Alkylations intramolecular

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),... 

Gumylphenol. -Cumylphenol (PGP) or 4-(1-methyl-l-phenylethyl)phenol is produced by the alkylation of phenol with a-methylstyrene under acid catalysis. a-Methylstyrene is a by-product from the production of phenol via the cumene oxidation process. The principal by-products from the production of 4-cumylphenol result from the dimerization and intramolecular alkylation of a-methylstyrene to yield substituted indanes. 4-Cumylphenol [599-64-4] is purified by either fractional distillation or crystallization from a suitable solvent. Purification by crystallization results in the easy separation of the substituted indanes from the product and yields a soHd material which is packaged in plastic or paper bags (20 kg net weight). Purification of 4-cumylphenol by fractional distillation yields a product which is almost totally free of any dicumylphenol. The molten product resulting from purification by distillation can be flaked to yield a soHd form however, the soHd form of 4-cumylphenol sinters severely over time. PGP is best stored and transported as a molten material. 

An interesting case of ipso intramolecular alkylation has been observed in the case of the acid-promoted cyclization of the amino alcohols (61). With trifluoroacetic acid the major product was the rearranged thienopyridine (62), whereas with polyphosphoric acid the product formed exclusively was the non-rearranged thienopyridine (63) (82CC793). 

Oxidative Ring Closure Reactions 4.03.4.1.1 C—N bond formation N—N bond formation C—S bond formation N—S bond formation O—C bond formation O—N bond formation S—S, S—Se and Se—Se bond formation Electrophilic Ring Closures via Acylium Ions and Related Intermediates Ring Closures via Intramolecular Alkylations... 

Chloromethylpyrrolidine (309) when treated with CS2 in DMF in the presence of potassium carbonate readily formed the dithiocarbamate (310). In the presence of base, intramolecular alkylation on sulfur occurred to give (311) (63JOC981). 

Electrophilic attack on the sulfur atom of thiiranes by alkyl halides does not give thiiranium salts but rather products derived from attack of the halide ion on the intermediate cyclic salt (B-81MI50602). Treatment of a s-2,3-dimethylthiirane with methyl iodide yields cis-2-butene by two possible mechanisms (Scheme 31). A stereoselective isomerization of alkenes is accomplished by conversion to a thiirane of opposite stereochemistry followed by desulfurization by methyl iodide (75TL2709). Treatment of thiiranes with alkyl chlorides and bromides gives 2-chloro- or 2-bromo-ethyl sulfides (Scheme 32). Intramolecular alkylation of the sulfur atom of a thiirane may occur if the geometry is favorable the intermediate sulfonium ions are unstable to nucleophilic attack and rearrangement may occur (Scheme 33). 

Adenine, N -ethyl-N -hydroxyethyl-intramolecular alkylation, 5, 531 Adenine, N -formylmethyl-... 

Imidazo[4,5-6]pyridine, 3-(2,3-0-isopropylidene-5-p-toluenesulfonyl-jS-D-ribofuranosyl)-intramolecular alkylation, 5, 616 Imidazo[4,5-6]pyridine, 1-methyl-bromination, 5, 617 nitration, 5, 617... 

Many Jluonnaled aromatic compounds are alkylated with alkyl halides under Fnedel-Crafis conditions For example, the intramolecular alkylation of 3-fluoro-At-(chloroaee-tyl)amhne with alununum chlonde gives 6-fluorooxmdole [5] (equation 5) Similarly, 3 -chloro-4-fluoropropiophenone affords 5-fluoromdanone [6] (equation 6)... 

Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

A pseudo 1,2 cycloaddition (actually a 1,3 cycloaddition, but may be considered a 1,2 type if a three-membered ring is considered analogous to an alkene) is observed when the pyrrolidine enamine of cyclohexanone is allowed to react with N-carbethoxyaziridine (129) to produce octahydro-indole 130 91). Octahydroindoles and pyrrolidines can also be produced through the intramolecular alkylation of the enamines of certain halo-ketourethanes 176a). 

Addition to 1,2-dimethyl- -piperideine or 1,2-dimethyl- -pyrroline is followed by intramolecular alkylation by the ester group as a side reaction to give 140 and 141 ( = 1, 2), respectively. Cyclization products 142 and... 

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

A related route to the protoberberine skeleton was reported by Lete, in which substrate 54 underwent Bischler-Napieralski reaction followed by intramolecular alkylation of an in situ generated alkyl chloride to afford 55. °... 

Stork s elegant use of a protected cyanohydrin function in the synthesis of PGF2a (2) is also noteworthy. The electron-withdrawing cyano substituent in intermediate 21 (Scheme 7) confers nucleophilic potential to C-9 and permits the construction of the saturated cyclopentane nucleus of PGF2a (2) through intramolecular alkylation. In addition, the C-9 cyanohydrin function contained within 40 is stable under the acidic conditions used to accomplish the conversion of 39 to 40 (see Scheme 7), and it thus provides suitable protection for an otherwise labile /J-hydroxy ketone. 

Helquist and coworkers60 have developed a six-membered ring annulation via a conjugate addition of aryllithium generated by metal-halogen exchange and subsequent intramolecular alkylation. This is illustrated in equation 71. 

The tandem intramolecular conjugate addition to 99 followed by an intramolecular alkylation reaction leads to a bis-cyclized product in good yield (equation 80)66. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

It is also well known that alkyl groups can be tran.sferred intramolecularly from one position to another on the same ring and intermoiccularly from one aromatic ring to another through dealkylation reactions catalyzed by Lewis acid. The intramolecular alkyl-transfer is called reorientation or isomerization and the intermolecular alkyl transfer is referred to as disproportionation. Reorientation processes arc normally faster than disproportionation. 

The common atoms are marked in (25a) and the best disconnections correspond to the intramolecular alkylation of ketone (26) or (27). 

Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular alkylation reactions. Additional examples of intramolecular alkylation are considered in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched substituent leads to a trans orientation of the methyl group. 

An intramolecular alkylation following this stereochemical pattern was used in the synthesis of (-)-fumagillol, with the alkadienyl substituent exerting the dominant conformational effect.88... 

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Intramolecular alkylation of enolates can be used to synthesize bi- and tricyclic compounds. Identify all the bonds in the following compounds that could be formed by intramolecular enolate alkylation. Select the one that you think is most likely to succeed and suggest reasonable reactants and reaction conditions for cyclization. 

Chapter 1 deals with alkylation of carbon nucleophiles by alkyl halides and tosylates. We discuss the major factors affecting stereoselectivity in both cyclic and acyclic compounds and consider intramolecular alkylation and the use of chiral auxiliaries. 

Some dyes can be formed from triphenylmethane leuco materials by simple thermolysis. For example, when 28 is heated an irreversible intramolecular alkylation reaction occurs to form the stable dye41 29 (Eq. 1). 

A simple one-pot preparation of cA-cyclopropanes from y,8-ketoal-kenes using intramolecular alkylation under aqueous conditions was reported. Sequential treatment of y,8-keto alkenes with aqueous NBS in DMSO and then with solid KOH provides cA-cyclopropanes in good overall yields with a diastereoselective excess >99% (Eq. 6.18).38... 

Diethyl 1,1-cyclobutanedicarboxylate has been prepared by the alkylation of diethyl sodiomalonate with trimethylene dibromide 8i4>6 7 or with trimethylene chlorobromide 6-8 and by the peroxide-catalyzed addition of hydrogen bromide to diethyl allylmalonate followed by intramolecular alkylation.9 The procedure described here is that of Mariella and Raube.6... 

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