Indanone, 2-methylene

The tnmethylsilyl enol ether of 1 indanone (3 2 mmol) m 2 mL of methylene chloride is added to a mixture of xenon difluonde (4 mmol) and a catalytic amount of pyndimum poly(hydrogen fluoride) in 5 mL of methylene chloride The mixture is stirred at 0 °C for 2 h and poured into dilute sodium bicarbonate solution, the organic layer is separated and dned After concentration and column chromatogra phy (silica gel, hexanes), 2-fluoro-1 -mdanone (mp, 59 °C) is obtained m 87% yield... 

Later it was described the synthesis of the donepezil HCI from 5,6-dimethoxy-2-(pyridin-4-yl)methylene-indan-l-one by the reaction with H2 over platinum dioxide at room temperature in acetic acid-methanol mixture to give 4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidine. The last one yielded donepesyl HCI by refluxing with benzyl bromide and triethylamine for 4 hours with the following addition of methanolic HCI (10%). 

Oxidation of alcohols or methylene groups. In the presence of PCC or pyr-idinium fluorochromate (PFC)2 as catalyst, t-BuOOH can oxidize alcohols in good yield. This combination also effects oxidation of a benzylic or a propargylic methylene group to a keto group in moderate yield for example indane — 1-indanone, 46-63% yield fluorene — fluorenone, 53% yield. 

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). 

It has been known for several decades, that alkyl aryl ketones with a methyl or a methylene group in (3-position to the keto functionality can undergo a threefold condensation reaction resulting in 1,3,5-triarylsubstituted benzenes. This transformation is catalyzed in most cases by Bronsted or Lewis acids, but bases have also been applied occasionally. If the steric demand is not too high, 1-indanones and acenaphthenones can be trimerized to the corresponding truxene and decacyclene derivatives (e.g. 112 —> 113) respectively (see Scheme 52... 

Bromocamphor has been employed as the chiral starting material in an enantiospecific synthesis (ref. 146) which involved the formation of an indanone (CD moiety) related structurally to that used by Hoffmann-La Roche and led finally to (-)-estrone. Attempts to alkylate the a,p-unsaturated ketone with 2-(3-methoxyphenyl)ethyl iodide failed, not surprisingly, due to an elimination rather than the desired substitution reaction and accordingly the use of an a-methylenic derivative of the ketone and 3-methoxybenzyl chloride were obligatory. By the use of (-)-3-bromocamphor, which is readily available from (-)-borneol by oxidation to (-)-camphor and bromination, natural (+)-estrone could be obtained. 

The application of the Forster reaction to the synthesis of a-diazo ketones is particularly important for derivatives of indanone and steroidal ketones with a methylene group in the a-position to the carbonyl function. The reaction allows functionalization of the a-methylene group. Examples include the synthesis of 2-diazo-3,3-diphenyl-indan-l-one (2-42 Cava et al., 1958) and 16-diazo-3)ff-hydro-xy-androst-5-en-17-one (2-43, Muller et al., 1962 Wheeler and Meinwald, 1988). 

Annelation of Cr(CO)s complexes. The reaction of either endo- or exo-1-methyl-l-indanone-Cr(CO)3 complex (1) with methyl vinyl ketone gives (2) as the major product. The minor product undergoes cyclization, as expected, to (4). The major product (2), however, on cyclization gives only minor amounts of the expected enone (5). The major products are the two isomers (6) and (7). Evidently the complexed benzene ring activates the a-methylene protons. 

In an attempted explanation, the initial ketyl cyclizes to 2-methyl indanone, which is always detected in the initial stages of the stirred reaction, and the liberated amide base deprotonates the allylic methylene group. The resulting carban-ion cyclizes to a-naphthol. Thus, sonication probably accelerates the formation of the ketyl in such a manner that only cyclization to 2-methyl indanone occurs. If valid, this interpretation would confirm the rule according to which polar processes are not affected by sonication, in contrast to SET reactions. 

Indanone was prepared by chlorosulfonation of indane to give both the 4- and 5-positional isomers (2), which are difficult to separate. However, we could aminate the sulfonylchlorides and metallate the activated methylene of the 4-isomer in the mixture to give, upon quenching with oxygen, the indanol S2. This could be easily separated from any other products, in 25% yield from the sulfonamide mixture (Scheme XI). 

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