions employed 1.1 equiv. of 5b and 1.0 equiv. of 4-
iodoacetophenone at room temperature.
Yield of isolated 6b.
5% of 4-iodoacetophenone was recovered.
19% of 4-iodoacetophenone was recovered.
b
c
d

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S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
Table 3. Palladium-catalyzed cross-coupling of 5 with aryl iodidesa
Entry
Substrate, n
R1
R2
R3
Pd(dba)2,
mol%
Time, min
Product
Yield,b %
1
2
3
4
5
6
7
8
5a, 0
5b, 1
5b, 1
5b, 1
5b, 1
5b, 1
5b, 1
5b, 1
5c, 1
5d, 1
5e, 2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
4-CO2Et
4-COMe
4-OMe
3-CO2Et
2-Me
3.0
5.0
3.0
3.0
3.0
3.0
5.0
5.0
3.0
10.0
3.0
30
10
30
30
30
90
180
360
45
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
90c
92
93
89
86
90
84
83
81
85c
2-NO2
2-CH2OH
2-CO2Me
2-Me
3-CO2Et
4-OMe
9
10d
11
C6H13
H
24 h
30
6j
6k
H
a
All reactions employed: 5 (1.1 equiv.), TBAF (2.0 equiv.), aryl iodide (1.0 equiv.) and Pd(dba)2 (3.0 mol%) at room temperature unless otherwise
specified.
Yields of analytically pure materials.
Yield of chromatographically homogeneous material.
Pd(dba)2 (2.5 mol%/3 h) and (0.25 mmol/3 h) were added portionwise.
b
c
d
optimized conditions: 3.0–5.0 mol% of Pd(dba)2 as the
contained a substantial amount of self-coupling of ethyl 3-
iodobenzoate. The use of additives4c (AsPh3 or t-Bu3P)
and/or slightly elevated temperatures (35–45 8C) did not
improve the results. Fortunately, the addition of the iodide
in portions satisfactorily suppressed the formation of the
self-coupling product.4g Moreover, increasing the loading
and portionwise addition of the Pd(0) complex also
provided complete conversion and kept the palladium
from precipitating in this slow reaction. By using a
10 mol% catalyst loading, the coupling product 6j can be
obtained in 81% yield after 24 h. Finally, the reaction of
7-membered siloxane 5e with 4-iodoanisole proceeded
similarly to give 6k in 85% yield (entry 11).
catalyst and 2.0 equiv. of TBAF as the activator at ambient
temperature. The results with all aryl iodides examined are
complied in Table 3. The coupling of 5-membered siloxane
5a with ethyl 4-iodobenzoate using a 3.0 mol% catalyst
loading, was complete in 30 min to afford 6a in 85% yield
with excellent stereospecificity (Table 3, entry 1). The
coupling products showed slight decomposition upon
distillation. However, they could be secured in analytically
pure form after silica gel chromatography. Although the
stereospecificity could not be determined by GC, no other
1
isomer was see by H NMR analysis. The 11.6 Hz vicinal
coupling constant between the olefinic protons indicated
that the Z-olefin geometry was maintained. The reaction of
the 6-membered siloxane 5b with 4-iodoacetophenone
gave, as expected, 6b in 90% yield in 10 min with a
5.0 mol% catalyst loading (entry 2). Electrophiles bearing
an electron-donation group (entry 3) or an electron-
withdrawing group (entry 4), both gave the desired products
6c and 6d in 92 and 93% yield, respectively. Sterically
hindered substrates, such as in 2-iodotoluene (entry 5) or
2-nitroiodobenzene (entry 6), also gave the expected
products 6e and 6f in excellent yield (89 and 86%,
respectively). The reaction of 2-iodobenzyl alcohol (entry
7) and methyl 2-iodobenzoate (entry 8) proceeded more
slowly than the previously mentioned electrophiles to afford
6g (90%) and 6h (84%). Even using a 5.0 mol% catalyst
loading, reactions of these substrates still required 3–6 h to
reach completion. The effect of substitution on the a- and
b-positions of the alkenylsilyl group, such as in siloxanes
5c and 5d, was also examined with various aryl iodides.
Cross-coupling of 5c with 2-iodotoluene proceeded to
completion in 45 min to afford 6i in 83% yield (entry 9).
The a-substituted alkenylsilane 5d did undergo the
coupling process with ethyl 3-iodobenzoate (entry 10),
however, at a significantly reduced reaction rate compared
to the related silanes. Moreover, the reaction mixture
The cross-coupling of 5b was also successful with (E)-2-
bromostyrene (Scheme 3). The reaction rate and yield were
slightly lower than those obtained with aryl iodides. After
5 h, 7 could be isolated in 78% yield with 2.5 mol% of
[allylPdCl]2 as the catalyst.
Scheme 3. Cross-coupling of 5b with (E)-2-bromostyrene.
2.2. Sequential RCM/Pd-catalyzed, Si-assisted
intramolecular cross-coupling reactions
With the sequential RCM/Pd-catalyzed, silicon-assisted
intermolecular cross-coupling reaction successfully demon-
strated, we turned our attention toward investigation of the
intramolecular coupling process. The strategy, outlined in
Scheme 4, involves the generation of cyclic silyl ethers 15

S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
9699
isomerization of internal alkynyl alcohols 8 (xZ1–3) with
sodium 2-aminoethylamide generated in situ from sodium
hydride and ethylenediamine.20 Iodination of 9 with iodine
in aqueous KOH gave the iodoalkynyl alcohols 10 in
excellent yield (90–95%). Next, cis-reduction of 10 with
diimide, (generated in situ from potassium azodicarbox-
ylate), afforded the corresponding iodoalkenyl alcohols 11
in moderate yield (56–64%). A small amount of the over-
reduction product could be easily removed by treatment of
crude material with n-BuNH2. Oxidation by the method of
Swern was chosen to convert the primary alcohol to the
aldehyde in 82–88% yield. The addition of various Grignard
reagents to the aldehydes afforded the desired iododienyl
Scheme 4. Strategy for intramolecular silicon-assisted cross-coupling.
Scheme 5. Synthesis of 15, precursors for intramolecular cross-coupling.
by Mo-catalyzed RCM and their subsequent participation as
nucleophilic partners in Pd-catalyzed intramolecular cross-
coupling with an alkenyl iodide appended at a remote
position. In these siloxanes, variables, m and n combine to
determine the size of the ring and the location of the
hydroxyl group relative to the diene unit.
alcohols 13 in 85–93% yield. Finally, silylation of 13 with
commercially available chlorodimethylvinylsilane gave the
targeted vinylsilyl ethers 14 in 86–95% yield. From earlier
studies, we already knew that RCM of vinylsilyl ethers
required the use of Schrock’s molybdenum complex 3.
