Oxime ethers reactions with enolates

An in situ method for the preparation of N-methyleneamines has been devised by Overman and Osawa for use in condensation reactions with enolates and organometallic reagents. These species, with the exception of very hindered N-methyleneamines, cannot be isolated in the condensed phase because they rapidly trimerize to hexahydro-l,3,5-triazines. In this in situ method, A -methyleneamines (230) are generated from N-(cyanomethyl)amines (228) by deprotonation with an equivalent of enolate to give an intermediate amide (229) which loses LiCN (equation 22). When two equivalents of enolate are present, addition to the N-methyleneamine occurs and 3-lactams (233) are obtained in 60-70% yield upon warming the reaction mixture to 25 C (Scheme 48 Table 26). Uncyclized 3-amino esters can be isolated if the reaction is quenched at lower temperature a possible cycloaddition mechanism is thus ruled out. It is not clear to what extent, if any, the reaction is limited to a,a-disubstituted enolates. N-Methyleneamines, like oxime ethers, are useful for the synthesis of 4-unsubstituted 3-lactams and should also have important applications in the synthesis of monobactam antibiotics. 

As one would expect, oximes and nitroso-compounds are frequently encountered starting materials throughout the chemistry of this group of heterocycles. Further examples of their reactions have appeared. Reaction with enol ethers produces dihydro-oxazines (260), which may be converted to pyridine N-oxides upon treatment with HCl. Dihydro-oxazines are also obtained upon treatment of 7,6-unsaturated dicarbonyl compounds with nitrous acid. Thermolysis of these products leads to nitrones (261). 

Diazonium salts react with oximes to give aryl oximes, which are easily hydrolyzed to aldehydes (R = H) or ketones." A copper sulfate-sodium sulfite catalyst is essential. In most cases higher yields (40-60%) are obtained when the reaction is used for aldehydes than for ketones. In another method for achieving the conversion ArNj —> ArCOR, diazonium salts are treated with R4Sn and CO with palladium acetate as catalyst. In a different kind of reaction, silyl enol ethers of aryl ketones, Ar C(OSiMe3)=CHR, react with sohd diazonium fluoroborates, ArNj BF4, to give ketones, ArCHRCOAr. " This is, in effect, an arylation of the aryl ketone. 

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

Alcohols react with diazo compounds to form ethers, but diazomethane and diazo ketones are most readily available, giving methyl ethers or a-keto ethers, respectively. With diazomethane " the method is expensive and requires great caution, but the conditions are mild and high yields are obtained. Diazomethane is used chiefly to methylate alcohols and phenols that are expensive or available in small amounts. Hydroxy compounds react better as their acidity increases ordinary alcohols do not react at all unless a catalyst, such as HBp4 or silica gel, is present. The more acidic phenols react very well in the absence of a catalyst. The reaction of oximes, and ketones that have substantial enolic contributions. 

Trapping of the Beckmann intermediates with enol silyl ethers affords facile entry to a variety of en-amino ketones. This condensation takes place with retention of regiochemical integrity in both oxime sulfonates and enol silyl ethers. Reaction of 6-methyl-l-(trimethylsiloxy)-l-cyclohexene (41) or 1-methyl-2-(trimethylsiloxy)-l-cyclohexene (42) with cyclohexanone oxime mesylate furnishes (43) or (44), respectively, as the sole isolable products (equation 25). Another striking feature of the reaction is the high chemospecificity. The condensation of the enol silyl ether (45), derived from p-acetoxyaceto-phenone, occurs in a chemospecific fashion with cyclododecanone oxime mesylate, the acetoxy moiety remaining intact (equation 26). Oxime sulfonates of aromatic ketones and cyclopentanones are not employable since complex reaction mixtures are formed. 

A useful application of an enolate-oxime ether condensation, described by Weeks, Volkmann and co-woricers, is found in the synthesis of 6-aminomethylpenicillin derivative (218), a potent -lactamase inhibitor. As shown in Scheme 45, the sensitive penicillin Grignard (216) is condensed with ethyl formaldoxime at -80 C in the presence of Bp3-OEt2 to afford adduct (217). The use of Bp3-OEt2 is critical because it allows the reaction to proceed at the low temperature required for the stability of enolate (216). Hydrogenolysis of (217) simultaneously results in removal of the ethoxy, bromo and benzyl groups, affording (218). 

As in the Japp-Klingemann reaction, when Z is an acyl or carboxyl group (in the case of R2CH—Z), it can be cleaved. Since oximes and nitroso compounds can be reduced to primary amines, this reaction often provides a route to amino acids. As in the case of 12-4, the silyl enol ether of a ketone can be used instead of the ketone itself. Good yields of a-oximinoketones (20) can be obtained by treating ketones with fert-butyl thionitrate. ... 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

A new reaction of iV-acyl thiazolidinethione enolates with enolizable aldoxime ethers has been reported to give 2-(thiazolidine-2-thione)-l-azetines 608 with excellent diastereoselectivity (Equation 235) <2003JA3690>. The absence of either a methoxy or a carbonyl group in the 1-azetines indicated a complex mechanism rather than a simple addition reaction. The formation of azetines has been rationalized by combination of the oxime and TiCh to give a highly electrophilic trichlorotitanium iminium intermediate 609, which adds onto enolate 610 to form intermediate 611, which cyclizes to azetidines 612 (Scheme 81). An irreversible elimination of bis-trichlorotitanium oxide provides the ultimate driving force to produce azetines. 

Combination of silyl enol ethers with the organoaluminum-promoted Beckmann rearrangement of oxime sulfonates resulted in a novel reaction system that leads to the formation of enaminones [44]. Treatment of a mixture of anfr-2-methylcyclohexa-none oxime sulfonate (33) and 2-(trimethylsiloxy)-l-octene in dry CH2CI2 with Et2AlCl at -78 °C for 30 min, and at 20 °C for additional 1 h resulted in formation of the enaminone 34 in 90 % yield (Sch. 21). 

The enol ether is dissolved in 25 mL of rm-butyl methyl ether/mmol of alkene, and treated with 0.5-1.0 equiv of a-chloroacetophenone oxime. Then 6-10 equiv of freshly ground anhyd Na,C03 are added and the mixture is stirred for 6-10d at 20°C. The progress of the reaction is monitored by TLC. Filtration through a short pad of Celite followed by evaporation provides the crude 1,2-oxazines which are purified by column chromatography (aluminum oxide III, neutral, pentane/fert-butyl methyl ether 9 1) to furnish the pure cycloadducts. 

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