Methyl 2,4-pentadienoate, reaction

N-Methyldihydro-j3-carboUne (29) was subjected to the imino Diels-Alder reaction in the presence of methyl pentadienoate (31) to give a mixture of adducts 32,34, and 36 (total yield 71 %). The mixture of adducts was alkylated, affording compound 38 as a single diastereomer. 

Enamines have been observed to act both as dienophiles (46-48) and dienes (47,49) (dienamines in this case) in one-step, Diels-Alder type of 1,4 cycloadditions with acrylate esters and their vinylogs. This is illustrated by the reaction between l-(N-pyrrolidino)cyclohexene (34) and methyl t/-a i-2,4-pentadienoate (35), where the enamine acts as the dienophile to give the adduct 36 (47). In a competitive type of reaction, however, the... 

The earlier examples of [2 + 1] cycloaddition of a carbene (or carbenoid) on the double bond of alkylidenecyelopropanes to yield spiropentane derivatives were observed as undesired side reactions in the synthesis of alkylidenecyelopropanes through the addition of a carbene to a substituted allene [161]. In some cases the spiropentane derivative was obtained as the major product [161a, c] especially when a large excess of the carbene reagent was used. For example, when methyl 3,4-pentadienoate (610) was treated with a ten-fold excess of methylene iodide and zinc-copper couple the two products 611 and 612 were isolated in 1 4.5 ratio (Scheme 86) [161a]. 

Structurally rather complicated target molecules can be synthesized with the aid of thi-olate 1,6-addition reactions to acceptor-substituted dienes as well. For example, a richly functionalized proline derivative with a 2,4-pentadienal side chain was converted into the corresponding 6-phenylthio-3-hexen-2-one derivative by 1,6-addition of phenylthiolate, treatment of the adduct with methyl lithium and oxidation (equation 46)127. The product was transformed into acromelic acid A, the toxic principle of clitocybe acromelalga ichimura. Similarly, the 1,6-addition reaction of cesium triphenylmethylthiolate to methyl 2,4-pentadienoate served for the construction of the disulfide bridge of the macrobicyclic antitumor depsipeptide FR-901,228128. 

To understand how to control process conditions to give methyl, 4-pentadienoate, the reaction mechanism must be examined. (See Equation 2.). -palladium hydride elimination from 4 gives rise to trans and cis-methyl penta-, 4-dienoate which is the desired monocarbonylation intermediate for sebacic acid. The desired mono-carbonylation reaction is promoted by low carbon monoxide pressure ( 1000 psig) while high pressure (1800 psig) gives excellent 1,4-dicarbonylation product yield. The mono-carbonylation reaction is also facilitated by using a Lewis Acid as a co-catalyst and iodide as the preferred palladium counter-ion (Table III.). Chloride is the preferred palladium counter-ion for 1,4-dicarbonylation. 

Methyl 2, -pentadienoate self-dimerization as a potential route to sebacic acid precursors was extensively evaluated. Homogeneous metal catalyzed dimerization of compounds containing conjugated double bonds is known to give cyclic, branched, and linear dimers(43-45). At higher temperatures or in the presence of many zero-valent metal catalysts, cyclodimerization (Equation 12.) is the only observable reaction. 

The reaction proceeds well with unhindered secondary amines as both nucleophiles and bases. The yield of allylic amine formed depends upon how easily palladium hydride elimination occurs from the intermediate. In cases such as the phenylation of 2,4-pentadienoic acid, elimination is very facile and no allylic amines are formed with secondary amine nucleophiles, while phenylation of isoprene in the presence of piperidine gives 29% phenylated diene and 69% phenylated allylic amine (equation 30).84 Arylation occurs at the least-substituted and least-hindered terminal diene carbon and the amine attacks the least-hindered terminal ir-allyl carbon. If one of the terminal ir-allyl carbons is substituted with two methyl groups, however, then amine substitution takes place at this carbon. The reasons for this unexpected result are not clear but perhaps the intermediate reacts in a a- rather than a ir-form and the tertiary center is more accessible to the nucleophile. Primary amines have been used in this reaction also, but yields are only low to moderate.85 A cyclic version occurs with o-iodoaniline and isoprene.85... 

