2- Hydroxy-l,3-diketones

A key step in the approach to 3(2//)-furanone ring systems via the acid-catalyzed cyclization-dehydration of appropriately substituted a -hydroxy-l,3-diketones involves the acylation of a-hydroxy-ketone dianions 11141... 

Scheme 3.38 Two pathways in the reaction of 2-hydroxy-l,5-diketone with 1,2-DAB...

The regio- and stereoselective reductions of 2-substituted-l,3-diketones were extensively studied by Smonou and her coworkers [55]. In this work, the corresponding optically pure hydroxy ketones and diols were synthesized utilizing isolated NADPH-dependent ketoreductases (KRED). Although most... 

Oxidation of [1,3- " C]acetone with selenium dioxide provided [1,3- C]methylglyoxal 12921 in 25 0% radiochemical yield . Aldol reaction with doubly deprotonated /3-keto acid 293 and simultaneous decarboxylation converted 292 to the 3-hydroxy-2,5-[l,3- ]diketone 294. This cyclized upon treatment with base to give doubly labeled aUethrolone 12951. the alcohol component of allethrine, a potent synthetic insecticide ... 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

The palladium [Pd(Ph3)4]-catalysed 3 + 3-cycloaddition of trimethylenemethane with azomethineimines produced hexahydropyridazine derivatives under mild conditions (40 °C).171 The Lewis acid-catalysed formal oxa-[3 + 3]-cycloaddition of a,f+ unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and viny-logous silyl esters yielded a variety of pyrones at room temperature.172 Croton-aldehyde has been converted to 6-hydroxy-4-methylcyclohex-l-enecarboxaldehyde by an enantioselective 3 + 3-cycloaddition catalysed by proline. This methodology was used in the synthesis of (—)-isopulegol hydrate, (—)-cubebaol, and (—)-6-hydroxy-4-methylcyclohex-l-ene-1-methanol acetate, an intermediate in the total synthesis of the alkaloid magellanine.173... 

Diethyl 4-hydroxyisoxazole-3,5-dicarboxylate (334) was prepared by the reaction of acetonedicarboxylic acid ester with nitrosyl chloride (78JHC1519). Other 4-hydroxyisoxazoles have been prepared by the reaction of 2-hydroxy(or acetoxy)-l,3-diketones with hydroxylamine (34JA2190, 62HC(l7)l, p. 149), and by hydrolysis of 4-isoxazolediazonium salts (62HC(17)1, p. 149). The parent 4-hydroxyisoxazole has not yet been reported. 

Corey and coworkers , in a synthesis of prostaglandins, prepared diene 34 by alkylation of the lithiodithiane 32 with 2-bromomethyl-l,3-butadiene (equation 41). A synthesis of jasmone (35), in an overall yield of 50%, has been reported by Ellison and Woessner in which the bisdithianylethane 33 was sequentially alkylated, followed by hydrolysis and cyclization (equation 42). A similar route for preparation of 4-hydroxy-2-cyclopenten-l-ones has been reported . This method appears to provide a general route to 1,4-diketones via 1,3-dithianes. 

We reported that smooth oxidative addition of organic halides such as aryl, benzyl, and allyl halides to metallic nickel proceeded to afford organonickel halides under mild conditions, which yielded homocoupled products [11, 41] or ketones by the reaction with acid chlorides [42] or alkyl oxalyl chlorides [43]. We describe here a new method for the preparation of 3-aryl-2-hydroxy-l-propanones (4) in good yield by the Grignard-type addition of benzyl halides to 1,2-diketones mediated by metallic nickel under neutral conditions [44]. 

The reaction of singlet oxygen with the enolic tautomers of l-(2, 4 6 -trialkylphenyl)-2-methyl 1,3-diketones is proposed to proceed via one of two transition states, one in which the incoming singlet oxygen interacts with the allylic hydrogen atoms (less polar), and the other in which it interacts with the enol hydroxyl group (more polar). The former case leads to the 3-hydroxy peroxide, which is converted into the enedione and the epoxy ketone the latter is converted directly into the hydroperoxy ketone. 

The reversible ring-deavage of the chromone system to (2-hydroxy)phenyl-l,3-diketones 2 (see above) can also occur on acid catalysis. If an additional OH function is present in the 5-position of the benzo part of chromone, it also can participate in the re-cyclization. Chromones and especially flavones with an unsymmetrically substituted benzene ring undergo isomerization by this route when treated with strong acids (Wesseley-Moser rearrangement), for example, 7 —> 8 ... 

The most frequently used method for the synthesis of chromones 10 is the acid-catalyzed cyclization of (2-hydroxy)aryl-l,3-diketones 9 which are obtained from (2-hydroxy)acetophenones (advantageously in their O-silyl protected form [61]) by a Claisen condensation. Bis-(trichloromethyl)carbonate/DMF (dimethylformamide) effects the cydization 9 10 very efficiently [62]. 

The formation of the pyrrolo[l,2-a]quinoxaline stmcture in this reaction can be represented in one of two ways (Scheme 3.38) (a) isomerization of the 2-hydroxy-1,5-diketone 118 to the 5-hydroxy-l,4-diketone 121 with the subsequent formation of the o-aminophenylpyrrole 122 and closure of the dihydroquinoxaline structure 123 (b) reaction of the a-hydroxyketone fragment with 1,2-DAB with the formation of the hydroquinoxaline derivative 125 and subsequent closure of the dihydropyrrole ring and isomerization of the 3,3a-dihydropyrrolo[l,2-a]quinoxaline structure 124 to the more stable 4,5-dihydropyrrolo[l,2-a]quinoxaline structure 123. 

Hydroxy-5-MC (29a) was itself prepared (87) by a modification of the synthetic sequence employed in the preparation of 2-chrysenol (Figure 13). Reaction of 2-(l-(3-methylnaphthyl) ethyl bromide with the 1-lithio salt of 1,5-dimethoxycyclohexa-1,4-diene furnished the diketone 8a (Figure 18). Cyclization of the latter in polyphos-phoric acid afforded the 1-keto derivative which underwent dehydrogenation over a palladium catalyst to yield 29. 

Stereoselective hydrogenation ofl -diketones. Hydrogenation of 1,3-alkane-diones catalyzed by Ru2Cl4[(R)-l][N(C2H5)3] results in anf/-l,3-diols with high dias-tereoisomeric and enantiomeric excesses (equation I). Under the same conditions l-phenyl-l,3-butanedione (2) is reduced mainly to the (3-hydroxy ketone 3 in 98%... 

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