A-Alkylidene ketones

Some representative examples of the [3+2] annulatlon are listed in Table 1. Both cyclic and acyclic allenophiles participate in the reaction, a-Alkylidene ketones undergo annulation to provide access to spiro-fused systems, and acetylenic allenophiles react to form cyclopentadiene derivatives. The reactions of (E)- and (Z)-3-methy1-3-penten-2-one illustrate the stereochemical course of the annulation, which proceeds with a strong preference for the suprafacial addition of the allene to the two-carbon allenophile. The high stereoselectivity displayed by the reaction permits the stereocontrol led synthesis of a variety of mono- and polycyclic systems. 

This very useful reaction resulted from a failed attempt to introduce a new protected methyl vinyl ketone equivalent for the all important Robinson annul-lation reaction. This failure turned out to be quite rewarding, for it allowed for a fast, simple, mild, and high yielding construction of a-alkylidene ketones, esters, and nitriles, as well as /3-methylenebutyrolactones, a family of compounds with several representatives among the tumor growth inhibitors. The method, unfortunately, has its own limitations, which will be discussed after exposing probable mechanisms. 

Substituted-3-methoxy-l,3-dienes a-alkylidene ketones. A route to these compounds from methoxyallene is shown in equation (I). The organoheterocu-prate reagent is prepared from RMgX and CuBr and is activated with LiBr. ... 

Note. Like acylation, alkylidenation is often carried out with a view to subsequent cyclization. Such alkylidenation is almost invariably done with an arene- or heteroarenecarbaldehyde, a related ketone, or occasionally an ethynylarene appropriate procedures are exemplified here. 

The reaction of titanocene-alkylidenes generated from thioacetals with nitriles followed by hydrolysis affords ketones. Like the reaction of titanocene-methylidene, this reaction may proceed via the azatitanacydobutene 87 and/or the vinylimido complex 88, which reacts with an organic halide to form an a-substituted ketone [80] (Scheme 14.37). 

The C=C bond in a 5-(alkylidene)oxazoline 644 is activated for electrophilic reactions similar to that in analogous vinyl acetates. Rohm Haas researchers exploited this property to prepare chloromethyl ketone fungicides 646 (Scheme 8.203). The overall process constitutes an indirect chlorination of a-amido ketones since the 5-(vinylidene)oxazolines were prepared from a-amido ketones. 

Reactions of unsymmetrical methylene 1,3-dicarbonyl compounds with enol ethers have been investigated by Yamauchi et al. [137]. As we have mentioned earlier, the a,/ -unsaturated ketone moiety in alkylidene-/ -ketoesters reacts exclusively as the oxabutadiene. However, high regioselectivity is also observed with mixed alkyl-phenyl-1,3-diketones with exclusive reaction of the aliphatic carbonyl group, whereas in alkylidene-1,3-dicarbonyl compounds bearing an aldehyde and a keto-moiety, the a,/J-unsaturated aldehyde reacts preferentially as oxabutadiene, but not exclusively [130a]. 

Vinylcyclopropanols can be prepared either from the readily available cyclopro-panone hemiacetaP, from 1-hydroxycyclopropanecarboxaldehyde derivativesfrom a,a -dichloroacetone, from the silver Simmons-Smith cyclopropanation of a-ethylenic ketone silyl enol ethers from the dye-sensitized photo-oxygenation of alkylidene-cyclopropanes or from the ring-opening of oxaspiropentanes (cf. Section III.C). Consequently, they become participants of choice in a number of useful chemical transformations (see also Section IV.A). 

As shown in Scheme 38, several primary alkyl-substituted cyclohexanones have been prepared by Lewis acid catalyzed phenylthioalkylation of the TMS enol ether of cyclohexanone followed by reductive removal of a phenylsulfenyl group. The two-step neopentylation sequence is particularly noteworthy. This methodology has been used to prepare numerous a-alkylated cyclic and acyclic ketones. a-Alkylated aldehydes can be produced in a like manner. a-Alkylidenation can also be accomplished by oxidative removal of sulfur. Lee and coworkers have found that TMS triflate-catalyzed reactions of silyl enol ethers of cyclic ketones and aldehydes with saturated and unsaturated l,l-dimethoxy-(i>-tri-methylstannanes, followed by addition of titanium tetrachloride, provide novel routes to fused and spiro-cyclic ring systems. Phenylthiomethylstannylations of silyl enol ethers have also been reported. ... 

