Dicarbonyl compounds Methyl acetoacetate

Nifedipin Nifedipine, dimethyl ether l,4-dihydro-2,6-dimethyl-4-(2 -nitrophenyl)-3,5-piridindicarboxylic acid (19.3.16), is synthesized by a Hantsch synthesis from two molecules of a j3-dicarbonyl compound—methyl acetoacetate, using as the aldehyde component—2-nitrobenzaldehyde and ammonia. The sequence of the intermediate stages of synthesis has not been completely established [20-23]. 

Ketones such as methyl cyclohexyl ketone 1284 react with DMSO/TCS 14, via their enol form, to give 21% of the chloroketone 1285 a and 63% of the a-methyl mercaptoketone 1286 [70]. Reaction of 1284 with DMSO/MesSiBr (TBS) 16 affords 85% of the bromo compound 1285 b and 12% hexahydrophenacyl bromide 1287 but no 1286 [71]. Whereas reaction of tra s-4-phenyl-3-buten-2-one (benzalacetone) 1288 with DMSO/TCS 14 gives 81% of the sulfonium salt 1289 [70], the y9-dicar-bonyl compound ethyl acetoacetate furnishes 69% of 1290 [70]. In contrast with DMSO/TCS 14, the combination DMSO/TBS 16 effects selective monobromina-tion of y9-dicarbonyl compounds [71] (Scheme 8.28). 

Nicardipine Nicardipine, l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-methyl-2-[(methyl-phenylmethyl)-amino]ethyl ester 3,5-pirididincarboxylic acid (19.3.7), is synthesized in a manner analogous to the synthesis of nifedipine, the only difference being that in the Hantsch synthesis, two different )3-dicarbonyl compounds are used simultaneously with o-nitrobenzaldehyde. During this, one of these in the enamine form of acetoacetic ester is simultaneously used as an amine component. A heterocycUzation reaction is accomplished by reacting, the methyl ester of 8-aminocrotonic acid with the 2-methyl-2-benzyl-aminoethyl ester of acetoacetic acid [24-27]. 

Much more studied is the reaction of /8-dicarbonyl compounds with 2-amino-2-deoxyaldoses in particular, with 2-amino-2-deoxy-D-glu-cose (55), both in neutral and alkaline medium. In neutral methanol or aqueous acetone, 2-amino-2-deoxy-D-glucose reacts with 2,4-pen-tanedione to give52 54 3-acetyl-2-methyl-5-(D-arabino-tetrahydroxy-butyl)pyrrole (56a), and, with ethyl acetoacetate,55 the pyrrole 56b. Similar (tetrahydroxybutyl)pyrroles have been prepared from other /3-keto esters, such as ethyl 3-oxohexanoate, ethyl thiolacetoacetate, and diethyl 3-oxopentanedioate.53,56,56a... 

As shown below, polyphenol-based benzo[A furans were biosynthetically made from catechols and 1,3-dicarbonyl compounds in the presence of laccase <07T10958 07TL5073>. A similar type of benzo[A]furan was also obtained via electrochemical oxidation of catechols and methyl acetoacetate <07T3894>. 

The l,3-bis(trimethylsililoxy)butadienes 130-132, as the equivalent of methyl acetoacetate dianion, constitute the three-carbon fragments with two nucleophilic sites (equation 110). Condensation of 130-132 with various equivalents of -dicarbonyl compounds and titanium(IV) chloride gives substituted methyl salicylates. The differential reactivity of the electrophiles which increases in the order conjugated position of enone > ketone > monothioacetal, acetal and of 130-132 (4-position > 2-position) ensures complete regioselectivity in this combination of two three-carbon units to form phenols such as 133 and 134 °° °. ... 

Michael addition of the dianions derived from -dicarbonyl compounds facilitated yet another annulation - Michael addition of a dianion then intramolecular aldol condensation (Scheme 6.89) [112]. Complexation of ATPH with trans-chal-cone (112) in CH2CI2 at -78 °C, followed by treatment with the dianion of methyl acetoacetate gave, after quenching with aqueous HCl, bicyclic product 113 in a nearly quantitative yield. This system can be used for elaboration of the bicyclo [3,5,l]undecane ring system in 114, as can be found in the backbones of terpenoids and the taxol family. 

Lithium477 and potassium478 enolates of P-dicarbonyl compounds are aminated by azodicarboxylic esters in good to excellent yields. Diethyl malonate, ethyl acetoacetate, /V,/V-diethyI acetoacetamide, and acetylacetone have also been aminated with diethyl azodicarboxylate under nickel acetylacetonate catalysis,479 and nickel salicylideneimine complexes catalyze the analogous amination of acetylacetone and its 2-methyl derivative.480... 

In the experiments first described, 2-amino-2-deoxy-D-glucose was heated with an excess of the /3-dicarbonyl compound in the absence of solvent. The product so obtained from ethyl acetoacetate, m.p. 142°, [a]n 49.7°, had an analysis corresponding to that for ethyl 2-methyl-5-(D-ara6mo-tetrahydroxybutyl)pyrrole-3-carboxylate and was considered to have this structure (1). In the reaction with 2,4-pentanedione, a material (m.p. 98°, Md — 25.1°) was obtained which was described as 3-acetyl-2-methyl-5-(D-ara5fno-tetrahydroxybutyl)pyrrole (2). Boyer and Furth" repeated the latter reaction, but in methanol solution, and obtained a product, m.p. 133°, whose analytical data were in agreement with those for structure (2). 

