Reprint of "Allene-alkyne cross-coupling for stereoselective synthesis of substituted 1,4-dienes and cross-conjugated trienes"

Article abstract of DOI:10.1016/j.tet.2008.03.086

Titanium-mediated cross-coupling of allenic alcohols with alkynes has been investigated. Divergent reaction pathways were discovered that provide either stereodefined 1,4-dienes or substituted cross-conjugated trienes. In short, allene substitution plays a critical role in the determination of reaction pathway.

Full text of DOI:10.1016/j.tet.2008.03.086

Tetrahedron 64 (2008) 6831–6837
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reprint of ‘‘Allene–alkyne cross-coupling for stereoselective synthesis of
substituted 1,4-dienes and cross-conjugated trienes’’q
*
Heidi L. Shimp, Alissa Hare, Martin McLaughlin, Glenn C. Micalizio
Department of Chemistry, Yale Univeristy, New Haven, CT 06520-8107, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Titanium-mediated cross-coupling of allenic alcohols with alkynes has been investigated. Divergent
reaction pathways were discovered that provide either stereodefined 1,4-dienes or substituted cross-
conjugated trienes. In short, allene substitution plays a critical role in the determination of reaction
pathway.
Received 28 December 2007
Received in revised form 4 February 2008
Accepted 5 February 2008
Available online 16 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor John Hartwig on his
receipt of the Tetrahedron Prize
1. Introduction
tetrasubstituted 1,3-dienes (1), branched allylic systems (2) and
1,4-dienes (3), they represent only a small sample of the potential
The direct cross-coupling of unactivated
p
-systems could rep-
cross-coupling reactions possible based on the reactivity of metal–
p complexes.
resent a powerful strategy for the convergent synthesis of complex
molecules. Such processes provide an advantage over metal-cata-
lyzed cross-coupling reactions1 that typically require the use of
activated coupling partners (i.e., functionalized organometallic
reagents and organic halides), as these ‘starting materials’ often
require numerous stoichiometric reactions for their preparation.
While numerous examples of metal-mediated coupling reactions
alkyne–alkyne cross-coupling:
R3
HO
R1
OH
R4
R5
R5
+
R1
R4
R2
R2 R3
1
of unactivated
p-systems have been described in intramolecular
alkene–alkyne cross-coupling:
settings, few reports describe the success of such processes for
intermolecular C–C bond formation.2 Where, in intramolecular C–C
bond forming reactions, reactivity and selectivity are controlled by
OH
R3
OH
R1
R4
R4
+
R3
the enforced proximity of the reacting
p-systems, the analogous
R2
R1 R2
bimolecular processes are significantly more complex. To realize
such intermolecular cross-coupling reactions, one must be able
to control site-selectivity (in the functionalization of each reacting
2
allylic alcohol–alkyne cross-coupling:
p
-component) and facial selectivity, while overcoming barriers
OH
R1
R4
associated with general reactivity.
R1
+
R2
R4
Recently, we have described a variety of titanium-mediated
cross-coupling reactions for the fusion of substituted and unactived
R3
R3
R2
p
-systems (Scheme 1).3 While these coupling reactions have pro-
3
vided a convergent pathway to the synthesis of stereodefined
Scheme 1. Directed cross-coupling reactions of unactivated
p-systems.
q
A publisher’s error resulted in this article appearing in the wrong issue. The
Metal-mediated allene–alkyne cross-coupling is a relatively un-
derdeveloped process.4 In the context of convergent synthesis of di-
enes, this mode of cross-coupling is known to be effective with only
a limited subset of coupling partners, providing access to di- and tri-
subtitutedproducts (Scheme2). Forexample, allene hydrozirconation
followed by MAO-catalyzed allylzirconation of terminal alkynes
article is reprinted here for the reader’s convenience and for the continuity of this
special issue. Anyone wishing to cite this article should use the details of the
original publication [Heidi L. Shimp et al. Tetrahedron 2008, 64(16), 3437-3445;
doi:10.1016/j.tet.2008.02.015].
* Corresponding author. Tel.: þ1 203 432 9403.
E-mail address: glenn.micalizio@yale.edu (G.C. Micalizio).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.086

6832
H.L. Shimp et al. / Tetrahedron 64 (2008) 6831–6837
provides a regio- and stereoselective route to 1,4-disubstituted 1,4-
dienes (4þ5/6).4d,e For more highly substituted products, cross-
coupling between preformed titanium–alkyne complexes and
monosubstituted allenes has been reported to provide trisubstituted
1,4-dienes, albeit with varying degrees of stereoselection (4þ7/8).4a
While cross-coupling of an alkyl substituted allene bearing a tethered
benzyl ether (R1¼(CH2)2OBn) with a symmetrical alkyne (R2 and
R3¼Bu) provides 1,4-dienes with a slight preference for the formation
of the E-disubstituted olefin (E:Z¼64:36), selectivity is a complex
functionof thenature of thealkyne. Forexample, couplingof thesame
allene with a TMS substituted alkyne provides 1,4-diene products
with a modest preference for the formation of the Z-olefin-containing
1,4-diene (E:Z¼25:75).
