Methylene groups, active

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 ... 

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). 

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). 

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). 

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. 

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. 

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. 

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

Other classes of yellow couplers reported ia the Hterature include the iadazolones (71) and the benzisoxazolones (72). Neither of these stmctures contains an active methylene group dye formation is beUeved to occur through a ring-opening process. 

Other classes of magenta dye-forming couplers reported in the Hterature include the pyra2oloben2imidazoles (90) and the inda2olones (91). The latter are unique because they do not contain an active methylene group and are proposed to form magenta dyes with a 2witterionic stmcture. 

Cyclopentadiene contains conjugated double bonds and an active methylene group and can thus undergo a Diels-Alder diene addition reaction with almost any unsaturated compound, eg, olefins, acetylene, maleic anhydride, etc. The number of its derivatives is extensive only the reactions and derivatives considered most important are discussed. 

The peioxy free radicals can abstract hydrogens from other activated methylene groups between double bonds to form additional hydroperoxides and generate additional free radicals like (1). Thus a chain reaction is estabhshed resulting in autoxidation. The free radicals participate in these reactions, and also react with each other resulting in cross-linking by combination. 

Halogenopyrimidines react with active methylene groups, such as those in diethyl malonate, ethyl cyanoacetate, ketene diethylacetal, etc. For example, 4-chloro-6-methyl-5-nitropyrimidin-2-amine (454) and dimethyl sodiomalonate give dimethyl 2-amino-6-methyl-5-nitropyrimidin-4-ylmalonate (455) (63ZOB3132) 2-chloro-4,6-... 

This variation provides a regiospecific synthesis of isoxazoles with a great variety of substituents. The nitrile A-oxide does not react with the doubly activated methylene group in neutral or acidic medium, but under alkaline conditions the reaction proceeds exother-... 

JAPP KLINGEMANN Hydrazone Synthesis Synthesis ot hydrazones trom diazonum saKs and an activated methylene group (or enamlne)... 

KNOEVENAGEL OOEBNER STOBBE Condensation Base catalyzed aldol condensation of aldehydes or ketones with an activated methylene group of a malonic ester (Knoevenagel Doebner) or a succinic ester (Stobbe)... 

Knoevenagel reaction is the synthesis of a, p-unsaturated acids by reaction of aldehydes and compounds with active methylene groups in the presence of an organic base... 

Michael condensation is the addition of a compound with an active methylene group to an a, p-unsaturated keto-compound... 

A zinc-free alternative to the Knorr pyrrole synthesis employs catalytic hydrogenation, as for 17 + 18 to 19. Oximes such as 17 are readily prepared by nitrosation (NaNOa, HO Ac) of the active methylene group. 

Ohta and Kato found that in the presence of bases the OMe group of 22 may be displaced by compounds with active methylene groups (ethyl cyanoacetate, malonodinitrile), yielding 27, which can be deprotonated to a methylenepyran derivative (28, R = CN, B =CNorC02Et). 

The more conventional nucleophiles obtained from compounds with active methylene groups, such as malonodinitrile or ethyl cyanoacetate give similar methylenepyrans (28, R = Il =CN... 

Methyl- and 4-methyl-pyridinium methiodides yield cyanine-type dyes with chloroform and alcohohc potassium hydroxide, e.g. via the methylene dihydropyridine (51) with attack by dichlorocarbene at the active methylene group (cf. ref. 92a). 

Compounds of the type HC=C—CH=CHXR are not involved in a primary reaction with weak nucleophiles such as CH acids meanwhile, a final (secondary) cyclization with participation of active methylene groups happens to be feasible. Evidently, in most cases the energy gain in the heteroaromatic system realization is the decisive factor (81UK1252). 

Etryptamine (23) is a tryptamine derivative which has been used as an antidepressant. Its synthesis involves the condensation of indole-3-carboxaldehyde (21) with the active methylene group of 1-nitropropane to form the inner nitronium salt of the substituted nitrovinyl indole (22). This then is readily reduced to etryptamine (23)... 

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