The reaction of 1-amino-l-deoxy-D-fructose with /3-dicarbonyl compounds in aqueous acetone at neutral pH has also been studied. The acetate of this amino sugar affords, with ethyl acetoacetate, ethyl 2-methyl-4-(D-om6wo-tetrahydroxybutyl)pyrrole-3-carboxylate (17). As in previous... 

The reaction of amino sugars with (8-dicarbonyl compounds in alkaline solution produces (tetrahydroxybutyl) pyrroles together with simpler pyrrole compounds lacking the tetrahydroxybutyl side-chain. 2-Amino-2-deoxy-D-glucose hydrochloride and ethyl acetoacetate, heated in aqueous solution at pH 9.7, give a mixture of ethyl 2-methyl-5-(D-ara )mo-tetra-hydroxybutyl)pyrrole-3-carboxylate (1) and ethyl 2-methylpyrrole-3-carboxylate. The yields of these compounds are in the approximate ratio... 

In the reactions of 2-amino-2-deoxy-D-glucose with some /3-dicarbonyl compounds (such as ethyl acetoacetate, 2,4-pentanedione, or pyruvic acid) in alkaline solution, pyrroles lacking the tetrahydroxybutyl chain are obtained. The loss of this group cannot occur with the already formed (tetrahydroxybutyl)pyrroles, because these compounds, as exemplified by 3-acetyl-2-methyl-5-(D-ora wo-tetrahydroxybutyl)pyrrole (2), remain unchanged at the pH (9-10) of the reaction. The fission of the sugar chain most probably occurs for one of the intermediates of the reaction, for instance (79), and it may be formulated as a concerted-elimination reaction catalyzed by the hydroxyl ion, as indicated in Scheme C. The... 

Pyrroles.—Formation. A general synthesis of 2-aryl-pyrroles (112) is by cycliz-ation of the esters (111), which are obtained from unsaturated aldehydes and methyl azidoacetate. Thermolysis of the acetylene (113 Ar = p-MeC6H4) gives Al-(p-tolyl)pyrrole with the elimination of p-thiocresol. The pyrrole derivative (115) is the product of the action of benzylamine on tri-(t-butylthio)cyclopropenylium perchlorate (114). Azoalkenes combine with fi-dicarbonyl compounds or with enamines to yield derivatives of Al-aminopyrrole thus the ester (116) and ethyl acetoacetate form (117). The base-catalysed addition of methyl propiolate to toluene-p-sulphonylmethyl isocyanide, T0SCH2NC, gives the ester (118). The dipolar cyclo-adduct (120) of piperidinocyclopentene to the azo-compound (119) forms the A-(tosyl-amino)pyrrole derivative (121) and piperidine on heating. ... 

After these initial results by Tsuji, this elementary step was incorporated into a catalytic process by Hata and co-workers at Toray Industries and by Atkins and co-workers at Union Carbide. These groups reported reactions of allylic phenyl ethers, allylic alcohols, and allylic acetates with carboxylates, alcohols, primary and secondary amines, and methyl acetoacetate catalyzed by Pd(0) complexes and precursors to Pd(0) complexes (Equation 20.3). - After these initial reports, early developments focused on reactions of "soft" carbanions derived from 3-dicarbonyl compounds, cyanoesters, and related compounds containing two electron-withdrawing groups attached to the nucleophilic carbon. Although these reactions occur with allylic halides in the absence of a catalyst, these reactions are greatly accelerated by palladium catalysts. Thus, the palladium catalyst allows these reactions to occur under mild conditions with allylic acfetates, which are more accessible than allylic halides, and with selectivities that are altered by the metal catalyst. 

The question of whether (22) is produced by Path D1 or D2 really amounts to the question of whether an enzyme can form an enol or enolate of a methyl ketone, e.g. at C-4 of acetoacetate or at C-3 of hygrine (16). Current thinking on the role of hygrine (16) in tropane alkaloid biosynthesis would suggest that this is not possible. If one considers all four pathways of Scheme 8 and the subsequent steps required to convert (16) or (22) into tropinone (18), shown in Scheme 10, one can see that pathways Cl, C2 and Dl, respectively, involve enolization of a methyl ketone, which is not nearly as easy as enolization of a -dicarbonyl compound. Only Path D2, which invokes (21) and (22) as intermediates, postulates that all of the carbon-carbon bond-forming reactions receive the benefit of stabilization of the nucleophile via a -dicarbonyl system (assiuning the acetate imits are intro duced stepwise via malonate or its CoA ester). The only experimental fact not in accord with this last proposal is the failure so far to achieve incorporation of (21) into (1) or (19). A new proposal for the formation of (22) which circiun-vents this problem will be introduced in Section 5 of this contribution. 

Additional reports have appeared on the direct derivation of -glycosides from glycal esters. B-Dicarbonyl compounds, e.g., methyl acetoacetate, in the presence of boron trifluoride or... 

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