2. Results
2.1. Synthesis of stereodefined 1,4-dienes
Our studies began with examination of the cross-coupling re-
action between 2,3-butadiene-1-ol 12 and the symmetrical alkyne
13. As illustrated in Scheme 4, preformation of the metal–alkyne
complex of 13, followed by addition of the lithium alkoxide of
allene 12 and aqueous work-up provided a 3:1 mixture of coupled
products in 53% yield. The major component of this mixture,
identified as the stereodefined 1,4-diene 14, was accompanied by
a small amount of a cross-conjugated triene (15). This initial result
was viewed as quite promising, as no stereoisomeric 1,4-dienes
were detected in the product mixture. Further, the stereoselection
observed was consistent with a directed C–C bond forming process
in preference to a non-directed process (the expected product from
a non-directed cross-coupling is a 1,4-diene bearing a Z-allylic
alcohol;4a not shown).
R1
(i) allene hydrozirconation
R1
R2
+
R2
•
4
(ii) MAO-catalyzed allylzirconation
of terminal alkyne
5
6
(i) formation of titanium–alkyne
R3
complex
R1
R3
R1
OPMB
+
R2
•
4
(ii) carbometalation of allene
R2
OH
7
8
OPMB
when R1 = alkyl
E:Z varies from 64:36 to 25:75
OPMB
14
a
HO
+
+
(3:1)
•
OPMB
53%
Scheme 2. Known pathways to 1,4-dienes based on allene–alkyne cross-coupling.
OPMB
12
13
OPMB
Major challenges that exist in the development of a general
allene–alkyne cross-coupling reaction include the following:
15
a = alkyne (1.0 equiv), ClTi(Oi-Pr)3 (2.0 equiv), c-C5H9MgCl (4.0 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (0.7 equiv)
(–78 to 0 °C).
(1) control in the functionalization of di- and trisubstituted
allenes,
(2) regioselection (for the functionalization of each
allene and alkyne), and
p-component:
Scheme 4. A stereodefined 1,4-diene and cross-conjugated triene from an alkoxide-
directed allene–alkyne coupling.
(3) stereoselection (in the formation of the substituted olefins
resident in the products).
Cross-conjugated triene 15 was reasoned to be derived from
a competition between the directed carbometalation pathway (A)
and a formal metallo-[3,3] rearrangement process (B) (Scheme 3).
In considering this competing pathway, it was reasoned that the
mechanism of the reaction could derive from a pathway whereby
C–C bond formation occurs in concert with C–O bond breaking (C;
Fig. 1),7 or by a pathway where directed carbometalation provides
an intermediate bicyclo[3.2.0] metallacyclopentane, which then
undergoes syn elimination (D/E/15).
If production of the cross-conjugated triene proceeded by
a pathway that involved full, or partial, C–Ti bond formation in the
transition state (i.e., D), then allene substitution proximal to the
alkoxide (R1¼alkyl) was anticipated to greatly impact the viability
of this pathway. With R1¼alkyl, progression through D would re-
quire formation of a tertiary metal–carbon bond, a fact which was
anticipated to greatly disfavor this pathway, and hence formation of
a cross-conjugated triene. Alternatively, the reaction pathway for
production of 1,4-dienes was not anticipated to be adversely af-
fected by such substitution (see A; Scheme 3). In accord with these
expectations, cross-coupling of 2-methyl-2,3-butadiene-1-ol 16
with alkyne 13 proceeds with good efficiency, and high selectivity
for the formation of the E,E-1,4-diene 17 (Scheme 5). In this
reaction, no evidence was found for the production of a cross-
conjugated triene, or a stereoisomeric coupling product.
To address these issues, we initiated studies aimed at defining an
alkoxide-directed allene–alkyne cross-coupling reaction.5 As
depicted in Scheme 3, it was anticipated that formation of a titanium
complex of 7, followed by exposure to a preformed allenic alkoxide
(9) would afford a mixed titanate ester in a transient fashion. This
reactive intermediate could then rearrange via directed carbome-
talation (A/10) or formal metallo-[3,3] rearrangment (B/11).6
Here, we describe titanium-mediated cross-coupling reactions be-
tween allenes and alkynes that provide either 1,4-dienes (10) or
cross-conjugated trienes (11) in a stereoselective fashion.
R4
R3
R1
Ti
(Oi-Pr)n
R4
O
Ti
R1
(Oi-Pr)n
R4
R1
a
O
M+ –
O
or
•
+
•
H
•
R2
R3
R3
A
R2
R2
9
7
B
directed
carbometalation
formal metallo-
[3,3]-rearrangement
R1
R2
R3
OH
R3
R4
R4
R1 R2
10b
H
Table 1 illustrates that the 1,4-diene-selective cross-coupling of
1,1-disubstituted allenes with internal alkynes can be accomplished
with a variety of functionalized substrates. For example, coupling of
the methoxy-substituted allene 18 with symmetrical alkyne 13
affords the stereodefined enol ether-containing 1,4-diene 19 in 87%
yield with ꢀ20:1 selectivity for the establishment of each
11b
a = formation of a titanium–alkyne complex followed by introduction of the
allenic alkoxide.
b = obtained after aqueous work up.
