S-Unsaturated Acids

CLAISEN - IRELAND Rearrangment Rearrangement ol allyl phenyl ethers to o (or p-)allylphenols or of allyl vinyl ethers to y.S-unsaturated aldehydes or ketones (Claisen) Rearrangement ol allyl esters as enolale anions to y.S-unsaturated acids (Ireland)... 

The wide variety of methods available for the synthesis of orga-noselenides,36 and the observation that the carbon-selenium bond can be easily cleaved homolytically to give a carbon-centered radical creates interesting possibilities in organic synthesis. For example, Burke and coworkers have shown that phenylselenolactone 86 (see Scheme 16), produced by phenylselenolactonization of y,S-unsaturated acid 85, can be converted to free radical intermediate 87 with triphenyltin hydride. In the presence of excess methyl acrylate, 87 is trapped stereoselectively, affording compound 88 in 70% yield 37 it is noteworthy that the intramolecular carbon-carbon bond forming event takes place on the less hindered convex face of bicyclic radical 87. 

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... 

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. 

Asymmetric bromolactonization (8, 421-423). Full details for synthesis of a,a-disubstituted a-hydroxy acids from a,/S-unsaturated acids by bromolactonization have been published.1... 

Crotonic acid is an example of an a(S-unsaturated acid, whilst vinylacetio acid is a (3y-unsaturated acid. Upon heating the latter with a solution of an alkali hydroxide at 100° or with sulphuric acid, it passes almost completely into the forrper. Actually an equilibrium mixture is produced containing 98 per cent, of crotonic acid ... 

Preparation of Bromoketones and cia-a,/S-Unsaturated Acids from Methyl Ketones... 

Homologated (E)-unsaturated carboxylic acids The anion (2) of 1, formed with LDA in THF at — 50°, is alkylated exclusively at the /-position. The products (3) are converted into a,/S-unsaturated acids (4) on oxidation and thermolysis. This behavior contrasts with that of the anion of the corresponding silyl enol ether, CH3SCH2CH=C(CN)OSi(CH3)3, which undergoes exclusively a-alkylation.2... 

Claisen rearrangement of allyl a-hydroxy acetates, a-hydroxy-y,S-unsaturated acids. Allyl a-hydroxy acetates undergo Claisen rearrangement when treated with LDA (2 equiv.) to give, after aqueous workup, a-hydroxy-)1,6-unsaturated acids. 1 Example ... 

Cyclopentenone annelation (cf. 10,444). The reagent undergoes a Nazarov-type cyclization with an a,/S-unsaturated acid chloride to give an annelated 3-phenylthio-cyclopentenone. This reaction was used to prepare the bicyclic cyclopentenone 3, a useful intermediate in synthesis of cyclopentenoid natural products, such as hirsutene (4).3... 

Selenolactonization.1 Chlorinated by-products can be formed when selenolac-tonization is effected with the usual reagent, C Sed (8, 26-28 13, 26). Reaction of y,5- and 5,s-unsaturated acids with C6H5SeOTf proceeds even at -78° to give y-and 8-lactones, respectively, in high yield. 

Acyclic a,/3-unsaturated acid chlorides do not undergo this acylation. However, cyclic vinylsilanes also undergo Friedel-Crafts acylation with a,/S-unsaturated acid chlorides to give dienones of type a, which are cyciized by SnCl to cyclopentenones. A typical example is formulated for the reaction of 5-methyl-l-tri-methylsilylcyclopentene (3) with j3,iS-dimethylacryloyl chloride. The first step is conducted with AICI3 and gives 4, which after isolation is cyciized with SnCU to a mixture of 5 and 6. The cyclopentenone 6 is obtained in 55% overall yield after isomerization with RhCU. 

Ring fission occurs readily in many of these compounds. For example, azlactones, i.e. 4JT-oxazolin-5-ones containing an exocyclic C=C bond at the 4-position (508), are hydrolyzed to a-benzamido-a,/S-unsaturated acids (509), further hydrolysis of which gives a-keto acids (510). Reduction and subsequent hydrolysis in situ of azlactones is used in the synthesis of a-amino acids (e.g. 508 - 507). 

Lactones are among the most abundant substructures in natural products." This fact had kindled enormous activity in the field of y-lactone synthesis." 7-Lactones have been prepared by direct cycloacylation of 7-hydroxy acids, eiAer as such or generated as transient intermediates, and by cycloalkyl ation, either of 7-halocarboxylates or of 3,7- or 7,S-unsaturated acids by additions to the double bond. 

