Heterocycles 21. Reaction of 2-phenyl-thiazol-4-carbaldehyde with 2-bromoacetophenone

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In previous papers we described the preparation of some heterochalcones by condensation of thiazolcarbaldehydes and thiazolo [3,2-b] [1,2,4]triazolcarbaldehydes with a series of acetophenones [1][2][3][4].Data related to the reaction of some α-substituted chalcones with nitrogen dinucleophiles, as well as the antifungal and antiprotozoar properties of these chalcones were already described [5,6].The substituents in the α-position with respect to the carbonyl group affect the biological and chemical behaviour of the above mentioned compounds, both by electronic effects and by molecular geometry.These derivatives can be used also as intermediates in synthesis of chiral heterocyclic compounds, due to their tetrahedral stereocenters which appear as a result of the cyclisation reaction.

Experimental part
Melting points are uncorrected.Elemental analysis was performed on a VarioEL analyzer.Infrared spectra were recorded as KBr pellets with a FTTI spectrophotometer Nicolet 210.Mass spectra were recorded on a MAT 311 mass spectrometer with EI ion source, at ionization energy of 70 eV with direct inlet probe. 1 H and 13 C NMR spectra were recorded on a BRUKER DRX 400 instrument operating at 400.13 and 100.61MHz, respectively, with TMS as internal standard.The chemical shifts are reported in δ units (ppm) relative to the residual peak of the deuterated solvent (ref. CDCl 3 1 H 7.26, 13 C 77.00 ppm).

3-Acetoxy-2-phenyl-4,5-bis(2-phenyl-thiazol-4-yl)-furane (6).
To compound 3 (0.2 g, 0.38 mmol) acetic anhydride (0.5 ml, 5.3 mmol) was added and the mixture was boiled for 5 minutes.Decreasing the temperature to 25 o C a precipitate was obtained and separated by filtration.M.p = 187 o C, Yield: 75%; elemental analysis: C% 69.Crystal structure determination X-ray quality crystals of compound 4 were obtained from a chloroform / n-hexane mixture (1/4 v/v).A colourless block crystal of 4 was mounted on a cryoloop.Data collection and processing was carried out on a Bruker SMART APEX CCD X-ray machine (Babes-Bolyai University, Cluj-Napoca) using graphite-monochromated Mo-Ká radiation (λ= 0.71073 Å).Details of the crystal structure determination and refinement for compound 4 are given in table 1.The structure was solved by direct methods [11] and refined using SHELX-97 [12].All of the non-hydrogen atoms were treated anisotropically.All hydrogen atoms were included in idealized positions with isotropic thermal parameters set at 1.2 times that of the carbon or oxygen atoms, respectively, to which they are attached.The drawings were created with the Diamond program [13].

