Heterocycles chromones

In contrast, the anodic fluorination Scheme 117. of Q , 8-unsaturated cyclic heterocycles The regioselective electrohalomethoxy-such as flavone [222] or thioflavone lation of chromone derivatives is followed... 

In contrast to the benzoannelated nitrogen heterocycles, only a few kinds of benzoannelated systems without nitrogen have been described (Fig. 3.15). Five-mem-bered rings such as benzo[b]furans (336) [184, 461] and hydrobenzo[b]furans (337) (Scheme 3.41) [337, 462, 463] and six-membered rings like 4H-l-benzopyran-4-ones (4-chromones) (338) and 2H-l-benzopyran-2-ones (coumarines) (339) [96, 464, 465] 2,3-dihydro-4H-l-benzopyran-4-ones (chroman-4-ones) (340) [466] and 3,4-dihydro-lH-2-benzopyrans (isochromans) (341) [444] have been reported. 

Comparison of Basicity of Some Heterocyclic Analogues of Chromone,... 

Chromones differ marginally in their chemistry from coumarins (ben-zopyran-2-ones) because the carbonyl group is now conjugated with the oxygen atom via the double bond of the heterocycle (see Box 5.2). This conjugation does not involve the benzene ring. 

A The Mannich reaction proceeds through the intervention of the N,A dimethylmethyleniininium cation [Me N =CHJ, This is insufficiently electrophilic to react with the benzene ring under the mild reaction conditions. Similarly, were the electrophile to react with the carbonyl oxygen atom of the heterocycle, this reaction would be reversible, as an aminomethyl ether is relatively unstable in acidic media. Thus, it seems plausible that the chromone utilizes enol or enolate character to trap the electrophile at C-3, followed by deprotonation of the adduct to reform the chromone ring system ( heme 5.9). 

Unsaturated 5(4//)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride/ antipyrine/ " chromone/ indoles/ pyridines/" ° quinolines/" diazines/" benzoxazoles/" and benzimidazoles " " have been prepared. Reaction with nitrogen nucleophiles and subsequent cycliza-tion leads to the expected 5(477)-imidazolones. 

Alkynones e.g. 51 are efficiently converted into chromones via the enaminoketones in a one-pot reaction offering an attractive route to the heterocycle from salicylic acids by way of a chlorination-Sonogashira coupling sequence which lends itself to combinatorial chemistry (Scheme 30) <99TL2469>. 

The scarcity of reviews1 and recent interest in thiochromanones and related compounds calls for a comprehensive summary of this area of heterocyclic chemistry. The apparent similarity between these systems and the naturally occurring chromanones, chromones (flavones), chromenes, etc., is responsible for the continued importance of these sulfur heterocycles. Chemical Abstracts (through November, 1973) has been employed as the principal reference source and nomenclature guide for this review. 

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. 

Two disadvantages are associated with this synthesis. Yields range from low to moderate and, of more significance, cyclization of the initially formed ester can give rise to chromones or coumarins or to mixtures of the two heterocycles. With the wide range of analytical techniques now available, it is not difficult to distinguish the isomeric benzopyranones. However, some of the structural assignments in early work have been shown to be erroneous and care is therefore advised in the interpretation of results. 

In general, the synthetic routes described provide adequate and convenient routes to chromones, such that their synthesis from other oxygen heterocyclic compounds is not of significant value. The following examples are therefore better considered as reactions of the heterocycle and are dealt with in more detail in the appropriate sections of Chapter 2.23. 

Numerous examples of stilbene-to-dihydrophenanthrene photocyclization incorporating oxygen and sulfur heterocycles have been reported. Oxidation to the phenanthrene is usually effected by added iodine or by oxygen. Thus, irradiation of 2,3-diphenylchromone (37) results in the formation of phenanthro[9,10 -2,3]chromone (38)29 analogous photocyclizations have... 

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... 

Photodimerizations have been observed in a variety of sulfur-containing heterocycles notable examples include the photodimerization of 2- and 3-ary lbenzo[b]thiophens,287 benzo[h]thiophen 1-oxide,288 benzo[h]thiophen 1,1-dioxide,289 and its 2-bromo289 and 2-methyl derivatives.290 All four possible dimers were obtained on irradiation of thio-chromone in aromatic solvents,291 and 1-thiauracil (345) is converted into... 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

Treatment of 3-formyl chromones 436 with arylhydrazides gave the corresponding hydrazones (e.g., 437, Scheme 75). In the presence of acetic anhydride the aroylhydrazones undergo heterocyclizations to give chromones such as 438 <2004CHE214>. 

Chemistry of Heterocyclic Compounds 1977 , Volume 31 (Chromenes, Chromanones, and Chromones). 

According to our previous reports [74,76], the anti-inflammatory activity of ethers of 4-bromomethyl coumarins can be significantly modified by using different aryl systems. Here we have modified the aryl moieties to heterocyclic moieties like chromone, benzofuran and coumarin... 

The pyrilium cation 9.1, 2-pyrone 9.2, 4-pyrone 9.3, and their benzo-fused analogues the benzopyrilium cation 9.4, coumarin 9.5, chromone 9.6, are the parent structures of a series of six-membered ring heterocycles containing one oxygen atom. The impetus for research in this area comes from the enormous number of plant-derived natural products based on the benzopyrilium, coumarin, and chromone structures. 

An important difference between the monocyclic and benzo-fused series is that reactions with amines do not lead to the corresponding heterocycles in the benzo-fused series. For instance, aminolysis of chromone 9.29 affords phenol 9.30. Benzopyridone 9.32 is not produced. The facile tautomerisation between 9.25 and 9.26 would analogously give ketone 9.31 in this series. This high-energy intermediate is not aromatic, and the reaction stops at phenol 9.30. 

Other examples of twin drugs are the antioxidant probucol, which lowers the cholesterol level in blood, and cromolyn, a chromone heterocycle, which is useful in the inhalational treatment of bronchial asthma (Fig. 1.11). 

Another interesting reaction is the addition of an enaminoester to phenyl 4-chromone sulphonate, leading to a mixture of fused heterocyclic products in nearly equimolar amounts103 (equation 72). 

Heterocycles such as 4-trifluoromethylimidazole, phenoxazine, 3-formyl-chromone, coumarin derivatives, and vitamin K2 derivatives were investigated for their cytotoxicity against human normal and tumor cells. These compounds induced moderate tumor-specific cytotoxicity. VitaminK2 derivatives and prenylalcohols displayed disappointingly low tumor-specific cytotoxicity, although they have been reported to induce apoptosis-inducing activity. Human oral squamous cell carcinoma cell lines showed considerable variation in drug sensitivity. The type of cell death induced depended both on which types of cells and which inducers were used. 

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