2- Indanone

Submitted by J. E. Horan and R. W. Schiessler.1 Checked by William E. Parham, Wayland E. Noland, and Abdel-Moneim M. Makky. 

In a 2-1. three-necked flask fitted with stirrer, dropping funnel, and thermometer are placed 700 ml. of formic acid (88%) and 140 ml. of hydrogen peroxide (30%, 1.37 moles). While the temperature is kept at 35-40° (Note 1), 116.2 g. (117.3 ml., 1.00 mole) of indene (98%) (Note 2) is added dropwise, with stirring, over a period of 2 hours. An additional 100 ml. of formic acid is used to rinse the last of the indene from the dropping funnel into the reaction flask. The reaction solution is stirred at room temperature for 7 hours to ensure complete reaction (Note 3). The solution is transferred to a 2- or 3-1. Claisen flask, and the formic acid is removed under aspirator pressure (b.p. 35-40°/20-30 mm), care being taken to maintain the boiler temperature below 60° (Note 4). The residue, after being cooled to room temperature, is a yellowish brown crystalline solid (Note 5), the color being due to contamination by a small amount of brownish oil. 

In a 5-1. flask fitted with a long condenser (about 40 cm.) connected to an ice-cooled receiver is placed 2 1. of 7% (by volume) sulfuric acid. The solution is heated to boiling, and the crude monoformate of 1,2-indanediol is added. Steam is introduced and the mixture is steam distilled, while external heat is applied with a flame in order to maintain the boiler contents at a constant volume of 2 1. The steam distillation is carried out at the rate of about 1 1. per hour until 5-6 1. of distillate have been collected and the 2-indanone has stopped distilling (Note 6). The dark-brown oily residue becomes semisolid at room temperature. 

The cold distillate is filtered with suction, and the white crystalline solid is sucked thoroughly dry on the filter (Note 7). The crystals are dried further in a vacuum desiccator (at about 1 mm.) at room temperature or below for about 12 hours. The melting point of the 2-indanone is 57-58° (Note 8). The yield is 90-107 g. (69-81%). 

This is the best temperature at which to control the reaction. At higher temperatures, the reaction becomes too vigorous. 

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Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

Quinolin-2-one, 3-cyano-4-hydroxy-synthesis, 2, 428 Quinolin-2-one, 3,4-dialkyl-Knorr synthesis, 2, 425 Quinolin-2-one, dihydro-Camps synthesis, 2, 418 synthesis, 2, 402 from benzazepinones, 2, 506 from indanone oxime, 2, 487 from indanones, 2, 488 by intramolecular Friedel-Crafts reactions, 2, 421... 

Dimethoxy-l-indanone [2107-69-9] M 192.2, m 118-120 . Crystd from MeOH, then sublimed in a vacuum. 

Perfluoroindene and 3-chloroperfluoroindene both react with fuming sulfuric acid [27] However, whereas the former gives only heptafluoro-l-indanone-2-sul-fonic acid (equation 29), the latter yields both this product and 3-chloropenta-fluoromdanone (equation 30). 

Prepai ation ot 2-Fluoro-l -indanone, 166 Tetrabutylammonium Fluoride Preparation, 193... 

An unusual cyclization, which results in carbocycles rather than heterocycles, was described in (69JCS2453). The reaction between o-iodobenzamides and copper phenylacetylides in pyridine leads to indanone (74%) rather than tolane (Scheme 124). 

Schmidt reaction of indanones 803 by treatment with HN3-BF3 etherate gave 4,5-dihydro[5,l-a]tetrazoloquinoline 804 (92IJC(B)610)) (Scheme 142). 

Alkylation of 1-indanone with 2-dimethylaminoethyl chloride affords the substituted ketone (1). Condensation with the lithium reagent obtained from 2-ethylpyridine affords the alcohol (2). Dehydration under acidic conditions gives dimethyl-pyrindene (3). ... 

A rather simple derivative of 1-indanone itself has been reported to possess analgesic activity. This is particularly noteworthy in that this agent, drindene ( ),... 

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]. 

The carboxylation of ketones is carried out essentially as in the preceding experiment, but at slightly higher temperatures (requiring an oil bath or mantle). Thus, acetophenone (6 g, 0.05 mole) in 100 ml of approx. 2 M MMC is stirred and heated at 110-120° for 1 hour. After cooling, hydrolysis in the acid-ice mixture, and isolation from ether, benzoylacetic acid, mp 99-100°, is obtained in 68% yield. Similarly, 1-indanone gives l-indanone-2-carboxylic acid, mp 100-101°, in 91 % yield. 

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. 

The Fries rearrangement can be viewed as a type of Friedel-Crafts acylation reaction. Two examples of this reaction are given in Scheme 5.1-61. The first is the rearrangement of 4,4 -diacetoxybiphenyl to 4,4 -dihydroxy-3,3 -diacetoxybiphenyl in a NaCl/AlCl3 (X(A1C13) = 0.69) molten salt [93]. The second example is the rearrangement of phenyl 3-chloropropionate to 2 -hydroxy-3-chloropropiophenone, followed by cyclization to an indanone [94]. 

When phthalates are added to a solution of sodium methoxide in DMSO 2-(methanesulphinyl)-l,3-indanone 469 is readily formed541 (equation 280). 

Imidazoles 775 /J-Iminosulphones 640 /J-Iminosulphoxides, synthesis of 69 Inclusion compounds 59, 287 Indanols 256 Indanones 338 Indenes 267 Indoles 323... 

In 1986 Yamashida et al. found that the reaction of the (morpholino)phenyl-carbene complex 46 with symmetric alkynes 47 gave the morpholinylindene derivatives 48 and 49, as well as the indanones 50 derived from the latter by hydrolysis, in excellent yields (Scheme 9) [54]. This contrasts with the behavior of the corresponding (methoxy)phenylcarbene complex, which solely undergoes the Dotz reaction [55]. This transformation of the amino-substituted complex 46 apparently does not involve a CO insertion, which is an important feature of the Dotz benzannelation. 

The unconventional structure of fulvenes with a unique C=C bond conjugation leads to unusual cycloaddition reactions with other unsaturated systems. For example, alkenylcarbene complexes react with fulvenes leading to indanone or indene derivatives which can be considered as derived from a [6S+3C] cycloaddition process [118] (Scheme 72). The reaction pathway is well explained by an initial 1,2-addition of the fulvene to the carbene carbon followed by [1,2]-Cr(CO)5-promoted cyclisation. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

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