Methylcyclopentane-1,3-dione

Submitted by Joseph P. John, S. Swaiunathan, and P. S. Venkataramani 1 Checked by J. A. Berezowsky and Peter Yates 

2-Methyl-4-eihoxalylcyclopenlane-l,3,5-trione. A solution of sodium ethoxide is prepared in a 2-1. three-necked, round-bottomed flask fitted with a mercury-sealed stirrer, a reflux condenser carrying a drying tube, and a stopper by the addition of 69.0 g. (3 moles) of sodium to 950 ml. of absolute ethanol. The solution is cooled to 0-5° in an ice bath and stirred. The stopper is replaced by a dropping funnel, and a cold mixture (5-15°) of 108 g. (1.50 moles) of freshly distilled 2-butanone and 482 g. (3.30 moles) of diethyl oxalate (Note 1) is added gradually over a 

2-Methylcyclopenlane-l,3,5-trione hydrate. A mixture of 200 g. (0.89 mole) of the keto ester prepared above, 910 ml. of water, and 100 ml. of 85% phosphoric acid is healed under reflux for 4 hours and then cooled in an ice-salt bath to —5°. The trione mixed with oxalic acid separates and is collected by filtration and dried under reduced pressure. The dried material is extracted with boiling ether (250-300 ml.) under reflux, and the ethereal extract is separated from the undissolved oxalic acid. The original aqueous filtrate is also extracted with ether in a continuous extractor. The two extracts are combined, and ether is removed by distillation. The crude trione separates as a dark brown solid and is crystallized from ca. 250 ml. of hot water. The once-crystallized, faintly yellow product weighs 95-105 g. (74-82%), m.p. 70-74°. This product is used in the next step without further purification. A better specimen, m.p. 77-78°, which is almost colorless, can be obtained by recrystallization from hot water after treatment with Norit activated carbon. 

2-Methylcyclopentane-l,3,5-trione 5-semicarbazone. The above trione hydrate (144 g., 1.00 mole) is dissolved in a mixture 

Eastman Organic Chemicals or B.D.H. Laboratory reagent grade diethyl oxalate was used. 

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Reaction of the heterocycle with 2-methylcyclopentane-1,3-dione in the presence of pyridine leads directly to tetracyclic intermediate 20. 5 The first step in this transformation probably consists in formation of the olefin 18 by elimination of dimethylamine. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

Azasteroids.p-Toluenesulfonic acid added to a soln.of2-[2 -(l,2,3,4-tetrahydro-7-methoxy-N-tosyl - 4 - quinolylidene) ethyl] -2 - methylcyclopentane-1,3 - dione in benzene, and gently refluxed 10 min. at an oil bath temp, of 100-110° dl-N-tosyl-6-azabisdehydro-8,14-estrone methyl ether. Y 75%. H. O. Huisman, W. N. Speckamp, and U. K. Pandit, R. 82, 898 (1963). 

A mixture of 2-butanone and 2.2 moles diethyl oxalate added gradually at 0-5° during 0.5 hr. to a stirred soln. of Na in ahs. ethanol, allowed to warm to room temp, with continued stirring, and refluxed 0.5 hr. crude 2-methyl-4-ethoxalylcyclopentane-l,3,5-trione (Y 53-59%) refluxed 4 hrs. with aq. phosphoric acid crude 2-methylcyclopentane-l,3,5-trione hydrate (Y 74-82%) allowed to react with semicarbazide hydrochloride and Na-acetate in ethanol-water crude 2-methylcyclopentane-l,3,5-trione 5-semicarbazone (Y 60-66%) added at 130° during 30-40 min. to KOH, ethylene glycol, and water, then heated ca. 0.5 hr. at 150° and ca. 2 hrs. at 180-185° 2-methylcyclopentane-1,3-dione (Y 60-67%). J. P. John, S. Swaminathan, and P. S. Venkataramani, Org. Synth. 47, 83 (1967) improved procedure s. Z. G. Hajos, D. R. Parrish, and E. P. Oliveto, Tetrahedron 24, 2039 (1968). 

Methylcyclopentane-l,3-dione has been prepared in 15% yield by the catalytic reduction of 2-mcthylcyclopentane-l,3,5-trione over platinum.2 The present method is based on the original procedure 3 of Panouse and Sannie with improvements as effected by Boyce and Whitehurst4 and the submitters.6... 

