Sequential Claisen Rearrangement and Intramolecular Heck Reaction as a Route to Medium-Ring Oxacycle-Fused Heterocycles

Abstract

A synthetic strategy based on tandem application of Claisen rearrangement and intramolecular Heck reaction as key steps has been developed for the synthesis of various hitherto unknown benzoxocine-and benzoxonine-fused coumarin and quinolone derivatives.Various normal-ring-size heterocycle-fused heterocyclic systems display interesting properties and there has been a continuous evolution of newer methodologies for the synthesis of such ring systems. 1 In contrast, medium-ring heterocycle-annulated heterocyclic systems are less known until recently when various metal-catalysed organic transformations made medium-sized rings more accessible. 2 The palladium-catalysed intramolecular Heck-type arylation reaction has been extensively used for the synthesis of heterocyclic rings of varying size and complexity. 3 However, medium-ring formation through such a procedure still poses challenges and therefore remains as an explorable exercise. Whereas with activated olefins (Michael-type olefinic fragments) only one mode of cyclisation (electronic controlled) is mostly observed, 4 mixtures of endo-and exo-cyclisation products are usually formed 5 during medium-sized-ring formation from intramolecular Heck reaction with unactivated olefins. 6 This difference in regioselectivity has been explained by the difficulties associated with the attainment of coplanar eclipsed orientation of the relevant moieties during the carbopalladation step ( Figure 1). However, with the increase in chain length exclusive endo-cyclisation leading to nine-or ten-membered heterocyclic rings has also been observed. 7 Figure 1We have been engaged for some time in the synthesis of medium-ring heterocycle-fused heterocyclic systems culminating in the development of synthetic routes to hitherto unknown oxepin-and oxocin-fused coumarins, 8 quinolones, 9 carbazole 10 and naphthalene derivatives, 11 based on tandem applications of Claisen rearrangement and ring-closing diene-or enyne metathesis. 12 The methodology has found application 13 in the synthesis of other medium-ring heteroannulated compounds. Herein, we report 14 a new methodology for the synthesis of mediumring oxacycle-annulated heterocycles based on tandem Claisen rearrangement 15 and Heck-type arylation reaction as key steps. In view of the known importance of furo-and pyranocoumarins 16 and their isosteric analogues furo-and pyrano-2-quinolones 17 we have chosen coumarin and 2-quinolone as the heterocyclic frameworks for the exploration in the present study.

Palladium-Catalysed Synthesis and Transformation of Quinolones

“…The intramolecular Heck reaction of the benzylallylquinolin-2(1 H )-one precursor 207 originated a benzoxocine-fused quinolin-2(1 H )-one 208 (Scheme 70) [91]. The reaction led to the regioselective formation of the 8- exo cyclization product 208 and no 9- endo product was observed in this case.…”

“…Synthesis of benzoxocine-fused quinolin-2(1 H )-one 208 by intramolecular Heck reaction of benzylallylquinolin-2(1 H )-one 207 [91]. …”

Evaluation of Coumarin and Neoflavone Derivatives as HCV NS5B Polymerase Inhibitors

“…The O-allylated derivatives 6a-c and 7a-c were obtained by reaction of the corresponding phenols with allybromide, as previously described by several research groups (32)(33)(34)(35)(36)(37)(38). The C-allylated products, 8b-c and 9a-c, were synthesized from the corresponding O-allylated precursors by Claisen rearrangement, as reported in the literature (32,36,37,(39)(40)(41)(42). Coumarin 8a, bearing the allyl group attached to the carbon atom at A-ring, was newly synthesized from 6a through Claisen rearrangement (Scheme 1) as described below.…”

Eight-Membered Rings With One Oxygen Atom

“…147 Lactone 162 or few dibenzoxocenes 163-166 were synthesized through Hecktype arylation reaction of 2-halo ether (or ester)-tethered 2-(prop-2-en-1-yloxy)benzenes 158-161, carried out in the presence of palladium(II) acetate, tri-O-tolylphosphine and triethylamine in refluxing acetonitrile (Scheme 18). 148 A series of alkylidendibenzo[c, f]oxocines were prepared via Heck-Suzuki tandem reaction of 1-bromo-2-{[2-(alkynyl)benzyloxy]methyl}benzenes with phenyl boronic acid, Pd 2 (dba) 3• CHCl 3 (3 mol%) and Xantphos in a 5:1 mixture of DMF:water for 2.5 h. 149 Further derivatives arise from regioselective reductive Heck 8-exo-dig cyclization reaction of the same substrates carried out in the presence of Pd(PPh 3 ) 4 (2 mol%), HCOONa (3 equiv.) at 100 C in a 5:1 mixture of DMF:water for 3 h 149 or in the presence of Ni(PPh 3 ) 2 Cl 2 (10 mol%), HCOONa (3 equiv.)…”