Methylene Groups to Ketones

One of the first RuO -catalysed oxidations of a methylene to a ketone group (Fig. 4.1) was effected by RuCyaq. Na(10/CCl -CH3CN, e.g. with R=Me(CH3), and R =H or Me thus 6-fert-butylspiro[2.5]octane gave the corresponding ketone [16], 

Estrone acetate 3-Acetoxy-9a-hydroxy-1,3,5(10) estratiiene-6,17-dione K[67] 

Cyclo-octane Cyclo-octyl tiifluoroacetate + cylcohexanone L [65] 

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Freshly prepared Mn02 is a useful reagent in organic chemistry and has been used in a large variety of oxidative transformations.311 These reactions involve the allylic oxidation of alkene to a,/3-unsaturated carbonyl compounds, the transformation of methylarenes to benzaldehyde and benzoic acid derivatives, the oxidation of secondary methylene groups to ketones, and the oxidation of alcohols to carbonyl compounds.311 The yields are generally fair to good. 

Oxidation of Ben Iic Methylene Compounds. The peroxy intermediate (1) generated from sulfonyl chloride (3) oxidized compounds containing benzylic methylene groups to ketones under mild conditions (—35 °C) (eq 3). ... 

Scheme 3.8 Green, clean, and selective oxidation of activated methylene groups to ketones.

Zhang, W., Tang, W.L, Wang, D.I.C., and Li, Z. (2011) Concurrent oxidations with tandem biocatalysts in one pot green, selective and clean oxidations of methylene groups to ketones. Chem. Commun., 47, 3284-3286. 

The unique chemical behavior of KO2 is a result of its dual character as a radical anion and a strong oxidizing agent (68). The reactivity and solubiHty of KO2 is gready enhanced by a crown ether (69). Its usefiilness in furnishing oxygen anions is demonstrated by its appHcations in SN2-type reactions to displace methanesulfonate and bromine groups (70,71), the oxidation of benzyHc methylene compounds to ketones (72), and the syntheses of a-hydroxyketones from ketones (73). 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

Aldehydes condense with compounds containing a reactive methyl-or methylene-group to form unsaturated ketones, e.g. 

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],... 

Permanganate ion is a strong oxidant and tends to cleave aromatic side chains. However, when used under phase-transfer conditions,109,849 it converts benzylic methine groups into alcohols, and benzylic methylene compounds to ketones. Convenient oxidations can be carried out when KMn04 is applied in Et3N, an organic solvent (CHC13), and traces of water at room temperature.850... 

Approaches of type (i) include the Michael type addition of ester activated methylene groups to a,( -unsaturated carbonyls with subsequent cyclization to afford 277-pyran-2-ones <1984CHEC, 1996CHEC-II>. In this manner, 3-acylamino-277-pyran-2-ones are prepared by the reaction of (3-ethoxyvinyl ketones or P-(dimethylamino)vinyl ketones with iV-acylglycines (Scheme 138) <2005S1269, 2004HAC85>. 

Selenium dioxide (SeOi) oxidation Selenium dioxide is an excellent oxidizing agent for the oxidation of allylic and benzylic C-H fragments to allylic or benzylic alcohol. It also oxidizes the aldehydes and ketones to 1,2-dicarbonyl compounds (i.e. oxidation of active methylene groups to carbonyl groups). 

Compounds having active methylene groups react with nitrous acid to form oximino derivatives. The attack on the a-methylene group of ketones is illustrated by the action of ethyl nitrite on methyl ethyl ketone, and by the action of methyl nitrite on propiophenone, to form biacetyl monoxime (60%) and isonitrosopropiophenone (68%), respectively. Methyl and ethyl nitrites are passed in gaseous form into the ketones in the presence of hydrochloric acid. In other preparations, n-butyl, amyl, or octyl nitrite in liquid form is employed. ... 