Scheme 3. A titanium-mediated, alkoxide-directed allene–alkyne cross-coupling
reaction.

H.L. Shimp et al. / Tetrahedron 64 (2008) 6831–6837
6833
OPMB
OPMB
of a stereoisomeric diene or cross-conjugated triene in this re-
action, a minor isomer derived from regioisomeric functionaliza-
tion of the TMS-alkyne was observed (rs¼4:1). This observation
speaks to the complexity of the present cross-coupling reaction,
where site- and stereoselective functionalization of each unsym-
R2
R1(Oi-Pr)
n
Ti
O
R1
R1
H2O
R2
OPMB
OPMB
H
•
[M]
H
15; R1 = H
C
metric p-system is accomplished simultaneously.
or
As depicted in entry 3, the heterocycle-containing TMS-alkyne
22 is also a suitable substrate for this cross-coupling process. Re-
action with allene 16 provides the 1,4-diene product 23 as a single
isomer (48% isolated yield). As observed previously, a minor isomer
derived from regioisomeric functionalization of the unsymmetrical
alkyne was generated (rs¼4:1). Finally, cross-coupling of allene 16
with the unsymmetrically substituted internal alkyne 24 provides
1,4-diene 25 in 62% yield (entry 4). This example demonstrates that
site- and stereoselective C–C bond formation proceeds with free
R2
R1(Oi-Pr)
O
n
(Oi-Pr)n
Ti
O
R2
Ti
R2
R1
H
•
R2
H
D
E
Figure 1. Possible origins of the cross-conjugated triene product 15.
OPMB
hydroxyl functionality tethered to each reacting p-system.
OPMB
Me
While allenic alkoxides uniformly provide 1,4-diene products
with high levels of stereoselection in coupling reactions with internal
alkynes (regio- and diastereoselection is ꢀ20:1), the homoallenic
alkoxide derived from 26 does not provide high levels of stereo-
selection in cross-coupling reactions with alkyne 13 (Scheme 6).
Whereas the 1,4-diene 27 is the major product in this coupling
reaction, the isomeric diene 28 is formed as a minor product
(27:28¼3:1). This erosion in selectivity, from allenic alcohol to
homoallenic alcohol, is presumed to derive from a competition be-
tweendirectedandnon-directedC–Cbondformingprocesses(Fig. 2).
Trisubstituted allenes are also useful substrates in this stereo-
selective cross-coupling reaction. As depicted in Scheme 7, coupling
of allene (ꢁ)-29 with the symmetrical alkyne 13 provides the
highly substituted, stereodefined E,E-1,4-diene 30 in 53% yield.
While the yield of the substituted diene is sufficient to render this
reaction useful for the synthesis of highly substituted 1,4-dienes,
a
OH
HO
+
•
OPMB
74%
OPMB
Me
16
13
17
a = alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.3 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
Scheme 5. Cross-coupling of 1,1-disubstituted allenes with internal alkynes proceeds
with high levels of site-selectivity.
stereodefined olefin (entry 1). In a more complex example, allene
18 can be coupled to the unsymmetrical alkyne 20 in a site- and
stereoselective manner. In this case, the 1,4-diene 21, containing
both a stereodefined enol ether and vinylsilane, is produced in 66%
yield (entry 2). Although no evidence was found for the production
Table 1
R3
OH
OH
R4
alkoxide-directed
cross-coupling
R4
•
+
R1
R1
R3
R2
R2
Entrya
Allene
Alkyne
Yield (%)
87
E:Zb
1,4-Diene
OH
OH
OPMB
OPMB
•
Ph
Ph
Ph
1
13
ꢀ1:20
ꢀ1:20
OMe
18
OH
OMe
OH
19
OPMB
OPMB
TMS
•
Ph
2
3
66
48
62
OMe
OMe
TMS
21c
TMS
18
20
TMS
OH
OH
•
ꢀ1:20
ꢀ20:1
N
Me
Me
N
16
23c
22
OH
Me Me
OH
Me Me
HO OBn
Me
OBn
•
4
OH
Me
25d
Me
Me
24
16
a
Typical reaction conditions: alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe (ꢂ78 to ꢂ30 ꢃC), cool to ꢂ78 ꢃC, then add allenyl alkoxide (1 equiv)
(ꢂ78 to 0 ꢃC).
b
c
Selectivity refers to the olefin formed from the allene coupling partner.
rs¼4:1.
d
rr¼2:1.

