The regio- and stereochemical course of reductive cross-coupling reactions between 1,3-disubstituted allenes and vinylsilanes: Synthesis of (Z)-dienes

Article abstract of DOI:10.1016/j.tet.2010.02.062

In investigations aimed at exploring the potential of disubstituted allenes in stereoselective synthesis, we report studies that explore the reductive cross-coupling reaction of vinylsilanes with a range of substituted allenes. Regiochemical control is attained by employing allenic alkoxides, where the proximal heteroatom dictates the site-selectivity in a process that proceeds by net formal metallo-[3,3] rearrangement (directed carbometalation/elimination). Stereoselectivity in these reactions is complex, with both the nature of allene substitution and relative stereochemistry of the substrate impacting the stereoselective generation of each alkene of a substituted 1,3-diene.

Full text of DOI:10.1016/j.tet.2010.02.062

Tetrahedron 66 (2010) 4775–4783
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The regio- and stereochemical course of reductive cross-coupling reactions
between 1,3-disubstituted allenes and vinylsilanes: synthesis of (Z)-dienes
*
Allan U. Barlan, Glenn C. Micalizio
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 January 2010
Received in revised form 12 February 2010
Accepted 16 February 2010
Available online 21 February 2010
In investigations aimed at exploring the potential of disubstituted allenes in stereoselective synthesis, we
report studies that explore the reductive cross-coupling reaction of vinylsilanes with a range of
substituted allenes. Regiochemical control is attained by employing allenic alkoxides, where the proxi-
mal heteroatom dictates the site-selectivity in a process that proceeds by net formal metallo-[3,3]
rearrangement (directed carbometalation/elimination). Stereoselectivity in these reactions is complex,
with both the nature of allene substitution and relative stereochemistry of the substrate impacting the
stereoselective generation of each alkene of a substituted 1,3-diene.
Keywords:
Allenes
Titanium
Ó 2010 Published by Elsevier Ltd.
Reductive Cross-Coupling
Z-dienes
1. Introduction
Homoallylic alcohol–alkyne coupling:
RL
OH
OH
Me
Reductive cross-coupling is emerging as a useful strategy for
bimolecular C–C bond formation.1 While a great many reports
continue to appear for the coupling of substituted alkynes with
carbonyl-based reaction partners,2 studies that describe the related
bimolecular union of coupling partners that diverge from these
well-studied processes are rare.3 In a program aimed at the eluci-
dation of reductive cross-coupling reactions between alkynes,
allenes, and alkenes, we have put forth a variety of heteroatom-
directed reaction designs to accomplish selective cross-coupling.4
These designs, which vary by the sequence of steps that result in
encapsulation of the metal during the metal-centered [2þ2þ1]
process, have proven to be useful for: (1) control of hetero- vs
homo-coupling, (2) control of regioselectivity, (3) control of relative
stereochemistry, and in some cases, (4) provide a means of over-
coming the typical sluggish reactivity of highly substituted sub-
strates in reductive cross-coupling chemistry (Fig. 1).5
RL
+
Me Me
Me Me
Me
Allylic alcohol–alkyne coupling:
TMS
Me
Me R2
HO
TMS
+
R1
R1
R2
Allylic alcohol–vinylsilane coupling:
Me
Me
+
HO
OH
SiMe2Cl
R1
R1
Allene–alkyne coupling:
TMS
In the course of a recent campaign in total synthesis, we expe-
rienced a great deal of difficulty associated with the efficient
preparation of a trisubstituted (Z,E)-1,3-diene (Fig. 2).6 While we
were able to forge the C7–C8 sigma bond of callystatin A by ap-
plication of well-known palladium-catalyzed coupling chemistry,7
the synthesis of the stereodefined trisubstituted vinyliodide 1
was quite challenging. Initial explorations relied on multistep
R2
•
TMS
HO
+
HO
R1
R1
R2
TMS
R2
•
R1
TMS
+
HO
R2
R1
Figure 1. Recent examples of heteroatom-directed reductive cross-coupling reactions
* Corresponding author. E-mail address: glenn.micalizio@yale.edu (G.C. Micalizio).
of alkynes and alkenes.
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.02.062

4776
A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
Me
Me
I
1, ZnCl2, t-BuLi, Et2O
then
O
Oi-Pr
H
Me
+
Me
Me
I
O
Oi-Pr
7
2, Pd(PPh3)4
H
8
72%
O
O
H
Me
TMS
OH
O
1
2
3
Me
Me
Routes explored to establish the trisubstituted olefin:
Me Me
I
Me Me
Me
1) Multi-step sequence from a dibromo olefin
(highly selective, but poor step economy)
callystatin A
2) Unselective Wittig olefination
TMS
(acceptable step economy, but poor stereoselectivity)
1
Figure 2. Difficulties experienced in establishing the C6–C9-(Z,E)-diene of callystatin A.
functionalization of a dibromo-olefin that proceeded through
conversion to a TMS-alkyne, hydrozirconation, iodination, and Pd-
catalyzed ethylation.8 In an effort to increase step-economy for the
synthesis of 1, we ultimately pursued Wittig chemistry between an
basic bond construction proved feasible. Reaction of the isomeric
allenic alcohols 10 and 12 with a preformed Ti-complex of vinyl-
trimethylsilane resulted in formation of the stereo-undefined
TMS
a
-chrial aldehyde and an iodoethyl-substituted ylid. While this
H
a
revised route provided a concise entry to the desired vinyliodide,
stereoselectivity for the Wittig olefination was 1.7:1, favoring the
formation of the undesired isomer.6,9 Fortunately, chromatographic
separation of these isomers was possible and a total synthesis of
callystatin A was accomplished in 11 steps from a commercially
available chiral alcohol.
The difficulty in establishing the C6–C9 1,3-(Z,E)-diene in cally-
statin prompted us to develop an alternative pathway to establish
this type of stereodefined motif. Previous studies in our laboratory
had revealed that alkoxide-directed reductive cross-coupling of
disubstituted allenes with internal alkynes defined a regio- and
stereoselective pathway to cross-conjugated trienes (4þ5/6;
Fig. 3).4i We speculated that a related reductive cross-coupling re-
action between substituted allenes and terminal alkenes could
provide a useful pathway to trisubstituted (Z,E)-dienes (7þ8/9) of
the substitution pattern seen in C6–C9 of callystatin A. Here, we
discuss our studies of this proposed process, and present the scope
and limitations of a stereoselective reductive cross-coupling re-
action between disubstituted allenes and vinylsilanes for the syn-
thesis of (Z)-olefin-containing 1,3-dienes.
OH
(1)
Me
•
51%
Me Me
10
Me
11
TMS
H
a
OH
(2)
(3)
Me
•
54%
Me
Me
13
Me
12
TMS
H
a
OH
H
•
56%
Me
Me
14
(+/–)
15
Z:E = 3:1
TMS
H
OH
a, b
H
•
(4)
51%
O
TBS
HO
16
17
Z:E = 3:1
TMS
Allene–alkyne coupling: Synthesis of cross-conjugated trienes
(+/–)
TMS
H
H
R
Ti(Oi-Pr)4-mediated
OH
OH
a
TMS
+
•
H
•
(5)
(6)
H
reductive cross-coupling
50%
Me
Me
R
5
RL
RL
Me
Me
4
6
18
(+/–)
H
19
•
Z:E 20:1
Allene–alkene coupling:
TMS
R2
OH
H
H
•
a
Ti(Oi-Pr)4-mediated
OH
R1
R2
+
•
H
53%
R1
reductive cross-coupling
RL
RL
7
8
9
20
21
(+/–)
Z:E • 20:1
Figure 3. Allene–alkene reductive cross-coupling for the synthesis of Z-dienes.
Reaction conditions: a) vinyltrimethylsilane, Ti(Oi-Pr)4, c-C5H9MgCl, Et2O (–78 to
–50 °C), then add lithium alkoxide of the allenyl alcohol. b) TBAF, THF.
2. Results and discussion
TMS
Exploring the utility of a reaction design based on stepwise
encapsulation of the metal center in a reductive cross-coupling
reaction of allenes with alkenes, we initiated studies of this pro-
cess with vinyltrimethylsilaneda simple monosubstituted alkene,
that is, well known to be a substrate for Ti(IV) alkoxide-mediated
coupling reactions.10 As illustrated in Eqs. 1 and 2 of Figure 4, the
H
Stereochemical assignment of the (Z)-diene
Z-17
products was accomplished by nOe analysis.
H
For example:
OH
Figure 4. Exploring the basic bond construction: reductive crosscoupling between
substituted allenes and vinyltrimethylsilane.

A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
4777
trisubstituted 1,3-dienes 11 and 13 in 51 and 53% yield. In addition
to validating the proposed coupling process, Eq. 2 demonstrated
that this allene–alkene union is effective for establishing a tetra-
substituted alkene.
utility. As such, we briefly explored the potential of employing this
(Z)-selective coupling reaction for the union of allenes with other
coupling partners. Coupling of allene 16 with styrene was suc-
cessful, but led to the production of the (Z)-diene 23 in 52% yield
(Fig. 5).11 As would be anticipated from our earlier investigation of
allene 16, this coupling reaction proceeded with low levels of
stereoselectivity (Z:E¼2:1). Unfortunately, all attempts to accom-
plish this reductive cross-coupling with simple terminal alkenes
was met with failure; in all cases resulting in the formation of
complex product mixtures.
