Masked ketones

For internal olefins, the Wacker oxidation is sometimes surprisingly regioselective. By using aqueous dioxane or THF, oxidation of P,y-unsaturated esters can be achieved selectively to generate y-keto-esters (Eq. 3.18).86 Under appropriate conditions, Wacker oxidation can be used very efficiently in transforming an olefin to a carbonyl compound. Thus, olefins become masked ketones. An example is its application in the synthesis of (+)-19-nortestosterone (3.11) carried out by Tsuji (Scheme 3.5).87... 

Thus, an alkene can be considered as a masked ketone that can be unmasked by ozonolysis. This is illustrated by the synthesis of N-acetylneuraminic acid via the ozonolysis of the precursor acrylic acid in THF/aqueous media (Eq. 3.22). The use of aqueous media facilitated the solubility of the polyhydroxyacids.92... 

The Stille adduct of 2-bromothiophene and l-ethoxy-2-tributyl-n-stannylethene or 1-ethoxy-l-tri-n-butylstannylethene is a masked thienyl aldehyde or a masked ketone, respectively [77-80]. Vinylstannane 93, derived exclusively as the -isomer from hydrostannation of bis(trimethyl-silyl)propargyl amine (92), was coupled with 2-bromothiophene to form ( )-cinnamyl amine 94 upon acidic hydrolysis [81, 82], In another case, stereoisomerically pure phenyl ( )-2-tributylstannyl-2-alkenoate 95, arising from Pd-mediated hydrostannation of phenyl ( )-2-alkynoate, was joined with 2-iodothiophene to deliver the stereodefmed trisubstituted a,p-unsaturated ester 96 [83, 84],... 

This motif is easily accessible from the condensation under acidic conditions of substituted hydroxymethyl pyrroli-done with a ketone, an aldehyde, or a masked ketone or aldehyde. Benzaldehyde <1996T3719, 1999JA10478, 2002JOC8688>, methoxypropene <1998T10295>, and dimethoxypropane <2001JOV8831, 2002TA647,... 

The above reactions in this section have been examples of addition alone or addition followed by elimination. Ligand reactions involving nucleophilic substitution are also known and these are of the dealkylation type. Lewis acids such as aluminum chloride or tin(IV) chloride have been used for many years in the selective demethylation of aromatic methyl ethers, where chelation is involved (Scheme 27). Similar cleavage of thioethers, specially using mercury(II) salts, is commonly used to remove thioacetal functions masking ketones (equation 27).104 In some cases, reactions of metal ions with thioether ligands result in isolation of complexes of the dealkylated organic moiety (equations 28 and 29).105-107... 

Relatively less acidic ketones compared to 1,3-dicarbonyl compounds are also suitable substrates for the palladium catalyzed coupling. a-Aryl ketones are obtained as products. In the early examples, masked ketone enolates such as silyl enol ethers [42] and enol acetates [43-45] were used in the presence of a tin source. These reactions involve tin enolates or acylmethyltins as intermediates and thus proceed by transmetalation (mechanism B in Scheme 1). 

A new synthetic method for steroids has been developed using a butadiene dimer (66) as a building block and the palladium-catalyzed oxidation as the key reaction.3-Acetoxy-l,7-octadiene (66), prepared by the palladium-catalyzed reaction of butadiene with acetic acid, is hydrolyzed and oxidized to l,7-octadien-3-one (67) in high yield. The enone (67) is a very useful reagent for bisanellation because its termiiud double bond can be regarded as a masked ketone which can be readily unmasked by the palladium catalyst to form the l,S-diketone (68) after Michael addition at the enone moiety of (67 Scheme 20). Thus, the enone (67) is the cheapest and most readily available bisanellation reagent, permitting a simple total synthesis of steroids. 

The final example of 1,2-additions of organoaluminums to masked ketone substrates is outlined in equation (15). The addition of a large excess (10 equiv.) of trimethylaluminum to a variety of triol acetals and ketals proceeds in relatively high overall yield. Although ketal substrates where R did not equal were not attempted, a number of acetals were prepared and upon exposure to MesAl they afforded the corresponding diastereomeric ethers with poor diastereoselectivity (33-17% de). 