Sodium dichromate hydroxylates tertiary carbons [620] and oxidizes methylene groups to carbonyls [622, 623, 625, 626, 631] methyl and methylene groups, especially as side chains in aromatic compounds, to carboxylic groups [624, 632, 633, 634, 635] and benzene rings to quinones [630, 636, 637] or carboxylic acids [638]. The reagent is often used for the conversion of primary alcohols into aldehydes [629, 630, 639] or, less frequently, into carboxylic acids or their esters [640] of secondary alcohols into ketones [621, 629, 630, 641, 642, 643, 644] of phenylhydroxylamine into nitroso-benzene [645] and of alkylboranes into carbonyl compounds [646]. 

The most commonly used reagents to effect the addition of a methylene group to an aldehyde or ketone are sulfur ylides such as dimethylsulfonium methylide (1) or dimethyloxosulfonium methylide (2) (Corey-Chaykovsky reaction). This reaction is well reviewed in standard treatises of organic synthesis - and several useful monographs. - This update will concentrate on progress attained from 1975. The reader is also encouraged to consult reviews on the chemistry of the related sulfoximine-derived ylides such as (3). -"... 

Epoxidation and dehydration led to 3,4-epoxycyclohexene which, on treatment with lithium isopropenylcuprocyanide gave the alcohol 539. This was then oxidized to the ketone 538. Stevens and Albizati made 538 by addition of a methylene group to the acetyl carbonyl group in 4-acetylcyclohexanone. Somewhat more interesting is their synthesis of the (/ )-isomer of 538 from (-)-perilla alcohol (536, R = H) following Scheme 54. ... 

The versatility of the product of cyclization, in terms of further manipulations, is illustrated in the next two examples. Thus, oxidative cleavage of the exocyclic methylene group to form the corresponding ketone induces elimination of benzenesulfinic acid, providing the cyclopen-tenone in high yield58. 

The addition of ketones having a-methylene groups to pyrido[2,3-ii]pyrimidine 3-oxide at elevated temperatures without a basic catalyst leads in low yields to 1,8-naphthyridines bearing carbon side chains in the 2- or 2,3-position (see Section 7.2.2.1.1.5.5.). 

The electrochemical oxidation of 2-furyl-2-thienylmethane in methanol resulted in loss of aromaticity of the furan ring and gave 70 (R = 2-thienyl). The reaction took a different course with 2,2 -dithienylmethane, which oxidized at the methylene group to give methoxybis(2-thienyl)methane (71) and di-2-thienyl ketone.106... 

The intermediate ketone (7.49) possesses the same spirane system as the target and it remains only to remove one oxygen atom, introduce one other, saturate the double bond and add an isopropylidene group. The two functions to be added must, of course be added at the correct sites and it can be seen that the existing functionalisation of (7.49) will allow this to be done selectively. The methylene group to be oxidised is allylic and so the oxidation will be relatively easy. The isopropylidene group must be added adjacent to the ketone of (7.49) and selectively on one side of it. Steric effects allow the required selectivity. The complete synthesis is outlined in Figure 7.12. 

Dimethylcarbonate (DMC) is an environmentally friendly substitute for dimethylsulfate (DMS) and methyl halides in methylation reactions. It is also a very selective reagent. The reactions of DMC with methylene-active compounds produce monomethylated derivatives with a selectivity not previously observed. The batchwise monomethylation of arylacetonitriles, arylacetoesters, aroxyacetonitriles, methyl aroxyacetates, ben larylsulfones and alkylarylsulfones with DMC achieve >99% selectivity at 180-220°C in the presence of K2CO3. Mono- -methylation of primary aromatic amines at 120-150 °C in the presence of Y- and X-type zeolites, achieved selectivities up to 97%. At high temperature (200°C) and in the presence of potassium carbonate as the catalyst, DMC splits benzylic and aliphatic ketones into two methyl esters in contrast, DMC converts ketone oximes bearing a methylene group to 3-methyl-4,5-disubstituted-4-oxazolin-2-ones. Dibenzylcarbonate... 

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