diyne functionalizations involving chiral gold complexes
(Scheme 1).7 Therein, we found that 3-alkoxy-1,4-diynes
Scheme 2. Preparation of 3-Hydroxyethyl-diynes and
3-Hydroxypropyl-diynes from Acetylacetone
Scheme 1. Endo-Cyclization of 1,4-Diynes Derived from
3-Alkoxy-1,4-diynes Using a Gold Catalyst
showed a surprising tendency to undergo endo-cyclization
to form seven-membered heterocycles selectively. In order
to allow access to structures bearing quaternary carbon
centers we investigated transformations involving diynes with
a quaternary carbon atom in the 3-position. We thought that
such studies could contribute to a deeper understanding of
the factors leading to preferential endo- or exo-cyclization
of 1,4-diynes as well as related gold-catalyzed transforma-
tions involving propargylic carboxylates.8 In this publication
we report a general synthetic access to 3,3-disubstituted 1,4-
diynes and their successful cyclization to the corresponding
enol ethers using gold catalysts. The products of this process,
exo-enol ethers, are versatile and useful building blocks for
the preparation of functionalized saturated heterocycles.
In contrast to the starting materials as depicted in Scheme
1 which are easily obtained by addition of metal acetylides
to the corresponding esters followed by O-alkylation, 1,4-
diynes bearing only aryl- or alkyl-substituents are signifi-
cantly more difficult to prepare. In fact, at the outset of this
study a general synthetic pathway toward this compound
class was still pending.
Initial attempts to prepare 3,3-disubstituted 1,4-diynes by
arylation/alkylation of malonic acid derivatives revealed that
decarboxylation and decarbonylation processes severely
hampered the formation of the diyne functional group. In
order to circumvent this issue acetylacetone derivatives were
investigated. In particular, 3-aryl-acetylacetones 4 were
synthesized by copper-mediated reaction of aryl iodides with
2,4-pentanedione (Scheme 2).9 While benzylation10 of acety-
lacetone was straightforward the introduction of a cyclohexyl
substituent gave the best results with 3-bromo-cyclohexene
followed by catalytic hydrogenation.11 Subsequent alkylation
to the 3,3-disubstituted compounds proved difficult with
various haloalkanes incorporating protected hydroxy func-
tionalities and gave product mixtures due to concomitant
O-alkylation. It was found that solely allyl iodide gave
satisfying results by preferential C-alkylation. Transformation
of the diketones 5 to the 1,4-diynes 6 was achieved Via the
enol phosphates following a procedure by Negishi.12 At this
point the stage was set to transform the allyl substituent into
the corresponding alcohol functionality serving as the nu-
cleophile in the gold-catalyzed cyclization. We were pleased
to find that dihydroxylations showed a high degree of
chemoselectivity. In this respect, catalytic use of potassium
osmate gave superior results compared to perruthenate
reagents with respect to yield and product purity. In order
to generate a hydroxyethyl substituent in the 3-position the
diols were cleaved by sodium periodate and the intermediate
aldehyde was reduced using NaBH4.
(7) (a) Wilckens, K.; Uhlemann, M.; Czekelius, C. Chem.sEur. J. 2009,
15, 13323. (b) Hashmi, A. S. K.; Hamzic´, M.; Rominger, F.; Bats, J. W.
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W. M.; Wiest, O.; Helquist, P. Org. Lett. 2008, 10, 3903. (d) Ito, H.; Ohmiya,
H.; Sawamura, M. Org. Lett. 2010, 12, 4380. For reviews on enantioselective
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Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178.
Initial trials for the gold-catalyzed cyclization of 3-hy-
droxyethyl-1,4-diynes 7 employing reaction conditions de-
veloped earlier for substrates as depicted in Scheme 1
([Cy3P]AuCl/AgBF4 in toluene) showed very poor conver-
sions. Screening experiments revealed that a catalyst obtained
from [Ph3P]AuCl and AgBF4 gave better results, in particular
when THF was employed as solvent.13 All hydroxyethyl-
substituted 1,4-diynes 7 underwent fast cyclization under
these conditions (Table 1, entries 1-7). Branched and
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alone led to product formation.
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