Reformatsky-type10 reaction into zinc enolates (2) by treatment with zinc dust in a refluxing aromatic hydrocarbon solvent. These undergo Claisen rearrangement to zinc carboxylates (3) of y,unsaturated acids. Yields are depressed by a-alkyl substitution of (1) thus (3) is obtained in 100% yield when R = R2 = CH3 and R3 = R4 = H. When R1 = CH3, R2 and R4 = H, and R3 = C6H5, the yield of (3) is only 16%. 

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)... 

A new synthesis of a)S-unsaturated acids has been developed through alkylation of dibenzyl phosphite anion followed by carboxylation to give the phosphonate (11), which gives the olefin on reaction with aldehydes and two... 

Vinylcyclobutanones (51) can be prepared by cycloaddition of vinylketenes such as 49 (generated in situ by elimination of hydrogen chloride with triethylamine from a,)S-unsaturated acid chlorides) to ) ,j -dialkyl enamines such as 50 (equation 8) . This type of reaction was originally reported by Hickmott and coworkers. ... 

Similar to the ketene thioacetal. vinyl and alkynyl thioelhers react with 2-oxazolidinone derivatives of s ,/ -unsaturated acids to give the corresponding cyclobutanes and cyclobutenes with almost complete asymmetric induction0,31-35. From a [2 + 2] adduct, prepared by use of a chiral titanium Lewis acid, a carbocyclic analog of the four-membered nucleoside oxetanocin A has been readily prepared in optically pure form10. 

A synthesis of a-substituted S-unsaturated acids exploits the facile Claisen rearrangement of allyl ester enolates, which can be generated by conjugate addition of organocopper reagents to ally 2-alkenoates. ... 

Claisen rearrangement of ally silyl ethers (4,307-308). Katzenellenbogen and Christy have extended the rearrangement of silyl enol ether derivatives of allylic acetates to y,S-unsaturated acids to systems in which a trisubstituted double bond is generated. Thus 3-acetoxy-2-methyl-l-nonene (1) was treated with lithium N-isopropylcyclohexylamide (LilCA) in THF at -78° and then with f-butyldimethylchlorosilane to give the f-butyldimethylsiloxyvinyl ether... 

Reactions of Thiazolium Salts. The thiazolium salt (45 R = benzyl, X = OH, Y = Cl) catalyses the addition of aldehydes to activated double-bonds, e.g. a/S-unsaturated acids, esters, and nitriles. A novel route to 4-alkyl-2H-l,4-thiazin-3-ones (46 R = alkyl or benzyl) involves the quaternization of 2-methylthiazole with RI, iodination with I2 and NEta, and treatment of the 2-(iodomethyl)thiazolium iodides with potassium hydroxide. ... 

Complexation of a/S-unsaturated acids and amides has been extensively studied/ In such cases, both diastereomers of a species involving coordination of both olefin and carboxylate group are observed, usually in comparable proportions. The extent of complexation is enhanced and the rate of exchange of free and bound substrate reduced when base is added, or a preformed tetraalkylammonium carboxylate is employed. This suggests that structures (62) and (63) best describe the complex. The spectra observed are almost identical to those derived from E-dehydroamino acid derivatives, implying that the latter have structure (64) in accord with labeling studies. ... 

Di- and trisubstituted 1,3-dienes were converted to y-S-unsaturated acids by using the previously described catalytic system involving formic acid, carbon monoxide, and Pd-C/PPhj/dppb in 1,2-dimethoxyethane (DME). The hydrocarboxylation of isoprene, for example, occurs under 6.2 atm of CO and at 110 °C to form the corresponding jS-y-unsat-urated acid in 52% yield (Eq. 

The metallation of thiophen and 2- and 3-methylthiophen with butylcaesium and butylpotassium has been studied. Thienylcopper reagents have been used for the synthesis of iodo-thiophens. Thienyltin(iv) compounds have been prepared. The chemistry of thienyl-lead(iv)tricarboxylate has been investigated. The cleavage of the thiophen-silicon bond in tris(trichloro-2-thienyl)-methylsilane with butyl-lithium to give thienyl-lithium derivatives has been achieved. Considerable work on the synthesis and reactions of compounds containing thiophen-phosphorus bonds has appeared/ " and the reactions with a/S-unsaturated acid derivatives have been extensively studied. ... 

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