Claisen condensation starting compounds

The method described is that of Hampton, Harris, and Hauser6 and is an improvement over the benzyne method, which gives poor yields.6,7 This /J-diketone has been prepared by Claisen condensation of ethyl phenylacetate with acetone,8 but the yield is poorer and the product has been shown by gas chromatography to be impure.6 The j8-diketone has also been prepared by the hydrolysis of 4-methoxy-5-phenyl-3-penten-2-one and by hydrolysis and decarboxylation of ethyl a-acetyl-/3-oxo-y-phenylbutyrate10 but these compounds are more difficult to obtain than the starting materials used in the present synthesis. 

In the typical old-fashioned Reformatsky protocol12a d, a mixture of a-bromoester, carbonyl compound and zinc powder is heated in a solvent, generally benzene, for several hours. Under these conditions, the chemical yields often suffer from the concurrence of side-reactions, such as self-condensation of enolizable aldehydes, Claisen condensation of bromoesters or crotonization of the Reformatsky products. However, ever since the outset of Reformatsky studies, chemists have been aware about the need to activate the zinc surface in order to get higher reaction rates and shorter induction times before the process starts, with lower by-product formation. Thus, it became common practice to... 

The mevalonate pathway starts with a sequence of two Claisen condensations that afford (6 )-3-hydroxy-3-methyl-glutaryl-CoA (84) from three acetyl-CoA moieties. The pathway affords IPP that can be converted into DMAPP by isomerization. The first committed intermediate of the nonmevalonate pathway is 2C-methyl-D-erythritol 4-phosphate (90) obtained from 1-deoxy-D-xylulose 5-phosphate (43), which is a compound also involved in the biosynthesis of vitamins Bi (46, cf. Fig. 4) and Be (39, cf. Fig. 5), by rearrangement and subsequent reduction. Three enzyme-catalyzed steps are required to convert the compound into the cognate cyclic diphosphate 91 that is then converted reductively into a mixture of IPP and DMAPP by the consecutive action of two iron/sulfur proteins. 

This synthesis was carried out by Claisen and the reaction is known as the Claisen condensation. The acetoacetate (8) we used in Chapter 13 is also made this way. This time the starting materials are two molecules of the same compound. The synthesis, known as the Claisen ester condensation, simply involves treating ethyl acetate with base. 

Oxysparteine was also the intermediate which furnished conclusive proof of the ring structure of all the Cw lupin alkaloids. Clemo, Morgan, and Raper in 1936 (260) announced the synthesis, from non-alkaloid starting materials, of a compound with structure XCV and established the identity of this compound with the d/-oxysparteine obtained by alkaline ferricyanide oxidation of dZ-sparteine. The s3Tithesis of dZ-oxy-sparteine (XCV) was accomplished as outlined below. The Claisen condensation of ethyl 2-pyridylacetate (XCVI) with ethyl orthoformate... 

It will sometimes be necessary to work retrosynthetically (How To 14.2) from the product of a Claisen condensation. Following are the steps for determining the starting compounds used in a Claisen condensation. 

Hay and Harris 153,157) have reported a biogenetic-type synthesis of lichexanthone (Scheme 14). To circumvent problems arising from numerous cyclisation pathways of a long polyketide chain these workers chose a starting compound with a pre-formed aromatic ring (132). Claisen condensation of the polyketide side chain of (132) in aqueous potassium hydroxide yielded a mixture of the benzophenone (133) and 3-0-methylnorlichexanthone (134). The benzophenone (133) could be converted into (134) by treatment with methanolic potassium hydroxide. Subsequent O-methylation of (134) with diazomethane yielded lichexanthone (135). 

What starting materials could be used in a crossed Claisen condensation to prepare the following compound ... 

