"On water" synthesis of aurones: first synthesis of 4,5,3',4',5'-pentamethoxy-6-hydroxyaurone from Smilax riparia

A simple and green method for the synthesis of aurones by condensation of benzofuranone with aromatic aldehyde in neat water has been developed. The main advantages of this protocol include good yields, absence of catalyst, reagent, organic solvent, work-up and chromatographic purification. 4,5,3',4',5'-Pentamethoxy-6- hydroxyaurone, isolated from Smilax riparia was synthesized for the first time from 3-benzyloxy-4,5-dimethoxybenzaldehyde in five steps.

Nowadays, major chemical processes employ large amounts of hazardous and toxic solvents, reagents.The challenges in organic synthesis are to develop convenient processes, reaction media, conditions and utility of materials based on the green chemistry principles.The 'green chemistry' concept is focused on the design of products and processes that minimize the use and generation of hazardous substances.
Most of the methods reported early for synthesis of aurones use the organic solvents and reagents.Due to our interest on aurones and isoaurones, 9,14,28 here we report a simple, green and environment friendly method for the synthesis of aurones from readily available benzofuranones and benzaldehydes.

Results and Discussion
Water plays an essential role in life processes.However, its use as a solvent has been limited in organic synthesis.Despite the fact that it is the cheapest, safest and non-toxic solvent in the world, its presence is generally avoided through the dehydrative drying of substances and solvents.Therefore, the use of water as a reaction medium for organic reactions is one of the latest challenges for modern organic chemists. 29,30Condensation of benzofuranone with benzaldehyde in water is investigated as shown in scheme 1.

Scheme 1.
Green method for the synthesis of aurones.
Initially, the reaction of benzofuranone (1a) with benzaldehyde (2a) at various temperatures was investigated and the results were presented in table 1.The reaction of 1a with 2a at rt for 24 h gave exclusively β-hydroxy product (3) 31 with low yield and the reaction not completed even after 96 h (entry 1 and 2).It was interesting to observe that the exclusive formation of β-hydroxy product (3) without detectable amount of aurone (4a) at rt.At higher temperatures, the reaction gave a mixture of β-hydroxy product (3) and aurone (4a), which were separated by column chromatography (entry 3-5).Surprisingly at reflux temperature, the reaction proceeded cleanly and exclusively gave aurone (4a) in good yield.At reflux condition, absence of β-hydroxy product indicates that the dehydration reaction is fast under these conditions.Few initial experiments revealed that 1.1 eq of benzaldehyde is required for completion of the reaction (entry 6-8).Thus, reaction of benzofuranone (1a) with benzaldehyde (2a) in water at reflux temperature for 8 h gave aurone (4a) in 86% yield, after simple filtration of the aqueous reaction mixture (entry 7).The structure of the product has been deduced from its spectroscopic data and finally confirmed by comparing with that described in the literature. 23The proposed mechanism for the reaction based on the isolated hydroxy product (3) was shown in scheme 2. First, enol form of the benzofuranone is reacted with benzaldehyde to give β-hydroxy product and this converts into the desired aurone by simple dehydration at reflux temperature.Scheme 2. Proposed mechanism for synthesis of aurones.a Reaction conditions: Benzofuran-3(2H)-one 1a (2.0 mmol, 1.0 equiv), benzaldehyde 2a (1.0-1.2 equiv) and water (5 mL).b Isolated yield.c Reaction not completed and absence of aurone by TLC.
After having the optimized condition in hand, the scope and generality of this green method has been established and generated substituted aurones 4a-k were summarized in table 2. A wide variety of substituents on the benzofuranone and benzaldehyde were tolerated including methoxy, hydroxy, nitro and halogen.The reaction worked well with electron-donating and electron-withdrawing groups either on benzofuranone or benzaldehyde.Sulfuretin (5), maritimetin (6) are two important natural aurones isolated from various sources 9,32-34 and having potent biological activities.Structurally sulfuretin and maritimetin have three and four hydroxy groups respectively.One of the synthetic route for preparation of this hydroxy substituted aurones uses the basic catalyst, but after completion of the reaction, it need to be acidified to get the desired products. 6In another method acetic anhydride is used as condensation agent, but in this method the hydroxy groups will be acylated, and to get the desired product an additional hydrolysis step is needed. 9However, the present green method does not require either hydrolysis or protection/deprotection of hydroxy groups.Thus, the condensation of benzofuranones 1c and 1d with 3,4-dihydroxybenzaldehyde in water at reflux temperature for 10 h gave sulfuretin (5), maritimetin (6) in 81% and 80% yields respectively (scheme 3).Scheme 3. Application of green method for the synthesis of sulfuretin ( 5) and maritimetin (6)   All the compounds (3, 4a-k, 5 & 6) were well characterized by their spectral (NMR and MS) data.It is evident from the spectral data that a single geometric isomer (Z) was obtained in all the cases, as the Z-isomer is known to be thermodynamically more stable than E-isomer.The geometry of the double bond has been established based on chemical shift (δ) value of the vinylic proton as well as carbon observed in the corresponding 1 H and 13 C NMR spectra. 14,35hus the present method does not require any use of organic solvent or acid or base or catalyst.In fact aurones were isolated in a practically pure form by simple Buchner filtration of the final aqueous reaction mixture, require neither work-up/extraction nor silica column purification.Using water as the reaction medium made the isolation of aurones from reaction mixture much easier than any organic solvents.4,5,3',4',5'-Pentamethoxy-6-hydroxyaurone ( 13) was isolated from Smilax riparia and its structure was deduced from spectroscopic data. 36The present green method for aurones was extended to the first synthesis of 13 by condensation of corresponding benzofuranone (11) with 3,4,5-trimethoxybenzaldehyde.The desired benzofuranone (11) was prepared, in turn, from 7 as depicted in scheme 4.
Oxidation of 3-benzyloxy-4,5-dimethoxybenzaldehyde (7) 37 using performic acid gave 8 in good yield.Treatment of 8 with ethyl bromoacetate in presence of K2CO3 gave 9, which on hydrolysis afforded 10.Debenzylation of 10 with H2/Pd-C followed by cyclization using BF3.OEt2 afforded two isomeric benzofuranones 11 & 12, which were well separated by column chromatography.Next, condensation of 11 with 3,4,5trimethoxybenzaldehyde using the present green method gave aurone 13 in 79% yield.Similarly, condensation of 12 with 3,4,5-trimethoxybenzaldehyde gave aurone 14 in 81% yield.Structures of the two isomeric aurones were confirmed based on spectroscopic data including 2D NMR techniques.The NMR data of synthetic 13 were exactly identical with those of natural 13 and is presented in Table -3