Next, in a brief study, the structural requirements for (Z)-se-
lectivity were examined. Reductive cross-coupling of disubstituted
allenes that contain an unbranched substituent distal to the
hydroxymethyl group (14 and 16; Eqs. 3 and 4) proved to be
relatively poor substrates for this process. While these coupling
reactions proceeded with acceptable conversions (51–56% yield),
the resulting dienes (15 and 17) were formed with only moderate
levels of selectivity (Z:E¼3:1). In accord with previous observations
made in our study of allene–imine4k and allene–alkyne4h,i re-
ductive cross-coupling reactions, (Z)-selectivity is markedly en-
hanced with substrates that contain branched alkyl substituents
distal to the hydroxymethyl group. As illustrated in Eqs. 5 and 6, the
isopropyl- and cyclohexyl-substituted allenes 18 and 20 were
converted to the dienes 19 and 21 in 50 and 53% yield, each with
ꢀ20:1 selectivity for the formation of the (Z)-diene product.
While we were pleased with the success of our initial in-
vestigation, we recognized that the tetraalkylsilane products de-
rived from this coupling process are of limited general synthetic
Inspired by the Kulinkovich reaction,12 we hoped that we could
employ EtMgBr as a coupling partner in this (Z)-diene-forming
coupling reaction. Based on the presumed mechanistic course of
the Kulinkovich reaction, that is, thought to proceed by the con-
version of EtMgBr to a Ti–ethylene complex,12b coupling with
allenyl alcohols should result in a net stereoselective ethylation.13
Such a process would define a direct approach to the synthesis of
the (Z,E)-diene of callystatin A. Unfortunately, all attempts to ac-
complish this transformation were also unsuccessful and led to the
formation of complex product mixtures.14
Moving on, we refocused our attention on an inexpensive and
readily available vinylsilane that, when coupled to substituted
allenes would provide a product that could be easily functionalized.
This concept was validated as described in Eq. 8 (Fig. 5). Here,
coupling of the tertiary alcohol 10 with vinyldimethylchlorosilane
24, followed by oxidation of the sC–Si, provided the primary car-
binol 25 in 51% yield (over two steps). Illustrated in Eqs. 9 and 10,
a two-step process of reductive cross-coupling and oxidation de-
livered the stereodefined (Z)-diene-containing primary alcohols 26
and 28 from the racemic allenes 20 and 27. In each case, the (Z)-
diene product was formed with ꢀ20:1 stereoelectivity.
Ph
H
OH
Ph
a, b
H
•
+
(7)
52%
TBS O
HO
16
22
23
Z:E = 2:1
(+/–)
Returning to our initial problem, defined by the goal of de-
signing a reductive cross-coupling reaction for the establishment of
each stereodefined alkene of a (Z,E)-diene, we questioned whether
the present allene–vinylsilane coupling reaction proceeds in a ste-
reospecific fashion (Fig. 6). If ligand exchange is a prerequisite for
carbometalation (A/B/C) in this reductive cross-coupling re-
action, the conversion of preformed metallacyclopropanes (A) to
1,3-diene products was anticipated to follow from a precise se-
quence of steps whereby the (Z)-trisubstituted alkene would derive
from stereoselective carbometalation anti to R2 (B/C), and the (E)-
disubstituted alkene would result from stereospecific elimination
(C/D).
HO
H
a, c
SiMe2Cl
OH
Me
Me
(8)
(9)
+
+
•
51%
Me Me
10
H
25
24
HO
OH
H
•
a, c
24
55%
20
26
Z:E • 20:1
(+/–)
In an effort to explore this proposal, two stereodefined allenes
were prepared as described in Figure 7. The isomerically pure diols
29 and 31 were accessed from syn-dihydroxylation of the corre-
sponding (Z)- and (E)-enynes, each prepared from Sonogashira
coupling with TMS–acetylene.15 Stereoselective conversion to the
isomerically defined allenes 30 and 32 followed from a two-step
sequence composed of carbonate formation and SN20 addition.16
Thecouplingof allenes 30 and 32 with vinyldimethylchlorosilane
is depicted in Figure 8. These reactions, performed as previously
discussed in Figure 5, provided substituted 1,3-dienes 33 and 34
with varying levels of selectivity. While in each case, the (Z)-tri-
substituted alkene of the products was established with high levels
H
HO
OH
H
•
a, c
+
(10)
24
53%
27
28
(+/–)
Z:E 20:1
•
Reaction conditions: a) alkene, Ti(Oi-Pr)4, c-C5H9MgCl, Et2O (–78 to –50 °C), then
add lithium alkoxide of the allenyl alcohol. b) TBAF, THF, c) KF, KHCO3, H2O2,
MeOH, THF.
Figure 5. Reductive cross-coupling reactions of allenyl alcohols with styrene and
chlorodimethylvinylsilane.
H
Li+ –
H
R3
O
stereospecific?
(i-PrO)n
Ti
O
H
R1
O
(Oi-Pr)n
•
R2
R1
R3
R3
Oi-Pr
Ti
R1
R3
R1
i-PrO
H
Ti
R3
H
[Ti]
•
R1
R2
R2
R2
R2
H
A
B
D
C
stereoselective
stereospecific
syn-elimination
stereoselective
carbometalation
ligand exchange
hydrolysis
Figure 6. Allene–alkene reductive cross-coupling for the synthesis of (Z)-dienes.

4778
A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
H
observation may relate to the increased reactivity of allenes in bi-
OH
a, b
Me
Me
molecular metal-mediated reductive cross-coupling.18 Overall, this
enhanced reactivity (and associated competing non-directed car-
bometalation) may represent an inherent limitation to the use of
allenic alkoxides in stereoselective reductive cross-coupling
chemistry. That said, the examples described here demonstrate
the potential to employ reductive cross-coupling for the stereo-
selective synthesis of (Z,E)- and (Z,Z)-trisubstituted 1,3-dienes from
isomerically pure disubstituted allenyl alcohols.
(11)
OBn
•
OBn
51%
OH
OH
H
29
(+/–)
30
(+/–)
H
OH
a, b
Me
Me
(12)
•
OBn
OBn
40%
OH
OH
H
3. Conclusion
31
32
(+/–)
(+/–)
While reductive cross-coupling chemistry is well known for the
Reaction conditions: a) CDI, PhH, reflux. b) i-PrMgCl, CuBr•SMe2.
Figure 7. Preparation of isomeric allenes.
union of alkynes with polarized
is only beginning to emerge as a useful strategy for union of more
substituted and electronically unactivated -systems (i.e., alkenes,
p-bonds (carbonyl electrophiles), it
p
alkynes, and allenes). In efforts directed at the application of an
alkyne–alkyne reductive cross-coupling reaction in natural product
synthesis, we identified a significant challenge in the establishment
of the C6–C9 (Z,E)-1,3-diene of callystatin A. Here, we describe the
design and investigation of a new allene–alkene reductive cross-
coupling to address this problem in stereoselective synthesis. Our
results lead us to conclude that the present coupling reaction
provides a highly stereoselective route to the generation of 1,3-di-
enes that contain a (Z)-trisubstituted alkene. While our data reveals
that this coupling process does not proceed in a stereospecific
fashion, we have discovered a reductive cross-coupling reaction
that forges a central C–C bond in concert with the establishment of
two stereodefined alkenes.
of selectivity (Z:Eꢀ20:1), the disubstituted alkenes of these products
was accessed with only moderate levels of selectivity (E:Z¼5:1 and
1:3). This observation is consistent with a mechanistic picture
composed of: (1) stereoselective syn-carbometalation, and (2)
competition between syn- and anti-elimination of the organome-
tallic intermediate.
E :Z = 5:1
HO
H
a, b
Me
OBn
(13)
•
OBn
Me
Me
52%
Me
OH
H
Z:E 20:1
•
30
(+/–)
33
4. Experimental section
4.1. General experimental information
BnO
All reactions were conducted in flame-dried glassware under
nitrogen or argon using anhydrous solvents. Toluene, tetrahydro-
furan, and diethyl ether were used after passing through an acti-
vated alumina column. Ti(Oi-Pr)4 was used after distillation of the
commercially available reagent. All other commercially available
reagents were used as received (Aldrich). 1H NMR data were
recorded at 400 MHz on a Bruker AM-400 in CDCl3. 13C NMR data
were recorded at 100 MHz on a Bruker AM-400. Infrared spectra
were recorded on a PerkinElmer SpectrumOne FTIR instrument.
Low resolution mass spectra were acquired on a Varian 500-MS
mass spectrometer under soft ionization mode. HRMS data (ESI-
TOF-MS) were obtained by the University of Florida Mass Spec-
trometry lab. 1H NMR chemical shifts are reported relative to
residual CHCl3 (7.26 ppm). 13C chemical shifts are reported relative
to the central line of CDCl3 (77.16 ppm). Chromatographic purifi-
H
Z:E = 3:1
a, b
Me
Me
HO
(14)
•
OBn
57%
Me
Me
OH
H
Z:E 20:1
•
32
(+/–)
34
Reaction conditions: a) alkene, Ti(Oi-Pr)4, c-C5H9MgCl, Et2O (–78 to –50 °C),
then add lithium alkoxide of the allenyl alcohol. c) KF, KHCO3, H2O2, MeOH, THF.
H
H
OBn
HO
Stereochemical assignment of 33 was
33
based on the following observed nOe:
Me
Me
cation was performed using 60 Å, 35–75
m particle size silica gel
Figure 8. Stereoselective access to (Z,E)- and (Z,Z)-1,3-dienes by reductive cross-
coupling.
from Silicycle. All compounds purified by chromatography were
sufficiently pure for use in further experiments, unless indicated
otherwise. Semi-preparative HPLC normal phase separations were
performed using an HPLC system composed of two Dynamax SD-1
pumps, a Rheodyne injector, and a Dynamax UV-1 absorbance
detector.
