Dimethyl acetone dicarboxylate

Irie and co-workers (37) have recently observed that the double Michael reaction of dimethyl acetone dicarboxylate on dienone 104 gave the cis decal-in product 106. This result indicates that intermediate 105 underwent a stereoelectronically controlled internal Michael addition to give 106. Without stereoelectronic control in the Michael reaction, there is no apparent reason to prevent the formation of the trans isomer 107. However, if this factor is taken into consideration, examination of molecular models indicates that it seems impossible to obtain isomer 107. 

Stevens and Lee (28) have reported an elegant synthesis of coccinelline (69). Treatment of 66 at pH=l gave intermediate 67 which was then treated with dimethyl acetone dicarboxylate at pH=5.5 to give a single tricyclic isomer, the ketodiester 68, in 75% yield. Compound 68 was then converted into coccinelline (59). This result shows that the Robinson-Schopf reaction (29, 30) can take place with a remarkable control of stereochemistry. 

Consequently, the condensation of 67 with dimethyl acetone dicarboxyl ate must yield the trans intermediate 74 which after conversion into 75 can be transformed, again with stereoelectronic control, into the cis-trans tricyclic ketodiester 68. 

The methoxycarbonylmethyl radical I is obtained by Kolbe electrolysis from methyl-malonate [Eq. (4, path a)], and in homogeneous solution by reductive fragmentation of the hydroperoxide of dimethyl acetone dicarboxylate [Eq. (4, path b)]. Radical I forms with styrene the adduct II, which reacts by disproportionation to III and IV, by coupling with I to V and by dimerization to VI. The yields and product ratios for the electrolysis and the reductive fragmentation correspond surprisingly well, and no extensive polymerization was found for the homogeneous reaction. 

The horizontal approach for the DEF synthon was more rewarding due to its simplicity and more importantly due to its straightforwardness. The easily obtainable acetylene precursor 107 underwent synchronous Michael-aldol condensation reaction with dimethyl acetone dicarboxylate to give 108 which was smoothly transformed into 86a (Scheme 22). 

In an alternative approach [89], the known compound 110 and dimethyl acetone dicarboxylate were condensed in the presence of a base and the resulting isocoumarin derivative 111 was taken to 112 (Scheme 23). 

To a mixture of 360 g 50% KOH and 138 ml methanol, add with stirring at -5° 70.5 g dimethyl ester of acetone dicarboxylic acid (dimethyl-beta-ketoglutarate — see method 3 for preparation) and let temperature rise to about 25° over V2 hour. Let stand ten minutes, cool to 0° and add 65 ml ether. Filter, wash precipitate with 65 ml ethanol and 150 ml ether at 0C to get 75 g (III). To 322 ml 1N HCI at 80c, add 41.1 g (I I) and stir twenty minutes cool to 10°, add 211 ml IN HCI, 98.2 g (Ml). 26.4 g Na acetate and 28.2 g methylamine HCI. Stir four hours at room temperature, cool to 10°, and saturate with 410 g KOH. Extract four times with methyl-Cl or benzene (75 ml each, fifteen minutes stirring) and evaporate in vacuum to get the methyl ester of tropan-3-one-2-COOH (IV), which precipitates from the oil (can distill 85/0,2). Test for activity. Dissolve 28.3 g (IV) in 170 ml 10% sulfuric acid cool to -5° and treat with 3.63 kg 1.5% Na-Hg amalgam with vigorous stirring at 0°. See below for easier methods of reducing (IV),... 

The first naphtho[a]cyclopropene 68d was also obtained by that route. 3H-indazole was proposed as an intermediate in this reaction 78>. The reaction proceeds equally well from the triplet state of 7. However with acetone light capture from the sensitizer may not have been complete. A trapping of the diradical intermediate 67 to give the known indene 69 by photolysing 7 in dimethyl-acetylene-dicarboxylate (ADC) afforded only a trace of 69. However the yield of 68a was reduced to 40%. Either trapping of 67 was not effective enough or ADC may have acted as quencher. Trapping with furan or cyclopentadiene was also not effective 78a). 

Two pathways for the preparation of 1,4-dihydropyridazine derivatives were envisaged. According to the first, dimethyl 3-oxopentane-l,5-dioate (dimethyl acetone-1,3-dicarboxylate) (1) was treated in ethanol and sodium acetate at 0 °C with acidic aqueous diazonium salts, prepared from aromatic or heteroaromatic amines, to give hydrazones 69 in 35-94% yields. They were next treated with DMFDMA in dichloromethane at room temperature to form the (dimethylamino) methylidene derivatives 70 as intermediates, which immediately cyclized into dimethyl 1 -(hetero)aryl-4-oxo-l, 4-dihydropyridazine-3,5-dicarboxy-lates 71 in 72-94% yields, except for 71 (R=lH-l,2,4-triazol-3-yl), which was obtained in 35% yield (08ZN(63b)407) (Scheme 23). 

Dimethyl acetone-l,3-dicarboxylate (1) reacts with benzamidine to form methyl 2-(6-hydroxy-2-phenylpyrimidin-4-yl)acetate (72). With DMFDMA in refluxing toluene the reactive methylene group of 72 was transformed into an N,N-dimethylaminomethylidene derivative. While methylation of the hydroxyl group was taking place to give methyl (E)-3-(dimethylamino)-2-(6-methoxy-2-phenylpyrimidin-4-yl)propenoate (73) (Scheme 24). 