Results and disscusion
The investigation of the condensation reaction between 2-phenyl-thiazol-4-carbaldehyde and 2-bromoacetophenone allowed us to isolate derivatives 1 -4, as depicted in scheme 1.The epoxyketone 1 precipitated from the initial reaction mixture, while derivatives 2 and 4 were separated as a mixture of solids after acidulation of the clear solution.From this mixture, the compound 2 and the condensation product 4, respectively, were separated by selective recr ystallization.In CDCl 3 solution the dicarbonylic compound 2 undergoes a tautomeric process, resulting in the formation of enol 3. The equilibrium is strongly shifted in favor of the enolic form, as it was suggested by the 1 H NMR spectrum.
The epoxyketone 1 is formed by an aldolic condensation reaction, when the 2-bromo-acetophenone carbanion, formed under the action of a basic catalyst (NaOH), is added to the aldehydic carbonyl group, leading to an intermediate.Subsequently, an intramolecular nucleophilic substitution of halogen by anionic oxygen takes place (scheme 2).We presume that epoxyketone 1 is able to isomerise partially to the dicarbonylic compound 2, although in the literature only the transformation of epoxyketones into isomeric 1,3-dicarbonylic compounds under the action of BF 3 ' Et 2 O [14] or by heating it in toluene in the presence of small quantities of (Ph 3 P) 4 Pd and 1,2bis(diphenylphosphino)ethane [15] are reported.
To explain the formation of derivatives 1 -3 and to elucidate their structure we performed the condensation reaction between 2-phenyl-thiazol-4-carbaldehyde with 2hydroxyacetophenone using the same reaction conditions (scheme 3).The same tautomeric process involving the species 2 and 3 was evidenced in this case again by 1 H NMR. The presence of the enolic hydroxyl in 3, and of the mobile hydrogen atom in 4 was tested by solubility in basic the reaction with FeCl 3 (red color), as well as by transformation of compounds 3 and 4 in the corresponding acetyl derivatives 5 and 6 by reacting them with acetic anhydride (scheme 4).
The compounds were characterized by IR, NMR and mass spectrometry.In addition, for the derivative 4 the molecular structure was determined by single crystal Xray diffraction.
The dicarbonylic derivative 2 was detected by 1 H-NMR as 10 % component in mixture with the enolic form 3 in CDCl 3 solution.The IR spectrum of 2 is consistent with a dicarbonylic structure.The higher stability of the enolic form towards the dicarbonilic tautomer 2 in solution might be explained by an extended conjugation of the electrons in the C=C bond and the aromatic system.This behaviour is supported also by the low field shifted resonance of the CH=C proton in the enolic form (δ 6.45 ppm).
The IR spectrum of derivative 1 presents characteristic vibrations for the C=O group (1690 cm -1 ) and for the oxyranic ring (1227 cm -1 ), respectively.The 1 H-NMR spectrum is consistent with the desired epoxyketone 1.The epoxy protons appear as doublets at δ 4.28 and 4.87 ppm, respectively.The small value of the coupling constant of the resonances of the epoxy protons in the 1 H-NMR spectrum of 1 ( 3 J HH 1.6 Hz) suggests a trans configuration of the oxyranic ring.
The 1 H-NMR data for the mixture of species 2 and 3 are consistent with a keto-enolic tautomerism.The presence of two singlets at δ 4.32 and 6.45 ppm, respectively, can be assigned to protons from CH 2 and CH groups from the two tautomeric forms in CDCl 3 solution, while the singlet resonance from δ 11.04 ppm may be assigned to the enol proton.From the ratio of the intensities of the CH and CH 2 , and of OH and CH 2 resonances, respectively, we were able to establish the proportion of enol form in the mixture as being 90 %.The IR spectrum shows three absorption bands at 1708 and 1639 cm -1 , assigned to the valence vibrations of the C=O groups.
The formation of the enol form in solution was confirmed also by the acylation reaction with acetic anhydride.
In the IR spectrum of compound 5 the vibration bands characteristic for both the esther and the ketone carbonyl groups (1765 and 1689 cm -1 ) were observed, as well as the valence vibration of the C=C group (1650 cm -1 ).
In the 1 H-NMR spectrum of 5 the resonance corresponding to the vinylic proton (δ 7.19 ppm) is lowfield shifted in comparison with the vinylic proton resonance in the non-acetilated derivative 3 (δ 6.45 ppm).
The 13 C NMR spectra revealed the expected number of resonances for the described derivatives.
The mass spectra (EI) of the title compounds present the molecular peaks with medium to high intensities and the fragmentation behaviour is in accordance with the proposed structures, i.e.: -for the epoxyketone 1 are present fragments resulted by elimination of CO (m/z 279) and formyl groups (m/z 278), as well as peaks corresponding to the benzoyl group (m/z 105); -for the dicarbonilic derivative 2 the molecular peak (m/z 307) confirms the isomerism relation with the epoxyketone 1.Other peaks appear due both to the lability of the CO-CO bond or to the stabilization of the two acyl groups by conjugation, as well as due to elimination of CO.The peak at m/z 174 (M -benzoyl -CO) supports a 1,2dicarbonylic structure; -in case of the derivative 4, the molecular peak (m/z 478) is accompanied by fragmentation of either the furanic (m/z 345) or the thiazol (m/z 242) ring.
The ORTEP-like diagram of 4 with the atom numbering scheme is shown in figure 1, while selected bond lengths and angles are given in table 2.