Ketoesters, synthesis

Ketoesters, synthesis of 608, 615 Ketones - see also a-Cyanoketones, Hydroxyketones, Sulphinylketones synthesis of 811-814 y-Ketonitriles, synthesis of 322 /3-Ketosulphones... 

Of course, one can also carry out Wolff rearrangements in the presence of nucleophiles other than H20. Ketenes are then produced in their presence, and the addition products of these nucleophiles are therefore isolated. Figure 14.28 shows how one can add an alcohol to a ketene in this way. An alcohol addition to a ketene is also involved in the /3-ketoester synthesis discussed in Side Note 6.2. 

Hellou,J. Kingston, J. F. Fallis, A. G., Diethyl Dicarbonate A Convenient Reagent for the Preparation of P-Ketoesters. Synthesis 1984,1014. 

Davis, J.R., Kane, P.D., Moody, C.J. and Slawin, A.M.Z. (2005) Control of competing N-H insertion and Wolff rearrangement in dirhodium(II)-catalysed reactions of 3-indolyl diazo-ketoesters. Synthesis of a potential precursor to the marine 5-(3-indolyl)oxazole martefragin A. The Journal of Organic Chemistry, 70, 5840-5851. 

J. Kassanyi, J. Perales, A. Laachach, I. Kawenoki and J.P. Morizur. Preparation of w-Formylalkenoates from cyclic B-Ketoesters, Synthesis 1979, 279-281. 

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

The Pechmaim reaction has found extensive appHcations for the synthesis of numerous coumarin derivatives (39). Coumarin derivatives substituted in the pyrone ring can be obtained by condensing phenol with beta-ketoesters. For example, 4-methylcoumarin (3) is obtained with ethyl acetoacetate... 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

Senzopyranone synthesis from phenols and ketoesters or unsaturated acids... 

S I M O N I S Benzopyrone synthesis Benzopyrene synthesis Irem phenols and p ketoesters... 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

Tetrasubstituted thiophenes obtained by the Gewald reaction serve as templates for structural diversification and semi-automated library synthesis. Thiophene 31, prepared from 3-ketoester 29 and t-butylcyanoacetate 30, could be selectively derivatized at three of the four substituents to maximize library diversity. This procedure represents an improvement over previously published methods for utilizing 1,3-dicarbonyl compounds in the Gewald reaction. 

Carpino et al. recently disclosed the synthesis of the fused pyrazolinone-piperidine dipeptide 56 with potent growth hormone secretagogue activity. The synthesis of the intermediate pyrazolone was accomplished by reacting the ketoester 54 with methyl hydrazine in refluxing ethanol. ... 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

The Knorr quinoline synthesis refers to the formation of a-hydroxyquinolines 4 from P-ketoesters 2 and aryl amines 1. The reaction usually requires heating well above 100°C. However, some cases do exist when the cyclization takes place in the presence of a catalytic amount of mineral acid at temperatures as low as -10 °C. The intermediate anilide 3 undergoes cyclization by dehydration with concentrated sulfuric acid. The reaction is conceptually close to the Doebner-Miller and Gould-Jacobs reactions. ... 

The Knorr quinoline synthesis has been nicely extended by Hodgkinson and Staskun to include P-ketoesters that do not have protons at the 2 position of the starting keto-ester. 2,2 -dichloroanilides of type 14 can cyclize to provide quinolines such as 15 and 16 in good respective yields. ... 

A five-step synthesis of ethyl ester of eyelie hydrazonie aeid 314 used in the synthesis of natural produets has been deseribed [94JCA(CC)1867]. The eonden-sation of methoxybutenone with EtCOaCN (t-BuOK, THF, —78°C) is eompleted with the formation of ketoester 310 in 72% yield. The addition of methanol to the latter (Triton B, MeOH, room temperature, 88%) and the reduetion with NaBH4 (EtOH, —78°C) leads to the aleohol 312, yield 90%. The dianion of 312 (EDA, THE, -78°C) reaets with t-butylazodiearboxylate (t-BuOaC—N=N—COaBu-t) to form adduet 313, the treatment of whieh with trifluoroaeetie aeid affords the ester 314 in 55% yield [94JCA(CC)1867]. 

The preparation of the selenazolyl-pyrazolones was then effected by a second method, in which first the pyrazolone ring and afterward the selenazole ring was formed. For this purpose -ketoester seleno-semicarbazones were first converted to the corresponding 1-seleno-carbamoyl-3-aIkylpyrazol-5-one. These, by condensation with a-halo-genocarbonyl compounds according to the Hantzsch synthesis, formed the selenazole ring as a second step (17). 

A general method for the construction of a pyridine ring is the Hantzsch synthesis. A condensation reaction of two equivalents of a /3-ketoester 1 with an aldehyde 2 and ammonia leads to a 1,4-dihydropyridine 3, which can be oxidized to the corresponding pyridine 4—for example by nitric acid ... 

The initial step of the Hantzsch synthesis is likely to be a Knoevenagel condensation reaction of aldehyde 2 and /3-ketoester 1 to give the a ,/3-unsaturated ketoester 6 ... 

The ring synthesis then proceeds in subsequent steps by condensation of the unsaturated ketoester 6 and enamine 7 to yield a 1,4-dihydropyridine 3 ... 

In addition to /3-diketones, /3-ketoacids and /3-ketoesters, cyanoacetic ester and related compounds are suitable starting materials. The arylhydrazones 4 thus obtained are of great importance as starting materials for the Fischer indole synthesis, as well as for the preparation of other iV-heterocycles. ... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

SYNTHESIS AND RU(II)-BINAP REDUCTION OF A KETOESTER DERIVED FROM HYDROXYPROLINE 2(S)-(p tert-BUTOXYCARBONYL-a-(S) and a-(R)-HYDROXYETHYL)-4(R)-HYDROXYPYRROLIDINE-1 -CARBOXYLIC ACID, tert-BUTYL... 

R = Aliphatic, aromatic, X = -OR, -NR2 R = Aromatic Scheme 20 Two step synthesis of pyrazoles from /3-ketoesters... 

More versatile seemed the synthesis of 2,3-dihydro-lH-pyridin-4-ones 176, that starts from the acrylic /3-ketoester 174 (Scheme 63). This product, pre-... 

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