Enol aminocarbonylation

For stereoselective synthesis of a-aminocarbonyl compounds, a number of protocols have been reported using chiral enolates and A-(alkoxycarbonyl)-0-(arenesulfonyl) hydroxylamines. 

For stereoselective synthesis of a-aminocarbonyl compounds using 0-phosphinyl-hydroxylamines, a few procedures have been developed. Attempted amination of enolates of chiral alkyl 3-hydroxybutanoates with 0-(diphenylphosphinyl)hydroxylamine 4a or with its A,A-diisopropyl derivative 4d were found to be unsuccessful". ... 

The isoquinoline system is conveniently prepared from treatment of o-iodobenzylamines with the enolate ions derived from symmetrical ketones (or ketones with one a-position blocked), aldehydes, or the dimethyl acetal of pyruvaldehyde, to give aminocarbonyl compounds which condensed in situ to give 2- and/or 3-substituted 1,2-dihydroisoquinolines. Catalytic dehydrogenation or borohydride reduction of these products then led to the corresponding isoquinolines or tetrahydroisoquinolines in moderate to high... 

Aminocarbonyl compounds have been prepared via Lewis base-catalysed Man-nich reaction of TMS enol ethers and iV-tosylaldimines, ArCH=N-Ts, with excellent anti selectivity in some cases.30... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

Azetines 575, synthesized by the reaction of IV-acyl thiazolidinethione enolates with enolizable aldoxime ethers, have been successfully converted into the corresponding iV-acyl-substituted /3-aminocarbonyl compounds 576 by simple exposure to benzoyl chloride <2003JA3690>. The reactions presumably involved an acyliminium salt 577, which hydrolyzed to yield 576 (Scheme 74). 

The Mannich reaction of an aldehyde enol (example Formula C in Figure 12.14) or a ketonic enol (example Formula C in Figure 12.15) often proceeds beyond the hydrochloride of a /l-aminocarbonyl compound or the Mannich base. The reason is that the secondary amine or its hydrochloride, which has previously been incorporated as part of the iminium ion, is relatively easy to eliminate from these two types of product. The elimination product is an a,fi-unsaturated aldehyde (example Formula E in Figure 12.14) or an a,/l-unsaturated ketone (example Formula D in Figure 12.15)—that is, an a,/l-unsaturated carbowyl compound. Figure 13.51 will show how the Mannich reaction of a carboxylated lactonic enol provides access to an a-methylene lactone, that is, an a,/l-unsaturated carboxyl compound. 

For the application of trialkylamine/TMSOTf as a selective method for the formation of kinetic silyl enol ethers of some a-aminocarbonyl cyclohexanones see L. Rossi and A. Pecunioso, Tetrahedron Lett.,... 

It is well recognized fhat aldimines are less reactive than aldehydes toward nucleophilic addition. In the presence of a catalytic amount of Yb(OTf)3, however, silyl enolates react with aldimines exclusively to afford / -aminocarbonyl compounds in high yield, even when aldehydes are present (Scheme 10.74) [209]. Selective formation of aldimine-Yb(OTf)3 complexes rather than aldehyde-Yb(OTf)3 complexes is attributable to fhe inverted reactivity. Polyallylscandium trifylamide ditriflate (PA-Sc-TAD), a polymer-supported Sc catalyst, also has high aldimine-selectivity. 

Since free a-aminocarbonyl compounds self-condense very readily producing dihydropyrazines (section 11.13.3.1), they have traditionally been prepared and used in the form of their salts, to be liberated for reaction by the base present in the reaction mixture. Alternatively, carbonyl-protected amines, such as aminoacetal (H2NCH2CH(OEt)2), have been used, in this case with the enol ether of a 1,3-diketone as synthon for the activated carbonyl component. ... 

From PM3 studies, the ring closure of 2-(aminocarbonyl)benzenediazonium ion to 3,4-dihydro-1,2,3-benzotriazin-4-one 3 has been proposed to proceed through an enol-type intermediate. A 6-NO2 group in the starting material is predicted to accelerate and a 6-MeO group to retard the cyclization <2001JMT(535)199>. 

Mannich reaction Alkylation of enols by electrophilic iminium ions, giving f)-aminocarbonyl compounds. Markovnikov rule Regioselectivity in electrophilic addition to alkenes whereby an electrophile attacks... 

The enol form of the active hydrogen compound reacts with the iminium cation to form a -aminocarbonyl compound (a Mannich base). 

Bismuth triflate was found to be an efficient catalyst in the Mannich-type reaction of silyl enolates with N-alkoxycarbonylamino sulfones. The reaction proceeded smoothly with a low catalyst loading of bismuth triflate (0.5-1.0 mol%) to afford the corresponding protected -aminocarbonyl compounds in very good yield (Equation 7) [29]. 

In the aldol reaction, an enolate ion attacks the carbonyl group of an aldehyde or ketone (Section 18-5) to furnish a j8-hydroxycarbonyl product. A process that is quite analogous is the Mannich reaction. Here, however, it is an enol that functions as the nucleophile and an iminium ion, derived by condensation of a second carbonyl component with an amine, as the substrate. The outcome is a j8-aminocarbonyl product. 

In Summary Condensation of aldehydes (e.g., formaldehyde) with amines furnishes imin-ium ions, which are electrophihc and may be attacked by the enols of ketones (or other aldehydes) in the Mannich reaction. The products are j8-aminocarbonyl compounds. 

Imines (like carbonyl compounds that form enols) are in equilibrium with their tautomeric forms, enamines (Section 17-9). If we write this form for our oxime, we arrive at an aminocarbonyl compound that is poised to undergo fast intramolecular formation of another hemiaminal. Dehydration produces a new cyclic enamine, which, upon inspection, is nothing but a hydrated pyridine. Finally, the driving force of aromaticity facilitates the rapid loss of water and generation of the pyridine product. 

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