Chroman variations

A variation on this general theme which has not been as widely applied as the previous examples, but which is nevertheless of value, involves the use of 3-phenoxypropan-l-ols (66JOC3032, 67JCS(B)859). Here again it is observed that the m-substituted isomer cyclizes to a mixture of two chromans. 

The cyclobutanone ring in the ether 7, derived by ring expansion of an oxaspiropentane, intramolecularly alkylates the activated aromatic system on treatment with PTSA, leading to 2W-cyclobuta[c]chroman-4-ols 8 (X = OH). Subsequent fission of the four-membered ring yields 3,4-disubstituted 2//-chromenes <02SL796>. A variation of this approach allows the synthesis of the 4P-phenylsulfanyl derivative of 8 (X = SPh), oxidation of which affords the cyclopropa[c]chroman entity <02OL2565>. 

The structure-activity relationship of the prime region of con-formationally restricted hydroxyethylamine (HEA) BACE inhibitors was described by Ng et al. [398], Variation of the PI region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2 substituent of chromane-HEA with polar substituents provided improvements in the compound s in vitro permeability. 

Sinninghe Damste J.S., Keeley B.J., Betts S.E., Baas M., MaxwellJ.R., de LeeuwJ.W. (1993b)Variations in abundances and distributions of isoprenoid chromans and long-chain alkylbenzenes in sediments of the Mulhouse Basin a molecular sedimentary record of palaeosalinity. Org. Geochem. 20, 1201—15. 

Because of the wide variation in reactions between the Vilsmeier reagent and these different non-aromatic substrates, ranging from the production of -chloroenals via malonaldehydes to quinolines and chromans, the usual comparison with other methods cannot be made. Each separate class of product would require its own set of comparisons, and this would tax the patience of authors, editors, and readers. 

The cyclisation of aryl ethers is a well established route to chromans and several variations on this theme have been reported. Prenylphenols result from the Pd-catalysed coupling of iodophenols with 2-methylbut-3-yn-2-ol, reduction of the alkynic function and dehydration. The intermediate hydroxyalkylphenols can also be dehydrated to the chroman (94H1487). 

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