Insights into the triple self-condensation reaction of thiophene-based methyl ketones and related compounds

The acid catalysed triple self-condensation of 1-thien-2-ylethanone (2-acetylthiophene) and five related compounds is presented. Tetrachlorosilane used as the Lewis acid produces dry hydrogen chloride which catalyzes the self-condensation process. Depending on the reaction conditions and the substitution of the carbonyl substrates, the reaction can proceed as a [2+2+2] cyclotrimerization towards C 3 -symmetric 1,3,5-trisubstituted benzenes, or as the single-type aldol condensation leading to 1,3-disubstituted ( E )- β -methyl- chalcones. This is important for the design of new aromatic/olefinic compounds beyond the model structures. Synthesis of 4 ' -fluoro-3,5-di-(2-thienyl)biphenyl through a mixed-type aldol reaction using erbium triflate is discussed. Mechanistic rationale is provided.


Introduction
Star-shaped molecules based on 1,3,5-triarylbenzenes have long been recognized as a family of amorphous glasses stable above room temperature. 1,2The bioisosteric replacement of benzene by thiophene has extended the family of C 3 -symmetric compounds 3,4 and their applications in electroluminescent (EL) devices, 5 liquid crystalline materials 6 and as fluorescent probes. 7In contrast to polymers used in similar applications, amorphous molecular materials are pure materials with well-defined molecular structures and definite molecular weights without any distribution.Consequently, 1,3,5-tri(het)arylbenzenes serve as versatile platforms in the design of organic light emitting diodes (OLEDs), 8,9 dendrimers, 10 polycyclic aromatic hydrocarbons (PAH), 11 bulky ligands 12 and truxenes (derivatives of 10,15-dihydro-5H-diindeno[1,2-a; 1',2'c]fluorene). 13The classical one-directional convergent synthetic approach, originally developed by Clapps and Morton, 14 is that most frequently reported in the literature.

Effects of solvent, temperature and reaction time
The [2+2+2] cyclotrimerization of starting ketones 1a-d was carried out at room temperature (25 °C).The same approach with ketones 1e and 1f was conducted at 100 °C.Generally, a relatively low temperature of the triple self-condensation towards 1,3,5-triarylbenzenes has to be maintained to form thermodynamically stable enol-silyl ether reactive intermediates of the excited state followed by in situ formation of gaseous HCl. 17,36,41Although in the triple self-condensation process promoted by SiCl 4 as the weak Lewis acid, ethanol proves to be the most universal solvent (Method A), 18,19,36,39 the solubility of some hetaryl methyl ketones 1a-f in ethanol might be insufficient.Since the enhanced solubility of substrates together with the activity of tetrachlorosilane was crucial, we performed the [2+2+2] cyclotrimerization with the starting substrates 1a-d in a mixture of ethanol/toluene (Method B) 16,20 as well as by using 2-ethoxyethanol instead of ethanol (Method C).Use of a double and threefold excess of SiCl 4 /EtOH (Method A and B) leads directly to 1,3,5-triarylbenzenes 3a-d, 3 while use of excess of catalyst (4 equiv.) in 2-ethoxyethanol (Method C) gave good yields of βmethylchalcones 2b-d. 17,36Since, fluorenylidene-substituted hetaryl methyl ketones 1e and 1f were insoluble in the solvents used according to Methods A-C, we turned to Method D, performing the reaction with trifluoromethane sulfonic acid (TFSA, 2 mol %) in toluene.The optimal reaction time during which the formation of unidentifiable polymers was suppressed was 14 h with SiCl 4 (Methods A-C) and 30 h with CF 3 SO 3 H (Method D).The results on reaction conditions for 1a-f are summarized in Table 1.

Mechanism
To the best of our knowledge, two possible mechanisms of acid catalysed [2+2+2] cyclotrimerization of aryland hetaryl methyl ketones have been reported recently. 36,375][36] Since (E)β-methylchalcones/dypnones were stable compounds, in several cases they were isolated as the final products and the subsequent formation of 1,3,5-trisubstituted benzenes was not observed.The reactivity of (E)-β-methylchalcone/dypnone was crucial in the subsequent cyclization and aromatization reaction sequence, which may occur in the reaction with another amount of the starting carbonyl compound in the single-type aldol condensation (route A) 34 subsequently followed by intramolecular rearrangement supporting the ring closure (Scheme 2).In the second approach (route B) 35 the single-type aldol condensation occurs first between two equivalents of the (E)-β-methylchalcone/dypnone, continuing as intramolecular [2+2] cycloaddition and subsequent retro [2+2] cycloaddition leading to 1,3,5-trisubstituted benzenes (Scheme 2).The bulky substituent may inhibit either the aldol condensation with another equivalent of the starting ketone (route A) 34 or the aldol addition with another equivalent of the dypnone (route B). 35 The dypnone's ability to precipitate from the reaction mixture as well as the solubility of the carbonyl substrate influences the process of [2+2+2] cyclotrimerization to a large extent.Again, the use of SiCl 4 generates -OSiCl 3 protected hydroxyl compounds, allowing to stop the addition at the aldol step. 17 Scheme 2. Proposed mechanism of a triple self-condensation reaction sequence of 1-thien-2-ylethanone (1a). 34,35The H + cation originates from dry HCl (g) which is generated in situ from SiCl 4 through the the excited state enolsilyl reactive intermediates. 17,34,41
Taken together, we assumed that the self-condensation reactions of thiophene-based methyl ketones and related compounds were governed by several factors, such as electronic and steric effects of substituents at C5 position of the heterocyclic core together with reaction conditions (Methods A-D) applied for a particular substrate.
1,3,5-Symmetrically-substituted benzenes 3a-d appear in their 1 H NMR spectra as singlets at 7.75-7.40ppm due to aromatic hydrogen and in the range of 7.10-7.75ppm as doublets or triplets of the thiophene core hydrogens.The H-α proton of the double bond for (E)-β-methylchalcones 2a-f resonate in the range of 6.85-7.10ppm as singlets or quartets as the result of the field interaction between olefinic hydrogen and hydrogen on C-β position of the thiophene together with interactions with the neighbouring methyl group.The methyl group signals appeared at 2.50 ppm

