2,3 Dibromopropionaldehyde

A. 2,3-Dibromopropionaldehyde diethyl acetal. A 500-ml., three-necked, round-bottomed flask is equipped with a mechanical stirrer, a pressure-equalizing dropping funnel fitted with a calcium chloride drying tube, and a thermometer. The flask and dropping funnel are charged with 28.0 g. (0.5 mole) of freshly distilled acrolein and 80.0 g. (0.5 mole) of bromine, respectively. The acrolein is stirred rapidly and cooled to 0° in an ice-salt bath, then bromine is added at a rate such that the temperature is kept at... 

An early synthesis of folic acid developed by chemists at American Cyanamid involved condensation of 2,4,5-triamino-6-hydroxypyrimidine, 2,3-dibromopropionaldehyde and p-aminobenzoylglutamic acid (Scheme 3.9) [55a-d].This three-component procedure has become known as the Waller condensation, and has been widely employed for the synthesis of analogues because of the ease with which the various components of the condensation can be varied. Products from this three-component reaction, however, are mixtures of 6- and 7-substituted regioisomers. 

The first synthesis of a 3-deaza analogue, 3-deazaFA (70), was accomplished, albeit in poor yield, via the Waller condensation of 2,3,6-triamino-4-hydroxypy-ridine hydrochloride, 2,3-dibromopropionaldehyde and p-aminobenzoyl-L-glutamic acid, as shown in Scheme 3.14. This approach suffered from its equivocal nature as well as from a lengthy work-up involving repeated centrifugations and column chromatographic separations which were necessary to obtain (70) sufficiently pure to be characterized and evaluated [71]. 

An early structural modification of FA and AP involved alkylation at C-9 and/or N-10. 10-MethylFA (447) [197] was prepared by reaction of 2,4,5-triamino-6-hydroxypyrimidine, 2,3-dibromopropionaldehyde and diethyl p-methylaminobenzoylglutamate (35), followed by alkaline hydrolysis (the Waller condensation). Analogous utilization of 2,2,3-trichlorobutyraldehyde and the requisite p-(JV-substituted amino)benzoylglutamate furnished (448a-c) (Scheme 3.88) [198]. The preparation of (450) by condensation of 2,4,5,6-tetraaminopyrimidine and the a-ketoacetal (449) was reported without details (Scheme 3.89) [199],... 

A number of 4-alkyl derivatives of AP (654a-c) were prepared from 2,4,5-triamino-6-alkylaminopyrimidines, 2,3-dibromopropionaldehyde and p-ami-nobenzoylglutamic acid (Scheme 3.144) [264]. A corresponding derivative of... 

MTX (654d) was prepared by an analogous three-component condensation of 2,4,5-triamino-6-dimethylaminopyrimidine, 2,3-dibromopropionaldehyde and p-methylaminobenzoylglutamic acid. 

Compound (VIII.98), a folic acid analogue with a y-fluoro substituent in the side-chain was described first by Alekseeva e/ al. [281] and several years later by Bergmann and Chun-Hsu [282]. The synthesis of (VIII.98), as mixture of threo and erythro isomers, was achieved via the Waller method from V-(4-ami-nobenzoyl)-y-fluoroglutamic acid, 2,4,5-triamino-6(lif)-pyrimidinone, and 2,3-dibromopropionaldehyde, but the yield was low (5.6%). y-Fluoroglutamic acid, as a mixture of D- and L-enantiomers, was prepared from diethyl 2-fluoromalonate by condensation with ethyl 2-acetamidoacrylate followed by hydrolysis and decarboxylation in refluxing 12 M HCl, or from ethyl 3-chloro-2-hydroxypropanoate by a sequence consisting of (i) 0-t-butylation with CH2 = C(CH3)2, (ii) condensation with diethyl 2-acetamidomalonate, (hi)... 

The first reported example of an MTX analogue containing a basic amino-acid side-chain was the lysine derivative (VIII.264), which was prepared in low yield [196] from 2,4,5,6-tetraaminopyrimidine, 2,3-dibromopropionaldehyde, and methyl Af -Cbz-A -[4-(A -methylaminobenzoyl]-L-lysinate via a Waller synthesis. After hydrolysis of ester (VIII.265) with HBr, ion-exchange chromatographic purification gave (VIII.264) in only 6.5% overall yield. Subsequently an improved synthesis of (VIII.264) was described [365], in which... 

Acrolein dibromide. See 2,3-Dibromopropionaldehyde Acroiex] Acronai DS 3429] Acronai DS 3458. See Acrylic resin... 

Polydibromophenylene oxide Dibromopropanal. See 2,3-Dibromopropionaldehyde Dibromopropanol 2,3-Dibromopropanol. See... 

Propanal, 2,3-dibromo-. See 2,3-Dibromopropionaldehyde Propanal, 2-methyl-2-(methylthio)-, O-((methylamino) carbonyl) oxime. See Aldicarb Propanal, 2-methyl-2-(methylthio)-, oxime. See Aldicarb oxime... 

Bromo-p-nitrostyrene Chloroethylenebisthiocyanate Copper nitrate (ic) Dialkyl methyl benzyl ammonium chloride 2,2-Dibromo-3-nitrilopropionamide 2,3-Dibromopropionaldehyde 3,5-Dimethyl tetrahydro-2-H,1,3,5-thiadiazone-2-thione Disodium cyanodithioimidocarbonate Dodecylguanidine hydrochloride Glutaral... 

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