Methylene activated

The mechanism of the reaction, which is of the aldol type, involves the car-bonyl group of tlie aldehyde and an active methylene group of the anhydride the function of the basic catalyst B (acetate ion 0H3000 or triethylamine N(0,Hb)j) is to form the anion of the active hydrogen component, i.e., by the extraction of a proton from the anhydride ... 

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 reaction probably proceeds by an initial cyclisation of the acylamlnoacetic acid, followed by a Perkin type of condensation of the aldehyde with the active methylene unit ... 

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 ... 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

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... 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

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],... 

The same products can be also obtained from 267 and benzaldehyde. This behavior indicates the presence of an active methylene group and supports the thiazolone structure (267a). Alkyl or aryl ethers of 267 are prepared by two different procedures (Scheme 139). 

Just as most other aldehydes do, furfural condenses with compounds possessing active methylene groups such as aUphatic carboxyUc esters and anhydrides, ketones, aldehydes, nitriles, and nitroparaffins. 

Acetic anhydride adds to acetaldehyde in the presence of dilute acid to form ethyUdene diacetate [542-10-9], boron fluoride also catalyzes the reaction (78). Ethyfldene diacetate decomposes to the anhydride and aldehyde at temperatures of 220—268°C and initial pressures of 14.6—21.3 kPa (110—160 mm Hg) (79), or upon heating to 150°C in the presence of a zinc chloride catalyst (80). Acetone (qv) [67-64-1] has been prepared in 90% yield by heating an aqueous solution of acetaldehyde to 410°C in the presence of a catalyst (81). Active methylene groups condense acetaldehyde. The reaction of isobutfyene/715-11-7] and aqueous solutions of acetaldehyde in the presence of 1—2% sulfuric acid yields alkyl-y -dioxanes 2,4,4,6-tetramethyl-y -dioxane [5182-37-6] is produced in yields up to 90% (82). 

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... 

Reactions at G-5. The C-5 atom of hydantoins can be considered as an active methylene group, and therefore is a suitable position for base-cataly2ed condensation reactions with aldehydes (44). 2-Thiohydantoins give the reaction more readily than their oxygen counterparts ... 

Miscellaneous. The reaction products of sahcylaldehyde with certain compounds containing active methylene groups, eg, acetylacetone, are excellent uv absorbers. Films containing these compounds can be used as uv filters to protect light-sensitive foods, wood products, paper, dyes, fibers, and plastics (95). 

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. 

Shown ate glycidyl methacrylate to introduce epoxide fiinctionahty, acetoacetoxyethyl methacrylate to introduce active methylene groups, dimethylaminoethyl methacrylate to introduce amine fiinctionahty, phosphoethyl methacrylate for strong acid fiinctionahty, and isocyanatoethyl methacrylate to introduce isocyanate fiinctionahty, which may then react with a wide variety of nucleophiles. 

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). 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

Aldehydes and Ketones. Pyrrole aldehydes and ketones are somewhat less reactive than the corresponding benzenoid derivatives. The aldehydes do not undergo Cannizzaro or Perkin reactions but condense with a variety of compounds that contain active methylene groups. They also react with pyrroles under acidic conditions to form dipyrryhnethenes (26). The aldehydes can be reduced to the methyl or carbinol stmctures. The ketones undergo normal carbonyl reactions. 

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. 

Succinic acid and anhydride undergo most of the reactions characteristic of dicarboxyhc acids and cycHc acid anhydrides, respectively. Other interesting reactions take place at the active methylene groups. 

Halogenation. Succinic acid and succinic anhydride react with halogens through the active methylene groups. Succinic acid heated in a closed vessel at 100°C with bromine yields 2,3-dibromosuccinic acid almost quantitatively. The yield is reduced in the presence of excess water as a result of the formation of brominated hydrocarbons. The anhydride gives the mono- or dibromo derivative, depending on the equivalents of bromine used. 

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). 

Aldol additions of benzaldehyde with active methylene groups produce other aldehydes. 

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 ... 

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