Aromatic acids from malonic ester

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]. 

Anhydrides—Continued reduction to alcohols, 155 reduction to lactones, 535 Arenes, see Hydrocarbons, aromatic Amdt-Eistert reaction, 433, 487, 573 Aryl esters. Fries rearrangement, 344 hydrolysis, 169 preparation, 169 Aryl halides, see Halides Atyloxy acids, preparation, by aceto-acetic ester synthesis, 430 by malonic ester synthesis, 429 from atyloxy alcohols, 419 from atyloxy cyanides, 414 preparations listed in table 48, 460 Aryloxy acyl halides, preparation, 547 preparations listed in table 61, 553 Aryloxy esters, preparations listed in table 55, 516... 

Nitriles are directly converted to esters by heating with an alcohol and sulfuric or hydrochloric acid. When water is absent, the imino ester salt is readily isolated (method 402). Aliphatic,aromatic, and heterocycliccyano compounds react in this manner. Most of the aromatic compounds contain a cyanomethyl group although the cyanide radical may be attached directly to the aromatic nucleus. Monosub-stituted malonic esters free from unsubstituted and disubstituted malonic esters are made from the corresponding a-cyano esters by this method. Malonic ester and disubstituted malonic esters have been similarly prepared. ... 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

Selenophene-2-aldehyde takes part in the Hantzsch synthesis [Eq. (I)]108 and reacts readily with ammonia, aromatic amines and diamines,109 hippuric, barbituric, and malonic acids, malononitrile,70 and rhodanine.109 /3-(Selenien-2-yl)acrylic acid has been obtained from selenophene-2-aldehyde by the Perkin reaction and by Knoevenagel condensation with malonic acid.70 Esters of /9-(selenien-2-yl)acrylic acid are easily formed by condensation of the aldehyde... 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

According to the acyl-polymalonate hypothesis, chain-starter units other than acetate may be involved in the biosynthetic process (c/. Scheme 1). In this connection, the naturally occurring stilbenes and derivatives are produced by condensation of a cinnamate unit with three malonate units followed by aldol condensation of the enzyme-bound P-triketo-ester intermediate (77). " Secondary transformations (p. 183) may also occur at a pre-aromatic or postaromatic stage in the biosynthesis. Previous attempts to demonstrate the intermediacy of P-triketo-esters in the biosynthesis of stilbenes resulted in the reported conversion of cinnamoyltriacetic acid (77 R = H, as acid) into pinosylvin (79) by acetone powders prepared from leaves of a mutant of Eucalyptus sideroxylon. However, a subsequent report has indicated that this conversion cannot be repeated and this has prompted the explanation that P-polyketo-ester intermediates are bound to the enzyme and do not occur in the free state. Several difTerent preparations of acetone powder from E. 

Carboxylic acid triethylamine salts yield mixed anhydrides which, when treated with ethoxymagnesiomalonic esters give the benzoylated malonate. Alternatively, treatment of the mixed anhydrides with sodium tetracarbonylferrate(II) produces the aldehyde derived from the parent aliphatic or aromatic carboxylic acid in good yield. ... 

---