Gratifyingly, substrates 14 also underwent the RCM process
smoothly with 3 without competitive reaction of the vinyl
iodide unit. Unfortunately, substrate 14g (for a five-
membered ring precursor) did not lead to a successful
closure in the RCM process. Even using 12 mol% of catalyst
3, only a 21% conversion of 15g was observed after 60 h at
ambient temperature according to 1H NMR analysis. Under
slightly harsher conditions (45 8C), no improvement in
2.2.1. Synthesis of siloxanes 15. To test the feasibility and
generality of the overall transformation, substrates 15 were
prepared from terminal alkynyl alcohols 9 as depicted in
Scheme 5. The results of the overall transformation are
compiled in Tables 4 and 5. Alkynyl alcohols 9a–b are
commercially available materials and substrates 9c–e were
readily available in 82–84% yield by base-promoted
Table 5. Preparation of alcohols 13, silyl ethers 14, and siloxanes 15
Table 4. Preparation of 9, 10, 11, and 12
m, n
Alcohol 13
(yield, %)a
Silyl ether 14
(yield, %)a
Siloxane 15
(yield, %)a
m
9
10
(yield, %)a
11
(yield, %)a
12
(yield, %)a
(yield, %)a
1, 1
2, 1
3, 1
4, 1
5, 1
2, 2
4, 0
13a (93)
13b (91)
13c (88)
13d (92)
13e (91)
13f (91)
13g (85)
14a (86)
14b (95)
14c (94)
14d (93)
14e (93)
14f (95)
14g (87)
15a (83)
15b (81)
15c (82)
15d (81)
15e (83)
15f (80)
15g (–)
1
2
3
4
5
9a (–)
10a (91)
10b (94)
10c (94)
10d (95)
10e (90)
11a (56)
11b (61)
11c (60)
11d (64)b
11e (61)b
12a (85)
12b (85)
12c (86)b
12d (82)b
12e (88)b
9b (–)
9c (83)
9d (84)
9e (82)
a
Yields of chromatographically homogeneous material.
Yields of analytically pure material.
b
a
Yields of analytically pure materials.

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S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
Table 6. Optimization of the intramolecular cross-coupling reaction of 15ca
Entry
15c (M, in THF)
APC, mol%
TBAF, equiv.
Time, h
16c (%)b
1c
2d
3
4
5
6
7
8
—
0.5
0.1
0.1
0.05
0.1
0.1
0.1
0.1
0.1
3.0
3.0
3.0
3.0
3.0
5.0
5.0
7.5
10.0
7.5
2.0
2.0
30
20
32
34
50
40
40
40
40
43
!10
14
45
32
46
62
44
74
75
75
10.0
20.0
10.0
10.0
5.0
10.0
10.0
10.0
9
10d
a
All reactions were performed on a 0.1 mmol scale by slow addition a solution of 15c to a mixture of APC and TBAF solution unless otherwise specified.
The percentage of product was determined by 1H NMR analysis comparing the integrated area of the diene to the total integrated area of H(C1).
The reaction was run in THF (0.01 M, dilute condition).
b
c
d
0.5 mmol scale.
conversion was observed. Not surprisingly, the yields of
these reactions are not influenced by chain length.
slow addition of substrate, entry 2) did not promote this
intramolecular process well. Under these conditions,
1
unreacted vinylsilanes and oligomers were observed by H
NMR analysis. Therefore, to maintain efficient fluoride
activation, promote transmetalation and maintain a low
concentration of 15c (to prevent oligomerization), the
amount of TBAF solution was increased. To our delight,
the percentage of the desired product, 16c, increased
dramatically to 45% (entry 3). Neither increasing the
amount of TBAF solution nor adding more dilute solutions
of 15c had a beneficial effect (entries 4–5). However, we
found that the catalyst loading did have a significant effect
on the success of this intramolecular process (entries 3, 6, 8,
and 10). A great improvement in the production of 16c to
2.2.2. Optimization of intramolecular cross-coupling
reaction. Optimization of the Pd-catalyzed, intramolecular
cross-coupling reaction of 15c (to form a 10-membered
ring) employed allylpalladium chloride dimer (APC) as the
catalyst and a 1.0 M solution of tetrabutylammonium
fluoride (TBAF) in THF as the activator. We chose this
substrate because in cycloalkenes, the maximum strain is
found in the 10-membered ring.14 The results from studies
of the catalyst loading and the amount of activator are
collected in Table 6. Typical conditions, which would favor
intra- vs intermolecular coupling (high dilution, entry 1, or
Table 7. Pd-catalyzed intramolecular cross-coupling reactions of 15a
Entry
Substrate 15
APC, mol%
Time, h
Product 16, yield/%b
16aC16a0 (60%,1:1)c,d
16b (70%)
16c (63%)
16d (55%)
16e (72%)
16f (71%)
1
2
3
4
5
6
15a
15b
15c
15d
15e
15f
7.5
7.5
7.5
10.0
10.0
10.0
60
45
45
75
75
60
a
All reactions were performed on a 1.0 mmol scale (0.1 M in THF), with TBAF (10.0 equiv.), and slow addition condition at room temperature.
Yield of analytically pure materials.
Yield of chromatographically homogeneous material.
b
c
d
The ratio was determined by 1H NMR analysis.

S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
9701
62% was obtained by using 5.0 mol% of APC (entry 6).
Decreasing the amount of TBAF solution, decreased the
percentage of 16c to 44% (entry 7). Finally, by employing
7.5 mol% of APC, the percentage of 16c in the coupling
products jumped to 75% (entries 8 and 10). No further
improvement was observed using even with 10 mol% of
APC (entry 9).
