Indanones enol acidity

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

Enol acidity can be increased by simply ensuring that conjugation is present in the enolic form but not the carbonyl form. 2-Indanone (49) has greater enolic acidity than both 2-tetralone (50) and 2-benzosuberone (51) due to more efficient tt-overlap with the adjacent aryl ring . By comparison, conjugation present in both the ketonic and enolic forms, such as in 1-tetralone (52) and 4-chromanone 52 ), increases enol acidity relative to saturated compounds such as acetone (45 ). 

For the synthesis of (69), the enol ether (71) from the indanone (70) was carboxylated with COa-n-butyl-Iithium in THF at —70 C to yield (72). The methyl ester (73) was converted into (75) via the maleic anhydride adduct (74), essentially as described in earlier work. Lithium aluminium hydride reduction followed by oxidation with dicyclohexylcarbodi-imide afforded the aldehyde (76). This was condensed with excess (77) to yield a mixture of the diastereomers (78). Oxidation with chromium trioxide-pyridine in methylene dichloride gave (79), which could be converted into the diketone (80) by treatment with excess benzenesulphonylazide. The diketo-lactam (81) was prepared from (80) as described for the synthesis of the analogous intermediate used in the synthesis of napelline. Reduction of (81) with lithium tri-t butoxyaluminohydride gave the desired dihydroxy-lactam (82). Methylation of (82) with methyl iodide-sodium hydride gave (83). Reduction of this lactam to the amine (84) with lithium aluminium hydride, followed by oxidation with potassium permanganate in acetic acid, gave (69). 

The liquid reagent has high solvent power, particularly for oxygen-containing substances and for aromatic compounds. It is an effective dehydrating and condensing agent comparable to coned, sulfuric acid but less prone to permit secondary reactions such as enolization and aromatic substitution. Treatment with liquid HF at room temperature provides a simple and efficient method for the cyclization of /3-arylpropionic acids and y-arylbutyric acids to 1-indanones and 1-tetralones, as shown by the yields cited under the formulas of typical ketones. It is far superior... 

The reaction of the lithium enolate of 2-methyl-1-indanone with the thiophenium salt (35) leading to the 2-trifluoromethyl derivative in 51% yield is an exception. With all other in situ generated enolates of ketones, no trifluoromethylation was observed. To moderate the reactivity of the enolates, a boron Lewis acid (40) was added to form the boron complexes. This made a regio-, diastereo- and enantio-selective trifluoromethylation possible in good to high yields. ... 

Even simple enols have substantial lifetimes, provided that bases or acids are completely excluded173. Thus, an aromatic enol 4 is prepared in situ by Norrish-type fragmentation of 2. If (-)-ephedrine is present in the reaction mixture, the enol reverts enantioselectively to (/ )-2-rnethy 1 -1 -indanone (3). With as little as 0.01 mol % catalyst, 45% ee is obtained176. The crucial enol 4 has also been generated from either the benzyl enol ester 5 by palladium on charcoal and hydrogen or from the allyl ester 6 by palladium acetate, triphenylphosphine and ammonium formate. In the presence of a chiral 1.2-hydroxyamine, e.g., ephedrine, substantial stereogenic induction in 2-methylindanone 3 was observed175. 

Isocoumarins. - Indanones such as (203), as their enol esters, have been ozon-olysed to give the dihydroisocoumarin-3-ol, which yielded the isocoumarin (204) when heated with toluene-p-sulphonic acid. 3-Arylisocoumarins have been synthesized, in good yield, by heating homophthalic acids with aroyl chlorides. Phthalaldehydic esters (205) react with A/ -acylglycines to give isocoumarin-3-carboxylic acids, e.g (206). ... 

The reagent was also able to convert carbonyl compounds into enol trifluoroacetates. 3- and 4-phenylalkanoic acids were readily cyclized to 1-indanones and 1-tetralones, respectively, through the intermediary of a mixed anhydride formed with CF3S03H29 (equation 13). 

The enantioselective protonation of silyl enol ethers, such as (12.39), by a catalyst has been achieved using 2 mol% of the proton source (12.40). The acidity of (12.40) is enhanced by coordination to a Lewis acid. The silyloxy group is activated by fluoride ion and up to 99% ee in the asymmetric protonation of a-aryl substituted cyclic silyl enol ethers such as (12.39) has been obtained using a Lewis acidic BINAP. / F complex.In a similar vein, silyl enol ethers of tetralones and indanones undergo asymmetric protonation with moderate to good ee using catalytic quantities of hydrogen fluoride salts of cinchona alkaloids in the presence of acyl fluorides and ethanol, which act as a stoichiometric source of HE 28... 

Akiyama developed an enantioselective fluorination of indanone-derived p-ketoesters 63 with Af-fluorobis(phenylsulfonyl)amine (NFSI, 64) with the use of ehiral phosphorie acid 62 and Na2COs (Scheme 2.38). The simultaneous formation of the sodium enolate from 63 and chiral sodium phosphate from 62 under basie eonditions was the key to achieving high yield... 

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