Synthesis of polycyclic compounds by a cascade cycloisomerisation/ dielsalder reaction

Article abstract of DOI:10.1002/chem.201000515

(Figure Presented) Running rings around gold: A new cascade reaction catalysed by AuCl₃ that is based upon an initial cycloisomerisation reaction of enynol or enynamine derivatives, which form 1,3-buta-diene derivatives, followed by a DielsAlder cycloaddition reaction to give fused or spirocyclic compounds is reported (see scheme).

Full text of DOI:10.1002/chem.201000515

DOI: 10.1002/chem.201000515
Synthesis of Polycyclic Compounds by a Cascade Cycloisomerisation/Diels–
Alder Reaction
Josꢀ Barluenga,* Jonꢁs Calleja, Abraham Mendoza, Fꢀlix Rodrꢂguez, and
Francisco J. FaÇanꢁs[a]
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Cascade (domino) reactions provide an efficient way to
construct complex molecular structures from readily avail-
able organic compounds.[1] Particularly interesting is the syn-
thesis of heterocycles through cascade reactions, involving
the intramolecular addition of a heteroatomic nucleophile
to an alkyne that is activated by a p-acid[2] (as defined by
Fꢀrstner and Davies).[3] The increasing interest in this field
of research is probably due to the ability of gold complexes
to promote unusual processes. For example, some elegant
new gold-catalysed reactions involving atypical intramolecu-
lar redox processes have recently been published.[4] In this
context, we have developed several transition-metal-cata-
lysed reactions of w-alkynols based on the initial formation
of enol ethers, through an intramolecular hydroalkoxylation
process,[4] which react in situ with nucleophiles and/or elec-
Scheme 1. Concept of the cascade cycloisomerisation/Diels–Alder cyclo-
addition reaction.
trophiles.[5] Following on with our interest in this field, we
thought that the cycloisomerisation of functionalised enynes
1 would afford 1,3-butadiene derivatives 2 (or 2’), which
might then react in situ with appropriate dienophiles 3 to
afford interesting fused bicyclic compounds 4 or spirocycles
5, depending upon the initial mode of cyclisation (endo or
exo) of enyne derivative, 1 (Scheme 1). The preliminary re-
sults of this reaction are given here.
First, we evaluated the reactivity of a series of functional-
ised enynes 1 (n=1), derived from 3-butyn-1-ol or 3-butyn-
1-amine, in the presence of dienophiles, such as N-phenyl-
maleimide (3a) and tetracyanoethylene (3b). After screen-
ing catalysts we discovered that goldACTHUNGTERN(NUG III) chloride (AuCl3)
was the most suitable to perform the desired cascade 5-endo
cycloisomerisation/Diels–Alder cycloaddition reaction.[6,7]
When the reaction was carried out in dichloromethane, at
room temperature, we obtained compounds 4 in high yields
(Scheme 2). Structural assignments of these new compounds
1
were based on a series of H NMR studies. Additionally, the
structures of compounds 4d and k were confirmed by
single-crystal X-ray diffraction analyses.[8]
Compounds 4 are the result of an initial intramolecular
hydroalkoxylation (products 4a–l) or hydroamination (prod-
ucts 4m–o) of the triple bond in 1, followed by cycloaddi-
[a] Prof. Dr. J. Barluenga, J. Calleja, Dr. A. Mendoza, Dr. F. Rodrꢁguez,
Dr. F. J. FaÇanꢂs
tion of the formed diene 2 with the corresponding di
AHCTUNGTREGpNNNU hile 3. In those cases in which N-phenylmaleimide 3a was
ACHTUNGTRENNUNGeno-
Instituto Universitario de Quꢁmica Organometꢂlica
“Enrique Moles”, Unidad Asociada al CSIC
Universidad de Oviedo, Juliꢂn Claverꢁa 8
33006 Oviedo (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
used, the corresponding products 4 were obtained as single
diastereoisomers, because of an endo-cycloaddition of the
corresponding intermediate 2 with N-phenylmaleimide (3a).
It should be noted that in compounds 4a and o isomerisa-
tion of the double bond into an endocyclic position occurs
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000515.
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COMMUNICATION
described (room temperature). However, by heating the
mixture at reflux in dichloromethane overnight we observed
