5-Lactones alkylation

Another pioneering experiment in lactone alkylations is the transformation of the tricyclic y-lactone 3 to the methylated derivative 4. This has been achieved by treating 3 successively with excess triphenylmethyllithium in dimethoxyethane, iodomethane and aqueous acid to give 4 in good yield9. 

It has been shown in the previous examples of 5-lactone alkylations that a substituent in the /(-position strongly induces attack of the electrophile from the opposite side (e.g., see references 60 and 61). These findings correspond to common sense first approximations. However, an interesting example has been reported where this effect is nearly completely suppressed by a second stereochemical barrier. Alkylation of the enolate 18 can either give 19a or 19b. 

The direct detection of monomer radicals according to this kind of procedure as well as using other experiments allowed to deeply investigate a large variety of thiyl [292], heterocyclic thiyl [293], lactone alkyl [294], silyl [127], aminoakyl [295], oxyl and peroxyl [296] radicals, and so on. Many addition rate constants of various initiating radicals to monomer double bonds have therefore been determined they correspond to the usual initiation rate constant kr Examples are shown in Table 10.2. 

Epoxides, strained-ring lactones, alkyl sulfates, alkyl halides... 

Alkylation by esters, lactones, alkyl sulfates, or alkyl sulfonates... 

Compound Wpes Mass values Alkanes Alkenes, Mono- cyclo- alkanes Alkynes, Dienes, Cyclo- alkenes Poly- cyclic alicycles Alkanones, Alkanals Alcohols, Alkyl ethers Cyclic alcohols Cyclo- alkanones Aliphat.. acids. Esters, Lactones Alkyl- amines... 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

The reaction of perfluoroalkyl iodides with alkenes affords the perfluoro-alkylated alkyl iodides 931. Q.a-Difluoro-functionalized phosphonates are prepared by the addition of the iododifluoromethylphosphonate (932) at room temperature[778], A one-electron transfer-initiated radical mechanism has been proposed for the addition reaction. Addition to alkynes affords 1-perfluoro-alkyl-2-iodoalkenes (933)[779-781]. The fluorine-containing oxirane 934 is obtained by the reaction of allyl aicohol[782]. Under a CO atmosphere, the carbocarbonylation of the alkenol 935 and the alkynol 937 takes place with perfluoroalkyl iodides to give the fluorine-containing lactones 936 and 938[783]. 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

The reaction can be applied to allyl malonates. Alkylation of diallyl mal-onate (734) with bromoacetate and acetoxymethylation afford the mixed triester 735. Treatment of the tricster 735 with Pd catalyst affords allyl ethyl itaconate (736). In a similar way, a-methylene lactone and the lactam 737 can be prepared[462]. 

The telomer 145 of nitroethane was used for the synthesis of recifeiolide (148)[121], The nitro group was converted into a hydroxy group via the ketone and the terminal double bond was converted into iodide to give 146. The ester 147 of phenythioacetic acid was prepared and its intramolecular alkylation afforded the 12-membered lactone, which was converted into recifeiolide (148),... 

Indoles can also be alkylated by lactones[l4]. Base-catalysed reactions have been reported for (3-propiolactone[15], y-butyrolactone[10] and 5-valerolac-tone[10]. These reactions probably reflect the thermodynamic instability of the N -acylindole intermediate which would be formed by attack at the carbonyl group relative to reclosure to the lactone. The reversibility of the JV-acylation would permit the thermodynamically favourable N-alkylation to occur. 

The use of epoxides as alkylating agents for diethyl malonate provides a useful route to y lactones Wnte equations illustrating such a sequence for styrene oxide as the starting epoxide Is the lactone formed by this reaction 3 phenylbutanohde or is it 4 phenylbutanohde ... 

Stereoselective All lations. Ben2ene is stereoselectively alkylated with chiral 4-valerolactone in the presence of aluminum chloride with 50% net inversion of configuration (32). The stereoselectivity is explained by the coordination of the Lewis acid with the carbonyl oxygen of the lactone, resulting in the typ displacement at the C—O bond. Partial racemi2ation of the substrate (incomplete inversion of configuration) results by internal... 

Double Fiiedel-Ciafts alkylation of configuiationally pure pyiocene (a substituted lactone) with aiomatics results in the formation of cycloalkylation product with retention of configuration at the chiral center (63). 

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

Oxiranones (a-lactones) (Section 5.05.3.2.1), e.g. (6), in accord with their putative facile opening to zwitterions (Scheme 18), usually react readily with nucleophiles by alkyl-oxygen cleavage (Scheme 41) (71JA557), rather than the acyl-oxygen cleavage common for esters. 

This represents hydrastine as a seeondary amine and a free acid, though the alkaloid reacts with alkyl iodides on the whole as a tertiary amine and forms salts with alkalis rather as a lactone than as a free acid. These and other considerations led Freund and Rosenberg to suggest the alternative formula (IV), based on Roser s formula for narcotine (p. 204). 

Lithium aluminum hydride (LiAlH4) is the most powerful of the hydride reagents. It reduces acid chlorides, esters, lactones, acids, anhydrides, aldehydes, ketones and epoxides to alcohols amides, nitriles, imines and oximes to amines primary and secondary alkyl halides and toluenesulfonates to... 

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