Contingency and Serendipity in the Reactions of Fischer Carbene Complexes with Conjugated Triynes

Article abstract of DOI:10.1021/ja049836i

The first examples of reactions of Fischer carbene complexes with triynes are reported. The regioselectivity of the reaction of the two different alkyne functions in the symmetrical triyne depends on the nature of the substituent of the triyne. Bis-silyl-substituted triynes react at the central alkyne unit, whereas bis-aryl- and bis-alkyl-substituted triynes react at the end alkyne unit. The reaction of a Fischer carbene complex with a phenyl substituent also reacts with a bis-silyl-substituted triyne at the central alkyne unit but gives a furan product rather than the normal phenol product. It was also demonstrated that all three of the alkyne units in conjugated triynes could react in turn with a Fischer carbene complex to give access to trisquinones. Copyright

Full text of DOI:10.1021/ja049836i

Published on Web 04/24/2004
Contingency and Serendipity in the Reactions of Fischer Carbene Complexes
with Conjugated Triynes
May Xiao-Wu Jiang, Manish Rawat, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received January 10, 2004; E-mail: wulff@cem.msu.edu
Scheme 1
The reaction of Fischer carbene complexes with alkynes is one
of the most flexible methods for the synthesis of phenols and
quinones.1 The reaction has been extended to conjugated diynes,
and it was found to proceed as expected in a stepwise fashion with
2 equiv of the carbene complexes to give biaryl compounds in which
the bond connecting the two newly formed aryl rings is the bond
connecting the two alkyne units in the starting diyne.2 With this as
a precedent, we were encouraged to consider an approach to the
biologically active trisquinone family of natural products3 that
unfolds from the sequential reaction of conjugated triynes with 3
equiv of a Fischer carbene complex. We report herein the first
examples of reactions of triynes 4 with Fischer carbene complexes,
the unexpected regioselectivity of the two different alkynes in 4,
and the serendipitous solution for regioselective control.
Scheme 2
The regioselectivity of the reactions of Fischer carbene complexes
with unsymmetrical alkynes has been extensively examined, and
the summation of the findings is that the regioselectivity is much
more sensitive to the steric difference between the two substituents
of the alkyne than any electronic perturbation these substituents
may have.1,4 On the basis of the importance of sterics in control of
the regiochemistry in mono-alkynes, it was expected that the
reaction of the first equivalent of carbene complex would react at
the central alkyne of 4 to give the dialkynyl phenol 2 (Scheme 1).
The alternative is that the carbene complex would preferentially
Scheme 3
react at the end alkynes in 4 and give the diaryl acetylene 5.5 The
intermediacy of 5 on the pathway to trisquinones was considered
much less desirable than 2 because it is generally the case that the
benzannulation of highly sterically congested alkynes tends to give
increasing amounts of side products.1,2 Again, for the reasons
mentioned above, the reaction of the carbene complex 3 with the
end alkynes in 4 to give 5 would be considered the least likely
outcome.
We were thus taken unaware to find that the reaction of the
cyclohexenyl complex 6 with 1,6-diphenylhexatriyne 4a gave a
mixture of the products 7a and 8a which both resulted from the
reaction of the carbene complex at the end alkynes of the triyne
As the investigation was further pursued, the reaction of triynes
with Fischer carbene complexes continued to offer up surprises.
(Scheme 2). The reaction could be driven to give only the double-
benzannulation product 8a in 69% yield with 5 equiv of the carbene
The reaction of carbene complex 6 with silyl-substituted triyne 4d
complex, and the formation of 8a could be prevented if 5 equiv of
gives the mono-benzannulated product 9d in which the reaction
the triyne was used in which case 7a was obtained in 43% yield.
has occurred at the central alkyne unit (Scheme 3). The regiose-
The use of the larger adamantyl groups on the triyne did not result
in the formation of any detectable amount of the product resulting
from reaction of the central alkyne unit. The structure of 7b and
1
lectivity of this reaction was assigned by symmetry in the H and
13C NMR spectra after methylation of the phenol and desilylation
to give 15a. The yield of 9d could be improved to 81% in toluene.
