A convenient one-pot synthesis of 7-hydroxy-isoflavones from resorcinol with substituted phenylacetic acids q Himanshu Singh and Ram Pratap * Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India Received 22 June 2006; revised 30 August 2006; accepted 7 September 2006 Available online 29 September 2006 Abstract—A mild and highly efficient one-pot synthesis of 7-hydroxy-isoflavones is reported. The acylation of resorcinol with various phenyl acetic acids in molten zinc chloride affords an intermediate deoxybenzoin which without isolation is subjected to cyclization with N,N-dimethylformamide in the presence of boron trifluoride diethyl etherate and methanesulfonyl chloride to afford the 7-hydroxy-isoflavone without the formation of any by-product. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Flavonoids and isoflavonoids are a diverse group of phenolic compounds produced by various higher plants 1 to protect themselves from environmental stress and are present in foods such as beans, cabbage, soya beans, grains and hops. They are structurally similar to mammalian oestrogen and oestradiol, and have oestrogenic properties. Com- pounds in this class show a wide variety of biological activities such as anti-viral, anti-inflammatory, anti- bacterial, anti-fungal and anti-cancer. 2 Other potential areas of benefit include diabetes, osteoporosis, heart disease and cognitive function. The antioxidant properties 3 of these molecules have been implicated as a reason for the above activities. We therefore became interested in these molecules to design drugs for antidiabetic activity. This encouraged us to investigate a simple synthesis of 4H-1-benzopyran- 4-one derivatives. The literature synthesis for isoflavones in general in- volves two steps wherein a phenol is reacted in the pres- ence of a Lewis acid with phenylacetic acid to generate an intermediate deoxybenzoin 2, 4 which is then cyclized with a one carbon electrophile. A convenient approach is that of Baker et al. 5 who used oxalyl chloride and pyr- idine as the cyclizing agent, whereas others have used ethyl formate, 6 triethyl orthoformate, 7 or carbon disul- fide. 8 Deoxybenzoins have been utilized as starting materials in some reported methods but need to be pre- pared prior to the cyclization. 9 Long cyclization periods are another disadvantage, for example, with POCl 3 and DMF. 10 Also, additional hydroxy groups have to be protected. 8 During the synthesis of 7-hydroxy-isoflavone via the two-step procedure where we utilized the crude deoxy- benzoin, obtained by electrophilic substitution of resor- cinol with phenylacetic acid using ZnCl 2 4 followed by cyclization with DMF and MeSO 2 Cl in BF 3 OEt 2 , 11 a by-product was isolated in an appreciable yield (35%). The structure of by-product 4 was established by spectral analysis. Elemental analysis 13 and the mole- cular ion peak (M+1) at 357 suggested a molecular for- mula C 23 H 16 O 4 . In the IR spectrum, there was a band at 1627 cm 1 corresponding to an a,b-unsaturated car- bonyl. In the proton NMR spectrum, the proton peri to the carbonyl at C-5 appeared as an ortho coupled doublet at d 8.30. The proton at C-2 appeared as a sin- glet at d 7.98. The presence of these two protons sug- gested an isoflavone skeleton. However, in comparison with an isoflavone structure, the by-product had no meta coupled doublet at d 6.79 for the C-8 proton, which suggested the attachment of a benzyl ketone at C-8. A two- proton singlet at d 3.91 suggested the 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.09.034 Keywords: 7-Hydroxy-isoflavones; Deoxybenzoin. q CDRI Communicaion No 6997. * Corresponding author. Fax: +91 522 2623405; e-mail: rpcdri@ yahoo.com Tetrahedron Letters 47 (2006) 8161–8163