An alkoxide-directed carbometalation of internal alkynes

Article abstract of DOI:10.1021/ja057352w

A mild and efficient alkoxide-directed carbometalation is described. Regioselective carbon-carbon bond formation occurs in all cases at the site distal to the tethered alkoxide. This reaction provides a convenient means to prepare differentially functionalized tetrasubstituted 1,3-dienes in a regio- and stereoselective manner. Copyright

Full text of DOI:10.1021/ja057352w

Published on Web 02/10/2006
An Alkoxide-Directed Carbometalation of Internal Alkynes
Jamie Ryan and Glenn C. Micalizio*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received October 27, 2005; E-mail: glenn.micalizio@yale.edu
The discovery and development of regio- and stereoselective
carbon-carbon and carbon-heteroatom bond-forming reactions is
an ongoing challenge in organic chemistry. A common strategy
for the design of such transformations targets preassociation of a
reagent with a substrate as a means to render a reaction intramo-
lecular.1 Reactions that proceed by such preorganization often
provide products with exquisite levels of regio- and stereoselection
as a function of the highly ordered transition-state geometries
through which they proceed. Directed carbon-carbon bond con-
struction represents a growing class of substrate-directable reactions
with great potential to enable the efficient construction of complex
Figure 1. Background to the control of regioselection in group 4 metal-
organic architecture.1-4 Of these, directed carbometalation reactions
mediated coupling reactions of internal alkynes with terminal alkynes.
have the potential to be among the most powerful, as regio- and/or
stereoselective carbon-carbon bond construction is accompanied
by the formation of a new organometallic species with a diverse
reactivity profile. However, only a few examples of directed
carbometalation reactions have been described, and many of these
proceed under vigorous reaction conditions.1,4 We herein present
an approach to the control of site selectivity in intermolecular C-C
bond formation between two differentially functionalized internal
alkynes that defines the utility of alkoxide tethering as a means to
control regioselection in group 4 metal-mediated bond construction.
Figure 2. Directed carbometalation reaction for 1,3-diene synthesis.
Intermolecular carbometalation reactions of terminal alkynes with
preformed metallacyclopropenes are known.5 However, substrate
scope in these reactions is limited based on factors influencing
regioselection and reactivity. For example, regioselection across
the internal alkyne is typically controlled by the relative steric
environment about each side of the metallacyclopropene (Figure
1), with only a few substituents known that provide high levels of
selectivity.5 Additionally, to have sufficient reactivity with the
preformed metallacyclopropene, the structure of the second π-com-
ponent is generally limited to terminal alkynes.5a
Given the challenges associated with accomplishing site-selective
C-C bond formation across internal alkynes, we sought an
alternative means to control regioselection in such functionalization
reactions. We speculated that the participation of a tethered
alkoxide6 on the second π-electrophile in a group 4 metal alkoxide-
mediated coupling reaction could provide a unique means to control
regioselection in carbometalation processes across internal alkynes.
As depicted in Figure 2, preformation of a titanacyclopropene 2
via exposure of the corresponding symmetrical alkyne to the
combination of a titanium(IV) alkoxide and Grignard reagent7
Figure 3. Presence of the tethered alkoxide and the length of the tether
influence reactivity as well as regioselectivity.
metallacyclopropene 8 (formed by treatment of diphenylacetylene
followed by exposure to an unsaturated alkoxide 1 was anticipated
to result in rapid transesterification and transiently provide the mixed
titanate ester 3. Ensuing intramolecular carbometalation would then
furnish the stereodefined bicyclic titanacyclopentadiene 4, which
on protonation would deliver the stereodefined 1,3-diene 5 as a
single regioisomer.
