A-METHYLENE KETONES AND

Cyclic a-methylene ketones and lactones, in which the syn conformation is enforced, give predominantly exo adducts.14... 

Reaction of 2-aminobenzophenone with acetyl acetone in the presence of Bi(OTf)3 (5 mol%) results in the formation of 3-acetyl-2-methyl-4-phenylquinoline [117]. Various 1,3-diketones, acyclic ketones and cyclic ketone undergo the condensation with 2-aminoaryl ketones. The scope and generality of this process is illustrated with respect to various 2-aminoaryl ketones and a wide array of a-methylene ketones, and the results are summarized in Table 6. This method is free from side reactions such as the self-condensation of ketones, which is normally observed under basic conditions. Unlike reported methods, the present protocol does not require high temperature or drastic conditions to produce quinoline derivatives. 

This sequence transforms acyclic ketones and aldehydes into a-methylene ketones and a-methyl-a,)5-unsaturated ketones and aldehydes It has been illustrated by the synthesis of eucarvone, ( )-nuciferal and ( )-manicone This ring-opening of chlorosiloxycyc-lopropanes with ClSiMea elimination appears to be a practical route to Z or a,)5-ethylenic aldehydes and ketones depending on the stereochemistry of the reactants. For example, conversion in MeOH-NEta at 20°C of the 2-chloro-2-methyl-3-pentyl-l-trimethylsiloxycyclopropanes (derived from the addition of the chloromethylcarbene to the E and Z silyl enol ethers of n-heptanal) leads either to or Z 2-methyl-oct-2-enal (equation 65). ... 

From Sulfur, a-Methylene-Ketones and Malononitrile or Cyanoacetate The Gewald Synthesis ... 

An alternative synthesis of a-methylene ketones and esters is provided by enolate alkylation using benzyl bromomethyl sulfide followed by oxidative elimination (Scheme 10). The addition of sodium thiophenoxide to a-methylenebutyrolactones has been recommended for protection of the sensitive double bond, which can be regenerated by oxidative elimination. ... 

In the alkaline medium, isatin is cleaved at the amide bond and converted to the salt 82 of isatinic acid, which undergoes aldol condensation with a-methylene ketones and cyclization with H2O elimination affording quinoline-4-carboxyhc acids (83). Notably, N-acetylisatins (84), after base-induced ring-opening (— -85), undergo an intramolecular aldol condensation giving rise to 2-quinolone-4-carboxylic acids (86). 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid. (In acetic acid the Mannich bases undergo elimination of dimethylamine to give a-methylene ketones.) This method is rapid and affords products having an isomeric purity of at least 90% without difficult separations. The 49-57% yield of l-(di-methylamino)-4-methyl-3-pentanone obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously. 

As a model for his synthesis of vitamin D, Lythgoe " made triene C 2). Disconnection (Wittig) of the central double bond is likely to give the greatest simplification and an a-methylene ketone (43) is one of the starting materials. 

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. 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

The a-oxoketene dithioacetals 6 (6.1-6.43) employed in this work as three carbon 1,3-biselectrophilic components have been drawn from various active methylene ketones and are described in the Table-1. The corresponding a-oxoketene N,S- and 0,S-acetals (17.1- 17.15) which are usually derived from a-oxoketene dithioacetals are described in Table-2. These examples are only a representative groups to demonstrate the general application of the new Jl-heteroaromatic annulation methodology... 

A third, not too widely used, approach is transformation of an iV-aminotriazine compound, as shown in Scheme 56. The 3-mercapto-4-amino[l,2,4]triazine derivative 361 was treated with an active methylene ketone and NBS in ethanol to yield the cyclized product 362 in moderate to excellent yield <2001JHC711>. A similar synthetic strategy was also applied in another case <2003KGS1844>. 

These compounds are relatively unstable, and treatment with hydrogen peroxide promotes telluroxide elimination to give the corresponding a-methylene ketones. 

The reaction of TeCl4 with siloxycyclopropanes, followed by treatment with DMSO, or bases such TMEDA, EtjN and pyridine, gives a-methylene ketones via the intermediacy of jS-oxoalkyl- or bis(/l-oxoalkyl)tellurium trichlorides or dichlorides. ... 

