Mohr’s Salt Hexahydrate: A Novel, Cheap and Powerful Reagent for Green Synthesis of Biscoumarins on Water Saeed Khodabakhshi* and Mojtaba Baghernejad Young Researchers Club, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran (Received: Sept. 11, 2012; Accepted: Dec. 21, 2012; Published Online: Feb. 1, 2013; DOI: 10.1002/jccs.201200489) A new and convenient method for the synthesis of biscoumarins based on the condensation of 4-hydroxy- coumarin and aromatic aldehydes in the presence of Mohr’s salt hexahydrate (ferrous ammonium sulfate hexahydrate) as a novel catalyst on water is developed. This method has advantages such as the use of in- expensive and available reagent, avoidance of organic solvents, short reaction times, and high product yields. Keywords: Mohr’s salt; Biscoumarin; On-water; Aldehyde; Ferrous ammonium sulfate hexahydrate. INTRODUCTION Coumarins have attracted the attention of chemists because they are biologically active so that they reduce the HIV activity and some coumarins have shown cytostatic activity and therefore can be considered as potential candi- dates for anti-cancer therapy. 1 Biscoumarins, the bridge substituted dimers of 4-hydroxycoumarin, have enormous potential as anticoagulants. 2 Dicoumarol is also an antico- agulant that functions as a vitamin K antagonist. 3 It is the hemorrhagic agent responsible for the sweet clover disease of cattle, 4 and has also been employed for the prevention and treatment of thrombosis. 5 There are some methods de- scribed in the literature for the synthesis of bis-4-hydroxy- coumarins using different catalysts or reagents in various conditions. 6-12 Bis-4-hydroxycoumarins have been gener- ally synthesized by refluxing 4-hydroxycoumarin and vari- ous aldehydes in ethanol for several hours. However, some of the reported methods suffer from drawbacks, such as the use of expensive or synthetic reagents and organic sol- vents. 6,8 Also, some of them require harsh conditions, 10 te- dious work-up in certain cases 12 and long reaction times to complete. 11 With an objective to develop environmentally benign reaction conditions and media for organic transformations with excellent efficiency and selectivity, water has been shown to be a useful solvent or media. 13 Recently, organic synthesis on water was reviewed by Fokin and co-work- ers. 14 In this context, we report the use of Mohr’s salt hexa- hydrate (ferrous ammonium sulfate hexahydrate) as an eco-friendly and readily available reagent for the synthesis of substituted biscoumarins on water. RESULTS AND DISCUSSION As a part of our continual efforts toward the develop- ment of novel, efficient, and green procedures for organic reactions, 15-18 we turned our attention toward the condensa- tion of 4-hydroxycoumarin (1) and aromatic aldehydes 2 in the presence of Mohr’s salt hexahydrate as catalyst to pro- duce bis-4-hydroxycoumarin derivatives 3 (Scheme I). 19 To identify the suitable reaction conditions for the synthesis of 3 using Mohr’s salt, the reaction of 4-hydroxy- coumarin (1) and benzaldehyde (2a) was selected as a model (Scheme II). As can be seen in Table 1, we found that in the ab- sence of the catalyst, the reaction was not completed, even at long reaction times in several solvents (Entry 1-3). In an- other experiment, in order to show the effect of solvent or media on the reaction progress, we employed several sol- vents which the results have been shown in Table 1. It can be concluded that protonic solvents such as EtOH, MeOH, and H 2 O can accelerate the condensation reaction. It should be also noted that 4-hydroxycoumarin is soluble in alcohol, acetone and ether, but it has low solubility in water. J. Chin. Chem. Soc. 2013, 60, 495-498 © 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 495 JOURNAL OF THE CHINESE CHEMICAL SOCIETY Article * Corresponding author. Tel: +98 742 333923; Fax: +98 742 3332003; E-mail: saeidkhm@yahoo.com O O OH O O HO O O OH H O X O O HO N H H H H Fe 2 + S O O O O X + H 2 O, Reflux 1 1 2 2 2 25-40 min. 3 Scheme I Synthesis of biscoumarins using Mohr’s salt under reflux in water