Synthesis of linked 1,3,5-triaroylbenzenes via enamine-directed alkyne cyclotrimerization

Article abstract of DOI:10.1016/S0040-4039(00)01125-4

Triaroylbenzenes connected via m-xylyl, p-xylyl, 4,4'-biphenyl, and 1,3,5-benzenetriyl linking units have been prepared in good yield by condensation of bis(enaminones) with aryl ethynyl ketones. The required bis(enaminones) were conveniently prepared sta

Full text of DOI:10.1016/S0040-4039(00)01125-4

Tetrahedron Letters 41 (2000) 6545±6549
Synthesis of linked 1,3,5-triaroylbenzenes via
enamine-directed alkyne cyclotrimerization
F. Christopher Pigge* and Fatemeh Ghasedi
Department of Chemistry, University of Missouri±St. Louis, St. Louis, MO 63121-4499, USA
Received 8 June 2000; accepted 4 July 2000
Abstract
Triaroylbenzenes connected via m-xylyl, p-xylyl, 4,40-biphenyl, and 1,3,5-benzenetriyl linking units have
been prepared in good yield by condensation of bis(enaminones) with aryl ethynyl ketones. The required
bis(enaminones) were conveniently prepared starting from the corresponding bis- or tris(halomethyl)
linking units and 3-hydroxybenzaldehyde. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkynes; cyclotrimerization; enamines; arenes.
The design and synthesis of molecular hosts capable of operating in solution and/or the solid-
phase continues to attract the attention of an increasingly interdisciplinary cross-section of the
chemical community. Synthetic solution phase receptors have provided valuable insight into the
factors responsible for molecular recognition events occurring in biological systems.1 In addition,
such receptors have great potential for use in the development of new catalysts, sensors, and
sequestering agents.2 Solid-phase host±guest complexes provide a means to study weak
3
...
intermolecular interactions (such as C±H O hydrogen bonding) and also may have applications
in areas such as non-linear optics4 and separations technology.5
* Corresponding author. Fax: 1-314-516-5342; e-mail: piggec@jinx.umsl.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01125-4

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In connection with a study aimed at developing new molecular receptors capable of parti-
cipating in supramolecular assemblies, we have begun exploring the suitability of 1,3,5-triaroyl-
benzene derivatives (possessing the general structure illustrated for the parent compound 1) as a
central architectural motif. Simple 1,3,5-triaroylbenzenes are easily prepared using a method ®rst
reported by Balasubramanian that entails amine-catalyzed cyclotrimerization of aryl ethynyl
ketones.6 Reports from this laboratory have described the ability of methoxy- and nitro-
substituted derivatives to serve as solid-state inclusion hosts for various small molecule guests.7
Given these preliminary ®ndings, it was deemed worthwhile to investigate the feasibility of
constructing more elaborate `linked' triaroylbenzenes with the aim of using these materials as
precursors for new molecular receptor frameworks.
The synthetic route envisioned for the preparation of the target structures is illustrated in
Scheme 1. Attachment of 3-hydroxybenzaldehyde moieties to appropriately functionalized
`spacer' units (e.g. m-xylyl) followed by conversion of the aldehyde residues to aryl ethynyl
ketones should give 2. Cross-trimerization of 2 with a second aryl ethynyl ketone reactant should
then a€ord the desired `linked' triaroylbenzenes 3. The success of this route is predicated upon
the ability to perform cross-cyclotrimerizations leading to unsymmetrically substituted 1,3,5-
triaroylbenzene derivatives. Iwamura has reported a successful cross-trimerization between two
di€erent aryl ethynyl ketones in the presence of a catalytic amount of diethylamine.8 The desired
triaroylbenzene, however, was isolated in 31% yield after separation from a statistical mixture of
other symmetrical and unsymmetrical cyclotrimers. Application of this method for the
trimerization of 2 (linker=m-xylyl)9,10 and the aryl ethynyl ketone derived from m-anisaldehyde
did indeed provide the desired linked bis(triaroylbenzene); unfortunately, the isolated yield of
20% and the extensive chromatography required to obtain homogeneous material rendered this
approach unacceptable.
Scheme 1.
Consequently, an alternative means of e€ecting the desired cross-cyclotrimerization was
required. Mechanistic studies of the cyclotimerization reaction, also reported by Iwamura,

6547
Scheme 2.
strongly suggest that the amine catalyst initially reacts with an alkynyl moiety to form an enamine.11
Sequential condensation of this enamine with two additional molecules of aryl ethynyl ketone
result in formation of a cyclic diene from which the amine is eliminated, thereby generating a new
arene ring. Other experiments established that the initially formed enamine is not in equilibrium
with the free amine and aryl ethynyl ketone. Thus, if the alkyne residues in 2 were ®rst converted
to the corresponding enaminones prior to condensation with the second aryl ethynyl ketone
reaction partner, unwanted oligomerization of 2 should be suppressed and enamine-directed
cross-cyclotimerization should be favored.
To test this theory, bis(ethynyl ketones) exhibiting the general structure depicted in 2 were
.
transformed to the corresponding N,N-dimethyl enaminones (4) by treatment with Me2NH HCl
in the presence of K2CO3 (Scheme 2). Gratifyingly, heating a mixture of 4 and an excess of an
aryl ethynyl ketone 5 (ꢀ8 equiv.) in toluene resulted in smooth trimerization to a€ord the desired
linked 1,3,5-triaroylbenzenes (6) in good isolated yields,10 especially given the fact that six new
C±C bonds are formed during the course of the reaction. In addition, isolation of 6 from the
crude reaction mixture was accomplished by application of routine chromatographic techniques
as the only tractable by-product generated was the symmetrical cyclotrimer of 5.12 Both electron
rich (R=OMe) and electron de®cient (R=NO2) aryl ethynyl ketones proved to be suitable reac-
tants, although nitro-substituted linked triaroylbenzenes were isolated in slightly lower yields.
The nature of the linker moiety connecting the 1,3,5-triaroylbenzene frameworks could be varied
as well. This protocol was also suitable for the preparation of tris(triaroylbenzene) derivative
7 in which the individual cyclotrimers are connected via a 1,3,5-trisubstituted phenyl ring
(Eq. (1)).10,13

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ꢁ1†
In summary, an ecient and modular synthetic route for the preparation of linked bis- and
tris(1,3,5-triaroylbenzenes) has been established in which an enamine-directed alkyne cross-
cyclotimerization is the key transformation. The ability of these linked triaroylbenzenes to
function as novel solid-state inclusion hosts is currently under investigation. Additionally, further
synthetic elaboration of the triaroylbenzene framework to ultimately deliver new cyclophanes and
cage compounds is being examined.
Acknowledgements
Financial support for this work was provided by the University of Missouri±St. Louis
Department of Chemistry. Support for departmental NMR facilities was provided by the NSF
(CHE-9318696).
References
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9. Compounds possessing the general structure 2 were prepared by alkylation of the bis(halomethyl) linking unit with
3-hydroxybenzaldehyde. The aldehyde residues were then treated with ethynyl magnesium bromide. The resulting
alcohols were oxidized to the corresponding bis(aryl ethynyl ketones) 2 using the Jones reagent.
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with the assigned structures.
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Cochrane, W. P.; Pauson, P. L.; Stevens, T. S. J. Chem. Soc. C 1968, 630.