Indanones reduction

In order to avoid as far as possible double bond positional isomers, a problem quite common in drugs with indene moieties, N-trityl-2-hydroxymethylmorpholine (23) was reacted with the potassium. salt of 4-hydroxy-1-indanone (24) in DMSO solvent to give condensation product 25 in good yield. Reduction of 25 with LLAIH produced the hydroxyindane which was dehydrated and deprotected with HCl to give indeloxazine (26) [8]. 

This result stands in contrast to hydrogenation of 2-oximino-]-indanone (R = H), which stopped spontaneously at the 2-amino-1-indanol stage under similar conditions (43). This latter result accords with the general exp>erience in reduction of aromatic -oximino ketones (35,37 38,39,40). The amino function usually severely inhibits hydrogenolysis of the alcohol. 

Alkenyl Fischer carbene complexes can serve as three-carbon components in the [6 + 3]-reactions of vinylchro-mium carbenes and fulvenes (Equations (23)—(25)), providing rapid access to indanone and indene structures.132 This reaction tolerates substitution of the fulvene, but the carbene complex requires extended conjugation to a carbonyl or aromatic ring. This reaction is proposed to be initiated by 1,2-addition of the electron-rich fulvene to the chromium carbene followed by a 1,2-shift of the chromium with simultaneous ring closure. Reductive elimination of the chromium metal and elimination/isomerization gives the products (Scheme 41). 

The medicinal chemistry of Alzheimers is complicated by the fact that the etiology of this disease is still far from clear. Evidence points to an association with decreased levels of acetyl choline in the brain. Many of the drugs that have been introduced to date for treating this disease thus comprise agents intended to raise the deficient levels of that neurotransmitter by inhibiting the loss of existing acetylcholine due to the action of cholinesterase. A compound based on an indene that, perhaps surprisingly, inhibits that enzyme has been proposed for the treatment of Alzheimer s. Aldol condensation of piperidine aldehyde (4-2) with the indanone (4-1) from cyclization of 3,4-dimethoxycinnamic acid leads to the olefin (4-3). Catalytic reduction removes the double bond to afford donepezil (4-4) [3]. 

The mechanism of the catalytic cycle is outlined in Scheme 1.37 [11]. It involves the formation of a reactive 16-electron tricarbonyliron species by coordination of allyl alcohol to pentacarbonyliron and sequential loss of two carbon monoxide ligands. Oxidative addition to a Jt-allyl hydride complex with iron in the oxidation state +2, followed by reductive elimination, affords an alkene-tricarbonyliron complex. As a result of the [1, 3]-hydride shift the allyl alcohol has been converted to an enol, which is released and the catalytically active tricarbonyliron species is regenerated. This example demonstrates that oxidation and reduction steps can be merged to a one-pot procedure by transferring them into oxidative addition and reductive elimination using the transition metal as a reversible switch. Recently, this reaction has been integrated into a tandem isomerization-aldolization reaction which was applied to the synthesis of indanones and indenones [81] and for the transformation of vinylic furanoses into cydopentenones [82]. 

A new method [16] for the preparation of donepezil involved the reaction of l-benzyl-4-piperidine-l-carboxaldehyde 1 in the presence of strong base such as lithium diisopropylamide under inert atmosphere with 5,6-dimethoxy-l-endanone 2 followed by reduction of the resulting compound (l-benzyl-4-[5,6-dimethoxy-l-indanon)-2-yli-dinyl]methyl piperidine 3 to give the donepezil HC1 4 according to Scheme 3.4. 

A synthetic method for preparation of donepezil comprised the condensation of 5,6-dimethoxy-l-indanone 1 with l-benzyl-4-piperidine-carboxaldehyde 2 followed by reduction of the obtained compound 3 and the column chromatography of the crude donepezil base on silica gel [17], according to Scheme 3.5. 

A total synthesis of dihydrolycorine (85), y-lycorane (87) and 8-lyco-rane (92), has been achieved starting from the indanone carboxylic acid 77. This, in turn, was obtained, like the tetralone ester 76, from the known anhydride (75) via Friedel-Crafts cyclization of the monomethyl esters obtained from 75 by treatment with 1 mole of methanol. Reduction of the methyl ester of 77 (LiAlH4), followed by Mn02 oxidation,... 

Racemic substituted aminoindanol 9 was synthesized in a 5-step sequence by nitration of 1-indanone, followed by ketone reduction and dehydration to give 6-nitro-l-indene and subsequent epoxidation of the olefin and final regioselective animation (Scheme 8.5). Optically pure (IR,2R)-and (1 S,2S)-6-nitro-1 -amino-2-indanol 9 were eventually obtained by resolution with mandelic... 

The photostimulated reactions with the enolate anions of 1-indanone and a-tetra-lone lead to the reduction product benzamide (23% and 44%, respectively), together with the target fused isoquinolinones (51% and 42%, respectively) [65]. The formation of benzamide can probably be ascribed to the hydrogen atom abstraction from the cyclic ketone. 

In 1993, Bolm reported that these reactions could be performed using catalytic quantities (10 mol%) of the chiral P-hydroxy sulfoximine.132 The enantiomeric purities of the product alcohols ranged from 52% (1-indanone) to 93% (PhCOCHjOSiRj). In many cases the enantiomeric purities were enhanced using sodium borohydride as reductant in the presence of chlorotrimethylsilane.133 These methods have been extended to the asymmetric reductions of imines.134 /V-SPh-substituted imines gave the highest enantioselectivities and these reductions proceeded in the same stereochemical sense as the reductions of ketones. 

Indanyl)-phenol 16 was obtained by reacting p-methoxy-phenyl-acetic acid ethyl ester with benzylchloride to form a-benzyl-p-methoxyphenyl ethyl acetate, saponification into the acid, conversion of the acid with thionylchloride into the chloride, cyclization to 2-p-methoxy-phenyl-l-indanone, NaBH4 reduction to 2-p-methoxyphenyl-l-indanole, dehydration with p-toluene-sulphonic acid in toluene to 2-p-methoxyphenyl-indene, catalytic hydrogenation to 2-p-methoxyphenyl-indene, and treating the ether with HBr [Eq. (5)]. 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

Metal-alcohol reductions of substituted indanone (73 equation 20) which afford mixtures of alcohols (74) and (75) have been described. Although alcohol (75) is the more stable isomer, Li and Na both afford alcohol (74) as the major reduction product (74 75 = 60 40). Aluminum gives a (74) (75) ratio of 90 10, but with K it is 30 10. Prolonged (12 h) heating of the A1 and K reactions changes the ratios to (70) (30) and (10) (90), respectively. It is apparent that some equilibration is occurring under these conditions, but it is not clear if the results after 3 h represent partial equilibration or if they are truly the result of kinetically controlled reductions. 

Indanones also undergo reductive alkylation, although not as well as 1-tetralones. Good yields were obtained with methyl iodide and 1-indanone as well as its 4-, 6- or 7-methoxy derivatives to give the di-hydroindanones (173) to (176). ... 

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