Facile synthesis of 1,3,5-triaroylbenzenes by direct cyclotrimerization of ketone enolates

Article abstract of DOI:10.1080/00397911.2012.658944

Based on the improvement of the synthesis of 1,3,5-triaroylbenzenes, a convenient acid catalytic strategy was carried out and a series of 1,3,5-triaroylbenzenes were synthesized. The reaction temperature effect was investigated, and a mechanism of the cyclotrimerization has been proposed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2012.658944

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Facile Synthesis of 1,3,5-
Triaroylbenzenes by Direct
Cyclotrimerization of Ketone Enolates
Feng-Shou Liu a , Xue-Hong Liu a , Kang-Zhi Ye a & Dong-Sheng Shen a
a School of Chemistry and Chemical Engineering, Guangdong
Pharmaceutical University, Zhongshan, China
Accepted author version posted online: 08 Aug 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Feng-Shou Liu , Xue-Hong Liu , Kang-Zhi Ye & Dong-Sheng Shen (2013): Facile
Synthesis of 1,3,5-Triaroylbenzenes by Direct Cyclotrimerization of Ketone Enolates, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:12, 1640-1645
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Synthetic Communications1, 43: 1640–1645, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.658944
FACILE SYNTHESIS OF 1,3,5-TRIAROYLBENZENES
BY DIRECT CYCLOTRIMERIZATION OF
KETONE ENOLATES
Feng-Shou Liu, Xue-Hong Liu, Kang-Zhi Ye, and
Dong-Sheng Shen
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University, Zhongshan, China
GRAPHICAL ABSTRACT
Abstract Based on the improvement of the synthesis of 1,3,5-triaroylbenzenes, a convenient
acid catalytic strategy was carried out and a series of 1,3,5-triaroylbenzenes were
synthesized. The reaction temperature effect was investigated, and a mechanism of the
cyclotrimerization has been proposed.
Keywords Acid; cyclotrimerization; ketone enolate; 1,3,5-triaroylbenzene
INTRODUCTION
1,3,5-Triaroylbenzenes are an important class of compounds with a distinct
structure, and they have attracted significant interest in recent years because of their
numerous applications in medicine,[1] nonlinear optical materials,[2] supermolecular
assemblies,[3] and the functional polymer materials.[4] Traditionally, 1,3,5-triaroyl-
benzene compounds have been synthesized through several routes, including the
oxidation of secondary alcohols[3n] and ethynylarycarbinols,[3o] cyclotrimerization
of ethylene epoxide,[3p] aroylvinyl sulfonium salts[3q] and aryl ethynyl ketones.[3r–v]
Moreover, they also can be obtained by aromatic electrophilic substitution reactions
such as Friedel–Crafts acylation,[5] cross-coupling reactions of acyl chlorides with
Received October 3, 2011.
Address correspondence to Feng-Shou Liu or Dong-Sheng Shen School of Chemistry and
Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China. E-mail:
fengshou2004@126.com; sds8@163.com
1640

SYNTHESIS OF 1,3,5-TRIAROYLBENZENES
1641
organometallic reagents,[6] and a variety of metal-mediated multistep coupling
reactions.[7] Although the synthetic methods mentioned exhibit moderate to satisfac-
tory yields, they suffer drawbacks either in the use of expensive staring materials, the
need for relatively harsh conditions, or poor regioselectivity.
Recently, some new approaches have been developed to produce 1,3,5-triaroyl-
benezes. Elnagdi et al. synthesized a series of substituted enaminones, which were
converted into 1,3,5-triaroylbenezes an acid mediated reaction.[8] Subsequently,
Elghamry improved the reaction conditions by changing the solvent system and
attained excellent yields.[9] Another synthetic method for preparing 1,3,5-triaroylbe-
nezes, reported by Joseph et al., entails cyclotrimerization of b-aryl-b-haloacroleins in
the presence of diethylamine.[10] In view of the proposed mechanism of the cyclotri-
merization, both nucleophilic and electrophilic substituents on b-aryl-b-haloacroleins
are required.
Notably, ketone enolates are easy to assess, and they have been used as precur-
sors for the synthesis of enol thioethers, enaminones, enol ethers, a-formyl-a,b-
unsaturated ketones, a-methylene ketones, and triacylbenzenes.[11] Moreover, Eiden
and Haverland have described an example where a-formyl-a,b-unsaturated ketone
(3-(2-methoxyphenyl)-3-oxopropanal) was used as starting material for the syn-
thesis of triaroylbeneze in the presence of benzaldehyde and sodium hydroxide.[12]
However, the mechanism of the reaction was not discussed and the spectrum of
the desired product was not provided. In light of the [2 þ 2 þ 2] cyclotrimerization
mentioned previously, we contemplated the cyclotrimerization of ketone enolates
as a means of accessing the 1,3,5-triaroylbenezes that would demonstrate both atom
economy and easy synthesis. As a demonstration of the advantages of this strategy,
we report here a novel, one-step synthesis of triaroylbenzenes through the cyclotri-
merization of ketone enolates.
RESULTS AND DISCUSSION
The ketone enolates utilized in this study were designed for their potential
ability to undergo self-cyclotrimerization and generate triaroylbenzenes. The ketone
enolate sodium salts were prepared from aryl ethyl ketones by classical Claisen
condensation with sodium ethoxide and ethyl formate in a one-step reaction.
Addition of acetic acid gave ketone enolates in situ and afforded triaroylbenzenes
(1a–e) in a 78–88% overall yield (Scheme 1).
Scheme 1. Synthetic route to 1a–e.

