In the Laboratory edited by Green Chemistry Mary M Kirchhoff ACS Green Chemistry Institute Washington DC 20036 One Pot Synthesis of 7 Hydroxy 3 carboxycoumarin in Water W Francesco Fringuelli Oriana Piermatti and Ferdinando Pizzo Dipartimento di Chimica Universit di Perugia Via Elce di Sotto 8 06123 Perugia Italy frifra unipg it Developing cleaner safer and environmentally friendly chemical processes is an important goal for chemists in both academia and industry 1 It is no longer acceptable to make products without being concerned about environmental pollution Several strategies have been developed based on the idea that it is not only important what is produced but also how it is produced To remove organic solvents from chemical processes many old reactions have been revised and carried out in water 2 under solventless conditions 3 in supercritical fluids 4 in ionic liquids 5 in microemulsions 6 under high pressure 7 and by ultrasound 8 and microwaves 9 One pot multicomponent processes1 and one pot consecutive processes2 have been discovered that allow compounds to be prepared without having to isolate and purify the intermediates Water is a unique and extraordinary reaction medium and chemists have only recently begun to discover its benefits 2 In addition to practical advantages abundant cheap nontoxic nonflammable nonexplosive the aqueous medium is more convenient than organic solvents because i it can avoid protection of functional groups such as OH and COOH ii water soluble compounds can be used directly without derivatization iii the high heat capacity of water allows the reaction temperature to be easily controlled and iv mineral salts surfactants and cyclodextrins can be used as additives Two other important advantages of using water in organic synthesis are the possibility of controlling the pH of the reaction medium and isolating solid hydrophobic products by decanting or by filtering thereby avoiding the use of any organic solvent Many Lewis acids work well in aqueous medium and recently we discovered that even AlCl3 SnCl4 and TiCl4 recommended for use under anhydrous conditions are excellent catalysts in aqueous medium 10 Many of the organic reactions carried out in aqueous media occur quickly with high selectivity and with excellent yield Reactions previously thought impossible in water are today a reality Coumarin 2H 1 benzopyran 2 one and its derivatives are widespread in nature 11 Owing to their importance in many fields of everyday life 12 such as pharmaceutical cosmetic perfume and nutrition their chemistry has been widely investigated and many natural and nonnatural coumarins have been synthesized 3 Carboxycoumarins are a prominent target for study in the field of coumarins because the carboxylic acid group allows new functionalities to be easily prepared by introducing units of biological interest to increase the chemical activity of the compound for example units of cephalosporin 13 triazole 14 thiadiazine 14 thiadiazole 14 penicillin 15 and isourea 16 3Carboxycoumarins were recently prepared following the green 874 Journal of Chemical Education chemistry approach 17 19 The conjugative position of the hydroxy group in 7 hydroxy 3 carboxycoumarin 7 facilitates the opening reaction of the lactone ring of this benzopyrane system in the presence of bases which allows glycosides to be prepared aliphatic hydrocarbon chains to be introduced and oxocyclic rings to be built 20 The glycosylation of 7hydroxy 4 methylcoumarin was recently proposed for an undergraduate organic chemistry laboratory class for fourth year organic chemistry students 21 Synthesis This article describes the preparation of 7 hydroxy 3 carboxycoumarin 7 starting from 2 4 dihydroxybenzaldehyde 1 and malononitrile 2 by one pot consecutive reactions carried out exclusively in water under heterogeneous conditions The experiment consists of four fundamental steps Scheme I i Knoevenagel reaction 1 2 3 aldol like CHO CN HO CN OH 1 pH 8 3 NaHCO3 r t 2 CN CN HO O CN HO OH 3 NH 4 COONa pH 1 0 HCl 90 C HO O CN pH 8 3 NaHCO3 HO O O O 6 90 C pH 2 0 HCl r t 5 5 HO 4 COOH 4a 6 3 7 8a 8 O 2 O 1 7 Scheme I Reaction pathway to synthesize 7 hydroxy 3 carboxycoumarin 7 Vol 81 No 6 June 2004 www JCE DivCHED org In the Laboratory The students are introduced to condensation and the Pinner reaction 3 4 ii acid catalyzed hydrolysis of the imino functionality 4 5 iii basic hydrolysis of cyano group 5 6 and iv acid base equilibrium 6 7 The Knoevenagel condensation and the Pinner reaction were carried out in aqueous NaHCO3 solution at room temperature and were completed in 1 5 h while the hydrolysis of iminocyanide 4 required heating at 90 C for 1 h under acidic conditions At this stage the pH of the reaction medium was again changed to hydrolyze the cyanolactone 5 pH 8 3 2 h 90 C Acidification of the final solution at room temperature produced a 98 pure 7hydroxy 3 carboxycoumarin 7 with 85 overall yield obtained by simple filtration The process can be stopped after completion of the first two reactions 1 2 3 and 3 4 1 5 h or after the hydrolysis of iminocyanide 4 4 5 allowing the intermediate 4 or 5 respectively to be isolated with high yield and purity 95 by simple vacuum filtration These can be suitable stopping points for two or three lab periods in this case the aqueous reaction mixture must be stored at room temperature and the subsequent reactions carried out the next day The one pot synthesis can be monitored by TLC aluminium sheets 5 cm 10 cm silica gel 60 F254 ethyl acetate as eluent at the three fundamental steps Knoevenagel Pinner reactions acid hydrolysis at 90 C basic hydrolysis at 90 C and final acidification displaying the starting material 1 the cyanoimine 4 the cyanocoumarin 5 and the carboxycoumarin 7 respectively that have very distinct Rf values TLC analysis is a powerful analytical tool that allows students to monitor the progress of their reactions All chemicals are commercially available from Aldrich Chemical Co and the experiment can be carried out with standard laboratory equipment Detailed experimental procedures TLC analysis IR and NMR spectra and their interpretation are provided in the Supplemental Material W To our knowledge no analogous experimental procedure has appeared in this Journal and the use of coumarins in a lab experiment is rare 11a 22 Instructions for the students notes for the instructor and interpretation of the TLC plates and IR 1H and 13C NMR spectra are available in this