Chromones, addition

In an alternative strategy functionalized phenols, such as iodophenol, were involved in palladium-catalyzed carbonylation of alkynes or allenes, producing coumarin or chromone derivatives (Scheme 23) [130-133]. After oxidative addition of the iodoarene to the Pd(0) catalyst the order of insertion of either CO or the unsaturated substrate mainly depends on the nature of the substrate. In fact, Alper et al. reported that CO insertion occurs prior to allene insertion leading to methylene- or vinyl-benzopyranone derivatives [130]. On the contrary, insertion of alkynes precedes insertion of CO, affording couma-rine derivatives, as reported by Larock et al. According to the authors, this unusual selectivity can be explained by the inability of the acyl palladium species to further react with the alkyne, hence the decarbonylation step occurs preferentially [131-133]. 

Method A The 2-hydroxyacetophenone (3 mmol) and acyl chloride (3.6 mmol) in PhH (20 ml) are stirred at 80°C with aqueous K,CO, (I0%, 20 ml) and TBA-HS04 (0.5 g, 1.5 mmol) for 2-3 h until the ester is completely formed. The PhH phase is separated, washed with H.O (3 x 20 ml) and dried by azeotropic distillation. Ring closure is effected by the addition of TosOH (1.55 g, 9 mmol) in PhH (20 ml) and azeotropic distillation. The organic solution is washed with aqueous NaHCO, (10%, 50 ml) and evaporated to yield the chromone. 

The stereochemistry of 338 and 339 in each case results from initial conjugate addition of MeO" at position 2 of the chromone ring. Ensuing attack of the formed enolate 342 upon PhI(OMe)2 occurs in an anti manner because of steric interaction. Sequential addition of MeO to the carbonyl group of 343 gives 344, and intramolecular reductive elimination of C6H5I then occurs with inversion of configuration, 344 345. The reaction is... 

Electrophilic aromatic substitution of other benzo-fused v-deficient systems generally follows predictable pathways. Thus, benzopyrylium salts are in general resistant to electrophilic substitution even in the benzo-fused ring. Chromones behave somewhat similarly, although substitution can be effected under forcing conditions. Coumarins, on the other hand, undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

In principle, the relative configuration in these and related cases can be identified by spectroscopic analysis, however, in practice this is not always simple to achieve. For example, the conjugate addition of a methyl group to the racemic chromone rac-9 could generate four pairs of diastereomeric chromanones (rac-10-rac-13). In the event, two main products in a 4 1 ratio were obtained. The relative configuration was not clear from the H-NMR coupling constants (J2,3) and was, therefore, determined by chemical reactions108 (see pp 472 and 480). 

The problems of configurational assignment are principally the same for the cases discussed in Sections 4.3.3.2.2. (Formation of Chiral, Racemic Products) and 4.3.3.2.3.1. [Formation of Nonracemic Products with Known Configuration at (at least) One Chiral Unit]. This can be illustrated by the example of the conjugate addition of a methyl group to a chromone (9 on p 411) which has been performed both with racemic and with enantiomerically pure material. Thus the (relative) configuration of the reaction products was determined making use of both the racemic and the nonracemic series (see pp 472 and 480)108. 

The chromone cromolyn sodium (5-5) was at one time considered the forerunner of a novel class of antiallergic and antiasthmatic drugs that act at one of the earliest stages of the allergic reaction. Detailed experiments, acmally conducted after the dmg s clinical effectiveness had been confirmed, suggested that the compound inhibited the release of mediators of the allergic reaction from mast cells. The dmg is not very active when taken orally and is usually applied topically to the lung by insufflation as its sodium salt. Considerable efforts to uncover additional structurally related mediator release inhibitors have had only limited success. 

A structurally unusual 3-blocker that uses a second molecule of itself as the substituent on nitrogen is included here in spite of the ubiquity of this class of compounds. Exhaustive hydrogenation of the chromone (13-1) leads to a reduction of both the double bond and the carbonyl group, as in the case of (11-2). The car-boxyhc acid is then reduced to an aldehyde (13-2) by means of diisobutylaluminum hydride. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (13-3) via the addition-displacement process discussed earlier (see Chapters 3 and 8). Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (13-4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (13-5) [16]. The presence of four chiral centers in the product predicts the existence of 16 chiral pairs. 

The dibenzopyranone ring system may be viewed as a chromone with an additional fused benzene ring and thus generally related to the antiasthmatic mediator release inhibitor cromolyn (see Chapter 11). Two dibenzopyranones have in fact been investigated for this indication in the clinic. Friedel-Crafts cyclization of the substituted cresyloxybenzoic acid (2-1) in sulfuric acid leads to the dibenzopyranone (2-2). The methyl group is then oxidized to a carboxylic acid by means of chromic acid. The acid is then converted to its sodium salt, xanoxate sodium (2-3) [2]. 

