Nitro malonates preparation

Dioxo-6-nitro-cyclam was prepared by reaction of 2-nitro-malonic ester with 2,3,2-tet, and reduced to 6-amino-cyclam.75 6,13-Dinitro-5,7,12,14-tetramethyl-l,4,8,l 1-tetraazacyclotetradeca-l,5,7,12-tetraene)copper(II) was prepared by reaction of bis(3-nitro-2,4-pentanedionato)Cun with en (cf. (37)).76... 

Z-Furan. 3-(5-Nitro-2-furanyl)-2-propenamide, is prepared by condensation of 5-nitro-2-furancarboxaldehyde diacetate with malonic ester followed by PCl chlorination and amination (29). The product was marketed in Japan as a food preservative. 

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

This reaction was easily performed with malonic ester derivatives using approaches described above for nitro carbanions. It should be noted that the anion of malonic ester can be prepared not only by the reactions of bases with malonates but also by desilylation of silyl ketene acetal (449) with fluoride anion. 

Diethyl (5-nitro-2-pyridyl)malonate was prepared in the reaction of 5-... 

When (3-substituted phenyl)aminomethylenemaIonate (1163, 3-R = H) was applied, a mixture of 5-substituted and 7-substituted 4-hydroxyquino-lines (1164, 5-R + H and 7-R + H) was obtained. For example, the thermal cyclization of (3-nitrophenyl)aminomethylenemalonate in dibenzyl ether at 250°C afforded a 3 1 mixture of 7-nitro- and 5-nitro-4-hydroxy-quinolines (1164, R = 7-N02 and 5-NO ). 4-Hydroxyquinolines (1164) could also be prepared when a mixture of anilines, triethyl orthoformate, and isopropylidene malonate was slowly heated to 100°C in Dowtherm A, stirred over a period of 30 minutes, and then raised to a temperature of... 

CB585). In addition to the reductive cyclization included in Table 11, 1-hydroxyindole-2-carboxylate can also be prepared by base-catalyzed cyclization of dimethyl o-nitrobenzyl-malonate, a reaction which is formulated as involving a nucleophilic attack on the nitro group 72CRV627). 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Reaction of 3,4-dihydro-7-nitro-2//-l, 4-benzoxazine-4,5-dicarboxylic anhydride with diethyl malonate in the presence of 60% NaH in N, yV-dimethylacetamide at 120°C afforded ethyl 7-hydroxy-9-nitro-5-oxo-2,3-dihydro-5//-pyrido[l,2,3-cte]-l,4-benzoxazine-6-carboxylate (93MIP4). 9-Chloro-2,3-dihydro-7-hydroxy-6-(jV,./V-disubstituted thiocarbamoyl)-5//-pyrido[l,2,3-de]-l,4-benzoxazin-5-ones were prepared from 7-chloro-3,4-dihydro-2//-1,4-benzoxazine-4,5-dicarboxylic anhydride with 3-(N,N-disubstituted amino)-3-thioxopropionates in the presence of 60% NaH in yV,yV-dimethylacetamide (95MIP5). 

Spiro-biscyclam (133) has been prepared by reduction of the spiro-bis(dioxo-cyclam) (131),171 formed from the spiro-octaamine (130) by reaction with diethyl malonate (Scheme 31). A nitroethane/methanal Mannich condensation of the Cu11 compound of (130) formed the spiro-bis(nitro-methyl-cyclam) (132), which reduces to the spiro-bis(amino-methyl-cyclam) compound (134).175... 

For purposes of classification the 4-aminopyrazoles are considered to be 4-imino-2-pyrazolines and analogs of 2-pyrazolin-4-ones. These compounds are listed in Table XL. Such compounds can be prepared by direct cyclization using ethyl diazoacetate and ethyl cyanoacetate.92 This is the same as eq. 243, except that the malonic ester is replaced by ethyl cyanoacetate. Purines can be hydrolyzed to 4-imino-2-pyrazolines by using strong acid.1210 1846 By far the most frequently used preparation is reduction of appropriately substituted pyrazoles, such as 4-nitro,368,812,819,1015,1019,1049 4-nitroso1165 or 4-aryl-azo.671 974,995 The hydrolysis of the carbethoxy 4-imino-2-pyrazolines derived from ethyl cyanoacetate and ethyl diazoacetate forms 4-imino-2-pyrazolin-3-carboxylic acid which is readily decarboxylated to the parent compound.92... 

Hydrazine hydrate, in preparation of sulfonylhydrazides, 40, 93, 95 in reduction of 2-nitrofluorene to 2-aminofluorene, 40, 5 Hydriodic acid in reduction of m-nitro-benzenesulfonyl chloride to m-nitrophenyl disulfide, 40, 80 Hydrogenation, of diethylisonitroso-malonate to diethyl aminomalo-nate over palladium-on-charcoal,... 

The N -substituted N-imines can be prepared by the reaction of the N-aminoazonium salts, in the presence or absence of base, with anhydrides or acyl halides,8,13-17,20,21,45,46 diketene,47 diethyl malonate,48 sulfonyl chloride,8,15,49,50 /i-halovinyl ketones and esters,51-54 diethyl ethoxymeth-ylenemalonate and related compounds,53,55-57 isocyanates,17,58 thioiso-cyanates,17,58 imidoyl chlorides and imidates,59,60 nitro acetate,8,61 and active halobenzenes.62,63 Some representative pyridine -(substituted imines) prepared in this way are shown in Scheme 1. 

The use of ethyl [2-13C]acetoacetate instead of diethyl [2-13C]malonate in the condensation reaction with 4H-pyran-4-one afforded ethyl 4-hydroxy[1-13C]benzoate in 87% yield. In this case, 1.1 equiv of 4H-pyran-4-one and 1.1 equiv of potassium tert-butoxide were optimal. The addition of catalytic amounts of the base was not satisfactory. Ethyl [2-13C]acetoacetate was prepared from ethyl [2-13C]acetate as described for diethyl [2-,3C]malonate.18 The maximum yield for this reaction on a 10-mmol scale was only 70% after distillation. 4H-Pyran-4-one reacted with nitromethane and potassium tert-butoxide (each 1.1 equh/) fo afford 4-nitrophenol in 75% yield after purification by flash chromatography. This gives easy access to 4-nitro[4-13C]phenol. With 2,4-pentanedione, the condensation with 4H-pyran-4-one under the same reaction conditions gave 4-hydroxyacetophenone in 45-50% yield after purification. 

For the preparation of o- and p-nitroacetophenone by direct oximation of o- and -ethyl-nitrobenzene see page 430,213 and for synthesis by the malonic ester route from o- and p-nitro-benzoyl chloride see reference 214. 

Similar to Cr(CO)3 complexes, less stabilized carbon nucleophiles such as MeLi and acetone enolate add irreversibly at the position ortho to chloride in (chlo-robenzene)FeCp [84]. Nucleophiles stabilized by a nitro, p-dicarbonyl, or related groups add reversibly with ultimate formation of a substitution product [66, 85]. Ketoarene complexes 35 can be prepared by addition of a malonate derivative followed by acid-induced decarboxylation [86]. 

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