Active methylene substrates

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. 

Methylthio)imidazolidine, the analogue of 74, can undergo the same reaction, but more active methylene substrates are required39. 

The second general method into the thiochrom-4-one ring involves the interaction of a thiophenol with compounds possessing a carbon atom bonded by at least two electron withdrawing groups, usually in the presence of a dehydrating agent (phosphorus pentoxide or poly-phosphoric acid). The first application of this was by Simonis and Elias and is illustrated in Eq. (19). The most successful active methylene substrates have been /3-ketoesters, i )3-cyanoketones, ... 

Huisgen and his collaborators have also prepared 1-phenyl-1,2,3-triazole in excellent yield from the azide and an active methylene substrate (Eq. 17). 

The reaction of azides with active methylene compounds is an especially attractive route to the acid derivatives. An early report involving aryliodo-azides (Eq. 34) showed excellent yields. llie methyltropolonyl azide (4.2-11) reacts smoothly with several active methylene substrates (Eq. 35), most of which give amino products that are to be discussed in Chapter X. Sodamide has also shown good results as a catalyst for these reactions (Eq. 36). ... 

The metallocarbene intermediates are most often formed from thermal, photolytic, or metal-catalyzed deconposition of diazocarbonyl compounds, with concomitant loss of dinitrogen. Under transition metal catalysis, the initially formed species is a metallocarbene rather than a free carbene, and this is usually desirable due to the moderated reactivity (and, hence, fewer undesired side reactions) of the metal-complexed carbene. The two most common methods for introduction of the diazo group are acylation of diazoalkanes with suitably activated carboxylic acid derivatives and diazo transfer reactions in the case of more acidic active methylene substrates fScheme 16.12T... 

Rational substrate design, with appropriately functionalized aryl azides, has been shown to afford a variety of fused heteroaromatic polycycles. One report by Smalley et al. from the University of Salford describes exploitation of the Dimroth process to afford l,2,3-triazolo[l,5-a]quinazolines from o-azidobenz-aldehyde (42), o-azidoacetophenone, and benzonitrile with various active methylene substrates. It is interesting that the authors found an organic base, piperidine, was optimal for some substrates, while either sodium ethoxide or Amberlite resin worked better for others. 

Keywords 8-Alkynyl-p-ketoesters, iodine, dichloromethane, room temperature, lodonium-promoted 5-endo-dig carbocycUzation of active methylene substrates onto alkynes iodocyclopentenes... 

Knoevenagel reactions can be carried out at ambient temperature using an ionic liquid, dimethylethanolammonium acetate it features wide substrate tolerance, and ease of workup and reuse. " ° Its catalytic effect has been demonstrated by a solvatochromic study which identifies dual functions the cation hydrogen-bonds to the aldehyde, and the anion acts as acceptor to the active methylene substrate, facilitating the formation of carbanion. 

Michael Additions. Cu(OAc)2 in combination with chiral ligands has been extensively utilized as a catalyst for enantioselective conjugated-additions of organometallics and active methylene substrates to o , -unsaturated systems. The latter process, in particular, has been very useful synthetically, leading to the formation of quaternary chiral centers under mild, neutral conditions. Easily accessible natural a-amino acids or their derivatives were employed as efficient chiral auxiliaries and these could be recovered at the end of the reaction (eq 33). ... 

The association of RuH2(CO)(PPh3)3 (0.5 mol%) with Xantphos hgand (0.5 mol%) led to the formation of the RuH2(CO)(diphosphine)(PPh3) complex, which had a positive effect on the reactivity of the ruthenium catalyst for alkylation of activated methylene substrates including malonates, ketonitriles and ester nitriles [40]. 

Mashraqui and coworkers have reported a three-component coupling of phenols, aromatic aldehydes and activated methylene substrates such as P-ketoesters, which under the influence of BF3 OEt2, give benzopyranyl product (159) in moderate yield (Equation 94) [96]. Attempts to effect the reaction with other Lewis acids gave complex mixtures. 

Apparently the alkoxy radical, R O , abstracts a hydrogen from the substrate, H, and the resulting radical, R" , is oxidized by Cu " (one-electron transfer) to form a carbonium ion that reacts with the carboxylate ion, RCO - The overall process is a chain reaction in which copper ion cycles between + 1 and +2 oxidation states. Suitable substrates include olefins, alcohols, mercaptans, ethers, dienes, sulfides, amines, amides, and various active methylene compounds (44). This reaction can also be used with tert-huty peroxycarbamates to introduce carbamoyloxy groups to these substrates (243). 

Xenon difluoride [4, 5, 7, 8,10] is a white crystalline material obtained through the combination of fluorine and xenon m the presence of light The reagent is commercially available and possesses a relatively long shelf-life when stored cold (freezer) Xenon difluoride is very effective for small-scale fluormation of alkenes and activated nucleophilic substrates. The reactions are usually conducted between 0 °C and room temperature in chloroform or methylene chloride solutions Hydrogen fluoride catalysis is sometimes helpful Xenon difluoride reacts in a manner that usually involves some complexation between the substrate and reagent followed by the formation of radical and radical cation intermediates... 

The diazo transfer reaction between p-toluenesulfonyl azide and active methylene compounds is a useful synthetic method for the preparation of a-diazo carbonyl compounds. However, the reaction of di-tert-butyl malonate and p-toluenesulfonyl azide to form di-tert-butyl diazomalonate proceeded to the extent of only 47% after 4 weeks with the usual procedure." The present procedure, which utilizes a two-phase medium and methyltri-n-octylammonium chloride (Aliquat 336) as phase-transfer catalyst, effects this same diazo transfer in 2 hours and has the additional advantage of avoiding the use of anhydrous solvents. This procedure has been employed for the preparation of diazoacetoacetates, diazoacetates, and diazomalonates (Table I). Ethyl and ten-butyl acetoacetate are converted to the corresponding a-diazoacetoacetates with saturated sodium carbonate as the aqueous phase. When aqueous sodium hydroxide is used with the acetoace-tates, the initially formed a-diazoacetoacetates undergo deacylation to the diazoacetates. Methyl esters are not suitable substrates, since they are too easily saponified under these conditions. 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

When the 1,3-dicarbonyl substrate reacts twice via its activated methylene due to the presence of heteroatoms blocking the enolization process on other positions, spiranic systems are formed in the presence of two equivalents of aldehyde and an equivalent of urea (Scheme 15) [85]. The reaction can be promoted either in acetic acid as solvent or neat under microwave irradiations or in the presence of H3PW12O40 as catalyst. Finally, this technique for generating spiroheterocyclic products has been transferred to solid-supported methodology by immobilizing the 1,3-dicarbonyl partner onto a resin [86]. 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

Active methylene compounds attack the more electrophilic C-5 position of 1,4,2-dithiazolium salts (see Section 4.14.2) to give various products as outlined in Scheme 10. The reaction course is greatly affected by the applied conditions (base and solvent used) as well as by the the nature of the substrate itself. 

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