A series of l-[4-(3-substituted-acryloyl)-phenyl]-pyrrole-2,5-diones was synthesized and characterized by Aravind and Ganesh (2013). All the compounds were synthesized from l-(4-acetyl-phenyl)-pyrrole-2,5-dione and substituted benzalde-hydes by using Claisen-Schmidt condensation reaction under conventional heating and microwave irradiation. The starting compound 1-(4-acetyl-phenyl )-pyrrole-2,5-dione is the precursor for the preparation of l-[4-(3-substituted-acryloyl)-phenyl]-pyrrole-2,5-diones and it was obtained by a reaction involving maleic anhydride and 4-aminoacetophenone in diethyl ether. The yield of product was 58-71% under conventional heating in 7-8 h, which increases to 84-90% in 3-5 min under micro-wave irradiation. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Alkoxyallenes turned out to be excellent starting materials also for the synthesis of highly functionalized 1,3-dienes, two examples being depicted in Schemes 8.61 and 8.62. As described by Kantlehner et al., 1,3-dienes such as 238 were obtained from methoxyallene derivative 50 by condensation with CH-acidic compounds 237 [135]. Hoppe and co-workers explored the stereochemical course of the allene Claisen rearrangement under Johnson s conditions, e.g. the reaction of 239 with trimethyl orthoacetate, which furnished intermediate 240 followed by rearrangement to the isomeric dienes 241a,b [136],... 

The five-membered ring pyrazoles are even simpler as the starting material is a 1,3-dicarbonyl compound available from the aldol or Claisen ester condensations. 

Apart from sotolon, the other compounds in Fig. 5 can be explained as the products of a Maillard reaction, and their carbon skeletons simply originate from the active Amadori intermediate in other words, they still preserve the straight carbon chain structure of monosaccharides. In spite of being a simple Cg lactone, sotolon has a branched carbon skeleton, which implies another formation process in the Maillard reaction. Sulser e al.(6) reported that ethyl sotolon (ll) was prepared from threonine with sulfuric acid, and that 2-oxobutyric acid, a degradation product of threonine, was a better starting material to obtain II. This final reaction is a Claisen type of condensation, which would proceed more smoothly under alkaline conditions. As we(lO) obtained II from 2-oxobutyric acid (see figure 6) with a high yield in the presence of potassium carbonate in ethanol, a mixed condensation of 2-oxobutyric and 2-oxo-propanoic (pyruvic) acids was attempted under the same conditions, and a mixture of sotolon (22% yield) and II were obtained however, the... 

Methylation can be carried out with either acid or basic catalysts, and catalyst properties affect the distribution of the products, especially when different positions for methylation are present. Acid zeolites are very active catalysts in alkylation of phenol derivatives however, the considerable formation of heavy compounds leads to a fast deactivation of the catalyst. Basic catalysts, such as single oxides (MgO) and Mg-Al mixed oxides, have been found to be less active than the acid ones, but did not form heavy products [4]. Mg-Al mixed oxides, prepared starting from hydrotalcite precursors, have shown the best basic features, and indeed in recent years these materials have been reported as catalysts for different basic reactions, such as the Claisen-Schmidt condensation, the Knoevenagel condensation, and many others [5-9]. 

The reductive coupling of carbonyl compounds with active metals (Na, Mg, Al) yields pinacols. An electron transfer from the metal surface to the carbonyl oxygen (ketyl formation), a soft-soft interaction, is undoubtedly involved. The conversion of esters to acyloins (22, 23) on the surface of metallic sodium is well known. Here the enediolate products can be trapped in situ by Me3SiCl (24). The chlorosilane does not interfere with the coupling, yet it effectively removes the alkoxide ions and neutralizes the enediolate ions immediately on formation. The elimination of RO is imperative, for otherwise Claisen or Dieckmann condensations would compete with the normal course of reaction. These complicating processes require a hard base (e.g. RO ) to abstract a proton from the starting esters, whereas the desired coupling is accomplished by a soft base which is the electrons on the metal surface. 

The product of the reaction above, the acetoacetyl derivative of the acyl carrier protein, is the starting point for the biosynthesis of other compounds besides fatty acids. Steroids derive from a sequence of enzyme-catalyzed Claisen-like condensations that produce the branched five-carbon skeleton of 2-methyl-1,3-butadiene (isoprene), the building block of... 

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