C-Alkylations of Active Methylenes

Several monoalkylations of functionalized acetates (Eq. 35) have been described in a series of papers the reactions were performed on potassium carbonate, either pure or mixed with potassium hydroxide. Some significant results are given in Tab. 5.13. 

Rapid monoalkylations are achieved in good yield compared with classical methods. Of particular interest is the synthesis of ot-amino acids by alkylation of aldimines with microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides leucine, serine, or phenylalanine in preparatively useful yields within 1-5 min [50], Alkylation of phenylacetonitrile was performed by solid-liquid PTC in 1-3 min under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subsequently be quickly hydrolyzed in a microwave oven to yield the corresponding amides or acids [56]. 

Functional groups were selectively introduced at the C-2 position of isophorone by epoxide ring-opening by several nucleophiles with active methylene groups. Different behavior was observed depending on the reaction conditions and the nature of the nucleophilic agents [57]. The best experimental systems involved PTC or KF-alumina under solvent-free conditions and MW irradiation (Eq. 37 and Tab. 5.15). 

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Usually, the aqueous salt could be too hydrophilic to allow the quaternary salt to dissolve in the organic phase, and resided exclusively in the aqueous phase anion exchange occured at or near the interface. The mechanism is applied to carbanion reactions, carbene reactions, condensation of polymerization, and C-alkylation of active methylene compounds such as activated benzylic nitriles, activated hydrocarbons, and activated ketones under PTC/OH. In most cases, the reaction involves the Q OH complex because QOH is highly hydrophilic and has extremely low solubility in the organic phase. 

Shimizu, S. Suzuki, T. Sasaki. Y. Hirai, C. Water-soluble calixarenes as new inverse phase-transfer catalysts. Their application to C-alkylations of active methylene compounds in water. Synlett 2000, 1664— 1666. 

Runhua et al. (1994a 1994b) have reported phase transfer promoted microwave-assisted C-alkylation of active methylenes. 

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g. the Dieckmann reaction (,cf 51 — 52) and alkylation of active methylene compounds (e.g. 53 —+ 54). 

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g., the Dieckmann reaction (cf. 66 67) and alkylation of active methylene compounds (e.g., 68 69). An example of the application of the Dieckmann reaction to the preparation of 3-thiepanone 70 is shown in Scheme 42 <1952JA917>. Several more recent examples of applications of the Dieckmann condensation in the synthesis of substituted 4- and 3-piperidones are discussed in CHEC-III . 

The use of [ C]formaldehyde resulted in the formation of 80% of the dilabeled ethylene glycol, indicating that the ethylene glycol formation proceeds preferentially via reductive carbon-carbon coupling over hydro-formylation of formddehyde the catalytic turnover is not given (766). Ru3(CO),2 was also found to catalyze the reductive alkylation of active methylene compounds with formaldehyde under synthesis gas. For example, pentan-2,4-dione is converted into 3-methylpentan-2,4-dione... 

The synthesis of gm-diallyl derivatives can be achieved by double alkylation of active methylene groups. We realized that installation of gem-diallyl functionality on a carbon atom, not activated by any electron-withdrawing group, is a difficult proposition. The problem becomes insurmountable on carbohydrate precursors because base-catalyzed reactions lead to tandem elimination of water molecules, resulting in the formation of complex mixtures, We observed interesting reactions with carbohydrate cyclopropyl precursors. For example, the radical-mediated cyclopropyl scission of the spirocyclopropyl bromide (86) with n-BusSnH gave the C-aUyl derivative (87) in a stereo-controlled fashion. On the other hand, hydrogenation of the cyclopropylaldehyde derivative (88) over Pd/C provided 89 with a quaternary chiral center (Scheme 30.14). 

Calix[n]arenes 1-3 were used as inverse PT catalysts in the alkylation of active methylene compounds with alkyl halides in aqueous NaOH solutions,and in aldol-type eondensation and Michael addition reactions. In the aikylation of phenylacetone with octyl bromide, the IPTC procedure enhanced the alkylation versus hydrolysis and C versus O alkylation selectivities with respect to those observed xmder classical PTC reactions in the presence of tetrabutylammonium bromide (TBAB) or hexadecyltributylammonium bromide (HTPB). Moreover, the aqueous catalyst solution was easily separated from the organic phase eontaining the products, and no organic solvent was required. In the case of the aldol-type condensation of benzaldehyde with indene or acetophenone in aqueous NaOH (Fig. 9), IPTC reaetions eatalyzed by I were compared with those conducted in aqueous micelles in the presence of cetyltrimethylammonium bromide (CTAB) as the sufactant. Although selectivities and yields were similar, the IPTC proeedure avoided the formation of emulsions, thus faciUtating product separation and catalyst recovery. In the light of the results obtained, water-soluble calix[ ]arenes 1-3 were proposed... 

Optically active benzyl c S-2-(hydroxymethyl)cyclohexylldimethylammonium bromide acts as a chiral phase-transfer catalyst for the alkylation of active methylene-containing compounds. ... 

The use of C-H bonds is obviously one of the simplest and most straightforward methods in organic synthesis. From the synthetic point of view, the alkylation, alkenylation, arylation, and silylation of C-H bonds are regarded as practical tools since these reactions exhibit high selectivity, high efficiency, and are widely applicable, all of which are essential for practical organic synthesis. The hydroacylation of olefins provides unsymmetrical ketones, which are highly versatile synthetic intermediates. Transition-metal-catalyzed aldol and Michael addition reactions of active methylene compounds are now widely used for enantioselective and di-astereoselective C-C bond formation reactions under neutral conditions. 

Conventional methylation reactions use methyl halides or methyl sulfate. These compounds are toxic and cause severe environmental damage. Also, the methylation of active methylene compounds often involves uncontrollable multiple alkylations. A method to methylate selectively using dimethylcarbonate has been developed by reacting arylacetonitriles with dimethylcarbonate at 18-22°C in the presence of potassium carbonate (see Fig. 9.33). The product is 2-arylpropionitriles with high selectivity (>99%). This process does not produce inorganic salts. This reaction can be carried out in continuous-flow and batch modes of operation. 

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). 

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). 

The imide nitrogen atom was also most reactive to a variety of electrophilic species (hydrogen halides, pseudohalogens, and alkyl halides) in the parent Rimidophosphazenes, R(C—NH)-N=PPh3. With t-butyl hypochlorite the /V-chloro-derivatives, R(C=NCl)-N=PPh3, were obtained. R/ -Vinyl-phenylphosphazenes have been prepared by condensation of aldehydes with active methylene compounds ... 

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],... 

In the reaction with ferrocene, allyldimethylchlorosilane reacts at 0 °C, allyl-(methyl)dichlorosilane reacts at the reflux temperature of methylene chloride, but allylsilanes containing two or more chlorine substituents at the silicon do not give alkylation products. In alkylations of ferrocene, allyldimethylchlorosilane shows the highest activity, allyl(methyl)dichlorosilane is less reactive, and allylsilanes containing two or more chlorine-substituents at the silicon have no activity. Allyl-trimethylsilane reacts with both benzene and ferrocene to give allylsilylation products but no alkylation product. 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

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