If ligand exchange was a prerequisite to C–C bond formation, we
would expect that the coupling reaction between allene 30 and
vinyldimethylchlorosilane would deliver the (Z,E)-1,3-diene 33 with
very high levels of stereochemical purity. This expectation follows
from a rationale based on facile syn-elimination of the resulting
bicyclic metallacyclopentane (C; Fig. 8) in preference to ring open-
ing and anti-elimination to deliver the (Z)-disubstituted alkene
product.17 The appreciable quantity of (Z,Z)-diene observed (17% of
the 1,3-diene product isolated) is consistent with anti-elimination
by way of a stereodefined monocyclic metallacyclopentaneditself,
likely derived from a competing reaction pathway that does not
proceed through alkoxide-directed carbometalation. While such
stereochemical erosion has not been observed in related coupling
reactions of substituted allylic alcohols,4j,4l–p the current
4.2. Cross-coupling between substituted allenes
and vinyltrimethylsilane
4.2.1. General synthesis of diene 6. To a ꢁ78 ꢂC solution of alkene 5
(1.1 equiv) in diethyl ether (0.1 M) was added ClTi(Oi-Pr)3
(1.1 equiv) and c-C5H9MgCl (2.2 equiv) dropwise via gas-tight sy-
ringe. The resulting clear, yellow solution turned dark red-brown
while warming to ꢁ50 ꢂC over 1 h. The reaction mixture was stirred
at ꢁ50 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC

A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
4779
solution of allene 4 (1 equiv) in THF (0.5 M) was added n-BuLi
(1.1 equiv) dropwise via gas-tight syringe. The resulting solution
was stirred for 15 min, removed from the cold bath, and added to
the ꢁ78 ꢂC solution of alkene dropwise via cannula. After warming
slowly to 0 ꢂC over 2 h, the reaction was quenched with 5 mL of satd
aq NH4Cl solution. The mixture was warmed to room temperature
before the resulting solution was filtered through a plug of silica,
eluting with 100 mL EtOAc. The crude material was purified by
column chromatography on silica gel (ethyl acetate/hexanes) to
yield diene 6 as a clear oil.
2.6 mmol) dropwise via gas-tight syringe. The resulting clear, yel-
low solution turned dark red-brown while warming to ꢁ50 ꢂC over
1 h. The reaction mixture was stirred at ꢁ50 ꢂC for 1 h and then
cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene 14 (0.165 g,
1.17 mmol) in 2 mL THF was added 0.518 mL of n-BuLi (2.50 M in
hexanes, 1.3 mmol) dropwise via gas-tight syringe. The resulting
solution was stirred for 15 min, removed from the cold bath, and
added to the ꢁ78 ꢂC solution of alkene dropwise via cannula. After
warming slowly to 0 ꢂC over 2 h, the reaction was quenched with
5 mL of satd aq NH4Cl solution. The mixture was warmed to room
temperature before the resulting solution was filtered through
a plug of silica, eluting with 100 mL EtOAc. Z:E selectivity was de-
termined by 1H NMR of the crude mixture after work-up. The crude
material was purified by column chromatography on silica gel
(hexanes) to yield diene 15 as a clear oil (147.3 mg, 56%, Z:E 3:1).
The stereochemistry of the major product was assigned by analogy
to previous examples. (peaks correlating to the major Z-isomer
were extracted from the spectrum of the 3:1 mixture) 1H NMR
4.2.2. 1-Trimethylsilyl-3-methylene-5-methyl-hex-4-ene (11). To
a ꢁ78 ꢂC solution of vinyltrimethylsilane (0.161 mL, 1.1 mmol) in
11 mL of diethyl ether (0.1 M) was added 1.1 mL of ClTi(Oi-Pr)3
(1.00 M in hexanes, 1.1 mmol) and 1.1 mL of c-C5H9MgCl (2.00 M in
ether, 2 mmol) dropwise via gas-tight syringe. The resulting clear,
yellow solution turned dark red-brown while warming to ꢁ50 ꢂC
over 1 h. The reaction mixture was stirred at ꢁ50 ꢂC for 1 h and
then cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene 10
(0.119 mL, 1 mmol) in 2 mL THF was added 0.440 mL of n-BuLi
(2.54 M in hexanes, 1.1 mmol) dropwise via gas-tight syringe. The
resulting solution was stirred for 15 min, removed from the cold
bath, and added to the ꢁ78 ꢂC solution of alkene dropwise via
cannula. After warming slowly to 0 ꢂC over 2 h, the reaction was
quenched with 5 mL of satd aq NH4Cl solution. The mixture was
warmed to room temperature before the resulting solution was
filtered through a plug of silica, eluting with 100 mL EtOAc. The
crude material was purified by column chromatography on silica
gel (hexanes) to yield diene 11 as a clear oil (93 mg, 51%). 1H NMR
(400 MHz, CDCl3)
d
6.67 (dd, J¼10.8, 17.2 Hz, 1H), 5.43–5.37 (m, 1H),
5.17 (d, J¼17.6 Hz, 1H), 5.06 (d, J¼17.6 Hz, 1H), 2.20–2.12 (m,
2Hþ2H), 1.37–1.27 (m, 2Hþ2Hþ2H), 0.89 (t, 3H), 0.70 (m, 2H), 0.01
(s, 9H); 13C NMR (15 ZþE) (100 MHz, CDCl3)
d 141.4, 140.2, 138.9,
133.0, 132.3, 129.8, 112.8, 110.1, 31.8, 29.8, 29.5, 28.1, 27.5, 22.8, 22.7,
16.8, 16.1, 14.3, ꢁ1.6, ꢁ1.8; IR (thin film, NaCl) 3444, 2954, 2860,
1755, 1714, 1463, 1248, 837, 757, 692 cmꢁ1; HRMS (EI, Mþ) calcd for
C14H28Si, 224.1960 m/z (M); observed 225.2028 (MþH)þ m/z.
4.2.5. Synthesis of allene 16. To a mixture of n-BuLi (2.51 M in
hexanes,1.1 equiv) in THF (0.16 M) was added dropwise tetrahydro-
2(2-propynyloxy)-2H-2-pyran (1 equiv) at ꢁ78 ꢂC under Ar. After
the mixture was stirred for 1 h, 5-(tert-butyldimethylsiloxy)-pen-
tanal (1.11 equiv) was added dropwise. The reaction mixture was
stirred for 1 h at ꢁ78 ꢂC, warmed to room temperature, stirred for
24 h, and added 20 mL of satd aq NH4Cl. The mixture was extracted
with 3ꢃ50 mL EtOAc, dried over MgSO4, filtered, and concentrated.
The crude material was purified by column chromatography on
silica gel (10–15% ethyl acetate/hexanes) to yield alcohol of 16 as
a clear oil. (1.451 g, 61%). To a solution of triphenylphosphine
(1.3 equiv) in THF (0.16 M) in a flame-dried round bottom flask at
ꢁ15 ꢂC under Ar was added diethyl azodicarboxylate (1.3 equiv)
and stirred for 10 min. To the above solution was then added
alcohol (1 equiv) and stirred for 10 min. Then o-nitro-
benzenesulfonylhydrazine (1.3 equiv) was added, stirred for 1 h at
ꢁ15 ꢂC, warmed to room temperature, and stirred for 17 h. Sub-
sequently, the solution was concentrated in vacuo and was purified
by column chromatography on silica gel (10% ethyl acetate/hex-
anes) to yield THP-protected allene of 16 as a clear oil (1.407 g, 62%).
To a solution of THP-protected allene of 16 (1 equiv) in Et2O (0.1 M)
was added MgBr2–Et2O (3 equiv). The resulting solution was stirred
at room temperature for 17 h and then added 10 mL of Et2O. The
resulting mixture was washed with brine, dried over MgSO4, fil-
tered, and concentrated. The crude material was purified by column
chromatography on silica gel (10% ethyl acetate/hexanes) to yield
allene 16 as a clear oil (0.424 g, 54%). 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
2.06–2.02 (m, 2H), 1.80 (s, 3H), 1.79 (s, 3H), 0.65–0.60 (m, 2H), 0.001
(s, 9H); 13C NMR (100 MHz, CDCl3)
149.2, 134.9, 126.3, 111.0, 31.9,
d
5.61 (s, 1H), 4.97 (d, J¼4.8 Hz, 1H), 4.72 (d, 1H),
d
26.8, 19.7, 15.5, ꢁ1.6; IR (thin film, NaCl) 3443, 2953, 1731, 1377,
1248, 1178, 1064, 838, 758, 691 cmꢁ1; HRMS (EI, Mþ) calcd for
C11H22Si, 182.1491 m/z (M); observed 183.1560 (MþH)þ m/z.
4.2.3. 1-Trimethylsilyl-4-methyl-3-vinyl-pent-3-ene (13). To a ꢁ78 ꢂC
solution of vinyltrimethylsilane (0.352 mL, 2.4 mmol) in 24 mL of
diethyl ether (0.1 M) was added 2.4 mL of ClTi(Oi-Pr)3 (1.00 M in
hexanes, 2.4 mmol) and 2.4 mL of c-C5H9MgCl (2.00 M in ether,
4.8 mmol) dropwise via gas-tight syringe. The resulting clear, yel-
low solution turned dark red-brown while warming to ꢁ50 ꢂC over
1 h. The reaction mixture was stirred at ꢁ50 ꢂC for 1 h and then
cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene 12
(0.235 g, 2 mmol) in 2 mL of THF was added 0.880 mL of n-BuLi
(2.50 M in hexanes, 2.2 mmol) dropwise via gas-tight syringe. The
resulting solution was stirred for 15 min, removed from the cold
bath, and added to the ꢁ78 ꢂC solution of alkene dropwise via
cannula. After warming slowly to 0 ꢂC over 2 h, the reaction
was quenched with 5 mL of satd aq NH4Cl solution. The mixture
was warmed to room temperature before the resulting solution was
filtered through a plug of silica, eluting with 100 mL EtOAc. The
crude material was purified by column chromatography on silica
gel (hexanes) to yield diene 13 as a clear oil (196.5 mg, 54%). 1H
NMR (400 MHz, CDCl3)
d
6.71 (dd, J¼11.0, 17.4 Hz, 1H), 5.06
d
5.34–5.29 (m, 1Hþ1H), 4.13–4.09 (m, 2H), 3.64–3.60 (m, 2H),
2.07–2.03 (m, 2H),1.60–1.58 (m, 2H),1.57–1.49 (m, 2H), 0.90 (s, 9H),
0.05 (s, 6H); 13C NMR (100 MHz, CDCl3)
203.3, 93.9, 92.2, 63.2,
(d, J¼17.4 Hz, 1H), 4.96 (d, J¼11.0 Hz, 1H), 2.22–2.18 (m, 2H),1.80
(s, 3H), 1.77 (s, 3H), 0.62–0.58 (m, 2H) 0.03 (s, 9H); 13C NMR
d
(100 MHz, CDCl3)
d
134.4, 134.4, 130.3, 110.1, 22.8, 21.8, 21.3, 16.5,
61.0, 32.2, 28.4, 26.1, 25.4, 18.5, ꢁ5.1; IR (thin film, NaCl) 3380, 2857,
1964, 1727, 1655, 1471, 1360, 1255, 1105, 1024, 836, 775, 663,
565 cmꢁ1; LRMS (EI, Mþ) calcd for C14H28O2Si, 256.1859 m/z (M);
observed 255.10 (MꢁH)þm/z.
ꢁ1.7; IR (thin film, NaCl) 3444, 2954, 1731, 1464, 1383, 1248, 861,
757, 691, 466 cmꢁ1; HRMS (EI, Mþ) calcd for C11H22Si, 182.1491 m/z
(M); observed 183.1566 (MþH)þ m/z.
4.2.4. (Z)-1-Trimethylsilyl-3-vinyl-non-3-ene (15). To a ꢁ78 ꢂC so-
lution of vinyltrimethylsilane (0.190 mL, 1.3 mmol) in 15 mL of
diethyl ether (0.1 M) was added 1.3 mL of ClTi(Oi-Pr)3 (1.00 M in
hexanes, 1.3 mmol) and 1.3 mL of c-C5H9MgCl (2.00 M in ether,
4.2.6. (Z)-6-(2-(Trimethylsilyl)ethyl)octa-5,7-dien-1-ol
(17). To
a ꢁ78 ꢂC solution of vinyltrimethylsilane (0.431 mL, 2.94 mmol,
1 equiv) in 29 mL of diethyl ether (0.1 M) was added 2.94 mL of
ClTi(Oi-Pr)3 (1.00 M in hexanes, 2.94 mmol, 1 equiv) and 2.93 mL of

4780
A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
c-C5H9MgCl (2.01 M in ether, 5.88 mmol, 3 equiv) dropwise via gas-
tight syringe. The resulting clear, yellow solution turned dark red-
brown while warming to ꢁ50 ꢂC over 1 h. The reaction mixture was
stirred at ꢁ50 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a separate
ꢁ78 ꢂC solution of allene 16 (0.256 g, 1 mmol, 0.34 equiv) in 2 mL
THF (0.5 M) was added 0.465 mL of n-BuLi (2.54 M in hexanes,
1.18 mmol, 0.4 equiv) dropwise via gas-tight syringe. The resulting
solution was stirred for 15 min, removed from the cold bath, and
added to the ꢁ78 ꢂC solution of alkene dropwise via cannula. After
warming slowly to 0 ꢂC over 2 h, the reaction was quenched with
5 mL of satd aq NH4Cl solution. The mixture was warmed to room
temperature before the resulting solutionwas filtered through a plug
of silica, eluting with 100 mL EtOAc. After concentration, the crude
material was subjected to TBAF (1 mmol) in 10 mL THF. After stirred
for 2 h,10 mL of H2O was added, and the product was extracted with
50 mL of EtOAc, dried over Na2SO4, and concentrated. Z:E Selectivity
was determined by 1H NMR of the crude mixture after work-up. The
crude material was purified by column chromatography on silica gel
(15% ethyl acetate: hexanes) to yield diene 17 as a clear oil (114.8 mg,
51%, Z:E 3:1). The stereochemistry of the major isomer was de-
termined by NOE analysis. The major alkene isomer was separated by
HPLC [EtOAc/hexanes: 15–30% (0–30 min, 20 mL/min), on a Micro-
sorb (Si 80-120 C5 H410119) column] to yield pure 17. 1H NMR
ClTi(Oi-Pr)3 (1.00 M in hexanes, 1.1 mmol) and 1.1 mL of
c-C5H9MgCl (2.00 M in ether, 2.2 mmol) dropwise via gas-tight
syringe. The resulting clear, yellow solution turned dark red-
brown while warming to ꢁ50 ꢂC over 1 h. The reaction mixture was
stirred at ꢁ50 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a separate
ꢁ78 ꢂC solution of allene 20 (0.155 mL, 1 mmol) in 2 mL THF was
added 0.440 mL of n-BuLi (2.50 M in hexanes, 1.1 mmol) dropwise
via gas-tight syringe. The resulting solution was stirred for 15 min,
removed from the cold bath, and added to the ꢁ78 ꢂC solution of
alkene dropwise via cannula. After warming slowly to 0 ꢂC over 2 h,
the reaction was quenched with 5 mL of satd aq NH4Cl solution. The
mixture was warmed to room temperature before the resulting
solution was filtered through a plug of silica, eluting with 100 mL
EtOAc. Z:E Selectivity was determined by 1H NMR of the crude
mixture after work-up. The crude material was purified by column
chromatography on silica gel (hexanes) to yield diene 21 as a clear
oil (125.7 mg, 53%, 20:1 Z:E). The stereochemistry of the major
product was assigned by analogy to previous examples. The major
alkene isomer was separated by HPLC [hexanes: 100% (0–30 min,
20 mL/min), on a Microsorb (Si 80-120 C5 H410119) column] to
yield pure 21. 1H NMR (400 MHz, CDCl3)
d
6.68 (dd, J¼11.6, 17.2 Hz,
1H), 5.25–5.16 (m, 1Hþ1H), 5.06 (d, J¼14.8 Hz, 1H), 2.44–2.36 (m,
1H), 2.18–2.14 (m, 2H), 1.69–1.54 (m, 2Hþ2H), 1.31–1.27 (m, 4H),
1.08–0.90 (m, 2H), 0.70–0.65 (m, 2H), 0.01 (s, 9H); 13C NMR
(400 MHz, CDCl3)
d
6.67 (dd, J¼11.2, 17.6 Hz, 1H), 5.41 (t, J¼7.6 Hz,
1H), 5.22 (d, J¼3.0 Hz, 1H), 5.08 (d, J¼11.0 Hz, 1H), 3.65 (t, J¼5.6 Hz,
2H), 2.20–2.15 (m, 2Hþ2H),1.59–1.57 (m, 2H),1.47–1.46 (m, 2H),1.26
(br s,1H), 0.70–0.65 (m, 2H), 0.01 (s, 9H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3) d 137.1, 135.7, 133.3, 112.8, 36.4, 33.6, 33.0, 27.3,
26.1,16.0, ꢁ1.5; IR (thin film, NaCl) 3417, 2854,1714,1450,1248, 860,
758, 692 cmꢁ1; HRMS (EI, Mþ) calcd for C15H28Si, 236.1960 m/z (M);
observed 237.2042 (MþH) m/z.
d
139.4, 132.8, 129.0, 113.2, 63.1, 32.5, 27.4, 27.2, 26.2, 16.1, ꢁ1.6; IR
(thin film, NaCl) 3334, 3088, 2952, 1639, 1455, 1248, 1059, 990, 862,
837, 758, 690 cmꢁ1; HRMS (EI, Na) calcd for C13H26OSi, 226.1753 m/z
(M); observed 226.1752 (M) m/z.
4.3. Cross-coupling reactions of allenyl alcohols with
styrene and chlorodimethyvinylsilane
4.2.7. (Z)-3-Trimethylsilylethyl-4-isopropyl-1,3-butadiene (19). To
a ꢁ78 ꢂC solution of vinyltrimethylsilane (0.161 mL, 1.1 mmol) in
11 mL of diethyl ether (0.1 M) was added 1.1 mL of ClTi(Oi-Pr)3
(1.00 M in hexanes, 1.1 mmol) and 1.1 mL of c-C5H9MgCl (2.06 M in
ether, 2.2 mmol) dropwise via gas-tight syringe. The resulting clear,
yellow solution turned dark red-brown while warming to ꢁ50 ꢂC
over 1 h. The reaction mixture was stirred at ꢁ50 ꢂC for 1 h and then
cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene 18
(0.134 mL, 1.0 mmol) in 2 mL THF was added 0.440 mL of n-BuLi
(2.50 M in hexanes, 1.1 mmol) dropwise via gas-tight syringe. The
resulting solutionwas stirred for 15 min, removed from the cold bath,
and added to the ꢁ78 ꢂC solution of alkene dropwise via cannula.
After warming slowly to 0 ꢂC over 2 h, the reaction was quenched
with 5 mL of satd aq NH4Cl solution. The mixture was warmed to
room temperature before the resulting solution was filtered through
a plug of silica, eluting with 100 mL EtOAc. The crude material was
purified by column chromatography on silica gel (hexanes) to yield
diene 19 as a clear oil (96.2 mg, 50%, 20:1 Z:E). Z:E Selectivity was
determined by 1H NMR of the crude mixture after work-up. The
stereochemistry of the major product was assigned by analogy to
previous examples. The major alkene isomer was separated by HPLC
[hexanes: 100% (0–30 min, 20 mL/min), on a Microsorb (Si 80-120 C5
4.3.1. (Z)-6-(2-Phenylethyl)octa-5,7-dien-1-ol (23). To a ꢁ78 ꢂC so-
lution of alkene 22 (0.182 mL, 1.92 mmol, 1 equiv) in 19.1 mL of
diethyl ether (0.1 M) was added 1.92 mL of ClTi(Oi-Pr)3 (1.00 M in
hexanes, 1.92 mmol, 1 equiv) and 1.91 mL of c-C5H9MgCl (2.01 M in
ether, 3.84 mmol, 3 equiv) dropwise via gas-tight syringe. The
resulting clear, yellow solution turned dark red-brown while
warming to ꢁ50 ꢂC over 1 h. The reaction mixture was stirred at
ꢁ50 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC so-
lution of allene 16 (0.168 g, 0.65 mmol, 0.34 equiv) in 2 mL THF
(0.5 M) wasadded 0.306 mL of n-BuLi (2.54 M in hexanes, 0.77 mmol,
1.1 equiv) dropwise via gas-tight syringe. The resulting solution was
stirred for 15 min, removed from the cold bath, and added to the
ꢁ78 ꢂC solution of alkene dropwise via cannula. After warming
slowly to 0 ꢂC over 2 h, the reaction was quenched with 5 mL of satd
aq NH4Cl solution. The mixture was warmed to room temperature,
and the resulting solutionwas filtered through a plug of silica, eluting
with 100 mL EtOAc. After concentration, the crude material was
subjected to TBAF (0.65 mmol) in 6.5 mL THF. After stirred for 2 h,
10 mL of H2O was added, and the product was extracted with 50 mL
of EtOAc, dried over Na2SO4, and concentrated. Z:E Selectivity was
determined by 1H NMRof the crude mixture after work-up. The crude
material was purified by column chromatography on silica gel (15%
ethyl acetate: hexanes) to yield diene 23 as a clear oil (120.4 mg, 52%,
Z:E 2:1). The stereochemistry of the major isomer was determined by
NOE analysis. The major alkene isomer was separated by HPLC
[EtOAc/hexanes: 15–30% (0–30 min, 20 mL/min), on a Microsorb
(Si 80-120 C5 H410119) column] to yield pure 23. 1H NMR (400 MHz,
H410119) column] to yield pure 19. 1H NMR (400 MHz, CDCl3)
d 6.68
(dd, J¼10.8, 17.3 Hz, 1H), 5.23–5.16 (m, 1Hþ1H), 5.06 (dd, J¼1.6,
3.2 Hz, 1H), 2.75 (septet, J¼6.6, 9.4, 13.3 Hz, 1H), 2.18–2.13 (m, 2H),
0.97 (d, J¼8.0 Hz, 6H), 0.70–0.65 (m, 2H), 0.01 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d
137.1,136.7,133.2,112.9, 27.3, 26.5, 23.4,15.9, ꢁ1.6;
IR (thin film, NaCl) 3444, 2956, 1731, 1248, 1177, 837, 758, 692,
468 cmꢁ1; HRMS (EI, Mþ) calcd for C12H24Si, 196.1647 m/z (M); ob-
served 197.1726 (MþH)þ m/z.
CDCl3)
d
7.28–7.17 (m, 5H), 6.69 (dd, J¼8.0,17.6 Hz,1H), 5.33–5.28 (m,
1Hþ1H), 5.14 (d, J¼12.8 Hz, 1H), 3.62 (m, 2H), 2.78–2.74 (m, 2H),
2.51–2.47 (m, 2H), 2.21–2.15 (m, 2H),1.55–1.51 (m, 2H),1.42–1.40 (m,
4.2.8. (Z)-1-Trimethylsilyl-3(cyclohexymethylene)pent-4-ene
2H), 1.17 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 142.6, 136.1, 132.7,
(21). To
a
ꢁ78 ꢂC solution of vinyltrimethylsilane (0.161 mL,
131.1,128.6,128.4,125.9,113.4, 63.0, 35.5, 35.4, 32.4, 27.1, 26.0; IR (thin
film, NaCl) 3351, 2932, 2860, 1635, 1603, 1495, 1454, 1059, 899, 747,
1.1 mmol) in 11 mL of diethyl ether (0.1 M) was added 1.1 mL of

A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
4781
698 cmꢁ1; HRMS (EI, Na) calcd for C16H22O, 231.1671 m/z (MþH);
observed 231.1755 (MþH)þ m/z.
stereochemistry of the major product was assigned by analogy to
previous examples. The major alkene isomer was separated by
HPLC [EtOAc/hexanes: 15–30% (0–30 min, 20 mL/min), on a Micro-
sorb (Si 80-120 C5 H410119) column] to yield analytically pure 26.
4.3.2. 5-Methyl-3-methylenehex-4-en-1-ol (25). To a ꢁ78 ꢂC solu-
tion of alkene 24 (0.870 mL, 6 mmol) in 60 mL of diethyl ether
(0.1 M) was added 6 mL of ClTi(Oi-Pr)3 (1.00 M in hexanes, 6 mmol)
and 6 mL of c-C5H9MgCl (2.01 M in ether, 12 mmol) dropwise via
gas-tight syringe. The resulting clear, yellow solution turned dark
red-brown while warming to ꢁ50 ꢂC over 1 h. The reaction mixture
was stirred at ꢁ50 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a separate
ꢁ78 ꢂC solution of allene 10 (0.238 mL, 2 mmol) in 2 mL THF was
added 0.880 mL of n-BuLi (2.54 M in hexanes, 2.2 mmol) dropwise
via gas-tight syringe. The resulting solution was stirred for 15 min,
removed from the cold bath, and added to the ꢁ78 ꢂC solution of
alkene dropwise via cannula. After warming slowly to 0 ꢂC over 2 h,
the reaction was quenched with 5 mL of satd aq NH4Cl solution. The
mixture was warmed to room temperature before the resulting
solution was filtered through a plug of silica, eluting with 100 mL
EtOAc. After concentrated in vacuo, the crude material was purified
by column chromatography on silica gel (hexanes) to yield diene as
an impure, clear oil. This impure product was carried on to the
subsequent step without further purification. The impure diene was
dissolved in 10 mL 1:1 MeOH/THF, and KHCO3 (8 mmol) and KF
(16 mmol) were added. The reaction mixture was stirred for five
additional minutes, 30% H2O2 (10.0 mmol) was added, and the re-
action mixture was stirred for 17 h at room temperature. To the
reaction was added aqueous Na2S2O3 dropwise, and the resulting
solution was filtered through a plug of silica, eluting with 100 mL
EtOAc. The crude material was purified by column chromatography
on silica gel (15% ethyl acetate/hexanes) to yield diene 25 as a clear
1H NMR (400 MHz, CDCl3)
d
6.69 (dd, J¼11.0, 17.5 Hz, 1H), 5.31 (d,
J¼9.4 Hz, 1H), 5.24 (d, J¼16.0 Hz, 1H), 5.11 (d, J¼11.0 Hz, 1H), 3.68 (t,
J¼6.1 Hz, 2H), 2.47–2.43 (dtþm, J¼1.0, 6.0, 12.7 Hz, 2Hþ1H), 1.73–
1.62 (m, 4H), 1.31–1.01 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 139.8,
132.8, 130.7, 113.8, 61.5, 36.7, 36.6, 33.6, 26.1, 26.0; IR (thin film,
NaCl) 3418, 2852, 1727, 1449, 1267, 1122, 1042, 891, 737 cmꢁ1
;
HRMS (EI, MþþH) calcd for C12H20O, 181.1514 m/z (MþH); observed
181.1590 (MþH)þ m/z.
4.3.4. (Z)-3-(Cyclopentylmethylene)pent-4-en-1-ol (28). To a ꢁ78 ꢂC
solution of alkene 24 (0.208 mL, 1.5 mmol) in 15 mL of diethyl ether
(0.1 M) was added 1.5 mL of ClTi(Oi-Pr)3 (1.00 M in hexanes,
1.5 mmol) and 1.5 mL of c-C5H9MgCl (2.00 M in ether, 3 mmol)
dropwise via gas-tight syringe. The resulting clear, yellow solution
turned dark red-brown while warming to ꢁ50 ꢂC over 1 h. The re-
action mixture was stirred at ꢁ50 ꢂC for 1 h and then cooled to
ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene 27 (0.069 g,
0.5 mmol) in 2 mL THF was added 0.220 mL of n-BuLi (2.54 M in
hexanes, 0.55 mmol) dropwise via gas-tight syringe. The resulting
solution was stirred for 15 min, removed from the cold bath and
added to the ꢁ78 ꢂC solution of alkene dropwise via cannula. After
warming slowly to 0 ꢂC over 2 h, the reaction was quenched with
5 mL of satd aq NH4Cl solution. The mixture was warmed to room
temperature before running through a silica plug and washing with
100 mL EtOAc. After concentrated in vacuo, the crude material was
purified by column chromatography on silica gel (hexanes) to yield
diene as an impure, clear oil. This impure product was carried on to
the subsequent step without further purification. The impure diene
was dissolved in 10 mL 1:1 MeOH/THF, and KHCO3 (2 mmol) and KF
(4 mmol) were added. The reaction mixture was stirred for five ad-
ditional minutes, 30% H2O2 (2.5 mmol) was added, and the reaction
mixture was stirred for 17 h at room temperature. To the reaction
was added aqueous Na2S2O3 dropwise, and the resulting solution
was filtered through a plug of silica, eluting with 100 mL EtOAc. Z:E
Selectivity was determined by 1H NMR of the crude mixture after
work-up. The crude material was purified by column chromatogra-
phy on silica gel (15% ethyl acetate: hexanes) to yield diene 28 as
a clear oil (44.1 mg, 53%, 20:1 Z:E). The stereochemistry of the major
product was assigned by analogy to previous examples. The major
alkene isomer was separated by HPLC [EtOAc/hexanes: 15–30% (0–
30 min, 20 mL/min), on a Microsorb (Si 80-120 C5 H410119) column]
oil (128.4 mg, 53%). 1H NMR (400 MHz, CDCl3)
1H), 4.91 (s, 1H), 3.67 (dt, J¼6.0, 12.0, 18.0 Hz, 2H), 2.35 (t, J¼6.2 Hz,
2H),1.80 (s, 6H),1.38 (t, O–H,1H); 13C NMR (100 MHz, CDCl3)
142.7,
d 5.60 (s, 1H), 5.06 (s,
d
136.3, 125.3, 115.4, 61.2, 41.1, 26.8, 19.7; IR (thin film, NaCl) 3417,
2924, 1257, 1042, 799 cmꢁ1; HRMS (EI, Mþ) calcd for C8H14O,
126.1045 m/z (M); observed 127.1127 (MþH)þ m/z.