2.2.4. Formation of medium-sized ring ethers. To
demonstrate the versatility and effectiveness of this process,
we next investigated extension to medium-sized hetero-
cycles. Medium ring ethers have attracted a great deal of
attention as synthesis targets in view of their occurrence in
several classes of marine natural product structures.21 Thus,
the diastereomeric silyl ethers 23a–b were selected to test
this application by generation of the corresponding
9-membered oxacyclic dienes22 (Scheme 6). The prep-
aration of 23a–b began with the reduction of pyruvic
aldehyde dimethoxy acetal with NaBH4 in MeOH/THF to
afford hydroxyl acetal 17 in 84% yield. Alkylation of the
sodium alkoxide of 17 (from sodium hydride in DMF) with
propargyl bromide afforded 18 in 85% yield. Conversion of
18 to 20 was achieved by iodination followed by a cis-
reduction of iodoalkyne 19 to iodoalkene 20 employing the
condition established above. Hydrolysis of dimethoxy
acetal was effected by treatment of 20 with p-toluene-
sulfonic acid in an acetone/H2O mixture to give aldehyde 21
in 94% yield. Treatment of aldehyde 21 with allyl-
magnesium bromide for 0.5 h afforded hydroxyl dienyl-
iodide 22a–b in 95% yield as a 56:44 mixture of
diastereomers, which were easily separated by silica gel
chromatography. Finally, silylation of the alcohols with
chlorodimethylvinylsilane in CH2Cl2 for 30 min furnished
23a–b in 94 and 95% yield, respectively.
2.2.3. Scope and limitations of Si-assisted intramolecular
cross-coupling reactions. The scope of this silicon-
assisted, intramolecular cross-coupling process with regard
to ring size was examined under the following conditions:
7.5–10.0 mol% of APC and 10.0 equiv. of TBAF solution at
room temperature. The results with all substrates examined
are compiled in Table 7. Under the optimal conditions, the
9-membered carbocycle 16b containing a 1,3-cis–cis diene
unit was obtained in 70% yield from siloxane 15b after 45 h
addition time (entry 2). Moreover, intramolecular coupling
of 15c gave the corresponding 10-membered cyclic product
16c in 63% yield (entry 3). In the coupling of 15d, the
amount of 16d observed was only 42% by 1H NMR analysis
under these conditions. Increasing the catalyst loading to
10 mol%, increased the yield of 16d to 59% after a 42 h
addition. Finally, by using 10 mol% of APC and increasing
the addition time to 75 h, we were able to produce 16d in
1
55% yield (67% by H NMR). Similarly, only 49% of 16e
and 55% of 16f were observed by H NMR analysis under
1
With these materials in hand, the ring closing metathesis of
23a was carried out using 10 mol% of the Mo complex 3 to
afford the target siloxane 24a in 81% yield. Similarly, RCM
of 23b proceeded smoothly to afford cyclic silyl ethers 24b
in 80% yield under the same conditions (Scheme 7).
Gratifyingly, exposure of the siloxanes to the optimal
conditions established above promoted the intramolecular
the standard conditions. By employing similar conditions
used for 15d, the desired coupling products 16e and 16f
were obtained in 72 and 71% yield, respectively (entries
5–6). Unfortunately, substrate 15a afforded a mixture of
desired product 16a and cine rearrangement product 16a0 in
60% yield in a 1:1 ratio, presumably due to the more
difficult construction of a cyclooctadiene.
Scheme 6. Synthesis of 23a–b.

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S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
reversible process. Thus, 5a with a sterically more
demanding phenyl group deters RCM of the product.
3.2. Ring-closing metathesis of trienes
In formulating the intramolecular cross-coupling reaction, it
was not lost upon us that the iodo alcohols 13 could also be
converted to cycloalkadienes 16 by an inverted sequence of
cross-coupling (vinylation) followed by RCM of the triene.
Indeed, RCM of trienes have been reported recently for
construction of macrolides containing a 1,3-diene system.
Moreover, the more sterically sensitive Ru-complex 1 has
been shown to react preferentially with the terminal double
bond of a diene preferably to afford macrocycles with a
internal diene unit.25 To the best of our knowledge,
formation of medium-sized ring with a diene unit by
RCM is still rare.26 Thus, to determine whether the
intramolecular cross-coupling was of any tactical advant-
age, we undertook the preparation of the requisite trienes 26
and assayed their potential for RCM to dienes (Scheme 8).
Vinylation of 13 was readily accomplished by our recently
described method using 1,3,5,7-tetramethyl-1,3,5,7-tetra-
vinylcyclotetrasiloxane (DV4 ) to afford the desired trienes
26a–c in 56–65% yield.4h Initial studies on the RCM of
trienes, 26a, using Grubbs alkylidene complex 1 (5.0 mol%)
produced only the six-membered ring compound 27a in
greater than 95% conversion in 6 h at room temperature.
However, only 22% of the seven-membered ring product
27b was obtained along with 58% of 26b recovered under
the same conditions. Furthermore, none of closure products
of 27c were observed under these conditions and complex
mixtures were obtained in refluxing CH2Cl2. Clearly,
closure on the internal double bond of the diene to afford
smaller rings predominated.27,28 We thus demonstrated the
utility and further substantiated the advantages of the
intramolecular cross-coupling method.
Scheme 7. Formation of medium-sized ring ethers 25. Reagents and
conditions: (a) 3 (10.0 mol%), benzene (0.1 M), rt, 36 h, 24a (81%); 24b
(80%). (b) APC (7.5 mol%), TBAF (10.0 equiv.), rt, 45 h, 25a (72%); 25b
(77%).
cross-coupling effectively. Both diastereomers reacted with
equal facility to afford the oxonane dienes 25a and 25b, in
72 and 77% yield, respectively with no difference in rate or
efficiency.
3. Discussion
3.1. Ring-closing metathesis of olefinic alkenylsilyl ethers
The RCM of alkenylsilyl ethers 4 proceeded smoothly as
expected from the literature reports.12 The more reactive
Mo complex 3 is the catalyst of choice for all of the variants
examined as the Ru-based complexes were ineffective. The
formation of 5- or 7-membered siloxanes 5a and 5e
(Table 1, entries 1 and 6) as well as substitution on the
double bond (Table 1, entries 3–4) were associated with
lower RCM reaction rates. This behavior was particularly
apparent in the case of 4e; all attempts to effect ring closure
led to failure presumably due to the significant steric
hindrance at both ends of the alkene. Interestingly, in the
cases of 14a–f, the RCM proceeded smoothly in the
presence of an alkenyl iodide function. In fact, alkylidene
1 has been shown to react with acetylenic halides through
halide exchange. Moreover, some dienes or dienynes
containing a vinyl halide (Br or I) also failed to cyclize
using either 1 or Mo-complex 3.12e,23 It has been
hypothesized that formation of more stable and unreactive
Fischer-type carbene complexes from vinyl bromides or
vinyl ethers and Ru-alkylidene complexes might prevent the
initiation step at the terminal alkene.11c,23b,24 Although the
reason for the failure of RCM with vinyl bromide containing
dienes using catalyst 3 has not been determined, the
successful ring closure of 14 indicated that the initiation
step at the terminal alkene did occur, and that subsequent
combination with the alkenylsilyl species proceeded with-
out interference of the iodoalkenyl group. RCM of 14g (a
five-membered siloxane precursor) was not successful; only
21% conversion was observed. This was surprising in light
of the successful RCM of 4a to oxasilacyclopentene 5a
(Table 1). Perhaps, the smaller substituent at the allylic
position of the oxasilacyclopentene ring permits the strained
RCM product to compete with the starting material in this
Scheme 8. RCM of trienes 26.
