Y ,5-Unsaturated acids

Bicyclic ketone (33) was needed for a chrysanthemic acid synthesis. tarbene disconnection next to the ketone group (Chapter T30) reveals y. (5-unsaturated acid (35) as an intermediate, available by a Claisen-Cope rearrangement. 

The overall process (lactonization/NaBH4 reduction) therefore constitutes a formal protective method for y 5-unsaturated acids. 

The conversion of p,y- or y,<5-unsaturated acids into iodolactones (Halo-... 

It is possible to treat ketones with allyl alcohol and an acid catalyst to give y,8-unsaturated ketones directly, presumably by initial formation of the vinylic ethers, and then Claisen rearrangement. In an analogous procedure, the enolates (134) of allylic esters [formed by treatment of the esters with lithium isopropylcyclohexyla-mide (LICA)] rearrange to y,5-unsaturated acids. Allylic alcohols can be treated with a catalytic amount of mercuric acetate, and in the presence of an excess of allyl vinyl ethers give an alkene-aldehyde via a Claisen rearrangement. 

Claisen rearrangement of allyl esters. Ireland and Mueller6 report that lithium enolates of allyl esters rearrange rapidly at room temperature or slightly above to the corresponding y,<5-unsaturated acids. Thus the allyl ester (1) is converted into the lithium enolate (2) by treatment with lithium isopropylcyclohexylamide in THF at —78°. The solution of (2) is then allowed to warm to 25° for 10 min. The y,S-unsaturated acid (3)... 

CLAISEN-IRELAND Rearrangement Rearrangement of allyl phenyl ethers to o-(or p)-allylphenols or of allyl vinyl ethers to y,8-unsaturated aldehydes or ketones (Claisen). Rearrangement of allyl esters as enolate anions or silyl enol ethers to y,5-unsaturated acids (Ireland). Also rearrangement of N-allylanilines (an aza-Cope rearrangement) (see 1st edition). 

Conversion of oxathianone 20 to the y,<5-unsaturated acid 21 demonstrates the basic procedure for auxiliary removal through hydrolysis and reduction of the resulting a-thio carboxylic acid118. 

As an extension, A-acylated A-chlorohydantoins have been shown to be competent sources of C1+ in the asymmetric chlorolactonization of y,5-unsaturated acids catalysed by (DHQD)2PHAL (dihydroquinidine 1,4-phthalazinediyl diether). The same i system can also catalyse asymmetric chlorocyclization of allylic amides to produce the corresponding chlorinated oxazolidines. ... 

The Claisen rearrangement of the enolate of the ester 12 generated with LDA, afforded the y,<5-unsaturated acid 13 which served as an intermediate in the total synthesis of (+)-artemisinin (Scheme 5.1.17) [28]. 

Room temperature imidazolium ionic liquids have been shown to be useful solvents for the Michaelis-Arbuzov rearrangement, sometimes allowing the reaction to be performed at room temperature in a short period of tirne. Halolactones, which are the products of halolactonisation of y,5-unsaturated acids, have been shown to be dehalogenated by trialkyphosphites in the presence of water. This makes a useful alternative to the commonly used reduction by tributyltin hydride. The reactions of dibromoethane and dibromopropane with silyl phosphites have been studied. Mono and diphosphonoalkanes (37) and (38) were prepared and their chemical properties were studied. In the reaction of trifluoromethylated P-alkoxyketones with tris(trimethylsilyl)phosphite, a mixture of the 1,2- and 1,4-adducts (39) and (40) is produced. 

A parallel study of the isotope-exchange reactions of malonate ion in Na0D-D20 has shown that the rate of exchange of malonate in D2O decreases to a minimum and then increases with increased [NaOD]." The oxidation of y,5-unsaturated acids to lactones with H2O2 is catalysed by methyltrioxorhenium a concerted mechanism is proposed. The activation of carboxylic acids by carbonates has been reviewed (79 references). Among the topics discussed is the esterification of A-protected amino acids (46) using di-f-butyl carbonate (47) " the putative active intermediate is the mixed anhydride (48). The reaction between maleic anhydride and f-butyl... 

A preliminary report has appeared on a new, potentially general method for the preparation of y,5-unsaturated acids based on a Claisen rearrangement... 

Vinyllithium [917-57-7] can be formed direcdy from vinyl chloride by means of a lithium [7439-93-2] dispersion containing 2 wt % sodium [7440-23-5] at 0—10°C. This compound is a reactive intermediate for the formation of vinyl alcohols from aldehydes, vinyl ketones from organic acids, vinyl sulfides from disulfides, and monosubstituted alkenes from organic halides. It can also be converted to vinylcopper [37616-22-1] or divinylcopper lithium [22903-99-7], which can then be used to introduce a vinyl group stereoselectively into a variety of a, P-unsaturated systems (26), or simply add a vinyl group to other a, P-unsaturated compounds to give y, 5-unsaturated compounds. Vinyllithium reagents can also be converted to secondary alcohols with trialkylb o r ane s. 

CsF induces the ring-opening cyclization of the thus obtained l-[2-(trimethylsilylmethyl)cyclopropylcarbonyl] imidazole 154 with diethyl fumar-ate or diethyl maleate to give the cyclobutanone 155 [80], The facile ring fission of 154 also occurs in the presence of BF3OEt with the formation of the corresponding y,<5-unsaturated carboxylic acid. (Scheme 55)... 