the formation of compound 4g. These experiments indicate
that the gold catalyst promotes the Diels–Alder reaction.
It should be noted that the formation of fused compounds
4 is due exclusively to the reaction of enyne derivatives 1
(n=1) through a 5-endo-type cycloisomerisation to give in-
termediates 2. In accordance with Baldwinꢄs rules, the alter-
native 4-exo cycloisomerisation reactions, to give the hypo-
thetical exocyclic dienes analogous to 2’, are disfavoured
processes. In this context, we were intrigued about the be-
haviour of enynol derivatives with a longer chain between
the hydroxyl group and the triple bond [see enyne deriva-
tives 1 (n=2, 3) in Scheme 3]. In these cases competitive 5-
Scheme 2. Products 4 obtained by the cascade, 5-endo cycloisomerisation/
Diels–Alder cycloaddition reaction. [a] The reaction was performed in
1,2-dichloroethane at reflux.
Scheme 3. Products 5 obtained by the cascade 5-exo or 6-exo cycloisomer-
isation/Diels–Alder cycloaddition reaction.
under the reaction conditions. We have no clear explanation
for this isomerisation reaction. This unusual behaviour was
observed only when N-phenylmaleimide 3a reacted with
dienes derived from styryl-substituted alkynes 1. The reac-
tions that form compounds 4c, d and k are remarkable. As
shown, these compounds are derived from chiral alkynol de-
rivatives 1. In these cases, we only observed the formation
of a single diastereoisomer corresponding to those structures
shown in Scheme 2. These results are significant as they in-
dicate that the substrate-controlled synthesis of enantiomeri-
cally pure derivatives 4 from enantiomerically pure enynes
1 is possible.
The role of the gold catalyst in the Diels–Alder reaction
was investigated by the independent synthesis of diene 5-
[(E)-styryl]-2,3-dihydrofuran (2g). We observed that this
diene did not react with tetracyanoethylene in the absence
of the gold catalyst, under the reaction conditions previously
exo/6-endo or 6-exo/7-endo processes may occur and so
fused compounds analogous to 4 or spirocyclic products 5
could, in theory, be obtained (see Scheme 1). However,
when we performed the reactions of these enynol deriva-
tives (1; n=2 or 3) with dienophiles 3a or b, in the presence
of AuCl3 (3 mol%) in dichloroethane at reflux, we were
able to isolate only the spirocyclic products 5 (Scheme 3).
Compounds 5 are the result of an initial 5-exo- (for furan
derivatives 5a–h) or 6-exo-cyclcloisomerisation reaction (for
pyran derivative 5i) of the corresponding enynol derivatives
1 (n=2 or 3) to give dienes 2’. We did not observe, in any
case, the formation of products derived from the competi-
tive, initial endo-cycloisomerisation reactions that would fur-
nish dienes 2. Structural assignments of compounds 5 were
based on a series of 1H NMR studies. Additionally, the
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In conclusion, a new AuCl3-catalysed cascade reaction
based upon an initial cycloisomerisation reaction of enynol
or enynamine derivatives to form 1,3-butadiene derivatives
that then undergo an in situ Diels–Alder cycloaddition reac-
tion with appropriate dienophiles has been described. This
new process affords interesting fused or spirocyclic com-
pounds in an efficient and simple manner. The scope of
these reactions and the possibility of applying this strategy
to the synthesis of natural products are currently being in-
vestigated in our laboratory.
Acknowledgements
We gratefully acknowledge financial support from the MICINN
(CTQ2007-61048/BQU) and PRINCAST (IB08-088). J.C. and A.M. also
acknowledge MEC for grants.
[6] Other catalysts such as AuCl, PtCl2, [PtMe2ACHTNUTRGNE(NUG cod)], PtCl4 and [{(co-
d)IrCl}2] gave similar results in the reaction that forms 4k. However,
we decided to use AuCl3 in the successive experiments due to its high
activity and ease of handling.
Keywords: coupling reactions
· Diels–Alder reactions ·
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Received: February 26, 2010
Published online: May 12, 2010
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