Ketones reaction with active methylene compounds

Reactions with Active Methylene Compounds. Enolates of ketones," esters," enediolates," 1,3-dicarbonyl compounds," amides and lactams," as well as nitrile-stabilized carbanions," can be alkylated with benzyl bromide. Cyclohexanone may be benzylated in 92% ee using a chiral amide base." Amide bases as well as alkoxides have been employed in the case of nitrile alkylations." Benzylation of metalloenamines may be achieved and enantioselective reactions are possible using a chiral imine (eq 3). However, reactions between benzyl bromide and enamines proceed in low yield. The benzylation of a ketone via its enol silyl ether, promoted by fluoride, has been observed. ... 

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

Some reactions of 2-methylsulfonylquinoxaline (169) have recently been investigated by Hayashi and his co-workers.176 Reaction of 169 with ketones in benzene in the presence of sodamide yields 2-(2-quinoxalinyl) ketones (see Section IV,F149,161) with active methylene compounds, e.g., ethyl cyanoacetate, the 2-substituted quinoxaline (170) is isolated.176 It was also found that reaction of 2-methylsulfonyl-... 

Ring synthesis from non-heterocycles by closure y to the heteroatom are reported. Sulfonium ylides (135) with active methylene compounds such as malononitrile give a C-phenacyl product (136) however, when reacted with /3-diketones and /3-ketonic esters they produce furans quantitatively (74CL101). In these cases O-phenacylation takes place followed by cyclization to give the 3-hydroxydihydrofuran (137), which is dehydrated to the furan (138) (Scheme 30). These furans differ from those formed by the reaction of the diketone or ketonic esters with phenacyl halides. The latter reaction takes place by C-phenacylation, yielding the isomeric furans (139). 

Azide addition to enolizable ketones is regiospecific and may be considered as a 1,3-dipolar cycloaddition occurring at the double bond of the enolate, similar to the addition of azides to electron-rich olefins. However, a stepwise reaction appears more probable because glycosyl azides exhibit anomerism when they react with activated methylene compounds, thus indicating the presence of a triazene intermediate.264 On the other hand, the formation of the triazene intermediate may be considered as a limited case of 1,3-dipolar cycloaddition where one of the bonds is formed completely before the other one starts,2 such a limited case being observed for the Diels-Alder reaction.265... 

Dithiolylium cations (see Chapter 4.31) unsubstituted on the 3- or 5-position react with active methylene compounds, in most cases with simultaneous oxidation, as shown in equation (15). This reaction has been performed with a large variety of ketones, acylic or cyclic, /3-diketones, /3-keto dithioesters and a-cyano ketones (71AHC(13)161,pp. 174,188, 80AHC(27)151,p. 183). 

The addition of a base to an acetylenic ester or ketone provides another method of preparation of enaminones594,595. A convenient one-pot synthesis of enaminones from trimethylsilylethynyl ketones and amines was described596. The reaction of activated methylene compounds, such as cycloalkanones, MeCOPh and PhCH2COOMe, with amide acetals gave high yields of enaminones597 (equation 39). 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

The reaction of quinazoline 3-oxide with active methylene compounds or ketones without a base catalyst similarly results in transformation into quinoline derivatives although in very poor yields (a few percent). ... 

The substitution reaction of a chlorine atom or a methylsulfonyl group with active methylene compounds and ketones is a useful method for the introduction of functionalized carbons into the purine ring. Purinecarboxylic acids have been synthesized by condensation of 6-chlorop-urine with diethyl sodiomalonate. This method was applied also to 2- ° and 8-chloropuri-nes. ... 

Simple aliphatic thioketones (6) readily condense with active methylene compounds in a Knoevenagel-type reaction (Scheme 11). The reaction in Scheme 11 proceeds more easily than with ketones, often without catalysts, and involves nucleophilic attack by the X(NC)HC moiety. 

A similar dramatic influence of ionic liquid was also reported by Ranu s group in the Michael reaction of active methylene compounds with methyl vinyl ketone and methyl acrylate in the presence of an ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmImjOH). Interestingly, open-chain 1,3-dicarbonyl compounds reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products (Scheme 5.55). 

A basic ionic liquid, l-butyl-3-methyl imidazolium hydroxide, [bmImjOH, was found to catalyze the Knoevenagel condensation of aliphatic aldehydes and ketones with active methylene compounds elSciently in the absence of any organic solvent (Scheme 5.58). Coumarins have been obtained in one step from the reaction of o-hydroxy aldehydes following this procedure. ... 

The moisture- and air-stable ionic liquids, l-butyl-3-methylimidazolium tetra-lluoroborate [bmim]BF and l-butyl-3-methylimidazolium hexafluorophosphate [bmim]PFg, were used as green recyclable alternatives to volatile organic solvents for the ethylenediaimnonium diacetate-catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. As described by Su et al. [57], the ionic hquids containing a catalyst were recycled several times without decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarin derivatives in high yields of up to 95% (Scheme 17.11). When ethyl cyanoacetate was used, 2-imino-27f-l-benzopyran-3-carboxyhc acid ethyl ester was formed. 

The corresponding -acylaminovinyl ketones are intermediates in the transformation of the 3-azapyrylium salts into 3-azathiapyrylium (l,3-thiazin-l-ium ) ions Polyunsaturated enamides are isolable in reactions of salts 48 with active methylene compounds (equation 18). The action of bases on 4-alkyl-substituted 3-azapyrylium salts 373 leads to 4-alkylidene-l,3-oxazines 374. These anhydro bases can be regarded as cyclic enamides. It has been shown that the treatment of 4-alkylidene-benzo-l,3-oxazines 375 with acids results in protonation of the nitrogen to give 376 rather than at the alkylidene group (equation 107). 

Knoevenagel reaction. As surrogate for benzaldehyde in the condensation with active methylene compounds, the benzenesulfonimine is superior. In the presence of EtjN in chloroform the reaction with, inter alia, /8-diketones, )3-keto esters, a-sulfonyl ketones, a-nitro esters, and malononitrile proceeds at room temperature. 

It consists in the condensation of aldehydes or ketones with active methylene compounds in the presence of a base [288]. The first organocatalytic enantiose-lective domino multicomponent reaction, which was developed by Barbas et al. 

The condensation of aldehydes or ketones, with active methylene compounds (especially malonic ester) in presence of a weak base like ammonia or amine (primary or secondary) is known as Knoevenagel reaction. However, when condensation is carried out in presence of pyridine as a base, decarboxylation usually occurs during the condensation. This is known as Doebner modification. Some examples are given (Scheme 37). 

In 1991, Wright et al. reported a procedure for the preparation of substituted 1-benzyl-1//-1,2,3-triazoles 21 and 23 from benzyl azides 20 under very mild conditions (Scheme 4.7) [9]. Benzyl azides 20 reacted with active methylene compounds in DMSO induced by potassium carbonate at 35-40 C to give 1-benzyl-1//-1,2,3-triazoles 21 and 23 usually in good yield. Acetonitrile derivatives 10 gave 5-amino-l-benzyl-l//-l,2,3-triazoles 21, whereas diethyl malonate gave 5-hydroxy-l-benzyl-l//-l,2,3-triazoles. l//-l,2,3-Triazole-4-carboxylate esters and l//-l,2,3-triazole-4-ketones were obtained from ethyl acetoacetate and P-diketones, respectively. Benzyl methyl ketone reacted to give a 5-methyl-4-phenyl-l//-l,2,3-triazole, but acetone and acetophenone failed to react. Other active methylene compounds that did not react under these reaction conditions included ethyl cyanoacetate, ethyl fluoroacetate, and ethyl nitroacetate. 

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