318
J. Comb. Chem. 2010, 12, 318–320
compounds, with the general formula 7 (Scheme 1) was
prepared using a variety of terminal and highly unsym-
metric internal alkynes. Yields ranging between 60 to 95%,
after purification, were obtained for compounds 14-45.
While this protocol was successful with a variety of
alkynes, examples with N-heterocyclic and other amino
alkynes failed to yield the desired products. To counter
this problem, as well as enhance the diversity of the
library, stannane 10 was synthesized in moderate yield
by reacting 6 with ethynyltributylstannane (8). Stannane
10 is an unknown compound and offers the opportunity
to synthesize derivatives of this system by the Stille cross-
coupling protocol.10-13 However rather than use the Stille
reaction, stannane 10 was quantitatively converted to the
corresponding unknown vinyl iodide (12). This was done
to eliminate any potential problems with carryover of tin
into the library members synthesized with this substrate.
Iodide 12 was also prepared by reacting 6 with the less
expensive ethynlytrimethylsilane (9) to obtain the corre-
sponding trimethylsilyl cyclohexa-2,4-dienone (11), fol-
lowed by treatment with iodine monochloride14 and
hydrolysis. Vinyl iodide 12 was subjected to a Suzuki
cross-coupling protocol11 employing a variety of boronic
acids to obtain products such as 13 (Scheme 2). Figure 1
contains the first set of compounds synthesized, either
using different alkynes (14-45) or by the Suzuki reaction
on iodide 12 (46-48) (Figure 2). These examples illustrate
that while alkyne containing heterocycles can be prob-
lematic in the Fischer carbene annulation this problem can
be circumvented thru the use of iodides such as 12.
Running the reaction on bromophenyl alkynes provided
products (49) that can then be modified further by palladium
catalyzed reactions (Scheme 3). The bromides on compounds
36 and 38 were utilized in a series of Suzuki reactions to
provide compounds (54-74). The 21 compounds that were
synthesized consisted of meta and para biphenyls as well
as a few examples where aromatic heterocycles were
attached. The Suzuki reactions were run under microwave
conditions and proceeded in 60 to 95% yield in 15 to 20
min.
Design, Synthesis, and Diversification of
5,5-Dimethyl Cyclohexen-1,4-dione Library
Eric A. Tanifum and Scott R. Gilbertson*
Department of Chemistry, UniVersity of Houston, Houston
Texas 77204-5003
ReceiVed February 26, 2010
Quinones play important roles in a wide variety of
different biological systems and as such they should be
interesting molecules to include in small molecule librar-
ies. However, when they have been included in libraries,
quinones have often been found to be nonselective in their
activity. The similarity of a cyclohexen-1,4-dione scaffold
to the quinone structure suggests that it could be a
potential source for interesting biological activity. Such
molecules present the possibility of synthesizing libraries
of molecules that have structures similar to quinones
without having the relatively promiscuous redox activity
that can lead to nonspecific activity. As an effort to explore
methods to generate cyclohexen-1,4-diones for high-
throughput screening a collection of molecules has been
designed and synthesized.
The reaction of vinyl Fischer carbene complexes such
as 1, with alkynes1-7 has been shown to form either
hydroquinone or cyclohexadienone type products depend-
ing on whether R is H or an alkyl group (Scheme 1). Even
though the mechanism of this reaction has not been fully
established,5,8,9 the chemical and regioselective outcomes
are well understood.1,5,9 Given the variety of commercially
available alkynes, different molecules are accessible from
the combination of these alkynes with a single Fischer
carbene complex. Compound 1 (where R ) H), reacts with
alkynes to give substituted phenols (2), which can be
further oxidized to the corresponding quinones (3) (Scheme
1). Terminal alkynes generally form a single product in
which the substitution is ortho to the phenol (2). When R
is an alkyl group (1), aromatization is blocked, resulting
in cyclohexa-2,4-dienones (4), which can be used as
synthetic intermediates or hydrolyzed to give cyclohexen-
1,4-diones (5). This second manifold, the formation of
cyclohexen-1,4-dione (5), is the reaction that has been
exploited in the work reported here.
The annulation reaction tolerates free hydroxyl and
phenolic groups to provide products that can be further
modified (21, 35, 42, and 45). Endiones 21 and 35 were
esterified with a variety of acyl chlorides (Scheme 3) to form
a series of compounds (75-92) (Figure 3).
In addition to performing the Suzuki reaction on
endiones, two examples of a microwave-assisted Sono-
gashira coupling15 (Scheme 4) were performed. Reaction
of bromide 38 with p-methylphenylacetylene and p-
methoxyphenylacetylene provided unique compounds 93
and 94.
The synthesis was designed with vinyl carbene complex
6 (Scheme 1) as the key intermediate. This complex is
easily accessed from chromium(0) hexacarbonyl and the
commercially available 1-bromo-2-methyl-1-propene, un-
der mild conditions, and is stable for months in the
refrigerator. Reactions of this complex with alkynes
proceed in high purity and under mild conditions. Using
a protocol adapted from the Wulff group,5 gram quantities
of 6 were prepared in moderate yield. The initial set of
Seventy-seven compounds have been synthesized either
by using unique alkynes, the Suzuki reaction, esterfication
or in two cases Sonogashira coupling. It has been shown
that through the reaction of a vinyl Fischer carbene
* To whom correspondence should be addressed. E-mail: srgilbe2@
central.uh.edu.
10.1021/cc100030h 2010 American Chemical Society
Published on Web 04/13/2010
Tanifum, Eric A.
