An alkoxide-directed alkyne-allene cross-coupling for stereoselective synthesis of 1,4-dienes

Article abstract of DOI:10.1039/b708256h

A titanium alkoxide-mediated convergent coupling between internal alkynes and allenes is described for the regio- and stereocontrolled synthesis of substituted acyclic 1,4-dienes. The Royal Society of Chemistry.

Full text of DOI:10.1039/b708256h

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An alkoxide-directed alkyne–allene cross-coupling for stereoselective
synthesis of 1,4-dienes{
Heidi L. Shimp and Glenn C. Micalizio*
Received (in Bloomington, IN, USA) 31st May 2007, Accepted 9th August 2007
First published as an Advance Article on the web 23rd August 2007
DOI: 10.1039/b708256h
trisubstituted olefin-containing product (represented by generic
structure 3, Fig. 1).
A titanium alkoxide-mediated convergent coupling between
internal alkynes and allenes is described for the regio- and
stereocontrolled synthesis of substituted acyclic 1,4-dienes.
We expected that high regio- and stereoselection would result
from the sequence of events proposed in Fig. 2. Preformation of a
titanium–alkyne complex, followed by exposure to an allenic
alkoxide would result in rapid and reversible ligand exchange to
provide the mixed titanate ester A. Intramolecular carbometalla-
tion via B would then deliver the fused bicyclic metallacyclopen-
tene C. Selectivity in this process was expected to result from
formation of a bicyclo[3.3.0]-ring system in preference to the
regioisomeric bicyclo[3.2.0]-ring system that would result from
C–C bond formation at the central position of the substituted
allene (intermediate not shown). Finally, protonation of C would
deliver 1,4-diene 3 in preference to the isomeric 1,4-diene 4.
Initial studies were performed by exposing preformed allenic
alkoxides to titanacyclopropenes (generated in situ from internal
alkynes), followed by protonation of the presumed intermediate
organometallic species. As depicted in entry 1 of Table 1, coupling
of 2,3-butadiene-1-ol (5) with the symmetrical alkyne 6 leads to
effective cross-coupling and furnishes the stereodefined 1,4-diene
7.6 Cross-coupling of the methyl-substituted allene 8 with alkyne 6
is similarly effective and provides 1,4-diene product 9 as a single
isomer in 74% yield (entry 2). Coupling of allene 10, where the
tethered hydroxyl is positioned further away from the cumulated
diene, with alkyne 6 leads to the production of 1,4-diene products
in good yield (64%), but with modest stereoselectivity (E : Z =
3 : 1, entry 3). The observed product ratio may reflect a
competition between directed and non-directed cross-coupling at
the least substituted CLC of the allene. In this case, intramolecular
The direct cross-coupling of unactivated p-systems is a powerful
strategy for bimolecular C–C bond formation. Whereas palla-
dium-catalyzed cross-coupling has become commonplace for
bimolecular C–C bond formation,1 these catalytic transformations
dictate the use of activated coupling partners, often prepared by
multiple stoichiometric functionalization processes (i.e. unsatu-
rated organic halides and functionalized organometallic reagents).
The direct cross-coupling of unactivated p-systems provides an
alternative, and perhaps more powerful, strategy for bimolecular
C–C bond formation, as pre-activation of the reactive partners is
not required. The reactivity of metal–p complexes is ideally suited
for such bond construction. To date, numerous reports describe
intramolecular C–C bond formation between unactivated p-sys-
tems via the intermediacy of metallacyclopentanes; however,
bimolecular processes based on such reactivity are rare due to
challenges associated with the control of regioselectivity, reactivity
and stereoselectivity in the C–C bond forming event.2 Here, we
describe a cross-coupling reaction between substituted allenes (1)
and internal alkynes (2) that provides a convergent and highly
stereoselective route to substituted 1,4-dienes of general structure 3
(Fig. 1).
As part of our ongoing studies aimed at defining a suite of
convergent coupling reactions between unactivated p-systems,3,4
we began to explore a reaction for the stereoselective union of
alkynes with allenes. Whereas alkyne–allene cross-coupling has
been reported for the synthesis of 1,4-dienes, the bimolecular C–C
bond forming event often proceeds with relatively modest levels of
selectivity (ca. 2–3 : 1).5 In general, alkoxy- or silyl-substituted
allenes are required for high levels of (Z)-selectivity. Here, we
describe a new allene–alkyne cross-coupling for 1,4-diene synthesis
that favors the formation of the stereoisomeric (E)-di- or
Fig. 1 Allene–alkyne cross-coupling for 1,4-diene synthesis.
Department of Chemistry, Yale University, New Haven, CT, USA.
E-mail: glenn.micalizio@yale.edu; Fax: +1 (213) 423 6144
{ Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for all new compounds. See DOI: 10.1039/
b708256h
Fig. 2 Proposed pathway for site- and stereoselective bimolecular
coupling of allenes and alkynes.
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Table 1 An alkyne–allene cross-coupling for the stereodefined synthesis of substituted 1,4-dienes
aTypical reaction conditions: alkyne (1.4 eq.), Ti(Oi-Pr)4 (2.1 eq.), c-C5H9MgCl (4.2 eq.), PhMe (278 to 230 uC), cool to 278 uC then add
