Methylene- 1,3-dicarbonyl compound

The competition between Michael addition of a,(3-unsaturated ketones and Diels-Alder reactions involving furan and 2-methylfuran is affected by the catalyst used. Methyl vinyl ketone gives the alkylation product with furan and 2-methylfuran in the presence of silica gel (88TL175). Bis(alkylated) products have also been obtained in reactions of 2-methylene-1,3-dicarbonyl compounds (90H(31)1699). An intramolecular proton catalyzed alkylation reaction of an a,(3-unsaturated ketone provided a straightforward synthesis of norpinguisone (90TL4343) and in the example shown in Equation (4) the cyclization reaction involved an a,(3-y,8-dienone (94TL4887). 

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]. 

Methylthiomethylenation.1 The reagent is useful for methylthiomethylenation of 1,3-dicarbonyl compounds. The products are useful precursors to 2-methylene-1,3-dicarbonyl compounds. 

Vinyl ethers and aJA-unsaturated carbonyl compounds cyclize in a hetero-Diels-Alder reaction when heated together in an autoclave with small amounts of hydroquinone added to inhibit polymerization. Acrolein gives 3,4-dihydro-2-methoxy-2H-pyran (234,235), which can easily be hydrolyzed to glutaraldehyde (236) or hydrogenated to 1,5-pentanediol (237). With 2-methylene-1,3-dicarbonyl compounds the reaction is nearly quantitative (238). 

Compared with aUylic C-H bond, benzylic C-H bond has similar BDE. Under the oxidative conditions, it is still susceptible to undergo SET to form a benzyl radical or carbocation, which would like to be trapped by a series of C(sp )-H nucleophiles or electron-rich aromatic rings (Scheme 2.30). For example, active methylenic 1,3-dicarbonyl compounds [148-153], nitrogen nucleophiles (amines or amides or almidine), [154—158] IV-hydroxyamides [159], ketones [160, 161], aldehydes [162], electron-rich alkenes [163], aromatic rings [164, 165], and terminal alkynes [166] are good coupling partners in the oxidative benzylic C-H bond... 

This reaction is an example of fluorination of the methylene-group of /i-dicarbonyl compounds [15]. 

In the presence of a very strong base, such as an alkyllithium, sodium or potassium hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be converted to their dianions by two sequential deprotonations.79 For example, reaction of benzoylacetone with sodium amide leads first to the enolate generated by deprotonation at the more acidic methylene group between the two carbonyl groups. A second equivalent of base deprotonates the benzyl methylene group to give a dienediolate. 

Open-chain 1,3-dicarbonyl compounds did not lead to methylene cyclopropenes when reacted with the cation 75 by the DIPEA method. However, 4,4-diacyl triaful-venes 83 can be prepared very easily and in high yields (60—80%) from cations 80 and copper (or zinc) chelates 81 of 1,3-dicarbonyl compounds (known to be capable... 

Several 3-(2H)pyridazinones have been prepared from monophenyl hydrazones of 1,2-dicarbonyl compounds and a variety of active methylene compounds within 1-20 min without solvent under focused irradiation in the presence of carefully adjusted amounts of piperidine or solid potassium tert-butoxide (isolated yields 50-89%), in accordance with Scheme 8.49 [72, 73]. 

The 1,3-dipolar cycloaddition of azido-l,2,5-oxadiazoles (azidofurazans) to dicarbonyl compounds has been studied and a new procedure for the synthesis of (l,2,3-triazol-l-yl)-l,2,5-oxadiazoles was proposed <2002MC159>. The cycloaddition of 4-amino-3-azido-l,2,5-oxadiazole 168 to nitriles with activated methylene groups has been studied, and 3-amino-4-(5-amino-l/7-l,2,3-triazol-l-yl)-l,2,5-oxadiazoles 169 and the products of their Dimroth rearrangement 170 have been synthesized <2004MC76>. 

Catalysed alkylation of tosylmethylisocyanate (TOSMIC) [63, 64] has extended its versatility in the preparation of l, 4-dicarbonyl compounds and as a l, 3-dipolar precursor for the synthesis of heterocyclic compounds. The alkylation reactions should not be conducted in carbon disulphide, as nucleophilic attack by the methylene group on the carbon disulphide leads, after ring closure and S-alkylation, to a 4-alkylthio-1,3-thiazole system [65]. 

Examples of the Michael-type addition of carbanions, derived from activated methylene compounds, with electron-deficient alkenes under phase-transfer catalytic conditions have been reported [e.g. 1-17] (Table 6.16). Although the basic conditions are normally provided by sodium hydroxide or potassium carbonate, fluoride and cyanide salts have also been used [e.g. 1, 12-14]. Soliddiquid two-phase systems, with or without added organic solvent [e.g. 15-18] and polymer-supported catalysts [11] have been employed, as well as normal liquiddiquid conditions. The micellar ammonium catalysts have also been used, e.g. for the condensation of p-dicarbonyl compounds with but-3-en-2-one [19], and they are reported to be superior to tetra-n-butylammonium bromide at low base concentrations. 

Elaborate organic substrates and dicarbonyl compounds can also be methylenated in high yields with the Tebbe reagent (Table 3.8) [699-702]. Acid chlorides or... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

More recently, a zinc-catalyzed tandem 1,4-addition/carbocychzation, involving propar-gyl alcohol and 2-alkylidene-l,3-dicarbonyl compounds of type 400 as partners, was reported257. These compounds were stirred in the presence of Zn(OTf)2 and Et3N and afforded the 3-methylene tetrahydrofurans 401 in excellent yields (equation 175)258. 