6834
H.L. Shimp et al. / Tetrahedron 64 (2008) 6831–6837
OPMB
OPMB
OPMB
OPMB
Me
OH
a
HO
+
OPMB
OPMB
•
53%
OH Me
Me
Me
Me Me
OPMB
OPMB
27
a
30
(+ 31% of cross-conjugated triene)
•
+
29
13
OPMB
+
(3:1)
64%
HO
Me
a = alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
OPMB
26
13
HO
28
Scheme 7. Cross-coupling of trisubstituted allenes with internal alkynes.
a = alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
Scheme 6. Cross-coupling of homoallenic alcohols with alkynes leads to diminished
stereoselection.
Blomquist and Verdol, 1955:
AcO OAc
O
O
O
O
maleic
O
unlike previously described cross-couplings, this reaction produces
a significant amount of cross-conjugated triene (31%).
anhydride
81%
O
31
32
33
2.2. Convergent synthesis of stereodefined poly-substituted
cross-conjugated trienes
Scheme 8. Synthesis of 2-vinyl-1,3-butadiene and its diene-transmissive Diels–Alder
reaction with maleic anhydride.
development of the intermediate bicyclo[3.3.0] metallacycle. Cross-
coupling by C–C bond formation at the central carbon of the allene
would avoid these destabilizing interactions, yet would require the
formation (partial or full, depending on the mechanism) of a ter-
tiary metal–carbon bond (G). Following this analysis, we reasoned
that the reaction pathway for cross-coupling of allenes with
alkynes could be diverted from the production of 1,4-dienes to
stereodefined cross-conjugated trienes if the requirement of gen-
erating a tertiary metal–carbon bond was removed, while retaining
the substitution at the terminus of the allene.
In line with this expectation, we were pleased to find that
coupling of (ꢁ)-2,3-pentadiene-1-ol 34 with alkyne 13 affords the
stereodefined cross-conjugated triene 35 (41% post HPLC; Scheme
9). Although this unoptimized coupling reaction did not proceed
with high efficiency, no evidence was found for the production of
a 1,4-diene.
A variety of substituted allenes and alkynes can be employed in
this site- and stereoselective cross-conjugated triene synthesis. As
depicted in entry 1 of Table 2, coupling of the isopropyl-substituted
allenic alcohol 36 with alkyne 13 provides the substituted triene 37
in 69% yield with ꢀ20:1 selectivity for the formation of each
stereodefined trisubstituted olefin. Entry 2 demonstrates that this
convergent coupling reaction can be employed to generate tetra-
substituted olefins. In this case, triene 39 can be prepared as a sin-
gle isomer in 62% yield.
Aside from controlling olefin geometry and site-selectivity in
allene-functionalization, one can also control site-selectivity in the
functionalization of unsymmetrical alkynes. As illustrated in entry
3, the branched alkyne 40 can be selectively coupled to allene 36. In
2.2.1. Background to the utility of cross-conjugated trienes in
complex molecule synthesis
Cross-conjugated trienes are a functional group with great
potential in complex molecule synthesis.8 Since Blomquist and Ver-
dol’s synthesis of 2-vinyl-1,3-butadiene (32), and subsequent dem-
onstration of its diene-transmissive Diels–Alder reactionwith maleic
anhydride,9 many have explored the potential of cross-conjugated
trienes in carbocycle and heterocycle construction (Scheme 8).4h,10
Despite great interest in the use of this reactive structural motif,
barriers still exist in the preparation of highly substituted and ster-
eodefined cross-conjugated trienes. Whereas cyclic cross-conju-
gated trienes are accessible via metal-mediated cycloisomerization
processes,11 the synthesis of acyclic cross-conjugated trienes is
limited to the preparation of a small subset of sparsely substituted
trienes.9,12 In such processes, issues concerning stereoselection in
the generation of the substituted olefins of the cross-conjugated
triene are pronounced.
Based on the potential utility of substituted cross-conjugated
trienes in complex molecule synthesis, and the lack of general
convergent pathways for their synthesis, we focused our attention
on optimizing the allene–alkyne cross-coupling reaction for the
synthesis of stereodefined cross-conjugated trienes.
2.2.2. Synthesis of cross-conjugated trienes
The decreased regioselection observed in cross-coupling of
trisubstituted allene 29 with alkyne 13 could be derived from
a destabilization of the transition state for directed carbometalation
in pathway F (Fig. 3). This destabilization would likely be based on
the required build-up of non-bonded 1,2-steric interactions in the
R
O
Ti
(Oi-Pr)n
Me
R
•
R
Me
OH
+ –O
Me
R
M
R
E,E-1,4-diene
directed
carbometalation
+
•
O– +
M
R
(Oi-Pr)n
R
Me
Ti
R
26
13
Me
HO
R
•
R
non-directed
Z,E-1,4-diene
carbometalation
Figure 2. Competition between directed and non-directed carbometalation.

H.L. Shimp et al. / Tetrahedron 64 (2008) 6831–6837
6835
(Oi-Pr)n
Me
O
Ti
R
(Oi-Pr)n
Ti
cross-conjugated
triene
O
R
Me
vs.