A number patents and publications describe sedative or antidepressant properties for quinazolinethiones such as 3 related to the efavirenz lead Chemical instability of the lead structure 1, due to the masked ketone at the 4-position, was addressed by replacing the ethoxy group with a carbon linked substituent." A focus on replacing the thiourea functionality because of potential toxicity led to urea analogs, and subsequent efforts were directed toward solving the low metabolic stability of the /V-methyl group. This was attained by a switch to the benzoxazinone system... 

Reaction of cis- and tra i-l,3-diphenyl-2,3-epoxy-4-bromo-l-butanones with triethyl phosphite at 120°C goes to completion to give diethyl cis- or tra i-l,3-diphenyl-4-oxo-2,3-epoxybutylphospho-nates as the only isolated products in high yields." Several preparations of 4-oxoaIkylphosphonates are based on the use of masked ketones. For example, the Michaelis-Arbuzov reaction of 5-chloro-2-pentanone ethylene ketal with triethyl phosphite followed by unmasking of the latent carbonyl group gives diethyl 4-oxopentylphosphonate in modest yield (38%)." ° ... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

The annelation of phenols with 2,3-epoxycycloalkanones via a Lewis acid-promoted intramolecular acylation-rearrangement of a lactone intermediate, e.g. (184), has been shown to give tricyclic benzofurans, e.g. (183), in excellent yields (Scheme 38). The methyl-substituted furan double bond in (183) is effectively a masked ketone carbonyl that is easily liberated by ozonolysis, producing the diketone (182). 

In conventional, wet, chemistry, an oxime is merely a masked ketone, and said ketone can usually be hberated by hydrolysis of the oxime. However, such an approach to ethenedione appears to be quixotic under conventional solution conditions not only would the (probable) ultrashort lifetime of the ketone be an impediment to its spectroscopic observation, but even the generation of this molecule seems unlikely here, because of the sensitivity of the required intermediates along the Itydrolysis pathway, e.g. 0=C=C(OH)NHOH. The synthesis of ethenedione oxime, while clearly interesting, probably ties off the path to the elusive diketone. 

Two pyrimidine monomers containing masked ketone functionalities were synthesized in this way. One of the monomers featured a free ketone group, while the other contained a ketene dithioacetal moiety. Reaction between the ketone and ketene dithioacetal groups then led to the formation of... 

An alkyne can be considered as a masked ketone and, therefore, several examples of metal-catalyzed spiroketalization of alkyne diols have been described in the literature (2011ACIE8739 20100L4528). However, these reactions require a control of the regioselectivity and a mixture of 6,6- and 5,7-spiroketals 23 and 24 was formed (Scheme 13) (2012S3699). 

Since it would be difficult to deal with a series of pairs of geometric isomers througout the synthesis of 17, we turned to 2-bromo-l-butene (8) and the derived Grignard reagent (9) as the means for introducing the masked ketone functionality. No good route to pure 8 was found in the literature, and we turned to bromoboration of 1-butyne to 7 and subsequent protolysis to 8, which proved satisfactory (Scheme 3). 

The Cu(acac)2-catalyzed cycloaddition between a TBDMS enol ether and alkyl diazoacetates provides a useful method for the preparation of siloxycyclopropanecarboxylates (eq 44). Since these siloxycyclopropane derivatives possess a masked ketone group, and serve as important building blocks for the synthesis of the corresponding y-oxo esters (eq 45). ... 

The reaction is a unique method for the one-step synthesis of ketones from alkenes, and allows alkenes to be regarded as masked ketones which are stable to acids, bases, and nucleophiles. Particularly useful is the oxidation of terminal alkenes, which provides methyl ketones (eq 3). As a typical application, the allylation of a ketone, followed by the oxidation, affords a 1,4-diketone. A cyclopentenone can then be prepared by an aldol condensation (eq 4). The annulation method has widespread uses in the synthesis of natural products such as pentalenene, muscone, and coriolin. 1,5-Diketones are prepared by 3-butenylation of a ketone followed by the oxidation. This process has been used to prepare cyclohexenones (eq 5). ... 

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