3.3. Si-assisted cross-coupling reactions
The intermolecular cross-coupling of cycloalkenylsiloxanes
5 with various aryl iodides proceeded rapidly and
efficiently. For all aryl iodides examined, the reaction
conditions were mild and gave uniformly high yields.
Noteworthy features of this process include: (1) electron-
withdrawing or donating groups exhibit similar reactivity
(Table 3, entries 2–4), (2) the steric effect of ortho
substituents is minimal (Table 3, entry 5) except in the
cases where possible coordination of the palladium may
slow the reductive elimination step (Table 3, entries 6–8),
(3) the reaction tolerates diverse functional groups such as

S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
9703
ester, ether, nitro and even a free hydroxyl group, and (4) the
5. Experimental
reactions of all iodides were stereospecific. The influence of
the siloxane ring size as well as the substitution on the
double bond in coupling reactions was systematically
investigated. The results in Table 3 reveal that: (1) different
cyclic alkenyl silanes exhibit similar reactivity in the
coupling reaction (Table 3, entries 1, 3 and 11) and (2)
substitution on the b-trans-position of the silyl group did not
affect the reactivity significantly (Table 3, entry 9).
5.1. General
All reactions were performed in oven-dried (140 8C) or
flame-dried glassware under an inert atmosphere of dry Ar
or N2. The following reaction solvents were distilled from
the indicated drying agents: diethyl ether (Na, benzo-
phenone), THF (Na, benzophenone), CH2Cl2 (P2O5),
benzene (Na), toluene (Na), methanol (Mg(OMe)2),
triethylamine (CaH2). n-Butyllithium solutions were titrated
following the method of Gilman.31 Brine refers to a
saturated aqueous solution of NaCl. Grignard solutions
were titrated using 2,20 -phenanthroline as an indicator.
Kugelrohr distillations were performed on a Bu¨chi GKR-50
Kugelrohr; boiling points (bp) corresponding to uncorrected
air-bath temperatures (ABT). All reaction temperatures
correspond to internal temperatures measured by Teflon-
coated thermocouples unless otherwise noted.
A comparison between these results and those described
previously reveals that mono-substitution of alkenyl silanes
(silacyclobutanes4a–d and silanols4e) in either the a- or
the b-position does not affect the rate of the cross-coupling
process significantly. The disubstituted alkenylsilanes
including cyclic siloxanes4g and silyl hydrides4f are also
very reactive in the coupling process except in the case of
substitution on both of a- and b-cis-positions, as in 5d. The
steric influence may slow the coupling reaction and allow a
competitive homocoupling of the aryl iodides to intervene.
1H NMR spectra and 13C NMR spectra were recorded on a
Varian Unity 400 (400 MHz, 1H; 100 MHz, 13C), Unity 500
In the cases of intramolecular cross-coupling, the results,
compiled in Table 7, reveal good generality for the
construction of 9-, 10-, 11-, and 12-membered cyclo-
alkadienes, (Table 7, entries 2–6). With the exception of
15a, all of the substrates examined gave the corresponding
medium-sized rings bearing the 1,3-cis–cis diene unit
stereospecifically in respectable yield from highly flexible
starting materials without significant conformational con-
straints.29 Notably, modulation of the location of the
hydroxy group was successfully achieved by adjustment
of chain length and ring size of the silyl ether (cf. Table 7,
entries 3 and 6). An extension of the intramolecular
coupling process for construction medium-sized ether
rings, such as 25a and 25b, was examined under the
standard reaction conditions. Interestingly, both dia-
stereomers reacted similarly without significant difference
in reaction rate and yield. This observation bodes well for
the application of the process in the synthesis of complex,
medium-ring ether natural products.30
1
(500 MHz, H; 126 MHz, 13C). Spectra are referenced to
residual chloroform (d 7.26 ppm, H; d 77.0 ppm, 13C) and
1
residual acetone (d 2.04 ppm, 1H; d 29.8 ppm, 13C).
Chemical shifts are reported in ppm (d); multiplicities are
indicated by s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet) and br (broad). Coupling constants, J, are
reported in Hertz. Mass spectroscopy was performed by
the University of Illinois Mass Spectrometer Center.
Electron impact (EI) spectra were performed on a
Finnigan-MAT CH-5 spectrometer. Data are reported in
the form of m/z (intensity relative to base peakZ100).
Infrared spectra (IR) were recorded on a Mattson Galaxy
5020 spectrophotometer. Peaks are reported in cmK1 with
indicated relative intensities: s (strong, 67–100%); m
(medium, 34–66%); w (weak, 0–33%). Elemental
analyses were performed by the University of Illinois
Microanalytical Service Laboratory.
Analytical thin-layer chromatography was performed on
Merck silica or aluminum oxide, basic gel plates with QF-
254 indicator. Visualization was accomplished with UV
light and/or Iodide. Diethyl ether was of reagent grade and
used as received; other solvents for chromatography and
filtration were technical grade and distilled from the
indicated drying agents: hexane and pentane (CaCl2);
CH2Cl2 (CaCl2); ethyl acetate (K2CO3). Column chroma-
tography was performed using EM Science 230–400-mesh
silica gel or Aldrich 150-mesh aluminum oxide, activated,
basic, Brockmann I.
4. Conclusion
The sequential RCM/cross-coupling reactions of olefinic
alkenylsilyl ethers has been demonstrated. The cyclo-
alkenylsiloxanes serve as competent donors in rapid and
high-yielding cross-coupling reactions with various aryl and
alkenyl halides. The intermolecular cross-coupling reac-
tions proceeded with high stereospecificity and good
functional group compatibility. In addition, the influences
of siloxane ring size and olefin substitution are similar to
those observed in the acyclic coupling processes. The Pd-
catalyzed, silicon-assisted intramolecular cross-coupling
reaction provides an effective and potentially powerful
method for construction of medium-sized rings with an
internal 1,3-cis–cis diene unit. Noteworthy features of this
intramolecular process include: (1) a highly stereospecific
intramolecular coupling process, (2) the flexible positioning
of hydroxy group, and (3) the potential extension to other
medium-sized carbocycles and heterocycles.