1,4-diene
R
H
•
Me
R
F
G
Me
non-bonded steric
interaction
Figure 3. Competition between directed carbometalation and formal metallo-[3,3] rearrangement with trisubstituted allenes.
this reaction, C–C bond formation occurs preferentially distal to the
branched architecture of alkyne 40, and affords cross-conjugated
triene 41 in 57% yield (rs¼3:1, E:Z ꢀ20:1). The stereochemistry of
these products was assigned on the basis of spectroscopic data, as
depicted for 37 (Fig. 4).
OPMB
OPMB
OPMB
a
HO
+
•
OPMB
Similarly, entries 4–7 demonstrate that selective functionaliza-
tion of silyl-substituted alkynes is possible.8 In these cases, the
cross-conjugated triene products 43, 45, 46 and 48 can be gener-
ated in >70% yield, with high levels of stereoselection (regiose-
lection with respect to alkyne functionalization¼4:1).
Me
Me
35
34
13
a = alkyne (1.4 equiv), Ti(Oi-Pr)4 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
The stereoselectivity observed in these reactions is consistent
with C–C bond formation occurring anti to the distal alkyl sub-
stituent of the allene via geometry B (Scheme 3). To further explore
Scheme 9. Coupling of (ꢁ)-2,3-pentadiene-1-ol 34 with alkyne 13.
Table 2
R3
R3
R1
R4
R2
OH
titanium-mediated
+
•
cross-coupling
R1 R2
E:Zb
R4
Entrya
Allene
Alkyne
Yield (%)
rsc
Product
OPMB
OH
1
13
69
ꢀ20:1
d
iPr
•
OPMB
OPMB
36
iPr
37
Me
•
OH
OH
Me
2
3
13
62
d
d
OPMB
Me
Me
39
Me Me Me
38
Me Me
i-Pr
•
57d
ꢀ20:1
3:1
Me
TESO
40
OBn
OBn
HO
i-Pr
36
41
R
BnO
OH
OH
OBn
i-Pr
•
R
i-Pr
4
5
36
44; R¼TMS
44; R¼TIPS
75
82
ꢀ20:1
ꢀ20:1
4:1
4:1
45; R¼TMS
45; R¼TIPS
R
PMBO
Me
Me
OPMB
•
R
Me
Me
6
7
38
47; R¼TMS
47; R¼TIPS
71
74
d
d
4:1
4:1
48; R¼TMS
48; R¼TIPS
a
Typical reaction conditions: alkyne (1.4 equiv), ClTi(Oi-Pr)3 or Ti(Oi-Pr)4 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe (ꢂ78 to ꢂ30 ꢃC), cool to ꢂ78 ꢃC, then add allenyl
alkoxide (1 equiv) (ꢂ78 to 0 ꢃC).
b
Refers to the establishment of the substituted olefin derived from the allene (the other stereodefined olefin, derived from the alkyne is formed as a single isomer).
Refers to the site of alkyne functionalization.
Yield after deprotection with TBAF (see supplementary data for details).
c
d

6836
H.L. Shimp et al. / Tetrahedron 64 (2008) 6831–6837
nOe
HH
OPMB
OPMB
OPMB
OPMB
PMBO
O
O
OPMB
OPMB
H
H
H
OPMB
PhMe
nOe
+
N Me
N Me
90 °C
50%
i-Pr
Me Me
H
O
O
i-Pr
i-Pr
52
37
37
51
dr = 6:1
Figure 4. Stereochemical assignment of the cross-conjugated triene products was
accomplished by analysis of NOE data as depicted for 37.
Scheme 11. Thermal intermolecular site- and stereoselective Diels–Alder reaction of
a trisubstituted cross-conjugated triene and an activated dienophile.
the validity of this model, the cross-coupling reaction of a diaste-
reomerically pure chiral allene, bearing a secondary hydroxyl
directing group, with a symmetrical alkyne was investigated
(Scheme 10). Coupling of allene 49 with alkyne 13 provides triene
50 in 50% yield. The observed stereoselection is consistent with
reaction by way of a boat-like geometry H,3d where C–C bond
formation occurs anti to the terminal butyl substituent of the
allene, with the allenic substituent (R1) occupying an equatorial
position.
