Isopropylidene malonate reactions with

These model reactions were of great value in the extension of the C-glycosylation reaction with malonic esters to five-membered ring-systems. Treatment of 2,3 5,6-di-O-isopropylidene-a-D-manno-furanosyl bromide122,123 (150) with diethyl sodiomalonate led to an anomeric mixture of C-glycosyl compounds that could be separated by column chromatography, with the a (151) and /B (152) anomers in... 

Potent nucleophiles can be generated from C-H acidic compounds by deprotonation. Diethyl malonate reacted with diethyl cyclopropane-1,1-dicarboxylate (1) in the presence of sodium ethoxide to give tetraethyl butane-1,1,4,4-tetraoate (2). Isopropylidene cyelo-propanedicarboxylate (3) underwent an analogous reaction when treated with dimethyl malonate or methyl 2-oxocyclohexanecarboxylate. ... 

Chiral allylic cyclic carbonates such as 551 or 552 undergo excellent regioselective alkylation reactions with soft nucleophiles in the presence of palladium(O) in refluxing THF to provide ( )-allylic alcohols. The reaction of 4-0-benzyl-2,3-isopropylidene-L-threose (167) with the appropriate ylid, followed by deprotection of the isopropylidene ring with acidic resin and cyclic carbonate formation, provides a good overall yield of either 551 or 552. Ring opening with diethyl malonate in the presence of tetrakis(triphenylphosphine)palladium(0) provides in excellent yield the allylic alcohols 553 or 554, where the diastereoselectivity exceeds 99%. This reaction represents an efficient method of 1,3-chirality transfer [180] (Scheme 122). 

The first milder method for this transformation, developed by Buchwald and Hennessy in 2002 [66], employed CuI/2-phenylphenol as a catalytic system to perform the arylation of diethyl malonates. The reaction worked well at 70 °C, but for some substrates such as isopropylidene malonate, l,3desired products were observed. In addition, only aryl iodides were compatible with these reaction conditions. 

The synthesis of derivatives of L-iduronic acid from 1,2-0-isopropylidene-a-D-xy/o-pentodialdo- 1,4-furanose by way of an acetylenic intermediate is mentioned in Chapter 12 (see Scheme 58). A related sequence of reactions with methyl 2,3-0-isopropylidene-P-D-nho-pentodialdo-l,4-furanoside has furnished methyl (methyl 2,3-0-isopropylidene-a-L-talofuranosid)uronate and its P-D-a//o analogue from acetylenic precursors. Malonic acid reacted with methyl 2,3-0-isopropylidene-P-D-riho-pentodialdo-l,4-furanoside to give the unsaturated uronic acid derivative (420). 

Microwaves also provide an easy access to 2-alkyl and 2-aryl-4-quinolones by the addition-elimination reaction of 5-methylthioalkylidene isopropylidene malonates with arylamine, followed by cyclization (Huang et al., 2000). A condensation, addition, cyclization and elimination reactions of aromatic aldehydes, 5,5-dimethyl-l,3-cyclohexandione and isopropylidene malonate afforded a series of 4-aryl-7,7-dimethyl-2, 5-dioxo-l,2,3,4,5,6,7,8-octahydroquinoline and 4-aiyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydroconmarin under microwaves only in 3-5 min (Tu et al., 2002). Basic silica gel (NaOH/SiO ) in solvent-free conditions and microwave exposure acts as a very efficient medium for the p-elimination (dehydrosulfe-nylation) of sulfoxides (Moghaddam and Jamshidi, 2001). 

Isopropenyl Acetate as a Source of Acetone. Under certain reaction conditions, isopropenyl acetate reacts to deliver an equivalent of acetone for acetonide formation or for oxidative addition to an enol. Under acidic conditions, isopropenyl acetate has been used to generate isopropylidene derivatives of malonic acids. Isopropenyl acetate also undergoes an oxidative addition reaction with ketones in the presence of Manganese(IlI) Acetate An acetone subunit is added to the a-position of a ketone to give a 1,4-diketone. 

The reaction of 2-aminothiazole and isopropylidene bis(methylthio)-methylenemalonate (459, R2 = R3 = SMe) or 1-methylthioalkylidenema-lonates (459, R2 = Me, Et, Ph R3 = SMe) in boiling ethanol for 2.5 hr or in dimethylformamide at 120-130°C for 4-5 hr, gave 2-substituted 5-oxo-5//-thiazolo[3,2-a]pyrimidine-6-carboxylates (462) in good yields (89S-317). Similarly, in boiling ethanol, 2-substituted 4-oxo-4//-pyrido[l,2-a]-pyrimidine-3-carboxylic acids (463) were obtained in 80-85% yields. When anilines were reacted with isopropylidene bis(methylthio)methy-lenemalonate (459, R2 = R3 = MeS), (methylthio)(arylamino)methylene-malonates (464) were obtained 61-88% yields. 

Dhimane et al. studied the flash vacuum pyrolysis of isopropylidene [l-(a>-chloroalkyl)-l-azacycloalk-2-ylidene]malonates (1274) at 570°C and 1CT4 torr (87TL885 89T6161) (Scheme 52). They obtained bicyclic esters (1276) in 35-45% yields when the pyrolytic products were condensed on a cold finger at -196°C, covered with methanol, and triethylamine was introduced at the end of the reaction. Pyrolysis of the pyrrrolidine derivative (1274, n = 0, m = 1) without methanol on the cold finger afforded the bicyclic carboxylic chloride (1275, n = 0, m = 1), which was converted to ester (1276, n - 0, m = 1) by treatment with a mixture of methanol and triethylamine. 

Isopropylidene [l-(3-chloropropyl)piperidin-2-ylidene]malonate (1624) in refluxing ethanol in the presence of boron trifluroide etherate was transformed into ethyl [l-(3-chloropropyl)piperidin-2-ylidene]acetate (1625) in 90% yield (87H2335, 89T6161). Similar reaction was also carried out with isopropylidene [l-(2-chloroethyl)pyrrolidin-2-ylidene]malonate (89T6161). 

Thermal cyclization of the isopropylidene ester of the malonates (70) was accompanied by decarboxylation at position 3, whereby 4-oxo-4H-pyrido-[l,2-fl]pyrimidines (74 R1 = H) were obtained.79,142,143 When the cyclization was performed in phosphoryl chloride-polyphosphoric acid and the reaction mixture was treated with alcohol, 4-oxo-4H-pyrido[l,2-a]pyri-midine-3-carboxylic acid esters were isolated.151 Treatment of the reaction mixture with water gave carboxylic acids. 

B. Ethyl a.-(hexahydt oaaepinylidene-S)aoetate. A solution of sodium ethoxide is prepared from 8.3 g (0.36 mol) of freshly cut sodium and 600 mL of freshly distilled absolute ethanol (Note 5) in a 1-L, round-bottomed flask equipped with a magnetic stirrer and fitted with a reflux condenser. To the stirred solution is added in one portion 71.7 g (0.30 mol) of freshly recrystallized isopropylidene a-(hexahydroazepinylidene-2)malonate. The mixture is refluxed and a white precipitate begins to appear. Refluxing is continued for 12 hr. The solvent is removed with a rotary evaporator and the white precipitate is placed in a 2-L beaker. Water (300 mL) is added and a 1 N hydrochloric solution is added dropwise to pH 6. The reaction mixture is extracted with four 100-mL portions of chloroform. The extracts are dried over anhydrous sodium sulfate and the solvent is removed with a rotary evaporator. The yellow solid residue is recrystallized from methanol to give 43-44 g (78-80%) of white powder, mp 55-56 C (Note 6). 

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