Methylene compound, active

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

Wylation under neutral conditions. Reactions which proceed under neutral conditions are highly desirable, Allylation with allylic acetates and phosphates is carried out under basic conditions. Almost no reaction of these allylic Compounds takes place in the absence of bases. The useful allylation under neutral conditions is possible with some allylic compounds. Among them, allylic carbonates 218 are the most reactive and their reactions proceed under neutral conditions[13,14,134], In the mechanism shown, the oxidative addition of the allyl carbonates 218 is followed by decarboxylation as an irreversible process to afford the 7r-allylpalladium alkoxide 219. and the generated alkoxide is sufficiently basic to pick up a proton from active methylene compounds, yielding 220. This in situ formation of the alkoxide. which is a... 

When active methylene compounds are used as nucleophiles in carbonyla-tion at 50 °C and I atm, ketones are obtained. As an example, the reaction of l,3-cyclohexanedione affords the trione 32(17],... 

Michael condensations are catalyzed by alkaU alkoxides, tertiary amines, and quaternary bases and salts. Active methylene compounds and aUphatic nitro compounds add to form P-substituted propionates. These addition reactions are frequendy reversible at high temperatures. Exceptions are the tertiary nitro adducts which are converted to olefins at elevated temperatures (24). 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Diketene is used to C-acetoacetylate aromatic compounds in the presence of aluminum trichloride [7446-70-0]. Benzene [71-43-2] and diketene react to produce acetoacet5lben2ene [93-91-4]. Pyrrole [109-97-7] and diketene react to produce 2-acetoacet5lpyrrole [22441-25-4]. The C-acetoacetyl derivatives of active methylene compounds such as cyanoacetates, malonodinitrile [109-77-3] and Meldmm s acid [2033-24-1], and olefins can be prepared using diketene. 

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). 

With active methylene compounds, the carbanion substitutes for the hydroxyl group of aHyl alcohol (17,20). Reaction of aHyl alcohol with acetylacetone at 85°C for 3 h yields 70% monoaHyl compound and 26% diaHyl compound. Malonic acid ester in which the hydrogen atom of its active methylene is substituted by A/-acetyl, undergoes the same substitution reaction with aHyl alcohol and subsequendy yields a-amino acid by decarboxylation (21). 

Quinone monoacetals such as 2-methoxyben2oquinonemonoacetal [64701-03-7] (66) show regiospeciftc addition of active methylene compounds (66), yielding 83% (67) and 63% (68) on reactions with ethyl malonate. 

Organosodium compounds are prepared from sodium and other organometaUic compounds or active methylene compounds by reaction with organic haUdes, cleavage of ethers, or addition to unsaturated compounds. Some aromatic vinyl compounds and aHyUc compounds also give sodium derivatives. 

Other Applications. Hydroxylamine-O-sulfonic acid [2950-43-8] h.2is many applications in the area of organic synthesis. The use of this material for organic transformations has been thoroughly reviewed (125,126). The preparation of the acid involves the reaction of hydroxjlamine [5470-11-1] with oleum in the presence of ammonium sulfate [7783-20-2] (127). The acid has found appHcation in the preparation of hydra2ines from amines, aUphatic amines from activated methylene compounds, aromatic amines from activated aromatic compounds, amides from esters, and oximes. It is also an important reagent in reductive deamination and specialty nitrile production. 

The organic chemistry of sulfuryl chloride involves its use in chlorination and sulfonation (172,175,196,197). As a chlorinating agent, sulfuryl chloride is often mote selective than elemental chlorine. The use of sulfuryl chloride as a chlorinating agent often allows mote convenient handling and measurement as well as better temperature control because of the lower heat of reaction as compared with chlorine. Sulfuryl chloride sometimes affords better selectivity than chlorine in chlorination of active methylene compounds (198—200) ... 

MSC undergoes reactions with alcohols, amines, active methylene compounds (in the presence of bases), and aromatic hydrocarbons (in the presence of Friedel-Crafts catalysts) to replace, generally, a hydrogen atom by a methanesulfonyl group (382—401). 

The widespread use of cinnamic derivatives has led to the pursuit of reUable methods for thek dkect synthesis. Commercial processes have focused on condensation reactions between ben2aldehyde and a number of active methylene compounds for assembly of the requisite carbon skeleton. The presence of a disubstituted carbon—carbon double bond in the sidechain of these chemicals also gives rise to the existence of two distinct stereoisomers, the cis or (Z)- and trans or (E)- isomers ... 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

Alkylidene-2,3-dihydropyridazines (124) are synthesized by coupling of 3-thiomethyl-pyridazinium salts with active methylene compounds in the presence of potassium carbonate in DMF (Scheme 39) (79TL4837). 

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-methylated via its sodium or potassium salt and O-methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (81AG(E)882>. In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(P1)2004). 

Rates of debromination of bromonitro-thiophenes and -selenophenes with sodium thio-phenoxide and sodium selenophenoxide have been studied. Selenophene compounds were about four times more reactive than the corresponding thiophene derivatives. The rate ratio was not significantly different whether attack was occurring at the a- or /3-position. As in benzenoid chemistry, numerous nucleophilic displacement reactions are found to be copper catalyzed. Illustrative of these reactions is the displacement of bromide from 3-bromothiophene-2-carboxylic acid and 3-bromothiophene-4-carboxylic acid by active methylene compounds (e.g. AcCH2C02Et) in the presence of copper and sodium ethoxide (Scheme 77) (75JCS(P1)1390). 

Active methylene compounds can add to 1,3-dithiolylium ions to give 2-substituted 1,2-dihydro-1,3-dithioles (206). Again, addition is often followed by oxidation (to 207). Alternatively, further addition can occur (to 208) (80AHC(27)151). In this reaction, (205) can be CH2(CN)2, CH2(COMe)2 or even MeCOMe. Somewhat similar reactions are shown by 1,3-diarylimidazolium ions. 

Table 15 Isoxazoles from Nitrile iV-Oxides and Doubly Activated Methylene Compounds...

Another well-established process to generate fluoro ketones proceeds via acylation ofenolates [68, 69] or activated methylene compounds [70 71] as well as by Claisen type condensation reactions [72] Because of the electrophilic power of the acylating agents, there is usually no need tor a catalyst [68]... 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Taylor and Bartulin have recently shown that anthranil (106) reacts with a variety of active methylene compounds to give quinoline... 

Chloroisoquinoline (404) reacts well with methanolic methoxide (65°, 2 hr, 87% yield) or alkoxides (80°, 3 hr) and with carbanions of active methylene compounds (45-100% yields). 

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