Analytical capillary gas chromatography (GC) was per-
formed using the following gas chromatography fitted with
a flame ionization detector (H2 carrier gas, 1 mL/min):
Hewlett Packard 5890 Series II. The following column was
used: HP-5 50-m cross-linked 5%-Phenyl methyl silicone
gum phase or Ultra-2 50-m cross-linked 5%-Phenyl methyl
silicone gum phase. The detector temperature was 300 8C.
Retention times (tR) and integrated ratios were obtained
from Hewlett Packard 3393A integrators.
All commercial reagents were purified by distillation or

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S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
recrystallization prior to use. A 1.0 M solution of tetra-
butylammonium fluoride in THF was prepared from solid
tetrabutylammonium fluoride trihydrate (TBAF$3H2O,
Fluka) and distilled THF in a volumetric flask and was
stored in a Schlenk bottle. Palladium bis(dibenzylidene-
acetone) (Pd(dba)2) was purchased from Jansen and used
without purification. p-Allylpalladium chloride dimer
[allylPdCl]2 (APC) was purchased from ACROS and was
recrystallized from benzene prior to use.
gel, hexane/EtOAc, 49/1) followed by Kugelrohr distillation
to afford 5.0 g (95%) of 14b as a colorless liquid. Bp 120–
125 8C (0.05 mm Hg, ABT); Rf 0.39 (silica gel, hexane/
EtOAc, 49/1, PMA); IR (neat) n 3073 (m), 2942 (s), 2861
(m), 1641 (m), 1407 (m), 1276 (m), 1251 (s), 1089 (s), 914
(s), 835 (s) cmK1; 1H NMR (500 MHz, CDCl3) d 6.20–6.12
(m, 3H), 6.00 (dd, JZ15.0, 4.0 Hz, 1H), 5.83–5.76 (m, 1H),
5.77 (dd, JZ20.5, 4.0 Hz, 1H), 5.06–5.03 (m, 2H), 3.71
(quint, JZ6.0 Hz, 1H), 2.21 (dd, JZ7.5, 6.0 Hz, 2H), 2.13
(q, JZ7.0 Hz, 2H), 1.57–1.39 (m, 4H), 0.19 (s, 6H); 13C
NMR (126 MHz, CDCl3) d 141.2, 138.1, 135.1, 133.0,
117.0, 82.5, 72.1, 42.1, 36.1, 34.6, 23.9, K1.37, K1.39; MS
(EI, 70 eV) 349 (1, MCK1), 335 (10), 323 (8), 309 (73),
207 (13), 180 (8), 155 (14), 121 (15), 97 (38), 85 (100).
Anal. Calcd for C13H23IOSi: C, 44.57; H, 6.62; I, 36.23.
Found: C, 44.66; H, 6.56; I, 35.92.
5.2. Representative experiments
5.2.1. General procedure I: silylation with chloro-
dimethylvinylsilane. To a solution of the requisite
unsaturated alcohol in CH2Cl2 was added Et3N
(1.5 equiv.) and dimethylvinylchlorosilane (1.2 equiv.)
sequentially under N2 atmosphere at 0 8C. The white
suspension was allowed to warm to room temperature and
was stirred for 0.5–1.0 h. The mixture was poured into ice
water and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, then were
dried (Na2SO4), and filtered. After removal of solvent, the
residue was purified by silica gel chromatography followed
by Kugelrohr distillation to afford the corresponding silyl
ether.
5.2.1.3. Preparation of dimethyl{(2S*,3S*)-{2-{[(Z)-3-
iodo-2-propenyl]oxy}-5-hexenyl}-3-oxy}vinylsilane (23a).
Following General procedure I, a solution of 22a (4.23 g,
15 mmol) in CH2Cl2 (15 mL), chlorodimethylvinylslane
(2.48 mL, 18.0 mmol, 1.2 equiv.), and Et3N (3.13 mL,
22.5 mmol, 1.5 equiv.) were combined. After being stirred at
room temperature for 30 min, the mixture was poured into ice
water (30 mL) and the aqueous layer was extracted with
CH2Cl2 (3!30 mL). The combined organic layers were
washed with brine (50 mL), then were dried (Na2SO4), and
filtered. After removal of solvent, the residue was purified by
chromatography (silica gel, hexane/EtOAc, 100/0 to 19/1)
followed by Kugelrohr distillation to afford 5.16 g (94%) of
23a as a colorless liquid. Bp 145–150 8C (0.3 mm Hg, ABT);
Rf 0.16 (silica gel, hexane/EtOAc, 49/1, PMA); IR (neat) n
3075 (m), 2971 (s), 2900 (m), 1691 (m), 1639 (m), 1616 (m),
1407 (m), 1276 (s), 1253 (s), 1093 (s), 1006 (s), 956 (m), 914
(s), 836(s) cmK1;1HNMR:(500 MHz, CDCl3)d 6.43(dt, JZ
7.5, 5.5 Hz, 1H), 6.33 (dt, JZ7.5, 1.5 Hz, 1H), 6.15 (dd, JZ
20.5, 15.0 Hz, 1H), 5.99 (dd, JZ15.0, 4.0 Hz, 1H), 5.80 (ddt,
JZ17.5, 10.5, 7.5 Hz, 1H), 5.76 (dd, JZ20.5, 4.0 Hz, 1H),
5.09–5.02 (m, 2H), 4.14 (ddd, JZ13.5, 5.0, 1.5 Hz, 1H), 4.05
(ddd, JZ13.5, 5.5, 1.5 Hz, 1H), 3.65 (dt, JZ8.0, 4.5 Hz, 1H),
3.38 (qd, JZ6.5, 4.5 Hz, 1H), 2.32 (dddt, JZ14.0, 7.0, 6.0,
1.5 Hz, 1H), 2.15 (dtt, JZ14.0, 7.5, 1.5 Hz, 1H), 1.12 (d, JZ
6.5 Hz, 3H), 0.19 (s, 6H); 13C NMR: (126 MHz, CDCl3) d
139.0, 138.1, 135.5, 132.9, 116.9, 82.2, 77.5, 74.9, 72.0, 37.1,
15.0, K1.32, K1.33; MS (EI, 70 eV) 366 (0.3, MC), 351
(0.5), 325 (4), 241 (7), 211 (12), 167 (78), 155 (100), 131 (35),
85 (74); GC: tR 23a, 9.57 min (HP-5, 200 8C, 15 psi). Anal.