On the basis of this proposal, we examined unsaturated alcohols
of general structure 1 in coupling reactions with symmetric
titanacyclopropenes 2. As illustrated in Figure 3, deprotonation of
the unsaturated alcohol 7, followed by exposure to the preformed
with Ti(Oi-Pr)4 and C5H9MgCl, PhMe -78 to -50 °C) and aqueous
workup, provided the stereodefined diene 10 with high regiose-
lection (rs g 42:1).8 Interestingly, in a related experiment, exposure
of an internal alkyne lacking a free hydroxyl (11) to the preformed
titanium alkyne complex 8 led only to a complex mixture of
products. As such, the tethered alkoxide plays a central role in
determining regioselection, as well as in realizing a productive mode
of reactivity, in these C-C bond-forming reactions.
The significance of tether length was then explored. Whereas
the bis-homopropargylic alcohol 12 provided similarly high levels
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10.1021/ja057352w CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1
Overall, we have defined an approach to control regioselection
in intermolecular group 4 metal-mediated C-C bond formation
based on alkoxide tethering. Our preliminary studies in this area
have resulted in a mild method for the stereoselective synthesis of
tetrasubstituted 1,3-dienes via a new regiospecific directed carbo-
metalation reaction. We further speculate that this general control
element, defined by transient preorganization of organic architecture
around a group 4 metal center, can provide a unique means for the
control of reactiVity and selectiVity in new carbon-carbon bond-
forming reactions. Studies aimed at the discovery and development
of such processes are currently underway, and progress made along
these lines will be reported in due course.
Acknowledgment. We thank Ken-Shing Law for the prepara-
tion of ent-28. We also gratefully acknowledge the financial support
of this work by the Arnold and Mabel Beckman Foundation,
Boehringer Ingelheim, Eli Lilly & Co., and Yale University.
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For a general review on substrate-directable reactions, see: Hoveyda, A.
H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(2) Some recent examples of heteroatom-directed C-C bond formation
include: Directed allylic substitution reactions: (a) Didiuk, M. T.; Morken,
J. P.; Hoveyda, A. H. Tetrahedron 1998, 54, 1117-1130 and references
therein. (b) Itami, K.; Koike, T.; Yoshida, J. J. Am. Chem. Soc. 2001,
123, 6957-6958. Phosphine-directed hydroformylation: (c) Krauss, I. J.;
Wang, C. C.-Y.; Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 11514-
11515. Hydroxyl-directed SN2′ addition reactions: (d) Xie, C.; Nowak,
P.; Kishi, Y. Org. Lett. 2002, 4, 4427-4429. (e) Fu¨rstner, A.; Me´ndez,
M. Angew. Chem., Int. Ed. 2003, 42, 5355-5357. Directed C-H
activation/C-C bond formation: (f) Murai, S.; Kakiuchi, F.; Sekine, S.;
Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366,
529-531. (g) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J.
A. J. Am. Chem. Soc. 2001, 123, 9692-9693.
a These internal alkynes serve as the substrates for the formation of the
reactive titanacyclopropene. b 1H NMR spectra of these coupling reactions
provided no evidence for the production of a second regioisomer.
of regioselection in coupling reactions with the titanacyclopropene
8 (rs g 65:1),8 alkynes 15 and 16 were not suitable substrates for
this reaction, each leading to a complex mixture of products.
The generality of this directed carbometalation reaction was then
investigated (Table 1). Symmetrical metallacyclopropenes derived
from 17 and 19 (Ti(Oi-Pr)4, C5H9MgCl, PhMe, -78 to -50 °C)
were found to be similarly effective coupling partners with the
homopropargylic alcohol 7 and provided the stereodefined 1,3-
dienes 18 and 20 (entries 1 and 2). The substitution of the unsatu-
rated alcohol did not significantly influence the effectiveness of
this site-selective bond construction. As depicted in entries 3-5,
the ethyl-, isopropyl-, and t-Bu-substituted alkynes 21, 24, and 26
were all viable substrates for this reaction and provided the
stereodefined tetrasubstituted 1,3-dienes 23, 25, and 27 in coupling
reactions with diphenylacetylene. In all cases, the new carbon-
carbon bond is formed at the site distal to the free hydroxyl,
independent of substitution on the alkyne.
