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LETTER
Ruthenium Carbene Mediated [2+2+2] Cyclotrimerizations
R
uthenium Carbe
n
l
e
M
ed
v
[
2+2+2
a
]
Cyclotrim
r
erization
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s
Mallagaray, Sandra Medina, Gema Domínguez, Javier Pérez-Castells*
Facultad de Farmacia, Dpto. Química, Universidad San Pablo CEU, Urb. Montepríncipe, ctra. Boadilla km 5,300 Boadilla del Monte,
28668 Madrid, Spain
Fax +34(91)3510496; E-mail: jpercas@ceu.es
Received 21 May 2010
Dedicated to Prof. José Barluenga on the occasion of his 70th birthday
On the other hand, second-generation Grubbs catalysts
Abstract: Second-generation Grubbs’ catalyst and Hoveyda–
[Ru]-II, and reusable Hoveyda–Grubbs complex [Ru]-
Grubbs’ catalyst are able to catalyze both crossed [2+2+2] cyclotri-
III, have not been used for these cyclotrimerizations.
merization of diynes with alkynes and di- or trimerizations of
diynes. Selection of the reaction conditions allows us to favor one
particular process. The process is selective when applied to unsym-
metric diynes.
We present here the synthesis of functionalized poly-
cycles through an easy experimental procedure based on
[Ru]-III and [Ru]-I catalysts.
Key words: cyclization, ruthenium, carbenes, alkynes, arenes
In order to optimize the reaction, dipropargyl ether 1a was
reacted with phenylacetylene under a variety of reaction
conditions (Table 1). The first tests were carried out in tol-
uene with 2 mol% of catalyst [Ru]-III and 3 equivalents
of phenylacetylene. They showed the need for heating up
to 60 °C to reach moderate yields of product 2a (entries 1
and 2, Table 1). The reaction was complete after 16 hours
(TLC). Increasing the concentration of diyne up to 1.25 M
allowed a better yield while the amount of dimerization
product 3a was only slightly higher (entries 2–5). A reac-
tion in a sealed tube (entry 6) at 95 °C showed no im-
provement in yield. The need to use an excess of alkyne
was verified under conditions of entry 7, where a reaction
with one equivalent of phenylacetylene provided a low
yield of 2a, with 3a being the major product in this case.
Increasing to 5 equivalents of alkyne did not lead to a sig-
nificant improvement (entry 8). The next study was the se-
lection of the best solvent (entries 9–14). Polar solvents
revealed a better performance, with acetone providing the
best yield of 2a (88%) and selectivity as neither starting
material nor product 3a were detected in the crude mix-
ture (entry 10). Reaction time could be reduced to 30 min-
utes without significant decrease in yields (entry 15),
although further reduction to 5 minutes resulted in a 77%
yield of 2a and the presence of the starting diyne in the
crude mixture (entry 16). Using a lower catalyst loading
(1 mol%) in acetone led to an important decrease in yields
(entry 17). Finally, for comparison reasons, we used our
best conditions (1.25 M of diyne, 3 equiv of alkyne, in ac-
etone at 60 °C, reaction time 30 min), with Grubbs cata-
lysts [Ru]-I and [Ru]-II (entries 18 and 19), showing poor
performance of these catalysts in terms of both yield and
selectivity.
Multisubstituted benzenes and pyridines have traditional-
ly been synthesized by aromatic electrophilic substitution.
As an elegant alternative, the [2+2+2]-cycloaddition reac-
tion of alkynes is remarkable because it is atom efficient
and group tolerant and involves the formation of several
C–C bonds in a single step.1 Cyclotrimerization of acety-
lenes is catalyzed by a variety of transition-metal catalyst,
being CpCo(CO)2 one of the most commonly utilized.2
Other extensively used catalysts are [IrCl(cod)]2,
Ni(cod)2, and much commonly rhodium complexes such
as Wilkinson’s catalyst, [RhCl(PPh3)3], or other RhLn
complexes which are becoming the catalyst of choice in
many recent applications. Ruthenium catalyst such as
[Cp*RuCl(cod)] are able to catalyze trimerization of
alkynes,3 and are useful in the [2+2+2] cycloaddition of
1,6-diynes with nitriles, isocyanates, and isothiocyanates
to afford pyridines, bicyclic pyridones, and thiopyridones
in good yields.4
There are a few precedents in using Grubbs’ first-genera-
tion catalyst [Ru]-I to mediate in cyclotrimerization
[2+2+2] reactions. Blechert et al. reported for the first
time that [Ru]-I is an efficient catalyst for the intramolec-
ular cyclotrimerization of alkynes. A cascade metathetic
mechanism is postulated in these examples where vinyl
carbene complexes would be the reactive intermediates.5
Roy and Das prepared a carbohydrate derivative by a
[Ru]-I-catalyzed cyclotrimerization of a terminal alkyne.6
Certain 1,6-diynes were crossed cyclotrimerized with
alkynes with [Ru]-I,7 and this catalyst has been used in
solid supported cyclotrimerizations8 and in the synthesis
of indacenes from triynes.9
Once the best conditions for the crossed cyclotrimeriza-
tion of diynes with alkynes were selected, we studied the
scope of the process reacting different diynes with alkynes
(Table 2).11 Dipropargyl ether 1a reacted smoothly with
terminal alkynes such as propargyl alcohol. Although this
reagent gave a better yield when protected as silyl ether
(entry 1), the presence of the free hydroxy group did not
prevent the reaction from taking place (entry 2). Hex-1-
SYNLETT 2010, No. 14, pp 2114–2118
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Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258521; Art ID: G13410ST
© Georg Thieme Verlag Stuttgart · New York