The highly substituted cross-conjugated trienes produced from
this cross-coupling reaction have great potential for facilitating the
syntheses of complex carbocyclic and heterocyclic ring systems via
site- and stereoselective cycloaddition processes. Whereas the
reactivity of less-substituted acyclic cross-conjugated trienes is dif-
ficult to control in bimolecular [4þ2] cycloadditions, as multiple
cycloadditions often predominate,4h,9,10,12 the substituted trienes
generated here cleanly undergo mono-cycloaddition with activated
OH
R1
R2
R1
R3
titanium-mediated
cross-coupling
R3
+
+
HO
HO
R2
•
53
54
55
R2
R3
R3
titanium-mediated
cross-coupling
•
R2
R1
R1
H
56
54
57
Scheme 12. Allene–alkyne cross-coupling for the synthesis of 1,4-dienes or cross-
conjugated trienes.
stereoselective mono [4þ2] cycloaddition with activated dien-
ophiles. Overall, these highly site-selective cross-coupling reactions
provide stereoselective convergent access to structural motifs that
are anticipated to be of great utility in the synthesis of complex
molecules. Research directed at exploring these processes, both
mechanistically and in the context of target-oriented synthesis, is
underway.
dienophiles. For example, heating
a toluene solution of 37
with maleimide 51 provides the cycloadduct 52 in 50% yield
(endo:exo¼6:1; Scheme 11). This reactivity pattern is consistent with
the decreased reactivity of (Z)-dienes in Diels–Alder reactions.13
3. Conclusion
The cross-coupling of allenic alcohols with alkynes can be ac-
complished in a highly regio- and stereoselective manner. Applying
an alkoxide-directed coupling reaction, tetrasubstituted 1,4-dienes
are prepared by titanium-mediated coupling of 1,1-disubstituted
allenes with internal alkynes. In these cases, stereoselection is con-
sistent with the proposition that these processes proceed through
the formation of bicyclo[3.3.0] metallacyclopentenes, protonation of
which affords 1,4-dienes 55 (Scheme 12). Alternatively, alkoxide-
directed cross-coupling of 1,3-disubstituted allenes with internal
alkynes provides a general strategy for the synthesis of substituted
cross-conjugated trienes 57. These stereodefined substituted
cross-conjugated trienes are useful intermediates in the synthesis
of complex polycyclic systems, as they undergo site- and
4. Experimental section
4.1. General experimental information
All reactions were conducted in flame-dried glassware under
nitrogen using anhydrous solvents. Toluene and tetrahydrofuran
were distilled from sodium/benzophenone ketyl before use. Diethyl
ether was used after passing through an activated alumina column.
Titanium(IV) isopropoxide was used after distillation of the com-
mercially available reagent. ClTi(Oi-Pr)3 was purchased as a 1 M
solution in hexanes from Aldrich and was used without further
analysis or purification. All other commercially available reagents
were used as received.
stereoselection?
R3
R3
R2
R3
R3
OH
R1 *
cross-coupling
H
R1
R3
R3
+
+
•
or
R1
R2
H
R2
Bu
H
H
(i-PrO)n
Ti
Bu
H
R2
R2
OH
OPMB
a
O
BnO
•
13
R1
H
•
50%
OPMB
H
Bu
BnO
49
H
(E) 50
a = alkyne 9 (1.4 equiv), Ti(Oi-Pr)4 (2.1 equiv), c-C5H9MgCl (4.3 equiv), PhMe (–78 to –30 °C), cool to –78 °C, then add allenyl alkoxide
(1 equiv) –78 °C to 0 °C.
Scheme 10. Allene–alkyne coupling for the synthesis of stereodefined tetrasubstituted cross-conjugated trienes.

H.L. Shimp et al. / Tetrahedron 64 (2008) 6831–6837
6837
4.2. Representative procedure for the stereoselective
synthesis of 1,4-dienes
138.5, 138.1, 132.6, 130.7, 130.6, 129.2, 129.1, 126.6, 116.4, 113.69,
113.65, 72.44, 72.39, 69.7, 68.7, 55.21, 55.20, 30.2, 28.8, 26.9, 23.1; IR
(thin film, NaCl) 2957, 2864,1613,1513,1464,1360,1302,1248,1173,
1097, 1037, 820 cmꢂ1; LRMS (EI, Na) calcd for C29H38O4Na, 473.28
m/z (MþNa); observed, 473.5 m/z (MþNa)þ.
4.2.1. Synthesis of (2E,5Z)-8-(4-methoxybenzyloxy)-5-(2-(4-
methoxybenzyloxy)ethyl)-2-methylocta-2,5-dien-1-ol, 17
To a ꢂ78 ꢃC solution of alkyne 13 (200 mg, 0.56 mmol) in 3.7 mL
Acknowledgements
of PhMe were added 850
0.85 mmol) and 860
mL of ClTi(Oi-Pr)3 (1.0 M in hexanes,
L of c-C5H9MgCl (1.96 M in Et2O, 1.69 mmol)
m
We gratefully acknowledge financial support of this work by the
American Cancer Society (RSG-06-117-–01), the American Chem-
ical Society (PRF-45334-G1), the Arnold and Mabel Beckman
Foundation, Boehringer Ingelheim, Eli Lilly & Co., and the National
Institutes of Health – NIGMS (GM80266). H.L.S. acknowledges
support from BMS in the form of a graduate student fellowship.
dropwise via a gas-tight syringe. The resulting clear, yellow solution
turned dark reddish brownwhilewarming slowly to ꢂ30 ꢃC over 1 h.
