Dicarbonyls, Group preparation

This preparation describes a convenient and general method of synthesis of substituted pyrimidines from compounds containing a /3-dicarbonyl group, either intact or as the corresponding ketal. The usefulness of the 2-mercaptopyrimidines is enhanced by the ease of removal of the mercapto group by desulfurization 9 or oxidation 10 and its replacement by other functional groups.1 ... 

Several 1,4-dicarbonyl compounds are prepared based on this oxidation. Typically, the 1,4-diketone 10 or the 1,4-keto aldehyde 12 can be prepared by the allylation of a ketone[24] or aldehyde[61,62], followed by oxidation. The reaction is a good annulation method for cyclopentenones (11 and 13). Syntheses of pentalenene[78], laurenene[67], descarboxyquadrone[79], muscone (14 R = Me)[80]) and the coriolin intermediate 15[71] have been carried out by using allyl group as the masked methyl ketone (facing page). 

Synthesis and Properties. A number of monomers have been used to prepare PQs and PPQs, including aromatic bis((9-diamines) and tetramines, aromatic bis(a-dicarbonyl) monomers (bisglyoxals), bis(phenyl-a-diketones) and a-ketones, bis(phenyl-a-diketones) containing amide, imide, and ester groups between the a-diketones. Significant problems encountered are that the tetraamines are carcinogenic, difficult to purify, and have poor stabihty, and the bisglyoxals require an arduous synthesis. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

In the case of NH2OH with a sharp difference in the nucleophilicity of the two functions, the primary amino group reacts with the carbocation C-1 center. For example, the reaction of l-alkylaminoalk-l-en-3-ynes with hydroxylamine leads to selective synthesis of alkylisoxazoles (69ZOR1179). A preparative value of this method is evident because the use of dicarbonyl compounds as starting materials for the synthesis of alkylisoxazoles results in a mixture of isomers. 

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group. A series of experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system. As an example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzo-thiazines below). Toward this end, reaction of... 

Hydroxycoumarins and 4-hydroxyquinolinones have also been applied as 1,3-dicarbonyl compounds. Using these compounds, Raghunathan and coworkers prepared pyrano[3,2-c]coumarins [387] and pyranoquinolinones [388] under traditional conditions, while the group of Yadav synthesized similar pyrano[3,2-c]coumarins employing ionic liquids as solvents [389]. 

Stetter et al. start either from diketone (45)189-190 or from diene 39.191 Each of the carbonyls in 45 is protected as the enamine (168) and then treated with sulfur dichloride to give 4,8-dicarbonyl-2-thiaadamantane (167). The two carbonyl groups in 167 are reduced by WolfT Kischner reduction to 2-thiaadamantane (166), which is also obtained by LAH reduction of 4,8-dichloro-2-thiaadamantane (169), prepared in turn from diene 39 and sulfur dichloride. 

Catalysed alkylation of tosylmethylisocyanate (TOSMIC) [63, 64] has extended its versatility in the preparation of l, 4-dicarbonyl compounds and as a l, 3-dipolar precursor for the synthesis of heterocyclic compounds. The alkylation reactions should not be conducted in carbon disulphide, as nucleophilic attack by the methylene group on the carbon disulphide leads, after ring closure and S-alkylation, to a 4-alkylthio-1,3-thiazole system [65]. 

The preparation of (128) (Scheme 34) highlights the use of the trifluoromethyl group to increase the dipolarophilicity of a ketone. This activating effect of electron withdrawing groups is also taken advantage of in the preparation of 3-carbonyl substituted 1,2,4-trioxolanes (131) via the ozonolysis of a vinyl ethers in the presence of a 1,2-dicarbonyl compound (Scheme 36) <9iJOC659l>. 

Nucleophilic additions were studied using the same TSIL with pyrrolidine and thiophenol as models. As with the Diels-Alder reaction above, the reaction gave the required adducts which were then transesterified to give the final products. Heck coupling catalyzed by a transition metal and the Stetter reaction, Scheme 30, to prepare 1,4-dicarbonyl compounds were also studied by the same group using similar TSILs. 

In the second study, diketones were used as electrophiles and reacted with N-benzoylglycine to give a (Z/E) mixture of oxazolones 366 and 367 derived from condensation at the less hindered carbonyl group of the 1,2-dicarbonyl compound (Scheme 7.116). The ( )-isomers 367 were used as starting materials to prepare (Z) -5 - alky lidene- 3 - (benzoy lamino) -2(5//)-furanones 368... 

Whereas it was reported in CHEC-II(1996) <1996CHEC-II(7)229> that examples of this system were rare, the increase in synthetic activity since then has been significant. Such compounds can be obtained using either a thiophene or a pyrazine precursor. Virtually all of the molecules prepared from thiophene precursors follow the pathway shown in Equation (185). The appropriate diaminothiophenes 491, usually obtained by reduction of the corresponding nitro groups, are condensed with the desired 1,2-dicarbonyl compound under generally mild conditions to yield 492. 

The classical method for preparing isoxazole involves the condensation of 1,3-dicarbonyl compounds with hydroxylamine, a reagent that contains the preformed N—O bond. The regiochemistry of the reactions can usually be rationalized by assuming that the first step involves imine bond formation at the more reactive carbonyl group. Thus, reaction of formyl ketone (44-1) with hydroxylamine gives... 

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