Pyrrole synthesis from at-dicarbonyl compounds.15 A new approach to N-benzyl-pyrroles is formulated for biacetyl as starting material (equation I). The method is also suitable for annelation of a pyrrole group to an a-methylene carbonyl compound. 

Dihydro-1,3-benzoxazines (196) are formed by the reaction of phenols with a mixture of formaldehyde and primary aromatic amines in the molar ratio 2 1. Presumably the phenol first reacts with the appropriate iminium species to form an intermediate amine (195), which is then cyclized in a Pictet-Spengler type reaction (Scheme 81) (44JA1875). If 2-hydroxybenzylamines are employed then methylene derivatives are obtained, and if the formaldehyde is replaced by a-dicarbonyl compounds dehydro dimers (197) are produced (Scheme 82) <70BCJ226>. 

Alkyl methyl ketones undergo nitrosation at the reactive methylene group when treated with nitrous acid or an alkyl nitrite [Method (fi)]. The presence of hydrogen on the a-carbon permits tautomeric rearrangement to the oxime of a 1,2-dicarbonyl compound. Acidic hydrolysis of the oxime, which is best carried out in the presence of a hydroxylamine acceptor such as laevulinic acid,143 affords a further useful route to the 1,2-dicarbonyl system. 

Unsaturated 1,5-dicarbonyl compounds. The phenylthioalkylation of silyl enol ethers of carbonyl compounds (9, 521-522) can be extended to the synthesis of unsaturated 1,5-dicarbonyl compounds. In a typical reaction the enol silyl ether of a ketone is alkylated with the unsaturated chloride 1 under ZnBr2 catalysis to give a homoallyl sulfide. Ozonolysis of the methylene group is accompanied by oxidation of the phenylthio group sulfoxide elimination results in an unsaturated 1,5-aldehydo ketone (equation I). Alkylation with 2 results in a methyl ketone (equation II). 

Alkynyl(phenyl)iodonium salts can be used for the preparation of substituted alkynes by the reaction with carbon nucleophiles. The parent ethynyliodonium tetrafluoroborate 124 reacts with various enolates of /J-dicarbonyl compounds 123 to give the respective alkynylated products 125 in a high yield (Scheme 51) [109]. The anion of nitrocyclohexane can also be ethynylated under these conditions. A similar alkynylation of 2-methyl-1,3-cyclopentanedione by ethynyliodonium salt 124 was applied in the key step of the synthesis of chiral methylene lactones [110]. 

The resulting 5-methylene-2-oxa-l-silacyclohexanes are insufficiently Lewis acidic to react with a second equivalent of the carbonyl compound. However, the incipient allylsilane does react with dimethyl acetals in decent yields in the presence of external Lewis acids including BF3-Et20 or AICI3. Based on these results, double allylation of dicarbonyl compounds with 3-methylene-l,l-diphenyl-l-silacyclobutane was examined, leading to the formation of 3-methylene-oxabicyclo[3.2.1]octanes. This transformation proceeded in one pot and in the presence of BF3-Et20 (Scheme 42). 

The prerequisite 1,5-dicarbonyl compounds and their equivalents can be formed in situ by a Michael addition of activated methylene groups onto O Ji-unsaturated systems <1996CHEC-II>. In this manner, 5-alkylidene-2-thioxo-dihydropyrimidincM,6(l //,5//)-dione 84 reacts with ethyl 3-oxobutanoate under microwave irradiation to from the intermediate 1,5-dicarbonyl compound 85, which spontaneously cyclize to afford the corresponding 4//-pyrans in high yield (Scheme 28) <2003SC3747>. 

In a one-pot three-component reaction, aromatic aldehydes, malononitrile and 1,3-dicarbonyl compounds react to form 2-amino-5-carboxy-4-aryl-47/-pyran-3-carbonitriles 87. The reaction proceeds by an initial Knoevenagel condensation of malononitrile with the aromatic aldehyde to afford the 2-benzylidenemalononitrile intermediate 88. Michael addition of the activated methylene group forms the 1,5-dicarbonyl equivalent 89, which upon ring closure affords 477-pyrans (Scheme 29) <2004SL871, 1999H(51)1101 >. 

Approaches that represent a type (ii) synthesis of 277-pyran-2-ones include the self-condensation of 1,3-dicarbonyl compounds, the reaction of cyclopropanones with pyridinium enolbetaines and the reaction of activated methylene groups with acetylenic esters <1984CHEC, 1996CHEC-II>. 4-Perfluoroalkyl-6-aryl-pyran-2-ones are formed by the reaction of the phosphonium salts 631 with 2-perfluoroalkynoates (Equation 254) <1999JFC(95)135, 1998JFC(91)99>. Dimedone reacts with dimethyl acetylenedicarboxylate to afford the pyran-2-one 632 in excellent yield (Equation 255) <2003PS2627>. 

Electrolysis of sodium salts of 1,3-dicarbonyl compounds often does not yield the wanted dimer, but ist methylene derivative 81 (Eq. (158) ) 351 <367) since the alcohol serving as solvent is oxidized to an aldehyde which reacts with the... 

Dicarbonyl compounds, such as malonate derivatives, can also be classified under two categories. As well as reacting simply as a three-atom bis-electrophilic fragment (as in the synthesis of barbiturate 10.25 (page 77), an alternative reactivity is available. Condensation (by nucleophilic attack) of the active methylene carbon and electrophilic reaction at just one of the carbonyl groups is a two-atom nucleophilic/electrophilic profile, as seen in the preparation of coumarin 9.16. 

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