The reaction mixture was stirred at ꢂ30 ꢃC for 1 h and then cooled to
ꢂ78 ꢃC. To
a
separate ꢂ78 ꢃC solution of allene 16 (69 mg,
0.39 mmol) in 1.0 mL PhMe was added 160 mL of nBuLi (2.45 M in
hexanes, 0.39 mmol) dropwise via gas-tight syringe. The resulting
solution was stirred for 15 min, removed from the cold bath, and
added to the ꢂ78 ꢃC titanium solution dropwise via cannula. After
warming slowly to 0 ꢃC over 2 h, the reaction was quenched with
5 mL of satd NH4Cl solution. The mixture was warmed to room
temperature before extracting with EtOAc (3ꢄ15 mL). The combined
organic layer was washed with satd NaHCO3 solution (1ꢄ30 mL),
brine (1ꢄ30 mL) and dried over anhydrous Na2SO4. Flash column
chromatographyof thecrude material(20%EtOAc/hexanes, then50%
EtOAc/hexanes) provided 127 mg (74%) of diene 17 as a clear, color-
less oil. A small portion was further purified by HPLC [EtOAc/hex-
anes: gradient from 35% to 55% (0–20 min, 25 mL/min) on
a Microsorb (Si 80-120-C5 H410119) column] to obtain a sample for
Supplementary data
Complete experimental details for all preparative procedures
along with spectral data for all products are provided. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2008.03.086.
References and notes
1. For a recent review of palladium-catalyzed cross-coupling in total synthesis,
see: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44,
4442–4489.
2. For recent reviews of such metal-mediated coupling, see: (a) Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002;
p 512; (b) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890–3908; (c) Trost,
B. M.; Toste, F. D.; Pinkerson, A. B. Chem. Rev. 2001, 101, 2067–2096; (d)
Buchwald, S. L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047–1058.
3. For alkyne–alkyne cross-coupling, see: (a) Ryan, J.; Micalizio, G. C. J. Am. Chem.
Soc. 2006, 128, 2764–2765; (b) Shimp, H. L.; Micalizio, G. C. Org. Lett. 2005, 7,
5111–5114; For alkene–alkyne cross-coupling, see: (c) Reichard, H. A.; Micalizio,
G. C. Angew. Chem., Int. Ed. 2007, 46, 1440–1443; For allylic alcohol–alkyne
cross-coupling, see: (d) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129,
15112–15113; For alkyne–imine cross-coupling, see: (e) McLaughlin, M.;
Takahashi, M.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 3912–3914; For
alkene–imine cross-coupling, see: (f) Takahashi, M.; Micalizio, G. C. J. Am. Chem.
Soc. 2007, 129, 7514–7516.
analyticalcharacterization.1HNMR(400 MHz, CDCl3)
d7.26–7.23(m,
4H), 6.89–6.85 (m, 4H), 5.42–5.37 (m,1H), 5.24 (t, J¼7.1 Hz,1H), 4.42
(s, 2H), 4.41 (s, 2H), 4.00 (d, J¼5.8 Hz, 2H), 3.80 (s, 3H), 3.80 (s, 3H),
3.46–3.39 (m, 4H), 2.75 (d, J¼7.3 Hz, 2H), 2.34 (dt, J¼14.7, 7.6 Hz, 2H),
2.33 (t, J¼7.3 Hz, 2H), 1.64 (s, 3H), 1.34 (t, J¼6.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d 159.1, 136.6, 136.0, 130.6, 130.5, 129.21, 129.16,
123.8, 123.1, 113.7, 77.2, 72.5, 69.8, 68.8, 68.6, 55.2, 35.7, 31.1, 28.6,
13.6; IR (thin film, NaCl) 3433, 2907, 2857, 1613, 1513, 1464, 1360,
1302,1173,1093,1035, 802 cmꢂ1;LRMS(EI,Na)calcd forC27H36O5Na,
463.26 m/z (MþNa); observed, 463.3 m/z (MþNa)þ.
4. For examples of metal-mediated cross-coupling of allenes and alkynes, see: (a)
Hideura, D.; Urabe, H.; Sato, F. Chem. Commun. 1998, 271–272; (b) Tanaka, R.;
Sasaki, M.; Sato, F.; Urabe, H. Tetrahedron Lett. 2005, 46, 329–332; (c) Suzuki, K.;
Imai, T.; Yamanoi, S.; Chino, M.; Matsumoto, T. Angew. Chem., Int. Ed. 1997, 36,
2469–2471; (d) Yamanoi, S.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 1998,
39, 9727–9730; (e) Yamanoi, S.; Imai, T.; Matsumoto, T.; Suzuki, K. Tetrahedron
Lett. 1997, 38, 3031–3034; (f) Trost, B. M.; Kottirsch, G. J. Am. Chem. Soc. 1990,
112, 2816–2818; For examples of metal-mediated intramolecular coupling of
allenes with alkynes, see: (g) Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron
Lett. 1995, 36, 2407–2410; (h) Brummond, K. M.; You, L. Tetrahedron 2005, 61,
6180–6185; (i) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 9450–9451; (j) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 5881–5898; (k) Urabe, H.; Takeda, T.; Hideura, D.; Sato, F.