More than a century ago, Fileti and Ponzio reported that 1,2-diketones can be prepared by treating a-methylene ketones with sodium nitrite in aqueous HCl . However, this procedure has been limited to a few applications of water-soluble substrates. 

Paquette and Han chose to append their sidechain to 580 by preforming the a-methylene ketone 581 and carrying out a conjugate addition of a vinyl silane organo-... 

The most important synthesis within this subgroup is the Biginelli reaction, which involves reaction between a methylene ketone 715, an aldehyde 716, and either a urea 717 (Z = 0) or thiourea 717 (Z = S) to give a dihydro-2-pyrimidinone 718 (Z = 0) or dihydro-2-pyrimidinethione 718 (Z=S) <1993T6937, 2000ACR879, 20040R1>. 

In recent work67, it has been demonstrated that simple a-diazo ketones and esters can, in fact, be induced to undergo 1,5-insertion in preparatively useful yields. It was already known51 that in the rhodium-catalyzed insertion process, methyl C-H is electronically less reactive than methylene C-H or methine C-H. It therefore seemed likely that competing -hydride elimination would be least likely with a diazoethyl ketone. Indeed, on cyclization of 2-diazo-3-tetrade-canone, only a trace of the enone product from /J-hydride elimination is observed. The predominant side reaction competing with 1,5-insertion is dimer formation. 

It was assumed (59LA(625)74) that the reaction proceeds through acylation of the non-conjugated methylene ketone and the Russian work certainly supports this view. The observation that 4-methylpent-4-en-2-one gives a vastly improved yield of 2,4,6-trimethylpyrylium perchlorate compared with 4-methylpent-3-en-2-one on reaction with acetic anhydride and perchloric acid also favours this suggestion and led to a proposed mechanism (Scheme 249) (61JCS3573). 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

Dehydrostannation ot, -enones.1 A novel route to a-methylene ketones involves cleavage of 1-alkyl-1-silyloxycyclopropanes with SnCl4 in CH2C12 at 15° to provide p-trichlorostannyl ketones in 70-90% yield. These products undergo dehydrostannation when treated with excess DMSO in CHC13 at 60° to furnish a-methylene ketones in usually good yield. Pyridine and DMF are less useful than DMSO. 

Iodine-Mercury(II) oxide, 149 a-METHYLENE ALDEHYDES AND KETONES 1,4-Diazabicyclo[2.2.2]octane, 92 Dimethyl sulfoxide, 124 Formaldehyde, 136 Methoxyallene, 177 Methylene cycloalkanes By cyclization reactions Diacetatobis(triphenylphos-phine)palladium(II), 91 l-Hydroxy-3-trimethylsilylmethyl-3-butene, 147... 

Bromination-desilylbromination of fS-silyl ketones. The preliminary work on protection of oc,/ -enones by this sequence (8, 196-197) has been perfected in several respects1 and shown to be generally applicable to synthesis of oy8-enones.2 Either bromine or phenyltrimethylammonium tribromide (PTAB, 1,855 2,328 4, 386) can be used. In either case, bromine is introduced mainly at the a-position adjacent to the /1-silyl group. Surprisingly, the undesired a -bromo-/(-silyl ketone is converted to the a-bromo-/)-silyl ketone on exposure to hydrogen bromide at 20°. No other acids can clTccl this conversion. Desilylbromination is generally effected with DBU or F". The sequence is applicable to synthesis of a-methylene ketones (equation I) and lactones. 

BTI is suitable for the direct hydroxylation of ketones. Aliphatic, aromatic and heterocyclic ketones in acetonitrile-water and trifluoroacetic acid afforded a-hydroxymethyl ketones (in the range of 70%), whereas a-methylene ketones, such as propiophenone, gave less satisfactory yields. 

The use of dimethylsulphoxonium methylide, as a specific methylene insertion reagent for a, / -unsaturated ketones and esters, is illustrated by its reaction with ethyl crotonate in dimethylformamide solution to form (39) (Expt 7.16).12 The sulphur ylide initially attacks the /J-carbon of the conjugated system (Michael acceptor site), and this is followed by cyclisation and loss of dimethyl sulphoxide. 

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