The role of substitution along the chain bearing the homopro-
pargylic alkoxide was then explored. Coupling of the syn-anti
homopropargylic alcohol 285b with the symmetrical metallacycle
derived from diphenylacetylene 22 provided diene 29 in 54% yield,
again as the only observable regioisomer (entry 6).
Finally, this directed carbometalation was extended to the
coupling of two different unsymmetrical internal alkynes. As
illustrated in entry 7, directed carbometalation of bis-homo-
propargylic alcohol 12 with internal alkyne 30 provided diene 31
in 55% yield. Similarly, the syn-anti homopropargylic alcohol
ent-28 was coupled to internal alkyne 325b to provide the complex
tetrasubstituted 1,3-diene 33 in 58% yield (entry 8).
(3) For olefin-directed regioselective nickel-catalyzed reductive coupling
reactions, see: (a) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am.
Chem. Soc. 2004, 126, 3698-3699. (b) Miller, K. M.; Jamison, T. F. J.
Am. Chem. Soc. 2004, 126, 15342-15343.
(4) For hydroxyl-directed carbometalation reactions based on titanium, see:
(a) Coleman, R. A.; O’Doherty, C. M.; Tweedy, H. E.; Harris, T. V.;
Thompson, D. W. J. Organomet. Chem. 1976, 107, C15-C17. For
hydroxyl-directed carbometalation based on magnesium, see: (b) Eisch,
J. J.; Merkley, J. H. J. Organomet. Chem. 1969, 20, P27-P31. (c) Richey,
H. G.; Von Rein, F. W. J. Organomet. Chem. 1969, 20, P32-P35. (d)
Hoveyda, A. H.; Xu, Z. J. Am. Chem. Soc. 1991, 113, 5079-5080. (e)
Itami, K.; Mitsudo, K.; Yoshida, J. Angew. Chem., Int. Ed. 2001, 40,
2337-2339. For directed carbometalation based on tantalum, see: (f)
Takai, K.; Yamada, M.; Odaka, H.; Utimoto, K. J. Org. Chem. 1994, 59,
5852-5853. For directed carbometalation based on aluminum/zirconium,
see: (g) Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784-785.
(5) For coupling of TMS-substituted alkynes and 2-alkynoates with terminal
alkynes, see: (a) Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 1999, 121, 7342-7344. For regioselective coupling of internal alkynes
bearing branched polyketide architecture with terminal alkynes, see: (b)
Shimp, H. L.; Micalizio, G. C. Org. Lett. 2005, 7, 5111-5114. For a
report describing the effect of a tethered alkoxide in regioselective
reductive coupling reactions of internal alkynes and aldehydes, see: (c)
Bahadoor, A.; Micalizio, G. C. Org. Lett. 2006, 8, in press.
(6) For examples of metallacyclopropanes bearing a tethered alkoxide
(presumed formation of intermediate saturated oxabicyclo[3.1.0] titana-
cyclopropanes), see: (a) Shevchuk, T. A.; Kulinkovich, O. G. Russ. J.
Org. Chem. 2000, 36, 1124-1126. (b) Quan, L. G.; Kim, S.; Lee, J. C.;
Cha, J. K. Angew. Chem., Int. Ed. 2002, 41, 2160-2162. (c) Masalov,
N.; Cha, J. K. Org. Lett. 2004, 6, 2365-2368. (d) Epstein, O. L.; Seo, J.
M.; Masalov, N.; Cha, J. K. Org. Lett. 2005, 7, 2105-2108.
(7) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203-3206.
(8) The other regioisomer possible was prepared independently and compared
to the product mixture obtained from this reaction. The regioselectivity
was then determined based on the signal-to-noise ratio of the spectrum.
See Supporting Information for details.
JA057352W
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