Studies in Furobenzopyran Chemistry

Abstract

A series of 3-acyl(thio)chromones has been prepared. These compounds were acetalised with a variety of diols, with p-TsOH catalysis, under azeotropic conditions, to give the corresponding 3-acyl(thio)chromone acetals. A new rearrangement accompanies the formation of acetals from 3-acetyl- or 3-benzoyl- chromone giving a 2-methyl- or 2-phenyl- 3-formylchromone acetal. The rearrangement is initiated by conjugate addition of the diol to the chromone ring.

The C-2 lithio derivatives of 3-acyl(thio)chromone acetals are generated by treatment with lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidide (LTMP) in THF at low temperature. The anions have been intercepted with a variety of electrophiles. It was found that metallation with LTMP proceeds more efficiently. A number of novel 3-acyl-2-(1-hydroxyalkyl)(thio)chromone acetals has been prepared by electrophilic trapping with aldehydes. Three novel self-condensation dimers were obtained from lithiations of 3-acyl(thio)chromone acetals; the structures of two were established by X-ray crystallography. Mechanisms for their formation are presented. Whilst C-2 lithiation of 2-(4-oxo-4H[1]benzopyran-3-yl)-1,3-dioxane
with n-BuLi does occur, the reaction is complex and leads, ultimately, to a benzofuranone derivative. The structure and relative stereochemistry of this compound, which possesses two 1,4-disposed stereogenic centres, was established by X-ray crystallography. The reaction also provides another compound, derived from 1,2-addition of n-BuLi to 2-(4-oxo-4H[1]benzopyran-3-yl)-1,3-dioxane.

Lithiation of 2-(hydroxymethyl)chromone with LTMP initiates reduction ofthe pyranone ring, probably via a Single Electron Transfer mechanism. Electrophilic trapping of the intermediate anion with CICO2Et proceeds in a regio- and diastereospecific manner.

Unmasking of the acetal function in 3-acyl-2- (1-hydroxyalkyl)(thio)chromone acetals is facile (p-TsOH in toluene) and proceeds with concomitant cyclisation to give novel 9H-furo[3,4-b][l]benzo(thio)pyran-9-ones. Cycloaddition reactions of the furobenzo(thio)pyranones have been investigated. When 3-methyl-9H-furo[3,4)[1]benzopyran-9-onereacts with methyl propiolate a pincer Diels-Alder reaction prevails, to give an octacyclic 2:1 adduct with complete regio- and stereo- specificity. The stereochemistry was established as syn exo-endo by X-ray crystallography. Dimethyl acetylenedicarboxylate reacts with 3-(4-methylphenyl)-9H-furo[3,4-b][1]benzopyran -9-one to give a mixture of the 1:1 and the anti exo-exo 2:1 adducts. 3H,9H-Furo[3,4b[1]benzopyran-1,9-dione has been obtained via a tandem acylation-SnAr reaction of ethyl 2-fluorobenzoylacetate.

Protolysis of dimethyl 1,4-dihydro-1,4-epoxy4-(4-methylphenyl)-9-oxo-9H-thioxanthene-2,3-dicarboxylate gives the expected 1-hydroxythioxanthone derivative. However, the analogous 1,4-epoxyxanthene underwent an unprecedented hydrolytic cycloreversion to dimethyl 2-(4-methylphenyl) furan-3,4-dicarboxylate and 4-hydroxycoumarin.

The acylation of 3-pyrrolidinodihydrothiophenes with 2-fluorobenzoyl chloride has been investigated as an entry to the 9H-thieno[3,4-b]benzopyran-9-one system. An unexpected product, 2,4-bis(2-fluorobenzoyl)-3-pyrrolidino-2,5-dihydrothiophene is formed predominantly.