MeO OH MeO O CO2H I O MeO O 1 2 3 4 O MeO O CH X O MeO CH X OH OCH2CH2A 1 iii ii i vi O MeO CH X 2a bc d X = Cl X = F X = Br X = H a b c d e f g h i j X = Cl, A = NMe2 X = Cl, A = N(CH2CH2)2O X = Cl, A = N(CH2CH2)2CH2 X = Cl, A = N(Et)2 X = Cl, A = N(CH2CH2)2 X = F, A = NMe2 X = F, A = N(CH2CH2)2O X = F, A = N(CH2CH2)2CH2 X = F, A = N(CH2CH2)2 X = F, A = N(Et)2 4 Y OCH2CH2A a b c d e f g h i j k X = Cl, A = NMe2, Y = H X = Cl, A = N(CH2CH2)2O, Y = H X = Cl, A = N(CH2CH2)2CH2, Y = H X = Cl, A = N(CH2CH2)2, Y = H X = Cl, A = N(Et)2, Y = H X = F, A = NMe2, Y = H X = F, A = N(CH2CH2)2O, Y = H X = F, A = N(CH2CH2)2CH2, Y = H X = F, A = N(CH2CH2)2, Y = H X = Cl, A = NMe2, Y = OH X = Cl, A = NMe2, Y = OMe 5 O MeO O CH2 X iv, v vi, vii 3a X = Cl viii, ix viii, x viii, xi O Ar OH CH Ar O Ar O+MgBr Br– CH Ar O CH Ar Ar + Br– O CH Ar O CH Ar O CH Ar Ar + Nu Ar + Br– Nu = H–, MeO– Nu Ar MgBr2•O(Et)2 202 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 202–203 J.Chem. Research (M), 1997, 1412–1422 Synthesis of 3-(p-Halobenzyl)-4-aryl-2H-chromenes as Selective Ligands for Antiestrogen-binding Sites Natarajan Srikanth,a Oi-Lian Kon,b Siu-Choon Nga and Keng-Yeow Sim*a aDepartment of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 bDepartment of Biochemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 A series of 3-(p-halobenzyl)-4-aryl-2H-chromenes is prepared in good yields via a two-step sequence from the corresponding 3-benzylidenechromanones (homoisoflavanones).Non-steroidal antiestrogens of triphenylethylene type, principally tamoxifen, have been successfully used in the treatment of hormone-dependent tumours, especially breast cancer.1,2 Antiestrogens bind to two intracellular proteins, viz. the estrogen receptor (ER) and antiestrogen-binding sites (AEBS). Whether AEBS have any role in mediating the nonreceptor- dependent inhibition of cellular proliferation is unresolved.We have previously reported the synthesis and biological studies of a series of basic ethers of 3-(p-halophenyl)- 4-aryl-2H-chromenes3,4 and benzofurans5,6 which bind to AEBS with equivalent or greater affinity than tamoxifen and display no significant interaction with ER. We report herein the synthesis of a series of basic ethers of 3-(p-halobenzyl- 4-aryl-2H-chromenes derived from 3-benzylidenechromanones as a continuation of a project to prepare nonisomerizable antiestrogens for structure–activity studies which could provide an insight into the functional role of antiestrogen-binding sites. The methodology used for the synthesis of the title compounds 5a–i is depicted in Scheme 1.The precursor chromanone 1 was synthesised by treating m-methoxyphenol with 3-bromopropionic acid, followed by cyclisation of acid I using polyphosphoric acid (PPA).7 Base catalysed condensation of the desired aldehydes with the chromanone 1, in the presence of a catalytic amount of sodium hydroxide in refluxing ethanol, afforded the 3-benzylidenechromanones 2a–d in good yields.8 Conjugative reduction of the 3-benzylidenechromanone 2a with sodium borohydride and nickel hexahydrate9 followed by oxidation with pyridinium chlorochromate (PCC)10 afforded 3-benzylchromanone (3a).Reaction of 3a with the arylorganolithium reagent followed by acidcatalysed dehydration of the tertiary alcohol afforded 5a in moderate yield, which might be due to the enolisation of the keto group and subsequent preferential deprotonation of the enol hydroxy moiety.This prompted us to explore an alternative approach of reacting the 3-benzylidenechromanones 2a–d with the arylorganolithium reagents to give good yields of the allylic alcohols 4a–j which were transformed into the target compounds 5a–i by treatment with magnesium bromide etherate followed by lithium aluminium hydride.6 This interesting transformation must involve an allylic rearrangement, presumably via the intermediacy of carbocations, as previously observed for the benzofuran analogues. 6 A possible mechanism for this interesting transformation is illustrated in Scheme 2. Quenching of the highly coloured magnesium complex (intermediate) with water or methanol yielded the *To receive any correspondence. Scheme 1 Reagents and conditions: i, BrCH2CH2COOH, NaHCO3, NaOH, H2O, reflux; ii, PPA, 90 °C, 1 h; iii, p-XC6H4CHO, NaOH, EtOH, r.t.; iv, NiCl2.6H2O, NaBH4, THF, MeOH; v, PCC, CH2Cl2, r.t.; vi, p-BrC6H4OCH2CH2A, BuLi, THF, µ78 °C, aq.NH4Cl; vii, H+, MeOH, reflux; viii, MgBr2.OEt2, Et2O, r.t.; ix, LiAlH4, x, H2O; xi, MeOH Scheme 2 Allylic transformationJ. CHEM. RESEARCH (S), 1997 203 rearranged allylic alcohol 5j and the corresponding methyl ether 5k, respectively. Preliminary screening of compounds 5a–c in the breast cancer-derived cell line Molt 4 cells indicates that they display similar interesting biological properties as the chromenes3,4 and benzofurans.5,6 The results will be reported elsewhere in due course.We thank the National University of Singapore for a grant in support of this research and for the award of a Research Scholarship to N. S. Techniques used: IR, 1H NMR, mass spectrometry, elemental analysis, flash and thin layer chromatography References: 11 Schemes: 2 Table 1: Analytical, physical and spectral data for compounds 1–3 Table 2: Analytical, physical and spectral data for compounds 4–5 Received, 24th January 1997; Accepted, 12th March 1997 Paper E/7/00565B References cited in this synopsis 1 V. C. Jordan, Pharmacol. Rev., 1984, 36, 245. 2 L. J. Lerner and V. C. Jordan, Cancer Res., 1990, 50, 4177. 3 C. C. Teo, O. L. Kon and K. Y. Sim, J. Chem. Res, 1990, (S) 4; (M) 0171. 4 C. C. Teo and K. Y. Sim, Bull. Singapore Nat. Inst. Chem., 1994, 22, 69. 5 C. C. Teo, O. L. Kon, K. Y. Sim and S. C. Ng, J. Med. Chem., 1992, 35, 1330. 6 S. C. Ng, O. L. Kon, K. Y. Sim and N. Srikanth, Synth. Commun., 1993, 23, 1843. 7 P. Perkin, A. Ray and T. Robinson, J. Chem. Soc., 1926, 941. 8 P. Pfeiffer, E. Breith and H. Hoyer, J. Prakt. Chem., 1931, 237, 31. 9 D. Dhawan and S. K. Grover, Synth. Commun., 1992, 22, 2405. 10 F. A. 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