Angewandte
Chemie
DOI: 10.1002/anie.200903859
Synthetic Methods
The Synthesis of Highly Substituted Cyclooctatetraene Scaffolds by
Metal-Catalyzed [2+2+2+2] Cycloadditions: Studies on
Regioselectivity, Dynamic Properties, and Metal Chelation**
Paul A. Wender,* Justin P. Christy, Adam B. Lesser, and Marc T. Gieseler
Cyclooctatetraenes (COTs) are a fascinating class of mole-
cules with great potential utility as building blocks for
synthesis,[1] scaffolds for drug discovery, designed carbohy-
drate mimics,[2] ligands for d- and f-block metals[3] including
those for asymmetric catalysis,[4] and components for molec-
ular detection devices (e.g. dynamic molecular tweezers)[5]
and novel materials.[6] For many applications including the use
of COTs in fluxional materials,[7] conducting polymers,[8] and
light emitting devices,[9] the type and degree of COT
substitution play a critical role in controlling the redox and
electronic properties of the system. For other applications,
substitution determines COT topological chirality and the
rate of COT racemization by tub-to-tub ring inversion.[10]
Notwithstanding their considerable potential, highly substi-
tuted and functionalized COTs have received limited atten-
tion partly due to the relative paucity of methods for their
general and efficient synthesis.[11]
COTs, reaction regioselectivity, and tolerance of heteroatom
substitution are unexplored. We now report that the lack of
reactivity of internal alkynes can be overcome through a
mixed inter/intramolecular nickel(0)-catalyzed [2+2+2+2]
cycloaddition of commercially or readily available 1,6-diynes,
providing access to hexa- and octa-substituted COTs with a
variety of functionalities. We also report the first study of the
regioselectivity of this process, the first example of a fully
intramolecular [2+2+2+2] cycloaddition, and the initial study
of the use of these novel ligands in metal complexation.
Our studies initially focused on diynes which incorporate
both an internal and a terminal alkyne, which provide
hexasubstituted COTs in good yields (Table 1). Only trace
amounts of [2+2+2] products were observed. Significantly,
the regioselectivities of the process range from 4.6:1 when the
substituent is CH2OCH3 (entry 2) to > 20:1 when it is
aromatic or heteroaromatic (entries 3–6). It is noteworthy,
both synthetically and mechanistically, that the corresponding
fully intermolecular reactions of propyne and propargyl
alcohol proceed with minimal regioselectivity to provide
complex and difficult to separate mixtures of regio- and other
isomers.[19] A wide variety of functional groups are tolerated
in this process including an ether (entry 2), an ester (entry 5),
a Boc-protected nitrogen heterocycle (entry 6) and even a
free phenolic group (entry 4). The rapid increase in molecular
complexity attending this four-component cycloaddition pro-
While Reppeꢀs Ni0-catalyzed tetramerization of acetylene
provides cyclooctatetraene itself,[12] related cyclo-tetrameri-
zations of terminal alkynes lead to complex mixtures and
those of internal alkynes encounter reactivity problems.[13]
Two classes of alternative methods for the synthesis of hexa-
and octa-substituted COTs have been developed, those based
on the metal-mediated coupling of two dienes,[14] and high-
temperature rearrangement of semibullvalenes,[15] barre-
lenes,[16] or cyclobutadiene dimers.[17] However, these
approaches have been limited mainly to the construction of
simple alkyl and/or aryl substituted COTs. Recently, we
reported that the favored metal-catalyzed [2+2+2] cyclo-
addition of diynes can be completely reversed with certain
nickel catalysts to produce [2+2+2+2] cycloaddition prod-
ucts.[18] However, key issues related to the applications of
COTs such as the formation of hexa- and octa-substituted
À
cess is noteworthy and rare as four carbon carbon bonds and
three rings are formed in a single operation.
Diynes containing two internal alkynes were next studied
(Table 2). Alkyl- (entry 4), functionalized alkyl- (entries 2
and 3), and aryl substituted alkynes, the last with both
electron donating (entry 5) and withdrawing groups (entry 6),
work well. X-ray structures were obtained for COTs 2 and 14,
which verified the double bond isomer in both cases, as well as
the regiochemistry of COT 2 (Figure 1).[20]
While the preceding studies provide access to fully
substituted and 1,2,3,5,6,7-hexa-substituted COTs, the first
study of a fully intramolecular [2+2+2+2] cycloaddition
involving tetrayne 25 was explored for the synthesis of
1,2,3,4,5,6-hexa-substituted COTs (Scheme 1). This mecha-
nistically and synthetically intriguing process proceeds in
[*] Prof. P. A. Wender, J. P. Christy, A. B. Lesser, M. T. Gieseler
Department of Chemistry, Department of Chemical and Systems
Biology, Stanford University, Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0259
E-mail: wenderp@stanford.edu
[**] This research was supported by a grant (CHE-0450638) from the
National Science Foundation. J.P.C and A.B.L. thank Amgen for
financial support. M.T.G thanks the Deutscher Akademischer
Austauschdienst for financial support. We thank Allen Oliver at the
University of California, Santa Cruz and Prateek Verma at Stanford
University for X-ray crystal structures. We also thank Kristen
Brownell for assisting in substrate preparation.
À
66% yield with the formation of four carbon carbon bonds
and four rings, an uncommon bond and ring-forming event.
Our interest in this methodology is prompted partly by the
potential use of highly substituted COTs as tunable ligands
for catalysis, fluxional scaffolds for drug discovery and
conformational switches for functional devices. These appli-
cations could further benefit from the topological chirality of
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 7687 –7690
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7687
Wender, Paul A.
