Reaction of Substituted Furan-2-carboxaldehydes and Furo[b]pyrrole Type Aldehydes with Hippuric Acid

4-Heteroarylidene-2-phenyl-1,3-oxazol-5(4H)-ones were prepared by reactions of hippuric acid with substituted furan-2-carboxaldehydes or furo[b]pyrrole type aldehydes. The reactivity of various furan-2-carboxaldehyde derivatives in this reaction is discussed. The effect of microwave irradiation on some condensation reactions was compared with " classical " conditions. The results show that microwave irradiation shortens the reaction times while affording comparable yields. Elementary analysis, UV, IR and 1D NMR proved the structure of new synthesised compounds. 2D NMR spectroscopic measurements confirmed that the configuration at the carbon-carbon double bond corresponds to the pure E isomers of the products.


Introduction
During the past few decades many results have been published in the area of the synthesis and the study of physical and chemical properties of heterocyclic compounds containing a furan ring connected to or fused with a benzene ring or with different heterocyclic systems.Substituted furans are ubiquitous structural units in natural products and pharmaceuticals [1] and have been widely used as synthetic intermediates [2,3].
Substituted furan-2-carboxaldehydes 1a-e and furo[b]pyrrole type aldehydes 2a-e, 3a,b are heteroaromatic compounds which posses a C2 carbonyl group that may act as a reactive centre for various condensation reactions.Many of the published condensation products are biologically active compounds [4,5] or can be used as intermediates in organic synthesis [6,7].
Reaction of aldehydes 1a-3b with hippuric acid led to the products 4a-6b containing a 1,3-oxazol-5(4H)-one ring.The use of 1,3-oxazol-5(4H)-ones as starting materials for synthesis is well known.They are used as convenient reagents for the synthesis of α,β unsaturated α-amino acids [8], cyclic analogues of natural amino acids [9] or as intermediates for the synthesis of new heterocyclic compounds [10].The most common method for their preparation is the Erlenmeyer-Plöchl reaction, a cyclodehydration-condensation of the appropriate aldehyde and hippuric acid in dry acetic anhydride catalysed by acetate anion (using sodium or calcium acetate as a support/catalyst) [11][12][13][14].The formation of the carbon-carbon double bond usually leads to the creation of 1,3-oxazol-5(4H)-ones as a mixture of Z and E isomers; for example, furan-2-carboxaldehyde and thiophene-2-carboxaldehyde [11,12] and also substituted benzaldehydes [13] give oxazolones as such mixtures of two isomers.
The aim of this study was to synthesise some new condensation products of 1a-e, 2a-e and 3a,b by their reactions with hippuric acid (Schemes 2-4).We aimed to incorporate these heterocyclic biologically active moieties into new heterocyclic systems.We also wished to compare the "classical" method with the effect of microwave irradiation and to find conditions to increase the yield or the rate of condensations.Microwave irradiation is an unconventional method of chemical reaction activation indicated to be suitable for use in reactions of thermolabile compounds because it shortens the exposure of the reaction mixtures to high temperatures [15][16][17][18].

Scheme 1
The condensation products of aldehydes 1a-3b with hippuric acid catalysed by potassium acetate [18] were prepared in dry acetic anhydride as shown in Schemes 2-4.The condensations of 1a-e were also performed under microwave conditions, reducing the reaction times while affording yields comparable to those achieved in the reactions carried out under "classical" conditions (Table 1).Microwave irradiated procedures were performed using irradiation at a power output of 350W.Reaction times were only 1-2 minutes and work up was very easy.The reaction conditions were the same in both procedures except for the amounts of acetic anhydride and potassium acetate used (see Experimental).In the microwave assisted procedure the reaction mixture was fully dissolved after irradiation and the reaction started immediately upon dissolution.The reaction mixture was irradiated in 30 seconds intervals (TLC controlled) to prevent overheating which causes unselective reactions and for certain aldehydes more degradation products were also observed when the reaction times were longer than is listed in Table 1.The yield of the other two condensation products, (4E)-2-phenyl-4-[(4,5-dimethylfuran-2yl]methylene-1,3-oxazol-5(4H)-one (3d) and (4E)-2-phenyl-4-[(1-benzofuran-2-yl]methylene-1,3oxazol-5(4H)-one (3e) (Scheme 2) was about 10-20% lower.The same situation was observed in the case of furo [3,2-b]pyrrole type aldehydes 2a-d and furo [2,3-b]pyrrole type aldehydes 3a,b (Schemes 3 and 4).The products, methyl- were obtained in yields of 53-81%.During the reaction of both systems we found that 5-arylated furan-2-carboxaldehydes (1a-c) are more reactive than 4,5dimethylfuran-2-carboxaldehyde (1d), benzofuran-2-carboxaldehyde (1e) and furo[b]pyrrole type aldehydes (2a-3b).Furo[b]type aldehydes are heterocyclic analogues of the pentalene dianion and their electron-rich system [20] makes the carbonyl group attached at C2 of the fused system less reactive than the carbonyl group in the 5-arylated furan-2-carboxaldehydes used in this reaction.
The reaction time of the condensation depends on both the solubility of the starting aldehydes and their properties.Substituted furan-2-carboxaldehydes 1a-e are more soluble in acetic anhydride than furo[b]pyrrole type aldehydes 2a-3b.Electron-withdrawing groups on the benzene ring of 1a-c activate the C2 carbonyl group and the reactions are fast (reaction time max.30 minutes).The carbonyl group at C2 of the aldehydes 1e, 2a-3b is less active in these reactions than in the case of 1a-c and the reaction time is at least 60 minutes.All condensation products are stable solids, which are rather sparingly soluble in common solvents, and with high melting points.They display characteristic colours, a feature that is also observed in their corresponding UV-VIS spectra.The absorption maximum appears in the VIS area at around 400-470 nm.The characteristic bands found in the IR spectra correspond to the carbon-carbon double bond (1650-1640 cm -1 ) and C=O lactone (1790-1770 cm -1 ).