Calcd for C13H23O2ISi: C, 42.63; H, 6.33; I, 34.64. Found: C,
42.79; H, 6.43; I, 34.81.
5.2.1.1. Preparation of dimethyl[(1-phenyl-3-
butenyl)oxy]vinylsilane (4b). Following General
procedure I, a solution of 1-phenyl-3-buten-1-ol (3.19 g,
21.5 mmol) in CH2Cl2 (30 mL), chlorodimethylvinylsilane
(3.86 mL, 28.0 mmol, 1.2 equiv.), and Et3N (4.48 mL,
32.3 mmol, 1.5 equiv.) were combined. After being stirred
at room temperature for 2 h, the mixture was then poured to
ice water (30 mL) and the aqueous layer was extracted with
CH2Cl2 (2!30 mL). The combined organic layers were
dried (Na2SO4), filtered and the solvent was removed by
rotary evaporation. The residue was distilled under reduced
pressure to afford 4.59 g (92%) of 4b as a colorless liquid.
Bp 74–75 8C (0.1 mm Hg); Rf 0.13 (silica gel, hexane,
PMA); IR (neat) n 2960 (s), 1641 (m), 1407 (m), 1253 (s),
1087 (s), 1068 (s), 1009 (s), 916 (s), 836 (s), 785 (s) cmK1
;
1H NMR (400 MHz, CDCl3) d 7.38–7.26 (m, 5H), 6.11 (dd,
JZ19.8, 14.9 Hz, 1H), 6.00 (dd, JZ14.9, 4.4 Hz, 1H),
5.80–5.78 (m, 1H), 5.77 (dd, JZ20.0, 4.4 Hz, 1H), 5.11–
5.05 (m, 2H), 4.74 (dd, JZ7.6, 5.5 Hz, 1H), 2.59–2.43 (m,
2H), 0.18 (s, 3H), 0.13 (s, 3H); 13C NMR (100.6 MHz,
CDCl3) d 144.6, 137.7, 135.1, 133.0, 128.0 (2 C), 127.0,
126.0 (2 C), 116.9, 75.0, 45.0, K1.5, K1.7; MS (CI,
130 eV) 233 (4, MCC1), 217 (34), 205 (35), 191 (100), 155
(23), 131 (37), 85 (19). Anal. Calcd for C14H20OSi: C:
72.36; H: 8.67. Found: C: 72.22; H: 8.56.
5.2.2. General procedure II: molybdenum-catalyzed
ring-closing metathesis of 4, 14, or 23. In a flame-dried,
25-mL flask was placed freshly distilled benzene which was
then moved into a dry box. Schrock’s catalyst (0.05–
0.1 equiv.) and compound 4, 14, or 23 (1.0 equiv.) were
added sequentially to the flask. The yellow-brown solution
was stirred at room temperature in the dry box and the
5.2.1.2. Preparation of dimethyl{[(Z)-9-iodo-1,8-non-
adienyl]-4-oxy}vinylsilane (14b). Following General pro-
cedure I, a solution of 13b (3.99 g, 15 mmol) in CH2Cl2
(25 mL), chlorodimethylvinylslane (2.49 mL, 18.0 mmol,
1.2 equiv.), and Et3N (3.13 mL, 22.5 mmol, 1.5 equiv.)
were combined. After being stirred at room temperature for
1 h, the mixture was poured into ice water (50 mL) and the
aqueous layer was extracted with CH2Cl2 (3!50 mL). The
combined organic layers were washed with brine (50 mL),
then were dried (Na2SO4), and filtered. After removal of
solvent, the residue was purified by chromatography (silica
1
reaction was monitored by H NMR analysis. When the
reaction was complete, the solvent was removed by rotary
evaporation to give a brown residue, which was filtered
through a short column of silica gel and was further eluted
with hexane/EtOAc, 49/1. The filtrate was concentrated in

S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
9705
vacuo followed by Kugelrohr distillation to afford the
product 5, 15, or 24.
(m), 1587 (s), 1382 (m), 1276 (s), 1249 (s), 1157 (m), 1101
1
(s), 1062 (s), 952 (s), 902 (s), 842 (s) cmK1; H NMR
(500 MHz, CDCl3) d 6.79 (ddd, JZ14.0, 6.0, 2.0 Hz, 1H),
6.44 (dt, JZ7.5, 5.5 Hz, 1H), 6.34 (dt, JZ7.5, 1.5 Hz, 1H),
5.73 (ddd, JZ14.0, 3.0, 1.0 Hz, 1H), 4.19 (ddd, JZ13.5,
5.5, 1.5 Hz, 1H), 4.13 (ddd, JZ13.5, 6.0, 1.5 Hz, 1H), 3.94
(ddd, JZ11.0, 4.5, 2.5 Hz, 1H), 3.49 (qd, JZ6.5, 4.5 Hz,
1H), 2.29 (dddd, JZ17.5, 11.0, 3.0, 2.5 Hz, 1H), 2.07 (dddd,
JZ17.5, 6.0, 2.5, 1.0 Hz, 1H), 1.17 (d, JZ6.5 Hz, 3H), 0.19
(s, 6H); 13C NMR (126 MHz, CDCl3) d 147.2, 139.0, 127.0,
82.4, 77.9, 73.4, 72.1, 31.0, 15.0, K0.4, K0.6; MS (EI,
70 eV) 338 (0.2, MC), 323 (1), 211 (2), 167 (22), 155 (14),
138 (9), 127 (100), 111 (13), 75 (15). Anal. Calcd for
C11H19O2ISi: C, 39.06; H, 5.66; I, 37.52. Found: C, 39.06;
H, 5.66; I, 37.47.
5.2.2.1. Preparation of 2,2-Dimethyl-6-phenyl-1-oxa-
2-silacyclohex-3-ene (5b). Following General procedure II,
benzene (10 mL), Schrock’s catalyst (38 mg, 0.05 mmol,
0.05 equiv.), and 4b (232 mg, 1.0 mmol) were combined
and the mixture was stirred at room temperature for 1 h in
the dry box. After removal of the solvent by rotary
evaporation, the residue was filtered through a short column
of silica gel which was eluted with 100 mL of hexane/
EtOAc, 49/1. The filtrate was concentrated followed by
Kugelrohr distillation to afford 193 mg (95%) of 5b as a
colorless liquid. Bp 95–100 8C (0.4 mm Hg ABT); Rf 0.15
(silica gel, hexane/EtOAc, 49/1, PMA); IR (neat) n 1587 (s),
1521 (s), 1064 (s), 957 (s), 837 (s), 789 (s) cmK1; 1H NMR
(400 MHz, CDCl3) d 7.43 (dd, JZ8.8, 1.6 Hz, 2H), 7.37 (td,
JZ8.8, 1.6 Hz, 2H), 7.28 (tt, JZ8.8, 1.6 Hz, 1H), 6.86 (ddd,
JZ14.0, 6.0, 2.4 Hz, 1H), 5.88 (ddd, JZ14.0, 2.8, 0.8 Hz,
1H), 5.01 (dd, JZ10.0, 3.6 Hz, 1H), 2.43–2.38 (m, 2H), 0.3
(s, 3H), 0.28 (s, 3H); 13C NMR (100.6 MHz, CDCl3) d
147.0, 144.4, 128.3 (2 C), 127.4, 127.2, 125.6 (2 C), 73.3,
39.0, K0.2, K0.6; MS (EI, 70 eV) 204 (37, MC), 189 (7),
130 (100), 98 (35), 83 (22). Anal. Calcd for C12H16OSi: C,
70.53; H, 7.89. Found: C, 70.34; H, 7.96.
5.2.3. General procedure III: palladium-catalyzed inter-
molecular cross-coupling of 5 with aryl or alkenyl
halides. Substrate 5 (1.1 equiv.) was dissolved in a solution
of TBAF (1.0 M in THF, 2.0 equiv.) under an Ar
atmosphere at ambient temperature. After 2 min, aryl or
alkenyl halide (1.0 equiv.) and the palladium catalyst (0.03–
0.1 equiv.) were then added sequentially. The reaction was
monitored by TLC analysis. When the halide was
consumed, 2 mL of EtOAc/hexane, 7/3 were added. The
mixture was filtered through a short column of silica gel,
which was then eluted with EtOAc/hexane, 7/3 (150–
200 mL). The filtrate was concentrated by rotary evapor-
ation to give a crude product which was purified by silica gel
chromatography.
5.2.2.2. Preparation of 2,2-dimethyl-6-[(Z)-5-iodo-4-
pentenyl]-1-oxa-2-silacyclohex-3-ene (15b). Following
General procedure II, benzene (10 mL), 14b (350 mg,
1.0 mmol), and Schrock’s catalyst (61.2 mg, 0.08 mmol,
0.08 equiv.) were combined and the mixture was stirred at
room temperature for 24 h in the dry box. After removal of
solvent by rotary evaporation, the residue was purified by
chromatography (silica gel, hexane/CH2Cl2, 19/1 to 4/1)
followed by Kugelrohr distillation to afford 261 mg (81%)
of 15b as a colorless liquid. Bp 85–90 8C (0.02 mm Hg,
ABT); Rf 0.30 (silica gel, hexane/EtOAc, 49/1, PMA); IR
(neat) n 2985 (m), 2926 (s), 1608 (m), 1587 (m), 1352 (m),
1275 (m), 1249 (s), 1163 (m), 1087 (m), 953 (s), 901 (m),
842 (s) cmK1; 1H NMR (500 MHz, CDCl3) d 6.75 (ddd, JZ
14.5, 4.5, 3.5 Hz, 1H), 6.19–6.15 (m, 2H), 5.73 (dt, JZ14.5,
1.5 Hz, 1H), 3.93–3.88 (m, 1H), 2.20–2.09 (m, 4H), 1.65–
1.45 (m, 4H), 0.178 (s, 3H), 0.176 (s, 3H); 13C NMR
(126 MHz, CDCl3) d 147.1, 141.3, 127.1, 82.4, 71.0, 37.1,
36.4, 34.5, 23.9, K0.4, K0.6; MS (EI, 70 eV) 322 (12,
MC), 307 (5), 195 (60), 180 (18), 153 (35), 127 (93), 98
(100), 75 (90). Anal. Calcd for C11H19IOSi: C, 41.00; H,
5.94; I, 39.38. Found: C, 41.03; H, 5.97; I, 38.97.
5.2.3.1. Coupling reaction of 5b with ethyl 3-iodo-
benzoate. Preparation of ethyl 3-[(Z)-4-hydroxy-4-
phenyl-1-butenyl]benzoate (6d). Following General pro-
cedure III, 5b (225 mg, 1.1 mmol, 1.1 equiv.), a solution of
TBAF in THF (1.0 M, 2.0 mL, 2.0 mmol, 2.0 equiv.), ethyl
3-iodobenzoate (276 mg, 1.0 mmol) and Pd(dba)2 (17.2 mg,
0.03 mmol, 0.03 equiv.) were combined. The mixture was
stirred at room temperature for 30 min and then 2 mL of
EtOAc/hexane, 7/3 were added. The mixture was filtered
through a short column of silica gel which was eluted with
150 mL of EtOAc/hexane, 7/3. The filtrate was concentrated
to give a crude product which was purified by chromato-
graphy (silica gel, hexane/EtOAc, 9/1 to 4/1) to afford
276 mg (93%) of 6d as a pale yellow (non-distillable) oil. Rf
0.34 (silica gel, hexane/EtOAc, 3/1, PMA); IR (neat) n 3465
(s), 1718 (s), 1602 (m), 1280 (s), 1188 (s), 1106 (s), 759 (s),
1
701 (s) cmK1; H NMR (400 MHz, CDCl3) d 7.96 (s, 1H),
7.90 (dd, JZ7.6, 1.2 Hz, 1H), 7.43 (d, JZ7.6 Hz, 1H),
7.39–7.26 (m, 6H), 6.58 (d, JZ11.6 Hz, 1H), 5.80 (dt, JZ
11.6, 7.2 Hz, 1H), 4.82 (dd, JZ7.6, 5.6 Hz, 1H), 4.37 (q,
JZ7.2 Hz, 2H), 2.83 (dtd, JZ15.2, 7.6, 1.6 Hz, 1H), 2.76–
2.69 (m, 1H), 2.26 (br s, 1H, HO), 1.39 (t, JZ7.2 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) d 166.6, 143.8, 137.3, 132.9,
130.6, 130.3, 129.8, 129.0, 128.4 (2 C), 128.2, 127.8, 127.6,
125.8 (2 C), 74.0, 61.0, 38.0, 14.3; MS (EI, 70 eV) 296 (0.2,
MC), 278 (2), 251 (5), 205 (3), 191 (100), 117 (54), 107
(39). Anal. Calcd for C19H20O3: C: 76.99; H: 6.81. Found:
C: 76.85; H: 6.75.
