Methylenation enolizable ketones

Ketone methylenation is usually effected with Ph,P=CH2, scarcely an atom-efficient process. Tu-Hsin Yan of National Chung-Hsing University reports (Organic Lett. 2004,6,4961) that reduction of CHjClj with Mg powder in the presence of TIC14 leads to a reagent that efficiently homologates even easily-enolizable ketones such as 1. The reagent also converts esters such as 3 to alkenes, albeit more slowly. 

Benzofuran-3(2/f)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2-acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[6]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3-substituted benzo[6]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. 

Azide addition to enolizable ketones is regiospecific and may be considered as a 1,3-dipolar cycloaddition occurring at the double bond of the enolate, similar to the addition of azides to electron-rich olefins. However, a stepwise reaction appears more probable because glycosyl azides exhibit anomerism when they react with activated methylene compounds, thus indicating the presence of a triazene intermediate.264 On the other hand, the formation of the triazene intermediate may be considered as a limited case of 1,3-dipolar cycloaddition where one of the bonds is formed completely before the other one starts,2 such a limited case being observed for the Diels-Alder reaction.265... 

Methylenation of ketones. The Tebbe reagent (1) or the unstable 3,pdisubstituted titanacyclobutane 2 methylenate even easily enolizable ketones rapidly at room temperature. Yields are generally high except in reactions with a very hindered ketone. 

A reaction that appears to be mechanistically similar to the Tebbe reaction was developed by Oshima in 1978. Diiodomethane or dibromomethane in the presence of zinc is treated with a Lewis acid to form, presumably, a divalent complex (72), which reacts with aldehydes and ketones to produce the corresponding methylene derivative (73 Scheme 18). This reagent complements the reactivity of the Tebbe reagent, in that the zinc methylenation is not reactive towards esters or lactones. Because it is an electrophilic reagent, it is suitable for the methylenation of enolizable ketones and aldehydes. 

Methylenation of aldehydes and ketones. A reagent prepared in CH2CI2 from CH2I2, Zn, and TiCh is considerably more reactive than one prepared from CH2Br2, Zn, and TiCh (8, 339,11, 337,12, 322). Moreover, it affords less of the coupled products. This new reagent does not react with esters. It is particularly useful for methylenation of easily enolizable ketones, for which the Wittig reagent is not useful. The isolated yields of some methylenated products are shown. 

The superiority of this reagent system was demonstrated by the reactions shown in Scheme 5.6. Methylenations of the highly enolizable ketones, a- and yfi-tetralone, were performed with the reagent system. As mentioned in the introduction, treatment of these ketones with methylenetriphenylphosphorane did not give any me-thylenated product [12]. 

Scheme 5.6. Methylenation of highly enolizable ketones with Zn-CH2l2 TiCl4.

The possible general mechanism for the enolate-mediated synthesis of 1,2,3-triazoles from active methylene compounds, enolizable aldehydes 69, enolizable ketones 71, and substituted acetonitriles 73 is illustrated in Scheme 4.26. First, the reaction of the catalyst (base) with the CH acid 76 generated the enolate A, which on in situ treatment with Ar-Ng 2 selectively furnished the adduct 1,2,3-triazolines B through a concerted [3-1-2]-cycloaddition or stepwise amination-cyclization reaction. Adduct B further transformed into the 1,2,3-triazole 77 through the rapid elimination of water under ambient conditions induced by the basic nature of the catalyst. 

Peterson methylenation (10, 433 11, 581). Methylenation with trimethyl-silylmethyllithium, (CH3),SiCH2Li, is not widely used in synthesis because of lack of selectivity and moderate yields. However, a modified reagent prepared from (CH3)3SiCH2Li and CeCl, adds to aldehydes or ketones (even enolizable ones) to form adducts in generally high yield, particularly in the presence of TMEDA. The 2-hydroxysilanes are converted into methylene compounds by aqueous HF (with or without pyridine).4... 

Tosyl azide reacts with enolizable methylene compounds 89 in the presence of bases at room or lower temperature to give a-diazo ketones 91 or related products probably through the... 

The corresponding Wittig reagent, CHj PPhj, reacts smoothly with both aldehydes and ketones to give methylenated products In high yield but with one subtle limitation. The problem cannot be detected with aldehydes because they react rapidly even at temperatures as low as -78°C, but ketones react more slowly, and an adjacent enolizable chiral center can be epimerized as a result of competitive reversible enolization. This limitation of the Wittig... 

Methylenation.1 When heated in THF at 60-65°, this reagent effects methy-lenation of ketones, even readily enolizable ones, in 60-90% yield and of aldehydes (45-60% yield). It also converts esters and lactones into enol ethers, but this reaction is generally slower. It is thus an attractive alternative to the Tebbe and Grubbs reagent. 

In direct analogy to the Peterson methylenation, the triaryl- and trialkyl-stannylmethyllithiurn reagent (91) can be added to aldehydes and ketones (90), followed by elimination of the hydroxystannane (92) to obtain the methylene derivative (93 Scheme 20). This reaction, like the titanium and cerium modifications of the Peterson methylenation of Kaufmann and Johnson, may prove advantageous, in comparison to the Wittig reaction, for enolizible substrates. 

Activated easily enolizable aliphatic ketones, such as j8-diketones, j8-ketoamides, and /3-ketoesters, are extensively hydrogenolyzed. Hydrogenolysis depends on the catalyst type, amount of catalyst, solvent, and substrate structure. The methylene compound is favored in acetic acid, alcohols, and H2O, with larger amount of catalyst and Pt is often used. For instance, hydrogenation of cohulupone 1 over platinum oxide in methanol affords mainly 2 [equation (d)]. ... 

Acdve methylene compounds ranging in acidity from -keto esters, malonates and nitroalkanes pK = 9-13) to ketones (pATa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (p/iTa = 25) appears to be due to their weaker acidity or to transamination and/or hydrolysis side reactions. Enolizable aldehydes have also been used in certain instances however, side products arising from subsequent aldol condensation of the resulting -amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. 

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