Reductive desulphonylation of a-alkylidene fi-oxosulphones (typical procedure) To a solntion of NaTeH, prepared from tellurium (0.65 g, 5 mmol) and NaBH (0.45 g, 12 mmol) in EtOH (20 mL) under Nj, is added, while stirring, a solution of a-(p-bromoben-zylidene) )3-ketosulphone (0.73 g, 2 mmol) in DMF (15 mL). The solution, which immediately turns red-black, is stirred at room temperature for 3 h, and after addition of HjO (30 mL) is exposed to air for 30 min, to precipitate tellurium. The mixture is fdtered, the filtrate extracted with EtjO (3x40 mL) and the combined ether extracts dried (MgS04) and concentrated in vacuo to give the crude product, which is purified by SiOj chromatography (elution with benzene/EtOAc, 10 1), giving pure 2-(p-bromophenyl)ethyl phenyl ketone (0.46 g (80%) m.p. 65-66°C). 

As was mentioned in Section IV.4, zl4-thiazoline-2-thiones (CXXXI) can be synthesized by the isomerization of 5-alkylidene thiazolidine-2-thiones (method B). A simpler route of preparing these compounds is the reaction of a-chloro ketones with dithiocarbamic acids (23, 35, 142, 184, 249, 250, 257, 325, 363) (method Aj). 

The intermediates of the reaction of dithiocarbamic acids with a-halo ketones, the 4-hydroxy thiazohdine-2-thiones (CXCIIb), can sometimes be isolated 184, 257, 863 ). On treatment with acid these split off water and are converted into Zl4-thiazoline-2-thiones. However, when there is no hydrogen on the Cg carbon atom, as with the thiazolidine-2-thione obtained from -bromobenzylideneacetone, the elimination of water involves the hydrogen atom of the 4-alkyl group so that 4-alkylidene-5-benzylidene thiazolidme-2-thiones (CXCIII) are formed. Il, in (CXCIIb), Ra is an aromatic group as in the thiazolidine-2-thione obtained from... 

The lithium dianion of 2,4-oxazolidinedione (122) reacts with a-halo ketones to give alkylidene compounds that can be transformed into 3,5-dihydroxy-2(5fl)-furanones (123) by oxidation, followed by hydrolysis (Scheme 47) <92JOC4558>. 

Alkylidenecyclopropyl ketones 2, accessible by the Rh-catalysed cyclopropanation of allenes with a-diazo ketones, afford 4//-pyrans through a Pd-catalysed cycloisomerisation. In one instance, where the substrate lacked a hydrogen atom on the alkylidene moiety, a 2//-pyran was obtained <04JA9645>. 

Ketone Oder Aldehyde reagieren in Gegenwart starker Basen (z. B. Natriumhydrid, -metha-nolat, Kalium-tert.-butanolat) mit Bernsteinsaure-diestern zu a-Alkyliden- oder a-Aralky-liden-bernsteinsaure-estern (Mechanismus792 793) ... 

B.V. The Stobbe Condensation. When succinic ester derivatives (such as diethyl succinate, 215) are condensed with non-enolizable ketones or aldehydes in the presence of base, the initial condensation product is 216. The alkoxide reacts with the distal ester via acyl substitution to give a lactone intermediate (217). In the original version of this reaction, saponification of 217 gave the a-alkylidene monoester, 218. The reaction is not completely general and is limited to those a, co-diesters for which the Dieckmann condensation is not a... 

Carbonylations. Carbonylation reactions concomitant with cyclization of iodoalkenes leading to cyclopentenones or fZ>a-alkylidene-7-butyrolactones are of apparent interest to chemists in the field of synthesis. Other processes that unite three different components result in allyl ketones and a-methylenephenones. ... 

Aldol reaction between a ketone and an aldehyde can be controlled by prior conversion of the ketone into the ethyloxalyl derivative before reaction with the aldehyde. The keto-lactone so formed is decomposed to an alkene moiety with base. This method is particularly well suited to the formation of a-alkylidene-cyclo-alkanones (ring size >6) and a-alkylidene-y-lactones (Scheme 73). ... 

Condensation of aldehydes or ketones with diethyl succinate in the presence of a strong base to form monoesters of a-alkylidene (or arylidene) succinic acids ... 

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