Ketone Alkylation, intramolecular

Thioamides exhibit a pronounced nucleophilic character due to their nitrogen atom. Alkyl halides often react at room temperature to give thioimi-doester salts which may be subsequently used. This reaction was applied [134] to the preparation of an enaminoketone, the cyclohexenone ring being formed by base treatment of a ketone and intramolecular reaction with the iminium salt. A similar sequence [135] was mentioned in Scheme 28. 

Macrocyclic ketones. A recent method for synthesis of macrocyclic ketones involves intramolecular alkylation of protected cyanohydrins. Sodium hexamethyidisilazide... 

Other applications of this method include, e.g. the synthesis of the antibiotic A26771B (5i) [118] and the marine cembranolide isolobophytolide [119], Trost and Warner [120] reported that a-sulfonyl sulfones can also serve as the substrates of ir-allylpalladium complexes for macrocyclization. Furthermore, an a-hydroxy-carbonyl ketone was alkylated intramolecularly by a a-allylpalladium complex in the total synthesis of the macrocyclic sesquiterpene humulene [121]. 

Intramolecular aldol/Perkin type condensation of orf/to-formylaryloxyacetic acids and arylthioacetic esters produces benzofuran- and benzothiophene-2-esters respectively, as illustrated below. The synthesis can be performed in one pot, thus ortfto-hydroxyaryl-aldehydes or -ketones, are 0-alkylated with a-halo-ketones, then intramolecular aldol condensation in situ produces 2-acyl or 2-aroyl-benzofurans. ° For benzothiophenes, the ring-closure substrates can also be obtained via methyl thioacetate displacement of fluoride from orf/to-fluoro-araldehydes. ... 

The dianions derived from acetoacetates are hard nucleophiles and usually react in a [1,2] fashion with a, 3-unsaturated carbonyls. Complementary to this are the reactions of bis-silyloxydiene (108), which reacts in a Michael sense with, for example, ethyl acrylate the initial product undergoes intramolecular condensation leading to the cyclobutane (109)Preliminary work also indicates that this potentially useful diene condenses cleanly with saturated aldehydes and ketones. Alkyl-lithiums (R Li) add conjugatively to ethoxymethylenemalonates... 

The first synthetically useful Schmidt reactions of alkyl azides with ketones were intramolecular. Thus, it was shown that azido-tethered ketones, when treated with Brpnsted or Lewis adds in CH2CI2 at room temperature, were converted to lactams in good to excellent yields (Table 7.1). Mono- and bicyclic ketones are attractive substrates for the preparation of fused bi- and tricyclic lactams and the range of ring sizes accommodated... 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

Various organotin reagents react with acyl and aroyl halides under mild conditions without decarbonylation to give carbonyl compounds[390,39l]. Alkyl- or alkenyltin reagents react with acyl and aroyl chlorides to give ketones[548.733,734]. One example is the preparation of the a,/3-dnsaturated 7-keto esters 860 and 861, carried out under a CO atmosphere[735]. The reaction has been applied intramolecularly to the synthesis of the macrocyclic keto... 

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),... 

Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group. 

In ketones having propyl or longer alkyl groups as a carbonyl substituent, intramolecular hydrogen abstraction can be followed by either cleavage of the bond between the a and P carbon atoms or by formation of a cyclobutanol ... 

The most efficient intramolecular secondary processes competing with the acyl-alkyl diradical recombination in five-membered and larger cyclic ketones are hydrogen shifts resulting in the disproportionation of the diradical to either ketenes or unsaturated aldehydes [cf. (5) (4) (6)]. 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

An unusual solvent system was chosen for the intramolecular reductive alkylation of the masked amino ketone (15). The purpose of the strongly acid system was to prevent cyclization of the deblocked amino ketone to 16, further hydrogenation of which gives the unwanted isomer 17 by attack at the convex face. The desired opposite isomer can be obtained by reduction of 16 with UAIH4 (52). 

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. 

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

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. 

Longifolene has also been synthesized from ( ) Wieland-Miescher ketone by a series of reactions that feature an intramolecular enolate alkylation and ring expansion, as shown in Scheme 13.26. The starting material was converted to a dibromo ketone via the Mr-silyl enol ether in the first sequence of reactions. This intermediate underwent an intramolecular enolate alkylation to form the C(7)—C(10) bond. The ring expansion was then done by conversion of the ketone to a silyl enol ether, cyclopropanation, and treatment of the siloxycyclopropane with FeCl3. 

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cydization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(ll) iodide induced a 6-exo-trig cydization, furnishing a samarium enolate intermediate... 

The addition of halomethyl metal reagents provides another Darzens-like route to aziridines <06JOC9373>. Reaction of ICH2C1 with MeLi generates a chloromethyllithium reagent, which then adds to the inline 74. A subsequent intramolecular /V-alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene. 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

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