Conclusions
We have developed a simple, convenient and green method for the synthesis of aurones from benzofuranones and aromatic aldehydes in good yields.Water as a solvent and absence of reagent/catalyst/chromatography make this protocol clean, inexpensive and valuable from an environmental point of view.Moreover, the method is also suitable for hydroxy substituted aurones without protection and deprotection of hydroxy groups.So far, this is the most efficient and green protocol for the synthesis of aurones.In terms of both economical and environmental considerations, we believe that the method holds a potential value in laboratory and industry in near future.4,5,3',4',5'-Pentamethoxy-6-hydroxyaurone, isolated from Smilax riparia was synthesized for the first time from 3-benzyloxy-4,5-dimethoxybenzaldehyde in five steps.The spectral data of synthetic aurone is in good agreement with those of natural product.

Experimental Section
General.Reagents and solvents were analytical grade and were used without further purification.Melting points were recorded on a Mel-Temp melting point apparatus, in open capillaries and are uncorrected.IR spectra were recorded on a Bruker (Alpha) FTIR Spectrophotometer. 1 H NMR (400 MHz), 13 C NMR-DEPT (100 MHz) spectra were recorded on a Bruker AMX 400 MHz NMR spectrometer.The chemical shifts (δ ppm) and coupling constants (Hz) are reported in the standard fashion.In the 13 C NMR spectra, the nature of the carbons (C, CH, CH2 or CH3) was determined by DEPT-135 spectra.Mass spectra were recorded on Agilent 1100 LC/MSD.HRMS were recorded on Micromass Q-TOF spectrometer using electro-spray ionization mode.

3-Benzyloxy-4,5-dimethoxyphenol (8).
To an ice cold solution of 7 (4.4 g) in chloroform (44 mL) was added performic acid (44 mL) slowly for 30 min.The reaction mixture was allowed to rt and stirred for 4 h.Chloroform layer was separated and aqueous layer was extracted with chloroform (2 × 100 mL).The combined chloroform layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4.The solution was filtered and evaporated the solvent.The residue was dissolved in methanol (80 mL) and triethylamine (4 mL) was added at rt.The reaction mixture was stirred for 1 h and poured into ice cold water (100 mL).The solution was acidified with dil HCl and extracted with EtOAc (3 × 100 mL).The combined EtOAc layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4.The solution was filtered and evaporated the solvent.The residue was chromatographed over silica gel column using chloroform-methanol (98:02) as eluents to give Cyclization: To a solution of 10 (3.9 g) in methanol (80 mL) was added 10% Pd-C (100 mg) and hydrogenated using hydrogen balloon at rt for 1 h.The mixture was filtered through hyflow gel and washed the bed with methanol (10 mL).The filtrate was evaporated to dryness to give the debenzylated product, which was used without further purification.To the residue, BF3.OEt2 (30 mL) was added and stirred at 60-70 o C for 4 h.The mixture was allowed to rt and poured into ice cold water.The solution was basified with aq 10% NaOAc (20 mL) and extracted with chloroform (3 × 100 mL).The combined chloroform layer was washed with water, brine and dried over Na2SO4.The solution was filtered and evaporated the solvent.The residue was chromatographed over silica gel column using chloroform as eluents to give

Table 2 .
Green method for the synthesis of aurones a b Isolated yield.