J. Am. Chem. Soc. 1997, 119, 11295–11305; (l) Urabe, H.; Sato, F. Tetrahedron
Lett. 1998, 7329–7332.
4.3. Representative procedure for the stereoselective
synthesis of cross-conjugated trienes
4.3.1. Synthesis of (3E,5E)-1-(4-methoxybenzyloxy)-(4-(2-
methoxybenzyloxy)ethyl)-5-vinyl-7-methyl-3,5-octadiene, 37
To a ꢂ78 ꢃC solution of alkyne 13 (200 mg, 0.56 mmol) in 3.7 mL
of PhMe was added 850
0.85 mmol) and 860
mL of ClTi(Oi-Pr)3 (1.0 M in hexanes,
L of c-C5H9MgCl (1.96 M in Et2O, 1.68 mmol)
m
dropwise via a gas-tight syringe. The resulting clear, yellow solution
turned dark reddish brown while warming slowly to ꢂ30 ꢃC over
1 h. The reaction mixture was stirred at ꢂ30 ꢃC for 1 h and then
cooled to ꢂ78 ꢃC. To a separate ꢂ78 ꢃC solution of allene 36 (44 mg,
5. For a preliminary account, see: Shimp, H. L.; Micalizio, G. C. Chem. Commun.
2007, 4531–4533.
6. For an example of such a metal-mediated alkylation with allylic transposition,
see Ref. 3d.
0.39 mmol) in 1.0 mL PhMe was added 160
m
L of nBuLi (2.45 M in
hexanes, 0.39 mmol) dropwise via gas-tight syringe. The resulting
solution was stirred for 15 min, removed from the cold bath, and
added to the ꢂ78 ꢃC titanium solution dropwise via cannula. After
warming slowly to ꢂ30 ꢃC over 1 h, the reaction was quenched with
5 mL of satd NH4Cl solution. The mixture was warmed to room
temperature beforeextracting with EtOAc (3ꢄ15 mL). The combined
organic layer was washed with satd NaHCO3 solution (1ꢄ30 mL),
brine (1ꢄ30 mL) and dried over anhydrous Na2SO4. Flash column
chromatography of the crude material (5% EtOAc/hexanes, then 7.5%
EtOAc/hexanes) provided 121 mg (69%) of triene 37 as a clear, col-
7. (a) Vogel, E.; Ott, K. H.; Gajek, K. Liebigs Ann. Chem. 1961, 644, 172–188; (b)
Doering, W.; von, E.; Roth, W. R. Tetrahedron 1963, 19, 715–737; For an example
of a metallo-[3,3] rearrangement for isomerization of allylic alcohols, see: (c)
Chabardes, P.; Kuntz, E.; Varagnat, J. Tetrahedron 1977, 33, 1775–1783.
8. Winkler, J. D. Chem. Rev. 1996, 96, 167–176.
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(c) Bailey, W. J.; Economy, J.; Hermes, M. E. J. Org. Chem. 1962, 27, 3295–3299.
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573–575; (b) Kwon, O.; Park, S. B.; Schreiber, S. L. J. Am. Chem. Soc. 2002, 124,
13402–13404.
11. (a) Llerena, D.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1996, 37, 7027–7030; (b)
Yamazaki, T.; Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7333–7336; (c) Brum-
mond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem. Soc. 2002, 124, 15186–15187.
12. (a) Tsuge, O.; Wada, E.; Kanemasa, S. Chem. Lett. 1983, 239–242; (b) Arisawa, M.;
Sugihara, T.; Yamaguchi, M. Chem. Commun. 1998, 2615–2616; (c) Shi, M.; Shao,
L.-X. Synlett 2004, 807–810; (d) Bradford, T. A.; Payne, A. D.; Willis, A. C.; Paddon-
Row, M. N.; Sherburn, M. S. Org. Lett. 2007, 9, 4861–4864. See also Ref. 10a.
13. Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402–7403 and references
cited therein.
orless oil. 1H NMR (400 MHz, CDCl3)
d 7.26–7.21 (m, 4H), 6.88–6.83
(m, 4H), 6.53 (dd, J¼17.4, 10.6 Hz, 1H), 5.36 (t, J¼7.3 Hz, 1H), 5.15 (d,
J¼10.1 Hz, 1H), 5.13–5.06 (m, 2H), 4.42 (s, 2H), 4.37 (s, 2H), 3.78 (s,
3H), 3.78 (s, 3H), 3.46 (t, J¼7.1 Hz, 2H), 3.36 (t, J¼7.3 Hz, 2H), 2.74–
2.65 (m, 1H), 2.51 (t, J¼7.6 Hz, 2H), 2.42 (dt, J¼14.1, 7.3 Hz, 2H), 0.95
(d, J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 159.1, 159.0, 138.7,