A similar reaction occurs with 2-methylcyclopentane-l,3-dione,176 and can be done enantioselectively by using the amino acid L-proline to form an enamine intermediate. The (S)-enantiomer of the product is obtained in high enantiomeric excess.177... 

Acetyl-4-methylcyclopentane-1,3-dione, 52, 4 Acid anhydride, mixed, with... 

The retrosynthetic process (Scheme 6.2) involves the following operations i) substitution of the conjugated double bond by an OH group ii) retro-aldol disconnection of the 1,3-C system, and iii) disconnection at the a-position of the resulting 1,4-D system which leads to 2-methylcyclopentane-l,3-dione and an umpoled three-carbon atom fragment. This retrosynthetic process offers, however, only a theoretical scheme which, in practice, presents some difficulties. For example. Table 5.1 gives 2-nitropropene (3) as a possible equivalent of the umpoled C3 fragment, in which case the process in the synthetic direction would be as... 

The diacylation of isopropenyl acetate with anhydrides of dicarboxylic acids is applicable for the synthesis of several other cyclic jS-triketones in moderate yield. - It has been used for the synthesis of 2-acetylcyclohexane-l,3-dione (40% yield), 2-acetyl-4-methylcyclopentane-l,3-dione (10% yield), 2-acetyl-4,4-dimethylcyclopentane-l,3-dione (10% yield), 2-acetyl-5,5-dimethylcyclohexane-l,3-dione (10% yield), 2-acetylcyclo-heptane-l,3-dione (12% yield) and 2-acetylindane-l,3-dione (26% yield). Maleic anhydrides under more drastic conditions give acetylcyclopent-4-ene-l,3-diones in yields from 5% to 12%. The corresponding acylation of the enol acetate of 2-butanone with succinic anhydride has been used to prepare 2-methylcyclopentane-l,3-dione, an important intermediate in steroid synthesis. - ... 

A modification of this method utilizes the direct conversion of l,2-bis(trimethyl-siloxy)cyclobutene in one step to 2,2-disubstituted cyclopentane-1,3-diones. For example, 2-ethyl-2-methylcyclopentane-l,3-dione (3) was obtained in 91% yield from 1.2-bis(trimethyl-siloxy)cyclobutene and butan-2-one 2,2-dimethylpropane-l,3-diyl acetal.41 Further examples... 

Cyclopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcyclopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsuccinate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic add or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

During the reductive isomerization of 7/3-methyl- 14-isoestr-4-ene-3,17-dione 272 in HF SbF5/methylcyclopentane at 0°C, it was found879 that a 1,3-hydride shift occurs followed by kinetically controlled hydride transfer (Scheme 5.91). The mechanism of the reaction was confirmed by employing the deuteriated donor cyclohexane- as well as a specifically deuterium-labeled starting steroid. 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

The third group of cyclic compounds formed by intramolecular carbanion addition to the carbonyl group are the target molecules 5,5-dimethylcyclo-hexane-l,3-dione (dimedone, 30) and 3-methylcyclopentane-l,2,4-trione (31). 

Maple Svrup. The typical flavor of maple syrup which originates during the heat concentration of maple sap in the presence of air has also been extensively investigated (70-80). Important sugar-based degradation products present in maple syrup include 3-methylcyclopentane-l,2-dione and 2,5-dimethyl-4-hydroxy-3(2H)-furanone. 

Methylcyclopentane-l,3-dione has found increasing use as an intermediate in the synthesis of steroids.6-12 The method described is the only practicable method available for the preparation of 2-methylcyclopentane-l,3-dione in large amounts. 

Compounds of special interest whose preparation is described include 1,2,3-benzothiadiazole 1,1-dioxide (a benzyne precursor under exceptionally mild conditions), bis(l,3-diphenylimida-zolidinylidene-2) (whose chemistry is quite remarkable), 6-(di-methylamino)fulvene (a useful intermediate for fused-ring non-benzenoid aromatic compounds), diphenylcyclopropenone (the synthesis of which is a milestone in theoretical organic chemistry), ketene di(2-melhoxyethyl) acetal (the easiest ketene acetal to prepare), 2-methylcyclopentane-l,3-dione (a useful intermediate in steroid synthesis), and 2-phenyl-S-oxazolone (an important intermediate in amino acid chemistry). 

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