Enol amidation

A direct application of the ring-opening reaction of an epoxide by a metal enolate amide for the synthesis of a complex molecule can be found in the synthesis of the trisubstituted cyclopentane core of brefeldin A (Scheme 8.35) [68a]. For this purpose, treatment of epoxy amide 137 with excess KH in THF gave a smooth cyclization to amide 138, which was subsequently converted into the natural product. No base/solvent combination that would effect cyclization of the corresponding aldehyde or ester could be found. 

The electrochemical results suggested to explore the possibility of creating a C-C bond between the electrogenerated a-carbanion fi and carbon nucleophiles. Results of practical importance have hitherto been obtained upon electroreduction of 2-bromoisobutyramides in acetonitrile at Hg or Pt cathodes, in the presence of carbon dioxide and an alkylating agent. The enolate-amide fi undergoes quantitative carboxy-alkylation, to yield ester amides of 2,2-dimethylmalonic acid (ref. 16). 

Amination of ketene has been studied by ab initio methods.Reactions of ammonia, its dimer, and its (mono)hydrate with ketene have been calculated and compared with earlier smdies of ammonia (at lower levels of theory), of water, and of water dimer. In general, the results favour initial addition of ammonia to the C=0 bond (giving the enol amide), as against addition to the C=C bond (which gives the amide directly). Amide formation is compared with the corresponding hydration reaction where enol acid and acid are the alternative immediate products. Most of the reactions, i.e. both additions and tautomerizations, are suggested to involve cyclic six-membered transition states. 

Nitrones photoisomerize to oxaziranes (212,213). The oxaziranes often undergo thermal isomerization to amides (214,215). In certain cases the amide (or the enolic amide) is isolated directly from the irradiation. The nitrone Formula 472 photoisomerizes to Formula 473 (35%) (212). 

N-Oxides of aromatic bases photoisomerize to enolic amides. Thus irradiation of quinoxaline-1,4-dioxide (Formula 476) gives Formula 477... 

Ketone dilithio-c /S-dianions (30, formed by treatment of /3 -stannylketones, RCOCH2-CH2SnBuCl2, with 4 equiv. of BuLi) react with imines and hydrazone selectively at the /3-anion portion to give dilithium enolate amides (31).82 Subsequent reaction with electrophiles gives y-amino ketones and related heterocycles. 

A triple anion complex containing enolate, amide, and halide functionalities can be isolated from the mixture of n-butyl bromide, hexamethyldisilazane, TMEDA, Bu Li and pinacolone (Bu COMe). The resulting solution of LiBr, LiN(SiMc3)2, LiOC(Bu )=CH2, and TMEDA produces crystals of Li4(/.t4-Br)( u-OC(Bu )=CH2)2(M-N(SiMe3)2)(TMEDA)2, which, instead of forming a ladder-type structure, consists of a planar butterfly of four lithium atoms bonded to a //4-Br the stability of this arrangement has been studied with semi-empirical (PM3) and ab initio HE/ LANL2DZ computations. ... 

Thermodynamic control. Note that it is also possible for the aldolate adduct to revert to aldehyde and enolate, and equilibration to the thermodynamic product may afford a different diastereomer (the anti aldolate is often the more stable). The tendency for aldolates to undergo the retro aldol addition increases with the acidity of the enolate amides < esters < ketones (the more stable enolates are more likely to fragment), and with the steric bulk of the substituents (bulky substituents tend to destabilize the aldolate and promote fragmentation). On the other hand, a highly chelating metal stabilizes the aldolate and retards fragmentation. The slowest equilibration is with boron aldolates, and increases in the series lithium < sodium < potassium, and (with alkali metal enolates) also increases in the presence of crown ethers. ... 

The reactions of bis(diethylamino)carbenium salt 113 are summarized in Scheme 28 [65]. Nucleophilic additions of Grignard reagents, organolithium reagents, enolates, amides, thiolates, and phosphite take place regioselectively... 

It soon became apparent, however, that the system is severely limited attempts to cyclize the corresponding ketones (enol), amides, or amines failed... 

A special focus of modem research in Pd-catalyzed Heck-coupling reactions is to investigate the ligand-free reaction in ionic liquids using Pd(OAc)2, PdQz or Pd/C as catalyst precursors [210]. In these examples the role of the ionic liquid is as either solvent, ligand or both. Of special interest for these studies is the regioselectivity of the Heck products when electron-rich olefins, such as acyclic enol ethers, silanes, and enol amides are applied as substrates. Possible products are the branched olefin (a. Scheme 5.3-24) and the linear olefin (P, Scheme 5.3-24). 

Spectroscopic methodologies have provided a wealth of information concerning the amination of ketenes. Scaiano and co-workers have measured rate constants for ketene reactions with various classes of amines in acetonitrile. The reaction rate is influenced by the basicity of the amine as well as by steric factors in both the ketene and the amine. Ketene amination has also been studied by time-resolved infrared (TRIR) spectroscopy. The strong ketene IR band near 2100 cm" makes it an excellent candidate for study by this spectroscopic technique. Scaiano, Wagner, Lusztyk, and co-workers provided evidence for the first nucleophilic attack being rate determining and that the transition state involves an enol amide. They further found that the asymmetric stretching IR band of substituted ketenes... 

The proposed mechanism hypothesized the nucleophilic attack of the oxygen to the Pd-complexed C-C triple bond, through the enol amide form, producing the oxazole skeleton by formation of the c-alkenylpalladium complex. The intervention of water provided, through its enol form, the 4,5-dihydrooxazole-5-carbaldehyde. The oxidizing system also promoted the dehydrogenation step (Scheme 54). 

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