Methyl 2-amino-4-(2-methoxy-2-oxoethyl)thiazole-5-carboxylate (80), prepared from dimethyl acetone-l,3-dicarboxylate (1), sulphuryl chloride and thiourea (46JA266), was transformed with DMFDMA into methyl 4-[l-(dimethylamino)-3-ethoxy-3-oxoprop-l-en-2-yl]-2-[(dimethylamino) methyleneamino]thiazole-5-carboxylate (81) in 96% peld (Scheme 27). Thiazole 64 was treated with 2-aminopyridine in hot ethanol to )deld... 

The Hantzsch pyrrole synthesis was employed to prepare pyrrole-2-acetic acids as anti-inflammatory agents. A transient precipitate of a white crystalline solid was formed when diethyl acetone-dicarboxylate was mixed with aqueous methylamine. After chloroacetone was added rapidly with cooling before the disappearance of the precipitate, a good yield of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate was produced. Further functional group transformations then produced pyrrole-2-acetic acids as anti-inflammatory agents. 

Treibs and Ohorodnik [4] prepared this ring system by the reaction of ethyl 2-methyl-4-hydroxypyrrole-3-carboxylate (IV) with ethyl acetoacetate (EAA) in the presence of sodium ethoxide and in this way ethyl 2,6-dimethyl-7-oxopyrano[3,2-b]pyrrole-3-carboxylate (V) was prepared. A similar reaction of (IV) with acetone dicarboxylic ester (ADE) gave (VI), but, no yields were given for either reaction. 

IsoxazoIidine-3,3-dicarboxylic acid, 2-methoxy-dimethyl ester reaction with bases, 6, 47 Isoxazolidine-3,5-diones synthesis, 6, 112, 113 Isoxazoli dines conformation, 6, 10 3,5-disubstituted synthesis, 6, 109 oxidation, 6, 45-46 PE spectra, 6, 5 photolysis, 6, 46 pyrolysis, 6, 46 reactions, 6, 45-47 with acetone, 6, 47 with bases, 6, 47 reduction, 6, 45 ring fission, S, 80 spectroscopy, 6, 6 synthesis, 6, 3, 108-112 thermochemistry, 6, 10 Isoxazolidin-3-ol synthesis, 6, 111 Isoxazolidin-5-oI synthesis, 6, 111... 

Dimethyl 2,3-pentadienedioate has also been prepared from the enol phosphate of diethyl acetone-1,3-dicarboxylate. ... 

A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of aminocrotonic acid methyl ester, and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100°C in an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20 1 mixture of chloroform and acetone. The effluent containing the subject product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone and after adjusting the solution with an ethanol solution saturated with hydrogen chloride to pH 1 -2, the solution was concentrated to provide 2 g of 2,6-dimethyl-4-(3 -nitrophenyl)-1,4-dihydropyridlne-3,5-dicarboxylic acid 3-methylester-5- -(N-benzyl-N-methylamino)ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone mixture, melting point 136°Cto 140°C (decomposed). 

The oxidation of dimethyl 3-methyl-3//-3-benzazepine-2,4-dicarboxylate (1) with potassium permanganate in acetone solution brings about destruction of the azepine ring and formation of phthalic anhydride (2).24... 

Oxidation of dimethyl l-phenyl-2-oxo-l,2-dihydro-llb//-pyrimido[2,l-a]-isoquinoline-3,4-dicarboxylate (64) by potassium permanganate either in acetone or in aqueous potassium hydroxide, followed by treatment with ethereal diazomethane, gave isocarbostyril and methyl oxanilate, respectively (67CB1094). Oxidation of 4-phenyl-2//-pyrimido[2,l-a]isoquinolin-2-one with potassium permanganate in a 1 5 mixture of pyridine and 2 N potassium hydroxide yielded 2-(2-carboxyphenyl)-6-phenylpyrimidin-4(3//)-one (72CB108). 2-Methyl-4//-pyrimido[2,l-a]isoquinolin-4-one and 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione with potassium permanganate afforded phthalimide in low yield. 

The amino moiety of the 3-carbohydrazide group of unsaturated and 6,7,8,9-tetrahydro-4-oxo-47/-pyrido[l,2-n]pyrimidine-3-carbohydrazides was condensed with acetone and 5-nitro-2-furoaldehyde (830MR687 88EUP252809). The reaction of 6-methyl-6,7,8,9-tetrahydro-4-oxo-4//-pyrido[l,2-a]pyrimidine-3-carbohydrazide with diethyl 2-[2-dimethyl-amino)vinyl]-6-methylpyridine-3,5-dicarboxylate in boiling ethanol for 4 hours afforded N-( 1,6-naphthyridin-6-yl)-4-oxo-4//-pyrido[ 1,2-a]pyrimi-dine-3-carboxamide 426 (85MIP1). 

The l,4-dihydro-2,6-dimethyl-4-(2- or 3-nitrophenyl)-3,5-pyridine-dicarboxylate derivatives nifedipine (NF), nitrendipine (NT), and nimodipine (NM) were supplied by Bayer AG (Wuppertal, Germany). Analytical grade reagents were used at all times, toluene AR (Riedel-de-Haen AG, Seelze, Germany) was distilled over a 50 cm Vigreux column before use. Sodium hydroxide, 0.5 mol/L, was purchased from J.T. Baker Chemical Corp. (USA) and the amber screw-cap autosampler bottles (2 mL) were obtained from Pierce Biotechnology Inc. (Rockford IL USA) and rinsed with acetone before use. 

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