allenyl alkoxide (1 eq.), (278 to 0 uC). bProducts formed as single olefin isomers unless otherwise noted. cFormed as a 3 : 1 mixture of
products containing a minor cross-conjugated triene (see ESI for details). dIn addition, 31% of a cross-conjugated triene was isolated from this
e
f
reaction. rs = 4 : 1. rr (regioisomeric ratio) = 2 : 1
carbometallation would proceed via a six-membered tether, as
opposed to a five-membered tether (see B A C; Fig. 2).
Heteroatom substitution on the allene is tolerated in this
coupling reaction, providing a convenient pathway to the
synthesis of stereodefined enol ethers. For example, reaction
of methoxy-substituted allene 12 with alkyne 6 affords the
enol ether 13 in 87% yield (entry 4). In this transformation, no
evidence was found for the production of stereoisomeric 1,4-diene
products.
This cross-coupling reaction is similarly effective with more
complex coupling partners. As illustrated in entry 5, reaction of the
trisubstituted allene 14 with the internal alkyne 6 provides a
convenient means of preparing 1,4-dienes bearing a central alkyl
substituent. As observed in coupling reactions of less complex
substrates, the substituted 1,4-diene 15 is produced as a single
isomer.
This allene–alkyne cross-coupling reaction can be extended
to unsymmetrical alkynes. As depicted in entry 6, selective
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functionalization of two unsymmetrically substituted p-systems
can be achieved. In this case, cross-coupling of allene 12 with
TMS-alkyne 16 provides the 1,4-diene 17 (rs = 4 : 1).7
Heteroaromatic-containing substrates are also suitable for cross-
coupling. As illustrated in entry 7, cross-coupling of the indole-
containing TMS-alkyne 18 with allene 8 provides the stereodefined
1,4-diene 19 in 48% yield (rs = 4 : 1). Finally, alkynes containing
free hydroxyl functionality are viable substrates in this reaction.
For example, coupling of allene 8 with the functionalized internal
alkyne 20 furnishes the 1,4-diene-containing diol 21 in 62% yield,
albeit with modest regioselectivity, and demonstrates the tolerance
of this stereoselective bimolecular C–C bond forming reaction to
free hydroxyls on both of the coupling partners (entry 8).
In summary, we document a bimolecular metal-mediated
allene–alkyne cross-coupling reaction for the stereoselective
synthesis of 1,4-dienes. Whereas coupling reactions of this
class have previously been known to provide access to stereo-
defined 1,4-dienes with modest levels of stereoselection, the present
contribution provides a highly stereoselective pathway for the
formation of (E)-di- and trisubstituted olefins; in most cases, the
1,4-diene products are isolated as single olefin isomers. We have
also demonstrated that this coupling process can be extended to
unsymmetrical alkynes, where regio- and stereoselective func-
tionalization of each p-component is accomplished. The utility of
the present convergent coupling reaction in complex molecule
synthesis, and the potential to transfer axial chirality in the
generation of a C-3 stereodefined 1,4-diene are the topics of
ongoing studies.
Chemical Society (PRF-45334-G1), the Arnold and Mabel
Beckman Foundation, Boehringer Ingelheim, Bristol-Myers
Squibb (for a graduate fellowship to H. L. S.), Eli Lilly & Co.,
and the National Institutes of Health – NIGMS (GM80266).
Notes and references
1 For a recent review of palladium-catalyzed cross-coupling in total
synthesis, see: K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew.
Chem., Int. Ed., 2005, 44, 4442.
2 For recent reviews of metal-mediated C–C bond formation, with Group
4 metals, see: (a) Titanium and Zirconium in Organic Synthesis, ed.
I. Marek, Wiley-VCH, Weinheim, 2002, p.512; with nickel, see: (b)
J. Montgomery, Angew. Chem., Int. Ed., 2004, 43, 3890; with ruthenium,
see: (c) B. M. Trost, F. D. Toste and A. B. Pinkerton, Chem. Rev., 2001,
101, 2067.
3 J. Ryan and G. C. Micalizio, J. Am. Chem. Soc., 2006, 128, 2764.
4 H. A. Reichard and G. C. Micalizio, Angew. Chem., Int. Ed., 2007, 46,
1440.
5 For examples of metal-mediated cross-coupling of allenes and alkynes,
see: (a) D. Hideura, H. Urabe and F. Sato, Chem. Commun., 1998, 271;
(b) R. Tanaka, M. Sasaki, F. Sato and H. Urabe, Tetrahedron Lett., 2005,
46, 329. For intramolecular allene–alkyne coupling, see: (c) J. L. Kent,
H. Wan and K. M. Brummond, Tetrahedron Lett., 1995, 36, 2407; (d)
F. A. Hicks, N. M. Kablaoui and S. L. Buchwald, J. Am. Chem. Soc.,
1996, 118, 9450; (e) F. A. Hicks, N. M. Kablaoui and S. L. Buchwald,
J. Am. Chem. Soc., 1999, 121, 5881; (f) H. Urabe, T. Takeda, D. Hideura
and F. Sato, J. Am. Chem. Soc., 1997, 119, 11295.
6 The minor product in this cross-coupling reaction was a cross-conjugated
triene (see ESI for details{). Cross-conjugated trienes have been observed
in intramolecular reactions of alkynes with allenes bearing allenic leaving
groups, see: T. Yamazaki, H. Urabe and F. Sato, Tetrahedron Lett., 1998,
39, 7333.
7 For representative examples of regioselective functionalization of TMS-
substituted alkynes via metallacyclopropenes, see: (a) F. Sato, H. Urabe
and S. Okamoto, Chem. Rev., 2000, 100, 2835 and (b) ref 5a.
We gratefully acknowledge financial support of this work by the
American Cancer Society (RSG-06-117-01), the American
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