4.3.3. (Z)-3-(Cyclohexylmethylene)pent-4-en-1-ol (26). To a ꢁ78 ꢂC
solution of alkene 24 (0.416 mL, 3 mmol) in 30 mL of diethyl ether
(0.1 M) was added 3 mL of ClTi(Oi-Pr)3 (1.00 M in hexanes, 3 mmol)
and 3 mL of c-C5H9MgCl (2.00 M in ether, 6 mmol) dropwise via
gas-tight syringe. The resulting clear, yellow solution turned dark
red-brown while warming to ꢁ50 ꢂC over 1 h. The reaction mixture
was stirred at ꢁ50 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a sep-
arate ꢁ78 ꢂC solution of allene 20 (0.115 mL, 1 mmol) in 2 mL THF
was added 0.440 mL of n-BuLi (2.50 M in hexanes, 1.1 mmol)
dropwise via gas-tight syringe. The resulting solution was stirred
for 15 min, removed from the cold bath, and added to the ꢁ78 ꢂC
solution of alkene dropwise via cannula. After warming slowly to
0 ꢂC over 2 h, the reaction was quenched with 5 mL of satd aq
NH4Cl solution. The mixture was warmed to room temperature
before running through a silica plug and washing with 100 mL
EtOAc. After concentrated in vacuo, the crude material was purified
by column chromatography on silica gel (hexanes) to yield diene as
an impure, clear oil. This impure product was carried on to the
subsequent step without further purification. The impure diene
was dissolved in 10 mL 1:1 MeOH/THF, and KHCO3 (4 mmol) and KF
(8 mmol) were added. The reaction mixture was stirred for five
additional minutes, 30% H2O2 (5 mmol) was added, and the re-
action mixture was stirred for 17 h at room temperature. To the
reaction was added aqueous Na2S2O3 dropwise, and the resulting
solution was filtered through a plug of silica, eluting with 100 mL
EtOAc. Z:E Selectivity was determined by 1H NMR of the crude
mixture after work-up. The crude material was purified by column
chromatography on silica gel (15% ethyl acetate/hexanes) to yield
to yield pure 28.1H NMR (400 MHz, CDCl3)
d
6.72 (dd, J¼11.0,17.6 Hz,
1H), 5.41 (d, J¼9.0 Hz, 1H), 5.24 (dd, J¼3.0, 17.5 Hz, 1H), 5.11 (d,
J¼11.0 Hz, 1H), 3.69 (t, J¼6.4 Hz, 2H), 2.91–2.85 (m, 1H), 2.49 (t,
J¼8.8 Hz, 2H),1.83–1.70 (m, 2H),1.60–1.58 (m, 2H),1.58–1.57 (m, 2H),
1.27–1.24 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 139.2, 132.9, 131.3,
113.7, 61.5, 38.5, 36.7, 34.2, 25.5; IR (thin film, NaCl) 3417, 2869, 1727,
1451, 1258, 1043, 842, 798, 471 cmꢁ1; HRMS (EI, Mþ) calcd for
C11H18O, 167.1358 m/z (MþH); observed 167.1437 (M)þ m/z.
4.4. Preparation of isomeric allenes
4.4.1. Synthesis of allene 30. To a solution of carbonyl diimidazole
(1 equiv) in benzene (0.1 M) in a flame-dried round bottom flask,
diol 29 (1 equiv) was added and the solution was refluxed under Ar
for 17 h. Subsequently, the solution was cooled to room tempera-
ture, and water (10 mL) was added. The resulting mixture was
extracted with ether, dried over MgSO4, filtered, and concentrated
by vacuum. The crude material was purified by column chroma-
tography on silica gel (25% ethyl acetate/hexanes) to yield carbonate
as a clear oil (87% yield). To a ꢁ78 ꢂC solution of CuBr–Me2S (2.381 g,
11.58 mmol) in 50 mL of THF was added 6.08 mL of i-PrMgCl 2.00 M
diene 26 as
a clear oil (100.3 mg, 55%, 20:1 Z:E). The

4782
A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
(12.16 mmol) dropwise via gas-tight syringe. The resulting clear,
yellow solution was stirred at ꢁ78 ꢂC for 1 h, then the carbonate of
29 (5.79 mmol, 1.339 g) in 10 mL THF was added dropwise via gas-
tight syringe. The resulting solution was stirred for 15 min, at
ꢁ78 ꢂC, then 5 mL of satd aq NH4Cl was added. The mixture was
warmed to room temperature before aqueous workup and extrac-
tion with 3ꢃ30 mL EtOAc. The crude material was purified by col-
umn chromatography on silica gel (10–30% ethyl acetate/hexanes)
to yield allene 30 as a clear oil. (0.966 g, 83%). 1H NMR (400 MHz,
five additional minutes, 30% H2O2 (1.3 mmol) was added, and the
resulting solution was stirred for 17 h at room temperature. To the
reaction was added aqueous Na2S2O3 dropwise, and the resulting
solution was filtered through a plug of silica, eluting with 100 mL
EtOAc. Z:E Selectivity was determined by 1H NMR of the crude
mixture after work-up. The crude material was purified by column
chromatography on silica gel (20% ethyl acetate/hexanes) to yield
diene 33 as a clear oil (38.8 mg, 52%, 5:1 Z,E: Z,Z). The major alkene
isomer was separated by HPLC [EtOAc/hexanes: 15–30% (0–30 min,
20 mL/min), on a Microsorb (Si 80-120 C5 H410119) column] to yield
pure 33. The stereochemistry of the major isomer was determined
by NOE (see the analysis following the synthesis of 34). 1H NMR
CDCl3)
d 7.36–7.26 (m, 5H), 5.35–5.31 (m, 1H), 5.28–5.24 (m, 1H),
4.58 (s, 2H), 4.36–4.35 (m, 1H), 3.56 (dd, J¼3.6, 9.6 Hz, 1H), 3.45 (dd,
J¼7.6, 9.6 Hz, 1H), 2.36–2.29 (m, 1Hþ1H), 1.00 (d, J¼8.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3)
d
201.8, 138.1, 128.6, 128.4, 127.9, 101.6, 93.0,
(400 MHz, CDCl3)
d
7.36–7.26 (m, 5H), 6.58 (d, J¼15.9 Hz, 1H), 5.83
74.5, 73.6, 69.1, 27.9, 22.5; IR (thin film, NaCl) 3422, 2925,1962,1454,
1363, 1105, 873, 737, 698, 610 cmꢁ1; HRMS (EI, Mþ) calcd for
C15H20O2, 232.1463 m/z (M); observed 231.1393 (MꢁH)þm/z.
(dt, J¼6.2, 12.3, 15.9 Hz, 1H), 5.29 (d, J¼9.4 Hz, 1H), 4.54 (s, 2H), 4.11
(d, J¼8.0 Hz, 2H), 3.68 (m, 2H), 2.81–2.75 (m, 1H), 2.45 (t, J¼6.4 Hz,
2H), 1.29 (O–H, 1H), 0.99 (d, J¼6.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3) d 141.4,138.4,137.2,129.5,128.6,128.0,127.8,126.0, 72.5, 71.3,
4.4.2. Synthesis of allene 32. To a solution of carbonyl diimidazole
(1 equiv) in benzene (0.1 M) in a flame-dried round bottom flask,
diol 31 (1 equiv) was added and the solution was refluxed under Ar
for 17 h. Subsequently, the solutionwas cooled to room temperature
and water (10 mL) was added. The resulting mixture was extracted
with ether, dried over MgSO4, filtered, and concentrated by vacuum.
The crude material was purified by column chromatography on
silica gel (25% ethyl acetate/hexanes) to yield carbonate as a clear oil
(84% yield). To a ꢁ78 ꢂC solution of CuBr–Me2S (1.99 g, 9.66 mmol)
in 50 mL of THF was added 5.07 mL of i-PrMgCl 2.00 M (10.14 mmol)
dropwise via gas-tight syringe. The resulting clear, yellow solution
was stirred at ꢁ78 ꢂC for 1 h, then the carbonate of 31 (4.83 mmol,
1.117 g) in 10 mL THF was added dropwise via gas-tight syringe. The
resulting solution was stirred for 15 min, at ꢁ78 ꢂC, then 5 mL of
satd aq NH4Cl was added. The mixture was warmed to room tem-
perature before aqueous workup and extraction with 3ꢃ30 mL
EtOAc. The crude material was purified by column chromatography
on silica gel (10–30% ethyl acetate/hexanes) to yield allene 32 as
61.4, 37.4, 26.9, 23.4; IR (thin film, NaCl) 3391, 2958, 2866, 1454,
1360, 1043, 966, 736, 697, 470 cmꢁ1; HRMS (EI, Na) calcd for
C17H24O2, 261.1776 m/z (MþH); observed 261.1843 (MþH)þ m/z.
