Ketones intramolecular additions

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. 

Tl mediated Inter or intramolecular addition of allytic silanes to ouMnsaiurated ketones or to aldehydes. 

Other nucleophiles add to conjugated systems to give Michael-type products. Aniline derivatives add to conjugated aldehydes in the presence of a catalytic amount of DBU (p. 488). Amines add to conjugated esters in the presence of InCla, La(OTf)3, or YTb(OTf)3 at 3kbar, for example, to give P-amino esters. This reaction can be initiated photochemically. An intramolecular addition of an amine unit to a conjugated ketone in the presence of a palladium catalyst, or... 

Diketones give furans when treated with acids. This is actually an example of an intramolecular addition of an alcohol to a ketone, since it is the enol form that adds ... 

Rhodium carboxylates have been found to be effective catalysts for intramolecular C—H insertion reactions of a-diazo ketones and esters.215 In flexible systems, five-membered rings are formed in preference to six-membered ones. Insertion into methine hydrogen is preferred to a methylene hydrogen. Intramolecular insertion can be competitive with intramolecular addition. Product ratios can to some extent be controlled by the specific rhodium catalyst that is used.216 In the example shown, insertion is the exclusive reaction with Rh2(02CC4F9)4, whereas only addition occurs with Rh2(caprolactamate)4, which indicates that the more electrophilic carbenoids favor insertion. 

Perhaps the most elusive variant of the aldol reaction involves the addition of metallo-aldehyde enolates to ketones. A single stoichiometric variant of this transformation is known [29]. As aldolization is driven by chelation, intramolecular addition to afford a robust transition metal aldolate should bias the enolate-aldolate equilibria toward the latter [30, 31]. Indeed, upon exposure to basic hydrogenation conditions, keto-enal substrates provide the corresponding cycloal-dol products, though competitive 1,4-reduction is observed (Scheme 22.7) [24 d]. 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Acylpalladium intermediates can be involved in intramolecular processes leading to the formation of carbo- or heterocycles. In this chapter we discuss the cyclizations via the attack of acylpalladium intemediates at carbon centers and formation of new G-G bonds. The basic scheme (Scheme 7) of such processes includes the oxidative addition of Pd(0) to G(j )-X bonds (X = halogen or triflate), migratory insertion of GO, and subsequent intramolecular addition of acylpalladium intermediate to double or triple bonds to yield cyclic ketones. 

In the case of an intramolecular 1,4-addition, no activation is required . The iodoenone 238 is readily converted into the conesponding alkylzinc iodide, which undergoes an intramolecular addition at 25 "C in THF affording the bicyclic ketone 239 in 65-67%... 

The acid-mediated intramolecular addition of the azide to the ketone proceeds by way of addition followed by a pinacol-type rearrangement, to give the amide 12. The regioselectivity of the bond migration is remarkable. Reduction of the amide then gave 3. 

In this case, because the ketone has no a hydrogen, the base removed a 3 hydrogen (from a CH3 group), and the intramolecular addition to the C=0 followed.399... 

Substituted, 2,3-disubstituted, and 2,3-annulated thiophenes can be prepared by reactions of ketone enolates with carbonodithioic acid O-ethyl 5-(2-oxoethyl)ester. Hydrolysis of the resulting aldols, intramolecular addition of thiol group to the carbonyl group, and elimination of two molecules of water lead to the thiophenes (116) (Scheme 38) (92HCA907). 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

In 1986, Belotti, Pete and Portella reported that intramolecular ketone/olefin coupling could be achieved via photoinduced electron transfer (irradiation of an aliphatic ketone in HMPA)78. Several examples of this chemistry are highlighted below (Scheme 26). Intramolecular additions to C=C and allenes were also reported with yields in the range 70-80% however, additions to C=N were unsuccessful. 

The presence of an or /zo-hydroxyphenyl substituent in an a,(3-unsaturated ketone (e.g., 94) can complicate the reaction with intramolecular addition of a hydroxyl group to the double bond of dihydripyrimidine [93] (Scheme 3.28). 

Cardenas, D. J. Echavarren, A. M. Selectivity in the aliphatic palladation of ketone hydra-zones. An example of Pd-promoted intramolecular addition of a N, N-dimethylhydrazone to an alkene. Organometattics 1995, 14, 4427— 4430. 

Molander and co-workers have studied the stereoselective intramolecular addition of ketyl radicals to olefins [95JOC872]. The ketyl radicals are generated from ketone by treatment with samarium(II) diiodide. A similar reaction sequence using 61 gave only elimination products. 

Metal-mediated intramolecular addition of silyl enolates to alkynes is also valuable for the synthesis of cyclic ketones. A stoichiometric amount of HgCl2 or EtAlCl2 effectively promotes the cycloalkenylation via anti-addition to alkynes (Equations (87) and (88)).319 320a The -addition mode can be explained by a metal coordination to the triple bond and subsequent attack of the enolate moiety from the opposite side to the metal. The resultant alkenylmetals can be used for carbon-carbon and carbon-heteroatom bond formation as well as protonation. 

A perusal of the literature discloses that ketones and aldehydes have rarely been reacted with 44. In view of the tendency of ynamines to add water and alkohols, it is obvious that ynamines 56 undergo intramolecular addition of water (Meyer-Schuster rearrangement) quite readily (96). This process is provoked already by silicagel, alumina or it even occurs spontaneously 146). 

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