1642
F.-S. LIU ET AL.
The reaction temperature played an important role in the cyclotrimerization
reaction. At room temperature, the ketone enolate sodium salts were only converted
into their corresponding ketone enolates, which is consistent with an earlier
report.[11b] However, upon elevating the temperature to reflux, the product was
obtained in satisfactory yield. Under these reaction conditions, the symmetric
1,3,5-triaroylbenzene was confirmed as the sole product in all cases except for
1
1,2,4-substituted analogs. As can be seen in Fig. 1, the H NMR spectrum of 1a
revealed four kinds of protons. One singlet at d ¼ 8.40 ppm can be ascribed to the
signal of the arene backbone of H1, along with one doublet-doublet for H2 and
two multiplets for H3 and H4, respectively.
In the light of the mechanism mentioned by Abdel-Khalik and Elnagdi,[8a] the
regioselective reactions demand both nucleophilic and electrophilic substituents on
the reactant. In the case of ketone enolates, nucleophiles can attack at the b-carbon
of carbonyl groups, while electrophiles can attack at the a -carbon. Therefore,
a rational explanation of the transformations that are responsible for the production
of the triaroylbenzenes might be a series of Michael reactions. As depicted in
Scheme 2, upon the addition of a proton, a ketone enolate (3) might be expected
to form a new electrophile (4) and then added to a ketone enolate to yield the inter-
mediates 5 and 6. Subsequently, this reaction would repeat once again to generate
intermediate 7, which in turn could undergo an internal cyclization to give
a six-membered ring (intermediate 8) with the resultant elimination of three mole-
cules of water to afford the desired triaroylbenzenes. Considering the requirement
for the elimination of water in the reaction process, the greater reaction temperature
is consistent with the proposed mechanism.
The yields of triaroylbenzenes obtained from cyclotrimerization of ketone
enolates were comparable to the good yields obtained by cyclotrimerization of
enaminones. Moreover, there are some noteworthy features of this cyclotrimeri-
zation process that merit further comment. For instance, the cyclotrimerization of
Figure 1. 1H NMR spectrum of 1a.

SYNTHESIS OF 1,3,5-TRIAROYLBENZENES
1643
Scheme 2. Proposed mechanism of direct cyclotrimerization of ketone enolate.
ketone enolates demonstrates atom economy relative to the cyclotrimerization of
enaminones. Also, the reaction is a direct cyclotrimerization of ketone enolates
in the absence of dimethylamine. Moreover, the reaction proceeded with high regios-
electivity wherein the 1,3,5-triaroylbenzene was obtained as the sole product.
CONCLUSION
In summary, we have developed a simple route for the synthesis of 1,3,5-triar-
oylbenzenes by the acid catalytic ketone enolates in a one-step strategy. It is crucial
to increase the reaction temperature, which can promote the yield of products.
Furthermore, a mechanism of the cyclotrimerization has been proposed.
EXPERIMENTAL
Toluene was purchased from Guangzhou Chemical Reagent Factory and was
used after it was refluxed over metallic sodium for 8 h. Acetic acid, ethanol, and
sodium ethoxide were purchased from Guangzhou Chemical Reagent Factory and
used as recieved. Ethyl formate, acetophenone, 4-methylacetophenone, 4-methyoxy-
lacetophenone, 4-chloroacetophenone, and 4-bromoacetophenone were purchased
from Shanghai Chemical Reagent Factory and used as received. NMR spectra were
recorded on a Varian Mercury-Plus 500-MHz NMR spectrometer and referenced
versus tetramethylsilane (TMS) as standard. Elemental analyses were determined
with a Vario EL series elemental analyzer from Elementar.
A solution of acetophenone (10 mmol) in ethyl formate (1.48 g, 20 mmol) was
added dropwise to a stirred suspension of sodium ethoxide (0.68 g, 10 mmol) in
anhydrous toluene (50 ml). After stirring for 4 h at room temperature, 25 ml
acetic acid was added dropwise to the stirred suspended matter, and it was refluxed
for another 2 h. Then, water (400 ml) was added, the organic phase was separated,

1644
F.-S. LIU ET AL.
and the water phase was extracted with ether (2 ꢀ 40 ml). After combining with the
organic phase and drying over anhydrous sodium sulfate, the solvent was removed
on a rotary evaporator, and the residue was recrystallized in ethanol to afford the
title compound.
ACKNOWLEDGMENTS
We acknowledge the National Natural Science Foundation of China (No.
21004014) and the Foundation for Distinguished Young Talents in Higher Edu-
cation of Guangdong (No. LYM10091) for financial support.
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