Gassman and co-workers have recently investigated the photoinduced cy-clization of y,5-unsaturated carboxylic acids to y-lactones [100]. 5-Methyl-4-hexenoic acid 51 is converted into the radical cation 52. The cyclization of 52 is expected to yield the distonic radical cations 53 and 54, which leads to the anti-Markonikow products 55 and 56 in ratio 5 1. Fine-tuning of the sensitizer improved combined yields up to 89% [101],... 

The acid-catalysed transannular cyclization of 8-10-membered y,5-unsaturated cyclic sulfides (59) or (60) yields c/x-fused bicyclic sulfonium salts (61) independently of the geometry of the double bond. The rate varies linearly with the acidity function -(Ho h with a slope of 1. The rate variations span a range of about 10 , the maximum rate difference being observed for the ( /Z)-thiacyclooct-4-ene pair. The data are consistent with the classical interpretation of the intramolecular reactivity in terms of internal strain of the substrate and/or of the transition state. ... 

It has been shown that the Claisen rearrangement of lithium enolates of amino acid enynol esters allows the synthesis of very sensitive y, 5-unsaturated amino acids with conjugated enyne side chains.The chelate-enolate Claisen rearrangement has also been applied to the synthesis of unsaturated polyhydroxylated amino acids, polyhydroxylated piperidines, and unsaturated peptides. ... 

Non-stabilized a, p y, 5-unsaturated azomethine ylides (158), generated by the decarboxylation method from 3,3-diarylpropenals (156) and secondary amino acids (157), have been found to undergo [1,7]-electrocyclization followed by a [1,5]-hydrogen shift, to yield 2,3-dihydro-17/-2-benzazepines (159). 

Heating of an allylic alcohol with an excess of trialkyl orthoacetate in the presence of trace amounts of a weak acid to give a mixed orthoester. The orthoester loses ethanol to generate the ketene acetal, which undergoes [3,3]-sigmatropic rearrangement to give a Y,5-unsaturated ester. 

By treatment of the dichloroteUurolactone with excess NaBH4, the fission of the Te-C bond takes place with recovery of the starting y 5-unsaturated carboxylic acid. ... 

Reaction of dichloroteUurolactones with excess NaBH regeneration of y,S-unsaturated acids (general procedure) The dichloroteUurolactone (1 mmol) in THF (10 mL) at room temperature is treated with NaBH4 (0.1 g, 2.6 mmol) in H2O (5 mL). An immediate reaction takes place and the solution turns dark red. After stirring for 10 min at room temperature, the reaction mixture is diluted with ether (30 mL) and extracted with 2 N NaOH (2x5 mL). The organic phase is washed wiUi H2O, dried (MgS04) and evaporated, furnishing bis(p-methoxyphenyl) ditelluride in a quantitative yield. The cooled aqueous... 

There are several variations of the Claisen rearrangement that make it a powerfid tool for the synthesis of y,<5-unsaturated carboxylic acids. The ortho ester modification of the Claisen rearrangement allows carboalkoxymethyl groups to be introduced at the /-position of allylic alcohols.157 A mixed ortho ester is formed as an intermediate and undergoes sequential elimination and sigmatropic rearrangement. 

Esters of allylic alcohols can be rearranged to y,<5-unsaturated carboxylic acids via the O-trimcthylsilyl ether of the ester enolate.161 This rearrangement takes place under much milder conditions than the ortho ester method. The reaction occurs at or slightly above room temperature. Entries 14 and 15 of Scheme 6.12 are examples. The example in entry 16 is a rearrangement of the enolate without intervention of the silyl enol ether. 

The procedure described illustrates a new general synthetic method for the preparation of (E)-3-allyloxyacryl ic acids and their conversion to a-unsubstituted y,5-unsaturated aldehydes by subsequent Claisen rearrangement-decarboxyl at ion. Such aldehydes are traditionally prepared by Claisen rearrangements of allyl vinyl ethers. Allyl vinyl ethers are typically prepared by either mercury-catalyzed vinyl ether exchange with allylic alcohols or acid-catalyzed vinylation of allylic alcohols with acetals. The basic conditions required for alkoxide addition to the betaine to produce carboxyvinyl allyl ethers, as described in this report, nicely complements these two methods. In addition, this Claisen rearrangement is an... 

This reaction has been used mostly to prepare iodo lactones, but bromo lactones and, to a lesser extent, chloro lactones, have also been prepared. In the case of -y.S-unsaturated acids, 5-membered rings (y-lactones) are predominantly formed (as shown above note that Mar-kovnikov s rule is followed), but 6-membered and even 4-membered lactones have also been made by this procedure. Thallium reagents, along with the halogen, have also been used.653 For a method of iodoacetyl addition, see 5-35. 

Cyclopentenones (6, 67-68). Details of the Lewis acid catalyzed decomposition of /3,y-unsaturated diazo ketones to form cyclopentenones have been published. Similar decomposition of y,<5-unsaturated diazo ketones to /Ly-unsaturated cyclo-hexenones is possible, but yields are significantly lower.5... 

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