The reaction of the phenyl complex 10 with the bis-(triisopropyl-
silyl)triyne 4d also occurred at the central alkyne unit, but in this
case the reaction did not produce the phenol product but instead
gave the furan 11d in 69% yield. The regioselectivity in this case
was confirmed by removal of the silyl groups which produced a
compound with two terminal alkynes. The formation of furan
products has been reported from the reaction of carbene complexes
8a (via its quinone) was confirmed by X-ray diffraction. As was
anticipated, the diaryl alkyne 8 cannot be used as an entry point to
trisquinones. The reaction of 8a with carbene complex 6 in THF
led to complete consumption of the starting carbene complex and
the formation of only trace amounts of silica gel mobile compounds
which were not characterized. This is undoubtedly due to the steric
hindrance around the alkyne in 8 and not to the presence of phenol
hydroxyls.2
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10.1021/ja049836i CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 5
favored for R as a carbon group. The formation of the furan product
11d suggests that the reaction of the aryl complex 10 with 4d gives
the η1,η3-vinyl carbene complexed intermediate 13a with a Z-
double-bond (methoxy and phenyl reversed).6b Further studies of
this and other mechanistic issues are ongoing.
The serendipitous finding that the silyl-substituted triyne 4d reacts
at the central alkyne has led to the realization of the synthesis of
trisquinones. Acetylation and desilylation of 9d gave the bis-alkyne
15b in 58% yield (Scheme 5). The reaction of 15b with 2 equiv of
carbene complex 6 in acetonitrile at 55 °C gave 16 in 67% yield.
Reduction with LiAlH4 gave the trisphenol which was oxidized
with CAN to give the trisquinone 17 in 57% yield. With the viability
of this approach established, the scope of this method for the
synthesis of trisquinones is being actively pursued.
Acknowledgment. This work was supported by a grant from
the NIH (GM 33589).
with mono-alkynes,1,6 but not as the major product from the reaction
with the phenyl complex 8.
A mechanism1,7 to account for the difference in regioselectivity
of triynes 4a and 4b versus 4d is shown in Scheme 4. Rate-
determining loss of a CO ligand followed by insertion of the central
alkyne in 4 gives the η1,η3-vinyl carbene complexed intermediate
13a. Insertion of the end alkyne of 4 would lead to the η1,η3-vinyl
carbene complexed intermediate 13b. On the basis of previous
studies, it is assumed that these intermediates are in rapid
equilibrium with respect to CO insertion which gives the vinyl
ketene intermediates 14a and 14b.7d Previous work has established
that cyclization and aromatization of the vinyl ketene intermediate
is faster than deinsertion of the carbon monoxide which regenerates
the η1,η3-vinyl carbene complexed intermediate. This conclusion
has been reached in computational studies7b and in experiment.6b
However, these studies did not include alkynes that have silicon
substituents. We propose that the cylization of the vinyl ketene
intermediate 14b (but not 14a) is slow relative to CO deinsertion
when the substituent R is a silicon group (k-3 > k4). Support for
this proposal comes from the known ability of silicon to greatly
increase the stability of metal-free ketenes8 and from observations
that stable metal-free silyl-substituted vinyl ketenes can be isolated
from the reaction of Fischer carbene complexes and silyl-substituted
alkynes.9 The observation that the silyl-substituted triynes produce
9 from reaction at the central alkyne can then be accounted for by
CO deinsertion in 14b to give 13b, and then a depletion of the
equilibrium between 13a and 13b via CO insertion and cyclization
of 14a. The reason that the triynes 4a and 4b with carbon
substituents produce 7 is not clear, but one explanation is that η1,η3-
vinyl carbene complexed intermediate 13b is more stable than 13a
and thus that the equilibrium favors 13b. It is not possible to rule
out another scenario that involves a nonreversible CO insertion and
a product determination that is the result of an equilibrium between
13b and 13a where 13b is favored for R as silicon and 13a is
Supporting Information Available: Experimental procedures and
spectral data for all new compounds and X-ray data for 7b and the
quinone of 8a (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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