1.3- dicarbonyl component

Scheme 4 also represents the classical route to isoxazoles, first studied in 1888 by Claisen and his coworkers (1888CB1149). Reaction of a 1,3-diketone with hydroxylamine gives, via the isolable monoxime (108) and the 4-hydroxyisoxazole (109), the isoxazole (110). Unsym-metrical 1,3-diketones result in both possible isomers (110) and (111), but the ratio of the isomeric products can be controlled by the right combination of the 1,3-dicarbonyl component and the reaction conditions used. These important considerations are described in Chapter 4.16, along with the variations possible in the 1,3-dicarbonyl component designed to yield diverse substituents in the resultant isoxazole. 

The 1,3-dicarbonyl components can be replaced by an enol ether, which can be prepared by Claisen condensation from an ortho ester and a reactive methylene compound. ... 

Reaction of 1,3-dicarbonyl compounds with vinyl sulfides gives the corresponding medium- and large-sized ring substituted furans 78 in moderate to good yields. In addition to cyclohexane-1,3-diones, 4-hydroxycoumarins and 4-hydroxyquinone can also be used as 1,3-dicarbonyl components . 

Zinc chloride is also used in an alternative approach to 4-hydroxycoumarins, in which malonic acid is used as the 1,3-dicarbonyl component, although additionally the presence of phosphorus oxychloride is vital to success (60JOC677). 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Dihydroquinoline-5-ones are obtained by cyclocondensation of 3-aminoacroleins with cyclohexan-l,3-diones or 3-ethoxyacrylaldehydes and aminocyclohexenone. The corresponding ketone (R1 = Me) behaves analogously235 (equation 169). The unexpected pattern of the quinoline substitution therefore can be reasonably ascribed to intermediate transamination between the 1,3-dicarbonyl components. 

More often, unsymmetrical 1,4-dihydropyridines are produced by conducting the Hantzsch synthesis in two stages, i.e. by making the (presumed) aldol condensation product separately, then reacting with ammonia and a different 1,3-dicarbonyl component, or an enamino-ketone, in a second step. ... 

If the 1,3-dicarbonyl component is at the 1,3-keto acid oxidation level, then the product is a quinolone. Anilines and P-keto esters react at lower temperatures to give the kinetic product, a P-aminoacrylate, cyclisation of which gives a 4-quinolone. At higher temperatures, P-keto acid anilides are formed and cyclisation of these affords 2-quinolones. 

Aldol condensation between a 1,3-dicarbonyl component and a ketone with an a-methylene, under acidic, dehydrating conditions, prodnces pyrylinm salts.It is likely that the initial condensation is followed by a dehydration before the cyclic hemiacetal formation and loss of a second water molecule. The use of the bis-acetal of malondialdehyde, as a synthon for malondialdehyde, is one of the few ways available for preparing a-unsubstitnted pyrylinms. ... 

Variations on this theme include the use, as synthons for the 1,3-dicarbonyl component, of P-chloro-a,P-unsaturated ketones, or of conjugated alkynyl aldehydes. ... 

Subject to the restrictions set out below, phenols react with 1,3-dicarbonyl compounds to produce 1-benzopyryliums or coumarins, depending on the oxidation level of the 1,3-dicarbonyl component. 

Each of the diazines can be constructed from an appropriate source of two nitrogens and a dicarbonyl compound. In the case of pyridazines, the nitrogen source is, of course, hydrazine and this in combination with 1,4-dicarbonyl compounds readily produces dihydro-pyridazines, which are very easily dehydrogenated to the aromatic heterocycle. Pyrimidines result from the interaction of a 1,3-dicarbonyl component and an amidine (as shown) or a urea (giving 2-pyrimidones) or a guanidine (giving 2-amino-pyrimidines), without the requirement for an oxidation step. 

The most general pyrimidine ring synthesis involves the combination of a 1,3-dicarbonyl component with an N-C-N fragment snch as a urea, an amidine or a guanidine. 

Pyrazoles and isoxazoles can be made from a 1,3-dicarbonyl component and a hydrazine or hydroxylamine,... 

Generally speaking, unsymmetrical 1,3-dicarbonyl components produce mixtures of 1,2-azole products. This difficulty can be circumvented in a number of ways by the use of acetylenic aldehydes or ketones (as synthons), where a hydrazone or oxime can be formed first by reaction at the carbonyl group, and this can then be cyclised in a separate, second step. "" A nice example of this is the formation of... 

Later, Narasaka and coworkers reported that the scope of this transformation could be substantially improved with the use of Mn(III) catalysis [313]. These new reaction conditions allowed highly efficient employment of differently substituted simple non-activated alkyl-, aryl-, hetaryl- and even cydic vinyl azides 328 (Scheme 8.117). In addition, previously unreactive 1,3-diketones 33S could serve as feasible 1,3-dicarbonyl components in this formal [3 + 2] cycloaddition reaction, affording 2,3,5-tri-and 2,3,4,5-tetra-substituted pyrroles 336 in moderate to excellent yields... 

If two equivalents of the 2-halo-carbonyl compound (or 2-halo-nitrile) are utilised to react with an enolate/carbon disulfide adduct, double S-alkylation and then double ring closure produce thieno[2,3-h]thiophenes [129] Scheme 82 shows how this works. Taking this idea further, if a malonate is used as the 1,3-dicarbonyl component, 3,4-dihydroxythieno[2,3-h]thiophenes are the final result (Scheme 83) [130], the ring closure steps then having the character of Claisen condensations. If malononitrile is used instead of a 1,3-dicarbonyl compound, the product is a 3,4-diaminothieno[2,3-6]thiophene - product 60 in Scheme 84 is the result of using chloroacetonitrile in the alkylation step [131]. 

Ten years later, Lubineau et al. reported the direct reaction of unprotected carbohydrates with acetylacetone in aqueous alkali media [11]. By application of this method, an access to different mixtures of furanoid and pyranoid structures of a- and P-configured C-glycosides [12] was obtained. The ratio of the products depends on the conditions of execution for this reaction and the carbohydrates deployed (Eq. 2, Scheme 2.1). This Knoevenagel/Michael/retro-Claisen-aldol cascade is carried out at high temperature (60-90°C) and is associated with the loss of a C2 fragment of the starting 1,3-dicarbonyl component (when used with acetylacetone). 

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