4.5.2. (2Z,4Z)-1-Benzyloxy-4-hydroxyethyl-5-isopropyl-2,4-penta-
diene (34). To a ꢁ78 ꢂC solution of alkene 24 (0.142 mL, 1.03 mmol)
in 11 mL of diethyl ether (0.1 M) was added 1.03 mL of ClTi(Oi-Pr)3
(1.00 M in hexanes, 1.03 mmol) and 1.03 mL of c-C5H9MgCl (2.01 M
in ether, 2.05 mmol) dropwise via gas-tight syringe. The resulting
clear, yellow solution turned dark red-brown while warming to
ꢁ50 ꢂC over 1 h. The reaction mixture was stirred at ꢁ50 ꢂC for 1 h
and then cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene
32 (79.5 mg, 0.34 mmol) in 2 mL THF was added 0.150 mL of n-BuLi
(2.54 M in hexanes, 0.38 mmol) dropwise via gas-tight syringe. The
resulting solution was stirred for 15 min, removed from the cold
bath and added to the ꢁ78 ꢂC solution of alkene dropwise via
cannula. After warming slowly to 0 ꢂC over 2.5 h, 5 mL of satd aq
NH4Cl solution was added. The mixture was warmed to room
temperature before the resulting solution was filtered through
a plug of silica, eluting with 100 mL EtOAc. The crude material was
purified by column chromatography on silica gel (5% ethyl acetate/
hexanes) to yield an impure diene as a clear oil. This impure sample
was dissolved in 10 mL 1:1 MeOH/THF and KHCO3 (1.37 mmol) and
KF (2.73 mmol) were added. The reaction mixture was stirred for
five additional minutes, 30% H2O2 (1.71 mmol) was added, and the
resulting solution was stirred for 17 h at room temperature. To the
reaction was added aqueous Na2S2O3 dropwise, and the resulting
solution was filtered through a plug of silica, eluting with 100 mL
EtOAc. Z:E Selectivity was determined by 1H NMR of the crude
mixture after work-up. Z:E Selectivity was determined by 1H NMR
of the crude mixture after work-up. The crude material was purified
by column chromatography on silica gel (20% ethyl acetate/hex-
anes) to yield diene as a clear oil (44.8 mg, 53%, 3:1 Z,Z:Z,E). The
major alkene isomer was separated by HPLC [EtOAc/hexanes: 15–
30% (0–30 min, 20 mL/min), on a Microsorb (Si 80-120 C5 H410119)
a clear oil. (0.698 g, 63%). 1H NMR (400 MHz, CDCl3)
d 7.36–7.26 (m,
5H), 5.35–5.33 (m, 1H), 5.28–5.26 (m, 1H), 4.56 (s, 2H), 4.36 (m, 1H),
3.56 (dd, J¼3.6 Hz, 9.6 Hz,1H), 3.50 (dd, J¼7.6, 9.6 Hz,1H), 2.33–2.32
(m, 1Hþ1H), 1.01 (d, J¼4.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
201.7, 138.1, 128.6, 128.0, 127.9, 101.9, 93.2, 74.4, 73.5, 68.8, 27.9,
22.6; IR (thin film, NaCl) 3392, 2960, 1962, 1725, 1454, 1364, 1076,
875, 743, 698 cmꢁ1; HRMS (EI, Mþ) calcd for C15H20O2, 232.1463 m/z
(M); observed 231.1755 (MꢁH)þm/z.
4.5. Stereoselective access to (Z,E)- and (Z,Z)-1,3-dienes
4.5.1. (2E,4Z)-1-Benzyloxy-4-hydroxyethyl-5-isopropyl-2,4-penta-
diene (33). To a ꢁ78 ꢂC solution of alkene 24 (0.215 mL, 1.56 mmol)
in 16 mL of diethyl ether (0.1 M) was added 1.56 mL of ClTi(Oi-Pr)3
(1.00 M in hexanes, 1.56 mmol) and 1.56 mL of c-C5H9MgCl (2.01 M
in ether, 3.12 mmol) dropwise via gas-tight syringe. The resulting
clear, yellow solution turned dark red-brown while warming to
ꢁ50 ꢂC over 1 h. The reaction mixture was stirred at ꢁ50 ꢂC for 1 h
and then cooled to ꢁ78 ꢂC. To a separate ꢁ78 ꢂC solution of allene 30
(60.0 mg, 0.26 mmol) in 2 mL THF was added 0.112 mL of n-BuLi
(2.54 M in hexanes, 0.286 mmol) dropwise via gas-tight syringe.
The resulting solution was stirred for 15 min, removed from the cold
bath, and added to the ꢁ78 ꢂC solution of alkene dropwise via
cannula. After warming slowly to 0 ꢂC over 2 h, 5 mL of satd aq
NH4Cl solution was added. The mixture was warmed to room
temperature before the resulting solution was filtered through
a plug of silica, eluting with 100 mL EtOAc. The crude material was
purified by column chromatography on silica gel (5% ethyl acetate/
hexanes) to yield an impure diene as a clear oil. This impure sample
was dissolved in 10 mL 1:1 MeOH/THF and KHCO3 (1.04 mmol) and
KF (2.08 mmol) were added. The reaction mixture was stirred for
column] to yield pure 34. 1H NMR (400 MHz, CDCl3)
d 7.33–7.26 (m,
5H), 6.00 (d, J¼11.7 Hz, 1H), 5.77 (dt, J¼6.6, 11.7, 13.1 Hz, 1H), 5.18 (d,
J¼9.7 Hz, 1H), 4.51 (s, 2H), 4.01 (d, J¼8.0 Hz, 2H), 3.61 (t, J¼11.7 Hz,
2H), 2.40–2.36 (m, 1H), 2.27 (t, J¼6.2 Hz, 2H), 1.62 (O–H, 1H), 0.90
(d, J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 138.9, 138.2, 130.6,
130.0, 128.6, 128.4, 128.1, 127.9, 72.9, 67.2, 60.1, 41.1, 28.2, 22.9; IR
(thin film, NaCl) 3401, 3030, 2900, 2867, 1454, 1360, 1094,1071, 736,
697, 608 cmꢁ1; HRMS (EI, Na) calcd for C17H24O2, 261.1776 m/z
(MþH); observed 261.1858 (MþH)þ m/z.
Acknowledgements
We gratefully acknowledge financial support of this work by the
American Cancer Society (RSG-06-117-01), the Arnold and Mabel

A.U. Barlan, G.C. Micalizio / Tetrahedron 66 (2010) 4775–4783
4783
Soc. 2002, 124, 9696–9697; (s) Chang, H.-T.; Jayanth, T. T.; Wang, C.-C.; Cheng, C.-
H. J. Am. Chem. Soc. 2007, 129, 12032–12041; For the coupling of alkynes with
enols, see: (t) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128,
11368–11369; For the coupling of allenes with enones, see: (u) Chang, H.-T.;
Jayanth, T. T.; Cheng, C.-H. J. Am. Chem. Soc. 2007, 129, 4166–4167; (v) Trost, B. M.;
Pinkerton, A. B.; Seidel, M. J. Am. Chem. Soc. 2001, 123, 12466–12476; (w) Trost, B.
M.; McClory, A. Org. Lett. 2006, 8, 3627–3629; For the coupling of 1,3-dienes to
aldehydes or imines, see: (x) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am.
Chem. Soc. 1998, 120, 4033–4034; (y) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka,
S.; Tamaru, Y. J. Am. Chem. Soc. 2004, 126, 14360–14361; (z) Kojima, K.; Kimura,
M.; Ueda, S.; Tamaru, Y. Tetrahedron 2006, 62, 7512–7520; For the coupling of
homoallylic alcohols to acylpyrroles, see: (aa) Epstein, O. L.; Seo, J. M.; Masalov,
N.; Cha, J. K. Org. Lett. 2005, 7, 2105–2108; For coupling of internal alkynes with
allylic halides or allylic alcohols, see: (ab) Suzuki, N.; Kondakov, D. Y.; Kageyama,
M.; Kotora, M.; Hara, R.; Takahashi, T. Tetrahedron 1995, 51, 4519–4540; (ac)
Takai, K.; Yamada, M.; Odaka, G.; Utimoto, K.; Fujii, T.; Furukawa, I. Chem. Lett.
1995, 315–316.
4. For a discussion of the general design strategy, see Ref. 1g. For the coupling of
an internal alkyne with a terminal alkyne, see: (a) Shimp, H. L.; Micalizio, G. C.
Org. Lett. 2005, 7, 5111–5114; (b) Perez, L. J.; Shimp, H. L.; Micalizio, G. C. J. Org.
Chem. 2009, 74, 7211–7219; For the cross-coupling of two different internal
alkynes, see: (c) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006, 128, 2764–2765;
For the coupling of internal alkynes with alkenes, see: (d) Reichard, H. A.;
Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 1440–1443; For the coupling of
internal alkynes with imines, see: (e) McLaughlin, M.; Takahashi, M.; Micalizio,
G. C. Angew. Chem., Int. Ed. 2007, 46, 3912–3914; (f) Chen, M. Z.; Micalizio, G. C.
Org. Lett. 2009, 11, 4982–4985; For the coupling of alkenes with imines, see: (g)
Takahashi, M.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514–7516; For the
coupling of allenes with alkynes, see: (h) Shimp, H. L.; Micalizio, G. C. Chem.