Scheme 3
The 1 H-NMR spectra of the synthesised compounds 4a-6b display the signals of the double bond H-5 in the 7.07-7.89ppm range.The chemical shift of the C-5 double bond carbon in the 13 C-NMR spectra of 4a-e typically ranges from 116-118 ppm.The 1 H and 13 C chemical shifts for compounds 4a-e were assigned using gs (gradient selected)-H,H COSY (Correlated spectroscopy); 1D-gs-NOESY (Nuclear Overhauser spectroscopy); gs-HSQC (Heteronuclear Quantum Coherence spectroscopy) and HMBC (Heteronuclear Multiple Bond Correlation spectroscopy).H,H-COSY provided us protonproton connectivity and 1D-NOESY showed through-space interactions of the olefínic proton H-6 and the furan H-3´ β-proton.Determination of the actual position of the H-6 protons compared to the carbonyl group of the heterocyclic ring system was established by using the size of the scalar coupling between H-6 and the carbonyl carbon.It turns out that the coupling constant is 4.6 Hz.According to the literature [23] this size is indicative of a situation where the proton and the carbonyl are in a Z arrangement, which means that this compound exists as a pure E isomer.The other compounds 4a-e behave similarly.The 13 C chemical shifts assignment was straightforward using HSQC and HMBC spectra. 1 H-NMR spectra were measured for products 5a-6b.These products are structural analogues of 4e and their proton spectra are similar to that of 4e.Based on this observation we can declare that products 5a-6b also exist as a pure E isomers.The signal of the NH proton of 5a,b and also the signals of the protons in methyl or ethyl group in the ester moieties were the same before [24][25][26][27] and after condensation, which proved that amino and ester group did not undergo any reaction with the hippuric acid.The complete chemical shifts for all synthesised compounds are listed in Experimental part.carboxaldehydes, which were performed under "classical" conditions as well as using microwave irradiation, showed that the yields were almost the same, but the reactions in the microwave oven were noticeably faster.All synthesised compounds were characterised by spectroscopic measurements and were proven to be the pure E isomers.

General
The following starting compounds were prepared according to literature procedures: 1d [21], 1e [22], 2a-d, and 3a,b [24][25][26][27].Melting points were determined using a Kofler hotplate apparatus and are uncorrected.All solvents were pre-distilled and dried appropriately prior to use.The terms "concentration and evaporation" refer to the removal of volatile materials under reduced pressure on a Buchi Rotovapor.Substances stated to be identical were so with respect to mps, mixed mps and IR spectra.Microwave assisted reactions were carried out in a Whirlpool domestic type microwave oven at 350 W. The apparatus was adapted for laboratory applications -n-heptane was used as coolant for the condenser.Elemental analyses were determined using a Carlo Erba CHNS-OEA 1108-Elemental Analyser.Infrared spectra were recorded on the following spectrophotometers: Magna IR-760 (Nicolet) (compounds 1a, 4a-c) and FTIR Galaxy 7020 (for 4d,e) using KBr pellets (1 mg/300 mg KBr) with only major absorbencies being quoted.UV spectra were measured on a WPA UV/VIS Diode-Array spectrophotometer (Cambridge, UK) in methanol.Results are reported as λ max (log ε) (λ max in nm, ε in m 2 mol -1 ). 1 H (500 MHz)-and 13 C (125 MHz)-NMR spectra of compounds 4a-e were measured at 320K on a BRUKER AVANCE spectrometer equipped with a 5mm broadband probe with z-gradients and a SGI computer.Two dimensional gs (gradient selected)-H,H-COSY; 1D-gs-NOESY; gs-HSQC, gs-HMBC techniques were measured using standard software programs provided by Bruker.The 1 H-NMR (400 MHz) spectra of compound 1a, 5a-6b were measured on a BRUKER B-ACS-60 instrument.The measurements were done using DMSO-d 6 as solvent with TMS as an internal standard reference.Coupling constants (J) are quoted to the nearest 0.1 Hz.Chemical shifts (δ-scale) are quoted in parts per million and following abbreviations are used: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad.