Methylene groups, activated alkylation

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 liquickliquid alkylation of methylene groups activated by a carbonyl or nitrile group... 

The reactivity of phenylacetic esters with electron-deficient alkenes is generally fairly poor, even under phase-transfer catalytic conditions. The reaction with cinnamic esters is often accompanied by hydrolysis and the yield of the adduct with chalcone is generally <60% [10]. The activity of the methylene group towards alkylation has been enhanced by the initial complexation of the phenyl ring with chromium tricarbonyl (see Section 6.2), but this procedure has not been applied to the Michael reaction. 

Alkylation or acylation of ethyl malonate, ethyl acetoacetate, or other compounds containing methylene groups activated by strongly electron-attracting groups are very fruitful preparative methods. Reactions according to the schemes ... 

In the presence of a very strong base, such as amide ion or an organolithium reagent, it is possible to convert dicarbonyl compounds to their dianions. Subsequent alkylation of such dianions leads to alkylation at the more strongly basic enolate site, rather than at the carbon atom between the two carbonyl carbons. The more acidic methylene group activated by two carbonyl substituents is the preferred site in the monoanion, as discussed earlier. The ability to determine the site of monoalkylation by choice of the amount and nature of the basic catalyst has significantly expanded the synthetic utility of enolate alkylations. Scheme 1.7 gives some examples of formation and alkylation of dianions. 

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). 

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). 

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. 

Reaction of ethyl cyanoacetate with ethyl thiol acetate produces a and mixture of the dihydrothiazole derivative 80. This is ji-alkylated with methyl iodide and base (8 ), the active methylene group is brominated (82), and then a displacement with piperidine (83) is performed. Hydrolysis completes the synthesis of the diuretic agent, ozolinone (84). 

Nitration by nitric acid in sulphuric acid has also been by Modro and Ridd52 in a kinetic study of the mechanism by which the substituent effects of positive poles are transmitted in electrophilic substitution. The rate coefficients for nitration of the compounds Pl CHi NMej (n = 0-3) given in Table 10 show that insertion of methylene groups causes a substantial decrease in deactivation by the NMej group as expected. Since analysis of this effect is complicated by the superimposed activation by the introduced alkyl group, the reactivities of the... 

The versatility of this method for the alkylation of compounds containing active methylene groups is illustrated by Table I. Review articles have recently appeared,34 and the application to the Hofmann carbylamine reaction is described in the following procedure in this volume, p. 96. 

Conventional conversion of amide, lactam, imide, and urea carbonyl groups into enaminones, enamino esters, or enamino nitriles requires prior activation of the carbonyl groups either by alkylation to imino ethers, followed by reaction with activated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groups followed by alkylation (and possibly also oxidation), and, again, subsequent reac-... 

The active enzyme abstracts a hydrogen atom stereospecifically from the intervening methylene group of a PUFA in a rate-limiting step, with the iron being reduced to Fe(II). The enzyme-alkyl radical complex is then oxidized by molecular oxygen to an enzyme-peroxy radical complex under aerobic conditions, before the electron is transferred from the ferrous atom to the peroxy group. Protonation and dissociation from... 

The lack of clear-cut hallucinogen-type activity for the 2-aminotetralins could be explained in several ways. The known deleterious effect of molecular bulk in the alpha-position would seem to direct attention to the steric effect of the reduced ring of the tetralins as detrimental to activity. In 18b, however, it has been noted (156) that the 5-methoxy group is forced out of plane by the adjacent 6-methyl and 4-methylene groups. The importance to activity of maintaining the methoxy groups coplanar with the aromatic ring has been emphasized earlier. Both substituent orientation and N-alkylation must also be important to activity, and it may not be realistic to make direct comparisons between the phenethyl-amines and the 2-aminotetralins. 

The low acidity of methylene groups, which are activated by only one electron-withdrawing mesomeric substituent, generally results in a lower reactivity under phase-transfer catalytic conditions. Monoalkylation normally occurs, sometimes to the complete exclusion of dialkylation, and further alkylation is generally only... 

Dibromoethane normally reacts with activated methylene groups to produce cyclopropyl derivatives [e.g. 25, 27], but not with 1,3-diphenylpropanone. Unlike the corresponding reaction of 1,3-dibromopropane with the ketone to form 2,6-diphenylcyclohexanone, 1,2-dibromoethane produces 2-benzylidene-3-phenyl-tetrahydrofuran and the isomeric 2-benzyl-3-phenyl-4,5-dihydrofuran via initial C-alkylation followed by ring closure onto the carbonyl oxygen atom (Scheme 6.2) [28],... 

The reaction of methylenesulphones with allyl halides in the presence of quaternary ammonium salts produces the 1-allyl derivatives [52], unlike the corresponding reaction in the absence of the catalyst in which the SN- product is formed (Scheme 6.5). In contrast, alkylation of resonance stabilized anions derived from allyl sulphones produces complex mixtures [51] (Scheme 6.6). Encumbered allyl sulphones (e.g. 2-methylprop-2-enyl sulphones) tend to give the normal monoalkyl-ated products. Methylene groups, which are activated by two benzenesulphonyl substituents, are readily monoalkylated hydride reduction leads to the dithioacetal and subsequent hydrolysis affords the aldehyde [61]. 

Highly acidic triply-activated methylene groups are readily alkylated under mildly basic conditions, e.g. dicyanoacetic esters are converted into the quaternary ammonium salts, which give the 2,2-dicyanopropionic esters upon reaction with iodomethane [129]. 

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