Chromones, ring synthesis

Khellin is a natural product closely related to the psoralens in which a chromone ring has been substituted for the cou-marin. The plant material has been used since ancient times as a folk remedy modern pharmacologic work has confirmed the bronchio-dilating and antispasmodic activity of khellin. The synthesis outlined below, it should be noted, is selected from a half-dozen or so reported within the last quarter century. 

Ring synthesis of chromones from ortho-hydroxyacylarenes and esters... 

As an initial step to the introduction of a carbonyl group at the 3-position of the chromone ring, we started with the synthesis of 3-formyl derivatives on which only a few reports (7., had been published. The 4-oxo-4H-l-... 

Intramolecular Wittig-type cyclizations have been used successfully in many ring-synthesis applications, and some further examples reported this year include the preparation of chromones by cyclization of the carbonate (149) and an indole synthesis from O-acyl benzyltriphenylphosphonium salts. The bicyclo[3.3.0]oct-A -en-3-one ring system lacking substituents at C-2 and C-5 is produced by ring closure of the phosphonates (150), although in the case of the parent member of the series (150, R = R = H) a novel dimer is formed... 

Chromone, 2-amino-3-chloro-synthesis, 3, 713 diacetate, 3, 714 Chromone, 3-aroyl-photochemistry, 3, 695 Chromone, 2-benzhydryl-3-benzoyl-photoenolization, 3, 695 Chromone, 3-benzoyl-2-benzyl-photoenolization, 3, 695 Chromone, 3-benzoyl-2-methyl-synthesis, 3, 823 Chromone, 2-benzyl-in photochromic processes, 1, 387 Chromone, 3-benzyl-photolysis, 3, 695 Chromone, 3-bromo-synthesis, 3, 828 Chromone, 3-bromoacetyl-ring opening, 3, 713 Chromone, 3-bromo-2-methyl-reactions... 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

Chloromethylation of suitably activated chromones yields useful intermediates for further synthesis, for example, in the preparation of methyl, aminomethyl, cyanomethyl or carboxal-dehyde derivatives. A methoxy group in the benzene ring is sufficiently electron-releasing to promote this reaction, for instance 7-methoxy-2-methylchromone is converted into the 8-chloromethyl analogue (62JIC507). 

A wide variety of chromones has been prepared by this method since its introduction (01CB2475), and the literature abounds with examples. A fully detailed preparation of 3-ethylchromone is available (5SOSC(3)387). The presence of substituents in the aromatic ring of the acetophenone has minimal effect on the course of the reaction both electronreleasing and electron-withdrawing substituents are compatible with the synthesis. 

It has since been shown that the enol ester (451) is an intermediate in the synthesis (69T715). Indeed such esters readily form chromones on treatment with alkali and the ortho acyloxy group becomes part of the pyranone ring as a result of a Baker-Venkataraman rearrangement (Scheme 160) (69T707). 

Three benzopyranobenzothiazepine systems, depending on the different annelation of the benzopyrano nucleus to the thiazepine ring, are known. The synthesis was generally achieved by condensation reaction of amino-thiophenol with chromone or coumarin derivatives. 

The photo-cycloaddition of ethylene to 3-alkoxy chromones such as 315 has been applied to the synthesis of marine sesquiterpene filiformin and congeners (Scheme 43) <1996JOC4391>. Tandem [2+2] 7i-photo-cycloaddi-tion and y-hydrogen abstraction provided tetracyclic intermediate 316 which was converted to terpene 317 by subsequent oxetane ring reduction and acid-catalyzed rearrangement. 

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