A-Methylene ketone

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. 

An interesting application with a methylene ketone was described by Boyd for the synthesis of pseudo azulepes from the oxalene ... 

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. 

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

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>. 

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. 

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. 

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 enedione (15), a tetracyclic intermediate on a synthetic route to fusidic acid, has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3). This compound (24) has also been prepared by degradation of fusidic acid. Attempts to introduce the C-11 oxygen function necessary for the synthesis of fusidic acid have not been very... 

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>. 

Die Addition von Dialkylaminen an cyclische a-Methylen-ketone (z. B. 2-Methylen-l-oxo-tetralin und 3-Methylen-2-oxo-bicyclo[2.2.1]heptan) kann an Aluminiumoxid als Kata-lysator durchgefuhrt werden4 ... 

Die Anwendung dieser Methode auf cyclische a-Methylen-ketone mit dem Grundgeriist von Diterpen-alkaloiden liefert die entsprechenden a-(Dialkylamino-methyl)-ketone in guten Ausbeuten1. 

Table 3. Synthesis a-methylene ketones via mercurio ketones (Ref. [8])...

Table 4. Synthesis of a-methylene ketones from stannyl ketones (Rev. [3])...

Epoxides of a-methylene ketones f poxidulion of a-methylene ketones is generally unsatisfactory. The desired epoxides have usually been prepared by epoxidation of allylic alcohols followed by oxidation. Another route involves oxidation of salts of Munnich bases with alkaline hydrogen peroxide (equation 1). 

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. 

The biologically significant a-methylene ketones have been prepared by a similar strategy, entailing a Pd°-catalyzed decarboxylation-deacetoxylation of allyl-a-acetoxymethyl 0-ketocarboxylates. The crucial allylpalladium enolate now 0-eliminates OAc rather than H (equation 143).368... 

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. 

Fig. 12.15. Aminomethyla-tion of a ketone via its enol (C) ("Mannich reaction"). This transformation can then be employed (as shown) to obtain an a-methylenated ketone (D).

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. 

C—C—N + O—C. A general synthesis of oxazoles is the reaction of oximes of a-methylene ketones with aliphatic or aromatic acyl chlorides (equation 128) (81IJC(B)322). 

The procedure described herein demonstrates a general synthetic method to form a-methylene ketones by direct methylene transfer. A number of methods have been previously described and reviewed.2 3 The advantages of direct methylene transfer for the formation of a-methylene ketones are the aprotic, nearly neutral conditions utilized. Although the reaction is not regiospecific, it is highly sensitive to steric hindrance, and transfer occurs at the less hindered site of unsymmetrical ketones. The reaction has been applied to cyclic and acyclic ketones4 and extended to the synthesis of vinyl ketones3 and a-methylenealdehydes. It is not applicable to y- or 8-lactones, or strained cyclic ketones such as norcamphor or cyclobutanone. With cyclohexanone, cyclopentanone, or aldehydes as substrates, pre-formation of the iminium intermediate... 

The reaction can be monitored by TLC. The a-methylene ketones exhibit higher Rf values than starting material when eluted in a diethyl ether-pentane (1 1) solvent system. 

OL-Methylenecyclohutanones. The reagent reacts regioselectively with activated alkenes (vinyl ethers, silyl enol ethers) to give cyclobutanones. These products undergo ring expansion with diazomethane to cyclopentanones. Both products undergo desilylative elimination in the presence of fluoride ion to form a-methylene ketones. 

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