5.2.2.3. Preparation of (6S*)-2,2-dimethyl-6-{(1S*)-1-
{[(Z)-3-iodo-2-propenyl]oxy}ethyl}-1-oxa-2-silacyclo-
hex-3-ene (24a). Following General procedure II, benzene
(10 mL), 23a (366 mg, 1.0 mmol), and Schrock’s catalyst
(61.2 mg, 0.08 mmol, 0.08 equiv.) were combined and the
mixture was stirred at room temperature for 24 h in the dry
box. Additional Schrock’s catalyst (15.3 mg, 0.02 mmol,
0.02 equiv.) was added and then was stirred for 12 h. After
removal of solvent by rotary evaporation, the residue was
purified by chromatography (silica gel, hexane/Et2O, 49/1 to
97/3) followed by Kugelrohr distillation to afford 273 mg
(81%) of 24a as a colorless liquid. Bp 125–130 8C
(0.2 mm Hg, ABT); Rf 0.17 (silica gel, hexane/EtOAc, 97/
3, PMA); IR (neat) n 3070 (m), 2985 (s), 2896 (m), 1608
5.2.4. General procedure IV: Pd-catalyzed intramolecu-
lar cross-coupling of 15 or 24. Catalyst [allylPdCl]2
(0.075–0.10 equiv.) was dissolved in a solution of TBAF in

9706
S. E. Denmark, S.-M. Yang / Tetrahedron 60 (2004) 9695–9708
THF (1.0 M, 10.0 equiv.) under an N2 atmosphere at
ambient temperature. To the mixture was added slowly a
solution of 15 or 24 in THF (0.1 M) by syringe pump. After
complete addition of 15 or 24, the deep brown solution was
stirred for additional 2 h. The solvent was removed by
rotary evaporation and 5 mL of EtOAc/hexane, 7/3, were
then added. The mixture was filtered through a short column
of silica gel, which was then eluted with EtOAc/hexane, 7/3
(300–400 mL). The eluate was concentrated by rotary
evaporation to give a crude product, which was purified
by silica gel chromatography followed by Kugelrohr
distillation to afford 16 or 25.
1H), 3.65 (dd, JZ12.5, 7.5 Hz, 1H), 3.55 (td, JZ9.5,
4.5 Hz, 1H), 2.63 (dt, JZ12.5, 11.0 Hz, 1H), 2.28 (dddt, JZ
12.5, 5.5, 4.5, 1.5 Hz, 1H), 1.79 (br s, 1H, HO), 1.22 (d, JZ
6.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) d 132.5, 129.61,
129.55, 129.45, 81.6, 73.5, 70.3, 35.7, 17.9; MS (EI, 70 eV)
154 (3, MC), 139 (34), 128 (32), 115 (53), 92 (17), 77 (100),
64 (28). Anal. Calcd for C9H14O2: C, 70.08; H, 9.16. Found:
C, 69.98; H, 9.31.
Acknowledgements
We are grateful for the National Institutes of Health for
generous financial support (R01 GM63167-01A1).
5.2.4.1. Preparation of (3Z,5Z)-cyclononadienol (16b).
Following General procedure IV, [allylPdCl]2 (27.5 mg,
0.075 mmol, 0.075 equiv.) and a solution of TBAF in THF
(1.0 M, 10.0 mL, 10.0 mmol, 10.0 equiv.) were combined.
The solution of 15b in THF (0.1 M, 322 mg, 1.0 mmol) was
added slowly by syringe pump for 43 h. The solvent was
removed by rotary evaporation and 5 mL of EtOAc/hexane,
7/3, were then added. The mixture was filtered through a
short column of silica gel, which was then eluted with
EtOAc/hexane, 7/3 (350 mL). The eluate was concentrated
by rotary evaporation to give a crude product, which was
purified by chromatography (silica gel, hexane/EtOAc, 9/1
to 4/1) followed by Kugelrohr distillation to afford 97 mg
(70%) of 16b as a colorless oil. Bp 75–80 8C (0.2 mm Hg,
ABT); Rf 0.17 (silica gel, hexane/EtOAc, 4/1, PMA); IR
(neat) n 3350 (s), 3002 (s), 2929 (s), 2858 (s), 1637 (m),
1454 (s), 1356 (m), 1258 (m), 1064 (s), 996 (s), 903 (m), 803
Supplementary data
Complete experimental details for all preparative pro-
cedures along with full characterization of all starting
materials and products (94 pages) are provided.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.06.
149
1
(m) cmK1; H NMR (500 MHz, CDCl3) d 5.96 (ddd, JZ
11.0, 2.0, 1.0 Hz, 1H), 5.81 (d, JZ11.0 Hz, 1H), 5.76–5.66
(m), 3.90 (quint, JZ5.5 Hz, 1H), 2.39 (t, JZ7.3 Hz, 2H),
2.15–2.00 (m, 2H), 1.84–1.78 (m, 2H), 1.60–1.52 (m, 2H),
1.40–1.33 (m, 1H); 13C NMR (126 MHz, CDCl3) d 133.1,
129.9, 128.5, 127.3, 71.2, 38.3, 36.2, 30.9, 19.7; MS (EI,
70 eV) 138 (12, MC), 120 (5), 109 (27), 94 (47), 79(100), 67
(42). Anal. Calcd for C9H14O: C, 78.21; H, 10.21. Found: C,
78.16; H, 10.29.
References and notes
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10.0 mL, 10.0 mmol, 10.0 equiv.) were combined. The
solution of 24a in THF (0.1 M, 338 mg, 1.0 mmol) was
added slowly by syringe pump for 43 h. The solvent was
removed by rotary evaporation and 5 mL of EtOAc/hexane,
7/3, were then added. The mixture was filtered through a
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to 17/3) followed by Kugelrohr distillation to afford 111 mg
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1081 (s), 1052 (s), 1016 (s), 989 (s), 863 (m) cmK1; H
NMR (500 MHz, CDCl3) d 6.07 (ddq, JZ11.5, 3.0, 1.5 Hz,
1H), 6.00 (dd, JZ11.0, 1.0 Hz, 1H), 5.84 (dddd, JZ11.5,
7.5, 6.5, 1,0 Hz, 1H), 5.68 (tdd, JZ11.0, 5.5, 1.0 Hz, 1H),
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