Mono- and bi-cyclic pyran-4-ones undergo photoaddition with unsaturated organic compounds (73BCJ690,66TL1419). When chromone is irradiated with an alkene or alkyne, addition... 

In addition to the chromone carboxylic acids mentioned in Section 2.23.8.1, a number of other chromones ha,ve shown promising activity as antiallergic compounds, for example 3-hydroxymethyl-8-methoxychromone (76MI22300), chromone-3-carboxylic acid (74CPB2959) and V-tetrazolyl chromonecarboxamides (78JMC1120). 

Hydroxyacetophenone requires an additional carbon atom, which will become C-2 of the heterocyclic product, before cyclization to the chromone can be effected. Direct C-formylation is not easy and the following syntheses illustrate the various techniques used to introduce this fragment. 

A chlorocarbonyl group ortho to a fluorine atom activates the halogen towards nucleophilic displacement. In the synthesis of a number of polyfluorinated chromones the 1,3-diketo side-chain is introduced using ethyl acetoacetate in the presence of magnesium ethoxide. Cyclization occurs on addition of sulfuric acid (70JOC930). 

Addition of other molecules to the double bond is not common, but 2,3-dihalogeno-chroman-4-ones have been prepared from chromones using sulfuryl chloride (67CHE624) or bromine in carbon disulfide (25CB1612). Reaction with NBS in aqueous DMSO affords 3-bromo-2-hydroxychroman-4-one (75JHC981). 

The phenolics include anthocyanins, anthraquinones, benzofurans, chromones, chromenes, coumarins, flavonoids, isoflavonoids, lignans, phenolic acids, phenylpropanoids, quinones, stilbenes and xanthones. Some phenolics can be very complex in structure through additional substitution or polymerization of simpler entities. Thus xanthones can be prenylated and flavonoids, lignans and other phenolics can be glycosylated. Condensed tannins involve the polymerization of procyaninidin or prodelphinidin monomers and hydrolysable tannins involve gallic acid residues esterified with monosaccharides. As detailed in this review, representatives of some major classes of plant-derived phenolics are potent protein kinase inhibitors. 

Unlike coumarin, chromone (206) undergoes efficient unsensitized photoaddition to tetramethylethylene, cyclopentene, ketene dimethyl acetal, and but-2-yne.180 The major product of such an addition to tetramethylene is the cis-fused cyclobutane derivative (207) the formation of the two minor products (208 and 209) is easily rationalized. Added benzophenone has no visible effect on this cycloaddition, which is therefore believed to involve the attack of triplet chromone on the ground-state alkene. Photoaddition to furo-chromones has also been studied,179 and the photosensitized cyclo-... 

Addition to six-membered oxygen heterocycles is also common. The photocycloaddition of 5,7-dimethoxycoumarin to tetramethylethylene has been described,269 and 4-hydroxycoumarin (326) undergoes facile addition to cyclohexene on direct irradiation to give the cyclobutane (327)270 analogous additions to a variety of other alkenes have been reported, and the cycloaddition of 4-methoxycoumarin to 2-methylpropene has been employed in a synthesis of l,2-dihydrocyclobuta[c]coumarin.271 Photoaddition of the 1,2-bisenol lactone (328) to tran.s-stilbene yields propellane (329),272 and [ 2 + 2] cycloaddition is observed along with other competing photoreactions on irradiation of chromone in the presence of alkenes.273... 

The cycloaddition of ketene acetals to 3-formylchromone exhibits good diastereoselectivity and meihanolysis of the pyrano[4,3- ] -pyran affords the chromanone ester (21) without racemisation. The chiral auxiliary, the diol (22), can be recyclised and the overall process represents an asymmetric conjugate addition to the chromone (95 JCS(P1 )2293). 

Ring enlargement of chromone to benzoxepins has been reported (see also Section 7.07.5). The in situ generation of benzopyrylium triflate 335 by reaction of 334 with Me3SiOTf followed by addition of ethyldiazoacetate and catalytic copper(ll) triflate yielded cyclopropane 336 as a single diastereomer. Treatment of compound 336 with trifluoroacetic acid resulted in the formation of 2,3-benzoxepin 337 (Scheme 47). 

Methylchromones and chromone-2-carbaldehyde are converted to 3-chlorochromones in good yield upon reaction with sodium hypochlorite (Scheme 49). The selective substitution of chlorine at C-3 is considered to involve the addition of NaO Cl1 to the C(2)-C(3) double bond followed by elimination of NaOH <1998SC3827>. 

Deprotonation of chromone 369 with lithium 2,2,6,6-tetramethylpiperidide followed by addition to aldehydes provided substrates which were converted directly to furo[3,4- ][l]benzopyran-9-ones (e.g., 371) upon acetal deprotection (Scheme 57) <2002S2341>. 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

Benzannelated 4-oxa-2-cydohexenones (chromones) react in a similar fashion to deliver the respective cydobutanes in a syn-sclccti vc addition. The reaction has been recently applied to the formal synthesis of ( )-heliannuol D [70]. 

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