Stereochemistry is largely lost in die diene vinylation, at least at 100 C, as evidenced by die reaction of (Z,E)-3-methyl-2,4-pentadienoic acid shown in equation (40). 

Fig. 9.5 The prototypical Diels-Alder reaction is that between 1,3-butadiene and ethene, to form cyclohexene. The Diels-Alder reaction has been used in the synthesis of complex natural products above, methyl 2,4-pentadienoate reacts with 1,4-benzoquinone to form an intermediate in the synthesis of the drug reserpine. In a one-pot reaction two carbon-carbon bonds are made and three chiral centers ( ) are created with the correct relative orientations (i.e. essentially one diastereomer is formed)...

Interestingly, the role of methyl toms-2,4-pentadienoate changes from that of a diene, in its reaction with enamines,29 to a y,(5-dienophile in its reaction with dienamines32 (Scheme 18). 

By contrast, starting from methyl ( ,.E)-5-aryl-2,4-pentadienoates and nitrosoarenes, a mixture of regioisomers 6 and 7 is observed in the H-NMR spectra of the crude reaction product, since chromatographic separation on silica gel is not effective56-60. 

Simple, neutral electron-rich imines are generally not useful dienophiles unless q>propriately reactive dienes are used. Thus it is possible to effect cycloadditions of neutral imines with some electron-deficient dienes. - In a series of p rs, Langlois and coworkers have described Diels-Alder reactions of cyclic imines and methyl 2,4-pentadienoate to afford adducts used in alkaloid synthesis. For example, the cycloadditicMi shown in equation (IS) was used in a total synthesis of the indole alkaloid vincamine (45). 

In a very similar manner, tandem 1,6- and 1,4-additions of -dicarbonyl compounds to methyl 2,4-pentadienoate were utilized by Danishefsky and coworkers- foi the formation of several bi- and tricyclic ring systems. For example, reaction of the enolate of dimedone with this ester gave the expected 1,6-addition product protonation/deprotonation set the stage for a subsequent intramolecular 1,4-addition (equation 9). Likewise, a ketodiester was used to transform the pentadienoate in a one-pot procedure by consecutive 1,6- and 1,4-additions into a richly functionalized tricyclic product which was then converted into the natural product ( )-cpiclovane (equation 10). According to this principle, Irie and coworkers obtained several decalin-2,7-diones by treatment of 2-methylen-2-cyclohexenones with dimethyl 3-oxoglutarate. 

Addition of hydrogen is selective for the double bond further from the electron-withdrawing group thus, the major alkene formed on selective reduction of ethyl 4-methyl-2,4-pentadienoate is the a,/3-unsaluralcd ester (equation 1). The reaction proceeds under mild conditions and in the presence of oxygen. 

The rate of Diels-Alder reactions can be increased by the application of high pressure. An early example by Dauben and Kozikowski demonstrated that methyl 1-pentadienoate reacted with 126 to give 127 in 88% yield. 27 Applications of high-pressure techniques to organic synthesis are enumerated in an excellent review by Matsumoto 28 as well as in his monograph. 29 jiie second part of this review 29 deals with high-pressure pericyclic reactions, including Diels-Alder reactions. 

While the intermolecular reactions of butadiene and related methyl or simple alkyl-substituted dienes have been investigated extensively, relatively few examples of the Pd-catalyzed linear dimerization of higher dienes have been reported. Brun and co-work-ers in an isolated paper reported that, under palladium catalysis, reaction of methyl 2,4-pentadienoate (Scheme 9, 28) affords the linear dimer 29 in high yield (95%). Two aspects of this reaction are of particular interest, (i) The dimerization yields essentially only the tail-to-tail dimer 29, not the head-to-tail or head-to-head isomers (30 or 31, respectively). This is in contrast to the behavior of alkyl-substituted dienes under similar conditions vide infra), (ii) Although no details are given, the authors imply that 29 is... 

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