Mixed-type aldol condensation
The scope of dypnone-involved organic synthesis was expanded performing the reaction of 2a (2.0 equiv.)with p-fluoroacetophenone (1.0 equiv.)as the aldol-type addition promoted by erbium triflate [Er(OTf) 3 , 1.0 mol %]. 42,43The strong electron-withdrawing capacity of the methanesulfonate anion enhances the Lewis acid character of the catalyst and among the lanthanoid(III) triflates Er 3+ was one of the most active cations. 44To the best our knowledge, this is the first example of the dypnone-like aldol reaction catalysed by erbium triflate.Unsymmetricaly substituted 1,3,5-benzene 4 was isolated after heating at the boiling point of toluene (8 h, 62%, Scheme 3).In the 1

Conclusions
In this study we have complemented and compared the known aspects of the [2+2+2] cyclotrimerization reactions of acetophenones and related compounds with our current results.The course of the selfcondensation process is indeed challenging providing the possibility of formation of different type of compounds: the C 3 -symmetric aromatic derivatives or the unsaturated (E)-β-methylchalcones (dypnones).We have highlighted, that by varying the substitution of carbonyl substrates in combination with different reaction conditions the reaction can be directed either in a triple [2+2+2] cyclotrimerization manner towards 1,3,5tris(thien-2-yl)benzenes 3a-d (Table 2, Entries 1-5), or in accordance with a single-type aldol condensation producing 1,3-disubstituted (E)-β-methylchalcones 2a-f (Table 2, Entries 6-11).The ability to access new compounds 2b-f through the general and simple protocols (Method B) or by their slight variations (Method Cuse of ethyleneglycole monoethylether as solvent, Method D -use of trifluoromethane sulfonic acid as acid catalyst) is also described.The outlook of the synthetic application of (E)-β-methylchalcones yielding unsymmetrical 1,3,5-triarylbenzene derivatives is presented on the example of synthesis of (E)-3-(2,2'dithienyl)-5-(fluorenyl)benzene (4).Both types of designed structures are important in a broad range of applications; 1,3,5-trisubstituted benzenes in the synthesis of star-shaped molecules acting as the π-conjugated units in opto-electronic materials and 1,3-disubstituted (E)-β-methylchalcones as intermediades in organic synthesis.

Experimental Section
General.All commercially available chemicals were used as received without further purification.Solvents were purified by standard methods and dried if necessary.Reactions were monitored by thin layer chromatography (TLC) on plates precoated with silica gel (Merck 60 F 254 ) and visualized using a UV hand lamp operating at 254/365 nm wavelengths.Melting points were recorded on a Kofler block and are uncorrected.The infrared spectra were taken on Agilent Cary 630 FTIR spectrometer with diamond ATR.Elemental analyses (EA) were performed on a Flash EA 2000 CHNS/O-OEA analyser.ESI-MS spectrum of compound 4 containing fluorine in the structure was recorded on Mass Quattro LC.NMR spectra ( 1 H at 300 and 13 C at 75 MHz) were obtained on the Varian VXR-300 spectrometer and products were reported relative to tetrametylsilane (TMS, 0.00 ppm) or CDCl 3 (7.24ppm) or DMSO-d 6 (2.49 ppm) for 1 H NMR data, CDCl 3 (77.0ppm) or DMSO-d 6 (39.7 ppm) for 13 C NMR data.Spectral data are presented as follows: chemical shifts in part per million (ppm), coupling constants J (Hz) and splitting patterns as s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, m = multiplet.Absorption spectra of the solutions in chloroform (CHCl 3 ), or dichloromethane (CH 2 Cl 2 ) with concentration 1.10 -5 mol•dm -3 measured on a UV 1650PC spectrometer (Shimadzu, Japan).

Figure 1 .
Figure 1.Structures of the starting carbonyl substrates under investigation.

Table 1 .
The

Table 2 .
Summary of triple self-condensation of heterocyclic methyl ketones 1a-f