Commun. 2007, 4531–4533; (i) Shimp, H. L.; Hare, A.; McLaughlin, M.; Micalizio,
G. C. Tetrahedron 2008, 64, 6831–6837; For allylic alcohol–alkyne coupling, see:
(j) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 15112–15113; For
allene–imine coupling, see: (k) McLaughlin, M.; Shimp, H. L.; Navarro, R.;
Micalizio, G. C. Synlett 2008, 735–738; For allylic alcohol–vinylsilane coupling,
see: (l) Belardi, J. K.; Micalizio, G. C. J. Am. Chem. Soc. 2008, 130, 16870–16872;
For allylic alcohol–imine coupling, see: (m) Takashi, M.; McLaughlin, M.; Mi-
calizio, G. C. Angew. Chem., Int. Ed. 2009, 48, 3648–3652; (n) Tarselli, M. A.;
Micalizio, G. C. Org. Lett. 2009, 11, 4596–4599; (o) Umemura, S.; McLaughlin, M.;
Micalizio, G. C. Org. Lett. 2009, 11, 5402–5405; (p) Yang, D.; Micalizio, G. C. J. Am.
Chem. Soc. 2009, 131, 17548–17549.
Beckman Foundation, Boehringer Ingelheim, Eli Lilly & Co., and the
National Institutes of Health (GM080266).
Supplementary data
Complete experimental details for preparative procedures along
with spectral data for all products are provided. Supplementary
data associated with this article can be found in the online version
at doi:10.1016/j.tet.2010.02.062.
References and notes
1. For recent reviews, see: (a) Montgomery, J.; Sormunen, G. J. Top. Curr. Chem. 2007,
279, 1–23; (b) Ng, S.-S.; Ho, C.-Y.; Schleicher, K. D.; Jamison, T. F. Pure Appl. Chem.
2008, 929–939; (c) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun.
2007, 4441–4449; (d) Patman, R. L.; Bower, J. F.; Kim, I. S.; Krische, M. J.
Aldrichemica Acta 2008, 41, 95–104; (e) Skucas, E.; Ngai, M.-Y.; Komanduri, V.;
Krische, M. J. Acc. Chem. Res. 2007, 40, 1394–1401; (f) Jeganmohan, M.; Chen, C.-H.
Chem.dEur. J. 2008, 14, 10876–10886; (g) Reichard, H. A.; McLaughlin, M.; Chen,
M. Z.; Micalizio, G. C. Eur. J. Org. Chem. 2009. doi:10.1002/ejoc.200901094
2. (a) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203–3206; (b) Gao,
Y.; Harada, K.; Sato, F. Tetrahedron Lett. 1995, 36, 5913–5916; (c) Qi, X.; Mont-
gomery, J. J. Org. Chem. 1999, 64, 9310–9313; (d) Mahandru, G. M.; Liu, G.;
Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698–3699; (e) Sa-ei, K.; Mont-
gomery, J. Org. Lett. 2006, 8, 4441–4443; (f) Chaulagain, M. R.; Sormunen, G. J.;
Montgomery, F. J. Am. Chem. Soc. 2007, 129, 9568–9569; (g) Baxter, R. D.;
Montgomery, J. J. Am. Chem. Soc. 2008, 130, 9662–9663; (h) Huang, W.-S.; Chan,
J.; Jamison, T. F. Org. Lett. 2000, 2, 4221–4223; (i) Colby, E. A.; Jamison, T. F. J. Org.
Chem. 2003, 68, 156–166; (j) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003,
42, 1364–1367; (k) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc.
2003, 125, 3442–3443; (l) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126,
15342–15343; (m) Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett.
2005, 7, 2937–2940; (n) Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077–
3080; (o) Moslin, R. M.; Miller, K. M.; Jamison, T. F. Tetrahedron 2006, 62, 7598–
7610; (p) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
4664–4668; (q) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127,
11269–11276; (r) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128,
16448–16449; (s) Cho, C.-W.; Krische, M. J. Org. Lett. 2006, 8, 3873–3876; (t)
Barchuk, A.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432–8433;
(u) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 280–281;
(v) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12644–
12645; (w) Skucas, E.; Kong, J. R.; Krische, M. J. J. Am. Chem. Soc. 2007, 129,
7242–7243; (x) Cho, C.-W.; Skucas, E.; Krische, M. J. Organomet. 2007, 26, 3860–
3867; (y) Hong, Y.-T.; Cho, C.-W.; Skucas, E.; Krische, M. J. Org. Lett. 2007, 9,
3745–3748; (z) Han, S. B.; Kong, J. R.; Krische, M. J. Org. Lett. 2008, 10, 4133–
4135; (aa) Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am.
Chem. Soc. 2009, 131, 2066–2067; (ab) Neva´rez, Z.; Woerpel, K. A. Org. Lett.
2007, 9, 3773–3776; (ac) Bourque, L. E.; Woerpel, K. A. Org. Lett. 2008, 10, 5257–
5260; (ad) Anderson, L. L.; Woerpel, K. A. Org. Lett. 2009, 11, 425–428; (ae)
Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 2005, 127, 3694–3695;
(af) Bahadoor, A. B.; Micalizio, G. C. Org. Lett. 2006, 8, 1181–1184.
3. For the coupling of two alkynes and an enone for the formation of a substituted
cyclohexene, see: (a) Lozanov, M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124,
2106–2107; For the coupling of cyclopropyl ketones to enones, see: (b) Liu, L.;
Montgomery, J. J. Am. Chem. Soc. 2006, 128, 5348–5349; For the coupling of an
imine with an enone, see: (c) Liu, L.; Montgomery, J. Org. Lett. 2007, 9, 3885–
3887; For the coupling of an alkyne with an enone, see: (d) Herath, A.;
Thompson, B. B.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 8712–8713; For
aldehyde–epoxide coupling, see: (e) Molinaro, C.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2005, 44, 129–132; For enyne–epoxide coupling, see: (f) Miller, K. M.;
Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126,
4130–4131; For the coupling of terminal alkenes to enones, see: (g) Ho, C.-Y.;
Ohmiya, H.; Jamison, T. F. Angew. Chem., Int. Ed. 2008, 47, 1893–1895; For the
coupling of allenes with aldehydes, see: (h) Ng, S.-S.; Jamison, T. F. J. Am. Chem.
Soc. 2005, 127, 7320–7321; (i) Ng, S.-S.; Jamison, T. F. Tetrahedron 2006, 62,
11350–11359; For the coupling of aldehydes to terminal alkenes, see: (j) Ng, S.-S.;
Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 14194–14195; (k) Ng, S.-S.; Ho, C.-Y.;
Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 11513–11528; (l) Ho, C.-Y.; Ng, S.-S.;
Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 5362–5363; (m) Ho, C.-Y.; Jamison, T. F.
Angew. Chem., Int. Ed. 2007, 46, 782–785; For coupling of a terminal alkene with
an isocyanate, see: (o) Schleicher, K. D.; Jamison, T. F. Org. Lett. 2007, 9, 875–878;
For the coupling of N-sulfonyl imines with 2-vinylpyridines, see: (p) Komanduri,
V.; Grant, C. D.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 12592–12593; For
alkene–alkyne coupling, see: (q) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705
(and references cited therein); (r) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H. J. Am. Chem.
5. Internal alkynes and substituted alkenes are notoriously unreactive substrates
in a variety of bimolecular metal-centered [2þ2þ1] chemistry. Examples that
highlight the ability to overcome this characteristic include Refs. 4c,d,g,j,l,m–p.
6. Reichard, H. A.; Rieger, J. C.; Micalizio, G. C. Angew. Chem., Int. Ed. 2008, 47,
7837–7840.
7. Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340–348.
8. Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3203–3206.
9. For study and application of related ylids, see the following selected references:
(a) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827–2828; (b)
Arimoto, H.; Kaufman, M. D.; Kobayashi, K.; Qiu, Y.; Smith, A. B., III. Synlett 1998,
765–767; (c) Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129,
8960–8961.
10. For examples of reductive cross-coupling chemistry with vinylsilanes, see: (a)
Mizojiri, R.; Urabe, H.; Sato, F. J. Org. Chem. 2000, 65, 6217–6222; (b) Ref. 4l.
11. For the use of styrene in related Ti-mediated coupling reactions, see: (a)
Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc. 2008, 130, 15997–
16002; For an early example of olefin exchange in the context of the Kulinkovich
reaction, see: (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198–4199.
12. (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A.; Prityckaja, T. S. Zh. Org.
Khim. 1989, 25, 2244; (b) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100,
2789–2834.
13. Reductive ethylation processes have been reported in Ti-mediated reactions of
EtMgBr with allylic ethers and allylic alcohols, see: (a) Kulinkovich, O. G.;
Epstein, O. L.; Isakov, V. E.; Khmel’nitskaya, E. A. Synlett 2001, 49–52; (b)
Matyushenkov, E. A.; Churikov, D. G.; Sokolov, N. A.; Kulinkovich, O. G. Russ. J.
Org. Chem. 2003, 39, 478–485 Also, the reductive ethylation of homoallylic
alcohols has been reported; (c) Kulinkovich, O. G.; Shevchuk, T. A.; Isakov, V. E.;
Prokhorevich, K. N. Russ. J. Org. Chem. 2006, 42, 659–664 See also, Ref. 11a..
14. In no case could a clean sample of (Z)-diene be obtained in any of attempted
ethylation of an allenyl alcohol with EtMgBr.
15. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470.
16. Kang, S.-K.; Kim, S.-G.; Cho, D.-G. Tetrahedron: Asymmetry 1992, 3, 1509–1510.
17. This mechanistic proposal is consistent with the high levels of selectivity ob-
served in related reductive cross-coupling reactions of allylic alkoxides with
alkynes, vinylsilanes and imines (see Refs. 4j,4l,4m–o).
18. In comparison to the poor levels of reactivity associated with substituted al-
kenes in bimolecular metal-centered [2þ2þ1], Ti-mediated reactions of allenes
are known: Hideura, D.; Urabe, H.; Sato, F. Chem. Commun. 1998, 271–272.