Chroman-4-ols

Cyclobuta[fc]chroman-4-ols, derived from chromones by a [2+2] photocycloaddition to ethylene, are prone to acid-catalysed rearrangements. Elaboration of the parent system prior to rearrangement has enabled the marine sesquiterpene filiformin <96JOC4391>, the henzo-1,3-dioxan nucleus of averufin <96JOC9164> and cyclobuta[h][l]benzoxepin-8,9-diones <96CC1965> to be synthesised. 

Hydroboration of chrom-3-ene, followed by H202 oxidation, gives predominantly chroman-4-ol, with little 3-isomer.244 The same happens for flavene, which gives a-flavan-4-ol,122 but when the aromatic ring bears electron-releasing substituents, boration occurs preferably at position 3.245... 

It is possible to distinguish axial and equatorial hydroxy groups in chroman-4-ols on the basis of their chemical shifts in DMSO (79BCJ2163). The pseudoaxial OH proton resonates at a significantly higher field the different behaviour is attributed to solute-solvent hydrogen bonding. 

The 13C spectra indicate a preference for a pseudoaxial orientation of the hydroxy group in chroman-4-ol and frans-2-methylchroman-4-ol (78). The cis isomer (79) has a pseudoequatorial hydroxy group and the resonances for C-2, C-3 and C-4 appear at lower field than those of the trans compound (77JCS(P1)217). A similar situation obtains for the related flavanols. 

The principal ions from chroman-4-ol correspond to [M-H]+, [M-OH]+, and [M-H20]+. RDA expulsion of ethylene from the molecular ion occurs producing an abundant peak at m/e 122, which is surpassed in intensity by the derived [RDA-H]+ ion, m/e 121 (64T1185). 

Substituted chroman-4-ols behave in a similar manner and yield 3-substituted chromenes, and the dehydration of 3-phenylchromanols provides a convenient route to isoflavenes (66JCS(C)629). 

The oxidation of chroman-4-ols to chroman-4-ones, on the other hand, is more easily accomplished, using chromium trioxide in acetic acid (66JCS(C)2013). The same oxidant in pyridine converts chroman-3,4-diols to the 3-hydroxychroman-4-one (65CB1498). 

The cyclisation of o-alkenylphenols features in two approaches to the chroman ring system. The Hg-mediated cyclisation of (7) affords the chroman-4-ols (8) and (9) which can be separated after debenzylation, providing the chroman unit of the calophyllum coumarins (95S630). 2-Cyclohexenylphenols undergo a 6-endo cyclisation to fused chromans on treatment with pyridine hydrobromide perbromide (95CJC1727). 

The transformation of chroman-4-ones into (S)-chroman-4-ols by Mortierella isabellina has been applied to naphtho[2,3-b]pyran-4-one to provide a synthesis of naturally occurring (S)-4-hydroxy-lapachone (95CJC1399) and various chroman-4-ones have been enantioselectively reduced by NaBTLt in the presence of optically active Co (II) complexes (95AG(E)2145). 

In the synthesis of some biologically active 3-substituted chroman 4-ols, for example, 395, it was found that reductions of 3-piperidino-, morpholino-, and pyrrol idino l//-chrornoncs could be efficiently achieved by sodium borohydride in methanol (Scheme 63) <2002SC2227>. 

Phenoxymethyl)cyclobutanones 477 undergo intramolecular alkylation of the aromatic ring to afford cyclobu-ta[c]chroman-4-ols 478 (Equation 196) <2002SL796, 2004T449>. A similar procedure allows entry to 4-thiophenyl cyclobuta[r]chromans (Scheme 107) <2002OL2565>. 

Salicylaldehyde reacts with trimethylsilylketene dithioacetal in the presence of a Lewis acid to form the chroman 502, the product of a deoxygenative divinylation (Equation 208) <2001JOC3924>. This reaction can also be applied to salicylaldimines <2003JOC4947>. Treatment of 3,5-dibromosalicylaldehyde with methyl vinyl ketone (MVK) in the presence of DABCO leads to a chroman-4-ol as the major product <2002J(P1)1318>. A stereoselective one-pot synthesis of vy/z-fused chromans from salicylaldehydes, aromatic amines and cyclic enol ethers is carried out in the... 

There has been a number of developments in the use of salicylaldehydes as precursors of both chromenes and chromans. Alkenes activated by acyl, formyl, nitrile and phenylsulfonyl groups react with 2-hydroxybenzaldehydes and 2-hydroxy-1-naphthaldehyde under Bayliss-Hillman conditions to yield 3-substituted chromenes via the in situ dehydration of the initially formed chroman-4-ol <02JCS(P1)1318>. In like manner, P-nitrostyrenes yield 2- and 2,2-substituted derivatives of 3-nitrochromenes <02H(57)1033>. A simple route to 2-phenyl-2H-chromenes starting from salicylaldehyde and utilising a Pd(0)-catalysed cyclisation of an allylic acetate has been described <02SC3667>. 

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>. 

Formylation of 5,7-dihydroxy -( -propyl)-coumarin (1) provided on 8-formy-lated product (26). Treatment of the compound 26 with 3-chloro-3-methyl-l-butyne to introduce regioselectively the chromene 27 because the phenolic hydroxyl group at the C position was less accessible for formylated substitution because of a presumed hydrogen-bonding interaction. To construct the enantiomerically pure rra i-2,3-dimethyl chroman-4-ol system, Deshpande et al." ° used organoborone... 

The kinetic resolution of racemic compounds enzymatically has been successively achieved for 2-hydroxymethyl-2,5,7,8-tetramethylchroman-6-ol, valuable for the synthesis of tocols <97TA523>, and chroman-4-ols <97TA3059>. 

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